CN108864080B

CN108864080B - Tetracyclic compounds as selective estrogen receptor down-regulating agents and application thereof

Info

Publication number: CN108864080B
Application number: CN201810429737.3A
Authority: CN
Inventors: 王勇; 赵立文; 王小伟; 钮嘉辉; 程青; 庞司林; 王辉; 肖学兵
Original assignee: Nanjing Sanhome Pharmaceutical Co Ltd
Current assignee: Nanjing Sanhome Pharmaceutical Co Ltd
Priority date: 2017-05-09
Filing date: 2018-05-08
Publication date: 2021-10-15
Anticipated expiration: 2038-05-08
Also published as: CN108864080A

Abstract

The invention belongs to the field of medical chemistry, relates to tetracyclic compounds serving as selective estrogen receptor modulators and application thereof, and particularly provides compounds shown as a formula I or isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs thereof, preparation methods of the compounds, pharmaceutical compositions containing the compounds, and application of the compounds or the compositions in treating and/or preventing estrogen receptor related diseases. The compound of the present invention has more excellent antitumor activity and is very promising as a breast cancer therapeutic agent.

Description

Tetracyclic compounds as selective estrogen receptor down-regulating agents 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,

X¹、X²、X⁴each X³Are each independently selected from C (R)¹R²)、N(R³) O, S, sulfones and sulfoxides;

R¹、R²each 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, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl, and aryl; or R¹、R²To carbon atoms bound theretoTogether form a carbonyl group; r³Selected from the group consisting of hydrogen, alkanoyl, aminoacyl, alkylaminoacyl, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl, and aryl, which may be substituted with one or more halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, dialkylamino, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R⁴selected from the group consisting of hydrogen, alkanoyl, aminoacyl, alkylaminoacyl, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl, and aryl, which may be substituted with one or more halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, dialkylamino, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R⁵selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkylacylamino, alkanoyl, aminoacyl, alkylaminoacyl, dialkylamino, alkenyl, alkynyl, and cycloalkyl;

each R⁶Each R⁷Each 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, dialkylamino, alkenyl, alkynyl, cycloalkyl, and boronic acid;

y is selected from the group consisting of alkoxy, cycloalkylalkoxy, heterocyclylalkoxy, arylalkoxy, heteroarylalkoxy, alkylamino, cycloalkylalkylamino, heterocyclylalkylamino, arylalkylamino, heteroarylalkylamino, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkenyl, and alkynyl, said alkoxy, cycloalkylalkoxy, heterocyclylalkoxy, arylalkoxy, heteroarylalkoxy, alkylamino, cycloalkylalkylamino, heterocyclylalkylamino, arylalkylamino, heteroarylalkylamino, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkenyl, and alkynyl groups may be substituted with one or more halogens, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, alkylacylamino, alkanoyl, aminoacyl, amino, alkylamino, and alkynyl groups, Alkylaminoacyl, dialkylamino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, and oxo substituted; and

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

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,

R¹、R²each 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, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl, and aryl; or R¹、R²Together with the carbon atom to which it is attached form a carbonyl group; r³Selected from the group consisting of hydrogen, alkanoyl, aminoacyl, alkylaminoacyl, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl, and aryl, which may be substituted with one or more halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, dialkylamino, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R⁵selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkylacylamino, alkanoyl, aminoAcyl, alkylaminoacyl, dialkylamino, alkenyl, alkynyl, and cycloalkyl groups;

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

In some particular embodiments, the compounds of the invention are of formula I or an isomer, pharmaceutically acceptable salt, solvate, crystal, isostere or prodrug thereof, wherein when o is 1, X is¹、X²、X³、X⁴One of them is C (R)¹R²) The other three are N (R)³) O, S, sulfone or sulfoxide.

In other specific embodiments, the compounds of the present invention are of formula I or isomers, pharmaceutically acceptable salts, solvates, crystals, electrons, thereofIsosteres or prodrugs wherein when o is 1, X¹、X²、X³、X⁴Two of them are C (R)¹R²) And the other two are N (R)³) O, S, sulfone or sulfoxide.

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 when o is 1, X¹、X²、X³、X⁴Three of them are C (R)¹R²) And the other one is N (R)³) O, S, sulfone or sulfoxide.

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 X¹、X²Each X³Are all C (R)¹R²)，X⁴Is N (R)³) O, S, sulfone or sulfoxide.

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 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_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl radical, C_1-10Heterocyclic group, C_6-18Aryl and C_1-18A heteroaryl group;

further preferably, R¹、R²Each 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_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8Cycloalkyl radical, C_1-8Heterocyclic group, C_6-12Aryl and C_1-12A heteroaryl group;

even more preferably, R¹、R²Each independently selected from the group consisting of hydrogen, halogen, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, pentafluoroethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, 2-hydroxypropyl, methoxy, ethoxy, propoxy, isopropoxy, nitro, carboxy, cyano, amino, methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, diethylamino, methylethylamino, dipropylamino, methylpropylamino, ethylpropylamino, methylacylamino, ethylacylamino, vinylacylamino, methylacyl, ethylaccyl, aminoacyl, methylaminoacyl, ethylaminoacyl, vinyl, propenyl, allyl, butenyl, alkenylbutyl, 3-methyl-2-butenyl, ethynyl, propynyl, propargyl, butynyl, and the like, Propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C_1-6Heterocyclic group, C_6-10Aryl and C_1-10A heteroaryl group.

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、R²Together with the carbon atom to which it is attached form a carbonyl group.

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 R is³Selected from hydrogen, 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_1-10Heterocyclic group, C_6-18Aryl and C_1-18Heteroaryl, 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, R³Is selected from hydrogen and C independently_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_1-8Heterocyclic group, C_6-12Aryl and C_1-12Heteroaryl, 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_1-10Heterocyclic group, C_6-18Aryl and C_1-18Heteroaryl substitution;

even more preferably, R³Selected from the group consisting of hydrogen, formyl, acetyl, propionyl, aminoacyl, methylaminoacyl, ethylaminoacyl, propylaminoylmethyl, 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 radicalSaid radicals 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_1-6Heterocyclic group, C_6-10Aryl and C_1-10Heteroaryl substituted.

R⁴selected from hydrogen, 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_1-10Heterocyclic group, C_6-18Aryl and C_1-18Heteroaryl, 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, R⁴Is selected from hydrogen and C independently_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_1-8Heterocyclic group, C_6-12Aryl and C_1-12Heteroaryl, 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, bisC_1-6Alkylamino radical, C_3-10Cycloalkyl radical, C_1-10Heterocyclic group, C_6-18Aryl and C_1-18Heteroaryl substitution;

even more preferably, R⁴Selected from the group consisting of hydrogen, formyl, acetyl, propionyl, aminoacyl, methylaminoacyl, ethylaminoacyl, propylaminoylmethyl, 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_1-6Heterocyclic group, C_6-10Aryl and C_1-10Heteroaryl substituted.

R⁵selected 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_2-10Alkenyl radical, C_2-10Alkynyl and C_3-10A cycloalkyl group;

go toPreferably, R⁵Selected 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_2-6Alkenyl radical, C_2-6Alkynyl and C_3-8A cycloalkyl group;

even more preferably, R⁵Selected from the group consisting of hydrogen, halogen, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, pentafluoroethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, 2-hydroxypropyl, methoxy, ethoxy, propoxy, isopropoxy, nitro, carboxy, cyano, amino, methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, diethylamino, methylethylamino, dipropylamino, methylpropylamino, ethylpropylamino, methylacylamino, ethylacylamino, vinylacylamino, methylacyl, ethylacylamino, ethylacoyl, vinylacyl, aminoacyl, methylaminoacyl, ethylaminoacyl, vinyl, propenyl, allyl, butenyl, alkenylbutyl, 3-methyl-2-butenyl, ethynyl, propynyl, propargyl, butynyl, and butynyl, Cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

each R⁶Each R⁷Each 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_2-10Alkenyl radical, C_2-10Alkynyl, C_3-10Cycloalkyl and boronic acids;

further preferably, each R⁶Each R⁷Each 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_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8Cycloalkyl and boronic acids;

even more preferably, each R⁶Each R⁷Each independently selected from the group consisting of hydrogen, halogen, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, pentafluoroethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, 2-hydroxypropyl, methoxy, ethoxy, propoxy, isopropoxy, nitro, carboxy, cyano, amino, methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, diethylamino, methylethylamino, dipropylamino, methylpropylamino, ethylpropylamino, methylacylamino, ethylacylamino, vinylacylamino, methylacyl, ethylaccyl, aminoacyl, methylaminoacyl, ethylaminoacyl, vinyl, propenyl, allyl, butenyl, alkenylbutyl, 3-methyl-2-butenyl, ethynyl, propynyl, propargyl, butynyl, and the like, Propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and boronic acids.

y is selected from C_1-6Alkoxy radical, C_3-10Cycloalkyl radical C_1-6Alkoxy radical, C_1-10Heterocyclyl radical C_1-6Alkoxy radical, C_6-18Aryl radical C_1-6Alkoxy radical, C_1-18Heteroaryl C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_3-10Cycloalkyl radical C_1-6Alkylamino radical, C_1-10Heterocyclyl radical C_1-6Alkylamino radical, C_6-18Aryl radical C_1-6Alkylamino radical, C_1-18Heteroaryl C_1-6Alkylamino radical, C_3-10Cycloalkyl radical, C_1-10Heterocyclic group, C_6-18Aryl radical, C_1-18Heteroaryl group, C_2-10Alkenyl and C_2-10Alkynyl, said alkoxy, cycloalkylalkoxy, heterocyclylalkoxy, arylalkoxy, heteroarylalkoxy, alkylamino, cycloalkylalkylamino, heterocyclylalkylamino, arylalkylamino, heteroarylalkylamino, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkenyl, and alkynyl groups may be substituted with 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 radical, C_1-6Alkylacylamino group, C_1-6Alkyl acyl, amino acyl, C_1-6Alkylaminoacyl, di-C_1-6Alkylamino radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_1-10Heterocyclic group, C_3-10Cycloalkyl and oxo groups;

further preferably, Y is selected from C_1-3Alkoxy radical, C_3-8Cycloalkyl radical C_1-3Alkoxy radical, C_1-8Heterocyclyl radical C_1-3Alkoxy radical, C_6-12Aryl radical C_1-3Alkoxy radical, C_1-12Heteroaryl C_1-3Alkoxy radical, C_1-3Alkylamino radical, C_3-8Cycloalkyl radical C_1-3Alkylamino radical, C_1-8Heterocyclyl radical C_1-3Alkylamino radical, C_6-12Aryl radical C_1-3Alkylamino radical, C_1-8Heteroaryl C_1-3Alkylamino radical, C_3-8Cycloalkyl radical, C_1-8Heterocyclic group, C_6-12Aryl radical, C_1-12Heteroaryl group, C_2-6Alkenyl and C_2-6Alkynyl, said alkoxy, cycloalkylalkoxy, heterocyclylalkoxy, arylalkoxy, heteroarylalkoxy, alkylamino, cycloalkylalkylamino, heterocyclylalkylamino, arylalkylamino, heteroarylalkylamino, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkenyl, and alkynyl groups may be substituted with 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 radical, C_1-6Alkylacylamino group, C_1-6Alkyl acyl, amino acyl, C_1-6Alkylaminoacyl, di-C_1-6Alkylamino radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_1-10Heterocyclic group, C_3-10Cycloalkyl and oxo groups;

even more preferably, Y is selected from C_1-3Alkoxy radical, C_3-8Cycloalkyl radical C_1-3Alkoxy radical, C_1-8Heterocyclyl radical C_1-3Alkoxy radical, C_6-12Aryl radical C_1-3Alkoxy radical, C_1-12Heteroaryl C_1-3Alkoxy radical, C_1-3Alkylamino radical, C_3-8Cycloalkyl radical C_1-3Alkylamino radical, C_1-8Heterocyclyl radical C_1-3Alkylamino radical, C_6-12Aryl radical C_1-3Alkylamino radical, C_1-8Heteroaryl C_1-3Alkylamino radical, C_3-8Cycloalkyl radical, C_1-8Heterocyclic group, C_6-12Aryl radical, C_1-12Heteroaryl group, C_2-6Alkenyl and C_2-6Alkynyl, said alkoxy, cycloalkylalkoxy, heterocyclylalkoxy, arylalkoxy, heteroarylalkoxy, alkylamino, cycloalkylalkylamino, heterocyclylalkylamino, arylalkylamino, heteroarylalkylamino, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkenyl, and alkynyl groups may be substituted with 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, carboxylCyano, 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_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8Cycloalkyl radical, C_1-8Heterocyclyl and oxo groups.

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 Y is

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

wherein each R is⁶Each R⁷、R⁴M and n are as defined in formula I.

In some particular embodiments, the compounds of general formula Ia according to the present invention, or isomers, pharmaceutically acceptable salts, solvates, crystals, isosteres or prodrugs thereof, wherein each R⁶Each R⁷Each independently selected from the group consisting of fluoro, chloro, bromo, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, fluoroethoxy, difluoroethoxy, R⁴Is selected from

The present invention provides the following specific compounds or isomers, pharmaceutically acceptable salts, solvates, crystals, isosteres or prodrugs 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:

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

wherein the compound of formula 1 can be represented by formula 3

And a compound of formula 4

The compound of formula 4 can be prepared by reacting the compound of formula 5

Is reacted with trifluoromethanesulfonic anhydride, the compound of formula 2, the compound of formula 3, the compound of formula 5 can be prepared by commercially available or conventional preparation methods known in the art,

X¹、X²、X³、X⁴、R⁴、R⁵、R⁶、R⁷m, n, o, Y are as defined above for formula I.

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" and "carbon" 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。

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 means having ring carbon atoms (preferably 1-10 carbon atoms, i.e., C)_1-10) And a group of 3-to 12-membered non-aromatic ring systems of 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3-12 membered heterocyclyl"). 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 heterocycles in a ring system, as defined aboveAre fused to one or more aryl or heteroaryl groups (where the point of attachment is on the heterocyclic ring), and in such cases the number of ring members continues to be referred to as the number of ring members in the heterocyclic ring 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 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.

"heteroaryl" in the context of the present invention means an aryl group having at least one carbon atom replaced by a heteroatom, consisting of 5 to 20 atoms, more preferably 5 to 12 atoms, said heteroatom being O, S, N, suitable heteroaryl groups preferably having 1 to 18 carbon atoms (i.e. C)_1-18) Including, but not limited to, imidazolyl, benzimidazolyl, imidazopyridinyl, quinazolinyl, pyrrolyl, imidazolonyl, furanyl, thienyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, pyrimidinyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidopyrazolyl, pyrimidoimidazolyl, and the like. Heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents may be onAny available connection points.

"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 1(E) -3- (3, 5-difluoro-4- ((5R) -4- (2-fluoro-2-methylpropyl) -1,2,3,3a,4,5,6,10 c-octahydrocyclopenta [5,6] pyrido [3,4-b ] indol-5-yl) phenyl) acrylic acid

Step a Synthesis of 2- (1H-indol-3-yl) cyclopentyl-1-one

In a 100mL single neck flask, indole (1.98g, 16.9mmol) and dichlorocyclopentanone (2g,16.9mmol) were added, 35mL trifluoroethanol was dissolved, stirred at room temperature, and anhydrous sodium carbonate (2.15g,20.28mmol) was added and the reaction was continued for 48h while maintaining the temperature. After the reaction is finished, sequentially filtering, concentrating and carrying out column chromatography to obtain a target product. ESI-Ms M/z 200.1[ M + H ]]⁺。

Step b Synthesis of 2- (1H-indol-3-yl) cyclopentyl-1-amine

In a 200mL single-necked flask, 2- (1H-indol-3-yl) cyclopentyl-1-one (4.78g, 24.02mmol) and 60mL of methanol were added and dissolved, and ammonium acetate (20.18g,262mmol) and sodium cyanoborohydride (1.67g, 26.42mmol) were added and stirred at room temperature for 48 hours. Adjust pH to 2 with 2M HCl%, concentrate the solvent, then add 50mL water, extract with 40mL dichloromethane, collect the aqueous phase, adjust pH to 12 with 4M sodium hydroxide solution, extract with 3 × 60mL dichloromethane, combine the organic phases, wash with water, wash with saturated brine, and concentrate to give the title product. ESI-Ms M/z 201.13[ M + H ]]⁺。

Step c Synthesis of 2-fluoro-2-methylpropyl trifluoromethanesulfonate

In a 250mL reaction flask, 2-fluoro-2-methylpropan-1-ol (7.25g, 78.75mmol), 2, 6-lutidine (12.75mL, 110.25mmol) were added, dissolved in 60mL of dichloromethane, and then cooled to-10 ℃ under reduced temperature. Trifluoromethanesulfonic anhydride (14.58mL, 86.75mmol) 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 (2X 20mL), a saturated aqueous sodium bicarbonate solution (2X 20mL) and a saturated brine (2X 20mL), 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 d N Synthesis of- (2-fluoro-2-methylpropyl) -2- (1H-indol-3-yl) cyclopentyl-1-amine

Adding the 2-fluoro-2-methylpropyltrimethyl obtained in the step c into a 250mL reaction bottleFluoromethanesulfonate (5g, 22.32mmol), 2- (1H-indol-3-yl) cyclopentyl-1-amine (3.5g, 17.5mmol) and diisopropylethylamine (4.52g, 35mmol) were dissolved in 50mL dioxane, reacted at 90 ℃ for 2H under argon protection, stopped, concentrated, and purified by column chromatography to give the title compound 1.7 g. ESI-Ms M/z 275.19[ M + H ]]⁺. Step e Synthesis of (E) -methyl 3- (4-carbonyl-3, 5-difluoro-phenyl) prop-2-enoate

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 DMF (70mL) and degassed. Methyl acrylate (4.3mL, 45.0mmol) was then added and the reaction 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 organics were washed successively with 2N HCl (200mL), then dried over anhydrous sodium sulfate and concentrated, and the crude product was purified by column chromatography to afford the title compound. ESI-Ms M/z 227.04[ M + H ]]⁺。

Step f Synthesis of methyl (E) -3- (3, 5-difluoro-4- ((5R) -4- (2-fluoro-2-methylpropyl) -1,2,3,3a,4,5,6,10 c-octahydrocyclopenta [5,6] pyrido [3,4-b ] indol-5-yl) phenyl) acrylate

In a 100mL reaction flask, the product obtained in step d (300mg,1.1mmol), methyl (E) -methyl-3- (3, 5-difluoro-4-formylphenyl) acrylate (251mg,1.1mmol) and glacial acetic acid (0.6mL,11mmol) were added, and 25mL of toluene was added to dissolve the mixture, and the mixture was reacted at 90 ℃ for 6 hours, then the reaction mixture was concentrated and purified by column chromatography to obtain the title compound. ESI-Ms M/z 483.2[ M + H ]]⁺。

Step g Synthesis of (E) -3- (3, 5-difluoro-4- ((5R) -4- (2-fluoro-2-methylpropyl) -1,2,3,3a,4,5,6,10 c-octahydrocyclopenta [5,6] pyrido [3,4-b ] indol-5-yl) phenyl) acrylic acid

Weighing the (E) -3- (3, 5-difluoro-4- ((5R) -4- (2-fluoro-2-methylpropyl) -1,2,3,3a,4,5,6,10 c-octahydrocyclopentadiene [5,6] obtained in the step f]Pyrido [3,4-b]Indol-5-yl) phenyl) methyl acrylate (215mg,0.45mmol) was dissolved in tetrahydrofuran/methanol (10mL/5mL) in a 100mL single-neck flask and added dropwise with a 7.5M NaOH% solution (0.5mL), stirred at room temperature for 2 hours, reacted completely, concentrated under reduced pressure, added dropwise with 1M HCl%, adjusted to pH 6.5, added with 15mL of water, extracted with 3 × 15mL of ethyl acetate, the organic phases were combined, concentrated, and subjected to column chromatography to give the title compound.¹H-NMR(400MHz,DMSO-d₆)δ:12.17(s,1H),10.16(s,1H),7.55(s,1H),7.51-7.15(m,4H),7.18-7.16(d,1H),7.02-6.92(m,1H),6.71-6.67(d,1H),5.20(s,1H),3.15-3.12(m,1H),2.39-2.28(m,1H),2.15-2.13(m,1H),2.08(s,1H),1.91-1.77(m,1H),1.65-1.49(m,1H),1.15(s,2H),1.09(s,6H),1.01(s,2H).ESI-Ms m/z:469.2[M+H]⁺。

Example 2(E) -3- (3-chloro-5-fluoro-4- ((5R) -4- (2-fluoro-2-methylpropyl) -1,2,3,3a,4,5,6,10 c-octahydrocyclopenta [5,6] pyrido [3,4-b ] indol-5-yl) phenyl) acrylic acid

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

In a 100mL reaction flask, 4-bromo-2-chloro-6-fluoro-benzaldehyde (2.37g,10mmol), methyl acrylate (1.72g,20mmol), tris (o-toluene) phosphine (0.33g,1.0mmol), palladium acetate (0.13g,0.5mmol) and triethylamine (1.99g,20mmol) were added, dissolved in 25mL DMF and reacted at 80 ℃ under argon for 6 h. 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 243.0[ M + H ]]⁺。

Step b: (E) synthesis of (E) -3- (3-chloro-5-fluoro-4- ((5R) -4- (2-fluoro-2-methylpropyl) -1,2,3,3a,4,5,6,10 c-octahydrocyclopenta [5,6] pyrido [3,4-b ] indol-5-yl) phenyl) acrylic acid

The title compound was prepared by the method of steps f-g in example 1 starting from N- (2-fluoro-2-methylpropyl) -2- (1H-indol-3-yl) cyclopentyl-1-amine, obtained in step d, and methyl (E) -3- (3-chloro-5-fluoro-4-formylphenyl) acrylate, obtained in step a in example 2.¹H-NMR(400MHz,DMSO-d₆)δ:12.23(s,1H),10.38(s,1H),8.07(s,1H),7.92-7.45(m,4H),7.01-6.92(m,2H),6.77-6.69(m,1H),5.41(s,1H),3.95-3.89(m,1H),3.03-2.95(m,1H),2.18-1.93(m,1H),1.91-1.52(m,2H),1.65-1.49(m,1H),1.31-0.99(m,10H).ESI-Ms m/z:485.2[M+H]⁺。

Example 3(E) -3- (3-fluoro-4- ((5R) -4- (2-fluoro-2-methylpropyl) -1,2,3,3a,4,5,6,10 c-octahydrocyclopenta [5,6] pyrido [3,4-b ] indol-5-yl) -5-methoxyphenyl) acrylic acid

The title compound was obtained in a similar manner to the preparation of example 1 except that the starting material, 4-bromo-2, 6-difluoro-1-benzaldehyde, was replaced with 4-bromo-2-fluoro-6-methoxybenzaldehyde.

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

Example 4(E) -3- (3, 5-difluoro-4- ((5R) -9-fluoro-4- (2-fluoro-2-methylpropyl) -1,2,3,3a,4,5,6,10 c-octahydrocyclopenta [5,6] pyrido [3,4-b ] indol-5-yl) phenyl) acrylic acid

The preparation was carried out in analogy to the preparation of example 1, except that indole was replaced by 5-fluoro-indole to give the title compound.

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

Example 5(E) -3- (3-fluoro-4- ((5R) -9-fluoro-4- (2-fluoro-2-methylpropyl) -1,2,3,3a,4,5,6,10 c-octahydrocyclopenta [5,6] pyrido [3,4-b ] indol-5-yl) -5-methoxyphenyl) acrylic acid

The title compound was prepared in analogy to the preparation of example 1, except that indole was replaced with 5-fluoro-indole and 4-bromo-2, 6-difluoro-1-benzaldehyde was replaced with 4-bromo-2-fluoro-6-methoxybenzaldehyde.

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

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

1. Experimental Material

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 ATCC;

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

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

488conjugate), 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 Charocal-stripped 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. The cell culture medium was prepared using Charcol-streamed FBS.

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

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 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; cells were washed 2 times with PBS-T (0.05% Tween-20 in PBS), diluted Estrogen Receptor alpha (D8H8) Rabbit mAb (1:1000, diluted 1% in PBS-T) was added to the ER level assay, and incubated for 1.5H at room temperature; PBS-T washing cells for 3 times, adding 2. mu.g/mL Hochest 33342 in Goat anti-Rabbit IgG (H + L) subcordary Antibody dilution (1:1000 diluted with 1% mil in PBS), 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.

TABLE 1

From the above experimental results, it can be seen that the compounds of the present invention have a good inhibitory activity against ER level at a cell level, and are highly expected to be more therapeutically effective as cancer therapeutic agents.

Experimental example 2 evaluation of cell Activity of Compounds in vitro

1. Experimental Material

Test compounds: the compounds of the present invention prepared in the above examples, each of which was formulated in DMSO to 10mM, were then sequentially diluted 3-fold to 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 blank 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 to obtain IC (integrated circuit) through fitting₅₀The results are shown in Table 2.

TABLE 2

As can be seen from the experiments, the compound of the invention has good inhibitory activity on MCF-7 breast cancer cells, and is very promising to be used as a breast cancer therapeutic agent.

Experimental example 3 evaluation of Compound pharmacokinetics in vivo

Test compounds: the compounds of the present invention prepared in the above examples were each formulated with vehicle (2% Solutol, 98% normal saline) into 2mg/kg for oral test and 1mg/kg for intravenous test.

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 3.

TABLE 3

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

The experimental results show that the compound has good exposure in mice and high oral bioavailability, and can be used for oral administration.

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,

X¹、X²、X³are each independently C (R)¹R²) Wherein R is¹、R²Each independently is hydrogen; x⁴Is NH;

R⁴selected from halogen C_1-10An alkyl group;

R⁵is hydrogen;

each R⁶Each R⁷Each 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_1-6An alkoxy group;

y is

And

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

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein each R⁶Each R⁷Each independently selected from hydrogen, halogen, C_1-6An alkoxy group.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein formula I has the structure of formula Ia below,

wherein R is⁴Each R⁶Each R⁷M, n are defined according to formula I in claim 1 or 2.

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound selected from the group consisting of:

5. a pharmaceutical composition comprising a compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

6. Use of a compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 5 in the manufacture of a medicament for the treatment and/or prophylaxis of estrogen receptor related disorders.