A bifunctional degradable androgen receptor heterocyclic compound and application thereof

Abstract

The present application belongs to the field of pharmaceutical chemistry, and particularly relates to a compound shown in formula (I), a pharmaceutically acceptable salt thereof, a deuterated compound thereof, a stereoisomer thereof, a tautomer thereof or a mixture thereof, which can be used as a protein degradation agent for degrading androgen receptor or a cleaved body thereof; and the compound can be used for preparing a drug for treating and / or preventing diseases related to androgen receptor or the cleaved body thereof.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, specifically to a bifunctional heterocyclic compound that degrades androgen receptors, its preparation method, and its use in treating and / or preventing diseases related to androgen receptors or their splice bodies. Background Technology

[0002] Prostate cancer is one of the most common malignant tumors in men. It occurs in the epithelial cells of the prostate gland and accounts for 13.5% of all male malignant tumors, ranking second globally (Shin et al, 2021). The current survival rate for this cancer is only 3-5 years. Early-stage patients can be effectively treated with surgery and chemotherapy. The main treatment for advanced-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] The androgen receptor (AR) is a steroid belonging to the nuclear receptor superfamily, primarily comprising four domains: the N-terminal transcriptional activation domain (NTD), the DNA-binding domain (DBD), the hinge domain, and the ligand-binding domain (LBD) (Fujita and Nonomura, 2019). In the cytoplasm, the AR mainly binds to heat shock proteins (HSP90 / 70). Upon binding to the ligand via the LBD, the AR undergoes a conformational change, leading to dissociation from the HSP and nuclear translocation. Once in the nucleus, the AR binds to the androgen response element (ARE), interacting with other transcription factors to regulate the transcription and expression of genes related to tumor cell proliferation and apoptosis (Miller et al., 2023). Currently marketed AR inhibitors, such as darolutamide, enzalutamide, apalutamide, and bicalutamide, primarily inhibit AR signaling by binding to the LBD (Schmidt et al., 2021). Although ARLBD inhibitors have shown some clinical efficacy, most patients develop resistance to castration therapy (CRPC) 18-24 weeks after treatment. This is primarily due to point mutations in ARLBD, such as T878A, H875Y, L702H, and F877L, which reduce the specificity of AR and allow it to bind to a wider range of steroid hormones. Studies have shown that W742L / C and F877L mutations cause AR antagonists to functionally transform into AR agonists (Rathkopfet et al., 2017). Furthermore, the high expression of AR splice variants (AR-SVs) lacking the LBD domain, such as AR-V7, in CRPC patients is also a significant factor contributing to LBD inhibitor resistance (Schmidt et al., 2021).

[0004] In recent years, protein degradation-targeting chimeric (protac) technology has attracted widespread attention due to its ability to target targets that are difficult to drug with traditional methods. Arvinas' AR degradation agent ARV-110, developed based on this technology, showed significant anti-tumor effects against CRPC in preclinical trials. Its phase II clinical trial results showed that ARV-110 had good efficacy against some wild-type prostate cancer patients (PSA50: 11%) and LBD T878X / H875Y mutation patients (PSA50: 75%). Among the 7 T878X / H875Y mutation patients, 6 showed tumor shrinkage and 2 achieved partial remission (PR). However, its efficacy was poor in patients with L702H mutation and those expressing AR-V7 (24%) (PSA50: 4%). This is because ARV-110 primarily targets AR LBD, and therefore cannot effectively bind to and degrade AR-SVs lacking LBD, such as AR-V7. Studies have shown that up to 58.7% of CRPC patients express AR-V7 (Qu et al, 2015). Therefore, it is particularly important to develop novel degradative agents that can simultaneously target and degrade both AR and AR-SVs.

[0005] The present invention aims to develop a protac that can bind to ARNTDs. Due to the high conservation of NTDs 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, with the aim of significantly improving the efficacy of treatment for CRPC patients. Summary of the Invention

[0006] The present invention aims to provide a compound of formula (I), a pharmaceutically acceptable salt thereof, a deuterated thereof, a stereoisomer thereof, a tautomer thereof, or a mixture thereof.

[0007]

[0008] PTC is the target recognition or binding part, LI is the linker part, and U is selected from E3 ligase ligands or HSP90 inhibitors; the three parts are linked by chemical bonds.

[0009] In some implementations, the PTC has the structure shown in formula (II):

[0010]

[0011] in:

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

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

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

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

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

[0017] W is selected from chemical bonds, -(CR) 8a R 9a )n5-、-C(=O)-、-NR 7 -N(R) 7 CO-, -CONR 7 -or-NSO2R 7 C3-C can be arbitrarily replaced 10 Carbon rings or arbitrarily substituted 3-10 membered heterocycles;

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

[0019] V is selected from chemical bonds, -(CR) 8a R 9a )m-、-CR 8a =CR 9a -or-(3-15 elemental 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 is independently selected from H, halogen, -CN, -CF3, -OH, any substituted C1-C6 alkyl, any substituted C1-C6 alkoxy, any substituted (C1-C6 alkoxy)-(C1-C6 alkyl), (C1-C6 alkylamino)-(C1-C6 alkyl), any substituted -(C1-C6 alkyl)-OH, oxo, -NR 13 R 14 , any substituted -(C1-C6 alkyl)-NR 13 R 14 -NR 14 SO2R 16 , any substituted -(C1-C6 alkyl)NR 14 SO2R 16 -NR 14 COR 16 , any substituted -(C1-C6 alkyl)NR 14 COR 16 -CONR 13 R 14 , any substituted -(C1-C6 alkyl)-CONR 14 R 15 -SO2R 14 R 15 , any substituted -(C1-C6 alkyl)-SO2NR 14 R 15 arbitrarily replaceable -SO2R 16 Or any 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 SO2R 16 -(C1-C3 alkyl)NR 14 SO2R 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), any substituted C5-C 15 The group may be a carbocyclic group, an arbitrarily substituted 5-15 membered heterocyclic group, an arbitrarily substituted 5-15 membered aryl group, or an arbitrarily substituted 5-15 heteroaryl group; wherein the carbocyclic group, heterocyclic group, aryl group, or heteroaryl group may be selected from monocyclic, spirocyclic, fused, or bridged rings.

[0023] R 5 and R 6 Each of the following is 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 alkylsulfonyl: The C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C1-C6 alkylthiol may optionally be substituted with H, halogen, -CN, -OH, -SH, or oxo:

[0024] Or, R 5 and R 6 Together with the adjacent atoms, they form arbitrarily substituted C3-C bonds. 15 Carbocyclic group or any substituted 3-15 membered heterocyclic group; the C3-C 15 Carbon rings or 3-15 membered heterocyclic rings include fused rings, bridged rings, or spiro rings;

[0025] R 7 Selected from H, halogens, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl;

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

[0027] R 8a and R 9a Each element is independently selected from H, -OH, halogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C l -C3 alkoxy group, -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 adjacent atoms, they can form any substituted C3-C6 membered carbon cyclic groups or 3-6 membered heterocyclic groups;

[0028] R 10 It is selected from H, any substituted C1-C6 alkyl, any substituted C2-C6 alkenyl, any substituted C2-C6 ynyl, any substituted carbocyclic, any substituted heterocyclic, any substituted aryl or any substituted heteroaryl.

[0029] R 11 and R 12 Each is independently selected from H, any substituted C1-C6 alkyl, any substituted C2-C6 alkenyl, any substituted C2-C6 ynyl, any substituted carbocyclic, any substituted heterocyclic, any substituted aryl, or any substituted heteroaryl.

[0030] Or, R 11 and R 12 Together with the adjacent atoms, they form arbitrarily substituted heterocyclic groups;

[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 adjacent atoms, they can form arbitrarily substituted 3-6 membered heterocyclic groups;

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

[0033] R 17 Selected from H, any substituted C1-C3 alkyl, any substituted C2-C3 alkenyl or any 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] In this case, 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] Among them, LI1 is selected from -(CH2)m1-, -(CH2)m2-O-, and -(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-(heterocyclic)-(CH2)m2-, -(CH2)m2-(heterocyclic)-(CH2)m2-(CH2CH2-W1)m1-(CH2CH2-W2)-(CH2)m2-, -(CH2)m2-(CO)m3-(heterocyclic)-(CH2)m2-(heterocyclic)-(CH2)m2- or -(CH2)m2-(CO)m3-(carbocyclic)-(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 chemical bonds, -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 LI can be arbitrarily substituted; an atom or a chemical group in PTC is substituted to form a covalent bond with LXA or LXB;

[0047] The U-structure is as follows:

[0048]

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

[0050] D is any 3-15 member ring that can be substituted;

[0051] E is selected from 5-10 member rings that are either nonexistent or arbitrarily substituted;

[0052] Z is selected from non-existent, 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 compounds described in any one of the foregoing embodiments, their pharmaceutically acceptable salts, their deuterated derivatives, their stereoisomers, their tautomers, or mixtures thereof, are selected from, but are 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 the use of any of the compounds described above, their pharmaceutically acceptable salts, their deuterated derivatives, their stereoisomers, their tautomers, or mixtures thereof in the preparation of protein degradation-targeting chimeric (PROTAC) for androgen receptors.

[0067] Another object of the present invention is to provide the use of any of the compounds described above, their pharmaceutically acceptable salts, their deuterated derivatives, their stereoisomers, their tautomers, or mixtures thereof in the preparation of medicaments 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, alopecia, acne, hirsutism, ovarian cysts, polycystic ovary syndrome, precocious puberty, spinal cord, COVID-19 infection, or bulbar muscular atrophy or age-related macular degeneration.

[0069] More 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] 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 androgen receptor alternative splice variant 7. Detailed Implementation

[0072] The present invention will be further described in detail below with reference to embodiments, but this is not intended to limit the present invention. Any equivalent substitutions made in the art based on the disclosure of the present invention shall fall within the protection scope of the present invention.

[0073] The structure of the compound was determined by mass spectrometry (MS) or nuclear magnetic resonance (NMR). 1 It was determined by HNMR.

[0074] Nuclear magnetic resonance (NMR) 1 HNMR shift (δ) is given in parts per million (ppm); nuclear magnetic resonance (NMR) 1 H NMR measurements were performed using a Bruker Avance-400 NMR spectrometer. The solvent was deuterated dimethyl sulfoxide (DMSO), and the internal standard was tetramethylsilane (TMS). Chemical shifts were expressed as 10⁻⁶ ppm. -6 (ppm) is given as the unit.

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

[0076] Terms and definitions:

[0077] The terminology used in this invention is explained below. If the meaning of a particular term differs from that commonly understood by those skilled in the art, the meaning as used in this invention shall prevail. If not defined in this invention, it shall have the meaning commonly understood by those skilled in the art. Unless otherwise stated, the terms used in this invention have the following meanings:

[0078] The term "substitution" in this invention refers to the selective replacement of one or more (e.g., one, two, three, or four) H atoms on a specified atom by a designated group, provided that the substitution does not exceed the normal valence of the specified atom in the present case and that the substitution forms a stable compound. Combinations of substituents and / or variables are permitted only if such combinations form a stable compound. It should be understood that, as needed, other atoms, such as hydrogen atoms or substituents as described herein, may be present to satisfy the valence of the atom.

[0079] As used herein, the term "arbitrarily substituted" means that one or more H atoms on a group may be optionally substituted or not substituted by one or more identical or different substituents; preferably, the arbitraryly substituted substituents of 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 aryl, 5-12 heteroaryl, or 3-15 heterocyclic groups; specific examples include, but are not limited to, methyl, ethyl, propyl, trifluoromethyl, cyclopropyl, fluorine, chlorine, methoxy, phenyl, naphthyl, pyridyl, pyrazinyl, etc.

[0080] As used herein, the term “independently” means that when one or more substituents are selected from a number of possible substituents, those substituents may be the same or different; or when a substituent appears multiple times at the same time, each appearance may be selected from the same or different substituents.

[0081] The term "fused ring" or "fused ring" as used in this article refers to a ring structure in which two or more rings share one or more bonds.

[0082] The term "spiroring" as used in this article refers to a ring structure in which two or more rings share one or more atoms.

[0083] As used herein, the term "ring" can be selected from heterocyclic, carbocyclic, aromatic, or heteroaromatic rings without limitation, and can be a bridged ring, fused ring (condensed ring), or spirocyclic system of monocyclic or polycyclic systems; for example, the "3-15 membered ring" described in this invention includes C3-C 15 Carbocyclic rings, 3-15 membered heterocyclic rings, 3-15 membered aromatic rings, or 3-15 membered heteroaromatic rings; exemplary examples include, but are not limited to, cyclopropyl, cyclobutyl, phenyl, pyridine, thiophene, etc.

[0084] As used herein, the term "aryl" refers to a monocyclic or polycyclic group of all carbon atoms having a conjugated π-electron system. According to the purposes of this invention, the polycyclic group may be a bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems. At least one ring in the polycyclic group is an aromatic ring, and the other rings may be aromatic rings, saturated or unsaturated carbon rings, such as aryl benzoaryl, aryl benzocarbocyclic, etc.

[0085] As used herein, the term "carbocyclic group" or "carbocyclic" refers to a stable, non-aromatic monocyclic or polycyclic hydrocarbon group (including fused ring, bridged ring, or spirocyclic systems) consisting only of carbon and hydrogen atoms, which can be connected to the remainder of the parent compound via one or more single bonds through any suitable carbon atom. In some embodiments, C3-C 10Specific examples of carbocyclic groups include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, etc. For the purposes of this invention, the carbocyclic groups described herein include cycloalkyl and cycloalkenyl groups.

[0086] As used herein, the term "heteroaryl" refers to an aromatic monocyclic or polycyclic group (where at least one ring is a heteroaryl ring) containing one or more heteroatoms (preferably 1-3) selected from N, O, or S, said polycyclic group including bicyclic, tricyclic, or more fused ring, bridged ring, or spirocyclic systems.

[0087] As used herein, the term "heterocyclic group" or "heterocycle" refers to a heterocyclic hydrocarbon group having a stable, saturated or unsaturated (non-aromatic) monocyclic or polycyclic (e.g., bicyclic, tricyclic or more ring-bridged, fused (fused) or spirocyclic system) consisting of a carbon atom and one or more heteroatoms or heteroatomic groups selected from O, S, and N (e.g., C(=O), S(=O), S(=O)2).

[0088] The term "alkyl" as used alone or in combination herein refers to a straight-chain or branched saturated hydrocarbon group consisting only of carbon 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 groups, the following straight-chain or branched saturated hydrocarbon groups can be listed: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl and seven other isomers, n-hexyl and sixteen other isomers. For example, "C1-C6 alkyl" includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and all their isomers.

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

[0090] The terms “alkylamino” or “alkylamino” appearing alone or in combination in this document refer to the substitution of the H in “-NH2” with a saturated or unsaturated branched or straight-chain alkyl group, i.e., -NH-alkyl or -N-(alkyl)(alkyl). For example, “C1-C6 alkylamino” refers to the substitution of one or two hydrogens in -NH2 with a saturated or unsaturated branched or straight-chain alkyl group with 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 alone or in combination in this article refers to a straight-chain or branched hydrocarbon chain group having one or more carbon-carbon double bonds; each alkenyl is connected to the rest of the molecule by a single bond.

[0092] The term “alkynyl” as used alone or in combination in this article refers to a straight-chain or branched hydrocarbon chain group having one or more carbon-carbon triple bonds; each alkynyl group is connected to the rest of the molecule by a single bond.

[0093] The term "alkylthiol" as used alone or in combination in this article refers to a group having a "-S-(C1-C6 alkyl)" structure.

[0094] As used in this article, the term "halogen" refers to bromine, chlorine, fluorine, or iodine groups, including their radioactive isotopes.

[0095] The term "oxo" as used in this article refers to the "=O" group;

[0096] The compounds of this invention may contain one or more asymmetric centers, and thus may produce enantiomers, diastereomers, and other stereoisomers. This invention is intended to include all such possible isomers, as well as their racemic and optically pure forms, whether or not they are specifically described herein. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers can be prepared using chiral synthesis or chiral reagents, or resolved using conventional techniques, such as chromatography and fractional crystallization. Conventional techniques for preparing / separating individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of racemic mixtures (or racemic mixtures of salts or derivatives) using, for example, chiral high-performance liquid chromatography (HPLC). When the compounds described herein contain an alkene double bond or other geometrically asymmetric centers, unless otherwise stated, the compound is intended to include both E and Z geometric isomers. Similarly, all tautomers are also intended to be included.

[0097] "Stereoisomer" refers to a stable isomer that has a vertically asymmetric plane due to having at least one chiral element (including a chiral center, chiral axis, chiral surface, etc.), thereby enabling the rotation of plane-polarized light; this disclosure considers various stereoisomers and mixtures thereof, and includes "enantiomers". The term "stereoisomer" includes cis-trans isomers, enantiomers, non-corresponding isomers, and conformational isomers.

[0098] "Tautomer" (or "tautomer form") refers to structural isomers with different energies that can be interconverted through a low energy barrier. For example, proton tautomers (or proton transfer tautomers) include (but are not limited to) interconversions through proton transfer, such as keto-enol isomerization, imine-enamine isomerization, amide-imine alcohol isomerization, etc. This disclosure includes tautomers of any of the compounds described.

[0099] Furthermore, the compounds of the present invention may contain one or more isotopic forms, namely, hydrogen isotopes of D or T, or isotopes of any atom, such as all isotopes of C and N. Any isotopic forms of C, N, or H in compounds with optional structures of the present invention are covered within the scope of protection of the present invention. The terms "comprising," "including," and "containing," and their equivalents, should be understood in an open, non-exclusive sense, meaning "including but not limited to," implying that in addition to the listed elements, components, and steps, other unspecified elements, components, and steps may also be covered.

[0100] The raw materials or intermediates used in this article can be prepared by or in accordance with methods known in the art or by the methods disclosed herein, or can be purchased from commercial entities.

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

[0102] Unless otherwise specified in this invention, the solutions mentioned in the reactions of this invention are aqueous solutions.

[0103] In the terminology of this invention, "room temperature" 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 for intermediate 1 is as follows:

[0107]

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

[0109] Tetrahydro-4H-pyran-4-one (10 g, 0.1 mol) was added to 150 mL of concentrated hydrochloric acid, followed by phenol (18.785 g, 0.2 mol). After the addition was complete, the mixture was stirred at room temperature for 3 hours under nitrogen protection, and the reaction was monitored for completeness by LC-MS. The mixture was then quenched with 150 mL of water, extracted with ethyl acetate (100 mL x 3 times), 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 give the title compound (16 g, yield: 59%) as a white solid. ESI-MS: m / z [M+H] + =269.1

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

[0111] 4,4'-(tetrahydro-2H-pyran-4,4-diyl)diol (3.553 g, 13.158 mmol) was dissolved in tetrahydrofuran (90 mL), followed by the addition of (1r,3r)-3-hydroxycyclobutyl)carbamate tert-butyl ester (1.971 g, 10.527 mmol) and triphenylphosphine (5.177 g, 19.739 mmol). Diisopropyl azodicarbonate (3.91 mL, 19.739 mmol) was then added under nitrogen protection at 0 °C. After stirring at 60 °C for 16 hours, the reaction was monitored for completion by LC-MS. The reaction mixture was evaporated to dryness and column chromatography (petroleum ether / ethyl acetate = 3 / 1) yielded the title compound (1.5 g, 25% yield) as a white solid. ESI-MS: m / z [M+Na] + =462.0

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

[0113] (3-(4-(4-(4-hydroxyphenyl)tetrahydro-2H-pyran-4-yl)phenoxy)cyclobutyl)carbamate tert-butyl ester (38 mg, 0.0867 mmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (0.2 mL) was added. The mixture was stirred at room temperature under nitrogen protection for 1 hour, and the reaction was monitored by LC-MS to indicate completion. The reaction solution was directly concentrated under reduced pressure to give the title compound (29 mg, 100% yield) as a white solid. 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-dioxoisoindoline-5-yl)amino)cyclobutyl4-methylbenzenesulfonate

[0115]

[0116] The synthetic route for 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, along with methanol (90 mL), tetrahydrofuran (30 mL), and palladium on carbon (530 mg, 5 mmol). The mixture was purged with hydrogen three times, and then reacted overnight at room temperature under a hydrogen atmosphere. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give the title compound (10.45 g, 100% yield) as a white solid.

[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), and acetic acid (6 g, 100 mmol) was added dropwise. The mixture was reacted at room temperature for 30 minutes, followed by the addition of sodium triacetoxyborohydride (31.8 g, 150 mmol, CAS: 56553-60-7) in portions. The reaction mixture was stirred overnight at room temperature. The reaction was quenched by adding saturated sodium bicarbonate solution, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate / dichloromethane = 5:1:1) to give the title compound as a white solid (15.68 g, 85% yield).

[0122] Step 3: Preparation of 4-((3-(benzyloxy)cyclobutyl)amino)phthalic acid (intermediates 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. The mixture was reacted overnight at 50 °C. The reaction solution was concentrated under reduced pressure, and 10% citric acid (80 mL) was added. The mixture was extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound as a white solid (14.49 g, 100% yield).

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

[0125] 4-((3-(benzyloxy)cyclobutyl)amino)phthalic acid (14.49 g, 42.5 mmol) was added to acetonitrile (100 mL). N,N-diisopropylethylamine (21.93 g, 170 mmol) was added in portions at 0 °C, and the mixture was stirred at 0 °C for 10 min. Then, HATU (32.3 g, 85 mmol, CAS: 148893-10-1) was added, and the mixture was stirred at 0 °C for 20 min. Subsequently, 3-amino-2,6-piperidinidone hydrochloride (7 g, 42.5 mmol, CAS: 24666-56-6) was added in portions, and the mixture was stirred at room temperature for 2 h. The reaction solution was concentrated under reduced pressure and purified by column chromatography (petroleum ether / ethyl acetate = 1:1) to give the title compound as a yellow solid (12.88 g, 70% yield). 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 (intermediates 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 on carbon (315 mg, 2.975 mmol), and the mixture was purged three times with hydrogen. The mixture was stirred overnight at room temperature under a hydrogen atmosphere. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give the title compound (10.2 g, 100% yield) as a yellow solid. LC-MS: m / z [M+H] + =344.

[0128] Step 6: Preparation of 3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)amino)cyclobutyl 4-methylbenzenesulfonate (intermediates 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), and triethylamine (6.0 g, 59.5 mmol) was added dropwise at 0 °C. The mixture was stirred for 20 minutes, followed by the addition of p-toluenesulfonyl chloride (6.82 g, 35.7 mmol) in portions. The mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure and purified by column chromatography (petroleum ether / ethyl acetate = 1:1) to give the title compound as a yellow solid (11.85 g, 80% yield). 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-dioxoisoindoline-5-yl)amino)cyclobutyl 4-methylbenzenesulfonate (Intermediate 2)

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

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

[0133]

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

[0135]

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

[0137] Under nitrogen atmosphere, 4,4'-dihydroxybenzophenone (1.5 g, 7 mmol, CAS: 611-99-4) was added to dichloromethane (20 mL), followed by the dropwise addition of ethylenedithiol (1.3 g, 14 mmol), and then the dropwise addition of boron trifluoride diethyl ether (1.3 g, 9.3 mmol) and trifluoroacetic acid (2 mL) at 0 °C. The mixture was reacted at 40 °C for 72 hours. The reaction was quenched by adding 5% sodium bicarbonate solution, and the mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (1.99 g, 98% yield) as a yellow solid.

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

[0139] 4,4'-(1,3-dithiacyclopentan-2,2-diyl)diol (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), followed by pyridine 4-methylbenzenesulfonic acid (173 mg, 0.69 mmol, CAS: 24057-28-1). 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 give 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-aminocyclobutoxy)phenyl)prop-2-yl)phenol

[0141]

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

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

[0144]

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

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

[0147]

[0148] Intermediate 6 was synthesized in a similar manner to intermediate 1, 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-thiaran-4,4-diyl)diphenol

[0150]

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

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

[0153]

[0154] 4,4'-(tetrahydro-2H-thiaran-4,4-diyl)diol (2 g, 6.98 mmol, intermediate 7) was dissolved in methanol (50 mL), and an aqueous solution of potassium peroxymonosulfate complex salt (9.6 g, 15.7 mmol, CAS: 37222-66-5) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was poured into a saturated sodium sulfite aqueous solution (100 mL), and extracted three times with ethyl acetate (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound as a white solid (1.9 g, yield 85.5%). LC-MS: m / z [MH] - =317.

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

[0156]

[0157] Intermediate 9 was synthesized in a similar manner to intermediate 1, replacing 4,4'-(tetrahydro-2H-pyran-4,4-diyl)diol (intermediates 1-2) with 4,4-bis(4-hydroxyphenyl)tetrahydro-2H-thiaran-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), and palladium / carbon (0.4 g) was added. The mixture was purged with hydrogen three times, and stirred at 30 °C for 24 hours under a hydrogen atmosphere. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give the yellow oily title compound (4.0 g, 97% yield).

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

[0162]

[0163] Intermediate 11 was synthesized in a similar manner to intermediate 1, 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-aminocyclobutoxy)phenyl)tetrahydro-2H-pyran-4-yl)phenoxy)pyridazin-3-yl)ethyl-1-one

[0168]

[0169] The synthetic route for 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] (3-(4-(4-(4-hydroxyphenyl)tetrahydro-2H-pyran-4-yl)phenoxy)cyclobutyl)carbamate tert-butyl ester (2.00 g, 4.55 mmol, intermediates 1-3) was dissolved in N,N-dimethylformamide (20 mL), and 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. The mixture was reacted at room temperature for 3 hours. The reaction solution was diluted with water (150 mL), 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 give a yellow oily title compound (2.10 g, yield 85%).

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

[0174] (3-(4-(4-(((6-cyanopyridazin-3-yl)oxy)phenyl)tetrahydro-2H-pyran-4-yl)phenoxy)cyclobutyl)carbamate tert-butyl ester (2.00 g, 3.69 mol) was dissolved in anhydrous tetrahydrofuran (30 mL). 1 M methyl magnesium bromide tetrahydrofuran solution (20 mL, 19.90 mmol) was slowly added dropwise under ice bath conditions. The mixture was kept at this temperature for 5 minutes, then allowed to react at room temperature for 2 hours. The reaction was quenched by slowly adding saturated ammonium chloride aqueous solution (10 mL) under ice bath conditions. The mixture was extracted twice with ethyl acetate (50 mL), and 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 give the title compound (1.84 g, 89% yield) as a white, foamy solid.

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

[0176] (3-(4-(4-(4-(((6-acetyridazin-3-yl)oxy)phenyl)tetrahydro-2H-pyran-4-yl)phenoxy)cyclobutyl)carbamate tert-butyl ester (1.80 g, 3.22 mmol) was dissolved in dichloromethane (15 mL), and trifluoroacetic acid (7.5 mL) was added under ice bath conditions. The mixture was stirred at room temperature for 3 hours. The reaction mixture was then slowly poured into a saturated sodium bicarbonate solution (200 mL) under ice bath conditions. The mixture was extracted three times with a mixed solvent of dichloromethane / methanol (100 mL, 10 / 1). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (dichloromethane / methanol = 40:1) to give the title compound (0.98 g, 66% yield) as a white solid. 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)piperidin-2,6-dione

[0178]

[0179] 3-(6-bromo-2-oxobenzo[cd]indol-1(2H)-yl)piperidin-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). Under nitrogen protection, 1,8-diazabicyclo[5.4.0]undec-7-ene (782.8 mg, 5.15 mmol, CAS: 6674-22-2) was added. 2-(trimethylsilyl)ethoxymethyl chloride (855 mg, 5.15 mmol, CAS: 76513-69-4) was added dropwise in an ice bath. The compound was reacted at room temperature for 2 hours. The reaction was quenched by adding a saturated ammonium chloride aqueous solution. The mixture was extracted twice with ethyl acetate, and the organic phases were combined, washed once with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give the title compound (715 mg, 57% yield) as an orange-yellow solid. ESI-MS: m / z [MH] - =487.

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

[0181]

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

[0183]

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

[0185] To a 500 mL three-necked flask under nitrogen protection and equipped with a thermometer, add 20 g (0.0847 mol) of 1,4-dibromobenzene and 200 mL of anhydrous THF. Then, cool the flask to -78 °C in a cold well. Add n-BuLi (20.4 mL, 0.051 mol) (2.5 M, in THF) dropwise over 10 min at -78 °C, stirring at the same temperature for 30 min. Next, add tetrahydro-4H-pyran-4-one (4.24 g, 0.0424 mol). After the addition is complete, slowly raise the temperature to room temperature and stir for 1 h. After quenching with saturated ammonium chloride, monitor the reaction by TLC. The starting material reacted completely, and the product was the predominant site. In the system, 200 mL of saturated ammonium chloride solution was slowly added at low temperature, followed by 400 mL of water. The mixture was extracted three times with ethyl acetate (50 mL each). The organic phases were combined, washed with saturated brine, concentrated under reduced pressure, dried, and then subjected to column chromatography (petroleum ether / ethyl acetate = 3:1) to give 9.93 g of the title compound, yield: 45.78%.

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

[0187] 4-(4-bromophenyl)tetrahydro-2H-pyran-4-ol (9.18 g, 0.0359 mol), phenol (6.75 g, 0.0717 mol), and concentrated hydrochloric acid (90 mL) were added to a 250 mL single-necked flask. The mixture was stirred overnight at room temperature. TLC monitoring showed that the reactants reacted completely, and the product was the predominant sample. 200 mL of water was added, and the mixture was extracted three times with ethyl acetate (50 mL). The combined organic phases were washed with saturated brine, concentrated under reduced pressure, dried, and then subjected to column chromatography (petroleum ether / ethyl acetate = 4:1) to give 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)azacyclobut-3-carboxylic acid (intermediate 15-3)

[0189] 4-(4-(4-bromophenyl)tetrahydro-2H-pyran-4-yl)phenol (200 mg, 0.602 mmol), methyl 3-carboxylate aziridine hydrochloride (117 mg, 0.783 mmol, CAS: 343238-58-4), tris(dibenzylacetone)palladium (27 mg, 0.03 mmol), 2-dicyclohexylphosphine-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), purged with nitrogen three times, and the mixture was stirred overnight at 100 °C under nitrogen protection. The reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted three times with ethyl acetate (10 mL). The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and subjected to column chromatography (petroleum ether / ethyl acetate = 5:1) to give the title compound (80 mg, yield 36%) as a white solid. LC-MS: m / z [MH] - =366.

[0190] Step 4: Preparation of methyl 1-(4-(4-(((6-acetylpyridin-3-yl)oxy)phenyl)tetrahydro-2H-pyran-4-yl)phenyl)azacyclobut-3-carboxylic acid (intermediate 15-4)

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

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

[0193] Methyl 1-(4-(4-(4-(((6-acetylpyridin-3-yl)oxy)phenyl)tetrahydro-2H-pyran-4-yl)phenyl)azacyclobut-3-carboxylic acid (100 mg, 0.205 mmol) was dissolved in a tetrahydrofuran / water (6 mL / 2 mL) mixture. Lithium hydroxide (30 mg, 1.23 mmol) was added, and the mixture was reacted at room temperature for 2 hours. The reaction solution was diluted with water (20 mL), extracted once with ethyl acetate (30 mL), and the aqueous phase was adjusted to pH 5–6 with 2 M hydrochloric acid. The aqueous phase was extracted three times with ethyl acetate (10 mL). The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (70 mg, 72% yield) as a white solid. 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-isopropylphenyl-1,3-diol

[0195]

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

[0197] Intermediate 17: 3-(4-(4-((1-(methanesulfonyl)azacyclobut-3-yl)methoxy)phenyl)tetrahydro-2H-pyran-4-yl)phenoxy)cyclobut-1-amine

[0198]

[0199] The synthetic route for 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)azacyclobut-1-carboxylic acid (intermediate 17-1)

[0202] 4,4'-(tetrahydro-2H-pyran-4,4-diyl)diol (964 mg, 3.58 mmol, intermediates 1-2), 3-((p-toluenesulfonyl)methyl)azacyclobut-1-carboxylic acid tert-butyl ester (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. The reaction mixture was diluted with water (150 mL), extracted twice with ethyl acetate (50 mL), and 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 give a yellow oily title compound (740 mg, yield 47%). LC-MS: m / z [MH]- = 438.

[0203] Step 2: Preparation of 4-(4-(4-(azacyclobut-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)azacyclobutane-1-carboxylic acid tert-butyl ester (740 mg, 1.69 mmol) was added to dichloromethane (6 mL), and trifluoroacetic acid (2 mL) was added under ice bath conditions. The mixture was stirred at room temperature for 3 hours. The reaction mixture was then slowly poured into a saturated sodium bicarbonate solution (50 mL) under ice bath conditions. The mixture was extracted three times with dichloromethane, and the organic phases were combined. After drying with anhydrous sodium sulfate, the organic phase was concentrated under reduced pressure and purified by column chromatography (dichloromethane / methanol = 15:1) to give the title compound as a white solid (490 mg, yield 83%). LC-MS: m / z [MH] - =338.

[0205] Step 3: Preparation of 4-(4-(4-((1-(methanesulfonyl)azacyclobut-3-yl)methoxy)phenyl)tetrahydro-2H-pyran-4-yl)phenol (intermediate 17-3)

[0206] 4-(4-(4-(azacyclobut-3-ylmethoxy)phenyl)tetrahydro-2H-pyran-4-yl)phenol (490 mg, 1.4 mmol) and triethylamine (425 mg, 4.2 mmol) were added to tetrahydrofuran (6 mL), and methanesulfonyl chloride (150 mg, 1.3 mmol) was added under ice-water bath. The mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with water (150 mL), 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 = 1:9) to give the title compound as a yellow solid (410 mg, 70% yield). LC-MS: m / z [M+H] + =418.

[0207] Step 4: Preparation of tert-butyl carbamate (3-(4-(4-(((1-(methanesulfonyl)azacyclobut-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-(methanesulfonyl)azacyclobut-3-yl)methoxy)phenyl)tetrahydro-2H-pyran-4-yl)phenoxy)cyclobut-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 for 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)diol (5.0 g, 18.5 mmol, intermediates 1-2) was dissolved in dichloromethane (50 mL), and tert-butyldimethylchlorosilane (2.5 g, 16.7 mmol) and imidazole (1.4 g, 20.4 mmol) were added. The mixture was stirred at 25 °C for 16 hours. The reaction solution was diluted with water, extracted three times with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give the title compound (3.2 g, 45% yield) as a white solid.

[0217] Step 2: Preparation of 4-(4-(4-((tert-butyldimethylsilyl)oxy)phenyl)tetrahydro-2H-pyran-4-yl)phenyltrifluoromethanesulfonate (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), and trifluoromethanesulfonyl chloride (1.5 g, 8.8 mmol) and triethylamine (3.2 g, 32 mmol) were added under ice bath conditions. 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 give a colorless, transparent oily title compound (3.4 g, yield 81%).

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

[0220] 4-(4-(4-((tert-butyldimethylsilyl)oxy)phenyl)tetrahydro-2H-pyran-4-yl)phenyltrifluoromethanesulfonate (3.4 g, 6.5 mmol), tributyl(1-ethoxyvinyl)tin (3.5 g, 9.8 mmol, CAS: 97674-02-7) and tetra(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 mixture was poured into 3M hydrochloric acid (30 mL), and the mixture was stirred at room temperature for 30 minutes and extracted three times with ethyl acetate. The combined organic phases were 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 give 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)ethyl-1-one (904 mg, 2.2 mmol) was dissolved in pyridine (5 mL), and selenium dioxide (488 mg, 4.4 mmol) was added. The mixture was stirred at 90 °C for 16 hours. The reaction solution was diluted with water, extracted three times with ethyl acetate, and the combined organic phases were washed once with 3 M hydrochloric acid, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (794 mg, 83% yield) 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 1 M tetrabutylammonium fluoride solution in tetrahydrofuran (2 mL). The mixture was stirred at 25 °C for 16 hours. The reaction mixture was diluted with water, extracted three times with ethyl acetate, and the combined organic phases were 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 (222 mg, 100% yield) as a yellow oil. LC-MS: m / z [MH] - =325.

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

[0226]

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

[0228] Intermediate 20: (1-(methanesulfonyl)azacyclobutane-3-yl)methylmethanesulfonate

[0229]

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

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

[0232]

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

[0234] Intermediate 22: (5-(3-aminocyclobutoxy)pyridin-2-yl)(4-hydroxyphenyl)methyl ketone

[0235]

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

[0237]

[0238] Step 1: Preparation of 5-hydroxy-N-methoxy-N-methylpyridine amide (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-methylpyridine amide (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), and cesium carbonate (2.78 g, 8.55 mmol) and potassium iodide (355 mg, 2.14 mmol) were added. The mixture was purged with nitrogen three times and stirred overnight at 95 °C. The reaction solution was quenched in a saturated ammonium chloride solution (50 mL), extracted twice with ethyl acetate (40 mL), the organic phases were combined, washed once with water (40 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (100% ethyl acetate) to give the title compound (1.436 g, 96% yield) as a white solid. LC-MS: m / z [M+H] + =352.

[0242] Step 3: Preparation of tert-butyl carbamate (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), purged with nitrogen three times, and the solution was cooled to -78 °C. Then, n-butyllithium (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. Subsequently, a tetrahydrofuran (10 mL) solution of (3-((6-(methoxy(methyl)carbamoyl)pyridin-3-yl)oxy)cyclobutyl)carbamate (1.636 g, 4.66 mmol) was slowly added dropwise. The reaction mixture was stirred at -78 °C for 2 hours. The reaction mixture was quenched in a saturated ammonium chloride solution (50 mL), extracted twice with ethyl acetate (40 mL), the organic phases were combined, washed once with water (40 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate = 2:1) to give 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-aminocyclobutoxy)pyridin-2-yl)(4-hydroxyphenyl)methyl ketone (Intermediate 22)

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

[0246] Intermediate 23: 4-(3-(4-(3-aminocyclobutoxy)phenyl)oxetane-3-yl)phenol

[0247]

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

[0249] Intermediate 24: (4-(3-aminocyclobutoxy)phenyl)(4-hydroxyphenyl) methyl ketone

[0250]

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

[0252]

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

[0254] 4,4'-Dihydroxybenzophenone (1.455 g, 6.79 mmol, CAS: 611-99-4) was dissolved in tetrahydrofuran (25 mL), and tert-butyl (3-hydroxycyclobutyl)carbamate (890 mg, 4.76 mmol, CAS: 154748-63-7) and triphenylphosphine (2.672 g, 10.2 mmol) were added. Under nitrogen protection, diisopropyl azodicarbonate (2.06 g, 10.2 mmol, CAS: 2446-83-5) was added dropwise at 0 °C. After the addition was complete, the mixture was heated to 65 °C and stirred for 3 hours. The reaction mixture was quenched in a saturated ammonium chloride solution (120 mL), 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, concentrated under reduced pressure, and purified by reverse-phase column chromatography (acetonitrile / water = 52:48) to give the title compound (1.1 g, 60% yield) as a white solid. LC-MS: m / z [M-55] + =328.

[0255] Step 2: Preparation of (4-(3-aminocyclobutoxy)phenyl)(4-hydroxyphenyl)methyl ketone (Intermediate 24)

[0256] 300 mg (0.78 mmol) of tert-butyl (3-(4-(4-hydroxybenzoyl)phenoxy)cyclobutyl)carbamate was dissolved in 3 mL of 4 M ethyl hydrochloride solution. The mixture was stirred at 25 °C for 1 hour under nitrogen protection. The reaction solution was directly concentrated under reduced pressure to give a white solid, the title compound (280 mg crude), which was used directly 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 the European Journal of Medicinal Chemistry, 2019, vol. 166, pp. 65-74.

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

[0261]

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

[0263] Intermediate 27: (4-(3-aminocyclobutoxy)phenyl)(4-((1-(methylsulfonyl)azacyclobutane-3-yl)methoxy)phenyl)methyl ketone

[0264]

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

[0266]

[0267] Step 1: Preparation of tert-butyl carbamate (3-(4-(4-((1-(methanesulfonyl)azacyclobutane-3-yl)methoxy)benzoyl)phenoxy)cyclobutyl)carbamate (intermediate 27-1)

[0268] (3-(4-(4-hydroxybenzoyl)phenoxy)cyclobutyl)carbamate tert-butyl ester (100 mg, 0.26 mmol, intermediate 24-1) was dissolved in N-methylpyrrolidone (3 mL), and (1-(methanesulfonyl)azacyclobutane-3-yl)methylmethanesulfonate (76 mg, 0.31 mmol, intermediate 20) and cesium carbonate (170 mg, 0.52 mmol) were added. The mixture was stirred at 90 °C for 3 hours. The reaction solution was cooled to room temperature and quenched in saturated ammonium chloride solution (80 mL). The mixture was 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, concentrated under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate = 3:1) to give 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-aminocyclobutoxy)phenyl)(4-((1-(methylsulfonyl)azacyclobutane-3-yl)methoxy)phenyl)methyl ketone (Intermediate 27)

[0270] (93 mg, 0.18 mmol) of tert-butyl carbamate (3-(4-(4-((1-(methanesulfonyl)azacyclobutane-3-yl)methoxy)benzoyl)phenoxy)cyclobutyl)carbamate) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added. The mixture was stirred at 25 °C for 1 hour. The reaction solution was directly concentrated under reduced pressure to give a yellow oily title compound (87 mg crude product), which was used directly in the next reaction. LC-MS: m / z [M+H] + =431.

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

[0272]

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

[0274]

[0275] Step 1: Preparation of 4-(2-(4-bromophenyl)prop-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 = 10:1–5:1) to give a colorless oily title compound (12.0 g, 98% yield). LC-MS: m / z [M+H] + =291 / 293.

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

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

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

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

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

[0282]

[0283] Intermediate 29 was synthesized in a similar manner to intermediate 18, replacing 1-(4-(2-(4-((tert-butyldimethylsilyl)oxy)phenyl)prop-2-yl)phenyl)ethane-1-one (intermediate 18-3) with 1-(4-(4-(4-((tert-butyldimethylsilyl)oxy)phenyl)tetrahydro-2H-pyran-4-yl)phenyl)ethyl-1-one.

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

[0285]

[0286] The synthetic route for 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), the mixture was purged with nitrogen three times, and stirred overnight at 110 °C under nitrogen protection. The reaction solution was cooled to room temperature, diluted with water (100 mL), and extracted three times with ethyl acetate (30 mL). The organic phases were combined, washed twice with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and subjected to column chromatography (petroleum ether / ethyl acetate = 2:1) to give the title compound (2.5 g, yield 58%) as a white solid. 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-onitrile (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), and cesium carbonate (3.64 g, 11 mmol) and 3-cyano-6-chloropyridazine (1.01 g, 7.3 mmol, CAS: 35857-89-7) were added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (100 mL), extracted three times with ethyl acetate (30 mL), and the organic phases were combined, washed twice with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate = 3:1) to give 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-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)tetrahydro-2H-pyran-4-yl)phenoxy)pyridazin-3-yl)ethane-1-one (intermediate 30-3)

[0293] 1.2 g (2.3 mol) of 6-(4-(4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)tetrahydro-2H-pyran-4-yl)phenoxy)pyridazine-3-onitrile (20 mL) was dissolved in anhydrous tetrahydrofuran. 5.4 mL (16 mmol) of 3 M methylmagnesium bromide tetrahydrofuran solution was slowly added dropwise at -78 °C, and the mixture was incubated for 30 min. The reaction was quenched by slowly adding 50 mL of saturated citric acid aqueous solution to the reaction mixture under ice bath conditions. The mixture was extracted three times with 50 mL of ethyl acetate. The organic phases were combined, washed twice with 100 mL of saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate = 3:1) to give the title compound (550 mg, 45% yield) as a white solid. 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 overnight at room temperature. The reaction solution was directly concentrated under reduced pressure and purified by column chromatography (dichloromethane / methanol = 30:1) to give 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)azacyclobutane-3-carboxaldehyde

[0297]

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

[0299]

[0300] Step 1: Preparation of 4-(4-(4-(3-(hydroxymethyl)azacyclobutane-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 aziridine-3-ylmethanol hydrochloride (1.11 g, 9 mmol, CAS: 928038-44-2), tris(dibenzylideneacetone)palladium (0.55 g, 0.6 mmol, CAS: 51364-51-3), cesium carbonate (5.86 g, 1.8 mmol), and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (0.7 g, 1.2 mmol, CAS: 161265-03-8) were added. The mixture was purged with nitrogen three times, and stirred at 110 °C for 16 hours under nitrogen protection. The reaction mixture was cooled to room temperature and poured into water (40 mL). It was 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 give the title compound as a white solid (0.68 g, 33% yield). LC-MS: m / z [M+H] + =340.

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

[0303] 4-(4-(4-(3-(hydroxymethyl)azacyclobutan-1-yl)phenyl)tetrahydro-2H-pyran-4-yl)phenol (0.68 g, 2 mmol) was dissolved in N,N-dimethylformamide (7 mL), and cesium carbonate (0.98 g, 3 mmol) and 3-acetyl-6-chloropyridazine (0.47 g, 3 mmol, CAS: 214701-31-2) were added. The mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with water (50 mL), extracted three times with ethyl acetate (20 mL), and the organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate = 1:2) to give 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)azacyclobutane-3-carboxaldehyde (Intermediate 31)

[0305] 1-(6-(4-(4-(4-(3-(hydroxymethyl)azacyclobutane-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), and 2-iodobenzoic acid (0.183 g, 0.653 mmol, CAS: 61717-82-6) was added. The mixture was stirred at 50 °C for 1 hour. The reaction solution was cooled to room temperature, diluted with water (20 mL), and extracted three 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 give 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-aminocyclobutoxy)phenyl)tetrahydro-2H-thiaran-4-yl)phenol

[0307]

[0308] Intermediate 32 is synthesized in a similar manner to intermediate 1, replacing 4,4'-(tetrahydro-2H-thiaran-4,4-diyl)diol (intermediate 7) with 4,4'-(tetrahydro-2H-pyran-4,4-diyl)diol (intermediate 1-2).

[0309] Intermediate 33: 1-(4-(fluoromethyl)pyrimidin-2-yl)ethane-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-((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 method is shown in the following formula:

[0315]

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

[0317] 2-(4-bromo-2,6-difluorophenyl)acetonitrile (1 g, 4.3 mmol) was dissolved in 10 mL of anhydrous tetrahydrofuran. Nitrogen gas was purged three times. A 2.0 mol / L solution of lithium diisopropylaminotetrahydrofuran (2.4 mL, 4.8 mmol) was slowly added dropwise at -65 °C. The reaction was carried out for 1 h under this stable condition. Then, ethyl 3-bromopropionate (0.7 mL, 1.1 mmol) was added dropwise, and the reaction was carried out at -65 °C for 0.5 h. The temperature was then slowly raised to room temperature for 1 h. The reaction was monitored by LC-MS to indicate completion. The solution was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate (30 mL x 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was directly column-chromatographically separated (PE:EA = 4:1) to give a colorless liquid title compound (890 mg, 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] Ethyl 4-(4-bromo-2,6-difluorophenyl)-4-cyanobutyrate (890 mg, 2.69 mmol) was dissolved in tetrahydrofuran / water (9 mL / 3 mL) under nitrogen protection. Lithium hydroxide (338 mg, 8.06 mmol) was added, and the reaction was allowed to proceed overnight at room temperature. The reaction was monitored by LCMS until completion. The reaction solution was quenched with 10 mL of water, and then adjusted to pH 4 with 1.0 mol / L hydrochloric acid. Extraction was performed with ethyl acetate (30 mL x 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product (a colorless, oily title compound) was concentrated under reduced pressure. The crude product was then directly proceeded to the next reaction (845 mg, 100% yield). 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] 4-(4-bromo-2,6-difluorophenyl)-4-cyanobutyric acid (845 mg, 2.79 mmol) was dissolved in toluene (6 mL), and then concentrated sulfuric acid (0.3 g, 3.068 mmol) was added. The reaction was carried out at 100 °C for 1 hour, and the reaction was monitored by LCMS until completion. The solution was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate (30 mL * 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude white solid, which was directly added to the next step (796 mg, 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] 3-(4-bromo-2,6-difluorophenyl)piperidine-2,6-dione (202 mg, 0.67 mmol) was dissolved in anhydrous N,N-dimethylformamide under nitrogen protection. 1,8-diazobisspirocyclic [5.4.0]undecyl-7-ene (202.16 mg, 1.33 mmol) was added, followed by the addition of 2-(trimethylsilyl)ethoxymethyl chloride (221 mg, 1.33 mmol) at 0 °C. The reaction was carried out at room temperature for 2 hours, and the reaction was monitored by LC-MS until completion. The reaction was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate (30 mL * 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the residue was concentrated under reduced pressure and directly column-chromatographically purified to give 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-(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-aminocyclobutoxy)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), 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-11'-biphenyl (25 mg, 0.046 mmol), and tridibenzylacetone dipalladium (21 mg, 0.023 mmol) were added. Nitrogen gas was purged three times, and the reaction was carried out overnight at 90 °C. The reaction was monitored by LCMS until completion. The extract was quenched with saturated ammonium chloride aqueous 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 then directly subjected to column chromatography to give 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-(((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-(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, followed by 3-acetyl-6-chloropyridazine (12 mg, 0.07 mmol, CAS: 214701-31-2). The reaction was carried out at room temperature for 1 h, and the reaction was monitored by TLC until it ended. The solution was quenched with saturated ammonium chloride aqueous solution, extracted three times with ethyl acetate, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the residue was concentrated under reduced pressure and directly precipitated by column chromatography to give a white solid (29 mg, yield: 72%).

[0328] Step 7: Preparation of 3-(4-((3-(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-(((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 then trifluoroacetic acid (0.2 mL) was added. The reaction was carried out at room temperature for 1 h. The reaction was monitored by LCMS until the reaction was complete. The crude product was concentrated under reduced pressure, dissolved in acetonitrile (4 mL), and ammonia water (0.3 mL) was added. The reaction was carried out at room temperature for 1 h. The reaction was monitored by LCMS until the reaction was complete. The solution was quenched with saturated ammonium chloride aqueous solution, extracted three times with ethyl acetate, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the residue was concentrated under reduced pressure and directly column chromatography was performed to obtain Example 1 (16 mg, HPLC purity: 95%, yield: 65%).

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

[0331] Example 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-((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 method is shown in the following formula:

[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(diphenylphosphine)ferrocene palladium dichloromethane complex (229 mg, 0.314 mmol, CAS: 95464-05-4) were added. The mixture was purged with nitrogen three times, and the reaction solution was stirred at 80 °C for 16 hours under nitrogen protection. The reaction solution was quenched in a saturated ammonium chloride solution, extracted twice with ethyl acetate and washed once with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by direct column chromatography (PE:EA = 15:1) to give 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)cyclobutoxy)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-aminocyclobutoxy)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(diphenylphosphine)-9,9-dimethyloxanthracene (120 mg, 0.21 mmol, CAS: 161265-03-8) and tris(dibenzylideneacetone)palladium (95 mg, 0.1 mmol, CAS: 51364-51-3) were added. Nitrogen gas was purged three times and the mixture was incubated overnight at 100 °C. After the addition of 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (120 mg, 0.21 mmol) and tris(dibenzylacetone)dipalladium (95 mg, 0.1 mmol), the reaction mixture was incubated overnight at 100 °C under nitrogen protection. The reaction solution was quenched in a saturated ammonium chloride solution, extracted twice with ethyl acetate and washed once with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by direct column chromatography (PE:EA = 3:2) to give 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-(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)cyclobutoxy)phenyl)tetrahydro-2H-pyran-4-yl)phenol (361 mg, 0.49 mmol) was dissolved in 1,4-dioxane (5 mL), and palladium on carbon (361 mg) and palladium hydroxide (361 mg) were added. Hydrogen gas was purged 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 give the crude white solid title compound (335 mg, 100% yield). ESI-MS: m / z [M+H] + =563.

[0342] Step 4: Preparation of 3-(4-((3-(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-(4-hydroxyphenyl)tetrahydro-2H-pyran-4-yl)phenoxy)cyclobutyl)amino)phenyl)piperidin-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. The reaction was carried out 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] Example 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-dithiacyclopentan-2-yl)phenoxy)cyclobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0347]

[0348] The preparation method is shown in the following formula:

[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-dithiacyclopentan-2-yl)phenoxy)cyclobutyl)amino)isoindoline-1,3-dione (3-1)

[0351] 4-(2-(4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-1,3-dithiacyclopentan-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-dioxoisoindoline-5-yl)amino)cyclobutyl4-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 give 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-dithiacyclopentan-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-dithiacyclopentan-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 three times with ethyl acetate, 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 give 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-dithiacyclopentan-2-yl)phenoxy)cyclobutyl)amino)-2-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)isoindoline-1,3-dione)

[0355] 2-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-5-((3-(4-(2-(4-hydroxyphenyl)-1,3-dithiacyclopentan-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 three times with ethyl acetate, 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 give 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-dithiacyclopentan-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-(4-hydroxyphenyl)tetrahydro-2H-pyran-4-yl)phenoxy)cyclobutyl)amino)phenyl)piperidin-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. The reaction was carried out 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-dithiacyclopentan-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), followed by the addition of trifluoroacetic acid (1 mL). The mixture was reacted at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and acetonitrile (5 mL) and ammonia (0.1 mL) were added to the residue. The mixture was reacted at room temperature for 1 hour, followed by the addition of saturated ammonium chloride solution. The mixture was extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate = 1:1) to give the title compound as a yellow solid (107 mg, 90% yield).

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

[0360] Example 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)propane-2-yl)phenoxy)cyclobutyl)amino)-2,6-difluorophenyl)piperidine-2,6-dione

[0362]

[0363] The title compound was synthesized in a manner similar to that in Example 1, with 4-(4-(4-(3-aminocyclobutoxy)phenyl)prop-2-yl)phenol (intermediate 4) replacing 4-(4-(4-(3-aminocyclobutoxy)phenyl)tetrahydro-2H-pyran-4-yl)phenol (intermediate 1) and 1-(5-fluoropyrimidin-2-yl)acetone (CAS: 905587-44-2) replacing 3-acetyl-6-chloropyridazine (CAS: 214701-31-2).

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

[0365] Example 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 manner similar to that in Example 2, replacing 4-(4-(4-(3-aminocyclobutoxy)phenyl)-4-methoxycyclohexyl)phenol (intermediate 5) with 4-(1-(4-(3-aminocyclobutoxy)phenyl)tetrahydro-2H-pyran-4-yl)phenol (intermediate 1).

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

[0370] Example 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 manner similar to that in Example 2, replacing 4-(4-(4-(3-aminocyclobutoxy)phenyl)-4,4-difluorocyclohexyl)phenol (intermediate 6) with 4-(1-(4-(3-aminocyclobutoxy)phenyl)tetrahydro-2H-pyran-4-yl)phenol (intermediate 1).

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

[0375] Example 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-((6-acetylpyridazin-3-yl)oxy)phenyl)-1,1-tetrahydro-2H-thiaran-4-yl)phenoxy)cyclobutyl)amino)-2,6-difluorophenyl)piperidine-2,6-dione

[0377]

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

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

[0380] Example 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 method is shown in the following formula:

[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)piperidin-2,6-dione (110 mg, 0.186 mmol, synthesized by replacing 4-(4-(4-(3-aminocyclobutoxy)phenyl)-4-methoxycyclohexyl)phenol (intermediate 5) with 4-(1-(4-(3-aminocyclobutanoxy)phenyl)tetrahydro-2H-pyran-4-yl)phenol (intermediate 1) in a similar manner to 2-4) was dissolved in acetonitrile (10 mL), and trimethyliodosilane (373 mg, 1.864 mmol) and sodium iodide (280 mg, 1.864 mmol) were added. The mixture was reacted at room temperature for 1 hour. The reaction was quenched by adding a saturated sodium sulfite solution. The mixture was extracted twice with ethyl acetate, washed once with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 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), and cesium carbonate (169 mg, 0.52 mmol) and 3-acetyl-6-chloropyridazine (33 mg, 0.2 mmol, CAS: 214701-31-2) were added. The mixture was reacted at room temperature for 2 hours. The reaction solution was directly purified by reverse column chromatography to give the title compound as a pink solid (15.33 mg, yield 12.4%).

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

[0390] Example 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-((6-acetylpyridazin-3-yl)oxy)phenyl)-1,1-tetrahydro-2H-thiaran-4-yl)phenoxy)cyclobutyl)amino)-2,6-difluorophenyl)piperidine-2,6-dione

[0392]

[0393] The title compound was synthesized in a manner similar to that in Example 2, replacing 4-(4-(4-(3-aminocyclobutoxy)phenyl)-2,6-dimethyltetrahydro-2H-pyran-4-yl)phenol (intermediate 11).

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

[0395] Example 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)piperidin-2,6-dione (50 mg, 0.07 mmol, Example 8) was dissolved in dimethyl sulfoxide (5 mL), and 2-iodobenzoic acid (80 mg, 0.287 mmol, CAS: 61717-82-6) was added. The mixture was reacted at 50 °C for 1 hour. The reaction solution was directly purified by reverse column chromatography to give a pink solid compound (8.93 mg, yield 17.9%).

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

[0400] Example 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-(((6-acetylpyridazin-3-yl)oxy)phenyl)tetrahydro-2H-pyran-4-yl)phenoxy)cyclobutyl)amino)-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)piperidine-2,6-dione

[0402]

[0403] 3-(6-fluoro-4-oxobenzo[d][1,2,3]triazine-3(4H)-yl)piperidin-2,6-dione (145 mg, 0.52 mmol, intermediate 12) and 1-(6-(4-(4-(4-(3-aminocyclobutoxy)phenyl)tetrahydro-2H-pyran-4-yl)phenoxy)pyridazine-3-yl)ethyl-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. The mixture was reacted at 120 °C for 16 hours. The reaction was quenched by slowly adding water (100 mL) to the reaction solution. 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 phases were dried with anhydrous sodium sulfate, concentrated under reduced pressure, and purified by preparative liquid chromatography to obtain the white solid title compound (8 mg, yield 2%).

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

[0405] Example 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 manner similar to that in Example 1, by replacing 3-(4-bromo-2,6-difluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (intermediate 14) with 3-(6-bromo-2-oxobenzo[cd]indol-1(2H)-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (1-5).

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

[0410] Example 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)azacyclobut-1-yl)phenyl)tetrahydro-2H-pyran-4-yl)phenoxy)pyridazine-3-yl)acet-1-one

[0412]

[0413] 1-(4-(4-(4-(((6-acetyridazin-3-yl)oxy)phenyl)tetrahydro-2H-pyran-4-yl)phenyl)azacyclobut-3-carboxylic acid (150 mg, 0.316 mmol, intermediate 15) was dissolved in dichloromethane (5 mL) and N,N-dimethylformamide (0.5 mL), and N,N-diisopropylethylamine (204 mg, 1.59 mmol) was added. 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, add 4-(5-hydroxy-4-(4-(piperazin-1-ylmethyl)phenyl)-4H-1,2,4-triazol-3-yl)-6-isopropylbenzene-1,3-diol (194 mg, 0.475 mmol, intermediate 16), and stir the reaction solution overnight at room temperature. Dilute the reaction solution with water (20 mL).

[0414] Extracted three times with ethyl acetate (10 mL), the organic phases were combined and 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 and purified by column chromatography (petroleum ether / ethyl acetate = 3:1) to give the white solid title compound (20 mg, yield 7%).

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

[0416] Example 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-(4-((1-(methanesulfonyl)azacyclobut-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 manner similar to that in Example 11, by replacing 3-(6-fluoro-4-oxobenzo[d][1,2,3]triazine-3(4H)-yl)piperidin-2,6-dione (intermediate 12) with 2-(2,6-dioxo-3-piperidinyl)-5-fluoro-1,3-isoindolinedione (CAS: 835616-61-0) and 3-(4-(4-(4-((1-(methanesulfonyl)azacyclobutan-3-yl)methoxy)phenyl)tetrahydro-2H-pyran-4-yl)phenoxy)cyclobutan-1-amine (intermediate 17) with 1-(6-(4-(4-(4-(3-aminocyclobutoxy)phenyl)tetrahydro-2H-pyran-4-yl)phenoxy)pyridazine-3-yl)ethyl-1-one (intermediate 13).

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

[0421] Example 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-dioxoisoindoline-5-yl)-2-oxoacetamide

[0423]

[0424] The preparation method is shown in the following formula:

[0425]

[0426] Step 1: 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), and 1-(5-fluoropyrimidin-2-yl)acetone (95 mg, 0.68 mmol, CAS: 905587-44-2) and cesium carbonate (443 mg, 1.36 mmol) were added. The mixture was stirred at 25 °C for 2 hours. The reaction solution was poured into water, and the pH was adjusted to 5 with 1N hydrochloric acid. The mixture was extracted three times with ethyl acetate, and the combined organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a yellow oily crude title compound (333 mg).

[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-dioxoisoindoline-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) and 5-amino-2-(2,6-dioxopiperidin-3-yl)isodihydroindole-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 sequentially in an ice bath, and the mixture was stirred at 0 °C for 2 hours. The reaction mixture was poured into water and extracted three times with dichloromethane. The organic phases were combined, concentrated under reduced pressure, and purified by preparative thin-layer chromatography (eluent: ethyl acetate) to give the title compound as a white solid (30 mg, yield 6%).

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

[0431] Example 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]non-7-yl)phenoxy)cyclobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0433]

[0434] The preparation method is shown in the following formula:

[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-aminocyclobutoxy)phenyl)-2-oxaspiro[3.5]non-7-yl)phenol (213 mg, 0.43 mmol, intermediate 19) was dissolved in dimethyl sulfoxide (2 mL), and 2-(2,6-dioxo-3-piperidinyl)-5-fluoro-1,3-isoindolindione (178 mg, 0.64 mmol, CAS: 835616-61-0) and N,N-diisopropylethylamine (222 mg, 1.72 mmol) were added. The mixture was stirred at 110 °C for 3 hours under nitrogen protection. The reaction solution was cooled to room temperature and poured into a saturated ammonium chloride aqueous solution (40 mL). The solution was extracted three times with ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by reverse column chromatography to give 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]non-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), and cesium carbonate (125 mg, 0.384 mmol) and 3-acetyl-6-chloropyridazine (45 mg, 0.288 mmol, CAS: 214701-31-2) were added. The mixture was stirred at 40 °C for 1 hour under nitrogen protection. The reaction solution was poured into a saturated ammonium chloride solution (50 mL), extracted three times with ethyl acetate (30 mL), and the organic phase was dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography to give the title compound as a white solid (41 mg, yield 28%).

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

[0441] Example 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]triazine-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 manner similar to that in Example 15, with 1-(5-fluoro-2-pyrimidinyl) acetone (CAS: 905587-44-2) replaced by 5-fluoro-N-methyl-2-pyridinecarboxamide (intermediate 26) and 3-(6-amino-4-oxobenzo[d][1,2,3]triazine-3(4H)-yl)piperidin-2,6-dione (intermediate 25) replaced by 5-amino-2-(2,6-dioxopiperidin-3-yl)isodihydroindole-1,3-dione (CAS: 191732-76-0).

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

[0446] Example 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 manner similar to that in Example 2, with 1-bromo-2,5-difluoro-4-iodobenzene (CAS:145349-66-2) replaced by 2,6-difluoro-4-bromoiodobenzene (CAS:160976-02-3), 4-(1-(4-(3-aminocyclobutoxy)phenyl)-4,4-difluorocyclohexyl)phenol (intermediate 6) replaced by 4-(4-(4-(3-aminocyclobutoxy)phenyl)tetrahydro-2H-pyran-4-yl)phenol (intermediate 1), and 1-(5-fluoro-2-pyrimidinyl)acetone (CAS:905587-44-2) replaced by 3-acetyl-6-chloropyridazine (CAS:214701-31-2).

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

[0451] Example 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)cyclobutoxy)phenyl)tetrahydro-2H-pyran-4-yl)phenoxy)-2-pyridinecarboxamide

[0453]

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

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

[0456] Example 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)cyclobutoxy)phenyl)tetrahydro-2H-pyran-4-yl)phenoxy)-N-methyl-2-pyridinecarboxamide

[0458]

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

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

[0461] Example 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-(((6-acetylpyridazin-3-yl)oxy)phenyl)tetrahydro-2H-thiaran-4-yl)phenoxy)cyclobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0463]

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

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

[0466] Example 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 manner similar to that in Example 16, with 3-acetyl-6-chloropyridazine (CAS: 214701-31-2) replaced by 4-(2-chloroethyl)morpholine (CAS: 3240-94-6).

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

[0471] Example 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-(methanesulfonyl)azacyclobutane-3-yl)methoxy)phenyl)-2-oxaspiro[3.5]non-7-yl)phenoxy)cyclobutyl)amino)isoindoline-1,3-dione

[0473]

[0474] The title compound was synthesized in a manner similar to that in Example 16, replacing 3-acetyl-6-chloropyridazine (CAS: 214701-31-2) with (1-(methylsulfonyl)azacyclobutane-3-yl)methylmethanesulfonate (intermediate 20).

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

[0476] Example 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]non-7-yl)phenoxy)cyclobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0478]

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

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

[0481] Example 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-(methanesulfonyl)azacyclobutane-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 manner similar to that in Example 2, with 2,6-difluoro-4-bromoiodobenzene (CAS:160976-02-3) replacing 1-bromo-2,5-difluoro-4-iodobenzene (CAS:145349-66-2) and 1-(5-fluoro-2-pyrimidinyl)acetone (intermediate 20) replacing 3-acetyl-6-chloropyridazine (CAS:214701-31-2).

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

[0486] Example 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-dithiopentan-2-yl)pyridin-3-yl)oxy)cyclobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0488]

[0489] The preparation method is shown in the following formula:

[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-aminocyclobutoxy)pyridin-2-yl)(4-hydroxyphenyl) methyl ketone (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, 2.05 mmol), 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-triisopropyl-1,1'-biphenyl (73 mg, 0.136 mmol, CAS: 1070663-78-3), tris(dibenzylacetone)dipalladium (63 mg, 0.068 mmol, CAS: 51364-51-3), purged with nitrogen three times, and stirred at 90 °C for 16 hours. After the reaction solution cooled to room temperature, it was quenched in a saturated ammonium chloride solution (20 mL), extracted twice with ethyl acetate (15 mL), the organic phases were combined, washed once with water (15 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate = 1:2) to give the title compound as a yellow solid (40 mg, 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-dithiopentane-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-ethylenedithiol (7 mg, 0.074 mmol, CAS: 540-63-6) were dissolved in dichloromethane and tetrahydrofuran (2 mL / 2 mL), and boron trifluoride ether (21 mg, 0.148 mmol, CAS: 109-63-7) was added under ice bath conditions. The mixture was stirred at 40 °C for 4 hours. After the reaction solution cooled to room temperature, it was quenched in a saturated ammonium chloride solution (20 mL), extracted twice with ethyl acetate (15 mL), the organic phases were combined, washed once with water (15 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate = 1:2) to give 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-dithiopentan-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-dithiopentane-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), and cesium carbonate (94 mg, 0.29 mmol) and 3-acetyl-6-chloropyridazine (18 mg, 0.117 mmol, CAS: 214701-31-2) were added. The mixture was stirred at 40 °C for 2 hours under nitrogen protection. The reaction solution was directly purified by reverse column chromatography to give the title compound as a yellow solid (26.23 mg, yield 37%).

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

[0498] Example 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 manner similar to that in Example 26, with 3-acetyl-6-chloropyridazine (CAS: 214701-31-2) replaced by 1-(5-fluoropyrimidin-2-yl)acetone (CAS: 905587-44-2).

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

[0503] Example 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)oxetane-3-yl)phenoxy)cyclobutyl)amino)-2,6-difluorophenyl)piperidine-2,6-dione

[0505]

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

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

[0508] Example 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-dithiacyclopentan-2-yl)phenoxy)cyclobutyl)amino)-2,5-difluorophenyl)piperidine-2,6-dione

[0510]

[0511] The preparation method is shown in the following formula:

[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-aminocyclobutoxy)phenyl)(4-hydroxyphenyl) methyl ketone (intermediate 24) with 4-(4-(4-(3-aminocyclobutanoxy)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-dioxadiazine-3-yl)-5-((3-((6-(4-hydroxybenzoyl)pyridin-3-yl)oxy)cyclobutyl)amino)phenyl)piperidin-2,6-dione (29-1).

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

[0516] The title compound was synthesized in a manner similar to that in 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-dithiopentane-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] Example 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-(methanesulfonyl)azacyclobutane-3-yl)methoxy)phenyl)-1,3-dithiopentane-2-yl)phenoxy)cyclobutyl)amino)isoindoline-1,3-dione

[0520]

[0521] The preparation method is shown in the following formula:

[0522]

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

[0524] (4-(3-aminocyclobutoxy)phenyl)(4-((1-(methanesulfonyl)azacyclobutane-3-yl)methoxy)phenyl) methyl ketone (87 mg, 0.20 mmol, intermediate 27) was dissolved in N-methylpyrrolidone (2 mL), and 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. The mixture was stirred at 110 °C for 16 hours under nitrogen protection. The reaction solution was cooled to room temperature and poured into a saturated ammonium chloride aqueous solution (40 mL). The mixture was extracted three times with ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by reverse-phase column chromatography (acetonitrile / water = 52:48) to give 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-(methanesulfonyl)azacyclobutane-3-yl)methoxy)phenyl)-1,3-dithiopentane-2-yl)phenoxy)cyclobutyl)amino)isoindoline-1,3-dione (Example 30)

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

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

[0528] Example 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)prop-2-yl)phenyl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)-2-oxoacetamide

[0530]

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

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

[0533] Example 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)prop-2-yl)phenyl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)-2-oxoacetamide

[0535]

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

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

[0538] Example 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)prop-2-yl)phenyl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)-2-oxoacetamide

[0540]

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

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

[0543] Example 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)ethane-1-one

[0545]

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

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

[0548] Example 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)azacyclobutane-1-yl)phenyl)tetrahydro-2H-pyran-4-yl)phenoxy)pyridazin-3-yl)ethane-1-one

[0550]

[0551] The title compound was synthesized in a manner similar to that in Example 34, replacing 1-(4-(4-(((6-acetylpyridazin-3-yl)oxy)phenyl)tetrahydro-2H-pyran-4-yl)phenyl)azacyclobutane-3-carboxaldehyde (intermediate 31).

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

[0553] Example 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)prop-2-yl)phenoxy)cyclobutyl)amino)phenyl)piperidin-2,6-dione)

[0555]

[0556] The preparation method is shown in the following formula:

[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)cyclobutoxy)phenyl)prop-2-yl)phenoxy)pyrimidine-2-onitrile (36-2)

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

[0560] 3-(2,6-difluoro-4-((3-(4-(2-(4-hydroxyphenyl)prop-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-pyridinecarboxylic acid (4 mg, 0.031 mmol, CAS: 98-98-6) and cuprous iodide (6 mg, 0.031 mmol) were added sequentially. The mixture was purged with nitrogen three times, and then heated to 100 °C for 2 hours under nitrogen protection. The reaction solution was cooled to room temperature and poured into a saturated ammonium chloride aqueous solution (100 mL). It was 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 give the yellow oily title compound (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)prop-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)cyclobutoxy)phenyl)prop-2-yl)phenoxy)pyrimidin-2-onitrile (58 mg, 0.077 mmol) was dissolved in ethanol (3 mL), and hydroxylamine hydrochloride (7 mg, 0.1 mmol, CAS: 5470-11-1) was added. The mixture was reacted at 70 °C for 3 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure to give a white solid crude product (59 mg). The crude product was dissolved in pyridine (2 mL), and acetyl chloride (9 mg, 0.107 mmol) was added. The mixture was heated to 100 °C and reacted for 16 hours. The reaction solution was cooled to room temperature and poured into a saturated ammonium chloride aqueous 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-phase column chromatography (acetonitrile / water = 51:49) to give 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)prop-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)prop-2-yl)phenoxy)cyclobutyl)amino)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-2,6-dione (32 mg, 0.039 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (0.5 mL) was added. 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), and ammonia water (0.5 mL) was added. The mixture was stirred at room temperature for 1 hour. The reaction solution was directly purified by reverse-phase column chromatography (acetonitrile / water = 51:49) to give a white solid title compound (10.25 mg, yield 38%).

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

[0566] Example 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 a similar preparation procedure as described above, using the intermediates stated above, and by appropriately changing the amounts of reactants, reaction conditions and reagents.

[0568]

[0569]

[0570]

[0571]

[0572] Experiment 1: Cell Experiment (22RV1 Cell Proliferation Inhibition Assay)

[0573] Day 1: Cell Plating

[0574] 1) Collect the 22RV1 cell suspension from the culture flask into a 15mL 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 suspension, add 20 μL of LAO / PI staining solution, and count the cells using Counterstar.

[0576] 3) Based on the viable cell density and the required number of cells for plating, calculate the required volume of cell suspension and complete culture medium. The plating density for 22RV1 cells is 5 × 10⁻⁶ cells / cm².3 80 μL / well.

[0577] 4) Using a manual pipette, add 80 μL of the cell suspension to 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. Incubate the 96-well plate overnight.

[0578] Day 2: Compound Preparation

[0579] 1) Take out the compound of this application dissolved in DMSO and the positive control ARV-110, and perform serial dilutions (dilutions in 96-well cell culture plates, from left to right: column A, column B, etc., up to column J).

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

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

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

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

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

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

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

[0587] H column: Take 20 μL of G column solution and dilute it in 60 μL of DMSO to obtain a final concentration of 0.61025 μM;

[0588] Column I: Take 20 μL of Column H solution and dilute it in 60 μL of DMSO to obtain a final concentration of 0.1526 μM;

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

[0590] Mix the obtained 96-well cell culture plate on a shaker.

[0591] 2) Preparation of 5× compound: (dilution in 96-well cell culture plates)

[0592] Using a 10 μL manual pipette, 4 μL of solutions from columns B to J were added to 196 μL of 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, respectively. 4 μL of LDMSO was added to 196 μL of complete culture medium as a control (blank control). The resulting 96-well cell culture plates were then thoroughly mixed using a shaker.

[0593] Compound treatment:

[0594] 1) Using a manual pipette with a volume of 20 μL, pipette the prepared 5× compound solutions of the above concentrations into the corresponding wells of a 96-well plate after overnight culture on the first day, with a total culture volume of 100 μL per well. This will result in final compound concentrations of 10 μM, 2.5 μM, 625 nM, 156.3 nM, 39.06 nM, 9.766 nM, 2.441 nM, 0.6104 nM, and 0.1526 nM in the 96-well cell culture plate. Mix the resulting 96-well cell culture plate using a shaker.

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

[0596] Results testing (day 5):

[0597] 1) Using a pipette, with a volume of 10 μL, add CCK-8 detection solution to a 96-well cell culture plate at a rate of 10 μL / well.

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

[0599] 3) Use an MD microplate reader to read the 450 nm absorbance value, calculate the inhibition rate, and use GraphPad to calculate the IC50 value.

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

[0601]

[0602]

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

[0604] Experiment 2: Degradation 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 the cells were cultured at 37℃ in a 5% CO2 incubator. On the first day, cells in the exponential growth phase were collected, and the cell suspension was adjusted to the appropriate concentration using complete culture medium. 2 mL of complete culture medium was used per well in 6-well plates, with a cell count of 500,000 cells / well. On the second day, complete culture medium containing the target compound was added, with one well containing 0.1% DMSO as a DMSO solvent control. The 6-well plates were cultured at 37℃ in a 5% CO2 incubator. After 6 or 24 hours, the cells were trypsinized and collected into 1.5 mL centrifuge tubes. 40 μL of IRIPA lysis buffer (containing 1× protease inhibitor mixture) was added to each well, and the cells were lysed on ice for 30 minutes. The cells were then centrifuged at 12000g, 4℃ for 10 minutes. The supernatant protein sample was collected, and protein quantification was performed using the BCA method. The experimental procedure is as follows: the target protein concentration was diluted to 1 mg / mL. The prepared samples were denatured at 95°C for 10 minutes and then placed on ice for later use. The primary antibodies were diluted with primary antibody dilution buffer. The primary antibodies were AR-V7 (abcam, ab198394) and GAPDH (Abclonal, A19056) at dilution ratios of 1:1000 and 1:10000, respectively. The secondary antibody was 1:10000 goat anti-rabbit secondary antibody, and the chromogenic solution was Clarity Western ECL Substrate. The prepared reagents were added to the detection plate according to the kit instructions, and the Westem bands were detected. The degradation rate of AR-V7 relative to the solvent control was calculated according to formula (1) at different drug concentrations. Among them, AR-V7 compound The relative peak area of ​​AR-V7 in the treatment group is AR-V7. solvent This represents the relative peak area of ​​AR-V7 in the solvent control group. AR-V7% = (1 - AR-V7) compound / AR-V7 solvent Formula (1) × 100%

[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] Experimental Example 3: Liver S9 Stability Test

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

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

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

Claims

1. A compound of formula (I), a pharmaceutically acceptable salt thereof, a deuterated thereof, a stereoisomer thereof, a tautomer thereof, or a mixture thereof, in, PTC is the target recognition or binding moiety, LI is the linker moiety, and U is selected from E3 ligase ligands or HSP90 inhibitors; the three moieties are linked by chemical bonds; the compound is selected from:

2. Use of the compound of claim 1, its pharmaceutically acceptable salt, its deuterated form, its stereoisomer, its tautomer, or mixtures thereof in the preparation of a protein degradation-targeting chimeric (PROTAC) for the androgen receptor.

3. Use of the compound of claim 1, its pharmaceutically acceptable salt, its deuterated form, its stereoisomer, its tautomer, or mixtures thereof in the preparation of medicaments for the treatment and / or prevention of diseases related to androgen receptors or their cleavages.

4. The use according to claim 3, characterized in that, The diseases associated with androgen receptors or their splice variants are selected from prostate cancer, breast cancer, ovarian cancer, bladder cancer, pancreatic cancer, hepatocellular carcinoma, endometrial cancer, salivary gland cancer, alopecia, acne, hirsutism, ovarian cysts, polycystic ovary syndrome, precocious puberty, spinal cord disease, COVID-19, or bulbar muscular atrophy or age-related macular degeneration.

5. The use according to claim 4, characterized in that, The diseases associated with androgen receptors or their splice variants are selected from prostate cancer, breast cancer, ovarian cancer, bladder cancer, pancreatic cancer, hepatocellular carcinoma, endometrial cancer, or salivary gland cancer.

6. The use according to claim 5, characterized in that, The disease associated with the androgen receptor or its splice variant is prostate cancer.

Images