A dual degrader of estrogen and androgen receptors and its application

Abstract

The present invention belongs to the field of pharmaceutical chemistry and relates to a class of dual degraders of estrogen and androgen receptors and their applications. Specifically, the dual degraders of estrogen and androgen receptors have a structure represented by the following formula (I) and can be used to treat diseases or disorders related to estrogen and / or androgen receptors.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry, and specifically relates to a class of dual degraders of estrogen and androgen receptors with high biological activity, a preparation method, a pharmaceutical composition and use thereof in medicine. Background Art

[0002] The incidence of breast cancer involves many factors, including lifestyle, social environment, mental health, and heredity or gene changes. In 2020, female breast cancer has surpassed lung cancer to become the most common cancer in the world, accounting for 11.7% of all cancers. In 2020, there were more than 2.26 million new cases of female breast cancer and about 685,000 deaths worldwide, accounting for 24.5% and 15.5% of the total number of new cancer cases and deaths in women, respectively.

[0003] Breast cancer is a systemic disease for which endocrine therapy is an important treatment. However, endocrine therapy resistance has become a difficult clinical problem. Studies have shown that women not only have estrogen and estrogen receptors (ER), but also widely express androgens and androgen receptors (AR). At the same time, AR is highly expressed in a considerable proportion of breast cancers and may play an important role in the occurrence and development of breast cancer: (1) ER α Positive breast cancer. Studies have shown that AR and ER α There is signal crosstalk in breast cancer, such as the N-terminus of AR can interact with ER α The ligand binding domain of AR binds to ER α There are common co-activator proteins; AR in ER α The expression of ER positive breast cancer is as high as 86.8%, and is significantly associated with tamoxifen treatment failure. α Potential targets for androgen receptor-positive breast cancer (Yang Man, Wei Wei, Research progress on androgen receptor in breast cancer treatment [J], Chinese Journal of Breast Disease (Electronic Edition), 2017, 11(05): 296-299). (2) Triple-negative breast cancer (TNBC), TNBC is a type of breast cancer that lacks ER α There is still a lack of effective clinical therapeutic targets for breast cancer subtypes that express AR. Studies have found that AR is also highly expressed in TNBC tissues, and as the only hormone receptor type, it accounts for 37%. AR is closely related to the prognosis of TNBC and can promote the growth and metastasis of TNBC cells. Currently, the clinical use of anti-androgen drugs alone to treat TNBC has shown a certain sensitivity, and AR inhibitors combined with other classic targeted therapeutic drugs have more potential value for the treatment of TNBC (Lu Yang, Wang Jinqiu, Guo Yu, Research progress on the role of androgen receptor in the treatment and prognosis of triple-negative breast cancer [J], Tumor, 2018, 38(12): 1155-1159+1164).

[0004] Currently, AR inhibitor drugs such as enzalutamide have entered clinical research for the treatment of breast cancer (Chen Junqing, Chen Zhanhong, Wang Xiaojia, Research progress of 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, with a 16-week clinical benefit rate of 35% (26 / 75) and a 24-week clinical benefit rate of 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 remission rate of AR-positive TNBC.

[0005] PROTAC (Proteolysis Targeting Chimeras) is a heterobifunctional molecule, one end of the molecule is connected to a ligand that binds to the target protein, and the other end is connected to a ligand of an E3 ligase, and the middle is connected by a suitable linker. PROTAC degrades the target protein through the ubiquitin proteasome system, directly mediating the degradation of the pathogenic target protein, which can overcome the drug resistance problem of traditional drugs. PROTAC mediates the formation of a ternary complex and labels the target protein with ubiquitination, which can be recycled in theory, so the amount of catalyst can play a role. Compared with traditional small molecule inhibitors, PROTAC can not only achieve selectivity that is difficult to achieve with traditional small molecules on certain targets, but also has significant advantages in improving activity. As a revolutionary technology, PROTAC has developed for 20 years, especially in the past 5 years. It has developed rapidly and has become a new direction for new drug research and development.

[0006] ARV-471 is a new anti-breast cancer drug developed by Arvinas, a leading company in the PROTAC field. 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). The results showed good clinical benefits: Among 47 patients who were evaluable for clinical benefit (confirmed complete remission, partial remission, or stable disease ≥24 weeks), the clinical benefit rate of ARV-471 treatment was 40%, of which 3 cases achieved PR (another 1 case did not confirm PR), and the ORR was 7.89% (3 / 38). This result also shows that in order to achieve better clinical benefits, anti-breast cancer drugs based on ER degradation mechanisms need to be further studied.

[0007] In view of 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 there is currently a lack of development or reports of such dual-mechanism drugs in the world. Summary of the invention

[0008] The technical problem to be solved by the present invention is the significant drug resistance problem that is inevitable in existing anti-breast cancer drugs. The compounds of the present invention have created a completely new technical path: ER and AR dual degraders. In vitro model activity studies have shown that such compounds have significant degradation activity on ER and AR at the nanomolar (nM) level. This invention is expected to bring great benefits to patients with tumors such as breast cancer.

[0009] In order to solve the above technical problems, the technical solution adopted by the present invention is:

[0010] A compound represented by the following formula (I) or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope-labeled substance thereof:

[0011]

[0012] in:

[0013] R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 each independently represents hydrogen, hydroxyl, thiol, halogen, cyano, nitro, substituted or unsubstituted amine, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C2-C6 alkenyloxy, substituted or unsubstituted C2-C6 alkynyloxy, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted C1-C6 ester, substituted or unsubstituted C1-C6 amide, substituted or unsubstituted C1-C6 acyl;

[0014] Or, R 2 , R 3 , R 4 Two of them are connected to each other to form substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted three to eight-membered heterocycloalkyl, substituted or unsubstituted C6-C 10 aryl or substituted or unsubstituted five- to ten-membered heteroaryl;

[0015] are each independently substituted or unsubstituted C3-C10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocycloalkyl, substituted or unsubstituted C3-C 10 Spirocyclyl, substituted or unsubstituted C3-C 10 Heterospirocyclic group, substituted or unsubstituted C3-C 10 Bridged ring group, substituted or unsubstituted C3-C 10 Heterobridged ring group, substituted or unsubstituted C3-C 10 Arylene, substituted or unsubstituted C3-C 10 heteroarylene;

[0016] is substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, substituted or unsubstituted C3-C8 heterocycloalkenyl;

[0017] X is CR 8 R 9 Or C=O, where R 8 and R 9 Each is independently hydrogen or C1-C4 alkyl;

[0018] Or, R 8 , R 9 are connected to each other to form a three- to eight-membered cycloalkyl group;

[0019] Y is CR 10 or N, where R 10 is hydrogen, hydroxy, halogen, cyano, nitro, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C2-C6 alkenyloxy, substituted or unsubstituted C2-C6 alkynyloxy, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl;

[0020] n is an integer from 1 to 6.

[0021] In order to solve the above technical problems, another technical solution adopted by the present invention is:

[0022] A pharmaceutical composition comprising the compound as described above or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope-labeled substance thereof, and a pharmaceutically acceptable carrier.

[0023] Preferably, the pharmaceutical composition is in the form of an aqueous dispersion, liquid, gel, syrup, elixir, slurry, suspension, aerosol, controlled release, fast dissolving agent, effervescent agent, lyophilized agent, tablet, powder, pill, dragee, capsule, delayed release, extended release, pulse controlled release, multiparticulate or immediate release.

[0024] In order to solve the above technical problems, another technical solution adopted by the present invention is:

[0025] Use of 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 a drug for treating estrogen and / or androgen receptor-related diseases.

[0026] Preferably, the estrogen and / or androgen receptor-related disease is breast cancer or prostate cancer.

[0027] Preferably, the estrogen and / or androgen receptor-related disease is triple-negative breast cancer.

[0028] Preferably, the estrogen and / or androgen receptor-related disease is further preferably advanced breast cancer.

[0029] Due to the adoption of the above technical solution, the present invention has the following advantages compared with the prior art:

[0030] 1. Compared with other single-target ER degraders for the treatment of breast cancer, the compounds of the present invention can simultaneously degrade AR and have more prominent in vitro activity;

[0031] 2. The biological activity of the compounds of the present invention shows that The fragment plays an important role in degrading AR;

[0032] 3. The compounds of the present invention degrade ER and AR simultaneously, have a synergistic effect, and may have better in vivo activity and clinical effectiveness. DETAILED DESCRIPTION

[0033] In order to make the technical solution and beneficial effects of the present invention more obvious and easy to understand, the following is a detailed description by listing specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and are not used to limit the scope of the present invention.

[0034] If no specific techniques or conditions are specified in the examples, they are usually carried out according to conventional techniques or conditions described in the literature in the art, or according to the product instructions and the conditions recommended by the manufacturer.

[0035] Unless otherwise indicated, various starting materials and reagents were either commercially available or synthesized according to known methods.

[0036] Definitions and Conventions

[0037] In the present invention, the terms not clearly defined should be understood as the meanings that can be derived by those skilled in the art according to the context. Unless otherwise specifically defined, the terms used in the present invention have the meanings shown and comply with relevant conventions.

[0038] Unless otherwise defined, the term "substituted" as used herein means substituted by the following substituents: alkyl, cycloalkyl, aryl, heterocyclic, halogen, hydroxy, alkoxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amino (wherein the two amino substituents are independently selected from alkyl, aryl or arylalkyl), alkanoylamino, aroylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkanoylamino, thio, alkylthio, arylthio, arylalkylthio, arylthiocarbonyl, arylalkylthiocarbonyl, alkylsulfonyl, Arylsulfonyl, arylalkylsulfonyl, sulfonylamino such as -SO2NH2, substituted sulfonylamino, nitro, cyano, carboxyl, carbamoyl such as -CONH2, substituted carbamoyl such as -CONHalkyl, -CONHRyl, -CONHRylalkyl or in the case of having two substituents on nitrogen selected from alkyl, aryl or arylalkyl, alkoxycarbonyl, aryl, substituted aryl, guanidinyl, heterocyclic group such as indolyl, imidazolyl, furanyl, thienyl, thiazolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, homopiperazinyl and the like and substituted heterocyclic group.

[0039] As used herein, the term "alkyl" or "alkylene" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, "C1-C6 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 (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, tert-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl).

[0040] The term "alkenyl" refers to a straight or branched hydrocarbon group containing one or more double bonds and generally having a length of 2 to 20 carbon atoms. For example, a "C2-C6 alkenyl" contains two to six carbon atoms. Alkenyl includes, but is not limited to, for example, vinyl, propenyl, butenyl, 1-methyl-2-butene-1-yl, hexenyl, etc.

[0041] The term "alkynyl" refers to a straight or branched hydrocarbon group containing one or more triple bonds and generally having a length of 2 to 20 carbon atoms. For example, a "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, etc.

[0042] The term "heteroalkenyl" means that one or more carbon atoms in the above-defined "alkenyl" are replaced by a heteroatom selected from N, O, and S, or are substituted by a group containing a heteroatom selected from N, O, and S.

[0043] The term "heteroalkynyl" means that one or more carbon atoms in the above-defined "alkynyl" are replaced by a heteroatom selected from N, O, and S, or are substituted by a group containing a heteroatom selected from N, O, and S.

[0044] The term "alkoxy" or "alkyloxy" refers to an -O-alkyl group. 10 Alkoxy" (or alkyloxy) is intended to include C1-C 10 Alkoxy. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy) and tert-butoxy, and the alkoxy may carry multiple oxygen atoms, such as 1-10 oxygen atoms. Similarly, "alkylthio" or "thioalkoxy" means an alkyl group as defined above with a specified number of carbon atoms connected by a sulfur bridge; for example, methyl-S- and ethyl-S-.

[0045] The term "alkenyloxy" or "alkenyloxy" refers to an -O-alkenyl group. 2-10 Alkenyloxy" (or alkenyloxy) is intended to include C2-C 10 Examples of alkenyloxy groups include, but are not limited to, allyloxy and allyloxy groups, and the alkenyloxy group may contain multiple oxygen atoms, such as 1 to 10 oxygen atoms.

[0046] The term "alkynyloxy" or "alkynyloxy" refers to an -O-alkynyl group. 2-10 Alkynyloxy" (or alkynyloxy) is intended to include C2-C 10 Examples of alkynyloxy include, but are not limited to, acetylenylethoxy and propargyloxy. The alkynyloxy group may contain multiple oxygen atoms, such as 1 to 10 oxygen atoms.

[0047] The term "cyano" refers to a -CN group.

[0048] The term "amino" means a -NH2 group.

[0049] The term "hydroxy" means an -OH group.

[0050] The term "nitro" means a -NO2 group.

[0051] The term "mercapto" refers to a -SH group.

[0052] The term "carbonyl" refers to an organic functional group consisting of carbon and oxygen atoms connected by a double bond (C=O).

[0053] The term "cycloalkyl" refers to a monocyclic or bicyclic cyclic alkyl. Monocyclic cyclic alkyl refers to a C3-C8 cyclic alkyl, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and norbornyl etc. Branched cycloalkyls such as 1-methylcyclopropyl and 2-methylcyclopropyl are included in the definition of "cycloalkyl". Bicyclic cyclic alkyls include cycloalkyls of bridged rings, spiro rings or fused rings.

[0054] The term "cycloalkenyl" refers to a monocyclic or bicyclic cyclic alkenyl. Monocyclic cyclic alkenyl refers to a C3-C8 cyclic alkenyl, including but not limited to cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and norbornyl. Branched cycloalkenyls such as 1-methylcyclopropenyl and 2-methylcyclopropenyl are included in the definition of "cycloalkenyl". Bicyclic cyclic alkenyls include cyclic alkenyls of bridged rings, spiro rings or fused rings.

[0055] "Halo" or "halogen" includes fluorine, chlorine, bromine and iodine. "Haloalkyl" is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms and 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, heptafluoropropyl and heptachloropropyl. Examples of haloalkyl also include "fluoroalkyl" which is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms and substituted with one or more fluorine atoms.

[0056] "Haloalkoxy" or "haloalkyloxy" means a haloalkyl group as defined above connected via an oxygen bridge with a specified number of carbon atoms. For example, "C1-C6 haloalkoxy" is intended to include C1, C2, C3, C4, C5 and C6 haloalkoxy. Examples of haloalkoxy include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy and pentafluoroethoxy. Similarly, "haloalkylthio" or "thiohaloalkoxy" means a haloalkyl group as defined above connected via a sulfur bridge with a specified number of carbon atoms; for example, trifluoromethyl-S- and pentafluoroethyl-S-.

[0057] The term "aryl" / "arylene", alone or as part of a larger moiety such as "aralkyl", "aralkyloxy" or "aryloxyalkyl", refers to a monocyclic, bicyclic or tricyclic ring system having a total of 6 to 10 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, which includes but is not limited to phenyl, indanyl, 1-naphthyl, 2-naphthyl and tetrahydronaphthyl. The fused aryl group may be attached to another group at a suitable position on the cycloalkyl ring or the aromatic ring. For example, an arrow line drawn from a ring system indicates that the bond may be attached to any suitable ring atom.

[0058] The term "heteroaryl" / "heteroarylidene", "heteroaromatic ring", "aromatic heteroyl", "aromatic heteroyl", "heteroaromatic ring radical" or "heteroaromatic ring group" means a stable 3-, 4-, 5-, or 7-membered aromatic monocyclic or aromatic bicyclic or 7-, 8-, 9-, 10-, 11-, 12-, 13- or 14-membered aromatic polycyclic heterocyclic ring, which is fully unsaturated, partially unsaturated, and which 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 defined above is fused to a benzene ring. Nitrogen and sulfur heteroatoms may be optionally oxidized. The nitrogen atom is substituted or unsubstituted (i.e., N or NR, wherein R is H or, if defined, another substituent). The heterocyclic ring may be attached to its side group at any heteroatom or carbon atom that results in a stable structure. If the resulting compound is stable, the heterocyclic radical described in the present invention may be substituted on a carbon or nitrogen atom. The nitrogen in the heterocycle may be optionally 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 1.Examples of aromatic heterocycles include, but are not limited to, acridinyl, azetidinyl, azinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuranyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, imidazopyridinyl, indolinyl, indolizinyl, indolyl, 3H- indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolopyridinyl, oxazolidinyl, perylene, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiyl, phenoxazinyl, phthalazinyl, piperazinyl , piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolidinonyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidine, tetrazolyl, tetrahydrofuranyl, tetrahydroisoquinolyl, tetrahydroquinolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthracene 1,2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, 5,6,7,8-tetrahydro-quinolyl, 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 heterocycles such as those described above.

[0059] The term "heterocycloalkyl" used in the present invention refers to a monocyclic heterocycloalkyl system, or a bicyclic heteroalkyl system. A monocyclic cycloheteroalkyl refers to a 3-8 membered cyclic alkyl system containing at least one saturated or unsaturated but non-aromatic alkyl selected from O, N, S, P. A bicyclic heteroalkyl system refers to a heterocycloalkyl fused to a phenyl, or a cycloalkyl, or a cycloalkenyl, or a cycloheteroalkyl, or a heteroaryl.

[0060] The terms "bridged ring group" and "bridged cyclic hydrocarbon" used in the present invention refer to a polycyclic system that shares two or more carbon atoms, which can be divided into a bicyclic bridged cyclic hydrocarbon group and a polycyclic bridged cyclic hydrocarbon group. The former is composed of two alicyclic rings sharing two or more carbon atoms; the latter is a bridged cyclic hydrocarbon group composed of three or more rings.

[0061] The term "heterobridged ring group" as used herein refers to a polycyclic heterocyclic group in which two rings share two non-adjacent carbon atoms or heteroatoms.

[0062] 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).

[0063] The term "heterospirocyclic group" used in the present invention refers to a polycyclic heterocyclic group in which two rings share a common carbon atom or heteroatom.

[0064] The term "substituted" as used herein means that at least one hydrogen atom is replaced by a non-hydrogen group, provided that normal valence is maintained and the substitution results in a stable compound. A ring double bond as used herein is a double bond formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N).

[0065] In the case of nitrogen atoms (e.g., amines) present on the compounds of the invention, these nitrogen atoms can be converted to N-oxides by treatment with an oxidizing agent (e.g., mCPBA and / or hydrogen peroxide) to obtain other compounds of the invention. Thus, the nitrogen atoms shown and claimed are considered to encompass both the shown nitrogen and its N-oxide (N→O) derivatives.

[0066] When any variable occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown substituted with 0-3 R, then the group may be optionally substituted with up to three R groups, and at each occurrence R is independently selected from the definition of R. Furthermore, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0067] 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 substituents are listed without indicating the atom in the substituent that is bonded to the rest of the compound of a given formula, then such 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.

[0068] The term "amino" or "amine" alone or in combination means a primary amine group (-NH2), a secondary amine group (-NH-) or a tertiary amine group.

[0069] The term "C1-C6 alkylamino" alone or in combination represents an amino group as defined above, wherein the hydrogen atom of the amino group is substituted by at least one C1-C6 alkyl group, wherein "alkyl" represents as defined above, and accordingly, "C1-C6 alkylamino" includes methylamino, ethylamino, propylamino, isopropylamino, n-butylamino, isobutylamino, 2-butylamino, tert-butylamino, n-pentylamino, 2-pentylamino, 3-pentylamino, 2-methyl-2-butylamino, 3-methyl-2-butylamino, 3-methyl-1-butylamino, 2-methyl-1-butylamino, n-hexylamino, 2-hexylamino, 3-hexylamino, 2-methyl-2-pentylamino, 3-methyl-2-pentylamino, 4-methyl-2-pentylamino, 3-methyl-3-pentylamino, 2-methyl-3-pentylamino, 2,3-dimethyl-2-butylamino, 3,3-dimethyl-2-butylamino, etc. Specific "C1-C6 alkylamino" is methylamino, ethylamino, isopropylamino, tert-butylamino, etc.

[0070] The term "isomer" includes all isomeric forms including enantiomers, diastereomers, tautomers and geometric isomers (including cis-trans isomers). Therefore, the single stereochemical isomers of the compounds designed in the present invention or mixtures of their enantiomers, diastereomers, tautomers or geometric isomers (or cis-trans isomers) all belong to the scope of the present invention.

[0071] The "pharmaceutically acceptable salt" used in the present invention refers to a derivative of the compound of the present invention, wherein the parent compound is modified by preparing its acid or base salt. 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 salts or quaternary ammonium salts of the parent compound formed by (for example) non-toxic inorganic or organic acids. For example, the above conventional non-toxic salts include those derived from, for example, the following inorganic acids: hydrochloric acid, hydrobromic acid, sulfuric acid, aminosulfonic acid, phosphoric acid and nitric acid; and salts prepared from, for example, the following organic acids: 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, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, benzenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid and isethionic acid, etc.

[0072] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing basic or acidic moieties by conventional chemical methods. Generally, the above salts can be prepared by reacting the free acid or base form 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; generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred. A list of suitable salts can be found in Remington: The Science and Practice of Pharmacy, 22nd Edition, 25 Allen, LV Jr., Ed.; Pharmaceutical Press, London, UK (2012), the disclosure of which is incorporated herein by reference.

[0073] The term "solvate" means a physical association of a compound of the invention with one or more solvent molecules, whether organic or inorganic. The physical association includes hydrogen bonding. In certain cases, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate will be able to be separated. The solvent molecules in the solvate may exist in a regular arrangement and / or a disordered arrangement. The solvate may contain stoichiometric or non-stoichiometric amounts of solvent molecules. "Solvate" encompasses solution phases and separable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.

[0074] The term "ester" is used to refer to organic esters, including monoesters, diesters, triesters, and more generally polyesters.

[0075] The term "isotopic derivative" refers to an isotopic derivative obtained by replacing the hydrogen atoms in the general formula I with 1 to 6 deuterium atoms (D), replacing the carbon atoms in the general formula I with 1 to 3 carbon 14 atoms ( 14C) isotopic derivatives obtained by substitution.

[0076] As used herein, the term "treat" includes any effect resulting in improvement of a condition, disease, disorder, etc., such as alleviation, reduction, regulation, improvement or elimination, or amelioration of the symptoms thereof.

[0077] The term "pharmaceutical composition" used in the present invention refers to a combination of an active agent and an inert or active carrier, making the composition particularly suitable for in vivo or ex vivo diagnosis or treatment. Examples of bases include, but are not limited to, alkali metal (e.g., sodium) hydroxides, alkaline earth metal (e.g., magnesium) hydroxides, ammonia, etc. For therapeutic use, salts of the compounds of the present invention are expected to be medicinal. However, salts of non-pharmaceutical acids and bases can also be used, for example, in the preparation or purification of pharmaceutical compounds.

[0078] Specific pharmaceutical and medical terms

[0079] The term "cancer", as used herein, refers to an abnormal growth of cells that cannot be controlled and can metastasize (spread) under certain conditions. This type of cancer includes, but is not limited to, solid tumors (such as bladder, intestine, brain, chest, uterus, heart, kidney, lung), lymphoid tissue (lymphoma), ovary, pancreas or other endocrine organs (such as thyroid), prostate, skin (melanoma) or blood tumors (such as non-leukemic leukemia).

[0080] Drug composition and dosage

[0081] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of one or more compounds of formula (I) formulated with one or more pharmaceutical carriers (additives) and / or diluents, and optionally one or more of the above-mentioned other therapeutic agents. The compounds of the present invention can be administered in any suitable manner for any of the above-mentioned uses, for example, orally, such as tablets, capsules (each including sustained release or timed release preparations), pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, spray-dried dispersions), syrups and emulsions; sublingually; buccally; parenterally, such as by subcutaneous, intravenous, intramuscular or intrasternal injection or infusion techniques (e.g., in the form of sterile injectable aqueous or non-aqueous solutions or suspensions); nasally, including administration to the nasal membrane, such as by inhalation spray; topically, such as in the form of creams or ointments; or rectally, such as in the form of suppositories. They can be administered alone, but are usually administered using a pharmaceutical carrier selected based on the selected route of administration and standard pharmaceutical practice.

[0082] Pharmaceutical carriers are formulated based on a number of factors that are 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 targeted therapeutic indication. Pharmaceutical carriers include aqueous and non-aqueous liquid media and various solid and semisolid dosage forms.

[0083] The carriers may include many different ingredients and additives in addition to the active agent, which are included in the formulation for various reasons known to those skilled in the art, such as stabilizing the active agent, binders, etc. Descriptions of suitable pharmaceutical carriers and factors involved in carrier selection can be found in a number of readily available sources, such as Allen, LV Jr. et.al. Remington: The Science and Practice of Pharmacy (2 Volumes), 22nd Edition (2012), Pharmaceutical Press.

[0084] Of course, the dosage regimen of the compounds of the invention varies depending on known factors, such as the pharmacodynamic properties of the specific agent and its mode and route of administration; the species, age, sex, health condition, medical condition and weight of the recipient; the nature and extent of symptoms; the type of concurrent treatment; the frequency of treatment; the route of administration, the patient's renal and liver function and the desired effect. According to general guidance, when used for a specified effect, the daily oral dosage of each active ingredient should be about 0.001 mg / day to about 10-5000 mg / day, preferably about 0.01 mg / day to about 1000 mg / day, and most preferably about 0.1 mg / day to about 600 mg / day. During a constant rate infusion, the most preferred intravenous dosage should be about 0.01 mg / kg / minute to about 10 mg / kg / minute. The compounds of the invention can be administered in a single daily dose, or the total daily dose can be administered in divided doses twice, three times or four times a day.

[0085] The compound can usually be administered in a mixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to as pharmaceutical carriers in the present invention) appropriately selected according to the intended administration form (eg, oral tablets, capsules, elixirs and syrups) and in accordance with conventional pharmaceutical practice.

[0086] 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.

[0087] A typical injectable preparation can be prepared as follows: at least one compound of the present invention (250 mg) is aseptically placed in a vial, lyophilized in an aseptic manner and sealed. For use, the vial contents are mixed with 2 mL of physiological saline to produce an injectable preparation.

[0088] The scope of the present invention includes (alone or in combination with a pharmaceutical carrier) a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of the present invention as an active ingredient. Optionally, the compound of the present invention can be used alone, in combination with other compounds of the present invention, or in combination with one or more other therapeutic agents (e.g., anticancer agents or other pharmaceutically active substances).

[0089] Regardless of the selected administration route, the compound of the present invention (which may be used in a suitable hydrated form) and / or the pharmaceutical composition of the present invention are formulated into a pharmaceutical dosage form by conventional methods known to those skilled in the art.

[0090] Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present invention may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0091] The selected dosage level will depend upon a variety of factors, including the activity of the specific compound of the present invention being employed, or its ester, salt or amide; the route of administration; the time of administration; the rate of excretion of the specific compound being employed; the rate and extent of absorption; the duration of the treatment; other drugs, compounds and / or substances used in combination with the specific compound being employed; and the age, sex, weight, condition, general health and prior medical history of the patient being treated and other factors well known in the medical art.

[0092] A doctor or veterinarian with ordinary skills in the art can easily determine and prescribe the desired pharmaceutical composition of an effective amount. For example, in order to achieve the desired therapeutic effect, a physician or veterinarian can start the dosage of the compound of the present invention used in the pharmaceutical composition at a level lower than the desired level, and gradually increase the dosage until the desired effect is achieved. Generally, the compound of the present invention of a suitable daily dose will be the amount of the compound of the lowest dose that effectively produces a therapeutic effect. Such an effective dose generally depends on the above factors. Generally, the range of the compound of the present invention for oral, intravenous, intraventricular and subcutaneous doses for patients is about 0.01 to about 1000 mg / kg body weight / day. If necessary, the active compound of the effective daily dose can be administered separately at appropriate intervals in two, three, four, five, six or more subdoses in a day, optionally in a unit dosage form. In certain aspects of the present invention, medication is administered once a day.

[0093] While it is possible for a compound of the present invention to be administered alone, it is preferable to administer the compound as a pharmaceutical formulation (composition).

[0094] The above features mentioned in the present invention or the features mentioned in the embodiments can be combined in any way. All the features disclosed in the present specification can be used in any combination form, and each feature disclosed in the specification can be replaced by any alternative feature that can provide the same, equal or similar purpose. Therefore, unless otherwise specified, the disclosed features are only general examples of equal or similar features.

[0095] A compound represented by the following formula (I) or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope-labeled substance thereof:

[0096]

[0097] in:

[0098] R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 each independently represents hydrogen, hydroxyl, thiol, halogen, cyano, nitro, substituted or unsubstituted amine, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C2-C6 alkenyloxy, substituted or unsubstituted C2-C6 alkynyloxy, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted C1-C6 ester, substituted or unsubstituted C1-C6 amide, substituted or unsubstituted C1-C6 acyl;

[0099] Or, R 2 , R 3 , R 4 Two of them are connected to each other to form substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted three to eight-membered heterocycloalkyl, substituted or unsubstituted C6-C 10 aryl or substituted or unsubstituted five- to ten-membered heteroaryl;

[0100] are each independently substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocycloalkyl, substituted or unsubstituted C3-C 10 Spirocyclyl, substituted or unsubstituted C3-C 10 Heterospirocyclic group, substituted or unsubstituted C3-C 10 Bridged ring group, substituted or unsubstituted C3-C 10 Heterobridged ring group, substituted or unsubstituted C3-C10 Arylene, substituted or unsubstituted C3-C 10 heteroarylene;

[0101] is substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted C3-C8 cycloalkenyl, substituted or unsubstituted C3-C8 heterocycloalkenyl;

[0102] X is CR 8 R 9 Or C=O, where R 8 and R 9 Each is independently hydrogen or C1-C4 alkyl;

[0103] Or, R 8 , R 9 are connected to each other to form a three- to eight-membered cycloalkyl group;

[0104] Y is CR 10 or N, where R 10 is hydrogen, hydroxy, halogen, cyano, nitro, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C2-C6 alkenyloxy, substituted or unsubstituted C2-C6 alkynyloxy, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl;

[0105] n is an integer from 1 to 6.

[0106] In some embodiments, R 1 It is hydrogen, hydroxy, halogen, cyano, nitro, substituted or unsubstituted amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy.

[0107] In some preferred embodiments, R 1 It is hydrogen, fluorine, chlorine, bromine, cyano, amino, nitro, trifluoromethyl or trifluoromethoxy.

[0108] In some further preferred embodiments, R 1 is hydrogen or fluorine.

[0109] In some embodiments, R 2 It is hydrogen, hydroxy, halogen, cyano, nitro, substituted or unsubstituted amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy.

[0110] In some preferred embodiments, R 2 It is hydrogen, fluorine, chlorine, bromine, cyano, amino, nitro, trifluoromethyl or trifluoromethoxy.

[0111] In some further preferred embodiments, R 2 is hydrogen or fluorine.

[0112] In some more preferred embodiments, R 2 For hydrogen.

[0113] In some embodiments, R 3 It is hydrogen, hydroxy, halogen, cyano, nitro, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C1-C6 alkoxy.

[0114] In some preferred embodiments, R 3 It is hydrogen, halogen, or C1-C6 alkyl substituted by halogen.

[0115] In some further preferred embodiments, R 3 is hydrogen, chlorine or trifluoromethyl.

[0116] In some more preferred embodiments, R 3 It is trifluoromethyl.

[0117] In some embodiments, R 4 It is hydrogen, hydroxy, halogen, cyano, nitro, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C1-C6 alkoxy.

[0118] In some preferred embodiments, R 4 It is hydrogen, halogen, cyano, and nitro.

[0119] In some further preferred embodiments, R 4 It is cyano or nitro.

[0120] In some more preferred embodiments, R 4 It is cyano (-CN).

[0121] In some embodiments, R 5 It is hydrogen, hydroxy, halogen, cyano, nitro, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C1-C6 alkoxy.

[0122] In some preferred embodiments, R 5 It is hydrogen, hydroxy, halogen, or C1-C6 alkyl substituted by halogen.

[0123] In some further preferred embodiments, R 5 is hydrogen or fluorine.

[0124] In some more preferred embodiments, R 5 For hydrogen.

[0125] In some embodiments, R 6 It is hydrogen, hydroxy, halogen, cyano, nitro, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C1-C6 alkoxy.

[0126] In some preferred embodiments, R 6 It is hydrogen, hydroxy, halogen, or C1-C6 alkyl substituted by halogen.

[0127] In some further preferred embodiments, R 6 It is hydroxyl.

[0128] In some embodiments, R 7 It is hydrogen, hydroxy, halogen, cyano, nitro, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C1-C6 alkoxy.

[0129] In some preferred embodiments, R 7 It is hydrogen, hydroxy, halogen, or C1-C6 alkyl substituted by halogen.

[0130] In some further preferred embodiments, R 7 is hydrogen, fluorine, hydroxy or trifluoromethyl.

[0131] In some more preferred embodiments, R 7 For hydrogen.

[0132] In some embodiments, Each is independently a substituted or unsubstituted 3-10 membered heterocycloalkyl, heterospirocyclic group or heterobridged ring group containing 1-4 oxygen atoms and / or nitrogen atoms, wherein the substitution is by a substituent selected from halogen, -OH, -CN, -NH2, C1-C6 alkoxy, C1-C6 alkyl.

[0133] In some preferred embodiments, Each is independently a substituted or unsubstituted 4-8 membered heterocycloalkyl, heterospirocyclic group or heterobridged ring group containing 1-2 nitrogen atoms, wherein the substitution is by a substituent selected from halogen, -OH, -CN, -NH2, C1-C6 alkoxy and C1-C6 alkyl.

[0134] In some embodiments, It is a substituted or unsubstituted C3-C8 cycloalkyl group, or a substituted or unsubstituted C3-C8 heterocycloalkyl group.

[0135] In some preferred embodiments, It is a C3-C8 cycloalkyl group which is substituted or unsubstituted by a C1-C6 alkyl group.

[0136] In some further preferred embodiments, It is cyclohexyl or cyclobutane substituted by C1-C6 alkyl.

[0137] In some more preferred embodiments, It is cyclohexyl.

[0138] In some embodiments, X is CR 8 R 9 Or C=O, where R 8 , R 9 As defined above, and do not form a ring with each other.

[0139] In some preferred embodiments, X is CH2 or C=O.

[0140] In some further preferred embodiments, X is CH2.

[0141] In some embodiments, Y is CR 10 or N, where R 10 As defined above.

[0142] In some preferred embodiments, Y is CH or N.

[0143] In some further preferred embodiments, Y is CH.

[0144] The present invention also provides a compound or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope-labeled substance thereof, wherein the compound is selected from:

[0145]

[0146] 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 known to those skilled in the art, and preferred methods include (but are not limited to) the methods described below, wherein the starting materials are commercially available or prepared by methods disclosed in the literature.

[0147] An exemplary method suitable for preparing the compounds of the present invention comprises the following steps:

[0148]

[0149] Compounds I-1 and I-2 are condensed under the action of a condensing agent to obtain intermediate I-3; intermediate I-3 reacts with 1,1,2,2,3,3,4,4,5-nonafluorobutane-1-sulfonyl fluoride under alkaline conditions to obtain intermediate I-4; intermediate I-4 undergoes a coupling reaction with compound I-5 to obtain intermediate I-6; intermediate I-6 is subjected to Raney nickel catalytic hydrogenation under a hydrogen atmosphere to obtain intermediate I-7; intermediate I-7 reacts with compound I-8 under strong alkaline 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 are subjected to reductive amination to obtain the target product I-12.

[0150] in,

[0151] The general synthetic method for preparing the key intermediate I-1 includes:

[0152]

[0153] Compound II-1 reacts with 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide under strong alkaline conditions to obtain intermediate II-2; intermediate II-2 and intermediate II-3 undergo coupling reaction under palladium catalyst to obtain intermediate II-4; intermediate II-4 is brominated with NBS to obtain intermediate II-5; intermediate II-5 is coupled with compound II-6 under palladium catalyst to obtain intermediate II-7; intermediate II-7 is deprotected under acidic conditions to obtain intermediate I-1.

[0154] The general synthetic method for preparing the key intermediate I-2 includes:

[0155]

[0156] Compound III-1 reacts with benzyl bromide under the action of a strong base to obtain III-2; III-2 is deprotected under acidic conditions to obtain I-2.

[0157] The general synthetic method for preparing the key intermediate I-5 includes:

[0158]

[0159] 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.

[0160] The general synthetic method for preparing the key intermediate I-11 includes:

[0161]

[0162] Compound V-1 undergoes nucleophilic substitution with N-Boc piperazine under alkaline conditions to obtain intermediate V-2; intermediate V-2 is deprotected under acidic conditions to obtain intermediate I-11.

[0163] The present invention also provides a pharmaceutical composition comprising the compound as described above or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope-labeled substance thereof and a pharmaceutically acceptable carrier.

[0164] In a preferred embodiment, the pharmaceutical composition is in the form of an aqueous dispersion, liquid, gel, syrup, elixir, slurry, suspension, aerosol, controlled release agent, fast dissolving agent, effervescent agent, lyophilized agent, tablet, powder, pill, dragee, capsule, delayed release agent, extended release agent, pulse controlled release agent, multi-particulate or immediate release agent.

[0165] The present invention also provides the use of the above compound or its pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope label, or the above pharmaceutical composition in the preparation of drugs for treating estrogen and / or androgen receptor-related diseases.

[0166] In a preferred embodiment, the estrogen and / or androgen receptor-related disease is breast cancer or prostate cancer.

[0167] In a preferred embodiment, the estrogen and / or androgen receptor-related disease is advanced breast cancer.

[0168] In a preferred embodiment, the estrogen and / or androgen receptor-related disease is triple-negative breast cancer.

[0169] The above features mentioned in the present invention or the features mentioned in the embodiments can be combined in any way. All the features disclosed in the specification of this case can be used in any combination form, and each feature disclosed in the specification can be replaced by any alternative feature that can provide the same, equal or similar purpose. Therefore, unless otherwise specified, the disclosed features are only general examples of equal or similar features.

[0170] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended only to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples without specifying specific conditions are usually performed under normal conditions or according to the conditions recommended by the manufacturer. Unless otherwise stated, all percentages, ratios, proportions, or parts are by weight.

[0171] The units of weight-volume percentage in the present invention are well known to those skilled in the art, for example, refer to the weight of the solute in 100 ml of solution.

[0172] Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred implementation methods and materials described herein are for demonstration purposes only.

[0173] These examples are for illustrative purposes only and are not intended to limit the scope of the claims presented herein.

[0174] Unless otherwise specified, the H NMR spectra in this invention are 1 H-NMR) was collected from a Bruker-400 or OXFORD-AS500 nuclear magnetic resonance instrument, the unit of chemical shift is one part per million, and the internal standard is tetramethylsilane. The coupling constant (J) is close to 0.1 Hz. The abbreviations used are as follows: s, singlet; d, doublet; t, triplet; q, quartet; qu, quintet; m, multiplet; brs, broad peak. The mass spectrometer uses a Quattro Micro API triple quadrupole mass spectrometer.

[0175] Example 1 Preparation of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(4-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-methyl)-2-(6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)benzamide (Compound 1)

[0176]

[0177] Compound 1

[0178] Preparation of 6-(tert-Butoxy)-3,4-dihydronaphthalen-1(2H)-one

[0179]

[0180] The compound 6-hydroxy-3,4-dihydronaphthalene-1(2H)-one (100g, 0.62mol) and tert-butyl 2,2,2-trichloroacetate (269g, 1.23mol) were dissolved in dichloromethane (500mL), and a solution of boron trifluoride in ether (0.88g, 6.17mmol) was slowly added at 0°C, and the mixture was transferred to room temperature for reaction overnight. TLC detected that the reaction was not complete. After continuing the reaction for 12h, the reaction system was quenched with water, extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was separated by rapid column chromatography. 66.2g of the target product was obtained with a yield of 49%.

[0181] 1H-NMR (400MHz, CDCl3) δ7.96(d,J=8.6Hz,1H),6.90(d,J=8.6Hz,1H),6.80(s, 1H), 2.91 (t, J = 6.0Hz, 2H), 2.65-2.57 (m, 2H), 2.15-2.06 (m, 2H), 1.42 (s, 9H).

[0182] Preparation of 6-(tert-Butoxy)-3,4-dihydronaphthalen-1-yl trifluoromethanesulfonate

[0183]

[0184] The compound 6-(tert-butoxy)-3,4-dihydronaphthalene-1(2H)-one (66.2g, 0.3mol) and 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (141g, 0.39mol) were dissolved in anhydrous tetrahydrofuran, cooled to -78°C, and a 1M tetrahydrofuran solution of KHMDS (394mL, 0.39mol) was added dropwise. After the addition of the materials was completed, the low temperature was turned off and the reaction was carried out at room temperature under nitrogen protection overnight. TLC showed that 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 evaporated under reduced pressure, and the residue was separated by rapid column chromatography. 86.1g of the target product was obtained with a yield of 81%.

[0185] 1 H-NMR (400MHz, CDCl3) 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).

[0186] Preparation of methyl 2-bromo-5-hydroxybenzoate

[0187]

[0188] Sulfuric acid (38 mL) was slowly added to a methanol solution (250 mL) of 2-bromo-5-hydroxybenzoic acid (25 g, 115.2 mmol) and reacted at 65° C. After 12 h, TLC showed that the reaction was complete. The solvent was evaporated under reduced pressure, extracted with dichloromethane, washed with saturated sodium bicarbonate solution, and the organic phase was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 25 g of the target product with a yield of 94%.

[0189] MS-ESI: m / z 232.1[M+H] + .

[0190] Preparation of methyl 5-hydroxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxoborin-2-yl)benzoate

[0191]

[0192] Dissolve methyl 2-bromo-5-hydroxybenzoate (25g, 108mmol), pinacol borate (55g, 216mmol), potassium acetate (21.3g, 216mmol), and Pd(dppf)Cl2 (3.9g, 5.4mmol) in 1,4-dioxance (250mL) and react at 90°C for 3h under nitrogen protection. TLC shows that the reaction is complete. Filter, extract the filtrate with ethyl acetate, and dry it with anhydrous sodium sulfate. Evaporate the solvent under reduced pressure, and separate the residue by rapid column chromatography. Obtain 28g of the target product with a yield of 93%.

[0193] MS-ESI: m / z 279.1[M+H] + .

[0194] Preparation of methyl 2-(6-(tert-butoxy)-3,4-dihydronaphthalen-1-yl)-5-hydroxybenzoate

[0195]

[0196] To a 1,4-dioxane solution (200 mL) of the compound 6-(tert-butoxy)-3,4-dihydronaphthalen-1-yl trifluoromethanesulfonate (21 g, 0.06 mol) and 5-hydroxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxybenzofuran-2-yl)benzoic acid methyl ester (20 g, 0.07 mmol), H2O (20 mL), potassium carbonate (16.6 g, 0.12 mol) and Pd(dppf)Cl2 (1.3 g, 1.8 mmol) were added, and the mixture was reacted at 100°C under nitrogen protection. After 4 h, the reaction was complete as determined by TLC. The mixture was filtered, the filtrate was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was separated by rapid column chromatography. 17 g of the target product was obtained, with a yield of 80%.

[0197] MS-ESI: m / z 352.5[M+H] + .

[0198] 1H-NMR (400MHz, CDCl3) 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).

[0199] Preparation of methyl 2-(2-bromo-6-(tert-butoxy)-3,4-dihydronaphthalen-1-yl)-5-hydroxybenzoate

[0200]

[0201] At 0°C, slowly drop N-bromosuccinimide (10g, 57.8mmol) in acetonitrile solution to a solution of methyl 2-(6-(tert-butoxy)-3,4-dihydronaphthalen-1-yl)-5-hydroxybenzoate (17g, 48.2mmol) in acetonitrile (50mL). After the addition is complete, turn off the low temperature and allow the mixture to rise to room temperature naturally for reaction. After 12h, TLC shows that the reaction is complete. Evaporate the solvent under reduced pressure, extract with ethyl acetate, and dry the organic phase with anhydrous sodium sulfate. Evaporate the solvent under reduced pressure from the organic phase, and separate the residue by rapid column chromatography. 17.3g of the target product is obtained, with a yield of 83%.

[0202] MS-ESI: m / z 432.3[M+H] + .

[0203] 1 H-NMR (400MHz, CDCl3) δ7.74(d,J=2.5Hz,1H),7.26(s,1H),7.24(d,J=2.6Hz,1H),6.97(d,J=2.3Hz,1H),6.8 2(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).

[0204] Preparation of methyl 2-(6-(tert-butoxy)-2-phenyl-3,4-dihydronaphthalen-1-yl)-5-hydroxybenzoate

[0205]

[0206] To a solution (100 mL) of methyl 2-(2-bromo-6-(tert-butoxy)-3,4-dihydronaphthalen-1-yl)-5-hydroxybenzoate (17.3 g, 40.05 mmol) and phenylboronic acid (5.1 g, 42.05 mmol) in 1,4-dioxane, add H2O (10 mL), potassium carbonate (11 g, 80.1 mmol) and Pd(dppf)Cl2 (880 mg, 1.2 mmol), and react at 100°C under nitrogen protection. After 4 h, TLC detected that the reaction was complete, filtered, the filtrate was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was separated by rapid column chromatography. 11.5 g of the target product was obtained, and the yield was 67%.

[0207] MS-ESI: m / z 429.5[M+H] + .

[0208] 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).

[0209] Preparation of 2-(6-(tert-butoxy)-2-phenyl-3,4-dihydronaphthalen-1-yl)-5-hydroxybenzoic acid

[0210]

[0211] The compound 2-(6-(tert-butoxy)-2-phenyl-3,4-dihydronaphthalen-1-yl)-5-hydroxybenzoic acid methyl ester (11.5 g, 26.8 mmol) was dissolved in an ethanol solution, potassium hydroxide (7.5 g, 134.2 mmol) was added, and the reaction was carried out at 100°C. After 12 hours, TLC detected that the reaction was complete, and the pH was adjusted to weak alkalinity with 2M HCl solution. The solvent was evaporated under reduced pressure in the reaction system. 17.5 g of the target product was obtained, which was directly used in the next step without further purification.

[0212] MS-ESI: m / z 452.5[M+39] + .

[0213] Preparation of tert-butyl ((1r,4r)-4-(benzyloxy)cyclohexyl)carbamate

[0214]

[0215] Dissolve the compound tert-butyl ((1r, 4r)-4-hydroxycyclohexyl) carbamate (5g, 23.2mmol) and bromomethylbenzene (4g, 23.2mmol) in anhydrous N,N-dimethylformamide (30mL), add sodium hydride (670mg, 27.8mmol), and react at room temperature. After 12h, TLC detection shows that the reaction is basically complete, add saturated ammonium chloride solution to quench, extract with ethyl acetate, and dry the organic phase with anhydrous sodium sulfate. Evaporate the solvent under reduced pressure, and separate the residue by rapid column chromatography. 3.8g of the target product is obtained, and the yield is 54%.

[0216] MS-ESI: m / z 250.4[M+H-56] + .

[0217] 1 H-NMR (400MHz, CDCl3) 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=13.6,7.0Hz,2H),1.45(s,9H),1.49-1.39(m,2H),1.20-1.09(m,2H).

[0218] Preparation of (1r,4r)-4-(Benzyloxy)cyclohexane-1-amine

[0219]

[0220] The compound tert-butyl ((1r, 4r)-4-(benzyloxy) cyclohexyl) carbamate (3.8 g, 12.5 mmol) was dissolved in dichloromethane (10 mL), and 4M HCl / 1,4-dioxane (20 mL) was added to react at room temperature. After 12 h, the reaction was complete by TLC detection, and the solvent was evaporated under reduced pressure in the reaction system. 2.8 g of the target product was obtained, which was used directly in the next step without further purification.

[0221] MS-ESI: m / z 205.3[M+H] + .

[0222] Preparation of N-((1r,4r)-4-(benzyloxy)cyclohexyl)-2-(6-(tert-butoxy)-2-phenyl-3,4-dihydronaphthalen-1-yl)-5-hydroxybenzamide

[0223]

[0224] The compound 2-(6-(tert-butoxy)-2-phenyl-3,4-dihydronaphthalen-1-yl)-5-hydroxybenzoic acid (2g, 4.83mmol) and triethylamine (1.5mL, 10.6mmol) were 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 the reaction was allowed to proceed overnight at room temperature. The reaction was complete after TLC detection, and the product was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The organic phase was evaporated under reduced pressure to remove the solvent, and the residue was separated by rapid column chromatography. 1.14g of the target product was obtained with a yield of 39%.

[0225] MS-ESI: m / z 602.7[M+H] + .

[0226] 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).

[0227] Preparation of 3-((1r,4r)-4-(benzyloxy)cyclohexyl)carbamoyl)-4-(6-(tert-butoxy)-2-phenyl-3,4-dihydronaphthalen-1-yl)phenyl 1,1,2,2,3,3,4,4,5-nonafluorobutane-1-sulfonate

[0228]

[0229] The compound N-((1r,4r)-4-(benzyloxy)cyclohexyl)-2-(6-(tert-butoxy)-2-phenyl-3,4-dihydronaphthalen-1-yl)-5-hydroxybenzamide (1.2 g, 1.99 mmol) was dissolved in a mixed solution of tetrahydrofuran (5 mL) and acetonitrile (5 mL), and 1,1,2,2,3,3,4,4,5-nonafluorobutane-1-sulfonyl fluoride (910 mg, 2.99 mmol) and cesium carbonate (970 mg, 2.99 mmol) were added, and the reaction was carried out at room temperature for 2 h. The reaction was complete after TLC detection, and the mixture was filtered. The filtrate was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was separated by flash column chromatography. 1.26 g of the target product was obtained, and the yield was 72%.

[0230] MS-ESI: m / z 884.8[M+H] + .

[0231] 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),7.11-7.0 2(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).

[0232] Preparation of 4-(dimethoxymethyl)piperidine-1-carboxylic acid benzyl ester

[0233]

[0234] To a methanol solution (20 mL) of compound 4-formylpiperidine-1-carboxylic acid benzyl ester (5 g, 20.2 mmol), trimethyl orthoformate (10.7 g, 101.1 mmol) and p-toluenesulfonic acid (0.19 g, 1.01 mmol) were added and reacted at room temperature for 12 h. TLC detected that the reaction was complete, and water was added to quench, and the mixture was extracted with dichloromethane and dried over anhydrous sodium sulfate. The organic phase was evaporated under reduced pressure to remove the solvent, and the residue was separated by rapid column chromatography. 5.53 g of the target product was obtained with a yield of 93%.

[0235] MS-ESI: m / z 294.3[M+H] + .

[0236] Preparation of 4-(dimethoxymethyl)piperidine

[0237]

[0238] The compound 4-(dimethoxymethyl)piperidine-1-carboxylic acid benzyl ester (5.53 g, 18.8 mmol) was dissolved in a methanol solution (20 mL), and Pd / C (550 mg) was added to react at room temperature under a hydrogen atmosphere. After 12 h, the reaction was complete by TLC detection, and the filtrate was filtered and the solvent was evaporated under reduced pressure to obtain 3.15 g of the target product, which was used directly in the next step without further purification.

[0239] MS-ESI: m / z 160.2[M+H] + .

[0240] Preparation of N-((1r,4r)-4-(benzyloxy)cyclohexyl)-2-(6-(tert-butoxy)-2-phenyl-3,4-dihydronaphthalen-1-yl)-5-(4-(dimethoxymethyl)piperidin-1-ylbenzamide

[0241]

[0242] The compound 3-((1r,4r)-4-(benzyloxy)cyclohexyl)carbamoyl)-4-(6-(tert-butoxy)-2-phenyl-3,4-dihydronaphthalen-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), 4-(dimethoxymethyl)piperidine (176 mg, 1.08 mmol) was added, and then 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (24 mg, 0.0045 mmol), sodium tert-butoxide (260 mg, 2.7 mmol), palladium acetate (12 mg, 0.0045 mmol) were added, and the mixture was reacted at 90° C. under nitrogen protection. After 3 h, the reaction was complete by TLC detection, and the mixture was 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 to obtain 205 mg of the target product with a yield of 30%.

[0243] MS-ESI: m / z 744.0[M+H] + .

[0244] 1H-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).

[0245] Preparation of 2-(6-(tert-butoxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)-5-(4-(dimethoxymethyl)piperidin-1-methyl)-N-((1r,4r)-4-hydroxycyclohexyl)benzamide

[0246]

[0247] The compound N-((1r,4r)-4-(benzyloxy)cyclohexyl)-2-(6-(tert-butoxy)-2-phenyl-3,4-dihydronaphthalen-1-yl)-5-(4-(dimethoxymethyl)piperidin-1-ylbenzamide (205 mg, 0.28 mmol) was dissolved in methanol (5 mL), and Raney nickel catalyst (200 mg) was added. After the addition of the materials, the reaction system was reacted at room temperature under a hydrogen atmosphere for 12 h. The reaction was complete by TLC detection, and the organic phase was extracted with ethyl acetate and dried over 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 with a yield of 92%.

[0248] MS-ESI: m / z 655.8[M+H] + .

[0249] Preparation of 2-(6-(tert-butoxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)-N-(1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(4-(dimethoxymethyl)piperidin-1-ylbenzamide

[0250]

[0251] The compound 2-(6-(tert-butoxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)-5-(4-(dimethoxymethyl)piperidin-1-methyl)-N-((1r,4r)-4-hydroxycyclohexyl)benzamide (167 mg, 0.24 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), sodium hydride (9 mg, 0.36 mmol) was added at 0°C, reacted for 1 h, 1,2-dichloro-4-fluorobenzene was added, the mixture was transferred to room temperature for 1 h, and the temperature was slowly raised to 70°C for reaction. After the reaction was complete by TLC detection, the mixture was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was separated by rapid column chromatography. 103 mg of the target product was obtained with a yield of 54%.

[0252] MS-ESI: m / z 791.4[M+H] + .

[0253] 1H-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=1 1.9,7.7Hz,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=14.1H z,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).

[0254] Preparation of 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

[0255]

[0256] The compound 2-(6-(tert-butoxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-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), and 4M HCl / 1,4-dioxane (3 mL) was added and reacted at room temperature. After 2 h, TLC detected that the reaction was complete, and the reaction system was evaporated under reduced pressure to remove the solvent. The pH was adjusted to neutral with saturated sodium carbonate solution, and the organic phase was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. 66 mg of the target product was obtained with a yield of 74%.

[0257] MS-ESI: m / z 689.3[M+H] + .

[0258] Preparation of tert-butyl 4-(3-cyano-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate

[0259]

[0260] Dissolve the compound 2-cyano-4-fluorobenzoic acid methyl ester (5g, 27.9mmol) and piperazine-1-carboxylic acid tert-butyl ester (7.8g, 41.8mmol) in N,N-dimethylacetamide (30mL), add potassium carbonate (5.8g, 41.8mmol), and react at 80°C. After 5h, TLC detection shows that the reaction is complete, extract with ethyl acetate, and dry the organic phase with anhydrous sodium sulfate. Evaporate the solvent under reduced pressure, and separate the residue by rapid column chromatography. 8.878g of the target product is obtained, and the yield is 92%.

[0261] MS-ESI: m / z 290.4[M+H-56] + .

[0262] 1 H-NMR (400MHz, CDCl3) 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).

[0263] Preparation of tert-butyl 4-(3-cyano-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate

[0264]

[0265] Dissolve the compound 4-(3-cyano-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester (8.67g, 25.06mmol) in a mixed solution of pyridine (18mL, 0.23mol), H2O (15mL), and acetic acid (15mL), add Raney-Ni (4.35g), raise the system temperature to 60°C, and slowly add Na2PO2·H2O (12.8g). After 12h, TLC detection shows that the reaction is complete, extract with ethyl acetate, and dry with anhydrous sodium sulfate. The organic phase is evaporated under reduced pressure to remove the solvent, and the residue is separated by rapid column chromatography. 5.39g of the target product is obtained, and the yield is 62%.

[0266] MS-ESI: m / z 293.4[M+H-56] + .

[0267] 1H-NMR (400MHz, CDCl3) 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).

[0268] Preparation of tert-butyl (S)-5-amino-4-((benzyloxy)carbonyl)amino)-5-oxopentanoate

[0269]

[0270] The compound (S)-2-((benzyloxy)carbonyl)amino)-5-(tert-butoxy)-5-oxopentanoic acid (25 g, 74.1 mmol) was dissolved in 1,4-dioxane (150 mL), and (Boc)2O (26 g, 118.6 mmol) and pyridine (11.7 mL, 148.2 mmol) were added under ice bath. After reacting for 30 min, ammonium bicarbonate (17.5 g, 222.3 mmol) was added and reacted at room temperature. After 12 h, the reaction was complete by TLC detection, and the product was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The organic phase was evaporated under reduced pressure to remove the solvent, and the residue was separated by rapid column chromatography. 24.4 g of the target product was obtained with a yield of 97%.

[0271] MS-ESI: m / z 281.3[M+H-56] + .

[0272] Preparation of (S)-tert-Butyl 4,5-diamino-5-oxopentanoate

[0273]

[0274] Compound (S)-5-amino-4-((benzyloxy)carbonyl)amino)-5-oxopentanoic acid tert-butyl ester (24.4 g, 71.76 mmol) was dissolved in methanol (100 mL), Pd / C (3 g) was added, and the mixture was reacted at room temperature for 12 h under a hydrogen atmosphere. The reaction was complete by TLC detection, and the mixture was filtered and the solvent was evaporated under reduced pressure. 15 g of the target product was obtained, which was used directly in the next step without further purification.

[0275] MS-ESI: m / z 147.2[M+H-56] + .

[0276] Preparation of tert-butyl (S)-4-(2-(1-amino-5-(tert-butoxy)-1,5-dioxolan-2-yl)-1-oxoisoxidolin-5-yl)piperazine-1-carboxylate

[0277]

[0278] Dissolve 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-oxopentanoic acid tert-butyl ester (3.8g, 19.7mmol) in methanol (30mL) solution, add acetic acid (1.37g, 22.8mmol) at 0°C, react for 30min, add NaCNBH3 (1.9g, 30.4mmol), and transfer to room temperature for reaction. After 2h, TLC detection shows that the reaction is complete, the solvent is evaporated under reduced pressure, extracted with ethyl acetate, washed with 1N HCl and saturated brine, and the organic phase is dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, and the residue is separated by rapid column chromatography. 6.8g of the target product is obtained with a yield of 89%.

[0279] MS-ESI: m / z 391.6[M+H-112] + .

[0280] 1 H-NMR (400MHz, CDCl3) 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).

[0281] Preparation of (S)-3-(1-oxo-5-(piperazin-1-yl)isoindol-2-yl)piperidine-2,6-dione

[0282]

[0283] The compound tert-butyl (S)-4-(2-(1-amino-5-(tert-butoxy)-1,5-dioxolane-2-yl)-1-oxoisoxindol-5-yl)piperazine-1-carboxylate (500 mg, 0.99 mmol) was dissolved in acetonitrile (5 mL), and benzenesulfonic acid (315 mg, 1.98 mmol) was added and reacted at 85° C. After 12 h, TLC detected that the reaction was complete, the solvent was evaporated under reduced pressure, ethyl acetate was slurried for 30 min, 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.

[0284] MS-ESI: m / z 329.4[M+H] + .

[0285] 1 H-NMR (400MHz, CDCl3) 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,1 H), 2.36 (dt, J=13.4, 8.9Hz, 1H), 1.96 (dd, J=9.0, 3.7Hz, 1H), 1.77 (s, 1H).

[0286] Preparation of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(4-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoxidolin-5-yl)piperazin-1-yl)methyl)piperidin-1-methyl)-2-(6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-ylbenzamide (Compound 1)

[0287]

[0288] Compound (S)-3-(1-oxo-5-(piperazin-1-yl)isoindol-2-yl)piperidine-2,6-dione (67 mg, 138 mmol) was dissolved in a mixed solution of dichloromethane (1 mL) and methanol (3 mL), sodium acetate (34 mg, 414 mmol) was added, and the mixture was reacted at room temperature for 10 min, and N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(4-formylpiperidin-1-yl)-2-(6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalene-1 -ylbenzamide (66mg, 97mmol), react at room temperature for 30min, add acetic acid (0.05mL) and sodium cyanoborohydride (17mg, 276mmol), react at room temperature. After 1h, TLC detected that the reaction was complete, evaporated the solvent under reduced pressure, added tetrahydrofuran and H2O and stirred for 20min, adjusted the pH to 8-9 with saturated NaHCO3, extracted with ethyl acetate:tetrahydrofuran (2:1), and dried over anhydrous sodium sulfate. The organic phase was evaporated under reduced pressure to remove the solvent, and the residue was separated by rapid column chromatography. 47mg of the target product was obtained, and the yield was 48%.

[0289] MS-ESI: m / z 1001.6[M+H] + .

[0290] 1H-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),2.43-2.2 4(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, 14.0Hz, 5H), 1.20-1.10 (m, 2H).

[0291] Example 2 Preparation of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline)-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-(6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)benzamide (Compound 2)

[0292]

[0293] Preparation of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole-5-yl)piperazine-1-carboxylate

[0294]

[0295] To a DMSO solution (35 mL) of the compound 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione (3.6 g, 13.03 mmol), piperazine-1-carboxylic acid tert-butyl ester (2.6 g, 14.3 mmol) and N,N-diisopropylethylamine (4.5 mL, 26 mmol) were added and reacted at 110°C. After 4 hours, the reaction was complete by TLC detection, and the mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The organic phase was evaporated under reduced pressure to remove the solvent, and the residue was separated by rapid column chromatography. 4.46 g of the target product was obtained with a yield of 77%.

[0296] MS-ESI: m / z 387.5[M+H-56] + .

[0297] 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,1 H),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).

[0298] Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindole-1,3-dione trifluoroacetate

[0299]

[0300] The compound 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole-5-yl)piperazine-1-carboxylic acid tert-butyl ester (4.46 g, 10.09 mmol) was dissolved in dichloromethane (40 mL), trifluoroacetic acid (10 mL) was slowly added, and the mixture was reacted at room temperature. After 12 h, the reaction was complete by TLC detection, and the solvent was evaporated under reduced pressure in the reaction system. 5.42 g of the target product was obtained, which was used directly in the next step without further purification.

[0301] MS-ESI: m / z 343.5[M+H] + .

[0302] Preparation of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin)-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-(6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)benzamide (Compound 2)

[0303]

[0304] The synthesis of compound 2 was consistent with that of compound 1 in Example 1, except that 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindole-1,3-dione trifluoroacetate was used instead of (S)-3-(1-oxo-5-(piperazin-1-yl)isoindol-2-yl)piperidine-2,6-dione benzenesulfonate, and the yield was 55%.

[0305] MS-ESI: m / z 1015.6[M+H] + .

[0306] 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),2.5 1(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).

[0307] Example 3 Preparation of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoisoidol-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-(6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalene-1-yl)benzamide (Compound 3)

[0308]

[0309] Preparation of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindole-5-yl)piperazine-1-carboxylate

[0310]

[0311] The synthesis of compound 4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindol-5-yl)piperazine-1-carboxylic acid tert-butyl ester was consistent with that of 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)piperazine-1-carboxylic acid tert-butyl ester in Example 2, except that 2-(2,6-dioxopiperidin-3-yl)-5,6-difluoroindole-1,3-dione was used instead of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione, and the yield was 93%.

[0312] MS-ESI: m / z 405.5[M+H-56] + .

[0313] Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindole-1,3-dione trifluoroacetate

[0314]

[0315] The synthesis of compound 2-(2,6-dioxopiperidin-3-yl)-5-(piperazine-1-yl)isoindole-1,3-dione trifluoroacetate was consistent with that of 2-(2,6-dioxopiperidin-3-yl)-5-(piperazine-1-yl)isoindole-1,3-dione trifluoroacetate in Example 2, except that 4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindole-5-yl)piperazine-1-carboxylic acid tert-butyl ester was used instead of 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole-5-yl)piperazine-1-carboxylic acid tert-butyl ester, and 8.17 g of the target product was obtained, which was directly used in the next step without further purification.

[0316] MS-ESI: m / z 361.5[M+H] + .

[0317] Preparation of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindole-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-(6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalene-1-yl)benzamide (Compound 3)

[0318]

[0319] The synthesis of compound 3 was consistent with that of compound 1 in Example 1, except that 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindole-1,3-dione trifluoroacetate was used instead of (S)-3-(1-oxo-5-(piperazin-1-yl)isoindol-2-yl)piperidine-2,6-dione benzenesulfonate, and the yield was 67%.

[0320] MS-ESI: m / z 1033.6[M+H] + .

[0321] 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=1 6.1Hz,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=35.4,22.6Hz,6H),1.49-1.24(m,5H),1.18(d,J=10.6Hz,2H).

[0322] Example 4 Preparation of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline)-5-yl)-1,4-diazepan-1-yl)methyl)piperidin-1-yl)-2-(6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)benzamide (Compound 4)

[0323]

[0324] Preparation of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,4-diazepane-1-carboxylate

[0325]

[0326] The synthesis of compound 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,4-diazepane-1-carboxylic acid tert-butyl ester was consistent with 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)piperazine-1-carboxylic acid tert-butyl ester in Example 2, with a yield of 81%.

[0327] MS-ESI: m / z 401.5[M+H-56] + .

[0328] 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),2.6 2-2.51(m,2H),2.03-1.92(m,1H),1.79(d,J=30.8Hz,2H),1.28(s,4H),1.12(s,5H).

[0329] Preparation of 5-(1,4-diazepan-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione hydrochloride

[0330]

[0331] Slowly add HCl / 1,4-dioxane (10 mL) to a dichloromethane solution (5 mL) of the compound 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,4-diazepane-1-carboxylic acid tert-butyl ester (1.66 g, 3.64 mmol) and react at room temperature. After 12 h, 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 used directly in the next step without further purification.

[0332] MS-ESI: m / z 343.4[M+H] + .

[0333] Preparation of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin)-5-yl)-1,4-diazepan-1-yl)methyl)piperidin-1-yl)-2-(6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)benzamide (Compound 4)

[0334]

[0335] The synthesis of compound 4 was consistent with that of compound 1 in Example 1, except that 5-(1,4-diazepan-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione hydrochloride was used instead of (S)-3-(1-oxo-5-(piperazin-1-yl)isoindol-2-yl)piperidine-2,6-dione benzenesulfonate, and the yield was 89%.

[0336] MS-ESI: m / z 1029.6[M+H] + .

[0337] 1H-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).

[0338] Example 5 Preparation of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(4-((8-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole-5-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl]methyl)piperidin-1-yl)-2-(6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalene-1-yl)benzamide (Compound 5)

[0339]

[0340] Preparation of tert-butyl 8-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole-5-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

[0341]

[0342] The synthesis of tert-butyl 8-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoiindol-5-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate was consistent with tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoiindol-5-yl)-1,4-diazacycloheptane-1-carboxylate in Example 4, except that tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate was used instead of tert-butyl 1,4-diazacycloheptane-1-carboxylate. The yield was 39%.

[0343] MS-ESI:413.54[M+H-56] + .

[0344] 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).

[0345] Preparation of 5-(3,8-diazabicyclo[3.2.1]octan-8-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione hydrochloride

[0346]

[0347] The synthesis of 5-(3,8-diazabicyclo[3.2.1]octan-8-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione hydrochloride was the same as the synthesis of 5-(1,4-diazacycloheptan-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione hydrochloride in Example 4, except that 8-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester was used instead of 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-1,4-diazacycloheptane-1-carboxylic acid tert-butyl ester.

[0348] MS-ESI:369.4[M+H] + .

[0349] Preparation of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(4-((8-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole-5-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl]methyl)piperidin-1-yl)-2-(6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalene-1-yl)benzamide (Compound 5)

[0350]

[0351] The synthesis of compound 5 was consistent with compound 4, except that 5-(3,8-diazabicyclo[3.2.1]octan-8-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione hydrochloride was used instead of 5-(1,4-diazepan-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione hydrochloride. The yield was 48%.

[0352] MS-ESI:1041.8[M+H] + .

[0353] 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,1 H),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).

[0354] Example 6 Preparation of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(4-(7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoxim-5-yl)-2,7-diazaspiro[3.5]non-2-yl)methyl)piperidin-1-yl)-3-(3-hydroxy-7-phenyl-5,6,7,8-tetrahydronaphthalen-1-ylbenzamide (Compound 6)

[0355]

[0356] Preparation of tert-butyl 7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole-5-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

[0357]

[0358] The synthesis of tert-butyl 7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)-2,7-diazapyridine[3.5]nonane-2-carboxylate was consistent with the synthesis of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)-1,4-diazacycloheptane-1-carboxylate in Example 4, except that tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate was used instead of tert-butyl 1,4-diazaheptane-1-carboxylate. The yield was 85.7%.

[0359] MS-ESI:427.4[M+H-56] + .

[0360] 1 H-NMR (400MHz, DMSO-d6) δ11.07(s,1H),7.64(d,J=8.6Hz,1H),7.30(d,J=1.8Hz,1H),7.2 4(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,1 H), 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).

[0361] Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-(2,7-diazaspiro[3.5]nonan-7-yl)isoindole-1,3-dione hydrochloride

[0362]

[0363] The synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-(2,7-diazaspiro[3.5]nonan-7-yl)isoindole-1,3-dione hydrochloride was consistent with that of 5-(1,4-diazacycloheptan-1-yl)-2-(2,6-dioxopiperidin-3-yl)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione hydrochloride in Example 4, except that tert-butyl 7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate was used instead of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-1,4-diazacycloheptane-1-carboxylate.

[0364] MS-ESI:383.1[M+H] + .

[0365] Preparation of N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(4-(7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoxindolin-5-yl)-2,7-diazaspiro[3.5]nonan-2-yl)methyl)piperidin-1-yl)-3-(3-hydroxy-7-phenyl-5,6,7,8-tetrahydronaphthalen-1-ylbenzamide (Compound 6)

[0366]

[0367] The synthesis of compound 6 was consistent with that of compound 4 in Example 4, except that 2-(2,6-dioxopiperidin-3-yl)-5-(2,7-diazaspiro[3.5]nonan-7-yl)isoindole-1,3-dione hydrochloride was used instead of 5-(1,4-diazepan-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione hydrochloride. The yield was 88.8%.

[0368] MS-ESI:1055.7[M+H] + .

[0369] 1H-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).

[0370] Example 7 In vitro study of the AR and ER degradation activity of the compounds (WB experiment)

[0371] AR degradation activity study: LnCap cells were plated in 12-well plates. The cell density reached 80%-90% the next day. Different compounds were added at final concentrations of 0.03, 0.1, 0.3, 1.0, 3.0, 10.0, 30.0, 100.0, 300.0 and 1000.0 nM. After 24 hours of drug addition, the cell culture medium was removed and the cells were washed with cold PBS. 60 μL of protein lysis solution was added to each well. The cells were scraped off with Tip and the cell lysis solution was mixed. Then, the cell lysis solution was centrifuged at 12000 rpm for 15 minutes at 4°C, the supernatant was taken and 15 μL of 5X protein loading buffer was added, mixed and placed in a 100°C water bath for 10 minutes; after taking out and cooling on ice, centrifuged for 1 minute, and the supernatant was used for protein immunoblotting detection. After protein immunoblotting detection, the expression of androgen receptor was statistically analyzed using Image J software, and the DC degradation of androgen receptor by each compound was calculated based on the expression of the receptor. 50 .

[0372] ER degradation activity study: The method of ER degradation activity study was similar to the AR degradation activity study described above, except that MCF-7 cells were used instead of LnCap cells.

[0373] Compound DC 50 According to the activity strength, it is divided into three levels, among which +++ (DC 50≦10nM);++(10 <DC 50 ≦100nM); +(DC 50 >100 nM). The following table shows the results of in vitro studies on the AR and ER degradation activities of the compounds.

[0374] Table 1 In vitro study results of the AR and ER degradation activities of the compounds

[0375] Compound AR ER ARV-110 +++ / ARV-471 / +++ Compound 1 +++ +++ Compound 2 +++ +++ Compound 3 +++ +++ Compound 4 +++ +++ Compound 5 +++ +++ Compound 6 +++ +++

[0376] The above results show that the patented compound is a new type of compound that has good degradation activity for both AR and ER; in view of the significant drug resistance problem that is inevitable in existing anti-breast cancer drugs, this type of compound has created a completely new technical path. This invention is expected to bring great benefits to the above-mentioned tumor patients.

[0377] It should be understood that the above embodiments are exemplary and are not intended to include all possible implementations included in the claims. Various modifications and changes may be made on the basis of the above embodiments without departing from the scope of the present disclosure. Similarly, the various technical features of the above embodiments may be arbitrarily combined to form other embodiments of the present invention that may not be explicitly described. Therefore, the above embodiments only express several implementations of the present invention and do not limit the scope of protection of the patent of the present invention.

Claims

1. A compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof: in: R 1 is hydrogen, fluorine, chlorine, bromine, cyano, -NH2 or nitro; R 2 is hydrogen, fluorine, chlorine, bromine, cyano, -NH2 or nitro; R 3 is hydrogen or halogen; R 4 is hydrogen, halogen, cyano or nitro; R 5 is hydrogen, hydroxyl or halogen; R 6 is hydrogen, hydroxyl or halogen; R 7 is hydrogen, hydroxyl or halogen; is an unsubstituted 4-8 membered heterocycloalkyl group containing 1-2 nitrogen atoms; is a 3-10 membered heterocycloalkyl, heterospirocyclic group or heterobridged cyclic group containing 1-4 nitrogen atoms; is cyclohexyl; X is CH2 or C=O; Y is CH or N; n is 1.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: R 1 is hydrogen or fluorine.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: R 2 For hydrogen.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: R 3 is hydrogen or chlorine.

5. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein: R 3 For chlorine.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: R 4 It is cyano.

7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: R 5 is hydrogen or fluorine.

8. The compound according to claim 7 or a pharmaceutically acceptable salt thereof, wherein: R 5 For hydrogen.

9. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: R 6 It is hydroxyl.

10. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: R 7 For hydrogen.

11. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: It is a 4-8 membered heterocycloalkyl, heterospirocyclic group or heterobridged ring group containing 1-2 nitrogen atoms.

12. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: Y is CH.

13. A compound or a pharmaceutically acceptable salt thereof, characterized in that: The compound is selected from:

14. A pharmaceutical composition comprising the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

15. A pharmaceutical composition according to claim 14, which is in the form of an aqueous dispersion, liquid, gel, elixir, aerosol, controlled release agent, fast dissolving agent, effervescent agent, lyophilized agent, tablet, powder, pill, capsule, multi-particulate or immediate release agent.

16. Use of the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to any one of claims 14 to 15 in the preparation of a medicament for treating estrogen and / or androgen receptor-related diseases.

17. The use according to claim 16, wherein the estrogen and / or androgen receptor-related disease is breast cancer or prostate cancer.

18. The use according to claim 17, wherein the disease related to lactogenic estrogen and / or androgen receptor is triple-negative breast cancer.

19. The use according to claim 18, wherein the estrogen and / or androgen receptor-related disease is advanced breast cancer.

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