Preparation method and application of a class of compounds

Abstract

The present invention provides a preparation method and application of a class of compounds, relating to the field of pharmaceutical chemistry technology. Such compounds are compounds represented by Formula I, or salts thereof, or stereoisomers thereof, or solvates thereof, or hydrates thereof, or prodrugs thereof. Such compounds can effectively inhibit the proliferation activity of various breast cancer cells, among which triple-negative breast cancer cells and doxorubicin-resistant cells have good proliferation inhibition activity, and can also effectively inhibit their migration; at the same time, such compounds have good estrogen receptor α downregulation activity, showing the application prospects of such compounds in cancer treatment, especially in breast cancer treatment. In addition, studies have found that such compounds have good inhibitory activity against coronaviruses, without obvious toxic side effects, and can be used as a new choice of drugs for the prevention and treatment of coronaviruses.

Description

Technical Field

[0001] The present invention relates to the technical field of medicinal chemistry, and in particular to a preparation method and application of a class of compounds. Background Art

[0002] Cancer has become one of the most common diseases worldwide. Breast cancer is divided into three categories based on receptor expression: estrogen receptor (ER)-positive, HER2-positive, and triple-negative breast cancer. Estrogen receptor-positive patients account for over 70% of all breast cancers, and endocrine therapy targeting the ER signaling pathway is currently one of the mainstays of clinical treatment. Most commonly used therapeutic drugs target the ER, but long-term use of endocrine therapy drugs, such as tamoxifen, can lead to drug resistance. ERα is highly expressed in 80% of patients with advanced breast cancer. Therefore, the use of selective estrogen receptor downregulators (SERDs) to degrade ERα, thereby truly blocking the ER signaling pathway at the protein level, is expected to overcome the drug resistance problem that occurs clinically.

[0003] Fulvestrant is currently the only FDA-approved SERD. Upon binding to the estrogen receptor, it enhances ubiquitination and degradation, significantly reducing ERα levels in cells. It can inhibit the proliferation of tamoxifen-resistant breast cancer cells, but poor oral bioavailability necessitates intramuscular administration, limiting its widespread application. Various structurally modified compounds based on the tamoxifen nucleus have been reported, but most are complex and difficult to synthesize.

[0004] Ophiobolin compounds belong to the class of dipterpenoids and have a characteristic C5-C8-C5 tricyclic nucleus structure. This class of compounds has significant cytotoxic activity against a variety of tumor cells. Literature reports that a series of ophiobolin derivatives were isolated and identified from the secondary metabolites of mangrove fungus 094102. Among them, 6-epi-ophiobolinG (abbreviated as MHO7) showed good estrogen receptor degradation activity and could inhibit ESR1 transcription and synthesis of hnRNA and corresponding mRNA in ER-positive breast cancer cells. It can also compete with estradiol for the binding site of estrogen receptors and inhibit the proliferation of cancer cells (Pharmacol Res, 146 (2019) 104294). However, there are still problems with low efficacy and bioavailability. Structural modification is conducive to its development into a new anti-tumor drug.

[0005] Crews et al. first proposed a technique for inducing degradation of HaloTag fusion proteins using a small molecule hydrophobic tag (Nat Chem Biol 7, 538–543 (2011)). They subsequently demonstrated the ability of Boc3-Arg to induce protein degradation. By linking the covalent inhibitor etacrynic acid to Boc3-Arg, glutathione S-transferase α1 (GST-α1) was targeted for degradation. Similarly, the non-covalent inhibitor trimethoprim, coupled to Boc3-Arg, was shown to degrade dihydrofolate reductase at micromolar concentrations.

[0006] By using chemical structure modification methods, hydrophobic tags are embedded into ophiopogonidin to synthesize new ophiopogonidin compounds, prepare new molecules for ERα degradation, and develop drugs targeting ERα. Summary of the Invention

[0007] The primary purpose of the present invention is to overcome the deficiencies of the prior art and provide a pyrocatechol compound and its application. The pyrocatechol compound has the activity of inhibiting the proliferation of ER-positive breast cancer cells and targeting ERα degradation, and also has a significant inhibitory effect on the growth and metastasis of triple-negative breast cancer and adriamycin-resistant breast cancer, and also has an inhibitory effect on viruses. It can be developed as a new anti-cancer and antiviral drug and has broad application prospects.

[0008] Another object of the present invention is to provide a method for preparing the above-mentioned ophiopogonin compounds. In the synthesis, different routes are used to efficiently obtain the target compound, and a synthetic route with strong applicability and high yield is summarized.

[0009] The third object of the present invention is to provide the use of the above-mentioned ophiopogonidin compounds as selective estrogen receptor degraders in the preparation of anti-tumor and antiviral drugs; in particular, it provides the use of the above-mentioned ophiopogonidin compounds in the preparation of anti-breast cancer drugs.

[0010] In order to achieve the above object, the present invention adopts the following technical solutions:

[0011] The present invention provides a compound represented by Formula I, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a hydrate thereof, or a prodrug thereof:

[0012]

[0013] in,

[0014] R1, R2, and R3 are independently selected from hydrogen, C1-C8 alkyl, hydroxyl, or halogen; or R3 and R2 are connected to form a double bond, and R1 is selected from hydrogen, C1-C8 alkyl, hydroxyl, or halogen;

[0015] R4, R5, R7, R8, R9, R 10 are independently selected from hydrogen or C1-C8 alkyl;

[0016] R6 is selected from hydrogen, C1-C8 alkyl, hydroxy-substituted C1-C8 alkyl or aldehyde;

[0017] R 11 、R 12 are independently selected from hydrogen or C1-C8 alkyl; or R 11 With R 12 connect to form a double bond;

[0018] n is 0 or 1;

[0019] R 13 Selected from hydrogen or C1-C8 alkyl;

[0020] m is 0 or 1;

[0021] L is selected from none, -O-, -NR 15 -or-CR 16 R 17 ;

[0022] R 15 、R 16 、R 17 are independently selected from hydrogen or C1-C8 alkyl;

[0023] R 14 Selected from substituted or unsubstituted C1-C 14 Alkyl, substituted or unsubstituted C1~C 14 Alkenyl, substituted or unsubstituted C1~C 14 Alkynyl, substituted or unsubstituted 5-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 3-6 membered heterocycloalkyl, -CH=CHR 18 、 Adamantyl, -(CH2) b OC(O)(CH2) c R 18 、-(CH2CH2O) b C(O)(CH2) c R 18 ;

[0024] a is an integer from 1 to 8;

[0025] b is an integer from 1 to 10;

[0026] c is an integer from 1 to 5;

[0027] R 18is selected from adamantyl, substituted or unsubstituted 5- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0028] The substituents of the alkyl, alkenyl and alkynyl groups are selected from carboxyl, substituted or unsubstituted 5-10 membered aryl, substituted or unsubstituted 5-10 membered heterocycloalkyl and adamantane;

[0029] The substituents of the aryl and heteroaryl groups are selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, trifluoromethyl, nitro, trifluoromethoxy, -C(O)CH=CHR 19 ;

[0030] The substituent of the heterocycloalkyl group is a C1-C8 alkyl group; or two substituents on the same carbon atom are connected to form =O;

[0031] R 19 Selected from 5-10 membered aryl groups,

[0032] The number of heteroatoms in the heteroaryl group is 1, 2 or 3, and the heteroatoms are selected from O, S or N;

[0033] The number of heteroatoms in the heterocycloalkyl group is 1, 2 or 3, and the heteroatoms are selected from O, S or N.

[0034] Furthermore, the compound is represented by Formula II:

[0035]

[0036] in,

[0037] R1, R2, and R3 are independently selected from hydrogen, C1-C8 alkyl, hydroxyl, or halogen; or R3 and R2 are connected to form a double bond, and R1 is selected from hydrogen, C1-C8 alkyl, hydroxyl, or halogen;

[0038] R5 is selected from hydrogen or C1-C8 alkyl;

[0039] for key or key;

[0040] R6 is selected from hydrogen, C1-C8 alkyl, hydroxy-substituted C1-C8 alkyl or aldehyde;

[0041] R 11 、R 12 are independently selected from hydrogen or C1-C8 alkyl; or R 11 With R 12 connect to form a double bond;

[0042] n is 0 or 1;

[0043] R13 Selected from hydrogen or C1-C8 alkyl;

[0044] m is 0 or 1;

[0045] L is selected from none, -O-, -NR 15 -or-CR 16 R 17 ;

[0046] R 15 、R 16 、R 17 are independently selected from hydrogen or C1-C8 alkyl;

[0047] R 14 Selected from substituted or unsubstituted C1-C 14 Alkyl, substituted or unsubstituted C1~C 14 Alkenyl, substituted or unsubstituted C1~C 14 Alkynyl, substituted or unsubstituted 5-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 3-6 membered heterocycloalkyl, -CH=CHR 18 、 Adamantyl, -(CH2) b OC(O)(CH2) c R 18 、-(CH2CH2O) b C(O)(CH2) c R 18 ;

[0048] a is an integer from 1 to 8;

[0049] b is an integer from 1 to 10;

[0050] c is an integer from 1 to 5;

[0051] R 18 is selected from adamantyl, substituted or unsubstituted 5- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0052] The substituents of the alkyl, alkenyl and alkynyl groups are selected from carboxyl, substituted or unsubstituted 5-10 membered aryl, substituted or unsubstituted 5-10 membered heterocycloalkyl and adamantane;

[0053] The substituents of the aryl and heteroaryl groups are selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, trifluoromethyl, nitro, trifluoromethoxy, -C(O)CH=CHR 19 ;

[0054] The substituent of the heterocycloalkyl group is a C1-C8 alkyl group; or two substituents on the same carbon atom are connected to form =O;

[0055] R 19 Selected from 5-10 membered aryl groups,

[0056] The number of heteroatoms in the heteroaryl group is 1, 2 or 3, and the heteroatoms are selected from O, S or N;

[0057] The number of heteroatoms in the heterocycloalkyl group is 1, 2 or 3, and the heteroatoms are selected from O, S or N.

[0058] Further,

[0059] R1, R2, and R3 are independently selected from hydrogen, C1-C3 alkyl, or hydroxyl; or R3 and R2 are connected to form a double bond, and R1 is selected from C1-C3 alkyl;

[0060] R5 is selected from hydrogen;

[0061] for key or key;

[0062] R6 is selected from C1-C3 alkyl, hydroxy-substituted C1-C3 alkyl or aldehyde;

[0063] R 11 、R 12 are independently selected from hydrogen or C1-C3 alkyl; or R 11 With R 12 connect to form a double bond;

[0064] n is 0 or 1;

[0065] R 13 Selected from hydrogen or C1-C3 alkyl;

[0066] m is 0 or 1;

[0067] L is selected from none, -O-, or -NR 15 -;

[0068] R 15 Selected from hydrogen or C1-C3 alkyl;

[0069] R 14 Selected from substituted or unsubstituted C1-C 12 Alkyl, C1-C4 alkenyl, C1-C4 alkynyl, substituted or unsubstituted phenyl, naphthyl, -CH=CHR 18 、 Adamantyl, -(CH2) b OC(O)(CH2) c R 18 or -(CH2CH2O)b C(O)(CH2) c R 18 ;

[0070] a is 1, 2, or 3;

[0071] b is 1, 2, 3, 4, 5, 6, 7 or 8;

[0072] c is 1, 2, or 3;

[0073] R 18 Selected from adamantyl, substituted or unsubstituted phenyl, thienyl, pyridyl, furyl or

[0074] The substituent of the alkyl group is selected from carboxyl, substituted or unsubstituted phenyl, or adamantane;

[0075] The substituents of the phenyl group are selected from C1-C3 alkyl, C1-C3 alkoxy, halogen, trifluoromethyl, nitro, trifluoromethoxy or -C(O)CH=CHR 19 ;

[0076] R 19 Selected from phenyl,

[0077] Furthermore, the compound is represented by formula III:

[0078]

[0079] in,

[0080] R 11 、R 12 are independently selected from hydrogen or C1-C3 alkyl; or R 11 With R 12 connect to form a double bond;

[0081] n is 0 or 1;

[0082] R 13 Selected from hydrogen or C1-C3 alkyl;

[0083] m is 0 or 1;

[0084] L is selected from none, -O-, or -NR 15 -;

[0085] R 15 Selected from hydrogen or C1-C3 alkyl;

[0086] R 14 Selected from substituted or unsubstituted C1-C 12Alkyl, C1-C4 alkenyl, C1-C4 alkynyl, substituted or unsubstituted phenyl, naphthyl, -CH=CHR 18 、 Adamantyl, -(CH2) b OC(O)(CH2) c R 18 or -(CH2CH2O) b C(O)(CH2) c R 18 ;

[0087] a is 1, 2, or 3;

[0088] b is 1, 2, 3, 4, 5, 6, 7 or 8;

[0089] c is 1, 2, or 3;

[0090] R 18 Selected from adamantyl, substituted or unsubstituted phenyl, thienyl, pyridyl, furyl or

[0091] The substituent of the alkyl group is selected from carboxyl, substituted or unsubstituted phenyl, or adamantane;

[0092] The substituents of the phenyl group are selected from C1-C3 alkyl, C1-C3 alkoxy, halogen, trifluoromethyl, nitro, trifluoromethoxy or -C(O)CH=CHR 19 ;

[0093] R 19 Selected from phenyl,

[0094] Alternatively, the compound is represented by formula IV:

[0095]

[0096] in,

[0097] R 11 、R 12 are independently selected from hydrogen or C1-C3 alkyl; or R 11 With R 12 connect to form a double bond;

[0098] n is 0 or 1;

[0099] R 13 Selected from hydrogen or C1-C3 alkyl;

[0100] m is 0 or 1;

[0101] L is selected from none, -O-, or -NR15 -;

[0102] R 15 Selected from hydrogen or C1-C3 alkyl;

[0103] R 14 Selected from substituted or unsubstituted C1-C 12 Alkyl, C1-C4 alkenyl, C1-C4 alkynyl, substituted or unsubstituted phenyl, naphthyl, -CH=CHR 18 、 Adamantyl, -(CH2) b OC(O)(CH2) c R 18 or -(CH2CH2O) b C(O)(CH2) c R 18 ;

[0104] a is 1, 2, or 3;

[0105] b is 1, 2, 3, 4, 5, 6, 7 or 8;

[0106] c is 1, 2, or 3;

[0107] R 18 Selected from adamantyl, substituted or unsubstituted phenyl, thienyl, pyridyl, furyl or

[0108] The substituent of the alkyl group is selected from carboxyl, substituted or unsubstituted phenyl, or adamantane;

[0109] The substituents of the phenyl group are selected from C1-C3 alkyl, C1-C3 alkoxy, halogen, trifluoromethyl, nitro, trifluoromethoxy or -C(O)CH=CHR 19 ;

[0110] R 19 Selected from phenyl,

[0111] Furthermore, the compound is represented by formula IIIa:

[0112]

[0113] in,

[0114] R 14 Selected from substituted or unsubstituted C1-C6 alkyl, -CH=CHR 18 ;

[0115] R 18Selected from adamantyl, substituted or unsubstituted phenyl, thienyl, pyridyl, furyl or

[0116] The substituent of the alkyl group is selected from carboxyl, substituted or unsubstituted phenyl, or adamantane;

[0117] The substituents of the phenyl group are selected from C1-C3 alkyl, C1-C3 alkoxy, halogen, trifluoromethyl, nitro, trifluoromethoxy or -C(O)CH=CHR 19 ;

[0118] R 19 Selected from phenyl,

[0119] Alternatively, the compound is represented by formula IIIb:

[0120]

[0121] in,

[0122] R 14 Selected from substituted or unsubstituted C1-C6 alkyl, -CH=CHR 18 ;

[0123] R 18 Selected from adamantyl, substituted or unsubstituted phenyl, thienyl, pyridyl, furyl or

[0124] The substituent of the alkyl group is selected from carboxyl, substituted or unsubstituted phenyl, or adamantane;

[0125] The substituents of the phenyl group are selected from C1-C3 alkyl, C1-C3 alkoxy, halogen, trifluoromethyl, nitro, trifluoromethoxy or -C(O)CH=CHR 19 ;

[0126] R 19 Selected from phenyl,

[0127] Alternatively, the compound is represented by formula IVa:

[0128]

[0129] in,

[0130] R 14 Selected from -(CH2CH2O) b C(O)(CH2) c R 18 ;

[0131] b is 1, 2, 3, 4, 5, 6, 7 or 8;

[0132] c is 1, 2, or 3;

[0133] R 18 selected from adamantyl groups;

[0134] Alternatively, the compound is represented by formula IVb:

[0135]

[0136] in,

[0137] R 14 Selected from -(CH2CH2O) b C(O)(CH2) c R 18 ;

[0138] b is 1, 2, 3, 4, 5, 6, 7 or 8;

[0139] c is 1, 2, or 3;

[0140] R 18 Selected from adamantyl groups.

[0141] Furthermore, the compound is represented by Formula V:

[0142]

[0143] in,

[0144] R 11 、R 12 are independently selected from hydrogen or C1-C8 alkyl; or R 11 With R 12 connect to form a double bond;

[0145] n is 0 or 1;

[0146] R 13 Selected from hydrogen or C1-C8 alkyl;

[0147] m is 0 or 1;

[0148] L is selected from none, -O-, -NR 15 -or-CR 16 R 17 ;

[0149] R 15 、R 16 、R 17 are independently selected from hydrogen or C1-C8 alkyl;

[0150] R 14Selected from substituted or unsubstituted C1-C 14 Alkyl, substituted or unsubstituted C1~C 14 Alkenyl, substituted or unsubstituted C1~C 14 Alkynyl, substituted or unsubstituted 5-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 3-6 membered heterocycloalkyl, -CH=CHR 18 、 Adamantyl, -(CH2) b OC(O)(CH2) c R 18 、-(CH2CH2O) b C(O)(CH2) c R 18 ;

[0151] a is an integer from 1 to 8;

[0152] b is an integer from 1 to 10;

[0153] c is an integer from 1 to 5;

[0154] R 18 is selected from adamantyl, substituted or unsubstituted 5- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0155] The substituents of the alkyl, alkenyl and alkynyl groups are selected from carboxyl, substituted or unsubstituted 5-10 membered aryl, substituted or unsubstituted 5-10 membered heterocycloalkyl and adamantane;

[0156] The substituents of the aryl and heteroaryl groups are selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, trifluoromethyl, nitro, trifluoromethoxy, -C(O)CH=CHR 19 ;

[0157] The substituent of the heterocycloalkyl group is a C1-C8 alkyl group; or two substituents on the same carbon atom are connected to form =O;

[0158] R 19 Selected from 5-10 membered aryl groups,

[0159] The number of heteroatoms in the heteroaryl group is 1, 2 or 3, and the heteroatoms are selected from O, S or N;

[0160] The number of heteroatoms of the heterocycloalkyl group is 1, 2 or 3, and the heteroatoms are selected from O, S or N;

[0161] Preferably,

[0162] R 11 、R 12 are independently selected from hydrogen or C1-C3 alkyl; or R11 With R 12 connect to form a double bond;

[0163] n is 0 or 1;

[0164] R 13 Selected from hydrogen or C1-C3 alkyl;

[0165] m is 0 or 1;

[0166] L is selected from none, -O-, or -NR 15 -;

[0167] R 15 Selected from hydrogen or C1-C3 alkyl;

[0168] R 14 Selected from substituted or unsubstituted C1-C 12 Alkyl, C1-C4 alkenyl, C1-C4 alkynyl, substituted or unsubstituted phenyl, naphthyl, -CH=CHR 18 、 Adamantyl, -(CH2) b OC(O)(CH2) c R 18 or -(CH2CH2O) b C(O)(CH2) c R 18 ;

[0169] a is 1, 2, or 3;

[0170] b is 1, 2, 3, 4, 5, 6, 7 or 8;

[0171] c is 1, 2, or 3;

[0172] R 18 Selected from adamantyl, substituted or unsubstituted phenyl, thienyl, pyridyl, furyl or

[0173] The substituent of the alkyl group is selected from carboxyl, substituted or unsubstituted phenyl, or adamantane;

[0174] The substituents of the phenyl group are selected from C1-C3 alkyl, C1-C3 alkoxy, halogen, trifluoromethyl, nitro, trifluoromethoxy or -C(O)CH=CHR 19 ;

[0175] R 19 Selected from phenyl,

[0176] Furthermore, the compound is represented by formula Va:

[0177]

[0178] in,

[0179] In the figure, when the dotted line is absent, it is a single bond; when the dotted line is a bond, it is a double bond;

[0180] R 14 Selected from substituted or unsubstituted C1-C 12 Alkyl, C1-C4 alkenyl, C1-C4 alkynyl, substituted or unsubstituted phenyl, naphthyl, -CH=CHR 18 、 Adamantyl, -(CH2) b OC(O)(CH2) c R 18 or -(CH2CH2O) b C(O)(CH2) c R 18 ;

[0181] a is 1, 2, or 3;

[0182] b is 1, 2, 3, 4, 5, 6, 7 or 8;

[0183] c is 1, 2, or 3;

[0184] R 18 Selected from adamantyl, substituted or unsubstituted phenyl, thienyl, pyridyl, furyl or

[0185] The substituent of the alkyl group is selected from carboxyl, substituted or unsubstituted phenyl, or adamantane;

[0186] The substituents of the phenyl group are selected from C1-C3 alkyl, C1-C3 alkoxy, halogen, trifluoromethyl, nitro, trifluoromethoxy or -C(O)CH=CHR 19 ;

[0187] R 19 Selected from phenyl,

[0188] Alternatively, the compound is represented by formula Vb:

[0189]

[0190]

[0191] in,

[0192] In the figure, when the dotted line is absent, it is a single bond; when the dotted line is a bond, it is a double bond;

[0193] X is -O- or -NR 15 -;

[0194] R 15 Selected from hydrogen or C1-C3 alkyl;

[0195] R 14 Selected from substituted or unsubstituted C1-C 12 Alkyl, C1-C4 alkenyl, C1-C4 alkynyl, substituted or unsubstituted phenyl, naphthyl, -CH=CHR 18 、 Adamantyl, -(CH2) b OC(O)(CH2) c R 18 or -(CH2CH2O) b C(O)(CH2) c R 18 ;

[0196] a is 1, 2, or 3;

[0197] b is 1, 2, 3, 4, 5, 6, 7 or 8;

[0198] c is 1, 2, or 3;

[0199] R 18 Selected from adamantyl, substituted or unsubstituted phenyl, thienyl, pyridyl, furyl or

[0200] The substituent of the alkyl group is selected from carboxyl, substituted or unsubstituted phenyl, or adamantane;

[0201] The substituents of the phenyl group are selected from C1-C3 alkyl, C1-C3 alkoxy, halogen, trifluoromethyl, nitro, trifluoromethoxy or -C(O)CH=CHR 19 ;

[0202] R 19 Selected from phenyl,

[0203] Alternatively, the compound is represented by formula Vc:

[0204]

[0205] in,

[0206] In the figure, when the dotted line is absent, it is a single bond; when the dotted line is a bond, it is a double bond;

[0207] R 14 Selected from substituted or unsubstituted C1-C 12 Alkyl, C1-C4 alkenyl, C1-C4 alkynyl, substituted or unsubstituted phenyl, naphthyl, -CH=CHR 18 、 Adamantyl, -(CH2) b OC(O)(CH2) c R 18 or -(CH2CH2O) b C(O)(CH2) c R 18 ;

[0208] a is 1, 2, or 3;

[0209] b is 1, 2, 3, 4, 5, 6, 7 or 8;

[0210] c is 1, 2, or 3;

[0211] R 18 Selected from adamantyl, substituted or unsubstituted phenyl, thienyl, pyridyl, furyl or

[0212] The substituent of the alkyl group is selected from carboxyl, substituted or unsubstituted phenyl, or adamantane;

[0213] The substituents of the phenyl group are selected from C1-C3 alkyl, C1-C3 alkoxy, halogen, trifluoromethyl, nitro, trifluoromethoxy or -C(O)CH=CHR 19 ;

[0214] R 19 Selected from phenyl,

[0215] Alternatively, the compound is represented by formula Vd:

[0216]

[0217] in,

[0218] R 14 Selected from substituted or unsubstituted C1-C 12 Alkyl, C1-C4 alkenyl, C1-C4 alkynyl, substituted or unsubstituted phenyl, naphthyl, -CH=CHR 18 、 Adamantyl, -(CH2) b OC(O)(CH2) c R 18 or -(CH2CH2O) bC(O)(CH2) c R 18 ;

[0219] a is 1, 2, or 3;

[0220] b is 1, 2, 3, 4, 5, 6, 7 or 8;

[0221] c is 1, 2, or 3;

[0222] R 18 Selected from adamantyl, substituted or unsubstituted phenyl, thienyl, pyridyl, furyl or

[0223] The substituent of the alkyl group is selected from carboxyl, substituted or unsubstituted phenyl, or adamantane;

[0224] The substituents of the phenyl group are selected from C1-C3 alkyl, C1-C3 alkoxy, halogen, trifluoromethyl, nitro, trifluoromethoxy or -C(O)CH=CHR 19 ;

[0225] R 19 Selected from phenyl,

[0226] Furthermore, the compound is one of the following compounds:

[0227]

[0228]

[0229]

[0230] The present invention also provides a method for preparing the compound represented by the aforementioned formula Va, wherein: The dotted line is the key, including the following steps:

[0231]

[0232] (1) At room temperature, raw material 1 and 1,3-dimethylimidazole-2-selenoketone are dissolved in a solvent, and iodophenyl diacetic acid is added to react to obtain compound 2; alternatively, raw material 1 is reacted with selenium dioxide, tert-butyl peroxide, and salicylic acid in a solvent under reflux conditions at 40-60°C to obtain compound 2;

[0233] (2) At room temperature, compound 2 reacts with a carboxyl derivative in the presence of condensing agents EDCI and DMAP to obtain the carboxyl derivative; the structure of the carboxyl derivative is COOR 14 ; R 14 As described in the above formula Va;

[0234] Preferably, the solvent is dichloromethane.

[0235] The present invention also provides a method for preparing the compound represented by the aforementioned formula Vb, wherein: The dotted line is a bond, X is -O-, and the steps are as follows:

[0236]

[0237] 1) At room temperature, raw material 1 and 1,3-dimethylimidazole-2-selenoketone are dissolved in a solvent, and iodophenyl diacetic acid is added to react to obtain compound 2; alternatively, raw material 1 is reacted with selenium dioxide, tert-butyl peroxide, and salicylic acid in a solvent at 40-60°C under reflux to obtain compound 2;

[0238] 2) At room temperature, compound 2 reacts with halide YR 14 And Ag2O reacts in a solvent to obtain;

[0239] The YR 14 Where Y is halogen, R 14 As described in the above formula Vb;

[0240] Preferably, the solvent is dichloromethane.

[0241] The present invention also provides a method for preparing the compound represented by the aforementioned formula Vb, wherein: The dotted line is a bond, X is -NH-, and the steps are as follows:

[0242]

[0243] a) at room temperature, raw material 1 and 1,3-dimethylimidazole-2-selenoketone are dissolved in a solvent, and iodophenyl diacetic acid is added to react to obtain compound 2; alternatively, raw material 1 is reacted with selenium dioxide, tert-butyl peroxide, and salicylic acid in a solvent under reflux conditions at 40-60°C to obtain compound 2;

[0244] b) At room temperature, compound 2 reacts with NH2-R 14 , triphenylphosphine and diiodoethane react in a solvent to obtain;

[0245] The NH2-R 14 In, R 14 As described in the above formula Vb;

[0246] Preferably, in step (1), the solvent is dichloromethane;

[0247] And / or, in the step (2), the solvent is DMF.

[0248] The present invention also provides a method for preparing the compounds represented by the aforementioned formula Vc and formula Vd. In formula Vc, The dotted line is the key, including the following steps:

[0249]

[0250] (A) The starting material 1 reacts with a terminal olefin derivative in a solvent under reflux conditions of 50-70°C in the presence of a Grubbs catalyst;

[0251] (B) The reactant obtained in step (1) was separated and purified by silica gel column chromatography using a mixture of petroleum ether and ethyl acetate in a volume ratio of 1:1 as an eluent to separate and obtain compounds represented by Formula Vc and Formula Vd;

[0252] The structure of the terminal olefin derivative is Among them, R 14 As described above for Formula Vc and Formula Vd.

[0253] The present invention also provides use of the aforementioned compound, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a hydrate thereof, or a prodrug thereof in the preparation of an estrogen receptor α degrader.

[0254] The present invention also provides the use of the aforementioned compound, or its salt, or its stereoisomer, or its solvate, or its hydrate, or its prodrug in the preparation of anti-tumor drugs and / or antiviral drugs;

[0255] Preferably, the tumor is breast cancer, prostate cancer, nasopharyngeal cancer, colorectal cancer, lung cancer, liver cancer, esophageal cancer, gastric cancer, intestinal cancer, kidney cancer, oral cancer, pancreatic cancer, colorectal cancer, cervical cancer, glioma, bladder cancer, or ovarian cancer;

[0256] And / or, the virus is coronavirus, HIV virus, cytomegalovirus, Epstein-Barr virus, adenovirus, herpes virus, human T-lymphotropic virus, hepatitis B virus, or hepatitis A virus.

[0257] The present invention also provides a drug, which is a preparation prepared by using the aforementioned compound, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a hydrate thereof, or a prodrug thereof as an active ingredient, and adding pharmaceutically acceptable auxiliary ingredients or excipients;

[0258] Preferably, the drug is an anti-tumor drug and / or an anti-viral drug;

[0259] More preferably, the tumor is breast cancer, prostate cancer, nasopharyngeal cancer, colorectal cancer, lung cancer, liver cancer, esophageal cancer, gastric cancer, intestinal cancer, kidney cancer, oral cancer, pancreatic cancer, colorectal cancer, cervical cancer, glioma, bladder cancer, or ovarian cancer;

[0260] And / or, the virus is coronavirus, HIV virus, cytomegalovirus, Epstein-Barr virus, adenovirus, herpes virus, human T-lymphotropic virus, hepatitis B virus, or hepatitis A virus.

[0261] The compounds and derivatives provided herein can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.

[0262] Definitions of terms used in the present invention: Unless otherwise stated, the initial definitions provided for groups or terms in this document apply to the groups or terms throughout the specification; for terms that are not specifically defined herein, they should be given the meaning that a person skilled in the art would give them based on the disclosure and context.

[0263] "Substitution" refers to the replacement of a hydrogen atom in a molecule by another different atom or molecule.

[0264] The structures of the compounds described in the present invention all refer to structures that can exist stably.

[0265] The minimum and maximum values ​​of the carbon atom content in the hydrocarbon groups of the present invention are indicated by prefixes, for example, the prefix (C a ~C b )alkyl refers to any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, C1-C 10 Alkyl refers to a straight or branched chain alkyl group containing 1 to 10 carbon atoms; C1 to C8 alkoxy refers to an alkoxy group containing 1 to 8 carbon atoms; C2 to C 10 Alkenyl refers to an alkenyl group containing 2 to 10 carbon atoms; C2 to C 10 The alkynyl group refers to an alkynyl group containing 2 to 10 carbon atoms.

[0266] In the present invention, halogen is fluorine, chlorine, bromine or iodine.

[0267] "Aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group with a conjugated π electron system, such as phenyl and naphthyl. The aryl ring may be fused to other cyclic groups (including saturated and unsaturated rings), but cannot contain heteroatoms such as nitrogen, oxygen, or sulfur, and the point of attachment to the parent moiety must be on a carbon atom in the ring with a conjugated π electron system. A 6- to 10-membered aryl group means an aryl group containing 6 to 10 carbon atoms.

[0268] "Heteroaryl" refers to an aromatic unsaturated ring containing at least one heteroatom; including single ring or multiple rings (including fused, bridged and spiro ring systems); wherein the heteroatom refers to a nitrogen atom, an oxygen atom, or a sulfur atom. Such as thienyl, furyl, pyridyl, pyrazinyl, pyrazolyl, and also includes wait.

[0269] "Heterocycloalkyl" refers to a saturated or partially saturated non-aromatic cyclic group containing at least one heteroatom; including single rings or multiple rings (including fused, bridged and spiro ring systems); wherein the heteroatom refers to a nitrogen atom, an oxygen atom, or a sulfur atom. Examples of heterocycloalkyl groups include, for example, piperidinyl, piperazinyl, morpholinyl,

[0270] When a is 1, the structure is When a is 2, the structure is When a is 3, the structure is And so on.

[0271] Adamantyl

[0272] The present invention provides a method for structurally modifying a class of snake cell pseudotoxin compounds. These compounds can effectively inhibit the proliferation of various breast cancer cells, particularly triple-negative breast cancer cells and adriamycin-resistant cells, and can also effectively inhibit their migration. Furthermore, these compounds have good estrogen receptor α downregulation activity, demonstrating their potential application in cancer treatment, particularly breast cancer. Furthermore, studies have found that these compounds have good inhibitory activity against coronaviruses, without significant toxic side effects, and may serve as a new option for the prevention and treatment of coronaviruses.

[0273] Obviously, based on the above contents of the present invention, according to common technical knowledge and customary means in this field, without departing from the above basic technical ideas of the present invention, other various forms of modifications, replacements or changes can be made.

[0274] The following further describes the above content of the present invention in detail through specific embodiments in the form of examples. However, this should not be construed as limiting the scope of the above subject matter of the present invention to the following examples. All technologies implemented based on the above content of the present invention fall within the scope of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0275] Figure 1 Western blot analysis of ERα in MCF-7 cells after treatment with fulvestrant, MHO7, and its derivatives

[0276] Figure 2 Western blotting analysis of ERα in MCF-7 cells after treatment with compound 16a.

[0277] Figure 3 The results show that compound 16a inhibits the migration of drug-resistant breast cancer cells.

[0278] Figure 4The results show that compound 16a inhibits the migration of triple-negative breast cancer cells. DETAILED DESCRIPTION

[0279] Starting materials can be obtained from commercial sources or prepared by methods known in the art or according to the methods provided herein.

[0280] Unless otherwise stated, the compounds in the examples can be synthesized by the following routes, as follows:

[0281] Route 1:

[0282]

[0283] Synthesis of intermediate 2:

[0284] The raw material 1 (1g, 0.272mol) was dissolved in 35ml of dichloromethane, and 1,3-dimethylimidazole-2-selenone (IMeSe, 190mg, 0.109mol) was slowly added. The mixture was stirred at room temperature for 30 minutes, and then iodophenyl diacetic acid (1.75g, 0.545mol) was added in batches. After the addition was completed, the mixture was reacted at room temperature for about 24 hours. The reaction was detected by TLC spot plate. The reaction was stopped after most of the raw material 1 was reacted. The reaction solution was concentrated and extracted three times with a mixed solution of ethyl acetate and saturated brine (1:1, v / v). The organic phases were combined and dried over anhydrous sodium sulfate for 1 hour. Finally, the mixture was concentrated, mixed with silica gel, and separated by column chromatography. The unreacted raw material 1 could be recycled to obtain 370mg of the intermediate (2). HRMS[ESI] + ,Calcd.For C 25 H 35 O3[M+H] + ,383.2586,found383.2574.

[0285] Intermediate 2: 1H NMR (400MHz, CDCl3) δ9.29 (s, 1H), 6.84 (d, J = 4.3Hz, 1H), 6.12 (t, J = 11.1Hz, 1H), 6.06 (s, 1H), 6.03 (d, J = 12.1Hz, 1H), 5.13 (t ,J=10.0Hz,1H),4.16(s,2H),3.41(d,J=3.8Hz,1H),2.94(d,J=20.4Hz,1H),2.68(dd,J=8.3,3.9Hz,1H),2.66–2.61(m,1H),2. 61–2.54(m,1H),2.29–2.22(m,1H),2.09(s,3H),2.08–2.03(m,1H),1.92(m,1H),1.82(s,3H),1.73–1.65(m,1H),1.55(dd,J= 11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.32–1.24(m,1H),1.18(t,J=13.1Hz,1H),1.01(d,J=6.7Hz,3H),0.89(s,3H). 13 CNMR(101MHz, CDCl3)δ207.58,192.99,177.56,157.72,140.04,138.48,138.36,130.28,123.17,119.15,68. 45,52.02,49.97,49.12,45.84,45.43,44.28,43.83,32.74,30.88,29.71,27.75,22.91,21.25,17.23,14.09.

[0286] Synthesis of compound X1:

[0287] Under ice bath, the derivative containing naked carboxyl group (1.5 mol) was completely dissolved in dichloromethane, followed by the addition of EDCI (1.5 mol) and DMAP (0.1 mol), and the mixture was stirred for 30 min. Finally, a dichloromethane solution of intermediate 2 (1.0 mol) was slowly added dropwise, and the mixture was stirred at room temperature for 3-12 h. After the reaction of intermediate 2 was complete as detected by TLC plate, the reaction was stopped, the reaction system was concentrated, and a mixed solution of ethyl acetate and saturated sodium bicarbonate solution (1:1, v / v) was added and extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, mixed, and purified by column chromatography to obtain compound X1.

[0288] Example 1. Synthesis of Compound 3a

[0289]

[0290] Compound 3a was prepared by the method of the above-mentioned synthetic route 1, wherein the derivative containing a naked carboxyl group was 1-cinnamic acid.

[0291] Yield: 87% 1 H NMR (400MHz, CDCl3) δ9.27 (s, 1H), 7.75 (d, J = 16.0 Hz, 1H), 7.56 (dd, J = 6.6, 3. 0Hz,3H),7.46–7.37(m,4H),6.84(dd,J=6.7,2.5Hz,1H),6.51(d,J=16.0Hz,1H ),6.39(d,J=11.6Hz,1H),6.18(t,J=11.2Hz,1H),6.06(s,2H),5.36(t,J=10. 2Hz,1H),4.85–4.65(m,2H),3.39(d,J=4.1Hz,1H),2.94(d,J=20.4Hz,1H),2.6 8(dd,J=8.3,3.9Hz,1H),2.66–2.61(m,1H),2.61–2.54(m,1H),2.29–2.22(m, 1H),2.09(s,3H),2.08–2.03(m,1H),1.92(m,1H),1.82(s,3H),1.73–1.65(m,1 H),1.55(dd,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.32–1.24(m, 1H),1.18(t,J=13.1Hz,1H),1.02(d,J=6.7Hz,3H),0.87(s,3H).ESI-HRMS:m / z calculated for C 34 H 40 O4[M+H] + :513.3005,found513.3001.

[0292] Example 2: Synthesis of Compound 3b

[0293]

[0294] Compound 3b was prepared by the method of the above-mentioned synthetic route 1, wherein the derivative containing a naked carboxyl group was 4-fluorocinnamic acid.

[0295] Yield: 84% 1H NMR (400MHz, CDCl3) δ9.27(s,1H),7.70(d,J=16.0Hz,1H),7.54(dd,J=8.6,5.5Hz,2H),7.11(t,J=8.6Hz,2H),6.84(dd,J=6.6,2.4Hz,1H),6.43(d,J=16 .0Hz,1H),6.17(t,J=11.2Hz,1H),6.05(t,J=1.7Hz,1H),5.44–5.26(m,1H), 4.83–4.64(m,2H),3.39(d,J=4.1Hz,1H),2.94(d,J=20.4Hz,1H),2.68(dd,J =8.3,3.9Hz,1H),2.66–2.61(m,1H),2.61–2.54(m,1H),2.29–2.22(m,1H),2 .09(s,3H),2.08–2.03(m,1H),1.92(m,1H),1.82(s,3H),1.73–1.65(m,1H), 1.55(dd,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.32–1.24(m,1H ),1.18(t,J=13.1Hz,1H),1.01(d,J=6.7Hz,3H),0.87(s,3H).ESI-HRMS:m / z calculated for C 34 H 39 FO4[M+H] + :531.2911,found 531.2907.

[0296] Example 3. Synthesis of Compound 3c

[0297]

[0298] Compound 3c was prepared by the method of the above-mentioned synthetic route 1, wherein the derivative containing a naked carboxyl group was 3-trifluoromethylcinnamic acid.

[0299] Yield: 86% 1H NMR (400MHz, CDCl3) δ9.27(s,1H),7.78(d,J=9.2Hz,2H),7.72(d,J=6.1Hz,2H),7.67(d,J=7.8Hz,1H),7.55(t,J=7.8Hz,1H),6.84(dd,J=6.6,2.4Hz,1H ),6.57(d,J=16.0Hz,1H),6.39(d,J=11.6Hz,1H),6.18(t,J=11.2Hz,1H),6. 06(s,1H),5.37(t,J=10.2Hz,1H),4.84–4.66(m,2H),3.39(d,J=4.1Hz,1H), 2.91–2.82(m,1H),2.66(td,J=13.5,12.7,5.7Hz,4H),2.29–2.22(m,1H),2 .09(s,3H),2.08–2.03(m,1H),1.92(m,1H),1.82(s,3H),1.73–1.65(m,1H), 1.55(dd,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.32–1.24(m,1H ),1.18(t,J=13.1Hz,1H),1.02(d,J=6.7Hz,3H),0.89(s,3H).ESI-HRMS:m / z calculated for C 35 H 39 F3O4[M+H] + :581.2879,found 581.2863.

[0300] Example 4. Synthesis of Compound 3d

[0301]

[0302] Compound 3d was prepared by the method of the above-mentioned synthetic route 1, wherein the derivative containing a naked carboxyl group was 3,4,5-trifluorocinnamic acid.

[0303] Yield: 76% 1H NMR(400MHz, CDCl3)δ9.28(s,1H),7.56(d,J=15.9Hz,1H),7.24–7.10(m,2H),6.83(dd,J=6.6,2.4Hz,1H),6.50–6.32(m,2H),6.17( t,J=11.2Hz,1H),6.06(s,1H),5.44–5.29(m,1H),4.86–4.64(m,2H),3.39(d,J=4.1Hz,1H),2.91–2.82(m,1H),2.66(td,J=13.5,12. 7,5.7Hz,4H),2.29–2.22(m,1H),2.09(s,3H),2.08–2.03(m,1H),1.92(m,1H),1.82(s,3H),1.73–1.65(m,1H),1.55(dd,J=11.8,5. 0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.32–1.24(m,1H),1.18(t,J=13.1Hz,1H),1.02(d,J=6.7Hz,3H),0.89(s,3H).ESI-HRMS:m / z calculated for C 34 H 37 F3O4[M+H] + :567.2722,found567.2708.

[0304] Example 5. Synthesis of Compound 3e

[0305]

[0306] Compound 3e was prepared by the method of the above-mentioned synthetic route 1, wherein the derivative containing a naked carboxyl group was 3-trifluoromethoxycinnamic acid.

[0307] Yield: 89% 1H NMR (400MHz, CDCl3) δ9.27(s,1H),7.70(d,J=16.0Hz,1H),7.46(d,J=7.5Hz,2H),7.39(s,1H),7.24(m,1H),6.84(dd,J=6.5,2.4Hz,1H),6.52(d,J=16 .0Hz,1H),6.38(d,J=11.6Hz,1H),6.18(t,J=11.2Hz,1H),6.06(t,J=1.6Hz ,1H),5.37(t,J=10.3Hz,1H),4.84–4.67(m,2H),3.39(d,J=4.1Hz,1H),2.9 1–2.82(m,1H),2.66(td,J=13.5,12.7,5.7Hz,4H),2.29–2.22(m,1H),2.09 (s,3H),2.08–2.03(m,1H),1.92(m,1H),1.82(s,3H),1.73–1.65(m,1H),1. 55(dd,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.32–1.24(m,1H) ,1.18(t,J=13.1Hz,1H),1.02(d,J=6.6Hz,3H),0.88(s,3H).ESI-HRMS:m / z calculated for C 35 H 39 F3O5[M+H] + :597.2828,found 597.2812.

[0308] Example 6. Synthesis of Compound 3f

[0309]

[0310] Compound 3f was prepared by the method of the above-mentioned synthetic route 1, wherein the derivative containing a naked carboxyl group was 4-bromocinnamic acid.

[0311] Yield: 77% 1H NMR (400MHz, CDCl3) δ9.27 (s, 1H), 7.67 (d, J = 16.0Hz, 1H), 7.60–7.51 (m, 2H ),7.47–7.38(m,2H),6.84(dd,J=6.5,2.4Hz,1H),6.49(d,J=16.0Hz,1H),6 .38(d,J=11.6Hz,1H),6.18(t,J=11.2Hz,1H),6.06(t,J=1.7Hz,1H),5.36( t,J=10.2Hz,1H),4.82–4.66(m,2H),3.39(d,J=4.1Hz,1H),2.91–2.82(m,1 H),2.66(td,J=13.5,12.7,5.7Hz,4H),2.29–2.22(m,1H),2.09(s,3H),2.0 8–2.03(m,1H),1.92(m,1H),1.82(s,3H),1.73–1.65(m,1H),1.55(dd,J=11 .8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.32–1.24(m,1H),1.18(t,J=13.1Hz,1H),1.01(d,J=6.5Hz,3H),0.88(s,3H).ESI-HRMS:m / zcalculated for C 34 H 39 BrO4[M+H] + :591.2110,found 591.2102.

[0312] Example 7. Synthesis of Compound 3g

[0313]

[0314] Compound 3g was prepared using the method of the above-mentioned synthetic route 1, wherein the derivative containing a naked carboxyl group was 3-chlorocinnamic acid.

[0315] Yield: 86% 1H NMR (400MHz, CDCl3) δ9.27(s,1H),7.67(d,J=16.0Hz,1H),7.54(d,J=1.9Hz,1H),7.45–7.32(m,3H),6.84(dd,J=6.6,2.4Hz,1H),6.51(d,J=16.0Hz,1H ),6.38(d,J=11.6Hz,1H),6.18(t,J=11.1Hz,1H),6.10–6.03(m,1H),5.36( t,J=10.2Hz,1H),4.85–4.65(m,2H),3.39(d,J=4.0Hz,1H),2.91–2.82(m,1 H),2.66(td,J=13.5,12.7,5.7Hz,4H),2.29–2.22(m,1H),2.09(s,3H),2.0 8–2.03(m,1H),1.92(m,1H),1.82(s,3H),1.73–1.65(m,1H),1.55(dd,J=11 .8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.32–1.24(m,1H),1.18(t,J=13.1Hz,1H),1.02(d,J=6.7Hz,3H),0.88(s,3H).ESI-HRMS:m / zcalculated for C 34 H 39 ClO4[M+H] + :547.2615,found 547.2619.

[0316] Example 8. Synthesis of Compound 3h

[0317]

[0318] Compound 3h was prepared using the method of the above-mentioned synthetic route 1, wherein the derivative containing a naked carboxyl group was 2-nitrocinnamic acid.

[0319] Yield: 75% 1H NMR (400MHz, CDCl3) δ9.28(s,1H),8.20(d,J=15.8Hz,1H),8.08(d,J=8.1Hz,1H),7.73–7.64(m,2H),7.58(ddd,J=8.6,6.1,2.7Hz,1H),6.87(dd,J=6.6 ,2.4Hz,1H),6.53–6.35(m,2H),6.18(t,J=11.2Hz,1H),6.05(s,1H),5.36( t,J=10.3Hz,1H),4.87–4.68(m,2H),3.40(d,J=4.1Hz,1H),2.91–2.82(m,1 H),2.66(td,J=13.5,12.7,5.7Hz,4H),2.29–2.22(m,1H),2.09(s,3H),2.0 8–2.03(m,1H),1.92(m,1H),1.82(s,3H),1.73–1.65(m,1H),1.55(dd,J=11 .8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.32–1.24(m,1H),1.18(t,J=13.1Hz,1H),1.01(d,J=6.5Hz,3H),0.89(s,3H).ESI-HRMS:m / zcalculated for C 34 H 39 NO6[M+H] + :558.2856,found 558.2831.

[0320] Example 9: Synthesis of Compound 3i

[0321]

[0322] Compound 3i was prepared by the method of the above-mentioned synthetic route 1, wherein the derivative containing a naked carboxyl group was 2-methylcinnamic acid.

[0323] Yield: 74% 1H NMR (400MHz, CDCl3) δ9.27(s,1H),8.05(d,J=15.8Hz,1H),7.59(d,J=7.5Hz,1H),7.23(d,J=7.4Hz,3H),6.87–6.81(m,1H),6.48–6.35( m,2H),6.19(t,J=11.2Hz,1H),6.06(s,1H),5.36(t,J=10.2Hz,1H),3.84(s,1H),3.39(d,J=4.1Hz,1H),2.91–2.82(m,1H),2.66(td,J=1 3.5,12.7,5.7Hz,4H),2.29–2.22(m,1H),2.09(s,3H),2.08–2.03(m,1H),1.92(m,1H),1.82(s,3H),1.73–1.65(m,1H),1.55(dd,J=11.8 ,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.32–1.24(m,1H),1.18(t,J=13.1Hz,1H),1.02(d,J=6.6Hz,3H),0.89(s,3H).ESI-HRMS:m / z calculated for C 35 H 42 O4[M+H] + :527.3161,found527.3145.

[0324] Example 10. Synthesis of Compound 3j

[0325]

[0326] Compound 3j was prepared by the method of the above-mentioned synthetic route 1, wherein the derivative containing a naked carboxyl group was 2-methoxycinnamic acid.

[0327] Yield: 71% 1H NMR (400MHz, CDCl3) δ9.27(s,1H),8.06(d,J=16.1Hz,1H),7.54(dd,J=7.6,1.7Hz,1H),7.42–7.34(m,1H),7.03–6.91(m,2H),6.88(dd,J=6.7,2.4Hz ,1H),6.18(t,J=11.2Hz,1H),6.08–6.03(m,1H),5.34(t,J=10.3Hz,1H),4 .84–4.64(m,2H),3.91(s,3H),3.38(d,J=4.2Hz,1H),2.91–2.82(m,1H),2 .66(td,J=13.5,12.7,5.7Hz,4H),2.29–2.22(m,1H),2.09(s,3H),2.08–2 .03(m,1H),1.92(m,1H),1.82(s,3H),1.73–1.65(m,1H),1.55(dd,J=11.8 ,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.32–1.24(m,1H),1.18(t,J=13.1Hz,1H),1.01(d,J=6.5Hz,3H),0.88(s,3H).ESI-HRMS:m / zcalculated for C 35 H 42 O5[M+H] + :543.3110,found 543.3102.

[0328] Example 11. Synthesis of Compound 3k

[0329]

[0330] Compound 3k was prepared by the method of the above-mentioned synthetic route 1, wherein the derivative containing a naked carboxyl group was 2,4-dimethoxycinnamic acid.

[0331] Yield: 79% 1H NMR (400MHz, CDCl3) δ9.26 (s, 1H), 7.97 (d, J = 16.0Hz, 1H), 6.88 (d, J = 2.5Hz, 1H), 6.60–6.42 (m, 3H), 6.39 (d, J = 11.6Hz, 1H), 6.17 (t, J = 11.3Hz, 1 H),6.05(s,1H),5.32(t,J=10.3Hz,1H),4.86–4.59(m,2H),4.14(q,J=7. 1Hz,1H),3.88(s,3H),3.86(s,3H),3.38(d,J=4.1Hz,1H),2.91–2.82(m, 1H),2.66(td,J=13.5,12.7,5.7Hz,4H),2.29–2.22(m,1H),2.09(s,3H) ,2.08–2.03(m,1H),1.92(m,1H),1.82(s,3H),1.73–1.65(m,1H),1.55(d d,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.32–1.24(m,1H),1.18(t,J=13.1Hz,1H),1.02(d,J=6.4Hz,3H),0.89(s,3H).ESI-HRMS:m / z calculated forC 36 H 44 O6[M+H] + :573.3216,found 573.3221.

[0332] Example 12: Synthesis of Compound 31

[0333]

[0334] Compound 31 was prepared by the method of the above-mentioned synthetic route 1, wherein the derivative containing a naked carboxyl group was 2,5-dimethoxycinnamic acid.

[0335] Yield: 81% 1H NMR (400MHz, CDCl3) δ9.27 (s, 1H), 8.04 (d, J = 16.1Hz, 1H), 7.07 (d, J = 3.1Hz, 1H),6.94(dd,J=9.0,3.0Hz,1H),6.88(q,J=5.1,4.1Hz,2H),6.56(d,J=16.2H z,1H),6.40(d,J=11.6Hz,1H),6.17(t,J=11.2Hz,1H),6.05(s,1H),5.34(t,J =10.3Hz,1H),4.85–4.62(m,1H),3.86(s,3H),3.81(s,3H),3.38(d,J=4.2Hz, 1H),2.91–2.82(m,1H),2.66(td,J=13.5,12.7,5.7Hz,4H),2.29–2.22(m,1H ),2.09(s,3H),2.08–2.03(m,1H),1.92(m,1H),1.82(s,3H),1.73–1.65(m,1H ),1.55(dd,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.32–1.24(m,1 H),1.18(t,J=13.1Hz,1H),1.01(d,J=6.6Hz,3H),0.88(s,3H).ESI-HRMS:m / z calculated for C 36 H 44 O6[M+H] + :573.3216,found573.3211.

[0336] Example 13. Synthesis of Compound 3m

[0337]

[0338] Compound 3m was prepared by the method of the above-mentioned synthetic route 1, wherein the derivative containing a naked carboxyl group was 3,4-dimethoxycinnamic acid.

[0339] Yield: 83% 1H NMR (400MHz, CDCl3) δ9.27(s,1H),7.68(d,J=15.9Hz,1H),7.13(dd,J=8.3,2 .0Hz,1H),7.07(d,J=1.9Hz,1H),6.89(d,J=8.3Hz,1H),6.85(dd,J=6.5,2.3H z,1H),6.39(s,1H),6.36(d,J=5.1Hz,1H),6.17(t,J=11.2Hz,1H),6.05(s,1 H),5.35(t,J=10.2Hz,1H),4.81–4.65(m,2H),3.93(s,6H),3.38(d,J=4.1Hz, 1H),2.91–2.82(m,1H),2.66(td,J=13.5,12.7,5.7Hz,4H),2.29–2.22(m,1H ),2.09(s,3H),2.08–2.03(m,1H),1.92(m,1H),1.82(s,3H),1.73–1.65(m,1H ),1.55(dd,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.32–1.24(m,1 H),1.18(t,J=13.1Hz,1H),1.01(d,J=6.5Hz,3H),0.87(s,3H).ESI-HRMS:m / z calculated for C 36 H 44 O6[M+H] + :573.3216,found 573.3217.

[0340] Example 14. Synthesis of Compound 3n

[0341]

[0342] Compound 3n was prepared by the method of the above-mentioned synthetic route 1, wherein the derivative containing a naked carboxyl group was 2,3,4-trimethoxycinnamic acid.

[0343] Yield: 85% 1H NMR (400MHz, CDCl3) δ9.26(s,1H),7.94(d,J=16.2Hz,1H),7.30(s,1H),6.86(dd,J=6.5,2.4Hz,1H),6.72(dd,J=8.8,4.1Hz,1H),6.48(d,J=16.1Hz,1 H),6.43–6.35(m,1H),6.17(t,J=11.2Hz,1H),6.05(s,1H),5.34(t,J=10.3 Hz,1H),4.83–4.62(m,2H),3.97–3.86(m,12H),3.39(d,J=4.1Hz,1H),2.91 –2.82(m,1H),2.66(td,J=13.5,12.7,5.7Hz,4H),2.29–2.22(m,1H),2.09 (s,3H),2.08–2.03(m,1H),1.92(m,1H),1.82(s,3H),1.73–1.65(m,1H),1. 55(dd,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.32–1.24(m,1H) ,1.18(t,J=13.1Hz,1H),1.02(d,J=6.5Hz,3H),0.88(s,3H).ESI-HRMS:m / z calculated for C 37 H 46 O7[M+H] + :603.3322,found 603.3314.

[0344] Example 15. Synthesis of Compound 3o

[0345]

[0346] Compound 3o was prepared by the method of the above-mentioned synthetic route 1, wherein the derivative containing a naked carboxyl group was 4-pyridine cinnamic acid.

[0347] Yield: 73% 1H NMR (400MHz, CDCl3) δ9.28 (s, 1H), 8.69 (d, J = 5.0Hz, 2H), 7.65 (d, J = 16.1Hz, 1 H),7.42(d,J=5.2Hz,2H),6.83(dd,J=6.6,2.4Hz,1H),6.67(d,J=16.1Hz,1H) ,6.38(d,J=11.6Hz,1H),6.17(t,J=11.3Hz,1H),6.06(d,J=1.7Hz,1H),5.37( t,J=10.3Hz,1H),4.84–4.64(m,2H),3.39(d,J=4.2Hz,1H),2.94(d,J=30.0Hz ,2H),2.91–2.82(m,1H),2.66(td,J=13.5,12.7,5.7Hz,4H),2.29–2.22(m,1H ),2.09(s,3H),2.08–2.03(m,1H),1.92(m,1H),1.82(s,3H),1.73–1.65(m,1H ),1.55(dd,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.32–1.24(m,1 H),1.18(t,J=13.1Hz,1H),1.02(d,J=6.6Hz,3H),0.88(s,3H).ESI-HRMS:m / z calculated for C 33 H 39 NO4[M+H] + :514.2957,found 514.2942.

[0348] Example 16. Synthesis of Compound 3p

[0349]

[0350] Compound 3p was prepared by the method of the above-mentioned synthetic route 1, wherein the derivative containing a naked carboxyl group was 3-furancinnamic acid.

[0351] Yield: 72% 1H NMR (400MHz, CDCl3) δ9.27(s,1H),7.68(s,1H),7.61(s,1H),7.46(d,J=2.9Hz,1H),6.87–6.82(m,1H),6.62(d,J=2.0Hz,1H),6.37(dd,J=13.9,4.7H z,1H),6.26–6.18(m,1H),6.05(s,1H),5.36(d,J=10.3Hz,1H),4.77–4.64 (m,2H),3.39(d,J=4.1Hz,1H),2.94(d,J=30.0Hz,2H),2.91–2.82(m,1H), 2.66(td,J=13.5,12.7,5.7Hz,4H),2.29–2.22(m,1H),2.09(s,3H),2.08– 2.03(m,1H),1.92(m,1H),1.82(s,3H),1.73–1.65(m,1H),1.55(dd,J=11. 8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.32–1.24(m,1H),1.18(t,J=13.1Hz,1H),1.02(d,J=6.6Hz,3H),0.88(s,3H).ESI-HRMS:m / zcalculated for C 32 H 38 O5[M+H] + :503.2797,found 503.2786.

[0352] Example 17. Synthesis of Compound 3q

[0353]

[0354] Compound 3q was prepared by the method of the above-mentioned synthetic route 1, wherein the derivative containing a naked carboxyl group was 3-thiophenecinnamic acid.

[0355] Yield 69%, 1H NMR (400MHz, CDCl3) δ9.26 (s, 1H), 7.53 (dd, J = 3.1, 1.2Hz, 1H), 7.37 (dd, J = 5.2 ,2.9Hz,1H),7.33(dd,J=5.1,1.3Hz,1H),6.84(dd,J=6.5,2.4Hz,1H),6.37(d, J=11.8Hz,1H),6.33(d,J=15.9Hz,1H),6.17(t,J=11.3Hz,1H),6.08–6.03(m,1 H),5.35(t,J=10.2Hz,1H),4.79–4.66(m,2H),3.39(d,J=4.1Hz,1H),2.94(d,J= 30.0Hz,2H),2.91–2.82(m,1H),2.66(td,J=13.5,12.7,5.7Hz,4H),2.29–2.22 (m,1H),2.09(s,3H),2.08–2.03(m,1H),1.92(m,1H),1.82(s,3H),1.73–1.65(m ,1H),1.55(dd,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.32–1.24(m ,1H),1.18(t,J=13.1Hz,1H),1.01(d,J=6.5Hz,3H),0.89(s,3H).ESI-HRMS:m / z calculated for C 32 H 48 O4S[M+H] + :519.2569,found 519.2537.

[0356] Example 18. Synthesis of Compound 3r

[0357]

[0358] Compound 3r was prepared by the method of the above-mentioned synthetic route 1, wherein the derivative containing a naked carboxyl group was 3,4-methyleneoxycinnamic acid.

[0359] Yield: 84% 1H NMR (400MHz, CDCl3) δ9.26 (s, 1H), 7.64 (d, J = 15.9Hz, 1H), 7.06 (d, J = 1.7Hz, 1H), 7.03 (dd, J = 8.1, 1.7Hz, 1H), 6.84 (d, J = 7.9Hz, 2H), 6.38 (d, J = 11.8Hz, 1H),6.33(d,J=15.9Hz,1H),6.18(t,J=11.2Hz,1H),6.05(s,2H),5.40–5.3 0(t,1H),4.81–4.62(m,2H),3.39(d,J=4.1Hz,1H),2.94(d,J=30.0Hz,2H),2 .91–2.82(m,1H),2.66(td,J=13.5,12.7,5.7Hz,4H),2.29–2.22(m,1H),2. 09(s,3H),2.08–2.03(m,1H),1.92(m,1H),1.82(s,3H),1.73–1.65(m,1H),1 .55(dd,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.32–1.24(m,1H ),1.18(t,J=13.1Hz,1H),1.02(d,J=6.5Hz,3H),0.88(s,3H).ESI-HRMS:m / z calculated for C 35 H 40 O6[M+H] + :557.2903,found557.2911.

[0360] Example 19. Synthesis of Compound 3s

[0361]

[0362] Compound 3s was prepared by the method of the above-mentioned synthetic route 1, wherein the derivative containing a naked carboxyl group was benzoic acid.

[0363] Yield: 89% 1H NMR (400MHz, CDCl3) δ9.18 (s, 1H), 8.16–8.05 (m, 2H), 7.61 (dt, J = 12.0, 7.3H z,1H),7.49(q,J=7.3Hz,2H),6.77(dd,J=6.5,2.4Hz,1H),6.44(d,J=11.6Hz ,1H),6.18(t,J=11.3Hz,1H),6.06(s,1H),5.35(t,J=10.3Hz,1H),4.97–4.7 5(m,2H),3.38(d,J=4.1Hz,1H),2.94(d,J=20.4Hz,1H),2.68(dd,J=8.3,3.9H z,1H),2.66–2.61(m,1H),2.61–2.54(m,1H),2.29–2.22(m,1H),2.09(s,3H) ,2.08–2.03(m,1H),1.92(m,1H),1.85(s,3H),1.79(s,3H),1.73–1.65(m,1H) ,1.55(dd,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.32–1.24(m,1 H),1.18(t,J=13.1Hz,1H),0.99(d,J=6.7Hz,3H),0.88(s,3H).ESI-HRMS:m / z calculated for C 32 H 38 O4[M+H] + :487.2848,found 487.2834.

[0364] Example 20: Synthesis of Compound 3t

[0365]

[0366] Compound 3t was prepared using the method of the above-mentioned synthetic route 1, wherein the derivative containing a naked carboxyl group was 3,4-dimethoxybenzoic acid.

[0367] Yield: 84% 1H NMR (400MHz, CDCl3) δ9.30 (s, 1H), 7.75 (dd, J = 15.2, 11.8Hz, 1H), 7.40 (d, J =8.2Hz,1H),7.09–6.98(m,1H),6.38(d,J=2.3Hz,1H),6.37–6.31(m,2H),6 .24–6.15(m,1H),6.07(s,1H),5.81(t,J=10.2Hz,1H),3.81(d,J=2.2Hz,6H ),3.38(d,J=4.6Hz,1H),2.94(d,J=20.4Hz,1H),2.68(dd,J=8.3,3.9Hz,1H) ,2.66–2.61(m,1H),2.61–2.54(m,1H),2.29–2.22(m,1H),2.09(s,3H),2.0 8–2.03(m,1H),1.92(m,1H),1.85(s,3H),1.79(s,3H),1.73–1.65(m,1H),1 .55(dd,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.32–1.24(m,1H ),1.18(t,J=13.1Hz,1H),1.02(d,J=6.5Hz,3H),0.89(s,3H).ESI-HRMS:m / z calculated for C 34 H 42 O6[M+H] + :547.3060,found 547.3046.

[0368] Example 21. Synthesis of Compound 3u

[0369]

[0370] Compound 3u was prepared using the method of the above-mentioned synthetic route 1, wherein the derivative containing a naked carboxyl group was 4-chlorobenzoic acid.

[0371] Yield: 79% 1H NMR (400MHz, CDCl3) δ9.23(s,1H),8.02(d,J=8.2Hz,2H),7.45(d,J=8.3Hz,2H),6.80–6.74(m,1H),6.41(d,J=11.6Hz,1H),6.18(t,J=11.2Hz,1H ),6.05(s,1H),5.37(d,J=10.2Hz,1H),5.00–4.75(m,2H),3.38(d,J=4.1Hz,1H),2.94(d,J=20.4Hz,1H),2.68(dd,J=8.3,3.9Hz,1H),2.66–2.61 (m,1H),2.61–2.54(m,1H),2.29–2.22(m,1H),2.09(s,3H),2.08–2.03( m,1H),1.92(m,1H),1.85(s,3H),1.79(s,3H),1.73–1.65(m,1H),1.55(d d,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.32–1.24(m,1H),1.18(t,J=13.1Hz,1H),1.01(d,J=6.6Hz,3H),0.89(s,3H).ESI-HRMS:m / z calculatedfor C 32 H 47 ClO4[M+H] + :521.2459,found 521.2441.

[0372] Example 22. Synthesis of Compound 3v

[0373]

[0374] Compound 3v was prepared using the method of the above-mentioned synthetic route 1, wherein the derivative containing a naked carboxyl group was 6-indolecarboxylic acid.

[0375] Yield: 77% 1H NMR(400MHz, CDCl3)δ9.11(s,1H),8.60(s,1H),7.39–7.33(m,1H),6.73(s, 1H),6.68(d,J=7.8Hz,1H),6.46(d,J=11.9Hz,1H),6.19(t,J=11.3Hz,1H), 6.06(d,J=8.1Hz,1H),5.33(t,J=10.3Hz,1H),4.99–4.76(m,2H),3.90(d,J =4.6Hz,1H),2.94(d,J=20.4Hz,1H),2.68(dd,J=8.3,3.9Hz,1H),2.66–2.61 (m,1H),2.61–2.54(m,1H),2.29–2.22(m,1H),2.09(s,3H),2.08–2.03(m,1 H),1.92(m,1H),1.85(s,3H),1.79(s,3H),1.73–1.65(m,1H),1.55(dd,J=1 1.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.32–1.24(m,1H),1.18(t,J=13.1Hz,1H),0.98(d,J=6.7Hz,3H),0.82(s,3H).ESI-HRMS:m / zcalculated for C 34 H 39 NO4[M+H] + :526.2957,found 526.2928.

[0376] Example 23. Synthesis of Compound 3w

[0377]

[0378] Compound 3w was prepared by the method of the above-mentioned synthetic route 1, wherein the derivative containing a naked carboxyl group was 7-quinolinecarboxylic acid.

[0379] Yield: 85% 1H NMR(400MHz, CDCl3) δ9.22(s,1H),9.05(dd,J=4.3,1.7Hz,1H),8.65(d,J=1.9Hz,1H ),8.34(ddd,J=19.5,8.7,1.8Hz,2H),8.20(d,J=8.8Hz,1H),7.60–7.49(m,1H),6.8 1(dd,J=6.5,2.4Hz,1H),6.51–6.44(m,1H),6.26–6.16(m,1H),6.08–6.03(m,1H),5 .38(t,J=10.3Hz,1H),5.00–4.86(m,2H),3.38(d,J=4.2Hz,1H),2.94(d,J=20.4Hz, 1H),2.68(dd,J=8.3,3.9Hz,1H),2.66–2.61(m,1H),2.61–2.54(m,1H),2.29–2.22( m,1H),2.09(s,3H),2.08–2.03(m,1H),1.92(m,1H),1.85(s,3H),1.79(s,3H),1.73 –1.65(m,1H),1.55(dd,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.32–1.2 4(m,1H),1.18(t,J=13.1Hz,1H),0.98(d,J=6.7Hz,3H),0.87(s,3H).ESI-HRMS:m / z calculatedfor C 35 H 39 NO4[M+H] + :538.2957,found 538.2937.

[0380] Example 24. Synthesis of Compound 3x

[0381]

[0382] Compound 3x was prepared by the method of the above-mentioned synthetic route 1, wherein the derivative containing a naked carboxyl group was 3,4-dimethoxyphenylpropionic acid.

[0383] Yield: 87% 1H NMR (400MHz, CDCl3) δ9.29(s,1H),6.80(dd,J=20.2,8.2Hz,4H),6.33(d,J=11.7Hz,1H),6.16(t,J=11.3Hz,1H),6.08(s,1H),5.36(t,J=10.2H z,1H),4.61(q,J=12.4Hz,2H),3.89(d,J=4.9,2.0Hz,6H),3.41(d,J=4.2Hz,1H),2.94(t,J=7.7Hz,2H),2.69(t,J=7.8Hz,2H),2.66–2.61(m,1 H),2.61–2.54(m,1H),2.29–2.22(m,1H),2.09(s,3H),2.08–2.03(m,1 H),1.92(m,1H),1.85(s,3H),1.79(s,3H),1.73–1.65(m,1H),1.55(dd, J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.32–1.24(m,1H),1.18(t,J=13.1Hz,1H),0.98(d,J=6.7Hz,3H),0.87(s,3H).ESI-HRMS:m / z calculated forC 36 H 46 O6[M+H] + :575.3373,found 575.3341.

[0384] Example 25. Synthesis of Compound 3y

[0385]

[0386] Compound 3y was prepared using the method of the above-mentioned synthetic route 1, wherein the derivative containing a naked carboxyl group was 1-adamantaneacetic acid.

[0387] Yield 90%, 1H NMR (400MHz, CDCl3) δ9.29(s,1H),6.83(dd,J=6.4,2.4Hz,1H),6.33(d,J=11.6Hz,1H),6.16(t,J=11.3Hz,1H),6.06(t,J=1.6Hz,1H),5.34(t, J=10.2Hz,1H),4.58(q,J=12.7Hz,2H),3.40(d,J=4.1Hz,1H),2.94(d,J=20.4Hz,1H),2.68(dd,J=8.3,3.9Hz,1H),2.66–2.61(m,1H),2.61–2.5 4(m,1H),2.31–2.27(m,1H),2.24(s,2H),2.09(s,3H),2.08–2.03(m,1H ),1.92(m,4H),1.85(s,3H),1.79(s,3H),1.73–1.65(m,1H),1.55(dd,J =11.8,5.0Hz,16H),1.46(td,J=12.3,4.9Hz,1H),1.32–1.24(m,1H),1.18(t,J=13.1Hz,1H),1.01(d,J=6.5Hz,3H),0.87(s,3H).ESI-HRMS:m / z calculated for C 37 H 50 NO4[M+H] + :559.3787,found 559.3739.

[0388] Example 26. Synthesis of Compound 3z

[0389]

[0390] Compound 3z was prepared by the method of the above-mentioned synthetic route 1, wherein the derivative containing a naked carboxyl group was succinic anhydride.

[0391] Yield: 89% 1H NMR(400MHz, CDCl3)δ9.17(s,1H),6.88(dd,J=6.8,2.3Hz,1H),6.31(d,J=11.5Hz,1H),6.13(dt,J=23.6,11.2Hz,1H),5.37–5.28(m,1H), 4.13(d,J=7.9Hz,2H),3.31(d,J=4.3Hz,1H),2.94(d,J=20.4Hz,1H),2.68(dd,J=8.3,3.9Hz,1H),2.66–2.61(m,4H),2.61–2.54(m,4H),2 .31–2.27(m,1H),2.24(s,2H),2.09(s,3H),2.08–2.03(m,1H),1.92(m,4H),1.85(s,3H),1.79(s,3H),1.73–1.65(m,1H),1.55(dd,J=11. 8,5.0Hz,16H),1.46(td,J=12.3,4.9Hz,1H),1.32–1.24(m,1H),1.18(t,J=13.1Hz,1H),1.01(d,J=6.5Hz,3H),0.87(s,3H).ESI-HRMS:m / z calculated for C 29 H 38 O6[M+H] + :483.2747,found 483.2711.

[0392] Route 2:

[0393]

[0394] Synthesis of intermediate 2:

[0395] The synthesis method of intermediate 2 is as shown in Scheme 1.

[0396] Synthesis of compound X2:

[0397] At room temperature, intermediate 2 (1.0 mol) was dissolved in dichloromethane, and Ag2O (2.0 mol) was slowly added, followed by the addition of different halides (2.0 mol). The mixture was then stirred at room temperature for three days. The reaction progress was monitored by TLC plate. After completion of the reaction, the mixture was concentrated and purified by column chromatography to obtain compound X2.

[0398] Example 27. Synthesis of Compound x2

[0399]

[0400] Compound x2 was prepared by the method of the above-mentioned synthetic route 2, wherein the halide was 1-bromooctane.

[0401] Yield: 39% 1 H NMR (400MHz, CDCl3) δ9.28(p,J=1.1Hz,1H),6.80(tq,J=7.3,1.8Hz,1H),6.08(p,J=1.6Hz,1H),6.09–6.00(m,2H),5.1 7(d,J=8.9Hz,1H),3.96(s,2H),3.47(d,J=9.5Hz,1H),3.40(t,J=6.2Hz,2H),2.73–2.60(m,2H),2.08(d,J=1.5Hz,3H) ,2.05–1.95(m,1H),1.94–1.83(m,2H),1.82–1.70(m,4H),1.57(tt,J=7.7,6.2Hz,2H),1.55–1.47(m,1H),1.49–1.39( m,2H),1.39–1.20(m,12H),1.00(dd,J=12.4,6.7Hz,1H),0.92(dt,J=6.2,1.2Hz,3H),0.90–0.83(m,6H).ESI-HRMS:m / z calculated for C 33 H 51 O3[M+H] + :495.3838,found 495.3814.

[0402] Route 3:

[0403]

[0404] Synthesis of intermediate 2:

[0405] The synthesis method of intermediate 2 is as shown in Scheme 1.

[0406] Synthesis of compound X3:

[0407] Intermediate 2 (0.5 mol) and triphenylphosphine (PPh3, 0.6 mol) were dissolved in anhydrous DMF. Under a nitrogen atmosphere, a solution of diiodoethane (0.6 mol) dissolved in DMF was slowly added dropwise using a needle. Finally, different types of amines were added. The reaction was allowed to react at room temperature for 12-24 h. The reaction was monitored by TLC. After the reaction was completed, a mixed solution of dichloromethane and saturated brine (1:1, v / v) was added. The mixture was extracted three times, and the organic phases were combined. Anhydrous sodium sulfate was added and dried for 2 h. The mixture was concentrated, mixed, and separated and purified by column chromatography to obtain compound X3.

[0408] Example 28. Synthesis of Compound x3

[0409]

[0410] Compound x3 was prepared by the method of the above synthetic route 3, wherein the amine was 3,4-dimethoxyphenethylamine.

[0411] Yield 46%, 1 H NMR (400MHz, CDCl3) δ9.28 (s, 1H), 6.84–6.76 (m, 2H), 6.76 (d, J = 8.4Hz, 1H) ,6.69(ddt,J=8.4,2.0,1.0Hz,1H),6.08(d,J=1.6Hz,1H),6.08–6.00(m,1H) ,6.02–5.96(m,1H),5.17(td,J=10.6,7.9,1.8,1.0Hz,1H),3.86(s,6H),3.4 7(dtt,J=9.7,1.8,0.8Hz,1H),3.22(dt,J=5.0,0.9Hz,2H),2.91(qd,J=5.0, 4.1Hz,1H),2.86(td,J=5.5,4.4Hz,2H),2.73–2.60(m,4H),2.08(d,J=1.4Hz ,3H),2.05–1.95(m,1H),1.94–1.83(m,2H),1.79–1.71(m,1H),1.70(t,J=1. 2Hz,3H),1.55–1.47(m,1H),1.39–1.30(m,1H),1.30–1.20(m,3H),1.00(dd, J=12.4,6.7Hz,1H),0.92(dt,J=6.2,1.2Hz,3H),0.85(s,3H).ESI-HRMS:m / z calculated for C 36 H 47 NO5[M+H] + :574.3532,found 574.3515.

[0412] Route 4:

[0413]

[0414] Take a two-necked flask, place a magnetic stirrer, bake at 105 ° C for 15 minutes, and then heat the device while hot. Operate in anhydrous and oxygen-free conditions. Under N2, weigh raw material 1 and dissolve it in anhydrous dichloromethane. Add raw material 1 (1.0 mol) dissolved in anhydrous dichloromethane under N2 atmosphere, then add Grubbs II (5%) catalyst and terminal olefin derivative (3.0 mol), and finally add Ti (OAc) 4 (1%). The reaction is refluxed for 12-24 hours. The reaction progress is monitored by TLC. The reaction is stopped and extracted three times with a mixed solution of dichloromethane and saturated brine (1:1, v / v). The organic phases are combined, dried over anhydrous sodium sulfate for 2 hours, concentrated, mixed, and separated and purified by silica gel column chromatography using a mixed solution of petroleum ether and ethyl acetate (volume ratio of petroleum ether to ethyl acetate 2:1) as eluent to obtain compounds X4 and X5, respectively. The mass ratio of compounds X4 and X5 is about 1:1.

[0415] Examples 29-30, Synthesis of Compounds 4a and 4b

[0416]

[0417] Compounds 4a and 4b were prepared using the method of synthetic route 4, wherein the terminal olefin derivative was n-butyl acrylate. The products were separated and purified by silica gel column chromatography using a mixed solution of petroleum ether and ethyl acetate (volume ratio of petroleum ether to ethyl acetate 2:1) as the eluent to obtain compounds 4a and 4b, respectively.

[0418] Compound 4a: yield 41%, 11H NMR (400 MHz, CDCl3) δ 9.29 (s, 1H), δ 7.59 (dd, J = 15.1, 11.7 Hz, 1H), 6.79 (dd, J = 6.5, 2.4 Hz, 1H), 6.12 (t, J = 11.3 Hz, 1H), 6.06 (t, J = 1.6 Hz, 1H), 5.97 (d, J = 15.2 Hz, 1H), 5.71 (t, J = 10.2 Hz, 1H), 4.20 (t, J = 6.7 Hz, 2H), 3.37 (d, J = 4.2 Hz, 1H)., 2.94 (d, J = 20.4 Hz, 1H), 2.68 (dd, J = 8.3, 3.9 Hz, 1H), 2.66–2.61 (m, 1H), 2.61–2.54 (m, 1H), 2.29–2.22 (m, 1H), 2.09 (s, 3H), 2.08–2.03 (m, 1H), δ 1.92 (m, 1H), 1.82–1.54 (m, 3H), 1.55 (dd, J = 11.8, 5.0 Hz, 1H), 1.46 (td, J = 12.3, 4.9 Hz, 1H), 1.32–1.24 (m, 3H), 1.18 (t, J = 13.1 Hz, 1H), 0.99 (d, J = 6.7 Hz, 3H), 0.96 (t, J = 7.4 Hz, 3H), 0.88 (s, 3H). 13 13C NMR (101 MHz, CDCl3) δ 207.43,​​​​​​​​​​H NMR(400MHz, CDCl3)δ9.30(s,1H),δ7.00–6.88(m,1H),6.80(dd,J=6.6,2.5Hz,1H),6.06(s,1H),5.86(d,J=15.9Hz,1H),4.17 (q,J=6.9Hz,1H),3.36(d,J=4.1Hz,1H),2.94(d,J=20.4Hz,1H),2.68(dd,J=8.3,3.9Hz,1H),2.66–2.61(m,1H),2.61–2.54(m ,1H),2.29–2.22(m,1H),2.09(s,3H),2.08–2.03(m,1H),δ1.92(m,1H),1.82–1.54(m,3H),1.55(dd,J=11.8,5.0Hz,1H),1.46 (td,J=12.3,4.9Hz,1H),1.32–1.24(m,3H),1.18(t,J=13.1Hz,1H),0.99(d,J=6.7Hz,3H),0.96(t,J=7.4Hz,3H),0.88(s,3H). 13 C NMR (101MHz, CDCl3) δ207.19,192.91,177.30,166.66,156.32,154.37,140.39,130.36,129.53,120.48,114.63,64.49,49.91,49.80 ,48.96,45.87,45.48,44.15,43.56,36.59,31.14,30.67,29.70,27.62,22.76,20.61,19.21,17.21,13.78.ESI-HRMS:m / zcalculated for C 26 H 37 O4[M+H] + :413.2692,found 413.2671.

[0420] Examples 31-32, Synthesis of Compounds 5a and 5b

[0421]

[0422] Compounds 5a and 5b were prepared using the method of synthetic route 4, wherein the terminal olefin derivative was n-pentyl acrylate. The products were separated and purified by silica gel column chromatography using a mixed solution of petroleum ether and ethyl acetate (volume ratio of petroleum ether to ethyl acetate 2:1) as the eluent to obtain compounds 5a and 5b, respectively.

[0423] Compound 5a: yield 43%,1 1H NMR (400 MHz, CDCl3) δ 9.29 (s, 1H), 7.59 (dd, J = 15.2, 11.7 Hz, 1H), 6.79 (dd, J = 6.3, 2.5 Hz, 1H), 6.13 (d, J = 11.2 Hz, 1H), 6.06 (s, 1H), 5.97 (d, J = 15.2 Hz, 1H), 5.71 (t, J = 10.2 Hz, 1H), 4.19 (t, J = 6.7 Hz, 2H), 3.37 (d, J = 4.1 Hz, 1H), 2.94 (d, J = 20.4 Hz, 1H), 2.68 (dd, J = 8.3, 3.9 Hz, 1H), 2.66–2.61 (m, 1H), 2.61–2.54 (m, 1H), 2.29–2.22 (m, 1H), 2.09 (s, 3H), 2.08–2.03 (m, 1H), δ 1.92 (m, 1H), 1.82–1.54 (m, 3H), 1.55 (dd, J = 11.8, 5.0 Hz, 1H), 1.46 (td, J = 12.3, 4.9 Hz, 1H), 1.38 (m, 2H) 1.32–1.24 (m, 3H), 1.18 (t, J = 13.1 Hz, 1H), 0.99 (d, J = 6.7 Hz, 3H), 0.96 (t, J = 7.4 Hz, 3H), 0.88 (s, 3H). 13 13C NMR (101 MHz, CDCl3) δ 192.93, 181.84, 176.83, 157.71, 147.55, 138.82, 128.72, 126.32, 123.15, 109.22, 65.26, 51.69, 49.95, 49.06, 45.86, 45.53, 44.15, 43.85, 38.16, 33.54, 29.72, 28.39, 28.13, 27.74, 22.86, 22.36, 21.50, 17.24, 14.01. ESI-HRMS: m / z calculated for C 29 H 40 O4 [M + H] + : 453.3005, found 453.3001.

[0424] Compound 5b: Yield 46%, 1H NMR(400MHz, CDCl3)δ9.31(s,1H),6.93(dd,J=15.9,8.2Hz,1H),6.81(dd,J=6.4,2.3Hz,1H),6.07(s,1H),5.87(d,J=15.9Hz,1H), 4.17(q,J=6.8Hz,2H),3.37(d,J=4.1Hz,1H),2.94(d,J=20.4Hz,1H),2.68(dd,J=8.3,3.9Hz,1H),2.66–2.61(m,1H),2.61–2.54(m, 1H),2.29–2.22(m,1H),2.09(s,3H),2.08–2.03(m,1H),δ1.92(m,1H),1.82–1.54(m,3H),1.55(dd,J=11.8,5.0Hz,1H),1.46(td,J= 12.3,4.9Hz,1H),1.38(m,2H)1.32–1.24(m,3H),1.18(t,J=13.1Hz,1H),0.99(d,J=6.7Hz,3H),0.96(t,J=7.4Hz,3H),0.88(s,3H). 13 C NMR (101MHz, CDCl3) δ207.19,192.93,177.28,166.67,156.31,154.37,140.41,130.38,120.49,77.23,64.80,49.92,49.80,48.9 6,45.88,45.49,44.16,43.57,36.60,31.15,29.71,29.39,28.31,28.11,27.62,22.77,22.37,20.62,17.22,14.00.ESI-HRMS:m / z calculated for C 27 H 38 O4[M+H] + :427.2848,found 427.2837.

[0425] Examples 33-34, Synthesis of Compounds 6a and 6b

[0426]

[0427] Compounds 6a and 6b were prepared by the method of synthetic route 4, wherein the terminal olefin derivative was n-hexyl acrylate. The products were separated and purified by silica gel column chromatography using a mixed solution of petroleum ether and ethyl acetate (volume ratio of petroleum ether to ethyl acetate 2:1) as the eluent to obtain compounds 6a and 6b, respectively.

[0428] Compound 6a: yield 39%, 1 H NMR (400MHz, CDCl3) δ9.28 (s, 1H), δ7.59 (dd, J=15.1, 11.6Hz, 1H), 6.79 (dd, J=6.4, 2.4Hz, 1H), 6.12 (t, J=11.2Hz, 1H), 6.03 (d, J=29.6Hz, 1H), 5.7 1(t,J=10.2Hz,1H),4.19(t,J=6.7Hz,2H),3.38(d,J=4.1Hz,1H),2.94(d, J=20.4Hz,1H),2.68(dd,J=8.3,3.9Hz,1H),2.66–2.61(m,1H),2.61–2.54 (m,1H),2.29–2.22(m,1H),2.09(s,3H),2.08–2.03(m,1H),δ1.92(m,1H) ,1.82–1.54(m,3H),1.67(dd,J=8.0,6.5Hz,2H),1.55(dd,J=11.8,5.0Hz, 1H),1.46(td,J=12.3,4.9Hz,1H),1.38(m,2H)1.32–1.24(m,3H),1.18(t, J=13.1Hz,1H),0.99(d,J=6.7Hz,3H),0.89(t,J=7.4Hz,3H),0.86(s,3H). 13 C NMR (101MHz, CDCl3) δ207.45,192.93,177.47,167.40,156.95,147.43,140. 19,138.81,130.32,125.66,122.50,64.71,51.68,49.94,49.06,45.85,45. 52,44.14,43.84,33.54,31.94,31.45,30.95,30.19,29.71,29.38,28.65,2 7.73,25.63,22.86,22.71,22.56,21.49,17.23,14.14,14.02.ESI-HRMS:m / z calculated for C 30 H 42 O4[M+H] + :467.3161,found 467.3157.

[0429] Compound 6b: yield 43%, 1H NMR(400MHz, CDCl3) δ9.30(s,1H),6.92(dd,J=15.8,8.2Hz,1H),6.81(dd,J=6.5,2.3Hz,1H),6.06(d,J=2.0Hz,1H),5.86(d,J=15.8Hz,1H), 4.23–4.08(m,2H),3.37(d,J=4.1Hz,1H),2.94(d,J=20.4Hz,1H),2.68(dd,J=8.3,3.9Hz,1H),2.66–2.61(m,1H),2.61–2.54(m,1H),2.29–2 .22(m,1H),2.09(s,3H),2.08–2.03(m,1H),δ1.92(m,1H),1.82–1.54(m,3H),1.67(dd,J=8.0,6.5Hz,2H),1.55(dd,J=11.8,5.0Hz,1H),1.4 6(td,J=12.3,4.9Hz,1H),1.38(m,2H)1.32–1.24(m,3H),1.18(t,J=13.1Hz,1H),0.99(d,J=6.7Hz,3H),0.89(t,J=7.4Hz,3H),0.86(s,3H). 13 C NMR (101MHz, CDCl3) δ207.19,192.92,177.30,166.66,156.32,154.37,140.39,130.36,120.48,64.81,49.91,49.80,48.96,4 5.87,45.48,44.16,43.57,36.59,31.47,31.14,29.70,28.56,27.61,25.63,22.76,22.54,20.61,17.21,14.03.ESI-HRMS:m / z calculated for C 28 H 40 O4[M+H] + :441.3005,found 441.3001.

[0430] Examples 35-36, Synthesis of Compounds 7a and 7b

[0431]

[0432] Compounds 7a and 7b were prepared by the method of synthetic route 4, wherein the terminal olefin derivative was n-heptyl acrylate. The products were separated and purified by silica gel column chromatography using a mixed solution of petroleum ether and ethyl acetate (volume ratio of petroleum ether to ethyl acetate 2:1) as the eluent to obtain compounds 7a and 7b, respectively.

[0433] Compound 7a: yield 38%, 1 H NMR (400MHz, CDCl3) δ9.28 (s, 1H), 7.59 (dd, J = 15.2, 11.7Hz, 1H), 6.81–6.78 (m, 1H),6.12(t,J=11.3Hz,1H),6.06(d,J=1.8Hz,2H),5.97(d,J=15.2Hz,1H),5.71 (t,J=10.3Hz,1H),5.08–4.99(m,1H),4.19(t,J=6.8Hz,2H),3.37(d,J=4.2Hz,1 H),2.94(d,J=20.4Hz,1H),2.68(dd,J=8.3,3.9Hz,1H),2.66–2.61(m,1H),2.61 –2.54(m,1H),2.29–2.22(m,1H),2.09(s,3H),2.08–2.03(m,1H),δ1.92(m,1H), 1.82–1.54(m,3H),1.67(dd,J=8.0,6.5Hz,2H),1.55(dd,J=11.8,5.0Hz,1H),1. 46(td,J=12.3,4.9Hz,1H),1.42–1.38(m,2H),1.38(m,2H),1.32–1.24(m,3H),1 .18(t,J=13.1Hz,1H),0.99(d,J=6.7Hz,3H),0.90(t,J=7.4Hz,3H),0.86(s,3H). 13 C NMR (101MHz, CDCl3) δ206.80,193.92,178.57,167.12,159.44,148.98,140.92,139.19,130.31,128.72,125.59,121.89,121. 24,114.61,66.69,63.90,53.44,49.60,48.24,43.83,32.88,30.95,30.10,26.93,24.53,19.93,17.22,14.12.ESI-HRMS:m / z calculated for C 31 H 44 O4[M+H] + :481.3318,found 481.3314.

[0434] Compound 7b: yield 42%, 1H NMR(400MHz, CDCl3)δ9.31(s,1H),6.93(dd,J=15.8,8.2Hz,1H),6.81(dd,J=6.5,2.3Hz,1H),6.06(t,J=1.7Hz,1H),5.86(d,J=15.9Hz,1H),4.23–4.08 (m,2H),3.37(d,J=4.2Hz,1H),2.94(d,J=20.4Hz,1H),2.68(dd,J=8.3,3.9 Hz,1H),2.66–2.61(m,1H),2.61–2.54(m,1H),2.29–2.22(m,1H),2.09(s,3H ),2.08–2.03(m,1H),δ1.92(m,1H),1.82–1.74(m,3H),1.67(dd,J=8.0,6.5 Hz,2H),1.64–1.58(m,2H),1.55(dd,J=11.8,5.0Hz,1H),1.46(td,J=12.3, 4.9Hz,1H),1.42–1.38(m,2H),1.38(m,2H),1.32–1.24(m,3H),1.18(t,J=1 3.1Hz, 1H), 0.99 (d, J = 6.7Hz, 3H), 0.90 (t, J = 7.4Hz, 3H), 0.94–0.86 (m, 6H). 13 C NMR (101MHz, CDCl3) δ207.20,192.93,177.30,166.67,156.33,154.37,140.40,130.37,120.49,64.82,49.91,49.80,48.96,45.88,45.48,4 4.16,36.60,31.73,31.15,29.71,28.96,28.61,27.62,26.55,26.43, 25.93,25.83,25.64,22.77,22.60,20.61,17.22,14.09.ESI-HRMS:m / z calculated for C 29 H 42 O4[M+H] + :455.3161,found 455.3143.

[0435] Examples 37-38, Synthesis of Compounds 8a and 8b

[0436]

[0437] Compounds 8a and 8b were prepared by the method of synthetic route 4, wherein the terminal olefin derivative was n-octyl acrylate. The products were separated and purified by silica gel column chromatography using a mixed solution of petroleum ether and ethyl acetate (volume ratio of petroleum ether to ethyl acetate 2:1) as the eluent to obtain compounds 8a and 8b, respectively.

[0438] Compound 8a: yield 37%, 1 H NMR (400MHz, CDCl3) δ9.30 (s, 1H), 7.59 (dd, J=15.2, 11.8Hz, 1H), 6.84 (dd, J=6 .6,2.5Hz,1H),6.11(t,J=11.4Hz,1H),6.06(s,2H),5.96(d,J=15.2Hz,1H),5.8 1–5.75(m,1H),5.10–4.96(m,2H),4.18(t,J=6.8Hz,1H),3.41(d,J=4.2Hz,1H), 3.10–2.98(m,1H),2.94(d,J=20.4Hz,1H),2.68(dd,J=8.3,3.9Hz,1H),2.66–2. 61(m,1H),2.61–2.54(m,1H),2.29–2.22(m,1H),2.09(s,3H),2.08–2.03(m,1H) , δ1.92(m,1H),1.82–1.54(m,3H),1.67(dd,J=8.0,6.5Hz,2H),1.55(dd,J=11.8 ,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.42–1.38(m,2H),1.38(m,2H),1.32 –1.24(m,3H),1.18(t,J=13.1Hz,1H),0.99(d,J=6.7Hz,3H),0.94–0.86(m,7H). 1313C NMR(101MHz,CDCl3)δ207.50,193.02,192.92,177.50,167.39,157.31,147.44,144.99,140.19,138.80,130.30,125.65,122.49,113.78,64.71,51.67,50.01,49.96,49.93,49.09,49.05,45.88,45.51,45.36,44.30,44.12,43.84,43.56,37.65,33.53,31.79,30.96,29.70,29.24,29.21,28.69,27.73,27.66,25.96,22.92,22.85,22.65,21.46,17.23,14.11.ESI-HRMS:m / z calculatedfor C 32 H 46 O4[M+H] + :495.3474,found 495.3467.

[0439] Compound 8b: Yield 45%, 1 1H NMR(400MHz,CDCl3)δ9.29(s,1H),6.92(dd,J = 15.8,8.2Hz,1H),6.80(dd,J = 6.5,2.3Hz,1H),6.05(s,1H),5.85(d,J = 15.8Hz,1H),4.15(q,J = 6.9Hz,3H),3.36(d,J = 4.1Hz,1H),3.10–2.98(m,1H),2.94(d,J = 20.4Hz,1H),2.68(dd,J = 8.3,3.9Hz,1H),2.66–2.61(m,1H),2.61–2.54(m,1H),2.29–2.22(m,1H),2.09(s,3H),2.08–2.03(m,1H),δ1.92(m,1H),1.82–1.54(m,3H),1.67(dd,J = 8.0,6.5Hz,2H),1.55(dd,J = 11.8,5.0Hz,1H),1.46(td,J = 12.3,4.9Hz,1H),1.42–1.38(m,2H),1.38(m,2H),1.32–1.24(m,3H),1.18(t,J = 13.1Hz,1H),0.99(d,J = 6.7Hz,3H),0.94–0.86(m,7H). 13C NMR (101MHz, CDCl3) δ207.16,192.90,177.29,166.65,156.32,154.36,140.38,130.34,120.47,64.80,49.90,49.79,48.95,45.86,45.47,44.1 4,43.56,36.58,31.79,31.13,29.24,29.18,28.59,27.61,26.87,26.76 ,26.20,26.03,25.96,22.75,22.64,20.60,17.20,14.10.ESI-HRMS:m / z calculated for C 30 H 44 O4[M+H] + :469.3318,found 469.3311.

[0440] Examples 39-40, Synthesis of Compounds 9a and 9b

[0441]

[0442] Compounds 9a and 9b were prepared by the method of synthetic route 4, wherein the terminal olefin derivative was n-nonyl acrylate, and separated and purified by silica gel column chromatography using a mixed solution of petroleum ether and ethyl acetate (volume ratio of petroleum ether to ethyl acetate 2:1) as eluent to obtain compounds 9a and 9b, respectively.

[0443] Compound 9a: yield 42%, 11H NMR (400 MHz, CDCl3) δ 9.29 (s, 1H), 7.59 (dd, J = 15.2, 11.8 Hz, 1H), 6.84 (dd, J = 6.6, 2.5 Hz, 1H), 6.12 (t, J = 11.2 Hz, 1H), 6.06 (d, J = 2.2 Hz, 2H), 5.97 (d, J = 15.2 Hz, 1H), 5.70 (t, J = 8.6 Hz, 1H), 5.12–4.98 (m, 2H), 4.18 (t, J = 6.6 Hz, 2H), 3.37 (d, J = 4.1 Hz, 1H), 3.10–2.98 (m, 1H), 2.94 (d, J = 20.4 Hz, 1H), 2.68 (dd, J = 8.3, 3.9 Hz, 1H), 2.66–2.61 (m, 1H), 2.61–2.54 (m, 1H), 2.29–2.22 (m, 1H), 2.09 (s, 3H), 2.08–2.03 (m, 1H), δ 1.92 (m, 1H), 1.82–1.54 (m, 3H), 1.67 (dd, J = 8.0, 6.5 Hz, 2H), 1.55 (dd, J = 11.8, 5.0 Hz, 1H), 1.46 (td, J = 12.3, 4.9 Hz, 1H), 1.42–1.38 (m, 2H), 1.38 (m, 2H), 1.32–1.24 (m, 5H), 1.18 (t, J = 13.1 Hz, 2H), 0.99 (d, J = 6.7 Hz, 3H), 0.94–0.86 (m, 6H). 13 13C NMR (101 MHz, CDCl3) δ 207.19, 192.92, 166.38, 158.52, 156.27, 155.30, 140.41, 130.36, 129.53, 121.13, 120.00, 114.63, 65.83, 62.97, 49.91, 49.78, 48.96, 45.84, 45.48, 44.15, 43.54, 36.68, 31.14, 29.71, 27.61, 22.77, 20.57, 17.22, 14.11. ESI-HRMS: m / z calculated for C 33 1HO4 [M + H] + : 509.3631, found 509.3634.

[0444] Compound 9b: Yield 43%, 1H NMR (400MHz, CDCl3) δ9.30(s,1H),6.92(dd,J=15.8,8.2Hz,1H),6.80(dd,J=6.5,2.3Hz,1H),6.06(s,1H),5.86(d,J=15.9Hz,1H),4.15(q,J=6. 9Hz,2H),3.36(d,J=4.2Hz,1H),3.10–2.98(m,1H),2.94(d,J=20.4Hz,1 H),2.68(dd,J=8.3,3.9Hz,1H),2.66–2.61(m,1H),2.61–2.54(m,1H),2. 29–2.22(m,1H),2.09(s,3H),2.08–2.03(m,1H),δ1.92(m,1H),1.82–1. 54(m,3H),1.67(dd,J=8.0,6.5Hz,2H),1.55(dd,J=11.8,5.0Hz,1H),1. 46(td,J=12.3,4.9Hz,1H),1.42–1.38(m,2H),1.38(m,2H),1.32–1.24( m,5H),1.18(t,J=13.1Hz,2H),0.99(d,J=6.7Hz,3H),0.94–0.86(m,6H). 13 C NMR (101MHz, CDCl3) δ207.20,192.93,177.30,166.66,156.37,154.37,140.39,130.36,120.49,64.83,49.91,49.79,48.95,45.87,45.49,4 4.15,43.55,36.61,31.94,31.87,31.15,29.71,29.50,29.31,29.27, 28.61,27.62,25.98,22.77,22.69,20.63,17.23,14.14.ESI-HRMS:m / z calculated for C 31 H 46 O4[M+H] + :483.3474,found 483.3467.

[0445] Examples 41-42, Synthesis of Compounds 10a and 10b

[0446]

[0447] Compounds 10a and 10b were prepared using the method of synthetic route 4, wherein the terminal olefin derivative was n-decyl acrylate. The products were separated and purified by silica gel column chromatography using a mixed solution of petroleum ether and ethyl acetate (volume ratio of petroleum ether to ethyl acetate 2:1) as the eluent to obtain compounds 10a and 10b, respectively.

[0448] Compound 10a: yield 36%, 1 H NMR(400MHz, CDCl3)δ9.31(s,1H),7.65–7.51(m,0H),7.00–6.91(m,1H),6.8 6–6.82(m,1H),6.80(d,J=2.4Hz,0H),6.07(d,J=1.8Hz,2H),5.90–5.81(m,1H ),5.10–5.00(m,1H),4.22–4.14(m,2H),3.38(d,J=4.2Hz,1H),3.10–2.98(m ,1H),2.94(d,J=20.4Hz,1H),2.68(dd,J=8.3,3.9Hz,1H),2.66–2.61(m,1H), 2.61–2.54(m,1H),2.29–2.22(m,1H),2.09(s,3H),2.08–2.03(m,1H),δ1.92 (m,1H),1.82–1.54(m,3H),1.67(dd,J=8.0,6.5Hz,2H),1.55(dd,J=11.8,5.0 Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.42–1.38(m,2H),1.38(m,2H),1.32–1 .24(m,7H),1.18(t,J=13.1Hz,2H),0.99(d,J=6.7Hz,3H),0.94–0.86(m,6H). 13 C NMR (101 MHz, CDCl3) 13 C NMR (101MHz, CDCl3) δ207.24,192.94,177.34,166.67,156.38,154.38,14 7.44,144.99,140.38,130.36,120.49,64.84,49.91,49.79,48.95,45.86, 45.48,44.15,43.55,36.61,31.91,31.14,29.71,29.56,29.54,29.32,29. 31,28.61,27.62,25.98,22.77,22.69,20.63,17.23,14.17.ESI-HRMS:m / z calculated for C34 H 50 O4[M+H] + :523.3787, found 523.3763.

[0449] Compound 10b: Yield 41%, 1 H NMR (400 MHz, CDCl3) δ 9.31 (s, 1H), 6.93 (dd, J = 15.9, 8.2 Hz, 1H), 6.81 (dd, J = 6.6, 2.3 Hz, 1H), 6.07 (t, J = 1.7 Hz, 1H), 5.86 (d, J = 15.9 Hz, 1H), 4.16 (q, J = 6.8 Hz, 3H), 3.37 (d, J = 4.1 Hz, 1H), 3.10–2.98 (m, 1H), 2.94 (d, J = 20.4 Hz, 1H), 2.68 (dd, J = 8.3, 3.9 Hz, 1H), 2.66–2.61 (m, 1H), 2.61–2.54 (m, 1H), 2.29–2.22 (m, 1H), 2.09 (s, 3H), 2.08–2.03 (m, 1H), δ 1.92 (m, 1H), 1.82–1.54 (m, 3H), 1.67 (dd, J = 8.0, 6.5 Hz, 2H), 1.55 (dd, J = 11.8, 5.0 Hz, 1H), 1.46 (td, J = 12.3, 4.9 Hz, 1H), 1.42–1.38 (m, 2H), 1.38 (m, 2H), 1.32–1.24 (m, 9H), 1.18 (t, J = 13.1 Hz, 2H), 0.99 (d, J = 6.7 Hz, 3H), 0.94–0.86 (m, 6H). 13 C NMR (101 MHz, CDCl3) δ 207.24, 192.94, 177.34, 166.67, 156.38, 154.38, 140.38, 130.36, 120.49, 64.84, 49.91, 49.79, 48.95, 45.86, 45.48, 44.15, 43.55, 36.61, 31.91, 31.14, 29.71, 29.56, 29.54, 29.32, 29.31, 28.61, 27.62, 25.98, 22.77, 22.69, 20.63, 17.23, 14.15. ESI-HRMS: m / z calculated for C 32 H 48 O4[M+H] + :497.3631, found 497.3627.

[0450] Examples 43-44. Synthesis of Compounds 11a and 11b

[0451]

[0452] Compounds 11a and 11b were prepared using the method of synthetic route 4, wherein the terminal olefin derivative was triethylene glycol methyl ether acrylate. The products were separated and purified by silica gel column chromatography using a mixed solution of petroleum ether and ethyl acetate (volume ratio of petroleum ether to ethyl acetate 2:1) as the eluent to obtain compounds 11a and 11b, respectively.

[0453] Compound 11a: yield 26%, 1 H NMR(400MHz, CDCl3)δ9.29(s,1H),7.61(dd,J=15.2,11.8Hz,1H),6.87–6.74(m,1H),6.12(t,J=11.2Hz,1H),6.06(s,1H),6.00(d,J=15.2Hz,1H),5. 73(t,J=10.1Hz,1H),4.35(t,J=4.9Hz,2H),4.24(t,J=4.8Hz,2H),3.85–3 .64(m,8H),3.37(d,J=4.1Hz,1H),3.31(s,3H),2.94(d,J=20.4Hz,1H),2.6 8(dd,J=8.3,3.9Hz,1H),2.66–2.61(m,1H),2.61–2.54(m,1H),2.29–2.22 (m,1H),2.09(s,3H),2.08–2.03(m,4H),1.92(m,1H),1.79(s,3H),1.73–1. 65(m,1H),1.55(dd,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.3 2–1.24(m,1H),1.18(t,J=13.1Hz,1H),0.98(d,J=6.7Hz,3H),0.89(s,3H). 1313C NMR (101 MHz, CDCl3) δ 207.38, 192.93, 171.74, 167.20, 156.89, 147.80, 140.21, 139.31, 130.32, 125.63, 122.06, 70.64, 70.55, 69.33, 63.64, 62.92, 51.67, 49.94, 49.05, 48.84, 45.85, 45.53, 44.13, 33.58, 30.95, 28.62, 27.74, 22.86, 21.52, 17.22. ESI-HRMS: m / z calculated for C 31 H 44 O7 [M + H] + : 529.3165, found 529.3153.

[0454] Compound 11b: Yield 31%, 1 1H NMR (400 MHz, CDCl3) δ 9.30 (s, 1H), 6.97 (dd, J = 15.9, 8.1 Hz, 1H), 6.88–6.73 (m, 1H), 6.06 (t, J = 1.7 Hz, 1H), 5.91 (d, J = 15.9 Hz, 1H), 4.33 (dtd, J = 12.1, 7.5, 4.8 Hz, 2H), 4.25–4.20 (m, 2H), 3.77 (t, J = 4.9 Hz, 2H), 3.73–3.70 (m, 2H), 3.68 (s, 4H), 3.36 (d, J = 4.2 Hz, 1H), 3.31 (s, 3H), 2.94 (d, J = 20.4 Hz, 1H), 2.68 (dd, J = 8.3, 3.9 Hz, 1H), 2.66–2.61 (m, 1H), 2.61–2.54 (m, 1H), 2.29–2.22 (m, 1H), 2.09 (s, 3H), 2.08–2.03 (m, 4H), 1.92 (m, 1H), 1.79 (s, 3H), 1.73–1.65 (m, 1H), 1.55 (dd, J = 11.8, 5.0 Hz, 1H), 1.46 (td, J = 12.3, 4.9 Hz, 1H), 1.32–1.24 (m, 1H), 1.18 (t, J = 13.1 Hz, 1H), 0.98 (d, J = 6.7 Hz, 3H), 0.89 (s, 3H). 13C NMR (101MHz, CDCl3) δ207.14,192.91,176.23,171.74,165.41,156.27,155.00,140.42,129.35,121.11,70.64,70.55,69.33,6 3.64,62.92,51.67,49.94,49.05,48.84,45.85,45.53,44.13,33.58,30.95,28.62,27.74,22.86,21.52,17.22.ESI-HRMS:m / z calculated for C 29 H 42 O7[M+H] + :503.3009,found 503.3007.

[0455] Examples 45-46, Synthesis of Compounds 12a and 12b

[0456]

[0457] Compounds 12a and 12b were prepared using the method of synthetic route 4, wherein the terminal olefin derivative was adamantyl acrylate. The products were separated and purified by silica gel column chromatography using a mixed solution of petroleum ether and ethyl acetate (volume ratio of petroleum ether to ethyl acetate 2:1) as the eluent to obtain compounds 12a and 12b, respectively.

[0458] Compound 12a: yield 43%, 11H NMR (400 MHz, CDCl3) δ 9.28 (s, 1H), 7.66–7.56 (m, 1H), 6.79 (dd, J = 6.5, 2.5 Hz, 1H), 6.14 (d, J = 11.3 Hz, 1H), 6.06 (t, J = 1.6 Hz, 1H), 5.70 (t, J = 10.2 Hz, 1H), 5.04 (s, 1H), 3.38 (d, J = 4.2 Hz, 1H), 2.94 (d, J = 20.4 Hz, 1H), 2.68 (dd, J = 8.3, 3.9 Hz, 1H), 2.66–2.61 (m, 1H), 2.61–2.54 (m, 1H), 2.29–2.22 (m, 1H), 2.09 (s, 3H), 2.08–2.03 (m, 5H), δ 1.92 (m, 1H), 1.85 (s, 3H), 1.79 (s, 3H), 1.75 (m, 8H), 1.73–1.65 (m, 1H), 1.55 (dd, J = 11.8, 5.0 Hz, 3H), 1.46 (td, J = 12.3, 4.9 Hz, 1H), 1.32–1.24 (m, 1H), 1.18 (t, J = 13.1 Hz, 1H), 0.99 (d, J = 6.7 Hz, 3H), 0.88 (s, 3H). 13 13C NMR (101 MHz, CDCl3) δ 207.41, 192.93, 181.85, 177.42, 166.69, 156.94, 147.19, 140.20, 138.53, 130.32, 129.31, 128.56, 126.05, 125.67, 123.22, 51.69, 49.94, 49.06, 45.87, 45.50, 44.15, 43.91, 37.41, 36.36, 3​​​​​​​​​​H NMR(400MHz, CDCl3)δ9.31(s,1H),6.94(dd,J=15.8,8.3Hz,1H),6.82(dd,J=6.6,2.4Hz,1H),5.94–5.83(m,1H),5.02(d,J=3.2H z,1H),3.37(d,J=4.2Hz,1H),2.94(d,J=20.4Hz,1H),2.68(dd,J=8.3,3.9Hz,1H),2.66–2.61(m,1H),2.61–2.54(m,1H),2.29–2 .22(m,1H),2.09(s,3H),2.08–2.03(m,5H),δ1.92(m,1H),1.85(s,3H),1.79(s,3H),1.75(m,8H),1.73–1.65(m,1H),1.55(dd,J =11.8,5.0Hz,3H),1.46(td,J=12.3,4.9Hz,1H),1.32–1.24(m,1H),1.18(t,J=13.1Hz,1H),0.99(d,J=6.7Hz,3H),0.88(s,3H). 13 C NMR (101MHz, CDCl3) δ207.15,192.94,177.25,165.99,156.33,154.03,140.40,130.37,121.11,49.91,49.85,48.96,45.87,45.46,44.17,4 3.64,37.41,36.57,36.35,36.32,31.95,31.83,31.80,31.22,29.70, 29.37,27.60,27.29,27.02,22.78,22.70,20.66,17.20.ESI-HRMS:m / z calculated for C 32 H 42 O4[M+H] + :491.3161,found 491.3158.

[0460] Examples 47-48, Synthesis of Compounds 13a and 13b

[0461]

[0462] Compounds 13a and 13b were prepared using the method of synthetic route 4, wherein the terminal olefin derivative was propylene glycol adamantyl acrylate. The products were separated and purified by silica gel column chromatography using a mixed solution of petroleum ether and ethyl acetate (volume ratio of petroleum ether to ethyl acetate 2:1) as the eluent to obtain compounds 13a and 13b, respectively.

[0463] Compound 13a: Yield 39%, 1 H NMR (400MHz, CDCl3) δ9.29(s,1H),7.60(dd,J=15.3,11.8Hz,1H),6.80(dd,J=6.5,2.5Hz,1H),6.13(d,J=11.3Hz,1H),5.96(d,J=15.2Hz,2H),5.73 (t,J=10.2Hz,1H),4.27(t,J=6.3Hz,2H),4.17(t,J=6.3Hz,2H),3.41(d,J=3.8Hz,1H),2.94(d,J=20.4Hz,1H),2.68(dd,J=8.3,3.9Hz,1H),2.66–2 .61(m,1H),2.61–2.54(m,1H),2.29–2.22(m,1H),2.09(s,3H),2.08–2.0 3(m,5H),1.97(m,3H),1.92(m,1H),1.85(s,3H),1.79(s,3H),1.73–1.65( m,17H),1.55(dd,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.32 –1.24(m,1H),1.18(t,J=13.1Hz,1H),0.99(d,J=6.7Hz,3H),0.86(s,3H). 13 C NMR (101MHz, CDCl3) δ214.18,192.57,171.64,166.07,156.28,147.92,141.98,138.81,132.26,126.99,122.10,61.79,60.74,51.03, 49.95,48.94,46.13,45.38,43.65,42.97,36.35,33.56,33.18,30.77,29.72,29.04,27.61,27.31,22.86,21.74,17.90.ESI-HRMS:m / z calculated for C 39 H 52 O6[M+H] + :617.3842,found 617.3840.

[0464] Compound 13b: yield 45%, 1H NMR (400MHz, CDCl3) δ9.30(s,1H),6.94(dd,J=15.9,8.2Hz,1H),6.81(dd,J=6.4,2.1Hz,1H),6.06(s,1H),5.86(d,J=15.6Hz,1H),4.26(q ,J=6.4Hz,2H),4.18(t,J=6.4Hz,2H),3.37(d,J=4.1Hz,1H),2.94(d,J=20.4Hz,1H),2.68(dd,J=8.3,3.9Hz,1H),2.66–2.61(m,1H),2.61– 2.54(m,1H),2.29–2.22(m,1H),2.09(s,3H),2.08–2.03(m,5H),1.97(m,3H),1.92(m,1H),1.85(s,3H),1.79(s,3H),1.73–1.65(m,17H), 1.55(dd,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.32–1.24(m,1H),1.18(t,J=13.1Hz,1H),0.98(d,J=6.7Hz,3H),0.89(s,3H). 13 C NMR (101MHz, CDCl3) δ207.19,192.89,177.31,171.84,166.36,156.27,154.86, 150.09,144.98,140.41,130.35,127.56,120.15,61.18,60.62,50.44,49.91,49 .79,49.00,48.95,48.91,45.83,45.49,44.14,43.53,42.39,37.25,36.71,36.6 1,32.76,31.13,29.69,28.58,27.96,27.60,22.76,20.57,17.21.ESI-HRMS:m / z calculated for C 37 H 50 O6[M+H] + :591.3686,found 591.3681.

[0465] Examples 49-50, Synthesis of Compounds 14a and 14b

[0466]

[0467] Compounds 14a and 14b were prepared using the method of synthetic route 4, wherein the terminal olefin derivative was adamantyl octanol acrylate. The products were separated and purified by silica gel column chromatography using a mixed solution of petroleum ether and ethyl acetate (volume ratio of petroleum ether to ethyl acetate 2:1) as the eluent to obtain compounds 14a and 14b, respectively.

[0468] Compound 14a: yield 36%, 1 H NMR (400MHz, CDCl3) δ9.30 (s, 1H), 7.59 (dd, J = 15.2, 11.8Hz, 1H), 6.84 (dd, J = 6. 6,2.5Hz,1H),6.11(t,J=11.4Hz,1H),6.06(s,2H),5.96(d,J=15.2Hz,1H),5.81 –5.75(m,1H),5.10–4.96(m,2H),4.18(t,J=6.8Hz,1H),3.41(d,J=4.2Hz,1H),3 .10–2.98(m,1H),2.94(d,J=20.4Hz,1H),2.68(dd,J=8.3,3.9Hz,1H),2.66–2.6 1(m,1H),2.61–2.54(m,1H),2.29–2.22(m,1H),2.09(s,3H),2.08–2.03(m,3H), δ1.92(m,4H),1.82–1.54(m,18H),1.67(dd,J=8.0,6.5Hz,2H),1.55(dd,J=11.8 ,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.42–1.38(m,2H),1.38(m,2H),1.32 –1.24(m,3H),1.18(t,J=13.1Hz,1H),0.99(d,J=6.7Hz,3H),0.94–0.86(m,7H). 1313C NMR (101 MHz, CDCl3) δ 207.50, 193.02, 192.92, 177.50, 167.39, 157.31, 147.44, 144.99, 140.19, 138.80, 130.30, 125.65, 122.49, 113.78, 64.71, 51.67, 50.01, 49.96, 49.93, 49.09, 49.05, 45.88, 45.51, 45.36, 44.30, 44.12, 43.84, 43.56, 37.65, 33.53, 31.79, 30.96, 29.70, 29.24, 29.21, 28.69, 27.73, 27.66, 25.96, 22.92, 22.85, 22.65, 21.46, 17.23. ESI-HRMS: m / z calculated for C 44 H 62 O6 [M + H] + : 687.4625, found 687.4631.

[0469] Compound 14b: Yield 38%, 1 1H NMR (400 MHz, CDCl3) δ 9.31 (s, 1H), 6.95 (d, J = 8.2 Hz, 0H), 6.81 (dd, J = 6.5, 2.3 Hz, 1H), 6.06 (q, J = 1.5 Hz, 1H), 5.86 (d, J = 15.8 Hz, 1H), 4.05 (t, J = 6.7 Hz, 2H), 3.37 (d, J = 4.2 Hz, 1H), 3.10–2.98 (m, 1H), 2.94 (d, J = 20.4 Hz, 1H), 2.68 (dd, J = 8.3, 3.9 Hz, 1H), 2.66–2.61 (m, 1H), 2.61–2.54 (m, 1H), 2.29–2.22 (m, 1H), 2.11 (s, 2H) 2.09 (s, 3H), 2.08–2.03 (m, 4H), δ 1.92 (m, 1H), 1.82–1.54 (m, 18H), 1.67 (dd, J = 8.0, 6.5 Hz, 2H), 1.55 (dd, J = 11.8, 5.0 Hz, 1H), 1.46 (td, J = 12.3, 4.9 Hz, 1H), 1.42–1.38 (m, 2H), 1.38 (m, 2H), 1.32–1.24 (m, 3H), 1.18 (t, J = 13.1 Hz, 1H), 0.99 (d, J = 6.7 Hz, 3H), 0.94–0.86 (m, 7H). 13C NMR (101MHz, CDCl3) δ207.23,192.93,177.35,172.03,166.65,156.40,154.4 4,140.38,130.35,120.44,64.73,64.04,49.91,49.78,49.08,48.95,45.85,4 5.49,44.15,43.53,42.41,42.33,36.75,36.61,32.74,31.14,29.71,29.19, 29.10,28.65,28.61,27.62,25.95,25.90,22.77,20.64,17.24.ESI-HRMS:m / z calculated for C 42 H 60 O6[M+H] + :661.4468,found 661.4461.

[0470] Examples 51-52, Synthesis of Compounds 15a and 15b

[0471]

[0472] Compounds 15a and 15b were prepared using the method of synthetic route 4, wherein the terminal olefin derivative was diethylene glycol adamantyl acrylate. The products were separated and purified by silica gel column chromatography using a mixed solution of petroleum ether and ethyl acetate (volume ratio of petroleum ether to ethyl acetate 2:1) as the eluent to obtain compounds 15a and 15b, respectively.

[0473] Compound 15a: yield 39%, 11H NMR (400 MHz, CDCl3) δ 9.28 (s, 1H), 7.61 (dd, J = 15.2, 11.8 Hz, 1H), 6.79 (dd, J = 6.5, 2.5 Hz, 1H), 6.11 (s, 1H), 6.06 (s, 1H), 6.00 (d, J = 15.2 Hz, 1H), 5.73 (t, J = 10.3 Hz, 1H), 4.35 (td, J = 4.4, 2.2 Hz, 2H), 4.25 (dd, J = 5.7, 4.0 Hz, 2H), 3.77 (t, J = 4.7 Hz, 2H), 3.75–3.73 (m, 4H), 3.41 (d, J = 3.8 Hz, 1H), 2.94 (d, J = 20.4 Hz, 1H), 2.68 (dd, J = 8.3, 3.9 Hz, 1H), 2.66–2.61 (m, 1H), 2.61–2.54 (m, 1H), 2.29–2.22 (m, 1H), 2.11 (s, 2H), 2.09 (s, 3H), 2.08–2.03 (m, 4H), 1.92 (m, 1H), 1.85 (s, 3H), 1.79 (s, 3H), 1.73–1.65 (m, 13H), 1.55 (dd, J = 11.8, 5.0 Hz, 1H), 1.46 (td, J = 12.3, 4.9 Hz, 1H), 1.32–1.24 (m, 1H), 1.18 (t, J = 13.1 Hz, 1H), 0.98 (d, J = 6.7 Hz, 3H), 0.87 (s, 3H). 13 13C NMR (101 MHz, CDCl3) δ 207.40, 192.92, 177.43, 171.72, 167.16, 156.87, 147.87, 140.22, 139.37, 130.32, 125.61, 121.97, 69.26, 69.08, 63.58, 62.84, 51.67, 49.94, 49.06, 48.82, 45.85, 45.53, 45.44, 44.13, 43.83, 42.3, 36.73, 33.58, 32.80, 31.44, 30.95, 29.70, 29.66, 28.60, 27.73, 22.85, 21.52, 17.22. ESI-HRMS: m / z calculated for C 40 1 54 37H647O7 [M + H] + : 647.3948, found 647.3931.

[0474] Compound 15b: Yield 42%, 1H NMR (400MHz, CDCl3) δ9.30(s,1H),7.12–6.92(m,1H),6.81(d,J=5.7Hz,1H),6.06(d,J=2.1Hz,1H),5.88(dd,J=19.8,15.7Hz,1H),4.32(t,J=5.1 Hz,2H),4.24(p,J=2.8Hz,2H),3.75(dq,J=15.7,4.6Hz,4H),3.37(d,J=4.1Hz,1H),2.94(d,J=20.4Hz,1H),2.68(dd,J=8.3,3.9Hz,1H),2.66–2.6 1(m,1H),2.61–2.54(m,1H),2.29–2.22(m,1H),2.11(s,2H),2.09(s,3H) ,2.08–2.03(m,4H),1.92(m,1H),1.85(s,3H),1.79(s,3H),1.73–1.65(m ,13H),1.55(dd,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1.32– 1.24(m,1H),1.18(t,J=13.1Hz,1H),0.98(d,J=6.7Hz,3H),0.87(s,3H). 13 C NMR (101MHz, CDCl3) δ207.79,195.26,173.50,170.44,167.87,162.33,148. 38,148.20,130.81,119.93,69.57,69.27,65.21,63.02,55.46,52.40,47.9 5,47.15,46.73,44.42,41.93,41.83,40.00,39.90,39.81,37.55,37.33,29 .71,29.61,29.50,29.39,27.03,26.60,25.89,21.48,18.28.ESI-HRMS:m / z calculated for C 38 H 52 O7[M+H] + :621.3791,found 621.3787.

[0475] Examples 53-54, Synthesis of Compounds 16a and 16b

[0476]

[0477] Compounds 16a and 16b were prepared using the method of synthetic route 4, wherein the terminal olefin derivative was triethylene glycol adamantyl acrylate. The products were separated and purified by silica gel column chromatography using a mixed solution of petroleum ether and ethyl acetate (volume ratio of petroleum ether to ethyl acetate 2:1) as the eluent to obtain compounds 16a and 16b, respectively.

[0478] Compound 16a: yield 36%, 1 H NMR (400MHz, CDCl3) δ9.29 (s, 1H), 7.61 (dd, J = 15.2, 11.8Hz, 1H), 6.87–6.7 4(m,1H),6.12(t,J=11.2Hz,1H),6.06(s,1H),6.00(d,J=15.2Hz,1H),5.73( t,J=10.1Hz,1H),4.35(t,J=4.9Hz,2H),4.24(t,J=4.8Hz,2H),3.85–3.64(m ,8H),3.37(d,J=4.1Hz,1H),2.94(d,J=20.4Hz,1H),2.68(dd,J=8.3,3.9Hz, 1H),2.66–2.61(m,1H),2.61–2.54(m,1H),2.29–2.22(m,1H),2.11(s,2H),2 .09(s,3H),2.08–2.03(m,4H),1.92(m,1H),1.85(s,3H),1.79(s,3H),1.73– 1.65(m,13H),1.55(dd,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1. 32–1.24(m,1H),1.18(t,J=13.1Hz,1H),0.98(d,J=6.7Hz,3H),0.89(s,3H). 13 C NMR (101MHz, CDCl3) δ207.38,192.93,177.41,171.74,167.20,156.89,147. 80,140.21,139.31,130.32,125.63,122.06,70.64,70.55,69.33,63.64,62. 92,51.67,49.94,49.05,48.84,45.85,45.53,44.13,43.83,42.35,36.74,3 3.58,32.79,30.95,29.71,28.62,27.74,22.86,21.52,17.22.ESI-HRMS:m / z calculated forC 42 H 58 O8[M+H]+ :691.4210,found691.4211.

[0479] Compound 16b: yield 41%, 1 H NMR (400MHz, CDCl3) δ9.30 (s, 1H), 6.97 (dd, J = 15.9, 8.1Hz, 1H), 6.88–6.73 ( m,1H),6.06(t,J=1.7Hz,1H),5.91(d,J=15.9Hz,1H),4.33(dtd,J=12.1,7.5, 4.8Hz,2H),4.25–4.20(m,2H),3.77(t,J=4.9Hz,2H),3.73–3.70(m,2H),3.6 8(s,4H),3.36(d,J=4.2Hz,1H),2.94(d,J=20.4Hz,1H),2.68(dd,J=8.3,3.9H z,1H),2.66–2.61(m,1H),2.61–2.54(m,1H),2.29–2.22(m,1H),2.11(s,2H) ,2.09(s,3H),2.08–2.03(m,4H),1.92(m,1H),1.85(s,3H),1.79(s,3H),1.73 –1.65(m,13H),1.55(dd,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1 .32–1.24(m,1H),1.18(t,J=13.1Hz,1H),1.06(d,J=6.7Hz,3H),0.86(s,3H). 13 C NMR (101MHz, CDCl3) δ207.14,192.91,177.27,171.74,166.46,156.27,1 55.00,140.42,130.35,120.11,70.54,70.50,69.30,69.22,63.53,62.9 4,49.90,49.76,48.95,48.83,45.86,45.48,44.15,43.53,42.34,36.73 ,36.62,32.78,31.13,28.61,27.60,22.76,20.56,17.21.ESI-HRMS:m / z calculated for C 40 H 57 O8[M+H] + :665.4053,found 665.4051.

[0480] Examples 55-56, Synthesis of Compounds 17a and 17b

[0481]

[0482] Compounds 17a and 17b were prepared using the method of synthetic route 4, wherein the terminal olefin derivative was tetraethylene glycol adamantyl acrylate. The products were separated and purified by silica gel column chromatography using a mixed solution of petroleum ether and ethyl acetate (volume ratio of petroleum ether to ethyl acetate 2:1) as the eluent to obtain compounds 17a and 17b, respectively.

[0483] Compound 17a: yield 35%, 1 H NMR (400MHz, CDCl3) δ9.31 (s, 1H), 7.60 (dd, J = 15.2, 11.8Hz, 1H), 6.85–6.74 (m,1H),6.12(t,J=11.2Hz,1H),6.06(s,1H),6.00(d,J=15.2Hz,1H),5.73(t ,J=10.1Hz,1H),4.35(t,J=4.9Hz,2H),4.24(t,J=4.8Hz,4H),3.85–3.64(m, 10H),3.37(d,J=4.1Hz,1H),2.94(d,J=20.4Hz,1H),2.68(dd,J=8.3,3.9Hz, 1H),2.66–2.61(m,1H),2.61–2.54(m,1H),2.29–2.22(m,1H),2.11(s,2H),2 .09(s,3H),2.08–2.03(m,4H),1.92(m,1H),1.85(s,3H),1.79(s,3H),1.73– 1.65(m,13H),1.55(dd,J=11.8,5.0Hz,1H),1.46(td,J=12.3,4.9Hz,1H),1. 32–1.24(m,1H),1.18(t,J=13.1Hz,1H),0.95(d,J=6.7Hz,3H),0.91(s,3H). 1313C NMR (101 MHz, CDCl3) δ 207.38, 192.93, 177.41, 171.74, 167.20, 156.89, 147.80, 140.21, 139.31, 130.32, 125.63, 122.06, 73.58, 70.64, 70.55, 69.33, 65.35, 63.64, 62.92, 51.67, 49.94, 49.05, 48.84, 45.85, 45.53, 44.13, 43.83, 42.35, 36.74, 33.58, 32.79, 30.95, 29.71, 28.62, 27.74, 22.86, 21.52, 17.22. ESI-HRMS: m / z calculated for C 44 H 62 O9 [M + H] + : 735.4472, found 735.4461.

[0484] Compound 17b: Yield 39%, 1 1H NMR (400 MHz, CDCl3) δ 9.29 (s, 1H), 6.91 (dd, J = 15.9, 8.1 Hz, 1H), 6.88–6.73 (m, 1H), 6.06 (t, J = 1.7 Hz, 1H), 5.91 (d, J = 15.9 Hz, 1H), 4.33 (dtd, J = 12.1, 7.5, 4.8 Hz, 2H), 4.25–4.20 (m, 2H), 3.73–3.70 (m, 2H), 3.68 (m, 10H), 3.36 (d, J = 4.2 Hz, 1H), 2.94 (d, J = 20.4 Hz, 1H), 2.68 (dd, J = 8. , 3.9 Hz, 1H), 2.66–2.61 (m, 1H), 2.61–2.54 (m, 1H), 2.29–2.22 (m, 1H), 2.11 (s, 2H), 2.09 (s, 3H), 2.08–2.03 (m, 4H), 1.92 (m, 1H), 1.85 (s, 3H), 1.79 (s, 3H), 1.73–1.65 (m, 13H), 1.55 (dd, J = 11.8, 5.0 Hz, 1H), 1.46 (td, J = 12.3, 4.9 Hz, 1H), 1.32–1.24 (m, 1H), 1.18 (t, J = 13.1 Hz, 1H), 1.03 (d, J = 6.7 Hz, 3H), 0.89 (s, 3H). 13C NMR (101MHz, CDCl3) δ207.14,192.91,177.27,171.74,166.46,156.27,155. 00,140.42,130.35,120.11,73.58,70.54,70.50,69.30,69.22,65.25,63.5 3,62.94,49.90,49.76,48.95,48.83,45.86,45.48,44.15,43.53,42.34,36 .73,36.62,32.78,31.13,28.61,27.60,22.76,20.56,17.21.ESI-HRMS:m / z calculated for C 42 H 60 O9[M+H] + :703.4316,found 703.4311.

[0485] Example 57, Synthesis of Compound 18

[0486]

[0487] A 5 mL eggplant-shaped flask was dried and placed in a magnetic stirrer. Compound 16a (20 mg, 1 equiv.) obtained in route 4 was added and dissolved in 2 mL of anhydrous ethanol. Sodium borohydride (6 mg, 0.8 equiv.) was added under ice-bath conditions and stirred for 1.5 h. The reaction was confirmed on a TLC plate. After the reaction, 1 mL of water was added to quench the reaction. The ethanol was removed under vacuum, and 10 mL of ethyl acetate and 10 mL of saturated brine were added. The mixture was extracted, dried, concentrated, and analyzed by column chromatography. Petroleum ether and ethyl acetate (ratio 2:1) were selected as the developing solvent to obtain 9 mg of compound 18.

[0488] Compound 18a: yield 36%, 11H NMR (400 MHz, CDCl3) δ 6.97 (dd, J = 15.9, 8.1 Hz, 1H), 6.88–6.73 (m, 1H), 6.06 (t, J = 1.7 Hz, 1H), 5.91 (d, J = 15.9 Hz, 1H), 4.33 (dtd, J = 12.1, 7.5, 4.8 Hz, 2H), 4.25–4.20 (m, 2H), 3.77 (t, J = 4.9 Hz, 2H), 3.73–3.70 (m, 2H), 3.68 (s, 4H), 3.36 (d, J = 4.2 Hz, 1H), 2.94 (d, J = 20.4 Hz, 1H), 2.68 (dd, J = 8.3, 3.9 Hz, 1H), 2.66–2.61 (m, 1H), 2.61–2.54 (m, 1H), 2.29–2.22 (m, 1H), 2.11 (s, 2H), 2.09 (s, 3H), 2.08–2.03 (m, 4H), 1.92 (m, 1H), 1.85 (s, 3H), 1.79 (s, 3H), 1.73–1.65 (m, 13H), 1.55 (dd, J = 11.8, 5.0 Hz, 1H), 1.46 (td, J = 12.3, 4.9 Hz, 1H), 1.32–1.24 (m, 1H), 1.18 (t, J = 13.1 Hz, 1H), 1.06 (d, J = 6.7 Hz, 3H), 0.86 (s, 3H). 13 13C NMR (101 MHz, CDCl3) δ 210.28, 180.00, 166.75, 159.07, 155.90, 137.46, 132.24, 130.14, 119.63, 72.26, 69.31, 67.74, 65.26, 62.99, 53.23, 50.78, 49.77, 48.85, 46.34, 45.03, 43.35, 42.34, 36.73, 36.38, 32.80, 31.95, 31.64, 29.73, 29.69, 29.64, 29.40, 28.60, 22.73, 17.17. ESI-HRMS: m / z calculated for C 40 H 58 O8 [M + H] + : 667.4210, found 667.4206.

[0489] Route 5:

[0490]

[0491] Take a two-necked flask, place a magnetic stirrer, bake at 105°C for 15 minutes, and then, while hot, operate in anhydrous and oxygen-free conditions. Under N2, weigh raw material 4 and dissolve it in anhydrous dichloromethane. Add raw material 4 (1.0 mol) dissolved in anhydrous dichloromethane under N2 atmosphere, then add Grubbs II (5%) catalyst and terminal olefin derivative (3.0 mol), and finally add Ti(OAc)4 (1%). The reaction is carried out under reflux for 10 hours. The reaction progress is monitored by TLC, the reaction is stopped, and a mixed solution of dichloromethane and saturated brine (1:1, v / v) is added and extracted three times. The organic phases are combined, dried over anhydrous sodium sulfate for 2 hours, concentrated, mixed, and purified by column chromatography. Finally, compound 4 can be completely reacted to obtain a single compound X6.

[0492] Example 58: Synthesis of Compound x6

[0493]

[0494] Compound x6 was prepared by the method of synthetic route 5, wherein the terminal olefin derivative was triethylene glycol adamantyl acrylate, and separated and purified by silica gel column chromatography using a mixed solution of petroleum ether and ethyl acetate (volume ratio of petroleum ether to ethyl acetate 2:1) as eluent to obtain compound x6.

[0495] Yield: 87% 1 H NMR (400MHz, CDCl3) δ9.28(s,1H),7.08(dt,J=16.1,6.2Hz,1H),6.86(tq,J=7.1,1.6Hz,1H),6.08(d,J=1.6Hz,1H),5.88(dt,J= 15.9,0.9Hz,1H),4.39–4.32(m,4H),3.77–3.71(m,4H),3.65(s,4H),3.47(d,J=9.5Hz,1H),2.69(dtd,J=9.7,6.7,1.8Hz,1H),2 .38(d,J=17.4Hz,1H),2.18–1.93(m,10H),1.80–1.73(m,1H),1.77–1.68(m,2H),1.60–1.47(m,13H),1.50–1.42(m,1H),1.45–1 .32(m,1H),1.30–1.24(m,1H),1.27–1.20(m,2H),1.13(dtd,J=12.3,8.7,6.4Hz,1H),1.00(d,J=12.4,6.7Hz,3H),0.88(s,3H). 13C NMR (101MHz, CDCl3) δ207.79,195.26,173.50,170.44,167.46,162.33,148.38,148.20, 130.81,121.32,70.78,70.69,69.57,69.27,65.21,63.02,55.20,52.40,47.95,46.99, 46.73,44.42,41.93,41.83,40.00,39.90,39.81,37.74,37.65,37.55,34.49,33.84,29 .71,29.61,29.50,29.39,26.84,26.61,25.89,21.48,14.13.ESI-HRMS:m / zcalculated for C 42 H 56 O8[M+H] + :689.4210,found 689.4203.

[0496] Example 59: Synthesis of Compound x7

[0497]

[0498] Compound 1 (1 mmol) was dissolved in dichloromethane. mCPBA (1 mmol) was added in batches under ice bath conditions and stirred for 30 min. The reaction was detected by TLC spot plate. After the reaction was terminated, saturated sodium bicarbonate was added to quench the reaction. Silica gel was directly added to mix the sample and separated by column chromatography to obtain the epoxy isomer compound (2:1) product.

[0499] Yield: 75% 1 H NMR (400MHz, CDCl3) δ9.28 (s, 1H), 6.84–6.76 (m, 1H), 6.08 (h, J = 1.6Hz, 1H), 5.42 (dd, J = 3.8, 1.9Hz, 2H), 3.63(tt,J=3.0,1.3Hz,1H),3.47(d,J=9.5Hz,1H),2.69(d,J=9.7Hz,1H),2.08(d,J=1.5Hz,3H),2.06–2. 00(m,2H),2.00–1.95(m,1H),1.88(m,1H),1.79–1.70(m,1H),1.51(ddd,J=12.1,7.4,5.7Hz,1H),1.39–1 .29(m,1H),1.29–1.20(m,9H),1.00(dd,J=12.4,6.7Hz,1H),0.88–0.82(m,6H).ESI-HRMS:m / zcalculated for C25 H 34 O3[M+H] + :383.2586,found 383.2569.

[0500] The following is the biological activity evaluation of some compounds of this invention, mainly including two aspects: cellular level and ERα protein degradation level.

[0501] Test Example 1: Inhibitory activity of some compounds of the present invention on various cancer cells

[0502] 1. Experimental methods

[0503] The cytotoxicity of the compounds against three breast cancer cell lines (MCF-7, MDA-MB-231, and MCF-7 / ADR, with MCF-7 / ADR being doxorubicin-resistant) was determined using the MTT assay. Cells were cultured in phenol red-containing DMEM supplemented with 10% fetal bovine serum. When the cell density reached 80%-90%, the cells were digested and the cell suspension was plated in phenol red-free DMEM supplemented with 10% FCS in a 96-well cell culture plate. After complete cell attachment, the original culture medium was discarded, and 100 μl of fresh compound solution prepared in 10% FCS-free DMEM was added to each well (positive controls were MCF-7 and ADR). After 48 hours of drug treatment, the plates were removed, and 20 μl of 5 mg / ml MTT working solution was added to each well. The plates were then incubated in a 37°C, 5% CO2 incubator for 4 hours. After that, the liquid in each well was aspirated, and 100 μl of dimethyl sulfoxide (DMSO) was added to each well. The plate was shaken on a microplate stirrer for 10 minutes to fully dissolve the crystals. The plate was read on a microplate reader, and the wavelength at 490 nm was selected as the main wavelength and the wavelength at 630 nm was selected as the reference wavelength. The experimental results were analyzed and the IC was calculated. 50 .

[0504] The structure of MHO7 is ADR is doxorubicin.

[0505] 2. Experimental results

[0506] The anti-proliferative activities of the compounds synthesized in the examples of the present invention on breast cancer cells are shown in Table 1.

[0507] Table 1. Antiproliferative activity of the compounds of the present invention against three breast cancer cells (IC 50 ,μM) a

[0508]

[0509]

[0510]

[0511] a IC 50 Values ​​are means of at least three independent experiments.

[0512] The experimental results show that most of the compounds of the present invention exhibited better anti-breast cancer cell proliferation activity than the original modified compound, the natural product MHO7. They also demonstrated good in vitro anti-proliferation activity against drug-resistant cells, demonstrating the excellent potential of this series of compounds in anti-breast cancer treatment. Among them, the compound modified with an adamantyl group with a side chain length of three PEG chains (16a) exhibited the best anti-breast cancer cell proliferation activity.

[0513] Test Example 2: Activity of some compounds of the present invention on ERα protein degradation

[0514] 1. Experimental samples and methods

[0515] Preparation of the test sample solution: The test samples were compounds 6a, 7a, 12a, 12b, 15a, 15b, 16a, 16b, 17a, and 17b of the present invention. Accurately weigh the appropriate amount of sample and prepare the solution with DMSO to the desired concentration for activity testing. MCF-7 cells were purchased from the China Center for Type Culture Collection and cultured in DMEM high-glucose medium supplemented with 10% fetal bovine serum (FBS) at 37°C and 5% carbon dioxide.

[0516] 1.1 MCF-7 cell treatment

[0517] (1) MCF-7 cells in the logarithmic growth phase were digested with 0.25% trypsin and then prepared into a cell suspension in fresh DMEM high-glucose medium at a concentration of 5 × 10 cells per well. 6 Cells were seeded in six-well plates at a density of approximately 100 cells.

[0518] (2) Add medium containing drugs to make the final concentration consistent with the test group setting, and culture for another 24 hours at 37°C and 5% carbon dioxide.

[0519] 1.2 Total cell protein extraction

[0520] (1) Remove the culture medium and wash once with PBS. Add 1 ml of PBS to each well of the six-well plate. Use a cell scraper to scrape the cells at the bottom of the dish and transfer the cell suspension into a 1.5 ml plastic centrifuge tube.

[0521] (2) Centrifuge the centrifuge tube containing the cell suspension at 4000 rpm for 5 minutes at 4°C, discard the supernatant, add 200 μl of RIPA lysis buffer (Biosha RP) to each centrifuge tube, pipette and blow to dissolve the precipitate, centrifuge at 12000 rpm for 15 minutes at 4°C, and take the supernatant as the total protein extract.

[0522] (3) Add 6× SDS-PAGE sample buffer and boil for 10 minutes. Centrifuge at 12,000×g for 10 minutes at room temperature. Take 10 μl of the supernatant for SDS-PAGE electrophoresis.

[0523] 1.3 Western blot detection

[0524] (1) Preparation of filter paper and membrane (preparation should start 20 minutes before the end of electrophoresis). Specifically include:

[0525] 1) Prepare sufficient 1× transfer buffer;

[0526] 2) Prepare filter paper and membrane of appropriate size;

[0527] 3) Soak the membrane in methanol for 1-2 minutes, then place it in 1× transfer buffer;

[0528] 4) Soak the filter paper on the gel side and the filter paper on the membrane side in 1× transfer buffer respectively.

[0529] (2) Transfer

[0530] 1) Place a black sponge on the clamp of the electroporator and place three layers of filter paper on top.

[0531] 2) Place the membrane on the filter paper near the membrane side, and then pour some transfer solution on the membrane to keep it moist;

[0532] 3) After peeling off the gel, cut off the concentrated gel, transfer the gel to the membrane and mark the gel position;

[0533] 4) Place a piece of filter paper on the gel, pour some transfer solution on it, and then place two more pieces of filter paper on top;

[0534] 6) Install the electroporator and adjust it to constant voltage mode, current 400mA, and time for 1 hour.

[0535] (3) Closed

[0536] The transferred membrane was placed in 5% skim milk powder and blocked at room temperature for 1 hour.

[0537] (4) Incubation with primary antibody

[0538] 1) Dilute the antibody with a mixture of TBS and 5% skim milk powder (3:1) according to the recommended ratio in the antibody manual;

[0539] 2) Place the membrane in the diluted antibody and incubate overnight at 4°C;

[0540] 3) Wash the membrane three times with TBST, 8 minutes each time.

[0541] (5) Incubation with secondary antibody

[0542] 1) Dilute the secondary antibody corresponding to the primary antibody in TBST at a ratio of 1:10,000;

[0543] 2) Place the membrane in the diluted antibody and incubate at room temperature for 1 hour;

[0544] 3) Wash the membrane three times with TBST, 8 minutes each time.

[0545] (6) Color development

[0546] 1) Mix equal volumes of colorimetric solutions A and B;

[0547] 2) Add the mixture to the membrane surface and shake to make it uniform;

[0548] 3) Wrap the membrane with plastic wrap and place it in a dark room;

[0549] 4) Expose once every 18 seconds in a dark room, with a total exposure time of 30 minutes.

[0550] 2. Results Analysis

[0551] The development results of compounds 6a, 7a, 12a, 12b, 15a, 15b, 16a, 16b, 17a, and 17b are as follows: Figure 1 At the same time, Image J software was used to perform grayscale analysis of the development results. The ratio of the grayscale value of each sample to the grayscale value of the blank control group reflected the changes in the protein level of estrogen receptor α. Compared with the control clinical drug fulvestrant, both compounds 6a and 16a showed a good ability to downregulate the ERα protein level in MCF-7, and this ability was concentration-dependent.

[0552] Figure 2 Compound 16a showed that the downregulation level of ERα protein was more than 90% at 1 μM.

[0553] Test Example 3: In vitro anti-coronavirus activity of the compounds of the present invention

[0554] 1. Virus strains: Human coronavirus OC43 (HCoV-OC43) and human coronavirus 229E (HCoV-229E), provided by the China Center for Type Culture Collection (CCTCC).

[0555] 2. Cell culture: Taking Vr1558 cells as an example: add 3 ml of 0.25% TrypsinEDTA to a culture flask full of Vr1558 cells, digest at 37°C for 1-2 minutes, discard the digestion solution, add culture medium, pipette through, subculture at a ratio of 1:3, and culture at 37°C, 5% CO2. Subculture once every 2-3 days. When seeding, prepare 150,000 cells per ml and inoculate 96-well cell culture plates with 0.1 ml per well. Culture at 37°C, 5% CO2 overnight. Experiments are performed after the cells have grown into a monolayer.

[0556] 3. Anti-HCoV-OC43 activity assay (CPE method)

[0557] The experiments were performed in passaged Vr1558 cells at a density of 1.5 × 10 4 Each well was inoculated with 100 TCID50 HCoV-OC43 virus solution in a 96-well plate. After overnight culture, the cells in the 96-well plate were infected with the 100 TCID50 HCoV-OC43 virus solution. The drug to be tested was diluted with culture medium and administered at the same time as infection for determination. The drug to be tested was tested with 8 doses of samples diluted threefold. Two parallel wells were set for each dose. The results were observed when the lesion in the virus control group reached 4+, and the half-maximal inhibitory concentration of the drug on the virus was calculated using the Reed-Muench method. The formula is: IC 50 =AntiLog(A+D×(B-50) / (50-C)).

[0558] Where: A = drug concentration at which cumulative inhibition rate is less than 50%, B = inhibition rate at which cumulative inhibition rate is greater than 50%, C = inhibition rate at which cumulative inhibition rate is less than 50%, and D = log dilution factor.

[0559] 4. Anti-HCoV-229E activity assay (CPE method)

[0560] The experiment was performed in passaged Vr740 cells, with 1.5×10 4 Each well was inoculated into a 96-well plate. After overnight culture, 100 TCID50 HCoV-229E virus solution was used to infect Vr740 cells in the 96-well plate. The drug to be tested was diluted with maintenance solution and administered at the same time as infection for determination. The drug to be tested was tested by three-fold dilution of 8 doses. Two parallel wells were set for each dose. The results were observed when the lesion in the virus control group reached 4+, and the half-maximal inhibitory concentration of the drug on the virus was calculated using the Reed-Muench method. The formula is: IC 50 =AntiLog(A+D×(B-50) / (50-C)) and Selectivity Index (SI=IC 50 / TC 50 Where: A = drug concentration at which cumulative inhibition rate is less than 50%, B = inhibition rate at which cumulative inhibition rate is greater than 50%, C = inhibition rate at which cumulative inhibition rate is less than 50%, and D = log dilution factor.

[0561] CC 50 The inhibition rate (%) of a compound's cytotoxicity is expressed as [1-(EN) / (PN)] x 100, where "E" represents the OD value of the treated group, "P" represents the OD value of the untreated group, and "N" represents the OD value of the blank group. The half-maximal inhibitory concentration (CC50) of the compound is used as an indicator of its cytotoxicity.

[0562] 5. Filter results

[0563] The results of in vitro screening of the inhibitory effects of MHO7 and the compounds of the present invention on two human coronaviruses are shown in Table 2. Test drugs: MHO7, compound 3m and compound 16a.

[0564] Table 2. Results of the anti-human coronavirus activity of the compounds of the present invention

[0565]

[0566] As can be seen from Table 2, compounds 3m and 16a have good inhibitory activity against both coronaviruses and are superior to the parent compound MHO7. In addition, the compounds all showed good selectivity, CC 50 All of them are greater than 100μg / ml, with no obvious toxic side effects, and can be used as a new option for the prevention and treatment of coronavirus.

[0567] Experimental Example 4: Compounds inhibit breast cancer cell migration

[0568] 1. Experimental Materials and Reagents

[0569] Breast cancer cell lines: MDA-MB-231 and MCF-7 / ADR were purchased from the Type Culture Collection of Wuhan University;

[0570] 2. Experimental methods

[0571] Cells in the logarithmic growth phase were seeded in well plates. When the cells grew to more than 70%, the cells were scratched and treated with compound 16a (0-2 μM). Photos were taken before and after administration to calculate the scratch area. After 24 hours of treatment, a transwell assay was performed to detect the cell invasion ability.

[0572] 3. Statistical analysis

[0573] IBM SPSS 22.0 software was used for statistical analysis, and all measurement data were expressed as mean ± standard deviation.

[0574] 4. Experimental results

[0575] according to Figure 3 and Figure 4The results showed that after 24 hours, the scratch area of ​​the control group (0 μM) was significantly reduced compared with that at 0 hours, that is, the cell healing area increased, while compound 16a could inhibit the migration of MCF-7 / ADR and MDA-MB-231 cells and reduce the relative cell healing area.

[0576] In summary, the present invention provides a method for structural modification of a class of snake cell pseudotoxin compounds. These compounds can effectively inhibit the proliferation activity of various breast cancer cells, especially triple-negative breast cancer cells and adriamycin-resistant cells, and can also effectively inhibit their migration. At the same time, these compounds have good estrogen receptor α downregulation activity, showing the application prospects of such compounds in cancer treatment, especially in breast cancer treatment. In addition, the study found that these compounds have good inhibitory activity against coronaviruses, without obvious toxic side effects, and can be used as a new option for the prevention and treatment of coronavirus drugs.

Claims

1. A compound, or a salt thereof, or a stereoisomer thereof, or a hydrate thereof, characterized in that: The compound is represented by formula IIIa: in, R 14 Selected from substituted or unsubstituted C1-C6 alkyl, -CH=CHR 18 ; R 18 Selected from adamantyl, substituted or unsubstituted phenyl, thienyl, pyridyl, furyl or The substituent of the alkyl group is selected from carboxyl, substituted or unsubstituted phenyl, or adamantane; The substituents of the phenyl group are selected from C1-C3 alkyl, C1-C3 alkoxy, halogen, trifluoromethyl, nitro, trifluoromethoxy or -C(O)CH=CHR 19 ; R 19 Selected from phenyl, Alternatively, the compound is represented by formula IIIb: in, R 14 Selected from substituted or unsubstituted C1-C6 alkyl, -CH=CHR 18 ; R 18 Selected from adamantyl, substituted or unsubstituted phenyl, thienyl, pyridyl, furyl or The substituent of the alkyl group is selected from carboxyl, substituted or unsubstituted phenyl, or adamantane; The substituents of the phenyl group are selected from C1-C3 alkyl, C1-C3 alkoxy, halogen, trifluoromethyl, nitro, trifluoromethoxy or -C(O)CH=CHR 19 ; R 19 Selected from phenyl, Alternatively, the compound is represented by formula IVa: in, R 14 Selected from -(CH2CH2O) b C(O)(CH2) c R 18 ; b is 1, 2, 3, 4, 5, 6, 7 or 8; c is 1, 2, or 3; R 18 selected from adamantyl groups; Alternatively, the compound is represented by formula IVb: in, R 14 Selected from -(CH2CH2O) b C(O)(CH2) c R 18 ; b is 1, 2, 3, 4, 5, 6, 7 or 8; c is 1, 2, or 3; R 18 Selected from adamantyl groups.

2. A compound, or a salt thereof, or a stereoisomer thereof, or a hydrate thereof, characterized in that: The compound is represented by formula Va: in, In the figure, when the dotted line is absent, it is a single bond; when the dotted line is a bond, it is a double bond; R 14 Selected from substituted or unsubstituted C1-C 12 Alkyl, C1-C4 alkenyl, C1-C4 alkynyl, substituted or unsubstituted phenyl, naphthyl, -CH=CHR 18 、 Adamantyl, -(CH2) b OC(O)(CH2) c R 18 or -(CH2CH2O) b C(O)(CH2) c R 18 ; a is 1, 2, or 3; b is 1, 2, 3, 4, 5, 6, 7 or 8; c is 1, 2, or 3; R 18 Selected from adamantyl, substituted or unsubstituted phenyl, thienyl, pyridyl, furyl or The substituent of the alkyl group is selected from carboxyl, substituted or unsubstituted phenyl, or adamantane; The substituents of the phenyl group are selected from C1-C3 alkyl, C1-C3 alkoxy, halogen, trifluoromethyl, nitro, trifluoromethoxy or -C(O)CH=CHR 19 ; R 19 Selected from phenyl, Alternatively, the compound is represented by formula Vb: in, In the figure, when the dotted line is absent, it is a single bond; when the dotted line is a bond, it is a double bond; X is -O- or -NR 15 -; R 15 Selected from hydrogen or C1-C3 alkyl; R 14 Selected from substituted or unsubstituted C1-C 12 Alkyl, C1-C4 alkenyl, C1-C4 alkynyl, substituted or unsubstituted phenyl, naphthyl, -CH=CHR 18 、 Adamantyl, -(CH2) b OC(O)(CH2) c R 18 or -(CH2CH2O) b C(O)(CH2) c R 18 ; a is 1, 2, or 3; b is 1, 2, 3, 4, 5, 6, 7 or 8; c is 1, 2, or 3; R 18 Selected from adamantyl, substituted or unsubstituted phenyl, thienyl, pyridyl, furyl or The substituent of the alkyl group is selected from carboxyl, substituted or unsubstituted phenyl, or adamantane; The substituents of the phenyl group are selected from C1-C3 alkyl, C1-C3 alkoxy, halogen, trifluoromethyl, nitro, trifluoromethoxy or -C(O)CH=CHR 19 ; R 19 Selected from phenyl, Alternatively, the compound is represented by formula Vc: in, In the figure, when the dotted line is absent, it is a single bond; when the dotted line is a bond, it is a double bond; R 14 Selected from substituted or unsubstituted C1-C 12 Alkyl, C1-C4 alkenyl, C1-C4 alkynyl, substituted or unsubstituted phenyl, naphthyl, -CH=CHR 18 、 Adamantyl, -(CH2) b OC(O)(CH2) c R 18 or -(CH2CH2O) b C(O)(CH2) c R 18 ; a is 1, 2, or 3; b is 1, 2, 3, 4, 5, 6, 7 or 8; c is 1, 2, or 3; R 18 Selected from adamantyl, substituted or unsubstituted phenyl, thienyl, pyridyl, furyl or The substituent of the alkyl group is selected from carboxyl, substituted or unsubstituted phenyl, or adamantane; The substituents of the phenyl group are selected from C1-C3 alkyl, C1-C3 alkoxy, halogen, trifluoromethyl, nitro, trifluoromethoxy or -C(O)CH=CHR 19 ; R 19 Selected from phenyl, Alternatively, the compound is represented by formula Vd: in, R 14 Selected from substituted or unsubstituted C1-C 12 Alkyl, C1-C4 alkenyl, C1-C4 alkynyl, substituted or unsubstituted phenyl, naphthyl, -CH=CHR 18 、 Adamantyl, -(CH2) b OC(O)(CH2) c R 18 or -(CH2CH2O) b C(O)(CH2) c R 18 ; a is 1, 2, or 3; b is 1, 2, 3, 4, 5, 6, 7 or 8; c is 1, 2, or 3; R 18 Selected from adamantyl, substituted or unsubstituted phenyl, thienyl, pyridyl, furyl or The substituent of the alkyl group is selected from carboxyl, substituted or unsubstituted phenyl, or adamantane; The substituents of the phenyl group are selected from C1-C3 alkyl, C1-C3 alkoxy, halogen, trifluoromethyl, nitro, trifluoromethoxy or -C(O)CH=CHR 19 ; R 19 Selected from phenyl, 3. A compound, or a salt thereof, or a stereoisomer thereof, or a hydrate thereof, characterized in that: The compound is one of the following compounds:

4. The method for preparing the compound of formula Va according to claim 2, wherein: The dotted line is a key, which is characterized by: The steps include: (1) At room temperature, raw material 1 and 1,3-dimethylimidazole-2-selenoketone are dissolved in a solvent, and iodophenyl diacetic acid is added to react to obtain compound 2; alternatively, raw material 1 is reacted with selenium dioxide, tert-butyl peroxide, and salicylic acid in a solvent under reflux conditions at 40-60°C to obtain compound 2; (2) At room temperature, compound 2 reacts with a carboxyl derivative in the presence of condensing agents EDCI and DMAP to obtain the carboxyl derivative; the structure of the carboxyl derivative is COOR 14 ; R 14 As described in formula Va in claim 2.

5. The preparation method according to claim 4, characterized in that: The solvent is dichloromethane.

6. The method for preparing the compound represented by formula Vb according to claim 2, wherein, The dotted line is a bond, X is -O-, and it is characterized in that: The steps include: 1) At room temperature, raw material 1 and 1,3-dimethylimidazole-2-selenoketone are dissolved in a solvent, and iodophenyl diacetic acid is added to react to obtain compound 2; alternatively, raw material 1 is reacted with selenium dioxide, tert-butyl peroxide, and salicylic acid in a solvent at 40-60°C under reflux to obtain compound 2; 2) At room temperature, compound 2 reacts with halide YR 14 And Ag2O reacts in a solvent to obtain; The YR 14 Where Y is halogen, R 14 As described in formula Vb in claim 2.

7. The preparation method according to claim 6, characterized in that: The solvent is dichloromethane.

8. The method for preparing the compound represented by formula Vb according to claim 2, wherein, The dotted line is a bond, X is -NH-, and it is characterized in that: The steps include: a) at room temperature, raw material 1 and 1,3-dimethylimidazole-2-selenoketone are dissolved in a solvent, and iodophenyl diacetic acid is added to react to obtain compound 2; alternatively, raw material 1 is reacted with selenium dioxide, tert-butyl peroxide, and salicylic acid in a solvent under reflux conditions at 40-60°C to obtain compound 2; b) At room temperature, compound 2 reacts with NH2-R 14 , triphenylphosphine and diiodoethane react in a solvent to obtain; The NH2-R 14 In, R 14 As described in formula Vb in claim 2.

9. The preparation method according to claim 8, characterized in that: In the step a), the solvent is dichloromethane; And / or, in the step b), the solvent is DMF.

10. The method for preparing the compound represented by formula Vc and formula Vd according to claim 2, wherein in formula Vc, The dotted line is a key, which is characterized by: The steps include: (A) The starting material 1 reacts with a terminal olefin derivative in a solvent under reflux conditions of 50-70°C in the presence of a Grubbs catalyst; (B) The reactant obtained in step (A) was separated and purified by silica gel column chromatography using a mixture of petroleum ether and ethyl acetate in a volume ratio of 1:1 as an eluent to separate and obtain compounds represented by Formula Vc and Formula Vd; The structure of the terminal olefin derivative is Among them, R 14 As described in Formula Vc and Formula Vd in claim 2.

11. Use of the compound according to any one of claims 1 to 3, or a salt thereof, or a stereoisomer thereof, or a hydrate thereof in the preparation of an estrogen receptor α degrader.

12. Use of the compound according to any one of claims 1 to 3, or a salt thereof, or a stereoisomer thereof, or a hydrate thereof in the preparation of an antitumor drug and / or an antiviral drug.

13. The use according to claim 12, characterized in that: The tumor is breast cancer, prostate cancer, nasopharyngeal cancer, colorectal cancer, lung cancer, liver cancer, esophageal cancer, gastric cancer, intestinal cancer, kidney cancer, oral cancer, pancreatic cancer, colorectal cancer, cervical cancer, glioma, bladder cancer, ovarian cancer; And / or, the virus is coronavirus, HIV virus, cytomegalovirus, Epstein-Barr virus, adenovirus, herpes virus, or human T-lymphotropic virus.

14. A medicine, which is a preparation comprising the compound according to any one of claims 1 to 3, or a salt thereof, or a stereoisomer thereof, or a hydrate thereof as an active ingredient, and pharmaceutically acceptable auxiliary ingredients or excipients.

15. The drug according to claim 14, characterized in that: The drug is an anti-tumor drug and / or an anti-viral drug.

16. The drug according to claim 15, characterized in that: The tumor is breast cancer, prostate cancer, nasopharyngeal cancer, colorectal cancer, lung cancer, liver cancer, esophageal cancer, gastric cancer, intestinal cancer, kidney cancer, oral cancer, pancreatic cancer, colorectal cancer, cervical cancer, glioma, bladder cancer, ovarian cancer; And / or, the virus is coronavirus, HIV virus, cytomegalovirus, Epstein-Barr virus, adenovirus, herpes virus, or human T-lymphotropic virus.

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