Estrogen receptor modulators and uses thereof

Abstract

The present application describes a compound having estrogen receptor modulating activity or function and a pharmaceutically acceptable salt thereof, wherein the compound has a structure of formula (I) and has substituents and structural features described in the present application. The present application also describes a pharmaceutical composition 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 preparation of a drug for preventing or treating estrogen receptor-related diseases. #imgabs0#

Description

[0001] This application claims priority to a prior application filed with the State Intellectual Property Office on June 22, 2020, with patent application number 202010572695.6 and invention name “Estrogen receptor modulators and uses thereof”. The entire text of the prior application is incorporated into this application by reference. Technical Field

[0002] The present application relates to an estrogen receptor modulator compound or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the compound, and the use thereof in preventing or treating estrogen receptor-related diseases. Background Art

[0003] Estrogen (E2) and estrogen α receptor (ERα) are important driving factors for the development of breast cancer. More than two-thirds of breast cancer patients express ER transcription factors, and in most ER-positive patients, ER is still a key driving factor even in tumors that progress after early endocrine therapy. Therefore, ER is a major target for breast cancer treatment (Pharmacology & Therapeutics 186 (2018) 1-24). The purpose of endocrine therapy is to reduce ER activity. There are three main types of endocrine therapy, including selective estrogen receptor modulators (SERMs), such as tamoxifen, which is an allosteric modulator of ER and inhibits its transcriptional activity after binding to ER; aromatase inhibitors (AIs), which reduce estrogen levels in the body by inhibiting the conversion of androgens to estrogens; and selective estrogen receptor downregulators, such as fulvestrant, which not only inhibits ER activity as an antagonist, but also has the effect of inducing ER protein degradation. Although endocrine therapy is the first choice for patients with estrogen receptor-positive breast cancer, about 30% of patients will relapse after treatment, and almost all patients with metastatic breast cancer will develop drug resistance and progress. There are two main mechanisms for endocrine therapy resistance. One is focused on the estrogen receptor signaling pathway itself, including activating mutations, amplification, fusion with other genes, and dysregulation of estrogen receptor coregulators and downstream cell cycle control factors in the gene ESR1 encoding the estrogen receptor; the other mechanism includes the activation of signaling pathways that cross-react with the estrogen receptor signaling pathway, such as the growth factor receptor pathway (Oncol Ther, 2017, 5:17–29).

[0004] Fulvestrant is the first and only clinically approved selective estrogen receptor downregulator (SERDs) for the treatment of postmenopausal patients with ER-positive, metastatic breast cancer after progression on tamoxifen or aromatase inhibitors. In addition, AstraZeneca (see patent application WO2018077630A1) and Genentech (see patent application WO2019245974A1) have also disclosed a series of novel SERD compounds and corresponding medical uses. Data from multiple studies have shown that ER degradation has not been completely achieved in patients treated with fulvestrant, but it may also be that the dose of fulvestrant (up to 500 mg, mainly due to its pharmacodynamic characteristics and intramuscular administration route, which limit the maximum dose that can be given to patients) limits its efficacy. Therefore, SERD drugs with higher bioavailability, higher antagonistic activity against ER, greater ER degradation, and convenient oral administration that can be used in premenopausal patients with high estrogen levels are urgently needed clinically. Summary of the invention

[0005] The present application relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof,

[0006]

[0007] in:

[0008] X 1 , X 2 , X 3 , X 4 Independently selected from CR 9 or N;

[0009] W is selected from NR 8 , O or S;

[0010] Het is selected from

[0011] R 5 Selected from C 1-6 Alkyl, C 2-8 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, the C 1-6 Alkyl, C 2-8 Alkenyl, C2-4 alkynyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted by one or more groups selected from the group consisting of F, Cl, Br, I, CN, OH, OCH3 and SO2CH3;

[0012] R 8 Selected from H, C1-6 Alkyl, C 2-8 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, the C 1-6 Alkyl, C 2-8 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted by one or more groups selected from the group consisting of F, Cl, Br, I, CN, OH, OCH3 and SO2CH3;

[0013] R 9 Selected from H, F, Cl, Br, I, OH, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 1-6 Alkoxy, C 3-6 Cycloalkyloxy or 3-6 membered heterocyclyloxy;

[0014] R 1 , R 2 , R 7 Each independently selected from hydrogen, OH, F, Cl, Br, I, C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl;

[0015] or R 1 , R 2 The carbon atom to which it is connected forms C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, the C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted by R a replace;

[0016] Or, R 1 , R 2 or R 7 Any one of them and R 8 and the C and N to which they are connected together form a 3-6 membered heterocyclic group;

[0017] R 3 Selected from H, OH, COOH, BR 10 R 11 、C(O)OR b 、OC(O)R b , C 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl or 5-10 membered heteroaryl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl or 5-10 membered heteroaryl is optionally substituted with one or more Rc replace;

[0018] R 4 Selected from C 6-10 Aryl or 5-10 membered heteroaryl, the C 6-10 Aryl or 5-10 membered heteroaryl is optionally substituted with one or more R d replace;

[0019] R 6 is selected from H, F, Cl, Br, I or OH;

[0020] R 10 , R 11 Independently selected from OH, or R 10 , R 11 The B connected thereto together forms a 5-6 membered heterocyclic alkyl group, wherein the 5-6 membered heterocyclic group is optionally substituted by C 1-10 Alkyl substitution;

[0021] R a Selected from F, Cl, Br, I, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 The cycloalkyl or 3-6 membered heterocyclyl is optionally substituted by halogen;

[0022] R b Independently selected from C 1-6 Alkyl, C 2-8 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0023] R c , R d Independently selected from F, Cl, Br, I, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C1-6 alkyl, C 1-6 Alkoxy, C 3-6 The cycloalkyl or 3-6 membered heterocyclyl is optionally substituted by one or more groups selected from halogen or OH;

[0024] n is 0, 1 or 2;

[0025] p is 1 or 2;

[0026] The conditions are: (1) When R 1 , R2 When the C not connected to it forms a ring and n=1 and W=NH, R 3 Not OH; (2) When R 1 , R 2 When the C not connected to it forms a ring and n=1 and W=O, R 3 Not OH, COOH or COOCH3.

[0027] In some embodiments, when R 1 , R 2 When the C not connected thereto forms a ring and W=O, n=0.

[0028] In some embodiments, the Het is selected from

[0029] In some embodiments, the Het is selected from Where R 1 , R 2 Both are H and R 7 Not with R 8 Form a ring.

[0030] In some embodiments, the Het is selected from Where R 1 , R 2 Both are H and R 7 Not with R 8 To form a ring, n is 0 or 1.

[0031] In some embodiments, the Het is selected from Where R 1 , R 2 Both are H and R 7 Not with R 8 To form a ring, n is 0.

[0032] In some embodiments, the Het is selected from Where R 1 , R 2 The carbon atom to which it is connected forms C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, the C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted by R a replace.

[0033] In some embodiments, the Het is selected from Where R 1 , R 2 The carbon atom to which it is connected forms C 3-6 Cycloalkyl, the C 3-6 The cycloalkyl group is optionally substituted by R a replace.

[0034] In some embodiments, the Het is selected from Where R 1 , R 2 The carbon atom to which it is attached together forms cyclopropane.

[0035] In some embodiments, the Het is selected from Where R 1 , R 2 or R 7 Any one of them and R 8 and the C and N to which they are connected together form a 3-6 membered heterocyclic group.

[0036] In some embodiments, the Het is selected from Where R 1 , R 2 or R 7 Any one of them and R 8 and the C and N to which they are connected together form a pyrrolidine ring or a piperidine ring.

[0037] In some embodiments, the R 1 For H.

[0038] In some embodiments, the R 2 For H.

[0039] In some embodiments, R a Selected from F, Cl, Br, OH, C 1-3 Alkyl or C 1-3 Alkoxy.

[0040] In some embodiments, the R 7 For H.

[0041] In some embodiments, n is 0 or 1.

[0042] In some embodiments, said n is 0.

[0043] In some embodiments, the Het is selected from

[0044] In some embodiments, p is 1.

[0045] In some embodiments, the Het is selected from

[0046] In some embodiments, the Het is selected from

[0047] In some embodiments, the Het is selected from

[0048] In some embodiments, the R 5 is C optionally substituted by F, Cl, Br, I, CN or OH 1-6 alkyl.

[0049] In some embodiments, the R 5 It is 3-fluoropropyl.

[0050] In some embodiments, X1 is selected from CR 9 or N, X2, X3, X4 are all CR 9 .

[0051] In some embodiments, the R 9 is selected from H, F, Cl, Br or I.

[0052] In some embodiments, X1, X2, X3, and X4 are all CH.

[0053] In some embodiments, W is selected from NR 8 or O.

[0054] In some embodiments, W is NH or O.

[0055] In some embodiments, the R 4 Selected from 1 or more R d Substituted phenyl or 5-6 membered heteroaryl.

[0056] In some embodiments, the R 4 Selected from 1 or more R d Substituted phenyl.

[0057] In some embodiments, the R d Selected from F, Cl, Br, I, OH, CN, C 1-6 Alkyl or C 1-6 Alkoxy.

[0058] In some embodiments, the R d is selected from F, Cl or methyl.

[0059] In some embodiments, the R 4 It is 2,4-dichlorophenyl.

[0060] In some embodiments, the R 3 Selected from H, OH, COOH, BR 10 R 11 、C(O)OR b , C 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl or 5-10 membered heteroaryl, the C1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl or 5-10 membered heteroaryl is optionally substituted with one or more R c replace.

[0061] In some embodiments, the R 3 Selected from OH, C 1-6 Alkyl, C 1-6 Alkoxy, BR 10 R 11 or a 5-10 membered heteroaryl group, wherein the C 1-6 Alkyl, C 1-6 The alkoxy or 5-10 membered heteroaryl group is optionally substituted with one or more R c replace.

[0062] In some embodiments, the R c Selected from F, Cl, Br, I or C 1-6 alkyl.

[0063] In some embodiments, the R c Selected from F or CH3.

[0064] In some embodiments, the R 10 , R 11 Independently selected from OH.

[0065] In some embodiments, the R b Independently selected from C 1-6 Alkyl or C 3-6 Cycloalkyl.

[0066] In some embodiments, the R 3 Selected from OH, COOH, B(OH)2, pyrazolyl, CH3 or methoxy, wherein the CH3 or methoxy is optionally substituted by one or more F groups.

[0067] In some embodiments, the R 3 Selected from OH, B(OH)2, pyrazolyl, CH3 or methoxy, wherein the CH3 or methoxy is optionally substituted by one or more F groups.

[0068] In some embodiments, the R 3 Selected from OH, COOH, B(OH)2, 1H-pyrazol-4-yl, CHF2 or OCHF2.

[0069] In some embodiments, the R 6 Selected from H or OH.

[0070] In some embodiments, when the atom to which Het is connected to W is a chiral carbon, the configuration is preferably (S)-configuration.

[0071] 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:

[0072]

[0073] Among them, R 3 , R 4 , W and Het are as described in formula (I).

[0074] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof:

[0075]

[0076]

[0077] In one aspect, the compounds described herein exist as racemic mixtures or in enantiomerically enriched or enantiomerically pure forms. In certain embodiments, the compounds described herein are prepared with their individual stereoisomers, which react the racemic mixture of the compound with an optically active resolving agent to form a pair of diastereomeric compounds / salts, separate the diastereoisomers and recycle the enantiomers with optical purity. In some embodiments, the resolution of enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein. In another embodiment, diastereoisomers are separated by separation / resolving techniques based on solubility differences. In certain embodiments, the compounds described herein are prepared as their individual stereoisomers by enzymatic resolution. In some embodiments, the resolution of individual stereoisomers is carried out using lipase or esterase. In some embodiments, the resolution of individual stereoisomers is carried out by asymmetric deacylation catalyzed by lipase or esterase. In other embodiments, separation of stereoisomers is performed by chromatography, or by forming diastereomeric salts and separating by recrystallization or chromatography, or any combination thereof. In some embodiments, stereoisomers are obtained by stereoselective synthesis.

[0078] The present application also provides a pharmaceutical composition, which comprises a compound of formula (I) of the present application or a pharmaceutically acceptable salt thereof 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.

[0079] In some embodiments, the pharmaceutical composition is a tablet, pill, capsule, liquid, suspension, gel, dispersion, solution, emulsion, ointment, or lotion.

[0080] Furthermore, the present invention relates to the use of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in the preparation of a drug for preventing or treating estrogen receptor-related diseases.

[0081] Furthermore, the present invention relates to the use of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in preventing or treating estrogen receptor-related diseases.

[0082] Furthermore, 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 estrogen receptor-related diseases.

[0083] The present invention also relates to a method for preventing or treating diseases mediated by estrogen receptors in mammals, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to a mammal, preferably a human being, in need of such treatment.

[0084] In a preferred embodiment of the present invention, the estrogen receptor-related diseases include but are not limited to cancer and autoimmune diseases.

[0085] Definitions and explanations of terms

[0086] Unless otherwise specified, the terms used in this application have the following meanings, and the groups and term definitions recorded in this application, including their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, definitions of specific compounds in the examples, etc., can be arbitrarily combined and combined with each other. A specific term should not be considered uncertain or unclear in the absence of a special definition, but should be understood according to the common meaning in the art. When a trade name appears in this article, it is intended to refer to its corresponding commodity or its active ingredient.

[0087] In this article Indicates the connection site.

[0088] The graphic representations of racemates or enantiomerically pure compounds herein are from Maehr, J. Chem. Ed. 1985, 62: 114-120. Unless otherwise indicated, the wedge and dotted wedge bonds ( and ) represents the absolute configuration of a stereocenter, with black real and imaginary bonds ( and ) represents the relative configuration of a stereocenter (such as the cis-trans configuration of an alicyclic compound).

[0089] The term "tautomer" refers to functional group isomers resulting from the rapid movement of an atom in two positions in a molecule. The compounds of the present invention may exhibit tautomerism. Tautomeric compounds may exist in two or more interconvertible species. Tautomers generally exist in equilibrium, and attempts to separate a single tautomer usually produce a mixture whose physical and chemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical characteristics within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates; while in phenols, the enol form predominates. The present invention includes all tautomeric forms of the compounds.

[0090] The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereomers and conformational isomers.

[0091] The compounds of the present invention may have asymmetric atoms such as carbon atoms, sulfur atoms, nitrogen atoms, phosphorus atoms or asymmetric double bonds, so the compounds of the present application may exist in specific geometric or stereoisomeric forms. Specific geometric or stereoisomeric forms may be cis and trans isomers, E-type and Z-type geometric isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures or other mixtures thereof, such as mixtures enriched in enantiomers or diastereomers, all of which are within the definition of the compounds of the present application and their mixtures. Additional asymmetric carbon atoms, asymmetric sulfur atoms, asymmetric nitrogen atoms or asymmetric phosphorus atoms may be present in substituents such as alkyl groups, and all of these isomers and their mixtures involved in all substituents are also within the definition of the compounds of the present application. The compounds of the present application containing an asymmetric atom can be isolated in an optically pure form or a racemic form. The optically pure form can be resolved from a racemic mixture or synthesized by using a chiral starting material or a chiral reagent.

[0092] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced, and oxo will not occur on an aromatic group.

[0093] The term "optional" or "optionally" means that the event or situation described subsequently may or may not occur, and the description includes the occurrence of the event or situation and the non-occurrence of the event or situation. For example, an ethyl group is "optionally" substituted with a halogen, meaning that the ethyl group may be unsubstituted (CH2CH3), monosubstituted (such as CH2CH2F), polysubstituted (such as CHFCH2F, CH2CHF2, etc.), or fully substituted (CF2CF3). It will be appreciated by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that is sterically impossible to exist and / or cannot be synthesized will be introduced.

[0094] In this article, C m-n , means that the moiety has an integer number of carbon atoms in a given range. For example, "C 1-6 ” means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.

[0095] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. For example, if a group is substituted with 2 R's, each R has an independent option.

[0096] When the number of a linking group is 0, such as -(CH2)0-, it means that the linking group is a bond. The term "halogen" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0097] The term "hydroxy" refers to an -OH group.

[0098] The term "cyano" refers to a -CN group.

[0099] The term "mercapto" refers to a -SH group.

[0100] The term "amino" refers to a -NH2 group.

[0101] The term "nitro" refers to a -NO2 group.

[0102] The term "alkyl" refers to a group of the formula C n H 2n+1 The alkyl group may be straight chain or branched. For example, the term "C 1-6 The term "alkyl" refers to an alkyl group containing 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, etc.). Similarly, the alkyl portion of an alkoxy group (i.e., alkyl) has the same definition as above.

[0103] This article describes "C 1-6 The alkyl group may contain1-3 Alkyl" and other ranges.

[0104] The term "alkoxy" refers to an alkyloxy group or -O-alkyl. For example, the term "C1-C6 alkoxy" can be understood as "C1-C6 alkyloxy" or "C1-C6 alkyl-O-", and preferably, "C1-C6 alkoxy" can include "C1-C3 alkoxy".

[0105] The term "alkenyl" refers to a linear or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms having at least one double bond. Non-limiting examples of alkenyl include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, etc.

[0106] The term "C 2-8 "Alkenyl" is understood to mean preferably a linear or branched, monovalent hydrocarbon radical which contains one or more double bonds and has 2, 3, 4, 5, 6, 7 or 8 carbon atoms.

[0107] The term "alkynyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms having at least one triple bond. Non-limiting examples of alkynyl include, but are not limited to, ethynyl (-C≡CH), 1-propynyl (-C≡C-CH3), 2-propynyl (-CH2-C≡CH), 1,3-butadiynyl (-C≡CC≡CH), etc.

[0108] The term "C 2-4 "Alkynyl" is understood as preferably meaning a linear or branched, monovalent hydrocarbon radical which contains one or more triple bonds and has 2, 3 or 4 carbon atoms.

[0109] The term "cycloalkyl" refers to a fully saturated carbocyclic ring that can exist as a monocyclic, bridged or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically a 3 to 10 membered ring. Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo [2.2.1] heptyl), bicyclo [2.2.2] octyl, adamantyl, etc.

[0110] The term "C 3-6 Cycloalkyl or "C 3-6 The "C" in "cycloalkyloxy" 3-6 "Cycloalkyl" is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3, 4, 5 or 6 carbon atoms, specific examples include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

[0111] The term "cycloalkyloxy" may be understood as "cycloalkyl-O-". For example, the term "C 3-6 "Cycloalkyloxy" can be understood as "C 3-6 Cycloalkyl-O-".

[0112] The term "heterocyclyl" refers to a fully saturated or partially unsaturated (not aromatic as a whole) monovalent monocyclic, fused, bridged or spirocyclic group containing 1-5 heteroatoms or heteroatomic groups (i.e., heteroatomic groups containing heteroatoms) in the ring atoms, wherein the "heteroatoms or heteroatomic groups" include but are not limited to nitrogen atom (N), oxygen atom (O), sulfur atom (S), phosphorus atom (P), boron atom (B), =O, =S, -ON=, -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-, etc. Unless otherwise indicated, the heterocycle 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 include, but are not limited to, oxirane, tetrahydrofuranyl, dihydrofuranyl, pyrrolidinyl, N-methylpyrrolidinyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyrazolidinyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl, etc.

[0113] The term "3-6 membered heterocyclyl" or "3-6 membered heterocyclyloxy" refers to a saturated or partially saturated monovalent monocyclic or bicyclic hydrocarbon ring containing 1, 2 or 3 heteroatoms selected from N, O and S. In particular, the heterocyclic group may include, but is not limited to, a 3-membered ring such as an oxirane ring; a 4-membered ring such as an azetidinyl group, an oxetane group; a 5-membered ring such as a tetrahydrofuranyl group, a dioxolyl group, a pyrrolidinyl group, an imidazolidinyl group, a pyrazolidinyl group, a pyrrolinyl group, a 4,5-dihydrooxazole group or a 2,5-dihydro-1H-pyrrolyl group; or a 6-membered ring such as a tetrahydropyranyl group, a piperidinyl group, a morpholinyl group, a dithianyl group, a thiomorpholinyl group, a piperazinyl group or a trithianyl group; or a partially saturated 6-membered ring such as a tetrahydropyridinyl group, a piperidinyl group, a morpholinyl group, a dithianyl group, a thiomorpholinyl group, a piperazinyl group, a trithianyl group, a tetrahydropyridinyl group or a 4H-[1,3,4]thiadiazinyl group. According to the present invention, the heterocyclic group is generally non-aromatic. Preferably, the "3-6 membered heterocyclyl" may include a "5-6 membered heterocyclyl" and the "3-6 membered heterocyclyloxy" may include a "5-6 membered heterocyclyloxy".

[0114] The term "heterocycloalkyl" refers to a monovalent cyclic group that is fully saturated and can exist as a monocyclic, fused, bridged or spirocyclic ring. Unless otherwise indicated, the heterocycle is typically a 3 to 7 membered ring containing 1, 2 or 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and / or nitrogen. Examples of 3-membered heterocycloalkyls include, but are not limited to, oxirane, thioethane, and cyclonitroethane. Non-limiting examples of 4-membered heterocycloalkyls include, but are not limited to, azetidinyl, oxadiazolyl, and thiazolinyl. Examples of 5-membered heterocycloalkyls include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, and tetrahydropyrazolyl. Examples of 6-membered heterocycloalkyls include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, and 1,4-dithianyl. Examples of 7-membered heterocycloalkyls include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Examples of the 5-6-membered heterocycloalkyls containing B formed in the present invention include, but are not limited to

[0115] The "3-6-membered heterocycloalkyl" in the term "3-6-membered heterocycloalkyl" or "3-6-membered heterocycloalkyloxy" refers to the heterocycloalkyl group having 3, 4, 5 or 6 ring atoms. Preferably, the "3-6-membered heterocycloalkyl" may include "5-6-membered heterocycloalkyl" and the "3-6-membered heterocycloalkyloxy" may include "5-6-membered heterocycloalkyloxy".

[0116] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π electron system. For example, an aryl group may have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, and 1,2,3,4-tetrahydronaphthalene, etc.

[0117] The term "C 6-10 The term "aryl" is understood to mean preferably a monovalent aromatic or partially aromatic monocyclic or bicyclic hydrocarbon ring having 6 to 10 carbon atoms. In particular, a ring having 6 carbon atoms ("C6 aryl"), such as phenyl; or a ring having 9 carbon atoms ("C9 aryl"), such as indanyl or indenyl, or a ring having 10 carbon atoms ("C 10 "aryl"), for example tetrahydronaphthyl, dihydronaphthyl or naphthyl.

[0118] The term "heteroaryl" refers to a monocyclic or fused polycyclic 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 ring, especially a single 5 to 8 ring, or a plurality of fused rings containing 6 to 14, especially 6 to 10 ring atoms. Non-limiting examples of heteroaryls include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, etc.

[0119] The term "5-10 membered heteroaryl" is understood to include monovalent monocyclic or bicyclic aromatic ring systems having 5, 6, 7, 8, 9 or 10 ring atoms, in particular 5 or 6 or 9 or 10 ring atoms, and containing 1 to 5, preferably 1 to 3 heteroatoms independently selected from N, O and S. In particular, heteroaryl is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, thiadiazolyl and the like and benzo derivatives thereof, for example benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl , indolyl, isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and benzo derivatives thereof, such as quinolyl, quinazolinyl, isoquinolyl, etc.; or acinyl, indolizinyl, purinyl, etc., and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, etc. The term "5-6 membered heteroaryl" refers to an aromatic ring system having 5 or 6 ring atoms, and it contains 1-3, preferably 1-2 heteroatoms independently selected from N, O and S, examples include but are not limited to thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl. Preferably, "5-10 membered heteroaryl" may contain "5-6 membered heteroaryl".

[0120] The term "therapeutically effective amount" means an amount of the compound of the present application that (i) treats or prevents a specific disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a specific disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a specific disease, condition, or disorder described herein. The amount of the 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 based on their own knowledge and the present disclosure.

[0121] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0122] The term "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable salt of a non-toxic acid or base, including a salt of an inorganic acid and a base, an organic acid and a base. As pharmaceutically acceptable salts, for example, metal salts, ammonium salts, salts formed with organic bases, salts formed with inorganic acids, salts formed with organic acids, salts formed with basic or acidic amino acids, etc. can be mentioned.

[0123] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or their salts and pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present application to an organism.

[0124] The term "pharmaceutically acceptable excipients" refers to those excipients that have no significant irritation to the organism and do not impair the biological activity and performance of the active compound. Suitable excipients 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, etc.

[0125] The word "comprise" or "comprises" and its English variations such as comprises or comprising should be construed in an open and non-exclusive sense, ie, "including but not limited to".

[0126] The present application also includes isotopically labeled compounds of the present application that are identical to those described herein, but in which one or more atoms are replaced by atoms 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 the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 123 I. 125I and 36 Cl et al.

[0127] Certain isotope-labeled compounds of the present application (e.g. 3 H and 14 C-labeled) can be used in compound and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e. 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. Positron emitting isotopes such as 15 O. 13 N. 11 C and 18 F 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 Examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0128] The pharmaceutical composition of the present application can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable excipients, for example, it can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.

[0129] Typical routes of administration of the compounds of the present application or their pharmaceutically acceptable salts or their pharmaceutical compositions include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0130] The pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, emulsification methods, freeze-drying methods, etc.

[0131] In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be prepared by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present application to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, etc., for oral administration to patients.

[0132] Solid oral compositions can be prepared by conventional mixing, filling or tableting methods. For example, they can be obtained by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into particles to obtain a tablet or dragee core. Suitable excipients include, but are not limited to, adhesives, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, etc.

[0133] The pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in appropriate unit dosage forms.

[0134] In all administration methods of the compounds of general formula (I) described herein, the daily dosage is 0.01 to 200 mg / kg body weight, preferably 0.05 to 50 mg / kg body weight, more preferably 0.1 to 30 mg / kg body weight, in the form of single or divided doses.

[0135] The term "IC 50 ” is the half-maximal inhibitory concentration, which represents the concentration of a specific compound required to obtain 50% inhibition of a biological process in vitro. IC 50 The value can be converted logarithmically to pIC 50 Value (-log IC 50 ), where higher values ​​indicate exponentially greater potency.

[0136] The compounds of the present application can 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 combining them with other chemical synthesis methods, and equivalent substitution methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present application.

[0137] The chemical reactions of the specific embodiments of the present application are carried out in a suitable solvent, which must be suitable for the chemical changes of the present application and the reagents and materials required. In order to obtain the compounds of the present application, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction processes based on the existing embodiments.

[0138] For the sake of clarity, the present application is further described with examples, but the examples do not limit the scope of the present application. All reagents used in the present application are commercially available and can be used without further purification. DETAILED DESCRIPTION

[0139] The following examples illustrate the technical solutions of the invention in detail, but the protection scope of the present invention includes but is not limited to them.

[0140] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The units of NMR shifts are 10 -6 The solvents for NMR measurement are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS).

[0141] 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

[0142]

[0143] Step 1: Synthesis of 9-(4-hydroxyphenyl)-6,7-dihydro-5H-benzo[7]cyclohepten-3-yl pivalate

[0144]

[0145] 9-((Trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]cyclohepten-3-yl pivalate (3.00 g, 7.65 mmol), 4-hydroxyphenylboronic acid pinacol ester (1.68 g, 7.65 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (Pd(dppf)Cl2) (560 mg, 0.76 mmol) and cesium carbonate (4.97 g, 1.53 mmol) were added to a mixture of dioxane / water (V (二氧六环 / 水) =4:1) (30 mL) mixed solvent, stirred at room temperature under argon protection for 3 hours. After the reaction was completed, the reaction solution was poured into 100 mL of water, extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and column chromatography to obtain the title product.

[0146] Step 2: Synthesis of 9-(4-((trifluoromethyl)sulfonyl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]cyclohepten-3-yl pivalate

[0147]

[0148] 9-(4-Hydroxyphenyl)-6,7-dihydro-5H-benzo[7]cycloheptene-3-yl pivalate (1.76 g, 5.20 mmol) was dissolved in anhydrous dichloromethane (DCM) (30 mL), and pyridine (496 mg, 6.30 mmol) was added. The resulting reaction solution was protected with argon and then cooled to -20°C. Trifluoromethanesulfonic anhydride (Tf2O) (2.95 g, 10.4 mmol) was slowly added dropwise at this temperature. After the addition was completed, the reaction was moved to room temperature and stirred for 4 hours. After the reaction was completed, the reaction solution was poured into 60 mL 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. The crude product was purified by column chromatography to obtain the title product.

[0149] Step 3: Synthesis of 1-tert-butyloxycarbonyl-3-((4-(3-(pivaloyloxy)-6,7-dihydro-5H-benzo[7]cyclohepten-9-yl)phenyl)amino)azetidine

[0150]

[0151] 9-(4-((trifluoromethyl)sulfonyl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]cycloheptene-3-yl pivalate (1.77 g, 3.70 mmol), 1-tert-butyloxycarbonyl-3-aminocyclobutylamine (960 mg, 5.6 mmol), cesium carbonate (3.62 g, 11.1 mmol), tris(dibenzylideneacetone)dipalladium (Pd2(dba)3) (340 mg, 0.370 mmol) and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (Xantphos) (430 mg, 0.740 mmol) were added to dioxane (25 mL). The resulting reaction solution was protected by argon and stirred at 110°C for 4 hours. After the reaction was completed, the solution was cooled, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to obtain the title product.

[0152] Step 4: Synthesis of 1-tert-butyloxycarbonyl-3-((4-(8-bromo-3-(pivaloyloxy)-6,7-dihydro-5H-benzo[7]cyclohepten-9-yl)phenyl)amino)azetidine

[0153]

[0154] 1-tert-Butyloxycarbonyl-3-((4-(3-(pivaloyloxy)-6,7-dihydro-5H-benzo[7]cycloheptene-9-yl)phenyl)amino)azetidine (590 mg, 1.20 mmol) was added to tetrahydrofuran (THF) (10 mL). The resulting reaction solution was cooled to -20°C, and then pyridinium tribromide (PyHBr3) (385 mg, 1.20 mmol) was added. The reaction was continued at -20°C for 30 minutes. After the reaction was completed, the reaction solution was poured into 50 mL 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 directly in the next reaction without purification.

[0155] Step 5: Synthesis of 1-tert-butyloxycarbonyl-3-((4-(8-(2,4-dichlorophenyl)-3-(pivaloyloxy)-6,7-dihydro-5H-benzo[7]cyclohepten-9-yl)phenyl)amino)azetidine

[0156]

[0157] Crude 1-tert-butyloxycarbonyl-3-((4-(8-bromo-3-(pivaloyloxy)-6,7-dihydro-5H-benzo[7]cyclohepten-9-yl)phenyl)amino)azetidine (1.20 mmol), 2,4-dichlorophenylboronic acid (344 mg, 1.80 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (87.8 mg, 0.120 mmol) and cesium carbonate (780 mg, 2.40 mmol) were added to dioxane / water (V (二氧六环 / 水) =4:1) (20 mL), the reaction solution was protected by argon and stirred at 100 ° C for 4 hours. After the reaction was completed, the reaction solution was cooled and poured into 80 mL 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 obtain the title product.

[0158] Step 6: Synthesis of 9-(4-(azetidin-3-ylamino)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]cyclohepten-3-yl neopentyl ester

[0159]

[0160] 1-tert-Butyloxycarbonyl-3-((4-(8-(2,4-dichlorophenyl)-3-(pivaloyloxy)-6,7-dihydro-5H-benzo[7]cycloheptene-9-yl)phenyl)amino)azetidine (200 mg, 0.315 mmol) was added to dichloromethane (4.7 mL), and the resulting reaction solution was cooled to 0°C, and then trifluoroacetic acid (TFA) (2.3 mL) was added, and stirring was continued at 0°C for 4 hours. After the reaction was completed, it was diluted with 30 mL of dichloromethane, and then poured into 30 mL of saturated sodium bicarbonate solution, extracted with dichloromethane, and 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 directly used in the next reaction without purification.

[0161] Step 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

[0162]

[0163] 9-(4-(azetidin-3-ylamino)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]cycloheptene-3-yl neopentyl ester (0.315mmol) was added to N-methylpyrrolidone (NMP) (4mL), and then 3-fluoro-1-iodopropane (59.2mg, 0.315mmol) and potassium carbonate (86.9mg, 0.630mmol) were added. The resulting reaction solution was stirred at room temperature overnight. 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 brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to obtain the title compound.

[0164] Step 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

[0165]

[0166] 8-(2,4-Dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-6,7-dihydro-5H-benzo[7]cyclohepten-3-yl pivalate (80 mg, 0.134 mmol) was added to tetrahydrofuran / methanol (MeOH) (V (四氢呋喃 / 甲醇)=2:1) ​​(3mL), add sodium hydroxide aqueous solution (0.22mL, 5M) under stirring at room temperature, and the resulting reaction solution is stirred at room temperature for 4 hours. After the reaction is completed, pour the reaction solution into 20mL of water, adjust the pH to 6-7 with 1M dilute hydrochloric acid, extract with ethyl acetate, combine the organic layers, wash with water, wash with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify by preparative liquid chromatography to obtain the title product.

[0167] 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),4.0 4–3.93(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).

[0168] LC / MS (m / z, MH + ):511.1

[0169] Example 2: (8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-6,7-dihydro-5H-benzo[7]cycloheptene-3-yl)boronic acid

[0170]

[0171] 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

[0172]

[0173] 3-Hydroxy-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-6,7-dihydro-5H-benzo[7]cycloheptene (1.06 g, 2.09 mmol), bis(trifluoromethanesulfonyl)aniline (PhNTf2) (1.49 g, 4.17 mmol), triethylamine (TEA) (0.63 g, 6.26 mmol) were added to 10 mL of dichloromethane, and the reaction was completed after stirring at room temperature for 12 hours. 100 mL of water was added to the reaction solution, extracted with ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate, and the organic layers were concentrated and column chromatography was performed to obtain the title compound.

[0174] 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

[0175]

[0176] 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-6,7-dihydro-5H-benzo[7]cycloheptene-3-trifluoromethanesulfonate (391 mg, 0.61 mmol), biboronic acid pinacol ester (310 mg, 1.22 mmol), potassium acetate (119 mg, 1.22 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (44 mg, 0.06 mmol) were added to 4 mL of 1,4-dioxane, and the reaction was completed after heating under reflux for 15 hours under argon protection. The reaction solution was concentrated and then subjected to column chromatography to obtain the title compound.

[0177] Step 3: Synthesis of (8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-6,7-dihydro-5H-benzo[7]cycloheptene-3-yl)boronic acid

[0178]

[0179] (N-(4-(8-(2,4-dichlorophenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]cycloheptene-9-yl)phenyl)-1-(3-fluoropropyl)azetidine-3-amine (248 mg, 0.40 mmol) and sodium periodate (171 mg, 0.80 mmol) were added to 15 mL of tetrahydrofuran / water = 4 / 1 system, and the reaction was completed after stirring at room temperature for 15 hours. After adjusting the pH to 6-7, the mixture was added to 50 mL of water, extracted with ethyl acetate, and the organic layers were combined, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain the title compound.

[0180] LC / MS (m / z, MH + ):539.2.

[0181] 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)azetidine-3-amine

[0182]

[0183] 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-6,7-dihydro-5H-benzo[7]cycloheptene-3 trifluoromethanesulfonate (192 mg, 0.30 mmol) was added to 5 mL of 1,4-dioxane / water = 4 / 1 system, and 4-pyrazoleboronic acid pinacol ester (58.0 mg, 0.30 mmol), potassium carbonate (84.0 mg, 0.61 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (22.3 mg, 0.03 mmol) were added. The mixture was heated to 100°C under argon protection, and the reaction was completed after 15 hours. The reaction solution was concentrated and column chromatography was performed to obtain the title compound.

[0184] LC / MS (m / z, MH + ):561.2

[0185] Example 4: (S)-4-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]cycloheptene-3-yl)-1H-pyrazole

[0186]

[0187] The starting material 1 was prepared according to Example 18 of WO2017140669A1. The starting material 1 (1.10 g, 2.09 mmol), bis(trifluoromethanesulfonyl)aniline (1.49 g, 4.17 mmol), N, N-diisopropylethylamine (i.e., DIPEA) (0.54 g, 4.18 mmol) were added to 10 mL of dichloromethane, and the reaction was completed after stirring at room temperature for 12 hours. 100 mL of water was added to the reaction solution, extracted with ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate, and the organic layers were concentrated and column chromatography was performed to obtain intermediate 2. Add intermediate 2 (198 mg, 0.30 mmol) to 5 mL of 1,4-dioxane / water = 4 / 1 system, add 4-pyrazoleboronic acid pinacol ester (58.0 mg, 0.30 mmol), potassium carbonate (84.0 mg, 0.61 mmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (22.3 mg, 0.03 mmol). Heat to 100°C under argon protection, and the reaction is complete after 15 hours. Concentrate the reaction solution and perform column chromatography to obtain the title compound.

[0188] 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).

[0189] LC / MS (m / z, MH + ):576.2

[0190] Example 5: (S)-4-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]cycloheptene-3-yl)-1H-pyrazole

[0191]

[0192] The synthesis method is similar to that of step 2 to step 3 of Example 2, except that the 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 is replaced by (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-(fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]cycloheptene-3 trifluoromethanesulfonate prepared in the above Example 4, and the title compound is prepared in the same manner.

[0193] 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,1 H),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).

[0194] LC / MS (m / z, MH + ):554.1

[0195] 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

[0196]

[0197] 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

[0198]

[0199] (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 Example 51 of WO2017140669A1. (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 (400 mg, 0.72 mmol) was dissolved in 2 mL of N,N-dimethylformamide, and N,N-diisopropylethylamine (465 mg, 3.61 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (547 mg, 1.44 mmol) and methoxymethylamine hydrochloride (140 mg, 1.44 mmol) were added. The reaction was completed after stirring at room temperature for 1.5 hours. 50 mL of water was added, and the mixture was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and the organic layer was concentrated and purified by column chromatography to obtain the title compound.

[0200] 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

[0201]

[0202] The 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 (420 mg, 0.72 mmol) was dissolved in 2 mL of tetrahydrofuran, and a 1 M tetrahydrofuran solution of diisobutylaluminum hydride (DIBAL-H) ​​(3 mL, 3.00 mmol) was added dropwise at -20°C. After reacting at -20°C for 1.5 hours, the reaction was completed, and a small amount of water was added dropwise to quench the reaction. The mixture was extracted with ethyl acetate and concentrated and then column chromatography was performed to obtain the title compound.

[0203] 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

[0204]

[0205] The crude product 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 (60.0 mg, 0.11 mmol) was dissolved in 2 mL of dichloromethane, diethylaminosulfur trifluoride (DAST) (0.15 mL, 0.50 mmol) was added dropwise at -20°C, the temperature was naturally raised to room temperature and the reaction was carried out for 16 hours, 30 mL of saturated aqueous sodium bicarbonate solution was added dropwise, the mixture was extracted with ethyl acetate, the organic layers were combined, concentrated and column chromatography was performed to obtain the title compound.

[0206] 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),2.7 8(s,1H),2.63(s,1H),2.45-2.37(m,2H),2.22-2.15(m,6H),1.83-1.65(m,4H).

[0207] LC / MS (m / z, M+H + ):560.2

[0208] Example 7: (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

[0209]

[0210] Step 1: Synthesis of (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

[0211]

[0212]

[0213] The intermediate 9-(4-((trifluoromethyl)sulfonyl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]cycloheptene-3-yl pivalate prepared in Example 1 was used as the starting material, and the same operation as in Step 3 to Step 8 in Example 1 was performed, except that (7S)-7-amino-5-azaspiro[2.4]heptane-5-carboxylic acid tert-butyl ester was used to replace 1-tert-butyloxycarbonyl-3-aminocyclobutylamine in Step 3 of Example to prepare Intermediate 4. Intermediate 5, i.e. (S)-8-(2,4-dichlorophenyl)-9-(4-((5-(3-fluoropropyl)-5-azaspiro[2.4]heptene-7-yl)amino)phenyl)-6,7-dihydro-5H-benzo[7]cycloheptene-3-trifluoromethanesulfonate, was prepared by the same method as in Step 1 of Example 2. (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-trifluoromethanesulfonate (340 mg, 0.50 mmol) was added to 8 mL of N,N-dimethylformamide, followed by 2 mL of triethylamine and 4 mL of methanol, and then [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (22.3 mg, 0.03 mmol). Carbon monoxide gas was introduced and heated to 70°C. The reaction was completed after 5 hours. The reaction solution was concentrated and then 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.

[0214] Step 2: Synthesis of (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

[0215]

[0216] (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 (300 mg, 0.50 mmol) was added to 10 mL of methanol, and 1 mL of sodium hydroxide aqueous solution (5 mol / L) was added. The mixture was heated to 60°C and stirred for 2 hours until the reaction was complete. The pH was adjusted to 3-4 with 2 mol / L dilute hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain the title compound.

[0217] DMSO-d6δ H7.85(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).

[0218] LC / MS (m / z, MH + ):579.2

[0219] Example 8: (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-boronic acid

[0220]

[0221] The synthesis method is similar to that of step 2 to step 3 of Example 2, except that the 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 is replaced by the intermediate 5 prepared in the above Example 7, namely (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-trifluoromethanesulfonate, and the title compound is prepared in the same way.

[0222] LC / MS (m / z, MH + ):579.2

[0223] 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

[0224]

[0225] The synthesis method is similar to that of Example 3, except that the 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 is replaced by the intermediate 5 prepared in the above Example 7, namely (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-trifluoromethanesulfonate, and the title compound is prepared in the same way.

[0226] LC / MS (m / z, MH + ):601.2

[0227] Example 10: (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-ol

[0228]

[0229] The synthesis method is similar to that of step 8 of Example 1, except that the 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-6,7-dihydro-5H-benzo[7]cycloheptene-3-yl pivalate in step 8 of Example 1 is replaced by the intermediate 3 prepared in the above Example 7, namely ((S)-8-(2,4-dichlorophenyl)-9-(4-((5-(3-fluoropropyl)-5-azaspiro[2.4]heptene-7-yl)amino)phenyl)-6,7-dihydro-5H-benzo[7]cycloheptene-3-yl pivalate, and the title compound is prepared in the same way.

[0230] DMSO-d6δ H9.44(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).

[0231] LC / MS (m / z, MH + ):551.2

[0232] Biological activity and related properties test examples

[0233] Experimental Example 1: Detection of the effect of the compounds of the present invention on the degradation of estrogen receptors in MCF7 cells

[0234] Experimental principle: Determine the degradation activity of the compounds of the present invention on the estrogen receptor endogenously expressed in MCF7 cells. 50 And the maximum degradation efficiency was used to evaluate the activity of the test compound.

[0235] Test method:

[0236] MCF7 cells (purchased from ATCC, HTB-22) were cultured with complete medium containing 10% fetal bovine serum in DMEM (purchased from Gibco, 11995-065). On the first day of the experiment, MCF7 cells were seeded in a 384-well plate at a density of 3000 cells / well using complete medium and cultured in a cell culture incubator at 37°C and 5% CO2. The compounds to be tested were dissolved in DMSO with a storage concentration of 10mM, diluted with Echo550 (purchased from Labcyte Inc.) and added to the cell culture plate. The starting concentration of each compound treatment was 100nM, 3-fold gradient dilution, 9 concentration points, a blank control containing 0.5% DMSO, and a double-duplicate control for each concentration point. Cultured in a cell culture incubator at 37°C and 5% CO2 for 24 hours. Paraformaldehyde was added to the cell culture medium in each cell culture well to a final concentration of about 3.7% to fix the cells. After 30 minutes, the supernatant was discarded and 50 μL PBS was added to each well for washing once; PBS containing 0.5% v / v Tween 20 was added to treat the cells for 30 minutes and washed once with PBS; blocking solution (self-made, PBS containing 5% BSA, 0.05% Tween 20) was added and incubated at room temperature for 1 hour; the blocking solution was removed and a primary antibody mixture was added (anti-ER monoclonal antibody, Estrogen Receptorα (D8H8) Rabbit mAb, purchased from GST, #8644S, 1:1000 dilution; anti-GAPDH monoclonal antibody, GAPDH (D4C6R) Mouse mAb, purchased from GST, #97166S, 1:2000 dilution) was incubated at room temperature for 3 hours; washed 3 times with PBST (homemade, PBS containing 0.05% Tween 20); added secondary detection antibodies (800CW-goat anti-rabbit IgG, purchased from LI-COR, P / N:926-32211, 1:1000 dilution; 680RD-goat anti-mouse IgG, purchased from LI-COR, #925-68070, 1:1000 dilution), incubated at room temperature, away from light for 45 minutes; washed 3 times with PBST, and the fluorescence signal of each well was read using Odyssey CLx. Data processing was performed using XLfit, and the inhibitory activity IC of each compound was calculated based on the concentration and fluorescence signal value of the compound. 50 And the maximum inhibition rate Imax.

[0237] Test results:

[0238] Under the experimental conditions, the test compound has good inhibitory activity on the ER level based on the cell level. The test results of the ER level activity of the test compound are shown in Table 1.

[0239] Table 1 Results of in vitro ER level activity test of test compounds based on cell level

[0240] Test compound <![CDATA[ER level IC 50 (nM)]]> Example 1 0.12 Example 4 0.64 Example 5 0.58 Example 10 0.35

[0241] Test Example 2: Detection of the inhibitory effect of the compounds of the present invention on T47D cell proliferation

[0242] Experimental principle: Determine the inhibitory effect of the compounds of the present invention on the proliferation of T47D cells in vitro. 50 The activity of the compounds was evaluated by the maximum inhibitory efficiency.

[0243] Test method:

[0244] T47D (T-47D) cells (purchased from ATCC, HTB-133) were cultured with RPMI-1640 (purchased from Gibco, A10491-01) complete medium containing 10% fetal bovine serum. On the first day of the experiment, T47D cells were seeded at a density of 500 cells / well in a 384-well plate using complete medium and cultured overnight in a 37°C, 5% CO2 cell culture incubator. On the second day, the compound to be tested was added for drug treatment. The compound solution with a storage concentration of 10mM was diluted and transferred to each cell culture well using Echo550 (purchased from Labcyte Inc.). The starting concentration of each compound in the cell was 100nM, with 3-fold gradient dilution and 10 concentration points. A blank control containing 0.3% DMSO was set up, and double-dip controls were set up for each concentration point. Cultured in a 37°C, 5% CO2 cell culture incubator for 7 days. On the eighth day, the cell culture plate was removed. Add Luminescent Cell Viability Assay (purchased from Promega, G7573) was placed at room temperature for 10 minutes, and then the luminescent signal value was read using the multi-label microplate reader EnVision (purchased from PerkinElmer). The inhibitory activity IC of each compound was calculated using XLfit based on the concentration and luminescent signal value of the compound. 50 .

[0245] Test results:

[0246] Under the experimental conditions, the test compound showed good inhibitory activity against T47D breast cancer cells. The inhibitory activity results of the test compound against the proliferation of MCF7 cells are shown in Table 2.

[0247] Table 2 Inhibitory activity of compounds on MCF7 cell proliferation

[0248] Test compound <![CDATA[T47D IC 50 (nM)]]> Example 4 2.98 Example 5 2.89

[0249] Test Example 3: Pharmacokinetic properties of the compounds of the present invention

[0250] Experimental principle: Using mice as test animals, the LC-MS / MS method is used to determine the drug concentration in the plasma at different times after oral administration and intravenous administration of the compound of the present invention to mice, to study the pharmacokinetic behavior of the compound of the present invention in mice, and to evaluate its pharmacokinetic characteristics.

[0251] Test method:

[0252] 3.1 Experimental animals

[0253] Twelve healthy adult BALB / c female mice were equally divided into 2 groups, with 6 mice in each group, 3 mice were gavaged and 3 mice were intravenously administered. The mice were purchased from Beijing Weitonglihua Experimental Animal Technology Co., Ltd., with animal production license number: SCXK (Zhejiang) 2019-0001.

[0254] 3.2 Drug preparation

[0255] Weigh a certain amount of drug and dissolve it in DMSO 5% + propylene glycol (PG) 20% + anhydrous ethanol (Polyethylene glycol-15 hydroxystearate) 10% + water 60%, prepared to 10mg / ml, for oral administration. Weigh a certain amount of drug and dissolve it in DMSO 1% + PG 4% + anhydrous ethanol 2% + water 92%, prepared into 1mg / ml, for intravenous injection.

[0256] 3.3 Administration

[0257] Oral gavage group: BALB / c mice were fasted overnight and then given the drug by oral gavage. The dosage was 10 mg / kg and the administration volume was 1 mL / kg.

[0258] Intravenous group: BALB / c mice were fasted overnight and intravenously administered. The dosage was 1 mg / kg and the administration volume was 1 mL / kg.

[0259] 3.4 Operation

[0260] After oral or intravenous administration, mice were given blood samples of 40 μL and 5 μL from the eye socket at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, and 24 h after administration. The plasma was separated by centrifugation at 12000 rpm, 4 °C, and stored at -20 °C after anticoagulation with EDTA-K2.

[0261] Determine the content of the test compound in mouse plasma after oral or intravenous administration of different concentrations of drugs: take the sample and melt it at room temperature, vortex for 1min; quantitatively transfer 15μL to a 2ml 96-well plate, add 150μL of internal standard precipitant tolbutamide acetonitrile solution, shake (1200rpm*3min); centrifuge (4000rpm*15min), transfer 100μL of supernatant to a 1mL 96-well plate; blow dry with nitrogen, add 100μL of re-solution (acetonitrile: water = 1:9), shake well (900rpm*3min), and inject 20μL for analysis. LC-MS / MS conditions: mobile phase A: 0.1% formic acid aqueous solution, mobile phase B: 0.1% formic acid acetonitrile, chromatographic column: ACE C18 5μm (3.0mm*50mm), column temperature: 35℃, flow rate 0.5ml / min.

[0262] Test results:

[0263] Under the experimental conditions, the test compound showed good pharmacokinetic properties, and the results are shown in Table 3.

[0264] Table 3 Pharmacokinetic parameters of the compounds after single oral administration in mice

[0265]

[0266] The above is an explanation of the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

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

2. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

3. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 2 in the preparation of a medicament for preventing or treating estrogen receptor-related diseases.

4. The use of claim 3 in preparing a drug for preventing or treating estrogen receptor-related diseases, wherein: The estrogen receptor-related disease is a tumor.

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