CN115611909A

CN115611909A - Tetrahydronaphthalene compound, preparation method and medical application thereof

Info

Publication number: CN115611909A
Application number: CN202210820985.7A
Authority: CN
Inventors: 杨方龙; 赵守莉; 郁楠; 贺峰; 陶维康
Original assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Current assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Priority date: 2021-07-12
Filing date: 2022-07-12
Publication date: 2023-01-17

Abstract

The disclosure relates to tetrahydronaphthalene compounds, a preparation method and application thereof in medicines. In particular to a tetrahydronaphthalene compound shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound and application of the compound as a therapeutic agent, in particular application of the compound as an estrogen receptor degradation agent and application of the compound in preparing a medicament for treating and/or preventing estrogen receptor-mediated or dependent diseases or symptoms.

Description

Tetrahydronaphthalene compound, preparation method and medical application thereof

Technical Field

The disclosure belongs to the field of medicines, and relates to a tetralin compound, a preparation method thereof and application thereof in medicines. In particular to a tetrahydronaphthalene compound shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound and application of the compound as a therapeutic agent, in particular application of the compound as an estrogen receptor degradation agent and application of the compound in preparing a medicament for treating and/or preventing estrogen receptor mediated or dependent diseases or symptoms.

Background

According to the latest cancer burden report of world health organization international agency for research on cancer (IARC) in 2020 worldwide, the number of female breast cancer attacks exceeds that of lung cancer for the first time, and the female breast cancer attacks become the most common cancer worldwide. More than 226 ten thousand women worldwide suffer from breast cancer, accounting for about 11.7 percent of all newly diagnosed cancers, 24.5 percent of the newly diagnosed cancers and the first part of the cancer attack number of the women. Of the newly diagnosed patients, 1 out of every 8 is a breast cancer patient. Meanwhile, over 68 thousands of people die from breast cancer, accounting for about 6.9% of all cancer deaths, 15.5% of women's cancer deaths worldwide, and the cancer with the greatest number of women's deaths worldwide.

About 70% of breast cancer patients are Estrogen Receptor (ER) positive breast cancers. Endocrine therapy plays an important role in the treatment of these breast cancer patients. Endocrine therapy is mainly divided into three categories, which are: aromatase Inhibitor (AI), which can inhibit the conversion of androgen into estrogen, reduces the level of estrogen in the body. Selective Estrogen Receptor Modulators (SERMs), can antagonize estrogen receptor activity. Selective Estrogen Receptor Degraders (SERDs), which not only antagonize the activity of estrogen receptors, but also promote the degradation of receptors (j.biol.chem.2006, 14, 9607-9615).

The only drug on the market that exerts its effect by degrading the estrogen receptor mechanism is Fulvestrant (Fulvestrant), which has been used in clinical doses increased from 250mg to 500mg to achieve better clinical efficacy. In a study using isotopically labeled estrogen to observe the level of estrogen receptor degradation in tumors in patients, it was found that high or low levels of estrogen receptor degradation correlate with clinical benefit in the patients. While incomplete degradation of estrogen receptors may be associated with early disease progression. However, fulvestrant has poor water solubility and low bioavailability, and the administration mode of intramuscular injection is difficult to further improve the administration dosage. Therefore, it is necessary to develop a drug having better degradation effect than fulvestrant estrogen receptor.

The proteolytic targeting chimera (PROTAC) is a hybrid bifunctional small molecule compound. The structure of the ligand contains two different ligands: one is an E3 ubiquitin ligase ligand, the other is a binding ligand with a target protein, and the two ligands are connected by a connecting arm. The PROTAC forms a target protein-PROTAC-E3 ternary complex by drawing a target protein and E3 ubiquitin ligase in cells close, then the E3 ubiquitin ligase labels ubiquitinated protein labels on the target protein, a strong ubiquitination hydrolysis process in the cells is started, and the target protein is specifically degraded by utilizing a ubiquitin-proteasome pathway. Compared with the traditional small-molecule inhibitor, the PROTAC has the unique advantages that 1, the PROTAC does not need to be combined with target proteins of interest for a long time and with high strength, and the target protein degradation process is similar to a catalytic reaction and can be used for circularly combining and degrading the target proteins. Thereby reducing the systemic exposure of the medicine and reducing the occurrence of toxic and side effects. 2. The target protein is degraded and needs to be synthesized again to restore the function, so that the degraded target protein shows more efficient and durable anti-tumor effect than the inhibition of the activity of the target protein, and the drug resistance caused by the mutation of the target protein can not occur. 3. ProTACs also have therapeutic potential for targets that are currently considered to be non-druggable, such as transcription factors, scaffold proteins, and regulatory proteins.

The discovery of E3 ligase ligands of the Cerebellin (CRBN) type has been associated with studies on the mechanism of action of thalidomide. In 2010, it was found that binding of thalidomide to CRBN in vivo was likely responsible for thalidomide teratogenicity when studied for thalidomide toxicity (Science 2010,327,1345). Subsequent researches find that thalidomide and derivatives thereof can be used as anti-inflammatory drugs, anti-angiogenesis drugs and anti-cancer drugs. Wherein, the safety of the lenalidomide and the pomalidomide is greatly improved, and the teratogenic effect is obviously reduced. Further studies have shown that lenalidomide acts by degrading two specific B-cell transcription factors, ikros family zinc finger structural proteins 1 and 3 (IKZF 1 and IKZF 3). This study reveals the mechanism of action of thalidomide and its derivatives: the target protein is further degraded by binding to the CRBN type E3 ubiquitin ligase protein complex (Science, 2014,343,301, 2014,343, 305.

On the basis, CRBN ligand is widely applied to the preparation of protein degradation agent, and a series of PROTAC molecules based on CRBN ligand are developed. The present disclosure synthesizes a novel class of tetrahydronaphthalene derivatives, and the molecules show the application of the tetrahydronaphthalene derivatives as estrogen receptor degraders in treating estrogen receptor mediated or dependent diseases.

Patent applications for published CRBN ligand-based PROTACS molecules include WO2015160845A2, WO2016197032A1, WO2016105518A1, WO2017197046A1, WO2017197051A1, WO2018144649A1, US10800770B1, WO2018102725A1 and WO2019199816A1.

Disclosure of Invention

The object of the present disclosure is to provide a compound represented by the general formula (I):

wherein:

R ^7a and R ^7b Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy and hydroxyalkyl, and R ^7a And R ^7b At least one of which is halogen;

R ¹ selected from the group consisting of hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups and-C (O) R ⁶ ；

Each R is ² The same or different and each is independently selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, and hydroxyalkyl;

x is oxygen or CH ₂ ；

R ^3a And R ^3b The same or different, and each is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally selected from the group consisting of halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR, and mixtures thereof ⁹ R ¹⁰ One or more of nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroarylSubstituted by one substituent;

or R ^3a And R ^3b Together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, wherein each of said cycloalkyl or heterocyclyl groups is independently optionally substituted by a group selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR ⁹ R ¹⁰ Nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ^4a and R ^4b Are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group and a hydroxyalkyl group;

G ¹ and G ² Are the same or different and are each independently a nitrogen atom or CR ⁷ ；

Z is a nitrogen atom or CR ⁸ ；

R ^5a And R ^5b Are the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group and a hydroxyalkyl group, or R ^5a And R ^5b Together form an oxo group;

R ⁷ and R ⁸ Are the same or different and are each independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, -NR ^9a R ^10a Hydroxy, -C (O) R ⁶ 、-C(O)OR ⁶ 、-C(O)NR ^9a R ^10a 、-S(O) _t R ^9a 、-S(O) _t NR ^9a R ^10a Cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from the group consisting of halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR ⁹ R ¹⁰ Nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ⁶ selected from the group consisting of alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ⁹ and R ¹⁰ Together with the nitrogen atom to which they are attached form a heterocyclic group, or R ^9a And R ^10a The same or different, and each is independently selected from the group consisting of a hydrogen atom, an alkyl group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclic group, wherein the alkyl group, the cycloalkyl group, and the heterocyclic group are each independently optionally substituted with one or more substituents selected from the group consisting of a halogen, an alkyl group, an alkoxy group, a haloalkyl group, and a haloalkoxy group;

or R ⁹ And R ¹⁰ 、R ^9a And R ^10a Together with the nitrogen atom to which they are attached, form a heterocyclic group optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

j is 0, 1,2,3,4, 5,6,7,8, 9 or 10;

t is 0, 1 or 2; and is

m is 0, 1,2 or 3.

In some preferred embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein m is 0.

In some preferred embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein X is CH ₂ 。

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (II):

wherein:

G ¹ 、G ² 、Z、R ¹ 、R ^3a 、R ^3b 、R ^4a 、R ^4b 、R ^5a 、R ^5b 、R ^7a 、R ^7b and j is as defined in formula (I).

In some preferred embodiments of the present disclosure, the compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, wherein R is ^3a And R ^3b Are the same or different and are each independently selected from the group consisting of a hydrogen atom, C _1-6 Alkyl, 3-to 8-membered cycloalkyl, 3-to 8-membered heterocyclyl, 6-to 10-membered aryl and 5-to 10-membered heteroaryl, wherein said C is _1-6 Alkyl, 3-to 8-membered cycloalkyl, 3-to 8-membered heterocyclyl, 6-to 10-membered aryl and 5-to 10-membered heteroaryl are each independently optionally selected from halogen, oxo, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, cyano, -NR ⁹ R ¹⁰ Nitro, hydroxy, C _1-6 Hydroxyalkyl, 3-to 8-membered cycloalkyl, 3-to 8-membered heterocyclyl, 6-to 10-membered aryl and 5-to 10-membered heteroaryl; r is ⁹ And R ¹⁰ Are the same or different and are each independently a hydrogen atom or C _1-6 An alkyl group; or R ⁹ And R ¹⁰ Together with the nitrogen atom to which they are attached form a 3-to 6-membered heterocyclic group, said 3-to 6-membered heterocyclic group formed optionally being selected from halogen, oxo, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, hydroxy and C _1-6 Substituted with one or more substituents in the hydroxyalkyl group. Preferably, R ^3a Selected from the group consisting of 3-to 6-membered cycloalkyl, 3-to 6-membered heterocyclyl, 6-to 10-membered aryl and 5-to 10-membered heteroaryl, wherein said 3-to 6-membered cycloalkyl, 3-to 6-membered heterocyclyl, 6-to 10-membered aryl and 5-to 10-membered heteroaryl are each independently optionally selected from the group consisting of halogen, oxo, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl and C _1-6 Substituted by one or more substituents of haloalkoxy, and R ^3b Is a hydrogen atom.

In some preferred embodiments of the present disclosure, the compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, wherein R is ^4a And R ^4b Are all hydrogen atoms.

In some preferred embodiments of the present disclosure, the compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereofSalt of formula (I), wherein R ^5a And R ^5b Are all hydrogen atoms.

In some preferred embodiments of the present disclosure, the compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, wherein G ¹ And G ² Are both CH.

In some preferred embodiments of the present disclosure, the compound represented by formula (I) or formula (II) or a pharmaceutically acceptable salt thereof is a compound represented by formula (III) or a pharmaceutically acceptable salt thereof:

wherein:

R ^3a selected from the group consisting of 3-to 6-membered cycloalkyl, 3-to 6-membered heterocyclyl, 6-to 10-membered aryl and 5-to 10-membered heteroaryl, wherein said 3-to 6-membered cycloalkyl, 3-to 6-membered heterocyclyl, 6-to 10-membered aryl and 5-to 10-membered heteroaryl are each independently optionally selected from the group consisting of halogen, oxo, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl and C _1-6 Substituted with one or more substituents of haloalkoxy;

Z、R ¹ 、R ^7a 、R ^7b and j is as defined in formula (I) or formula (II).

In some preferred embodiments of the present disclosure, the compound represented by formula (I), formula (II) or formula (III), or a pharmaceutically acceptable salt thereof, is a compound represented by formula (IV):

wherein:

Z、R ¹ 、R ^7a 、R ^7b and j is as defined in formula (I), formula (II) or formula (III).

In some preferred embodiments of the present disclosure, the compound of formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt thereof, wherein Z is CH.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III) or formula (IV) or a pharmaceutically acceptable salt thereof, wherein R is ¹ Is a hydrogen atom.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III) or formula (IV) or a pharmaceutically acceptable salt thereof, wherein R is ^3a Is a 5 to 6 membered heterocyclyl or phenyl, wherein said 5 to 6 membered heterocyclyl or phenyl is each independently optionally selected from halogen, oxo, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl and C _1-6 Substituted with one or more substituents of haloalkoxy; preferably, R ^3a Is tetrahydropyranyl or phenyl.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III) or formula (IV) or a pharmaceutically acceptable salt thereof, wherein R is ^3a Is selected from

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III) or formula (IV) or a pharmaceutically acceptable salt thereof, wherein R is ^7a And R ^7b Are identical or different and are each independently a hydrogen atom or a halogen, and R ^7a And R ^7b At least one of which is halogen; preferably, R ^7a Is fluorineAtom and R ^7b Is a hydrogen atom, or R ^7a Is a hydrogen atom and R ^7b Is a fluorine atom.

In some preferred embodiments of the present disclosure, the compound represented by formula (I), formula (II), formula (III) or formula (IV) or a pharmaceutically acceptable salt thereof, wherein j is 0.

In some preferred embodiments of the present disclosure, the compound of formula (III) or formula (IV) or a pharmaceutically acceptable salt thereof, wherein Z is CH and R is ¹ Is a hydrogen atom, R ^3a Is a 5 to 6 membered heterocyclyl or phenyl group, wherein said 5 to 6 membered heterocyclyl or phenyl group are each independently optionally selected from halogen, oxo, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl and C _1-6 Substituted by one or more substituents of haloalkoxy, R ^7a And R ^7b Are identical or different and are each independently a hydrogen atom or a halogen, and R ^7a And R ^7b At least one is halogen and j is 0.

Table a typical compounds of the present disclosure include, but are not limited to:

another aspect of the present disclosure relates to a compound represented by the general formula (Ia) or a salt thereof,

wherein:

R ^3a and R ^3b The same or different, and each independentlyIs selected from hydrogen atom, C _1-6 Alkyl, 3-to 6-membered cycloalkyl and 3-to 6-membered heterocyclyl, wherein said C is _1-6 Alkyl, 3-to 6-membered cycloalkyl and 3-to 6-membered heterocyclyl are each independently optionally selected from halogen, oxo, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, cyano, -NR ⁹ R ¹⁰ Nitro, hydroxy, C _1-6 Hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

G ¹ 、G ² 、R ¹ 、R ² 、R ^4a 、R ^4b 、R ^7a 、R ^7b 、R ⁹ 、R ¹⁰ m and j are as defined for the compound of formula (I).

Another aspect of the present disclosure relates to a compound of formula (IIa) or a salt thereof,

wherein:

R ^3a and R ^3b Are the same or different and are each independently selected from the group consisting of a hydrogen atom, C _1-6 Alkyl, 3-to 6-membered cycloalkyl and 3-to 6-membered heterocyclyl, wherein said C is _1-6 Alkyl, 3-to 6-membered cycloalkyl and 3-to 6-membered heterocyclyl are each independently optionally selected from halogen, oxo, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, cyano, -NR ⁹ R ¹⁰ Nitro, hydroxy, C _1-6 Hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

G ¹ 、G ² 、R ¹ 、R ^4a 、R ^4b 、R ^7a 、R ^7b 、R ⁹ 、R ¹⁰ and j is as defined for the compound of formula (II).

Another aspect of the present disclosure relates to a compound of formula (IIIa) or a salt thereof,

wherein:

R ^3a selected from 3-to 6-membered cycloalkyl and 3-to 6-membered heterocyclyl, wherein said 3-to 6-membered cycloalkyl and 3-to 6-membered heterocyclyl are each independently optionally selected from halogen, oxo, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl and C _1-6 Substituted with one or more substituents of haloalkoxy;

R ¹ 、R ^7a 、R ^7b and j is as defined for the compound of formula (III).

Another aspect of the present disclosure relates to a compound of formula (IVa) or a salt thereof,

wherein:

R ¹ 、R ^7a 、R ^7b and j is as defined for the compound of formula (IV).

Table B typical intermediate compounds of the present disclosure include, but are not limited to:

another aspect of the present disclosure relates to a method of preparing a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, comprising:

carrying out reductive amination reaction on the compound shown in the general formula (Ia) and the compound shown in the general formula (VI) or salts thereof to obtain the compound shown in the general formula (I) or pharmaceutically acceptable salts thereof;

wherein:

G ¹ 、G ² 、Z、R ¹ 、R ² 、R ^4a 、R ^4b 、R ^5a 、R ^5b 、R ^7a 、R ^7b 、R ⁹ 、R ¹⁰ m and j are as defined in formula (I).

Another aspect of the present disclosure relates to a method of preparing a compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, comprising:

subjecting a compound shown in a general formula (IIa) and a compound shown in a general formula (VI) or a salt thereof to a reductive amination reaction to obtain a compound shown in a general formula (II) or a pharmaceutically acceptable salt thereof;

wherein:

R ^3a and R ^3b Are the same or different and are each independently selected from the group consisting of a hydrogen atom, C _1-6 Alkyl, 3-to 6-membered cycloalkyl and 3-to 6-membered heterocyclyl, wherein said C _1-6 Alkyl, 3-to 6-membered cycloalkyl and 3-to 6-membered heterocyclyl are each independently optionally selected from halogen, oxo,C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, cyano, -NR ⁹ R ¹⁰ Nitro, hydroxy, C _1-6 Hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

G ¹ 、G ² 、Z、R ¹ 、R ^4a 、R ^4b 、R ^5a 、R ^5b 、R ^7a 、R ^7b 、R ⁹ 、R ¹⁰ and j is as defined in formula (II).

Another aspect of the present disclosure relates to a method of preparing a compound represented by the general formula (III), or a pharmaceutically acceptable salt thereof, comprising:

carrying out reductive amination reaction on the compound shown in the general formula (IIIa) and the compound shown in the general formula (VII) or salt thereof to obtain the compound shown in the general formula (III) or pharmaceutically acceptable salt thereof;

wherein:

Z、R ¹ 、R ^7a 、R ^7b and j is as defined in formula (III).

Another aspect of the present disclosure relates to a method of preparing a compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof, comprising:

carrying out reductive amination reaction on the compound shown in the general formula (IVa) and the compound shown in the general formula (VII') or salts thereof to obtain a compound shown in the general formula (IV) or pharmaceutically acceptable salts thereof;

wherein:

Z、R ¹ 、R ^7a 、R ^7b and j is as defined in formula (IV).

Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of the present disclosure represented by formula (I), formula (II), formula (III), formula (IV), and table a, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

The disclosure further relates to the use of compounds of formula (I), formula (II), formula (III), formula (IV) and table a, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for the manufacture of a medicament for the treatment and/or prevention of a disease or condition by degradation of a target protein.

The disclosure further relates to the use of a compound of formula (I), formula (II), formula (III), formula (IV) and table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for the treatment and/or prevention of an estrogen receptor mediated or dependent disease or condition.

The present disclosure also relates to a method of treating and/or preventing a disease or disorder by degrading a target protein, comprising administering to a patient in need thereof a therapeutically effective amount of a compound represented by formula (I), formula (II), formula (III), formula (IV), and table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The present disclosure also relates to a method of treating and/or preventing estrogen receptor mediated or dependent diseases or conditions comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), formula (II), formula (III), formula (IV), and table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The disclosure further relates to compounds of formula (I), formula (II), formula (III), formula (IV) and table a or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use as a medicament.

The present disclosure further relates to compounds of formula (I), formula (II), formula (III), formula (IV) and table a, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use in treating and/or preventing a disease or disorder by degrading a target protein.

The disclosure further relates to compounds of formula (I), formula (II), formula (III), formula (IV) and table a, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use in treating or preventing an estrogen receptor mediated or dependent disease or condition.

The disease or condition treated and/or prevented by degrading the target protein as described above in the present disclosure is preferably selected from the group consisting of abnormal cell proliferation, tumors, immune diseases, diabetes, cardiovascular diseases, infectious diseases and inflammatory diseases; more preferably tumors and infectious diseases. Wherein the tumor is a cancer; preferably selected from the group consisting of breast cancer, endometrial cancer, testicular cancer, cervical cancer, prostate cancer, ovarian cancer, fallopian tube tumors, leukemia, skin cancer, squamous cell carcinoma, basal cell carcinoma, bladder cancer, colorectal cancer (such as colon cancer and rectal cancer), esophageal cancer (also known as esophageal cancer), head and neck cancer, kidney cancer, liver cancer, lung cancer, pancreatic cancer, gastric cancer, lymphoma, melanoma, sarcoma, peripheral neuroepithelial tumors, gliomas, astrocytomas, ependymomas, glioblastoma, neuroblastoma, ganglioneuroblastomas, pineal cell tumors, meningiomas, neurofibromas, schwannoma, thyroid cancer, wilms' tumor, and teratocarcinoma; more preferably selected from breast cancer, endometrial cancer, testicular cancer, cervical cancer, prostate cancer, ovarian cancer, and fallopian tube tumors. Wherein said infectious disease is selected from the group consisting of viral pneumonia, influenza, avian influenza, meningitis, gonorrhea or infection with HIV, HBV, HCV, HSV, HPV, RSV, CMV, ebola virus, flavivirus, alphavirus, rotavirus, coronavirus, EBV, resistant virus, RNA virus, DNA virus, adenovirus, poxvirus, picornavirus, togavirus, orthomyxovirus, retrovirus, hepadnavirus, gram negative bacteria, gram positive bacteria, atypical bacteria, staphylococci, streptococci, escherichia coli, salmonella, helicobacter pylori, chlamydiaceae, mycoplasmataceae, fungi, protozoa, helminth, prion and parasites.

The active compound may be formulated so as to be suitable for administration by any suitable route, preferably in unit dose form, or in such a way that the patient may self-administer the active compound in a single dose. The unit dose of a compound or composition of the present disclosure may be expressed in the form of a tablet, capsule, cachet, bottled liquid, powder, granule, lozenge, suppository, reconstituted powder, or liquid.

As a general guide, a suitable unit dose may be 0.1 to 1000mg.

The pharmaceutical compositions of the present disclosure may contain, in addition to the active compound, one or more excipients selected from the following: fillers (diluents), binders, wetting agents, disintegrants, excipients, and the like. Depending on the method of administration, the compositions may contain from 0.1 to 99% by weight of active compound.

The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from the group consisting of: sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide a pleasant to the eye and palatable pharmaceutical preparation. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be inert excipients, granulating agents, disintegrating agents, binding agents and lubricating agents. These tablets may be uncoated or they may be coated by known techniques which mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.

Oral formulations may also be provided in soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or wherein the active ingredient is mixed with a water soluble carrier or oil vehicle.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending, dispersing or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.

Oil suspensions may be formulated by suspending the active ingredient in a vegetable or mineral oil. The oil suspension may contain a thickener. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of antioxidants.

The pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, a mineral oil or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsions may also contain sweetening, flavoring, preservative and antioxidant agents. Such formulations may also contain a demulcent, a preservative, a colorant and an antioxidant.

The pharmaceutical compositions of the present disclosure may be in the form of a sterile injectable aqueous solution. Among the acceptable vehicles or solvents that may be employed are water, ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oil phase, the injection or microemulsion being injectable into the bloodstream of a patient by local mass injection. Alternatively, it may be desirable to administer the solution and microemulsion in a manner that maintains a constant circulating concentration of the disclosed compounds. To maintain such a constant concentration, a continuous intravenous delivery device may be used. An example of such a device is an intravenous pump of the model Deltec CADD-PLUS. TM. 5400.

The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous or oleaginous suspensions for intramuscular and subcutaneous administration. The suspension may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a parenterally-acceptable, non-toxic diluent or solvent. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. Any blend fixed oil may be used for this purpose. In addition, fatty acids can also be used to prepare injections.

The compounds of the present disclosure may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and therefore will melt in the rectum to release the drug.

As is well known to those skilled in the art, the dosage of a drug administered depends on a variety of factors, including, but not limited to: the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, the severity of the disease, and the like; in addition, the optimal treatment regimen, such as mode of treatment, daily amount of compound or type of pharmaceutically acceptable salt, can be verified according to conventional treatment protocols.

Description of the terms

Unless stated to the contrary, terms used in the specification and claims have the following meanings.

The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl (i.e., C) group containing 1 to 12 (e.g., 1,2,3,4, 5,6,7,8, 9, 10, 11, and 12) carbon atoms _1-12 Alkyl), more preferably an alkyl group containing 1 to 6 carbon atoms (i.e., C) _1-6 Alkyl groups). Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylpentyl, 3234-methylbutyl, 2,3-dimethylbutyl, and the likeEthylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 3638 zxft, n-decyl, 3724 zhexyl, 4924-diethylhexyl, 4924-and the like, and branched isomers thereof. Alkyl groups may be substituted or unsubstituted and when substituted may be substituted at any available point of attachment, the substituents preferably being selected from one or more of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkenyl" refers to an alkyl compound containing at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above. Alkenyl radicals (i.e. C) containing from 2 to 12, for example 2,3,4, 5,6,7,8, 9, 10, 11 and 12, carbon atoms are preferred _2-12 Alkenyl), more preferably alkenyl having 2 to 6 carbon atoms (i.e., C) _2-6 Alkenyl). The alkenyl group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more substituents independently selected from the group consisting of alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms (i.e., 3 to 20 membered cycloalkyl), preferably 3 to 12 (e.g., 3,4, 5,6,7,8, 9, 10, 11, and 12) carbon atoms (i.e., 3 to 12 membered cycloalkyl), preferably 3 to 8 carbon atoms (i.e., 3 to 8 membered cycloalkyl), and more preferably 3 to 6 carbon atoms (i.e., 3 to 6 membered cycloalkyl). Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spirocycloalkyl, fused ring alkyl, and bridged cycloalkyl groups.

The term "spirocycloalkyl" refers to a 5 to 20 membered polycyclic group sharing one carbon atom (referred to as a spiro atom) between single rings, which may contain one or more double bonds (i.e., a 5 to 20 membered spirocycloalkyl). Preferably 6 to 14 membered (i.e. 6 to 14 membered spirocycloalkyl), more preferably 7 to 10 membered (e.g. 7,8, 9 or 10 membered) (i.e. 7 to 10 membered spirocycloalkyl). Spirocycloalkyl groups are classified into a single spirocycloalkyl group, a double spirocycloalkyl group or a multi spirocycloalkyl group, preferably a single spirocycloalkyl group and a double spirocycloalkyl group, according to the number of spiro atoms shared between rings. More preferably 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, 5-membered/6-membered or 6-membered/6-membered spirocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:

the term "fused cyclic alkyl" refers to a 5 to 20 membered all carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more double bonds (i.e., a 5 to 20 membered fused cyclic alkyl). Preferably 6 to 14 (i.e. 6 to 14 fused cycloalkyl) members, more preferably 7 to 10 (e.g. 7,8, 9 or 10) (i.e. 7 to 10 fused cycloalkyl) members. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl groups according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered and 6-membered/6-membered bicycloalkyl groups. Non-limiting examples of fused ring alkyl groups include:

the term "bridged cycloalkyl" refers to a 5 to 20 membered all carbon polycyclic group in which any two rings share two carbon atoms not directly attached, which may contain one or more double bonds (i.e., a 5 to 20 membered bridged cycloalkyl). Preferably 6 to 14 membered (i.e. 6 to 14 membered bridged cycloalkyl), more preferably 7 to 10 membered (e.g. 7,8, 9 or 10 membered) (i.e. 7 to 10 membered bridged cycloalkyl). They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

the cycloalkyl ring includes a cycloalkyl ring (including monocyclic cycloalkyl, spirocycloalkyl, fused ring alkyl, and bridged cycloalkyl) fused to an aryl, heteroaryl, or heterocycloalkyl ring as described above, wherein the rings attached together with the parent structure are cycloalkyl, non-limiting examples of which include

Etc.; preference is given to

Cycloalkyl groups may be substituted or unsubstituted, and when substituted, may be substituted at any available point of attachment, with the substituents preferably being selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkoxy" refers to-O- (alkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy and butoxy. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "heterocyclyl" refers to a saturated or partially unsaturated mono-or polycyclic cyclic substituent comprising from 3 to 20 ring atoms, one or more of which is a heteroatom selected from nitrogen, oxygen and sulfur, which may optionally be oxo (i.e., form a sulfoxide or sulfone), but does not include the ring portion of-O-, -O-S-or-S-, the remaining ring atoms being carbon (i.e., a 3-to 20-membered heterocyclyl). Preferably 3 to 12 (e.g., 3,4, 5,6,7,8, 9, 10, 11 and 12) ring atoms, of which 1 to 4 (e.g., 1,2,3 and 4) are heteroatoms (i.e., 3 to 12 membered heterocyclyl); more preferably 3 to 8 ring atoms (e.g., 3,4, 5,6,7 and 8), wherein 1-3 is a heteroatom (e.g., 1,2 and 3) (i.e., 3 to 8 membered heterocyclyl); more preferably 3 to 6 ring atoms, of which 1-3 are heteroatoms (i.e. 3 to 6 membered heterocyclyl); most preferably 5 or 6 ring atoms, of which 1-3 are heteroatoms (i.e. a 5-to 6-membered heterocyclyl group). Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups.

The term "spiroheterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group sharing one atom (referred to as a spiro atom) between single rings, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, which may optionally be oxo (i.e., to form a sulfoxide or sulfone), with the remaining ring atoms being carbon. Which may contain one or more double bonds (i.e., 5 to 20 membered spiroheterocyclyl). Preferably 6 to 14 membered (i.e. 6 to 14 membered spiroheterocyclyl), more preferably 7 to 10 membered (e.g. 7,8, 9 or 10 membered) (i.e. 7 to 10 membered spiroheterocyclyl). The spiro heterocyclic group is classified into a mono-spiro heterocyclic group, a di-spiro heterocyclic group or a multi-spiro heterocyclic group, preferably a mono-spiro heterocyclic group and a di-spiro heterocyclic group, according to the number of spiro atoms shared between rings. More preferred is a 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, 5-membered/6-membered or 6-membered/6-membered mono spiroheterocyclyl group. Non-limiting examples of spiro heterocyclic groups include:

the term "fused heterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with the other rings in the system, one or more of the rings may contain one or more double bonds, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, which may optionally be oxo (i.e., to form a sulfoxide or sulfone), and the remaining ring atoms are carbon (i.e., a 5 to 20 membered fused heterocyclyl). Preferably 6 to 14 membered (i.e. 6 to 14 membered fused heterocyclyl), more preferably 7 to 10 membered (e.g. 7,8, 9 or 10 membered) (i.e. 7 to 10 membered fused heterocyclyl). They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups according to the number of constituting rings, preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered and 6-membered/6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

the term "bridged heterocyclyl" refers to a 5 to 14 membered polycyclic heterocyclic group in which any two rings share two atoms not directly attached, which may contain one or more double bonds, wherein one or more ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, which may optionally be oxo (i.e., form a sulfoxide or sulfone), and the remaining ring atoms are carbon (i.e., a 5 to 14 membered bridged heterocyclyl). Preferably 6 to 14 (i.e. 6 to 14 bridged heterocyclyl) and more preferably 7 to 10 (e.g. 7,8, 9 or 10) (i.e. 7 to 10 bridged heterocyclyl). They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

the heterocyclyl ring includes heterocyclyl groups (including monocyclic heterocyclyl, spiro heterocyclyl, fused heterocyclyl and bridged heterocyclyl groups) as described above fused to an aryl, heteroaryl or cycloalkyl ring wherein the ring to which the parent structure is attached is heterocyclyl, non-limiting examples of which include:

and the like.

The heterocyclyl group may be substituted or unsubstituted and when substituted may be substituted at any available point of attachment, the substituents preferably being selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "aryl" refers to a 6 to 14 membered, all carbon monocyclic or fused polycyclic (fused polycyclic is a ring that shares adjacent pairs of carbon atoms) group having a conjugated pi-electron system (i.e., a 6 to 14 membered aryl), preferably 6 to 10 membered (e.g., 6,7,8, 9 or 10 membered) (i.e., a 6 to 10 membered aryl), such as phenyl and naphthyl. Such aryl rings include those wherein the aryl ring as described above is fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:

aryl groups may be substituted or unsubstituted, and when substituted, may be substituted at any available point of attachment, with the substituents preferably being selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms (e.g., 1,2,3, and 4), 5 to 14 ring atoms, wherein the heteroatoms are selected from the group consisting of oxygen, sulfur, and nitrogen (i.e., a 5-to 14-membered heteroaryl). Heteroaryl is preferably 5 to 10 membered (e.g., 5,6,7,8, 9 or 10 membered) (i.e., 5 to 10 membered heteroaryl), more preferably 5 or 6 membered (i.e., 5 or 6 membered heteroaryl), such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, and the like. The heteroaryl ring includes a heteroaryl fused to an aryl, heterocyclyl or cycloalkyl ring as described above, wherein the ring joined together with the parent structure is a heteroaryl ring, non-limiting examples of which include:

heteroaryl groups may be substituted or unsubstituted, and when substituted, may be substituted at any available point of attachment, with the substituents preferably being selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The above-mentioned cycloalkyl, heterocyclyl, aryl and heteroaryl groups include those derived by removal of one hydrogen atom from the parent ring atom, or those derived by removal of two hydrogen atoms from the parent ring atom or two different ring atoms, i.e., "divalent cycloalkyl", "divalent heterocyclyl", "arylene" and "heteroarylene".

The term "cycloalkyloxy" refers to cycloalkyl-O-wherein cycloalkyl is as defined above.

The term "heterocyclyloxy" refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.

The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein the alkyl group is as defined above.

The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.

The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxyl groups, wherein alkyl is as defined above.

The term "halogen" refers to fluorine, chlorine, bromine or iodine.

The term "hydroxy" refers to-OH.

The term "amino" refers to-NH ₂ 。

The term "cyano" refers to — CN.

The term "nitro" means-NO ₂ 。

The term "oxo" or "oxo" means "= O".

The term "carbonyl" refers to C = O.

The term "ubiquitin ligase" refers to a family of proteins that facilitate the transfer of ubiquitin to a specific substrate protein, targeting the substrate protein for degradation. For example, cereblon is an E3 ubiquitin ligase protein that alone or in combination with E2 ubiquitin-binding enzymes results in the attachment of ubiquitin to a lysine on the target protein and subsequent targeting of specific protein substrates for degradation by the proteasome. Thus, E3 ubiquitin ligase alone or complexed with E2 ubiquitin conjugating enzyme is responsible for ubiquitin transfer to the target protein. In general, ubiquitin ligases are involved in polyubiquitination, such that a second ubiquitin is joined to a first ubiquitin, a third ubiquitin is joined to a second ubiquitin, and so on. Polyubiquitinated marker proteins are used for degradation by the proteasome. However, there are some ubiquitination events that are limited to monoubiquitination, where only a single ubiquitin is added to the substrate molecule by ubiquitin ligase. Monoubiquinated proteins are not targeted to the proteasome for degradation, but may instead be altered in their cellular location or function, for example, via binding to other proteins with domains capable of binding ubiquitin. To complicate matters further, different lysines on ubiquitin can be targeted by E3 to prepare chains. The most common lysine is Lys48 on the ubiquitin chain. This is lysine, which is used to make polyubiquitin, which is recognized by the proteasome.

The term "target protein" refers to proteins and peptides having any biological function or activity, including structural, regulatory, hormonal, enzymatic, genetic, immunological, contractile, storage, trafficking, and signal transduction. In some embodiments, the target protein includes a structural protein, a receptor, an enzyme, a cell surface protein, a protein associated with an integrated function of a cell, including proteins involved in: catalytic activity, aromatase activity, locomotor activity, helicase activity, metabolic processes (anabolism and catabolism), antioxidant activity, proteolysis, biosynthesis, proteins with kinase activity, oxidoreductase activity, transferase activity, hydrolase activity, lyase activity, isomerase activity, ligase activity, enzyme regulator activity, signal transduction factor activity, structural molecule activity, binding activity (proteins, lipid carbohydrates), receptor activity, cell motility, membrane fusion, cell communication, biological process regulation, development, cell differentiation, stimulatory response, behavioral proteins, cell adhesion proteins, white matter involved in cell death, proteins involved in transport (including protein transport activity, nuclear transport, ion transport activity, channel transport activity, carrier activity), permease activity, secretion activity, electron transport activity, pathogenicity, chaperone regulatory factor activity, nucleic acid binding activity, transcription regulatory factor activity, extracellular conformation and biogenesis activity, translation regulatory factor activity. The proteins include proteins from eukaryotes and prokaryotes, including microorganisms, viruses, fungi, and parasites, as well as numerous others, including humans, microorganisms, viruses, fungi, and parasites as targets for drug therapy, other animals including domestic animals, microorganisms and other antimicrobial agents and plants for determining targets for antibiotics, and even viruses, among many others.

The compounds of the present disclosure may comprise atropisomers. The term "atropisomer" is a conformational stereoisomer that results from the hindered or greatly slowed rotation about a single bond in a molecule (due to steric interaction with other parts of the molecule and the asymmetric result of substituents at both ends of the single bond), which interconverts sufficiently slowly to allow separation and isolation under predetermined conditions. For example, certain compounds of the present disclosure may exist as a mixture of atropisomers (e.g., an equal ratio mixture, a mixture enriched in one atropisomer, etc.) or as a purified one atropisomer.

The compounds of the disclosure may exist in specific stereoisomeric forms. The term "stereoisomers" refers to isomers that are structurally identical but differ in the arrangement of the atoms in space. It includes cis and trans (or Z and E) isomers, (-) -and (+) -isomers, (R) -and (S) -enantiomers, diastereomers, (D) -and (L) -isomers, tautomers, atropisomers, conformers, and mixtures thereof (e.g., racemates, mixtures of diastereomers). Additional asymmetric atoms may be present in substituents in the compounds of the present disclosure. All such stereoisomers, as well as mixtures thereof, are included within the scope of the present disclosure. Optically active (-) -and (+) -isomers, (R) -and (S) -enantiomers, and (D) -and (L) -isomers can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. One isomer of a compound of the present disclosure may be prepared by asymmetric synthesis or chiral auxiliary, or, when a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl) is contained in the molecule, a diastereoisomeric salt is formed with an appropriate optically active acid or base, and then diastereoisomeric resolution is performed by a conventional method known in the art to obtain pure isomers. Furthermore, separation of enantiomers and diastereomers is typically accomplished by chromatography.

In the chemical structure of the compounds described in the present disclosure, a bond

Denotes an unspecified configuration, i.e. a bond if a chiral isomer is present in the chemical structure

Can be that

Or

Or at the same time contain

And

two configurations. In the chemical structure of the compounds described in the present disclosure, a bond

Indicates that no configuration is specified, i.e., either the Z configuration or the E configuration, or both configurations are included.

The chemical structure of the compounds of the present disclosure is such that two groups on two adjacent carbon atoms are bonded

Attached to two carbon atoms, respectively, indicates that the two groups are in cis configuration (cis). For example, (5,6) -cis-5- (4- (4- (dimethoxymethyl) piperidin-1-yl) -3-fluorophenyl) -6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol 1v,

it is of the (5,6) -cis configuration, i.e.

Two groups attached are on the same side, meaning that two groups may be on the paper or two groups may be under the paper at the same time.

The compounds of the present disclosure may exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to a structural isomer that exists in equilibrium and is readily converted from one isomeric form to another. It includes all possible tautomers, i.e. in the form of a single isomer or in the form of a mixture of said tautomers in any ratio. Non-limiting examples include: such as keto-enol tautomerism, imine-enamine tautomerism, lactam-lactim tautomerism, and the like. An example of a lactam-lactam equilibrium is between a and B as shown below:

when referring to pyrazolyl, it is understood to include any one of the following two structures or a mixture of two tautomers:

all tautomeric forms are within the scope of the disclosure, and the naming of the compounds does not exclude any tautomers.

The compounds of the present disclosure include all suitable isotopic derivatives of the compounds thereof. The term "isotopic derivative" refers to a compound wherein at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes that can be incorporated into compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, and the like, for example, respectively ² H (deuterium, D), ³ H (tritium, T), ¹¹ C、 ¹³ C、 ¹⁴ C、 ¹⁵ N、 ¹⁷ O、 ¹⁸ O、 ³² p、 ³³ p、 ³³ S、 ³⁴ S、 ³⁵ S、 ³⁶ S、 ¹⁸ F、 ³⁶ Cl、 ⁸² Br、 ¹²³ I、 ¹²⁴ I、 ¹²⁵ I、 ¹²⁹ I and ¹³¹ i, etc., preferably deuterium.

Compared with the non-deuterated drugs, the deuterated drugs have the advantages of reducing toxic and side effects, increasing the stability of the drugs, enhancing the curative effect, prolonging the biological half-life of the drugs and the like. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are intended to be encompassed within the scope of the present disclosure. Each available hydrogen atom attached to a carbon atom may be independently replaced by a deuterium atom, where replacement by deuterium may be partial or complete, partial replacement by deuterium meaning replacement of at least one hydrogen by at least one deuterium.

When a position is specifically designated as deuterium (D), that position is understood to be deuterium having an abundance that is at least 1000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 15% of deuterium incorporation). The compound of examples may have a natural abundance of deuterium greater than deuterium of at least 1000 times an abundance of deuterium (i.e., at least 15% deuterium incorporation), at least 2000 times an abundance of deuterium (i.e., at least 30% deuterium incorporation), at least 3000 times an abundance of deuterium (i.e., at least 45% deuterium incorporation), at least 3340 times an abundance of deuterium (i.e., at least 50.1% deuterium incorporation), at least 3500 times an abundance of deuterium (i.e., at least 52.5% deuterium incorporation), at least 4000 times an abundance of deuterium (i.e., at least 60% deuterium incorporation), at least 4500 times an abundance of deuterium (i.e., at least 67.5% deuterium incorporation), at least 5000 times an abundance of deuterium (i.e., at least 75% deuterium incorporation), at least 5500 times an abundance of deuterium (i.e., at least 82.5% deuterium incorporation), at least 6000 times an abundance of deuterium (i.e., at least 90% deuterium incorporation), at least 6333.3 times an abundance of deuterium (i.e., at least 95% deuterium incorporation), at least 6466.7 times an abundance of deuterium (i.97% of deuterium), at least 99% abundance of deuterium (i.99.99.99.99% deuterium incorporation of deuterium, or at least 6633.3.99% of deuterium incorporation of deuterium.

"optionally" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example "C optionally substituted by halogen or cyano _1-6 Alkyl "means that halogen or cyano may, but need not, be present, and the description includes the case where alkyl is substituted with halogen or cyano and the case where alkyl is not substituted with halogen and cyano.

"substituted" means that one or more, preferably 1 to 6, more preferably 1 to 3, hydrogen atoms in a group are independently substituted with a corresponding number of substituents. Those skilled in the art are able to ascertain (by experiment or theory) without undue effort, substitutions that are possible or impossible. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.

"pharmaceutical composition" means a mixture containing one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof in admixture with other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.

"pharmaceutically acceptable salt" refers to a salt of a compound of the disclosure, which may be selected from inorganic or organic salts. The salt has safety and effectiveness when being used in the body of a mammal, and has due biological activity. Salts may be prepared separately during the final isolation and purification of the compound, or by reacting the appropriate group with an appropriate base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases such as sodium hydroxide and potassium hydroxide, and organic bases such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids as well as organic acids.

The term "therapeutically effective amount" with respect to a drug or pharmacologically active agent refers to an amount of the drug or agent sufficient to achieve, or at least partially achieve, the desired effect. The determination of a therapeutically effective amount varies from person to person, depending on the age and general condition of the recipient and also on the particular active substance, and an appropriate therapeutically effective amount in an individual case can be determined by a person skilled in the art according to routine tests.

The term "pharmaceutically acceptable" as used herein means that the compounds, materials, compositions, and/or dosage forms are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio, and effective for the intended use.

As used herein, the singular forms "a", "an" and "the" include plural references and vice versa unless the context clearly dictates otherwise.

When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it is meant that the parameter may vary by ± 10%, and sometimes more preferably within ± 5%. As will be appreciated by those skilled in the art, when the parameters are not critical, the numbers are generally given for illustrative purposes only and are not limiting.

Synthesis of the Compounds of the disclosure

In order to achieve the purpose of the present disclosure, the following technical solutions are adopted in the present disclosure:

scheme one

carrying out reductive amination on a compound shown in a general formula (Ia) and a compound shown in a general formula (VI) or a salt thereof under an acidic condition (preferably acetic acid) in the presence of a reducing agent to obtain a compound shown in a general formula (I) or a pharmaceutically acceptable salt thereof; or the compound shown in the general formula (Ia) and the salt (preferably benzene sulfonate) of the compound shown in the general formula (VI) are subjected to reductive amination reaction under alkaline conditions (preferably sodium acetate) in the presence of a reducing agent to obtain the compound shown in the general formula (I) or pharmaceutically acceptable salt thereof;

wherein:

Scheme two

subjecting a compound represented by the general formula (IIa) and a compound represented by the general formula (VI) or a salt thereof to a reductive amination reaction under acidic conditions (preferably acetic acid) in the presence of a reducing agent to obtain a compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof; or the compound shown in the general formula (IIa) and the salt (preferably benzene sulfonate) of the compound shown in the general formula (VI) are subjected to reductive amination reaction under alkaline conditions (preferably sodium acetate) in the presence of a reducing agent to obtain the compound shown in the general formula (II) or pharmaceutically acceptable salt thereof;

wherein:

Scheme three

carrying out reductive amination on a compound shown in a general formula (IIIa) and a compound shown in a general formula (VII) or a salt thereof under an acidic condition (preferably acetic acid) in the presence of a reducing agent to obtain a compound shown in a general formula (III) or a pharmaceutically acceptable salt thereof; or the salt (preferably benzene sulfonate) of the compound shown in the general formula (IIIa) and the compound shown in the general formula (VII) is subjected to reductive amination reaction under alkaline conditions (preferably sodium acetate) and in the presence of a reducing agent to obtain the compound shown in the general formula (III) or pharmaceutically acceptable salt thereof;

wherein:

Z、R ¹ 、R ^7a 、R ^7b and j is as defined in formula (III).

Scheme four

carrying out reductive amination on a compound shown in a general formula (IVa) and a compound shown in a general formula (VII') or a salt thereof under an acidic condition (preferably acetic acid) in the presence of a reducing agent to obtain a compound shown in a general formula (IV) or a pharmaceutically acceptable salt thereof; or the salt (preferably benzene sulfonate) of the compound shown in the general formula (IVa) and the compound shown in the general formula (VII') is subjected to reductive amination reaction under alkaline conditions (preferably sodium acetate) and in the presence of a reducing agent to obtain the compound shown in the general formula (IV) or pharmaceutically acceptable salt thereof;

wherein:

R ^3a selected from 3 to 6 membered cycloalkyl and 3 to 6 membered cycloalkyl6-membered heterocyclyl, wherein said 3-to 6-membered cycloalkyl and 3-to 6-membered heterocyclyl are each independently optionally selected from halogen, oxo, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl and C _1-6 Substituted with one or more substituents of haloalkoxy;

Z、R ¹ 、R ^7a 、R ^7b and j is as defined in formula (IV).

In the above synthetic schemes, the acidic conditions may be provided by organic acids or inorganic acids, including but not limited to formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid and p-toluenesulfonic acid, preferably acetic acid; the inorganic acids include, but are not limited to, hydrogen chloride, 1,4-dioxane solution of hydrogen chloride, hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid.

In the above synthesis scheme, the reagent providing basic conditions comprises organic bases and inorganic bases, wherein the organic bases include but are not limited to triethylamine, N-diisopropylethylamine, N-butyllithium, lithium diisopropylamide, potassium acetate, sodium ethoxide, sodium tert-butoxide or potassium tert-butoxide, and the inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide monohydrate, lithium hydroxide and potassium hydroxide, preferably sodium acetate.

In the above synthesis scheme, the reducing agent includes, but is not limited to, sodium triacetoxyborohydride, sodium borohydride, lithium borohydride, sodium cyanoborohydride, sodium acetylborohydride, and the like, and sodium triacetoxyborohydride is preferred.

The above synthetic schemes are preferably carried out in solvents including, but not limited to: ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, N-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, N-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N-dimethylformamide, N-dimethylacetamide, and mixtures thereof.

Detailed Description

The present disclosure is further described below with reference to examples, but these examples do not limit the scope of the present disclosure.

Examples

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shift (. Delta.) of 10 ^-6 The units in (ppm) are given. NMR was measured using a Bruker AVANCE-400 nuclear magnetic instrument or Bruker AVANCE NEO 500M in deuterated dimethyl sulfoxide (DMSO-d) ₆ ) Deuterated chloroform (CDCl) ₃ ) Deuterated methanol (CD) ₃ OD), internal standard Tetramethylsilane (TMS).

MS was measured using an Agilent 1200/1290DAD-6110/6120Quadrupole MS LC MS (manufacturer: agilent, MS model: 6110/6120Quadrupole MS).

waters ACQuity UPLC-QD/SQD (manufacturer: waters, MS model: waters ACQuity Qda Detector/waters SQ Detector)

THERMO Ultimate 3000-Q active (manufacturer: THERMO, MS model: THERMO Q active)

High Performance Liquid Chromatography (HPLC) analysis was performed using Agilent HPLC1200 DAD, agilent HPLC1200VWD and Waters HPLC e2695-2489 HPLC.

Chiral HPLC assay using Agilent 1260DAD HPLC.

High Performance liquid preparation preparative chromatographs were prepared using Waters 2545-2767, waters 2767-SQ Detector 2, shimadzu LC-20AP and Gilson GX-281.

Chiral preparation a Shimadzu LC-20AP preparative chromatograph was used.

The CombiFlash rapid preparation instrument uses CombiFlash Rf200 (TELEDYNE ISCO).

The thin layer chromatography silica gel plate adopts HSGF254 of tobacco yellow sea or GF254 of Qingdao, the specification of the silica gel plate used by Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.

Silica gel column chromatography generally uses 200-300 mesh silica gel of the Litsea crassirhizomes as a carrier.

Average inhibition rate of kinase and IC ₅₀ The values were determined with a NovoStar microplate reader (BMG, germany).

Known starting materials of the present disclosure may be synthesized using or according to methods known in the art, or may be purchased from companies such as ABCR GmbH & co.kg, acros Organics, aldrich Chemical Company, nephelo Chemical science and technology (Accela ChemBio Inc), dare chemicals, and the like.

In the examples, the reaction can be carried out in an argon atmosphere or a nitrogen atmosphere, unless otherwise specified.

An argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to a balloon of argon or nitrogen with a volume of about 1L.

The hydrogen atmosphere refers to a reaction flask connected with a hydrogen balloon with a volume of about 1L.

The pressure hydrogenation reaction uses a hydrogenation apparatus of Parr 3916EKX type and a hydrogen generator of Qinglan QL-500 type or a hydrogenation apparatus of HC2-SS type.

The hydrogenation reaction was usually evacuated and charged with hydrogen and repeated 3 times.

The microwave reaction was carried out using a CEM Discover-S908860 microwave reactor.

In the examples, the solution means an aqueous solution unless otherwise specified.

In the examples, the reaction temperature is, unless otherwise specified, from 20 ℃ to 30 ℃ at room temperature.

The monitoring of the progress of the reaction in the examples employed Thin Layer Chromatography (TLC), a developing solvent used for the reaction, a system of eluents for column chromatography used for purifying compounds and a developing solvent system for thin layer chromatography including: a: dichloromethane/methanol system, B: the volume ratio of the n-hexane/ethyl acetate system is adjusted according to the different polarities of the compounds, and a small amount of basic or acidic reagents such as triethylamine, acetic acid and the like can be added for adjustment.

Example 1

(S) -3- (4- (4- ((1- (2-fluoro-4- ((1R, 2S) -6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl) phenyl) piperidin-4-yl) methyl) piperazin-1-yl) -8-oxo-6,8-dihydro-7H- [1,3] dioxolano [4,5-e ] isoindolin-7-yl) piperidine-2,6-dione 1-yl)

First step of

(S) -4- ((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -5-amino-5-oxopentanoic acid tert-butyl ester 1b

(S) -2- ((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -5- (tert-butoxy) -5-oxopentanoic acid 1a (40g, 94mmol, va Han Co., ltd., shanghai) and di-tert-butyl dicarbonate (32.83g, 150mmol) were added to 1,4-dioxane (300 mL), and pyridine (15mL, 188mmol) was added dropwise under a nitrogen atmosphere in an ice-water bath with the internal temperature kept below 5 ℃. After the dropwise addition, the mixture was cooled in an ice-water bath and reacted for 0.5 hour. Ammonium hydrogencarbonate (66.89g, 282mmol) was added thereto, and the mixture was warmed to room temperature to react for 12 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent, ethyl acetate (500 mL) was added, and the mixture was washed with dilute hydrochloric acid (500 mL. Times.3) and filtered. The filtrate was concentrated under reduced pressure to remove the solvent, to give the crude title compound 1b (45.26 g), which was used in the next reaction without purification.

MS m/z(ESI):369.1[M-55]

Second step of

(S) -4,5-diamino-5-oxopentanoic acid tert-butyl ester 1c

Compound 1b (45.26g, 94mmol) and diethylamine (50 mL) were added to dichloromethane (500 mL) and reacted at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent, and the residue was dissolved in methanol (150 mL), and washed with water (5 mL) and n-heptane (150 mL. Times.3). The methanol layer was concentrated under reduced pressure to remove the solvent, and the title compound, 1c, was obtained as a crude product (21.5 g) which was used in the next reaction without purification.

MS m/z(ESI):203.1[M+1]

The third step

3-fluoro-4,5-dihydroxybenzaldehyde 1e

3-fluoro-4-hydroxy-5-methoxybenzaldehyde 1d (5 g,29.4mmol, tokyi biomedical Co., ltd.) was dissolved in methylene chloride (70 mL). The mixture was cooled to 0 ℃ in an ice bath, and a boron tribromide-dichloromethane solution (1M, 73.5mL, 73.5mmol) was added dropwise. After the completion of the dropwise addition, the reaction was carried out at room temperature for 2 hours. The reaction was quenched by addition of methanol (40 mL), the reaction was concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 1e (4 g), yield: 87 percent.

MS m/z(ESI):156.9[M+1]。

The fourth step

2-bromo-5-fluoro-3,4-dihydroxybenzaldehyde 1f

Compound 1e (4.5g, 28.8mmol) was dissolved in acetic acid (50 mL). The reaction mixture was cooled to 0 ℃ in an ice bath, and a solution of liquid bromine (4.84g, 30.2mmol) in acetic acid (50 mL) was added dropwise thereto, followed by warming to room temperature slowly and reacting for 3 hours. N-hexane (50 mL) was added, the reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 1f (3.2 g), yield: and 47 percent.

MS m/z(ESI):234.9[M+1]。

The fifth step

4-bromo-7-fluorobenzo [ d ] [1,3] dioxole-5-carbaldehyde 1g

Compound 1f (3.2g, 13.62mmol) was dissolved in N, N-dimethylformamide (70 mL), dibromomethane (3.3g, 19.1mmol) and cesium carbonate (13.31g, 40.85mmol) were added, and the mixture was reacted at 70 ℃ for 3.5 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure to remove most of the N, N-dimethylformamide, ethyl acetate (50 mL), dichloromethane (50 mL) was added, the mixture was filtered through celite, and the filter cake was washed with ethyl acetate (50 mL), dichloromethane (50 mL). The combined organic phases were washed successively with water (50 mL), saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography with eluent system B to give the title compound 1g (2.3 g), yield: 68 percent.

MS m/z(ESI):246.8[M+1]。

The sixth step

4-bromo-5- (1,3-dioxolan-2-yl) -7-fluoropheno [ d ] [1,3] dioxole 1h

1g (1.1g, 4.45mmol) of the compound and ethylene glycol (829mg, 13.4 mmol) were added to toluene (40 mL), p-toluenesulfonic acid monohydrate (84.7 mg, 0.45mmol) was added, and the reaction was carried out at 80 ℃ for 1 hour and at 110 ℃ for 2 hours under reflux with a Dean-Stark trap. The reaction was cooled to room temperature and quenched by addition of triethylamine (1 mL). The reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 1h (1.23 g), yield: 95 percent.

MS m/z(ESI):290.8[M+1]。

Seventh step

5- (1,3-dioxolan-2-yl) -7-fluorobenzo [ d ] [1,3] dioxole-4-carboxylic acid ethyl ester 1i

Compound 1h (1.74g, 6 mmol) was dissolved in dry tetrahydrofuran (50 mL), cooled to-78 ℃ in a dry ice acetone bath, n-butyllithium (2.5M, 2.6mL, 6.5mmol) was slowly added dropwise, reacted at 78 ℃ for 1h, ethyl cyanoformate (829mg, 8.4 mmol) was added, and the reaction was continued at-78 ℃ for 1 h. The reaction was quenched by addition of saturated sodium bicarbonate solution (30 mL), extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (30 mL × 3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 1i (1.38 g), yield: 81 percent.

MS m/z(ESI):284.9[M+1]。

Eighth step

7-fluoro-5-formylbenzo [ d ] [1,3] dioxole-4-carboxylic acid ethyl ester 1j

Compound 1i (1.0g, 3.5 mmol) was dissolved in tetrahydrofuran (25 mL), and diluted sulfuric acid (2M, 18mL, 36mmol) was added thereto to conduct a reaction for 1 hour. Saturated sodium bicarbonate solution (60 mL) was added, extraction was performed with ethyl acetate (30 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (30 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 1j (810 mg), yield: 96 percent.

MS m/z(ESI):240.9[M+1]。

The ninth step

7-fluoro-5-formylbenzo [ d ] [1,3] dioxole 4-carboxylic acid 1k

Compound 1j (840 mg, 3.50mmol) was dissolved in tetrahydrofuran (16 mL), water (4 mL) and lithium hydroxide monohydrate (441mg, 10.50mmol) were added, and the reaction was stirred for 1 hour. Water (30 mL) was added, the reaction solution was adjusted to pH =6 with dilute hydrochloric acid (1M), extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent to give the title compound, 1k, crude product (740 mg), which was used in the next reaction without purification.

MS m/z(ESI):213.0[M+1]。

The tenth step

7- (4- (tert-Butoxycarbonyl) piperazin-1-yl) -5-formylbenzo [ d ] [1,3] dioxole 4-carboxylic acid 1l

Compound 1k (740mg, 3.5 mmol) and tert-butyl piperazine-1-carboxylate (1.95g, 10.47mmol) were dissolved in N-methylpyrrolidone (25 mL), and N, N-diisopropylethylamine (2.25g, 17.4 mmol) was added thereto, and the reaction was carried out at 95 ℃ for 24 hours. Most of N-methylpyrrolidone was removed by concentration under reduced pressure, water (30 mL) was added, and extraction was performed with ethyl acetate (50 mL. Times.3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL × 3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 1l (0.5 g), yield: 38 percent.

MS m/z(ESI):322.9[M-55]。

The eleventh step

(S) -5- (((1-amino-5- (tert-butoxy) -1,5-dioxopent-2-yl) amino) methyl) -7- (4- (tert-butoxycarbonyl) piperazin-1-yl) benzo [ d ] [1,3] dioxole-4-carboxylic acid 1m

1l (650mg, 1.7mmol) of the compound was dissolved in a mixed solution of methylene chloride and methanol (V/V =3/1, 40mL), and sodium acetate (516mg, 8.6mmol) was added and reacted for 10 minutes. Compound 1c (347mg, 1.7mmol) was added and reacted for 15 minutes. Sodium cyanoborohydride (103mg, 1.7 mmol) was added and reacted for 1 hour. The reaction mixture was concentrated under reduced pressure to remove the solvent, whereby the title compound (1 m) was obtained as a crude product (970 mg), which was used in the next reaction without purification.

MS m/z(ESI):565.1[M+1]。

The twelfth step

(S) -tert-butyl 4- (7- (1-amino-5- (tert-butoxy) -1,5-dioxopent-2-yl) -8-oxo-7,8-dihydro-6H- [1,3] dioxolano [4,5-e ] isoindolin-4-yl) piperazine-1-carboxylate 1n

Compound 1m (970mg, 1.72mmol) was dissolved in N, N-dimethylformamide (15 mL), and N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) urea hexafluorophosphate (HATU, 685mg,1.8 mmol) and N, N-diisopropylethylamine (665mg, 5.2mmol) were added and reacted at room temperature for 2 hours. Ethyl acetate (50 mL) was added and the mixture was washed with saturated sodium chloride solution (30 mL. Times.2). The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent, to give the title compound, 1n crude product (900 mg), which was used in the next reaction without purification.

MS m/z(ESI):547.1[M+1]

Thirteenth step

(S) -3- (8-oxo-4- (piperazin-1-yl) -6,8-dihydro-7H- [1,3] dioxolano [4,5-e ] isoindolin-7-yl) piperidine-2,6-dione benzenesulfonate 1o

Compound 1n (900mg, 1.6 mmol) was dissolved in acetonitrile (10 mL), benzenesulfonic acid (521mg, 3.3 mmol) was added, and the mixture was heated to 75 ℃ for reaction for 16 hours. The reaction solution was concentrated under reduced pressure, a mixed solution of n-hexane and dichloromethane (V/V = 10/1) was added, stirred, filtered, and the cake was collected and dried to obtain the title compound 1o (550 mg), yield: 62 percent.

MS m/z(ESI):373.1[M+1]。

Fourteenth step

4- (Dimethoxymethyl) piperidine-1-carboxylic acid benzyl ester 1q

Benzyl 4-formylpiperidine-1-carboxylate 1p (10g, 40.4mmol, from Shanghai Biao pharmaceutical science Co., ltd.) was dissolved in methanol (80 mL), and trimethyl orthoformate (40 mL) and p-toluenesulfonic acid monohydrate (385mg, 2mmol) were added to stir the reaction for 16 hours. The reaction mixture was concentrated under reduced pressure, and a saturated sodium bicarbonate solution (80 mL) was added to the mixture, followed by extraction with ethyl acetate (80 mL. Times.3). The combined organic phases were washed with saturated sodium chloride solution (80 mL. Times.3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound, 1q crude (12 g), which was used in the next reaction without purification.

The fifteenth step

4- (Dimethoxymethyl) piperidine 1r

Compound 1q (12g, 40.9mmol) was dissolved in methanol (100 mL), and palladium on carbon (1.3g, 10wt%) was added thereto, and the reaction was stirred under a hydrogen atmosphere for 3 hours. The reaction was filtered, and the filtrate was concentrated under reduced pressure to remove the solvent, to give the title compound 1r crude product (6 g), which was used in the next reaction without purification.

¹ H NMR(500MHz,DMSO-d ₆ )δ4.05(s,1H),3.4(s,6H),3.23-3.17(m,2H),2.68-2.60(m,2H),1.78-1.72(m,3H),1.29-1.23(m,2H)。

Sixteenth step

4- (6- (benzyloxy) -2-phenyl-3,4-dihydronaphthalen-1-yl) -2-fluorophenyl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate 1t

Compound 1s (3g, 7.1mmol, prepared by the method disclosed in patent US20180155322 A1) and perfluorobutylsulfonyl fluoride (4.29g, 14.2mmol, shanghai adalimus reagent, ltd) were added to a mixed solvent of tetrahydrofuran and acetonitrile (V/V =1/1,60ml). Potassium carbonate (2g, 14.2mmol) was added thereto, and the reaction was carried out at room temperature for 16 hours. The reaction solution was filtered through celite, the filtrate was concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 1t crude product (5 g).

Seventeenth step

1- (4- (6- (benzyloxy) -2-phenyl-3,4-dihydronaphthalen-1-yl) -2-fluorophenyl) -4- (dimethoxymethyl) piperidine 1u

Compound 1t (2g, 2.8mmol), compound 1r (678mg, 4.3mmol), 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl (X-Phos, 271mg, 0.57mmol), palladium acetate (128mg, 0.57mmol) and sodium tert-butoxide (819mg, 8.5 mmol) were added to toluene (40 mL) and reacted at 90 ℃ for 3 hours under an argon atmosphere. The reaction solution was cooled to room temperature, water (50 mL) was added, extraction was performed with ethyl acetate (50 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography with eluent system a to give the title compound 1u (970 mg), yield: 61 percent.

MS m/z(ESI):564.1[M+1]。

Eighteenth step (5,6) -cis-5- (4- (4- (dimethoxymethyl) piperidin-1-yl) -3-fluorophenyl) -6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol 1v

Compound 1u (970mg, 1.7mmol) was added to a mixed solvent of methanol and tetrahydrofuran (V/V =1/2, 36ml), and palladium on carbon (200mg, 10wt%) was added to react at room temperature for 16 hours under a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to remove the solvent, to give the title compound 1v crude product (700 mg), which was used in the next reaction without purification.

MS m/z(ESI):476.3[M+1]。

Nineteenth step

(5R, 6S) -5- (4- (4- (dimethoxymethyl) piperidin-1-yl) -3-fluorophenyl) -6-phenyl-5,6,7,8-tetrahydronaphthalene-2-ol 1w

The compound 1v (700mg, 1.5mmol) was chromatographed by chiral preparative chromatography (separation conditions: column: CHIRALPAK IE,20 mm. Times.250mm, 5um; mobile phase: A: n-hexane, B: ethanol (+ 20mmol NH) ₃ ) And A:70%, B: 30%), flow rate: 20 mL/min) to give the title compound 1w (230 mg).

MS m/z(ESI):476.3[M+1]。

Twentieth step

1- (2-fluoro-4- ((1R, 2S) -6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl) phenyl) piperidine-4-carbaldehyde 1x

Compound 1w (90mg, 0.18mmol) was added to tetrahydrofuran (2 mL), and diluted sulfuric acid (2M, 1.5mL) was added dropwise and the mixture was heated to 70 ℃ to react for 2 hours. The reaction solution was cooled to room temperature, and saturated sodium bicarbonate solution was added to adjust the pH of the reaction solution to neutrality, followed by extraction with ethyl acetate (10 mL. Times.3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to remove the solvent to give the title compound 1x (78 mg), which was used in the next reaction without purification.

MS m/z(ESI):430.2[M+1]。

The twentieth step

Compound 1o (41mg, 0.075mmol) was dissolved in a mixed solution of dichloromethane and methanol (V/V =3/1,3ml), and sodium acetate (31mg, 0.38mmol) was added to react for 10 minutes. Compound 1X (32mg, 0.074mmol) was added and reacted for 15 minutes. Sodium triacetoxyborohydride (32mg, 0.15mmol) was added thereto, and the reaction was carried out for 1 hour. Dichloromethane (10 mL) was added, washed with saturated sodium chloride solution (5 mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The resulting residue was prepared using a high performance liquid phase (Waters 2767-SQ Detector 2, elution: ammonium bicarbonate: 10mM, water: 60%, acetonitrile: 40%) to give the title compound 1 (25 mg), yield: and 43 percent.

MS m/z(ESI):786.4[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )δ10.95(s,1H),9.17(s,1H),7.20-7.14(m,3H),6.86(d,2H),6.68-6.62(m,4H),6.52-6.49(m,1H),6.11-6.09(m,3H),5.97(d,1H),5.05-5.03(m,1H),4.32,4.22(dd,2H),4.19-4.16(m,1H),3.34-3.18(m,8H),2.99-2.88(m,3H),2.60-2.51(m,4H),2.35-2.33(m,1H),2.20(d,2H),2.08-1.94(m,3H),1.77-1.74(m,3H),1.63-1.61(m,1H),1.25-1.20(m,3H)。

Example 2

(S) -3- (4- (4- ((1- (4- ((1R, 2S) -2- (4-fluorophenyl) -6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl) phenyl) piperidin-4-yl) methyl) piperazin-1-yl) -8-oxo-6,8-dihydro-7H- [1,3] dioxolano [4,5-e ] isoindolin-7-yl) piperidine-2,6-dione 2

First step of

4- (6- (benzyloxy) -2- (4-fluorophenyl) -3,4-dihydronaphthalen-1-yl) phenyl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate 2b

Compound 2a (1 g,2.37mmol, prepared by the method disclosed in patent US20180155322 A1) and perfluorobutanesulfonyl fluoride (1.1 g, 3.64mmol) were added to a mixed solvent of tetrahydrofuran and acetonitrile (V/V =1/1,30ml). Potassium carbonate (655mg, 4.74mmol) was added thereto, and the reaction was carried out at room temperature for 16 hours. The reaction solution was filtered through celite, the filtrate was concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 2B (1.5 g), yield: 90 percent.

Second step of

1- (4- (6- (benzyloxy) -2- (4-fluorophenyl) -3,4-dihydronaphthalen-1-yl) phenyl) -4- (dimethoxymethyl) piperidine 2c

Compound 2b (1.3g, 1.85mmol), compound 1r (588mg, 3.69mmol), 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl (X-Phos, 176mg, 0.37mmol), palladium acetate (42mg, 0.19mmol) and sodium tert-butoxide (532mg, 5.54mmol) were added to toluene (30 mL) and reacted at 90 ℃ for 18 hours under an argon atmosphere. The reaction solution was cooled to room temperature, water (50 mL) was added, extraction was performed with ethyl acetate (50 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 2c (400 mg), yield: 38 percent.

MS m/z(ESI):564.1[M+1]。

The third step

(5,6) -cis-5- (4- (4- (dimethoxymethyl) piperidin-1-yl) phenyl) -6- (4-fluorophenyl) -5,6,7,8-tetrahydronaphthalen-2-ol 2d

Compound 2c (400mg, 0.71mmol) was added to a mixed solvent of methanol and tetrahydrofuran (V/V =1/1, 30ml), palladium on carbon (80mg, 10wt%) was added, and the reaction was carried out at room temperature for 16 hours under a hydrogen atmosphere. The reaction was filtered, and the filtrate was concentrated under reduced pressure to remove the solvent, to give the title compound 2d crude product (300 mg), which was used in the next reaction without purification.

MS m/z(ESI):476.3[M+1]。

The fourth step

(5R, 6S) -5- (4- (4- (dimethoxymethyl) piperidin-1-yl) phenyl) -6- (4-fluorophenyl) -5,6,7,8-tetrahydronaphthalene-2-ol 2e

The compound 2d (240mg, 0.5mmol) was chromatographed using chiral preparative chromatography (separation conditions: column: CHIRALPAK IE,20 mm. Times.250mm, 5um; mobile phase: A: n-hexane, B: ethanol (+ 20mmol NH) ₃ ) And A:70%, B: 30%), flow rate: 20mL/min. The title compound 2e (90 mg) was obtained.

MS m/z(ESI):476.3[M+1]。

The fifth step

1- (4- ((1R, 2S) -2- (4-fluorophenyl) -6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl) phenyl) piperidine-4-carbaldehyde 2f

Compound 2e (90mg, 0.18mmol) was added to tetrahydrofuran (2 mL), diluted sulfuric acid (2M, 1.5mL) was added dropwise, and the reaction was heated to 70 ℃ and stirred for 2 hours. The reaction solution was cooled to room temperature, and saturated sodium bicarbonate solution was added to adjust the pH of the reaction solution to neutrality, followed by extraction with ethyl acetate (10 mL. Times.3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to remove the solvent to give the title compound 2f (80 mg), which was used in the next reaction without purification.

MS m/z(ESI):430.2[M+1]。

The sixth step

Compound 1o (46mg, 0.84mmol) was dissolved in a mixed solution of dichloromethane and methanol (V/V =3/1, 3ml), and sodium acetate (35mg, 0.43mmol) was added and reacted for 10 minutes. Compound 2f (36mg, 0.84mmol) was added and reacted for 15 minutes. Sodium triacetoxyborohydride (32mg, 0.15mmol) was added thereto, and the reaction was carried out for 1 hour. Dichloromethane (10 mL) was added, washed with saturated sodium chloride solution (5 mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The resulting residue was prepared with a high performance liquid phase (Waters 2767-SQ Detector 2, elution: ammonium bicarbonate: 10mM, water: 60%, acetonitrile: 40%) to give the title compound 2 (20 mg), yield: 30 percent.

MS m/z(ESI):786.4[M+1]

¹ H NMR(500MHz,DMSO-d ₆ )δ10.95(s,1H),9.11(s,1H),6.97(t,2H),6.87-6.84(m,2H),6.65-6.60(m,3H),6.56(d,2H),6.50-6.47(m,1H),6.22(d,2H),6.10(d,2H),5.05-5.03(m,1H),4.32,4.22(dd,2H),4.12(d,1H),3.54-3.44(m,8H),3.01-2.86(m,3H),2.65-2.52(m,4H),2.38-2.30(m,1H),2.19(d,2H),2.01-1.93(m,3H),1.77-1.61(m,4H),1.30-1.28(m,1H),1.19-1.12(m,2H)。

Example 3

(S) -3- (4- (4- ((1- (2-fluoro-4- ((1R, 2R) -6-hydroxy-2- (tetrahydro-2H-pyran-4-yl) -1,2,3,4-tetrahydronaphthalen-1-yl) phenyl) piperidin-4-yl) methyl) piperazin-1-yl) -8-oxo-6,8-dihydro-7H- [1,3] dioxolano [4,5-e ] isoindolin-7-yl) piperidine-2,6-dione 3

First step of

(1- (2-fluoro-4-nitrophenyl) piperidin-4-yl) methanol 3b

1,2-difluoro-4-nitrobenzene 3a (5g, 31.4mmol, shanghai Biao biomedical Co., ltd.), 4-piperidinemethanol (3.81g, 33.1mmol, shanghai Biao biomedical Co., ltd.) were added to N, N-dimethylformamide (20 mL), cooled in an ice bath, added with potassium carbonate (6.51g, 47.2mmol), and reacted at room temperature for 16 hours. The reaction solution was filtered through celite, the filtrate was concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 3B (7.9 g), yield: 99 percent.

MS m/z(ESI):255.1[M+1]。

Second step of

(1- (4-amino-2-fluorophenyl) piperidin-4-yl) methanol 3c

Compound 3b (7.8g, 30.7mmol) was dissolved in methanol (100 mL), and palladium on carbon (1.5g, 10wt%) was added to the solution to conduct a reaction under a hydrogen atmosphere for 16 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to remove the solvent, to give crude title compound 3c (6.8 g), which was used in the next reaction without purification.

MS m/z(ESI):225.1[M+1]。

The third step

(1- (4-bromo-2-fluorophenyl) piperidin-4-yl) methanol 3d

Copper bromide (6.4 g,28.7 mmol) was added to acetonitrile (30 mL), and tert-butyl nitrite (3.7 g,35.9mmol, shanghaitan chemical Co., ltd.) was added dropwise and reacted for 10 minutes. A solution of Compound 3c (5.3 g,23.6 mmol) in acetonitrile was added dropwise thereto, and the mixture was reacted at room temperature for 1 hour after completion of the addition. The reaction solution was filtered through celite, the filtrate was concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 3d (4.1 g), yield: 60 percent.

MS m/z(ESI):288.1[M+1]。

The fourth step

1- (4-bromo-2-fluorophenyl) piperidine-4-carbaldehyde 3e

Compound 3d (3.7g, 12.8mmol) was dissolved in methylene chloride (50 mL), and dess-Martin oxidant (6 g, 14.2mmol) was added and the reaction was allowed to proceed at room temperature for 1 hour. The reaction mixture was filtered through celite, and the filtrate was washed with saturated sodium bicarbonate (10 mL. Times.3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to remove the solvent to give the crude title compound 3e (2.1 g), which was used in the next reaction without purification.

MS m/z(ESI):286.1[M+1]。

The fifth step

1- (4-bromo-2-fluorophenyl) -4- (dimethoxymethyl) piperidine 3f

Compound 3e (2.1g, 7.3mmol) was dissolved in a mixed solvent of methanol and trimethyl orthoformate (V/V =1/1, 20 mL). P-toluenesulfonic acid monohydrate (70mg, 0.37mmol) was added and the reaction was carried out at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure to remove the solvent, and the obtained residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 3f (1.7 g), yield: 70 percent.

MS m/z(ESI):332.1[M+1]。

The sixth step

4- (Dimethoxymethyl) -1- (2-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperidine 3g

Compound 3f (1.7g, 5.1mmol) was dissolved in 1,4-dioxane (15 mL), pinacol diboron (2g, 7.9mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (205mg, 0.28mmol), potassium acetate (1.1g, 11.2mmol) were added, and the reaction was heated to 80 ℃ under a nitrogen atmosphere and stirred for 16 hours. The reaction solution was filtered with celite, the filtrate was concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 3g (1.4 g), yield: 72 percent.

MS m/z(ESI):380.1[M+1]。

Step seven

6- (benzyloxy) -3,4-dihydronaphthalen-1 (2H) -one 3i

6-hydroxy-3,4-dihydronaphthalen-1 (2H) -one (8g, 49.3mmol, shanghai Biao biomedical Co., ltd.) and potassium carbonate (10g, 72.4mmol) were added to acetonitrile (60 mL), benzyl bromide (10g, 58.5mmol, 7mL) was added dropwise, and the reaction was refluxed for 3 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was dissolved in ethyl acetate (100 mL) and washed with saturated sodium chloride solution (20 mL. Times.3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent to give the crude title compound 3i (12 g), which was used in the next reaction without purification.

MS m/z(ESI):253.1[M+1]。

Eighth step

6- (benzyloxy) -3,4-dihydronaphthalen-1-yl trifluoromethanesulfonate 3j

Compound 3i (8g, 31.7mmol) was dissolved in dry tetrahydrofuran (100 mL) under an argon atmosphere, the reaction was cooled to-78 deg.C, and [ bis (trimethylsilyl) amino ] lithium (1M, 50.8mL, 50.8mmol) was added dropwise. After the dropwise addition, the reaction was carried out at-78 ℃ for 30 minutes. 1,1,1-trifluoro-N-phenyl-N- (trifluoromethylsulfonyl) methanesulfonamide (17g, 47.6 mmol) was slowly added and the reaction was allowed to spontaneously warm to room temperature and stirred for 2 hours. The reaction was quenched by slow addition of water (100 mL), extracted with dichloromethane (50 mL. Times.3), the organic phases combined, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography with eluent system B to give the title compound 3j (10.1 g), yield: 83 percent.

MS m/z(ESI):385.2[M+1]。

The ninth step

1- (4- (6- (benzyloxy) -3,4-dihydronaphthalen-1-yl) -2-fluorophenyl) -4- (dimethoxymethyl) piperidine 3k

Compound 3j (800mg, 2.1mmol), compound 3g (790mg, 2.1mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (77mg, 0.1mmol) and potassium carbonate (432mg, 3.1mmol) were dissolved in a mixed solvent of 1,4-dioxane and water (V/V =6/1, 35mL). The reaction was heated to 100 ℃ for 2 hours under a nitrogen atmosphere. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography with eluent system B to give the title compound 3k (570 mg), yield: 56 percent.

MS m/z(ESI):488.3[M+1]。

The tenth step

1- (4- (6- (benzyloxy) -2-bromo-3,4-dihydronaphthalen-1-yl) -2-fluorophenyl) -4- (dimethoxymethyl) piperidine 3l

Compound 3k (560mg, 1.2mmol) and pyridine tribromide (441mg, 1.4mmol) were dissolved in dichloromethane (30 mL), and triethylamine (235mg, 2.3mmol) was added to react at room temperature for 2 hours. Saturated sodium bicarbonate solution (50 mL) was added, extracted with dichloromethane (10 mL. Times.3), the organic phases combined, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography with eluent system B to give the title compound 3l (520 mg), yield: 80 percent.

MS m/z(ESI):568.1[M+1]。

The eleventh step

1- (4- (6- (benzyloxy) -2- (3,6-dihydro-2H-pyran-4-yl) -3,4-dihydronaphthalen-1-yl) -2-fluorophenyl) -4- (dimethoxymethyl) piperidine 3m

Compound 3l (150mg, 0.26mmol), 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (91mg, 0.43mmol, shanghai Biao biomedical Co., ltd.), tetrakis (triphenylphosphine) palladium (35mg, 0.03mol) and sodium carbonate (61mg, 0.58mmol) were added to a mixed solvent of 1,4-dioxane and water (V/V =6/1, 21mL). The mixture was heated to 80 ℃ for 2 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, the solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 3m (113 mg), yield: and 75 percent. MS m/z (ESI) 570.3[ 2 ] M + 1.

The twelfth step

(5,6) -cis-5- (4- (4- (dimethoxymethyl) piperidin-1-yl) -3-fluorophenyl) -6- (tetrahydro-2H-pyran-4-yl) -5,6,7,8-tetrahydronaphthalene-2-ol 3n

Compound 3m (113mg, 0.2mmol) was dissolved in methanol (15 mL), palladium on carbon (20mg, 10wt%) was added, and the reaction was carried out for 16 hours under a hydrogen atmosphere. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to remove the solvent, to give the title compound, 3n crude product (80 mg), which was used in the next reaction without purification.

MS m/z(ESI):484.2[M+1]。

Thirteenth step

(5R, 6R) -5- (4- (4- (dimethoxymethyl) piperidin-1-yl) -3-fluorophenyl) -6- (tetrahydro-2H-pyran-4-yl) -5,6,7,8-tetrahydronaphthalen-2-ol 3o

Compound 3n (200mg, 0.41mmol) was chromatographed using chiral preparative chromatography (separation conditions: column: CHIRALPAK IE,250 mm. Times.21.2mm, 5um; mobile phase: A: n-hexane, B: ethanol (+ 20mmol NH) ₃ ) A:70%, B: 30%) to yield the title compound 3o (80 mg).

MS m/z(ESI):484.3[M+1]。

Fourteenth step

1- (2-fluoro-4- ((1R, 2R) -6-hydroxy-2- (tetrahydro-2H-pyran-4-yl) -1,2,3,4-tetrahydronaphthalen-1-yl) phenyl) piperidine-4-carbaldehyde 3p

Compound 3o (80mg, 0.16mmol) was dissolved in tetrahydrofuran (5 mL), diluted sulfuric acid (2M, 1mL, 2mmol) was added, and the mixture was heated to 70 ℃ for reaction for 2 hours. The reaction solution was cooled to room temperature, and saturated sodium bicarbonate solution was added to adjust the pH of the reaction solution to neutrality, followed by extraction with ethyl acetate (10 mL. Times.3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent, to give the title compound 3p (81 mg), which was used in the next reaction without purification.

MS m/z(ESI):438.1[M+1]。

The fifteenth step

Compound 1o (42mg, 0.096 mmol) was dissolved in a mixed solution of dichloromethane and methanol (V/V =2/1,3ml), and sodium acetate (47mg, 0.57mmol) was added and reacted for 10 minutes. Compound 3p (55mg, 0.1mmol) was added and reacted for 15 minutes. Sodium triacetoxyborohydride (41mg, 0.19mmol) was added and the reaction was carried out for 1 hour. Dichloromethane (20 mL) was added, washed with saturated sodium chloride solution (10 mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The resulting residue was prepared using a high performance liquid phase (Waters 2767-SQ Detector 2, elution: ammonium bicarbonate: 10mM, water: 60%, acetonitrile: 40%) to give the title compound 3 (28 mg), yield: and 37 percent.

MS m/z(ESI):794.4[M+1]

¹ H NMR(500MHz,DMSO-d ₆ )δ10.95(s,1H),9.08(s,1H),6.89(t,1H),6.75(d,2H),6.69-6.63(m,3H),6.53(s,1H),6.45-6.43(m,1H),6.10(d,2H),5.05-5.03(m,1H),4.46(d,1H),4.32,4.22(dd,2H),4.12(d,1H),3.86(d,1H),3.75(d,1H),3.29-3.17(m,6H),3.09(t,1H),2.93-2.87(m,2H),2.78-2.70(m,1H),2.64-2.50(m,6H),2.37-2.32(m,1H),2.22(d,2H),2.03-1.94(m,3H),1.81-1.76(m,3H),1.65-1.62(m,2H),1.48-1.46(m,2H),1.09-1.07(m,4H)。

Example 4

(S) -3- (4- (4- ((1- (3-fluoro-4- ((1S, 2S) -6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl) phenyl) piperidin-4-yl) methyl) piperazin-1-yl) -8-oxo-6,8-dihydro-7H- [1,3] dioxolano [4,5-e ] isoindolin-7-yl) piperidine-2,6-dione 4-oxo-3242

First step of

1- (4-bromo-3-fluorophenyl) -4- (dimethoxymethyl) piperidine 4b

1-bromo-2-fluoro-4-iodobenzene 4a (2g, 6.7mmol), compound 1r (1.1g, 6.9mmol), cuprous iodide (254mg, 1.3mmol), L-proline (306mg, 2.7mmol) and anhydrous potassium carbonate (1.84g, 13.3mmol) were added to N, N-dimethylformamide (20 mL), and the mixture was heated at 90 ℃ for 16 hours under a nitrogen atmosphere. The reaction was cooled to room temperature, filtered through celite, the filtrate was concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 4B (1.35 g), yield: 61 percent.

MS m/z(ESI):332.1[M+1]。

Second step of

4- (Dimethoxymethyl) -1- (3-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperidine 4c

Compound 4b (2g, 6 mmol), pinacol diboron ester (2.3g, 9.1mmol), potassium acetate (1.2g, 12.2mmol), 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl (X-phos, 575mg, 1.2mmol) and palladium acetate (136mg, 0.61mmol) were added to 1,4-dioxane (40 mL), and the mixture was heated at 100 ℃ for 16 hours under a nitrogen atmosphere. The reaction was cooled to room temperature, filtered through celite, the filtrate was concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 4c (1.7 g), yield: 74 percent. MS m/z (ESI) 380.3[ 2 ] M +1].

The third step

1- (4- (6- (benzyloxy) -3,4-dihydronaphthalen-1-yl) -3-fluorophenyl) -4- (dimethoxymethyl) piperidine 4d

Compound 3j (1.7g, 4.4mmol), compound 4c (1.7g, 4.5mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (325mg, 0.44mmol) and anhydrous potassium carbonate (1.3g, 9.4 mmol) were added to a mixed solvent of 1,4-dioxane and water (V/V =3/1, 20 mL), and reacted under a nitrogen atmosphere at 100 ℃ for 3 hours. The reaction was cooled to room temperature, filtered through celite, the filtrate was concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 4d (1.7 g), yield: 79 percent.

MS m/z(ESI):488.2[M+1]。

The fourth step

1- (4- (6- (benzyloxy) -2-bromo-3,4-dihydronaphthalen-1-yl) -3-fluorophenyl) -4- (dimethoxymethyl) piperidine 4e

Compound 4d (276mg, 0.57mmol) was dissolved in dichloromethane (15 mL) and cooled to-5 ℃ under an ice salt bath. Pyridine tribromide (218mg, 0.68mmol) and triethylamine (115mg, 1.1mmol) were added to the reaction solution, and the reaction was maintained at-5 ℃ for 30 minutes. To the reaction mixture was added a saturated sodium bicarbonate solution (20 mL). The aqueous phase was extracted with dichloromethane (10 mL. Times.3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography with eluent system B to give the title product 4e (150 mg), yield: and 47 percent.

MS m/z(ESI):568.1[M+1]。

The fifth step

1- (4- (6- (benzyloxy) -2-phenyl-3,4-dihydronaphthalen-1-yl) -3-fluorophenyl) -4- (dimethoxymethyl) piperidine 4f

Compound 4e (500mg, 0.88mmol), phenylboronic acid (162mg, 1.33mmol, shanghai Biao biomedical Co., ltd.), tetrakis (triphenylphosphine) palladium (102mg, 0.88mol) and sodium carbonate (281mg, 2.65mmol) were added to a mixed solvent of 1,4-dioxane and water (V/V =6/1,21 mL). The reaction was heated to 100 ℃ for 2 hours under a nitrogen atmosphere. The reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 4f (480 mg), yield: 96 percent.

MS m/z(ESI):564.3[M+1]。

The sixth step (5,6) -cis-5- (4- (4- (dimethoxymethyl) piperidin-1-yl) -2-fluorophenyl) -6-phenyl-7,8-dihydronaphthalen-2-ol 4h

Compound 4f (480 mg, 0.85mmol) was dissolved in methanol (15 mL), palladium on carbon (180mg, 10wt%) was added, and the reaction was carried out for 16 hours under a hydrogen atmosphere. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to remove the solvent, to give the title compound as a crude product (400 mg) for 4h, which was used in the next reaction without purification.

MS m/z(ESI):476.2[M+1]。

The seventh step (5S, 6S) -5- (4- (4- (dimethoxymethyl) piperidin-1-yl) -2-fluorophenyl) -6-phenyl-5,6,7,8-tetrahydronaphthalene-2-ol 4i

The compound 4h (400mg, 0.84mmol) was separated by chiral preparative chromatography (separation conditions: column: CHIRALPAK IE,250 mm. Times.21.2mm, 5um; mobile phase: A: n-hexane, B: ethanol (+ 20mmol NH) ₃ ) A:70%, B: 30%) to give the title compound 4i (180 mg).

MS m/z(ESI):476.2[M+1]。

Eighth step

1- (3-fluoro-4- ((1S, 2S) -6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl) phenyl) piperidine-4-carbaldehyde 4j

Compound 4i (180mg, 0.38mmol) was dissolved in tetrahydrofuran (5 mL), diluted sulfuric acid (2M, 0.6mL, 1.2mmol) was added, and the mixture was heated to 70 ℃ and reacted for 2 hours. The reaction solution was cooled to room temperature, and saturated sodium bicarbonate solution was added to adjust the pH of the reaction solution to neutrality, followed by extraction with ethyl acetate (10 mL. Times.3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to remove the solvent to give the crude title compound 4j (160 mg) which was used in the next reaction without purification.

MS m/z(ESI):430.2[M+1]。

The ninth step

Compound 1o (45mg, 0.82mmol) was dissolved in a mixed solution of dichloromethane and methanol (V/V =2/1,3 ml), and sodium acetate (33mg, 0.41mmol) was added and reacted for 10 minutes. Compound 4j (35mg, 0.81mmol) was added and reacted for 15 minutes. Sodium triacetoxyborohydride (34mg, 0.16mmol) was added and the reaction was carried out for 1 hour. Dichloromethane (20 mL) was added, washed with saturated sodium chloride solution (10 mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The resulting residue was prepared using a high performance liquid phase (Waters 2767-SQ Detector 2, elution: ammonium bicarbonate: 10mM, water: 60%, acetonitrile: 40%) to give the title compound 4 (25 mg), yield: 37 percent.

MS m/z(ESI):786.4[M+1]

¹ H NMR(500MHz,DMSO-d ₆ )δ10.95(s,1H),9.13(s,1H),7.11(d,3H),6.84-6.82(m,2H),6.62-6.60(m,3H),6.55-6.45(m,3H),6.26(d,1H),6.10(d,2H),5.05-5.03(m,1H),4.46(d,1H),4.32,4.22(dd,2H),3.58(d,2H),3.28-3.20(m,6H),3.01-2.86(m,3H),2.65-2.56(m,4H),2.37-2.32(m,1H),2.19(bs,2H),2.03-1.98(m,3H),1.77-1.68(m,4H),1.15-1.13(m,3H)。

Biological evaluation

The present disclosure is further described below in conjunction with test examples, which are not meant to limit the scope of the present disclosure.

Test example 1: inhibitory Effect of Compounds of the disclosure on MCF-7 cell proliferation

1. Purpose of experiment

The purpose of this experiment was to test the inhibitory effect of the compounds of the present disclosure on MCF-7 cell proliferation activity using the ATP method, according to IC ₅₀ Size compounds were evaluated for in vitro activity.

2. Experimental method

MCF-7 (TCTU 74, china academy of sciences type culture Collection cell Bank) was seeded in 96-well plates in a medium of 10% FBS (Gibco, 10099-141), 1% sodium pyruvate (sigma, S8636), 1% non-essential amino acids (sigma, M7145) in MEM (hyclone, SH30024.01B) at a density of 4,000 cells/well at 37 ℃ and 5 CO ₂ Culturing under the condition. Preparing the compound into 20mM stock solution, diluting with 100% DMSO gradient to 1000X final concentration, and diluting 20-fold with medium containing 2% FBS. After 24 hours of culture, the medium was removed, 90. Mu.L of 2 FBS-containing medium and 10. Mu.L of drug were added to each well, 10. Mu.L of DMSO was added to the control group, the mixture was gently shaken and mixed, the blank group contained only 100. Mu.L of 2 FBS-containing medium, and the mixture was left at 37 ℃ and 5% CO ₂ After 72 hours, 50. Mu.L of mixed Cell Titer-Glo (Promega, G7571) was added to each well, mixed by shaking, left at room temperature for 10 minutes, and the chemiluminescence signal value was measured.

3. Data analysis

The IC of the compound was determined by plotting the chemiluminescent signal value against the log concentration of the compound using Graphpad Prism ₅₀ Values, results are shown in table 1.

TABLE 1 inhibitory Effect of the Compounds of this disclosure on MCF-7 cell proliferation

Example numbering	IC ₅₀ (nM)
		1	0.5
2	0.8
		3	1.1
4	1.3

And (4) conclusion: the compound to be protected by the disclosure has obvious inhibition effect on MCF-7 cell proliferation.

Test example 2: biological evaluation of disclosed compound on inhibition experiment of cell proliferation of ER alpha expression mutant MCF7

1. Purpose of the experiment

The purpose of this experiment was to determine the inhibitory activity of the compounds of the present disclosure on the proliferation of cells expressing the ER α mutant MCF 7.

2. Experimental methods

2.1 site-directed mutagenesis and cell line construction

The mutant ER α Y537S of human estrogen receptor α (era) protein was obtained by site-directed mutagenesis using cDNA of wild-type ESR1 gene (Accession No. nm000125) as a template in a two-primer PCR manner. The primer sequences used for the mutations were as follows (the underlined nucleotides are the sites of the mutations): Y537S F-AAG AAC GTG GTG CCC CTC TCT GAC CTG CTG CTG GAG ATG(SEQ ID NO:1)；R-CAT CTC CAG CAG CAG GTC AGA GAG GGG CAC CAC GTT CTT (SEQ ID NO: 2). The cDNA of mutant ESR1 was cloned into the target lentiviral vector pCDH-CMV-MCS-EF 1-Puro. Then carrying the gene sequence of the mutant ESR1The listed lentiviral plasmids as well as the lentiviral packaging plasmids were transfected into HEK-293T cells (ATCC, CRL-3216) by Lipofectamine 3000 Transfection Reagent (ThermoFisher Scientific, cat # L3000075). 48 hours after transfection, the virus-containing culture medium supernatant was filtered, ultracentrifuged to obtain a virus pellet, resuspended and lysed with an appropriate amount of medium, added to MCF7 cells (ATCC, HTB-22), and incubated overnight with polybrene (polybrene) at a final concentration of 8. Mu.g/mL. After two days of transfection, puromycin at a concentration of 1. Mu.g/mL was added to the cell culture medium for resistance selection, and about two weeks later, an MCF7 cell line capable of stably expressing the ER α Y537S mutant was obtained.

2.2 cell proliferation inhibition assay

MCF7 cells expressing ER α mutants were cultured in MEM (GE Healthcare, SH 30024.01) complete medium containing 10% fetal bovine serum. The first day of the experiment, cells were seeded in 96-well plates at a density of 3,000 cells/well using complete medium, 100. Mu.L of cell suspension per well, left at 37 ℃,5% CO ₂ The cell culture chamber of (2) was cultured overnight. The following day the medium was aspirated, and each well was replaced with 135. Mu.L of 2% fetal bovine serum in MEM incomplete medium, while 15. Mu.L of test compound prepared in incomplete medium at different concentrations were added to each well, the final concentration of compound being 9 concentration points diluted in 4-fold gradient starting from 100nM, a blank containing 0.5% DMSO was set, and the mixture was left at 37 ℃ and 5% CO ₂ The cell culture chamber of (2) was cultured for 144 hours. On day eight, 96 well cell culture plates were removed and 150. Mu.L of each well was added

The luminescence signal value was read using a multi-label microplate reader (Perkinelmer, VICTOR 3) after the luminescence Cell Viability Assay (Promega, G7573) was left at room temperature for 10 minutes, and the IC of the inhibitory activity of the compound was calculated from the concentration of the compound and the luminescence signal value using Graphpad Prism software ₅₀ The values are shown in Table 2.

3. Test results

TABLE 2 IC inhibition of proliferation of cells expressing ER.alpha.mutant MCF7 by Compounds of the disclosure ₅₀ Value of

And (4) conclusion: the compound to be protected by the disclosure has obvious inhibition effect on MCF7 cell proliferation expressing ER alpha mutant.

Test example 3: the disclosed compound has degradation effect on ER alpha

1. Purpose of experiment

Compounds of the disclosure were tested for causing ER α degradation and the method was used to determine the degradation of ER α by compounds of the disclosure.

2. Experimental methods

ER α -positive breast cancer cell line MCF-7 cells were cultured in DMEM/F12 medium (HyClone, SH 30023.01) containing 10% fetal bovine serum (Corning, 35-010-CV). The first day of experiment, after digesting the cells, the cells were washed once with phenol red-free DMEM/F12 medium (ThermoFisher, 11039-021) containing 5% charcoal-treated fetal bovine serum (BIOSUN, BS-0004-500) and then resuspended and counted, and the cell density was adjusted to 1.79X 10 ⁵ one/mL. Add 280. Mu.L of cell suspension per well in 48-well plates (Corning, 3548), place the cells at 37 ℃ C. And 5% CO ₂ The culture was carried out overnight in an incubator. The next day of the experiment, the compounds were diluted with DMSO in gradient and further diluted with phenol red free DMEM/F12 medium containing 5% charcoal treated fetal bovine serum. mu.L of diluted compound was added to each well of 48-well plate cells to final concentrations of 3000, 300, 30,3,0.3,0.03 and 0.003nM, respectively. The 48-well plate was placed in the incubator for 16 to 18 hours. Total protein detection kit (R) for human ER alpha/NR 3A1&D, DYC 5715-5), the capture antibody was formulated with PBS to 1 μ g/mL, and 100 μ L was added to each well of a 96-well plate (Corning, 3590), and placed in an incubator at 26 ℃ overnight. On the third day of the experiment, the antibody-coated 96-well plate was washed once with PBS and 200. Mu.L of the antibody-containing solution was added to each well1% BSA in PBS, incubated at 37 ℃ for 1.5 hours for blocking. The cell culture supernatant was discarded, the cells were washed once with PBS, and 60. Mu.L of cell lysate was added to each well. The cell lysate was PBS containing 6M urea, 1mM EDTA, 0.5% TritonX-100, 1mM PMSF and protease inhibitor (Roche, 04693159001). Cells were lysed on ice for 15 minutes, and urea was diluted to 1M by adding 300. Mu.L per well of PBS containing 1mM EDTA and 0.5% Triton X-100. The blocking solution in the blocked 96-well plate is discarded, 100. Mu.L of diluted cell lysate is added to each well, the mixture is placed in an incubator at 37 ℃ for incubation for 2 hours, and the plate is washed with PBS for five times. The biotinylated detection antibody was diluted to 0.4. Mu.g/mL with PBS containing 1% BSA, and then 100. Mu.L of detection antibody was added to each well, which was incubated at 37 ℃ in an incubator for 1 hour. The well plate was then washed five more times, 100. Mu.L of avidin-HRP diluted 200-fold with 1% BSA-containing PBS was added to each well, and incubated at 37 ℃ for 30 minutes. The well plate was washed five more times, 100. Mu.L of TMB substrate was added to each well, incubated at room temperature until blue color appeared, and 100. Mu.L of stop solution was added to each well. OD450 signal values were read using a PHERAStar multifunctional microplate reader. IC of compound inhibitory activity was calculated using Graphpad Prism software ₅₀ The value is obtained.

3. Test results

IC measured by degradation of ER alpha by the disclosed compounds ₅₀ The values are shown in Table 3.

TABLE 3 degradation of ER α by Compounds of the present disclosure

Example numbering	IC ₅₀ (nM)
		1	0.9
2	0.8
		3	0.7
4	1.4

And (4) conclusion: the compounds to be protected by the present disclosure have a significant degradation effect on ER α.

Claims

1. A compound of the general formula (I) or a pharmaceutically acceptable salt thereof:

wherein:

x is oxygen atom or CH ₂ ；

R ^3a And R ^3b The same or different, and each is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally selected from the group consisting of halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR, and mixtures thereof ⁹ R ¹⁰ Nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

Z is a nitrogen atom or CR ⁸ ；

R ⁷ and R ⁸ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, -NR ^9a R ^10a Hydroxy, -C (O) R ⁶ 、-C(O)OR ⁶ 、-C(O)NR ^9a R ^10a 、-S(O) _t R ^9a 、-S(O) _t NR ^9a R ^10a Cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from the group consisting of halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, -NR ⁹ R ¹⁰ Nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ⁹ and R ¹⁰ 、R ^9a And R ^10a The same or different, and each is independently selected from the group consisting of a hydrogen atom, an alkyl group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclic group, wherein the alkyl group, the cycloalkyl group, and the heterocyclic group are each independently optionally substituted with one or more substituents selected from the group consisting of a halogen, an alkyl group, an alkoxy group, a haloalkyl group, and a haloalkoxy group;

or R ⁹ And R ¹⁰ Together with the nitrogen atom to which they are attached form a heterocyclic group, or R ^9a And R ^10a Together with the nitrogen atom to which they are attached, form a heterocyclic group optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

j is 0, 1,2,3,4, 5,6,7,8, 9 or 10;

t is 0, 1 or 2; and is

m is 0, 1,2 or 3.

2. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein m is 0.

3. The compound of the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or2, wherein X is CH ₂ 。

4. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, which is a compound represented by the general formula (II):

wherein:

G ¹ 、G ² 、Z、R ¹ 、R ^3a 、R ^3b 、R ^4a 、R ^4b 、R ^5a 、R ^5b 、R ^7a 、R ^7b and j are as defined in claimDefined in claim 1.

5. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R ^3a Selected from the group consisting of 3-to 6-membered cycloalkyl, 3-to 6-membered heterocyclyl, 6-to 10-membered aryl and 5-to 10-membered heteroaryl, wherein said 3-to 6-membered cycloalkyl, 3-to 6-membered heterocyclyl, 6-to 10-membered aryl and 5-to 10-membered heteroaryl are each independently optionally selected from the group consisting of halogen, oxo, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl and C _1-6 Substituted by one or more substituents of haloalkoxy, and R ^3b Is a hydrogen atom.

6. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein R ^4a And R ^4b Are all hydrogen atoms.

7. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein R ^5a And R ^5b Are all hydrogen atoms.

8. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein G ¹ And G ² Are both CH.

9. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, which is a compound represented by the general formula (III) or the general formula (IV):

wherein:

Z、R ¹ 、R ^7a 、R ^7b and j is as defined in claim 1.

10. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein Z is CH.

11. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein R ¹ Is a hydrogen atom.

12. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein R ^3a Is a 5 to 6 membered heterocyclyl or phenyl group, wherein said 5 to 6 membered heterocyclyl or phenyl group are each independently optionally selected from halogen, oxo, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl and C _1-6 One or more substituents of the haloalkoxy group.

13. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, wherein R ^7a And R ^7b Are identical or different and are each independently a hydrogen atom or a halogen, and R ^7a And R ^7b At least one of which is halogen.

14. The compound of formula (I) according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein j is 0.

15. A compound, or a pharmaceutically acceptable salt thereof, selected from the following compounds:

16. a compound represented by the general formula (Ia) or a salt thereof,

wherein:

G ¹ 、G ² 、R ¹ 、R ² 、R ^4a 、R ^4b 、R ^7a 、R ^7b 、R ⁹ 、R ¹⁰ m and j are as defined in claim 1.

17. The compound or salt thereof according to claim 16, which is the following compound:

18. a process for the preparation of a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, which comprises:

wherein:

G ¹ 、G ² 、Z、R ¹ 、R ² 、R ^4a 、R ^4b 、R ^5a 、R ^5b 、R ^7a 、R ^7b 、R ⁹ 、R ¹⁰ m and j are as defined in claim 1.

19. A pharmaceutical composition comprising a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

20. Use of a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 19 in the manufacture of a medicament for the treatment and/or prevention of a disease or condition by degradation of a target protein.

21. Use of a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 19, in the manufacture of a medicament for the treatment and/or prevention of an estrogen receptor-mediated or dependent disease or condition.

22. The use according to claim 20 or 21, wherein the disease or condition is selected from the group consisting of abnormal cell proliferation, tumors, immune diseases, diabetes, cardiovascular diseases, infectious diseases and inflammatory diseases; preferably tumors and infectious diseases.

23. The use of claim 22, wherein the tumor is a cancer; preferably selected from the group consisting of breast cancer, endometrial cancer, testicular cancer, cervical cancer, prostate cancer, ovarian cancer, fallopian tube tumors, leukemia, skin cancer, squamous cell carcinoma, basal cell carcinoma, bladder cancer, colorectal cancer, esophageal cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, pancreatic cancer, gastric cancer, lymphoma, melanoma, sarcoma, peripheral neuroepithelial tumors, glioma, astrocytoma, ependymoma, glioblastoma, neuroblastoma, ganglioneuroma, medulloblastoma, pinealocyte tumor, meningioma, neurofibroma, schwanoma, thyroid cancer, wilms' tumor and teratocarcinoma; more preferably selected from breast cancer, endometrial cancer, testicular cancer, cervical cancer, prostate cancer, ovarian cancer, and fallopian tube tumors.

24. The use according to claim 22, wherein the infectious disease is selected from the group consisting of viral pneumonia, influenza, avian influenza, meningitis, gonorrhea or a disease infected with HIV, HBV, HCV, HSV, HPV, RSV, CMV, ebola virus, flavivirus, chira virus, rotavirus, coronavirus, EBV, resistant virus, RNA virus, DNA virus, adenovirus, poxvirus, picornavirus, togavirus, orthomyxovirus, retrovirus, hepadnavirus, gram negative bacteria, gram positive bacteria, atypical bacteria, staphylococcus, streptococcus, escherichia coli, salmonella, helicobacter pylori, chlamydiaceae, protothecae, fungi, animals, helminths, prions or parasites.