Targeted chimeric compound, pharmaceutical composition containing same, preparation method and use thereof

Abstract

A targeted chimeric compound, a pharmaceutical composition containing the same, and its preparation method and use. The targeted chimeric compound is represented by general formula (I), and the substituents in general formula (I) have the same definitions as in the specification. Compared with fulvestrant in the prior art, the targeted chimeric compound has comparable or even superior antiproliferative activity against mutation-resistant cells of estrogen receptor α, and is thus expected to exhibit comparable or even superior therapeutic efficacy.

Description

Technical Field

[0001] The present invention relates to a targeted chimeric compound, a pharmaceutical composition containing the same, and a preparation method and use thereof. Background Art

[0002] The estrogen receptor (ER) is a key member of the nuclear hormone receptor family, acting as a ligand-activated transcription factor involved in both up- and downregulation of gene expression. Natural agonists of the ER include 17-β-estradiol (E2) and its closely related metabolites. Binding of these natural agonists to the ER leads to receptor dimerization, followed by binding to the corresponding response element (ERE) on DNA. The ER-DNA complex recruits other transcription factors responsible for transcribing the DNA downstream of the ERE into mRNA. Because the expression of numerous genes is regulated by the ER and because the ER is expressed in many cell types, modulation of the ER by binding to natural hormones or synthetic ER ligands can have profound effects on the physiology and pathophysiology of organisms.

[0003] There are two distinct forms of estrogen receptors in the human body, commonly referred to as estrogen receptor α (ERα) and estrogen receptor β (ERβ), each encoded by a corresponding gene. The two ERs have different distributions in different tissues. ERα is found in the endometrium, breast cancer cells, ovarian stromal cells, and the hypothalamus. ERβ is primarily found in the kidney, brain, bone, heart, prostate, and endothelial cells.

[0004] Estrogen plays an important role in maintaining bone density, regulating blood lipids, and protecting neurons. Clinical trials have shown that estrogen receptors mediate a variety of diseases, collectively referred to as estrogen-dependent diseases. Certain proliferative diseases, such as breast cancer, uterine cancer, and endometriosis, exhibit overexpression of estrogen receptors. Estrogen receptors play a key role in breast cancer cell proliferation, a fact reinforced by the promising efficacy of estrogen receptor antagonists in the treatment of breast cancer.

[0005] As the most common malignant tumor in women, the incidence of breast cancer is increasing annually worldwide. Estrogen receptor-positive breast cancer accounts for one-third of all breast cancer cases. Currently, treatment options for estrogen receptor-positive breast cancer include: For premenopausal women with advanced breast cancer, surgery, radiotherapy, or medical treatments are used to eliminate ovarian function. For postmenopausal women, aromatase inhibitors are used to inhibit estrogen synthesis.

[0006] In addition, estrogen receptor antagonists have also been widely used in the treatment of estrogen receptor-positive breast cancer, such as tamoxifen, a competitive ER antagonist, but their effectiveness is often limited by their partial agonist effects, which results in an inability to completely block the estrogen receptor-mediated pathway. In contrast, fulvestrant is a new class of estrogen receptor antagonists and an estrogen receptor protein degrader that is completely free of the side effects of partial agonists associated with currently available estrogen receptor antagonists such as tamoxifen.

[0007] Although fulvestrant has shown good effects in the treatment of breast cancer due to its unique mechanism of action, due to its non-oral administration method and its incomplete estrogen receptor protein degradation rate, the maximum protein degradation rate is around 61%, making the development of oral estrogen degraders with high protein degradation rates of great significance.

[0008] Proteolytic Targeted Chimeric Antibodies (PROTAC) is a cutting-edge technology that uses endogenous proteins to recruit E3 ubiquitin ligases for the degradation of specific target proteins. It utilizes the ubiquitin-proteasome system (UPS) and autophagy / lysosome pathways, essential for normal human physiology, to degrade disease-related target proteins, thereby achieving therapeutic effects on the corresponding diseases. This technology not only overcomes the shortcomings of large molecule antibodies and kinase-targeted small molecules, but also has the potential to break through the bottleneck of "non-druggable targets" and overcome tumor resistance. It is very likely to bring revolutionary changes to new drug development and improved tumor treatment.

[0009] Proteolysis-targeting chimeric compounds consist of three components: a target protein ligand, an E3 ubiquitin ligase ligand, and a linker chain. The target protein ligand directs the E3 ubiquitin ligase to the target protein, selectively leading to polyubiquitination of the target protein, enabling recognition and degradation by the proteasome. To date, PROTAC technology has been used to target a variety of proteins, including transcription factors, scaffolding proteins, enzymes, and regulatory factors. This technology has attracted significant attention from pharmaceutical companies worldwide. Through this mechanism, PROTAC technology provides a new platform for drug development. Summary of the Invention

[0010] The technical problem to be solved by the present invention is to provide a targeted chimeric compound, a pharmaceutical composition containing the same, and a preparation method and use thereof. Compared with the prior art fulvestrant, the targeted chimeric compound of the present invention has comparable or even superior inhibitory activity against the proliferation of mutant drug-resistant cells (specifically, against mutant drug-resistant cells MCF-7ERα). D538G The maximum inhibition percentage IH%max) is expected to show comparable or even better therapeutic efficacy.

[0011] The present invention provides a compound represented by general formula (I), its pharmaceutically acceptable salts, tautomers, stereoisomers, enantiomers, diastereomers, isotopic derivatives, crystal forms, solvates, prodrugs, metabolites, racemates containing the same, or mixtures containing the same, wherein "these" refers to the compound.

[0012]

[0013] in:

[0014] X is selected from CH and N, preferably CH;

[0015] -A- is selected from the group consisting of -CH=CH-, -N=N-, -S-, -O-, and -NH-;

[0016] -L1- is the connecting chain;

[0017] -L2- is a bond or -C(O)-;

[0018] -R1 is selected from hydroxy, -S(O)2-alkyl, -B(OH)2, -COOH, -CONH2, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0019] Each -R2 is independently selected from hydroxy, -S(O)2-alkyl, -B(OH)2, -COOH, -CONH2, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0020] -R3 and -R4 are each independently selected from -H, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0021] m is 0, 1, 2, 3, 4 or 5.

[0022] In some preferred embodiments, -A- is -CH=CH- or -N=N-, preferably -CH=CH-.

[0023] In some preferred embodiments, -A- is -S-.

[0024] In some preferred embodiments, -A- is -CH=CH-, and -L2- is a bond.

[0025] In some preferred embodiments, -A- is -S-, and -L2- is -C(O)-.

[0026] In the present invention, -L1- can be a connecting chain used in the prior art to connect a target protein ligand and an E3 ubiquitin ligase ligand, such as the connecting chain disclosed in CN110291087A.

[0027] In some preferred embodiments, the left end of -L1- is linked to the target protein ligand, and the right end of -L1- is linked to the E3 ubiquitin ligase ligand.

[0028] In some preferred embodiments, -L1- is selected from:

[0029] -M1 a -N(R5)-M1 b -O-M1 c -O-M1 d -C(O)-,

[0030] -(M1 a )n-M2-M1 b -O-M1 c -C(O)-, n is 0 or 1,

[0031] -M1 a -N(R5)-M1 b -O-M1 c -C(O)-,

[0032] -M1 a -N(R5)-M1 b -O-M1 c -O-M3-C(O)-,

[0033] -M1 a -N(R5)-M1 b -O-M1 c -O-M1 d -O-M3-C(O)-,

[0034] -M1 a -N(R5)-M1 b -O-M3-C(O)-,

[0035] -M1 a -N(R5)-M1 b -C(O)- and

[0036] -M1 a -M2-M1 b -C(O)-;

[0037] -M1 a -、-M1 b -、-M1 c -and-M1 d- is an alkylene group; -M2- is a heterocyclylene group; -M3- is an arylene group; each -M1 a -、-M1 b -、-M1 c -、-M1 d -, -M2- and -M3- are each independently optionally substituted by one or more substituents selected from hydroxy, -B(OH)2, -COOH, -CONH2, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, alkenyl, alkynyl, oxo, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0038] Each -R5 is independently selected from -H, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0039] In some preferred embodiments, -L1- is as defined above, and further, each -M1 a -, each -M1 b -, each -M1 c - and each -M1 d - Each independently C 1-6 Alkylene.

[0040] In some preferred embodiments, -L1- is as defined above, further, each -M2- is independently a 3-6 membered heterocyclic group, preferably a 3-6 membered nitrogen-containing heterocyclic group, more preferably

[0041] In some preferred embodiments, -L1- is as defined above, and further, each -M3- is a phenylene group.

[0042] In some preferred embodiments, -L1- is as defined above, and further, each -M1 a -、-M1 b -、-M1 c -、-M1 d -, -M2- and -M3- are not substituted.

[0043] In some preferred embodiments, -L1- is as defined above, further, each -R5 is independently an alkyl group, preferably C 1-6 Alkyl, more preferably ethyl.

[0044] In some preferred embodiments, in the general formula (I), -L1- is selected from:

[0045] -M1 a -N(R5)-M1 b-O-M1 c -O-M1 d -C(O)-,

[0046] -(M1 a )n-M2-M1 b -O-M1 c -C(O)-, n is 0 or 1,

[0047] -M1 a -N(R5)-M1 b -O-M1 c -C(O)-,

[0048] -M1 a -N(R5)-M1 b -O-M1 c -O-M3-C(O)-,

[0049] -M1 a -N(R5)-M1 b -O-M1 c -O-M1 d -O-M3-C(O)-,

[0050] -M1 a -N(R5)-M1 b -O-M3-C(O)-,

[0051] -M1 a -N(R5)-M1 b -C(O)- and

[0052] -M1 a -M2-M1 b -C(O)-;

[0053] Each -M1 a -、-M1 b -、-M1 c -and-M1 d - Each independently C 1-6 Alkylene; -M2- is a 3- to 6-membered heterocyclylene; -M3- is a phenylene;

[0054] Each -M1 a -、-M1 b -、-M1 c -、-M1 d -, -M2- and -M3- are each independently optionally selected from hydroxy, -B(OH)2, -COOH, -CONH2, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C1-6 Alkoxy, hydroxy C 1-6 Alkyl, cyano, amino, nitro, C 2-6 Alkenyl, C 2-6 substituted by one or more substituents selected from alkynyl, oxo, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl; and

[0055] Each -R5 is independently selected from -H, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, 3-6 membered cycloalkyl, heterocyclyl, phenyl and 5-6 membered heteroaryl.

[0056] In some preferred embodiments, in the general formula (I), -L1- is selected from:

[0057] -ethylene-N(ethyl)-ethylene-O-ethylene-O-methylene-C(O)-,

[0058] -azetidinyl-pentylene-O-methylene-C(O)-,

[0059] -ethylene-N(ethyl)-propylene-O-methylene-C(O)-,

[0060] -ethylene-N(ethyl)-pentylene-O-methylene-C(O)-,

[0061] -ethylene-N(ethyl)-ethylene-O-ethylidene-O-phenylene-C(O)-,

[0062] -ethylene-N(ethyl)-ethylene-O-ethylene-O-ethylene-O-phenylene-C(O)-,

[0063] -ethylene-N(ethyl)-butylene-O-phenylene-C(O)-,

[0064] -ethylene-N(ethyl)-ethylene-O-phenylene-C(O)-,

[0065] -ethylene-N(ethyl)-pentylene-O-phenylene-C(O)-,

[0066] -ethylene-N(ethyl)-methylene-C(O)-,

[0067] -ethylene-N(ethyl)-propylene-O-phenylene-C(O)-,

[0068] -ethylene-piperazinyl-ethylene-O-methylene-C(O)-,

[0069] -Azetidinyl-propylene-O-methylene-C(O)-,

[0070] -ethylene-piperazinylene-ethylene-C(O)- and

[0071] -ethylene-N(ethyl)-ethylene-O-methylene-C(O)-,

[0072] Each methylene, ethylene, propylene, butylene, pentylene, azetidinylene, piperazinylene and phenylene group is independently optionally selected from hydroxy, -B(OH)2, -COOH, -CONH2, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 is substituted by one or more substituents selected from the group consisting of alkyl, cyano, amino and nitro, and

[0073] Each ethyl group is optionally substituted with one or two hydroxy groups or halogen groups.

[0074] In some preferred embodiments, in the general formula (I), -L1- is selected from:

[0075] In some preferred embodiments, -R1 is as defined above, further, the -S(O)2-alkyl is -S(O)2-C 1-6 Alkyl, preferably -S(O)2-methyl.

[0076] In some preferred embodiments, -R1 is as defined above, and further, the halogen is selected from -F, -Cl, -Br and -I, preferably -F.

[0077] In some preferred embodiments, -R1 is as defined above, further, the alkyl group is C 1-6 Alkyl group, preferably methyl group.

[0078] In some preferred embodiments, -R1 is as defined above, further, the alkoxy group is C 1-6 Alkoxy group, preferably methoxy group.

[0079] In some preferred embodiments, -R1 is as defined above, further, the hydroxyalkyl group is hydroxy C 1-6 Alkyl, preferably -CH2OH.

[0080] In some preferred embodiments, -R1 is selected from hydroxy, -S(O)2-C 1-6 Alkyl, -B(OH)2, -COOH, -CONH2, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, cyano, amino and nitro groups.

[0081] In some preferred embodiments, -R1 is selected from hydroxy, -B(OH)2, -COOH, -CONH2, halogen, alkyl, alkoxy, hydroxyalkyl and cyano; wherein the hydroxyalkyl is preferably -CH2OH.

[0082] In some preferred embodiments, -R1 is selected from the group consisting of hydroxy, -B(OH)2, -COOH, -CONH2, -CH2OH, and cyano.

[0083] In some preferred embodiments, -R1 is selected from hydroxy, halogen, alkyl and alkoxy. 1-6 Alkyl, more preferably methyl. The alkoxy is preferably C 1-6 Alkoxy group, more preferably methoxy group.

[0084] In some preferred embodiments, -R1 is selected from hydroxy, amino, methyl and fluoro, preferably hydroxy.

[0085] In some preferred embodiments, each -R2 is as defined above, further, the -S(O)2-alkyl is -S(O)2-C 1-6 Alkyl, preferably -S(O)2-methyl.

[0086] In some preferred embodiments, each -R2 is as defined above, and further, the halogen is selected from -F, -Cl, -Br and -I, preferably -F.

[0087] In some preferred embodiments, each -R2 is as defined above, further, the alkyl group is C 1-6 Alkyl group, preferably methyl group.

[0088] In some preferred embodiments, each -R2 is as defined above, further, the alkoxy group is C 1-6 Alkoxy group, preferably methoxy group.

[0089] In some preferred embodiments, each -R2 is as defined above, further, the hydroxyalkyl group is a hydroxy C 1-6 Alkyl, preferably -CH2OH.

[0090] In some preferred embodiments, each -R2 is independently selected from hydroxy, -S(O)2-C 1-6 Alkyl, -COOH, -CONH2, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, cyano, amino and nitro groups.

[0091] In some preferred embodiments, each -R2 is independently selected from hydroxy, halogen, -S(O)2-C 1-6 Alkyl, C 1-6 Alkyl and C 1-6 Alkoxy, preferably halogen or -S(O)2-C 1-6 alkyl.

[0092] In some preferred embodiments, each -R2 is independently selected from hydroxy, amino, methyl and halogen, preferably halogen, more preferably -F.

[0093] In some preferred embodiments, each -R2 is independently -S(O)2-C 1-6 Alkyl, preferably -S(O)2-methyl.

[0094] In some preferred embodiments, -R3 and -R4 are each independently -H or alkyl. 1-6 Alkyl, more preferably methyl.

[0095] In some preferred embodiments, one of -R3 and -R4 is -H and the other is an alkyl group. 1-6 Alkyl, more preferably methyl.

[0096] In some preferred embodiments, -R3 and -R4 are both -H.

[0097] In some preferred embodiments, m is 1.

[0098] In some preferred embodiments, the general formula (I) is as shown in the general formula (II),

[0099]

[0100] in:

[0101] -L1-, -R1 and -R2 are as defined above.

[0102] In some preferred embodiments, in the general formula (II), -L1- is as defined above; -R1 is selected from -OH, -B(OH)2, -COOH, -CH2OH, -CN and -CONH2; -R2 is selected from -F, -Cl, -Br, -I, -OH, alkyl and alkoxy. 1-6 Alkyl, more preferably methyl; the alkoxy is preferably C 1-6 Alkoxy group, more preferably methoxy group.

[0103] In some preferred embodiments, in the general formula (II), -L1- is selected from:

[0104] -ethylene-N(ethyl)-pentylene-O-methylene-C(O)-,

[0105] -ethylene-N(ethyl)-propylene-O-methylene-C(O)-,

[0106] -Azetidinyl-propylene-O-methylene-C(O)-,

[0107] -ethylene-N(ethyl)-methylene-C(O)-,

[0108] -ethylene-piperazinylene-ethylene-C(O)- and

[0109] -ethylene-N(ethyl)-ethylene-O-methylene-C(O)-,

[0110] Each methylene, ethylene, propylene, pentylene, azetidinylene and piperazinylene group is independently optionally selected from hydroxy, -B(OH)2, -COOH, -CONH2, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 substituted by one or more substituents selected from alkyl, cyano, amino and nitro groups; each ethyl group is optionally substituted by one or two hydroxyl groups or halogen groups;

[0111] -R1 is selected from hydroxyl, -S(O)2-C 1-6 Alkyl, -B(OH)2, -COOH, -CONH2, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, cyano, amino and nitro; -R2 is selected from hydroxy, -S(O)2-C 1-6 Alkyl, -COOH, -CONH2, halogen, C 1-6Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, cyano, amino and nitro; or,

[0112] -R1 is selected from hydroxyl, -B(OH)2, -COOH, -CONH2, halogen, alkyl, alkoxy, hydroxyalkyl and cyano, wherein the hydroxyalkyl is preferably -CH2OH; -R2 is selected from hydroxyl, halogen, -S(O)2-C 1-6 Alkyl, C 1-6 Alkyl and C 1-6 Alkoxy, preferably halogen or -S(O)2-C 1-6 Alkyl; or

[0113] -R1 is selected from hydroxy, -B(OH)2, -COOH, -CONH2, -CH2OH and cyano; -R2 is selected from hydroxy, amino, methyl and halogen, preferably halogen, more preferably -F; or,

[0114] -R1 is selected from hydroxy, amino, methyl and fluorine; -R2 is selected from hydroxy, amino, methyl and halogen, preferably halogen, more preferably -F; or,

[0115] -R1 is hydroxy; -R2 is halogen, preferably -F.

[0116] In some preferred embodiments, in the general formula (II), -L1- is selected from:

[0117]

[0118] -R1 is selected from hydroxy, amino, methyl and fluoro, -R2 is selected from hydroxy, amino, methyl and halogen; or,

[0119] -R1 is hydroxy, -R2 is halogen, preferably -F.

[0120] In some preferred embodiments, the compound of formula (I) is a compound of formula (II), wherein:

[0121] -L1- is selected from: -ethylene-N(ethyl)-pentylene-O-methylene-C(O)-, -ethylene-N(ethyl)-propylene-O-methylene-C(O)- and -azetidinyl-propylene-O-methylene-C(O)-; each methylene, ethylene, propylene, pentylene and azetidinyl group is independently optionally selected from hydroxy, -B(OH)2, -COOH, -CONH2, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C1-6 Alkoxy, hydroxy C 1-6 substituted by one or more substituents selected from alkyl, cyano, amino and nitro; each ethyl group is optionally substituted by one or two hydroxyl groups or halogen groups. Preferably, -L1- is selected from: -R1 is selected from hydroxyl, amino, methyl and fluorine, preferably hydroxyl, -R2 is selected from hydroxyl, amino, methyl and halogen, preferably halogen, more preferably -F. In the above technical solution, the compound has a better degradation effect on the target protein in MCF-7 cells than the compounds shown in the prior art in Table 1 and fulvestrant, and has an inhibitory activity on the proliferation of MCF-7 cells comparable to that of fulvestrant, and has a stronger inhibitory effect on the mutation-resistant MCF-7ER D538G The cell proliferation inhibitory activity is better than that of fulvestrant.

[0122] In some preferred embodiments, the general formula (I) is as shown in the general formula (III),

[0123]

[0124] in:

[0125] -L1-, -R1, -R2, -R3 and -R4 are as defined above.

[0126] In some preferred embodiments, -R1 is selected from -F, -Cl, -Br, -I, -OH, alkyl and alkoxy, -R2 is -S(O)2-alkyl, -R3 is -H or alkyl, -R4 is -H or alkyl. 1-6 Alkyl, more preferably methyl; -R1, the alkoxy is preferably C 1-6 Alkoxy, more preferably methoxy; -R2, the -S(O)2-alkyl is preferably -S(O)2-C 1-6 Alkyl, more preferably -S(O)2-methyl; in -R3, the alkyl is preferably C 1-6 Alkyl, more preferably methyl; -R4, the alkyl is preferably C 1-6 Alkyl, more preferably methyl.

[0127] In some preferred embodiments, in the general formula (III), -R3 is -H, -R4 is C 1-6 Alkyl, preferably methyl; or, -R3 and -R4 are both -H.

[0128] In some preferred embodiments, the general formula (I) is as shown in the general formula (III-1) or (III-2),

[0129]

[0130] in:

[0131] -L1-Selected from:

[0132] -ethylene-N(ethyl)-ethylene-O-ethylene-O-methylene-C(O)-,

[0133] -azetidinyl-pentylene-O-methylene-C(O)-,

[0134] -ethylene-N(ethyl)-propylene-O-methylene-C(O)-,

[0135] -ethylene-N(ethyl)-pentylene-O-methylene-C(O)-,

[0136] -ethylene-N(ethyl)-ethylene-O-ethylidene-O-phenylene-C(O)-,

[0137] -ethylene-N(ethyl)-ethylene-O-ethylene-O-ethylene-O-phenylene-C(O)-,

[0138] -ethylene-N(ethyl)-butylene-O-phenylene-C(O)-,

[0139] -ethylene-N(ethyl)-ethylene-O-phenylene-C(O)-,

[0140] -ethylene-N(ethyl)-pentylene-O-phenylene-C(O)-,

[0141] -ethylene-N(ethyl)-methylene-C(O)-,

[0142] -ethylene-N(ethyl)-propylene-O-phenylene-C(O)- and

[0143] -ethylene-piperazinylene-ethylene-O-methylene-C(O)-,

[0144] Each methylene, ethylene, propylene, butylene, pentylene, azetidinylene, piperazinylene and phenylene group is independently optionally selected from hydroxy, -B(OH)2, -COOH, -CONH2, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 substituted by one or more substituents selected from alkyl, cyano, amino and nitro groups; each ethyl group is optionally substituted by one or two hydroxyl groups or halogen groups;

[0145] -R1 is selected from hydroxyl, -S(O)2-C 1-6 Alkyl, -B(OH)2, -COOH, -CONH2, halogen, C1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, cyano, amino and nitro; -R2 is selected from hydroxy, -S(O)2-C 1-6 Alkyl, -COOH, -CONH2, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, cyano, amino and nitro; or,

[0146] -R1 is selected from hydroxyl, -B(OH)2, -COOH, -CONH2, halogen, alkyl, alkoxy, hydroxyalkyl and cyano, wherein the hydroxyalkyl is preferably -CH2OH; -R2 is selected from hydroxyl, halogen, -S(O)2-C 1-6 Alkyl, C 1-6 Alkyl and C 1-6 Alkoxy, preferably halogen or -S(O)2-C 1-6 Alkyl; or

[0147] -R1 is selected from hydroxy, halogen, alkyl and alkoxy; -R2 is -S(O)2-alkyl; wherein the alkyl is preferably C 1-6 Alkyl, more preferably methyl; the alkoxy is preferably C 1-6 Alkoxy, more preferably methoxy; the -S(O)2-alkyl is preferably -S(O)2-C 1-6 Alkyl; or

[0148] -R1 is selected from hydroxy, amino, methyl and fluoro; -R2 is -S(O)2-C 1-6 Alkyl, preferably -S(O)2-methyl; or

[0149] -R1 is hydroxyl; -R2 is -S(O)2-methyl.

[0150] In some preferred embodiments, in the general formula (III-1) or (III-2), -L1- is selected from:

[0151] -R1 is selected from hydroxy, amino, methyl and fluoro; -R2 is -S(O)2-C 1-6 Alkyl, preferably -S(O)2-methyl; or, -R1 is hydroxy; -R2 is independently -S(O)2-methyl.

[0152] In some preferred embodiments, the compound of formula (I) is a compound of formula (III-1) or (III-2),

[0153]

[0154] in:

[0155] -L1- is selected from the group consisting of: -ethylene-N(ethyl)-pentylene-O-methylene-C(O)-, -ethylene-N(ethyl)-ethylene-O-ethylene-O-phenylene-C(O)-, -ethylene-N(ethyl)-ethylene-O-ethylene-O-ethylene-O-phenylene-C(O)-, -ethylene-N(ethyl)-butylene-O-phenylene-C(O)-, -ethylene-N(ethyl)-ethylene-O-phenylene-C(O)-, and -ethylene-N(ethyl)-pentylene-O-phenylene-C(O)-,

[0156] Each methylene, ethylene, butylene, pentylene and phenylene group is independently optionally selected from hydroxy, -B(OH)2, -COOH, -CONH2, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 substituted by one or more substituents selected from alkyl, cyano, amino and nitro groups; each ethyl group is optionally substituted by one or two hydroxyl groups or halogen groups;

[0157] In particular, -L1- is selected from:

[0158] -R1 is selected from hydroxy, amino, methyl and fluoro, preferably hydroxy;

[0159] -R2 is -S(O)2-C 1-6 In the above technical solution, the compound has a better degradation effect on the target protein in MCF-7 cells than the compounds shown in Table 1 and fulvestrant in the prior art, and has a better inhibitory activity on the proliferation of MCF-7 cells than the compounds shown in Table 1 in the prior art, and has a better inhibitory effect on the mutation-resistant MCF-7ER D538G The cell proliferation inhibitory activity is better than that of fulvestrant.

[0160] Typical compounds of the present invention include, but are not limited to:

[0161]

[0162]

[0163]

[0164]

[0165]

[0166] The present invention also provides a method for preparing the compound represented by the aforementioned general formula (I), the method comprising:

[0167]

[0168] The compound of general formula (IA) and the compound of general formula (IB) undergo condensation reaction to obtain a compound of general formula (I), wherein

[0169] X, -A-, -L1-, -L2-, -R1, -R2, -R3, -R4 and m are as defined above.

[0170] The present invention also provides a pharmaceutical composition comprising the aforementioned compound represented by general formula (I), its pharmaceutically acceptable salts, tautomers, stereoisomers, enantiomers, diastereomers, isotopic derivatives, crystal forms, solvates, prodrugs, metabolites, racemates or mixtures thereof, and pharmaceutically acceptable excipients.

[0171] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of the aforementioned compound represented by general formula (I), its pharmaceutically acceptable salts, tautomers, stereoisomers, enantiomers, diastereomers, isotopic derivatives, crystal forms, solvates, prodrugs, metabolites, racemates or mixtures thereof, and pharmaceutically acceptable excipients.

[0172] The present invention also provides the use of the aforementioned compound represented by general formula (I), its pharmaceutically acceptable salts, tautomers, stereoisomers, enantiomers, diastereomers, isotopic derivatives, crystalline forms, solvates, prodrugs, metabolites, racemates thereof, or mixtures thereof, or the aforementioned pharmaceutical compositions, in the preparation of a medicament for treating an estrogen-dependent disease. Preferably, the estrogen-dependent disease is selected from breast cancer, uterine cancer, endometriosis, endometrial cancer, cervical cancer, ovarian cancer, fallopian tube tumors, and ovarian tumors; more preferably, the estrogen-dependent disease is selected from breast cancer, uterine cancer, and endometriosis.

[0173] In some preferred embodiments of the present invention, the estrogen-dependent disease is breast cancer; preferably selected from Luminal A breast cancer, Luminal B breast cancer, HER2-positive breast cancer and triple-negative breast cancer; more preferably Luminal A breast cancer (Luminal A breast cancer is a type of breast cancer that is ER-positive and / or PR-positive and HER2-negative); further preferably selected from non-resistant non-mutated Luminal A breast cancer (corresponding to MCF-7 in the example), resistant non-mutated Luminal A breast cancer and resistant mutated Luminal A breast cancer.

[0174] The drug-resistant non-mutated Luminal A breast cancer is preferably tamoxifen-resistant and non-mutated Luminal A breast cancer (corresponding to TamR-MCF-7 in the examples).

[0175] Wherein, the luminal A breast cancer with drug resistance mutation is preferably tamoxifen and / or fulvestrant resistant and ER D538G Luminal A breast cancer with mutations, preferably tamoxifen and fulvestrant-resistant and ER D538G Mutated Luminal A breast cancer (corresponding to MCF-7ER D538G ).

[0176] The present invention also provides the aforementioned compound represented by general formula (I), its pharmaceutically acceptable salt, its tautomer, its stereoisomer, its enantiomer, its diastereomer, its isotopic derivative, its crystal form, its solvate, its prodrug, its metabolite, its racemate or mixture containing the same, or the aforementioned pharmaceutical composition, which is used as a drug.

[0177] The present invention also provides a compound represented by the aforementioned general formula (I), a pharmaceutically acceptable salt thereof, a tautomer thereof, a stereoisomer thereof, an enantiomer thereof, a diastereomer thereof, an isotopic derivative thereof, a crystalline form thereof, a solvate thereof, a prodrug thereof, a metabolite thereof, a racemate thereof, or a mixture thereof, or a pharmaceutical composition thereof, for use in treating an estrogen-dependent disease. Preferably, the estrogen-dependent disease is selected from breast cancer, uterine cancer, endometriosis, endometrial cancer, cervical cancer, ovarian cancer, fallopian tube tumors, and ovarian tumors; more preferably, the estrogen-dependent disease is selected from breast cancer, uterine cancer, and endometriosis.

[0178] In some preferred embodiments of the present invention, the estrogen-dependent disease is breast cancer; preferably selected from Luminal A breast cancer, Luminal B breast cancer, HER2-positive breast cancer and triple-negative breast cancer; more preferably Luminal A breast cancer (Luminal A breast cancer is a type of breast cancer that is ER-positive and / or PR-positive and HER2-negative); further preferably selected from non-resistant non-mutated Luminal A breast cancer (corresponding to MCF-7 in the example), resistant non-mutated Luminal A breast cancer and resistant mutated Luminal A breast cancer.

[0179] The drug-resistant non-mutated Luminal A breast cancer is preferably tamoxifen-resistant and non-mutated Luminal A breast cancer (corresponding to TamR-MCF-7 in the examples).

[0180] Wherein, the luminal A breast cancer with drug resistance mutation is preferably tamoxifen and / or fulvestrant resistant and ER D538G Luminal A breast cancer with mutations, preferably tamoxifen and fulvestrant-resistant and ER D538G Mutated Luminal A breast cancer (corresponding to MCF-7ER D538G ).

[0181] The present invention also provides a method for treating an estrogen-dependent disease, comprising administering to a patient in need thereof the compound of formula (I), its pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, diastereomer, isotopic derivative, crystalline form, solvate, prodrug, metabolite, racemate, or mixture thereof, or the pharmaceutical composition thereof. Preferably, the estrogen-dependent disease is selected from breast cancer, uterine cancer, endometriosis, endometrial cancer, cervical cancer, ovarian cancer, fallopian tube tumor, and ovarian tumor; more preferably, the estrogen-dependent disease is selected from breast cancer, uterine cancer, and endometriosis.

[0182] In some preferred embodiments of the present invention, the estrogen-dependent disease is breast cancer; preferably selected from Luminal A breast cancer, Luminal B breast cancer, HER2-positive breast cancer and triple-negative breast cancer; more preferably Luminal A breast cancer (Luminal A breast cancer is a type of breast cancer that is ER-positive and / or PR-positive and HER2-negative); further preferably selected from non-resistant non-mutated Luminal A breast cancer (corresponding to MCF-7 in the example), resistant non-mutated Luminal A breast cancer and resistant mutated Luminal A breast cancer.

[0183] The drug-resistant non-mutated Luminal A breast cancer is preferably tamoxifen-resistant and non-mutated Luminal A breast cancer (corresponding to TamR-MCF-7 in the examples).

[0184] Wherein, the luminal A breast cancer with drug resistance mutation is preferably tamoxifen and / or fulvestrant resistant and ER D538G Luminal A breast cancer with mutations, preferably tamoxifen and fulvestrant-resistant and ER D538G Mutated Luminal A breast cancer (corresponding to MCF-7ER D538G ).

[0185] Definition of terms

[0186] For terms not defined herein, they have the meanings commonly understood by those skilled in the art to which the present invention belongs. For terms defined herein, they have the meanings set forth in the specification.

[0187] The term "substituted" or "substituent" means that one or more hydrogen atoms are replaced by a specified group. When the position of the substitution is not specified, the substitution can be at any position, but only if a stable or chemically feasible compound is formed.

[0188] The terms "optional" or "optionally" mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0189] When any variable (e.g., R) occurs more than once in a compound's structure, its definition at each occurrence is independent. For example, if a group is substituted with 0-2 R, then the group may be optionally substituted with up to 2 R, and each occurrence of R is independently selectable.

[0190] The term "alkyl" refers to a saturated linear or branched monovalent hydrocarbon group having 1 to 20 carbon atoms, preferably C 1-12 Alkyl, more preferably C 1-6Alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 2,2-dimethylpropyl, 2-methylbutyl, n-hexyl, 2,2-dimethylbutyl, 2-methylpentyl, 3-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-3-ethylhexyl, n-decyl, and 3,3-diethylhexyl.

[0191] The term "alkenyl" refers to a linear or branched monovalent hydrocarbon group having 2 to 6 carbon atoms and at least one carbon-carbon double bond, wherein the carbon-carbon double bond may be located at any position within the alkenyl group, preferably C 2-5 Alkenyl. Examples of alkenyl groups include, but are not limited to, -CH2=CH2, -CH=CH-CH3, -CH2-CH=CH2, -CH=CH-CH2-CH3, -CH2-CH=CH-CH3, -CH=CH-CH=CH2, -CH=C(CH3)-CH3, and -CH2-C(CH3)=CH2.

[0192] The term "alkynyl" refers to a linear or branched monovalent hydrocarbon group having 2 to 6 carbon atoms and at least one carbon-carbon triple bond, wherein the carbon-carbon triple bond can be located at any position within the alkynyl group, preferably C 2-5 Alkynyl. Examples of alkynyl groups include, but are not limited to, -C≡CH, -C≡C-CH3, -CH2-C≡CH, -C≡C-CH2-CH3, -CH2-CH2-C≡CH, -CH2(CH3)C≡CH, and -CH2-C≡C-CH3.

[0193] The term "cycloalkyl" includes two types, one is a conventional cycloalkyl group and the other is a heterostructure cycloalkyl group.

[0194] Conventional cycloalkyl refers to an aliphatic, saturated or partially unsaturated monovalent cyclic hydrocarbon group having 3 to 20 carbon atoms, preferably C 3-12 Conventional cycloalkyl, more preferably C 3-10 Conventional cycloalkyl, more preferably C 3-8 Conventional cycloalkyl, most preferably C 3-6 Conventional cycloalkyl groups. Conventional cycloalkyl groups optionally contain one or more double or triple bonds.

[0195] Conventional cycloalkyl can be a monocyclic alkyl, and examples of monocyclic alkyl include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl and cyclooctyl. Conventional cycloalkyl can also be polycyclic alkyl (such as bicyclic alkyl and tricyclic alkyl), and polycyclic alkyl includes spirocyclic alkyl, fused cyclic alkyl and bridged cyclic alkyl.

[0196] The term "spirocycloalkyl" refers to a 5-20 membered spirocycloalkyl, preferably a 6-14 membered spirocycloalkyl, more preferably a 7-10 membered spirocycloalkyl. The spirocycloalkyl may be a monospirocycloalkyl, a bispirocycloalkyl, or a polyspirocycloalkyl, preferably a monospirocycloalkyl, more preferably a 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospirocycloalkyl. Examples of spirocycloalkyl include, but are not limited to:

[0197]

[0198] The term "fused cycloalkyl" refers to a 5-20 membered fused cycloalkyl, preferably a 6-14 membered fused cycloalkyl, more preferably a 7-10 membered fused cycloalkyl. The fused cycloalkyl may be bicyclic, tricyclic, tetracyclic, or pentacyclic or higher ring fused cycloalkyl, preferably a bicyclic or tricyclic fused cycloalkyl, more preferably a 5-membered / 5-membered or 5-membered / 6-membered fused cycloalkyl. Examples of fused cycloalkyls include, but are not limited to:

[0199]

[0200] The term "bridged cycloalkyl" refers to a 5-20 membered bridged cycloalkyl, preferably a 6-14 membered bridged cycloalkyl, more preferably a 7-10 membered bridged cycloalkyl. The bridged cycloalkyl may be bicyclic, tricyclic, tetracyclic or pentacyclic or higher cyclic bridged cycloalkyl, preferably a bicyclic, tricyclic or tetracyclic bridged cycloalkyl, more preferably a bicyclic or tricyclic bridged cycloalkyl. Examples of bridged cycloalkyl groups include, but are not limited to:

[0201]

[0202] The term "heterocyclic alkyl" includes monocyclic alkyl, spirocyclic alkyl, fused cyclic alkyl and bridged cyclic alkyl fused to any one of conventional aryl, conventional heteroaryl and conventional heterocyclic groups, and the connection point is located on the corresponding conventional cycloalkyl (referring to monocyclic alkyl, spirocyclic alkyl, fused cyclic alkyl or bridged cycloalkyl). Examples of heterocyclic alkyl groups include, but are not limited to:

[0203]

[0204] The term "heterocyclic group" includes two types, one is a conventional heterocyclic group and the other is a heterostructure heterocyclic group.

[0205] Conventional heterocyclic groups refer to aliphatic, saturated or partially unsaturated, monovalent cyclic hydrocarbon groups having 3 to 20 ring atoms, wherein one or more ring atoms are substituted by one or more elements selected from nitrogen, oxygen, S, S(O)2, and the substitution does not form -OO-, -OS- or -SS-; preferably C 3-12 Conventional heterocyclic groups, wherein 1 to 4 are heteroatoms; more preferably C 3-8 Conventional heterocyclic groups, wherein 1 to 3 are heteroatoms; most preferably C 5-7 Conventional heterocyclic groups, wherein 1-2 or 1-3 are heteroatoms.

[0206] Conventional heterocyclic groups may be monocyclic heterocyclic groups, examples of which include, but are not limited to, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and pyranyl, preferably 1,2,5-oxadiazolyl, pyranyl, or morpholinyl. Conventional heterocyclic groups may also be polycyclic heterocyclic groups, including spirocyclic heterocyclic groups, fused-ring heterocyclic groups, and bridged-ring heterocyclic groups.

[0207] The term "spiroheterocyclyl" refers to a 5-20 membered spiroheterocyclyl, preferably a 6-14 membered spiroheterocyclyl, more preferably a 7-10 membered spiroheterocyclyl. The spiroheterocyclyl may be a monospiroheterocyclyl, a bispiroheterocyclyl, or a polyspiroheterocyclyl, preferably a monospiroheterocyclyl or a bispiroheterocyclyl, more preferably a 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospiroheterocyclyl. Examples of spiroheterocyclyls include, but are not limited to:

[0208]

[0209] The term "fused heterocyclic group" refers to a 5-20 membered fused heterocyclic group, preferably a 6-14 membered fused heterocyclic group, more preferably a 7-10 membered fused heterocyclic group. The fused heterocyclic group may be a bicyclic, tricyclic, tetracyclic or pentacyclic or higher ring fused heterocyclic group, preferably a bicyclic or tricyclic fused heterocyclic group, more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group. Examples of fused heterocyclic groups include, but are not limited to:

[0210]

[0211] The term "bridged heterocyclic group" refers to a 5-14 membered bridged heterocyclic group, preferably a 6-14 membered bridged heterocyclic group, and more preferably a 7-10 membered bridged heterocyclic group. The bridged heterocyclic group may be a bicyclic, tricyclic, tetracyclic, or pentacyclic or higher bridged heterocyclic group, preferably a bicyclic, tricyclic, or tetracyclic bridged heterocyclic group, and more preferably a bicyclic or tricyclic bridged heterocyclic group. Examples of bridged heterocyclic groups include, but are not limited to:

[0212]

[0213] The term "heterocyclic group" includes monocyclic heterocyclic groups, spirocyclic heterocyclic groups, fused heterocyclic groups and bridged heterocyclic groups fused to any one of conventional aryl groups, conventional heteroaryl groups and conventional cycloalkyl groups, and the connection point is located on the corresponding conventional heterocyclic group (referring to monocyclic heterocyclic groups, spirocyclic heterocyclic groups, fused heterocyclic groups or bridged heterocyclic groups). Examples of heterocyclic groups include, but are not limited to:

[0214]

[0215] The term "aryl" includes two types, one is a conventional aryl group and the other is a heterostructure aryl group.

[0216] Conventional aryl refers to a 6-14 membered aromatic hydrocarbon group, preferably C 6-10 Conventional aryl groups are more preferably phenyl, naphthyl, phenanthrenyl or anthracenyl.

[0217] The term "heteroaryl" includes a conventional aryl fused to any one of conventional heteroaryl, conventional heterocyclyl and conventional cycloalkyl, with the attachment point being located on the conventional aryl. Examples of heteroaryl groups include, but are not limited to:

[0218]

[0219] The term "heteroaryl" includes two types, one is a conventional heteroaryl and the other is a heterostructural heteroaryl.

[0220] Conventional heteroaryl refers to replacing 1-4 carbon atoms in a 6-14 membered aromatic hydrocarbon group with heteroatoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Preferably, the number of ring atoms is 5-10, wherein 1-3 heteroatoms are contained. More preferably, the number of ring atoms is 5 or 6, wherein 1-2 heteroatoms are contained. Examples of conventional heteroaryl include, but are not limited to, imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole and pyrazinyl, preferably imidazolyl, thiazolyl, pyrazolyl, pyrimidinyl or thiazolyl, more preferably pyrazolyl or thiazolyl.

[0221] The term "heteroaryl" includes a conventional heteroaryl fused to any one of a conventional aryl, a conventional cycloalkyl, and a conventional heterocyclic group, with the point of attachment being located on the conventional heteroaryl. Examples of heteroaryl groups include, but are not limited to:

[0222]

[0223] The term "alkoxy" includes -O-alkyl and -O-cycloalkyl, wherein "alkyl" and "cycloalkyl" are as defined above. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy.

[0224] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0225] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0226] The term "hydroxy" refers to -OH.

[0227] The term "halogen" refers to -F, -Cl, -Br or -I.

[0228] The term "amino" refers to -NH2.

[0229] The term "cyano" refers to -CN.

[0230] The term "nitro" refers to -NO2.

[0231] The term "oxo" refers to =0.

[0232] The term "carboxyl" refers to -C(=O)OH.

[0233] The term "mercapto" refers to -SH.

[0234] The term "ester group" refers to a -C(=O)O-alkyl group or a -C(=O)O-cycloalkyl group, wherein alkyl and cycloalkyl are as defined above.

[0235] The term "acyl" refers to -C(=O)R, where R is selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0236] The term "alkylene" refers to a saturated straight or branched divalent hydrocarbon group of 1 to 20 carbon atoms, preferably C 1-12 Alkylene, more preferably C 1-6 Thus, C1 alkylene (i.e., methylene) refers to C2 alkylene (ie ethylene) refers to C3 alkylene refers to

[0237] The term "cycloalkylene" refers to a divalent conventional cycloalkyl group, and conventional cycloalkyl groups are as defined above.

[0238] The term "heterocyclylene" refers to a divalent conventional heterocyclyl group, and the definition of conventional heterocyclyl groups is as described above.

[0239] The term "arylene" refers to a divalent conventional aryl group, and conventional aryl groups are as defined above.

[0240] The term "heteroarylene" refers to a divalent conventional heteroaryl group, and the definition of conventional heteroaryl groups is as described above.

[0241] symbol Refers to the attachment site.

[0242] When the linking group -L1- listed in the present invention does not specify its connection direction, its connection direction can be connected in the same direction as the reading order from left to right, or it can be connected in the opposite direction to the above direction. Preferably, the connection direction of the linking group listed in the present invention is connected in the same direction as the reading order from left to right; an example is shown below. The connecting group -L1- is -CD-, in which case -CD- connects ring A and ring B in the same direction as the reading order from left to right to form Rather than constituting

[0243] The term "pharmaceutically acceptable" means that it is used to prepare a pharmaceutical composition that is generally safe, non-toxic, biologically satisfactory and acceptable for veterinary or human pharmaceutical use.

[0244] The term "pharmaceutically acceptable salt" should be understood to refer to the following salts, which are pharmaceutically acceptable salts and which possess the intended pharmacological activity of the parent compound (referring to the compound represented by the general formula). Such salts include:

[0245] (1) an acid addition salt formed with an inorganic acid or an acid addition salt formed with an organic acid; wherein the inorganic acid may be one or more of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid; and the organic acid may be one or more of formic acid, oxalic acid, succinic acid, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, dibenzoyl-L-tartaric acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid and trifluoroacetic acid; and

[0246] (2) The acid protons present in the parent compound are replaced by metal ions, such as alkali metal ions (e.g., Na + , K + or Li + ), alkaline earth metal ions (such as Ca 2+ or Mg 2+) or aluminum ion; or, a salt formed when coordinated with an organic base or an inorganic base; wherein the organic base may be one or more of pyridine, imidazole, pyrazine, indole, purine, tertiary amine and aniline organic bases, preferably one or more of pyridine, picoline, 4-dimethylaminopyridine, 2-methyl-5-ethylpyridine, triethylamine, N,N-diisopropylethylamine, N,N-dimethylaniline, diethanolamine, ethanolamine, N-methylglucamine, triethanolamine and tromethamine; the inorganic base may be one or more of aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.

[0247] The term "isotopic derivative" refers to a compound that differs from the parent compound described herein only in the presence of one or more isotopically enriched atoms. For example, a compound having the structure shown in the general formula with the substitution of "deuterium" or "tritium" for hydrogen and / or "isotopic derivative" for hydrogen. 18 F replaces fluorine, and / or, with 11 C. 13 C or 14 C replaces carbon, while the rest of the moiety remains unchanged. The above-mentioned isotopic derivatives can be used as analytical tools or probes in biological assays, or as in vivo diagnostic imaging tracers for diseases, or as tracers for pharmacodynamics, pharmacokinetics, or receptor studies. Deuterated compounds generally retain activity comparable to undeuterated compounds, and when deuterated at certain specific sites, they can achieve better metabolic stability, thereby obtaining certain therapeutic advantages (such as increased in vivo half-life or reduced dosage requirements). Therefore, the isotopic derivatives are preferably deuterated compounds.

[0248] The term "solvate" refers to a compound described herein formed with a suitable solvent, preferably water or an organic solvent.

[0249] The term "prodrug" refers to a derivative of a parent compound described herein that contains a bioreactive functional group, such that under biological conditions (in vitro or in vivo), the bioreactive functional group can be cleaved from the derivative or otherwise reacted to provide the parent compound described herein. Typically, the prodrug is inactive, or at least less active than the parent compound itself, such that the parent compound described herein cannot exert its activity until it is separated from the bioreactive functional group. The bioreactive functional group can be hydrolyzed or oxidized under biological conditions to provide the parent compound described herein. For example, the prodrug can contain a biohydrolyzable group; examples of biohydrolyzable groups include, but are not limited to, biohydrolyzable phosphates, biohydrolyzable esters, biohydrolyzable amides, biohydrolyzable carbonates, biohydrolyzable carbamates, and biohydrolyzable ureides.

[0250] The term "pharmaceutical composition" refers to a mixture containing a pharmaceutical compound (referring to one or more of the compounds represented by the general formula described herein, their pharmaceutically acceptable salts, tautomers, stereoisomers, enantiomers, diastereomers, isotopic derivatives, crystal forms, solvates, prodrugs, metabolites and racemates thereof) and pharmaceutically acceptable excipients.

[0251] The term "pharmaceutically acceptable excipient" refers to a pharmaceutically acceptable excipient used to deliver the pharmaceutical compound herein to a subject. Depending on the administration method, the pharmaceutical composition may contain 0.1 wt% to 99 wt% of the pharmaceutical compound.

[0252] The pharmaceutical composition of the present invention can be in various conventional dosage forms, such as tablets, aqueous suspensions, oil suspensions, dispersible powders, dispersible granules, emulsions, hard capsules, soft capsules, sterile injectable aqueous solutions, sterile injectable oil-in-water microemulsions, or suppositories. Each of the above dosage forms can be prepared by conventional preparation methods.

[0253] The excipients in the tablets of the present invention may be one or more of a filler, a binder, a lubricant, a glidant, and a disintegrant. The filler may be one or more of microcrystalline cellulose, starch, lactose monohydrate, and calcium hydrogen phosphate. The binder may be one or more of starch, gelatin, polyvinyl pyrrolidone, and gum arabic. The lubricant may be one or more of magnesium stearate, stearic acid, and sodium lauryl sulfate. The glidant may be one or both of micropowdered silica gel and talc. The disintegrant may be one or more of cross-linked polyvinylpyrrolidone, sodium starch glycolate, low-substituted hydroxypropyl cellulose, and cross-linked sodium carboxymethyl cellulose. The tablets may further include a coating. The tablets may also be prepared as sustained-release preparations, in which the sustained-release material may be one or both of hydroxypropyl methylcellulose and xanthan gum.

[0254] The excipients in the aqueous suspension of the present invention may be one or more of a suspending agent, a dispersing agent, a preservative, and a flavoring agent. The suspending agent may be one or more of sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinyl pyrrolidone, and gum arabic. The dispersing agent may be one or more of naturally occurring phospholipids (e.g., lecithin), condensation products of alkylene oxides and fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide and long-chain fatty alcohols (e.g., heptadecanethoxycetanol), condensation products of ethylene oxide and partial esters derived from fatty acids and hexitol (e.g., polyethylene oxide sorbitol monooleate), and condensation products of ethylene oxide and partial esters derived from fatty acids and hexitol anhydrides (e.g., polyethylene oxide dehydrated sorbitan monooleate). The preservative may be ethylparaben and / or n-propylparaben. The flavoring agent may be one or more of sucrose, saccharin, and aspartame.

[0255] The excipients in the oil suspension of the present invention may be one or more of a suspending agent, a thickening agent, a flavoring agent, and an antioxidant. The suspending agent may be a vegetable oil and / or a mineral oil. The vegetable oil may be one or more of peanut oil, olive oil, sesame oil, and coconut oil. The mineral oil may be liquid paraffin. The thickening agent may be one or more of beeswax, hard paraffin, and cetyl alcohol. The flavoring agent may be one or more of sucrose, saccharin, and aspartame. The antioxidant may be one or more of butylated hydroxyanisole, α-tocopherol, and ascorbic acid.

[0256] The excipients in the dispersible powder and dispersible granules of the present invention can be one or more of a suspending agent, a dispersant, a preservative, a flavoring agent, and an antioxidant. The specific selection of the above components is the same as the excipients in the aqueous suspension.

[0257] The excipients in the emulsion of the present invention may be one or more of a suspending agent, an emulsifier, a flavoring agent, a preservative, and an antioxidant. The suspending agent may be a vegetable oil and / or a mineral oil, the vegetable oil may be olive oil and / or peanut oil, and the mineral oil may be liquid paraffin. The emulsifier may be one or more of naturally occurring phospholipids (e.g., soybean lecithin), esters or partial esters derived from fatty acids and hexitol anhydrides (e.g., sorbitan monooleate), and condensation products of the partial esters and ethylene oxide (e.g., polyethylene oxide sorbitol monooleate). The flavoring agent may be one or more of glycerol, propylene glycol, sorbitol, and sucrose. The preservative may be ethylparaben and / or n-propylparaben. The antioxidant may be one or more of butylated hydroxyanisole, α-tocopherol, and ascorbic acid.

[0258] The auxiliary material in the hard capsule of the present invention can be a conventional inert solid diluent, for example, one or more of calcium carbonate, calcium phosphate and kaolin.

[0259] The auxiliary materials in the soft capsule of the present invention can be conventional water-soluble carriers and / or conventional oil solvents, for example, can be one or more of polyethylene glycol, peanut oil, liquid paraffin and olive oil.

[0260] The excipient in the sterile aqueous injection solution of the present invention can be a pharmaceutically acceptable solvent, such as water, Ringer's solution or isotonic sodium chloride solution.

[0261] The excipients in the sterile injectable oil-in-water microemulsion of the present invention can be oil phase excipients and water phase excipients. The oil phase excipient can be a mixture of soybean oil and lecithin, and the water phase excipient can be a mixture of water and glycerol.

[0262] The excipients in the suppository of the present invention may be one or more of cocoa butter, glycerin, gelatin, hydrogenated vegetable oil, polyethylene glycol and fatty acid esters of polyethylene glycol.

[0263] Herein, "breast cancer" includes various molecular types of breast cancer disclosed in the prior art, preferably selected from Luminal A breast cancer, Luminal B breast cancer, HER2-positive breast cancer and triple-negative breast cancer; more preferably Luminal A breast cancer (Luminal A breast cancer is a type of ER-positive and / or PR-positive, and HER2-negative breast cancer); further preferably selected from non-resistant and non-mutated Luminal A breast cancer (corresponding to MCF-7 in the embodiment), resistant and non-mutated Luminal A breast cancer and resistant and mutated Luminal A breast cancer.

[0264] The drug-resistant non-mutated Luminal A breast cancer is preferably tamoxifen-resistant and non-mutated Luminal A breast cancer (corresponding to TamR-MCF-7 in the examples).

[0265] Wherein, the luminal A breast cancer with drug resistance mutation is preferably tamoxifen and / or fulvestrant resistant and ER D538G Luminal A breast cancer with mutations, preferably tamoxifen and fulvestrant-resistant and ER D538G Mutated Luminal A breast cancer (corresponding to MCF-7ER D538G ).

[0266] The term "subject" refers to an animal, preferably a mammal. According to specific embodiments, the subject is a mammal, including, for example, camels, donkeys, zebras, cattle, pigs, horses, goats, sheep, cats, dogs, rats, rabbits, guinea pigs, mice, primates (e.g., humans). In some specific embodiments, the subject is a human. In some specific embodiments, the subject is a human who is susceptible to, suspected of having, or already has an estrogen-dependent disease.

[0267] The term "treat" refers to eliminating the disease, arresting the progression of the disease, slowing the progression of the disease, reducing the duration of one or more symptoms associated with the disease, improving or reversing at least one measurable parameter associated with the disease, or increasing the survival of a subject suffering from the disease.

[0268] The term "effective amount" refers to the amount of a pharmaceutically active ingredient (referring to a pharmaceutical compound) that elicits the desired effect in a subject. In specific embodiments, those skilled in the art can determine the selection of an effective amount based on consideration of a variety of factors (e.g., through clinical trials), including the disease to be treated, the symptoms involved, the route of administration, the severity of the disease, the patient's weight, the patient's immune status, and other factors known to those skilled in the art. The effective amount can be derived from dose-response curves derived from animal model test systems and can be determined based on the physician's judgment and the circumstances of each patient. The relationship between animal and human dosages is described in Freireich et al. 1966, Cancer Chemother Rep 50: 219, and the human body surface area can be approximately determined by the patient's height and weight. The effective amount of the pharmaceutical compound of the present invention can be 0.5 mg / kg to 500 mg / kg, preferably 1 mg / kg to 200 mg / kg, and more preferably 10 mg / kg to 100 mg / kg.

[0269] Herein, the same active pharmaceutical ingredient (referring to a single pharmaceutical compound) or different active pharmaceutical ingredients (referring to two or more pharmaceutical compounds) can be administered at once, or can be divided into many smaller doses and administered at certain time intervals. It should be understood that the exact dosage, duration, and interval of treatment are a function of the disease being treated and can be determined by inference using animal or clinical trial data. The administration may include a single administration, or two or more administrations separated by appropriate time intervals. The interval between two adjacent administrations may be 30 minutes, 40 minutes, 50 minutes, 60 minutes, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours, one and a half days, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months.

[0270] Each active pharmaceutical ingredient (each pharmaceutical compound) mentioned herein can be used as the sole active compound, or can be administered in combination with other active compounds (referring to compounds other than the pharmaceutical compounds described herein), as long as they do not produce other adverse effects, such as allergic reactions, etc. Combined administration includes the simultaneous or sequential use of the active compounds.

[0271] The term "combined administration" refers to a method in which two or more active compounds are administered to a subject simultaneously or sequentially for therapeutic purposes. When "combined administration" is used, the time interval between each administration is sufficient to achieve a synergistic effect between the active compounds administered.

[0272] Synthesis method of the compound of the present invention

[0273] In order to achieve the purpose of the present invention, the present invention adopts the following synthesis scheme to prepare the compound of general formula (I) of the present invention.

[0274]

[0275] Under alkaline conditions, in the presence of a condensing agent, the compound of general formula (IA) and the compound of general formula (IB) undergo condensation reaction to obtain a compound of general formula (I), wherein

[0276] X, -A-, -L1-, -L2-, -R1, -R2, -R3, -R4 and m are as defined in the general formula (I).

[0277] Reagents that provide basic conditions include, but are not limited to, triethylamine, N,N-diisopropylethylamine, 1,8-diazabicycloundec-7-ene, and pyridine.

[0278] Condensing agents include, but are not limited to, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole oxazole, O-benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate, 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate and benzotriazol-1-yl-oxytripyrrolidinylphosphonium hexafluorophosphate, preferably 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate.

[0279] The positive progress of the present invention is that compared with the prior art fulvestrant, the targeted chimeric compound of the present invention has comparable or even better inhibitory activity on the proliferation of mutant drug-resistant cells (specifically, on the proliferation of mutant drug-resistant cells MCF-7ER D538G The maximum inhibition percentage IH%max) is expected to show comparable or even better therapeutic efficacy. DETAILED DESCRIPTION

[0280] By reading the following examples, those skilled in the art will better understand the present invention. These examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention.

[0281] The compounds of the present invention are prepared using convenient starting materials and general preparation procedures. Typical or preferred reaction conditions, such as reaction temperature, time, solvent, pressure, and molar ratio of reactants, are provided herein. However, other reaction conditions may be employed unless otherwise specified. Optimized conditions may vary depending on the specific reactants or solvents used, but generally, optimized reaction procedures and conditions are determined.

[0282] In addition, some protecting groups may be used in the present invention to protect certain functional groups from unwanted reactions. Protecting groups suitable for various functional groups and their protection or deprotection conditions are widely known to those skilled in the art. For example, TW Greene and GM Wuts's "Protective Groups in Organic Preparations" (3rd edition, Wiley, New York, 1999 and references therein) describes in detail the protection or deprotection of a large number of protecting groups.

[0283] The separation and purification of compounds and intermediates can be performed using appropriate methods and steps depending on specific needs, such as filtration, extraction, distillation, crystallization, column chromatography, preparative thin layer plate chromatography, preparative high performance liquid chromatography, or a combination of the above methods. Specific methods of use can be found in the examples described herein. Of course, other similar separation and purification methods can also be used. Conventional methods (including physical constants and spectral data) can be used to characterize the compounds and intermediates.

[0284] Purity analysis was performed using Kinetex EVO C18 (50 × 4.6 mm, 5 μm, ) column, acetonitrile-water was used as the mobile phase for gradient elution, the flow rate was 1.5 mL / min, and the detection wavelength was 220 nm.

[0285] MS was measured using an LC (Agilent 1260 Infinity II) / MS (G6125B single quadrupole) mass spectrometer (manufacturer: Agilent) (Photodiode Array Detector).

[0286] The structure of the compound was confirmed by hydrogen spectrum using WNMR-I-400MHz.

[0287] Preparative liquid chromatography was performed using an Agilent 1260 Infinity II high performance liquid chromatograph (manufacturer: Agilent), with a Daisogel C18 10 μm 100A column (30 mm × 250 mm) and acetonitrile / water as the mobile phase.

[0288] Thin layer chromatography (TLC) used Qingdao Ocean Chemical GF254 silica gel plates. The silica gel plates used for reaction monitoring were of a size of 0.20 mm to 0.25 mm, and the silica gel plates used for separation and purification were of a size of 0.5 mm.

[0289] Silica gel column chromatography method uses Qingdao marine silica gel 100-200 mesh, 200-300 mesh and 300-400 mesh silica gel as the carrier.

[0290] The known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from online shopping malls, Beijing Coupling, Sigma, Bailingwei, Yishiming, Shanghai Shuya, Shanghai Yinuokai, Anaiji Chemical, Shanghai Bid, etc.

[0291] Unless otherwise specified in the examples, all reactions were carried out under a nitrogen atmosphere.

[0292] Nitrogen atmosphere means that the reaction bottle is connected to a nitrogen balloon with a capacity of about 1L.

[0293] The reaction solvent, organic solvent or inert solvent is each expressed as the solvent used that does not participate in the reaction under the described reaction conditions, including, for example, benzene, toluene, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform, dichloromethane, diethyl ether, methanol, N-methylpyrrolidone (NMP).

[0294] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0295] Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention.

[0296] Unless otherwise specified, the mixing ratios of different solvents are by volume.

[0297] Hereinafter, the mass fraction of palladium in wet palladium / carbon is 10%.

[0298] In the following text, the meanings of commonly used abbreviations are:

[0299] DPEPhos: bis(2-diphenylphosphine)phenyl ether

[0300] PE: Petroleum ether

[0301] EA: ethyl acetate

[0302] DDQ: 2,3-dichloro-5,6-dicyanobenzoquinone

[0303] DCM: dichloromethane

[0304] DMSO: dimethyl sulfoxide

[0305] DMF: N,N-dimethylformamide

[0306] THF:Tetrahydrofuran

[0307] TsCl: 4-Toluenesulfonyl chloride

[0308] DMAP: 4-dimethylaminopyridine

[0309] TEA: triethylamine

[0310] DIPEA: N,N-diisopropylethylamine

[0311] HATU: 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0312] FA: Formic acid 1

[0314] Example 1 Synthesis of (2S,4R)-12-ethyl-1-((S)-2-(tert-butyl)-14-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)-4-oxo-6,9-dioxa-3,12-diazatetradecanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound D1)

[0315] 1.1 Preparation of 5-(4-(2-(ethylamino)ethoxy)phenoxy)-6-(4-(methylsulfonyl)phenyl)naphthalen-2-ol (Compound A1)

[0316] The overall synthetic route is as follows:

[0317]

[0318] 6-Methoxy-3,4-dihydronaphthalene-1(2H)-one (Compound A1-1) (17.6 g, 100 mmol, 1 eq) and p-bromomethylsulfonylbenzene (Compound A1-2) (23.5 g, 100 mmol, 1 eq) were placed in a 500 mL round-bottom flask, 200 mL of toluene, sodium tert-butoxide (24 g, 250 mmol, 2.5 eq), DPEpHos (1.34 mg, 2.5 mmol, The reaction mixture was stirred for 2 hours at 85 ° C., and the mixture was concentrated. 200 mL of water and 100 mL × 2 of dichloromethane were added for extraction. The organic phase was dried and concentrated to obtain 32 g of 6-methoxy-2-(4-(methylsulfonyl)phenyl)-3,4-dihydronaphthalen-1(2H)-one (compound A1-3) with a purity of 90% and a yield of 96.9% as a light yellow solid.

[0319] 6-methoxy-2-(4-(methylsulfonyl)phenyl)-3,4-dihydronaphthalene-1(2H)-one (Compound A1-3) (32 g, 96.9 mmol, 1 eq) was placed in a 100 mL round-bottom flask, and phosphorus tribromide (78.7 g, 290.8 mmol, 3 eq) and 200 mL of anhydrous toluene were added. The mixture was refluxed for 20 h. After cooling, it was poured into 500 mL of ice water to quench the reaction solution and stirred for 1 h. The mixture was extracted with 150 mL × 2 dichloromethane, the organic phases were combined, and washed with 100 mL of saturated sodium bicarbonate aqueous solution. The liquids were separated and the organic phase was concentrated to obtain 32 g of crude product. PE:EA=50 mL:50 mL was used for slurrying and filtration to obtain 22 g of 7-methoxy-4-bromo-3-(4-(methylsulfonyl)phenyl)-1,2-dihydronaphthalene (Compound A1-4) with a purity of 80% and a yield of 57.9%, as a light yellow solid.

[0320] 7-Methoxy-4-bromo-3-(4-(methylsulfonyl)phenyl)-1,2-dihydronaphthalene (Compound A1-4) (22 g, 55.9 mmol, 1 eq) and DDQ (30 g, 132.1 mmol, 2.4 eq) were placed in a 500 mL round-bottom flask, 200 mL of anhydrous toluene was added, and the reaction was carried out at 70 ° C for 10 h. The reaction solution was concentrated, and the crude product was dissolved with 150 mL of DCM. The insoluble matter was filtered off, and the organic phase was washed three times with saturated potassium carbonate aqueous solution (100 mL x 3). The organic phases were combined and concentrated. The crude product was recrystallized from dichloromethane and petroleum ether to obtain 14 g of 1-bromo-6-methoxy-2-(4-(methylsulfonyl)phenyl)naphthalene (Compound A1-5) with a purity of 98% and a yield of 63.6% as a solid.

[0321] 1-Bromo-6-methoxy-2-(4-(methylsulfonyl)phenyl)naphthalene (Compound A1-5) (14 g, 35.78 mmol, 1 eq) and 4-((tetrahydro-2H-pyran-2-yl)oxy)phenol (Compound A1-6) (13.9 g, 71.56 mmol, 2 eq) and cesium carbonate (35.3 g, 107.34 mmol, 3 eq) were placed in a 250 mL round-bottom flask, and CuCl (1.79 g, 17.89 mmol, 0.5 eq) and anhydrous DMSO were added. 150mL, nitrogen replacement, reaction at 160℃ for 8h, added 500mL of water for dilution, extracted with dichloromethane (150mL×2), the organic phases were combined and dried and concentrated to obtain 2-(4-((6-methoxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)tetrahydro-2H-pyran (Compound A1-7) 21g as a gray solid.

[0322] 2-(4-((6-methoxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)tetrahydro-2H-pyran (Compound A1-7) (21 g, 41.7 mmol, 1 eq) was placed in 100 mL of methanol, p-toluenesulfonic acid (7.1 g, 41.7 mmol, 1 eq) was added, and the reaction was stirred at room temperature for 10 hours. The reaction solution was concentrated, and the crude product was dissolved with 150 mL of dichloromethane and then washed with 100 mL×2 saturated sodium bicarbonate. The organic phases were combined, dried and concentrated to obtain 14 g of 4-((6-methoxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenol (Compound A1-8) with a purity of 90% and a yield of 93% as a light yellow solid. 1 H-NMR (400MHz, DMSO-d6): δ9.07(s,1H),7.84-.99(m,5H),7.80(d,J=5.2Hz,1H),7.67(d,J=8.4Hz,1H ), 7.50 (d, J = 6.4Hz, 1H), 7.20 (dd, J = 9.2Hz, 2.4Hz, 1H), 6.50-6.58 (m, 4H), 3.93 (s, 3H), 3.25 (s, 3H).

[0323] 4-((6-methoxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenol (Compound A1-8) (1.0 g, 2.38 mmol, 1.0 eq), 1,2-dibromoethane (4.46 g, 23.74 mmol, 10.0 eq) and cesium carbonate (2.32 g, 7.13 mmol, 3.0 eq) were placed in 10 mL of acetonitrile and stirred at 70 ° C for 16 hours. After the reaction was completed, the reaction solution was filtered and concentrated to dryness to obtain an oily liquid, which was purified by silica gel column (DCM:EA=10:1) to obtain 1-(4-(2-bromoethoxy)phenoxy)-6-methoxy-2-(4-(methylsulfonyl)phenyl)naphthalene (Compound A1-9) 1 g with a purity of 90% and a yield of 80% as a white solid.

[0324] 1-(4-(2-bromoethoxy)phenoxy)-6-methoxy-2-(4-(methylsulfonyl)phenyl)naphthalene (Compound A1-9) (0.8 g, 1.52 mmol, 1.0 eq) and ethylamine solution (8 mL, 1 mol / L, solvent THF, 10.0 eq) were placed in 2 mL of DMF, heated to 80°C and stirred for 3 h. The mixture was concentrated in vacuo, and the crude product was purified by flash column chromatography (MeOH:DCM=10:1) to obtain 0.4 g of N-ethyl-2-(4-((6-methoxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)-1-ethylamine (Compound A1-10) with a purity of 96% and a yield of 53.6% as a white solid.

[0325] N-ethyl-2-(4-((6-methoxy-2-(4-(methylsulfonyl)phenyl)naphthalene-1-oxy)phenoxy)ethanamine (Compound A1-10) (0.4 g, 0.81 mmol, 1.0 eq) was dissolved in anhydrous DCM (12 mL) and added dropwise to a mixed solution of 4 mL of boron tribromide (1 mol / L, solvent DCM) and 4 mL of anhydrous DCM under an ice bath. After the addition was complete, the mixture was warmed to room temperature and stirred for 30 min. The reaction was quenched with methanol and concentrated. The crude product was freed and purified by flash column chromatography (MeOH:DCM=1:10) to obtain 0.3 g of 5-(4-(2-(ethylamine)ethoxy)phenoxy)-6-(4-(methylsulfonyl)phenyl)naphthalene-2-ol (Compound A1) with a purity of 92% and a yield of 77.2%, as a yellow oily liquid.

[0326] 1.2 Preparation of tert-butyl 2-(2-(2-(p-toluenesulfonyloxy)ethoxy)ethoxy)acetate (Compound B1)

[0327] The overall synthetic route is as follows:

[0328]

[0329] 2-(2-(Benzyloxy)ethoxy)ethane-1-hydroxy (Compound B1-1) (5 g, 25.5 mmol, 1 eq) was dissolved in 50 mL of anhydrous THF, cooled to 0 ° C, added NaH (1.224 g, 30.6 mmol, 1.2 eq), protected by nitrogen, stirred for 1 h, and slowly added tert-butyl bromoacetate (Compound B1-2) (5.96 g, 30.6 mmol, 1.2 eq). The reaction was reacted at room temperature for 10 h, and the reaction was quenched with 100 mL of 0.5 mol / L aqueous hydrochloric acid solution. 50 mL of ethyl acetate was added for extraction, the liquids were separated, and the organic phase was dried and concentrated under reduced pressure to obtain 6.8 g of tert-butyl 2-(2-(Benzyloxy)ethoxy)ethoxy)acetate (Compound B1-3) with a purity of 80% and a yield of 85.8%, as a light yellow oil.

[0330] tert-Butyl 2-(2-(2-(benzyloxy)ethoxy)ethoxy)acetate (Compound B1-3) (6.8 g, 21.9 mmol) was placed in 60 mL of THF, wet palladium / carbon (1.36 g, 10 wt%) was added, a hydrogen balloon was inserted, the air was ventilated, and the reaction was carried out at room temperature for 10 h. The mixture was filtered and the filtrate was concentrated to obtain 4.2 g of tert-butyl 2-(2-(2-hydroxyethyl)ethoxy)acetate (Compound B1-4), with a yield of 86.7%, as a yellow oily product.

[0331] Tert-butyl 2-(2-(2-hydroxyethyl)ethoxy)acetate (Compound B1-4) (4.2 g, 19.09 mmol, 1 eq) was dissolved in 50 mL of anhydrous DCM, TsCl (3.64 g, 19.1 mmol, 1 eq) was added, and triethylamine (2.89 g, 28.57 mmol, 1.5 eq) and 5 mg of DMAP were added at room temperature with stirring. The mixture was protected by nitrogen and reacted at room temperature for 5 h. The reaction solution was concentrated, and the crude product was purified by silica gel column (PE: EA = 3: 1-2: 1) to give 2.4 g of tert-butyl 2-(2-(2-(p-toluenesulfonyloxy)ethoxy)ethoxy)acetate (Compound B1) with a purity of 90% and a yield of 34.4% as a light yellow oil.

[0332] 1.3 Preparation of Compound C

[0333] The overall synthetic route is as follows:

[0334]

[0335] Di-tert-butyl dicarbonate (Compound C-2) (24.00 g, 0.11 mol) and triethylamine (11.13 g, 0.11 mol) were added to a solution of (S)-1-(4-bromophenyl)ethylamine (Compound C-1) (20.00 g, 0.1 mol) in dichloromethane (100 mL) and stirred at room temperature for 12 hours. After the reaction was complete, 100 mL of water was added to the reaction system, and the organic phase was washed with saturated brine after separation to obtain an organic phase. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a white solid product, tert-butyl (S)-1-((4-bromophenyl)ethyl)carbamate (Compound C-3) (30.00 g, yield 99.97%).

[0336] 4-Methylthiazole (Compound C-4) (19.82 g, 0.2 mol), palladium acetate (4.49 g, 0.2 mol), and potassium acetate (19.61 g, 0.2 mol) were sequentially added to a solution of (S)-tert-butyl 1-((4-bromophenyl)ethyl)carbamate (Compound C-3) (30.00 g, 0.1 mol) in N,N-dimethylformamide (150 mL) and stirred until uniform. After nitrogen replacement, the reaction mixture was stirred at 100°C for 4 hours. After the reaction was complete, the reaction mixture was filtered and extracted with ethyl acetate (200 mL × 2). The filtrate was concentrated to 50 mL and water (375 mL) was added to gradually precipitate a gray solid product. After stirring for 4 hours, the mixture was filtered and dried to obtain a gray solid product (S)-tert-butyl (1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamate (Compound C-5) (21.65 g, yield 68%).

[0337] A solution of tert-butyl (S)-(1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamate (Compound C-5) (21.65 g, 68 mmol) in ethyl acetate (65 mL) was slowly added dropwise to a solution of hydrogen chloride in ethyl acetate (2 M, 85 mL, 160 mmol) and reacted at room temperature for 12 hours. The reaction solution was filtered, and the filter cake was rinsed 2-3 times with ethyl acetate. The filter cake was dried to obtain an orange solid product, (S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl-1-amine hydrochloride (Compound C-6) (17.32 g, 100% yield).

[0338] (S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl-1-amine hydrochloride (Compound C-6) (17.32 g, 68 mmol), (2S,4R)-1-(tert-butoxycarbonyl)-2-carboxy-4-hydroxypyrrolidine (Compound C-7) (17.29 g, 0.75 mmol), and diisopropylethylamine (19.33 g, 150 mmol) were added sequentially to N,N-dimethylformamide (87 mL) and stirred to dissolve. HATU (31.02 g, 1.2 eq) was added to the system at room temperature, and the reaction was stirred for 3 hours. A saturated aqueous solution of lithium chloride and sodium chloride was added to the reaction solution, which was diluted with ethyl acetate. The organic phase was washed with a saturated aqueous solution of lithium chloride and sodium chloride (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude oil. Purification by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1 to 0:1) gave an off-white solid product (2S,4R)-tert-butyl 4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-carboxylate (Compound C-8) (16.60 g, yield 56.6%).

[0339] A solution of tert-butyl (2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-carboxylate (Compound C-8) (16.60 g, 39 mmol) in methanol (30 mL) was stirred and dissolved. A solution of hydrogen chloride in ethyl acetate (2M, 77 mL, 154 mmol) was added dropwise at room temperature and the mixture was stirred and reacted overnight. The reaction solution was concentrated to obtain a yellow solid product, (2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine hydrochloride (Compound C-9) (14.15 g, 100% yield).

[0340] (2S,4R)-4-Hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine hydrochloride (Compound C-9) (14.15 g, 39 mmol), (S)-2-((tert-Butoxycarbonyl)amino)-3,3-dimethylbutanoic acid (Compound C-10) (9.79 g, 43 mmol), and diisopropylethylamine (30.83 g, 240 mmol) were added sequentially to N,N-dimethylformamide (70 mL) and stirred evenly. HATU (17.55 g, 47 mmol) was added to the system at room temperature, and the reaction was stirred for 3 hours. 200 mL of water was added to the reaction solution to quench the reaction, resulting in the precipitation of a white solid product. The product was filtered and the filtrate was extracted with ethyl acetate. The organic phase was then washed 2-3 times with a saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude oil. The product was purified by column chromatography (petroleum ether:ethyl acetate = 1:1 to 0:1) and combined with the white solid product to obtain the product ((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamic acid tert-butyl ester (Compound C-11) (17.94 g, yield 85.6%).

[0341] A solution of tert-butyl ((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate (Compound C-11) (17.94 g, 33 mmol) in methanol (36 mL) was slowly added dropwise with a solution of hydrogen chloride in ethyl acetate (2 M, 66 mL, 132 mmol), and the reaction was stirred overnight. The reaction solution was concentrated, methyl tert-butyl ether (180 mL) was added, the mixture was beaten overnight, filtered, and the filter cake was dried to give a bright yellow solid product ((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amine hydrochloride (Compound C) (15.84 g, yield 99.98%).

[0342] 1. Preparation of 4(2S,4R)-12-ethyl-1-((S)-2-(tert-butyl)-14-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)-4-oxo-6,9-dioxa-3,12-diazatetradecanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound D1)

[0343] The overall synthetic route is as follows:

[0344]

[0345] The specific steps are as follows:

[0346] Tert-butyl 2-(2-(2-(p-toluenesulfonyloxy)ethoxy)ethoxy)acetate (Compound B1) (235 mg, 0.628 mmol, 2 eq) and 5-(4-(2-(ethylamino)ethoxy)phenoxy)-6-(4-(methylsulfonyl)phenyl)-2-naphthol (Compound A1) (150 mg, 0.314 mmol, 1 eq) were placed in 5 mL of DMF, and DIPEA (80 mg, 0.628 mmol, 2 eq) was added. The reaction mixture was stirred for 14 h at 70 ° C. The reaction mixture was concentrated and the crude product was purified by silica gel column chromatography (DCM: MeOH = 20: 1) to give 190 mg of tert-butyl 2-(2-(2-(ethyl(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)amino)ethoxy)ethoxy)acetate (compound D1-1) with a purity of 90% and a yield of 79% as a yellow solid.

[0347] This tert-butyl 2-(2-(2-(ethyl(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)amino)ethoxy)ethoxy)acetate (Compound D1-1) (190 mg, 0.279 mmol, 1 eq) was placed in 5 mL of a 2 mol / L HCl solution in dioxane, reacted at room temperature for 1 hour, and concentrated to dryness to obtain 200 mg of 2-(2-(2-(ethyl(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)amino)ethoxy)ethoxy)acetic acid hydrochloride (Compound D1-2) with a purity of 90% and a yield of 98% as a white solid.

[0348] 2-(2-(2-(ethyl(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)amino)ethoxy)ethoxy)acetic acid hydrochloride (Compound D1-2) (120 mg, 0.172 mmol, 1 eq) and (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (Compound C) (83 mg, 0.172 mmol, 1 eq) were placed in 5 mL of DMF, DIPEA (74 mg, 0.52 mmol, 3 eq) was added, and the mixture was stirred for 10 min. HATU (98 mg, 0.258 mmol, 1.5 eq) was added, and the mixture was reacted at room temperature for 30 min. The reaction solution was concentrated. The crude product was purified by pre-HPLC to give 10 mg of (2S,4R)-12-ethyl-1-((S)-2-(tert-butyl)-14-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)-4-oxo-6,9-dioxa-3,12-diazatetradecanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound D1) with a purity of 98% and a yield of 5.6% as a white solid. 1H-NMR (400MHz, DMSO-d6): δ9.00(s,1H),8.45(d,J=7.2Hz,1H),8.31(s,1H),7.84-7.99(m,5H),7.72-7.76(m,2H),7.60(d,J=8.4Hz,1H),7.46(d ,J=8.4Hz,2H),7.38(d,J=7.6Hz,2H),7.28(d,J=7.6Hz,1H),7.11(dd,J=9.2Hz,2.4Hz,1H),6.74-6.77(m,2H),6.60-6.62(m,2H),4.90-4.92(m, 1H),4.55(d,J=9.2Hz,1H),4.45-4.49(m,1H),4.30(s,1H),3.96(s,2H) ,3.81-3.89(m,2H),3.49-3.59(m,8H),3.25(s,3H),3.12(m,1H),2.96(s ,1H),2.77(m,2H),2.71(s,3H),2.66(m,2H),2.58(m,2H),2.48(s,3H),2 .03-2.08(m,1H),1.79-1.85(m,1H),1.40(d,J=7.2Hz,3H),0.88(s,9H). MS calculated value: 1049.4; MS found value: 1072.3 [M+Na] + . 2

[0350] Example 2 Synthesis of (2S,4R)-4-hydroxy-1-((S)-2-(2-((5-(3-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)azetidin-1-yl)n-pentyl)oxy)acetylamino)-3,3-dimethylbutyryl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound D2)

[0351] The overall synthetic route is as follows:

[0352]

[0353] The specific steps are as follows:

[0354] Take 4-((6-methoxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenol (Compound A2-1) (1.0 g, 2.38 mmol, 1.0 eq), tert-butyl 3-iodoazetidine-1-carboxylate (Compound A2-2) (0.8 g, 2.85 mmol, 1.2 eq) and cesium carbonate (2.3 g, 7.13 mmol, 3.0 eq) and place them in 10 mL of DMF and stir at 140°C for 3 hours. The mixture was diluted with 100 mL of water and extracted with ethyl acetate (150 mL x 3). The organic phases were combined and concentrated to give 1.9 g of crude product, which was purified by silica gel column (ethyl acetate: petroleum ether = 2:1) to give 3-(4-((6-methoxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)azetidine-1-carboxylic acid tert-butyl ester (Compound A2-3) 1.0 g with a purity of 96.4% and a yield of 73% as a white solid.

[0355] Tert-butyl 3-(4-((6-methoxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)azetidine-1-carboxylate (Compound A2-3) (1.0 g, 1.74 mmol, 1.0 eq) was placed in 20 mL of anhydrous dichloromethane. A dichloromethane solution of boron tribromide (5 mL, 1 mol / L, 5.0 eq) was added dropwise at 0°C. The mixture was stirred for 5 minutes, warmed to room temperature, and stirred for 0.5 hours. The mixture was quenched with methanol, concentrated, and freed with saturated aqueous sodium bicarbonate solution. The mixture was extracted with dichloromethane and separated. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain an oily liquid. The oily liquid was purified by silica gel column (MeOH:DCM=10:1) to obtain 0.6 g of 5-(4-(azetidin-3-yl)phenoxy)-6-(4-(methylsulfonyl)phenyl)naphthalen-2-ol (Compound A2) with a purity of 98% and a yield of 74.7% as a yellow oil.

[0356] Take 5-(4-(azetidin-3-oxy)phenoxy)-6-(4-(methylsulfonyl)phenyl)naphthalen-2-ol (Compound A2) (400 mg, 0.867 mmol, 1.0 eq), 2-((5-(toluenesulfonyloxy)pentyloxy]ethyl acetate (Compound B2) (358 mg, 1.04 mmol, 1.2 eq) and diisopropylethylamine (168 mg, 1.30 mmol, 1.5 eq) and place them in 5 mL The mixture was stirred in DMF and heated to 80°C. After 3 hours, the reaction was complete and the solvent was removed by concentration to give a crude oil. The crude oil was purified by flash silica gel column chromatography (MeOH / DCM=0%-9%) to give 120 mg of ethyl 2-((5-(3-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)azetidin-1-yl)pentyl)oxy)acetate (Compound D2-1) with a purity of 99% and a yield of 51.72% as a yellow oil.

[0357] Take 2-((5-(3-(4-((6-hydroxy-2-(4-(methylsulfonyl))phenyl)naphthalene-1-oxy)phenoxy)azetidin-1-yl)pentyloxy)acetic acid (compound D2-1) (120 mg, 0.189 mmol, 1.0 eq) and lithium hydroxide monohydrate (23.8 mg, 0.568 mmol, 3.0 eq) and place in 3 mL of ethanol and 2 mL of water, and react at 50 ° C for 30 min. The reaction solution was adjusted to pH 3-4 and then concentrated to dryness to obtain 2-((5-(3-(4-((6-hydroxy-2-(4-(methylsulfonyl))phenyl)naphthalene-1-oxy)phenoxy)azetidin-1-yl)pentyloxy)acetic acid (compound D2-2) 90 mg as a yellow solid.

[0358] Take 2-((5-(3-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)azetidin-1-yl)pentyloxy)acetic acid (Compound D2-2) (90 mg, 0.189 mmol, 1 eq) and HATU (86 mg, 0.227 mmol, 1.2 eq) and add 2 mL DMF, stirred at room temperature, (2S, 4R) -1- ((S) -2-amino-3,3-dimethylbutyryl) -4-hydroxy-N- ((S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidine-2-carboxamide hydrochloride (Compound C) (136 mg, 0.284 mmol, 1.5 eq) and diethylisopropylamine (122 mg, 0.945 mmol, 5.0 eq) DMF solution 3 mL was added dropwise, and stirred at room temperature for 0.5 h. After the reaction was completed, the mixture was concentrated to dryness to obtain a crude product, which was purified by reverse phase flash column chromatography (ACN / H2 O=1%-60%), to give (2S,4R)-4-hydroxy-1-((S)-2-(2-((5-(3-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)azetidin-1-yl)pentyl)oxy)acetylamino)-3,3-dimethylbutyryl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide 35 mg, purity 80%, yield 25.3%, and again purified by pre-HPLC (ACN / H2O=5%-70%, 0.1% FA in ACN solution, 0.1% FA in water) to give (2S,4R)-4-hydroxy-1-((S)-2-(2-((5-(3-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)azetidin-1-yl)pentyl)oxy)acetylamino)-3,3-dimethylbutyryl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound D2) 5.6 mg with a purity of 99% as a white solid. 1H-NMR (400MHz, DMSO-d6) δ9.00(s,1H),8.47(d,J=8.0Hz,1H),7.93(d,J=8.0Hz,1H),7.86(d,J=8.0Hz,1H),7.77(dd,J=8.0 ,16Hz,4H),7.61(d,J=8.0Hz,1H),7.46-7.39(m,4H),7.31(d,J=8.0Hz,2H),7.27(s,1H),7.11(d,J=8.0Hz,1H),6.66-6.59( m, 4H), 5.40-5.32 (m, 1H), 4.95-4.86 (m, 1H), 4.64-4.61 (m, 1H), 4.54 (d, J = 8.0 Hz, 1H), 4.48-4.44 (m, 1H), 4.28 (s, 1H), 3.59-3.55 (m, 4H), 3.54-3.52 (m, 4H), 3.26-3.23 (m, 4H), 2.48 (s, 2H), 1.80-1.74 (m, 4H), 1.51 (s, 2H), 1.26 (s, 3H), 0.94 (s, 9H). MS calculated value: 1031.4; MS experimental value: 1030.3 [MH] - . 3

[0360] Example 3 Synthesis of (2S,4R)-1-((S)-2-(2-(3-(ethyl(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)amino)propoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound D3)

[0361] The overall synthetic route is as follows

[0362]

[0363] The specific steps are as follows:

[0364] 5-(4-(2-(ethylamino)ethoxy)phenoxy)-6-(4-(methylsulfonyl)phenyl)naphthalen-2-ol (Compound A1) (200 mg, 0.42 mmol, 1.0 eq), ethyl 2-(3-(toluenesulfonyloxy)propoxy)acetate (Compound B3) (198 mg, 0.63 mmol, 1.5 eq) and DIPEA (54 mg, 0.63 mmol, 1.5 eq) were placed in 5 mL of DMF, stirred and heated to 80°C. After 3 hours, the reaction was completed and concentrated to give an oily crude product. The crude product was purified by silica gel column (MeOH / DCM=1:10) to give 120 mg of ethyl 2-(3-(ethyl(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)amino)propoxy)acetate (Compound D3-1) with a purity of 91% and a yield of 46.1% as a yellow solid.

[0365] Take 2-(3-(ethyl(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)amino)propoxy)acetic acid ethyl ester (compound D3-1) (100 mg, 0.16 mmol, 1.0 eq) and LiOH.H2O (20 mg, 0.48 mmol, 3.0 eq) and place them in 3 mL of ethanol and 2 mL of water, react at 50°C for half an hour, adjust the pH of the reaction solution to 3-4, and then concentrate to dryness to obtain 2-(3-(ethyl(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)amino)propoxy)acetic acid (compound D3-2) 100 mg as a solid.

[0366] 2-(3-(ethyl(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)amino)propoxy)acetic acid (compound D3-2) (100 mg, 0.16 mmol, 1 eq) and HATU (73.5 mg, 0.193 mmol, 1.2 eq) were placed in 2 mL of anhydrous DMF and stirred at room temperature. 3 mL of DMF solution of (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (compound C) (122 mg, 0.25 mmol, 1.5 eq) and DIPEA (109 mg, 0.84 mmol, 5.0 eq) were added dropwise, and the mixture was stirred at room temperature for 0.5 h. The mixture was concentrated to dryness to give a crude product, which was purified by pre-HPLC to give 7.2 mg of (2S,4R)-1-((S)-2-(2-(3-(ethyl(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)amino)propoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound D3) with a purity of 96.7% and a yield of 8.4% as a white solid. 1 H-NMR (400MHz, DMSO-d6) δ9.00(s,1H),8.48(d,J=7.1Hz,1H),7.93(d,J=8.0Hz,2H),7.86(d,J=8.0Hz,2H),7.78(d,J=8.0Hz,1H),7.74(d,J =8.0Hz,1H),7.60(d,J=8.0Hz,1H),7.46(d,J=8.0Hz,2H),7.38(d,J=8.0Hz,2H),7.32(d,J=9.1Hz,1H),7.27(s,1H),7.11(d,J=9.1Hz,1H), 6.75 (d, J = 8.0 Hz, 2H), 6.62 (d, J = 8.0 Hz, 2H), 5.32 (s, 1H), 5.16 (s, 1H), 4.54 (d, J = 9.0 Hz, 1H), 4.45 (d, J = 8.3 Hz, 1H), 4.30 (s, 1H), 4.22 (s, 1H), 3.88 (d, J = 8.2 Hz, 4H), 3.59 (s, 4H), 3.23 (s, 3H), 2.71 (s, 2H), 2.48 (s, 7H), 1.66 (s, 1H), 1.37 (d, J = 6.6 Hz, 3H), 1.26 (s, 3H), 0.92 (s, 9H). MS calculated value: 1019.4; MS found value: 1018.3 [MH]- . 4

[0368] Example 4 Synthesis of (2S,4R)-1-((S)-2-(2-((5-(ethyl(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)amino)n-pentyl)oxy)acetamido)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound D4)

[0369] The overall synthetic route is as follows:

[0370]

[0371] The specific steps are as follows:

[0372] Ethyl 2-((5-(p-toluenesulfonyloxy)pentyl)oxy)acetate (Compound B4) (92 mg, 0.293 mmol, 1 eq) and 5-(4-(2-(ethylamino)ethoxy)phenoxy)-6-(4-(methylsulfonyl)phenyl)-2-naphthol (Compound A1) (140 mg, 0.293 mmol, 1 eq) were dissolved in 5 mL of DMF, and DIPEA (76 mg, 0.59 mmol, 2 eq) was added. The reaction was carried out at 70° C. for 10 h, and the mixture was diluted with 20 mL of water. The mixture was extracted with 15 mL×2 of ethyl acetate. The organic phases were combined, dried, and concentrated to give a crude product, which was purified by silica gel column chromatography (PE:EA=0:1) to give 40 mg of ethyl 2-((5-(ethyl(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)amino)pentyl)oxy)acetic acid ethyl ester (compound D4-1) with a purity of 95% and a yield of 21%.

[0373] Ethyl 2-((5-(ethyl(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)amino)pentyl)oxy)acetic acid (compound D4-1) (40 mg, 0.06 mmol, 1 eq) was placed in 3 mL of THF and 1 mL of water, and sodium hydroxide (12 mg, 0.3 mmol, 5 eq) was added. The mixture was reacted at room temperature for 30 minutes, the pH was adjusted to neutral, and the mixture was concentrated and dried to obtain 45 mg of 2-((5-(ethyl(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)amino)pentyl)oxy)acetic acid (compound D4-2) as a white solid.

[0374] 2-((5-(ethyl(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)amino)pentyl)oxy)acetic acid (Compound D4-2) (45 mg, 0.072 mmol, 1 eq) and (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrole-2-carboxamide hydrochloride (Compound C) (52 mg, 0.11 mmol, 1.5 eq) were placed in 5 mL of DMF, DIPEA (27 mg, 0.21 mmol, 3 eq) was added, and the mixture was stirred for 10 min. HATU (41 mg, 0.11 mmol, 1.5 eq) was added, and the mixture was reacted at room temperature for 30 min. The reaction solution was concentrated. The crude product was purified by pre-HPLC to give 13.5 mg of (2S,4R)-1-((S)-2-(2-((5-(ethyl(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)amino)pentyl)oxy)acetamido)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound D4) with a purity of 99% and a yield of 17.7% as a white solid. 1 H-NMR (400MHz, DMSO-d6): δ9.33(s,1H),9.01(s,1H),8.44(d,J=7.2Hz,1H),7.86-7.97(m,4H),7.73-7.81(m,2H),7.62(d,J=8.4Hz,1H), 7.46(d,J=7.6Hz,2H),7.38(d,J=7.6Hz,2H),7.33(d,J=9.22Hz,1H),7.28(s,1H),7.11(d,J=8.8Hz,1H),6.80-6.83(m,2H),6.65-6.68(m, 2H), 4.85-4.89 (m, 1H), 4.53 (d, J = 9.2 Hz, 1H), 4.40-4.43 (m, 1H), 4.27 (s, 1H), 3.96 (s, 2H), 3.81-3.89 (m, 2H), 3.49-3.59 (m, 2H), 3.05-3.18 (m, 10H), 2.44 (s, 3H), 2.03-2.08 (m, 1H), 1.79-1.85 (m, 1H), 1.54-1.64 (m, 4H), 1.30 (d, J = 7.2 Hz, 3H), 1.16-1.22 (m, 5H), 0.90 (s, 9H). MS calcd: 1047.4; MS found: 1048.4 [M+H] + . 5

[0376] Example 5 Synthesis of (2S,4R)-1-((S)-2-(3-(2-(2-(ethyl(2-(4-((6-hydroxy-2-(4-(methylsulfonyl))phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)amino)ethoxy)ethoxy)benzamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound D5)

[0377] The overall synthetic route is as follows:

[0378]

[0379] The specific steps are as follows:

[0380] Take 5-(4-(2-(ethylamino)ethoxy)phenoxy)-6-(4-(methylsulfonyl)phenyl)naphthalen-2-ol (Compound A1) (160 mg, 0.34 mmol, 1.0 eq), 3-(2-(2-(p-toluenesulfonyloxy)ethoxy)ethoxy)benzoic acid methyl ester (Compound B5) (316 mg, 0.67 mmol, 2.0 eq) and DIPEA (0.5 mL, 3.0 eq) and place in 5 mL The mixture was stirred for 16 hours at 90 ° C. DMF was added and the reaction temperature was raised to 90 ° C. The reaction solvent was removed by concentration to give an oily crude product. The crude product was purified by flash column chromatography (MeOH / DCM = 0%-9%) to give 3-(2-(2-(ethyl(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)amino)ethoxy)ethoxy)benzoic acid methyl ester (compound D5-1) 105 mg with a purity of 99% and a yield of 44.9% as a yellow oil.

[0381] Take 3-(2-(2-(ethyl(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)amino)ethoxy)ethoxy)benzoic acid methyl ester (compound D5-1) (105 mg, 0.15 mmol, 1.0 eq) and lithium hydroxide monohydrate (20 mg, 0.45 mmol, 3.0 eq) and place them in 3 mL of ethanol and 2 mL of water, react at 50°C for half an hour, adjust the pH of the reaction solution to 3-4, and concentrate the reaction solution to obtain 80 mg of 3-(2-(2-(ethyl(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)amino)ethoxy)ethoxy)benzoic acid (compound D5-2) as a yellow solid.

[0382] 3-(2-(2-(ethyl(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)amino)ethoxy)ethoxy)benzoic acid (Compound D5-2) (80 mg, 0.15 mmol, 1 eq, crude) and HATU (85.5 mg, 0.23 mmol, 1.5 eq) were placed in 2 mL of anhydrous DMF and stirred at room temperature. 3 mL of DMF solution of (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (Compound C) (108.2 mg, 0.225 mmol, 1.2 eq) and DIPEA (97 mg, 0.75 mmol, 5.0 eq) were added dropwise, and the mixture was stirred at room temperature for 0.5 h. The crude product was concentrated to dryness and purified by reverse phase flash column chromatography (ACN / H2O=1%-60%) to give 89 mg of (2S,4R)-1-((S)-2-(3-(2-(2-(ethyl(2-(4-((6-hydroxy-2-(4-(methylsulfonyl))phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)amino)ethoxy)ethoxy)benzamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound D5) with a purity of 95% and a yield of 53.3% as a white solid. 1H-NMR (400MHz, DMSO-d6) δ10.06(s,1H),8.98(s,1H),8.42(d,J=7.7Hz,1H),7.97( d,J=9.0Hz,1H),7.90(d,J=8.0Hz,2H),7.83(d,J=7.9Hz,2H),7.74(dd,J=17.6,8.8 Hz,2H),7.57(d,J=8.5Hz,1H),7.41(dd,J=22.5,7.8Hz,6H),7.31(t,J=8.0Hz,1H) ,7.25(s,1H),7.07(t,J=10.5Hz,2H),6.71(d,J=8.5Hz,2H),6.58(d,J=8.3Hz,2H), 5.14(s,1H),4.93(t,J=7.0Hz,1H),4.75(d,J=9.2Hz,1H),4.45(t,J=8.0Hz,1H),4 .30(s,1H),4.12(s,2H),3.84(s,2H),3.69(d,J=14.9Hz,4H),3.50(t,J=5.8Hz,2H) , 3.21 (s, 3H), 2.74 (d, J = 6.1 Hz, 2H), 2.64 (t, J = 6.0 Hz, 2H), 2.45 (s, 3H), 2.03 (t, J = 9.6 Hz, 1H), 1.80 (s, 1H), 1.37 (d, J = 6.7 Hz, 3H), 1.02 (s, 9H), 0.92 (t, J = 6.4 Hz, 3H). MS calculated value: 1111.4; MS experimental value: 1112.4 [M+H] + . 6

[0384] Example 6 Synthesis of (2S,4R)-1-((S)-2-(3-(2-(2-(ethyl(2-(4-((6-hydroxy-2-(4-(methylsulfonyl))phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)amino)ethoxy)ethoxy)ethoxy)benzamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound D6)

[0385] The overall synthetic route is as follows:

[0386]

[0387] The specific steps are as follows:

[0388] Take 5-(4-(2-(ethylamino)ethoxy)phenoxy)-6-(4-(methylsulfonyl)phenyl)naphthalen-2-ol (Compound A1) (150 mg, 0.31 mmol, 1.0 eq), 3-(2-(2-(p-toluenesulfonyloxy)ethoxy)ethoxy)ethoxy)benzoic acid methyl ester (Compound B6) (220 mg, 0.63 mmol, 2.0 eq) and DIPEA (0.5 mL, 3.0 eq) and place in 5 mL The reaction mixture was stirred for 16 hours at 90 ° C. DMF was added and the reaction temperature was raised to 90 ° C. The reaction solvent was removed by concentration to give an oily crude product, which was purified by silica gel flash column chromatography (MeOH / DCM = 0%-9%) to give 3-(2-(2-(2-(ethyl(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)amino)ethoxy)ethoxy)ethoxy)methyl benzoate (compound D6-1) 120 mg with a purity of 92% and a yield of 72.9% as a yellow oil.

[0389] Take 3-(2-(2-(2-(ethyl(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)amino)ethoxy)ethoxy)ethoxy)benzoic acid methyl ester (compound D6-1) (120 mg, 0.18 mmol, 1.0 eq) and lithium hydroxide monohydrate (23 mg, 0.54 mmol, 3.0 eq) and place them in 3 mL of ethanol and 2 mL of water, react at 50°C for half an hour, adjust the pH of the reaction solution to 3-4, and concentrate to dryness to obtain 3-(2-(2-(2-(ethyl(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)amino)ethoxy)ethoxy)ethoxy)benzoic acid (compound D6-2) 85 mg as a white solid.

[0390] 3-(2-(2-(2-(ethyl(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)amino)ethoxy)ethoxy)ethoxy)benzoic acid (Compound D6-2) (85 mg, 0.12 mmol, 1 eq, crude product) and HATU (83.5 mg, 0.22 mmol, 2 eq) were placed in 2 mL of anhydrous DMF and stirred at room temperature. Then, ( A 3 mL DMF solution of 2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (Compound C) (86.6 mg, 0.18 mmol, 1.5 eq) and DIPEA (97 mg, 0.90 mmol, 5.0 eq) was stirred at room temperature for 0.5 h. The mixture was concentrated to dryness to give a crude product, which was purified by reverse phase flash column chromatography (ACN / H2O = 1%-70%) to give (2S,4R)-1-((S)-2-(3-(2-(2-(ethyl(2-(4-((6-hydroxy-2-(4-(methylsulfonyl))phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)amino)ethoxy)ethoxy)ethoxy)benzamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound D6) 40.3 mg with a purity of 99% and a yield of 31.7% as a white solid. 1H NMR (400MHz, DMSO-d6) δ10.09(s,1H),9.01(s,1H),8.45(d,J=7.7Hz,1H),8.01(d,J=9.0Hz,1H) ,7.93(d,J=8.3Hz,2H),7.85(d,J=8.3Hz,2H),7.76(dd,J=17.1,8.9Hz,2H),7.60(d,J=8.5Hz,1H ),7.46(d,J=7.9Hz,3H),7.41(d,J=8.3Hz,3H),7.36(t,J=7.9Hz,1H),7.27(d,J=1.9Hz,1H),7.1 1(dd,J=11.5,4.4Hz,2H),6.74(d,J=9.1Hz,2H),6.61(d,J=9.0Hz,2H),5.17(d,J=3.2Hz,1H),4. 95(t,J=7.2Hz,1H),4.78(d,J=9.1Hz,1H),4.48(t,J=8.1Hz,1H),4.33(s,1H),4.14(d,J=4.7Hz, 2H),3.86(t,J=5.9Hz,2H),3.73(dd,J=13.2,9.0Hz,4H),3.60–3.54(m,2H),3.54–3.49(m,2H),3 0.45 (t, J = 6.1 Hz, 2H), 3.24 (s, 4H), 2.75 (t, J = 6.0 Hz, 2H), 2.63 (t, J = 6.1 Hz, 2H), 2.48 (s, 3H), 2.10–2.01 (m, 1H), 1.83 (m, 1H), 1.40 (d, J = 6.9 Hz, 3H), 1.04 (d, J = 7.8 Hz, 9H), 0.93 (t, J = 7.0 Hz, 4H). MS calculated value: 1155.4; MS observed value: 579.0 [M / 2+H] + . 7

[0392] Example 7 Synthesis of (2S,4R)-1-((S)-2-(4-(2-(2-(ethyl(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)amino)ethoxy)ethoxy)benzamido)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound D7)

[0393] The overall synthetic route is as follows:

[0394]

[0395] The specific steps are as follows:

[0396] 5-(4-(2-(ethylamino)ethoxy)phenoxy)-6-(4-(methylsulfonyl)phenyl)-2-naphthol (Compound A1) (292 mg, 0.61 mmol, 1 eq) and methyl 4-(2-(2-(p-toluenesulfonyloxy)ethoxy)ethoxy)benzoate (Compound B7) (362 mg, 0.92 mmol, 1.5 eq) were placed in 10 mL of DMF, and DIPEA (155 mg, 1.5 eq) was added. The reaction mixture was stirred for 10 h at 80 ° C. The crude product was purified by silica gel column chromatography (DCM: MeOH = 20: 1) to give 4-(2-(2-(ethyl(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)amino)ethoxy)ethoxy)benzoic acid methyl ester (compound D7-1) 250 mg with a purity of 90% and a yield of 58.5% as a white solid.

[0397] The product methyl 4-(2-(2-(ethyl(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)amino)ethoxy)ethoxy)benzoate (compound D7-1) (250 mg, 0.358 mmol, 1 eq) was placed in a 50 mL round-bottom flask, 7 mL of THF and 4 mL of water and sodium hydroxide (143.2 mg, 3.58 mmol, 10 eq) were added, and the mixture was reacted at 70 ° C for 8 h. The pH was adjusted to neutral with 1 mol / L aqueous hydrochloric acid solution, and the mixture was concentrated and dried to obtain 300 mg of 4-(2-(2-(ethyl(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)amino)ethoxy)ethoxy)benzoic acid (compound D7-2) as a white solid.

[0398] 4-(2-(2-(ethyl(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)amino)ethoxy)ethoxy)benzoic acid (Compound D7-2) (300 mg, 0.437 mmol, 1 eq) and (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (Compound C) (210 mg, 0.437 mmol, 1 eq) were placed in a 50 mL round-bottom flask, 10 mL of DMF and TEA (180 mg, 1.73 mmol) were added, and the mixture was stirred for 10 min. HATU (249 mg, 0.655 mmol, The reaction mixture was stirred at room temperature for 20 min. The reaction mixture was concentrated and the crude product was purified by DCM:MeOH = 20:1-10:1 to give 150 mg of crude product with a purity of 84%. The product was then purified by reverse phase flash column chromatography to give 90 mg of crude product with a purity of 91%. The product was then purified by pre-HPLC to give (2S,4R)-1-((S)-2-(4-(2-(2-ethyl(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)amino)ethoxy)ethoxy)benzamido)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (compound D7) 30 mg with a purity of 99% and a yield of 6.1% as a white solid. 1H-NMR (400MHz, DMSO-d6): δ9.01 (s, 1H), 8.44 (d, J = 8Hz, 1H), 8.31 (s, 1H), 7.91-7. 93(m,2H),7.84-7.87(m,4H),7.72-7.79(m,3H),7.60(d,J=8.4Hz,1H),7.46(d,J=8 .4Hz,2H),7.40(d,J=8.0Hz,2H),7.27(d,J=2.0Hz,1H),7.11(dd,J=9.2Hz,2.0Hz,1 H),6.98(d,J=7.2Hz,2H),6.74(d,J=8.4Hz,2H),6.60(d,J=6.8Hz,2H),4.93-4.97( m,1H),4.76(d,J=9.2Hz,1H),4.45-4.49(m,1H),4.32(s,1H),4.13(m,2H),3.87(t, J=6Hz,2H),3.67-3.72(m,4H),3.52(t,J=6Hz,2H),3.23(s,3H),2.77(t,J=6Hz,2H) , 2.66 (t, J = 6 Hz, 2H), 2.57 (q, J = 6.8 Hz, 2H), 2.48 (s, 1H), 2.03-2.08 (m, 1H), 1.79-1.85 (m, 1H), 1.40 (d, J = 7.2 Hz, 2H), 1.26 (s, 1H), 1.03 (s, 9H), 0.92 (t, J = 7.2 Hz, 3H). MS calculated value: 1111.4; MS experimental value: 556.9 [M / 2+H] + . 8

[0400] Example 8 Synthesis of (2S,4R)-1-((S)-2-(3-(4-(ethyl(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)amino)n-butoxy)benzamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound D8)

[0401] The overall synthetic route is as follows:

[0402]

[0403] The specific steps are as follows:

[0404] Take 5-(4-(2-(ethylamino)ethoxy)phenoxy)-6-(4-(methylsulfonyl)phenyl)naphthalen-2-ol (Compound A1) (150 mg, 0.31 mmol, 1.0 eq), 3-(4-(p-toluenesulfonyloxy)n-butyl)benzoic acid methyl ester (Compound B8) (238 mg, 0.62 mmol, 2.0 eq) and DIPEA (0.5 mL, 3.0 eq) and place in 5 mL The reaction mixture was stirred in DMF, heated to 90°C for 16 hours, and the reaction solvent was removed by concentration to obtain an oily crude product. The crude product was purified by flash column chromatography (MeOH / DCM = 0%-9%) to obtain 3-(4-(ethyl(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)amino)n-butoxy)methyl benzoate (compound D8-1) 110 mg with a purity of 98% and a yield of 64.0% as a yellow oil.

[0405] Take 3-(4-(ethyl(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)amino)n-butoxy)benzoic acid methyl ester (compound D8-1) (110 mg, 0.16 mmol, 1.0 eq) and lithium hydroxide monohydrate (20 mg, 0.48 mmol, 3.0 eq) and place them in 3 mL of ethanol and 2 mL of water. React at 50°C for half an hour, adjust the pH of the reaction solution to 3-4, and concentrate the reaction solution to obtain 80 mg of 3-(4-(ethyl(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)amino)n-butoxy)benzoic acid (compound D8-2) as a white solid.

[0406] 3-(4-(ethyl(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)amino)n-butoxy)benzoic acid (compound D8-2) (80 mg, 0.16 mmol, 1 eq) and HATU (73.5 mg, 0.19 mmol, 1.2 eq) were placed in 2 mL of anhydrous DMF and stirred at room temperature. 3 mL of DMF solution of (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (compound C) (116 mg, 0.24 mmol, 1.5 eq) and DIPEA (104 mg, 0.81 mmol, 5.0 eq) were added dropwise, and the mixture was stirred at room temperature for 0.5 h. The reaction mixture was concentrated to dryness to give a crude product, which was then purified by reverse phase flash column chromatography (ACN / H2O = 1%-70%) to give (2S,4R)-1-((S)-2-(3-(4-(ethyl(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)amino)n-butoxy)benzamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound D8) 36 mg with a purity of 97.3% and a yield of 34.0% as a white solid. 1H-NMR (400MHz, DMSO-d6) δ10.12(s,1H),9.22(s,1H),9.03(s,1H),8.45(d,J=7.7Hz,1H),8.00–7.86(m,6H),7.82(d,J=8.5Hz,1H),7.76(d,J=9.1Hz ,1H),7.64(d,J=8.6Hz,1H),7.48(d,J=7.9Hz,3H),7.43(s,4H),7.38(d,J =7.7Hz,1H),7.30(s,1H),7.13(t,J=9.1Hz,2H),6.83(d,J=8.7Hz,2H),6.6 7(d,J=8.7Hz,2H),5.18(d,J=3.0Hz,1H),4.97(t,J=7.0Hz,1H),4.79(d,J =9.0Hz,1H),4.49(t,J=8.1Hz,1H),4.36(s,1H),4.14(d,J=33.6Hz,4H),3 .71(s,2H),3.51(s,2H),3.26(s,7H),2.51–2.48(m,3H),2.15–2.03(m,1H ), 1.83 (d, J = 12.8Hz, 4H), 1.42 (d, J = 6.8Hz, 3H), 1.23 (s, 3H), 1.06 (s, 9H). MS calculated value: 1095.4; MS experimental value: 548.9 [M / 2+H] + . 9

[0408] Example 9 Synthesis of (2S,4R)-1-((S)-2-(3-(2-(ethyl(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)amino)ethoxy)benzamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound D9)

[0409] The overall synthetic route is as follows:

[0410]

[0411] The specific steps are as follows:

[0412] Take 5-(4-(2-(ethylamino)ethoxy)phenoxy)-6-(4-(methylsulfonyl)phenyl)naphthalen-2-ol (Compound A1) (150 mg, 0.31 mmol, 1.0 eq), methyl 3-(2-(p-toluenesulfonyloxy)ethoxy)benzoate (Compound B9) (220 mg, 0.62 mmol, 2.0 eq) and DIPEA (0.5 mL, 3.0 eq) and place them in 5 mL The reaction mixture was stirred for 16 hours at 90 ° C. DMF was added and the reaction temperature was raised to 90 ° C. The reaction solvent was removed by concentration to give an oily crude product. The crude product was purified by flash column chromatography on silica gel (MeOH / DCM = 0%-9%) to give 3-(2-(ethyl(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)amino)ethoxy)benzoic acid methyl ester (compound D9-1) 120 mg with a purity of 92% and a yield of 72.9% as a yellow oil.

[0413] Take 3-(2-(ethyl(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)amino)ethoxy)benzoic acid methyl ester (compound D9-1) (120 mg, 0.18 mmol, 1.0 eq) and lithium hydroxide monohydrate (23 mg, 0.54 mmol, 3.0 eq) and place them in 3 mL of ethanol and 2 mL of water, react at 50°C for half an hour, adjust the pH of the reaction solution to 3-4, and concentrate the reaction solution to obtain 85 mg of 3-(2-(ethyl(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)amino)ethoxy)benzoic acid (compound D9-2) as a white solid.

[0414] 3-(2-(ethyl(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)amino)ethoxy)benzoic acid (compound D9-2) (85 mg, 0.18 mmol, 1 eq, crude) and HATU (83.5 mg, 0.22 mmol, 1.2 eq) were placed in 2 mL of anhydrous DMF and stirred at room temperature. 3 mL of DMF solution of (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (compound C) (132 mg, 0.27 mmol, 1.5 eq) and DIPEA (118 mg, 0.91 mmol, 5.0 eq) were added dropwise, and the mixture was stirred at room temperature for 0.5 h. The reaction mixture was concentrated to dryness to give a crude product, which was purified by pre-HPLC (ACN / H2O = 5%-70%, 0.1% FA in ACN solution, 0.1% FA in water) to give (2S,4R)-1-((S)-2-(3-(2-(ethyl(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)amino)ethoxy)benzamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound D9) 40.3 mg with a purity of 99% and a yield of 31.7% as a white solid. 1H-NMR (400MHz, DMSO-d6) δ10.08(s,1H),9.01(d,J=3.2Hz,1H),8.44(d,J=5.1Hz, 1H),7.91(ddd,J=25.0,16.5,6.0Hz,6H),7.76(ddd,J=17.3,8.9,2.9Hz,2H),7.60 (dd,J=8.5,3.1Hz,1H),7.49–7.44(m,3H),7.43–7.38(m,4H),7.37–7.31(m,1H),7 .27(s,1H),7.09(dd,J=17.3,8.4Hz,2H),6.75(dd,J=9.0,2.9Hz,2H),6.61(dd,J= 8.9,2.9Hz,2H),5.16(s,1H),4.95(d,J=6.9Hz,1H),4.77(d,J=8.7Hz,1H),4.47( t,J=6.5Hz,1H),4.33(s,1H),4.10(s,2H),3.91(s,2H),3.69(s,2H),3.23(d,J=3. 0 Hz, 4H), 2.90 (s, 2H), 2.85 (s, 2H), 2.68–2.61 (m, 2H), 2.48 (d, J=3.1 Hz, 3H), 2.05 (s, 1H), 1.83 (d, J=4.5 Hz, 1H), 1.41–1.37 (m, 3H), 1.03 (s, 9H), 1.00–0.96 (m, 3H). MS calculated value: 1067.4; MS experimental value: 1068.3 [M+H] + . 10

[0416] Example 10 Synthesis of (2S,4R)-1-((S)-2-(4-((5-(ethyl(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)amino)n-pentyl)oxy)benzamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound D10)

[0417] The overall synthetic route is as follows:

[0418]

[0419] The specific steps are as follows:

[0420] 5-(4-(2-(ethylamino)ethoxy)phenoxy)-6-(4-(methylsulfonyl)phenyl)-2-naphthol (Compound A1) (219 mg, 0.45 mmol, 1 eq) and methyl 4-((5-(p-toluenesulfonyloxy)pentyl)oxy)benzoate (Compound B10) (270 mg, 0.69 mmol, 1.5 eq) were placed in 5 mL of DMF, and DIPEA (111 mg, 0.9 mmol, 1 eq) was added. mol, 2eq), reacted at 80 ° C for 10 h, the reaction solution was concentrated, and the crude product was purified by silica gel column (DCM: MeOH = 20: 1-10: 1) to obtain 4-((5-(ethyl(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)amino)pentyl)oxy)benzoic acid methyl ester (compound D10-1) 100 mg, purity 95%, yield 31.8% as a white solid.

[0421] Methyl 4-((5-(ethyl(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)amino)pentyl)oxy)benzoate (compound D10-1) (120 mg, 0.172 mmol, 1 eq) was placed in a 50 mL round-bottom flask, 6 mL of THF and 2 mL of water and sodium hydroxide (69 mg, 1.72 mmol, 10 eq) were added, and the reaction was carried out at 70 ° C for 10 h. The pH was adjusted to neutral with 1 mol / L aqueous hydrochloric acid solution, and the mixture was concentrated and dried to obtain a crude product, which was washed with 10 mL of water, filtered and dried to obtain 4-((5-(ethyl(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)amino)pentyl)oxy)benzoic acid (compound D10-2), 100 mg, yield 85%, purity 95%, white solid.

[0422] 4-((5-(ethyl(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)amino)pentyl)oxy)benzoic acid (Compound D10-2) (100 mg, 0.146 mmol, 1 eq) and (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (Compound C) (84 mg, 0.175 mmol, 1.2 eq) were placed in a 25 mL round-bottom flask, and 5 mL of DMF and TEA (40 mg, 0.438 mmol, 3 eq) were added. The mixture was stirred for 10 min, HATU (83 mg, 0.219 mmol, 1.5 eq) was added, and the reaction was allowed to proceed at room temperature for 20 min. The reaction solution was concentrated, and the crude product was purified by pre-HPLC to give 12.5 mg of (2S,4R)-1-((S)-2-(4-((5-(ethyl(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)amino)pentyl)oxy)benzamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound D10) with a purity of 95% and a yield of 7.7% as a white solid. 1H-NMR (400MHz, DMSO-d6): δ9.01 (s, 1H), 8.44 (d, J = 8Hz, 1H), 8.33 (s, 2H), 7.91 -7.93(m,2H),7.84-7.87(m,4H),7.72-7.79(m,3H),7.60(d,J=8.4Hz,1H),7.4 6(d,J=8.4Hz,2H),7.40(d,J=8.0Hz,2H),7.27(d,J=2.0Hz,1H),7.11(dd,J=9. 2Hz, 2.0Hz, 1H), 6.98 (d, J = 7.2Hz, 2H), 6.74 (d, J = 8.4Hz, 2H), 6.60 (d, J = 6.8Hz, 2H),4.93-4.97(m,1H),4.76(d,J=9.2Hz,1H),4.45-4.49(m,1H),4.33(s,1H), 4.02(t,J=6.4Hz,2H),3.88(t,J=6.4Hz,2H),3.66-3.70(m,2H),3.23(s,3H),2. 71(t,J=6.0Hz,2H),2.44-2.48(m,5H),2.00-2.11(m,1H),1.81-1.85(m,1H),1 .71-1.73(m,2H),1.41-1.44(m,7H),1.03(s,9H),0.94(t,J=6.4Hz,7.2Hz,3H). MS calculated value: 1109.4; MS experimental value: 555.9 [M / 2+H] + . 11

[0424] Example 11 Synthesis of (2S,4R)-1-((S)-2-(2-(ethyl(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)amino)acetamido)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound D11)

[0425] The overall synthetic route is as follows:

[0426]

[0427] The specific steps are as follows:

[0428] 5-(4-(2-(Ethylamino)ethoxy)phenoxy)-6-(4-(methylsulfonyl)phenyl)naphthalen-2-ol (Compound A1) (150 mg, 0.31 mmol, 1.0 eq), benzyl 2-bromoacetate (Compound B11) (144 mg, 0.62 mmol, 2.0 eq) and DIPEA (95.3 mg, 3.0 eq) were placed in 5 mL of DMF and heated to 90° C. for 3 hours. The reaction solvent was removed by concentration to obtain a crude oil. The crude product was purified by flash column chromatography (MeOH / DCM=0%-9%) to obtain 120 mg of N-ethyl-N-(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)glycine benzyl ester (Compound D11-1) with a purity of 90% and a yield of 72.9% as a yellow oil.

[0429] N-ethyl-N-(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)glycine benzyl ester (Compound D11-1) (120 mg, 0.19 mmol, 1.0 eq) and lithium hydroxide monohydrate (24 mg, 0.57 mmol, 3.0 eq) were placed in 3 mL of ethanol and 2 mL of water, and the mixture was reacted at 50° C. for half an hour. The pH of the reaction solution was adjusted to 3-4, and the reaction solution was concentrated to dryness to obtain 80 mg of N-ethyl-N-(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)glycine (Compound D11-2) as a white solid.

[0430] N-ethyl-N-(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)glycine (Compound D11-2) (80 mg, 0.19 mmol, 1 eq) and HATU (95.0 mg, 0.25 mmol, 1.3 eq) were placed in 2 mL of anhydrous DMF and stirred at room temperature. 3 mL of DMF solution of (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (Compound C) (120 mg, 0.25 mmol, 1.3 eq) and DIPEA (124 mg, 0.96 mmol, 5.0 eq) were added dropwise, and the mixture was stirred at room temperature for 0.5 h. The reaction mixture was concentrated to dryness to give a crude product, which was purified by pre-HPLC (ACN / H2O = 5%-70%, 0.1% FA in water / 0.1% FA in ACN) to give (2S,4R)-1-((S)-2-(2-(ethyl(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)amino)acetamido)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound D11) 31.2 mg with a purity of 99% and a yield of 28.4% as a white solid. 1H-NMR (400MHz, DMSO-d6) δ9.01 (s, 1H), 8.43 (t, J = 7.8Hz, 1H), 8.26 (d, J = 10.2Hz, 1H) ,7.93(d,J=8.3Hz,2H),7.87(t,J=7.5Hz,2H),7.77(dd,J=14.9,8.9Hz,2H),7.60(d,J =8.6Hz,1H),7.47(d,J=8.0Hz,2H),7.42–7.34(m,2H),7.27(t,J=5.6Hz,1H),7.11(dt ,J=10.2,5.1Hz,1H),6.83(d,J=9.0Hz,2H),6.63(d,J=8.9Hz,2H),4.89(dt,J=12.8,6 .5Hz,1H),4.51(d,J=9.8Hz,1H),4.44(t,J=8.1Hz,1H),4.31(s,1H),3.94(t,J=5.1H z,3H),3.62(dd,J=10.3,3.2Hz,2H),3.56(d,J=10.6Hz,3H),3.24(s,3H),3.13(d,J=2 .7 Hz, 2H), 2.85 (t, J = 5.2 Hz, 2H), 2.65–2.56 (m, 2H), 2.48 (d, J = 4.7 Hz, 3H), 2.10–1.99 (m, 1H), 1.83–1.74 (m, 1H), 1.33 (d, J = 6.9 Hz, 3H), 0.97 (t, J = 7.0 Hz, 3H), 0.89 (s, 9H). MS calculated value: 961.3; MS experimental value: 481.9 [M / 2+H] + . 12

[0432] Example 12 Synthesis of (2S,4R)-1-((S)-2-(4-(3-(ethyl(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)amino)propoxy)benzamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound D12)

[0433] The overall synthetic route is as follows:

[0434]

[0435] The specific steps are as follows:

[0436] 5-(4-(2-(ethylamino)ethoxy)phenoxy)-6-(4-(methylsulfonyl)phenyl)-2-naphthol (Compound A1) (300 mg, 0.628 mmol, 1 eq) and methyl 4-(3-(p-toluenesulfonyloxy)propoxy)benzoate (Compound B12) (228 mg, 0.628 mmol, 1 eq) were placed in 5 mL of DMF, and DIPEA (154 mg, 1.25 mmol, 4 eq) was added. The reaction mixture was stirred for 10 h at 70 ° C. The crude product was purified by silica gel column chromatography (DCM: MeOH = 20: 1-10: 1) to give 80 mg of methyl 4-(3-(ethyl(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)amino)propoxy)benzoate (compound D12-1) with a purity of 95% and a yield of 19.1% as a white solid.

[0437] Methyl 4-(3-(ethyl(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)amino)propoxy)benzoate (compound D12-1) (80 mg, 0.12 mmol, 1 eq) was placed in a 25 mL round-bottom flask, 5 mL of THF and 3 mL of water and sodium hydroxide (48 mg, 1.2 mmol, 10 eq) were added, and the mixture was reacted at 70 ° C for 7 h. The pH was adjusted to neutral with 1 mol / L aqueous hydrochloric acid solution, and the mixture was concentrated and dried to obtain a crude product, which was washed with 10 mL of water and dried to obtain 4-(3-(ethyl(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)amino)propoxy)benzoic acid (compound D12-2) 90 mg, with a yield of 98%, a purity of 95%, and a white solid.

[0438] 4-(3-(ethyl(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)amino)propoxy)benzoic acid (Compound D12-2) (90 mg, 0.137 mmol, 1 eq) and (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (Compound C) (66 mg, 0.137 mmol, 1 eq) were placed in a 25 mL round-bottom flask, and 5 mL of DMF and DIPEA (68 mg, 0.548 mmol, 4 eq), stirred for 10 min, HATU (78 mg, 0.21 mmol, 1.5 eq) was added, and the reaction was reacted at room temperature for 20 min. The reaction solution was concentrated, and the crude product was purified by pre-HPLC to give (2S,4R)-1-((S)-2-(4-(3-(ethyl(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)amino)propoxy)benzamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (compound D12) 30 mg with a purity of 97% and a yield of 20.2% as a white solid. 1 H-NMR (400MHz, DMSO-d6): δ9.01(s,1H),8.44(d,J=8Hz,1H),7.85-7.94(m,7H),7.74-7.80(m,2H),7.69(d,J=8.4Hz,1H),7.56(s,1H),7.46( d,J=8.0Hz,2H),7.40(d,J=8.0Hz,1H),7.24(dd,J=9.2Hz,1.6Hz,2H),7.05(d,J=8.8Hz,2H),6.74(d,J=8.4Hz,2H),6.60(d,J=9.2Hz,2H),5. 16 (m, 1H), 4.94 (m, 1H), 4.76 (m, 1H), 4.46 (m, 1H), 4.33 (s, 3H), 4.27 (t, J = 5.6 Hz, 2H), 4.05 (t, J = 6 Hz, 2H), 3.77 (m, 2H), 3.23 (s, 4H), 2.96 (m, 2H), 2.45 (s, 3H), 2.30 (s, 3H), 2.03-2.08 (m, 1H), 1.79-1.85 (m, 1H), 1.40 (d, J = 7.2 Hz, 2H), 1.26 (s, 1H), 1.16 (t, J = 7.2 Hz, 3H), 1.03 (s, 9H). MS calculated value: 1081.4; MS found value: 1080.3 [MH]- . 13

[0440] Example 13 Synthesis of (2S,4R)-4-hydroxy-1-((S)-2-(2-(2-(4-(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)piperazin-1-yl)ethoxy)acetamido)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 13)

[0441] The overall synthetic route is as follows:

[0442]

[0443] The specific steps are as follows:

[0444] Tert-butyl bromoacetate (Compound B13-1) (13.8 g, 0.1 mol, 1 eq) was placed in 50 mL of anhydrous THF and cooled in an ice bath. NaH (4.8 g, 0.12 mmol, 1.2 eq, 60 wt%) was added in batches, replaced with nitrogen, and stirred for 30 min. 2-benzyloxyethanol (Compound B13-2) (13.5 g, 0.07 mol, 0.7 eq) was added and reacted at room temperature for 24 h. The reaction solution was diluted with 400 mL of ice water, separated, and the pH of the aqueous phase was adjusted to neutral with 6 mol / L aqueous hydrochloric acid solution. The solution was extracted with ethyl acetate (50 mL×2), separated, and the organic phase was dried and concentrated to obtain 4 g of 2-(2-(benzyloxy)ethoxy)acetic acid (Compound B13-3) with a yield of 27.6% as a colorless oil.

[0445] 2-(2-(Benzyloxy)ethoxy)acetic acid (Compound B13-3) (4 g, 17.8 mmol) was placed in 50 mL of methanol, cooled in an ice bath, and 5 mL of thionyl chloride was slowly added dropwise. The mixture was reacted at room temperature for 1 h, concentrated, dissolved in 20 mL of dichloromethane, and washed with 15 mL of water twice. After separation, the organic phase was concentrated and dried to obtain 4 g of methyl 2-(2-(benzyloxy)ethoxy)acetate (Compound B13-4) with a yield of 94% as a colorless oil.

[0446] 2-(2-(benzyloxy)ethoxy)acetic acid methyl ester (Compound B13-4) (4 g, 17.8 mmol, 1 eq) was placed in 50 mL of THF, 1 g of wet palladium / carbon (10 wt%) was added, and the reaction was hydrogenated at room temperature for 10 h. The mixture was filtered and the filtrate was concentrated to obtain 1.76 g of 2-(2-hydroxyethoxy)acetic acid methyl ester (Compound B13-5) with a yield of 73.3% as a colorless oil.

[0447] 2-(2-hydroxyethoxy)acetic acid methyl ester (compound B13-5) (1.76 g, 13.13 mmol, 1 eq) was placed in 30 mL of anhydrous dichloromethane, and TsCl (5 g, 26.26 mmol, 2 eq) and triethylamine (4 g, 39.39 mmol, 3 eq) were added. The reaction was carried out at room temperature for 24 h. The reaction solution was washed with 30 mL × 2 of water, the liquid was separated, the organic phase was concentrated, and the crude product was purified by silica gel column (PE: EA = 4: 1) to obtain 2-(2-(p-toluenesulfonyloxy)ethoxy)acetic acid methyl ester (compound B13) 1.8 g, with a yield of 47.6%, a purity of 95%, and a reddish-brown liquid.

[0448] 5-(4-(2-bromoethoxy)phenoxy)-6-(4-(methylsulfonyl)phenyl)-2-naphthol (Compound A1-9) (400 mg, 0.78 mmol, 1 eq) and tert-butyloxycarbonylpiperazine (Compound A3-1) (282 mg, 1.56 mmol, 2 eq) were placed in 10 mL of DMF, DIPEA (187 mg, 1.56 mmol, 2 eq) was added, and the mixture was reacted at 80°C for 10 h. The mixture was concentrated to dryness, and the crude product was purified by flash column chromatography (DCM:MeOH=10:1) to give 400 mg of tert-butyl 4-(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)piperazine-1-carboxylate (Compound A3-2) with a purity of 95% and a yield of 85% as a yellow solid.

[0449] tert-Butyl 4-(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)piperazine-1-carboxylate (Compound A3-2) (400 mg, 0.65 mmol, 1 eq) was placed in 5 mL of anhydrous dichloromethane and cooled in an ice bath. Boron tribromide (1.61 mL, 1.61 mmol, 2.5 eq, 1 mol / L, solvent DCM) was slowly added and the reaction was allowed to proceed for 20 min. 10 mL of methanol was slowly added under ice bath conditions to quench the reaction. The reaction solution was concentrated to give 700 mg of 6-(4-(methylsulfonyl)phenyl)-5-(4-(2-(piperazin-1-yl)ethoxy)phenoxy)-2-naphthol hydrobromide (Compound A3) with a purity of 60% as a gray solid.

[0450] 6-(4-(Methylsulfonyl)phenyl)-5-(4-(2-(piperazin-1-yl)ethoxy)phenoxy)-2-naphthol hydrobromide (Compound A3) (700 mg, 1.17 mmol, 1 eq) and Compound B13 (288 mg, 1 mmol, 1 eq) were placed in 10 mL of DMF, DIPEA (369 mg, 3 mmol, 3 eq) was added, and the mixture was reacted at 70°C for 8 h. The reaction solution was concentrated, and the crude product was purified by flash column chromatography to give 300 mg of methyl 2-(2-(4-(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)piperazin-1-yl)ethoxy)acetate (Compound D13-1) with a purity of 70% as a light yellow solid.

[0451] Methyl 2-(2-(4-(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)piperazin-1-yl)ethoxy)acetic acid (compound D13-1) (300 mg, 0.473 mmol, 1 eq) was placed in 5 mL of THF and 5 mL of water, and sodium hydroxide (94.6 mg, 2.37 mmol, 5 eq) was added. The mixture was reacted at 80° C. for 5 h. After cooling, the pH was adjusted to 7. The reaction solution was concentrated to dryness to obtain 300 mg of a crude product, which was washed with 10 mL of water, filtered, and dried to obtain 200 mg of 2-(2-(4-(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)piperazin-1-yl)ethoxy)acetic acid (compound D13-2) with a purity of 85% and a yield of 68.2% as a light yellow solid.

[0452] 2-(2-(4-(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)piperazin-1-yl)ethoxy)acetic acid (Compound D13-2) (100 mg, 0.161 mmol, 1 eq) and (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrole-2-carboxamide hydrochloride (Compound C) (77.4 mg, 0.161 mmol, 1 eq) were placed in 5 mL of anhydrous DMF, DIPEA (59.4 mg, 0.483 mmol, 3 eq) was added and stirred for 10 min. HATU (91 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated at 40 ° C. The crude product was dissolved in 20 mL of DCM and washed with water 15 mL × 2. The organic phase was dried and concentrated to give a crude product which was purified by pre-HPLC to give (2S, 4R)-4-hydroxy-1-((S)-2-(2-(2-(4-(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)piperidinyl-1-yl)ethoxy)acetamido)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (compound D13) 13 mg with a purity of 98% and a yield of 7.7% as a white solid. 1H-NMR (400MHz, DMSO-d6): δ10.07.01(s,1H),9.00(s,1H),8.45(d,J=7.6Hz,1H),7.91-7.93(d,J=8.4Hz,2H),7.85(d,J=8.0Hz,2H),7.72-7.7 9(m,2H),7.60(d,J=8.8Hz,1H),7.46(d,J=8.4Hz,2H),7.38(d,J=7.6Hz,2H),7.33(d,J=8.4Hz,1H),7.27(s,1H),7.11(dd,J=8.0Hz,1.2Hz,2H) ,6.75(d,J=7.2Hz,1H),6.60(d,J=4.8Hz,2H),5.15(s,1H),4.93-4.97 (m,1H),4.55(d,J=9.2Hz,1H),4.45-4.49(m,1H),4.32(s,1H),3.81-3. 95(m,6H),3.52-3.61(m,6H),3.25(s,3H),2.66(m,8H),2.48(s,3H),2. 03-2.08(m,1H),1.79-1.85(m,1H),1.40(d,J=7.2Hz,3H),0.88(s,9H). MS calculated value: 1046.4; MS experimental value: 1047.3 [M+H] + . 14

[0454] Example 14 Synthesis of (2S,4R)-1-((S)-2-(2-((5-(ethyl(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)amino)n-pentyl)oxy)acetamido)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Compound D14)

[0455] The overall synthetic route is as follows:

[0456]

[0457] The specific steps are as follows:

[0458] Take 5-(4-(2-(ethylamino)ethoxy)phenoxy)-6-(4-(methylsulfonyl)phenyl)naphthalen-2-ol (Compound A1) (200 mg, 0.42 mmol, 1.0 eq), 2-((5-(p-toluenesulfonyloxy)n-pentyl)oxy)ethyl acetate (Compound B14) (288 mg, 0.84 mmol, 2.0 eq) and DIPEA (163 mg, 1.26 mmol, 3.0 eq) and place them in 5 mL The reaction mixture was stirred in DMF, heated to 80°C for 3 hours, and the reaction solvent was removed by concentration to give an oily crude product. The crude product was purified by flash column chromatography on silica gel (MeOH / DCM = 0%-9%) to give 160 mg of ethyl 2-((5-(ethyl(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)amino)n-pentyl)oxy)acetic acid ethyl ester (compound D14-1) with a purity of 90% and a yield of 64.7% as a yellow oil.

[0459] Ethyl 2-((5-(ethyl(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)amino)n-pentyl)oxy)acetic acid (compound D14-1) (160 mg, 0.25 mmol, 1.0 eq) and lithium hydroxide monohydrate (31 mg, 0.74 mmol, 2.9 eq) were placed in 3 mL of ethanol and 2 mL of water, and the mixture was reacted at 50° C. for half an hour. The pH of the reaction solution was adjusted to 3-4, and the reaction solution was concentrated to dryness to obtain 200 mg of 2-((5-(ethyl(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)amino)n-pentyl)oxy)acetic acid (compound D14-2) as a white solid.

[0460] 2-((5-(ethyl(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)amino)n-pentyl)oxy)acetic acid (compound D14-2) (50 mg, 0.06 mmol, 1 eq) and HATU (30 mg, 0.08 mmol, 1.3 eq) were placed in 2 mL of anhydrous DMF and stirred at room temperature. 3 mL of DMF solution of (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride (compound C1) (34 mg, 0.08 mmol, 1.3 eq) and DIPEA (39 mg, 0.30 mmol, 5.0 eq) were added dropwise, and the mixture was stirred at room temperature for 0.5 h. Concentration to dryness gave a crude product, which was purified by pre-HPLC (ACN / H2O = 5%-70%, 0.1% FA in water / 0.1% FA in ACN) to afford 13.2 mg of (2S,4R)-1-((S)-2-(2-((5-(ethyl(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)amino)n-pentyl)oxy)acetamido)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Compound D14) with a purity of 97% and a yield of 20.7% as a white solid. MS calculated: 1033.4; MS observed: 1032.3 [MH] - . 15

[0462] Example 15 Synthesis of (2S,4R)-1-((S)-2-(4-(2-(ethyl(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)amino)ethoxy)benzamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound D15)

[0463] The overall synthetic route is as follows:

[0464]

[0465] The specific steps are as follows:

[0466] 5-(4-(2-(ethylamino)ethoxy)phenoxy)-6-(4-(methylsulfonyl)phenyl)-2-naphthol (Compound A1) (100 mg, 0.21 mmol, 1 eq) and methyl 4-(2-(p-toluenesulfonyloxy)ethoxy)benzoate (Compound B15) (183 mg, 0.52 mmol, 2.5 eq) were placed in 5 mL of DMF, and DIPEA (65 mg, 0.52 mmol, 1 eq) was added. The reaction mixture was stirred for 10 h at 70 ° C. The reaction mixture was concentrated and the crude product was purified by flash column chromatography (DCM:MeOH=20:1-10:1) to give 90 mg of methyl 4-(2-(ethyl(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)amino)ethoxy)benzoate (compound D15-1) with a purity of 95% and a yield of 65.6% as a white solid.

[0467] Methyl 4-(2-(ethyl(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)amino)ethoxy)benzoate (compound D15-1) (90 mg, 0.137 mmol, 1 eq) was placed in a 25 mL round-bottom flask, 5 mL of THF and 4 mL of water and sodium hydroxide (54.8 mg, 1.37 mmol, 10 eq) were added, and the mixture was reacted at 70 ° C for 8 h. The pH was adjusted to neutral with 1 mol / L aqueous hydrochloric acid solution, and the mixture was concentrated and dried to obtain 110 mg of 4-(2-(ethyl(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)amino)ethoxy)benzoic acid (compound D15-2) as a white solid.

[0468] 4-(2-(ethyl(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)amino)ethoxy)benzoic acid (Compound D15-2) (110 mg, 0.171 mmol, 1 eq) and (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (Compound C) (83 mg, 0.171 mmol, 1 eq) were placed in a 25 mL round-bottom flask, and 5 mL of DMF and DIPEA (62 mg, 0.51 mmol, The mixture was stirred for 10 min, HATU (97 mg, 0.26 mmol, 1.5 eq) was added, and the reaction was allowed to react at room temperature for 20 min. The reaction solution was concentrated, and the crude product was purified by pre-HPLC to give 8 mg of (2S,4R)-1-((S)-2-(4-(2-(ethyl(2-(4-((6-hydroxy-2-(4-(methylsulfonyl)phenyl)naphthalen-1-yl)oxy)phenoxy)ethyl)amino)ethoxy)benzamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (compound D15) with a purity of 97% and a yield of 4.3% as a white solid. 1H-NMR (400MHz, DMSO-d6): δ9.01(s,1H),8.42(d,J=7.6Hz,1H),7.85-7.95(m,7H),7.76-7.81(m,2H),7.69(d,J=8.4Hz,1H),7.60(s,1H),7.46( d,J=8.0Hz,2H),7.42(d,J=8.0Hz,1H),7.27(dd,J=9.2Hz,2.0Hz,2H),7.09(d,J=8.8Hz,2H),6.82(d,J=9.2Hz,2H),6.66(d,J=9.2Hz,2H),5.16 (m, 1H), 4.93-4.97 (m, 1H), 4.76 (d, J = 8.8 Hz, 1H), 4.45-4.52 (m, 5H), 4.33 (s, 1H), 4.05 (t, J = 4.8 Hz, 2H), 4.05 (t, J = 6 Hz, 2H), 3.71 (m, 2H), 3.27 (s, 5H), 2.96 (m, 2H), 2.45 (s, 3H), 2.03-2.08 (m, 1H), 1.79-1.85 (m, 1H), 1.40 (d, J = 6.8 Hz, 2H), 1.26 (s, 2H), 1.16 (t, J = 7.2 Hz, 3H), 1.03 (s, 9H). MS calculated value: 1067.4; MS experimental value: 1066.3 [MH] - . 16

[0470] Example 16 Synthesis of (2S,4R)-1-((S)-2-(2-((5-(ethyl(2-(4-((2-(3-fluorobenzoyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenoxy)ethyl)amino)pentyl)oxy)acetamido)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound D16):

[0471] (1) Synthesis of (3-(4-(2-(ethylamino)ethoxy)phenoxy)-6-hydroxybenzo[b]thiophen-2-yl)(3-fluorophenyl)methanone (Compound A4):

[0472]

[0473] Malonic acid (50 g, 480.5 mmol) was added to a pyridine solution (300 mL) of p-anisaldehyde (Compound A4-1) (33.2 g, 240.2 mmol). Under N₂ protection, piperidine (16 mL) was added and the mixture was heated to reflux for one hour. Upon completion of the reaction, the reaction solution was poured into ice water, and hydrochloric acid (200 mL) was slowly added. The solid was filtered and dried under vacuum to afford p-anisyl acrylate (Compound A4-2) (40 g, 94% yield).

[0474] To p-Methoxyphenylacrylic acid (Compound A4-2) (36.5 g, 203.9 mmol) was added N,N-dimethylformamide (8.7 mL) and pyridine (4.3 mL) in a three-necked flask. Under nitrogen protection, 100 mL of thionyl chloride was slowly added, and the mixture was heated to 140°C and allowed to react for 1.5 hours. Upon completion of the reaction, petroleum ether (500 mL) was added and heated to 80°C. After 30 minutes, the solution was decanted and cooled until a solid precipitated. The solid was then filtered to obtain 3-chloro-6-methoxybenzo[b]thiophene-2-carbonyl chloride (Compound A4-3) (12 g, 23% yield).

[0475] 3-Chloro-6-methoxybenzo[b]thiophene-2-carboxylic acid chloride (Compound A4-3) (12.0 g, 46.0 mmol) and N-methyl-N-methoxyamine hydrochloride (Compound A4-4) (5.7 g, 92.0 mmol) were stirred in dichloromethane for 10 minutes. Under nitrogen protection, triethylamine (39 mL, 276.0 mmol) was slowly added at approximately 0°C. The reaction was allowed to react overnight at room temperature. After monitoring the reaction for completion, the pH was adjusted to neutral with dilute hydrochloric acid. The mixture was then extracted with ethyl acetate (100 mL x 2). The organic phases were combined, washed with saturated brine (100 mL), and separated to obtain the organic phase. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on a silica gel column (petroleum ether:ethyl acetate = 5:1) to obtain 3-chloro-N,6-dimethoxy-N-methylbenzo[b]thiophene-2-carboxamide (Compound A4-5) (9 g, 68% yield).

[0476] A solution of 3-chloro-N,6-dimethoxy-N-methylbenzo[b]thiophene-2-carboxamide (Compound A4-5) (9.0 g, 31.6 mmol) in anhydrous tetrahydrofuran (100 mL) was purged with nitrogen and slowly added with m-fluorophenylmagnesium bromide (Compound A4-6) (70 mL) under ice-cooling. The mixture was allowed to react overnight and monitored for completion. The mixture was extracted with ethyl acetate (200 mL x 2). The organic phases were combined, washed with saturated brine (200 mL), and separated to obtain the organic phase. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on a silica gel column (petroleum ether:ethyl acetate = 20:1) to obtain (3-chloro-6-methoxybenzo[b]thiophen-2-yl)(3-fluorophenyl)methanone (Compound A4-7) (10 g, 98% yield).

[0477] (3-Chloro-6-methoxybenzo[b]thiophen-2-yl)(3-fluorophenyl)methanone (Compound A4-7) (11 g, 34.4 mmol) and p-bromophenol (Compound A4-8) (6.5 g, 37.8 mmol) were dissolved in N,N-dimethylformamide (20 mL). Cesium carbonate (34 g, 103.2 mmol) was added, the nitrogen atmosphere was replaced, and the mixture was allowed to react overnight at room temperature. TLC confirmed the completion of the reaction. Water (80 mL) and ethyl acetate (40 mL x 2) were added for extraction. The organic phases were combined, washed with saturated brine (80 mL), and separated to obtain an organic phase. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column (petroleum ether:ethyl acetate = 0-2%) to give (3-(4-bromophenol)-6-methoxybenzo[b]thiophen-2-yl)(3-fluorophenyl)methanone (compound A4-9) (10 g, yield 74%).

[0478] (3-(4-bromophenol)-6-methoxybenzo[b]thiophen-2-yl)(3-fluorophenyl)methanone (Compound A4-9) (12 g, 26.3 mmol) was dissolved in dioxane and water (20 mL), and potassium hydroxide (2.2 g, 39.4 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (8 g, 21.0 mmol), and tris(dibenzylideneacetone)dipalladium (4.8 mg, 5.2 mmol) were added respectively. The atmosphere was replaced with nitrogen three times and stirred at 115°C for 16 h. The starting material disappeared after TLC detection. Ethyl acetate (40 mL) was added for separation, and the aqueous phase was extracted once more with ethyl acetate (40 mL). The organic phases were combined, washed with saturated brine (40 mL), and separated to obtain the organic phase. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column (petroleum ether:ethyl acetate = 0-10%) to give (3-fluorophenyl)(3-(4-hydroxyphenoxy)-6-methoxybenzo[b]thiophen-2-ylmethanone (Compound A4-10) (6 g, yield 56%).

[0479] (3-Fluorophenyl)(3-(4-hydroxyphenoxy)-6-methoxybenzo[b]thiophen-2-ylmethanone (Compound A4-10) (6.5 g, 16.5 mmol) and dibromoethane (Compound A4-11) (15.5 g, 82.5 mmol) were dissolved in acetonitrile (50 mL), and cesium carbonate (16.2 g, 49.5 mmol) was added thereto. The nitrogen atmosphere was replaced, and the reaction system was heated to 90°C and stirred for 16 hours. The reaction was complete when detected by TLC. The solvent was dried and extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with saturated brine (50 mL), and separated to obtain an organic phase. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on a silica gel column (petroleum ether:ethyl acetate = 0-3%) to obtain (3-(4-(2-bromoethoxy)phenoxy)-6-methoxybenzo[b]thiophen-2-yl)(3-fluorophenyl)methanone (Compound A4-12) (3.5 g, yield 45%).

[0480] (3-(4-(2-bromoethoxy)phenoxy)-6-methoxybenzo[b]thiophen-2-yl)(3-fluorophenyl)methanone (Compound A4-12) (3.5 g, 7.0 mmol) was dissolved in N,N-dimethylformamide (20 mL), and a tetrahydrofuran solution of compound ethylamine (Compound A4-13) (35 mL, 1 M) was added. The mixture was then replaced with nitrogen three times, and the reaction system was heated to 80°C and stirred for 16 hours. TLC detected that the reaction was complete, and water (50 mL) and ethyl acetate (50 mL) were added, the layers were separated, and the aqueous phase was extracted once with ethyl acetate (50 mL). The organic phases were combined, washed with saturated brine (50 mL), and the layers were separated to obtain an organic phase. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column (dichloromethane:methanol ester = 0-10%) to give (3-(4-(2-(ethylamino)ethoxy)phenoxy)-6-methoxybenzo[b]thiophen-2-yl)(3-fluorophenyl)methanone (Compound A4-14) (1.4 g, yield 42%).

[0481] (3-(4-(2-(ethylamino)ethoxy)phenoxy)-6-methoxybenzo[b]thiophen-2-yl)(3-fluorophenyl)methanone (Compound A4-14) (1.4 g, 3.0 mmol) was dissolved in anhydrous dichloromethane (10 mL), and a dichloromethane solution of boron trifluoride dimethyl sulfide (2M, 15 mL) was added. The atmosphere was then replaced with nitrogen three times, and the reaction system was heated from 0°C to 40°C and stirred for 16 hours. TLC detected that the reaction was complete, and water (20 mL) and ethyl acetate (30 mL) were added, the liquids were separated, and the aqueous phase was extracted once with ethyl acetate (30 mL). The organic phases were combined, washed with saturated brine (30 mL), and the liquids were separated to obtain an organic phase. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (3-(4-(2-(ethylamino)ethoxy)phenoxy)-6-hydroxybenzo[b]thiophen-2-yl)(3-fluorophenyl)methanone (Compound A4) (1.3 g, yield 20%).

[0482] (2) Synthesis of Compound B16:

[0483]

[0484] 5-(Benzyloxy)pentan-1-ol (Compound B16-1) (5 g, 25.78 mmol) was dissolved in toluene (50 mL). The reaction system was cooled to 0°C, sodium hydride (2.58 g, 65 mmol) was added, the atmosphere was purged with nitrogen three times, and the mixture was stirred for 0.5 hours. Then, chloroacetic acid (B16-2) (3.1 g, 33 mmol) was added. The reaction system was heated to 100°C and stirred for 16 hours. TLC indicated that the reaction was complete. Dilute hydrochloric acid was added to adjust the mixture to acidity. Water (50 mL) and ethyl acetate (50 mL) were added, the mixture was separated, and the aqueous phase was extracted once with ethyl acetate (20 mL). The organic phases were combined, washed with saturated brine (50 mL), and the mixture was separated to obtain the organic phase. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude 2-((5-(benzyloxy)pentyl)oxy)acetic acid (Compound B16-3) (6 g, 92.2% yield).

[0485] 2-((5-(Benzyloxy)pentyl)oxy)acetic acid (Compound B16-3) (6 g, 23.78 mmol) was dissolved in methanol (30 mL), followed by the addition of concentrated sulfuric acid (0.5 mL), displacement of nitrogen, heating to reflux, and stirring for 0.5 hours. TLC confirmed the reaction was complete, and the reaction solution was cooled to room temperature, the pH was adjusted to neutral with saturated sodium bicarbonate aqueous solution, and extracted with ethyl acetate (30 mL × 2). The organic phases were combined, washed with saturated brine (30 mL), and separated to obtain an organic phase. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on a silica gel column (petroleum ether:ethyl acetate = 0-20%) to obtain methyl 2-((5-(benzyloxy)pentyl)oxy)acetate (Compound B16-4) (4.8 g, yield 75.84%).

[0486] Methyl 2-((5-(benzyloxy)pentyl)oxy)acetate (compound B16-4) (4.8 g, 18.03 mmol) was dissolved in methanol (40 mL), and wet palladium / carbon (1 g, 10 wt%) and acetic acid (0.5 mL) were added sequentially. The mixture was replaced with a hydrogen balloon three times, and the temperature was raised to 40° C. and stirred for 16 hours. The reaction was determined to be complete by TLC. The mixture was filtered through celite and concentrated under reduced pressure to obtain methyl 2-((5-hydroxypentyl)oxy)acetate (B16-5) (3 g, 94.42% yield).

[0487] Methyl 2-((5-hydroxypentyl)oxy)acetate (B16-5) (3 g, 17 mmol) and p-toluenesulfonyl chloride (8.12 g, 42.6 mmol) were dissolved in dichloromethane (50 mL), followed by the addition of pyridine (15 mL). The atmosphere was replaced with nitrogen three times, and the reaction system was cooled to 0°C and stirred for 16 hours. TLC indicated that the reaction was complete, and a small amount of methanol was added to quench the reaction. Water (50 mL) was added, and the mixture was extracted with dichloromethane (50 mL × 2). The organic phases were combined, washed with saturated brine (30 mL), and separated to obtain an organic phase. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on a silica gel column (ethyl acetate:petroleum ether = 0-20%) to obtain methyl 2-((5-(p-toluenesulfonyloxy)pentyl)oxy)acetate (Compound B16) (1.3 g, yield 23.14%).

[0488] (3) Synthesis of (2S,4R)-1-((S)-2-(2-((5-(ethyl(2-(4-((2-(3-fluorobenzoyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenoxy)ethyl)amino)pentyl)oxy)acetamido)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound D16):

[0489]

[0490] (3-(4-(2-(Ethylamino)ethoxy)phenoxy)-6-hydroxybenzo[b]thiophen-2-yl)(3-fluorophenyl)methanone (Compound A4) (300 mg, 0.6 mmol) and methyl 2-((5-(p-toluenesulfonyloxy)pentyl)oxy)acetate (Compound B16) (1 g, 3.2 mmol) were dissolved in N,N-dimethylformamide (8 mL), and N,N-diisopropylethylamine (420 mg, 3.2 mmol) was added. The mixture was then purged with nitrogen three times, and the temperature of the reaction system was raised to 80°C and stirred for 16 hours. The reaction was completed by spot plate detection, and water (20 mL) and ethyl acetate (20 mL) were added. The layers were separated, and the aqueous phase was extracted once with ethyl acetate (20 mL). The organic phases were combined, washed with saturated brine (20 mL), and separated to obtain the organic phase. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by thick prep plate (dichloromethane:methanol ester = 0-10%) to give methyl 2-((5-(ethyl(2-(4-((2-(3-fluorobenzoyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenoxy)ethyl)amino)pentyl)oxy)acetate (compound D16-1) (160 mg, yield 42.8%).

[0491] Methyl 2-((5-(ethyl(2-(4-((2-(3-fluorobenzoyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenoxy)ethyl)amino)pentyl)oxy)acetate (Compound D16-1) (160 mg, 0.22 mmol) was dissolved in methanol (3 mL), tetrahydrofuran (6 mL), and water (3 mL). Lithium hydroxide (11 mg, 0.44 mmol) was added, the atmosphere was replaced with nitrogen, and the mixture was stirred at room temperature for 0.5 hours. The reaction was complete upon spot plate detection. The pH was adjusted to neutral with dilute hydrochloric acid and extracted with ethyl acetate (10 mL × 2). The organic phases were combined, washed with saturated brine (10 mL), and separated to obtain the organic phase. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by thin layer chromatography (dichloromethane:methanol = 0-10%) to give 2-((5-(ethyl(2-(4-((2-(3-fluorobenzoyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenoxy)ethyl)amino)pentyl)oxy)acetic acid (compound D16-2) (80 mg, yield 59.8%).

[0492] 2-((5-(ethyl(2-(4-((2-(3-fluorobenzoyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenoxy)ethyl)amino)pentyl)oxy)acetic acid (Compound D16-2) (80 mg, 0.16 mmol) was dissolved in N,N-dimethylformamide (6 mL), and N,N-diisopropylethylamine (90 mg, 0.68 mmol), 2-(7-benzotriazole)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenoxy)ethyl)amino)pentyl)oxy)acetic acid (Compound D16-2) was added in sequence. To the mixture was added (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound C) (130 mg, 0.30 mmol). The atmosphere was replaced with nitrogen and stirred at room temperature for 16 hours. The reaction was complete after spot detection, and the mixture was extracted with ethyl acetate (5 mL × 2). The organic phases were combined, washed with saturated brine (5 mL), and separated to obtain the organic phase. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by thin layer chromatography (dichloromethane:methanol = 0-20%) to give (2S,4R)-1-((S)-2-(2-((5-(ethyl(2-(4-((2-(3-fluorobenzoyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenoxy)ethyl)amino)pentyl)oxy)acetamido)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound D16) (12.9 mg, yield 8.1%). 1 H-NMR (400MHz, DMSO-d6) δ8.85(s,1H),8.48(s,1H),7.45(s,1H),7.37(t,J=8.5Hz,6H),7.22(s,3H),6.84(d,J=8 .4Hz,1H),6.75(s,2H),6.56(d,J=8.6Hz,2H),4.96(d,J=7.1Hz,1H),4.66(s,1H),4.53(s,1H),4.41(s,1H),4.16( s, 2H), 3.94 (d, J = 8.6 Hz, 2H), 3.81 (d, J = 11.5 Hz, 1H), 3.72 (d, J = 11.4 Hz, 1H), 3.54 (t, J = 6.0 Hz, 2H), 3.36 (s, 2H), 3.12 (s, 4H), 2.44 (s, 3H), 2.18 (s, 1H), 1.92 (s, 1H), 1.68 (s, 4H), 1.46 (d, J = 6.8 Hz, 5H), 1.26 (s, 3H), 0.99 (s, 9H). MS calculated: 1021.4; MS found: 1020.2 [MH]- . 17

[0494] Example 17 Synthesis of (2S,4R)-1-((S)-2-(2-(3-(ethyl(2-(4-((2-(3-fluorobenzoyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenoxy)ethyl)amino)propoxy)acetamido)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound D17):

[0495] (1) Synthesis of ethyl 2-(3-(p-toluenesulfonyloxy)propoxy)acetate (Compound B17):

[0496]

[0497] 1-Benzyloxypropanol (Compound B17-1) (10 g, 60.2 mmol) was dissolved in tetrahydrofuran (50 mL). The reaction system was cooled to 0°C and sodium hydride (2.88 g, 66.2 mmol) was added. The atmosphere was replaced with nitrogen three times and stirred for 0.5 hours. Ethyl bromoacetate (Compound B17-2) (11.05 g, 66.2 mmol) was then added. The reaction solution was allowed to warm to room temperature and stirred for 16 hours. TLC confirmed the reaction was complete. Dilute hydrochloric acid was added to adjust the mixture to acidity. Water (50 mL) and ethyl acetate (50 mL) were added and the mixture was separated. The aqueous phase was extracted once more with ethyl acetate (20 mL). The organic phases were combined, washed with saturated brine (30 mL), and separated to obtain the organic phase. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column (ethyl acetate:petroleum ether = 0-20%) to give ethyl 2-(3-(phenoxy)propoxy)acetate (compound B17-3) (4.75 g, yield 29.5%).

[0498] Ethyl 2-(3-(phenoxy)propoxy)acetate (Compound B17-3) (4.75 g, 18.78 mmol) was dissolved in methanol (40 mL), and wet palladium / carbon (1 g, 10 wt%) and acetic acid (0.5 mL) were added sequentially. The mixture was purged with a hydrogen balloon three times. The reaction mixture was heated to 40°C and stirred for 16 hours. After TLC, the reaction was complete. The mixture was filtered through celite and concentrated under reduced pressure to give crude ethyl 2-(3-hydroxypropyl)acetate (Compound B17-4) (3.0 g, 98% yield).

[0499] Ethyl 2-(3-hydroxypropyl)acetate (Compound B17-4) (3 g, 18.4 mmol) and p-toluenesulfonyl chloride (5.73 g, 30 mmol) were dissolved in dichloromethane (50 mL), followed by the addition of triethylamine (8.5 mL). The atmosphere was then replaced with nitrogen three times, and the reaction system was stirred at room temperature for 16 hours. TLC confirmed the reaction was complete, and water (50 mL) was added. The mixture was extracted with dichloromethane (50 mL × 2). The organic phases were combined, washed with saturated brine (40 mL), and separated to obtain an organic phase. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on a silica gel column (ethyl acetate:petroleum ether = 0-20%) to obtain ethyl 2-(3-(p-toluenesulfonyloxy)propoxy)acetate (Compound B17) (4.3 g, yield 73.72%).

[0500] (2) Preparation of (2S,4R)-1-((S)-2-(2-(3-(ethyl(2-(4-((2-(3-fluorobenzoyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenoxy)ethyl)amino)propoxy)acetamido)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound D17):

[0501]

[0502] (3-(4-(2-(Ethylamino)ethoxy)phenoxy)-6-hydroxybenzo[b]thiophen-2-yl)(3-fluorophenyl)methanone (Compound A4) (300 mg, 0.6 mmol) and ethyl 2-(3-(p-toluenesulfonyloxy)propoxy)acetate (Compound B17) (1 g, 3.2 mmol) were dissolved in N,N-dimethylformamide (8 mL), and N,N-diisopropylethylamine (420 mg, 3.2 mmol) was added. The atmosphere was then purged with nitrogen three times, and the reaction system was heated to 80°C and stirred for 16 hours. The reaction was complete as determined by spot plate detection, and water (20 mL) and ethyl acetate (20 mL) were added for extraction. The aqueous phase was extracted once more with ethyl acetate (20 mL). The organic phases were combined, washed with saturated brine (2 mL), and separated to obtain the organic phase. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by thin layer chromatography (dichloromethane:methanol ester = 0-10%) to give ethyl 2-(3-(ethyl(2-(4-((2-(3-fluorobenzoyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenoxy)ethyl)amino)propoxy)acetic acid)ethyl ester (compound D17-1) (160 mg, yield 44.7%).

[0503] Ethyl 2-(3-(ethyl(2-(4-((2-(3-fluorobenzoyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenoxy)ethyl)amino)propoxy)acetate (Compound D17-1) (160 mg, 0.22 mmol) was dissolved in methanol (3 mL), tetrahydrofuran (6 mL), and water (3 mL). Lithium hydroxide (11 mg, 0.44 mmol) was added, the atmosphere was replaced with nitrogen, and the mixture was stirred at room temperature for 0.5 hours. The reaction was complete upon spot plate detection. The pH was adjusted to neutral with dilute hydrochloric acid and extracted with ethyl acetate (10 mL × 2). The organic phases were combined, washed with saturated brine (10 mL), and separated to obtain the organic phase. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by thin layer chromatography (dichloromethane:methanol = 0-10%) to give 2-(3-(ethyl(2-(4-((2-(3-fluorobenzoyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenoxy)ethyl)amino)propoxy)acetic acid (compound D17-2) (50 mg, yield 40%).

[0504] 2-(3-(ethyl(2-(4-((2-(3-fluorobenzoyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenoxy)ethyl)amino)propoxy)acetic acid (Compound D17-2) (50 mg, 0.1 mmol) was dissolved in N,N-dimethylformamide (6 mL), and N,N-diisopropylethylamine (57 mg, 0.4 mmol), 2-(7-benzotriazole oxide) and 1,2-dihydro-1,3-dihydro-2-nitrobenzoyl)- ... )-N,N,N',N'-tetramethyluronium hexafluorophosphate (37 mg, 0.1 mmol) was added, and finally (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound C) (79 mg, 0.2 mmol) was added. The atmosphere was replaced with nitrogen, and the mixture was stirred at room temperature for 16 hours. The reaction was completed after spot detection, and the mixture was extracted with ethyl acetate (5 mL × 2). The organic phases were combined, washed with saturated brine (5 mL), and separated to obtain the organic phase. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by thin layer chromatography (dichloromethane:methanol=0-20%) to give a crude product (30 mg), which was then purified by preparative liquid chromatography to give (2S,4R)-1-((S)-2-(2-(3-(ethyl(2-(4-((2-(3-fluorobenzoyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenoxy)ethyl)amino)propoxy)acetamido)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound D17) (4.3 mg, 4.3% yield). 1H-NMR (400MHz, DMSO-d6) δ8.84(s,1H),7.96(d,J=7.9Hz,1H),7.66(d,J=8.1Hz,2H),7.47-7.30(m,6H),7.22(s ,1H),7.15(d,J=6.6Hz,3H),7.02(s,1H),6.85-6.74(m,3H),6.59(d,J=7.9Hz,2H),4.55(s,2H),4.42(s,1H),4. 26 (s, 2H), 4.09 (s, 2H), 3.89 (d, J = 10.9 Hz, 1H), 3.77 (s, 1H), 3.45 (s, 1H), 2.98 (s, 3H), 2.81 (s, 0H), 2.74 (d, J = 7.0 Hz, 4H), 2.45 (s, 3H), 2.16 (s, 1H), 1.93 (s, 2H), 1.58 (s, 1H), 1.40 (d, J = 6.3 Hz, 2H), 1.27 (s, 3H), 1.05 (s, 7H). MS calculated: 993.4; MS found: 992.2 [MH] - . 18

[0506] Example 18 Synthesis of Compound 18:

[0507] (1) Synthesis of Compound A5:

[0508]

[0509] (3-Fluorophenyl)(3-(4-hydroxyphenoxy)-6-methoxybenzo[b]thiophen-2-yl)methanone (Compound A5-1) (2 g, 5.0 mmol) and 1-Boc-4-iodoazetidine (Compound A5-2) (7.1 g, 25.0 mmol) were dissolved in acetonitrile (50 mL), and cesium carbonate (4.9 g, 15 mmol) was added thereto to replace nitrogen. The reaction system was heated to 90 ° C and stirred for 16 hours. The reaction was completed by spot plate detection, the solvent was dried, 50 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL×2). After the organic phases were combined, they were washed with saturated brine (50 mL) and separated to obtain an organic phase. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column (petroleum ether:ethyl acetate = 0-3%) to give tert-butyl 3-(4-((2-(3-fluorobenzoyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenoxy)azetidine-1-carboxylate (compound A5-3) (1.2 g, yield 52%).

[0510] 3-(4-((2-(3-fluorobenzoyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenoxy)azetidine-1-carboxylic acid tert-butyl ester (Compound A5-3) (1.2 g, 2.2 mmol) was placed in a single-necked bottle and dissolved with ethyl acetate (5 mL). Then, a solution of hydrogen chloride in ethyl acetate (50 mL, 2 M) was added thereto. After stirring at room temperature for 2 hours, LCMS was sent to detect whether the reaction was complete. After drying by spin drying, (3-(4-(azetidine-3-oxy)phenoxy)-6-methoxybenzo[b]thiophen-2-yl)(3-fluorophenyl)methanone hydrochloride (Compound A5-4) (1.0 g, yield 40%) was obtained.

[0511] (3-(4-(azetidine-3-oxy)phenoxy)-6-methoxybenzo[b]thiophene-2-yl)(3-fluorophenyl)methanone hydrochloride (Compound A5-4) (0.9 g, 2.0 mmol) was dissolved in anhydrous dichloromethane (10 mL), and a dichloromethane solution of boron trifluoride dimethyl sulfide complex (2M, 8 mL) was added, and then nitrogen was replaced three times. The reaction system was heated to 40°C and stirred for 16 hours. The reaction was complete after spot plate detection, and water (20 mL) and ethyl acetate (30 mL) were added, the liquids were separated, and the aqueous phase was extracted once more with ethyl acetate (30 mL). The organic phases were combined, washed with saturated brine (30 mL), and the liquids were separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (3-(4-(azetidine-3-oxy)phenoxy)-6-hydroxybenzo[b]thiophene-2-yl)(3-fluorophenyl)methanone (Compound A5) (0.5 g, yield 57%).

[0512] (2) Synthesis of (2S,4R)-1-((S)-2-(2-(3-(3-(4-((2-(3-fluorobenzoyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenoxy)azetidin-1-yl)propoxy)acetamido)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound D18):

[0513]

[0514] (3-(4-(azetidine-3-oxy)phenoxy)-6-hydroxybenzo[b]thiophene-2-yl)(3-fluorophenyl)methanone (0.6 g, 1.3 mmol) (Compound A5) and ethyl 2-(3-(p-toluenesulfonyloxy)propoxy)acetate (Compound B17) (1.2 g, 3.8 mmol) were dissolved in N,N-dimethylformamide (8 mL), and N,N-diisopropylethylamine (0.82 g, 6.3 mmol) was added. The mixture was then replaced with nitrogen three times, and the reaction system was heated to 80°C and stirred for 16 hours. The reaction was complete after spot plate detection, and water (20 mL) and ethyl acetate (20 mL) were added, the liquids were separated, and the aqueous phase was extracted once with ethyl acetate (20 mL). The organic phases were combined, washed with saturated brine (2 mL), separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by thick preparative plate (dichloromethane:methanol ester = 0-10%) to give ethyl 2-(3-(3-(4-((2-(3-fluorobenzoyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenoxy)azetidin-1-yl)propoxy)acetate (compound D18-1) (0.5 g, yield 68%).

[0515] Ethyl 2-(3-(3-(4-((2-(3-fluorobenzoyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenoxy)azetidin-1-yl)propoxy)acetate (Compound D18-1) (500 mg, 0.86 mmol) was dissolved in methanol (3 mL), tetrahydrofuran (6 mL), and water (3 mL). Lithium hydroxide (42 mg, 1.73 mmol) was added, the atmosphere was replaced with nitrogen, and the mixture was stirred at room temperature for half an hour. The reaction was complete after spot plate detection. The pH was adjusted to neutral with dilute hydrochloric acid and extracted with ethyl acetate (10 mL × 2). The organic phases were combined, washed with saturated brine (10 mL), and separated to obtain the organic phase. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by thick preparative plate (dichloromethane:methanol = 0-10%) to give 2-(3-(3-(4-((2-(3-fluorobenzoyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenoxy)azetidin-1-yl)propoxy)acetic acid (compound D18-2) (160 mg, yield 34%).

[0516] 2-(3-(3-(4-((2-(3-fluorobenzoyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenoxy)azetidin-1-yl)propoxy)acetic acid (compound D18-2) (160 mg, 0.3 mmol) was dissolved in N,N-dimethylformamide (6 mL), and N,N-diisopropylethylamine (190 mg, 1.5 mmol), 2-(7-benzotriazole)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenoxy)azetidin-1-yl)propoxy)acetic acid was added in sequence. To the mixture was added (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound C) (79 mg, 0.2 mmol). The atmosphere was replaced with nitrogen and stirred at room temperature for 16 hours. The reaction was complete after spot detection, and the mixture was extracted with ethyl acetate (5 mL × 2). The organic phases were combined, washed with saturated brine (5 mL), and separated to obtain the organic phase. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by thick preparative plate (dichloromethane:methanol=0-20%) to give a crude product (100 mg), which was sent for purification by preparative liquid chromatography to give (2S,4R)-1-((S)-2-(2-(3-(3-(4-((2-(3-fluorobenzoyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenoxy)azetidin-1-yl)propoxy)acetamido)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound D18) (40.0 mg, yield 14%). 1 H-NMR (400MHz, DMSO-d6) δ8.85(s,1H),7.38(dd,J=17.4,8.2Hz,8H),7.24(d,J=16.9Hz,3H),6.85(d, J=8.8Hz,1H),6.64(d,J=8.6Hz,2H),6.55(d,J=8.9Hz,2H),4.94(s,3H),4.57(d,J=12.5Hz,3H),4.39 (s, 3H), 4.08 (s, 2H), 3.90 (d, J = 32.8 Hz, 3H), 3.69 (d, J = 10.1 Hz, 4H), 3.59 (s, 0H), 3.16 (s, 1H), 2.45 (s, 3H), 2.15 (d, J = 7.8 Hz, 1H), 1.89 (d, J = 17.1 Hz, 3H), 1.44 (d, J = 6.7 Hz, 3H), 1.27 (s, 4H), 1.03 (s, 9H). MS calcd: 977.4; MS found: 978.5 [M+H] + . 19

[0518] Example 19 Synthesis of (2S,4R)-1-((S)-2-(2-(ethyl(2-(4-((2-(3-fluorobenzoyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenoxy)ethyl)amino)acetamido)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound D19):

[0519] (1) Synthesis of ethyl 2-(p-toluenesulfonyloxy)acetate (Compound B18):

[0520]

[0521] Ethyl 2-hydroxyacetate (Compound B18-1) (1.0 g, 9.6 mmol) was dissolved in dichloromethane (10 mL), and pyridine (4 mL) and p-toluenesulfonyl chloride (3.6 g, 19.2 mmol) were added, respectively. The atmosphere was then purged with nitrogen three times, and the reaction system was warmed to room temperature and stirred for 3 hours. TLC confirmed the reaction was complete, and water (10 mL) and dichloromethane (10 mL) were added, followed by separation. The aqueous phase was extracted once with dichloromethane (10 mL). The organic phases were combined, washed with saturated brine (10 mL), and separated to obtain an organic phase. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on a silica gel column (petroleum ether:ethyl acetate = 0-30%) to obtain ethyl 2-(p-toluenesulfonyloxy)acetate (Compound B18) (1.0 g, 41% yield).

[0522] (2) Synthesis of (2S,4R)-1-((S)-2-(2-(ethyl(2-(4-((2-(3-fluorobenzoyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenoxy)ethyl)amino)acetamido)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound D19):

[0523]

[0524] (3-(4-(2-(Ethylamino)ethoxy)phenoxy)-6-hydroxybenzo[b]thiophen-2-yl)(3-fluorophenyl)methanone (Compound A4) (0.8 g, 1.8 mmol) and ethyl 2-(p-toluenesulfonyloxy)acetate (Compound B18) (1.3 g, 5.3 mmol) were dissolved in N,N-dimethylformamide (8 mL), and N,N-diisopropylethylamine (1.1 g, 8.9 mmol) was added. The atmosphere was then replaced with nitrogen three times, and the reaction system was heated to 80°C and stirred for 16 hours. The reaction was completed by spot plate detection, and water (20 mL) and ethyl acetate (20 mL) were added, the layers were separated, and the aqueous phase was extracted once with ethyl acetate (20 mL). The organic phases were combined, washed with saturated brine (2 mL), and the layers were separated to obtain the organic phase. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the organic solvent. The mixture was purified by thick preparative plate (dichloromethane:methanol ester = 0-10%) to give N-ethyl-N-(2-(4-((2-(3-fluorobenzoyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenoxy)ethyl)glycine ethyl ester (Compound D19-1) (0.5 g, yield 52%).

[0525] N-ethyl-N-(2-(4-((2-(3-fluorobenzoyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenoxy)ethyl)glycine ethyl ester (Compound D19-2) (Compound D19-1) (0.5 g, 0.9 mmol) was dissolved in methanol (3 mL), tetrahydrofuran (6 mL), and water (3 mL). Lithium hydroxide (0.05 mg, 1.9 mmol) was added, the atmosphere was replaced with nitrogen, and the mixture was stirred at room temperature for half an hour. The reaction was complete after spot plate detection. The pH was adjusted to neutral with dilute hydrochloric acid and extracted with ethyl acetate (10 mL × 2). The organic phases were combined, washed with saturated brine (10 mL), and separated to obtain the organic phase. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by thick preparative plate (dichloromethane:methanol = 0-10%) to give N-ethyl-N-(2-(4-((2-(3-fluorobenzoyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenoxy)ethyl)glycine (compound D19-2) (230 mg, yield 46%).

[0526] N-ethyl-N-(2-(4-((2-(3-fluorobenzoyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenoxy)ethyl)glycine (Compound D19-2) (0.23 g, 0.4 mmol) was dissolved in N,N-dimethylformamide (6 mL), and N,N-diisopropylethylamine (0.3 g, 2.3 mmol), 2-(7-benzotriazole oxide)- N,N,N',N'-tetramethyluronium hexafluorophosphate (0.2 g, 0.5 mmol) was added, and finally (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound C) (0.2 g, 0.5 mmol). The atmosphere was replaced with nitrogen and stirred at room temperature for 16 hours. The reaction was complete after spotting, and the mixture was extracted with ethyl acetate (5 mL x 2). The organic phases were combined, washed with saturated brine (5 mL), and separated to obtain the organic phase. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by thick preparative plate (dichloromethane:methanol=0-20%) to give a crude product (230 mg), which was then sent for preparative liquid chromatography to purify (2S,4R)-1-((S)-2-(2-(ethyl(2-(4-((2-(3-fluorobenzoyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenoxy)ethyl)amino)acetamido)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound D19) (98 mg, 23% yield). 1 H-NMR (400MHz, DMSO-d6) δ8.89 (s, 0H), 7.51-7.34 (m, 1H), 7.26 (d, J = 23.6Hz, 0H), 6. 83(dd,J=27.5,8.3Hz,0H),6.58(d,J=8.0Hz,0H),4.99(s,0H),4.78-4.68(m,0H),4. 52 (s, 0H), 4.24 (t, J = 69.1 Hz, 1H), 3.76 (dd, J = 63.7, 23.0 Hz, 0H), 3.49-3.30 (m, 1H), 2.46 (s, 0H), 2.04 (d, J = 83.9 Hz, 0H), 1.48 (d, J = 6.9 Hz, 3H), 1.34 (s, 3H), 1.02 (s, 9H). MS calculated: 935.3; MS found: 936.3 [M+H] + . 20

[0528] Example 20 Synthesis of (2S,4R)-1-((S)-2-(3-(4-(2-(4-((2-(3-fluorobenzoyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenoxy)ethyl)piperazin-1-yl)propionamido)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound D20):

[0529] (1) Synthesis of 1-piperazinylpropionic acid ethyl ester (Compound B19):

[0530]

[0531] Compound 1-Boc-piperazine (B19-1) (0.8 g, 1.6 mmol) and ethyl bromopropionate (compound B19-2) (0.6 g, 3.2 mmol) were dissolved in acetonitrile (50 mL), and potassium carbonate (1.1 g, 8.0 mmol) was added thereto to replace the nitrogen. The reaction system was heated to 90°C and stirred for 16 hours. TLC detection showed that the reaction was complete, and water (80 mL) and ethyl acetate (80 mL) were added, and the liquids were separated. The aqueous phase was extracted once with ethyl acetate (80 mL). The organic phases were combined, washed with saturated brine (80 mL), and separated to obtain an organic phase. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude tert-butyl 4-(3-ethoxy-3-oxopropyl)piperazine-1-carboxylate (compound B19-3) (15 g, yield 90%).

[0532] tert-Butyl 4-(3-ethoxy-3-oxopropyl)piperazine-1-carboxylate (Compound B19-3) (10.0 g, 35.0 mmol) was dissolved in ethyl acetate (50 mL), and then hydrogen chloride ethyl acetate solution (45 mL, 90 mmol, 2 M) was added thereto. The mixture was concentrated under reduced pressure to obtain crude ethyl 1-piperazinylpropionate (Compound B19) (12 g, yield 95%).

[0533] (2) Synthesis of (2S,4R)-1-((S)-2-(3-(4-(2-(4-((2-(3-fluorobenzoyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenoxy)ethyl)piperazin-1-yl)propionamido)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound D20):

[0534]

[0535] (3-(4-(2-bromoethoxy)phenoxy)-6-methoxybenzo[b]thiophen-2-yl)(3-fluorophenyl)methanone (Compound A4-12) (0.8 g, 1.6 mmol) and ethyl 1-piperazinylpropionate (Compound B19) (0.6 g, 3.2 mmol) were dissolved in acetonitrile (50 mL), and potassium carbonate (1.1 g, 8.0 mmol) was added thereto to replace nitrogen. The reaction system was heated to 90°C and stirred for 16 hours. The reaction was completed by spot plate detection, the solvent was dried, and the mixture was extracted with ethyl acetate (50 mL×2). The organic phases were combined, washed with saturated brine (50 mL), and separated to obtain an organic phase. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column (dichloromethane:methanol = 0-10%) to give ethyl 3-(4-(2-(4-((2-(3-fluorobenzoyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenoxy)ethyl)piperazin-1-yl)propanoate (compound D20-1) (0.4 g, yield 39%).

[0536] Ethyl 3-(4-(2-(4-((2-(3-fluorobenzoyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenoxy)ethyl)piperazin-1-yl)propanoate (Compound D20-1) (0.4 g, 0.6 mmol) was dissolved in anhydrous dichloromethane (10 mL), and a dichloromethane solution of boron trifluoride dimethyl sulfide complex (2M, 2 mL) was added. The atmosphere was then replaced with nitrogen three times, and the reaction system was heated to 40°C and stirred for 16 hours. The reaction was complete after spot plate detection, and water (20 mL) and ethyl acetate (30 mL) were added, the liquids were separated, and the aqueous phase was extracted once with ethyl acetate (30 mL). The organic phases were combined, washed with saturated brine (30 mL), and the liquids were separated to obtain the organic phase. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give ethyl 3-(4-(2-(4-((2-(3-fluorobenzoyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenoxy)ethyl)piperazin-1-yl)propanoate (compound D20-2) (0.1 g, yield 29%).

[0537] Ethyl 3-(4-(2-(4-((2-(3-fluorobenzoyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenoxy)ethyl)piperazin-1-yl)propanoate (Compound D20-2) (0.1 g, 0.2 mmol) was dissolved in methanol (3 mL), tetrahydrofuran (6 mL), and water (3 mL). Lithium hydroxide (9 mg, 0.4 mmol) was added, the atmosphere was replaced with nitrogen, and the mixture was stirred at room temperature for half an hour. The reaction was complete upon spot plate detection. The pH was adjusted to neutral with dilute hydrochloric acid and extracted with ethyl acetate (10 mL x 2). The organic phases were combined, washed with saturated brine (10 mL), and separated to obtain the organic phase. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by thick preparative plate (dichloromethane:methanol = 0-10%) to give 3-(4-(2-(4-((2-(3-fluorobenzoyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenoxy)ethyl)piperazin-1-yl)propanoic acid (Compound D20-3) (76 mg, yield 73%).

[0538] 3-(4-(2-(4-((2-(3-fluorobenzoyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenoxy)ethyl)piperazin-1-yl)propanoic acid (Compound D20-3) (76 mg, 0.135 mmol) and (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound C) (64.5 mg, 0.135 mmol) were dissolved in N,N-dimethylformamide (8 mL), and N,N-diisopropylethylamine (52 mg, 0.4 mmol), 2-(7-benzotriazole oxide)-N,N, N', N'-tetramethyluronium hexafluorophosphate (51.3 mg, 0.135 mmol) was replaced with nitrogen, reacted at room temperature for 30 min, and concentrated under reduced pressure. The crude product was purified by thick preparative plate (dichloromethane: methanol = 0-20%) to give a crude compound (120 mg), which was then sent to preparative liquid phase for purification to give (2S, 4R)-1-((S)-2-(3-(4-(2-(4-((2-(3-fluorobenzoyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenoxy)ethyl)piperazin-1-yl)propionamido)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (compound D20) (40 mg, yield 30%). 1H-NMR (400MHz, DMSO-d6) δ8.87(s,1H),8.47(s,0H),8.40(s,0H),7.39(d,J=7.2Hz,7H),7.23(s,3H),6.85(d,J=9.2Hz,1H) ,6.76(d,J=8.4Hz,2H),6.67-6.44(m,2H),4.99(d,J=7.1Hz,2H),4.61(s,1H),4.51(t,J=10.0Hz,1H),4.41(s,1H),4.12(d, J = 38.4 Hz, 2H), 3.85 (d, J = 10.3 Hz, 1H), 3.71 (d, J = 10.9 Hz, 1H), 3.58 (d, J = 10.6 Hz, 1H), 3.45 (s, 1H), 3.05 (d, J = 44.3 Hz, 9H), 2.57 (s, 2H), 2.44 (d, J = 10.8 Hz, 4H), 2.17 (s, 1H), 1.97 (d, J = 33.6 Hz, 1H), 1.56 (s, 2H), 1.47 (d, J = 6.9 Hz, 3H), 1.02 (s, 9H). MS calcd: 990.4; MS found: 991.3 [M+H] + . twenty one

[0540] Example 21 Synthesis of (2S,4R)-1-((S)-2-(2-(2-(ethyl(2-(4-((2-(3-fluorobenzoyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenoxy)ethyl)amino)ethoxy)acetamido)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound D21):

[0541] (1) Synthesis of ethyl 2-(2-(p-toluenesulfonyloxy)ethoxy)acetate (Compound B20):

[0542]

[0543] 2-Benzyloxyethanol (Compound B20-1) (6 g, 21.4 mmol) was dissolved in toluene (50 mL). The reaction mixture was cooled to 0°C, sodium hydride (2.8 g, 58.1 mmol) was added, the atmosphere was replaced with nitrogen three times, and the mixture was stirred for 0.5 hours. Ethyl bromoacetate (Reactant B20-2) (3.4 g, 35.5 mmol) was then added. The reaction mixture was heated to 100°C and stirred for 16 hours. TLC confirmed the reaction was complete, and dilute hydrochloric acid was added to adjust the mixture to acidity. Water (50 mL) and ethyl acetate (50 mL) were added, and the mixture was separated. The aqueous phase was extracted once more with ethyl acetate (50 mL). The organic phases were combined, washed with saturated brine (50 mL), and separated to obtain the organic phase. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude ethyl 2-(2-(benzyloxy)ethoxy)acetate (Compound B20-3) (2.5 g, 20% yield).

[0544] Ethyl 2-(2-(benzyloxy)ethoxy)acetate (Compound B20-3) (2.3 g, 9.6 mmol) was dissolved in methanol (40 mL), and wet palladium / carbon (0.5 g, 10 wt%) and acetic acid (0.5 mL) were added sequentially. The mixture was replaced with a hydrogen balloon three times, and the temperature was raised to 40° C. and stirred for 16 hours. The reaction was detected to be complete by TLC. The mixture was filtered through celite and concentrated under reduced pressure to obtain crude ethyl 2-(2-hydroxyethoxy)acetate (Compound B20-4) (1.3 g, 90% yield).

[0545] Ethyl 2-(2-hydroxyethoxy)acetate (Compound B20-4) (1.3 g, 8.8 mmol) and p-toluenesulfonyl chloride (2.5 g, 13.2 mmol) were dissolved in dichloromethane (50 mL). The reaction solution was cooled to 0°C, triethylamine (10 mL) was added, and then the atmosphere was replaced with nitrogen three times. Stirring was continued for 16 hours. TLC showed that the reaction was complete and a small amount of methanol was added to quench the reaction. Water (30 mL) was added and the mixture was extracted with dichloromethane (20 mL × 2). The organic phases were combined, washed with saturated brine (20 mL), and separated to obtain an organic phase. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on a silica gel column (ethyl acetate:petroleum ether = 0-30%) to obtain ethyl 2-(2-(p-toluenesulfonyloxy)ethoxy)acetate (Compound B20) (2 g, yield 80%).

[0546] (2) Synthesis of (2S,4R)-1-((S)-2-(2-(2-(ethyl(2-(4-((2-(3-fluorobenzoyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenoxy)ethyl)amino)ethoxy)acetamido)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound D21):

[0547]

[0548] (3-(4-(2-(Ethylamino)ethoxy)phenoxy)-6-hydroxybenzo[b]thiophen-2-yl)(3-fluorophenyl)methanone (Compound A4) (300 mg, 0.66 mmol) and ethyl 2-(2-(p-toluenesulfonyloxy)ethoxy)acetate (Compound B20) (402 mg, 1.34 mmol) were dissolved in N,N-dimethylformamide (5 mL), and N,N-diisopropylethylamine (430 mg, 3.3 mmol) was added. The mixture was then purged with nitrogen three times, and the reaction system was heated to 80°C and stirred for 16 hours. The reaction was completed by spot plate detection, and water (20 mL) and ethyl acetate (20 mL) were added. The layers were separated, and the aqueous phase was extracted once with ethyl acetate (20 mL). The organic phases were combined, washed with saturated brine (2 mL), and separated to obtain the organic phase. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by thin layer chromatography (dichloromethane:methanol ester = 0-10%) to give ethyl 2-(2-(ethyl(2-(4-((2-(3-fluorobenzoyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenoxy)ethyl)amino)ethoxy)acetic acid)ethyl ester (compound D21-1) (95 mg, yield 24.5%).

[0549] Ethyl 2-(2-(ethyl(2-(4-((2-(3-fluorobenzoyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenoxy)ethyl)amino)ethoxy)acetate (Compound D21-1) (95 mg, 0.17 mmol) was dissolved in methanol (3 mL), tetrahydrofuran (6 mL), and water (3 mL). Lithium hydroxide (8 mg, 0.34 mmol) was added, the atmosphere was replaced with nitrogen, and the mixture was stirred at room temperature for half an hour. The reaction was complete upon spot plate detection. The pH was adjusted to neutral with dilute hydrochloric acid and extracted with ethyl acetate (10 mL × 2). The organic phases were combined, washed with saturated brine (10 mL), and separated to obtain an organic phase. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the organic solvent. The mixture was purified by thin layer chromatography (dichloromethane:methanol = 0-10%) to give 2-(2-(ethyl(2-(4-((2-(3-fluorobenzoyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenoxy)ethyl)amino)ethoxy)acetic acid (compound D21-2) (75 mg, yield 82.8%).

[0550] 2-(2-(ethyl(2-(4-((2-(3-fluorobenzoyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenoxy)ethyl)amino)ethoxy)acetic acid (Compound D21-2) (75 mg, 0.14 mmol) was dissolved in N,N-dimethylformamide (6 mL), and N,N-diisopropylethylamine (87.5 mg, 0.68 mmol), 2-(7-benzoyloxy)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenoxy)ethyl)amino)ethoxy)acetic acid (Compound D21-2) was added in sequence. To the mixture was added (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound C) (90 mg, 0.2 mmol). The atmosphere was replaced with nitrogen and stirred at room temperature for 16 hours. The reaction was complete after spot detection, and the mixture was extracted with ethyl acetate (5 mL × 2). The organic phases were combined, washed with saturated brine (5 mL), and separated to obtain the organic phase. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by thin layer chromatography (dichloromethane:methanol = 0-20%) to give (2S,4R)-1-((S)-2-(2-(2-(ethyl(2-(4-((2-(3-fluorobenzoyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenoxy)ethyl)amino)ethoxy)acetamido)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound D21) (13.2 mg, yield 9.8%). 1 H-NMR (400MHz, DMSO-d6) δ8.92(s,1H),7.49–7.36(m,7H),7.25(d,J=21.8Hz,3H),6.86(d,J=9.1Hz,1H) ,6.77(d,J=8.5Hz,2H),6.55(d,J=9.1Hz,2H),4.96(s,1H),4.62(s,1H),4.51(s,2H),4.38(s,1H),4.27( s, 2H), 4.08 (t, J = 11.9 Hz, 2H), 3.84 (dd, J = 32.6, 11.8 Hz, 3H), 3.66 (d, J = 13.4 Hz, 3H), 3.47 (s, 2H), 3.39 (s, 2H), 2.46 (s, 3H), 2.17 (s, 1H), 1.92 (s, 1H), 1.46 (d, J = 7.2 Hz, 2H), 1.37 (s, 3H), 1.00 (d, J = 9.6 Hz, 9H). MS calculated: 979.3; MS found: 978.6 [MH] - .

[0551] Test Example 1

[0552] 1. Degradation effect on target protein

[0553] (1) Human breast cancer MCF-7 cells (ATCC; Catalog No.: HTB-22) were grown in a mixture containing 10% fetal bovine serum and 90% MEM medium and seeded into a 24-well transparent tissue culture plate at a concentration of 100,000 cells / mL.

[0554] (2) On the next day, a treatment solution consisting of the compound of the present invention and DMSO was added to the cell-containing mixture in step (1) to treat MCF-7 cells; the final concentrations of the compound of the present invention in each well were 1000 nM, 250 nM, 63 nM, 16 nM, 4 nM, 1 nM, 0.24 nM, 0.06 nM, 0.015 nM, and 0.004 nM, respectively, and each well contained 0.2 v% DMSO, with the remaining 99.8 v% in each well being the mixture in step (1).

[0555] (3) After 4 hours, remove the liquid from the wells and wash with cold phosphate buffer. Then, remove the phosphate buffer with a pipette and discard. Lyse the cells with 80 μL / well of 4°C cell lysis buffer (manufacturer: Cel1 Signaling Technology; Cat. No. 9803). Clarify the lysate at 16,000 x g for 10 minutes, and analyze 2 μg of protein by SDS-PAGE to separate the test protein ERα.

[0556] (4) Analysis was performed according to standard Western blotting methods, wherein the antibodies used were ERα (manufacturer: Cel1 Signaling Technology, catalog number: 13288) and GAPDH (manufacturer: Cel1 Signaling Technology; catalog number: 2118S); and the detection reagent was SuperSignal West Femto Maximum Sensitivity Substrate (manufacturer: Thermo scientific, catalog number: 34095).

[0557] DC50 (drug concentration corresponding to 50% protein degradation) was calculated based on the grayscale values ​​of the corresponding Western blotting bands after treatment with the compounds of the present invention using curve fitting of the Sigmoidal Dose-Response Model of XLFIT; Dmax = [(maximum ERα level - minimum ERα level) / (maximum ERα level)].

[0558] 2. Effect of inhibiting cell proliferation

[0559] 2.1 Cell lines

[0560] MCF-7 (ATCC; Catalog No.: HTB-22) is a non-drug-resistant and non-mutated Luminal A breast cancer cell line;

[0561] MCF-7ER D538G MCF-7 (ATCC; Catalog No.: HTB-22) was constructed by CRISPR-Cas9 gene editing technology. It is a tamoxifen and fulvestrant-resistant ER D538G Mutated Luminal A breast cancer cells;

[0562] TamR-MCF-7 (ATCC; Catalog No.: CRL-3435) is a tamoxifen-resistant and non-mutated breast cancer cell line.

[0563] 2.2 Reagents

[0564] Culture medium EMEM (Gibco, 1964507),

[0565] Fetal bovine serum (Gibco, 10091148)

[0566] Penicillin-streptomycin dual antibody (Gibco, S110JV)

[0567] DPBS (Gibco, 14190-144)

[0568] Detection kit (Promega, G7573)

[0569] Pancreatin (0.25%) (Gibco, 25200-056)

[0570] DMSO (Sigma, D2650)

[0571] 2.3 Instruments

[0572] Biological safety cabinet (Sujing Antai, BSC-1300A II)

[0573] Automated cell counter (Life Technologies, Countess II)

[0574] Multifunctional microplate reader (Biotek, H1FM)

[0575] Shaking table (Hangzhou Aosheng Instrument Co., Ltd., OS-100)

[0576] XLFIT 5.3 (Shanghai Jiuzhan Information Technology Co., Ltd.)

[0577] 4. Test Method

[0578] This test method is carried out in a biological safety cabinet. The specific steps are as follows:

[0579] (1) Cells were seeded in a 96-well plate (using EMEM as the culture medium). After one day, the previous EMEM medium was discarded and 5 mL of DPBS was added to wash the cells. The DPBS was then aspirated and discarded. 1 mL of trypsin was then added and the cells were incubated at 37°C in a cell culture incubator containing 5% CO2 for approximately 2-5 minutes. Fresh EMEM medium was added and the cells were pipetted up and down to resuspend them evenly. The cells were then counted using an automated cell counter.

[0580] (2) Each cell was seeded with 2000 or 1000 cells in 100 μL of EMEM (the seeding density was 2000 cells for MCF-7 and TamR-MCF-7, and 1000 cells for MCF-7ER). D538G Cells were seeded at a seeding density of 1000 cells per well in columns 1 to 11 of a 96-well plate (Corning, Cat. No. 3610). 100 μL of cell-free EMEM medium was added to the well in column 12. The plates were then incubated at 37°C, 5% CO2 for 24 hours.

[0581] (3) Then, the compound of the present invention and the control drug fulvestrant (selleck; catalog number: S1191) were diluted 4-fold starting at 10 μM to 10 dose points (wherein, there were 10 columns of well plates; the concentration of the first column of the well plate was the highest, and the concentration of the well plate in the last column was the lowest). 10 μL of the serially diluted compound was taken with a pipette and added to 100 μL of cells in columns 1 to 10. 10 μL of culture medium EMEM containing 0.33 v% DMSO was added to columns 11 and 12. The cells were placed in a 37°C, 5 v% CO2 incubator and incubated for 6 days (Note: column 11 was used as the MAX well, which contained cells but no compound; column 12 was used as the MIN well, which contained no cells or compound).

[0582] (4) After 6 days of treatment with the compound of the present invention, the above The cell activity detection reagent in the detection kit was added to a 96-well plate at 50 μL per well, placed on a shaker in the dark for 5-10 minutes, and then the cell activity was measured using a multifunctional microplate reader. Finally, the inhibition of cell proliferation by the compound of the present invention was plotted using XLFIT software and the half-inhibitory concentration (IC) of the compound of the present invention was calculated. 50 Value and maximum inhibition percentage IH%max.

[0583] Table 1 The degradation effect of each compound on the target protein and the cell proliferation inhibitory activity

[0584]

[0585]

[0586] In the above table, the prior art refers to the compound disclosed in Discovery of ERD-308 as a Highly Potent Proteolysis Targeting Chimera (PROTAC) Degrader of Estrogen Receptor (ER), and the structural formula is shown below:

[0587]

[0588] As can be seen from the table above, compared with the prior art fulvestrant, the targeted chimeric compound of the present invention has comparable or even better inhibitory activity on the proliferation of mutant drug-resistant cells against estrogen receptor α (specifically, against mutant drug-resistant cells MCF-7ER D538G The maximum inhibition percentage IH%max) is expected to show comparable or even better therapeutic efficacy.

[0589] Although specific embodiments of the present invention have been described above, those skilled in the art will appreciate that these are merely illustrative and that the scope of the present invention is defined by the appended claims. Those skilled in the art may make various changes or modifications to these embodiments without departing from the principles and essence of the present invention, and such changes and modifications are intended to fall within the scope of the present invention.

Claims

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

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

3. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 2 in the preparation of a medicament for treating estrogen-dependent diseases, The estrogen-dependent disease is tamoxifen and / or fulvestrant-resistant and ER D538G Mutated Luminal A breast cancer.

4. The use according to claim 3, wherein The estrogen-dependent disease is resistant to tamoxifen and fulvestrant and ER D538G Mutated Luminal A breast cancer.

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