CN113896669A - Estrogen receptor modulators and uses thereof - Google Patents

Abstract

Compounds having estrogen receptor modulating activity or function and pharmaceutically acceptable salts thereof are described, having the structure of formula (I) and having the substituents and structural features described herein. Also described are pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the prevention or treatment of an estrogen receptor related disorder.

Description

Estrogen receptor modulators and uses thereof

The present application claims priority from a prior application entitled "estrogen receptor modulators and uses thereof" filed on the national intellectual property office at 22/6/2020, patent application No. 202010572695.6. The entire contents of said prior application are incorporated by reference into the present application.

Technical Field

The present application relates to estrogen receptor modulator compounds or pharmaceutically acceptable salts thereof, pharmaceutical compositions containing the compounds, and their use in the prevention or treatment of estrogen receptor related diseases.

Background

Estrogen (E2) and estrogen α receptor (era) are important drivers of the development of breast cancer. In breast cancer patients over 2/3 express ER transcription factors, and in most ER-positive patients, ER remains a key driver even in tumors that progress after early endocrine therapy, and thus ER is a major target for breast cancer therapy (Pharmacology & Therapeutics 186(2018) 1-24). Endocrine therapy, aimed at reducing ER activity, is mainly divided into three classes, including Selective Estrogen Receptor Modulators (SERMs), such as tamoxifen (tamoxifen), which are allosteric modulators of the ER that inhibit its transcriptional activity when bound to the ER; aromatase Inhibitors (AIs) reduce the level of estrogen in the body by inhibiting the conversion of androgens to estrogens; and selective estrogen receptor down-regulators, such as fulvestrant (fulvestrant), not only act as an antagonist of ER inhibiting its activity, but also have the effect of inducing ER protein degradation. Although endocrine therapy is the first choice for estrogen receptor positive breast cancer patients, approximately 30% of post-treatment patients relapse and almost all metastatic breast cancer patients develop resistance to progress. Two main mechanisms for generating drug resistance in endocrine treatment are that the endocrine treatment focuses on an estrogen receptor signal pathway, including activation mutation, amplification and fusion with other genes of ESR1, an estrogen receptor co-regulatory factor, disorder of a downstream control cell cycle factor and the like; another class of mechanisms involves the activation of signaling pathways that cross-react with estrogen receptor signaling pathways, such as the growth factor receptor pathway, etc. (Oncol Ther, 2017,5: 17-29).

Fulvestrant is the first and only clinically approved Selective Estrogen Receptor Downregulator (SERDs) class of drugs for post-menopausal patients in the treatment of ER positive, metastatic breast cancer following tamoxifen or aromatase inhibitor progression. In addition, a series of SERD compounds with novel structures and corresponding medical application are disclosed by Asricon (see patent application WO2018077630A1) and Genetake (see patent application WO2019245974A 1). Multiple study data show that degradation of ER is not fully achieved in fulvestrant-treated patients, but it is also possible that fulvestrant doses (up to 500mg, primarily its pharmacodynamic profile and intramuscular route of administration limit the maximum dose that can be administered to patients) limit its efficacy. Therefore, there is a clinical need for SERD drugs that have higher bioavailability, higher ER antagonistic activity, and greater ER degradation, and that can be used in premenopausal patients with higher estrogen levels, and that are convenient for oral administration.

Disclosure of Invention

The present application relates to compounds of formula (I) or a pharmaceutically acceptable salt thereof,

wherein:

X¹、X²、X³、X⁴independently selected from CR⁹Or N;

w is selected from NR⁸O or S;

het is selected from

R⁵Is selected from C_1-6Alkyl radical, C_2-8Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl or 3-6 membered heterocycloalkyl, said C_1-6Alkyl radical, C_2-8Alkenyl radical, C₂-₄Alkynyl, C_3-6Cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted with 1 or more groups selected from: F. cl, Br, I, CN, OH, OCH₃And SO₂CH₃；

R⁸Selected from H, C_1-6Alkyl radical, C_2-8Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl or 3-6 membered heterocycloalkyl, said C_1-6Alkyl radical, C_2-8Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted with 1 or more groups selected from: F. cl, Br, I, CN, OH, OCH₃And SO₂CH₃；

R⁹Selected from H, F, Cl, Br, I, OH, CN, C_1-6Alkyl radical, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, C_1-6Alkoxy radical, C_3-6Cycloalkyloxy or 3-6 membered heterocyclyloxy;

R¹、R²、R⁷each independently selected from hydrogen, OH, F, Cl, Br, I, C_1-6Alkyl radical, C_3-6Cycloalkyl or 3-6 membered heterocycloalkyl;

or R¹、R²Together with the carbon atom to which they are attached form C_3-6Cycloalkyl or 3-6 membered heterocycloalkyl, said C_3-6Cycloalkyl or 3-6 membered heterocycloalkyl optionally substituted with R^aSubstitution;

or, R¹、R²Or R⁷Any of them with R⁸And C and N to which they are each attached, together form a 3-6 membered heterocyclyl;

R³selected from H, OH, COOH, BR¹⁰R¹¹、C(O)OR^b、OC(O)R^b、C_1-6Alkyl radical, C_1-6Alkoxy radical, C_6-10Aryl or 5-to 10-membered heteroaryl, said C_1-6Alkyl radical, C_1-6Alkoxy radical, C_6-10Aryl or 5-10 membered heteroaryl optionally substituted with 1 or more R^cSubstitution;

R⁴is selected from C_6-10Aryl or 5-to 10-membered heteroaryl, said C_6-10Aryl or 5-10 membered heteroaryl optionally substituted with 1 or more R^dSubstitution;

R⁶selected from H, F, Cl, Br, I or OH;

R¹⁰、R¹¹independently selected from OH, or R¹⁰、R¹¹Taken together with B to which it is attached form a 5-6 membered heterocycloalkyl group, said 5-6 membered heterocyclyl group being optionally substituted with C_1-10Alkyl substitution;

R^aselected from F, Cl, Br, I, OH, CN, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-6Cycloalkyl or 3-6 membered heterocyclyl, said C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-6Cycloalkyl or 3-6 membered heterocyclyl is optionally substituted with halogen;

R^bis independently selected from C_1-6Alkyl radical, C_2-8Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, C_6-10Aryl or 5-10 membered heteroaryl;

R^c、R^dindependently selected from F, Cl, Br, I, OH, CN, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-6Cycloalkyl or 3-6 membered heterocyclyl, said C₁-₆Alkyl radical, C_1-6Alkoxy radical, C_3-6Cycloalkyl or 3-6 membered heterocyclyl is optionally substituted with 1 or more groups selected from halogen or OH;

n is 0, 1 or 2;

p is 1 or 2;

with the following conditions: (1) when R is¹、R²When C not attached to it forms a ring and n is 1 and W is NH, R³Is not OH; (2) when R is¹、R²When C not bound thereto forms a ring and n is 1 and W is O, R³Not being OH, COOH or COOCH₃。

In some embodiments, when R¹、R²When C not linked thereto forms a ring and W ═ O, n is 0.

In some embodiments, the Het is selected from

In some embodiments, the Het is selected from

Wherein R is¹、R²Are all H, and R⁷Not with R⁸Looping.

In some embodiments, the Het is selected from

Wherein R is¹、R²Are all H, and R⁷Not with R⁸Forming a ring, wherein n is 0 or 1.

In some embodiments, the Het is selected from

Wherein R is¹、R²Are all H, and R⁷Not with R⁸Form a ring, and n is 0.

In some embodiments, the Het is selected from

Wherein R is¹、R²Together with the carbon atom to which they are attached form C_3-6Cycloalkyl or 3-6 membered heterocycloalkyl, said C_3-6Cycloalkyl or 3-6 membered heterocycloalkyl optionally substituted with R^aAnd (4) substitution.

In some embodiments, the Het is selected from

Wherein R is¹、R²Together with the carbon atom to which they are attached form C_3-6Cycloalkyl radical, said C_3-6Cycloalkyl is optionally substituted by R^aAnd (4) substitution.

In some embodiments, the Het is selected from

Wherein R is¹、R²Together with the carbon atom to which they are attached form a cyclopropane.

In some embodiments, the Het is selected from

Wherein R is¹、R²Or R⁷Any of them with R⁸And C and N to which they are each attached, together form a 3-6 membered heterocyclic group.

In some embodiments, the Het is selected from

Wherein R is¹、R²Or R⁷Any of them with R⁸And C and N to which they are each attached together form a pyrrolidine or piperidine ring.

In some embodiments, the R is¹Is H.

In some embodiments, the R is²Is H.

In some embodiments, R^aSelected from F, Cl, Br, OH, C_1-3Alkyl or C_1-3An alkoxy group.

In some embodiments, the R is⁷Is H.

In some embodiments, the n is 0 or 1.

In some embodiments, the n is 0.

In some embodiments, the Het is selected from

In some embodiments, p is 1.

In some embodiments, the Het is selected from

In some embodiments, the Het is selected from

In some embodimentsSaid Het is selected from

In some embodiments, the R is⁵Is C optionally substituted by F, Cl, Br, I, CN or OH_1-6An alkyl group.

In some embodiments, the R is⁵Is 3-fluoropropyl.

In some embodiments, said X is₁Selected from the group consisting of CR⁹Or N, X₂、X₃、X₄Are all CR⁹。

In some embodiments, the R is⁹Selected from H, F, Cl, Br or I.

In some embodiments, said X is₁、X₂、X₃、X₄Are both CH.

In some embodiments, the W is selected from NR⁸Or O.

In some embodiments, the W is NH or O.

In some embodiments, the R is⁴Selected from the group consisting of optionally substituted by 1 or more R^dSubstituted phenyl or 5-6 membered heteroaryl.

In some embodiments, the R is⁴Selected from the group consisting of optionally substituted by 1 or more R^dA substituted phenyl group.

In some embodiments, the R is^dSelected from F, Cl, Br, I, OH, CN, C_1-6Alkyl or C_1-6An alkoxy group.

In some embodiments, the R is^dSelected from F, Cl or methyl.

In some embodiments, the R is⁴Is 2, 4-dichlorophenyl.

In some embodiments, the R is³Selected from H, OH, COOH, BR¹⁰R¹¹、C(O)OR^b、C_1-6Alkyl radical, C_1-6Alkoxy radical, C_6-10Aryl or 5-to 10-membered heteroaryl, said C_1-6Alkyl radical, C_1-6Alkoxy radical, C_6-10Aryl or 5-to 10-membered heteroaryl optionally substituted by 1Or a plurality of R^cAnd (4) substitution.

In some embodiments, the R is³Selected from OH and C_1-6Alkyl radical, C_1-6Alkoxy radical, BR¹⁰R¹¹Or 5-10 membered heteroaryl, said C_1-6Alkyl radical, C_1-6Alkoxy or 5-10 membered heteroaryl optionally substituted with 1 or more R^cAnd (4) substitution.

In some embodiments, the R is^cSelected from F, Cl, Br, I or C_1-6An alkyl group.

In some embodiments, the R is^cIs selected from F or CH₃。

In some embodiments, the R is¹⁰、R¹¹Independently selected from OH.

In some embodiments, the R is^bIs independently selected from C_1-6Alkyl or C_3-6A cycloalkyl group.

In some embodiments, the R is³Selected from OH, COOH, B (OH)₂Pyrazolyl, CH₃Or methoxy, said CH₃Or methoxy optionally substituted with 1 or more F.

In some embodiments, the R is³Selected from OH and B (OH)₂Pyrazolyl, CH₃Or methoxy, said CH₃Or methoxy optionally substituted with 1 or more F.

In some embodiments, the R is³Selected from OH, COOH, B (OH)₂1H-pyrazol-4-yl, CHF₂Or OCHF₂。

In some embodiments, the R is⁶Selected from H or OH.

In some embodiments, when the atom to which Het is attached to W is a chiral carbon, its configuration is preferably the (S) -configuration.

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from a compound of formula (II) or a pharmaceutically acceptable salt thereof:

wherein R is³、R⁴W and Het are as described in formula (I).

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the following compounds or pharmaceutically acceptable salts thereof:

in one aspect, the compounds described herein exist as a racemic mixture or in enantiomerically enriched or enantiomerically pure form. In certain embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compounds with an optically active resolving agent to form a pair of diastereomeric compounds/salts, separating the diastereomers and recovering the enantiomers in optical purity. In some embodiments, resolution of enantiomers is performed using covalent diastereomeric derivatives of the compounds described herein. In another embodiment, the diastereomers are separated by separation/resolution techniques based on solubility differences. In certain embodiments, the compounds described herein are prepared as their individual stereoisomers by enzymatic resolution. In some embodiments, resolution of individual stereoisomers is performed using a lipase or esterase. In some embodiments, resolution of individual stereoisomers is performed by lipase or esterase catalyzed asymmetric deacylation. In other embodiments, separation of stereoisomers is performed by chromatography, or by forming salts of diastereomers and separating by recrystallization or chromatography, or any combination thereof. In some embodiments, the stereoisomers are obtained by stereoselective synthesis.

The present application also provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, as herein described, and a pharmaceutically acceptable carrier and/or excipient. In some embodiments, the pharmaceutical composition is formulated for intravenous injection, subcutaneous injection, oral administration, or topical administration.

In some embodiments, the pharmaceutical composition is a tablet, pill, capsule, liquid, suspension, gel, dispersion, solution, emulsion, ointment, or lotion.

Further, the invention relates to an application of the compound shown in the formula (I) or the pharmaceutically acceptable salt thereof or the pharmaceutical composition thereof in preparing a medicament for preventing or treating estrogen receptor related diseases.

Further, the invention relates to an application of the compound shown in the formula (I) or the pharmaceutically acceptable salt thereof or the pharmaceutical composition thereof in preventing or treating estrogen receptor related diseases.

Further, the present invention relates to a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for preventing or treating an estrogen receptor related disease.

The present invention also relates to a method of preventing or treating estrogen receptor mediated diseases in a mammal comprising administering to a mammal, preferably a human, in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

The preferred embodiment of the present invention, wherein the estrogen receptor related diseases include but are not limited to cancer, autoimmune diseases and the like.

Definition and description of terms

Unless otherwise indicated, the terms used in the present application have the following meanings and the group and term definitions described in the present application, including definitions thereof as examples, exemplary definitions, preferred definitions, definitions described in tables, definitions of specific compounds in the examples, etc., may be arbitrarily combined and combined with each other. A particular term should not be considered as ambiguous or unclear without special definition, but rather construed according to ordinary meaning in the art. When a trade name appears herein, it is intended to refer to its corresponding commodity or its active ingredient.

In this context

Indicates the attachment site.

The enantiomers or enantiomerically pure compounds herein are illustrated by Maehr, J.chem.Ed.1985,62: 114-120. Using wedge and virtual wedge keys, unless otherwise indicated (

And

) Representing the absolute configuration of a stereocenter, using black solid and imaginary bonds (

And

) Indicates the relative configuration of a stereocenter (e.g., cis-trans configuration of alicyclic compounds).

The term "tautomer" refers to an isomer of a functional group resulting from the rapid movement of an atom in two positions in a molecule. The compounds of the invention may exhibit tautomerism. Tautomeric compounds may exist in two or more interconvertible species. Tautomers generally exist in equilibrium, and attempts to isolate a single tautomer often result in a mixture whose physicochemical properties are consistent with the mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates; whereas in phenol the enol type predominates. The present invention encompasses all tautomeric forms of the compounds.

The term "stereoisomer" refers to isomers resulting from the different arrangement of atoms in a molecule, including cis-trans isomers, enantiomers, diastereomers, and conformers.

The compounds of the present invention may have asymmetric atoms such as carbon atoms, sulfur atoms, nitrogen atoms, phosphorus atoms, or asymmetric double bonds, and thus the compounds of the present application may exist in specific geometric or stereoisomeric forms. Specific geometric or stereoisomeric forms may be the cis and trans isomers, the E and Z geometric isomers, the (-) -and (+) -enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, and racemic or other mixtures thereof, e.g., enantiomerically or diastereomerically enriched mixtures, all of which, and mixtures thereof, are within the definition of compounds of the present application. The presence of additional asymmetric carbon, sulfur, nitrogen or phosphorus atoms in substituents such as alkyl groups is also included within the definition of compounds of the present application as are all isomers and mixtures thereof that may be involved in a substituent. The compounds containing asymmetric atoms of the present application can be isolated in optically pure form or in racemic form, the optically pure form can be resolved from a racemic mixture, or synthesized by using chiral starting materials or chiral reagents.

The term "substituted" means that any one or more hydrogen atoms on a particular atom is replaced with a substituent, so long as the valence of the particular atom is normal and the substituted compound is stable. When the substituent is oxo (i.e., ═ O), meaning that two hydrogen atoms are substituted, oxo does not occur on the aryl.

The terms "optionally" or "optionally" mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, ethyl is "optionally" substituted with halo, meaning that ethyl may be unsubstituted (CH)₂CH₃) Monosubstituted (e.g. CH)₂CH₂F) Polysubstituted (e.g. CHFCH)₂F、CH₂CHF₂Etc.) or completely substituted (CF)₂CF₃). It will be appreciated by those skilled in the art that any group containing one or more substituents will not introduce any steric impossibilityAnd/or non-synthesizable substitutions or substitution patterns.

Herein C_m-nIt means that the moiety has an integer number of carbon atoms in the given range. E.g. "C_1-6By "is meant that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.

When any variable (e.g., R) occurs more than one time in the composition or structure of a compound, its definition in each case is independent. For example, if a group is substituted with 2R, then each R has independent options.

When the number of one linking group is 0, e.g. - (CH)₂)₀-, denotes that the linking group is a bond. The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

The term "hydroxy" refers to an-OH group.

The term "cyano" refers to the group — CN.

The term "mercapto" refers to the-SH group.

The term "amino" refers to the group-NH₂A group.

The term "nitro" means-NO₂A group.

The term "alkyl" refers to a group of formula C_nH_2n+1A hydrocarbon group of (1). The alkyl group may be linear or branched. For example, the term "C_1-6Alkyl "means an alkyl group having 1,2,3,4, 5 or 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, and the like). Similarly, the alkyl portion of an alkoxy group (i.e., alkyl) has the same definition as above.

As described herein "C_1-6Alkyl groups "may contain" C_1-3Alkyl "and the like.

The term "alkoxy" refers to alkyloxy or-O-alkyl. For example, the term "C₁-C₆Alkoxy "is understood to mean" C₁-C₆Alkyloxy "or" C₁-C₆alkyl-O- ", preferably," C₁-C₆Alkoxy groups "may contain" C₁-C₃Alkoxy ".

The term "alkenyl" refers to a straight or branched chain unsaturated aliphatic hydrocarbon group having at least one double bond, consisting of carbon atoms and hydrogen atoms. Non-limiting examples of alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1, 3-butadienyl, and the like.

The term "C_2-8Alkenyl "is understood to preferably mean a straight-chain or branched monovalent hydrocarbon radical which contains one or more double bonds and has 2,3,4, 5,6, 7, 8 carbon atoms.

The term "alkynyl" refers to a straight or branched chain unsaturated aliphatic hydrocarbon group having at least one triple bond composed of carbon atoms and hydrogen atoms. Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl (-C ≡ CH), 1-propynyl (-C ≡ C-CH)₃) 2-propynyl (-CH)₂-C.ident.CH), 1, 3-butadiynyl (-C.ident.C-C.ident.CH), and the like.

The term "C_2-4Alkynyl "is understood as preferably meaning a straight-chain or branched, monovalent hydrocarbon radical which contains one or more triple bonds and has 2,3,4 carbon atoms.

The term "cycloalkyl" refers to a carbon ring that is fully saturated and may exist as a single ring, a bridged ring, or a spiro ring. Unless otherwise indicated, the carbocycle is typically a 3 to 10 membered ring. Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo [2.2.1] heptyl), bicyclo [2.2.2] octyl, adamantyl, and the like.

The term "C_3-6Cycloalkyl radicals or "C_3-6"C in" cycloalkyloxy_3-6Cycloalkyl "is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3,4, 5 or 6 carbon atoms, specific examples including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

The term "cycloalkyloxy" is understood to mean "cycloalkyl-O-". For example, the term "C_3-6Cycloalkyloxy "is understood to mean" C_3-6cycloalkyl-O- ".

Term(s) for"heterocyclyl" refers to a fully saturated or partially unsaturated (not heteroaromatic as a whole with aromaticity) monovalent monocyclic, fused, bridged or spiro ring group containing 1 to 5 heteroatoms or heteroatom groups (i.e., heteroatom-containing atomic groups) in the ring atoms, including, but not limited to, nitrogen (N), oxygen (O), sulfur (S), phosphorus (P), boron (B), O, ═ S, -O-N ═ C (═ O) O-, -C (═ O) -, -C (═ S) -, -S (═ O)₂-, -S (═ O) -, and optionally substituted-NH-, -S (═ O) (═ NH) -, -C (═ O) NH-, -C (═ NH) -, -S (═ O)₂NH-, S (═ O) NH-, -NHC (═ O) NH-, and the like. Unless otherwise indicated, the heterocyclic ring is typically a 3 to 7 membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and/or nitrogen. Non-limiting examples of heterocyclyl groups include, but are not limited to, oxiranyl, tetrahydrofuryl, dihydrofuranyl, pyrrolidinyl, N-methylpyrrolidinyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyrazolidinyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl, and the like.

The term "3-6 membered heterocyclyl" in the term "3-6 membered heterocyclyl" or "3-6 membered heterocyclyloxy" means a saturated or partially saturated monovalent monocyclic or bicyclic hydrocarbon ring comprising 1,2 or 3 heteroatoms selected from N, O and S. In particular, the heterocyclic group may include, but is not limited to: 3-membered rings such as oxirane rings; 4-membered rings such as azetidinyl, oxetanyl; a 5-membered ring such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, 4, 5-dihydrooxazole or 2, 5-dihydro-1H-pyrrolyl; or a 6-membered ring such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl; or a partially saturated 6-membered ring such as tetrahydropyridinyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, tetrahydropyridinyl or 4H- [1,3,4] thiadiazinyl. According to the invention, the heterocyclic group is wholly non-aromatic. Preferably, "3-6 membered heterocyclyl" may comprise "5-6 membered heterocyclyl" and "3-6 membered heterocyclyloxy" may comprise "5-6 membered heterocyclyloxy".

The term "heterocycleAlkyl "refers to a monovalent cyclic group that is fully saturated and may exist as a single ring, a fused ring, a bridged ring, or a spiro ring. Unless otherwise indicated, the heterocyclic ring is typically a 3 to 7 membered ring containing 1,2 or 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulphur, oxygen and/or nitrogen. Examples of 3-membered heterocycloalkyl include, but are not limited to, oxiranyl, thietanyl, cycloazenyl, non-limiting examples of 4-membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thiabutinyl, examples of 5-membered heterocycloalkyl include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, examples of tetrahydropyrazolyl, 6-membered heterocycloalkyl include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1, 4-thialkyl, 1, 4-dioxanyl, thiomorpholinyl, 1, 3-dithianyl, 1, 4-dithianyl, and examples of 7-membered heterocycloalkyl include, but are not limited to, azepanyl, oxepanyl, thiepanyl. Examples of the previously formed B-containing 5-6 membered heterocycloalkyl group of the present invention include, but are not limited to

The term "3-6 membered heterocycloalkyl" in "3-6 membered heterocycloalkyl" or "3-6 membered heterocycloalkyloxy" means said heterocycloalkyl having 3,4, 5 or 6 ring atoms. Preferably, "3-6 membered heterocycloalkyl" may comprise "5-6 membered heterocycloalkyl" and "3-6 membered heterocycloalkyloxy" may comprise "5-6 membered heterocycloalkyloxy".

The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated pi-electron system. For example, the aryl group can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, and 1,2,3, 4-tetrahydronaphthalene, and the like.

The term "C_6-10Aryl "is to be understood as being preferredRepresents a monocyclic or bicyclic hydrocarbon ring having a monovalent aromatic or partially aromatic character of 6 to 10 carbon atoms. In particular a ring having 6 carbon atoms ("C)₆Aryl "), such as phenyl; or a ring having 9 carbon atoms ("C)₉Aryl group), such as indanyl or indenyl, or a ring having 10 carbon atoms ("C)₁₀Aryl), such as tetralinyl, dihydronaphthyl, or naphthyl.

The term "heteroaryl" refers to a monocyclic or fused polycyclic ring system containing at least one ring atom selected from N, O, S, the remaining ring atoms being C, and having at least one aromatic ring. Preferred heteroaryls have a single 4-to 8-membered ring, especially a single 5-to 8-membered ring, or multiple fused rings containing 6 to 14, especially 6 to 10 ring atoms. Non-limiting examples of heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, and the like.

The term "5-to 10-membered heteroaryl" is understood to include such monovalent monocyclic or bicyclic aromatic ring systems: it has 5,6, 7, 8, 9 or 10 ring atoms, in particular 5 or 6 or 9 or 10 ring atoms, and it contains 1 to 5, preferably 1 to 3 heteroatoms independently selected from N, O and S. In particular, the heteroaryl group is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, thiadiazolyl and the like and their benzo derivatives, such as benzofuryl, benzothienyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like, and benzo derivatives thereof, such as quinolyl, quinazolinyl, isoquinolyl, and the like; or azocinyl, indolizinyl, purinyl and the like and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and the like. The term "5-6 membered heteroaryl" refers to an aromatic ring system having 5 or 6 ring atoms and which contains 1-3, preferably 1-2 heteroatoms independently selected from N, O and S, examples including but not limited to thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl. Preferably, "5-10 membered heteroaryl" may comprise "5-6 membered heteroaryl".

The term "therapeutically effective amount" means an amount of a compound of the present application that (i) treats or prevents a particular disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of a compound of the present application that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art with their own knowledge and this disclosure.

The term "pharmaceutically acceptable" is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salts" refers to pharmaceutically acceptable salts of non-toxic acids or bases, including salts of inorganic acids and bases, organic acids and bases. As the pharmaceutically acceptable salt, for example, a metal salt, an ammonium salt, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid, and the like can be mentioned.

The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or salts thereof and pharmaceutically acceptable excipients. The purpose of the pharmaceutical composition is to facilitate administration of the compounds of the present application to an organism.

The term "pharmaceutically acceptable adjuvants" refers to those adjuvants which do not have a significant irritating effect on the organism and do not impair the biological activity and properties of the active compound. Suitable adjuvants are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.

The words "comprise" or "comprise" and variations thereof such as "comprises" or "comprising," are to be understood in an open, non-exclusive sense, i.e., "including but not limited to.

The present application also includes isotopically-labeled compounds of the present application, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine, such as respectively²H、³H、¹¹C、¹³C、¹⁴C、¹³N、¹⁵N、¹⁵O、¹⁷O、¹⁸O、³¹P、³²P、³⁵S、¹⁸F、¹²³I、¹²⁵I and³⁶cl, and the like.

Certain isotopically-labelled compounds of the present application (e.g. with³H and¹⁴c-labeled ones) can be used in compound and/or substrate tissue distribution assays. Tritiated (i.e. by tritiation)³H) And carbon-14 (i.e.¹⁴C) Isotopes are particularly preferred for their ease of preparation and detectability. Positron emitting isotopes, such as¹⁵O、¹³N、¹¹C and¹⁸f can be used in Positron Emission Tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the present application can generally be prepared by following procedures analogous to those disclosed in the schemes and/or in the examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

The pharmaceutical compositions of the present application can be prepared by combining the compounds of the present application with suitable pharmaceutically acceptable excipients, for example, can be formulated into solid, semi-solid, liquid or gaseous formulations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres, aerosols, and the like.

Typical routes of administration of a compound of the present application or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.

The pharmaceutical compositions of the present application can be manufactured by methods well known in the art, such as conventional mixing, dissolving, granulating, emulsifying, lyophilizing, and the like.

In some embodiments, the pharmaceutical composition is in an oral form. For oral administration, the pharmaceutical compositions may be formulated by mixing the active compounds with pharmaceutically acceptable excipients well known in the art. These adjuvants enable the compounds of the present application to be formulated as tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions and the like, for oral administration to a patient.

Solid oral compositions may be prepared by conventional mixing, filling or tableting methods. For example, it can be obtained by the following method: the active compounds are mixed with solid adjuvants, optionally the mixture obtained is milled, if desired with further suitable adjuvants, and the mixture is then processed to granules, to give tablets or dragee cores. Suitable excipients include, but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.

The pharmaceutical compositions may also be adapted for parenteral administration, as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.

In all methods of administration of the compounds of general formula (I) described herein, the daily dose is from 0.01 to 200mg/kg body weight, preferably from 0.05 to 50mg/kg body weight, more preferably from 0.1 to 30mg/kg body weight, in single or divided doses.

The term "IC₅₀"is the half maximal inhibitory concentration, and refers to the concentration of a particular compound required to obtain 50% inhibition of a biological process in vitro. IC (integrated circuit)₅₀The values can be logarithmically converted into pIC₅₀Value (-log IC)₅₀) Wherein a higher value indicates a greater efficacy in an exponential manner.

The compounds of the present application may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combinations thereof with other chemical synthetic methods, and equivalents thereof known to those skilled in the art, with preferred embodiments including, but not limited to, the examples of the present application.

The chemical reactions of the embodiments herein are carried out in a suitable solvent that is compatible with the chemical changes of the present application and the reagents and materials required therefor. In order to obtain the compounds of the present application, it is sometimes necessary for a person skilled in the art to modify or select the synthesis steps or reaction schemes based on the existing embodiments.

For clarity, the present application is further illustrated by examples, which do not limit the scope of the present application. All reagents used herein were commercially available and used without further purification.

Detailed Description

The following examples illustrate the technical solutions of the present invention in detail, but the scope of the present invention includes but is not limited thereto.

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) and/or Mass Spectrometry (MS). NMR shift in units of 10^-6(ppm). Solvents for NMR measurement were deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and an internal standard was Tetramethylsilane (TMS).

Example 1: 8- (2, 4-dichlorophenyl) -9- (4- ((1- (3-fluoropropyl) azetidin-3-yl) amino) phenyl) -6, 7-dihydro-5H-benzo [7] cyclohepten-3-ol

Step 1: synthesis of 9- (4-hydroxyphenyl) -6, 7-dihydro-5H-benzo [7] cyclohepten-3-yl pivalate

Reacting 9- ((trifluoromethyl) sulfonyl) oxy) -6, 7-dihydro-5H-benzo [7]]Cyclohepten-3-yl pivalate (3.00g,7.65mmol), 4-hydroxyphenylboronic acid pinacol ester (1.68g,7.65mmol), [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (Pd (dppf) Cl₂) (560mg,0.76mmol) and cesium carbonate (4.97g,1.53mmol) were added to dioxane/water (V)_{(dioxane/water)}4:1) (30mL) was added to the mixed solvent, and the reaction was stirred at room temperature for 3 hours under an argon atmosphere. After the reaction was completed, the reaction solution was poured into 100mL of water, extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and subjected to column chromatography to give the title product.

Step 2: synthesis of 9- (4- ((trifluoromethyl) sulfonyl) oxy) phenyl) -6, 7-dihydro-5H-benzo [7] cyclohepten-3-yl pivalate

Reacting 9- (4-hydroxyphenyl) -6, 7-dihydro-5H-benzo [7]]Cyclohepten-3-yl pivalate (1.76g,5.20mmol) was dissolved in dry Dichloromethane (DCM) (30mL) and pyridine (496mg,6.30mmol) was added. The reaction solution was then cooled to-20 ℃ under argon blanket, and trifluoromethanesulfonic anhydride (Tf) was slowly added dropwise thereto at this temperature₂O) (2.95g,10.4 mmol). After the addition was complete, the reaction was allowed to warm to room temperature and stirred for 4 hours. After the reaction, the reaction solution was poured into 60mL of water, extracted with dichloromethane, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and the crude product was purified by column chromatography to give the title product.

And step 3: synthesis of 1-tert-butoxycarbonyl-3- ((4- (3- (pivaloyloxy) -6, 7-dihydro-5H-benzo [7] cyclohepten-9-yl) phenyl) amino) azetidine

Reacting 9- (4- ((trifluoromethyl) sulfonyl) oxy) phenyl) -6, 7-dihydro-5H-benzo [7]Cyclohepten-3-yl pivalate (1.77g,3.70mmol), 1-tert-butoxycarbonyl-3-aminocyclobutylamine (960mg,5.6mmol), cesium carbonate (3.62g,11.1mmol), tris (dibenzylideneacetone) dipalladium (Pd)₂(dba)₃) (340mg,0.370mmol) and 4, 5-bis diphenylphosphino-9, 9-dimethylxanthene (Xantphos) (430mg,0.740mmol) were added to dioxane (25 mL). The reaction solution was stirred at 110 ℃ for 4 hours under the protection of argon. After the reaction is finished, cooling, filtering, concentrating the filtrate under reduced pressure, and purifying by column chromatography to obtain the title product.

And 4, step 4: synthesis of 1-tert-butoxycarbonyl-3- ((4- (8-bromo-3- (pivaloyloxy) -6, 7-dihydro-5H-benzo [7] cyclohepten-9-yl) phenyl) amino) azetidine

Reacting 1-tert-butyloxycarbonyl-3- ((4- (3- (pivaloyloxy) -6, 7-dihydro-5H-benzo [7]]Cyclohepten-9-yl) phenyl) amino) azetidine (590mg,1.20mmol) was added to Tetrahydrofuran (THF) (10 mL). The resulting reaction solution was cooled to-20 ℃ and pyridine tribromide (PyHBr) was added thereto₃) (385mg,1.20 mmol). The reaction was continued for 30 minutes while maintaining-20 ℃. After the reaction, the reaction solution was poured into 50mL of saturated sodium bicarbonate solution, extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title product, which was used in the next reaction without purification.

And 5: synthesis of 1-tert-butoxycarbonyl-3- ((4- (8- (2, 4-dichlorophenyl) -3- (pivaloyloxy) -6, 7-dihydro-5H-benzo [7] cyclohepten-9-yl) phenyl) amino) azetidine

Crude product of 1-tert-butoxycarbonyl-3- ((4- (8-bromo-3- (pivaloyloxy) -6, 7-dihydro-5H-benzo [7]]Cyclohepten-9-yl) phenyl) amino) azetidine (1.20mmol), 2, 4-dichlorophenylboronic acid (344mg,1.80mmol), [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (87.8mg,0.120mmol) and cesium carbonate (780mg,2.40mmol) were added to dioxane/water (V)_{(dioxane/water)}4:1) (20mL), the resulting reaction mixture was stirred at 100 ℃ for 4 hours under argon atmosphere. After the reaction, the reaction mixture was cooled, poured into 80mL of water, extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to give the title product.

Step 6: synthesis of 9- (4- (azetidin-3-ylamino) phenyl) -8- (2, 4-dichlorophenyl) -6, 7-dihydro-5H-benzo [7] cyclohepten-3-yl pivalate

1-tert-Butoxycarbonyl-3- ((4- (8- (2, 4-dichlorophenyl) -3- (pivaloyloxy) -6, 7-dihydro-5H-benzo [7] cyclohepten-9-yl) phenyl) amino) azetidine (200mg,0.315mmol) was added to dichloromethane (4.7mL), the resulting reaction was cooled to 0 deg.C, trifluoroacetic acid (TFA) (2.3mL) was added, and stirring was continued at 0 deg.C for 4 hours. After the reaction was completed, the reaction mixture was diluted with 30mL of dichloromethane, and then poured into 30mL of saturated sodium bicarbonate solution, extracted with dichloromethane, the organic layers were combined, washed with saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title product, which was used in the next reaction without purification.

And 7: synthesis of 8- (2, 4-dichlorophenyl) -9- (4- ((1- (3-fluoropropyl) azetidin-3-yl) amino) phenyl) -6, 7-dihydro-5H-benzo [7] cyclohepten-3-yl pivalate

9- (4- (azetidin-3-ylamino) phenyl) -8- (2, 4-dichlorophenyl) -6, 7-dihydro-5H-benzo [7] cyclohepten-3-yl neopentyl ester (0.315mmol) was added to N-methylpyrrolidone (NMP) (4mL), followed by 3-fluoro-1-iodopropane (59.2mg,0.315mmol) and potassium carbonate (86.9mg,0.630 mmol). The resulting reaction solution was stirred at room temperature for overnight reaction. After the reaction was completed, the reaction solution was poured into 60mL of water, extracted with ethyl acetate, the organic layers were combined, washed with water, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to give the title compound.

And 8: synthesis of 3-hydroxy-8- (2, 4-dichlorophenyl) -9- (4- ((1- (3-fluoropropyl) azetidin-3-yl) amino) phenyl) -6, 7-dihydro-5H-benzo [7] cycloheptene

Reacting 8- (2, 4-dichlorophenyl) -9- (4- ((1- (3-fluoropropyl) azetidin-3-yl) amino) phenyl) -6, 7-dihydro-5H-benzo [7]]Cyclohepten-3-yl pivalate (80mg,0.134mmol) was added to tetrahydrofuran/methanol (MeOH) (V)_{(tetrahydrofuran/methanol)}To a mixed solvent of 2:1) (3mL), an aqueous sodium hydroxide solution (0.22mL,5M) was added with stirring at room temperature, and the resulting reaction mixture was reacted with stirring at room temperature for 4 hours. After the reaction, the reaction solution was poured into 20mL of water, the pH was adjusted to 6-7 with 1M dilute hydrochloric acid, extracted with ethyl acetate, the organic layers were combined, washed with water, washed with saturated salt solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by preparative liquid chromatography to give the title product.

CDCl₃δ_H 6.97–6.90(m,2H),6.72(d,J＝8.4Hz,1H),6.67(d,J＝2.5Hz,1H),6.60(d,J＝8.4Hz,2H),6.53(dd,J＝8.4,2.5Hz,1H),6.15(d,J＝8.4Hz,2H),4.47(t,J＝5.9Hz,1H),4.35(t,J＝5.9Hz,1H),4.04–3.93(m,1H),3.90–3.74(m,1H),3.71–3.59(m,2H),2.88–2.81(m,2H),2.75–2.63(m,2H),2.59–2.51(m,2H),2.24–2.15(m,2H),2.11–2.00(m,2H),1.77–1.71(m,1H),1.70–1.63(m,1H).

LC/MS(m/z,MH⁺):511.1

Example 2: (8- (2, 4-dichlorophenyl) -9- (4- ((1- (3-fluoropropyl) azetidin-3-yl) amino) phenyl) -6, 7-dihydro-5H-benzo [7] cyclohepten-3-yl) boronic acid

Step 1: synthesis of 8- (2, 4-dichlorophenyl) -9- (4- ((1- (3-fluoropropyl) azetidin-3-yl) amino) phenyl) -6, 7-dihydro-5H-benzo [7] cycloheptene-3-trifluoromethanesulfonate

Reacting 3-hydroxy-8- (2, 4-dichlorophenyl) -9- (4- ((1- (3-fluoropropyl) azetidin-3-yl) amino) phenyl) -6, 7-dihydro-5H-benzo [7]]Cycloheptene (1.06g, 2.09mmol), bis (trifluoromethanesulfonyl) aniline (PhNTf)₂) (1.49g, 4.17mmol) and Triethylamine (TEA) (0.63g, 6.26mmol) were added to 10mL of dichloromethane, and the reaction was completed after stirring at room temperature for 12 hours. Adding 100mL of water into the reaction solution, extracting with ethyl acetate, combining organic layers, drying with anhydrous sodium sulfate, concentrating the organic layer, and carrying out column chromatography to obtain the title compound.

Step 2: synthesis of N- (4- (8- (2, 4-dichlorophenyl) -3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -6, 7-dihydro-5H-benzo [7] cyclohepten-9-yl) phenyl) -1- (3-fluoropropyl) azetidin-3-amine

8- (2, 4-dichlorophenyl) -9- (4- ((1- (3-fluoropropyl) azetidin-3-yl) amino) phenyl) -6, 7-dihydro-5H-benzo [7] cycloheptene-3-trifluoromethanesulfonate (391mg, 0.61mmol), pinacol diboron diboride (310mg, 1.22mmol), potassium acetate (119mg, 1.22mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (44mg, 0.06mmol) was added to 4mL of 1, 4-dioxane and the reaction was completed after heating and refluxing for 15 hours under the protection of argon. The reaction was concentrated and column chromatographed to give the title compound.

And step 3: synthesis of (8- (2, 4-dichlorophenyl) -9- (4- ((1- (3-fluoropropyl) azetidin-3-yl) amino) phenyl) -6, 7-dihydro-5H-benzo [7] cyclohepten-3-yl) boronic acid

(N- (4- (8- (2, 4-dichlorophenyl) -3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -6, 7-dihydro-5H-benzo [7] cyclohepten-9-yl) phenyl) -1- (3-fluoropropyl) azetidin-3-amine (248mg, 0.40mmol) and sodium periodate (171mg, 0.80mmol) were added to a 15mL tetrahydrofuran/water-4/1 system, and after stirring at room temperature for 15 hours, the reaction was completed, PH 6-7 was adjusted and then added to 50mL water, ethyl acetate was extracted, and the organic layers were combined, dried over anhydrous sodium sulfate, and column chromatography was performed to give the title compound.

LC/MS(m/z,MH⁺):539.2.

Example 3: n- (4- (8- (2, 4-dichlorophenyl) -3- (1H-pyrazol-4-yl) -6, 7-dihydro-5H-benzo [7] cyclohepten-9-yl) phenyl) -1- (3-fluoropropyl) azetidin-3-amine

8- (2, 4-dichlorophenyl) -9- (4- ((1- (3-fluoropropyl) azetidin-3-yl) amino) phenyl) -6, 7-dihydro-5H-benzo [7] cycloheptene-3 trifluoromethanesulfonate (192mg, 0.30mmol) was added to a 5mL1, 4-dioxane/water ═ 4/1 system, and 4-pyrazoloboroic acid pinacol ester (58.0mg, 0.30mmol), potassium carbonate (84.0mg, 0.61mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (22.3mg, 0.03mmol) was added. Heating to 100 ℃ under the protection of argon, and finishing the reaction after 15 hours. The reaction was concentrated and column chromatographed to give the title compound.

LC/MS(m/z,MH⁺):561.2

Example 4: (S) -4- (8- (2, 4-dichlorophenyl) -9- (4- ((1- (3-fluoropropyl) pyrrolidin-3-yl) oxy) phenyl) -6, 7-dihydro-5H-benzo [7] cyclohepten-3-yl) -1H-pyrazole

Starting material 1 was prepared according to WO2017140669a1, example 18. Starting material 1(1.10g, 2.09mmol), bis (trifluoromethanesulfonyl) aniline (1.49g, 4.17mmol), N, N-diisopropylethylamine (i.e., DIPEA) (0.54g, 4.18mmol) was added to 10mL of dichloromethane and stirred at room temperature for 12 hours before completion of the reaction. Adding 100mL of water into the reaction solution, extracting with ethyl acetate, combining organic layers, drying with anhydrous sodium sulfate, concentrating the organic layer, and performing column chromatography to obtain an intermediate 2. Intermediate 2(198mg, 0.30mmol) was added to a 5mL system of 1, 4-dioxane/water (4/1), and 4-pyrazoloboronic acid pinacol ester (58.0mg, 0.30mmol), potassium carbonate (84.0mg, 0.61mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (22.3mg, 0.03mmol) was added. Heating to 100 ℃ under the protection of argon, and finishing the reaction after 15 hours. The reaction was concentrated and column chromatographed to give the title compound.

DMSO-d6δ_H 7.89(s,2H),7.43(m,1H),7.35-7.29(m,2H),7.08-6.98(m,2H),6.95-6.88(m,1H),6.85-6.79(m,2H),6.59-6.54(m,2H),4.80-4.73(s,1H),4.61-4.55(m,1H),4.48-4.43(m,1H),2.93-2.76(m,4H),2.76-2.65(s,3H),2.35-2.13(m,5H),2.17-1.87(m,4H).

LC/MS(m/z,MH⁺):576.2

Example 5: (S) -4- (8- (2, 4-dichlorophenyl) -9- (4- ((1- (3-fluoropropyl) pyrrolidin-3-yl) oxy) phenyl) -6, 7-dihydro-5H-benzo [7] cyclohepten-3-yl) -1H-pyrazole

In analogy to the procedure for the synthesis of example 2, step 2 to step 3, the difference was that 8- (2, 4-dichlorophenyl) -9- (4- ((1- (3-fluoropropyl) azetidin-3-yl) amino) phenyl) -6, 7-dihydro-5H-benzo [7] cycloheptene-3-trifluoromethanesulfonate from step 2 was replaced with (S) -8- (2, 4-dichlorophenyl) -9- (4- ((1- (3- (fluoropropyl) pyrrolidin-3-yl) oxy) phenyl) -6, 7-dihydro-5H-benzo [7] cycloheptene-3-trifluoromethanesulfonate, obtained in example 4 above, and the title compound was obtained in the same manner.

DMSO-d6δ_H 8.03(s,1H),7.74(s,1H),7.63-7.56(m,2H),7.32-7.15(m,2H),6.85-6.67(m,4H),5.07-4.98(s,1H),4.61-4.52(m,1H),4.49-4.43(m,1H),3.30-3.11(m,7H),2.92-2.77(s,2H),2.23-1.93(m,7H).

LC/MS(m/z,MH⁺):554.1

Example 6: (S) -3- (4- (8- (2, 4-dichlorophenyl) -3- (difluoromethyl) -6, 7-dihydro-5H-benzo [7] cyclohepten-9-yl) phenoxy) -1- (3-fluoropropyl) pyrrolidine

Step 1: synthesis of (S) -8- (2, 4-dichlorophenyl) -9- (4- ((1- (3-fluoropropyl) pyrrolidin-3-yl) oxy) phenyl) -N-methoxy-N-methyl-6, 7-dihydro-5H-benzo [7] cycloheptene-3-carboxamide

(S) -8- (2, 4-dichlorophenyl) -9- (4- ((1- (3-fluoropropyl) pyrrolidin-3-yl) oxy) phenyl) -6, 7-dihydro-5H-benzo [7] cycloheptene-3-carboxylic acid was prepared according to WO2017140669A1, example 51. (S) -8- (2, 4-dichlorophenyl) -9- (4- ((1- (3-fluoropropyl) pyrrolidin-3-yl) oxy) phenyl) -6, 7-dihydro-5H-benzo [7] cycloheptene-3-carboxylic acid (400mg, 0.72mmol) was dissolved in 2mL of N, N-dimethylformamide, N, N-diisopropylethylamine (465mg,3.61mmol), 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU) (547mg,1.44mmol), methoxymethylamine hydrochloride (140mg,1.44mmol) were added, after stirring at room temperature for 1.5 hours, 50mL of water was added, ethyl acetate was extracted, the organic layers were combined, dried over anhydrous sodium sulfate, the organic layer was concentrated and column chromatographed to give the title compound.

Step 2: synthesis of (S) -8- (2, 4-dichlorophenyl) -9- (4- ((1- (3- (fluoropropyl) pyrrolidin-3-yl) oxy) phenyl) -6, 7-dihydro-5H-benzo [7] cycloheptene-3-carbaldehyde

Dissolving a crude product of (S) -8- (2, 4-dichlorophenyl) -9- (4- ((1- (3-fluoropropyl) pyrrolidin-3-yl) oxy) phenyl) -N-methoxy-N-methyl-6, 7-dihydro-5H-benzo [7] cycloheptene-3-carboxamide (420mg, 0.72mmol) in 2mL of tetrahydrofuran, dropwise adding a diisobutylaluminum hydride (DIBAL-H)1M tetrahydrofuran solution (3mL, 3.00mmol) at 20 ℃, after the reaction is finished at 20 ℃ for 1.5 hours, dropwise adding a small amount of water to quench the reaction, extracting with ethyl acetate, and carrying out column chromatography after concentration to obtain the title compound.

And step 3: synthesis of (S) -3- (4- (8- (2, 4-dichlorophenyl) -3- (difluoromethyl) -6, 7-dihydro-5H-benzo [7] cyclohepten-9-yl) phenoxy) -1- (3-fluoropropyl) pyrrolidine

The crude ((S) -8- (2, 4-dichlorophenyl) -9- (4- ((1- (3- (fluoropropyl) pyrrolidin-3-yl) oxy) phenyl) -6, 7-dihydro-5H-benzo [7] cycloheptene-3-carbaldehyde (60.0mg, 0.11mmol) was dissolved in 2mL of dichloromethane, diethylamido sulfur trifluoride (DAST) (0.15mL, 0.50mmol) was added dropwise at-20 ℃, the mixture was allowed to naturally warm to room temperature for reaction for 16 hours, 30mL of a saturated aqueous sodium bicarbonate solution was added dropwise, extraction was performed with ethyl acetate, the organic layers were combined, and column chromatography was performed after concentration to give the title compound.

DMSO-d₆δ(ppm):7.60-7.59(m,1H),753(s,1H),7.39-7.37(m,1H),7.28-7.26(m,1H),7.20-7.03(m,2H),6.91-6.89(m,1H),6.74-6.72(m,2H),6.66-6.64(m,2H),4.73(s,1H),4.53-4.50(m,1H),4.41-4.38(m,1H),2.91-2.90(m,2H),2.78(s,1H),2.63(s,1H),2.45-2.37(m,2H),2.22-2.15(m,6H),1.83-1.65(m,4H).

LC/MS(m/z,M+H⁺):560.2

Example 7: (S) -8- (2, 4-dichlorophenyl) -9- (4- ((5- (3-fluoropropyl) -5-azaspiro [2.4] heptan-7-yl) amino) phenyl) -6, 7-dihydro-5H-benzo [7] cycloheptene-3-carboxylic acid

Step 1: synthesis of methyl (S) -8- (2, 4-dichlorophenyl) -9- (4- ((5- (3-fluoropropyl) -5-azaspiro [2.4] heptan-7-yl) amino) phenyl) -6, 7-dihydro-5H-benzo [7] cycloheptene-3-carboxylate

Starting from the intermediate 9- (4- ((trifluoromethyl) sulfonyl) oxy) phenyl) -6, 7-dihydro-5H-benzo [7] cyclohepten-3-yl pivalate obtained in example 1 above, the same procedures as in step 3 to step 8 in example 1 were carried out, except that tert-butyl (7S) -7-amino-5-azaspiro [2.4] heptane-5-carboxylate was used instead of 1-tert-butoxycarbonyl-3-aminocyclobutylamine in example 3, to obtain an intermediate 4 compound. Intermediate 5, i.e., (S) -8- (2, 4-dichlorophenyl) -9- (4- ((5- (3-fluoropropyl) -5-azaspiro [2.4] heptan-7-yl) amino) phenyl) -6, 7-dihydro-5H-benzo [7] cycloheptene-3-trifluoromethanesulfonate, was prepared in the same manner as in step 1 of example 2. (S) -8- (2, 4-dichlorophenyl) -9- (4- ((5- (3-fluoropropyl) -5-azaspiro [2.4] heptan-7-yl) amino) phenyl) -6, 7-dihydro-5H-benzo [7] cycloheptene-3-trifluoromethanesulfonate (340mg, 0.50mmol) was added to 8mL of N, N-dimethylformamide, 2mL of triethylamine, 4mL of methanol, followed by [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (22.3mg, 0.03 mmol). Introducing carbon monoxide gas, heating to 70 ℃, and finishing the reaction after 5 hours. The reaction solution is concentrated and then is subjected to column chromatography to prepare (S) -8- (2, 4-dichlorophenyl) -9- (4- ((5- (3-fluoropropyl) -5-azaspiro [2.4] heptane-7-yl) amino) phenyl) -6, 7-dihydro-5H-benzo [7] cycloheptene-3-carboxylic acid methyl ester.

Step 2: synthesis of (S) -8- (2, 4-dichlorophenyl) -9- (4- ((5- (3-fluoropropyl) -5-azaspiro [2.4] heptan-7-yl) amino) phenyl) -6, 7-dihydro-5H-benzo [7] cycloheptene-3-carboxylic acid

Adding (S) -8- (2, 4-dichlorophenyl) -9- (4- ((5- (3-fluoropropyl) -5-azaspiro [2.4] heptane-7-yl) amino) phenyl) -6, 7-dihydro-5H-benzo [7] cycloheptene-3-carboxylic acid methyl ester (300mg,0.50mmol) into 10mL of methanol, adding 1mL of sodium hydroxide aqueous solution (5mol/L), heating to 60 ℃, stirring for 2 hours, adjusting the pH to 3-4 by using 2mol/L dilute hydrochloric acid solution, extracting by using ethyl acetate, combining organic layers, drying by using sodium sulfate, concentrating the organic layer, and carrying out column chromatography to obtain the title compound.

DMSO-d6δ_H 7.85(s,1H),7.73-7.71(m,1H),7.58-7.55(m,1H),7.27-7.25(m,1H),7.18-7.15(m,1H),6.83-6.81(m,1H),6.49-6.47(m,2H),6.32-6.30(m,2H),5.44-5.42(m,1H),4.54-4.51(m,1H),4.42-4.39(m,1H),3.62-3.59(m,1H),3.00-2.91(m,1H),2.85-2.82(m,2H),2.59-2.55(m,1H),2.46-2.42(m,2H),2.33-2.30(m,1H),2.13-2.07(m,3H),1.81-1.71(m,2H),0.71-0.67(m,1H),0.57-0.51(m,2H),0.40-0.38(m,1H).

LC/MS(m/z,MH⁺):579.2

Example 8: (S) -8- (2, 4-dichlorophenyl) -9- (4- ((5- (3-fluoropropyl) -5-azaspiro [2.4] heptan-7-yl) amino) phenyl) -6, 7-dihydro-5H-benzo [7] cycloheptene-3-boronic acid

In analogy to the synthesis procedure of example 2, step 2-step 3, the difference being that 8- (2, 4-dichlorophenyl) -9- (4- ((1- (3-fluoropropyl) azetidin-3-yl) amino) phenyl) -6, 7-dihydro-5H-benzo [7] cycloheptene-3 trifluoromethanesulfonate in step 2 of example 2 was replaced by (S) -8- (2, 4-dichlorophenyl) -9- (4- ((5- (3-fluoropropyl) -5-azaspiro [2.4] heptan-7-yl) amino) phenyl) -6, 7-dihydro-5H-benzo [7] cycloheptene-3-trifluoromethanesulfonate, the intermediate obtained above in example 7, the title compound was prepared in the same manner.

LC/MS(m/z,MH⁺):579.2

Example 9: (S) -N- (4- (8- (2, 4-dichlorophenyl) -3- (1H-pyrazol-4-yl) -6, 7-dihydro-5H-benzo [7] cyclohepten-9-yl) phenyl) -5- (3-fluoropropyl) -5-azaspiro [2.4] hept-7-amine

Analogously to the synthesis procedure of example 3, with the difference that 8- (2, 4-dichlorophenyl) -9- (4- ((1- (3-fluoropropyl) azetidin-3-yl) amino) phenyl) -6, 7-dihydro-5H-benzo [7] cycloheptene-3 trifluoromethanesulfonate in example 3 was replaced by (S) -8- (2, 4-dichlorophenyl) -9- (4- ((5- (3-fluoropropyl) -5-azaspiro [2.4] heptan-7-yl) amino) phenyl) -6, 7-dihydro-5H-benzo [7] cycloheptene-3-trifluoromethanesulfonate, intermediate 5 prepared in example 7 above, the title compound was prepared in the same manner.

LC/MS(m/z,MH⁺):601.2

Example 10: (S) -8- (2, 4-dichlorophenyl) -9- (4- ((5- (3-fluoropropyl) -5-azaspiro [2.4] heptan-7-yl) amino) phenyl) -6, 7-dihydro-5H-benzo [7] cyclohepten-3-ol

In analogy to the procedure for the synthesis of step 8 of example 1, with the difference that 8- (2, 4-dichlorophenyl) -9- (4- ((1- (3-fluoropropyl) azetidin-3-yl) amino) phenyl) -6, 7-dihydro-5H-benzo [7] cyclohepten-3-yl pivalate in step 8 of example 1 was replaced with intermediate 3 prepared in example 7 above, i.e., ((S) -8- (2, 4-dichlorophenyl) -9- (4- ((5- (3-fluoropropyl) -5-azaspiro [2.4] heptan-7-yl) amino) phenyl) -6, 7-dihydro-5H-benzo [7] cyclohepten-3-yl pivalate, the title compound was prepared in the same manner.

DMSO-d6δ_H 9.44(s,1H),7.53(s,1H),7.23-7.21(m,1H),7.13-7.10(m,1H),6.69-6.68(m,1H),6.61-6.55(m,2H),6.49-6.47(m,2H),6.31-6.27(m,2H),5.40-5.38(m,1H),4.54-4.51(m,1H),4.42-4.39(m,1H),3.64-3.62(m,1H),3.04-3.00(m,1H),2.73-2.70(m,2H),2.59-2.57(m,1H),2.46-2.43(m,3H),2.34-2.30(m,1H),2.13-2.03(m,4H),1.83-1.70(m,2H),0.74-0.69(m,1H),0.60-0.50(m,2H),0.40-0.35(m,1H).

LC/MS(m/z,MH⁺):551.2

Examples of biological Activity and related Properties

Test example 1: detection of degradation effect of compound of the invention on MCF7 intracellular estrogen receptor

The test principle is as follows: determination of the degradative Activity of the Compounds of the invention on endogenously expressed Estrogen receptors in MCF7 cells, according to IC₅₀And evaluating the activity of the compound to be tested by the maximum degradation efficiency.

The test method comprises the following steps:

MCF7 cells (purchased from ATCC, HTB-22) were cultured in DMEM (purchased from Gibco, 11995-. The first day of experiment, MCF7 cells were seeded at 3000 cells/well in 384-well plates at 37 ℃ with 5% CO using complete medium₂And (5) culturing in a cell culture box. Test compounds were dissolved in DMSO at a stock concentration of 10mM, diluted with Echo550 (available from Labcyte Inc.) and added to the cell culture plate, each compound treatment was initiated at 100nM, diluted in a 3-fold gradient, 9 concentration points, a blank containing 0.5% DMSO was set up, and a duplicate well control was set up for each concentration point. 37 ℃ and 5% CO₂The cell culture box was cultured for 24 hours. Adding paraformaldehyde into each cell culture well, fixing cells at a final concentration of about 3.7%, reacting for 30min, removing supernatant, and washing with 50 μ L PBS once per well; PBS containing 0.5% v/v Tween 20 was added to treat the cells for 30 minutes, and washed once with PBS; adding blocking solution (self-made, 5% BSA contained in PBS, 0.05% Tween 20) and incubating at room temperature for 1 hour; removing the blocking solution, adding primary antibody mixture (anti-ER monoclonal antibody, Estrogen Receptor alpha (D8H8) Rabbit mAb purchased from GST, #8644S, diluted at 1: 1000; anti-GAPDH monoclonal antibody, GAPDH (D4C6R) Mouse mAb purchased from GST, #97166S, diluted at 1: 2000) and incubating at room temperature for 3 hours; washing with PBST (home-made, containing 0.05% Tween 20 in PBS) for 3 times; adding a detection secondary antibody (800 CW-goat anti-rabbit IgG, purchased from LI-COR, P/N:926-32211, diluted 1: 1000;680 RD-goat anti-mouse IgG, purchased from LI-COR, # 925-: 1000 dilution), room temperature, and incubation for 45 minutes in the dark; PBST was washed 3 times and the fluorescence signal from each well was read using the Odyssey CLx. XLFit was used for data processing, and the inhibitory activity IC of each compound was calculated from the concentration of the compound and the fluorescence signal value₅₀And a maximum suppression ratio Imax.

And (3) test results:

under the present experimental conditions, the test compounds have good inhibitory activity against ER level at a cell-based level. The results of the ER level activity assay for the test compounds are shown in Table 1.

TABLE 1 results of in vitro cell-level-based ER level Activity assay for test Compounds

Test compounds	ER level IC50(nM)
		Example 1	0.12
Example 4	0.64
		Example 5	0.58
Example 10	0.35

Test example 2: examination of inhibitory Effect of the Compound of the present invention on proliferation of T47D cells

The test principle is as follows: determining the inhibition effect of the Compounds of the invention on the in vitro proliferation of T47D cellsAccording to IC₅₀And the maximum inhibition efficiency to evaluate the activity of the compound.

The test method comprises the following steps:

T47D (T-47D) cells (purchased from ATCC, HTB-133) were cultured in RPMI-1640 (purchased from Gibco, A10491-01) complete medium containing 10% fetal bovine serum. On the first day of experiment, T47D cells were seeded at a density of 500 cells/well in 384-well plates at 37 ℃ with 5% CO using complete medium₂The cell culture box was cultured overnight. The next day, test compound was added for drug treatment, and a10 mM stock solution of each compound was diluted with Echo550 (available from labcell Inc.) and transferred to each cell culture well at an initial intracellular treatment concentration of 100nM, 3-fold gradient dilution, 10 concentration points, a blank containing 0.3% DMSO was set, and a duplicate well control was set for each concentration point. 37 ℃ and 5% CO₂The cell culture box is used for 7 days, and on the eighth day, the cell culture plate is taken out. Adding into

Luminescennt Cell visual Assay (available from Promega, G7573) was allowed to stand at room temperature for 10 minutes, and then the luminescence signal value was read using a multi-label microplate reader EnVision (available from PerkinElmer), and the inhibitory activity IC of each compound was calculated from the concentration of the compound and the luminescence signal value using XLfit₅₀。

And (3) test results:

under the conditions of this experiment, the test compound showed good inhibitory activity against T47D breast cancer cells. The results of the inhibitory activity of the test compounds on MCF7 cell proliferation are detailed in table 2.

TABLE 2 inhibitory Activity of Compounds on MCF7 cell proliferation

Test compounds	T47D IC50(nM)
		Example 4	2.98
Example 5	2.89

Test example 3: pharmacokinetic Property testing of Compounds of the invention

The test principle is as follows: the drug concentration in the blood plasma of the mice at different times after the mice are subjected to gastric lavage and intravenous administration of the compound is measured by using the LC-MS/MS method by taking the mice as test animals. The pharmacokinetic behavior of the compounds of the invention in mice was studied and their pharmacokinetic profile was evaluated.

The test method comprises the following steps:

3.1 test animals

Healthy adult BALB/c mice 12, female, divided into 2 groups on average, 6 per group, 3 gavage, 3 veins, mice purchased from beijing weitongli laboratory animal technology ltd, animal production license number: SCXK (Zhe) 2019-.

3.2 pharmaceutical preparation

Weighing a certain amount of medicine, dissolving in DMSO 5% + Propylene Glycol (PG) 20% + absolute ethyl alcohol

10 percent of (polyethylene glycol-15 hydroxystearate) and 60 percent of water are prepared into 10mg/ml for intragastric administration. Weighing a certain amount of medicine, dissolving in DMSO 1% + PG 4% + absolute ethyl alcohol

2% + 92% water, formulated at 1mg/ml for intravenous injection.

3.3 administration of drugs

And (3) gastric lavage group: BALB/c mice were fasted overnight and then gavaged at a dose of 10mg/kg and a volume of 1 mL/kg.

Vein group: BALB/c mice were administered intravenously after overnight fasting at a dose of 1mg/kg and a volume of 1 mL/kg.

3.4 operation

After the mice are administrated by gastric lavage or intravenous injection, blood is collected from orbit for 5min, 15min, 30min, 1h, 2h, 4h and 24h, and 40 mu L and 5 mu L are obtained. EDTA-K2 anticoagulation, 12000rpm, 4 ℃,5 minutes centrifugal separation of plasma, at-20 ℃ storage.

Determining the content of the compound to be tested in the plasma of the mouse after the drugs with different concentrations are administered by gastric lavage or vein: melting the sample at room temperature, and vortexing for 1 min; quantitatively transferring 15 mu L into a 96-well plate of 2ml, adding 150 mu L of an internal standard precipitator tolbutamide acetonitrile solution, and oscillating (1200rpm 3 min); centrifuge (4000rpm 15min), transfer supernatant 100 μ L to 1mL 96 well plates; after blowing dry with nitrogen, 100. mu.L of the double solution (acetonitrile: water 1: 9) was added, shaken (900rpm 3min) and 20. mu.L of the solution was injected for analysis. LC-MS/MS conditions: mobile phase A, 0.1% aqueous formic acid, mobile phase B: 0.1% formic acid acetonitrile, column: ACE C185 μm (3.0mm x 50mm), column temperature: flow rate 0.5ml/min at 35 ℃.

And (3) test results:

under the conditions of the experiment, the tested compounds show better pharmacokinetic properties, and the results are shown in table 3.

TABLE 3 pharmacokinetic parameters after single gavage administration of Compounds in mice

The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (14)

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

wherein:

X¹、X²、X³、X⁴independently selected from CR⁹Or N;

w is selected from NR⁸O or S;

het is selected from

R⁵Is selected from C_1-6Alkyl radical, C_2-8Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl or 3-6 membered heterocycloalkyl, said C_1-6Alkyl radical, C_2-8Alkenyl radical, C₂-₄Alkynyl, C_3-6Cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted with 1 or more groups selected from: F. cl, Br, I, CN, OH, OCH₃And SO₂CH₃；

R⁸Selected from H, C_1-6Alkyl radical, C_2-8Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl or 3-6 membered heterocycloalkyl, said C_1-6Alkyl radical, C_2-8Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted with 1 or more groups selected from: F. cl, Br, I, CN, OH, OCH₃And SO₂CH₃；

R⁹Selected from H, F, Cl, Br, I, OH, CN, C_1-6Alkyl radical, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, C_1-6Alkoxy radical, C_3-6Cycloalkyloxy or 3-6 membered heterocyclyloxy;

R¹、R²、R⁷each independently selected from hydrogen, OH, F, Cl, Br, I, C_1-6Alkyl radical, C_3-6Cycloalkyl or 3-6 membered heterocycloalkyl;

or R¹、R²Together with the carbon atom to which they are attached form C_3-6Cycloalkyl or 3-6 membered heterocycloalkyl, said C_3-6Cycloalkyl or 3-6 membered heterocycloalkyl optionally substituted with R^aSubstitution;

or, R¹、R²Or R⁷Any of them with R⁸And C and N to which they are each attached, together form a 3-6 membered heterocyclyl;

R³selected from H, OH, COOH, BR¹⁰R¹¹、C(O)OR^b、OC(O)R^b、C_1-6Alkyl radical, C_1-6Alkoxy radical, C_6-10Aryl or 5-to 10-membered heteroaryl, said C_1-6Alkyl radical, C_1-6Alkoxy radical, C_6-10Aryl or 5-10 membered heteroaryl optionally substituted with 1 or more R^cSubstitution;

R⁴is selected from C_6-10Aryl or 5-to 10-membered heteroaryl, said C_6-10Aryl or 5-10 membered heteroaryl optionally substituted with 1 or more R^dSubstitution;

R⁶selected from H, F, Cl, Br, I or OH;

R¹⁰、R¹¹independently selected from OH, or R¹⁰、R¹¹Taken together with B to which it is attached form a 5-6 membered heterocycloalkyl group, said 5-6 membered heterocyclyl group being optionally substituted with C_1-10Alkyl substitution;

R^aselected from F, Cl, Br, I, OH, CN, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-6Cycloalkyl or 3-6 membered heterocyclyl, said C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-6Cycloalkyl or 3-6 membered heterocyclyl is optionally substituted with halogen;

R^bis independently selected from C_1-6Alkyl radical, C_2-8Alkenyl radical, C_2-4Alkynyl, C_3-6Cycloalkyl, 3-6 membered heterocyclyl, C_6-10Aryl or 5-10 membered heteroaryl;

R^c、R^dindependently selected from F, Cl, Br, I, OH, CN, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-6Cycloalkyl or 3-6 membered heterocyclyl, said C₁-₆Alkyl radical, C_1-6Alkoxy radical, C_3-6Cycloalkyl or 3-6 membered heterocyclyl is optionally substituted with 1 or more groups selected from halogen or OH;

n is 0, 1 or 2;

p is 1 or 2;

with the following conditions: (1) when R is¹、R²C not linked to it forms a ring and N is 1 and W is NWhen H, R³Is not OH; (2) when R is¹、R²When C not bound thereto forms a ring and n is 1 and W is O, R³Not being OH, COOH or COOCH₃。

2. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein when R is¹、R²When C not linked thereto forms a ring and W ═ O, n is 0.

3. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1 wherein Het is selected from

4. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1 wherein when the atom to which Het is attached to W is a chiral carbon, it is in the (S) -configuration.

5. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1 wherein Het is selected from

Wherein R is¹、R²Are all H, and R⁷Not with R⁸Looping.

6. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 5 wherein n is 0 or 1, R³Selected from OH and C_1-6Alkyl radical, C_1-6Alkoxy radical, BR¹⁰R¹¹Or 5-10 membered heteroaryl, said C_1-6Alkyl radical, C_1-6Alkoxy or 5-10 membered heteroaryl optionally substituted with 1 or more R^cAnd (4) substitution.

7. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein H iset is selected from

Wherein R is¹、R²Together with the carbon atom to which they are attached form C_3-6Cycloalkyl or 3-6 membered heterocycloalkyl, said C_3-6Cycloalkyl or 3-6 membered heterocycloalkyl optionally substituted with R^aAnd (4) substitution.

8. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1 wherein Het is selected from

9. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 8 wherein Het is selected from

More preferably

10. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R is³Selected from H, OH, COOH, BR¹⁰R¹¹、C(O)OR^b、C_1-6Alkyl radical, C_1-6Alkoxy radical, C_6-10Aryl or 5-to 10-membered heteroaryl, said C_1-6Alkyl radical, C_1-6Alkoxy radical, C_6-10Aryl or 5-10 membered heteroaryl optionally substituted with 1 or more R^cSubstitution; the R is⁴Selected from the group consisting of optionally substituted by 1 or more R^dSubstituted C_6-10An aryl group; r⁵Is C optionally substituted by F, Cl, Br, I, CN or OH_1-6An alkyl group; r⁶Selected from H or OH.

11. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from a compound of formula (II) or a pharmaceutically acceptable salt thereof:

wherein R is³、R⁴W and Het are as defined in claim 1.

12. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from one of the following structures:

13. a pharmaceutical composition comprising a compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

14. Use of a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 13 for the manufacture of a medicament for the prevention or treatment of an estrogen receptor related disorder, preferably a tumour.