CN116253719A - Estrogen and androgen receptor dual degradation agent and application thereof - Google Patents

Abstract

The invention belongs to the field of medicinal chemistry, and relates to a class of dual degradation agents for estrogen and androgen receptors and applications thereof. Specifically, this type of estrogen and androgen receptor dual degrader has a structure represented by the following formula (I), and can be used for treating diseases or disorders related to estrogen and/or androgen receptor.

Description

A dual degradation agent of estrogen and androgen receptor and its application

technical field

The invention belongs to the field of medicinal chemistry, and in particular relates to a class of dual degradation agents of estrogen and androgen receptors with high biological activity, its preparation method, pharmaceutical composition and application in medicine.

Background technique

The incidence of breast cancer involves many factors such as living habits, social environment, mental health, and heredity or gene changes. In 2020, female breast cancer has surpassed lung cancer to become the cancer with the highest incidence of cancer in the world, accounting for 11.7% of all cancers. In 2020, there will be more than 2.26 million new cases of female breast cancer worldwide, and about 685,000 deaths, accounting for 24.5% and 15.5% of the total number of new cancer cases and deaths among women, respectively.

As a systemic disease, endocrine therapy is an important treatment for breast cancer, but resistance to endocrine therapy has become a difficult clinical problem. Studies have shown that not only estrogen and estrogen receptor (ER) are present in women, but also androgen and androgen receptor (AR) are widely expressed. At the same time, AR is highly expressed in a considerable proportion of breast cancer, which may play an important role in the occurrence and development of breast cancer: (1) ERα _- positive breast cancer. Studies have shown that AR and ER _α have signal crosstalk in breast cancer, such as _the N-terminal of AR can bind to the ligand binding domain of ER _α ; AR and ER _α have a common co-activator protein, etc.; The expression in breast cancer is as high as 86.8%, and it is significantly related to the failure of tamoxifen treatment. It is a potential target of _ERα- positive breast cancer (Yang Man, Wei Wei, Research progress of androgen receptor in breast cancer treatment[J ], Chinese Journal of Breast Diseases (Electronic Edition), 2017, 11(05): 296-299). (2) Triple-negative breast cancer (TNBC), TNBC is a subtype of breast cancer that lacks the expression of _ERα , and there is still a lack of effective clinical therapeutic targets. Studies have found that AR is also highly expressed in TNBC tissues, and as the only The type of hormone receptor accounted for 37%. AR is closely related to the prognosis of TNBC, and can promote the growth and metastasis of TNBC cells. At present, anti-androgen drugs alone have shown certain sensitivity in the treatment of TNBC, and AR inhibitors combined with other classic targeted therapy drugs have more potential value for the treatment of TNBC (Lu Yang, Wang Jinqiu, Guo Yu, Androgen Research progress on the role of receptors in the treatment and prognosis of triple-negative breast cancer [J], Tumor, 2018, 38(12): 1155-1159+1164).

At present, AR inhibitors, such as enzalutamide, have entered into clinical research for the treatment of breast cancer (Chen Junqing, Chen Zhanhong, Wang Xiaojia, Research progress in androgen receptor-targeted therapy for triple-negative breast cancer[J], Journal of Oncology , 2018, 24(05): 499-503). In the phase II clinical study (MDV3100-11) of the efficacy of enzalutamide in AR-positive advanced TNBC, 75 of the 118 patients enrolled were evaluable and the 16-week clinical benefit rate was 35% (26/75) , the 24-week clinical benefit rate was 29% (22/75). The phase IIB clinical study of enzalutamide combined with paclitaxel in the neoadjuvant treatment of triple-negative breast cancer (NCT02689427) will evaluate whether enzalutamide combined with weekly paclitaxel can further improve the pathological complete response rate of AR-positive TNBC.

PROTAC (Proteolysis Targeting Chimeras) is a heterobifunctional molecule, one end of the molecule is connected to the ligand that binds the target protein, the other end is connected to the ligand of E3 ligase, and the middle is connected by a suitable Linker. PROTAC degrades the target protein through the ubiquitin proteasome system, directly mediates the degradation of the disease target protein, and can overcome the problem of drug resistance of traditional drugs. PROTACs mediate the formation of ternary complexes and tag target proteins for ubiquitylation, which can theoretically be recycled, so the amount of catalyst can play a role. Compared with traditional small molecule inhibitors, PROTACs can not only achieve selectivity that is difficult to achieve with traditional small molecules on some targets, but also have significant advantages in improving activity. As a revolutionary technology, the development of PROTAC has gone through 20 years, especially in the past 5 years, it has developed rapidly and has become a new direction for new drug research and development.

ARV-471 is a new anti-breast cancer drug developed by Arvinas, a leading company in the PROTAC field, and it is currently in Phase II clinical trials abroad. In December 2021, Arvinas announced the safety and activity data of ARV-471 in patients with ER+/HER2- locally advanced or metastatic breast cancer at the 44th San Antonio Breast Cancer Symposium (2021SABCS). Good benefit: Among the 47 patients with evaluable clinical benefit (confirmed complete remission, partial remission or stable condition for ≥24 weeks), the clinical benefit rate of ARV-471 treatment was 40%, of which 3 cases achieved PR (otherwise 1 case did not confirm PR), ORR was 7.89% (3/38). This result also shows that in order to demand better clinical benefits, anti-breast cancer drugs based on ER degradation mechanism still need further research.

According to the clinical characteristics of breast cancer, in the in-depth development of anti-breast cancer drugs, ER/AR dual degraders are expected to become a novel and important technical path for anti-breast cancer drugs, but the development of the above-mentioned dual-mechanism drugs is still lacking in the world or report.

Contents of the invention

The technical problem to be solved by the present invention is to solve the obvious drug resistance problem that must exist in the existing anti-breast cancer drugs, and the compound of the present invention has created a completely new technical path: ER and AR dual degradation agent. In vitro model activity studies have shown that these compounds have significant degradation activity on ER and AR at the nanomolar (nM) level. The invention is expected to bring great benefits to tumor patients such as breast cancer.

In order to solve the above technical problems, the technical scheme that the present invention takes is:

A compound represented by the following formula (I) or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope labeling thereof:

in:

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁷ are each independently hydrogen, hydroxyl, mercapto, halogen, cyano, nitro, substituted or unsubstituted amino, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₂ -C ₆ alkenyl, substituted or unsubstituted C ₂ -C ₆ alkynyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₂ -C ₆ alkenyloxy, substituted or unsubstituted C ₂ -C ₆ alkynyloxy, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted C ₃ -C ₈ heterocycloalkyl, substituted or unsubstituted C ₁ -C ₆ ester group, substituted or unsubstituted C ₁ -C ₆ amido group, substituted or unsubstituted C ₁ -C ₆ acyl group;

Alternatively, R ² , R ³ , and R ⁴ are connected in pairs to form a substituted or unsubstituted C ₃ -C ₈ cycloalkyl, a substituted or unsubstituted three to eight-membered heterocycloalkyl, a substituted or unsubstituted C ₆ -C ₁₀ aryl or substituted or unsubstituted five to ten membered heteroaryl;

各自独立地为取代或未取代的C₃-C₁₀环烷基、取代或未取代的C₃-C₁₀杂环烷基、取代或未取代的C₃-C₁₀螺环基、取代或未取代的C₃-C₁₀杂螺环基、取代或未取代的C₃-C₁₀桥环基、取代或未取代的C₃-C₁₀杂桥环基、取代或未取代的C₃-C₁₀亚芳基、取代或未取代的C₃-C₁₀亚杂芳基；

Each is independently substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₃ -C ₁₀ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₁₀ spirocyclyl, substituted or unsubstituted Substituted C ₃ -C ₁₀ heterospirocyclic group, substituted or unsubstituted C ₃ -C ₁₀ bridged ring group, substituted or unsubstituted C ₃ -C ₁₀ heterobridged ring group, substituted or unsubstituted C ₃ -C ₁₀ arylene, substituted or unsubstituted C ₃ -C ₁₀ heteroarylene;

为取代或未取代的C₁-C₆烷基、取代或未取代的C₂-C₆烯基、取代或未取代的C₂-C₆炔基、取代或未取代的C₃-C₈环烷基、取代或未取代的C₃-C₈杂环烷基、取代或未取代的C₃-C₈环烯基、取代或未取代的C₃-C₈杂环烯基；

is substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₂ -C ₆ alkenyl, substituted or unsubstituted C ₂ -C ₆ alkynyl, substituted or unsubstituted C ₃ -C ₈ Cycloalkyl, substituted or unsubstituted C ₃ -C ₈ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkenyl, substituted or unsubstituted C ₃ -C ₈ heterocycloalkenyl;

X is CR ⁸ R ⁹ or C=O, wherein R ⁸ and R ⁹ are each independently hydrogen or C ₁ -C ₄ alkyl;

Alternatively, R ⁸ and R ⁹ are connected to each other to form a three- to eight-membered cycloalkyl group;

Y is CR ¹⁰ or N, wherein R ¹⁰ is hydrogen, hydroxyl, halogen, cyano, nitro, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₂ -C ₆ alkenyl, substituted or unsubstituted C ₂ -C ₆ alkynyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₂ -C ₆ alkenyloxy, substituted or unsubstituted C ₂ -C ₆ Alkynyloxy, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted C ₃ -C ₈ heterocycloalkyl;

n is an integer of 1-6.

In order to solve the above technical problems, another technical solution adopted by the present invention is:

A pharmaceutical composition, which comprises the above-mentioned compound or its pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope label, and a pharmaceutically acceptable carrier.

Preferably, the form of the pharmaceutical composition is an aqueous dispersion, liquid, jelly, syrup, elixir, syrup, suspension, aerosol, controlled release agent, fast solvent, effervescent agent, lyophilized agent, tablet , powder, pill, dragee, capsule, delayed release, prolonged release, pulsatile controlled release, multiparticulates or immediate release.

In order to solve the above technical problems, another technical solution adopted by the present invention is:

The above-mentioned compound or its pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope label, or the above-mentioned pharmaceutical composition in the preparation of treatment of estrogen and/or androgen receptor Drug application in related diseases.

Preferably, the estrogen and/or androgen receptor related disease is breast cancer or prostate cancer.

Preferably, the estrogen and/or androgen receptor related disease is triple negative breast cancer.

Preferably, estrogen and/or androgen receptor-related diseases are further preferably advanced breast cancer.

Due to the adoption of the above technical solutions, the present invention has the following advantages compared with the prior art:

1. Compared with other single-target ER degradation agents for treating breast cancer, the compound of the present invention can degrade AR at the same time, and has more prominent in vitro activity;

片段对于降解AR具有重要作用；2. The biological activity of the compound of the present invention shows that in formula I

Fragments play an important role in degrading AR;

3. The compound of the present invention degrades ER and AR at the same time, has a synergistic effect, and may have better in vivo activity and clinical effectiveness.

Detailed ways

In order to make the technical solutions and beneficial effects of the present invention more obvious and comprehensible, the following describes in detail by enumerating specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention.

If no specific technique or condition is indicated in the examples, it is usually carried out according to the conventional technique or condition described in the literature in this field, or according to the product specification and the conditions suggested by the manufacturer.

Unless otherwise indicated, various starting materials and reagents were either commercially available or synthesized according to known methods.

Definitions of terms and conventions

In the present invention, terms that are not explicitly defined should be understood as meanings that can be drawn by those skilled in the art according to the context. Unless otherwise specifically defined, the terms used in the present invention have the indicated meanings and follow the relevant conventions.

Unless otherwise defined, the term "substituted" used in the present invention is substituted by the following substituents: alkyl, cycloalkyl, aryl, heterocyclyl, halogen, hydroxy, alkoxy, oxo, alkanoyl, aryl yloxy, alkanoyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amino (wherein the 2 amino substituents are selected from alkyl, aryl or arylalkyl ), alkanoylamino, aroylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkanoylamino, thio, alkylthio, arylthio, arylalkane Alkylthio, arylthiocarbonyl, arylalkylthiocarbonyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, sulfonylamino such as -SO ₂ NH ₂ , substituted sulfonylamino, nitro group, cyano group, carboxyl group, carbamoyl group such as -CONH ₂ , substituted carbamoyl group such as -CONH alkyl group, -CONH aryl group, -CONH aryl alkyl group or two groups selected from alkyl, In the case of substituents of aryl or arylalkyl, alkoxycarbonyl, aryl, substituted aryl, guanidino, heterocyclic groups such as indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrole Alkyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, homopiperazinyl, etc. and substituted heterocyclic groups.

As used herein, the terms "alkyl" or "alkylene" are intended to include both branched and straight chain saturated aliphatic hydrocarbon groups having the indicated number of carbon atoms. For example, "C ₁ -C ₆ alkyl" means an alkyl group having 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (such as n-propyl and isopropyl), butyl (such as n-butyl, isobutyl, t-butyl), and Pentyl (eg n-pentyl, isopentyl, neopentyl).

The term "alkenyl" denotes a straight or branched chain hydrocarbon group containing one or more double bonds and generally having a length of 2 to 20 carbon atoms. For example, " _C2 - _C6 alkenyl" contains two to six carbon atoms. Alkenyl groups include, but are not limited to, for example, vinyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, hexenyl, and the like.

The term "alkynyl" denotes a straight or branched chain hydrocarbon group containing one or more triple bonds and generally having a length of 2 to 20 carbon atoms. For example, " _C2 - _C6 alkynyl" contains two to six carbon atoms. Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, pentynyl, hexynyl, and the like.

The term "heteroalkenyl" means that one or more carbon atoms in the "alkenyl" defined above are replaced by a heteroatom selected from N, O, S, or by a group containing a heteroatom selected from N, O, S replaced.

The term "heteroalkynyl" means that one or more carbon atoms in the above-defined "alkynyl" are replaced by a heteroatom selected from N, O, S, or by a group containing a heteroatom selected from N, O, S replaced.

The term "alkoxy" or "alkyloxy" refers to -O-alkyl. "C ₁ -C ₁₀ alkoxy" (or alkyloxy) is intended to include C ₁ -C ₁₀ alkoxy. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (such as n-propoxy and isopropoxy) and tert-butoxy, while alkoxy may carry multiple oxygen atoms Such as 1-10 oxygen atoms. Similarly, "alkylthio" or "thioalkoxy" denotes an alkyl group as defined above having the indicated number of carbon atoms attached through a sulfur bridge; eg methyl-S- and ethyl-S-.

The term "alkenyloxy" or "alkenyloxy" refers to the -O-alkenyl group. "C _2-10 alkenyloxy" (or alkenyloxy) is intended to include C ₂ -C ₁₀ alkenyloxy. Examples of alkenyloxy include, but are not limited to, allyloxy and allyloxy, and alkenyloxy may contain multiple oxygen atoms, such as 1-10 oxygen atoms.

The term "alkynyloxy" or "alkynyloxy" refers to an -O-alkynyl group. "C _2-10 alkynyloxy" (or alkynyloxy) is intended to include C ₂ -C ₁₀ alkynyloxy. Examples of alkynyloxy include but are not limited to acetylene ethoxy, propargyl oxy, and alkynyl oxy may have multiple oxygen atoms such as 1-10 oxygen atoms.

The term "cyano" means a -CN group.

The term "amino" means a _-NH2 group.

The term "hydroxyl" means a -OH group.

The term "nitro" means a _-NO2 group.

The term "mercapto" means a -SH group.

The term "carbonyl" refers to an organic functional group (C=O) composed of two atoms, carbon and oxygen, joined by a double bond.

The term "cycloalkyl" refers to a monocyclic or bicyclic cyclic alkyl group. Monocyclic cyclic alkyl refers to C ₃ -C ₈ cyclic alkyl, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbornyl. Branched cycloalkyl groups such as 1-methylcyclopropyl and 2-methylcyclopropyl are included within the definition of "cycloalkyl". Bicyclic cyclic alkyl groups include bridged, spiro, or fused ring cycloalkyls.

The term "cycloalkenyl" refers to a monocyclic or bicyclic cyclic alkenyl group. Monocyclic cyclic alkenyl refers to C ₃ -C ₈ cyclic alkenyl, including but not limited to cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and norbornenyl. Branched cycloalkenyl groups such as 1-methylcyclopropenyl and 2-methylcyclopropenyl are included within the definition of "cycloalkenyl". Bicyclic cyclic alkenyl groups include bridged, spiro, or fused ring cyclic alkenyl groups.

"Halo" or "halogen" includes fluoro, chloro, bromo and iodo. "Haloalkyl" is intended to include branched and straight chain saturated aliphatic hydrocarbon groups having the indicated number of carbon atoms substituted with one or more halogens. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoro Propyl and Heptachloropropyl. Examples of haloalkyl also include "fluoroalkyl" intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms and substituted with 1 or more fluorine atoms.

"Haloalkoxy" or "haloalkyloxy" means a haloalkyl group as defined above having the indicated number of carbon atoms attached through an oxygen bridge. For example, "C ₁ -C ₆ haloalkoxy" is intended to include C ₁ , C ₂ , C ₃ , C ₄ , C ₅ and C ₆ haloalkoxy. Examples of haloalkoxy include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluoroethoxy. Similarly, "haloalkylthio" or "thiohaloalkoxy" denotes a haloalkyl group as defined above having the indicated number of carbon atoms attached through a sulfur bridge; for example trifluoromethyl-S- and pentafluoroethyl -S-.

The terms "aryl"/"arylene", alone or as part of a larger moiety such as "aralkyl", "aralkoxy" or "aryloxyalkyl", refer to groups having a total of 6 to 10 A monocyclic, bicyclic or tricyclic ring system of 3 ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. In certain embodiments of the present invention, "aryl"/"arylene" refers to an aromatic ring system including, but not limited to, phenyl, indanyl, 1-naphthyl, 2-naphthyl, and tetra hydronaphthyl. A fused aryl group can be attached to another group at a suitable position on the cycloalkyl ring or aromatic ring. Arrow lines drawn eg from ring systems indicate that bonds may be attached to any suitable ring atom.

The term "heteroaryl"/"heteroarylene", "heteroaromatic ring", "heteroarylene", "heteroaryl", "heteroaryl ring group" or "heteroaryl ring group" means a stable 3-, 4-, 5-, or 7-membered aromatic monocyclic or aromatic bicyclic rings or 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-membered aromatic polycyclic heterocycles, It is fully unsaturated, partially unsaturated, and it contains carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S; and includes any of the following polycyclic groups , wherein any heterocyclic ring as defined above is fused with a benzene ring. Nitrogen and sulfur heteroatoms can be optionally oxidized. The nitrogen atom is substituted or unsubstituted (ie N or NR, where R is H or another substituent if defined). A heterocycle can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. The heterocyclic groups described herein may be substituted on carbon or nitrogen atoms if the resulting compound is stable. The nitrogen in the heterocycle can optionally be quaternized. Preferably, when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to each other. Preferably, the total number of S and O atoms in the heterocycle is not greater than one. Examples of aromatic heterocycles include, but are not limited to, acridinyl, azetidinyl, aziocinyl, benzimidazolyl, benzofuryl, benzothiofuranyl, benzothienyl, benzoxenyl Azolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2, 3-b] Tetrahydrofuryl, furyl, furanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, imidazopyridyl, indolinyl, indolyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuryl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolyl, isothiazolyl, Isothiazolopyridyl, isoxazolyl, isoxazolopyridyl, methylenedioxyphenyl, morpholinyl, naphthyridine, octahydroisoquinolinyl, oxadiazolyl, 1 ,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazole Base, oxazolopyridyl, oxazolidinyl, naphthiazaphenyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxa Thiyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidinyl, 4-piperidinyl, piperonyl, pteridyl, purinyl, pyranyl, pyrazinyl, Pyrazolidinyl, pyrazolinyl, pyrazolopyridyl, pyrazolyl, pyridazinyl, pyridoxazolyl, pyridimidazolyl, pyridothiazolyl, pyridyl, pyrimidinyl, pyrrolidinyl, Pyrrolinyl, 2-pyrrolidinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinazinyl, quinoxalinyl, quinuclidinyl, tetrazolyl, tetrahydrofuryl, tetra Hydroisoquinolyl, tetrahydroquinolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2 ,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthryl, thiazolyl, thienyl, thiazolopyridyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, Thienyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthenyl , quinolinyl, isoquinolyl, phthalazinyl, quinazolinyl, indolyl, isoindolyl, dihydroindolyl, 1H-indazolyl, benzimidazolyl, 1,2,3 ,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydro-quinolinyl, 2,3-dihydro-benzofuranyl , chromanyl, 1,2,3,4-tetrahydro-quinoxalinyl and 1,2,3,4-tetrahydro-quinazolinyl. The present invention also includes fused ring and spiro compounds containing, for example, the aforementioned heterocycles.

The term "heterocycloalkyl" as used herein refers to a monocyclic heterocycloalkyl system, or to a bicyclic heterocycloalkyl system. The monocyclic cycloheteroalkyl refers to a 3-8 membered, and contains at least one saturated or unsaturated but not aromatic cyclic alkyl system selected from O, N, S, and P. A bicycloheteroalkyl system refers to a heterocycloalkyl fused to a phenyl, or a cycloalkyl, or a cycloalkenyl, or a cycloheteroalkyl, or a heteroaryl.

The terms "bridged ring group" and "bridged ring hydrocarbon" used in the present invention refer to the polycyclic group system sharing two or more carbon atoms, which can be divided into bicyclic bridged ring hydrocarbon group and polycyclic bridged ring hydrocarbon group. The former is composed of two alicyclic rings sharing more than two carbon atoms; the latter is a bridged ring hydrocarbon group composed of more than three rings.

The term "heterobridged ring group" used in the present invention refers to a polycyclic heterocyclic group in which two rings share two non-adjacent carbon atoms or heteroatoms.

The terms "spirocyclyl" and "spirocyclic hydrocarbon" used in the present invention refer to a polycyclic hydrocarbon system in which two rings share one carbon atom (called a spiro atom).

The term "heterospirocyclyl" used in the present invention refers to a polycyclic heterocyclic group in which two rings share one carbon atom or heteroatom.

The term "substituted" as used in the present invention means that at least one hydrogen atom is replaced by a non-hydrogen group, provided that the normal valence is maintained and said substitution results in a stable compound. A ring double bond as used herein is a double bond formed between two adjacent ring atoms (eg C=C, C=N or N=N).

Where nitrogen atoms (e.g. amines) are present on compounds of the invention, these nitrogen atoms can be converted to N-oxides by treatment with oxidizing agents (e.g. mCPBA and/or hydrogen peroxide) to obtain other compounds of the invention . Accordingly, both shown and claimed nitrogen atoms are considered to cover both the shown nitrogen and its N-oxide (N→O) derivatives.

When any variable occurs more than one time in any composition or formula of a compound, its definition on each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-3 R, then said group may be optionally substituted with up to three R groups, and R at each occurrence is independently selected from the definition of R. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without specifying the atom in the substituent that is bonded to the rest of the compound of a given formula, then the above substituent may be bonded via any atom in the substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

The term "amino"/"amino" alone or in combination means a primary amino group (-NH ₂ ), a secondary amino group (-NH-) or a tertiary amino group

The term "C ₁ -C ₆ alkylamine", alone or in combination, denotes an amino group as defined above, wherein the hydrogen atom of the amino group is replaced by at least one C ₁ -C ₆ alkyl, wherein "Alkyl" means as defined above, correspondingly, "C ₁ -C ₆ alkylamino" includes methylamino, ethylamino, propylamino, isopropylamino, n-butylamino , isobutylamino, 2-butylamino, tert-butylamino, n-pentylamino, 2-pentylamino, 3-pentylamino, 2-methyl-2-butylamine Base, 3-methyl-2-butylamino group, 3-methyl-1-butylamino group, 2-methyl-1-butylamino group, n-hexylamino group, 2-hexylamino group, 3 -Hexylamino, 2-methyl-2-pentylamino, 3-methyl-2-pentylamino, 4-methyl-2-pentylamino, 3-methyl-3-pentyl Amino group, 2-methyl-3-pentylamino group, 2,3-dimethyl-2-butylamino group, 3,3-dimethyl-2-butylamino group, etc. Specific "C ₁ -C ₆ alkylamino groups" are methylamino, ethylamino, isopropylamino, tert-butylamino and the like.

The term "isomer" includes all isomeric forms including enantiomers, diastereomers, tautomers and geometric isomers (including cis and trans isomers). Therefore, the individual stereochemical isomers of the compounds contemplated in the present invention or their enantiomers, diastereomers, tautomers or geometric isomers (or cis-trans isomers) Mixtures are within the scope of the present invention.

As used herein, "pharmaceutically acceptable salts" refers to derivatives of compounds of the present invention wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic groups such as amines; and alkali metal or organic salts of acidic groups such as carboxylic acids. Pharmaceutically acceptable salts include conventional non-toxic or quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid; and salts prepared from organic acids such as acetic acid, propionic acid, succinic acid , glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfonamide, 2 -Acetoxybenzoic acid, fumaric acid, benzenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid and isethionic acid, etc.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. In general, the above-mentioned salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture of the two; Non-aqueous media such as isopropanol or acetonitrile. A list of suitable salts can be found in Remington: The Science and Practice of Pharmacy, 22nd Edition, 25 Allen, L.V.Jr., Ed.; Pharmaceutical Press, London, UK (2012), the disclosure of which is incorporated herein by reference.

The term "solvate" means a physical association of a compound of the invention with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In some cases, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, solvates will be able to be isolated. Solvent molecules in solvates may exist in regular and/or disordered arrangements. Solvates may contain stoichiometric or non-stoichiometric solvent molecules. "Solvate" encompasses both solution-phase and isolatable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.

The term "ester" is used to denote organic esters, including monoesters, diesters, triesters, and more generally polyesters.

The term "isotopic derivatives" means the isotopic derivatives obtained by replacing the hydrogen atoms in the general formula I with 1-6 deuterium atoms (D), and the carbon atoms in the general formula I with 1-3 carbon 14 atoms ( ¹⁴ C ) substituted isotopic derivatives.

The term "treating" as used herein includes any effect that results in amelioration of a condition, disease, disorder, etc., such as alleviation, reduction, regulation, amelioration or elimination, or amelioration of the symptoms thereof.

The term "pharmaceutical composition" as used in the present invention refers to the combination of an active agent with an inert or active carrier, making the composition especially suitable for in vivo or ex vivo diagnosis or therapy. Examples of bases include, but are not limited to, alkali metal (eg, sodium) hydroxides, alkaline earth metal (eg, magnesium) hydroxides, ammonia, and the like. For therapeutic use, the salts of the compounds of the invention For therapeutic use, the salts of the compounds of the invention are intended to be pharmaceutically acceptable. However, salts of acids and bases which are not pharmaceutically acceptable may also find use, for example, in the preparation or purification of pharmaceutically acceptable compounds.

Certain pharmaceutical and medical terms

The term "cancer", as used herein, refers to an abnormal growth of cells that cannot be controlled and, under certain conditions, is capable of metastasizing (spreading). Cancers of this type include, but are not limited to, solid tumors (eg, bladder, bowel, brain, chest, uterus, heart, kidney, lung), lymphoid tissue (lymphoma), ovary, pancreas, or other endocrine organs (eg, thyroid), Cancer of the prostate, skin (melanoma), or blood (such as nonleukemic leukemia).

Pharmaceutical Composition and Dosage

The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of one or more compounds of formula (I) formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents, and optionally One or more of the other therapeutic agents described above. The compounds of the invention may be administered for any of the above uses by any suitable means, for example orally, such as tablets, capsules (each including sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, spray-dried dispersions), syrups and emulsions; sublingual; buccal; parenteral, such as by subcutaneous, intravenous, intramuscular or intrasternal injection or infusion techniques ( For example, in the form of a sterile injectable aqueous or non-aqueous solution or suspension); nasally, including to the nasal membranes, such as by inhalation spray; topically, such as in the form of a cream or ointment; or rectally, such as in a suppository form. They can be administered alone, but generally will be administered using a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

Pharmaceutical carriers are formulated according to a number of factors within the purview of those skilled in the art. These factors include, but are not limited to: the type and nature of the active agent being formulated; the subject to whom the composition containing the active agent is to be administered; the intended route of administration of the composition; and the therapeutic indication being targeted. Pharmaceutical carriers include aqueous and non-aqueous liquid media and various solid and semisolid dosage forms.

Such carriers may include many different ingredients and additives other than the active agent, which are included in the formulation for various reasons known to those skilled in the art, such as to stabilize the active agent, binders, and the like. A description of suitable pharmaceutical carriers and the factors involved in carrier selection can be found in several readily available sources, such as Allen, L.V.Jr.et.al. Remington: The Science and Practice of Pharmacy (2 Volumes), 22nd Edition (2012 ), Pharmaceutical Press.

Dosage regimens for the compounds of the present invention will of course vary depending on known factors such as the pharmacodynamic properties of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition and weight of the recipient ; nature and extent of symptoms; type of concomitant therapy; frequency of therapy; route of administration, patient's renal and hepatic function, and desired effects. As a general guide, the daily oral dosage of each active ingredient should be from about 0.001 mg/day to about 10-5000 mg/day, preferably from about 0.01 mg/day to about 1000 mg/day, and most preferably From about 0.1 mg/day to about 600 mg/day. The most preferred dose intravenously will be about 0.01 mg/kg/minute to about 10 mg/kg/minute during a constant rate infusion. The compounds of the present invention may be administered in a single daily dose, or the total daily dose may be administered in divided doses of two, three or four times daily.

The compound can usually be appropriately selected according to the intended form of administration (such as oral tablets, capsules, elixirs and syrups) and a suitable pharmaceutical diluent, excipient or carrier (in the present invention) consistent with conventional pharmaceutical practice collectively referred to as drug carriers) in the form of mixtures for administration.

Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 0.1 mg to about 2000 mg of active ingredient per dosage unit. In these pharmaceutical compositions, the active ingredient will generally be present in an amount of about 0.1-95% by weight, based on the total weight of the composition.

A typical injectable formulation can be prepared by aseptically placing at least one compound of the present invention (250 mg) in a vial, lyophilizing in a sterile manner and sealing. For use, the vial contents are mixed with 2 mL of normal saline to produce an injectable formulation.

Included within the scope of the present invention are pharmaceutical compositions comprising (alone or in combination with a pharmaceutical carrier) a therapeutically effective amount of at least one compound of the present invention as an active ingredient. Optionally, compounds of the invention may be used alone, in combination with other compounds of the invention, or in combination with one or more other therapeutic agents (eg, anticancer agents or other pharmaceutically active substances).

Irrespective of the chosen route of administration, the compounds of the invention (which may be used in suitably hydrated form) and/or the pharmaceutical compositions of the invention are formulated into pharmaceutical dosage forms by conventional methods known to those skilled in the art.

Actual dosage levels of the active ingredient in the pharmaceutical compositions of the invention can be varied to obtain an amount of active ingredient effective to achieve the desired therapeutic response, composition and mode of administration for a particular patient without being toxic to the patient.

The selected dosage level will depend on a variety of factors, including the activity of the particular compound of the invention employed, or its ester, salt or amide; the route of administration; the time of administration; the rate of excretion of the particular compound employed; and the rate and extent of absorption. ; duration of treatment; other drugs, compounds and/or substances used in combination with the particular compound used; factors well known in the medical art such as age, sex, weight, condition, general health and prior medical history of the patient being treated.

A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian can start the doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. In general, a suitable daily dose of a compound of the invention will be that amount of the compound at the lowest dose effective to produce a therapeutic effect. Such effective dosage will generally depend on the factors mentioned above. Typically, oral, intravenous, intracerebroventricular and subcutaneous doses of the compounds of the invention to patients range from about 0.01 to about 1000 mg/kg body weight/day. If desired, an effective daily dose of the active compound may be administered in two, three, four, five, six or more sub-doses at appropriate intervals throughout the day, optionally in unit dosage form. In certain aspects of the invention, the administration is once daily.

Although the compounds of the present invention may be administered alone, it is preferred to administer the compounds in the form of pharmaceutical formulations (compositions).

The above-mentioned features mentioned in the present invention, or the features mentioned in the embodiments can be combined arbitrarily. All the features disclosed in the specification of the present invention can be used in combination with any combination, and each feature disclosed in the specification can be replaced by any alternative feature that can provide the same, equivalent or similar purpose. Therefore, unless otherwise specified, the disclosed features are only general examples of equivalent or similar features.

A compound represented by the following formula (I) or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope labeling thereof:

in:

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁷ are each independently hydrogen, hydroxyl, mercapto, halogen, cyano, nitro, substituted or unsubstituted amino, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₂ -C ₆ alkenyl, substituted or unsubstituted C ₂ -C ₆ alkynyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₂ -C ₆ alkenyloxy, substituted or unsubstituted C ₂ -C ₆ alkynyloxy, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted C ₃ -C ₈ heterocycloalkyl, substituted or unsubstituted C ₁ -C ₆ ester group, substituted or unsubstituted C ₁ -C ₆ amido group, substituted or unsubstituted C ₁ -C ₆ acyl group;

Alternatively, R ² , R ³ , and R ⁴ are connected in pairs to form a substituted or unsubstituted C ₃ -C ₈ cycloalkyl, a substituted or unsubstituted three to eight-membered heterocycloalkyl, a substituted or unsubstituted C ₆ -C ₁₀ aryl or substituted or unsubstituted five to ten membered heteroaryl;

各自独立地为取代或未取代的C₃-C₁₀环烷基、取代或未取代的C₃-C₁₀杂环烷基、取代或未取代的C₃-C₁₀螺环基、取代或未取代的C₃-C₁₀杂螺环基、取代或未取代的C₃-C₁₀桥环基、取代或未取代的C₃-C₁₀杂桥环基、取代或未取代的C₃-C₁₀亚芳基、取代或未取代的C₃-C₁₀亚杂芳基；

Each is independently substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₃ -C ₁₀ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₁₀ spirocyclyl, substituted or unsubstituted Substituted C ₃ -C ₁₀ heterospirocyclic group, substituted or unsubstituted C ₃ -C ₁₀ bridged ring group, substituted or unsubstituted C ₃ -C ₁₀ heterobridged ring group, substituted or unsubstituted C ₃ -C ₁₀ arylene, substituted or unsubstituted C ₃ -C ₁₀ heteroarylene;

为取代或未取代的C₁-C₆烷基、取代或未取代的C₂-C₆烯基、取代或未取代的C₂-C₆炔基、取代或未取代的C₃-C₈环烷基、取代或未取代的C₃-C₈杂环烷基、取代或未取代的C₃-C₈环烯基、取代或未取代的C₃-C₈杂环烯基；

is substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₂ -C ₆ alkenyl, substituted or unsubstituted C ₂ -C ₆ alkynyl, substituted or unsubstituted C ₃ -C ₈ Cycloalkyl, substituted or unsubstituted C ₃ -C ₈ heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkenyl, substituted or unsubstituted C ₃ -C ₈ heterocycloalkenyl;

X is CR ⁸ R ⁹ or C=O, wherein R ⁸ and R ⁹ are each independently hydrogen or C ₁ -C ₄ alkyl;

Alternatively, R ⁸ and R ⁹ are connected to each other to form a three- to eight-membered cycloalkyl group;

Y is CR ¹⁰ or N, wherein R ¹⁰ is hydrogen, hydroxyl, halogen, cyano, nitro, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₂ -C ₆ alkenyl, substituted or unsubstituted C ₂ -C ₆ alkynyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₂ -C ₆ alkenyloxy, substituted or unsubstituted C ₂ -C ₆ Alkynyloxy, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted C ₃ -C ₈ heterocycloalkyl;

n is an integer of 1-6.

In some embodiments, R ¹ is hydrogen, hydroxyl, halogen, cyano, nitro, substituted or unsubstituted amino, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ - C ₆ alkoxy.

In some preferred embodiments, ^R is hydrogen, fluoro, chloro, bromo, cyano, amine, nitro, trifluoromethyl or trifluoromethoxy.

In some further preferred embodiments, R ¹ is hydrogen or fluoro.

In some embodiments, R ² is hydrogen, hydroxyl, halogen, cyano, nitro, substituted or unsubstituted amino, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ - C ₆ alkoxy.

In some preferred embodiments, ^R is hydrogen, fluoro, chloro, bromo, cyano, amine, nitro, trifluoromethyl or trifluoromethoxy.

In some further preferred embodiments, ^R is hydrogen or fluoro.

In some more preferred embodiments, ^R2 is hydrogen.

In some embodiments, R ³ is hydrogen, hydroxyl, halogen, cyano, nitro, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy.

In some preferred embodiments, R ³ is hydrogen, halogen, C ₁ -C ₆ alkyl substituted by halogen.

In some further preferred embodiments, ^R3 is hydrogen, chloro or trifluoromethyl.

In some more preferred embodiments, ^R3 is trifluoromethyl.

In some embodiments, R ⁴ is hydrogen, hydroxyl, halogen, cyano, nitro, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy.

In some preferred embodiments, ^R4 is hydrogen, halo, cyano, nitro.

In some further preferred embodiments, ^R4 is cyano or nitro.

In some more preferred embodiments, ^R4 is cyano (-CN).

In some embodiments, R ⁵ is hydrogen, hydroxyl, halogen, cyano, nitro, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy.

In some preferred embodiments, R ⁵ is hydrogen, hydroxyl, halogen, C ₁ -C ₆ alkyl substituted by halogen.

In some further preferred embodiments, ^R5 is hydrogen or fluoro.

In some more preferred embodiments, ^R5 is hydrogen.

In some embodiments, R ⁶ is hydrogen, hydroxyl, halogen, cyano, nitro, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy.

In some preferred embodiments, R ⁶ is hydrogen, hydroxyl, halogen, C ₁ -C ₆ alkyl substituted by halogen.

In some further preferred embodiments, ^R6 is hydroxyl.

In some embodiments, R ⁷ is hydrogen, hydroxyl, halogen, cyano, nitro, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy.

In some preferred embodiments, R ⁷ is hydrogen, hydroxyl, halogen, C ₁ -C ₆ alkyl substituted by halogen.

In some further preferred embodiments, ^R7 is hydrogen, fluoro, hydroxy or trifluoromethyl.

In some more preferred embodiments, ^R7 is hydrogen.

各自独立地为含1-4个氧原子和/或氮原子的取代或未取代的3-10元的杂环烷基、杂螺环基或杂桥环基，所述取代是被选自卤素、-OH、-CN、-NH₂、C₁-C₆烷氧基、C₁-C₆烷基的取代基所取代。In some embodiments,

Each independently is a substituted or unsubstituted 3-10 membered heterocycloalkyl, heterospirocyclyl or heterobridged ring group containing 1-4 oxygen atoms and/or nitrogen atoms, and the substitution is selected from halogen , -OH, -CN, -NH ₂ , C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyl substituents.

各自独立地为含1-2个氮原子的取代或未取代的4-8元杂环烷基、杂螺环基或杂桥环基，所述取代是被选自卤素、-OH、-CN、-NH₂、C₁-C₆烷氧基和C₁-C₆烷基的取代基所取代。In some preferred embodiments,

Each independently is a substituted or unsubstituted 4-8 membered heterocycloalkyl, heterospirocyclyl or heterobridged ring group containing 1-2 nitrogen atoms, and the substitution is selected from halogen, -OH, -CN , -NH ₂ , C ₁ -C ₆ alkoxy and C ₁ -C ₆ alkyl substituents.

为取代或未取代的C₃-C₈环烷基、取代或未取代的C₃-C₈杂环烷基。In some embodiments,

is a substituted or unsubstituted C ₃ -C ₈ cycloalkyl group, a substituted or unsubstituted C ₃ -C ₈ heterocycloalkyl group.

为C₁-C₆烷基取代或未取代的C₃-C₈环烷基。In some preferred embodiments,

C ₁ -C ₆ alkyl substituted or unsubstituted C ₃ -C ₈ cycloalkyl.

为环己烷基、C₁-C₆烷基取代的环丁烷基。In some further preferred embodiments,

Cyclohexyl, C ₁ -C ₆ alkyl substituted cyclobutanyl.

为环己烷基。In some more preferred embodiments,

For cyclohexyl.

In some embodiments, X is CR ⁸ R ⁹ or C═O, wherein R ⁸ and R ⁹ are as defined above and do not form a ring with each other.

In some preferred embodiments, X is _CH2 or C=O.

In some further preferred embodiments, X is _CH2 .

In some embodiments, Y is CR ¹⁰ or N, wherein R ¹⁰ is as defined above.

In some preferred embodiments, Y is CH or N.

In some further preferred embodiments, Y is CH.

The present invention also provides a compound or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope label thereof, the compound is selected from:

In addition, the compounds of the present invention can be prepared using the methods described below, synthetic methods known in the field of synthetic organic chemistry, or methods mastered by those skilled in the art. Preferred methods include (but are not limited to) the methods described below , where the starting materials were either commercially available or prepared by methods disclosed in the literature.

Exemplary methods suitable for preparing compounds of the invention include the following steps:

Compounds I-1 and I-2 are condensed under the action of a condensing agent to obtain intermediate I-3; intermediate I-3 and 1,1,2,2,3,3,4,4,5-nonafluorobutane Alkane-1-sulfonyl fluoride is reacted under basic conditions to obtain intermediate I-4; intermediate I-4 is coupled with compound I-5 to obtain intermediate I-6; intermediate I-6 is Intermediate I-7 is obtained by Raney nickel-catalyzed hydrogenation; Intermediate I-7 is reacted with compound I-8 under strong base conditions to obtain Intermediate I-9; Intermediate I-9 is deprotected under acidic conditions to obtain Intermediate I-10; finally intermediate I-10 and compound I-11 were reductively aminated to obtain the target product I-12.

in,

The general synthetic method for preparing key intermediate product I-1 comprises:

Compound II-1 reacts with 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide under strong base conditions to obtain intermediate II-2; intermediate II -2 and intermediate II-3 undergo a coupling reaction under a palladium catalyst to obtain intermediate II-4; intermediate II-4 is brominated by NBS to obtain intermediate II-5; intermediate II-5 and compound II- 6 is coupled under the palladium catalyst to obtain intermediate II-7; intermediate II-7 is deprotected under acidic conditions to obtain intermediate I-1.

The general synthetic method for preparing key intermediate product 1-2 comprises:

Compound III-1 reacts with benzyl bromide under the action of a strong base to obtain III-2; III-2 removes the protecting group under acidic conditions to obtain I-2.

The general synthetic method for preparing key intermediate product I-5 comprises:

Compound IV-1 reacts with trimethyl orthoformate under the catalysis of p-toluenesulfonic acid to obtain intermediate IV-2; intermediate IV-2 is deprotected under the catalysis of palladium catalyst to obtain intermediate I-5.

The general synthetic method for preparing key intermediate product I-11 includes:

Nucleophilic substitution of compound Ⅴ-1 and N-Boc piperazine under basic conditions gives intermediate Ⅴ-2; intermediate Ⅴ-2 deprotects under acidic conditions to get intermediate 1-11.

The present invention also provides a pharmaceutical composition, which comprises the above-mentioned compound or its pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope label and a pharmaceutically acceptable carrier .

In a preferred embodiment, the above-mentioned pharmaceutical composition is in the form of aqueous dispersion, liquid, jelly, syrup, medicament, syrup, suspension, aerosol, controlled release agent, fast solvent, effervescent agent , lyophilized formulation, tablet, powder, pill, dragee, capsule, delayed release formulation, prolonged release formulation, pulsatile controlled release formulation, multiparticulate formulation or immediate release formulation.

The present invention also provides the above compounds or their pharmaceutically acceptable salts, esters, isomers, solvates, prodrugs or isotope labels, or the above pharmaceutical compositions in the preparation of estrogen and/or androgen receptor Drug application in related diseases.

In a preferred embodiment, the estrogen and/or androgen receptor related disease is breast cancer or prostate cancer.

In a preferred embodiment, the estrogen and/or androgen receptor-related disease is advanced breast cancer.

In a preferred embodiment, the estrogen and/or androgen receptor related disease is triple negative breast cancer.

The above-mentioned features mentioned in the present invention, or the features mentioned in the embodiments can be combined arbitrarily. All the features disclosed in the specification of this case can be used in combination with any combination, and each feature disclosed in the specification can be replaced by any alternative feature that can provide the same, equivalent or similar purpose. Therefore, unless otherwise specified, the disclosed features are only general examples of equivalent or similar features.

Below in conjunction with specific embodiment, further illustrate the present invention. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. For the experimental methods without specific conditions indicated in the following examples, usually follow the conventional conditions or the conditions suggested by the manufacturer. All percentages, ratios, ratios, or parts are by weight unless otherwise indicated.

The unit of weight volume percentage in the present invention is well known to those skilled in the art, for example, it refers to the weight of solute in 100 ml of solution.

Unless otherwise defined, all professional and scientific terms used herein have the same meanings as commonly understood by those skilled in the art. In addition, any methods and materials similar or equivalent to those described can be applied to the method of the present invention. The preferred implementation methods and materials described herein are for demonstration purposes only.

These examples are for illustrative purposes only and do not limit the scope of the claims presented herein.

Unless otherwise specified, the proton nuclear magnetic spectrum ( ¹ H-NMR) in the present invention is collected from Bruker-400 or OXFORD-AS500 nuclear magnetic resonance instrument, and the unit of chemical shift is one millionth, and internal standard is tetramethylsilane . The coupling constant (J) is close to 0.1 Hz. Abbreviations used are indicated as follows: s, singlet; d, doublet; t, triplet; q, quartet; qu, quintet; m, multiplet; brs, broad. Mass spectrometry was performed using a Quattro Micro API triple quadrupole mass spectrometer.

Example 1N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(4-((4-(2-((S)-2,6 -Dioxypiperidin-3-yl)-1-oxoisoindoline-5-yl)piperazin-1-yl)methyl)piperidin-1-methyl)-2-(6-hydroxyl- Preparation of 2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)benzamide (compound 1)

Compound 1

Preparation of 6-(tert-butoxy)-3,4-dihydronaphthalen-1(2H)-one

The compound 6-hydroxy-3,4-dihydronaphthalene-1(2H)-one (100g, 0.62mol), tert-butyl 2,2,2-trichloroacetate (269g, 1.23mol) were dissolved in dichloromethane (500 mL), slowly added a solution of boron trifluoride in ether (0.88 g, 6.17 mmol) at 0° C., and transferred to room temperature to react overnight. TLC detection reaction is not complete. After continuing to react for 12 hours, the reaction system was quenched with water, extracted with dichloromethane, and the organic phase was dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was separated by flash column chromatography. 66.2 g of the target product was obtained with a yield of 49%.

¹ H-NMR (400MHz, CDCl ₃ ) δ7.96(d, J=8.6Hz, 1H), 6.90(d, J=8.6Hz, 1H), 6.80(s, 1H), 2.91(t, J=6.0 Hz, 2H), 2.65-2.57(m, 2H), 2.15-2.06(m, 2H), 1.42(s, 9H).

Preparation of 6-(tert-butoxy)-3,4-dihydronaphthalen-1-yl trifluoromethanesulfonate

Compound 6-(tert-butoxy)-3,4-dihydronaphthalen-1(2H)-one (66.2g, 0.3mol) and 1,1,1-trifluoro-N-phenyl-N-( (Trifluoromethyl)sulfonyl)methanesulfonamide (141g, 0.39mol) was dissolved in anhydrous tetrahydrofuran, cooled to -78°C, and 1M KHMDS solution in tetrahydrofuran (394mL, 0.39mol) was added dropwise. , react overnight at room temperature under nitrogen protection. TLC showed the reaction was complete. The reaction system was quenched with water, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was separated by flash column chromatography. 86.1 g of the target product was obtained with a yield of 81%.

¹ H-NMR (400MHz, CDCl ₃ ) δ7.29(d, J=6.1Hz, 1H), 6.90(dd, J=8.4, 2.3Hz, 1H), 6.83(d, J=2.1Hz, 1H), 5.94 (t, J = 4.8Hz, 1H), 2.86 (t, J = 8.1Hz, 2H), 2.53 (td, J = 8.1, 4.8Hz, 2H), 1.40 (d, J = 5.3Hz, 9H).

Preparation of 2-bromo-5-hydroxybenzoic acid methyl ester

To a methanol solution (250 mL) of 2-bromo-5-hydroxybenzoic acid (25 g, 115.2 mmol), sulfuric acid (38 mL) was slowly added, and reacted at 65°C. After 12 hours, TLC showed that the reaction was complete. The solvent was evaporated under reduced pressure, extracted with dichloromethane, washed with saturated sodium bicarbonate solution, the organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 25 g of the target product, with a yield of 94 %.

MS-ESI: m/z 232.1 [M+H] ⁺ .

Preparation of methyl 5-hydroxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxoboronate-2-yl)benzoate

Methyl 2-bromo-5-hydroxybenzoate (25g, 108mmol), pinacol borate (55g, 216mmol), potassium acetate (21.3g, 216mmol), Pd(dppf)Cl ₂ (3.9g, 5.4 mmol) was dissolved in 1,4-dioxance (250mL), and reacted at 90°C for 3h under the protection of nitrogen. TLC showed the reaction was complete. After filtration, the filtrate was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was separated by flash column chromatography. 28 g of the target product was obtained with a yield of 93%.

MS-ESI: m/z 279.1 [M+H] ⁺ .

Preparation of 2-(6-(tert-butoxy)-3,4-dihydronaphthalen-1-yl)-5-hydroxybenzoic acid methyl ester

To compound 6-(tert-butoxy)-3,4-dihydronaphthalen-1-yl triflate (21g, 0.06mol) and 5-hydroxy-2-(4,4,5,5- Add H ₂ O (20mL ), potassium carbonate (16.6g, 0.12mol) and Pd(dppf)Cl ₂ (1.3g, 1.8mmol) were reacted at 100°C under nitrogen protection. After 4 h, TLC detected that the reaction was complete. After filtration, the filtrate was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was separated by flash column chromatography. 17 g of the target product was obtained with a yield of 80%.

MS-ESI: m/z 352.5 [M+H] ⁺ .

¹ H-NMR (400MHz, CDCl ₃ ) δ7.33(d, J=2.7Hz, 1H), 7.22(d, J=8.3Hz, 1H), 7.01(dd, J=8.3, 2.7Hz, 1H), 6.81(d, J=2.2Hz, 1H), 6.66(dd, J=8.3, 2.4Hz, 1H), 6.54(d, J=8.3Hz, 1H), 5.88(t, J=4.6Hz, 1H), 3.42 (s, 3H), 2.83 (dd, J=23.2, 12.4Hz, 2H), 2.38 (s, 2H), 1.33 (s, 9H).

Preparation of 2-(2-bromo-6-(tert-butoxy)-3,4-dihydronaphthalen-1-yl)-5-hydroxybenzoic acid methyl ester

Add the compound 2-(6-(tert-butoxy)-3,4-dihydronaphthalen-1-yl)-5-hydroxybenzoic acid methyl ester (17g, 48.2mmol) into acetonitrile (50mL) at 0°C The acetonitrile solution of N-bromosuccinimide (10 g, 57.8 mmol) was slowly added dropwise into the solution, and after the feeding was completed, the low temperature was turned off, and the reaction was naturally raised to room temperature. After 12h TLC showed the reaction was complete. The solvent was distilled off under reduced pressure, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate. The organic phase was evaporated to remove the solvent under reduced pressure, and the residue was separated by flash column chromatography. 17.3 g of the target product was obtained with a yield of 83%.

MS-ESI: m/z 432.3 [M+H] ⁺ .

¹ H-NMR (400MHz, CDCl ₃ ) δ7.74(d, J=2.5Hz, 1H), 7.26(s, 1H), 7.24(d, J=2.6Hz, 1H), 6.97(d, J=2.3 Hz,1H),6.82(dd,J=8.4,2.4Hz,1H),6.60(d,J=8.4Hz,1H),3.85-3.79(m,3H),3.21-3.05(m,4H),1.52 (d, J=2.8Hz, 9H).

Preparation of 2-(6-(tert-butoxy)-2-phenyl-3,4-dihydronaphthalen-1-yl)-5-hydroxybenzoic acid methyl ester

2-(2-Bromo-6-(tert-butoxy)-3,4-dihydronaphthalen-1-yl)-5-hydroxybenzoic acid methyl ester (17.3g, 40.05mmol) and phenylboronic acid (5.1g , 42.05mmol) in 1,4-dioxane solution (100mL) was added H ₂ O (10mL), potassium carbonate (11g, 80.1mmol) and Pd(dppf)Cl ₂ (880mg, 1.2mmol), under nitrogen React at 100°C under protection. After 4 hours, TLC detected that the reaction was complete, filtered, the filtrate was extracted with ethyl acetate, and the organic phase was dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was separated by flash column chromatography. 11.5 g of the target product was obtained with a yield of 67%.

MS-ESI: m/z 429.5 [M+H] ⁺ .

¹ H-NMR (400MHz, DMSO-d6) δ9.73(s, 1H), 7.14(dd, J=2.0, 0.8Hz, 1H), 7.10(t, J=7.3Hz, 2H), 7.03(dd, J=6.9,1.9Hz,1H),7.00-6.96(m,2H),6.83(d,J=2.4Hz,1H),6.79(d,J=2.0Hz,2H),6.61(dd,J=8.4 , 2.4Hz, 1H), 6.31(d, J=8.4Hz, 1H), 3.45(s, 3H), 2.97-2.70(m, 4H), 1.28(s, 9H).

Preparation of 2-(6-(tert-butoxy)-2-phenyl-3,4-dihydronaphthalen-1-yl)-5-hydroxybenzoic acid

The compound 2-(6-(tert-butoxy)-2-phenyl-3,4-dihydronaphthalen-1-yl)-5-hydroxybenzoic acid methyl ester (11.5g, 26.8mmol) was dissolved in ethanol solution In, potassium hydroxide (7.5g, 134.2mmol) was added and reacted at 100°C. After 12 hours, TLC detected that the reaction was complete, and the pH of the reaction system was adjusted to be weakly alkaline with 2M HCl solution, and the solvent was distilled off from the reaction system under reduced pressure. 17.5 g of the target product was obtained, which was directly used in the next step without further purification.

MS-ESI: m/z 452.5 [M+39] ⁺ .

Preparation of tert-butyl((1r,4r)-4-(benzyloxy)cyclohexyl)carbamate

The compound tert-butyl((1r,4r)-4-hydroxycyclohexyl)carbamate (5g, 23.2mmol) and bromomethylbenzene (4g, 23.2mmol) were dissolved in anhydrous N,N-dimethyl Sodium hydride (670 mg, 27.8 mmol) was added to formamide (30 mL), and reacted at room temperature. After 12 hours, TLC detected that the reaction was almost complete, quenched by adding saturated ammonium chloride solution, extracted with ethyl acetate, and dried the organic phase with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was separated by flash column chromatography. 3.8 g of the target product was obtained with a yield of 54%.

MS-ESI: m/z 250.4 [M+H-56] ⁺ .

¹ H-NMR (400MHz, CDCl ₃ )δ7.37-7.28(m,5H),4.55(s,2H),4.37(s,1H),3.36(s,1H),3.37-3.30(m,1H) , 2.06 (dt, J = 13.6, 7.0 Hz, 2H), 1.45 (s, 9H), 1.49-1.39 (m, 2H), 1.20-1.09 (m, 2H).

Preparation of (1r,4r)-4-(benzyloxy)cyclohexane-1-amine

The compound tert-butyl ((1r,4r)-4-(benzyloxy)cyclohexyl)carbamate (3.8g, 12.5mmol) was dissolved in dichloromethane (10mL), and 4M HCl/1,4 - Dioxane (20 mL), reacted at room temperature. After 12 hours, TLC detected that the reaction was complete, and the solvent was evaporated from the reaction system under reduced pressure. 2.8 g of the target product was obtained, which was directly used in the next step without further purification.

MS-ESI: m/z 205.3 [M+H] ⁺ .

N-((1r,4r)-4-(benzyloxy)cyclohexyl)-2-(6-(tert-butoxy)-2-phenyl-3,4-dihydronaphthalen-1-yl)- Preparation of 5-hydroxybenzamide

Compound 2-(6-(tert-butoxy)-2-phenyl-3,4-dihydronaphthalen-1-yl)-5-hydroxybenzoic acid (2g, 4.83mmol) and triethylamine (1.5mL , 10.6mmol) was dissolved in tetrahydrofuran (20mL), and diethyl chlorophosphate (875mg, 5.07mmol) was added at 0°C. After 3h, (1r,4r)-4-(benzyloxy)cyclohexane-1-amine (1.17g, 4.83mmol) was added to the reaction system and reacted overnight at room temperature. TLC detected that the reaction was complete, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The solvent of the organic phase was distilled off under reduced pressure, and the residue was separated by flash column chromatography. 1.14 g of the target product was obtained with a yield of 39%.

MS-ESI: m/z 602.7 [M+H] ⁺ .

¹ H-NMR (400MHz, DMSO-d6) δ9.51(s, 1H), 7.37-7.25(m, 6H), 7.19-7.15(m, 2H), 7.09(t, J=7.5Hz, 2H), 7.03(dd,J=13.0,5.8Hz,2H),6.87(d,J=1.3Hz,1H),6.80(d,J=2.4Hz,1H),6.58(d,J=1.2Hz,2H), 6.44(d, J=8.4Hz, 1H), 4.45(s, 2H), 3.45-3.35(m, 1H), 3.18-3.08(m, 1H), 2.96-2.74(m, 4H), 1.93(d, J＝11.9Hz, 1H), 1.78(d, J＝12.0Hz, 1H), 1.62(d, J＝12.5Hz, 1H), 1.45-1.34(m, 1H), 1.25-1.23(m, 9H), 1.17-0.96 (m, 3H), 0.74 (d, J=14.4Hz, 1H).

3-((1r,4r)-4-(benzyloxy)cyclohexyl)carbamoyl)-4-(6-(tert-butoxy)-2-phenyl-3,4-dihydronaphthalene-1 Preparation of -yl)phenyl 1,1,2,2,3,3,4,4,5-nonafluorobutane-1-sulfonate

Compound N-((1r,4r)-4-(benzyloxy)cyclohexyl)-2-(6-(tert-butoxy)-2-phenyl-3,4-dihydronaphthalen-1-yl )-5-Hydroxybenzamide (1.2g, 1.99mmol) was dissolved in a mixed solution of tetrahydrofuran (5mL) and acetonitrile (5mL), and 1,1,2,2,3,3,4,4,5- Nonafluorobutane-1-sulfonyl fluoride (910mg, 2.99mmol) and cesium carbonate (970mg, 2.99mmol) were reacted at room temperature for 2h. TLC detected that the reaction was complete, filtered, the filtrate was extracted with ethyl acetate, and the organic phase was dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was separated by flash column chromatography. 1.26 g of the target product was obtained with a yield of 72%.

MS-ESI: m/z 884.8 [M+H] ⁺ .

¹ H-NMR (400MHz, DMSO-d6) δ7.71(d, J=7.7Hz, 1H), 7.47(d, J=2.5Hz, 1H), 7.30(m, 5H), 7.15(d, J= 7.2Hz, 2H), 7.11-7.02(m, 4H), 6.98(d, J=8.5Hz, 1H), 6.84(s, 1H), 6.59(dd, J=8.4, 2.1Hz, 1H), 6.36( d,J=8.4Hz,1H),4.45(s,2H),3.41(m 2H),3.13(m,1H),2.87(m,4H),1.95(s,1H),1.77(d,J= 12.6Hz, 1H), 1.70(d, J=12.2Hz, 1H), 1.37(d, J=15.2Hz, 1H), 1.25(s, 9H), 1.11(dd, J=23.7, 12.2Hz, 3H) , 0.70 (d, J=13.6Hz, 1H).

Preparation of Benzyl 4-(Dimethoxymethyl)piperidine-1-carboxylate

To a methanol solution (20 mL) of the compound benzyl 4-formylpiperidine-1-carboxylate (5 g, 20.2 mmol) was added trimethyl orthoformate (10.7 g, 101.1 mmol) and p-toluenesulfonic acid (0.19g, 1.01mmol), react at room temperature for 12h. TLC detected that the reaction was complete, quenched by adding water, extracted with dichloromethane, and dried over anhydrous sodium sulfate. The organic phase was evaporated to remove the solvent under reduced pressure, and the residue was separated by flash column chromatography. 5.53 g of the target product was obtained with a yield of 93%.

MS-ESI: m/z 294.3 [M+H] ⁺ .

Preparation of 4-(dimethoxymethyl)piperidine

The compound 4-(dimethoxymethyl)piperidine-1-carboxylate benzyl ester (5.53g, 18.8mmol) was dissolved in methanol solution (20mL), added Pd/C (550mg), under hydrogen atmosphere React at room temperature. After 12 hours, TLC detected that the reaction was complete. After filtration, the filtrate was evaporated to remove the solvent under reduced pressure to obtain 3.15 g of the target product, which was directly used in the next step without further purification.

MS-ESI: m/z 160.2 [M+H] ⁺ .

N-((1r,4r)-4-(benzyloxy)cyclohexyl)-2-(6-(tert-butoxy)-2-phenyl-3,4-dihydronaphthalen-1-yl)- Preparation of 5-(4-(Dimethoxymethyl)piperidin-1-ylbenzamide

Compound 3-((1r,4r)-4-(benzyloxy)cyclohexyl)carbamoyl)-4-(6-(tert-butoxy)-2-phenyl-3,4-dihydronaphthalene -1-yl)phenyl 1,1,2,2,3,3,4,4,5-nonafluorobutane-1-sulfonate (800 mg, 0.9 mmol) was dissolved in toluene (5 mL), added 4-(dimethoxymethyl)piperidine (176mg, 1.08mmol), then add 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl (24mg, 0.0045mmol), tert-butanol Sodium (260mg, 2.7mmol) and palladium acetate (12mg, 0.0045mmol) were reacted at 90°C under nitrogen protection. After 3 hours, TLC detected that the reaction was complete, filtered, and the filtrate was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The organic phase was evaporated to remove the solvent under reduced pressure, and the residue was separated by flash column chromatography. 205 mg of the target product was obtained with a yield of 30%.

MS-ESI: m/z 744.0 [M+H] ⁺ .

¹ H-NMR (400MHz, DMSO-d6) δ7.35-7.25(m, 6H), 7.17(d, J=7.1Hz, 2H), 7.09(t, J=7.5Hz, 2H), 7.02(t, J＝7.2Hz, 1H), 6.97(d, J＝2.5Hz, 1H), 6.80(d, J＝2.4Hz, 1H), 6.76(dd, J＝8.5, 2.6Hz, 1H), 6.61(d, J＝8.4Hz, 1H), 6.57(dd, J＝8.4, 2.4Hz, 1H), 6.41(d, J＝8.4Hz, 1H), 4.45(s, 2H), 4.09(d, J＝6.5Hz, 1H), 3.69(d, J=10.5Hz, 2H), 3.44-3.38(m, 1H), 3.29-3.27(m, 6H), 3.18-3.08(m, 1H), 2.94-2.75(m, 4H) ,2.59(t,J=12.3Hz,2H),1.92(d,J=12.0Hz,1H),1.79(d,J=12.4Hz,1H),1.72(d,J=11.4Hz,3H),1.63 (d, J = 16.3Hz, 1H), 1.40 (s, 2H), 1.25 (s, 9H), 1.19-1.01 (m, 4H), 0.77 (d, J = 14.1Hz, 1H).

2-(6-(tert-butoxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)-5-(4-(dimethoxymethyl)piperidine- Preparation of 1-methyl)-N-((1r,4r)-4-hydroxycyclohexyl)benzamide

Compound N-((1r,4r)-4-(benzyloxy)cyclohexyl)-2-(6-(tert-butoxy)-2-phenyl-3,4-dihydronaphthalen-1-yl )-5-(4-(dimethoxymethyl)piperidin-1-ylbenzamide (205mg, 0.28mmol) was dissolved in methanol (5mL), Raney nickel catalyst (200mg) was added, and the feeding was completed. The reaction system was reacted at room temperature under a hydrogen atmosphere for 12 hours. TLC detected that the reaction was complete, extracted with ethyl acetate, and the organic phase was dried with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was separated by flash column chromatography. 167 mg of the target product was obtained , the yield was 92%.

MS-ESI: m/z 655.8 [M+H] ⁺ .

2-(6-(tert-butoxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)-N-(1r,4r)-4-(3-chloro-4 Preparation of -cyanophenoxy)cyclohexyl)-5-(4-(dimethoxymethyl)piperidin-1-ylbenzamide

The compound 2-(6-(tert-butoxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)-5-(4-(dimethoxymethyl)piper Pyridine-1-methyl)-N-((1r,4r)-4-hydroxycyclohexyl)benzamide (167mg, 0.24mmol) was dissolved in anhydrous tetrahydrofuran (5mL), and sodium hydride (9mg , 0.36mmol), reacted for 1h, added 1,2-dichloro-4-fluorobenzene, transferred to room temperature for 1h, and slowly raised the temperature to 70°C for reaction. After the reaction was detected by TLC, it was extracted with ethyl acetate, and the organic phase was dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was separated by flash column chromatography. 103 mg of the target product was obtained with a yield of 54%.

MS-ESI: m/z 791.4 [M+H] ⁺ .

¹ H-NMR (400MHz, DMSO-d6) δ7.86 (d, J = 8.8Hz, 1H), 7.38 (d, J = 2.2Hz, 1H), 7.14 (dd, J = 8.8, 2.3Hz, 1H) ,7.10(d,J=6.0Hz,3H),6.95(d,J=8.5Hz,1H),6.78(d,J=8.4Hz,2H),6.73(d,J=8.4Hz,3H),6.65 (dd,J=8.3,2.1Hz,1H),6.58(d,J=2.1Hz,1H),6.53(d,J=7.3Hz,1H),5.07(d,J=5.7Hz,1H),4.50 (dd, J=11.9,7.7Hz,1H),4.07(d,J=6.4Hz,1H),3.63(d,J=11.4Hz,2H),3.54-3.49(m,1H),3.29-3.27( m,1H),3.26(s,6H),3.10-2.90(m,3H),2.53(d,J=14.1Hz,2H),2.32(dd,J=11.3,5.3Hz,1H),2.06(d ,J=14.2Hz,3H),1.82(dd,J=37.9,21.4Hz,4H),1.68(d,J=10.1Hz,3H),1.28(s,9H),1.24(d,J=5.5Hz ,3H).

N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(4-formylpiperidin-1-yl)-2-(6-hydroxyl- Preparation of 2-phenyl-1,2,3,4-tetrahydronaphthalen-1-ylbenzamide

The compound 2-(6-(tert-butoxy)-2-phenyl-1,2,3,4-tetrahydronaphthalene-1-yl)-N-(1r,4r)-4-(3-chloro -4-cyanophenoxy)cyclohexyl)-5-(4-(dimethoxymethyl)piperidin-1-ylbenzamide (103 mg, 0.13 mmol) was dissolved in dichloromethane (1 mL) , add 4M HCl/1,4-dioxane (3mL), and react at room temperature. After 2 hours, TLC detects that the reaction is complete, and the reaction system is evaporated to remove the solvent under reduced pressure. The saturated sodium carbonate solution adjusts the pH to neutral, and extracts with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 66 mg of the target product with a yield of 74%.

MS-ESI: m/z 689.3 [M+H] ⁺ .

Preparation of tert-butyl 4-(3-cyano-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate

The compound 2-cyano-4-fluorobenzoic acid methyl ester (5 g, 27.9 mmol) and piperazine-1-carboxylic acid tert-butyl ester (7.8 g, 41.8 mmol) were dissolved in N,N-dimethylacetamide ( 30 mL), potassium carbonate (5.8 g, 41.8 mmol) was added and reacted at 80°C. After 5 hours, TLC detected that the reaction was complete, extracted with ethyl acetate, and dried the organic phase with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was separated by flash column chromatography. 8.878 g of the target product was obtained, and the yield was 92%.

MS-ESI: m/z 290.4 [M+H-56] ⁺ .

¹ H-NMR (400MHz, CDCl ₃ ) δ8.00(d, J=9.0Hz, 1H), 7.15(d, J=2.7Hz, 1H), 7.00(dd, J=9.0, 2.7Hz, 1H), 3.94 (s, 3H), 3.65-3.54 (m, 4H), 3.39-3.30 (m, 4H), 1.49 (s, 9H).

Preparation of tert-butyl 4-(3-cyano-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate

The compound tert-butyl 4-(3-cyano-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (8.67 g, 25.06 mmol) was dissolved in pyridine (18 mL, 0.23 mol), H ₂ O (15mL) and acetic acid (15mL) mixed solution, add Raney-Ni (4.35g), raise the temperature of the system to 60°C, and slowly add Na ₂ PO ₂ ·H ₂ O (12.8g). After 12 hours, TLC detected that the reaction was complete, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The organic phase was evaporated to remove the solvent under reduced pressure, and the residue was separated by flash column chromatography. 5.39 g of the target product was obtained with a yield of 62%.

MS-ESI: m/z 293.4 [M+H-56] ⁺ .

¹ H-NMR (400MHz, CDCl ₃ ) δ10.73(s, 1H), 7.94(d, J=8.8Hz, 1H), 7.33(d, J=2.8Hz, 1H), 7.00(dd, J=8.8 ,2.8Hz,1H),3.92(s,3H),3.62-3.51(m,4H),3.45-3.28(m,4H),1.48(s,9H).

Preparation of (S)-5-amino-4-((benzyloxy)carbonyl)amino)-5-oxopentanoic acid tert-butyl ester

Compound (S)-2-((benzyloxy)carbonyl)amino)-5-(tert-butoxy)-5-oxopentanoic acid (25 g, 74.1 mmol) was dissolved in 1,4-dioxane (150mL), (Boc) ₂ O (26g, 118.6mmol) and pyridine (11.7mL, 148.2mmol) were added under ice-cooling, after reacting for 30min, ammonium bicarbonate (17.5g, 222.3mmol) was added and reacted at room temperature. After 12 hours, TLC detected that the reaction was complete, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The organic phase was evaporated to remove the solvent under reduced pressure, and the residue was separated by flash column chromatography. 24.4 g of the target product was obtained with a yield of 97%.

MS-ESI: m/z 281.3 [M+H-56] ⁺ .

Preparation of (S)-4,5-diamino-5-oxopentanoic acid tert-butyl ester

Compound (S)-tert-butyl 5-amino-4-((benzyloxy)carbonyl)amino)-5-oxopentanoate (24.4 g, 71.76 mmol) was dissolved in methanol (100 mL), and Pd/C (3g), react at room temperature under hydrogen atmosphere for 12h. TLC detected that the reaction was complete, filtered, and evaporated the solvent under reduced pressure. 15 g of the target product was obtained, which was directly used in the next step without further purification.

MS-ESI: m/z 147.2 [M+H-56] ⁺ .

tert-butyl(S)-4-(2-(1-amino-5-(tert-butoxy)-1,5-dioxolan-2-yl)-1-oxoisocindoline-5 Preparation of -yl)piperazine-1-carboxylate

The compound 4-(3-cyano-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester (5.29g, 15.2mmol) and (S)-4,5-diamino-5 - Tert-butyl oxopentanoate (3.8g, 19.7mmol) was dissolved in methanol (30mL) solution, acetic acid (1.37g, 22.8mmol) was added at 0°C, and NaCNBH ₃ (1.9g, 30.4mmol) was added after reacting for 30min , transferred to room temperature for reaction. After 2 hours, TLC detected that the reaction was complete. The solvent was evaporated under reduced pressure, extracted with ethyl acetate, washed with 1N HCl and saturated brine, and the organic phase was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was separated by flash column chromatography. 6.8 g of the target product was obtained with a yield of 89%.

MS-ESI: m/z 391.6 [M+H-112] ⁺ .

¹ H-NMR (400MHz, CDCl ₃ ) δ7.70(d, J=8.5Hz, 1H), 7.03-6.95(m, 1H), 6.89(s, 1H), 6.37(s, 1H), 5.45-5.34 (m,1H),4.84(s,1H),4.39(d,J=7.4Hz,2H),3.65-3.54(m,4H),3.33-3.19(m,4H),2.34(s,4H), 1.49(s,9H),1.41(s,9H).

Preparation of (S)-3-(1-oxo-5-(piperazin-1-yl)isoindol-2-yl)piperidine-2,6-dione

The compound tert-butyl (S)-4-(2-(1-amino-5-(tert-butoxy)-1,5-dioxolan-2-yl)-1-oxoisocindoline -5-yl)piperazine-1-carboxylate (500mg, 0.99mmol) was dissolved in acetonitrile (5mL), added with benzenesulfonic acid (315mg, 1.98mmol), and reacted at 85°C. After 12 hours, TLC detected that the reaction was complete. The solvent was evaporated under reduced pressure, beaten with ethyl acetate for 30 minutes, filtered, and the filter cake was dried under high vacuum to obtain 480 mg of the product, which was directly used in the next step without further purification.

MS-ESI: m/z 329.4 [M+H] ⁺ .

¹ H-NMR (400MHz, CDCl ₃ ) δ10.97(s, 1H), 7.57(d, J=8.5Hz, 1H), 7.14(s, 1H), 7.11(dd, J=8.5, 1.9Hz, 1H ),5.05(dd,J＝13.3,5.1Hz,1H),4.39-4.21(m,2H),3.54-3.43(m,4H),3.24(s,4H),2.98-2.82(m,1H), 2.58 (d, J = 17.4Hz, 1H), 2.36 (dt, J = 13.4, 8.9Hz, 1H), 1.96 (dd, J = 9.0, 3.7Hz, 1H), 1.77 (s, 1H).

N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(4-(2-((S)-2,6-dioxopiperidine- 3-yl)-1-oxoisocindolin-5-yl)piperazin-1-yl)methyl)piperidine-1-methyl)-2-(6-hydroxyl-2-phenyl-1 , Preparation of 2,3,4-tetrahydronaphthalene-1-ylbenzamide (compound 1)

Compound (S)-3-(1-oxo-5-(piperazin-1-yl)isoindol-2-yl)piperidine-2,6-dione (67 mg, 138 mmol) was dissolved in dichloro Methane (1mL), methanol (3mL) mixed solution, add sodium acetate (34mg, 414mmol), react at room temperature for 10min, add N-((1r,4r)-4-(3-chloro-4-cyanophenoxy) Cyclohexyl)-5-(4-formylpiperidin-1-yl)-2-(6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-ylbenzamide ( 66 mg, 97 mmol), react at room temperature for 30 min, add acetic acid (0.05 mL), sodium cyanoborohydride (17 mg, 276 mmol), and react at room temperature. After 1 h, TLC detects that the reaction is complete, evaporate the solvent under reduced pressure, add tetrahydrofuran and H ₂ O and stir 20min, saturated NaHCO ₃ adjusted pH to 8-9, ethyl acetate: tetrahydrofuran (2: 1) extracted, dried over anhydrous sodium sulfate. The organic phase was distilled off the solvent under reduced pressure, and the residue was separated by flash column chromatography. The target Product 47mg, yield 48%.

MS-ESI: m/z 1001.6 [M+H] ⁺ .

¹ H-NMR (400MHz, DMSO-d6) δ10.93(s, 1H), 9.05(s, 1H), 7.85(d, J=8.8Hz, 1H), 7.52(d, J=8.7Hz, 1H) ,7.38(d,J=2.4Hz,1H),7.20-6.99(m,6H),6.83(d,J=8.5Hz,1H),6.80-6.68(m,4H),6.57(dd,J=6.4 ,2.2Hz,2H),6.53-6.41(m,2H),5.04(dd,J=13.2,5.1Hz,1H),4.99(d,J=5.5Hz,1H),4.50(dd,J=12.0, 7.5Hz, 1H), 4.26(dd, J＝49.6, 17.0Hz, 2H), 3.62(d, J＝10.5Hz, 2H), 3.56-3.44(m, 1H), 3.31-3.24(m, 4H), 3.25-3.18(m,1H),3.04-2.80(m,3H),2.58(d,J=15.9Hz,3H),2.54(d,J=1.8Hz,4H),2.43-2.24(m,2H) ,2.20(d,J=6.7Hz,2H),2.05(d,J=15.1Hz,2H),1.96(dd,J=11.0,5.6Hz,1H),1.81(t,J=20.7Hz,5H) , 1.38 (ddd, J = 29.7, 22.1, 14.0 Hz, 5H), 1.20-1.10 (m, 2H).

Example 2N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(4-((4-(2-(2,6-dioxo Piperidin-3-yl)-1,3-dioxoisoindoline)-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-(6-hydroxyl- Preparation of 2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)benzamide (compound 2)

Preparation of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)piperazine-1-carboxylate

To a solution (35 mL) of compound 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione (3.6 g, 13.03 mmol) in DMSO was added piperazine - tert-butyl 1-carboxylate (2.6g, 14.3mmol), N,N-diisopropylethylamine (4.5mL, 26mmol), react at 110°C. After 4 hours, TLC detected that the reaction was complete, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The organic phase was evaporated to remove the solvent under reduced pressure, and the residue was separated by flash column chromatography. 4.46 g of the target product was obtained with a yield of 77%.

MS-ESI: m/z 387.5 [M+H-56] ⁺ .

¹ H-NMR (400MHz, DMSO-d6) δ8.51 (s, 1H), 7.68 (d, J = 8.5Hz, 1H), 7.03 (dd, J = 8.5Hz, 2.2, 1H), 4.97-4.89 ( m,1H),3.63-3.52(m,4H),3.43-3.35(m,4H),2.89-2.66(m,3H),2.14-2.07(m,1H),1.83(s,1H),1.47( s, 9H).

Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindole-1,3-dione trifluoroacetate

Compound 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)piperazine-1-carboxylic acid tert-butyl ester (4.46g, 10.09mmol) was dissolved in dichloromethane (40mL), trifluoroacetic acid (10mL) was slowly added, and reacted at room temperature. After 12 hours, TLC detected that the reaction was complete, and the solvent was evaporated from the reaction system under reduced pressure. 5.42 g of the target product was obtained, which was directly used in the next step without further purification.

MS-ESI: m/z 343.5 [M+H] ⁺ .

N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(4-((4-(2-(2,6-dioxopiperidine -3-yl)-1,3-dioxoisoindoline)-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-(6-hydroxyl-2- Preparation of phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)benzamide (compound 2)

Except that (S)-3 -(1-oxo-5-(piperazin-1-yl)isoindol-2-yl)piperidine-2,6-dione benzenesulfonate, the synthesis of compound 2 and the compound in Example 1 1 consistent with a yield of 55%.

MS-ESI: m/z 1015.6 [M+H] ⁺ .

¹ H-NMR (400MHz, DMSO-d6) δ11.07(s, 1H), 9.05(s, 1H), 7.85(d, J=8.7Hz, 1H), 7.67(d, J=8.5Hz, 1H) ,7.38(d,J=2.3Hz,1H),7.33(s,1H),7.25(d,J=8.6Hz,1H),7.13(dd,J=8.8,2.4Hz,1H),7.10(d, J＝6.3Hz, 3H), 6.82(t, J＝7.8Hz, 1H), 6.79-6.69(m, 4H), 6.60-6.53(m, 2H), 6.46(dd, J＝14.3, 5.7Hz, 2H ),5.06(dd,J=12.9,5.3Hz,1H),4.99(d,J=5.6Hz,1H),4.54-4.44(m,1H),3.61(d,J=9.1Hz,2H),3.56 -3.47(m,1H),3.45-3.41(m,4H),3.25-3.19(m,1H),3.02-2.80(m,3H),2.63-2.52(m,4H),2.51(s,4H) ,2.29(s,1H),2.21(d,J=6.8Hz,2H),2.02(dd,J=18.9,13.2Hz,3H),1.80(dd,J=35.3,23.3Hz,6H),1.52- 1.41(m,2H),1.40-1.30(m,2H),1.21-1.15(m,2H).

Example 3N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(4-((4-(2-(2,6-dioxopipe Pyridin-3-yl)-6-fluoro-1,3-dioxoisoindol-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-(6-hydroxy - Preparation of 2-phenyl-1,2,3,4-tetrahydronaphthalene-1-yl)benzamide (compound 3)

Preparation of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindol-5-yl)piperazine-1-carboxylate

Except replacing 2-(2,6-dioxopiperidin-3-yl) with 2-(2,6-dioxopiperidin-3-yl)-5,6-difluoroindole-1,3-dione )-5-fluoroisoindole-1,3-dione, compound 4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindole Indol-5-yl)piperazine-1-carboxylate tert-butyl carboxylate and 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoiso Indol-5-yl)piperazine-1-carboxylic acid tert-butyl ester was the same, and the yield was 93%.

MS-ESI: m/z 405.5 [M+H-56] ⁺ .

Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindole-1,3-dione trifluoroacetate

Except for tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindol-5-yl)piperazine-1-carboxylate Instead of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)piperazine-1-carboxylate, compound 2- (2,6-Dioxopiperidin-3-yl)-5-(piperazin-1-yl) isoindole-1,3-diketone trifluoroacetate is synthesized and 2-( 2,6-Dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindole-1,3-dione trifluoroacetate was consistent, and 8.17g of the target product was obtained without further Purified and used directly in the next step.

MS-ESI: m/z 361.5 [M+H] ⁺ .

N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(4-((4-(2-(2,6-dioxopiperidine- 3-yl)-6-fluoro-1,3-dioxoisoindol-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-(6-hydroxyl-2 Preparation of -phenyl-1,2,3,4-tetrahydronaphthalene-1-yl)benzamide (compound 3)

Except that (S)-3 -(1-oxo-5-(piperazin-1-yl)isoindol-2-yl)piperidine-2,6-dione benzenesulfonate, the synthesis of compound 3 and the compound in Example 1 1, the yield was 67%.

MS-ESI: m/z 1033.6 [M+H] ⁺ .

¹ H-NMR (400MHz, DMSO-d6) δ11.09(s, 1H), 9.05(s, 1H), 7.85(d, J=8.8Hz, 1H), 7.71(d, J=11.4Hz, 1H) ,7.44(d,J=7.3Hz,1H),7.38(d,J=2.3Hz,1H),7.13(dd,J=8.8,2.4Hz,1H),7.10(d,J=6.2Hz,3H) ,6.83(d,J=8.5Hz,1H),6.80-6.69(m,4H),6.57(dd,J=6.8,2.0Hz,2H),6.46(dd,J=14.5,5.9Hz,2H), 5.10(dd,J=12.7,5.3Hz,1H),4.99(d,J=5.5Hz,1H),4.50(t,J=7.0Hz,1H),3.62(d,J=12.8Hz,2H), 3.57-3.45(m,1H),3.28-3.22(m,4H),3.17(s,1H),2.92(dt,J=25.4,13.4Hz,3H),2.59(d,J=16.1Hz,3H) ,2.52(d,J=5.5Hz,4H),2.28(s,1H),2.22(d,J=6.1Hz,2H),2.13-1.96(m,3H),1.79(dd,J=35.4,22.6 Hz, 6H), 1.49-1.24 (m, 5H), 1.18 (d, J = 10.6Hz, 2H).

Example 4N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(4-((4-(2-(2,6-dioxo Piperidin-3-yl)-1,3-dioxoisoindoline)-5-yl)-1,4-diazepan-1-yl)methyl)piperidin-1-yl Preparation of )-2-(6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)benzamide (compound 4)

4-(2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)-2,4-diazepane-1-carboxy Preparation of tert-butyl acid

Compound 4-(2-(2,6-dioxopiperidine-3- Base)-1,3-dioxoisoindoline-5-yl)-2,4-diazepane-1-carboxylic acid tert-butyl ester is the same as that of 4-(2-( 2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)piperazine-1-carboxylic acid tert-butyl ester was consistent, and the yield was 81%.

MS-ESI: m/z 401.5 [M+H-56] ⁺ .

¹ H-NMR (400MHz, DMSO-d6) δ11.05(s, 1H), 7.62(d, J=8.4Hz, 1H), 7.14(s, 1H), 7.06(d, J=8.7Hz, 1H) ,5.04(dd,J=12.9,5.3Hz,1H),3.76(dd,J=21.4,5.6Hz,2H),3.66(s,2H),3.60-3.47(m,2H),3.30-3.17(m ,2H),2.87(ddd,J=14.2,11.7Hz,5.0,1H),2.62-2.51(m,2H),2.03-1.92(m,1H),1.79(d,J=30.8Hz,2H), 1.28(s,4H), 1.12(s,5H).

Preparation of 5-(1,4-diazepan-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione hydrochloride

To compound 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)-2,4-diazepane-1 - To a dichloromethane solution (5 mL) of tert-butyl carboxylate (1.66 g, 3.64 mmol), slowly add HCl/1,4-dioxane (10 mL), and react at room temperature. After 12 hours, TLC detected that the reaction was complete, and the solvent was evaporated under reduced pressure. 1.39 g of the target product was obtained, and the obtained compound was directly used in the next step without further purification.

MS-ESI: m/z 343.4 [M+H] ⁺ .

N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(4-((4-(2-(2,6-dioxopiperidine -3-yl)-1,3-dioxoisoindoline)-5-yl)-1,4-diazepan-1-yl)methyl)piperidin-1-yl)- Preparation of 2-(6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)benzamide (compound 4)

Except replacing with 5-(1,4-diazepan-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione hydrochloride (S)-3-(1-oxo-5-(piperazin-1-yl)isoindol-2-yl)piperidine-2,6-dionebenzenesulfonate, the synthesis of compound 4 and Compound 1 is the same as in Example 1, and the yield is 89%.

MS-ESI: m/z 1029.6 [M+H] ⁺ .

¹ H-NMR (400MHz, DMSO-d6) δ11.06(s, 1H), 9.06(s, 1H), 7.86(d, J=8.8Hz, 1H), 7.62(d, J=8.3Hz, 1H) ,7.38(d,J=2.1Hz,1H),7.16-7.11(m,1H),7.09(d,J=6.0Hz,4H),7.02(d,J=8.5Hz,1H),6.82(d, J＝8.4Hz, 1H), 6.72(d, J＝9.2Hz, 4H), 6.55(s, 2H), 6.51-6.41(m, 2H), 5.04(dd, J＝12.8, 5.3Hz, 1H), 4.98(d,J=5.4Hz,1H),4.50(s,1H),3.71-3.54(m,6H),3.52-3.44(m,1H),3.25-3.18(m,1H),3.05-2.79( m,3H),2.74(s,2H),2.59(s,4H),2.29(d,J＝6.1Hz,3H),2.02(dd,J＝19.8,12.3Hz,4H),1.82(d,J =24.1Hz, 4H), 1.71(s, 3H), 1.57-1.31(m, 5H), 1.19-1.03(m, 3H).

Example 5N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(4-((8-(2-(2,6-dioxopipe Pyridin-3-yl)-1,3-dioxoisoindol-5-yl)-3,8-diazabicyclo[3.2.1]octane-3-yl]methyl)piperidine-1 Preparation of -yl)-2-(6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalene-1-yl)benzamide (compound 5)

8-(2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)-3,8-diazabicyclo[3.2.1]octane - Preparation of tert-butyl 3-carboxylate

In addition to replacing tert-butyl 1,4-diazepane-1-carboxylate with tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate, 8-( 2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)-3,8-diazabicyclo[3.2.1]octane-3- The synthesis of tert-butyl carboxylate and 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)-1 in Example 4, tert-butyl 4-diazepane-1-carboxylate agrees. The yield is 39%.

MS-ESI: 413.54[M+H-56] ⁺ .

¹ H-NMR (400MHz, DMSO-d6) δ11.08(s, 1H), 7.67(d, J=8.0Hz, 1H), 7.30(s, 1H), 7.18(dd, J=8.0, 4.0Hz, 1H), 5.06(dd, J＝16.0, 8.0Hz, 1H), 4.59(s, 2H), 3.74-3.55(m, 2H), 3.13(t, J＝12.0Hz, 1H), 3.04-2.80(m , 2H), 2.64-2.51 (m, 2H), 2.05-1.93 (m, 3H), 1.73 (d, J=4.0Hz, 2H), 1.40 (s, 9H).

5-(3,8-diazabicyclo[3.2.1]octane-8-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-di Preparation of ketone hydrochloride

In addition to using 8-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)-3,8-diazabicyclo[3.2.1] tert-butyl octane-3-carboxylate instead of 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-1,4 -Diazepane-1-carboxylic acid tert-butyl ester, 5-(3,8-diazabicyclo[3.2.1]octane-8-yl)-2-(2,6-di Oxypiperidin-3-yl) isoindole-1,3-dione hydrochloride is synthesized with 5-(1,4-diazepan-1-yl)-2-( The synthesis of 2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione hydrochloride was consistent.

MS-ESI: 369.4[M+H] ⁺ .

N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(4-((8-(2-(2,6-dioxopiperidine- 3-yl)-1,3-dioxoisoindol-5-yl)-3,8-diazabicyclo[3.2.1]octane-3-yl]methyl)piperidin-1-yl Preparation of )-2-(6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalene-1-yl)benzamide (compound 5)

In addition to using 5-(3,8-diazabicyclo[3.2.1]octan-8-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3 -diketone hydrochloride instead of 5-(1,4-diazepan-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3 The synthesis of compound 5 is consistent with that of compound 4 except for diketone hydrochloride. The yield is 48%.

MS-ESI: 1041.8[M+H] ⁺ .

¹ H-NMR (400MHz, DMSO-d6) δ11.07(s, 1H), 9.06(s, 1H), 7.86(d, J=8.0Hz, 1H), 7.63(d, J=8.0Hz, 1H) ,7.38(d,J=4.0Hz,1H),7.21(s,1H),7.13(s,1H),7.10(d,J=4.0Hz,3H),6.83(d,J=8.0Hz,1H) ,6.78-6.70(m,4H),6.57(s,2H),6.47(dd,J＝16.0,8.0Hz,2H),5.05(dd,J＝16.0,8.0Hz,1H),5.00(d,J =8.0Hz,1H),4.53(s,2H),3.59(t,J=8.0Hz,2H),3.55-3.46(m,1H),3.26-3.16(m,1H),3.04-2.76(m, 3H), 2.56(t, J=12.0Hz, 5H), 2.24(d, J=8.0Hz, 2H), 2.07-1.92(m, 9H), 1.74(s, 3H), 1.43(dd, J=20.0 , 8.0Hz, 3H), 1.33 (t, J = 12.0Hz, 2H), 1.29-1.19 (m, 6H), 1.13 (d, J = 12.0Hz, 1H).

Example 6N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(4-(7-(2-(2,6-dioxypiperidine -3-yl)-1,3-dioxoisocindolin-5-yl)-2,7-diazaspiro[3.5]non-2-yl)methyl)piperidin-1-yl)- Preparation of 3-(3-hydroxy-7-phenyl-5,6,7,8-tetrahydronaphthalen-1-ylbenzamide (compound 6)

7-(2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)-2,7-diazaspiro[3.5]nonane-2 -Preparation of tert-butyl carboxylate

In addition to replacing tert-butyl 1,4-diazepane-1-carboxylate with tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate, 7-(2-(2 ,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)-2,7-diazapyridin[3.5]nonane-2-carboxylic acid tert-butyl ester 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)-1,4-diazacycle in synthesis and Example 4 The synthesis of tert-butyl heptane-1-carboxylate was consistent. The yield was 85.7%.

MS-ESI: 427.4[M+H-56] ⁺ .

¹ H-NMR (400MHz, DMSO-d6) δ11.07(s, 1H), 7.64(d, J=8.6Hz, 1H), 7.30(d, J=1.8Hz, 1H), 7.24(dd, J= 8.6,2.1Hz,1H),5.03(dd,J＝12.7,5.4Hz,1H),3.71(ddd,J＝9.0,4.8,1.1Hz,1H),3.46-3.37(m,5H),2.85(ddd ,J=18.8,13.7,5.3Hz,1H),2.58(d,J=18.9Hz,1H),2.54(s,1H),2.53-2.45(m,1H),2.05-1.94(m,1H), 1.73(t, J=5.2Hz, 4H), 1.37(s, 9H), 1.21(s, 1H).

2-(2,6-dioxopiperidin-3-yl)-5-(2,7-diazaspiro[3.5]non-7-yl)isoindole-1,3-dione hydrochloride preparation of

In addition to using 7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonane -2-Tert-butyl carboxylate instead of 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)-1,4-di Except for tert-butyl azepane-1-carboxylate, 2-(2,6-dioxopiperidin-3-yl)-5-(2,7-diazaspiro[3.5]nonan-7- base) isoindole-1,3-dione hydrochloride and the synthesis of 5-(1,4-diazepan-1-yl)-2-(2,6-dioxo Piperidin-3-yl) isoindoline-1,3-dione hydrochloride is the same.

MS-ESI: 383.1 [M+H] ⁺ .

N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(4-(7-(2-(2,6-dioxopiperidine-3 -yl)-1,3-dioxoisocindolin-5-yl)-2,7-diazaspiro[3.5]non-2-yl)methyl)piperidin-1-yl)-3- (Preparation of 3-hydroxy-7-phenyl-5,6,7,8-tetrahydronaphthalene-1-ylbenzamide (compound 6)

In addition to using 2-(2,6-dioxopiperidin-3-yl)-5-(2,7-diazaspiro[3.5]non-7-yl)isoindole-1,3-dione salt salt instead of 5-(1,4-diazepan-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione salt Except for acid salt, the synthesis of compound 6 is consistent with that of compound 4 in Example 4. The yield was 88.8%.

MS-ESI: 1055.7 [M+H] ⁺ .

¹ H-NMR (400MHz, DMSO-d6) δ11.07(s, 1H), 9.06(s, 1H), 7.86(d, J=8.0Hz, 1H), 7.64(d, J=8.0Hz, 1H) ,7.38(s,1H),7.31(s,1H),7.23(d,J=8.0Hz,1H),7.15-7.09(m,4H),6.82(d,J=8.0Hz,1H),6.76- 6.71(m,4H),6.56(s,2H),6.49-6.44(m,2H),5.08-5.03(m,1H),4.99(d,J＝8.0Hz,1H),4.50(s,1H) ,3.57(s,2H),3.46(d,J=24.0Hz,7H),3.23-3.20(m,1H),2.96-2.85(m,6H),2.58(d,J=16.0Hz,3H), 2.33(s,2H),2.07-1.99(m,4H),1.83(s,2H),1.74(s,6H),1.47-1.30(m,6H),1.16(d,J＝12.0Hz,2H) .

In Vitro Research (WB Experiment) of Example 7 Compounds on AR and ER Downgrading Activity

AR degradation activity study: Spread LnCap cells on 12-well plate, the next day the cell density reaches 80%-90%, and the final concentration of adding is 0.03, 0.1, 0.3, 1.0, 3.0, 10.0, 30.0, 100.0, 300.0 and 1000.0nM of different compounds. 24 hours after adding the drug, the cell culture medium was removed and the cells were washed with cold PBS, 60 μL of protein lysate was added to each well, the cells were scraped off with a Tip and the cell lysate was mixed evenly. Then, centrifuge the cell lysate 15 solution at 12000rpm at 4°C for 15min, take the supernatant and add 15μL of 5X protein loading buffer, mix well and bathe in water at 100°C for 10min; take it out and cool it on ice, centrifuge for 1min, and use the supernatant for Western blot detection. After western blot detection, the detection results were counted by Image J software for the expression of androgen receptor, and then the DC ₅₀ for each compound to degrade the androgen receptor was calculated according to the expression of the receptor.

ER degradation activity study: Except that MCF-7 was used instead of LnCap cells, the method of ER degradation activity study was similar to the above-mentioned AR degradation activity study.

The compound DC ₅₀ is divided into three levels according to the intensity of activity, among which +++ (DC ₅₀ ≦10nM); ++ (10<DC ₅₀ ≦100nM); + (DC ₅₀ >100nM). The table below shows the results of in vitro studies of compounds on AR and ER downgrading activities.

Table 1 The results of in vitro studies of compounds on AR and ER downgrading activities

compound AR ER ARV-110 +++ / ARV-471 / +++ Compound 1 +++ +++ Compound 2 +++ +++ Compound 3 +++ +++ Compound 4 +++ +++ Compound 5 +++ +++ Compound 6 +++ +++

The above results show that the patented compound is a new type of compound that has good degrading activity on both AR and ER at the same time; in view of the obvious drug resistance problem that must exist in existing anti-breast cancer drugs, this type of compound has created a completely new type of compound. technology path. The invention is expected to bring great benefits to the above tumor patients.

It should be understood that the above embodiments are exemplary and not intended to encompass all possible implementations encompassed by the claims. Various modifications and changes can also be made on the basis of the above embodiments without departing from the scope of the present disclosure. Likewise, various technical features of the above embodiments can also be combined arbitrarily to form other embodiments of the present invention that may not be explicitly described. Therefore, the above-mentioned embodiments only express several implementation modes of the present invention, and do not limit the protection scope of the patent of the present invention.

Claims (10)

1. A compound represented by the following formula (i) or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof:

Wherein:

R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ each independently is hydrogen, hydroxy, mercapto, halogen, cyano, nitro, substituted or unsubstituted amino, substituted or unsubstituted C ₁ -C ₆ Alkyl, substituted or unsubstituted C ₂ -C ₆ Alkenyl, substituted or unsubstituted C ₂ -C ₆ Alkynyl, substituted or unsubstituted C ₁ -C ₆ Alkoxy, substituted or unsubstituted C ₂ -C ₆ Alkenyloxy, substituted or unsubstituted C ₂ -C ₆ Alkynyloxy, substituted or unsubstituted C ₃ -C ₈ Cycloalkyl, substituted or unsubstituted C ₃ -C ₈ Heterocycloalkyl, substituted or unsubstituted C ₁ -C ₆ Ester group, substituted or unsubstituted C ₁ -C ₆ Amide group, substituted or unsubstituted C ₁ -C ₆ An acyl group;

alternatively, R ² 、R ³ 、R ⁴ Are connected with each other in pairs to form a substituted or unsubstituted C ₃ -C ₈ Cycloalkyl, substituted or unsubstituted three-to eight-membered heterocycloalkyl, substituted or unsubstituted C ₆ -C ₁₀ Aryl or a substituted or unsubstituted five to ten membered heteroaryl;

each independently is a substituted or unsubstituted C ₃ -C ₁₀ Cycloalkyl, substituted or unsubstituted C ₃ -C ₁₀ Heterocycloalkyl, substituted or unsubstituted C ₃ -C ₁₀ Spiro-substituted or unsubstituted C ₃ -C ₁₀ Hetero spirocyclic groups, substituted or unsubstituted C ₃ -C ₁₀ Bridged ring radical, substituted or unsubstituted C ₃ -C ₁₀ Hetero-bridged ring radicals, substituted or unsubstituted C ₃ -C ₁₀ Arylene, substituted or unsubstituted C ₃ -C ₁₀ Heteroarylene;

is substituted or unsubstituted C ₁ -C ₆ Alkyl, substituted or unsubstituted C ₂ -C ₆ Alkenyl, substituted or unsubstituted C ₂ -C ₆ Alkynyl, substituted or unsubstituted C ₃ -C ₈ Cycloalkyl, substituted or unsubstituted C ₃ -C ₈ Heterocycloalkyl, substituted or unsubstituted C ₃ -C ₈ Cycloalkenyl, substituted or unsubstituted C ₃ -C ₈ Heterocycloalkenyl;

x is CR ⁸ R ⁹ Or c=o, wherein R ⁸ And R is ⁹ Each independently is hydrogen or C ₁ -C ₄ An alkyl group;

alternatively, R ⁸ 、R ⁹ Are connected with each other to form three-to eight-membered cycloalkyl;

y is CR ¹⁰ Or N, wherein R ¹⁰ Is hydrogen, hydroxy, halogen, cyano, nitro, substituted or unsubstituted C ₁ -C ₆ Alkyl, substituted or unsubstituted C ₂ -C ₆ Alkenyl, substituted or unsubstituted C ₂ -C ₆ Alkynyl, substituted or unsubstituted C ₁ -C ₆ Alkoxy, substituted or unsubstituted C ₂ -C ₆ Alkenyloxy, substituted or unsubstituted C ₂ -C ₆ Alkynyloxy, substituted or unsubstituted C ₃ -C ₈ Cycloalkyl, substituted or unsubstituted C ₃ -C ₈ A heterocycloalkyl group;

n is an integer of 1 to 6.

2. The compound of claim 1, or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof, wherein:

R ¹ is hydrogen or hydroxyA group, halogen, cyano, nitro, substituted or unsubstituted amino, substituted or unsubstituted C ₁ -C ₆ Alkyl, substituted or unsubstituted C ₁ -C ₆ Alkoxy, preferably hydrogen, fluorine, chlorine, bromine, cyano, amino, nitro, trifluoromethyl or trifluoromethoxy, further preferably hydrogen or fluorine;

Preferably, R ² Is hydrogen, hydroxy, halogen, cyano, nitro, substituted or unsubstituted amino, substituted or unsubstituted C ₁ -C ₆ Alkyl, substituted or unsubstituted C ₁ -C ₆ Alkoxy, preferably hydrogen, fluorine, chlorine, bromine, cyano, amino, nitro, trifluoromethyl or trifluoromethoxy, more preferably hydrogen or fluorine, still more preferably hydrogen;

preferably, R ³ Is hydrogen, hydroxy, halogen, cyano, nitro, substituted or unsubstituted C ₁ -C ₆ Alkyl, substituted or unsubstituted C ₁ -C ₆ Alkoxy, preferably hydrogen, halogen, C substituted by halogen ₁ -C ₆ Alkyl, more preferably hydrogen, chlorine or trifluoromethyl, still more preferably trifluoromethyl;

preferably, R ⁴ Is hydrogen, hydroxy, halogen, cyano, nitro, substituted or unsubstituted C ₁ -C ₆ Alkyl, substituted or unsubstituted C ₁ -C ₆ Alkoxy, preferably hydrogen, halogen, cyano, nitro, further preferably cyano (-CN);

preferably, R ⁵ Is hydrogen, hydroxy, halogen, cyano, nitro, substituted or unsubstituted C ₁ -C ₆ Alkyl, substituted or unsubstituted C ₁ -C ₆ Alkoxy, preferably hydrogen, hydroxy, halogen, C substituted by halogen ₁ -C ₆ Alkyl, further preferably hydrogen or fluorine, more preferably hydrogen;

preferably, R ⁶ Is hydrogen, hydroxy, halogen, cyano, nitro, substituted or unsubstituted C ₁ -C ₆ Alkyl, substituted or unsubstituted C ₁ -C ₆ Alkoxy, preferably hydrogen, hydroxy, halogen, C substituted by halogen ₁ -C ₆ Alkyl, further preferably hydroxy;

preferably, R ⁷ Is hydrogen, hydroxy, halogen, cyano, nitro, substituted or unsubstituted C ₁ -C ₆ Alkyl, substituted or unsubstituted C ₁ -C ₆ Alkoxy, preferably hydrogen, hydroxy, halogen, C substituted by halogen ₁ -C ₆ Alkyl, more preferably hydrogen, fluorine, hydroxyl or trifluoromethyl, and still more preferably hydrogen.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof, wherein:

each independently is a 3-10 membered heterocycloalkyl, heterospirocyclic or heterobridged ring group containing 1-4 oxygen and/or nitrogen atoms, substituted or unsubstituted, said substitution being by a member selected from the group consisting of halogen, -OH, -CN, -NH ₂ 、C ₁ -C ₆ Alkoxy, C ₁ -C ₆ Substituted by alkyl;

preferably a substituted or unsubstituted 4-8 membered heterocycloalkyl, heterospirocyclic or heterobridged ring radical containing 1 to 2 nitrogen atoms, said substitution being by a member selected from halogen, -OH, -CN, -NH ₂ 、C ₁ -C ₆ Alkoxy and C ₁ -C ₆ The substituent of the alkyl group is substituted.

4. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof, wherein:

Is substituted or unsubstituted C ₃ -C ₈ Cycloalkyl, substituted or unsubstituted C ₃ -C ₈ Heterocycloalkyl, preferably C ₁ -C ₆ C substituted or unsubstituted by alkyl ₃ -C ₈ Cycloalkyl, more preferably cyclohexenyl, C ₁ -C ₆ Alkyl substituted cyclobutyl, more preferably cyclohexyl.

5. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof, wherein:

x is CR ⁸ R ⁹ Or c=o, wherein R ⁸ 、R ⁹ As defined in claim 1, and do not form a ring with each other; preferably CH ₂ Or c=o, more preferably CH ₂ ；

Preferably, Y is CH or N, more preferably CH.

6. A compound or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof, wherein said compound is selected from the group consisting of:

7. a pharmaceutical composition comprising a compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof, and a pharmaceutically acceptable carrier.

8. A pharmaceutical composition according to claim 7 in the form of any one of an aqueous dispersion, a liquid, a gel, a syrup, a sirup, a slurry, a suspension, an aerosol, a controlled release agent, a fast-solvent, an effervescent agent, a lyophilisate, a tablet, a powder, a pill, a dragee, a capsule, a delayed release agent, an extended release agent, a pulsatile controlled release agent, a multiparticulate or an immediate release agent.

9. Use of a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof, or a pharmaceutical composition according to any one of claims 7 to 8, for the manufacture of a medicament for the treatment of an estrogen and/or androgen receptor related disorder.

10. The use according to claim 9, wherein the estrogen and/or androgen receptor related disorder is breast cancer or prostate cancer, preferably triple negative breast cancer, further preferably advanced breast cancer.