Bifunctional heterocyclic compound capable of degrading androgen receptor and application thereof

Abstract

The invention belongs to the field of medicinal chemistry, and particularly relates to a compound shown in a formula (I), pharmaceutically acceptable salt, deuterated substance, stereoisomer, tautomer or a mixture thereof, which can be used as a protein degradation agent for degrading an androgen receptor or a spliceosome thereof. The compound can be used for preparing medicines for treating and / or preventing diseases related to androgen receptors or spliceosomes thereof. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of medicinal chemistry, and in particular to a bifunctional heterocyclic compound capable of degrading androgen receptor, a preparation method thereof, and use thereof for treating and / or preventing diseases associated with androgen receptor or its splice form. Background Art

[0002] Prostate cancer is one of the most common male malignancies. It occurs in prostate epithelial cells and accounts for 13.5% of all male malignancies, ranking second in the world (Shin et al, 2021). The current survival period of this cancer is only 3-5 years. Early patients can be effectively treated by surgery and chemotherapy. The main treatment for late-stage patients is androgen and its receptor deprivation therapy (Aragon-Ching and Dahut, 2010), which mainly includes surgical castration (such as bilateral orchiectomy) and androgen receptor drug therapy.

[0003] Androgen receptor (AR) is a steroid of the nuclear receptor superfamily, mainly including four domains, N-terminal transcriptional activation region (NTD), DNA binding region (DBD), hinge region and ligand binding region (LBD) (Fujita and Nonomura, 2019). In the cytoplasm, AR mainly binds to heat shock protein (HSP90 / 70). When AR binds to the ligand through LBD, it undergoes conformational changes, causing it to dissociate from HSP and undergo nuclear translocation. After entering the nucleus, AR binds to the androgen response element (ARE) and interacts with other transcription factors to regulate the transcription and expression of genes related to tumor cell proliferation and apoptosis (Miller et al, 2023). Currently available AR inhibitors such as darolutamide, enzalutamide, apalutamide, and bicalutamide mainly inhibit AR signal transduction by binding to LBD (Schmidt et al, 2021). Although ARLBD inhibitors have achieved certain clinical effects, most patients develop castration resistance (CRPC) 18-24 weeks after treatment. The main reason is that point mutations in ARLBD such as T878A, H875Y, L702H and F877L reduce the specificity of AR and can bind to more steroid hormones. Studies have shown that W742L / C and F877L mutations cause AR antagonists to functionally transform into AR agonists (Rathkopfet al, 2017). In addition, the high expression of AR splice variants (AR splice variant, AR-SV) lacking the LBD domain, such as AR-V7, in CRPC patients is also an important factor leading to LBD inhibitor resistance (Schmidt et al, 2021).

[0004] In recent years, protein degradation targeted chimera (protac) technology has attracted widespread attention because it can target targets that are difficult to drug with traditional drugs. The AR degrader ARV-110 developed by Arvinas based on this technology has a significant anti-tumor effect on CRPC in preclinical trials. The results of its Phase II clinical trial showed that ARV-110 has good efficacy in some wild-type prostate cancer patients (PSA50:11%) and LBD T878X / H875Y mutation patients (PSA50:75%). Among the 7 patients with T878X / H875Y mutation, 6 had tumor shrinkage and 2 had PR. However, its efficacy in patients with L702H mutation and AR-V7 expression (24%) was poor (PSA50:4%)7. This is because ARV-110 mainly targets AR LBD, so it cannot effectively bind to and degrade AR-SVs that lack LBD, such as AR-V7. Studies have shown that up to 58.7% of CRPC patients express AR-V7 (Qu et al, 2015). In view of this, it is particularly important to develop new degraders that can simultaneously target and degrade AR and AR-SVs.

[0005] The present invention aims to develop a protac that can bind to ARNTD. Due to the high conservation of NTD in AR and AR-SVs, this degrader can simultaneously target wild-type and LBD mutant AR and AR-V7, thereby blocking the resistance mechanism of LBD antagonists and degraders, in order to significantly improve the efficacy of CRPC patients. Summary of the invention

[0006] The present invention is directed to a compound represented by formula (I), a pharmaceutically acceptable salt thereof, a deuterated substance thereof, a stereoisomer thereof, a tautomer thereof or a mixture thereof,

[0007]

[0008] Among them, PTC is the target recognition or binding part, LI is the connecting part, and U is selected from E3 ligase ligand or HSP90 inhibitor; the three parts are connected by chemical bonds.

[0009] In some embodiments, the PTC is a structure represented by formula (II):

[0010]

[0011] in:

[0012] A is selected from 5-15 membered aryl, C5-C 15 Carbocyclyl, 5-15 membered heteroaryl or 5-15 membered heterocyclyl;

[0013] B is selected from 5-15 membered aryl, C5-C 15Carbocyclyl, 5-15 membered heteroaryl or 5-15 membered heterocyclyl;

[0014] C is selected from 3-15 membered aryl, C3-C 15 Carbocyclyl, 3-15 membered heteroaryl or 3-15 membered heterocyclyl;

[0015] X is selected from a chemical bond, -(CR 5 R 6 )n4-, -C(=O)- or -NR 7 ;

[0016] Y is selected from a chemical bond, -(CR 8 R 9 )m-, -O-, -S-, -S(=O)-, -SO2-, -NR 7 or -N(COCH3)-;

[0017] W is selected from a chemical bond, -(CR 8a R 9a )n5-, -C(=O)-, -NR 7 、-N(R 7 )CO-、-CONR 7 -or-NSO2R 7 , any substituted C3-C 10 Carbocyclic or optionally substituted 3-10 membered heterocyclic ring;

[0018] Z is selected from a chemical bond, -CH2-, -C(CH3)H-, -O-, -S-, -NH-, -NCH3- or -N(COCH3)-;

[0019] V is selected from a chemical bond, -(CR 8a R 9a )m-、-CR 8a =CR 9a -or-(3-15 membered ring)-;

[0020] L is selected from H, halogen, -CF2R 10 、-CF3、-CN、-OR 10 、-SO2R 17 、-NR 11 R 12 or-CONR 11 R 12 ;

[0021] R 1 and R 2Each independently selected from H, halogen, -CN, -CF3, -OH, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted (C1-C6 alkoxy)-(C1-C6 alkyl), (C1-C6 alkylamino)-(C1-C6 alkyl), optionally substituted -(C1-C6 alkyl)-OH, oxo, -NR 13 R 14 , optionally substituted -(C1-C6 alkyl)-NR 13 R 14 、-NR 14 S02R 16 , optionally substituted -(C1-C6 alkyl)NR 14 S02R 16 、-NR 14 COR 16 , optionally substituted -(C1-C6 alkyl)NR 14 COR 16 、-CONR 13 R 14 , optionally substituted -(C1-C6 alkyl)-CONR 14 R 15 、-SO2R 14 R 15 , optionally substituted -(C1-C6 alkyl)-SO2NR 14 R 15 , any substituted -SO2R 16 or optionally substituted -(C1-C6 alkyl)-SO2R 16 ;

[0022] R 3 Selected from H, oxo, =S, =NR 16 , -CN, CF3, -OH, -S-(C1-C3 alkyl), C1-C3 alkyl, C2-C3 alkenyl, C1-C3 alkoxy, -NR 13 R 14 、-(C1-C3 alkyl)-NR 13 R 14 、-NR 14 S02R 16 、-(C1-C3 alkyl)NR 14 S02R 16 ,-N=S(=O)(C1-C3 alkyl)2, NR 14 COR 16 、-NR 14 COOR 16 、-(C1-C6 alkyl)-NR 14 COR 16、-CONR 14 R 15 、-(C1-C3 alkyl)-CONR 14 R 15 、-SO2NR 14 R 15 、-(C1-C3 alkyl)-SO2NR 14 R 15 , -SO2(C1-C3 alkyl), -(C1-C6 alkyl)-SO2(C1-C3 alkyl), optionally substituted C5-C 15 Carbocyclic group, optionally substituted 5-15 membered heterocyclic group, optionally substituted 5-15 membered aryl group or optionally substituted 5-15 membered heteroaryl group; the carbocyclic group, heterocyclic group, aryl group or heteroaryl group may be selected from a monocyclic ring, a spirocyclic ring, a condensed ring or a bridged ring;

[0023] R 5 and R 6 Each independently selected from H, halogen, -CN, -OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthiol or C1-C6 alkylsulfone: the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C1-C6 alkylthiol may be optionally substituted by H, halogen, -CN, -OH, -SH or oxo:

[0024] Or, R 5 and R 6 and the connected atoms together to form an arbitrarily substituted C3-C 15 A carbocyclic group or an optionally substituted 3-15 membered heterocyclic group; 15 Carbocyclic ring or 3-15 membered heterocyclic ring includes fused ring, bridged ring or spiro ring;

[0025] R 7 is selected from H, halogen, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl;

[0026] R 8 and R 9 Each is independently selected from H, halogen or C1-C3 alkyl;

[0027] R 8a and R 9a Each independently selected from H, -OH, halogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C l -C3 alkoxy, -NR 13 R 14 、-(C1-C3 alkyl)-NR 13 R 14 、-NR 14 COR16 、-(C1-C3 alkyl)-NR 14 COR 16 、-CONR 14 R 15 or -(C1-C3 alkyl)-CONR 14 R 15 or, R 8a and R 9a Together with the atoms to which it is connected, they are connected to form an optionally substituted C3-C6-membered carbocyclic group or a 3-6-membered heterocyclic group;

[0028] R 10 is selected from H, an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted carbocyclyl, an optionally substituted heterocyclyl, an optionally substituted aryl or an optionally substituted heteroaryl;

[0029] R 11 and R 12 Each independently selected from H, an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted carbocyclic group, an optionally substituted heterocyclic group, an optionally substituted aryl group or an optionally substituted heteroaryl group;

[0030] Or, R 11 and R 12 Together with the atoms to which they are attached, they form an optionally substituted heterocyclic group;

[0031] R 13 , R 14 and R 15 Each is independently selected from H, C1-C3 alkyl, C2-C3 alkenyl or C2-C3 alkynyl; or R 14 and R 15 Together with the atoms to which they are connected, they form an optionally substituted 3-6 membered heterocyclic group;

[0032] R 16 is selected from H, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, C3-C6 cycloalkyl or phenyl;

[0033] R 17 is selected from H, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl or optionally substituted C2-C3 alkynyl;

[0034] m is independently selected from 0, 1 or 2:

[0035] n1 and n2 are each independently selected from 0, 1 and 2:

[0036] n3 is 0, 1, 2, 3, 4, or 5;

[0037] n4 is 0, 1, or 2:

[0038] n5 is 0, 1, or 2:

[0039] wherein an atom or a chemical group in the PTC is replaced to form a covalent bond with the LI;

[0040] The LI structure is: LXA-LI1-LXB;

[0041] Wherein, LI1 is selected from -(CH2)m1-, -(CH2)m2-O-, -(CH2)m2-NR 20 -、-(CH2)-NR 20 C(O)NR 20 -C(CH2)m2-、-(CH2)m2C(O)NR 20 (CH2)m2-, -(CH2)m2-(CH2CH2-W1)m1-(CH2)m2-, -(CH2)m2-W2-(CH2CH2-W1)m1-(CH2)m2-, -(CH2 )m2-(CH2CH2-W1)m1-(CH2CH2-W2)-(CH2)m2-, -(CH2)m2-(CO)m3-(Heterocycle)-(CH2)m2-, -(CH2)m2-(W1 -(CH2CH2)m1-(CH2)m2-(heterocycle)-(CH2)m2-, -(CH2)m2-(heterocycle)-(CH2)m2-(CH2CH2-W1)m1-(CH2CH2-W2)-(CH2)m2-, -(CH2)m2-(CO)m3-(heterocycle)-(CH2)m2-(heterocycle)-(CH2)m2- or -(CH2)m2-(CO)m3-(carbocycle)-(CH2)m2-;

[0042] W1 and W2 are each independently selected from -O- or -N(R 20 )-;

[0043] R 20 Independently selected from H, C1-C3 alkyl or C1-C3 haloalkyl;

[0044] m1, m2 and m3 are each independently selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8;

[0045] LXA and LXB are each independently selected from a chemical bond, -CH2-, -CH2CH2-, -CH=CH-, -C≡C-, -O-, -S-, -S(O)-, -S(O)2-, -N(R 20)-, -C(O)-, -C(O)OCH2-, -C(O)CH2O-, -C(O)NR 20 -、-C(O)NR 20 CH2-、-C(O)NR 20 CH2CH2-、-NR 20 C(O)-、-NR 20 C(O)CH2-、NR 20 C(O)CH2CH2-、-OC(O)NR 20 -、-OC(O)NR 20 CH2-、-NR 20 C(O)O-、-NR 20 C(O)OCH2-、-NR 20 C(O)CH2O- or -NR 20 C(O)NR 20 ;

[0046] Each -CH2- in the LI can be arbitrarily substituted; an atom or a chemical group in the PTC is replaced to form a covalent bond with LXA or LXB;

[0047] The U structure is:

[0048]

[0049] in, Indicates the connection site with LI;

[0050] D is an optionally substituted 3-15 membered ring;

[0051] E is selected from a 5-10 membered ring which is absent or arbitrarily substituted;

[0052] Z is selected from absence, a chemical bond or -CO-.

[0053] In some preferred embodiments, the E3 ligase ligand is selected from CRBN, VHL or KEAP1.

[0054] In some preferred embodiments, the compound described in any one of the above, its pharmaceutically acceptable salt, its deuterated product, its stereoisomer, its tautomer or a mixture thereof, the compound is selected from but not limited to the following compounds:

[0055]

[0056]

[0057]

[0058]

[0059]

[0060]

[0061] In some preferred embodiments, the PTC is selected from

[0062] In some preferred embodiments, LI is selected from

[0063] In some preferred embodiments, U is selected from

[0064] In some more preferred embodiments, the compound is selected from:

[0065]

[0066] Another object of the present invention is to provide a use of any of the above compounds, pharmaceutically acceptable salts thereof, deuterated substances thereof, stereoisomers thereof, tautomers thereof or mixtures thereof in the preparation of protein degradation targeting chimeras (PROTACs) of androgen receptors.

[0067] Another object of the present invention is to provide a use of any of the above compounds, pharmaceutically acceptable salts thereof, deuterated substances thereof, stereoisomers thereof, tautomers thereof or mixtures thereof in the preparation of a drug for treating and / or preventing androgen receptor-mediated or dependent conditions or diseases;

[0068] Preferably, the androgen receptor-mediated or -dependent condition or disease is selected from prostate cancer, breast cancer, ovarian cancer, bladder cancer, pancreatic cancer, hepatocellular carcinoma, endometrial cancer, salivary gland cancer, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal cord, novel coronavirus infection COVID-19 or bulbar muscular atrophy or age-related macular degeneration;

[0069] Further preferably, the androgen receptor-mediated or -dependent condition or disease is selected from prostate cancer, breast cancer, ovarian cancer, bladder cancer, pancreatic cancer, hepatocellular carcinoma, endometrial cancer or salivary gland cancer;

[0070] Still more preferably, the androgen receptor-mediated or -dependent condition or disease is prostate cancer;

[0071] More preferably, the prostate cancer is a prostate cancer having a general androgen receptor and / or an androgen receptor alternative splicing variant 7. DETAILED DESCRIPTION

[0072] The present invention is further described in detail below in conjunction with the embodiments, but the present invention is not limited thereto. Any equivalent substitutions in the art made according to the disclosure of the present invention belong to the protection scope of the present invention.

[0073] The structures of compounds were determined by mass spectrometry (MS) or nuclear magnetic resonance (NMR). 1 HNMR) to determine.

[0074] Nuclear magnetic resonance (NMR) 1 HNMR) shifts (δ) are given in parts per million (ppm); nuclear magnetic resonance ( 1 HNMR) was measured using a Bruker AVANCE-400 NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO) as the solvent and tetramethylsilane (TMS) as the internal standard. The chemical shift was calculated based on 10 -6 (ppm) is given as the unit.

[0075] Mass spectrometry (MS) was performed using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Therm, model: Finnigan LCQ advantage MAX).

[0076] Terms and Definitions:

[0077] The following is an explanation of the terms of the present invention. For a specific term, if the meaning in the present invention is inconsistent with the meaning generally understood by those skilled in the art, the meaning in the present invention shall prevail; if there is no definition in the present invention, it has the meaning generally understood by those skilled in the art. Unless otherwise stated, the terms used in the present invention have the following meanings:

[0078] The term "substitution" of the present invention refers to one or more (e.g., one, two, three or four) H on the designated atom being replaced by a selection from the indicated group, provided that the normal atomic valence of the designated atom in the current situation is not exceeded and the substitution forms a stable compound. Combinations of substituents and / or variables are permitted only when such combinations form stable compounds. It should be understood that other atoms, such as hydrogen atoms or substituents as described herein, may be present as needed to satisfy the valence of the atom.

[0079] The term "arbitrarily substituted" as used herein means that one or more H atoms on the group may be optionally substituted by one or more identical or different substituents or may not be substituted; preferably, the arbitrarily substituted substituents described in the present invention may be selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, H, halogen, -CN, C3-C6 cycloalkyl, -OH, -NH2, 6-12 membered aryl, 5-12 membered heteroaryl or 3-15 membered heterocyclyl; specific examples include but are not limited to methyl, ethyl, propyl, trifluoromethyl, cyclopropyl, fluorine, chlorine, methoxy, phenyl, naphthyl, pyridyl, pyrazinyl and the like.

[0080] As used herein, the term "independently" means that when more than one substituent is selected from a number of possible substituents, those substituents may be the same or different; or when a substituent occurs multiple times, each occurrence may be selected from the same or different.

[0081] As used herein, "fused ring" or "fused ring" refers to a cyclic structure in which two or more rings share one or more bonds.

[0082] As used herein, "spirocycle" refers to a cyclic structure in which two or more rings share one or more atoms.

[0083] The term "ring" as used herein refers to a ring selected from a heterocyclic ring, a carbocyclic ring, an aromatic ring or a heteroaromatic ring without limitation, and may be a bridged ring, a fused ring or a spirocyclic ring system of a monocyclic or polycyclic system; for example, the "3-15 membered ring" of the present invention includes C3-C 15 Carbocyclic ring, 3-15 membered heterocyclic ring, 3-15 membered aromatic ring or 3-15 membered heteroaromatic ring; illustrative examples include, but are not limited to, cyclopropyl, cyclobutyl, phenyl, pyridine, thiophene, and the like.

[0084] The term "aryl" as used herein refers to an all-carbon monocyclic or polycyclic group having a conjugated π electron system. For the purposes of the present invention, the polycyclic group may be a bicyclic, tricyclic or tetracyclic ring system, which may include a fused or bridged ring system. At least one ring in the polycyclic group is an aromatic ring, and the other rings may be aromatic rings, saturated or unsaturated carbocyclic rings, for example: aryl-aryl, aryl-carbocyclic ring, etc.

[0085] The term "carbocyclyl" or "carbocycle" as used herein refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon group (including fused, bridged or spirocyclic systems) consisting only of carbon atoms and hydrogen atoms, which may be connected to the rest of the parent moiety via one or more single bonds via any suitable carbon atom. 10Specific examples of carbocyclic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, etc. According to the purpose of the present invention, the carbocyclic groups of the present invention include cycloalkyl and cycloalkenyl.

[0086] The term "heteroaryl" as used herein refers to a monocyclic or polycyclic group (wherein at least one ring is a heteroaromatic ring) having aromaticity and containing one to more heteroatoms (preferably 1-3) selected from N, O or S, wherein the polycyclic group includes a bicyclic, tricyclic or more fused ring, bridged ring or spiro ring system.

[0087] The term "heterocyclyl" or "heterocycle" as used herein refers to a stable, saturated or unsaturated (non-aromatic), monocyclic or polycyclic (e.g., bicyclic, tricyclic or more cyclic bridged, fused or spirocyclic) heterocyclic hydrocarbon group consisting of carbon atoms and one or more heteroatoms or heteroatom groups selected from O, S, and N (e.g., C(=O), S(=O), S(=O)2).

[0088] The term "alkyl" appearing alone or in combination herein refers to a straight or branched saturated hydrocarbon group consisting only of carbon atoms and hydrogen atoms, including, but not limited to, C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl and C1 alkyl (i.e., methyl). As non-limiting examples of alkyl, the following straight or branched saturated hydrocarbon groups can be cited: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl and seven other isomers thereof, n-hexyl and sixteen other isomers thereof. For example, "C1-C6 alkyl" includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and all isomers thereof.

[0089] The term "alkoxy" as used herein, alone or in combination, refers to an "-O-alkyl" group. For example, the term "C1-C6 alkoxy" refers to a saturated, straight or branched hydrocarbon moiety having at least 1 and at most 6 carbon atoms bonded by an oxygen linking atom. Specific exemplary embodiments include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, and tert-butoxy, etc.

[0090] The term "alkylamino" or "alkylamino" appearing alone or in combination herein means that the H in "-NH2" is replaced by a saturated or unsaturated branched or straight-chain alkyl group, that is, -NH-alkyl or -N-(alkyl)(alkyl). For example, "C1-C6 alkylamino" means that one or two hydrogens in -NH2 are replaced by a saturated or unsaturated branched or straight-chain alkyl group having 1 to 6 carbon atoms. Specific non-limiting examples include but are not limited to -NHCH3, -NHCH2CH3, -N(CH3)CH3, -NH(CH=CH2), etc.

[0091] The term "alkenyl" as used herein, alone or in combination, refers to a straight or branched hydrocarbon chain radical having one or more carbon-carbon double bonds; each alkenyl group is attached to the rest of the molecule by a single bond.

[0092] The term "alkynyl" as used herein, alone or in combination, refers to a straight or branched hydrocarbon chain radical having one or more carbon-carbon triple bonds; each alkynyl group is attached to the rest of the molecule by a single bond.

[0093] The term "alkanethio" appearing herein, alone or in combination, refers to a group having a "-S-(C1-C6 alkyl)" structure.

[0094] As used herein, the term "halogen" refers to a bromine, chlorine, fluorine or iodine radical, including their radioactive isotopes;

[0095] As used herein, the term "oxo" refers to a "=O" group;

[0096] The compounds of the present invention may contain one or more asymmetric centers, and thus may produce enantiomers, diastereomers, and other stereoisomeric forms. The present invention is intended to include all such possible isomers, as well as their racemic forms and optically pure forms, whether or not they are specifically described herein. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthesis or chiral reagents, or separated using conventional techniques, for example, chromatography and fractional crystallization. Conventional techniques for preparing / separating individual enantiomers include chiral synthesis from suitable optically pure precursors or separation of racemates (or racemates of salts or derivatives) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other geometric asymmetric centers, unless otherwise indicated, the compounds are intended to include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included:

[0097] "Stereoisomer" refers to a stable isomer that has a perpendicular asymmetric plane due to at least one chiral factor (including chiral center, chiral axis, chiral plane, etc.), thereby being able to rotate plane polarized light; the present disclosure contemplates various stereoisomers and mixtures thereof, and includes "enantiomers". The term "stereoisomer" includes cis-trans isomers, enantiomers, diastereomers, and conformational isomers.

[0098] "Tautomers" (or "tautomeric forms") refer to structural isomers with different energies that can be interconverted through a low energy barrier. For example, proton tautomers (or prototransfer tautomers) include (but are not limited to) interconversions via proton migration, such as keto-enol isomerization, imine-enamine isomerization, amide-imino alcohol isomerization, etc.; the present disclosure includes tautomers of any of the compounds.

[0099] In addition, the compounds of the present invention may contain one or more isotopic forms, i.e., hydrogen isotopic forms of D or T, or isotopes of any atoms, such as all isotopic forms of C and N. All isotopic forms of any C, N or H in the compounds of the optional structures of the present invention are included in the protection scope of the present invention. The words "include", "comprising" and "containing" and their equivalents should be understood as open, non-exclusive meanings, i.e., "including but not limited to", meaning that in addition to the listed elements, components and steps, other unspecified elements, components and steps may also be included.

[0100] The starting materials or intermediates used herein can be prepared by methods known in the art or by the methods disclosed herein, or can be purchased from commercial institutions.

[0101] In the present invention, column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as a carrier.

[0102] Unless otherwise specified in the present invention, the solution mentioned in the reaction of the present invention is an aqueous solution.

[0103] The term "room temperature" in the present invention refers to a temperature between 10°C and 25°C.

[0104] Intermediate 1: 4-(4-(4-(3-aminocyclobutaneoxy)phenyl)tetrahydro-2H-pyran-4-yl)phenol

[0105]

[0106] The synthetic route of intermediate 1 is as follows:

[0107]

[0108] Step 1: Synthesis of 4,4'-(tetrahydro-2H-pyran-4,4-diyl)diphenol (Intermediate 1-2)

[0109] Tetrahydro-4H-pyran-4-one (10g, 0.1mol) was added to 150mL of concentrated hydrochloric acid, and then phenol (18.785g, 0.2mol) was added. After the addition was completed, the mixture was stirred at room temperature for 3 hours under nitrogen protection. The reaction was monitored by LCMS. 150mL of water was added to the system to quench, and ethyl acetate (100mL*3 times) was used for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was subjected to column chromatography (PE:EA=4:1) to obtain the title compound as a white solid (16g, yield: 59%). ESI-MS: m / z[M+H] + =269.1

[0110] Step 2: tert-Butyl (3-(4-(4-(4-hydroxyphenyl)tetrahydro-2H-pyran-4-yl)phenoxy)cyclobutyl)carbamate (Intermediate 1-3)

[0111] Dissolve 4,4'-(tetrahydro-2H-pyran-4,4-diyl)diphenol (3.553g, 13.158mmol) in tetrahydrofuran (90mL), add tert-butyl (1r,3r)-3-hydroxycyclobutyl)carbamate (1.971g, 10.527mmol), add triphenylphosphine (5.177g, 19.739mmol), add diisopropyl azodicarboxylate (3.91mL, 19.739mmol) at 0℃ under nitrogen protection. After stirring at 60℃ for 16 hours, the reaction was completed after LCMS monitoring. The reaction solution was spin-dried and column chromatography (petroleum ether / ethyl acetate = 3 / 1) was used to obtain the title compound as a white solid (1.5g, yield 25%). ESI-MS: m / z[M+Na] + =462.0

[0112] Step 3: 4-(4-(4-(3-aminocyclobutyloxy)phenyl)tetrahydro-2H-pyran-4-yl)phenol (Intermediate 1)

[0113] Dissolve tert-butyl (3-(4-(4-(4-hydroxyphenyl)tetrahydro-2H-pyran-4-yl)phenoxy)cyclobutyl)carbamate (38 mg, 0.0867 mmol) in dichloromethane (1 mL), add trifluoroacetic acid (0.2 mL), stir at room temperature for 1 hour under nitrogen protection, and monitor the reaction completion by LCMS. The reaction solution is directly concentrated under reduced pressure to obtain the title compound as a white solid (29 mg, yield 100%). ESI-MS: m / z[M+H] + =340.0

[0114] Intermediate 2: 3-((2-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)cyclobutyl 4-methylbenzenesulfonate

[0115]

[0116] The synthetic route of intermediate 2 is as follows:

[0117]

[0118] Step 1: Preparation of dimethyl 4-aminophthalate (Intermediate 2-1)

[0119] Dimethyl 4-nitrophthalate (11.95 g, 50 mmol, CAS: 610-22-0) was added to a 200 mL round-bottom flask, and methanol (90 mL), tetrahydrofuran (30 mL) and palladium carbon (530 mg, 5 mmol) were added. The hydrogen was replaced three times, and the mixture was reacted at room temperature overnight under a hydrogen atmosphere. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain the title compound as a white solid (10.45 g, yield 100%).

[0120] Step 2: Preparation of dimethyl 4-((3-(benzyloxy)cyclobutyl)amino)phthalate (Intermediate 2-2)

[0121] 3-(Benzyloxy)-1-cyclobutanone (3.472 g, 50 mmol, CAS: 30830-27-4) and dimethyl 4-aminophthalate (8.8 g, 50 mmol) were dissolved in dichloroethane (50 mL), acetic acid (6 g, 100 mmol) was added dropwise, and the mixture was reacted at room temperature for 30 minutes, followed by addition of sodium triacetoxyborohydride (31.8 g, 150 mmol, CAS: 56553-60-7) in batches, and the reaction mixture was stirred at room temperature overnight. Saturated sodium bicarbonate solution was added to the reaction solution to quench the reaction, extracted with dichloromethane three times, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate / dichloromethane = 5:1:1) to obtain the title compound as a white solid (15.68 g, yield 85%).

[0122] Step 3: Preparation of 4-((3-(benzyloxy)cyclobutyl)amino)phthalic acid (Intermediate 2-3)

[0123] Dimethyl 4-((3-(benzyloxy)cyclobutyl)amino)phthalate (15.68 g, 42.5 mmol) was dissolved in methanol (150 mL) and tetrahydrofuran (50 mL), and 2M lithium hydroxide aqueous solution (85 mL, 170 mmol) was added, and the mixture was reacted at 50°C overnight. The reaction solution was concentrated under reduced pressure, 10% citric acid (80 mL) was added, and the mixture was extracted with ethyl acetate three times, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound as a white solid (14.49 g, yield 100%).

[0124] Step 4: Preparation of 5-((3-(benzyloxy)cyclobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Intermediate 2-4)

[0125] 4-((3-(Benzyloxy)cyclobutyl)amino)phthalic acid (14.49 g, 42.5 mmol) was added to acetonitrile (100 mL), and N,N-diisopropylethylamine (21.93 g, 170 mmol) was added in batches at 0°C, and stirred at 0°C for 10 minutes, and then HATU (32.3 g, 85 mmol, CAS: 148893-10-1) was added, and stirred at 0°C for 20 minutes, and then 3-amino-2,6-piperidinedione hydrochloride (7 g, 42.5 mmol, CAS: 24666-56-6) was added in batches, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure and purified by column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain the title compound as a yellow solid (12.88 g, yield 70%). LC-MS: m / z[M+H] + =434.

[0126] Step 5: Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-((3-hydroxycyclobutyl)amino)isoindoline-1,3-dione (Intermediate 2-5)

[0127] 5-((3-(Benzyloxy)cyclobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (12.88 g, 29.75 mmol) was added to methanol (50 mL), palladium carbon (315 mg, 2.975 mmol), and hydrogen was replaced 3 times. The mixture was stirred at room temperature overnight under a hydrogen atmosphere. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain the title compound as a yellow solid (10.2 g, yield 100%). LC-MS: m / z[M+H] + =344.

[0128] Step 6: Preparation of 3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)cyclobutyl 4-methylbenzenesulfonate (Intermediate 2-6)

[0129] 2-(2,6-dioxopiperidin-3-yl)-5-((3-hydroxycyclobutyl)amino)isoindoline-1,3-dione (10.2 g, 29.75 mmol) was added to dichloromethane (50 mL), triethylamine (6.0 g, 59.5 mmol) was added dropwise at 0°C, stirred for 20 minutes, and then p-toluenesulfonyl chloride (6.82 g, 35.7 mmol) was added in batches, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure and purified by column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain the title compound as a yellow solid (11.85 g, yield 80%). LC-MS: m / z[M+H] + =498.

[0130] Step 7: Preparation of 3-((2-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)cyclobutyl 4-methylbenzenesulfonate (Intermediate 2)

[0131] 3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)cyclobutyl 4-methylbenzenesulfonate (11.85 g, 23.8 mmol) was added to N,N-dimethylformamide (50 mL), sodium hydride (952 mg, 23.8 mmol) was added at 0°C, stirred for 20 minutes, and then 2-(trimethylsilyl)ethoxymethyl chloride (4.77 g, 28.56 mmol, CAS: 76513-69-4) was added in batches, and the mixture was reacted at room temperature for 1 hour. Saturated ammonium chloride solution was added to the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate three times. The organic phases were combined, washed with saturated brine three times, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain the title compound as a yellow solid (12.7 g, yield 85%). LC-MS: m / z[M+H] + =628.

[0132] Intermediate 3: 4-(2-(4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-1,3-dithiolan-2-yl)phenol

[0133]

[0134] The synthetic route of intermediate 3 is as follows:

[0135]

[0136] Step 1: Preparation of 4,4'-(1,3-dithiolane-2,2-diyl)diphenol (Intermediate 3-1)

[0137] Under nitrogen, 4,4'-dihydroxybenzophenone (1.5g, 7mmol, CAS: 611-99-4) was added to dichloromethane (20mL), ethanedithiol (1.3g, 14mmol) was added dropwise, and boron trifluoride etherate (1.3g, 9.3mmol) and trifluoroacetic acid (2mL) were added dropwise at 0°C, and the mixture was reacted at 40°C for 72 hours. 5% sodium bicarbonate solution was added to the reaction solution to quench the reaction, and the mixture was extracted with dichloromethane 3 times, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound as a yellow solid (1.99g, yield 98%).

[0138] Step 2: Preparation of 4-(2-(4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-1,3-dithiolan-2-yl)phenol (Intermediate 3)

[0139] 4,4'-(1,3-dithiolane-2,2-diyl)diphenol (1.99 g, 6.86 mmol) and 3,4-dihydro-2H-pyran (576 mg, 6.86 mmol, CAS: 110-87-2) were added to dichloromethane (20 mL), and then 4-methylbenzenesulfonic acid pyridine (173 mg, 0.69 mmol, CAS: 24057-28-1) was added, and the mixture was reacted at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure and purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain the title compound as a yellow solid (1.16 g, yield 45%). LC-MS: m / z[M+H] + =375.

[0140] Intermediate 4: 4-(2-(4-(3-aminocyclobutyloxy)phenyl)propan-2-yl)phenol

[0141]

[0142] Intermediate 4 was synthesized in a similar manner to Intermediate 1 by replacing 4,4′-(tetrahydro-2H-pyran-4,4-diyl)diphenol (Intermediate 1-2) with bisphenol A (CAS: 80-05-7).

[0143] Intermediate 5: 4-(1-(4-(3-aminocyclobutyloxy)phenyl)-4-methoxycyclohexyl)phenol

[0144]

[0145] Intermediate 5 was synthesized in a similar manner to Intermediate 1 by replacing tetrahydro-4H-pyran-4-one (CAS: 29943-42-8) with p-methoxycyclohexanone (CAS: 13482-23-0).

[0146] Intermediate 6: 4-(1-(4-(3-aminocyclobutyloxy)phenyl)-4,4-difluorocyclohexyl)phenol

[0147]

[0148] Intermediate 6 was synthesized in a similar manner to Intermediate 1 by replacing tetrahydro-4H-pyran-4-one (CAS: 29943-42-8) with 4,4-difluorocyclohexanone (CAS: 22515-18-0).

[0149] Intermediate 7: 4,4'-(tetrahydro-2H-thiopyran-4,4-diyl)diphenol

[0150]

[0151] Intermediate 7 was synthesized in a similar manner to Intermediate 1-2 by replacing tetrahydro-4H-pyran-4-one (CAS: 29943-42-8) with tetrahydrothiopyran-4-one (CAS: 1072-72-6).

[0152] Intermediate 8: 4,4-bis(4-hydroxyphenyl)tetrahydro-2H-thiopyran 1,1-dioxide

[0153]

[0154] Dissolve 4,4'-(tetrahydro-2H-thiopyran-4,4-diyl)diphenol (2g, 6.98mmol, intermediate 7) in methanol (50mL), add an aqueous solution of potassium persulfate complex salt (9.6g, 15.7mmol, CAS: 37222-66-5), and stir the mixture at room temperature for 2 hours. Pour the reaction solution into a saturated sodium sulfite aqueous solution (100mL), extract with ethyl acetate (50mL) three times, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the title compound as a white solid (1.9g, yield 85.5%). LC-MS: m / z [MH] - =317.

[0155] Intermediate 9: 4-(4-(3-aminocyclobutyloxy)phenyl)-4-(4-hydroxyphenyl)tetrahydro-2H-thiopyran 1,1-dioxide

[0156]

[0157] Intermediate 9 was synthesized in a similar manner to Intermediate 1 by replacing 4,4'-(tetrahydro-2H-pyran-4,4-diyl)diol (Intermediate 1-2) with 4,4-bis(4-hydroxyphenyl)tetrahydro-2H-thiopyran 1,1-dioxide (Intermediate 8).

[0158] Intermediate 10: 2,6-dimethyltetrahydro-4H-pyran-4-one

[0159]

[0160] 2,6-dimethyl-4H-pyran-4-one (4.0 g, 32.25 mmol, CAS: 1004-36-0) was dissolved in methanol (80 mL), palladium / carbon (0.4 g) was added, and hydrogen was replaced three times. The mixture was stirred at 30°C under a hydrogen atmosphere for 24 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain the title compound (4.0 g, yield 97%) as a yellow oil.

[0161] Intermediate 11: 4-(4-(4-(3-aminocyclobutyloxy)phenyl)-2,6-dimethyltetrahydro-2H-pyran-4-yl)phenol

[0162]

[0163] Intermediate 11 was synthesized in a similar manner to Intermediate 1 by replacing tetrahydro-4H-pyran-4-one (CAS: 29943-42-8) with 2,6-dimethyltetrahydro-4H-pyran-4-one (Intermediate 10).

[0164] Intermediate 12: 3-(6-fluoro-4-oxobenzo[d][1,2,3]triazine-3(4H)-yl)piperidine-2,6-dione

[0165]

[0166] Intermediate 12 was synthesized according to the method provided in the literature (European Journal of Medicinal Chemistry, 2020, vol. 208, art. no. 112769).

[0167] Intermediate 13: 1-(6-(4-(4-(4-(3-aminocyclobutyloxy)phenyl)tetrahydro-2H-pyran-4-yl)phenoxy)pyridazin-3-yl)ethan-1-one

[0168]

[0169] The synthetic route of intermediate 13 is as follows:

[0170]

[0171] Step 1: Preparation of tert-butyl (3-(4-(4-(4-((6-cyanopyridazin-3-yl)oxy)phenyl)tetrahydro-2H-pyran-4-yl)phenoxy)cyclobutyl)carbamate (Intermediate 13-1)

[0172] Tert-butyl (3-(4-(4-(4-hydroxyphenyl)tetrahydro-2H-pyran-4-yl)phenoxy)cyclobutyl)carbamate (2.00 g, 4.55 mmol, intermediate 1-3) was dissolved in N,N-dimethylformamide (20 mL), 3-cyano-6-chloropyridazine (0.63 g, 4.55 mmol, CAS: 35857-89-7) and cesium carbonate (2.97 g, 9.10 mmol) were added, and the mixture was reacted at room temperature for 3 hours. Water (150 mL) was added to the reaction solution for dilution, and the mixture was extracted twice with ethyl acetate (50 mL). The organic phases were combined and washed once with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain the title compound as a yellow oil (2.10 g, yield 85%).

[0173] Step 2: Preparation of tert-butyl (3-(4-(4-(4-((6-acetylpyridazin-3-yl)oxy)phenyl)tetrahydro-2H-pyran-4-yl)phenoxy)cyclobutyl)carbamate (Intermediate 13-2)

[0174] Tert-butyl (3-(4-(4-(4-((6-cyanopyridazin-3-yl)oxy)phenyl)tetrahydro-2H-pyran-4-yl)phenoxy)cyclobutyl)carbamate (2.00 g, 3.69 mol) was dissolved in anhydrous tetrahydrofuran (30 mL), and 1 M methylmagnesium bromide tetrahydrofuran solution (20 mL, 19.90 mmol) was slowly added dropwise under ice bath, and the mixture was kept warm for 5 minutes, and then warmed to room temperature for 2 hours. Saturated aqueous ammonium chloride solution (10 mL) was slowly added to the reaction solution under ice bath to quench the reaction, and extracted twice with ethyl acetate (50 mL), the organic phases were combined, washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain the title compound as a white foamy solid (1.84 g, yield 89%).

[0175] Step 3: Preparation of 1-(6-(4-(4-(4-(3-aminocyclobutyloxy)phenyl)tetrahydro-2H-pyran-4-yl)phenoxy)pyridazin-3-yl)ethan-1-one (Intermediate 13)

[0176] Dissolve tert-butyl (3-(4-(4-(4-((6-acetylpyridazin-3-yl)oxy)phenyl)tetrahydro-2H-pyran-4-yl)phenoxy)cyclobutyl)carbamate (1.80 g, 3.22 mmol) in dichloromethane (15 mL), add trifluoroacetic acid (7.5 mL) under ice bath, and stir the mixture at room temperature for 3 hours. Slowly pour the reaction solution into saturated sodium bicarbonate solution (200 mL) under ice bath, extract three times with mixed solvent of dichloromethane / methanol (100 mL, 10 / 1), combine the organic phases, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography (dichloromethane / methanol = 40:1) to obtain the title compound as a white solid (0.98 g, yield 66%). LC-MS: m / z[M+H] + =460.

[0177] Intermediate 14: 3-(6-bromo-2-oxobenzo[cd]indol-1(2H)-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione

[0178]

[0179] 3-(6-bromo-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione (0.92 g, 2.58 mmol, synthesized according to the method provided in patent application WO2020210630A1) was dissolved in anhydrous N,N-dimethylformamide (25 mL), 1,8-diazabicyclo[5.4.0]undec-7-ene (782.8 mg, 5.15 mmol, CAS: 6674-22-2) was added under nitrogen protection, and 2-(trimethylsilyl)ethoxymethyl chloride (855 mg, 5.15 mmol, CAS: 76513-69-4) was added dropwise under ice bath, and the compound was reacted at room temperature for 2 hours. Add saturated aqueous ammonium chloride to the reaction solution to quench the reaction, extract twice with ethyl acetate, combine the organic phases, wash once with water, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by column chromatography to obtain the title compound (715 mg, yield 57%) as an orange-yellow solid. ESI-MS: m / z [MH] - =487.

[0180] Intermediate 15: 1-(4-(4-(4-((6-acetylpyridazin-3-yl)oxy)phenyl)tetrahydro-2H-pyran-4-yl)phenyl)azetidine-3-carboxylic acid

[0181]

[0182] The synthetic route of intermediate 15 is as follows:

[0183]

[0184] Step 1: Preparation of 4-(4-bromophenyl)tetrahydro-2H-pyran-4-ol (Intermediate 15-1)

[0185] Add 1,4-dibromobenzene (20g, 0.0847mol) and 200mL anhydrous THF to a 500mL three-necked flask with a thermometer and nitrogen protection, then cool to -78°C in a cold well, and drip n-BuLi (20.4mL, 0.051mol) (2.5M, in THF) into the system at -78°C within 10min, and stir at the same temperature for 30min. Then drip tetrahydro-4H-pyran-4-one (4.24g, 0.0424mol), slowly warm to room temperature after dripping, and stir for 1h. After sampling and quenching with saturated ammonium chloride, TLC monitoring shows that the raw material is completely reacted, and the product is the main point. In the system, 200 mL of saturated ammonium chloride solution was slowly added at low temperature, followed by 400 mL of water, and extracted with ethyl acetate (50 mL) three times. The organic phases were combined and washed with saturated brine, concentrated under reduced pressure and dried, and then column chromatography (petroleum ether / ethyl acetate = 3:1) was performed to obtain 9.93 g of the title compound, with a yield of 45.78%.

[0186] Step 2: Preparation of 4-(4-(4-bromophenyl)tetrahydro-2H-pyran-4-yl)phenol (Intermediate 15-2)

[0187] Add 4-(4-bromophenyl)tetrahydro-2H-pyran-4-ol (9.18 g, 0.0359 mol), phenol (6.75 g, 0.0717 mol), concentrated hydrochloric acid (90 mL) to a 250 mL single-mouth bottle, stir at room temperature overnight, monitor by TLC, the raw materials react completely, and the product is the main point. Add 200 mL of water, extract three times with ethyl acetate (50 mL), then combine the organic phases, wash with saturated brine, concentrate under reduced pressure, dry, and column chromatography (petroleum ether / ethyl acetate = 4:1) to obtain 3.5 g of the title compound, yield: 29.31%.

[0188] Step 3: Preparation of methyl 1-(4-(4-(4-hydroxyphenyl)tetrahydro-2H-pyran-4-yl)phenyl)azetidine-3-carboxylate (Intermediate 15-3)

[0189] 4-(4-(4-bromophenyl)tetrahydro-2H-pyran-4-yl)phenol (200 mg, 0.602 mmol), 3-methylformate azetidine hydrochloride (117 mg, 0.783 mmol, CAS: 343238-58-4), tris(dibenzylideneacetone)dipalladium (27 mg, 0.03 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (34 mg, 0.048 mmol, CAS: 564483-18-7) and cesium carbonate (636 mg, 1.80 mmol) were added to N,N-dimethylformamide (40 mL), replaced with nitrogen three times, and the mixture was stirred at 100 ° C overnight under nitrogen protection. The reaction solution was cooled to room temperature, diluted with water (20 mL), extracted with ethyl acetate (10 mL) three times, the organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and column chromatography (petroleum ether / ethyl acetate = 5:1) gave the title compound as a white solid (80 mg, yield 36%). LC-MS: m / z [MH] - =366.

[0190] Step 4: Preparation of methyl 1-(4-(4-(4-((6-acetylpyridazin-3-yl)oxy)phenyl)tetrahydro-2H-pyran-4-yl)phenyl)azetidine-3-carboxylate (Intermediate 15-4)

[0191] 1-(4-(4-(4-hydroxyphenyl)tetrahydro-2H-pyran-4-yl)phenyl)azetidine-3-carboxylic acid methyl ester (500mg, 1.36mmol) was dissolved in N,N-dimethylformamide (3mL), cesium carbonate (1.43g, 4.08mmol) and 3-acetyl-6-chloropyridazine (424mg, 2.72mmol) were added, and the mixture was reacted at 60°C overnight under nitrogen protection. Water (20mL) was added to the reaction solution for dilution, and the mixture was extracted with ethyl acetate (30mL) for 3 times. The organic phases were combined and washed with saturated brine (20mL) for 2 times. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate = 3:1) to obtain the title compound as a white solid (100mg, yield 15%). LC-MS: m / z[M+H] + =488.

[0192] Step 5: Preparation of 1-(4-(4-(4-((6-acetylpyridazin-3-yl)oxy)phenyl)tetrahydro-2H-pyran-4-yl)phenyl)azetidine-3-carboxylic acid (Intermediate 15)

[0193] 1-(4-(4-(4-((6-acetylpyridazin-3-yl)oxy)phenyl)tetrahydro-2H-pyran-4-yl)phenyl)azetidine-3-carboxylic acid methyl ester (100 mg, 0.205 mmol) was dissolved in a tetrahydrofuran / water (6 mL / 2 mL) mixed solvent, lithium hydroxide (30 mg, 1.23 mmol) was added, and the mixture was reacted at room temperature for 2 hours. Water (20 mL) was added to the reaction solution for dilution, and it was extracted once with ethyl acetate (30 mL). The aqueous phase was adjusted to pH = 5-6 with 2M hydrochloric acid, extracted 3 times with ethyl acetate (10 mL), the organic phases were combined, washed twice with saturated brine (20 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound as a white solid (70 mg, yield 72%). LC-MS: m / z[MH] - =472.

[0194] Intermediate 16: 4-(5-hydroxy-4-(4-(piperazin-1-ylmethyl)phenyl)-4H-1,2,4-triazol-3-yl)-6-isopropylbenzene-1,3-diphenol

[0195]

[0196] Intermediate 16 was synthesized according to the method provided in the patent (WO2018112176A1).

[0197] Intermediate 17: 3-(4-(4-(4-((1-(methylsulfonyl)azetidin-3-yl)methoxy)phenyl)tetrahydro-2H-pyran-4-yl)phenoxy)cyclobutane-1-amine

[0198]

[0199] The synthetic route of intermediate 17 is as follows:

[0200]

[0201] Step 1: Preparation of tert-butyl 3-((4-(4-(4-hydroxyphenyl)tetrahydro-2H-pyran-4-yl)phenoxy)methyl)azetidine-1-carboxylate (Intermediate 17-1)

[0202] 4,4'-(tetrahydro-2H-pyran-4,4-diyl)diphenol (964 mg, 3.58 mmol, intermediate 1-2), tert-butyl 3-((p-toluenesulfonyl)methyl)azetidine-1-carboxylate (1.1 g, 3.2 mmol, CAS: 892408-42-3) and potassium carbonate (988 mg, 7.16 mmol) were added to N-methylpyrrolidone (35 mL), and the mixture was stirred at 90°C for 16 hours. Water (150 mL) was added to the reaction solution for dilution, and ethyl acetate (50 mL) was used for extraction twice. The organic phases were combined and washed once with saturated brine (50 mL). The organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain the title compound as a yellow oil (740 mg, yield 47%). LC-MS: m / z [MH]- = 438.

[0203] Step 2: Preparation of 4-(4-(4-(azetidin-3-ylmethoxy)phenyl)tetrahydro-2H-pyran-4-yl)phenol (Intermediate 17-2)

[0204] 3-((4-(4-(4-hydroxyphenyl)tetrahydro-2H-pyran-4-yl)phenoxy)methyl)azetidine-1-carboxylic acid tert-butyl ester (740mg, 1.69mmol) was added to dichloromethane (6mL), trifluoroacetic acid (2mL) was added under ice bath, and the mixture was stirred at room temperature for 3 hours. The reaction solution was slowly poured into saturated sodium bicarbonate solution (50mL) under ice bath, extracted with dichloromethane 3 times, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (dichloromethane / methanol = 15:1) to obtain the title compound as a white solid (490mg, yield 83%). LC-MS: m / z[MH] - =338.

[0205] Step 3: Preparation of 4-(4-(4-((1-(methylsulfonyl)azetidin-3-yl)methoxy)phenyl)tetrahydro-2H-pyran-4-yl)phenol (Intermediate 17-3)

[0206] 4-(4-(4-(azetidin-3-ylmethoxy)phenyl)tetrahydro-2H-pyran-4-yl)phenol (490mg, 1.4mmol) and triethylamine (425mg, 4.2mmol) were added to tetrahydrofuran (6mL), and methanesulfonyl chloride (150mg, 1.3mmol) was added under ice-water bath, and the mixture was stirred at room temperature for 3 hours. Water (150mL) was added to the reaction solution for dilution, and ethyl acetate (50mL) was used for extraction twice. The organic phases were combined and washed once with saturated brine (50mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate = 1:9) to obtain the title compound as a yellow solid (410mg, yield 70%). LC-MS: m / z[M+H] + =418.

[0207] Step 4: Preparation of tert-butyl (3-(4-(4-(4-((1-(methylsulfonyl)azetidin-3-yl)methoxy)phenyl)tetrahydro-2H-pyran-4-yl)phenoxy)cyclobutyl)carbamate (Intermediate 17-4)

[0208] Intermediate 17-4 was synthesized in a similar manner to Intermediate 1-3.

[0209] Step 5: Preparation of 3-(4-(4-(4-((1-(methylsulfonyl)azetidin-3-yl)methoxy)phenyl)tetrahydro-2H-pyran-4-yl)phenoxy)cyclobutane-1-amine (Intermediate 17)

[0210] Intermediate 17 was synthesized in a similar manner to Intermediate 1.

[0211] Intermediate 18: 2-(4-(4-(4-hydroxyphenyl)tetrahydro-2H-pyran-4-yl)phenyl)-2-oxoacetic acid

[0212]

[0213] The synthetic route of intermediate 18 is as follows:

[0214]

[0215] Step 1: Preparation of 4-(4-(4-((tert-butyldimethylsilyl)oxy)phenyl)tetrahydro-2H-pyran-4-yl)phenol (Intermediate 18-1)

[0216] 4,4'-(Tetrahydro-2H-pyran-4,4-diyl)diphenol (5.0 g, 18.5 mmol, intermediate 1-2) was dissolved in dichloromethane (50 mL), tert-butyldimethylsilyl chloride (2.5 g, 16.7 mmol) and imidazole (1.4 g, 20.4 mmol) were added, and the mixture was stirred at 25°C for 16 hours. The reaction solution was diluted with water and extracted with ethyl acetate three times. The combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain the title compound as a white solid (3.2 g, yield 45%).

[0217] Step 2: Preparation of 4-(4-(4-((tert-butyldimethylsilyl)oxy)phenyl)tetrahydro-2H-pyran-4-yl)phenyl trifluoromethanesulfonate (Intermediate 18-2)

[0218] 4-(4-(4-((tert-butyldimethylsilyl)oxy)phenyl)tetrahydro-2H-pyran-4-yl)phenol (3.1 g, 8.0 mmol) was dissolved in dichloromethane (24 mL), trifluoromethanesulfonyl chloride (1.5 g, 8.8 mmol) and triethylamine (3.2 g, 32 mmol) were added under ice bath, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure and purified by column chromatography (petroleum ether / ethyl acetate = 20:1) to obtain the title compound (3.4 g, yield 81%) as a colorless transparent oil.

[0219] Step 3: Preparation of 1-(4-(4-(4-((tert-butyldimethylsilyl)oxy)phenyl)tetrahydro-2H-pyran-4-yl)phenyl)ethan-1-one (Intermediate 18-3)

[0220] 4-(4-(4-((tert-butyldimethylsilyl)oxy)phenyl)tetrahydro-2H-pyran-4-yl)phenyl trifluoromethanesulfonate (3.4 g, 6.5 mmol), tributyl(1-ethoxyvinyl)tin (3.5 g, 9.8 mmol, CAS: 97674-02-7) and tetrakis(triphenylphosphine)palladium (751 mg, 0.65 mmol) were added to dioxane (20 mL), and the mixture was stirred at 100 ° C for 16 hours. The reaction solution was poured into 3M hydrochloric acid (30 mL), the mixture was stirred at room temperature for 30 minutes, and extracted with ethyl acetate three times. The combined organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain the title compound as a yellow solid (904 mg, yield 34%).

[0221] Step 4: Preparation of 2-(4-(4-(4-((tert-butyldimethylsilyl)oxy)phenyl)tetrahydro-2H-pyran-4-yl)phenyl)-2-oxoacetic acid (Intermediate 18-4)

[0222] 1-(4-(4-(4-((tert-butyldimethylsilyl)oxy)phenyl)tetrahydro-2H-pyran-4-yl)phenyl)ethan-1-one (904 mg, 2.2 mmol) was dissolved in pyridine (5 mL), selenium dioxide (488 mg, 4.4 mmol) was added, and the mixture was stirred at 90°C for 16 hours. The reaction solution was diluted with water, extracted with ethyl acetate three times, and the combined organic phase was washed once with 3M hydrochloric acid, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (794 mg, yield 83%) as a yellow oil.

[0223] Step 5: Preparation of 2-(4-(4-(4-hydroxyphenyl)tetrahydro-2H-pyran-4-yl)phenyl)-2-oxoacetic acid (Intermediate 18)

[0224] 2-(4-(4-(4-((tert-butyldimethylsilyl)oxy)phenyl)tetrahydro-2H-pyran-4-yl)phenyl)-2-oxoacetic acid (300 mg, 0.68 mmol) was dissolved in a 1M tetrabutylammonium fluoride tetrahydrofuran solution (2 mL), and the mixture was stirred at 25°C for 16 hours. The reaction solution was diluted with water, extracted with ethyl acetate three times, and the combined organic phase was washed once with a saturated aqueous ammonium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound as a yellow oil (222 mg, yield 100%). LC-MS: m / z[MH] - =325.

[0225] Intermediate 19: 4-(7-(4-(3-aminocyclobutyloxy)phenyl)-2-oxaspiro[3.5]non-7-yl)phenol

[0226]

[0227] Intermediate 19 was synthesized in a similar manner to Intermediate 1 by replacing tetrahydro-4H-pyran-4-one (CAS: 29943-42-8) with 2-oxaspiro[3.5]nonan-7-one (CAS: 1256546-74-3).

[0228] Intermediate 20: (1-(Methylsulfonyl)azetidin-3-yl)methyl methanesulfonate

[0229]

[0230] Intermediate 20 was synthesized according to the method provided in patent application WO2015062486A1.

[0231] Intermediate 21: 3-((tert-Butyloxycarbonyl)amino)cyclobutyl 4-methylbenzenesulfonate

[0232]

[0233] Intermediate 21 was synthesized according to the method provided in patent application WO2012028331A1.

[0234] Intermediate 22: (5-(3-aminocyclobutyloxy)pyridin-2-yl)(4-hydroxyphenyl)methanone

[0235]

[0236] The synthetic route of intermediate 22 is as follows:

[0237]

[0238] Step 1: Preparation of 5-hydroxy-N-methoxy-N-methylpicolinamide (Intermediate 22-1)

[0239] Intermediate 22-1 was synthesized according to the method provided in patent application WO2013097773A1.

[0240] Step 2: Preparation of tert-butyl (3-((6-(methoxy(methyl)carbamoyl)pyridin-3-yl)oxy)cyclobutyl)carbamate (Intermediate 22-2)

[0241] 5-Hydroxy-N-methoxy-N-methylpicolinamide (778 mg, 4.27 mmol) and 3-((tert-butyloxycarbonyl)amino)cyclobutyl 4-methylbenzenesulfonate (2.186 g, 6.41 mmol, intermediate 21) were dissolved in dimethyl sulfoxide (10 mL), cesium carbonate (2.78 g, 8.55 mmol) and potassium iodide (355 mg, 2.14 mmol) were added, and nitrogen was replaced three times. The mixture was stirred at 95 ° C overnight. The reaction solution was poured into a saturated ammonium chloride solution (50 mL) to quench, and ethyl acetate (40 mL) was extracted twice. The organic phases were combined, washed once with water (40 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and purified by column chromatography (100% ethyl acetate) to obtain the title compound as a white solid (1.436 g, yield 96%). LC-MS: m / z[M+H] + =352.

[0242] Step 3: Preparation of tert-butyl (3-((6-(4-((tetrahydro-2H-pyran-2-yl)oxy)benzoyl)pyridin-3-yl)oxy)cyclobutyl)carbamate (Intermediate 22-3)

[0243] 2-(4-Bromophenoxy)tetrahydro-2H-pyran (1.7 g, 6.66 mmol, CAS: 36603-49-3) was dissolved in tetrahydrofuran (10 mL), replaced with nitrogen three times, the solution was cooled to -78 ° C, and then n-butyl lithium (2.4 mL, 6 mmol, 2.5 M n-hexane solution) was slowly added dropwise, the mixture was stirred at -78 ° C for 30 minutes, and then a solution of tert-butyl (3-((6-(methoxy(methyl)carbamoyl)pyridin-3-yl)oxy)cyclobutyl)carbamate (1.636 g, 4.66 mmol) in tetrahydrofuran (10 mL) was slowly added dropwise, and the reaction mixture was stirred at -78 ° C for 2 hours. The reaction solution was poured into a saturated ammonium chloride solution (50 mL) to quench, extracted twice with ethyl acetate (40 mL), the organic phases were combined, washed once with water (40 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate = 2:1) to obtain the title compound as a white solid (897 mg, yield 29%). LC-MS: m / z [M+H] + =469.

[0244] Step 4: Preparation of (5-(3-aminocyclobutyloxy)pyridin-2-yl)(4-hydroxyphenyl)methanone (Intermediate 22)

[0245] Tert-butyl (3-((6-(4-((tetrahydro-2H-pyran-2-yl)oxy)benzoyl)pyridin-3-yl)oxy)cyclobutyl)carbamate (383 mg, 0.82 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (0.6 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was directly concentrated under reduced pressure to obtain the title compound (233 mg crude product) as a light yellow oil, which was directly subjected to the next step of reaction. LC-MS: m / z[M+H] + =285.

[0246] Intermediate 23: 4-(3-(4-(3-aminocyclobutyloxy)phenyl)oxetan-3-yl)phenol

[0247]

[0248] Intermediate 23 was synthesized in a similar manner to Intermediate 1 by replacing tetrahydro-4H-pyran-4-one (CAS: 29943-42-8) with 3-oxetanone (CAS: 6704-31-0).

[0249] Intermediate 24: (4-(3-aminocyclobutyloxy)phenyl)(4-hydroxyphenyl)methanone

[0250]

[0251] The synthetic route of intermediate 24 is as follows:

[0252]

[0253] Step 1: Preparation of tert-butyl (3-(4-(4-hydroxybenzoyl)phenoxy)cyclobutyl)carbamate (Intermediate 24-1)

[0254] Dissolve 4,4'-dihydroxybenzophenone (1.455 g, 6.79 mmol, CAS: 611-99-4) in tetrahydrofuran (25 mL), add tert-butyl (3-hydroxycyclobutyl)carbamate (890 mg, 4.76 mmol, CAS: 154748-63-7) and triphenylphosphine (2.672 g, 10.2 mmol), add diisopropyl azodicarboxylate (2.06 g, 10.2 mmol, CAS: 2446-83-5) dropwise at 0°C under nitrogen protection, after the addition is complete, heat the mixture to 65°C and stir for 3 hours. The reaction solution was poured into a saturated ammonium chloride solution (120 mL) to quench, extracted twice with ethyl acetate (80 mL), the organic phases were combined, washed once with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and purified by reverse phase column (acetonitrile / water = 52:48) to obtain the title compound as a white solid (1.1 g, yield 60%). LC-MS: m / z [M-55] + =328.

[0255] Step 2: Preparation of (4-(3-aminocyclobutyloxy)phenyl)(4-hydroxyphenyl)methanone (Intermediate 24)

[0256] Dissolve tert-butyl (3-(4-(4-hydroxybenzoyl)phenoxy)cyclobutyl)carbamate (300 mg, 0.78 mmol) in 4M hydrogen chloride ethyl acetate solution (3 mL), and stir the mixture at 25°C for 1 hour under nitrogen protection. The reaction solution is directly concentrated under reduced pressure to obtain the title compound as a white solid (280 mg crude product), which is directly used in the next reaction. LC-MS: m / z[M+H] + =284.

[0257] Intermediate 25: 3-(6-amino-4-oxobenzo[d][1,2,3]triazine-3(4H)-yl)piperidine-2,6-dione

[0258]

[0259] Intermediate 25 was synthesized according to the method provided in European Journal of Medicinal Chemistry, 2019, vol. 166, p. 65-74.

[0260] Intermediate 26: 5-Fluoro-N-methyl-2-pyridinecarboxamide

[0261]

[0262] Intermediate 26 was synthesized according to the method provided in Journal of Medicinal Chemistry, 2017, vol. 60, #13, p. 5472-5492.

[0263] Intermediate 27: (4-(3-aminocyclobutyloxy)phenyl)(4-((1-(methylsulfonyl)azetidin-3-yl)methoxy)phenyl)methanone

[0264]

[0265] The synthetic route of intermediate 27 is as follows:

[0266]

[0267] Step 1: Preparation of tert-butyl (3-(4-(4-((1-(methylsulfonyl)azetidin-3-yl)methoxy)benzoyl)phenoxy)cyclobutyl)carbamate (Intermediate 27-1)

[0268] Tert-butyl (3-(4-(4-hydroxybenzoyl)phenoxy)cyclobutyl)carbamate (100 mg, 0.26 mmol, intermediate 24-1) was dissolved in N-methylpyrrolidone (3 mL), and (1-(methylsulfonyl)azetidin-3-yl)methyl methanesulfonate (76 mg, 0.31 mmol, intermediate 20) and cesium carbonate (170 mg, 0.52 mmol) were added, and the mixture was stirred at 90°C for 3 hours. The reaction solution was cooled to room temperature, and the reaction solution was poured into a saturated ammonium chloride solution (80 mL) to quench, and extracted twice with ethyl acetate (50 mL), the organic phases were combined, washed once with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate = 3:1) to obtain the title compound as a white solid (93 mg, yield 67%). LC-MS: m / z[M-55] + =475.

[0269] Step 2: Preparation of (4-(3-aminocyclobutyloxy)phenyl)(4-((1-(methylsulfonyl)azetidin-3-yl)methoxy)phenyl)methanone (Intermediate 27)

[0270] Dissolve tert-butyl (3-(4-(4-((1-(methylsulfonyl)azetidin-3-yl)methoxy)benzoyl)phenoxy)cyclobutyl)carbamate (93 mg, 0.18 mmol) in dichloromethane (3 mL), add trifluoroacetic acid (1 mL), and stir the mixture at 25°C for 1 hour. The reaction solution is directly concentrated under reduced pressure to obtain the title compound (87 mg crude product) as a yellow oil, which is directly used in the next reaction. LC-MS: m / z[M+H] + =431.

[0271] Intermediate 28: 1-(4-(2-(4-((tert-butyldimethylsilyl)oxy)phenyl)propan-2-yl)phenyl)ethan-1-one

[0272]

[0273] The synthetic route of intermediate 28 is as follows:

[0274]

[0275] Step 1: Preparation of 4-(2-(4-bromophenyl)propan-2-yl)phenol (Intermediate 28-1)

[0276] 2-Hydroxy-2-(4-bromophenyl)propane (9.0 g, 41.9 mmol, CAS: 2077-19-2) and phenol (4.3 g, 46 mmol) were added to trifluoroacetic acid (50 mL), and the mixture was stirred at 25°C for 5 hours. The reaction solution was directly concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1 to 5:1) to obtain the title compound as a colorless oil (12.0 g, yield 98%). LC-MS: m / z [M+H] + =291 / 293.

[0277] Step 2: Preparation of 1-(4-(2-(4-hydroxyphenyl)propan-2-yl)phenyl)ethan-1-one (Intermediate 28-2)

[0278] 4-(2-(4-bromophenyl)propan-2-yl)phenol (2.0g, 6.86mmol), tributyl(1-ethoxyethylene)tin (2.7g, 7.55mmol, CAS:97674-02-7) and tetrakis(triphenylphosphine)palladium (793mg, 0.686mmol, CAS:14221-01-3) were added to dioxane (20.0mL), replaced with nitrogen three times, and the mixture was stirred at 90°C for 16 hours. The reaction solution was cooled to room temperature, poured into 2M hydrochloric acid (20mL), extracted three times with ethyl acetate (50mL), the organic phases were combined, washed once with saturated brine (50mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate = 50:1 to 10:1) to obtain the title compound as a yellow solid (920mg, yield 53%). LC-MS: m / z[M+H] + =255.

[0279] Step 3: Preparation of 1-(4-(2-(4-((tert-butyldimethylsilyl)oxy)phenyl)propan-2-yl)phenyl)ethan-1-one (Intermediate 28)

[0280] 1-(4-(2-(4-hydroxyphenyl)propan-2-yl)phenyl)ethane-1-one (1.1 g, 4.33 mmol) was dissolved in dichloromethane (10 mL), tert-butyldimethylsilyl chloride (980 mg, 6.5 mmol) and imidazole (883 mg, 13.0 mmol) were added, and the mixture was stirred at 25°C for 16 hours. Water (50 mL) was added to the reaction solution for dilution, and the mixture was extracted three times with ethyl acetate (30 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate = 100:1 to 20:1) to obtain the title compound as a yellow oil (1.6 g, yield 100%). LC-MS: m / z[M+H] + =369.

[0281] Intermediate 29: 2-(4-(2-(4-hydroxyphenyl)propan-2-yl)phenyl)-2-oxoacetic acid

[0282]

[0283] Intermediate 29 was synthesized in a similar manner to Intermediate 18 by replacing 1-(4-(4-(4-((tert-butyldimethylsilyl)oxy)phenyl)propan-2-yl)phenyl)ethan-1-one (Intermediate 28) with 1-(4-(2-(4-((tert-butyldimethylsilyl)oxy)phenyl)tetrahydro-2H-pyran-4-yl)phenyl)ethan-1-one (Intermediate 18-3).

[0284] Intermediate 30: 1-(4-(4-(4-((6-acetylpyridazin-3-yl)oxy)phenyl)tetrahydro-2H-pyran-4-yl)phenyl)piperidine-4-carbaldehyde

[0285]

[0286] The synthetic route of intermediate 30 is as follows:

[0287]

[0288] Step 1: Preparation of 4-(4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)tetrahydro-2H-pyran-4-yl)phenol (Intermediate 30-1)

[0289] 4-(4-(4-bromophenyl)tetrahydro-2H-pyran-4-yl)phenol (3.4 g, 11 mmol, intermediate 15-2), 4-(dimethoxymethyl)-piperidine (2.47 g, 15.8 mmol, CAS: 188646-83-5), RuPhos Pd G4 (433 mg, 0.51 mmol, CAS: 1599466-85-9) and cesium carbonate (6.85 g, 21 mmol) were added to N,N-dimethylformamide (40 mL), replaced with nitrogen three times, and the mixture was stirred at 110 ° C overnight under nitrogen protection. The reaction solution was cooled to room temperature, diluted with water (100 mL), extracted with ethyl acetate (30 mL) three times, the organic phases were combined, washed twice with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and column chromatography (petroleum ether / ethyl acetate = 2:1) gave the title compound as a white solid (2.5 g, yield 58%). LC-MS: m / z [M+H] + =412.

[0290] Step 2: Preparation of 6-(4-(4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)tetrahydro-2H-pyran-4-yl)phenoxy)pyridazine-3-carbonitrile (Intermediate 30-2)

[0291] 4-(4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)tetrahydro-2H-pyran-4-yl)phenol (2.3 g, 5.6 mmol) was dissolved in dimethyl sulfoxide (30 mL), cesium carbonate (3.64 g, 11 mmol) and 3-cyano-6-chloropyridazine (1.01 g, 7.3 mmol, CAS: 35857-89-7) were added, and the mixture was stirred at room temperature for 2 hours. Water (100 mL) was added to the reaction solution for dilution, and the mixture was extracted with ethyl acetate (30 mL) for 3 times. The organic phases were combined and washed with saturated brine (30 mL) for 2 times. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate = 3:1) to obtain the title compound as a white solid (1.41 g, yield 49%). LC-MS: m / z[M+H] + =515.

[0292] Step 3: Preparation of 1-(6-(4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)tetrahydro-2H-pyran-4-yl)phenoxy)pyridazin-3-yl)ethan-1-one (Intermediate 30-3)

[0293] 6-(4-(4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)tetrahydro-2H-pyran-4-yl)phenoxy)pyridazine-3-carbonitrile (1.2 g, 2.3 mol) was dissolved in anhydrous tetrahydrofuran (20 mL), and 3M methylmagnesium bromide tetrahydrofuran solution (5.4 mL, 16 mmol) was slowly added dropwise at -78°C. The mixture was kept warm for 30 minutes. Saturated citric acid aqueous solution (50 mL) was slowly added to the reaction solution under ice bath to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL) three times. The organic phases were combined and washed twice with saturated sodium bicarbonate solution (100 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate = 3:1) to obtain the title compound as a white solid (550 mg, yield 45%). LC-MS: m / z[M+H] + =532.

[0294] Step 4: Preparation of 1-(4-(4-(4-((6-acetylpyridazin-3-yl)oxy)phenyl)tetrahydro-2H-pyran-4-yl)phenyl)piperidine-4-carboxaldehyde (Intermediate 30)

[0295] 1-(6-(4-(4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)tetrahydro-2H-pyran-4-yl)phenoxy)pyridazin-3-yl)ethane-1-one (300 mg, 0.4 mmol) was added to formic acid (2 mL) and water (6 mL), and the mixture was reacted at room temperature overnight. The reaction solution was directly concentrated under reduced pressure and purified by column chromatography (dichloromethane / methanol = 30:1) to obtain the title compound as a white solid (185 mg, yield 68%). LC-MS: m / z[M+H] + =486.

[0296] Intermediate 31: 1-(4-(4-(4-((6-acetylpyridazin-3-yl)oxy)phenyl)tetrahydro-2H-pyran-4-yl)phenyl)azetidine-3-carbaldehyde

[0297]

[0298] The synthetic route of intermediate 31 is as follows:

[0299]

[0300] Step 1: Preparation of 4-(4-(4-(3-(hydroxymethyl)azetidin-1-yl)phenyl)tetrahydro-2H-pyran-4-yl)phenol (Intermediate 31-1)

[0301] 4-(4-(4-bromophenyl)tetrahydro-2H-pyran-4-yl)phenol (2.0 g, 6 mmol, intermediate 15-2) was dissolved in 1,4-dioxane (40 mL), and azetidin-3-ylmethanol hydrochloride (1.11 g, 9 mmol, CAS: 928038-44-2), tris(dibenzylideneacetone)dipalladium (0.55 g, 0.6 mmol, CAS: 51364-51-3), cesium carbonate (5.86 g, 1.8 mmol) and 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (0.7 g, 1.2 mmol, CAS: 161265-03-8) were added, and nitrogen was replaced three times. The mixture was stirred at 110 ° C for 16 hours under nitrogen protection. The reaction solution was cooled to room temperature, poured into water (40 mL), extracted three times with ethyl acetate (100 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate = 1:2) to obtain the title compound as a white solid (0.68 g, yield 33%). LC-MS: m / z [M+H] + =340.

[0302] Step 2: Preparation of 1-(6-(4-(4-(4-(3-(hydroxymethyl)azetidin-1-yl)phenyl)tetrahydro-2H-pyran-4-yl)phenoxy)pyridazin-3-yl)ethan-1-one (Intermediate 31-2)

[0303] 4-(4-(4-(3-(hydroxymethyl)azetidin-1-yl)phenyl)tetrahydro-2H-pyran-4-yl)phenol (0.68 g, 2 mmol) was dissolved in N,N-dimethylformamide (7 mL), cesium carbonate (0.98 g, 3 mmol) and 3-acetyl-6-chloropyridazine (0.47 g, 3 mmol, CAS: 214701-31-2) were added, and the mixture was stirred at room temperature for 2 hours. Water (50 mL) was added to the reaction solution for dilution, and the mixture was extracted with ethyl acetate (20 mL) for 3 times. The organic phases were combined and washed with saturated brine (20 mL) for 2 times. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate = 1:2) to obtain the title compound as a white solid (0.34 g, yield 37%). LC-MS: m / z[M+H] + =460.

[0304] Step 3: Preparation of 1-(4-(4-(4-((6-acetylpyridazin-3-yl)oxy)phenyl)tetrahydro-2H-pyran-4-yl)phenyl)azetidine-3-carbaldehyde (Intermediate 31)

[0305] 1-(6-(4-(4-(4-(3-(hydroxymethyl)azetidin-1-yl)phenyl)tetrahydro-2H-pyran-4-yl)phenoxy)pyridazin-3-yl)ethane-1-one (0.15 g, 0.327 mmol) was dissolved in dimethyl sulfoxide (5 mL), 2-iodoacylbenzoic acid (0.183 g, 0.653 mmol, CAS: 61717-82-6) was added, and the mixture was stirred at 50°C for 1 hour. The reaction solution was cooled to room temperature, water (20 mL) was added to dilute the reaction solution, and it was extracted 3 times with ethyl acetate (30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain the title compound as a white solid (80 mg, yield 54%). LC-MS: m / z[M+H] + =458.

[0306] Intermediate 32: 4-(4-(4-(3-aminocyclobutyloxy)phenyl)tetrahydro-2H-thiopyran-4-yl)phenol

[0307]

[0308] Intermediate 32 was synthesized in a similar manner to Intermediate 1 by replacing 4,4'-(tetrahydro-2H-thiopyran-4,4-diyl)diphenol (Intermediate 7) with 4,4'-(tetrahydro-2H-pyran-4,4-diyl)diphenol (Intermediate 1-2).

[0309] Intermediate 33: 1-(4-(Fluoromethyl)pyrimidin-2-yl)ethan-1-one

[0310]

[0311] Intermediate 33 was synthesized according to the method provided in patent application US2016168139A1.

[0312] Example 1: 3-(4-((3-(4-(4-(4-((6-acetylpyridazin-3-yl)oxy)phenyl)tetrahydro-2H-pyran-4-yl)phenoxy)cyclobutyl)amino)-2,6-difluorophenyl)piperidine-2,6-dione

[0313]

[0314] The preparation scheme is shown below:

[0315]

[0316] Step 1: Preparation of ethyl 4-(4-bromo-2,6-difluorophenyl)-4-cyanobutyrate (1-2)

[0317] Dissolve 2-(4-bromo-2,6-difluorophenyl)acetonitrile (1g, 4.3mmol) in (10mL) anhydrous tetrahydrofuran, replace nitrogen three times, slowly add 2.0mol / L lithium diisopropylamide tetrahydrofuran solution (2.4mL, 4.8mmoL) at -65℃, react for 1h, then add ethyl 3-bromopropionate (0.7mL, 1.1mmoL), react at -65℃ for 0.5h, then slowly warm to room temperature for 1h, and monitor the reaction by LCMS. Quench with saturated ammonium chloride aqueous solution, extract with ethyl acetate (30mL*3), wash with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and the residue is directly column chromatographed (PE:EA=4:1) to obtain the colorless liquid title compound (890mg, yield: 62%). ESI-MS: m / z[M+H] + =333.8

[0318] Step 2: Preparation of 4-(4-bromo-2,6-difluorophenyl)-4-cyanobutyric acid (1-3)

[0319] Under nitrogen protection, ethyl 4-(4-bromo-2,6-difluorophenyl)-4-cyanobutyrate (890mg, 2.69mmol) was dissolved in tetrahydrofuran / water (9mL / 3ml). Lithium hydroxide (338mg, 8.06mmol) was added and reacted at room temperature overnight. LCMS monitored the completion of the reaction. 10mL of water was added to the reaction solution to quench, and then the reaction solution was adjusted to acidic pH = 4 with (1.0moL / L) hydrochloric acid. Extract with ethyl acetate (30mL*3), wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude colorless oily title compound. Directly proceed to the next step reaction (845mg, yield 100%). ESI-MS: m / z[M+H] + =303.8

[0320] Step 3: Preparation of 3-(4-bromo-2,6-difluorophenyl)piperidine-2,6-dione (1-4)

[0321] Dissolve 4-(4-bromo-2,6-difluorophenyl)-4-cyanobutyric acid (845mg, 2.79mmol) in toluene (6mL), add concentrated sulfuric acid (0.3g, 3.068mmol) and react at 100℃ for 1 hour. LCMS monitors the reaction completion. Quench with saturated aqueous ammonium chloride solution, extract with ethyl acetate (30mL*3), wash with saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude white solid which is directly used in the next step (796mg, yield: 100%). ESI-MS: m / z[M+H] + =303.8

[0322] Step 4: Preparation of 3-(4-bromo-2,6-difluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (1-5)

[0323] Under nitrogen protection, 3-(4-bromo-2,6-difluorophenyl)piperidine-2,6-dione (202 mg, 0.67 mmol) was dissolved in anhydrous N,N-dimethylformamide, 1,8-diazobispiro[5.4.0]undec-7-ene (202.16 mg, 1.33 mmol) was added, 2-(trimethylsilyl)ethoxymethyl chloride (221 mg, 1.33 mmol) was added at 0°C and reacted at room temperature for 2 hours. The reaction was monitored by LCMS. It was quenched with saturated aqueous ammonium chloride, extracted with ethyl acetate (30 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was directly column chromatographed to obtain a colorless liquid (177 mg, yield 61%). ESI-MS: m / z[M+Na] + =455.8

[0324] Step 5: Preparation of 3-(2,6-difluoro-4-((3-(4-(4-(4-hydroxyphenyl)tetrahydro-2H-pyran-4-yl)phenoxy)cyclobutyl)amino)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (1-6)

[0325] 3-(4-Bromo-2,6-difluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (50 mg, 0.115 mmol) and 4-(4-(4-(3-aminocyclobutyloxy)phenyl)tetrahydro-2H-pyran-4-yl)phenol (59 mg, 0.173 mmol) were dissolved in 1,4-dioxane, cesium carbonate (112.6 mg, 0.346 mmol) and 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tri-I-propyl-11'-biphenyl (25 mg, 0.046 mmol) and trisdibenzylideneacetone dipalladium (21 mg, 0.023 mmol) were added, nitrogen was replaced three times, and the reaction was monitored by LCMS at 90°C overnight until completion. The mixture was quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate (30 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was directly subjected to column chromatography to obtain a colorless oil (34 mg, yield: 42%). ESI-MS: m / z [M+Na] + =715.2

[0326] Step 6: Preparation of 3-(4-((3-(4-(4-(4-((6-acetylpyridazin-3-yl)oxy)phenyl)tetrahydro-2H-pyran-4-yl)phenoxy)cyclobutyl)amino)-2,6-difluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (1-7)

[0327] 3-(2,6-difluoro-4-((3-(4-(4-(4-hydroxyphenyl)tetrahydro-2H-pyran-4-yl)phenoxy)cyclobutyl)amino)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (34 mg, 0.048 mmol) was dissolved in anhydrous N,N-dimethylformamide (2 mL), cesium carbonate (47 mg, 0.143 mmol) was added, and then 3-acetyl-6-chloropyridazine (12 mg, 0.07 mmol, CAS: 214701-31-2) was added, and the reaction was allowed to proceed at room temperature for 1 h. The reaction was monitored by TLC. The reaction was quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate 3 times, washed with saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was directly subjected to column chromatography to obtain a white solid (29 mg, yield: 72%).

[0328] Step 7: Preparation of 3-(4-((3-(4-(4-(4-((6-acetylpyridazin-3-yl)oxy)phenyl)tetrahydro-2H-pyran-4-yl)phenoxy)cyclobutyl)amino)-2,6-difluorophenyl)piperidine-2,6-dione (Example 1)

[0329] 3-(4-((3-(4-(4-(4-((6-acetylpyridazin-3-yl)oxy)phenyl)tetrahydro-2H-pyran-4-yl)phenoxy)cyclobutyl)amino)-2,6-difluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (29 mg, 0.036 mmol) was dissolved in dichloromethane (1.0 mL) and trifluoroacetic acid (0.2 mL) was added to react at room temperature for 1 h. The reaction was monitored by LCMS. The reaction solution was concentrated under reduced pressure and the crude product was dissolved in acetonitrile (4 mL) and ammonia water (0.3 mL) was added. The reaction was reacted at room temperature for 1 h, and the reaction was monitored by LCMS. It was quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate 3 times, washed with saturated brine once, dried over anhydrous sodium sulfate, filtered, and the residue was concentrated under reduced pressure and directly column chromatographed to obtain Example 1 (16 mg, HPLC purity: 95%, yield: 65%).

[0330] Example 1: ESI-MS: m / z [M+H] + =683.2;

[0331] Embodiment 1: 1 H NMR (400MHz, DMSO-d6) δ10.83(s,1H),8.15(d,J=9.2Hz,1H),7.55(d,J=9.2Hz,1H),7.43(d, J=8.8Hz,2H),7.29(d,J=8.8Hz,2H),7.19(d,J=8.8Hz,2H),6.81(d,J=8.8Hz,2H),6.59(d,J =6.9Hz,1H),6.17(d,J=11.7Hz,2H),4.52–4.38(m,1H),4.00-3.96(m,1H),3.72–3.49(m,5H ),3.02-2.95(m,2H),2.88–2.71(m,1H),2.68(s,3H),2.48–2.28(m,5H),2.16–1.78(m,4H).

[0332] Example 2: 3-(4-((3-(4-(4-(4-((6-acetylpyridazin-3-yl)oxy)phenyl)tetrahydro-2H-pyran-4-yl)phenoxy)cyclobutyl)amino)-2,5-difluorophenyl)piperidine-2,6-dione

[0333]

[0334] The preparation scheme is shown below:

[0335]

[0336] Step 1: Preparation of 2,6-bis(benzyloxy)-3-(4-bromo-2,5-difluorophenyl)pyridine (2-2)

[0337] 1-Bromo-2,5-difluoro-4-iodobenzene (1 g, 3.14 mmol, CAS: 145349-66-2) and 2,6-bis(benzyloxy)pyridine-3-boronic acid pinacol ester (1.3 g, 3.14 mmol, CAS: 2152673-80-6) were dissolved in 1,4-dioxane / water (10 mL / 2 mL), potassium phosphate (1.33 g, 6.27 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride dichloromethane complex (229 mg, 0.314 mmol, CAS: 95464-05-4) were added, nitrogen was replaced three times, and the reaction solution was stirred at 80 ° C for 16 hours under nitrogen protection. The reaction solution was poured into a saturated ammonium chloride solution to quench, extracted with ethyl acetate twice, washed with water once, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was directly purified by column chromatography (PE:EA=15:1) to obtain a white solid (1.1 g, yield 73%). ESI-MS: m / z[M+H] + =482 / 484.

[0338] Step 2: Preparation of 4-(4-(4-(3-((4-(2,6-bis(benzyloxy)pyridin-3-yl)-2,5-difluorophenyl)amino)cyclobutyloxy)phenyl)tetrahydro-2H-pyran-4-yl)phenol (2-3)

[0339] 2,6-bis(benzyloxy)-3-(4-bromo-2,5-difluorophenyl)pyridine (500 mg, 1.04 mmol) and 4-(4-(4-(3-aminocyclobutyloxy)phenyl)tetrahydro-2H-pyran-4-yl)phenol (529 mg, 1.6 mmol, intermediate 1) were dissolved in 1,4-dioxane (5 mL), and cesium carbonate (1.01 g, 3.1 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (120 mg, 0.21 mmol, CAS: 161265-03-8) and tris(dibenzylideneacetone)dipalladium (95 mg, 0.1 mmol, CAS: 51364-51-3) were added, and nitrogen was replaced three times and the mixture was heated at 100°C overnight. After adding 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (120 mg, 0.21 mmol) and tri(dibenzylideneacetone)dipalladium (95 mg, 0.1 mmol), the reaction mixture was kept at 100°C overnight under nitrogen protection. The reaction solution was poured into a saturated ammonium chloride solution to quench, extracted with ethyl acetate twice, washed with water once, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was directly purified by column chromatography (PE:EA=3:2) to obtain the title compound as a white solid (361 mg, yield 47%).

[0340] Step 3: Preparation of 3-(2,5-difluoro-4-((3-(4-(4-(4-hydroxyphenyl)tetrahydro-2H-pyran-4-yl)phenoxy)cyclobutyl)amino)phenyl)piperidine-2,6-dione (2-4)

[0341] 4-(4-(4-(3-((4-(2,6-bis(benzyloxy)pyridin-3-yl)-2,5-difluorophenyl)amino)cyclobutyloxy)phenyl)tetrahydro-2H-pyran-4-yl)phenol (361 mg, 0.49 mmol) was dissolved in 1,4-dioxane (5 mL), palladium carbon (361 mg) and palladium hydroxide (361 mg) were added, hydrogen was replaced three times, and the reaction was carried out at 30°C for 16 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain a crude white solid title compound (335 mg, yield 100%). ESI-MS: m / z[M+H] + =563.

[0342] Step 4: Preparation of 3-(4-((3-(4-(4-(4-((6-acetylpyridazin-3-yl)oxy)phenyl)tetrahydro-2H-pyran-4-yl)phenoxy)cyclobutyl)amino)-2,5-difluorophenyl)piperidine-2,6-dione (Example 2)

[0343] 3-(2,5-difluoro-4-((3-(4-(4-(4-hydroxyphenyl)tetrahydro-2H-pyran-4-yl)phenoxy)cyclobutyl)amino)phenyl)piperidine-2,6-dione (335 mg, 0.6 mmol) was dissolved in anhydrous N,N-dimethylformamide (5 mL), and cesium carbonate (581 mg, 1.8 mmol) and 3-acetyl-6-chloropyridazine (112 mg, 0.72 mmol, CAS: 214701-31-2) were added and reacted at room temperature for 2 hours. The reaction solution was directly purified by reverse column chromatography and then purified by column chromatography (PE:EA=2:1) ​​to obtain the title compound as a white solid (53 mg, HPLC purity: 99%, yield: 13%).

[0344] Example 2: ESI-MS: m / z [M+H] + =683.2;

[0345] Embodiment 2: 1 H NMR (400MHz, DMSO-d6) δ10.80(s,1H),8.15(d,J=9.2Hz,1H),7.55(d,J=9.2Hz,1H),7.43(d,J=8.8Hz, 2H),7.29(d,J=8.8Hz,2H),7.19(d,J=8.8Hz,2H),7.00-6.95(m,1H),6.81(d,J=8.8Hz,2H),6.48-6.4 2(m,1H),6.07(d,J=7.0Hz,1H),4.52–4.34(m,1H),3.88-3.83(m,1H),3.71–3.49(m,5H),3.00-2.94( m,2H),2.77–2.65(m,4H),2.55-2.50(m,1H),2.45-2.33(m,4H),2.20-2.10(m,1H),2.07–1.91(m,3H).

[0346] Example 3: 5-((3-(4-(2-(4-((6-acetylpyridazin-3-yl)oxy)phenyl)-1,3-dithiolan-2-yl)phenoxy)cyclobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0347]

[0348] The preparation scheme is shown below:

[0349]

[0350] Step 1: Preparation of 2-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-5-((3-(4-(2-(4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-1,3-dithiolan-2-yl)phenoxy)cyclobutyl)amino)isoindoline-1,3-dione (3-1)

[0351] 4-(2-(4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-1,3-dithiolan-2-yl)phenol (1.16 g, 3.09 mmol, intermediate 3), 3-((2-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)cyclobutyl 4-methylbenzenesulfonate (1.94 g, 3.09 mmol, intermediate 2) and potassium carbonate (1.28 g, 9.27 mmol) were added to dry acetone (15 mL), and the mixture was refluxed for 18 hours. The reaction solution was concentrated under reduced pressure and purified by column chromatography (petroleum ether / ethyl acetate = 2:1) to obtain the title compound as a yellow solid (200 mg, yield 7.8%).

[0352] Step 2: Preparation of 2-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-5-((3-(4-(2-(4-hydroxyphenyl)-1,3-dithiolan-2-yl)phenoxy)cyclobutyl)amino)isoindoline-1,3-dione (3-2)

[0353] 2-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-5-((3-(4-(2-(4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-1,3-dithiolan-2-yl)phenoxy)cyclobutyl)amino)isoindoline-1,3-dione (200 mg, 0.24 mmol) was added to acetic acid (5 mL) and water (1 mL), and the mixture was reacted at 50° C. for 6 hours. The reaction solution was cooled to room temperature, diluted with water, extracted with ethyl acetate 3 times, the organic phase was washed twice with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain the title compound as a yellow solid (150 mg, yield 84%).

[0354] Step 3: Preparation of 5-((3-(4-(2-(4-((6-acetylpyridazin-3-yl)oxy)phenyl)-1,3-dithiolan-2-yl)phenoxy)cyclobutyl)amino)-2-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)isoindoline-1,3-dione (3-3)

[0355] 2-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-5-((3-(4-(2-(4-hydroxyphenyl)-1,3-dithiolan-2-yl)phenoxy)cyclobutyl)amino)isoindoline-1,3-dione (150 mg, 0.2 mmol), 3-acetyl-6-chloropyridazine (63 mg, 0.4 mmol, CAS: 214701-31-2) and potassium carbonate (55 mg, 0.4 mmol) were added to N,N-dimethylformamide (5 mL), and the mixture was reacted at 80° C. for 2 hours. The reaction solution was cooled to room temperature, diluted with water, extracted with ethyl acetate 3 times, the organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain the title compound as a yellow solid (140 mg, yield 81%).

[0356] Step 4: Preparation of 5-((3-(4-(2-(4-((6-acetylpyridazin-3-yl)oxy)phenyl)-1,3-dithiolan-2-yl)phenoxy)cyclobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Example 3)

[0357] 3-(2,5-difluoro-4-((3-(4-(4-(4-hydroxyphenyl)tetrahydro-2H-pyran-4-yl)phenoxy)cyclobutyl)amino)phenyl)piperidine-2,6-dione (335 mg, 0.6 mmol) was dissolved in anhydrous N,N-dimethylformamide (5 mL), and cesium carbonate (581 mg, 1.8 mmol) and 3-acetyl-6-chloropyridazine (112 mg, 0.72 mmol, CAS: 214701-31-2) were added and reacted at room temperature for 2 hours. The reaction solution was directly purified by reverse column chromatography and then purified by column chromatography (PE:EA=2:1) ​​to obtain the title compound as a white solid (53 mg, HPLC purity: 99%, yield: 13%).

[0358] 5-((3-(4-(2-(4-((6-acetylpyridazin-3-yl)oxy)phenyl)-1,3-dithiolan-2-yl)phenoxy)cyclobutyl)amino)-2-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)isoindoline-1,3-dione (140 mg, 0.162 mmol) was added to dichloromethane (4 mL), and then trifluoroacetic acid (1 mL) was added, and the mixture was reacted at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, acetonitrile (5 mL) and ammonia water (0.1 mL) were added to the residue, the mixture was reacted at room temperature for 1 hour, and then saturated ammonium chloride solution was added, extracted with ethyl acetate 3 times, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain the title compound as a yellow solid (107 mg, yield 90%).

[0359] Example 3: ESI-MS: m / z [M+H] + =736.2;

[0360] Embodiment 3: 1 H NMR(500MHz, CDCl3)δ8.64(s,1H),8.13(d,J=9.1Hz,1H),7.66(d,J=8.3Hz,2H),7 .52-7.48(m,3H),7.26(s,1H),7.11(d,J=8.3Hz,2H),6.82(s,1H),6.69(d,J=8.5H z,2H),6.61(d,J=8.5Hz,1H),4.93-4.90(m,1H),4.50–4.42(m,1H),3.70-3.65(m ,1H),3.42–3.35(m,4H),3.08–3.00(m,2H),2.93–2.56(m,7H),2.11-1.98(m,3H).

[0361] Example 4: 3-(4-((3-(4-(2-(4-((2-acetylpyrimidin-5-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)-2,6-difluorophenyl)piperidine-2,6-dione

[0362]

[0363] The title compound was synthesized in a similar manner to Example 1 by replacing 4-(2-(4-(3-aminocyclobutyloxy)phenyl)propan-2-yl)phenol (Intermediate 4) with 4-(4-(4-(3-aminocyclobutaneoxy)phenyl)tetrahydro-2H-pyran-4-yl)phenol (Intermediate 1), and replacing 3-acetyl-6-chloropyridazine (CAS: 214701-31-2) with 1-(5-fluoropyrimidin-2-yl)ethanone (CAS: 905587-44-2).

[0364] Example 4: ESI-MS: m / z [M+H] + =641.4;

[0365] Embodiment 4: 1 H NMR (400MHz, DMSO-d6) δ10.88(s,1H),8.76(s,2H),7.36(d,J=8.6Hz,2H),7.20(d ,J=7.6Hz,4H),6.84(d,J=8.6Hz,2H),6.65(d,J=6.7Hz,1H),6.24(d,J=11.8Hz,2 H),4.54-4.47(m,1H),4.12–3.99(m,1H),3.68-3.60(m,1H),3.12–2.99(m,2H),2 .87-2.77(m,1H),2.71(s,3H),2.17-2.07(m,1H),2.05–1.90(m,4H),1.69(s,6H).

[0366] Example 5: 3-(4-((3-(4-(1-(4-((6-acetylpyridazin-3-yl)oxy)phenyl)-4-methoxycyclohexyl)phenoxy)cyclobutyl)amino)-2,6-difluorophenyl)piperidine-2,6-dione

[0367]

[0368] The title compound was synthesized in a similar manner to Example 2, replacing 4-(4-(4-(3-aminocyclobutaneoxy)phenyl)tetrahydro-2H-pyran-4-yl)phenol (Intermediate 1) with 4-(1-(4-(3-aminocyclobutaneoxy)phenyl)-4-methoxycyclohexyl)phenol (Intermediate 5).

[0369] Example 5: ESI-MS: m / z [M+H] + =711.2;

[0370] Embodiment 5: 1H NMR(400MHz,DMSO-d6)δ10.82(s,1H),8.16-8.13(m,1H),7.56-7.52(m,1H),7.43-7.36(m,2H),7.30-7.23 (m,2H),7.20–7.13(m,2H),6.83-6.77(m,2H),6.63–6.54(m,1H),6.19-6.15(m,2H),4.49-4.39(m,1H),4.0 0-3.96(m,1H),3.61-3.51(m,1H),3.30–3.25(m,1H),3.21(d,J=2.9Hz,3H),3.04-2.94(m,2H),2.78-2.76 (m,1H),2.68(d,J=3.6Hz,3H),2.47-2.42(m,1H),2.07-2.00(m,3H),1.98–1.69(m,6H),1.46-1.33(m,3H).

[0371] Example 6: 3-(4-((3-(4-(1-(4-((6-acetylpyridazin-3-yl)oxy)phenyl)-4,4-difluorocyclohexyl)phenoxy)cyclobutyl)amino)-2,6-difluorophenyl)piperidine-2,6-dione

[0372]

[0373] The title compound was synthesized in a similar manner to Example 2, replacing 4-(4-(4-(3-aminocyclobutaneoxy)phenyl)tetrahydro-2H-pyran-4-yl)phenol (Intermediate 1) with 4-(1-(4-(3-aminocyclobutaneoxy)phenyl)-4,4-difluorocyclohexyl)phenol (Intermediate 6).

[0374] Example 6: ESI-MS: m / z [M+H] + =717;

[0375] Embodiment 6: 1H NMR (400MHz, DMSO-d6) δ10.82(s,1H),8.15(d,J=9.2Hz,1H),7.56(d,J=9.2Hz,1H),7.45(d,J=8.8H z,2H),7.32(d,J=8.8Hz,2H),7.19(t,J=7.7Hz,2H),6.83(d,J=8.8Hz,2H),6.58(d,J=6.5Hz,1H),6 .17(d,J=11.7Hz,2H),4.54–4.37(m,1H),3.98(dd,J=12.5,5.1Hz,1H),3.68–3.47(m,1H),3.10–2. 93(m,2H),2.84–2.70(m,1H),2.68(s,3H),2.47–2.39(m,4H),2.12–2.01(m,1H),1.98–1.80(m,8H).

[0376] Example 7: 3-(4-((3-(4-(4-(4-((6-acetylpyridazin-3-yl)oxy)phenyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)phenoxy)cyclobutyl)amino)-2,6-difluorophenyl)piperidine-2,6-dione

[0377]

[0378] The title compound was synthesized in a similar manner to Example 2 by replacing 4-(4-(4-(3-aminocyclobutaneoxy)phenyl)-4-(4-hydroxyphenyl)tetrahydro-2H-thiopyran 1,1-dioxide (Intermediate 9) with 4-(4-(4-(3-aminocyclobutaneoxy)phenyl)tetrahydro-2H-pyran-4-yl)phenol (Intermediate 1).

[0379] Example 7: ESI-MS: m / z [M / 2+H] + =366;

[0380] Embodiment 7: 1H NMR (400MHz, DMSO-d6) δ10.83(s,1H),8.17(d,J=9.2Hz,1H),7.59(d,J=9.2Hz,1H),7.44 (d,J=8.6Hz,2H),7.33(d,J=6.9Hz,2H),7.25(d,J=8.6Hz,2H),6.89-6.83(m,2H),6.69- 6.59(m,1H),6.22–6.10(m,2H),4.87-4.50(m,1H),3.98(d,J=11.9Hz,2H),3.57(s,1H), 3.05(s,6H),2.83(s,5H),2.69(s,3H),2.39(s,1H),2.07(d,J=10.6Hz,1H),1.93(m,2H).

[0381] Example 8: 3-(4-((3-(4-(1-(4-((6-acetylpyridazin-3-yl)oxy)phenyl)-4-hydroxycyclohexyl)phenoxy)cyclobutyl)amino)-2,6-difluorophenyl)piperidine-2,6-dione

[0382]

[0383] The preparation scheme is shown below:

[0384]

[0385] Step 1: Preparation of 3-(2,6-difluoro-4-((3-(4-(4-hydroxy-1-(4-hydroxyphenyl)cyclohexyl)phenoxy)cyclobutyl)amino)phenyl)piperidine-2,6-dione (8-2)

[0386] 3-(2,6-difluoro-4-((3-(4-(1-(4-hydroxyphenyl)-4-methoxycyclohexyl)phenoxy)cyclobutyl)amino)phenyl)piperidine-2,6-dione (110 mg, 0.186 mmol, synthesized in a similar manner to 2-4 by replacing 4-(4-(4-(3-aminocyclobutaneoxy)phenyl)tetrahydro-2H-pyran-4-yl)phenol (Intermediate 1) with 4-(1-(4-(3-aminocyclobutyloxy)phenyl)-4-methoxycyclohexyl)phenol (Intermediate 5)) was dissolved in acetonitrile (10 mL), trimethylsilyl iodide (373 mg, 1.864 mmol) and sodium iodide (280 mg, 1.864 mmol) were added, and the mixture was reacted at room temperature for 1 hour. Saturated sodium sulfite solution was added to the reaction solution to quench the reaction, extracted twice with ethyl acetate, washed once with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a pink solid crude title compound (110 mg, yield: 100%). ESI-MS: m / z [M+Na]+ =599.

[0387] Step 2: Preparation of 3-(4-((3-(4-(1-(4-((6-acetylpyridazin-3-yl)oxy)phenyl)-4-hydroxycyclohexyl)phenoxy)cyclobutyl)amino)-2,6-difluorophenyl)piperidine-2,6-dione (Example 8)

[0388] 3-(2,6-difluoro-4-((3-(4-(4-hydroxy-1-(4-hydroxyphenyl)cyclohexyl)phenoxy)cyclobutyl)amino)phenyl)piperidine-2,6-dione (100 mg, 0.173 mmol) was dissolved in anhydrous N,N-dimethylformamide (5 mL), cesium carbonate (169 mg, 0.52 mmol) and 3-acetyl-6-chloropyridazine (33 mg, 0.2 mmol, CAS: 214701-31-2) were added, and the mixture was reacted at room temperature for 2 hours. The reaction solution was directly purified by reverse column to obtain the title compound as a pink solid (15.33 mg, yield 12.4%).

[0389] Example 8: ESI-MS: m / z [M+H] + =697;

[0390] Embodiment 8: 1 H NMR (400MHz, DMSO-d6) δ10.83(s,1H),8.17-8.12(m,1H),7.57-7.51(m,1H),7.45(d,J=8.7Hz,1H),7.35-7.29(m, 2H),7.22-7.18(m,2H),7.13(d,J=8.8Hz,1H),6.83(d,J=8.8Hz,1H),6.76(d,J=8.8Hz,1H),6.60-6.57(m,1H),6.1 9-6.15(m,2H),4.47-4.40(m,2H),4.00-3.95(m,1H),3.67–3.48(m,2H),3.04-2.94(m,2H),2.80-2.72(m,1H),2.6 8(d,J=5.1Hz,3H),2.62-2.57(m,2H),2.47-2.44(m,1H),2.15-1.78(m,6H),1.72-1.65(m,2H),1.40-1.29(m,2H).

[0391] Example 9: 3-(4-((3-(4-(4-(4-((6-acetylpyridazin-3-yl)oxy)phenyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)phenoxy)cyclobutyl)amino)-2,6-difluorophenyl)piperidine-2,6-dione

[0392]

[0393] The title compound was synthesized in a similar manner to Example 2, replacing 4-(4-(4-(3-aminocyclobutaneoxy)phenyl)tetrahydro-2H-pyran-4-yl)phenol (Intermediate 11) with 4-(4-(4-(3-aminocyclobutaneoxy)phenyl)tetrahydro-2H-pyran-4-yl)phenol (Intermediate 1).

[0394] Example 9: ESI-MS: m / z [M+H] + =711;

[0395] Embodiment 9: 1 H NMR(400MHz,DMSO-d6)δ10.83(s,1H),8.17-8.13(m,1H),7.59–7.46(m,2H),7.37–7.10(m, 5H),6.84-6.75(m,2H),6.60-6.57(m,1H),6.19-6.15(m,2H),4.48-4.40(m,1H),4.00-3.96 (m,1H),3.61–3.43(m,3H),3.03-2.95(m,2H),2.83-2.75(m,3H),2.68(d,J=5.7Hz,3H),2.4 8–2.45(m,1H),2.08–1.98(m,1H),1.95-1.80(m,3H),1.66–1.49(m,2H),1.16-1.14(m,6H).

[0396] Example 10: 3-(4-((3-(4-(1-(4-((6-acetylpyridazin-3-yl)oxy)phenyl)-4-oxocyclohexyl)phenoxy)cyclobutyl)amino)-2,6-difluorophenyl)piperidine-2,6-dione

[0397]

[0398] 3-(4-((3-(4-(1-(4-((6-acetylpyridazin-3-yl)oxy)phenyl)-4-hydroxycyclohexyl)phenoxy)cyclobutyl)amino)-2,6-difluorophenyl)piperidine-2,6-dione (50 mg, 0.07 mmol, Example 8) was dissolved in dimethyl sulfoxide (5 mL), 2-iodobenzoic acid (80 mg, 0.287 mmol, CAS: 61717-82-6) was added, and the mixture was reacted at 50° C. for 1 hour. The reaction solution was directly purified by reverse column to obtain a pink solid compound (8.93 mg, yield 17.9%).

[0399] Example 10: ESI-MS: m / z [M+H] + =695;

[0400] Embodiment 10: 1 H NMR (400MHz, DMSO-d6) δ10.82(s,1H),8.15(d,J=9.2Hz,1H),7.56(d,J=9.2Hz,1H),7.48(d,J=8.8Hz,2H), 7.36(d,J=8.9Hz,2H),7.21(d,J=8.8Hz,2H),6.84(d,J=8.8Hz,2H),6.58(d,J=6.6Hz,1H),6.17(d,J=11.7 Hz,2H),4.46(dd,J=12.8,5.4Hz,1H),3.98(dd,J=13.4,5.5Hz,1H),3.64–3.51(m,1H),3.06–2.95(m,2H), 2.84–2.73(m,1H),2.70–2.61(m,7H),2.48–2.43(m,1H),2.30(dd,J=12.8,8.0Hz,4H),2.10–1.82(m,4H).

[0401] Example 11: 3-(6-((3-(4-(4-(4-((6-acetylpyridazin-3-yl)oxy)phenyl)tetrahydro-2H-pyran-4-yl)phenoxy)cyclobutyl)amino)-4-oxobenzo[d][1,2,3]triazine-3(4H)-yl)piperidine-2,6-dione

[0402]

[0403] 3-(6-Fluoro-4-oxobenzo[d][1,2,3]triazine-3(4H)-yl)piperidine-2,6-dione (145 mg, 0.52 mmol, intermediate 12) and 1-(6-(4-(4-(4-(3-aminocyclobutyloxy)phenyl)tetrahydro-2H-pyran-4-yl)phenoxy)pyridazin-3-yl)ethan-1-one (260 mg, 0.52 mmol, intermediate 13) were dissolved in N,N-dimethylformamide (2 mL), and N,N-diisopropylethylamine (339 mg, 2.6 mmol) was added, and the mixture was reacted at 120°C for 16 hours. Water (100 mL) was slowly added to the reaction solution to quench the reaction, and the mixture was extracted twice with ethyl acetate (50 mL). The organic phases were combined and washed once with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The title compound (8 mg, yield 2%) was purified by preparative liquid chromatography to obtain a white solid.

[0404] Example 11: ESI-MS: m / z [M+H]+ =716;

[0405] Embodiment 11: 1 H NMR(400 MHz, CDCl-3)δ8.18(d,J=9.1Hz,1H),8.03-7.94(m,2H),7.35-7.29(m,3H),7.22-7.16(m,5H),7.12(dd,J=8.8,2.7Hz,1H),6.79-6.74 (m,2H),5.77(dd,J=11.5,5.4Hz,1H),4.93-4.88(m,1H),4.36-4.29(m,1H),3.83-3.74(m,5H),3.04–2.74(m,10H),2.49–2.37(m,5H).

[0406] Example 12: 3-(4-((3-(4-(1-(4-((6-acetylpyridazin-3-yl)oxy)phenyl)-4-methoxycyclohexyl)phenoxy)cyclobutyl)amino)-2,6-difluorophenyl)piperidine-2,6-dione

[0407]

[0408] The title compound was synthesized in a similar manner to Example 1 by replacing 3-(4-bromo-2,6-difluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (1-5) with 3-(6-bromo-2-oxobenzo[cd]indol-1(2H)-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (Intermediate 14).

[0409] Example 12: ESI-MS: m / z [M+H] + =738;

[0410] Embodiment 12: 1H NMR(400 MHz,DMSO-d6)δ11.07(s,1H),8.51(d,J=8.4Hz,1H),8.15(d,J=9.2Hz,1H),8.04(d,J=6.9Hz,1H),7.78–7.68(m,1H), 7.55(d,J=9.2Hz,1H),7.43(d,J=8.8Hz,2H),7.30(d,J=8.8Hz,2H),7.19(d,J=8.7Hz,2H),6.91(d,J=7.7Hz,1H),6.84 (d,J=8.8Hz,2H),6.64(d,J=7.2Hz,1H),6.26(d,J=8.2Hz,1H),5.41-5.33(m,1H),4.60-4.54(m,1H),3.78-3.70(m,1 H),3.65-3.55(m,4H),3.16-3.03(m,2H),3.01-2.86(m,1H),2.73-2.61(m,5H),2.43-2.38(m,4H),2.16-2.01(m,3H).

[0411] Example 13: 1-(6-(4-(4-(4-(3-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)piperazine-1-carbonyl)azetidin-1-yl)phenyl)tetrahydro-2H-pyran-4-yl)phenoxy)pyridazin-3-yl)ethan-1-one

[0412]

[0413] 1-(4-(4-(4-((6-acetylpyridazin-3-yl)oxy)phenyl)tetrahydro-2H-pyran-4-yl)phenyl)azetidine-3-carboxylic acid (150 mg, 0.316 mmol, intermediate 15) was dissolved in dichloromethane (5 mL) and N,N-dimethylformamide (0.5 mL), N,N-diisopropylethylamine (204 mg, 1.59 mmol) was added, and the mixture was stirred at room temperature for 0.5 hours. Then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (92 mg, 0.475 mmol, CAS: 25952-53-8) and 1-hydroxybenzotriazole (65 mg, 0.475 mmol, CAS: 2592-95-2) were added, and the reaction mixture was stirred at room temperature for 0.5 hours. Finally, 4-(5-hydroxy-4-(4-(piperazin-1-ylmethyl)phenyl)-4H-1,2,4-triazol-3-yl)-6-isopropylbenzene-1,3-diphenol (194 mg, 0.475 mmol, intermediate 16) was added, and the reaction solution was stirred at room temperature overnight. Water (20 mL) was added to dilute the reaction solution, and ethyl acetate was added.

[0414] The organic phase was combined and washed twice with saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (petroleum ether / ethyl acetate = 3:1) to give the title compound as a white solid (20 mg, yield 7%).

[0415] Example 13: ESI-MS: m / z [M+H] + =865;

[0416] Embodiment 13: 1 H NMR(400 MHz, DMSO-d6) δ11.93(s,1H),9.61(s,1H),9.40(s,1H),8.15(d,J=9.2Hz,1H),7.54(d,J= 9.2Hz,1H),7.41-7.37(m,2H),7.32(d,J=8.0Hz,2H),7.20-7.13(m,6H),6.78(s,1H),6.41 (d,J=8.2Hz,2H),6.27(s,1H),4.00–3.96(m,2H),3.85–3.76(m,3H),3.75–3.55(m,5H),3. 54–3.36(m,5H),3.00–2.94(m,1H),2.68(s,3H),2.44–2.30(m,8H),0.95(d,J=6.9Hz,6H).

[0417] Example 14: 2-(2,6-dioxopiperidin-3-yl)-5-((3-(4-(4-((1-(methylsulfonyl)azetidin-3-yl)methoxy)phenyl)tetrahydro-2H-pyran-4-yl)phenoxy)cyclobutyl)amino)isoindoline-1,3-dione

[0418]

[0419] The title compound was synthesized in a similar manner to Example 11 by replacing 3-(6-fluoro-4-oxobenzo[d][1,2,3]triazine-3(4H)-yl)piperidine-2,6-dione (Intermediate 12) with 2-(2,6-dioxo-3-piperidinyl)-5-fluoro-1,3-isoindolinedione (CAS: 835616-61-0), and replacing 1-(6-(4-(4-(4-((1-(methylsulfonyl)azetidin-3-yl)methoxy)phenyl)tetrahydro-2H-pyran-4-yl)phenoxy)cyclobutane-1-amine (Intermediate 17) with 1-(6-(4-(4-(4-(3-aminocyclobutoxy)phenyl)tetrahydro-2H-pyran-4-yl)phenoxy)pyridazin-3-yl)ethan-1-one (Intermediate 13).

[0420] Example 14: ESI-MS: m / z [M+H] + =743;

[0421] Embodiment 14: 1 H NMR(400MHz, CDCl3)δ8.01(s,1H),7.66(d,J=8.2Hz,1H),7.20–7.12(m,4H),6.91(d,J= 2.0Hz,1H),6.86–6.78(m,2H),6.76–6.68(m,3H),4.95(m,1H),4.87(dd,J=7.5,3.4Hz,1 H),4.29–4.22(m,1H),4.12–4.04(m,4H),3.91(dd,J=8.0,6.0Hz,2H),3.76(t,J=5.2Hz, 4H),3.10–3.03(m,1H),2.92(s,3H),2.91–2.67(m,6H),2.40(m,6H),2.17–2.12(m,1H).

[0422] Example 15: 2-(4-(4-(4-((2-acetylpyrimidin-5-yl)oxy)phenyl)tetrahydro-2H-pyran-4-yl)phenyl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2-oxoacetamide

[0423]

[0424] The preparation scheme is shown below:

[0425]

[0426] The first step: Preparation of 2-(4-(4-(4-((2-acetylpyrimidin-5-yl)oxy)phenyl)tetrahydro-2H-pyran-4-yl)phenyl)-2-oxoacetic acid (15-1)

[0427] 2-(4-(4-(4-hydroxyphenyl)tetrahydro-2H-pyran-4-yl)phenyl)-2-oxoacetic acid (222 mg, 0.68 mmol, intermediate 18) was dissolved in N,N-dimethylformamide (2 mL), 1-(5-fluoropyrimidin-2-yl)ethanone (95 mg, 0.68 mmol, CAS: 905587-44-2) and cesium carbonate (443 mg, 1.36 mmol) were added, and the mixture was stirred at 25°C for 2 hours. The reaction solution was poured into water, adjusted to pH = 5 with 1N hydrochloric acid, extracted with ethyl acetate three times, and the combined organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (333 mg) as a yellow oily crude product.

[0428] Step 2: Preparation of 2-(4-(4-(4-((2-acetylpyrimidin-5-yl)oxy)phenyl)tetrahydro-2H-pyran-4-yl)phenyl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2-oxoacetamide (Example 15)

[0429] Under nitrogen protection, 2-(4-(4-(4-((2-acetylpyrimidin-5-yl)oxy)phenyl)tetrahydro-2H-pyran-4-yl)phenyl)-2-oxoacetic acid (333 mg crude product) and 5-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (220 mg, 0.75 mmol, CAS: 191732-76-0) were dissolved in dichloromethane (5 mL), pyridine (1.8 g, 22.5 mmol) and phosphorus oxychloride (689 mg, 4.5 mmol) were added in turn under ice bath, and the mixture was stirred at 0°C for 2 hours. The reaction solution was poured into water and extracted with dichloromethane for 3 times. The organic phases were combined, concentrated under reduced pressure, and purified by thin layer preparative chromatography (developing solvent: ethyl acetate) to obtain the title compound as a white solid (30 mg, yield 6%).

[0430] Example 15: ESI-MS: m / z [M+H] + =702;

[0431] Embodiment 15: 1H NMR(500MHz, CDCl3)δ9.53(s,1H),8.52(s,2H),8.40–8.32(m,4H),8.03(dd,J=8.1,1.9Hz,1H),7.84(d,J=8.2Hz,1H),7.43(d,J=8.6Hz,2H), 7.38–7.31(m,2H),7.08–6.99(m,2H),5.00(m,1H),3.93–3.66(m,4H), 2.94–2.76(m,3H),2.73(s,3H),2.56–2.41(m,4H),2.17–2.13(m,1H).

[0432] Example 16: 5-((3-(4-(7-(4-((6-acetylpyridazin-3-yl)oxy)phenyl)-2-oxaspiro[3.5]nonan-7-yl)phenoxy)cyclobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0433]

[0434] The preparation scheme is shown below:

[0435]

[0436] Step 1: Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-((3-(4-(7-(4-hydroxyphenyl)-2-oxaspiro[3.5]non-7-yl)phenoxy)cyclobutyl)amino)isoindoline-1,3-dione (16-1)

[0437] 4-(7-(4-(3-aminocyclobutyloxy)phenyl)-2-oxaspiro[3.5]non-7-yl)phenol (213 mg, 0.43 mmol, intermediate 19) was dissolved in dimethyl sulfoxide (2 mL), 2-(2,6-dioxo-3-piperidinyl)-5-fluoro-1,3-isoindolinedione (178 mg, 0.64 mmol, CAS: 835616-61-0) and N,N-diisopropylethylamine (222 mg, 1.72 mmol) were added, and the mixture was stirred at 110°C for 3 hours under nitrogen protection. The reaction solution was cooled to room temperature, poured into saturated aqueous ammonium chloride solution (40 mL), extracted three times with ethyl acetate (30 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse column chromatography to obtain the title compound as a yellow solid (122 mg, yield 45%). ESI-MS: m / z[M+H] + =636.

[0438] Step 2: Preparation of 5-((3-(4-(7-(4-((6-acetylpyridazin-3-yl)oxy)phenyl)-2-oxaspiro[3.5]nonan-7-yl)phenoxy)cyclobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Example 16)

[0439] 2-(2,6-dioxopiperidin-3-yl)-5-((3-(4-(7-(4-hydroxyphenyl)-2-oxaspiro[3.5]non-7-yl)phenoxy)cyclobutyl)amino)isoindoline-1,3-dione (122 mg, 0.192 mmol) was dissolved in N,N-dimethylformamide (2.0 mL), cesium carbonate (125 mg, 0.384 mmol) and 3-acetyl-6-chloropyridazine (45 mg, 0.288 mmol, CAS: 214701-31-2) were added, and the mixture was stirred at 40°C for 1 hour under nitrogen protection. The reaction solution was poured into saturated ammonium chloride solution (50 mL), extracted three times with ethyl acetate (30 mL), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography to obtain the title compound as a white solid (41 mg, yield 28%).

[0440] Example 16: ESI-MS: m / z [M / 2+H] + =378.6;

[0441] Embodiment 16: 1 H NMR(400MHz,DMSO-d6)δ11.12(br.s.,1H),8.21(d,J=9.1Hz,1H),7.71-7.40(m,5H),7.39-7.28(m,2H),7.22 (d,J=8.4Hz,2H),7.00-6.75(m,4H),5.09(m,1H),4.96–4.88(m,0.5H),4.60–4.51(m,0.5H),4.34(s,2H),4. 31(s,2H),4.24–4.14(m,0.5H),3.90–3.77(m,0.5H),3.18-3.03(m,1H),3.00-2.88(m,1H),2.74(s,3H),2.6 8-2.59(m,1H),2.54-2.43(m,2H),2.43-2.37(m,1H),2.28(br.s.,4H),2.11-1.94(m,2H),1.82(br.s.,4H).

[0442] Example 17: 5-(4-(4-(4-(2-((3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrobenzo[d][1,2,3]triazin-6-yl)amino)-2-oxoacetyl)phenyl)tetrahydro-2H-pyran-4-yl)phenoxy)-N-methyl-2-pyridinecarboxamide

[0443]

[0444] The title compound was synthesized in a similar manner to Example 15 by replacing 1-(5-fluoro-2-pyrimidinyl)ethanone (CAS: 905587-44-2) with 5-fluoro-N-methyl-2-pyridinecarboxamide (Intermediate 26) and replacing 5-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (CAS: 191732-76-0) with 3-(6-amino-4-oxobenzo[d][1,2,3]triazine-3(4H)-yl)piperidine-2,6-dione (Intermediate 25).

[0445] Example 17: ESI-MS: m / z [M+H] + =716;

[0446] Embodiment 17: 1 H NMR (400MHz, DMSO-d6) δ11.16(s,1H),8.80(d,J=1.1Hz,1H),8.64(q,J=4.6Hz,1H),8.36(d,J=2.6Hz,1H ),8.31(d,J=2.4Hz,2H),8.05(d,J=8.6Hz,2H),8.00(d,J=8.6Hz,1H),7.64(d,J=8.6Hz,2H),7.46(dd,J =8.8,3.3Hz,3H),7.09(d,J=8.8Hz,2H),5.99(dd,J=12.3,5.4Hz,1H),3.72–3.51(m,4H),3.08–2.89(m, 1H),2.80(d,J=4.8Hz,3H),2.77–2.62(m,2H),2.57–2.51(m,1H),2.48–2.40(m,4H),2.36–2.21(m,1H).

[0447] Example 18: 3-(4-((3-(4-(1-(4-((2-acetylpyrimidin-5-yl)oxy)phenyl)-4,4-difluorocyclohexyl)phenoxy)cyclobutyl)amino)-2,6-difluorophenyl)piperidine-2,6-dione

[0448]

[0449] The title compound was synthesized in a similar manner to Example 2 by replacing 1-bromo-2,5-difluoro-4-iodobenzene (CAS: 145349-66-2) with 2,6-difluoro-4-bromoiodobenzene (CAS: 160976-02-3), 4-(1-(4-(3-aminocyclobutyloxy)phenyl)-4,4-difluorocyclohexyl)phenol (Intermediate 6) with 4-(4-(4-(3-aminocyclobutaneoxy)phenyl)tetrahydro-2H-pyran-4-yl)phenol (Intermediate 1), and 3-acetyl-6-chloropyridazine (CAS: 214701-31-2) with 1-(5-fluoro-2-pyrimidinyl)ethanone (CAS: 905587-44-2).

[0450] Example 18: ESI-MS: m / z [M+H] + =717;

[0451] Embodiment 18: 1 H NMR (400MHz, DMSO-d6) δ10.83(s,1H),8.71(s,2H),7.44(d,J=8.3Hz,2H),7.28(d,J=8.8Hz,2H),7.16(d,J=8. 8Hz,2H),6.79(dd,J=13.4,8.8Hz,2H),6.63(dd,J=33.4,6.1Hz,1H),6.15(dd,J=15.3,11.8Hz,2H),4.90–4.7 7(m,0.5H),4.52–4.38(m,0.5H),4.05–3.88(m,1.5H),3.63–3.49(m,0.5H),3.08–2.93(m,1H),2.83–2.71(m, 1H),2.68–2.62(m,3H),2.49–2.39(m,6H),2.34(dd,J=10.7,3.3Hz,1H),2.13–1.99(m,1H),1.98–1.78(m,6H).

[0452] Example 19: 5-(4-(4-(4-(3-((4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)amino)cyclobutyloxy)phenyl)tetrahydro-2H-pyran-4-yl)phenoxy)-2-pyridinecarboxamide

[0453]

[0454] The title compound was synthesized in a similar manner to Example 1 by replacing 3-acetyl-6-chloropyridazine (CAS: 214701-31-2) with 5-fluoropyridine-2-carboxamide (CAS: 499796-71-3).

[0455] Example 19: ESI-MS: m / z [M+H] + =683;

[0456] Embodiment 19: 1 H NMR (400MHz, DMSO-d6) δ10.83(s,1H),8.35(d,J=2.8Hz,1H),8.01(d,J=8.8Hz,1H),7.99(s,1H),7.56(s, 1H),7.45(dd,J=8.8,2.8Hz,1H),7.42–7.34(m,2H),7.30–7.19(m,2H),7.10–7.02(m,2H),6.85–6.75(m, 2H),6.59(d,J=6.8Hz,1H),6.21–6.12(m,2H),4.47–4.40(m,1H),3.98(dd,J=12.6,5.2Hz,1H),3.62–3.5 1(m,5H),3.02–2.96(m,2H),2.87–2.71(m,1H),2.47–2.28(m,5H),2.10–2.00(m,1H),1.98–1.78(m,3H).

[0457] Example 20: 5-(4-(4-(4-(3-((4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)amino)cyclobutyloxy)phenyl)tetrahydro-2H-pyran-4-yl)phenoxy)-N-methyl-2-pyridinecarboxamide

[0458]

[0459] The title compound was synthesized in a similar manner to Example 1 by substituting 5-fluoro-N-methyl-2-pyridinecarboxamide (Intermediate 26) for 3-acetyl-6-chloropyridazine (CAS: 214701-31-2).

[0460] Example 20: ESI-MS: m / z [M+H] + =697;

[0461] Embodiment 20: 1H NMR (400MHz, DMSO-d6) δ10.83(s,1H),8.64(q,J=4.8Hz,1H),8.36(d,J=2.8Hz,1H),8.00(d,J=8.6Hz,1H),7.4 5(dd,J=8.6,2.8Hz,1H),7.41–7.35(m,2H),7.29–7.23(m,2H),7.08–7.02(m,2H),6.83–6.75(m,2H),6.59(d, J=6.8Hz,1H),6.22–6.11(m,2H),4.47–4.40(m,1H),3.98(dd,J=12.4,5.2Hz,1H),3.60–3.53(m,5H),3.05–2. 93(m,2H),2.80(d,J=4.8Hz,3H),2.78–2.70(m,1H),2.47–2.44(m,1H),2.39–2.34(m,4H),2.06–1.79(m,4H).

[0462] Example 21: 5-((3-(4-(4-(4-((6-acetylpyridazin-3-yl)oxy)phenyl)tetrahydro-2H-thiopyran-4-yl)phenoxy)cyclobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0463]

[0464] The title compound was synthesized in a similar manner to Example 16 by replacing 4-(7-(4-(3-aminocyclobutoxy)phenyl)-2-oxaspiro[3.5]non-7-yl)phenol (Intermediate 19) with 4-(4-(4-(3-aminocyclobutoxy)phenyl)tetrahydro-2H-thiopyran-4-yl)phenol (Intermediate 32).

[0465] Example 21: ESI-MS: m / z [M+H] + =732;

[0466] Embodiment 21: 1H NMR (400MHz, DMSO-d6) δ11.06(s,1H),8.16(d,J=9.2Hz,1H),7.58(t,J=8.7Hz,2H),7.45(d,J=6 .5Hz,1H),7.39–7.32(m,2H),7.26–7.18(m,4H),6.90(d,J=2.0Hz,1H),6.88–6.79(m,3H),5.04( dd,J=12.9,5.4Hz,1H),4.52(p,J=7.1Hz,1H),3.78(q,J=7.4Hz,1H),3.12–3.02(m,2H),2.88(dd d,J=17.3,14.0,5.3Hz,1H),2.68(s,3H),2.67–2.52(m,10H),1.98(td,J=10.2,9.3,5.0Hz,3H).

[0467] Example 22: 2-(2,6-dioxopiperidin-3-yl)-5-((3-(4-(7-(4-(2-morpholinethoxy)phenyl)-2-oxaspiro[3.5]non-7-yl)phenoxy)cyclobutyl)amino)isoindoline-1,3-dione

[0468]

[0469] The title compound was synthesized in a similar manner to Example 16, substituting 4-(2-chloroethyl)morpholine (CAS: 3240-94-6) for 3-acetyl-6-chloropyridazine (CAS: 214701-31-2).

[0470] Example 22: ESI-MS: m / z [M+H] + =749;

[0471] Embodiment 22: 1H NMR (400MHz, DMSO-d6) δ11.06(s,1H),7.58(d,J=8.3Hz,1H),7.43(d,J=6.4Hz,1H),7.17(dd,J=8.7,3.3Hz,4H ),6.91–6.78(m,4H),6.75(d,J=8.8Hz,2H),5.03(dd,J=12.9,5.4Hz,1H),4.50–4.42(m,1H),4.23(d,J=7.7Hz ,4H),4.00(t,J=12.2,6.4Hz,2H),3.79–3.70(m,1H),3.63–3.49(m,5H),3.08–2.97(m,2H),2.92–2.81(m,1H) ,2.64(t,J=5.7Hz,2H),2.54(d,J=9.5Hz,1H),2.46–2.39(m,4H),2.13(s,4H),2.02–1.84(m,3H),1.70(s,4H).

[0472] Example 23: 2-(2,6-dioxopiperidin-3-yl)-5-((3-(4-(7-(4-((1-(methylsulfonyl)azetidin-3-yl)methoxy)phenyl)-2-oxaspiro[3.5]nonan-7-yl)phenoxy)cyclobutyl)amino)isoindoline-1,3-dione

[0473]

[0474] The title compound was synthesized in a similar manner to Example 16 by substituting (1-(methylsulfonyl)azetidin-3-yl)methyl methanesulfonate (Intermediate 20) for 3-acetyl-6-chloropyridazine (CAS: 214701-31-2).

[0475] Example 23: ESI-MS: m / z [M+H] + =783;

[0476] Embodiment 23: 1H NMR (400MHz, DMSO-d6) δ11.06(s,1H),7.58(d,J=8.3Hz,1H),7.43(d,J=6.5Hz,1H),7.19(dd,J=14. 3,8.7Hz,4H),6.91–6.70(m,6H),5.03(dd,J=12.8,5.4Hz,1H),4.73(d,J=94.5Hz,1H),4.52–4.40( m,1H),4.23(d,J=10.5Hz,2H),4.04(d,J=6.0Hz,2H),3.95(t,J=8.3Hz,2H),3.82–3.64(m,3H),3.0 6–2.97(m,5H),2.92–2.82(m,1H),2.16(s,4H),2.04–1.86(m,5H),1.71(s,3H),1.50-1.35(m,3H).

[0477] Example 24: 5-((3-(4-(7-(4-((2-acetylpyrimidin-4-yl)methoxy)phenyl)-2-oxaspiro[3.5]nonan-7-yl)phenoxy)cyclobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0478]

[0479] The title compound was synthesized in a similar manner to Example 16 by replacing 3-acetyl-6-chloropyridazine (CAS: 214701-31-2) with 1-(4-(fluoromethyl)pyrimidin-2-yl)ethan-1-one (Intermediate 33).

[0480] Example 24: ESI-MS: m / z [M+H] + =770;

[0481] Embodiment 24: 1H NMR (400MHz, DMSO-d6) δ11.06(s,1H),9.00(d,J=5.1Hz,1H),7.75(d,J=5.1Hz,1H),7.58(d,J=8.3Hz,1H),7.43( d,J=6.5Hz,1H),7.21(dd,J=18.0,8.7Hz,4H),6.95(d,J=8.8Hz,2H),6.89(s,1H),6.84–6.79(m,1H),6.75(d,J= 8.8Hz,2H),5.24(s,2H),5.03(dd,J=12.9,5.4Hz,1H),4.47(p,J=7.0Hz,1H),4.23(s,4H),3.82–3.71(m,1H),3. 08–2.96(m,2H),2.93–2.81(m,1H),2.66(s,3H),2.60–2.51(m,2H),2.08(s,4H),2.02–1.88(m,3H),1.70(s,4H).

[0482] Example 25: 3-(2,6-difluoro-4-((3-(4-(4-(4-((1-(methylsulfonyl)azetidin-3-yl)methoxy)phenyl)tetrahydro-2H-pyran-4-yl)phenoxy)cyclobutyl)amino)phenyl)piperidine-2,6-dione

[0483]

[0484] The title compound was synthesized in a similar manner to Example 2 by replacing 1-bromo-2,5-difluoro-4-iodobenzene (CAS: 145349-66-2) with 2,6-difluoro-4-bromoiodobenzene (CAS: 160976-02-3) and 3-acetyl-6-chloropyridazine (CAS: 214701-31-2) with 1-(5-fluoro-2-pyrimidinyl)ethanone (Intermediate 20).

[0485] Example 25: ESI-MS: m / z [M+H] + =710;

[0486] Embodiment 25: 1H NMR (400MHz, DMSO-d6) δ10.83(s,1H),7.21(dd,J=12.5,8.8Hz,4H),6.86(d,J=8.4Hz,2H ),6.72(d,J=8.5Hz,3H),6.13(d,J=11.8Hz,2H),4.85–4.70(m,0.7H),4.50–4.30(m,0.3 H),4.05(d,J=6.0Hz,2H),3.96(t,J=8.1Hz,3H),3.74(t,J=7.1Hz,2H),3.67–3.46(m,5H ),3.01(s,5H),2.78(dd,J=25.4,11.3Hz,1H),2.35(d,J=15.6Hz,6H),2.10–1.79(m,4H).

[0487] Example 26: 5-((3-((6-(2-(4-((6-acetylpyridazin-3-yl)oxy)phenyl)-1,3-dithiolan-2-yl)pyridin-3-yl)oxy)cyclobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0488]

[0489] The preparation scheme is shown below:

[0490]

[0491] Step 1: Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-((3-((6-(4-hydroxybenzoyl)pyridin-3-yl)oxy)cyclobutyl)amino)isoindoline-1,3-dione (26-1)

[0492] (5-(3-Aminocyclobutyloxy)pyridin-2-yl)(4-hydroxyphenyl)methanone (233 mg, 0.82 mmol, intermediate 22) and 5-bromo-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (230 mg, 0.682 mmol, CAS: 26166-92-7) were dissolved in 1,4-dioxane (5 mL), and cesium carbonate (665 mg, 2.05mmol), 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-triisopropyl-1,1'-biphenyl (73mg, 0.136mmol, CAS: 1070663-78-3), tris(dibenzylideneacetone)dipalladium (63mg, 0.068mmol, CAS: 51364-51-3), nitrogen replacement 3 times, the mixture was stirred at 90°C for 16 hours. After the reaction solution cooled to room temperature, it was poured into a saturated ammonium chloride solution (20mL) to quench, extracted twice with ethyl acetate (15mL), the organic phases were combined, washed once with water (15mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate = 1:2) to obtain the title compound as a yellow solid (40mg, yield 9%). LC-MS: m / z[M+H] + =541.

[0493] Step 2: Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-((3-((6-(2-(4-hydroxyphenyl)-1,3-dithiolane-2-yl)pyridin-3-yl)oxy)cyclobutyl)amino)isoindoline-1,3-dione (26-2)

[0494] 2-(2,6-dioxopiperidin-3-yl)-5-((3-((6-(4-hydroxybenzoyl)pyridin-3-yl)oxy)cyclobutyl)amino)isoindoline-1,3-dione (40 mg, 0.074 mmol) and 1,2-ethanedithiol (7 mg, 0.074 mmol, CAS: 540-63-6) were dissolved in dichloromethane and tetrahydrofuran (2 mL / 2 mL), and boron trifluoride etherate (21 mg, 0.148 mmol, CAS: 109-63-7) was added under ice bath, and the mixture was stirred at 40 ° C for 4 hours. After the reaction solution cooled to room temperature, it was poured into a saturated ammonium chloride solution (20 mL) to quench, extracted twice with ethyl acetate (15 mL), the organic phases were combined, washed once with water (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate = 1:2) to obtain the title compound as a yellow solid (60 mg, yield 131%). LC-MS: m / z[M+H] + =617.

[0495] Step 3: Preparation of 5-((3-((6-(2-(4-((6-acetylpyridazin-3-yl)oxy)phenyl)-1,3-dithiopentane-2-yl)pyridin-3-yl)oxy)cyclobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Example 26)

[0496] 2-(2,6-dioxopiperidin-3-yl)-5-((3-((6-(2-(4-hydroxyphenyl)-1,3-dithiolan-2-yl)pyridin-3-yl)oxy)cyclobutyl)amino)isoindoline-1,3-dione (60 mg, 0.097 mmol) was dissolved in anhydrous N,N-dimethylformamide (4 mL), cesium carbonate (94 mg, 0.29 mmol) and 3-acetyl-6-chloropyridazine (18 mg, 0.117 mmol, CAS: 214701-31-2) were added, and the mixture was stirred at 40°C for 2 hours under nitrogen protection. The reaction solution was directly purified by reverse column to obtain the title compound as a yellow solid (26.23 mg, yield 37%).

[0497] Example 26: ESI-MS: m / z [M+H] + =737;

[0498] Embodiment 26: 1 H NMR (400MHz, DMSO-d6) δ11.06(s,1H),8.23–8.10(m,2H),7.70(d,J=8.7Hz,1H),7.59(dd,J=8.9 ,2.0Hz,4H),7.46(d,J=6.4Hz,1H),7.34(dd,J=8.7,2.9Hz,1H),7.19(d,J=8.7Hz,2H),6.91(s,1 H),6.83(d,J=8.3Hz,1H),5.12–4.96(m,1H),4.71–4.53(m,1H),3.86–3.72(m,1H),3.53–3.39( m,4H),3.17–3.04(m,2H),2.96–2.79(m,1H),2.68(s,3H),2.62–2.51(m,2H),2.06–1.93(m,3H).

[0499] Example 27: 5-((3-((6-(2-(4-((2-acetylpyrimidin-5-yl)oxy)phenyl)-1,3-dithiopentan-2-yl)pyridin-3-yl)oxy)cyclobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0500]

[0501] The title compound was synthesized in a similar manner to Example 26, substituting 1-(5-fluoropyrimidin-2-yl)ethanone (CAS: 905587-44-2) for 3-acetyl-6-chloropyridazine (CAS: 214701-31-2).

[0502] Example 27: ESI-MS: m / z [M+H] + =737;

[0503] Embodiment 27: 1 H NMR (400MHz, DMSO-d6) δ11.06(s,1H),8.74(s,2H),8.17(t,J=3.9Hz,1H),7.65(d,J=8.8Hz,1H),7.6 2–7.55(m,3H),7.46(d,J=6.5Hz,1H),7.32(dd,J=8.7,2.9Hz,1H),7.13(d,J=8.8Hz,2H),6.90(s,1H ),6.83(d,J=8.3Hz,1H),5.04(dd,J=12.9,5.4Hz,1H),4.67–4.59(m,1H),3.82–3.77(m,1H),3.47–3 .44(m,4H),3.15–3.06(m,2H),2.92–2.83(m,1H),2.65(s,3H),2.62–2.55(m,2H),2.08–1.92(m,3H).

[0504] Example 28: 3-(4-((3-(4-(3-(4-((2-acetylpyrimidin-5-yl)oxy)phenyl)oxetan-3-yl)phenoxy)cyclobutyl)amino)-2,6-difluorophenyl)piperidine-2,6-dione

[0505]

[0506] The title compound was synthesized in a similar manner to Example 2 by replacing 1-bromo-2,5-difluoro-4-iodobenzene (CAS: 145349-66-2) with 2,6-difluoro-4-bromoiodobenzene (CAS: 160976-02-3), 4-(3-(4-(3-aminocyclobutoxy)phenyl)oxetan-3-yl)phenol (Intermediate 23) with 4-(4-(4-(3-aminocyclobutaneoxy)phenyl)tetrahydro-2H-pyran-4-yl)phenol (Intermediate 1), and 3-acetyl-6-chloropyridazine (CAS: 214701-31-2) with 1-(5-fluoro-2-pyrimidinyl)ethanone (CAS: 905587-44-2).

[0507] Example 28: ESI-MS: m / z [M+H]+ =655;

[0508] Embodiment 28: 1 H NMR (400MHz, DMSO-d6) δ10.82(s,1H),8.72(s,2H),7.32(d,J=8.7Hz,2H),7.19(dd,J= 8.8,2.1Hz,4H),6.85(d,J=8.7Hz,2H),6.59(d,J=6.6Hz,1H),6.17(d,J=11.6Hz,2H), 5.32(s,1H),4.46(s,1H),4.01–3.93(m,1H),3.29–3.27(m,4H),3.04–2.97(m,2H),2. 82–2.71(m,1H),2.65(s,3H),2.46–2.45(m,1H),2.05–2.00(m,2H),1.98–1.93(m,2H).

[0509] Example 29: 3-(4-((3-(4-(2-(4-((6-acetylpyridazin-3-yl)oxy)phenyl)-1,3-dithiolan-2-yl)phenoxy)cyclobutyl)amino)-2,5-difluorophenyl)piperidine-2,6-dione

[0510]

[0511] The preparation scheme is shown below:

[0512]

[0513] Step 1: Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-((3-((6-(4-hydroxybenzoyl)pyridin-3-yl)oxy)cyclobutyl)amino)isoindoline-1,3-dione (29-2)

[0514] 3-(2,5-difluoro-4-((3-(4-(4-hydroxybenzoyl)phenoxy)cyclobutyl)amino)phenyl)piperidine-2,6-dione (29-1) was synthesized in a similar manner to 2-4 by replacing 4-(4-(4-(3-aminocyclobutanyloxy)phenyl)(4-hydroxyphenyl)methanone (Intermediate 24) with 4-(4-(4-(3-aminocyclobutaneoxy)phenyl)tetrahydro-2H-pyran-4-yl)phenol (Intermediate 1). The title compound was synthesized in a similar manner to 26-2 by replacing 2-(2,6-dioxopiperidin-3-yl)-5-((3-((6-(4-hydroxybenzoyl)pyridin-3-yl)oxy)cyclobutyl)amino)isoindoline-1,3-dione (26-1) with 3-(2,5-difluoro-4-((3-(4-(4-hydroxybenzoyl)phenoxy)cyclobutyl)amino)phenyl)piperidine-2,6-dione (29-1).

[0515] Step 2: Preparation of 3-(4-((3-(4-(2-(4-((6-acetylpyridazin-3-yl)oxy)phenyl)-1,3-dithiolan-2-yl)phenoxy)cyclobutyl)amino)-2,5-difluorophenyl)piperidine-2,6-dione (Example 29)

[0516] The title compound was synthesized in a similar manner to Example 26 by replacing 2-(2,6-dioxopiperidin-3-yl)-5-((3-((6-(4-hydroxybenzoyl)pyridin-3-yl)oxy)cyclobutyl)amino)isoindoline-1,3-dione (29-2) with 2-(2,6-dioxopiperidin-3-yl)-5-((3-((6-(2-(4-hydroxyphenyl)-1,3-dithiolan-2-yl)pyridin-3-yl)oxy)cyclobutyl)amino)isoindoline-1,3-dione (26-2).

[0517] Example 29: ESI-MS: m / z [M+H] + =703;

[0518] Embodiment 29: 1H NMR (400MHz, DMSO-d6) δ10.82(s,1H),8.20(d,J=9.2Hz,1H),7.63(d,J=8.9Hz,3H),7.47(d,J=8. 8Hz,2H),7.26(d,J=8.7Hz,2H),7.00(dd,J=12.1,6.8Hz,1H),6.87(d,J=8.8Hz,2H),6.48(dd,J= 12.3,7.5Hz,1H),6.11(d,J=7.1Hz,1H),4.58–4.39(m,1H),3.94–3.81(m,1H),3.69–3.54(m,1H) ,3.52–3.40(m,4H),3.12–2.95(m,2H),2.79–2.65(m,4H),2.27–2.14(m,1H),2.11–1.94(m,4H).

[0519] Example 30: 2-(2,6-dioxopiperidin-3-yl)-5-((3-(4-(2-(4-((1-(methylsulfonyl)azetidin-3-yl)methoxy)phenyl)-1,3-dithiolan-2-yl)phenoxy)cyclobutyl)amino)isoindoline-1,3-dione

[0520]

[0521] The preparation scheme is shown below:

[0522]

[0523] Step 1: Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-((3-(4-(4-((1-(methylsulfonyl)azetidin-3-yl)methoxy)benzoyl)phenoxy)cyclobutyl)amino)isoindoline-1,3-dione (30-1)

[0524] (4-(3-Aminocyclobutyloxy)phenyl)(4-((1-(methylsulfonyl)azetidin-3-yl)methoxy)phenyl)methanone (87 mg, 0.20 mmol, intermediate 27) was dissolved in N-methylpyrrolidone (2 mL), 2-(2,6-dioxo-3-piperidinyl)-5-fluoro-1,3-isoindolindione (62 mg, 0.22 mmol, CAS: 835616-61-0) and N,N-diisopropylethylamine (52 mg, 0.41 mmol) were added, and the mixture was stirred at 110 ° C for 16 hours under nitrogen protection. The reaction solution was cooled to room temperature, poured into a saturated aqueous ammonium chloride solution (40 mL), extracted three times with ethyl acetate (30 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by reverse column chromatography (acetonitrile / water = 52:48) to obtain the title compound as a white solid (36 mg, yield 26%). LC-MS: m / z [M / 2+H] + =344.

[0525] Step 2: Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-((3-(4-(2-(4-((1-(methylsulfonyl)azetidin-3-yl)methoxy)phenyl)-1,3-dithiopentane-2-yl)phenoxy)cyclobutyl)amino)isoindoline-1,3-dione (Example 30)

[0526] 2-(2,6-dioxopiperidin-3-yl)-5-((3-(4-(4-((1-(methylsulfonyl)azetidin-3-yl)methoxy)benzoyl)phenoxy)cyclobutyl)amino)isoindoline-1,3-dione (26 mg, 0.04 mmol) and 1,2-ethanedithiol (6 mg, 0.06 mmol, CAS: 540-63-6) were dissolved in dichloromethane and tetrahydrofuran (1 mL / 2 mL), and boron trifluoride etherate (0.05 mL, 0.14 mmol, d=1.15 g / mL, CAS: 109-63-7) was added under ice bath, and the mixture was stirred at 45 ° C for 16 hours. After the reaction solution cooled to room temperature, it was poured into a saturated ammonium chloride solution (20 mL) to quench, extracted twice with ethyl acetate (15 mL), the organic phases were combined, washed once with water (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and purified by reverse column chromatography (acetonitrile / water = 42:58) to give the title compound (11.39 mg, yield 39%) as a yellow solid.

[0527] Example 30: ESI-MS: m / z [M+H] + =763;

[0528] Embodiment 30: 1H NMR(400MHz, DMSO-d6)δ11.07(s,1H),7.60(d,J=8.3Hz,1H),7.46–7.37(m,5H),6.90(d, J=8.8Hz,3H),6.83(dd,J=10.0,5.3Hz,3H),5.04(dd,J=12.9,5.4Hz,1H),4.52(d,J=6.8H z,1H),4.11(d,J=6.2Hz,2H),3.98(t,J=8.3Hz,2H),3.83–3.73(m,3H),3.39(d,J=3.6Hz ,4H),3.12–3.06(m,2H),3.03(s,3H),2.93–2.85(m,2H),2.60(s,1H),2.04–1.91(m,4H).

[0529] Example 31: 2-(4-(2-(4-((6-acetylpyridazin-3-yl)oxy)phenyl)propan-2-yl)phenyl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2-oxoacetamide

[0530]

[0531] The title compound was synthesized in a similar manner to Example 15 by replacing 2-(4-(4-(4-hydroxyphenyl)tetrahydro-2H-pyran-4-yl)phenyl)-2-oxoacetic acid (Intermediate 29) with 2-(4-(4-(4-hydroxyphenyl)tetrahydro-2H-pyran-4-yl)phenyl)-2-oxoacetic acid (Intermediate 18), and replacing 1-(5-fluoropyrimidin-2-yl)ethanone (CAS: 905587-44-2) with 3-acetyl-6-chloropyridazine (CAS: 214701-31-2).

[0532] Example 31: ESI-MS: m / z [M+H] + =660;

[0533] Embodiment 31: 1H NMR (400MHz, DMSO-d6) δ11.55(s,1H),11.13(s,1H),8.37(d,J=1.6Hz,1H),8.16(d,J =9.2Hz,1H),8.11(dd,J=1.6,8.4Hz,1H),8.06(d,J=8.4Hz,2H),7.97(d,J=8.4Hz,1H ),7.58-7.52(m,3H),7.34(d,J=8.8Hz,2H),7.21(d,J=8.8Hz,2H),5.18-5.13(m,1H) ,2.96-2.83(m,1H),2.69(s,3H),2.65-2.54(m,2H),2.12-2.03(m,1H),1.74(s,6H).

[0534] Example 32: 2-(4-(2-(4-((2-cyanopyrimidin-5-yl)oxy)phenyl)propan-2-yl)phenyl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2-oxoacetamide

[0535]

[0536] The title compound was synthesized in a similar manner to Example 15 by replacing 2-(4-(4-(4-hydroxyphenyl)tetrahydro-2H-pyran-4-yl)phenyl)-2-oxoacetic acid (Intermediate 29) with 2-(4-(4-(4-hydroxyphenyl)tetrahydro-2H-pyran-4-yl)phenyl)-2-oxoacetic acid (Intermediate 18), and replacing 1-(5-fluoropyrimidin-2-yl)ethanone (CAS: 905587-44-2) with 2-cyano-5-fluoropyrimidine (CAS: 38275-55-7).

[0537] Example 32: ESI-MS: m / z [M+H] + =643;

[0538] Embodiment 32: 1H NMR (400MHz, DMSO-d6) δ11.54(s,1H),11.12(s,1H),8.74(d,J=4.4Hz,2H),8.37(d, J=1.6Hz,1H),8.11(dd,J=1.6,8.4Hz,1H),8.04(d,J=8.4Hz,2H),7.97(d,J=8.4Hz,1 H),7.50(d,J=8.4Hz,2H),7.38-7.31(m,2H),7.21(d,J=8.8Hz,2H),5.15(dd,J=5.6 ,12.8Hz,1H),2.96-2.82(m,1H),2.67-2.63(m,2H),2.08-2.05(m,1H),1.69(s,6H).

[0539] Example 33: 2-(4-(2-(4-((2-acetylpyrimidin-5-yl)oxy)phenyl)propan-2-yl)phenyl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2-oxoacetamide

[0540]

[0541] The title compound was synthesized in a similar manner to Example 15 by replacing 2-(4-(4-(4-hydroxyphenyl)tetrahydro-2H-pyran-4-yl)phenyl)-2-oxoacetic acid (Intermediate 18) with 2-(4-(2-(4-hydroxyphenyl)propan-2-yl)phenyl)-2-oxoacetic acid (Intermediate 29).

[0542] Example 33: ESI-MS: m / z [M+H] + =660;

[0543] Embodiment 33: 1 H NMR (400MHz, DMSO-d6) δ11.56(s,1H),11.14(s,1H),8.73(d,J=4.8Hz,2H),8.39(d,J =1.6Hz,1H),8.12(dd,J=1.6,8.4Hz,1H),8.06(d,J=8.4Hz,2H),7.98(d,J=8.4Hz,1H ),7.52(d,J=8.4Hz,2H),7.35(d,J=8.8Hz,2H),7.20(d,J=8.8Hz,2H),5.17(dd,J=5. 2,12.8Hz,1H),2.99-2.87(m,1H),2.68-2.54(m,5H),2.14-2.03(m,1H),1.73(s,6H).

[0544] Example 34: 1-(6-(4-(4-(4-(4-(4-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)piperazin-1-yl)methyl)piperidin-1-yl)phenyl)tetrahydro-2H-pyran-4-yl)phenoxy)pyridazin-3-yl)ethan-1-one

[0545]

[0546] 1-(4-(4-(4-((6-acetylpyridazin-3-yl)oxy)phenyl)tetrahydro-2H-pyran-4-yl)phenyl)piperidine-4-carboxaldehyde (100 mg, 0.206 mmol, intermediate 30) and 4-(5-hydroxy-4-(4-(piperazin-1-ylmethyl)phenyl)-4H-1,2,4-triazol-3-yl)-6-isopropylbenzene-1,3-diol (84 mg, 0.206 mmol, intermediate 16) were dissolved in methanol (3 mL), sodium cyanoborohydride (9 mg, 62.84 mmol) was added in batches, and the mixture was stirred at room temperature overnight. The reaction solution was directly purified by preparative liquid chromatography to give the title compound as a white solid (16 mg, yield 9%).

[0547] Example 34: ESI-MS: m / z [M+H] + =879;

[0548] Embodiment 34: 1 H NMR (400MHz, DMSO-d6) δ11.93(s,1H),9.59(s,1H),9.41(s,1H),8.36(d,J=8.0Hz,0.3H),8.15(d,J=8.0Hz,0.7H),7.69(d,J=8 .0Hz,0.3H),7.55(d,J=8.0Hz,0.7H),7.41(d,J=8.8Hz,2H),7.29(d,J=8.0Hz,2H),7.23–7.10(m,6H),6.86(d,J=8.5Hz,2H),6. 77(s,1H),6.27(s,1H),3.62(d,J=12.8Hz,5H),3.43(s,2H),2.97(p,J=6.9Hz,2H),2.68(s,2H),2.59(t,J=11.7Hz,3H),2.38( d,J=21.3Hz,9H),2.13(s,2H),1.76(d,J=12.7Hz,2H),1.60(s,2H),1.24(s,2H),1.16(d,J=12.7Hz,2H),0.94(d,J=6.9Hz,6H).

[0549] Example 35: 1-(6-(4-(4-(4-(3-((4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)benzyl)piperazin-1-yl)methyl)azetidin-1-yl)phenyl)tetrahydro-2H-pyran-4-yl)phenoxy)pyridazin-3-yl)ethan-1-one

[0550]

[0551] The title compound was synthesized in a similar manner to Example 34 by replacing 1-(4-(4-(4-((6-acetylpyridazin-3-yl)oxy)phenyl)tetrahydro-2H-pyran-4-yl)phenyl)azetidine-3-carbaldehyde (Intermediate 31) with 1-(4-(4-((6-acetylpyridazin-3-yl)oxy)phenyl)tetrahydro-2H-pyran-4-yl)phenyl)piperidine-4-carbaldehyde (Intermediate 30).

[0552] Example 35: ESI-MS: m / z [M+H] + =851;

[0553] Embodiment 35: 1 H NMR (400MHz, CD3OD) δ8.19(d,J=9.2Hz,1H),7.49(d,J=8.3Hz,2H),7.43-7.37(m,3H),7.30(d,J=8.3Hz,2H), 7.20(d,J=8.7Hz,2H),7.13(d,J=8.8Hz,2H),6.76(s,1H),6.48(d,J=8.7Hz,2H),6.26(s,1H),4.04(t,J=7.5H z,2H),3.87-3.84(m,2H),3.79-3.68(m,4H),3.58(t,J=7.5Hz,2H),3.49-3.47(m,1H),3.37-3.32(m,3H),3. 23-3.08(m,4H),3.07-3.00(m,2H),2.96-2.77(m,2H),2.71(s,3H),2.50-2.40(m,4H),0.94(d,J=6.9Hz,6H).

[0554] Example 36: 3-(2,6-difluoro-4-((3-(4-(2-(4-((2-(5-methyl-1,2,4-oxadiazol-3-yl)pyrimidin-5-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)phenyl)piperidine-2,6-dione

[0555]

[0556] The preparation scheme is shown below:

[0557]

[0558] Step 1: Preparation of 5-(4-(2-(4-(3-((4-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-3,5-difluorophenyl)amino)cyclobutyloxy)phenyl)propan-2-yl)phenoxy)pyrimidine-2-carbonitrile (36-2)

[0559] 3-(2,6-difluoro-4-((3-(4-(2-(4-hydroxyphenyl)propan-2-yl)phenoxy)cyclobutyl)amino)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (36-1) was synthesized in a similar manner to 1-6 in Example 1 by replacing 4-(2-(4-(3-aminocyclobutyloxy)phenyl)propan-2-yl)phenol (Intermediate 4) with 4-(4-(4-(3-aminocyclobutaneoxy)phenyl)tetrahydro-2H-pyran-4-yl)phenol (Intermediate 1).

[0560] 3-(2,6-difluoro-4-((3-(4-(2-(4-hydroxyphenyl)propan-2-yl)phenoxy)cyclobutyl)amino)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (100 mg, 0.15 mmol) was dissolved in dimethyl sulfoxide (3 mL), and 5-bromo-2-cyanopyrimidine (43 mg, 0.23 mmol, CAS: 38275-57-9), potassium phosphate (66 mg, 0.308 mmol), 2-picolinic acid (4 mg, 0.031 mmol, CAS: 98-98-6) and cuprous iodide (6 mg, 0.031 mmol) were added in sequence. The mixture was replaced with nitrogen three times, and the mixture was heated to 100 ° C under nitrogen protection for 2 hours. The reaction solution was cooled to room temperature, poured into a saturated aqueous ammonium chloride solution (100 mL), extracted three times with ethyl acetate (50 mL), the organic phases were combined, washed once with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1) to obtain the title compound as a yellow oil (60 mg, yield 52%). LC-MS: m / z [M+H] + =754.

[0561] Step 2: Preparation of 3-(2,6-difluoro-4-((3-(4-(2-(4-((2-(5-methyl-1,2,4-oxadiazol-3-yl)pyrimidin-5-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (36-3)

[0562] 5-(4-(2-(4-(3-((4-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-3,5-difluorophenyl)amino)cyclobutyloxy)phenyl)propan-2-yl)phenoxy)pyrimidine-2-carbonitrile (58 mg, 0.077 mmol) was dissolved in ethanol (3 mL), hydroxylamine hydrochloride (7 mg, 0.1 mmol, CAS: 5470-11-1) was added, and the mixture was reacted at 70°C for 3 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain a white solid crude product (59 mg). The crude product was dissolved in pyridine (2 mL), acetyl chloride (9 mg, 0.107 mmol) was added, and the mixture was heated to 100°C for 16 hours. The reaction solution was cooled to room temperature and poured into a saturated aqueous ammonium chloride solution (100 mL). The mixture was extracted three times with ethyl acetate (40 mL). The organic phases were combined, concentrated under reduced pressure, and purified by reverse column chromatography (acetonitrile / water = 51:49) to obtain the title compound as a white solid (32 mg, yield 57%). LC-MS: m / z [M+H] + =811.

[0563] Step 3: Preparation of 3-(2,6-difluoro-4-((3-(4-(2-(4-((2-(5-methyl-1,2,4-oxadiazol-3-yl)pyrimidin-5-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)phenyl)piperidine-2,6-dione (Example 36)

[0564] 3-(2,6-difluoro-4-((3-(4-(2-(4-((2-(5-methyl-1,2,4-oxadiazol-3-yl)pyrimidin-5-yl)oxy)phenyl)propan-2-yl)phenoxy)cyclobutyl)amino)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (32 mg, 0.039 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (0.5 mL) was added, and the mixture was reacted at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was dissolved in acetonitrile (3 mL), ammonia water (0.5 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was directly purified by reverse column chromatography (acetonitrile / water = 51:49) to obtain the title compound as a white solid (10.25 mg, yield 38%).

[0565] Example 36: ESI-MS: m / z [M+H] + =681;

[0566] Embodiment 36: 1 H NMR (400MHz, DMSO-d6) δ10.83(s,1H),8.75(s,2H),7.30(d,J=8.9Hz,2H),7.15(dd,J=8.8 ,5.1Hz,4H),6.78(d,J=8.8Hz,2H),6.59(d,J=6.8Hz,1H),6.17(d,J=11.7Hz,2H),4.54–4. 32(m,1H),3.98(dd,J=12.5,4.9Hz,1H),3.63–3.51(m,1H),3.09–2.90(m,2H),2.85–2.72( m,1H),2.69(s,3H),2.48–2.43(m,1H),2.11–1.99(m,1H),1.99–1.82(m,3H),1.63(s,6H).

[0567] Other compounds of the present invention can be prepared according to similar preparation procedures as described above, using the intermediates described above and making appropriate changes to the reactants, reaction conditions and amounts of reagents.

[0568]

[0569]

[0570]

[0571]

[0572] Test Example 1: Cell experiment (22RV1 cell proliferation inhibition experiment)

[0573] Day 1: Cell plating

[0574] 1) Collect the 22RV1 cell suspension in the culture flask into a 15 mL centrifuge tube and centrifuge the cell suspension at 1000 rpm for 4 min.

[0575] 2) Discard the supernatant in the centrifuge tube, add an appropriate amount of fresh complete culture medium (1640+10% FBS+1% P / S), and resuspend the cells. Take 20 μL of cell fluid, add 20 μL AO / PI dye solution, and count with CounterStar.

[0576] 3) Calculate the required volume of cell suspension and complete medium based on the viable cell density and the number of cells required for plating. The plating density of 22RV1 cells is 5×103 / well, 80μL / well.

[0577] 4) Use a manual dispenser to draw 80 μL of the above cell suspension into a 96-well plate. Add 80 μL of complete culture medium to the blank control wells. Add an appropriate volume of PBS to the peripheral wells of the 96-well plate to prevent liquid evaporation. Place the 96-well plate in an incubator for overnight culture.

[0578] Day 2: Compound Preparation

[0579] 1) The compound of the present application and the positive control ARV-110 dissolved in DMSO were taken out and serially diluted (from left to right in a 96-well cell culture plate, column A, column B, etc., to column J).

[0580] Column A: initial concentration is 10 mM;

[0581] Column B: dilute 20 μL of the solution in column A into 60 μL of DMSO to obtain a final concentration of 2500 μM;

[0582] Column C: dilute 20 μL of the solution in column B into 60 μL of DMSO to obtain a final concentration of 625 μM;

[0583] Column D: dilute 20 μL of the solution in column C into 60 μL of DMSO to obtain a final concentration of 156.25 μM;

[0584] Column E: dilute 20 μL of the solution in column D into 60 μL of DMSO to obtain a final concentration of 39.075 μM;

[0585] Column F: dilute 20 μL of the solution in column E into 60 μL of DMSO to obtain a final concentration of 9.765 μM;

[0586] Column G: dilute 20 μL of the solution in column F into 60 μL DMSO to obtain a final concentration of 2.4415 μM;

[0587] Column H: dilute 20 μL of the solution in column G into 60 μL of DMSO to obtain a final concentration of 0.61025 μM;

[0588] Column I: dilute 20 μL of the solution in column H into 60 μL of DMSO to obtain a final concentration of 0.1526 μM;

[0589] Column J: dilute 20 μL of the solution in column I into 60 μL of DMSO to obtain a final concentration of 0.03815 μM;

[0590] The resulting 96-well cell culture plate was mixed on a shaker.

[0591] 2) 5× compound preparation: (dilution in 96-well cell culture plate)

[0592] Use a 10μL manual dispenser to take 4μL of columns B to J into 196μL complete culture medium to obtain 5× compound solutions with final concentrations of 50000, 12500, 3125, 781.5, 195.3, 48.83, 12.205, 3.052, and 0.763 nM; take 4μL DMSO into 196μL complete culture medium as a control. Mix the obtained 96-well cell culture plate on an oscillator.

[0593] Compound treatment:

[0594] 1) Use a manual dispenser with a volume of 20 μL to pipette the prepared 5× compound solutions of the above concentrations into the corresponding wells of the 96-well plate after overnight culture on the first day, with a total culture volume of 100 μL per well. Make the final concentrations of the compounds in the 96-well plate 10 μM, 2.5 μM, 625 nM, 156.3 nM, 39.06 nM, 9.766 nM, 2.441 nM, 0.6104 nM, 0.1526 nM. Mix the obtained 96-well cell culture plate on an oscillator.

[0595] 2) Place the 96-well plate in a CO2 incubator and culture for 72 hours.

[0596] Results (Fifth Day):

[0597] 1) Use a dispenser with the volume set to 10 μL and add CCK-8 detection solution to a 96-well cell culture plate at 10 μL / well.

[0598] 2) Place the 96-well cell culture plate in a CO2 incubator and incubate for 1 hour.

[0599] 3) The absorption value at 450 nm was read using an MD microplate reader, and the inhibition rate was calculated. The IC50 value was calculated using GraphPad.

[0600] The results of the cell proliferation experiment of the exemplary compounds of the present application are shown in Table 1.

[0601]

[0602]

[0603] The test results show that the specific compound of the present invention has a good inhibitory effect on 22RV1 cells, which is significantly better than the positive control ARV110.

[0604] Experimental Example 2: Degradation experiment of AR splicing mutant 7 (AR-V7) in 22RV1 cells

[0605] Prostate cancer cells 22RV1 were purchased from Nanjing Kebai Biotechnology Co., Ltd. The cell culture medium was RPMI-1640 + 10% FBS and cultured at 37 ° C, 5% CO2 incubator. On the first day, cells in the exponential growth phase were collected, and the cell suspension was adjusted to the corresponding concentration with complete culture medium for plating. 2 mL per well of a 6-well plate was used, and the number of cells was 500,000 per well. The next day, complete culture medium containing the compound to be tested was added, and one well was added with 0.1% DMSO complete culture medium as a DMSO solvent control 6-well plate was cultured in a 37 ° C, 5% CO2 incubator. After 6 hours or 24 hours, trypsin digestion, cells were collected in a 1.5 mL centrifuge tube, 40 μL RRIPA lysis solution (containing 1× protease inhibitor mixture) was added to each well, and lysed on ice for 30 minutes, 12000g, 4 ° C, centrifuged for 10 minutes. Supernatant protein samples were collected and protein quantification was performed using the BCA method. The experimental process is as follows: the concentration of the protein to be tested was diluted to 1 mg / mL. Denature the prepared samples at 95°C for 10 minutes and place on ice for later use. Use primary antibody diluent to dilute the primary antibody, the primary antibodies are AR-V7 (abcam, ab198394) and GAPDH (Abclonal, A19056), and the dilution ratios are 1:1000 and 1:10000 respectively. The secondary antibody is 1:10000 goat anti-rabbit secondary antibody, and the color developing solution is Clarity Western ECL Substrate. According to the instructions of the kit, add the prepared reagents to the detection plate in turn, and detect the Western bands on the machine. According to formula (1), the degradation rate of AR-V7 relative to the solvent control at different drug concentrations is calculated. Among them, AR-V7 compound is the relative peak area of ​​AR-V7 in the drug-treated group, AR-V7 solvent is the relative peak area of ​​AR-V7 in the vehicle control group. AR-V7% = (1-AR-V7 compound / AR-V7 solvent )×100% Formula (1)

[0606] Conclusion: The compounds of the present invention, such as the compounds in the examples, have a good degradation effect on AR-V7 in prostate cells 22RV1.

[0607] Test Example 3: Liver S9 Stability Test

[0608] In this experiment, human and mouse liver S9 were used as in vitro models to evaluate the metabolic stability of the test substance. At 37°C, 1 μM of the test substance was incubated with liver S9 protein and a cofactor system containing NADP, G6P, G6PDH, UDPGA, PAPS, and GSH. After a certain reaction time (5, 15, 30, 45, 60 min), ice-cold acetonitrile containing an internal standard was added to terminate the reaction. The concentration of the test substance in the sample was detected by LC-MS / MS, and T was calculated using the Ln value of the drug residual rate in the incubation system and the incubation time. 1 / 2 , and further calculated the liver S9 intrinsic clearance CL int (S9) and liver intrinsic clearance CL int (Liver).

[0609] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good liver S9 stability.

[0610] The above embodiments are merely illustrative of the implementation methods of the present invention. However, the present invention is not limited to the above implementation methods. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention shall be included in the protection scope of the present invention.

Claims

1. A compound represented by formula (I), a pharmaceutically acceptable salt thereof, a deuterated substance thereof, a stereoisomer thereof, a tautomer thereof or a mixture thereof, in, PTC is a target recognition or binding part, LI is a connecting part, and U is selected from an E3 ligase ligand or an HSP90 inhibitor; the three parts are connected by chemical bonds.

2. The compound according to claim 1, its pharmaceutically acceptable salt, its deuterated product, its stereoisomer, its tautomer or a mixture thereof, characterized in that: The PTC is a structure shown in formula (II): in: A is selected from 5-15 membered aryl, C5-C 15 Carbocyclyl, 5-15 membered heteroaryl or 5-15 membered heterocyclyl; B is selected from 5-15 membered aryl, C5-C 15 Carbocyclyl, 5-15 membered heteroaryl or 5-15 membered heterocyclyl; C is selected from 3-15 membered aryl, C3-C 15 Carbocyclyl, 3-15 membered heteroaryl or 3-15 membered heterocyclyl; X is selected from a chemical bond, -(CR 5 R 6 )n4-, -C(=O)- or -NR 7 ; Y is selected from a chemical bond, -(CR 8 R 9 )m-, -O-, -S-, -S(=O)-, -SO2-, -NR 7 or -N(COCH3)-; W is selected from a chemical bond, -(CR 8a R 9a )n5-, -C(=O)-, -NR 7 、-N(R 7 )CO-、-CONR 7 -or-NSO2R 7 -, any substituted C 3- C 10 Carbocyclic or optionally substituted 3-10 membered heterocyclic ring; Z is selected from a chemical bond, -CH2-, -C(CH3)H-, -O-, -S-, -NH-, -NCH3- or -N(COCH3)-; V is selected from a chemical bond, -(CR 8a R 9a )m-、-CR 8a =CR 9a -or-(3-15 membered ring)-; L is selected from H, halogen, -CF2R 10 、-CF3、-CN、-OR 10 、-SO2R 17 、-NR 11 R 12 or-CONR 11 R 12 ; R 1 and R 2 Each independently selected from H, halogen, -CN, -CF3, -OH, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted (C1-C6 alkoxy)-(C1-C6 alkyl), (C1-C6 alkylamino)-(C1-C6 alkyl), optionally substituted -(C1-C6 alkyl)-OH, oxo, -NR 13 R 14 , optionally substituted -(C1-C6 alkyl)-NR 13 R 14 、-NR 14 S02R 16 , optionally substituted -(C1-C6 alkyl)NR 14 S02R 16 、-NR 14 COR 16 , optionally substituted -(C1-C6 alkyl)NR 14 COR 16 、-CONR 13 R 14 , optionally substituted -(C1-C6 alkyl)-CONR 14 R 15 、-SO2R 14 R 15 , optionally substituted -(C1-C6 alkyl)-SO2NR 14 R 15 , any substituted -SO2R 16 or optionally substituted -(C1-C6 alkyl)-SO2R 16 ; R 3 Selected from H, oxo, =S, =NR 16 , -CN, CF3, -OH, -S-(C1-C3 alkyl), C1-C3 alkyl, C2-C3 alkenyl, C1-C3 alkoxy, -NR 13 R 14 、-(C1-C3 alkyl)-NR 13 R 14 、-NR 14 S02R 16 、-(C1-C3 alkyl)NR 14 S02R 16 ,-N=S(=O)(C1-C3 alkyl)2, NR 14 COR 16 、-NR 14 COOR 16 、-(C1-C6 alkyl)-NR 14 COR 16 、-CONR 14 R 15 、-(C1-C3 alkyl)-CONR 14 R 15 、-SO2NR 14 R 15 、-(C1-C3 alkyl)-SO2NR 14 R 15 , -SO2(C1-C3 alkyl), -(C1-C6 alkyl)-SO2(C1-C3 alkyl), optionally substituted C5-C 15 Carbocyclic group, optionally substituted 5-15 membered heterocyclic group, optionally substituted 5-15 membered aryl group or optionally substituted 5-15 membered heteroaryl group; the carbocyclic group, heterocyclic group, aryl group or heteroaryl group may be selected from a monocyclic ring, a spirocyclic ring, a condensed ring or a bridged ring; R 5 and R 6 Each independently selected from H, halogen, -CN, -OH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthiol or C1-C6 alkylsulfone; the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or C1-C6 alkylthiol may be optionally substituted by H, halogen, -CN, -OH, -SH or oxo; Or, R 5 and R 6 and the connected atoms together to form an arbitrarily substituted C3-C 15 A carbocyclic group or an optionally substituted 3-15 membered heterocyclic group; 15 Carbocyclic ring or 3-15 membered heterocyclic ring includes fused ring, bridged ring or spiro ring; R 7 is selected from H, halogen, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; R 8 and R 9 Each is independently selected from H, halogen or C1-C3 alkyl; R 8a and R 9a Each is independently selected from H, -OH, halogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C1-C3 alkoxy, -NR 13 R 14 、-(C1-C3 alkyl)-NR 13 R 14 、-NR 14 COR 16 、-(C1-C3 alkyl)-NR 14 COR 16 、-CONR 14 R 15 or -(C1-C3 alkyl)-CONR 14 R 15 or, R 8a and R 9a Together with the atoms to which it is connected, they are connected to form an optionally substituted C3-C6-membered carbocyclic group or a 3-6-membered heterocyclic group; R 10 is selected from H, an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted carbocyclyl, an optionally substituted heterocyclyl, an optionally substituted aryl or an optionally substituted heteroaryl; R 11 and R 12 Each independently selected from H, an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted carbocyclic group, an optionally substituted heterocyclic group, an optionally substituted aryl group or an optionally substituted heteroaryl group; Or, R 11 and R 12 Together with the atoms to which they are attached, they form an optionally substituted heterocyclic group; R 13 , R 14 and R 15 Each is independently selected from H, C1-C3 alkyl, C2-C3 alkenyl or C2-C3 alkynyl; or R 14 and R 15 Together with the atoms to which they are connected, they form an optionally substituted 3-6 membered heterocyclic group; R 16 is selected from H, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, C3-C6 cycloalkyl or phenyl; R 17 is selected from H, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl or optionally substituted C2-C3 alkynyl; m is each independently selected from 0, 1 or 2; n1 and n2 are each independently selected from 0, 1 and 2; n3 is 0, 1, 2, 3, 4, or 5; n4 is 0, 1, or 2; n5 is 0, 1, or 2; wherein an atom or a chemical group in the PTC is replaced to form a covalent bond with the LI; The LI structure is: LXA-LI1-LXB; wherein LI1 is selected from -(CH2)m1-, -(CH2)m2-O-, -(CH2)m2-NR 20 -、-(CH2)-NR 20 C(O)NR 20 -C(CH2)m2-、-(CH2)m2C(O)NR 20 (CH2)m2-, -(CH2)m2-(CH2CH2-W1)m1-(CH2)m2-, -(CH2)m2-W2-(CH2CH2-W1)m1-(CH2)m2-, -(CH2)m2-(CH2CH2-W1)m1-(C H2CH2-W2)-(CH2)m2-, -(CH2)m2-(CO)m3-(Heterocycle)-(CH2)m2-, -(CH2)m2-(W1-CH2CH2)m1-(CH2)m2-(Heterocycle)-(CH2)m2-, -(CH2)m 2- (heterocycle)-(CH2)m2-(CH2CH2-W1)m1-(CH2CH2-W2)-(CH2)m2-, -(CH2)m2-(CO)m3-(heterocycle)-(CH2)m2-(heterocycle)-(CH2)m2- or -(CH2)m2-(CO)m3-(carbocycle)-(CH2)m2-; W1 and W2 are each independently selected from -O- or -N(R 20 )-; R 20 Independently selected from H, C1-C3 alkyl or C1-C3 haloalkyl; m1, m2 and m3 are each independently selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8; LXA and LXB are each independently selected from a chemical bond, -CH2-, -CH2CH2-, -CH=CH-, -C≡C-, -O-, -S-, -S(O)-, -S(O)2-, -N(R 20 )-, -C(O)-, -C(O)OCH2-, -C(O)CH2O-, -C(O)NR 20 -、-C(O)NR 20 CH2-、-C(O)NR 20 CH2CH2-、-NR 20 C(O)-、-NR 20 C(O)CH2-、NR 20 C(O)CH2CH2-、-OC(O)NR 20 -、-OC(O)NR 20 CH2-、-NR 20 C(O)O-、-NR 20 C(O)OCH2-、-NR 20 C(O)CH2O- or -NR 20 C(O)NR 20 ; Each -CH2- in the LI can be arbitrarily substituted; an atom or a chemical group in the PTC is replaced to form a covalent bond with LXA or LXB; The U structure is: Wherein, D is an optionally substituted 3-15 membered ring; E is selected from a 5-10 membered ring which is absent or arbitrarily substituted; Z is selected from absence, a chemical bond or -CO-.

3. The compound according to claim 1 or 2, its pharmaceutically acceptable salt, its deuterated product, its stereoisomer, its tautomer or a mixture thereof, characterized in that: The compound is selected from:

4. The compound according to any one of claims 1 to 3, its pharmaceutically acceptable salt, its deuterated product, its stereoisomer, its tautomer or a mixture thereof, characterized in that: PTC is selected from LI is selected from U is selected from 5. Use of a compound according to any one of claims 1 to 4, a pharmaceutically acceptable salt thereof, a deuterated substance thereof, a stereoisomer thereof, a tautomer thereof or a mixture thereof in the preparation of a protein degradation targeting chimera (PROTAC) of an androgen receptor.

6. Use of the compound according to any one of claims 1 to 4, its pharmaceutically acceptable salt, its deuterated product, its stereoisomer, its tautomer or a mixture thereof in the preparation of a medicament for treating and / or preventing diseases associated with androgen receptor or its splice form.

7. The use according to claim 6, characterized in that The disease associated with androgen receptor or its splice body is selected from prostate cancer, breast cancer, ovarian cancer, bladder cancer, pancreatic cancer, hepatocellular carcinoma, endometrial cancer, salivary gland cancer, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal cord, novel coronavirus infection COVID-19 or bulbar muscular atrophy or age-related macular degeneration.

8. The use according to claim 7, characterized in that The disease associated with androgen receptor or its splice form is selected from prostate cancer, breast cancer, ovarian cancer, bladder cancer, pancreatic cancer, hepatocellular carcinoma, endometrial cancer or salivary gland cancer.

9. The use according to claim 8, characterized in that The disease associated with androgen receptor or its splice form is prostate cancer.

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