WO2018130124A1 - Tricyclic compound as selective estrogen receptor down-regulator and use thereof - Google Patents

Abstract

The present invention falls within the field of medical chemistry, and relates to a tricyclic compound as a selective estrogen receptor down-regulator and the use thereof. In particular, provided in the present invention are a compound as shown in formula I or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof, the preparation method therefor and pharmaceutical compositions containing the compounds and the use of the compounds or compositions for treating and/or preventing estrogen receptor-associated diseases. The compound of the present invention has an even better anti-tumour activity, a longer dosing interval and fewer side effects, and seems to be very promising as a therapeutic agent against breast cancer.

Description

Tricyclic compounds as selective downregulators for estrogen receptors and their applications Technical field

The invention belongs to the field of medical chemistry, and particularly relates to a compound as a selective estrogen receptor down-regulator (SERD) or an isomer thereof, a pharmaceutically acceptable salt, a solvate, a crystal, an electronic isostere or a prodrug And their preparation and pharmaceutical compositions containing these compounds and the use of these compounds or compositions for the treatment and/or prevention of estrogen receptor-related diseases.

Background technique

The Estrogen Receptor (ER) is a ligand-activated transcriptional regulatory protein that mediates the induction of multiple biological effects through interaction with endogenous estrogens. Endogenous estrogens include 17β-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, and ER-α is widely expressed in various tissues, ER- The expression of β is limited to the female reproductive system and tissues such as brain and bone. Both contain 6 domains and 4 functional regions, and the N-terminal A/B functional region has a non-ligand-dependent transcriptional activation domain AF-1 with constitutive activity through basal transcription factors. Co-activators and other transcription factors act to activate transcription of the target gene, in addition to multiple phosphorylation sites. The DNA binding domain (DBD) consisting of the C domain can specifically bind to the target DNA and contain a nuclear localization signal, and also has a dimerization interface, which plays an important role in the dimerization of the receptor. The D domain is the hinge region responsible for the connection of the DBD and the ligand binding domain (LBD). The C-terminal E domain constitutes LBD, which determines the specific binding of ER to ligands such as estrogen, has a ligand-dependent transcriptional activation domain AF-2, and LBD also has a strong dimerization interface, in the absence of In the case of the body, it still functions, and it is a key part of the receptor's dimerization. The LBD consists of 12 alpha helices and one beta fold, forming a three-layer anti-parallel sandwich structure in which H5, H6, H9 and H10 form the intermediate layer, and H1, H2, H3, H4 and H7, H8, H11 form the outer layers respectively. Two layers, wherein H12 contains AF-2 with a hydrophobic surface facing the ligand binding pocket and a hydrophilic surface facing outward. The LBD of the ER is wedge-shaped, and the H12 is in the groove of the ligand binding pocket and encloses the ligand binding pocket. When ER binds to an agonist, the conformation of H12 becomes more stable, suitable for the binding of coactivators, which in turn activates transcription of the target gene. When ER binds to the antagonist, the position of H12 changes and occupies the binding site of the coactivator, which in turn produces estrogen antagonism.

The research on drugs targeting estrogen receptors has been carried out for many years, and some successes have been made in the clinic. In particular, it has recently been found that selective estrogen receptor down-regulation has a stronger anti-estrogen effect, such as interfering with estrogen receptors. Stability and cause its degradation. However, there is still a need to develop more estrogen receptor down-regulators, especially selective estrogen receptor down-regulations, which make the drugs more excellent, such as better efficacy, less side effects, longer dosing intervals. Etc., thus better for preventing or treating estrogen receptor-related diseases.

Summary of the invention

It is an object of the present invention to provide a compound of the formula I having a selective estrogen receptor down-regulating activity or an isomer thereof, a pharmaceutically acceptable salt, a solvate, a crystal, an isostere or a former medicine,

among them,

R ¹ and R ² are each independently selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkyl. An amino group, an alkyl acylamino group, an alkyl acyl group, an amino acyl group, an alkylamino acyl group, a dialkylamino group, and a cycloalkyl group;

R ^{3 is} selected from the group consisting of alkyl, alkyl acyl, amino acyl, alkyl amino acyl, haloalkyl, hydroxyalkyl, alkenyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ⁴ and R ⁵ are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, halogen, haloalkyl and hydroxyalkyl; or R ⁴ , R ⁵ together with the carbon atom to which they are attached form a carbonyl or cycloalkyl group;

R ⁶ and R ⁷ are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, halogen, haloalkyl and hydroxyalkyl; or R ⁶ , R ⁷ together with the carbon atom to which they are attached form a carbonyl or cycloalkyl group;

R ⁴ and R ⁶ together with the carbon atom to which they are attached form a cycloalkyl group;

Each R ^{8 is} independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkyl An amino group, an alkyl acylamino group, an alkyl acyl group, an amino acyl group, an alkylamino acyl group, a bisalkylamino group, a cycloalkyl group, and a boronic acid;

和

其中R ⁹选自羧基、氰基、烷基、卤代烷基和羟基烷基，R ¹⁰选自氢和卤素，R ¹¹选自羟基、氨基、烷氧基和烷基氨基，环A选自环烷基、杂环基、芳基和杂芳基，所述的环烷基、杂环基、芳基和杂芳基可以被一个或多个氢、卤素、羟基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、单烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、双烷基氨基和环烷基取代，R ¹²选自氢、卤素、羟基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、单烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、双烷基氨基和环烷基，n为1、2或3，或者当n为2时，两个R ¹²基团与它们所连接的碳原子一起形成羰基、环烷基、杂环基、芳基、杂芳基，所述的环烷基、杂环基、芳基和杂芳基可以被一个或多个氢、卤素、羟基、烷基、卤代烷基、羟基烷 基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、单烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、双烷基氨基和环烷基取代，L ¹选自键、-NHCO-、-CONH-、-NHCONH-、-NH-、亚烷基、O、S、卤代亚烷基、羟基亚烷基、亚烷氧基、卤代亚烷氧基、羟基亚烷氧基、羰基和亚烷基氨基； Y is selected from

with

Wherein R ^{9 is} selected from the group consisting of carboxyl, cyano, alkyl, haloalkyl and hydroxyalkyl, R ^{10 is} selected from hydrogen and halogen, R ^{11 is} selected from hydroxy, amino, alkoxy and alkylamino, and ring A is selected from cycloalkane. a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, which may be one or more hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkane Alkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkyl acylamino, alkyl acyl, amino acyl, alkylamino acyl, bisalkyl Substituted with amino and cycloalkyl, R ^{12 is} selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, Monoalkylamino, alkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl, bisalkylamino and cycloalkyl, n is 1, 2 or 3, or when n is 2, two R ¹² The groups together with the carbon atom to which they are attached form a carbonyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, said cycloalkyl group Heterocyclyl, aryl and heteroaryl may be taken up by one or more of hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, acylamino group, an acyl group, an amino group, alkylamino group, dialkylamino and substituted cycloalkyl, L ¹ selected from a bond, -NHCO -, - CONH- , -NHCONH-, -NH-, alkylene, O, S, haloalkylene, hydroxyalkylene, alkyleneoxy, haloalkyleneoxy, hydroxyalkyleneoxy, carbonyl and alkylene Amino group

各自独立地为

或

Chemical bond

Independently

or

m is 1, 2, 3 or 4;

且R ¹、R ²都为氟，R ¹⁰为氢时，R ³选自

烯基和芳基，其中R ¹³选自卤素、羟基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、单烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、双烷基氨基和环烷基。 The condition is when Y is

And R ¹ and R ² are all fluorine, and when R ¹⁰ is hydrogen, R ^{3 is} selected from

Alkenyl and aryl, wherein R ^{13 is} selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkane Alkylamino, alkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl, bisalkylamino and cycloalkyl.

Another object of the present invention is to provide a process for the preparation of a compound of the formula I according to the invention, or an isomer thereof, a pharmaceutically acceptable salt, a solvate, a crystal, an isostere or a prodrug.

A further object of the present invention is to provide a combination of a compound of the formula I according to the invention or an isomer thereof, a pharmaceutically acceptable salt, a solvate, a crystal, an isostere or a prodrug and a pharmaceutically acceptable carrier And a composition comprising a compound of formula I of the invention, or an isomer thereof, a pharmaceutically acceptable salt, a solvate, a crystal, an isostere or a prodrug, and another drug or drugs.

A further object of the present invention is to provide a compound of the formula I according to the invention, or an isomer thereof, a pharmaceutically acceptable salt, a solvate, a crystal, an isostere or a prodrug for the treatment and/or prophylaxis of an estrogen receptor A method of related diseases, and a compound of the formula I according to the invention, or an isomer, pharmaceutically acceptable salt, solvate, crystal, electron isostere or prodrug thereof, for use in the treatment and/or prevention of a female The use of drugs for hormone receptor-related diseases.

In view of the above purposes, the present invention provides the following technical solutions:

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

among them,

R ¹ and R ² are each independently selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkyl. An amino group, an alkyl acylamino group, an alkyl acyl group, an amino acyl group, an alkylamino acyl group, a dialkylamino group, and a cycloalkyl group;

R ^{3 is} selected from the group consisting of alkyl, alkyl acyl, amino acyl, alkyl amino acyl, haloalkyl, hydroxyalkyl, alkenyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ⁴ and R ⁵ are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, halogen, haloalkyl and hydroxyalkyl; or R ⁴ , R ⁵ together with the carbon atom to which they are attached form a carbonyl or cycloalkyl group;

R ⁶ and R ⁷ are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, halogen, haloalkyl and hydroxyalkyl; or R ⁶ , R ⁷ together with the carbon atom to which they are attached form a carbonyl or cycloalkyl group;

R ⁴ and R ⁶ together with the carbon atom to which they are attached form a cycloalkyl group;

Each R ^{8 is} independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkyl An amino group, an alkyl acylamino group, an alkyl acyl group, an amino acyl group, an alkylamino acyl group, a bisalkylamino group, a cycloalkyl group, and a boronic acid;

和

其中R ⁹选自羧基、氰基、烷基、卤代烷基和羟基烷基，R ¹⁰选自氢和卤素，R ¹¹选自羟基、氨基、烷氧基和烷基氨基，环A选自环烷基、杂环基、芳基和杂芳基，所述的环烷基、杂环基、芳基和杂芳基可以被一个或多个氢、卤素、羟基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、单烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、双烷基氨基和环烷基取代，R ¹²选自氢、卤素、羟基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、单烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、双烷基氨基和环烷基，n为1、2或3，或者当n为2时，两个R ¹²基团与它们所连接的碳原子一起形成羰基、环烷基、杂环基、芳基、杂芳基，所述的环烷基、杂环基、芳基和杂芳基可以被一个或多个氢、卤素、羟基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、单烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、双烷基氨基和环烷基取代，L ¹选自键、-NHCO-、-CONH-、-NHCONH-、-NH-、亚烷基、O、S、卤代亚烷基、羟基亚烷基、亚烷氧基、卤代亚烷氧基、羟基亚烷氧基、羰基和亚烷基氨基； Y is selected from

with

Wherein R ^{9 is} selected from the group consisting of carboxyl, cyano, alkyl, haloalkyl and hydroxyalkyl, R ^{10 is} selected from hydrogen and halogen, R ^{11 is} selected from hydroxy, amino, alkoxy and alkylamino, and ring A is selected from cycloalkane. a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, which may be one or more hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkane Alkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkyl acylamino, alkyl acyl, amino acyl, alkylamino acyl, bisalkyl Substituted with amino and cycloalkyl, R ^{12 is} selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, Monoalkylamino, alkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl, bisalkylamino and cycloalkyl, n is 1, 2 or 3, or when n is 2, two R ¹² The groups together with the carbon atom to which they are attached form a carbonyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, said cycloalkyl group Heterocyclyl, aryl and heteroaryl may be taken up by one or more of hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, acylamino group, an acyl group, an amino group, alkylamino group, dialkylamino and substituted cycloalkyl, L ¹ selected from a bond, -NHCO -, - CONH- , -NHCONH-, -NH-, alkylene, O, S, haloalkylene, hydroxyalkylene, alkyleneoxy, haloalkyleneoxy, hydroxyalkyleneoxy, carbonyl and alkylene Amino group

各自独立地为

或

Chemical bond

Independently

or

m is 1, 2, 3 or 4;

且R ¹、R ²都为氟，R ¹⁰为氢时，R ³选自

烯基和芳基，其中R ¹³选自卤素、羟基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、单烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、双烷基氨基和环烷基。 The condition is when Y is

And R ¹ and R ² are all fluorine, and when R ¹⁰ is hydrogen, R ^{3 is} selected from

Alkenyl and aryl, wherein R ^{13 is} selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkane Alkylamino, alkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl, bisalkylamino and cycloalkyl.

的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶、电子等排体或前药。 In some specific embodiments, the compounds of the invention are of formula Ia

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

的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶、电子等排体或前药。 In some specific embodiments, the compounds of the invention are of formula Ib

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

的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶、电子等排体或前药。 In some specific embodiments, the compounds of the invention are of formula Ic

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

In some preferred embodiments, the compound of the invention is a compound of formula I or an isomer thereof, a pharmaceutically acceptable salt, solvate, crystal, ortho isomer or prodrug thereof, wherein:

R ¹ and R ² are each independently selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, C _1-6 alkyl, halogenated C _1-6 alkyl, hydroxy C _1-6 alkyl, C _1-6 alkoxy , halogenated C _1-6 alkoxy, hydroxy C _1-6 alkoxy, nitro, carboxy, cyano, amino, mono C _1-6 alkylamino, C _1-6 alkyl acylamino, C _{a 1-6} alkyl acyl group, an amino acyl group, a C _1-6 alkylamino acyl group, a bis C _1-6 alkylamino group, and a C _3-10 cycloalkyl group;

Further preferably, R ¹ and R ² are each independently selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, C _1-3 alkyl, halogenated C _1-3 alkyl, hydroxy C _1-3 alkyl, C _{1 -3} alkoxy, halo C _1-3 alkoxy, hydroxy C _1-3 alkoxy, nitro, carboxy, cyano, amino, mono C _1-3 alkylamino, C _1-3 alkyl An acylamino group, a C _1-3 alkyl acyl group, an amino acyl group, a C _1-3 alkylamino acyl group, a bis C _1-3 alkylamino group, and a C _3-6 cycloalkyl group;

Still more preferably, R ¹ and R ² are each independently selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, hydroxymethyl Base, hydroxyethyl, hydroxypropyl, 2-hydroxypropyl, methoxy, ethoxy, propoxy, isopropoxy, nitro, carboxyl, cyano, amino, methylamino, ethylamino, Propylamino, isopropylamino, dimethylamino, diethylamino, methylethylamino, dipropylamino, methylpropylamino, ethylpropylamino, methylacylamino, ethylacylamino, ethylene Alkylamino, methylacyl, ethylacyl, vinylacyl, aminoacyl, methylaminoacyl, ethylaminoacyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

In some preferred embodiments, the compound of the invention is a compound of formula I or an isomer thereof, a pharmaceutically acceptable salt, solvate, crystal, ortho isomer or prodrug thereof, wherein:

R ^{3 is} selected from C _1-10 alkyl, C _1-10 alkyl acyl, amino acyl, C _1-10 alkylamino acyl, halo C _1-10 alkyl, hydroxy C _1-10 alkyl, C _{2 a -10} alkenyl group, a C _3-10 cycloalkyl group, a C _3-10 heterocyclic group, a C _6-18 aryl group and a C _5-18 heteroaryl group, which group may be substituted by one or more halogens, hydroxyl groups, Alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, bisalkylamino, and optionally substituted cycloalkyl Replace

Further preferably, R ^{3 is} selected from C _1-6 alkyl, C _1-6 alkyl acyl, amino acyl, C _1-6 alkylamino acyl, halo C _1-6 alkyl, hydroxy C _1-6 alkane a group, a C _2-6 alkenyl group, a C _3-8 cycloalkyl group, a C _3-8 heterocyclic group, a C _6-12 aryl group and a C _5-12 heteroaryl group, the group may be one or more Halogen, hydroxy, C _1-6 alkyl, halo C _1-6 alkyl, hydroxy C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, hydroxy C _{1- 6} alkoxy, nitro, carboxy, cyano, amino, mono C _1-6 alkylamino, bis C _1-6 alkylamino and optionally substituted C _3-8 cycloalkyl;

Still more preferably, R ^{3 is} selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, neopentyl, hexyl, formyl, acetyl, propionyl , aminoacyl, methylaminoacyl, ethylaminoacyl, propylaminoacyl, trifluoromethyl, trifluoroethyl, 2,2-difluoropropyl, 2-fluoro-2-methylpropyl, ( S)-3-fluoro-2-methylpropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, 2-hydroxypropyl, vinyl, propenyl, butenyl, 3-methyl-2-butyl Alkenyl, cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, azacyclopentyl, phenyl and naphthyl, said group may be one or more halogen, hydroxy, C _{1- 3-} alkyl, halo C _1-3 alkyl, hydroxy C _1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, hydroxy C _1-3 alkoxy, nitro a carboxyl group, a cyano group, an amino group, a mono C _1-3 alkylamino group, or a bis C _1-3 alkylamino group.

In some preferred embodiments, the compound of the invention is a compound of formula I or an isomer thereof, a pharmaceutically acceptable salt, solvate, crystal, ortho isomer or prodrug thereof, wherein:

R ⁴ and R ⁵ are each independently selected from the group consisting of hydrogen, C _1-6 alkyl, C _1-6 alkoxy, halogen, halogenated C _1-6 alkyl and hydroxy C _1-6 alkyl;

Further preferably, R ⁴ and R ⁵ are each independently selected from the group consisting of hydrogen, C _1-3 alkyl, C _1-3 alkoxy, halogen, halogenated C _1-3 alkyl and hydroxy C _1-6 alkyl;

Still more preferably, R ⁴ and R ⁵ are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl Base, 2-hydroxypropyl, methoxy, ethoxy, propoxy, isopropoxy and halogen.

In some preferred embodiments, the compound of the invention is a compound of formula I or an isomer thereof, a pharmaceutically acceptable salt, solvate, crystal, ortho isomer or prodrug thereof, wherein:

R ⁴ , R ⁵ together with the carbon atom to which they are attached form a carbonyl group or a C _3-10 cycloalkyl group;

Further preferably, R ⁴ , R ⁵ together with the carbon atom to which they are attached form a carbonyl group, a C _3-6 cycloalkyl group;

Still more preferably, R ⁴ , R ⁵ together with the carbon atom to which they are attached form a carbonyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group and a cyclohexyl group.

In some preferred embodiments, the compound of the invention is a compound of formula I or an isomer thereof, a pharmaceutically acceptable salt, solvate, crystal, ortho isomer or prodrug thereof, wherein:

R ⁶ and R ⁷ are each independently selected from the group consisting of hydrogen, C _1-6 alkyl, C _1-6 alkoxy, halogen, halogenated C _1-6 alkyl and hydroxy C _1-6 alkyl;

Further preferably, R ⁶ and R ⁷ are each independently selected from the group consisting of hydrogen, C _1-3 alkyl, C _1-3 alkoxy, halogen, halogenated C _1-3 alkyl and hydroxy C _1-6 alkyl;

Still more preferably, R ⁶ and R ⁷ are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl Base, 2-hydroxypropyl, methoxy, ethoxy, propoxy, isopropoxy and halogen.

In some preferred embodiments, the compound of the invention is a compound of formula I or an isomer thereof, a pharmaceutically acceptable salt, solvate, crystal, ortho isomer or prodrug thereof, wherein:

R ⁶ and R ⁷ together with the carbon atom to which they are attached form a carbonyl group, a C _3-10 cycloalkyl group;

Further preferably, R ⁶ and R ⁷ together with the carbon atom to which they are attached form a carbonyl group, a C _3-6 cycloalkyl group;

Still more preferably, R ⁶ , R ⁷ together with the carbon atom to which they are attached form a carbonyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group and a cyclohexyl group.

In some preferred embodiments, the compound of the invention is a compound of formula I or an isomer thereof, a pharmaceutically acceptable salt, solvate, crystal, ortho isomer or prodrug thereof, wherein:

R ⁴ , R ⁶ together with the carbon atom to which they are attached form a C _3-10 cycloalkyl group;

Further preferably, R ⁴ , R ⁶ together with the carbon atom to which they are attached form a C _3-6 cycloalkyl group;

Still more preferably, R ⁴ , R ⁶ together with the carbon atom to which they are attached form a cyclopropyl group, a cyclobutyl group, a cyclopentyl group and a cyclohexyl group.

In some preferred embodiments, the compound of the invention is a compound of formula I or an isomer thereof, a pharmaceutically acceptable salt, solvate, crystal, ortho isomer or prodrug thereof, wherein:

Each R ^{8 is} independently selected from the group consisting of hydrogen, halogen, hydroxy, C _1-6 alkyl, halo C _1-6 alkyl, hydroxy C _1-6 alkyl, C _1-6 alkoxy, halo C _{1 -6} alkoxy, hydroxy C _1-6 alkoxy, nitro, carboxy, cyano, amino, mono C _1-6 alkylamino, C _1-6 alkyl acylamino, C _1-6 alkyl acyl , aminoacyl group, C _1-6 alkylamino acyl group, bis C _1-6 alkylamino group, C _3-10 cycloalkyl group and boric acid;

Further preferably, each R ^{8 is} independently selected from the group consisting of hydrogen, halogen, hydroxy, C _1-3 alkyl, halo C _1-3 alkyl, hydroxy C _1-3 alkyl, C _1-3 alkoxy, Halogen C _1-3 alkoxy, hydroxy C _1-3 alkoxy, nitro, carboxy, cyano, amino, mono C _1-3 alkylamino, C _1-3 alkyl acylamino, C _{1- a 3-} alkyl acyl group, an amino acyl group, a C _1-3 alkylamino acyl group, a bis C _1-3 alkylamino group, a C _3-6 cycloalkyl group, and a boronic acid;

Still more preferably, each R ^{8 is} independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, hydroxymethyl Base, hydroxyethyl, hydroxypropyl, 2-hydroxypropyl, methoxy, ethoxy, propoxy, isopropoxy, nitro, carboxyl, cyano, amino, methylamino, ethylamino, Propylamino, isopropylamino, dimethylamino, diethylamino, methylethylamino, dipropylamino, methylpropylamino, ethylpropylamino, methylacylamino, ethylacylamino, ethylene Alkylamino, methylacyl, ethylacyl, vinylacyl, aminoacyl, methylaminoacyl, ethylaminoacyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and boric acid.

In some preferred embodiments, the compound of the invention is a compound of formula I or an isomer thereof, a pharmaceutically acceptable salt, solvate, crystal, ortho isomer or prodrug thereof, wherein:

R ^{9 is} selected from the group consisting of a carboxyl group, a cyano group, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group, and a hydroxy C _1-6 alkyl group;

Further preferably, R ^{9 is} selected from the group consisting of a carboxyl group, a cyano group, a C _1-3 alkyl group, a halogenated C _1-3 alkyl group, and a hydroxy C _1-3 alkyl group;

Still more preferably, R ^{9 is} selected from the group consisting of carboxyl, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl and 2 - hydroxypropyl.

In some preferred embodiments, the compound of the invention is a compound of formula I or an isomer thereof, a pharmaceutically acceptable salt, solvate, crystal, ortho isomer or prodrug thereof, wherein:

R ^{11 is} selected from the group consisting of a hydroxyl group, an amino group, a C _1-6 alkoxy group, and a C _1-6 alkylamino group;

Further preferably, R ^{11 is} selected from the group consisting of a hydroxyl group, an amino group, a C _1-3 alkoxy group, and a C _1-3 alkylamino group;

Still more preferably, R ^{11 is} selected from the group consisting of hydroxyl, amino, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylamino, propylamino and isopropylamino.

In some preferred embodiments, the compound of the invention is a compound of formula I or an isomer thereof, a pharmaceutically acceptable salt, solvate, crystal, ortho isomer or prodrug thereof, wherein:

R ^{12 is} selected from the group consisting of hydrogen, halogen, hydroxy, C _1-6 alkyl, halo C _1-6 alkyl, hydroxy C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy a group, a hydroxy C _1-6 alkoxy group, a nitro group, a carboxyl group, a cyano group, an amino group, a mono C _1-6 alkylamino group, a C _1-6 alkyl acylamino group, a C _1-6 alkyl acyl group, an amino acyl group, a C _1-6 alkylamino acyl group, a bis C _1-6 alkylamino group, and a C _3-10 cycloalkyl group;

Further preferably, R ^{12 is} selected from the group consisting of hydrogen, halogen, hydroxy, C _1-3 alkyl, halo C _1-3 alkyl, hydroxy C _1-3 alkyl, C _1-3 alkoxy, halo C _{1 -3} alkoxy, hydroxy C _1-3 alkoxy, nitro, carboxy, cyano, amino, mono C _1-3 alkylamino, C _1-3 alkyl acylamino, C _1-3 alkyl acyl An aminoacyl group, a C _1-3 alkylamino acyl group, a bis C _1-3 alkylamino group, and a C _3-6 cycloalkyl group;

Still more preferably, R ^{12 is} selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, hydroxymethyl, hydroxyethyl Base, hydroxypropyl, 2-hydroxypropyl, methoxy, ethoxy, propoxy, isopropoxy, nitro, carboxyl, cyano, amino, methylamino, ethylamino, propylamino, Isopropylamino, dimethylamino, diethylamino, methylethylamino, dipropylamino, methylpropylamino, ethylpropylamino, methylacylamino, ethylacylamino, vinylacylamino, Methyl acyl, ethyl acyl, vinyl acyl, amino acyl, methyl amino acyl, ethyl amino acyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

In some preferred embodiments, the compound of the present invention is a compound of Formula I or an isomer, pharmaceutically acceptable salt, solvate, crystal, ortho isomer or prodrug thereof, wherein:

When n is 2, two R ¹² together with the carbon atom to which they are attached form a carbonyl group, a C _3-10 cycloalkyl group, a C _3-10 heterocyclic group, a C _6-18 aryl group, and a C _5-18 heteroaryl group. The cycloalkyl, heterocyclic, aryl and heteroaryl groups may be one or more halogen, hydroxy, C _1-6 alkyl, halo C _1-6 alkyl, hydroxy C _1-6 Alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, hydroxy C _1-6 alkoxy, nitro, carboxy, cyano, amino, mono C _1-6 alkylamino, double a C _1-6 alkylamino group and a C _3-10 cycloalkyl group;

Further preferably, when n is 2, two R ¹² together with the carbon atom to which they are attached form a carbonyl group, a C _3-6 cycloalkyl group, a C _3-6 heterocyclic group, a C _6-12 aryl group and a C ₅ group _{; a -12heteroaryl} group, said cycloalkyl group, heterocyclic group, aryl group and heteroaryl group may be one or more halogen, hydroxy group, C _1-6 alkyl group, halogenated C _1-6 alkyl group, hydroxy group C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy, hydroxy C _1-6 alkoxy, nitro, carboxyl, cyano, amino, mono C _1-6 alkane a base amino group, a di C _1-6 alkylamino group and a C _3-10 cycloalkyl group;

Still more preferably, when n is 2, two R ¹² together with the carbon atom to which they are attached form a carbonyl group, a C _3-6 cycloalkyl group, a C _3-6 heterocyclic group, a C _6-12 aryl group and C _{5-12heteroaryl} , said cycloalkyl, heterocyclic, aryl and heteroaryl may be substituted by one or more halogen, hydroxy, C _1-3 alkyl, halo C _1-3 alkyl, Hydroxy C _1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, hydroxy C _1-3 alkoxy, nitro, carboxy, cyano, amino, mono C _1-3 Alkylamino, bis-C _1-3 alkylamino and C _3-6 cycloalkyl substituted.

In some preferred embodiments, the compound of the invention is a compound of formula I or an isomer thereof, a pharmaceutically acceptable salt, solvate, crystal, ortho isomer or prodrug thereof, wherein:

R ^{13 is} selected from the group consisting of halogen, hydroxy, C _1-6 alkyl, halo C _1-6 alkyl, hydroxy C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, Hydroxy C _1-6 alkoxy, nitro, carboxy, cyano, amino, mono C _1-6 alkylamino, C _1-6 alkyl acylamino, C _1-6 alkyl acyl, amino acyl, C _{1 a -6} alkylamino acyl group, a bis C _1-6 alkylamino group and a C _3-10 cycloalkyl group;

Further preferably, R ^{13 is} selected from the group consisting of halogen, hydroxy, C _1-3 alkyl, halo C _1-3 alkyl, hydroxy C _1-3 alkyl, C _1-3 alkoxy, halo C _1-3 Alkoxy, hydroxy C _1-3 alkoxy, nitro, carboxy, cyano, amino, mono C _1-3 alkylamino, C _1-3 alkyl acylamino, C _1-3 alkyl acyl, amino An acyl group, a C _1-3 alkylamino acyl group, a bis C _1-3 alkylamino group, and a C _3-6 cycloalkyl group;

Still more preferably, R ^{13 is} selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, hydroxymethyl, hydroxyethyl, Hydroxypropyl, 2-hydroxypropyl, methoxy, ethoxy, propoxy, isopropoxy, nitro, carboxy, cyano, amino, methylamino, ethylamino, propylamino, isopropyl Amino, dimethylamino, diethylamino, methylethylamino, dipropylamino, methylpropylamino, ethylpropylamino, methylacylamino, ethylacylamino, vinylacylamino, methyl Acyl, ethyl acyl, vinyl acyl, amino acyl, methyl amino acyl, ethyl amino acyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

In some preferred embodiments, the compound of the invention is a compound of formula I or an isomer thereof, a pharmaceutically acceptable salt, solvate, crystal, ortho isomer or prodrug thereof, wherein:

L ^{1 is} selected from the group consisting of a bond, -NHCO-, -CONH-, -NHCONH-, -NH-, C _1-6 alkyl, O, S, halo C _1-6 alkyl, hydroxy C _1-6 An alkyl group, a C _1-6 alkoxy group, a halogenated C _1-6 alkoxy group, a hydroxy C _1-6 alkoxy group, a carbonyl group and a C _1-6 alkylamino group;

Further preferably, L ^{1 is} selected from the group consisting of a bond, -NHCO-, -CONH-, -NHCONH-, -NH-, a C _1-3 alkyl group, O, S, a halogenated C _1-3 alkyl group, a hydroxyl group C _1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, hydroxy C _1-3 alkoxy, carbonyl and C _1-3 alkylamino;

Still more preferably, L ^{1 is} selected from the group consisting of a bond, -NHCO-, -CONH-, -NHCONH-, -NH-, methylene, ethylene, propylene, isopropylidene, O, S, halogenated Methylene, haloethylene, halopropylene, haloisopropylidene, hydroxymethylene, hydroxyethylene, hydroxypropylene, hydroxyisopropylidene, hydroxyalkylene, sub Methoxy, ethyleneoxy, propyleneoxy, isopropylideneoxy, halomethyleneoxy, haloethyleneoxy, halopropoxy, haloisopropoxy, hydroxy Methyleneoxy, hydroxyethyleneoxy, hydroxypropyleneoxy, hydroxyisidineoxy, carbonyl, methyleneamino, ethyleneamino, propyleneamino and isopropylamino.

In some preferred embodiments, the compound of the invention is a compound of formula I or an isomer thereof, a pharmaceutically acceptable salt, solvate, crystal, ortho isomer or prodrug thereof, wherein:

Ring A is selected from the group consisting of C _3-10 cycloalkyl, C _3-10 heterocyclyl, C _6-18 aryl and C _5-18 heteroaryl, said cycloalkyl, heterocyclyl, aryl and hetero The aryl group may be one or more halogen, hydroxy, C _1-6 alkyl, halo C _1-6 alkyl, hydroxy C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 Alkoxy, hydroxy C _1-6 alkoxy, nitro, carboxy, cyano, amino, mono C _1-6 alkylamino, bis C _1-6 alkylamino and C _3-10 cycloalkyl substituted;

Further preferably, ring A is selected from the group consisting of C _3-6 cycloalkyl, C _3-6 heterocyclic, C _6-12 aryl and C _5-12 heteroaryl, said cycloalkyl, heterocyclic, The aryl and heteroaryl groups may be substituted by one or more halogen, hydroxy, C _1-6 alkyl, halo C _1-6 alkyl, hydroxy C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy, hydroxy C _1-6 alkoxy, nitro, carboxy, cyano, amino, mono C _1-6 alkylamino, bis C _1-6 alkylamino and C _3-10 ring Alkyl substitution

Still more preferably, ring A is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, aziridine, nitrogen Heterocyclic butane, tetrahydropyrrolyl, pyrrolyl, piperidinyl, dihydropyrrolyl, tetrahydropyridyl, pyridyl, propylene oxide, tetrahydrofuranyl, tetrahydropyranyl, dihydrofuranyl, Furanyl, dihydropyranyl, pyranyl, cyclothioethane, cyclobutylalkyl, tetrahydrothiophenyl, thienyl, cyclopentyl sulfide, dihydrothienyl, pyrazolidinyl, di Hydropyrazolyl, pyrazolyl, imidazolidinyl, dihydroimidazolyl, imidazolyl, dihydropyrazolyl, oxazolidinyl, dihydrooxazolyl, imidazolyl, thiazolidinyl, dihydrothiazolyl, Thiazolyl, isoxazolidinyl, dihydroisoxazolyl, isoxazolyl, isothiazolidinyl, dihydroisothiazolyl, isothiazolyl, hexahydropyrimidinyl, tetrahydropyrimidinyl, dihydropyrimidinyl , pyrimidinyl, hexahydropyridazinyl, tetrahydropyridazinyl, dihydropyridazinyl, pyridazinyl, piperazinyl, tetrahydropyrazinyl, dihydropyrazinyl, pyrazinyl, morpholine Base, thiomorpholinyl, dioxolane, dithioheptyl, taurosulfonyl, bicyclo[2.2.1]heptanyl, azaspiro[2.3]hexane, oxobicyclo[3.1. 0] hexane, phenyl, naphthyl, anthracenyl, tetrahydronaphthyl, anthracenyl and indanyl, said group optionally being one or more halogen, hydroxy, C _1-3 alkyl , halogenated C _1-3 alkyl, hydroxy C _1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, hydroxy C _1-3 alkoxy, nitro, carboxy, Cyano, amino, mono C _1-3 alkylamino, bis C _1-3 alkylamino and C _3-6 cycloalkyl substituted.

R ⁴为甲基，R ⁵、R ⁶、R ⁷为H，R ⁹为羧基，R ¹⁰为H或氟。 In some embodiments, the compound of formula Ia according to the invention or its isomer, pharmaceutically acceptable salt, solvate, crystalline, isosteres or prodrug thereof, in which R ¹ is selected from chloro, Methyl, ethyl, propyl, methoxy, ethoxy, propoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, fluoroethoxy, difluoroethane Oxyl and pentafluoroethoxy, R ^{2 is} selected from the group consisting of fluorine, chlorine, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, fluoromethoxy, difluoromethoxy , trifluoromethoxy, fluoroethoxy, difluoroethoxy and pentafluoroethoxy, R ^{3 is} selected from

R ⁴ is a methyl group, R ⁵ , R ⁶ and R ⁷ are H, R ⁹ is a carboxyl group, and R ¹⁰ is H or fluorine.

和

R ⁴为甲基，R ⁵、R ⁶、R ⁷为H，R ⁸选自氢、甲基、乙基、氟和氯，m为1，环A选自环丙基、环丁基、环戊基、环己基、环丙烯基、环丁烯基、环戊烯基、环己烯基、氮杂环丙烷基、氮杂环丁烷基、四氢吡咯基、吡咯基、哌啶基、二氢吡咯基、四氢吡啶基、吡啶基、环氧丙烷基、四氢呋喃基、四氢吡喃基、二氢呋喃基、呋喃基、二氢吡喃基、吡喃基、环硫乙烷基、硫化环丁烷基、四氢噻吩基、噻吩基、硫化环戊烷基、二氢噻吩基、吡唑烷基、二氢吡唑基、吡唑基、咪唑烷基、二氢咪唑基、咪唑基、二氢吡唑基、噁唑烷基、二氢噁唑基、咪唑基、噻唑烷基、二氢噻唑基、噻唑基、异噁唑烷基、二氢异噁唑基、异噁唑基、异噻唑烷基、二氢异噻唑基、异噻唑基、六氢嘧啶基、四氢嘧啶基、二氢嘧啶基、嘧啶基、六氢哒嗪基、四氢哒嗪基、二氢哒嗪基、哒嗪基、哌嗪基、四氢吡嗪基、二氢吡嗪基、吡嗪基、吗啉基、硫代吗啉基、二氧六环基、二硫六环基、牛磺胺基、双环[2.2.1]庚烷基、氮杂螺[2.3]己烷基、氧代双环[3.1.0]己烷基、苯基、萘基、蒽基、四氢萘基、芴基和茚满基，所述的基团任选可以被一个或多个卤素、羟基、C _1-3烷基、卤代C _1-3烷基、羟基C _1-3烷基、C _1-3烷氧基、卤代C _1-3烷氧基、羟基C _1-3烷氧基、硝基、羧基、氰基、氨基、单C _1-3烷基氨基、双C _1-3烷基氨基和C _3-6环烷基取代，R ¹¹为羟基。 In some specific embodiments, compounds of Formula Ib according to the invention, wherein R ¹ , R ² are each independently selected from fluoro, chloro, methyl, ethyl, propyl, methoxy, ethoxy, Propyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, fluoroethoxy, difluoroethoxy and pentafluoroethoxy, R ^{3 is} selected from

with

R ⁴ is methyl, R ⁵ , R ⁶ , and R ⁷ are H, R ^{8 is} selected from the group consisting of hydrogen, methyl, ethyl, fluorine, and chlorine, m is 1, and ring A is selected from the group consisting of cyclopropyl, cyclobutyl, and ring. Pentyl, cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, aziridine, azetidinyl, tetrahydropyrrolyl, pyrrolyl, piperidinyl, Dihydropyrrolyl, tetrahydropyridyl, pyridyl, propylene oxide, tetrahydrofuranyl, tetrahydropyranyl, dihydrofuranyl, furyl, dihydropyranyl, pyranyl, cyclothioethane , cycloalkylalkyl sulfide, tetrahydrothiophenyl, thienyl, cyclopentyl sulfide, dihydrothienyl, pyrazolidinyl, dihydropyrazolyl, pyrazolyl, imidazolidinyl, dihydroimidazolyl, Imidazolyl, dihydropyrazolyl, oxazolidinyl, dihydrooxazolyl, imidazolyl, thiazolidinyl, dihydrothiazolyl, thiazolyl, isoxazolidinyl, dihydroisoxazolyl, isomerism Azyl, isothiazolidinyl, dihydroisothiazolyl, isothiazolyl, hexahydropyrimidinyl, tetrahydropyrimidinyl, dihydropyrimidinyl, pyrimidinyl, hexahydropyridazinyl, tetrahydropyridazinyl, dihydrogen Pyridazinyl, pyridazinyl Piperazinyl, tetrahydropyrazinyl, dihydropyrazinyl, pyrazinyl, morpholinyl, thiomorpholinyl, dioxolane, dithioheptacyclyl, taurosulfonyl, bicyclo [2.2. 1] heptyl, azaspiro[2.3]hexane, oxobicyclo[3.1.0]hexane, phenyl, naphthyl, anthracenyl, tetrahydronaphthyl, anthracenyl and indane The group may be optionally substituted by one or more halogen, hydroxy, C _1-3 alkyl, halo C _1-3 alkyl, hydroxy C _1-3 alkyl, C _1-3 alkoxy, halogenated C _1-3 alkoxy, hydroxy C _1-3 alkoxy, nitro, carboxy, cyano, amino, mono C _1-3 alkylamino, bis C _1-3 alkylamino and C _3-6 ring Alkyl is substituted and R ¹¹ is a hydroxyl group.

The present invention provides the following specific compounds:

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

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

The compounds of formula I can be known in the art as a suitable compound for the Pictet-Spengler reaction (eg in the presence of an acid) by a) a compound of formula 1 and a compound of formula 2 And prepared by reacting at a suitable temperature in a suitable solvent,

或者

or

The compounds of the formula I can be known in the art as being suitable for the Pictet-Spengler reaction conditions (eg in the presence of acids) by b) the compounds of the formula 1 and the compounds of the formula 3 The reaction is carried out to obtain a compound of the formula 4, and the compound of the formula 4 is directly reacted with a suitable group or further subjected to other conventional reactions to obtain a compound of the formula I.

的化合物和式6

的化合物反应制得， Wherein the compound of formula 1 can be passed through formula 5

Compound and formula 6

By compound reaction,

的化合物与三氟甲磺酸酐反应制得， The compound of formula 6 can be passed through formula 7

The compound is prepared by reacting with a trifluoromethanesulfonic anhydride.

The compound of Formula 2, the compound of Formula 3, the compound of Formula 5, or the compound of Formula 7 can be obtained by a commercially available or conventionally known method known in the art.

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , m, Y are as defined in the above formula I, and X is a halogen.

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

In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of the present invention, or an isomer thereof, a pharmaceutically acceptable salt, a solvate, a crystal, an isostere or a prodrug, further comprising a selected from the group consisting of One or more agents in the composition group: SERD, SERM, tyrosinase 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 invention provides a compound of the invention, or an isomer, pharmaceutically acceptable salt, solvate, crystal, or isoster thereof or prodrug thereof, and a compound comprising the same, or an isomer thereof, Pharmaceutical compositions of pharmaceutically acceptable salts, solvates, crystals, electron isosteres or prodrugs for use in the treatment and/or prevention of estrogen receptor related diseases.

The compound of the present invention or an isomer thereof, a pharmaceutically acceptable salt, a solvate, a crystal, an isostere or a prodrug thereof may be mixed with a pharmaceutically acceptable carrier, diluent or excipient to prepare a pharmaceutical preparation. To be 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 formulation may be administered by any route, for example by infusion or bolus injection, by a route of absorption through the epithelium or skin mucosa (e.g., oral mucosa or rectum, etc.). Administration can be systemic or topical. Examples of the orally administered preparations 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 comprise carriers, diluents or excipients conventionally employed in the field of pharmaceutical formulations.

In a fourth aspect, the present invention provides a compound of the formula I of the present invention, or an isomer thereof, a pharmaceutically acceptable salt, a solvate, a crystal, an isostere or a prodrug thereof, or a pharmaceutical composition comprising the same Use of a medicament for the treatment and/or prevention of an estrogen receptor-related disease, wherein the estrogen receptor-associated disease or condition includes, but is not limited to, a cancer associated with ER-α dysfunction (eg, bone cancer) , breast cancer, colorectal cancer, endometrial cancer, prostate cancer, ovarian cancer, and uterine cancer, etc.), leiomyomas (such as uterine leiomyoma, etc.), central nervous system (CNS) defects (such as alcoholism, migraine) Etc., cardiovascular system defects (such as aortic aneurysm, myocardial infarction susceptibility, aortic valve sclerosis, cardiovascular disease, coronary artery disease, hypertension, etc.), blood system defects (such as deep vein thrombosis, etc.), immunity and Inflammatory diseases (such as Graves' disease, arthritis, multiple sclerosis, cirrhosis, etc.), susceptibility to infection (such as hepatitis B, chronic liver disease, etc.), metabolic defects (such as bone density, cholestasis, hypospadias) , obesity, osteoarthritis, osteopenia, osteoporosis, etc.), neurological deficits (eg Alzheimer's disease, Parkinson's disease, migraine, dizziness, etc.), mental disorders (eg anorexia nervosa, attention) Defective hyperactivity disorder (ADHD), dementia, major depressive disorder, psychosis, etc.) and reproductive defects (such as abnormal menarche age, endometriosis, infertility, etc.). In some embodiments, the invention relates to a method of treating an estrogen receptor-related disorder comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I or an isomer thereof, pharmaceutically acceptable a salt, solvate, crystallization, electron isostere or prodrug, or a pharmaceutical composition comprising the same, wherein the estrogen receptor related diseases include, but are not limited to, cancer associated with ER dysfunction (eg, bone cancer) , breast cancer, colorectal cancer, endometrial cancer, prostate cancer, ovarian cancer, and uterine cancer, etc.), leiomyomas (such as uterine leiomyoma, etc.), central nervous system (CNS) defects (such as alcoholism, migraine) Etc., cardiovascular system defects (such as aortic aneurysm, myocardial infarction susceptibility, aortic valve sclerosis, cardiovascular disease, coronary artery disease, hypertension, etc.), blood system defects (such as deep vein thrombosis, etc.), immunity and Inflammatory diseases (such as Graves' disease, arthritis, multiple sclerosis, cirrhosis, etc.), susceptibility to infection (such as hepatitis B, chronic liver disease, etc.), metabolic defects (such as bone density, cholestasis, Hypospadias, obesity, osteoarthritis, osteopenia, osteoporosis, etc., neurological deficits (eg Alzheimer's disease, Parkinson's disease, migraine, dizziness, etc.), mental disorders (eg anorexia nervosa) , attention deficit hyperactivity disorder (ADHD), dementia, major depressive disorder, mental illness, etc.) and reproductive defects (such as abnormal menarche age, endometriosis, infertility, etc.).

The compound of the present invention has more excellent antitumor activity, a longer dosing interval, and less side effects.

Terminology

Terms used in the specification and claims have the following meanings unless stated to the contrary.

"Hydrogen", "carbon", "oxygen" in the compounds of the invention include all isotopes thereof. Isotopes are understood to include those atoms having the same number of atoms but having different mass numbers. For example, isotopes of hydrogen include lanthanum and cerium, carbon isotopes include ¹³ C and ¹⁴ C, and oxygen isotopes include ¹⁶ O and ¹⁸ O.

The "halogen" of the present invention means fluorine, chlorine, bromine or iodine. "Halo" as used in the present invention means substituted by fluorine, chlorine, bromine or iodine.

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

The "alkylene group" of the present invention means a group in which an alkyl group is formally removed from a hydrogen atom, such as a methylene group (-CH ₂ -), an ethylene group (-CH ₂ -CH ₂ -), A propylene group (-CH ₂ -CH ₂ -CH ₂ -), etc., and a "C _1-10 alkyl group" as used herein means that a C _1-10 alkyl group is formally removed from a hydrogen atom. The lower group, the " _C1-6 alkyl group" means a group in which a _C1-6 alkyl group is formally removed from a hydrogen atom. The alkylene group can be substituted or unsubstituted, and when substituted, the substituent can be at any point of attachment that can be used.

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

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

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

The "cycloalkyl group" of 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.

The "heterocyclyl" of the present invention means 3- to 10-- having a ring carbon atom and 1 to 4 ring hetero atoms each of which is independently selected from the group consisting of nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. A group of a non-aromatic ring system (the "C _3-10 membered heterocyclic group" of the present invention has the same meaning as the "3-10 membered heterocyclic group"). In a heterocyclic group containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom as long as the valency permits. The heterocyclyl group may alternatively be a monocyclic ("monocyclic heterocyclic") or a fused, bridged or spiro ring system (eg, a bicyclic system ("bicyclic heterocyclyl")) And it 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 wherein a heterocycle, as defined above, is fused to one or more carbocyclyl groups (wherein the point of attachment is on a carbocyclic group or on a heterocyclic ring), or a ring system The heterocyclic ring, as defined above, is fused to one or more aryl or heteroaryl groups (wherein the point of attachment is on the heterocyclic ring), and in such cases, the number of ring members continues to be referred to as hetero The number of ring members in the ring system. Unless otherwise specified, each instance of a heterocyclic group is independently optionally substituted, that is, unsubstituted ("unsubstituted heterocyclic") or substituted with one or more substituents ("substituted hetero Ring base"). 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. Fused to the C ₆ aryl ring (also referred to as 5,6-bicyclic heterocycle) Exemplary 5-membered heterocyclyl groups include, but are not limited to, indolinyl, iso indolinyl, two Hydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinone, and the like. Exemplary 6-membered heterocyclyl groups (also referred to herein as 6,6-bicyclic heterocycles) fused to an aryl ring include, but are not limited to, tetrahydroquinolyl, tetrahydroisoquinolinyl, and the like. .

The "aryl" of the present invention means an aromatic system which may comprise a monocyclic or fused polycyclic ring, preferably a monocyclic or fused bicyclic aromatic system containing 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, anthracenyl, indanyl. The aryl group can be optionally substituted or unsubstituted, and when substituted, the substituent can be at any available point of attachment.

The "heteroaryl" of the present invention means an aryl group having at least one carbon atom replaced by a hetero atom, and the hetero atom is O, S, N. Suitable heteroaryl groups include, but are not limited to, imidazolyl, benzimidazolyl, imidazopyridyl, quinazolinone, pyrrolyl, imidazolidinyl, furyl, thienyl, pyrazolyl, oxazolyl, thiazole Base, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl and the like. Wherein the "heteroaryl group" of the present invention is preferably composed of 5 to 18 atoms (abbreviated as "5-18 membered heteroaryl group" or "C _5-18 membered heteroaryl group" in the present invention), further preferably A heteroaryl group having 5-12 atoms and at least one atom being a hetero atom. Suitable five- to twelve-membered heteroaryl groups include, but are not limited to, pyrimidinyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidopyrazolyl, pyrimidoimidazolyl, and the like. The heteroaryl group can be optionally substituted or unsubstituted, and when substituted, the substituent can be at any point of attachment that can be used.

The "isomer" of the present invention is a compound having the same molecular formula but differing in nature or on the bond sequence of its atom or in the spatial arrangement of its atoms. Stereoisomers are isomers whose atoms are spatially distinct. Stereoisomers that are not mirror images of each other are diastereomers and that the stereoisomers that are non-overlapping mirror images of each other are enantiomers. When a 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 by Rahn and S-sequence rules of Cahn and Prelog, or by methods of rotating the plane of polarized light by molecules and designated as right-handed or left-handed ( That is, as (+) or (-)-isomers, respectively. The chiral compound can exist as a single enantiomer or a mixture thereof. An equal proportion of mixtures comprising enantiomers is referred to as a "racemic mixture".

The "pharmaceutically acceptable salts" of the present invention refer to salts of the compounds of the present invention which are safe and effective for use in mammals and which have the desired biological activity.

The "solvate" of the present invention refers in a conventional sense to a complex formed by a combination of a solute (such as an active compound, a salt of an active compound) and a solvent (such as water). Solvent refers to a solvent known or readily determinable by those skilled in the art. In the case of water, the solvate is generally referred to as a hydrate such as a hemihydrate, a monohydrate, a dihydrate, a trihydrate or a substituted amount thereof.

The in vivo action of a compound of formula (I) can be exploited, in part, by one or more metabolites formed in the human or animal body following administration of a compound of formula (I). As described above, the in vivo action of the compound of formula (I) can also be exerted via metabolism of the precursor compound ("prodrug"). 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 converted by oxidation, reduction, hydrolysis or the like of an enzyme. A compound of the compound of (I) and/or a compound which is converted into a compound of the formula (I) by a hydrolysis reaction such as gastric acid or the like. Suitable pharmaceutically acceptable prodrugs of the compound of formula I having a carboxy group are, for example, cleavable esters thereof in vivo. An in vivo cleavable ester of a compound of formula I comprising a carboxyl group is, for example, a pharmaceutically acceptable ester which is cleaved in the human or animal body to produce the parent acid. Suitable pharmaceutically acceptable esters for carboxyl groups include alkyl esters such as methyl esters, ethyl esters and tert-butyl esters, alkoxymethyl esters such as methoxymethyl esters; alkanoyloxy groups a base such as pivaloyloxy ester; 3-decyl ester; a cycloalkylcarbonyloxyalkyl ester such as cyclopentylcarbonyloxymethyl ester and 1-cyclohexylcarbonyloxyethyl ester; -Oxo-1,3-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 the compound of formula I having a carboxy group are, for example, in vivo cleavable amides such as N-alkyl amides and N,N-dialkyl amides such as N-methyl amide, N Ethyl amide, N-propyl amide, N,N-dimethyl amide, N-ethyl-N-methyl amide or N,N-diethyl amide.

The bioisostere of the present invention (or simply "e-isostere") is used to define that one or more of the atoms (or radicals) have been similarly spatially and/or electronically characterized by those atoms to which they are substituted. A generally recognized term in the art for replacing a drug analog substituted with an atom (or group of atoms).

The "crystallization" of the present invention means that the internal structure is a solid formed by regularly repeating constituent atoms (or a group thereof) in three dimensions, and is different from an amorphous solid having an internal structure not having such a regularity.

A "pharmaceutical composition" according to the invention is meant to include any one of the compounds described herein, including the corresponding isomers, prodrugs, solvates, pharmaceutically acceptable salts or chemically protected forms thereof, and one or A mixture of a plurality of pharmaceutically acceptable carriers. The purpose of a pharmaceutical composition is to facilitate the administration of a compound to an organism. The compositions are typically used in the manufacture of a medicament for the treatment and/or prevention of a disease mediated by one or more kinases.

The "pharmaceutically acceptable carrier" of the present invention means a carrier which does not cause significant irritation to an organism and does not interfere with the biological activity and properties of the administered compound, and includes all solvents, diluents or other excipients, dispersing agents, Surfactant isotonicity agent, thickener or emulsifier, preservative, solid binder, lubricant, and the like. Unless any conventional carrier medium is incompatible with the compounds of the invention. Some examples of pharmaceutically acceptable carriers 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 carboxymethylcellulose, And cellulose and cellulose acetate; malt, gelatin and the like.

"Excipient" as used herein refers to an inert substance that is added to a pharmaceutical composition to further facilitate administration of the compound. Excipients can include calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols.

The "use in a medicament for treating and/or preventing an estrogen receptor-associated disease" of the present invention means that an estrogen receptor-related disease can be improved, and growth, development and/or inhibition of an estrogen receptor-related disease can be suppressed. Or transferring, or reducing the risk of an estrogen receptor-related disease, primarily administering a therapeutically and/or prophylactically effective amount of a compound of the invention to a human or animal in need thereof to inhibit, slow or reverse the estrogen receptor in the subject The growth, development, or spread of a body-related disease that improves or reduces the risk of estrogen receptor-related diseases, including diseases associated with estrogen receptor alpha and Diseases associated with estrogen receptor beta, such as cancers associated with estrogen receptor dysfunction (eg, bone cancer, breast cancer, colorectal cancer, endometrial cancer, prostate cancer, ovarian cancer, and uterine cancer), smoothing Fibroids (eg uterine leiomyoma, etc.), central nervous system (CNS) defects (eg alcoholism, migraine, etc.), cardiovascular system defects (eg aortic aneurysm, myocardial infarction susceptibility, aorta Plaque sclerosis, cardiovascular disease, coronary artery disease, hypertension, etc.), blood system defects (such as deep vein thrombosis, etc.), immune and inflammatory diseases (such as Graves' disease, arthritis, multiple sclerosis, cirrhosis, etc.) Susceptibility to infection (eg hepatitis B, chronic liver disease, etc.), metabolic defects (eg bone density, cholestasis, hypospadias, obesity, osteoarthritis, osteopenia, osteoporosis, etc.), neurological deficits ( For example, Alzheimer's disease, Parkinson's disease, migraine, dizziness, etc.), mental disorders (such as anorexia nervosa, attention deficit hyperactivity disorder (ADHD), dementia, major depressive disorder, psychosis, etc.) and reproductive defects ( For example, abnormal menarche age, endometriosis, infertility, etc.).

detailed description

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

Example 1 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)azetidin-3-carboxylic acid

Step a Synthesis of (S)-3-fluoro-2-methylpropionic acid methyl ester

Under a argon atmosphere, to a solution of methyl (R)-3-hydroxy-2-methylpropanoate (2.0 g, 16.93 mmol) dissolved in 20 mL of dichloromethane, N,N-diethyl- 1,1,2,3,3,3-hexafluoropropylamine. After the dropwise addition was completed, the reaction mixture was stirred at room temperature for one hour, then heated to reflux and stirred for 4 hours. The reaction mixture was again cooled to room temperature and stirred for 8 hours. After the reaction was completed, the reaction mixture was poured into EtOAc EtOAc. The title compound was obtained and used directly in the next reaction.

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

In a 500 mL three-necked flask, methyl (S)-3-fluoro-2-methylpropanoate (2.3 g, 19.15 mmol) was added, dissolved in 100 mL of anhydrous tetrahydrofuran, and the reactor was cooled to about 0 ° C in a low temperature reactor. Lithium aluminum hydride (0.78 g, 20.53 mmol) was slowly added. After the addition was completed, the reaction mixture was stirred at 0 ° C and room temperature for 1 h each. After the reaction was completed, sodium sulfate decahydrate was added portionwise, and the mixture was stirred for 1 hr.

Step c Synthesis of (S)-3-fluoro-2-methylpropyltrifluoromethanesulfonate

In a 250 mL reaction flask, (S)-3-fluoro-2-methylpropanol (1.8 g, 19.54 mmol), 2,6-lutidine (2.8 mL, 23.7 mmol), with 20 mL dichloromethane After dissolution, it was cooled to -10 ° C. Trifluoromethanesulfonic anhydride (3.13 mL, 18.63 mmol) was dissolved in 10 mL of dichloromethane, and then added dropwise to the above reaction mixture, and the reaction was continued for 1 h. After the reaction was completed, the reaction mixture was washed with EtOAc (2×20 mL) Methane gave the title compound.

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

In a 100 mL reaction flask, (S)-3-fluoro-2-methylpropyltrifluoromethanesulfonate (2.72 g, 12.10 mmol), (R)-1-(1H-indol-3-yl) was added. Propyl-2-amine (1.75 g, 10.04 mmol) and diisopropylethylamine (3.32 ml, 20.08 mmol) were dissolved in 30 mL of dioxane, and reacted under argon at 90 ° C for 2 h to stop the reaction and concentrate. Purification by column chromatography gave 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, Synthesis of 3,4,9-tetrahydro-1H-pyrido[3,4-b]indole

In a 50 mL single-mouth bottle, 4-bromo-2,6-difluorobenzaldehyde (0.535 g, 2.42 mmol) and (S)-N-((R)-1-(1H-indol-3-yl) were added. Prop-2-yl)-3-fluoro-2-methylpropyl-1-amine (0.50 g, 2.0 mmol), added 4 mL of acetic acid and 20 mL of toluene, reacted at 90 ° C for 3 h, concentrated, purified by column chromatography Compound 0.61 g. ESI-Ms m/z: 451.1 [M+H] ⁺ .

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

In a microwave reactor, (1R,3R)-1-(4-bromo-2,6-difluorophenyl)-2-((S)-3-fluoro-2-methylpropyl)-3- Methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (910 mg, 2.02 mmol), azetidine-3-carboxylic acid methyl ester hydrochloride (367 mg) , 2.42 mmol), tris(dibenzylideneacetone)dipalladium (370 mg, 0.404 mmol), 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (391 mg, 0.82 mmol) and cesium carbonate (2.0 g, 6.06 mmol) was added to dioxane (20 mL). After the argon gas was sufficiently replaced, the mixture was heated to 100 ° C for microwave reaction. After the reaction was completed, the mother liquor was filtered and concentrated. This reaction product was used directly in the next step. ESI-Ms m/z: 486.3 [M+H] ⁺ .

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

In a 50 mL single-mouth bottle, 1-(3,5-difluoro-4-((1R,3R)-2-((S)-3-fluoro-2-methylpropyl)-3-methyl-) Methyl 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)azetidin-3-carboxylate (0.62 g, 1.307 mmol) Dissolve with 10mL of tetrahydrofuran and 5mL of methanol, add 7.5M sodium hydroxide solution (3.0mL, 22.5mmol), react at room temperature for 3h, adjust the pH to 6.5 with 2N hydrochloric acid, extract with ethyl acetate, wash with saturated sodium chloride, anhydrous sulfuric acid The sodium was dried and concentrated to give the title compound. ^{1 H 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 2 1-(3-Chloro-5-fluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9 -tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)azetidin-3-carboxylic acid

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

The preparation method is similar to the preparation method of the step bd of the first embodiment, except that the raw material (S)-3-fluoro-2-methylpropionate methyl ester is replaced by methyl 2-fluoro-2-methylpropionate. The title compound was obtained. ESI-Ms m/z: 249.1 [M+H] ⁺ .

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

The preparation method is similar to the preparation method of the step eg of Example 1, except that the starting material (S)-N-((R)-1-(1H-indol-3-yl)propan-2-yl)-3- Replacement of fluoro-2-methylpropyl-1-amine with (R)-N-(1-(1H-indol-3-yl)propan-2-yl)-2-fluoro-2-methylpropane- 1-amine, and the starting material 4-bromo-2,6-difluorobenzaldehyde was replaced with 4-bromo-2-chloro-6-fluorobenzaldehyde to give the title compound. ^{1 H NMR (500MHz, DMSO-} d 6) δ: 12.57 (s, 1H), 10.31 (s, 1H), 7.36 (d, 1H), 7.18 (d, 1H), 6.97-6.92 (m, 2H), 6.33(s,1H), 6.20(d,1H), 5.17(s,1H), 4.02-3.99(m,2H),3.87-3.85(m,2H),3.01(d,1H),2.86(t, 1H), 2.58-2.56 (m, 2H), 2.33-2.30 (m, 2H), 1.11 (d, 3H), 1.05 (d, 3H), 1.00 (d, 3H). ESI-Ms m/z: 488.2 [M+H] ⁺ .

Example 3 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)azetidin-3-carboxylic acid

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

In a 250 mL three-necked flask, 2,2-difluoro-2-methylpropionic acid (5 g, 45.5 mmol) was added, dissolved in 100 mL of anhydrous tetrahydrofuran, and the reactor was cooled to about -10 ° C in a low temperature reactor. Lithium aluminum (2.1 g, 54.2 mmol) was maintained at this temperature for 1 h. After the reaction was completed, 2.1 mL of water, 2.1 mL of a 15% aqueous sodium hydroxide solution, and 4.2 mL of water were added dropwise, and the mixture was stirred for 15 min, then filtered, and the filter cake was washed with a small amount of THF. ESI-Ms m/z: 97.0 [M+H] ⁺ .

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

The preparation method is the same as the preparation method of the step cd of the first embodiment, except that the raw material (S)-3-fluoro-2-methylpropanol is replaced with 2,2-difluoro-2-methylpropyl-1-ol. The title compound was obtained. ESI-Ms m/z: 253.0 [M+H] ⁺ .

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

The preparation method is similar to the preparation method of the step eg of Example 1, except that the starting material (S)-N-((R)-1-(1H-indol-3-yl)propan-2-yl)-3- Replacement of fluoro-2-methylpropyl-1-amine with (R)-N-(1-(1H-indol-3-yl)propan-2-yl)-2,2-difluoropropyl-1 -Amine to give the title compound.

^{1 H NMR (500MHz, DMSO-} d 6) δ: 12.5 (s, 1H), 10.53 (s, 1H), 7.42-7.40 (d, 1H), 7.23-7.21 (d, 1H), 7.03-6.95 (m , 2H), 6.14-6.12 (d, 2H), 5.12 (s, 1H), 4.07-4.03 (m, 2H), 3.93-3.90 (m, 2H), 3.57-3.53 (m, 1H), 3.50-3.46 (m, 1H), 3.10-3.01 (m, 1H), 2.91-2.88 (m, 1H), 2.61-2.57 (m, 2H), 1.50-1.43 (t, 3H), 1.11-1.01 (d, 3H) .ESI-Ms m/z: 476.20 [M+H] ⁺ .

Example 4 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)phenyl)-3-methylazetidin-3-carboxylic acid

The preparation method was similar to the preparation method of Example 2, except that the starting material azetidine-3-carboxylic acid methyl ester hydrochloride was replaced with 3-methylazetidine-3-carboxylic acid methyl ester hydrochloride. The title compound was obtained. ^{1 H NMR (500MHz, DMSO-} d 6) δ: 12.5 (s, 1H), 10.46 (s, 1H), 7.38-7.36 (d, 1H), 7.18-7.17 (d, 1H), 6.97-6.92 (m , 2H), 6.09-6.06 (d, 2H), 5.06 (s, 1H), 4.03-4.01 (d, 2H), 3.64-3.61 (m, 2H), 3.54-3.50 (m, 1H), 2.89-2.76 (m, 2H), 2.55-2.54 (m, 1H), 2.39-2.29 (m, 1H), 1.49 (s, 3H), 1.20-1.10 (q, 6H), 1.04-1.02 (d, 3H). ESI -Ms m/z: 486.2 [M+H] ⁺ .

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

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

5-Fluororuthenium (1.65 g, 10 mmol) was dissolved in 50 mL of acetone, potassium carbonate (13 mg, 1.0 mmol) was added, and the reaction was stirred at room temperature for 5 h. The solvent was evaporated under reduced pressure. ESI-Ms m/z: 224.10 [M+H] ⁺ .

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

The 5-fluoro-3-hydroxy-3-(2-oxopropyl)-indololin-2-one (2.23 g, 10 mmol) obtained in the step a was dissolved in 20 mL of anhydrous tetrahydrofuran, and borane was added dropwise. Tetrahydrofuran solution (30 mL, 1 M, 30 mmol) was reacted at room temperature for 4 h. The reaction mixture was poured into a mixed solution of 50 mL of ethyl acetate and 50 mL of water. After filtration, the solvent was evaporated under reduced pressure tolu ESI-Ms m/z: 194.10 [M+H] ⁺ .

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

1-(5-Fluoro-1H-indol-3-yl)propyl-2-ol (1.93 g, 10 mmol) obtained in step b was dissolved in 20 mL dichloromethane, and 1,1,1-triacetyl was added. Oxy-1,1-dihydro-1,2-phenyliodo-3-(1H)-one (4.66 g, 11 mmol) was reacted at room temperature for 2 h. The reaction mixture was washed with 20 mL of water and 20 mL of brine, Column chromatography gave the title compound 1.76 g. ESI-Ms m/z: 192.10 [M+H] ⁺ .

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

1-(5-Fluoro-1H-indol-3-yl)propyl-2-one (1 g, 5.2 mmol) obtained from step c was dissolved in 20 mL of methanol, and ethyl acetate (4.45 g, 57. Sodium borohydride (0.37 g, 5.9 mmol) was reacted at room temperature for 48 h. The pH was adjusted to 2 by the addition of 1N aqueous hydrochloric acid, and the organic solvent was evaporated under reduced pressure, and 50 mL of dichloromethane. The aqueous layer was adjusted to pH 12 with aq. Column chromatography gave the title compound. ESI-Ms m/z: 193.10 [M+H] ⁺ .

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

The preparation method is similar to the preparation method of Example 2, except that the starting material (R)-1-(1H-indol-3-yl)propan-2-amine is replaced by 1-(5- obtained in the step d). Fluoro-1H-indol-3-yl)propyl-2-amine, and the starting material 4-bromo-2-chloro-6-fluorobenzaldehyde is replaced by 4-bromo-2,6-difluorobenzaldehyde. The title compound was obtained. ^{1 H NMR (500MHz, DMSO-} d 6) δ: 12.5 (s, 1H), 10.55 (s, 1H), 7.16-7.10 (m, 2H), 6.82-6.78 (m, 1H), 6.10-6.07 (d , 2H), 5.05 (s, 1H), 4.04-4.00 (m, 2H), 3.89-3.86 (m, 2H), 3.54-3.49 (m, 2H), 2.87-2.77 (m, 2H), 2.52-2.50 (m, 1H), 2.37-2.29 (m, 1H), 1.19-1.11 (t, 6H), 1.03-1.02 (d, 3H). ESI-Ms m/z: 490.20 [M+H] ⁺ .

Example 6 5-(3,5-Difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9- Tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-5-azaspiro[2.3]hexane-1-carboxylic acid

The preparation method is similar to the preparation method of Example 2, except that the starting material 4-bromo-2-chloro-6-fluorobenzaldehyde is replaced with 4-bromo-2,6-difluorobenzaldehyde, and the raw material nitrogen heterocycle is used. The butane-3-carboxylic acid methyl ester hydrochloride was replaced with methyl 5-azaspiro[2.3]hexane-1-carboxylate to give the title compound. ^{1 H NMR (500MHz, DMSO-} d 6) δ: 12.1 (s, 1H), 10.49 (s, 1H), 7.38-7.36 (d, 1H), 7.18-7.16 (d, 1H), 6.99-6.90 (m , 2H), 6.22-6.19 (d, 1H), 6.12-6.09 (d, 1H), 5.06-5.01 (m, 1H), 4.23-4.22 (m, 1H), 3.95-3.88 (m, 2H), 3.51 -3.48 (m, 1H), 3.25-3.19 (m, 2H), 2.87-2.75 (m, 2H), 2.38-2.28 (m, 1H), 2.04-2.01 (m, 0.5H),

1.84-1.80 (m, 0.5H), 1.50 (s, 0.5H), 1.44 (s, 0.5H), 1.39-1.36 (m, 0.5H), 1.28-1.25 (m, 0.5H), 1.20-1.10 ( m, 6H), 1.03-1.01 (m, 3H). ESI-Ms m/z: 498.3 [M+H] ⁺ .

Example 7 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)phenyl)-1H-pyrazole-4-carboxylic acid

The preparation method is similar to the preparation method of Example 2, except that the starting material 4-bromo-2-chloro-6-fluorobenzaldehyde is replaced with 4-bromo-2,6-difluorobenzaldehyde, and the raw material nitrogen heterocycle is used. The title compound was obtained by substituting methyl butane-3-carboxylate hydrochloride with ethyl 4-pyrazolecarboxylate. ^{1 H NMR (500MHz, DMSO-} d 6) δ: 12.5 (s, 1H), 10.59 (s, 1H), 9.14 (s, 1H), 8.12 (s, 1H), 7.71-7.68 (d, 2H), 7.43-7.40(d,1H), 7.20-7.18(d,1H),7.03-6.93(m,2H),5.23(s,1H),3.56-3.50(m,1H),2.95-2.82(m,2H) ), 2.62-2.56 (m, 1H), 2.44-2.32 (m, 1H), 1.26-1.11 (t, 6H), 1.07-1.05 (d, 3H). ESI-Ms m/z: 483.3 [M+H ] ⁺ .

Example 8 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)phenyl)-5-pyrrolidone-3-carboxylic acid

The preparation method is similar to the preparation method of Example 2, except that the starting material 4-bromo-2-chloro-6-fluorobenzaldehyde is replaced with 4-bromo-2,6-difluorobenzaldehyde, and the raw material nitrogen heterocycle is used. The butane-3-carboxylate methyl ester hydrochloride was replaced with methyl 5-pyrrolidone-3-carboxylate to give the title compound. ^{1 H NMR (500MHz, DMSO-} d 6) δ: 12.25 (s, 1H), 10.51 (s, 1H), 7.41-7.36 (t, 3H), 7.17 (d, 1H), 7.00-6.94 (m, 2H ), 5.16 (s, 1H), 4.00-3.92 (m, 2H) 3.50 (m, 1H), 3.24 (m, 1H), 2.88-2.57 (m, 4H), 2.57 (d, 1H), 2.32 (m) , 1H), 1.21-1.09 (d, 3H), 1.16 (d, 3H), 1.04 (d, 3H). ESI-Ms m/z: 500.2 [M+H] ⁺ .

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

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

4-Bromo-2,6-difluoro-1-benzaldehyde (6.66 g, 30 mmol), triethylamine (8.4 ml, 60 mmol), palladium acetate (0.34 g, 1.5 mmol) and trimethylphenyl phosphate (1.0 g) , 3.2 mmol) was dissolved in N,N-dimethylformamide (70 mL) and degassed. Methyl acrylate (4.3 mL, 45.0 mmol) was then added and the reaction was heated to 80 ° C for 4 h. After cooling, the mixture was taken into water (300 mL) andEtOAc. The combined organics were washed with EtOAc EtOAc EtOAc EtOAc. ESI-Ms m/z: 227.04 [M+H] ⁺ .

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

In a 100 mL reaction flask, (R)-N-(1-(1H-indol-3-yl)propan-2-yl)-2,2-difluoropropyl-1 obtained in Example 3 was added. -amine (0.252 g, 1 mmol), methyl (E)-3-(3,5-difluoro-4-formylphenyl)acrylate (0.181 g, 0.8 mmol), and glacial acetic acid (0.29 mL, 5 mmol). Further, 25 mL of toluene was added and dissolved, and the mixture was reacted at 90 ° C for 6 hours. The reaction mixture was concentrated and purified by column chromatography to give the title compound. ESI-Ms m/z: 461.2 [M+H] ⁺ .

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

In a 50 mL single-necked flask, the product obtained in step b (E)-3-(3,5-difluoro-4-((1R,3R)-2-(2,2-difluoro-2-methylpropyl) Methyl 3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate (0.221 g, 0.48 mmol), Dissolve with 8 mL of tetrahydrofuran and 4 mL of methanol, add 7.5 M aqueous sodium hydroxide solution (0.64 mL, 4.8 mmol), react at room temperature for 2 h, adjust pH to 6.5 with 2N diluted hydrochloric acid, extract with ethyl acetate, wash with saturated sodium chloride, anhydrous sulfuric acid The sodium was dried and concentrated to give the title compound. ^{1 H NMR (500MHz, DMSO-} d 6) δ: 12.29 (s, 1H), 10.63 (s, 1H), 7.58-7.55 (d, 1H), 7.49-7.47 (d, 2H), 7.45-7.44 (d , 1H), 7.24-7.22 (d, 1H), 7.06-7.02 (t, 1H), 7.00-6.97 (t, 1H), 6.71-6.68 (d, 1H), 5.25 (s, 1H), 3.40 (s , 1H), 3.18-3.09 (m, 2H), 2.94-2.90 (m, 2H), 1.54-1.46 (t, 3H), 1.12 (s, 3H). ESI-Ms m/z: 447.2 [M+H ] ⁺ .

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

The preparation method is similar to the preparation method of Example 9, except that the starting material 4-bromo-2,6-difluoro-1-benzaldehyde is replaced with 4-bromo-2-chloro-6-fluorobenzaldehyde, and the raw materials are used. (R)-N-(1-(1H-indol-3-yl)propan-2-yl)-2,2-difluoropropyl-1-amine was replaced with (R) obtained in Example 2. -N-(1-(1H-indol-3-yl)propan-2-yl)-2-fluoro-2-methylpropan-1-amine gave the title compound. ^{1 H NMR (500MHz, DMSO-} d 6) δ: 12.59 (s, 1H), 10.47 (s, 1H), 7.70 (s, 1H), 7.57-7.53 (d, 2H), 7.41 (d, 1H), 7.17(d,1H), 6.99-6.94(m,2H), 6.72(d,1H), 5.34(s,1H), 3.65(m,1H),3.07-2.91(m,2H),2.59(d, 1H), 2.28-2.24 (m, 1H), 1.14-1.03 (d, 3H), 1.09 (d, 3H), 1.05 (d, 3H). ESI-Ms m/z: 459.2 [M+H] ⁺ .

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

The preparation method was similar to the preparation method of Example 10 except that the starting material 4-bromo-2-chloro-6-fluorobenzaldehyde was replaced with 4-bromo-2-(difluoromethoxy)-6-hydroxybenzaldehyde. The title compound was obtained. ^{1 H NMR (500MHz, DMSO-} d 6) δ: 12.51 (s, 1H), 10.36 (s, 1H), 7.49 (d, 1H), 7.39-7.38 (m, 3H), 7.14 (m, 2H), 6.97-6.93 (m, 2H), 6.60 (d, 1H), 5.20 (s, 1H), 3.55 (m, 1H), 2.98 (d, 1H), 2.85 (dd, 1H), 2.58 (m, 1H) , 2.26 (dd, 1H), 1.15-0.98 (m, 9H). ESI-Ms m/z: 491.2 [M+H] ⁺ .

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

Synthesis of step a (Z)-3-(3,5-difluoro-4-formylphenyl)-2-fluoro-methyl acrylate

In a 100 mL reaction flask, 4-bromo-2,6-difluoro-1-benzaldehyde (1 g, 4.93 mmol), 2-fluoromethyl acrylate (1.54 g, 14.77 mmol), and tri-o-tolylphosphine (0.15) were added. g, 0.493 mmol), palladium acetate (0.06 g, 0.247 mmol) and triethylamine (1.00 g, 9.86 mmol) were dissolved in 20 mL of N,N-dimethylformamide and reacted at 80 ° C for 6 h under argon atmosphere. After the reaction is over. After adding 20 mL of ice water, the mixture was stirred with EtOAc. ESI-Ms m/z: 245.1 [M+H] ⁺ .

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

The preparation method is similar to the preparation method of the step bc of Example 9, except that the starting material (E) methyl 3-(3,5-difluoro-4-formylphenyl)acrylate is replaced with (Z)-3- (3,5-Difluoro-4-formylphenyl)-2-fluoro-methyl acrylate, and the starting material (R)-N-(1-(1H-indol-3-yl)propan-2- Substituting -2,2-difluoropropyl-1-amine for (R)-N-(1-(1H-indol-3-yl)propan-2-yl)-2-fluoro-2-methyl The propyl-1-amine gave the title compound. ^{1 H NMR (500MHz, DMSO-} d 6) δ: 12.60 (s, 1H), 10.49 (s, 1H), 7.71 (s, 1H), 7.61-7.58 (d, 1H), 7.44 (d, 1H), 7.20(d,1H), 6.99-6.95(m,2H), 6.72(d,1H), 5.32(s,1H), 3.65(m,1H),3.07-2.91(m,2H),2.59(d, 1H), 2.28-2.24 (m, 1H), 1.14, 1.04 (d, 3H), 1.09 (d, 3H), 1.03 (d, 3H). ESI-Ms m/z: 461.5 [M+H] ⁺ .

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

The preparation method was similar to the preparation method of Example 10 except that the starting material 4-bromo-2-chloro-6-fluorobenzaldehyde was replaced with 4-bromo-2,6-dichlorobenzaldehyde to give the title compound. ^{1 H NMR (300MHz, DMSO-} d 6) δ: 10.25 (s, 1H), 8.27 (s, 1H), 7.79 (s, 1H), 7.54 (s, 1H), 7.40-7.35 (m, 2H), 7.16-7.14(d,1H), 7.00-6.90(m,2H),6.61-6.58(d,1H),5.58(s,1H),3.67(s,1H),3.07-2.87(m,2H), 2.55-2.60 (s, 1H), 2.29-2.14 (m, 1H), 1.12-1.01 (s, 9H). ESI-Ms m/z: 475.2 [M+H] ⁺ .

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

The preparation method is similar to the preparation method of Example 10 except that the starting material 4-bromo-2-chloro-6-fluoro-benzaldehyde is replaced by 4-bromo-2-fluoro-6-methoxybenzaldehyde. Title compound. ^{1 H NMR (300MHz, DMSO-} d 6) δ: 10.36 (s, 1H), 7.50-7.47 (d, 1H), 7.41-7.40 (d, 1H), 7.25 (s, 1H), 7.19-7.17 (d , 1H), 7.02-6.94 (m, 3H), 6.69-6.60 (d, 1H), 5.35 (s, 1H), 3.90 (s, 3H), 3.60 (m, 2H), 3.00-2.97 (m, 1H) ), 2.88-2.84 (m, 1H), 2.60-2.59 (d, 1H), 2.38-2.29 (m, 1H), 1.20-1.09 (m, 9H). ESI-Ms m/z: 455.3 [M+H ] ⁺ .

Example 15 1-(3,5-Difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9- Tetrahydro-1H-pyridine[3,4-b]indol-1-yl)phenyl)azetidin-3-carboxylic acid

The preparation method was similar to the preparation method of Example 2 except that the starting material 4-bromo-2-chloro-6-fluorobenzaldehyde was replaced with 4-bromo-2,6-difluorobenzaldehyde to give the title compound. ^{1 H NMR (500MHz, DMSO-} d 6) δ: 12.15 (s, 1H), 10.38 (s, 1H), 7.36-7.30 (d, 1H), 7.23-7.19 (d, 1H), 7.02-6.85 (m , 2H), 6.15-6.05 (d, 2H), 5.05 (s, 1H), 4.15-3.98 (m, 2H), 3.95-3.80 (m, 2H), 3.65-3.47 (m, 2H), 3.90-3.75 (m, 2H), 2.75 (s, 1H), 2.42-2.30 (m, 1H), 1.26-1.01 (m, 9H). ESI-Ms m/z: 472.3 [M+H] ⁺ .

Example 16 1-(3-Fluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro- 1H-pyridine [3,4-b]indol-1-yl)-5-methoxyphenyl)azetidin-3-carboxylic acid

The preparation method is similar to the preparation method of Example 2, except that the starting material 4-bromo-2-chloro-6-fluoro-benzaldehyde is replaced by 4-bromo-2-fluoro-6-methoxybenzaldehyde. Title compound. ^{1 H NMR (300MHz, DMSO-} d 6) δ: 10.28 (s, 1H), 7.95-7.93 (d, 1H), 7.34-7.32 (d, 1H), 7.16-7.13 (d, 1H), 6.88-6.96 (m, 2H), 5.90 (s, 1H), 5.68-5.65 (m, 1H), 5.17 (s, 1H), 3.94-3.92 (m, 2H), 3.83-3.82 (m, 2H), 3.55-3.50 (m, 1H), 3.39-3.46 (m, 1H), 2.93-2.87 (m, 1H), 2.77-2.70 (m, 1H), 2.60-2.54 (d, 3H), 2.26-2.37 (m, 1H) , 2.01-1.95 (m, 1H), 1.10-1.05 (m, 6H), 1.00 (s, 3H). ESI-Ms m/z: 484.3 [M+H] ⁺ .

Example 17 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

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

(4-(Methoxycarbonyl)phenyl)boronic acid (1.97 g, 11 mmol), 4-bromo-2,6-difluorobenzaldehyde (2.21 g, 10 mmol), 1,3-bis(diphenylphosphine) Propane nickel chloride (54 mg, 0.1 mmol), potassium phosphate (8.48 g, 40 mmol) and 60 mL of dioxane were mixed in a 100 mL eggplant bottle, heated to 110 ° C under argon atmosphere, and reacted for 10 h at the same temperature. The organic solvent was concentrated under reduced pressure. EtOAc (EtOAc)EtOAc. The residue was purified by silica gel column chromatography eluting ESI-Ms m/z: 277.1 [M+H] ⁺ .

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

The preparation method is similar to the preparation method of the step bc of Example 9, except that the starting material (E) methyl 3-(3,5-difluoro-4-formylphenyl)acrylate is replaced by the above step a. Methyl 3',5'-difluoro-4'-formyl-[1,1'-biphenyl]-4-carboxylate, and the starting material (R)-N-(1-(1H-吲哚) -3-yl)propan-2-yl)-2,2-difluoropropyl-1-amine is replaced by (R)-N-(1-(1H-indol-3-yl)propan-2-yl 2-fluoro-2-methylpropan-1-amine to give the title compound. ^{1 H NMR (400MHz, DMSO-} d 6) 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 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]-3-carboxylic acid

The preparation method was similar to the preparation method of Example 17, except that the starting material (4-(methoxycarbonyl)phenyl)boronic acid was replaced by (3-(methoxycarbonyl)phenyl)boronic acid to give the title compound. ^{1 H NMR (400MHz, DMSO-} d 6) 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 19 5-(3,5-Difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9- Tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)thiazole-2-carboxylic acid

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

Ethyl 5-bromothiazole-2-carboxylate (4.68 g, 20 mmol), pinacol borate (5.59 g, 22 mmol), potassium acetate (5.88 g, 60 mmol), [1,1'-bis(diphenyl) Peptidyl) ferrocene] palladium dichloride (1.4g, 1.8mmol) dissolved in 100mL dioxane, argon-protected, stirred at 80 ° C for 12h, then distilled most of the solvent under reduced pressure, added 150mL of acetic acid The ester was washed with a saturated aqueous solution of sodium chloride (100 mL × 2), dried over anhydrous sodium sulfate ESI-Ms m/z: 284.1 [M+H] ⁺ .

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

Ethyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole-2-carboxylate (1.45 g, 5.1 mmol), 2,6-Difluoro-4-bromobenzaldehyde (936 mg, 4.26 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (62.3 mg, 0.085 mmol), 4.3 The aqueous sodium carbonate solution (2M) was dissolved in 10 mL of toluene, argon-protected, heated under reflux at 100 ° C for 16 h, added with saturated aqueous sodium chloride (50 mL), and then extracted with ethyl acetate (50 mL×3). The mixture was dried over sodium sulfate and evaporated to dryness to dryness crystals. ESI-Ms m/z: 298.0 [M+H] ⁺ .

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

The preparation method is similar to the preparation method of the step bc of Example 9, except that the starting material (E) methyl 3-(3,5-difluoro-4-formylphenyl)acrylate is replaced by the above step. Ethyl 5-(3,5-difluoro-4-formylphenyl)thiazole-2-carboxylate, and the starting material (R)-N-(1-(1H-indol-3-yl)propane-2 -yl)-2,2-difluoropropyl-1-amine was replaced by (R)-N-(1-(1H-indol-3-yl)propan-2-yl)-2-fluoro-2- Methyl propan-1-amine gave the title compound. ^{1 H NMR (400MHz, DMSO-} d 6) δ: 10.62 (s, 1H), 9.16 (s, 1H), 8.06 (s, 1H), 8.48 (s, 1H), 7.58-7.56 (d, 1H), 7.43-7.41(d,1H),7.42-7.18(d,1H),7.02-6.94(m,2H),5.25(s,1H),3.53-3.52(m,1H),2.90-2.84(m,2H ), 2.61-2.58 (m, 1H), 2.50-2.48 (m, 1H), 1.36-1.06 (m, 9H). ESI-Ms m/z: 500.1 [M+H] ⁺ .

Example 20 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 method was similar to the preparation method of Example 17, except that the starting material (4-(methoxycarbonyl)phenyl)boronic acid was replaced with (3-methoxy-4-(methoxycarbonyl)phenyl)boronic acid. The title compound was obtained by substituting 4-bromo-2,6-difluorobenzaldehyde as 4-bromo-2-methoxy-6-fluorobenzaldehyde. ^{1 H NMR (400MHz, DMSO-} d 6) 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 21 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)phenyl)azetidin-3-carboxamide

In a 50 mL single-mouth bottle, 1-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3 was added sequentially. ,4,9-tetrahydro-1H-pyridine [3,4-b]indol-1-yl)phenyl)azetidin-3-carboxylic acid methyl ester (180 mg, 0.37 mmol) and 10 mL of ammonia in methanol The solution was heated and stirred at 55 ° C for 12 h, and the reaction was quenched. ^{1 H NMR (400MHz, DMSO-} d 6) δ: 10.47 (s, 1H), 7.47 (s, 1H), 7.38-7.36 (d, 1H), 7.18-7.17 (d, 1H), 7.02-6.90 (m ,3H),6.07-6.04(d,2H),5.05(s,1H),3.97-3.93(m,2H),3.83-3.78(m,2H),3.53-3.51(m,1H),3.44-3.42 (m, 1H), 2.86-2.80 (m, 2H), 2.39-2.32 (m, 2H), 1.20-1.02 (m, 9H). ESI-Ms m/z: 471.2 [M+H] ⁺ .

Example 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)cyclopropane-1-carboxylic acid

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

4-Bromo-2,6-difluorobenzaldehyde (3156 mg, 14.2 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborane (3300 mg) , 21.4 mmol) was dissolved in a mixed solvent of 30 mL of dimethyl ether and 10 mL of water, and potassium carbonate (3897 mg, 28.2 mmol) and bis(triphenylphosphine)palladium dichloride (300 mg, 0.14 mmol) were added, and protected with argon gas. The mixture was heated to 80 ° C, and the reaction was stirred for 5 hr. ESI-Ms m/z: 169.1 [M+H] ⁺ .

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

2,6-Difluoro-4-vinylbenzaldehyde (2500 mg, 14.9 mmol) and ethylene glycol (1670 mg, 27 mmol) were dissolved in 30 mL of toluene, 490 mg of p-toluenesulfonic acid was added, and 2000 mg of silica gel was added thereto, and the reaction was carried out at 113 ° C. hour. Sanding and column chromatography gave the title compound. ESI-Ms m/z: 213.1 [M+H] ⁺ .

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

2-(2,6-Difluoro-4-vinylphenyl)-1,3-dioxolane (2120 mg, 10 mmol) and diammonium acetate (70 mg, 0.25 mmol) were dissolved in 30 ml of anhydrous dichloride. In methane, ethyl diazoacetate (4500 mg, 40 mmol) was dissolved in 30 mL of anhydrous dichloromethane and 2-(2,6-difluoro-4-vinylphenyl)-1,3-di was slowly added dropwise. A mixture of oxylanol and bismuth diacetate was added dropwise over 1 hour, and the mixture was reacted at room temperature for 1 hour to obtain a title compound. ESI-Ms m/z: 299.1 [M+H] ⁺ .

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

Ethyl 2-(4-(1,3-dioxolan-2-yl)-3,5-difluorophenyl)cyclopropane-1-carboxylate (1700 mg, 5.7 mmol) was dissolved in 6 mL of trifluoro Acetic acid, 4 mL of concentrated hydrochloric acid and 2 mL of water were added, and the mixture was stirred at room temperature for 1 hr. ESI-Ms m/z: 255.1 [M+H] ⁺ .

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

Ethyl 2-(3,5-difluoro-4-formylphenyl)cyclopropane-1-carboxylate (254 mg, 1 mmol) and (R)-N-(1-(1H-indol-3-yl) ) propan-2-yl)-2-fluoro-2-methylpropan-1-amine (248 mg, 1 mmol) dissolved in 20 mL of toluene, added 1 mL of acetic acid, reacted at 80 ° C for 4 hours, added water, extracted with ethyl acetate, organic layer Dry and concentrate to give the title compound. ESI-Ms m/z: 471.1 [M+H] ⁺ .

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

2-(3,5-Difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro Methyl-1H-pyrido[3,4-b]indol-1-yl)phenyl)cyclopropane-1-carboxylate (470 mg, 1 mmol) was dissolved in 10 mL of THF, 5 mL of methanol 1 ml of sodium aqueous solution was reacted at room temperature for 1 hour, and the pH was adjusted to about 5 by adding 2N diluted hydrochloric acid, and extracted with water and ethyl acetate. ^{1 H NMR (400MHz, DMSO-} d 6) δ12.61 (s, 1H), 10.57 (s, 1H), 7.72 (s, 1H), 7.52 (d, 1H), 7.46 (d, 1H), 7.40 ( d, 1H), 7.20 (d, 1H), 5.21 (s, 1H), 4.41 (m, 1H), 3.47-3.57 (m, 1H), 2.80-2.98 (m, 2H), 2.53-2.63 (m, 2H), 2.36 (dd, 1H), 2.21 (m, 1H), 1.45-1.70 (m, 2H), 1.08-1.28 (m, 6H), 1.07 (d, 3H). ESI-Ms m/z: 457.2 [M+H] ⁺ .

Example 23 3,5-Difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro- 1H-pyrido[3,4-b]indol-1-yl)-N-((1R,2S)-2-fluorocyclopropyl)benzamide

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

In a 1 L reaction flask, 2,6-difluoro-4-bromobenzaldehyde (17.76 g, 80.7 mmol), ethylene glycol (9.1 mL, 162.9 mmol), p-toluenesulfonic acid monohydrate (200 mg, 1.1 mmol) Dissolve in 250 mL of toluene, reflux at 110 ° C, remove water by water separator, and react for 6 h. After completion of the reaction, the mixture was cooled to room temperature, washed with water (100 mL×3), EtOAc.

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

In a 100 mL reaction flask, the product of step a was added 2-(4-bromo-2,6-difluorophenyl)-1,3-dioxolane (1.4 g, 5.3 mmol), 1,1'-double Diphenylphosphinoferrocene (300 mg, 0.5 mmol) and palladium acetate (300 mg, 1.3 mmol) were dissolved in a mixed solvent of 20 mL of methanol and 25 mL of N,N-dimethylformamide, and then 1.18 mL of triethylamine was added. The mixture was stirred at 70 ° C under a CO gas atmosphere for 3 hours. After completion of the reaction, the mixture was cooled to room temperature, concentrated, evaporated, evaporated, evaporated, evaporated, evaporated. The filtrate was concentrated and purified by column chromatography toiel ESI-Ms m/z: 245.1 [M+H] ⁺ .

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

In a 100 mL reaction flask, add the product of step b, 3,5-difluoro-4-(1,3-dioxolan-2-yl)-benzoic acid methyl ester (244 mg, 1 mmol), using 5 mL methanol and 5 mL The mixed solvent of tetrahydrofuran was dissolved, and 5 ml of an aqueous solution of sodium hydroxide (120 mg, 3 mmol) was added, and the mixture was stirred at room temperature for 0.5 h. After the reaction was completed, the reaction mixture was concentrated, evaporated, evaporated, evaporated, evaporated ESI-Ms m/z: 231.0 [M+H] ⁺ . Step d Synthesis of 4-(1,3-dioxolan-2-yl)-3,5-difluoro-N-((1S,2R)-2-fluorocyclopropyl)benzamide

In a 100 mL reaction flask, add the product of step c, 3,5-difluoro-4-(1,3-dioxolan-2-yl)-benzoic acid (230 mg, 1 mmol), 1-(3-dimethyl Aminopropyl)-3-ethylcarbodiimide hydrochloride (230 mg, 1.2 mmol) and 1-hydroxybenzotriazole (162 mg, 1.2 mmol) were dissolved in 15 mL dichloromethane. Further, (1S, 2R)-2-fluorocyclopropylamine p-toluenesulfonate (300 mg, 1 mmol) was added and stirred at room temperature for 2 h. After completion of the reaction, the reaction mixture was evaporated to dryness. ESI-Ms m/z: 288.1 [M+H] ⁺ .

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

In the 100 mL reaction flask, the product obtained in step d (1,3-dioxolan-2-yl)-3,5-difluoro-N-((1S,2R)-2-fluorocyclopropyl)benzene was added. Formamide (240 mg, 0.84 mmol) was dissolved in 20 mL of dichloromethane, and 1.5 mL of trifluoroacetic acid was added and stirred at room temperature overnight. After the reaction was completed, water (50 mL × 2) was evaporated. ESI-Ms m/z: 244.1 [M+H] ⁺ .

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

In a 100 mL reaction flask, 3,5-difluoro-N-((1S,2R)-2-fluorocyclopropyl)-4-formylbenzamide (200 mg, 0.82 mmol) and (R)-N were added. -(1-(1H-Indol-3-yl)propan-2-yl)-2-fluoro-2-methylpropan-1-amine (200 mg, 0.81 mmol), dissolved in 5 mL of toluene, Acetic acid, reacted at 80 ° C for 3 h. After the reaction was completed, the reaction mixture was added to EtOAc EtOAc EtOAc. ESI-Ms m/z: 474.2 [M+H] ⁺ . ^{1 H NMR (400MHz, DMSO-} d 6): δ10.57 (s, 1H), 7.72 (s, 1H), 7.52 (d, 1H), 7.46 (d, 2H), 7.40 (d, 1H), 7.20 (d, 1H), 6.92-7.06 (m, 1H), 5.21 (s, 1H), 4.41 (m, 1H), 3.47-3.57 (m, 1H), 2.80-2.98 (m, 2H), 2.53-2.58 (m, 2H), 2.36 (dd, 1H), 1.08-1.28 (m, 6H), 1.07 (d, 3H), 0.55-0.61 (m, 2H).

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

Table 1:

Experimental Example 1 Evaluation of ER level activity of compounds based on cell level in vitro

Experimental material

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

Reagents: phosphate buffer (DPBS), trypan blue, PolarScreen ER Alpha competitor Assay, purchased from Invitrogen;

Fetal bovine serum (FBS), trypsin, DMEM, penicillin-streptomycin (Pen/Strep), purchased from GIBCO;

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

MCF-7 cells, purchased from AATCC;

Estrogen Receptor alpha (D8H8) Rabbit mAb, purchased from CST;

488 conjugate，购自于Thermo公司；Tween 20，购自于EIA GRADE公司。 Goat anti-Rabbit IgG(H+L)Secondary Antibody,Alexa Fluor

488 conjugate, purchased from Thermo; Tween 20, purchased from EIA GRADE.

Instruments: Biosafety cabinet, CO ₂ incubator, purchased from Thermo Scientific;

Centrifuge, purchased from Eppendorf;

Cell counter, purchased from Invitrogen;

Inverted microscope, purchased from Olympus;

Multiflow, purchased from BioTeck;

Vortex mixer, purchased from IKA;

Envision, purchased from Perkin Elmer.

2. Experimental methods

2.1. Preparation of cell culture fluids and compounds

Preparation of serum-free FBS: Weigh 1g of activated carbon and 50mL fetal bovine serum at 4 ° C for 24h, then filter through 0.22μM filter, spare;

Preparation of cell culture medium: 50 mL of FBS, 5 mL of penicillin-streptomycin was added to 445 mL of DMEM, and mixed for use. Serum-free FBS was used in the preparation of serum-free cell culture media.

Compound Preparation: The compound of the present invention and the control compound prepared in the above examples, each compound was formulated into 100 mM with DMSO, and sequentially diluted to 10 nM, 3.33 nM, 1.11 nM, 0.37 nM, 0.123 nM, 0.041 nM, 0.014 nM, 0.0045. nM, 0.0015 nM, 0.0005 nM.

2.2. Inoculation of cells

The cell-discarded culture medium in the logarithmic growth phase of the T75 cell culture flask was washed once with 10 mL of DPBS. Add 2 mL of trypsin-digested cells, and place at 37 ° C for 2 minutes. Observe most of the cells in a round shape under microscope. Add 5 mL of serum-free cell culture solution to stop digestion. Pipette repeatedly and digest the cells to make cell suspension. Add 10 mL of cell culture solution, mix and count, dilute to 1500 cells/40 μL of cell suspension, and place the cells into a 384-well cell culture plate with a Multiflow instrument, 40 μL/well; equilibrate at room temperature for 20 min. Incubate in a 37 ° C cell culture incubator for 24 h.

2.3. Adding compounds

The compound was added to the cell culture plate with Acho instrument at a final concentration of 0.3% DMSO; it was centrifuged at 1000 rpm for 1 min at room temperature, and then cultured in a 37 ° C cell culture incubator for 24 h.

2.4. Immunofluorescence experiment

The cell culture medium was aspirated, the cells were washed once with PBS, and the cells were fixed with a final concentration of 3.7% paraformaldehyde solution (diluted in PBS) for 20 min at room temperature; the cells were washed twice with PBS and diluted with a final concentration of 0.5% Tween-20 (PBS). Penetrate for 1 h at room temperature; wash cells twice with PBS-T (0.05% Tween-20 in PBS), add ER antibody dilution (1:1000 in ER level assay, dilute with 1% milk in PBS-T) Incubate for 1.5 h at room temperature; wash cells three times with PBS-T, add a secondary antibody dilution (1:1000, diluted with 1% milk in PBS) 2 μg/mL of Hochest 33342, incubate for 40 min at room temperature; PBS-T wash The cells were washed 3 times and PBS was washed twice; Acumen read the ratio of ER positive signal value to nuclear signal value. The experimental results are shown in Table 2.

Table 2

"-" means untested

As can be seen from the above experimental results, the compounds of the present invention have a good inhibitory activity against ER levels based on cellular levels.

Experimental Example 2 Evaluation of in vitro cell viability of compounds

Experimental material

Test compound: The compound of the present invention and the control compound prepared in the above examples, each compound was formulated into 10 mM with DMSO, and then diluted 3 times to 100.00 nM, 33.33 nM, 11.11 nM, 3.70 nM, 1.23 nM, 0.41 nM, 0.14 nM, 0.045 nM, 0.015 nM.

The breast cancer cell line MCF-7 was purchased from Nanjing Kaiji Biotechnology Co., Ltd.

Luminescent Cell Viability Assay Kit，购自于美国Progema公司；Paclitaxel，购自于四川Tai Chi制药公司。 Reagents: MEM, FBS, Trypsin-EDTA, Penicillin-Streptomycin, purchased from GIBCO, USA;

Luminescent Cell Viability Assay Kit, purchased from Progema, USA; Paclitaxel, purchased from Sichuan Tai Chi Pharmaceutical Company.

2. Experimental methods

2.1. Cell seeding

Cultured expanded MCF-7 cells were trypsinized, resuspended in fresh medium and counted. The resuspended cells were adjusted to 2 × 10 ⁴ cells/mL, and 96-well cell culture plates were added, and 100 μL of each well was added to each well. Incubate for 24 h at 37 ° C, 5% CO ₂ .

2.2. Adding compounds

The compound was formulated into 200× working solution in DMSO, diluted to 2× working solution with the culture solution, and then transferred to 100 μL to the test well, and incubated at 37° C. under 5% CO ₂ for 96 h.

2.3. Fluorescence readings

Luminescent Cell Viability Assay buffer，并轻轻摇匀。10分钟后，置于Envison上读取荧光读数，并计算细胞存活率(cell survive(％))，计算公式为cell survive(％)＝(Com-Min)/(Max-Min)，其中Max为溶媒对照组的读数，Min为无细胞对照组的读数，Com为化合物处理组的读数，数据经XLfit处理，拟合得IC ₅₀，实验结果见表3。 Add 50 μL to the hole to be tested

Luminescent Cell Viability Assay buffer and shake gently. After 10 minutes, the fluorescence reading was read on the Envison and the cell survival rate (cell survival (%)) was calculated as the cell survival (%) = (Com-Min) / (Max-Min), where Max is For the control of the vehicle control group, Min is the reading of the cell-free control group, Com is the reading of the compound treatment group, and the data is processed by XLfit, and the IC _{50 is} fitted. The experimental results are shown in Table 3.

table 3

"-" means untested

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

Experimental Example 3 In vivo pharmacokinetic evaluation of compounds

Test compound: The compound of the present invention and the control compound prepared in the above examples were prepared in an amount of 2 mg/kg for oral administration and 1 mg/kg for the test sample.

Balb/c mice were purchased from Beijing Weitong Lihua Experimental Animal Co., Ltd.

The mice were orally administered with 2 mg/kg, and after a single dose of 1 mg/kg intravenously, blood was collected from the orbital venous plexus at 2 min, 5 min, 15 min, 30 min, 1 h, 2 h, 6 h, 10 h, 24 h, and centrifuged for plasma treatment. The LC-MS/MS was used for the detection, and the measured blood concentration at each time point was plotted as a drug concentration-time curve, and the pharmacokinetic parameters were calculated. The experimental results are shown in Table 4.

Table 4

Test compound T _1/2 (h) Cmax(ng/ml) AUC (h*ng/ml) F (%) AZD9496 1.1 703.7 1229.9 45.5 Example 1 1.3 647 1948.9 58.1 Example 2 3.2 583.4 3232.8 62.6 Example 3 4.3 410.2 2413.5 86.6 Example 4 3.7 793.4 4548.4 64.3 Example 5 5.7 493.7 4893.3 81.1 Example 6 3.2 1457.7 8373.5 80.5 Example 7 4 255.1 2768.2 86 Example 9 5.2 474.6 3115 115.5 Example 10 3.9 1102.7 4525.6 70.4 Example 12 3.4 125.4 767.9 28.8 Example 13 6.9 1326.1 16451.4 88 Example 14 2.7 1023.8 2895.8 62.4 Example 15 2.3 598.1 2441.3 39.9 Example 16 - - - - Example 17 12.1 1277.7 16073.7 80.5 Example 20 7.6 1210.7 13602.1 79.0 Example 22 6.4 1676.5 4991.7 77.5 Example 23 6.4 403.5 2100.1 41.3

"-" means untested

The above experimental results show that the half-life (T _1/2 ), peak concentration (Cmax), area under the curve (AUC) and bioavailability (F) of the compounds of the present invention are significantly superior to the control compounds. When the half-life of the compound is prolonged and the bioavailability is increased, the administration interval of the compound is prolonged, and the drug action time is prolonged, thereby improving the therapeutic effect of the compound and reducing the dose of the compound, thereby making the drug more effective and safer. Therefore, the compound of the present invention has more excellent antitumor activity in vivo, and the administration interval will be longer.

Experimental Example 4 Evaluation of the efficacy of compound in vivo MCF-7 subcutaneous xenograft model

Cell culture

MCF-7 breast cancer cells (purchased from KGI) were cultured in an ELISA medium containing 10% fetal calf serum, 100 U/ml penicillin and 100 μg/ml streptomycin in a 37 ° C, 5% CO ₂ incubator. . The initial concentration of the cell culture was 1×10 ⁶ /mL, and the cells were subcultured every 3 to 4 days after the cells were over. Tumor cells in the logarithmic growth phase are used for inoculation of tumors in vivo.

2. Sustained release tablets and cell inoculation

Two to three days before cell inoculation, a beta-estradiol sustained release tablet (Estradiol-17β 60 days SE121 0.72 mg, purchased from Innovative Research of America) was inoculated into the left back of each mouse. One week after the inoculation, the animals were urinated three times a week, and if necessary, the animals were urinated daily.

A PBS containing 10 × 10 ⁶ cells was mixed with 100 μL of Matrigel (final volume 200 μL) to inoculate the right rear side of the mouse. 3. Tumor measurement and experimental indicators

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

The experimental indicator is to investigate whether tumor growth is inhibited, delayed or cured. Tumor diameters were measured with vernier calipers three times a week. The calculation formula of tumor volume is: V = 0.5a × b ² , and a and b represent the long diameter and short diameter of the tumor, respectively.

The antitumor effect of the test compound was evaluated by relative tumor growth rate T/C (%) and tumor inhibition rate (%). The relative tumor growth rate T/C (%) was calculated as follows: T/C% = T _RTV / C _RTV × 100% (T _RTV : treatment group RTV; C _RTV : negative control group RTV). Relative tumor volume (RTV) was calculated according to the results of tumor measurement, and the formula was calculated as RTV=V _t /V ₀ , where V ₀ is the tumor volume measured at the time of group administration (ie, d ₀ ), and V _t is The tumor volume at one measurement, T _RTV and C _RTV took the same day data. Tumor inhibition rate (%) = (1-T/C) × 100%.

The experimental results of the antitumor efficacy evaluation of the test compound on the human breast cancer cell line MCF-7 subcutaneous xenograft model are shown in Table 5. The corresponding T/C (%) values of the compounds of the examples in the table are the respective examples. The T/C (%) mean of the tumor volume calculated on the 21st day after administration of the animals in each dose group of the compound.

table 5

The experimental results show that, unexpectedly, the compound of the present invention has a significantly better antitumor effect against breast cancer than the positive drug AZD9496. The compounds of the present invention, such as the compounds of Example 3, Example 10, Example 13, Example 17, and Example 20, are significantly more effective than the same dose of AZD9496 at a dose of 0.6 mg/kg at a dose of 2 mg/kg. The efficacy is much better than the AZD9496 6mg/kg dose. In addition, some of the compounds of the present invention produced an effect equivalent to the positive drug AZD9496 (0.6 mg/kg VS 6 mg/kg) at a tenth dose.

While the invention has been described hereinabove, it will be understood by those skilled in the art that various modifications and changes of the invention may be made without departing from the spirit and scope of the invention. The scope of the invention is not limited to the details described above, but rather to the claims.

Claims (10)

a compound of the formula I or an isomer thereof, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug,

among them, R ¹ and R ² are each independently selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkyl. An amino group, an alkyl acylamino group, an alkyl acyl group, an amino acyl group, an alkylamino acyl group, a dialkylamino group, and a cycloalkyl group; R ^{3 is} selected from the group consisting of alkyl, alkyl acyl, amino acyl, alkyl amino acyl, haloalkyl, hydroxyalkyl, alkenyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R ⁴ and R ⁵ are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, halogen, haloalkyl and hydroxyalkyl; or R ⁴ , R ⁵ together with the carbon atom to which they are attached form a carbonyl or cycloalkyl group; R ⁶ and R ⁷ are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, halogen, haloalkyl and hydroxyalkyl; or R ⁶ , R ⁷ together with the carbon atom to which they are attached form a carbonyl or cycloalkyl group; R ⁴ and R ⁶ together with the carbon atom to which they are attached form a cycloalkyl group; Each R ^{8 is} independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkyl An amino group, an alkyl acylamino group, an alkyl acyl group, an amino acyl group, an alkylamino acyl group, a bisalkylamino group, a cycloalkyl group, and a boronic acid; Y is selected from

Wherein R ^{9 is} selected from the group consisting of carboxyl, cyano, alkyl, haloalkyl and hydroxyalkyl, R ^{10 is} selected from hydrogen and halogen, R ^{11 is} selected from hydroxy, amino, alkoxy and alkylamino, and ring A is selected from cycloalkane. a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, which may be one or more hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkane Alkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkyl acylamino, alkyl acyl, amino acyl, alkylamino acyl, bisalkyl Substituted with amino and cycloalkyl, R ^{12 is} selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, Monoalkylamino, alkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl, bisalkylamino and cycloalkyl, n is 1, 2 or 3, or when n is 2, two R ¹² The groups together with the carbon atom to which they are attached form a carbonyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, said cycloalkyl group Heterocyclyl, aryl and heteroaryl may be taken up by one or more of hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, acylamino group, an acyl group, an amino group, alkylamino group, dialkylamino and substituted cycloalkyl, L ¹ selected from a bond, -NHCO -, - CONH- , -NHCONH-, -NH-, alkylene, O, S, haloalkylene, hydroxyalkylene, alkyleneoxy, haloalkyleneoxy, hydroxyalkyleneoxy, carbonyl and alkylene Amino group Chemical bond

Independently

m is 1, 2, 3 or 4; The condition is when Y is

And R ¹ and R ² are all fluorine, and when R ¹⁰ is hydrogen, R ^{3 is} selected from

Alkenyl and aryl, wherein R ^{13 is} selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkane Alkylamino, alkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl, bisalkylamino and cycloalkyl. The compound according to claim 1 or an isomer thereof, a pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein R ¹ and R ² are each independently selected from the group consisting of fluorine, chlorine, bromine, iodine, and hydroxyl groups. C _1-6 alkyl, halo C _1-6 alkyl, hydroxy C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, hydroxy C _1-6 alkoxy , nitro, carboxyl, cyano, amino, mono C _1-6 alkylamino, C _1-6 alkyl acylamino, C _1-6 alkyl acyl, amino acyl, C _1-6 alkylamino acyl, double C _1-6 alkylamino and C _3-10 cycloalkyl. The compound according to claim 1 or 2, or an isomer thereof, a pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein R ^{3 is} selected from a C _1-10 alkyl group, a C _1-10 alkyl acyl group. , aminoacyl, C _1-10 alkylamino acyl, halogenated C _1-10 alkyl, hydroxy C _1-10 alkyl, C _2-10 alkenyl, C _3-10 cycloalkyl, C _3-10 a cyclic group, a C _6-18 aryl group and a C _5-18 heteroaryl group, which group may be one or more halogen, hydroxy, C _1-6 alkyl, halo C _1-6 alkyl, hydroxy C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy, hydroxy C _1-6 alkoxy, nitro, carboxy, cyano, amino, mono C _1-6 alkyl Amino, a bi-C _1-6 alkylamino group and an optionally substituted C _3-8 cycloalkyl group are substituted. The compound according to any one of claims 1 to 3, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein R ⁴ and R ⁵ are each independently selected from hydrogen, C _{1 a -6} alkyl group, a C _1-6 alkoxy group, a halogen, a halogenated C _1-6 alkyl group and a hydroxy C _1-6 alkyl group, and R ⁶ and R ⁷ are each independently selected from hydrogen, C _1-6 alkyl group C _1-6 alkoxy, halogen, halogenated C _1-6 alkyl and hydroxy C _1-6 alkyl. A compound according to any one of claims 1 to 3, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein R ⁴ and R ⁵ are taken together with the carbon atom to which they are attached a carbonyl group or a C _3-10 cycloalkyl group; or R ⁶ , R ⁷ together with the carbon atom to which they are attached form a carbonyl group or a C _3-10 cycloalkyl group; or R ⁴ , R ⁶ together with the carbon atom to which they are attached C _3-10 cycloalkyl. The compound according to any one of claims 1 to 5, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein each R ^{8 is} independently selected from the group consisting of hydrogen, halogen, hydroxyl, C _1-6 alkyl, halo C _1-6 alkyl, hydroxy C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, hydroxy C _1-6 alkoxy , nitro, carboxyl, cyano, amino, mono C _1-6 alkylamino, C _1-6 alkyl acylamino, C _1-6 alkyl acyl, amino acyl, C _1-6 alkylamino acyl, double C _1-6 alkylamino, C _3-10 cycloalkyl and boric acid. The compound according to claim 1 or an isomer thereof, a pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein R ^{9 is} selected from the group consisting of a carboxyl group, a cyano group, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group, and a hydroxy C _1-6 alkyl group; R ^{11 is} selected from the group consisting of a hydroxyl group, an amino group, a C _1-6 alkoxy group, and a C _1-6 alkylamino group; Ring A is selected from the group consisting of C _3-10 cycloalkyl, C _3-10 heterocyclyl, C _6-18 aryl and C _5-18 heteroaryl, said cycloalkyl, heterocyclyl, aryl and hetero The aryl group may be one or more halogen, hydroxy, C _1-6 alkyl, halo C _1-6 alkyl, hydroxy C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 Alkoxy, hydroxy C _1-6 alkoxy, nitro, carboxy, cyano, amino, mono C _1-6 alkylamino, bis C _1-6 alkylamino and C _3-10 cycloalkyl substituted; R ^{12 is} selected from the group consisting of hydrogen, halogen, hydroxy, C _1-6 alkyl, halo C _1-6 alkyl, hydroxy C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy a group, a hydroxy C _1-6 alkoxy group, a nitro group, a carboxyl group, a cyano group, an amino group, a mono C _1-6 alkylamino group, a C _1-6 alkyl acylamino group, a C _1-6 alkyl acyl group, an amino acyl group, a C _1-6 alkylamino acyl group, a bis C _1-6 alkylamino group and a C _3-10 cycloalkyl group, n being 1, 2 or 3; or when n is 2, two R ¹² are attached thereto The carbon atoms together form a carbonyl group, a C _3-10 cycloalkyl group, a C _3-10 heterocyclic group, a C _6-18 aryl group, and a C _5-18 heteroaryl group, said cycloalkyl group, heterocyclic group, aryl group And a heteroaryl group may be one or more halogen, hydroxy, C _1-6 alkyl, halo C _1-6 alkyl, hydroxy C _1-6 alkyl, C _1-6 alkoxy, halogen C _{1 -6} alkoxy, hydroxy C _1-6 alkoxy, nitro, carboxy, cyano, amino, mono C _1-6 alkylamino, bis C _1-6 alkylamino and C _3-8 cycloalkyl Substituted; L ^{1 is} selected from the group consisting of a bond, -NHCO-, -CONH-, -NHCONH-, -NH-, C _1-6 alkyl, O, S, halo C _1-6 alkyl, hydroxy C _{1 -6} alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, hydroxy sub C _{1- 6} alkoxy, carbonyl group, and alkylene-C _1-6 alkylamino; and R ^{13 is} selected from the group consisting of halogen, hydroxy, C _1-6 alkyl, halo C _1-6 alkyl, hydroxy C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, Hydroxy C _1-6 alkoxy, nitro, carboxy, cyano, amino, mono C _1-6 alkylamino, C _1-6 alkyl acylamino, C _1-6 alkyl acyl, amino acyl, C _{1 -6} alkylamino acyl, bis C _1-6 alkylamino and C _3-10 cycloalkyl. A compound according to claim 1 or an isomer thereof, a pharmaceutically acceptable salt, solvate, crystal or prodrug, wherein the compound is a compound selected from the group consisting of:

A pharmaceutical composition comprising the compound of any one of claims 1 to 8, or an isomer thereof, a pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, and a pharmaceutically acceptable carrier. The compound of any one of claims 1-8, or an isomer thereof, a pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, or the pharmaceutical composition of claim 9 for use in the treatment and/or Or the use of drugs to prevent estrogen receptor-related diseases.