Steroid VDR regulator as well as preparation method and application thereof

Abstract

The invention relates to a steroidal VDR regulator as well as a preparation method and application thereof, and relates to a compound as shown in a general formula I or a stereoisomer, a solvate, a hydrate, a prodrug, a stable isotope derivative and a pharmaceutically acceptable salt thereof. The compound as the VDR regulator has a very high inhibition effect on a TGF-beta / SMAD3 signal channel; the traditional Chinese medicine composition has the effect of effectively resisting hepatic fibrosis, and meanwhile, the side effects such as hypercalcemia are reduced to the greatest extent; and the compound has excellent selectivity, excellent drug effect, solubility, in-vitro / in-vivo pharmacokinetic property and safety, and has a good clinical application prospect.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, and in particular to a steroidal VDR modifier, its preparation method, and its uses. Background Technology

[0002] Liver fibrosis is a complex pathophysiological process caused by excessive proliferation of connective tissue in the liver due to various etiologies. Any form of liver injury can trigger a fibrotic response during the tissue repair and regeneration stages. If the injury persists, the fibrotic response will gradually develop into an irreversible state, eventually leading to cirrhosis or even hepatocellular carcinoma, posing a serious threat to the patient's life and health. Therefore, developing safe and effective treatments for liver fibrosis is of great clinical significance.

[0003] Existing research confirms that the activation of hepatic stellate cells (HSCs) is the core mechanism driving liver fibrosis, and various pro-fibrotic factors primarily target HSCs. Among these, the TGF-β / SMAD3 signaling pathway plays a crucial regulatory role in HSC activation and is a core target for liver fibrosis intervention. Inhibiting this signaling pathway can effectively reverse the activation state of HSCs, thereby blocking the occurrence and progression of liver fibrosis. Currently, a key challenge is how to inhibit the TGF-β / SMAD3 signaling pathway while minimizing adverse reactions to achieve safe and effective treatment of liver fibrosis.

[0004] Activation of the vitamin D receptor (VDR) has been shown to effectively inhibit the TGF-β / SMAD3 signaling pathway, thereby alleviating liver fibrosis. Its mechanism of action is mainly as follows: after binding to its ligand, VDR can inhibit the transcription of pro-fibrotic genes by competing with the SMAD3 complex for promoter sites of target genes, or by directly interacting with the SMAD3 complex to achieve an inhibitory effect.

[0005] However, while steroidal VDR agonists (such as calcipotriol) have shown excellent anti-hepatic fibrosis activity in mouse models, and their conjugated triene structure allows for optimal binding with VDRs, and they can also bind to DBP in plasma, significantly prolonging their metabolic half-life, long-term administration at high doses can cause serious side effects such as hypercalcemia, greatly limiting their clinical application. Studies have shown that the root cause of hypercalcemia lies in the overactivation of VDRs: steroidal VDR agonists bind to DBP, prolonging their metabolic half-life, leading to drug accumulation in the body and causing overactivation of VDRs; overactivated VDRs upregulate the expression of calcium-binding proteins (such as calcium-binding protein-D9k) in intestinal epithelial cells, enhancing intestinal calcium absorption; simultaneously, they upregulate the expression of receptor activator of nuclear factor κB (RANKL) in osteoblasts and osteoclasts, activating osteoclasts to accelerate the release of calcium from bone into the blood; in addition, they promote renal tubular reabsorption of calcium. These multiple pathways together lead to increased blood calcium concentration, ultimately causing hypercalcemia.

[0006] Although reports have shown that nonsteroidal VDR agonists can mitigate the side effect of hypercalcemia to some extent in the treatment of liver fibrosis, there are several key issues affecting their drug development: First, their VDR agonist activity is significantly weaker than that of steroidal VDR agonists, requiring larger therapeutic doses to achieve antifibrotic effects; second, they have poor water solubility and low oral bioavailability, making it difficult to meet clinical dosing needs; third, they have poor selectivity and cannot specifically target hepatic stellate cells to inhibit their activation, resulting in insufficient therapeutic specificity and further limiting their clinical application value.

[0007] However, it is noteworthy that existing studies have shown that the antifibrotic activity of activated VDR does not entirely depend on its gene transcriptional activity. VDR itself can inhibit HSC activation by binding to the SMAD3 protein downstream of the TGF-β / SMAD3 signaling pathway. Therefore, by altering the ligand structure, the gene transcriptional function of VDR can be separated from its antifibrotic effect, thereby avoiding its hypercalcemic side effect.

[0008] In summary, there is an urgent clinical need for a novel VDR agonist that can effectively inhibit the TGF-β / SMAD3 signaling pathway and exert anti-liver fibrosis effects while minimizing side effects such as hypercalcemia, and that also possesses high activity, high selectivity, and excellent pharmacokinetic properties. Summary of the Invention

[0009] This invention provides a compound of general formula I or a stereoisomer thereof, a solvate, a hydrate, a prodrug, a stable isotopic derivative, and a pharmaceutically acceptable salt thereof: ; in: X is selected from , , and ; R1 is selected from H, D, hydroxyl, halogen, nitro, cyano, amino, mercapto, amide, carboxyl, -C(O)O-alkyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the amino, mercapto, amide, carboxyl, -C(O)O-alkyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted by one or more groups selected from H, D, hydroxyl, halogen, nitro, cyano, amino, mercapto, and aryl; R2 and R3 are each independently selected from H, D, hydroxyl, halogen, nitro, cyano, amino, mercapto, amide, carboxyl, -C(O)O-alkyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups, wherein the amino, mercapto, amide, carboxyl, -C(O)O-alkyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted by one or more groups selected from H, D, hydroxyl, halogen, nitro, cyano, amino, mercapto, and aryl groups; R4 and R5 are each independently selected from H, D, hydroxyl, halogen, nitro, cyano, amino, mercapto, amide, carboxyl, -C(O)O-alkyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups, wherein the amino, mercapto, amide, carboxyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted by one or more groups selected from H, D, hydroxyl, halogen, nitro, cyano, amino, mercapto, and aryl groups; R6 is selected from H, D, hydroxyl, halogen, nitro, cyano, amino, mercapto, carboxyl, -C(O)O-alkyl, and amide, wherein the amino, mercapto, carboxyl, -C(O)O-alkyl, and amide groups are optionally substituted by one or more R7 groups; Each time R7 appears, it is independently selected from H, D, hydroxyl, halogen, nitro, cyano, amino, mercapto, amide, carboxyl, -C(O)O-alkyl, alkyl, alkenyl, and alkynyl, wherein the amino, mercapto, amide, carboxyl, -C(O)O-alkyl, alkyl, alkenyl, and alkynyl groups are optionally substituted by one or more R8 groups. Alternatively, two R7s and the atoms attached thereto form a heteroaryl and a heterocyclic group, which are optionally substituted by one or more R8s; Each time R8 appears, it is independently selected from H, D, hydroxyl, halogen, nitro, cyano, amino, mercapto, amide, carboxyl, -C(O)O-alkyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the amino, mercapto, amide, carboxyl, -C(O)O-alkyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl are optionally substituted by one or more R9; Each time R9 appears, it is independently selected from H, D, hydroxyl, halogen, nitro, cyano, amino, mercapto, amide, carboxyl, -C(O)O-alkyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the amino, mercapto, amide, carboxyl, -C(O)O-alkyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted by one or more groups selected from H, D, hydroxyl, halogen, nitro, cyano, amino, mercapto, amide, carboxyl, -C(O)O-alkyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups.

[0010] The effects of the invention The compound disclosed herein, as a VDR modulator, exhibits a high inhibitory effect on the TGF-β / SMAD3 signaling pathway, effectively combating liver fibrosis while minimizing side effects such as hypercalcemia. It also demonstrates excellent selectivity, along with superior efficacy, solubility, in vitro / in vivo pharmacokinetic properties, and safety, indicating high potential for clinical application. Attached Figure Description

[0011] Figure 1 This is a bar chart showing the relative expression levels of the compounds of this invention on the CYP24A1 and Serpine 1 genes.

[0012] Figure 2 This is a bar chart showing the relative expression levels of the compounds of this invention on the COL1A1 and ACTA2 genes.

[0013] Figure 3 This is a graph showing the immunoblotting results of the compounds of this invention on the expression of Collagen 1 protein and α-SMA protein.

[0014] Figure 4 This is a bar chart showing the relative expression levels of the compounds of this invention on Collagen 1 and α-SMA proteins.

[0015] Figure 5 These are pathological sections of mouse liver tissue after administration of the compound of this invention, stained with hematoxylin and eosin (HE) and Masson staining.

[0016] Figure 6A bar chart showing the relative quantitative analysis of collagen deposition in mouse liver tissue after administration of the compounds of this invention. Detailed Implementation

[0017] To make the technical solution and beneficial effects of the present invention more apparent and understandable, a detailed description is provided below by listing specific embodiments. The accompanying drawings are not necessarily drawn to scale, and local features may be enlarged or reduced to more clearly show the details of the local features; unless otherwise defined, the technical and scientific terms used herein have the same meanings as those in the technical field to which this application pertains.

[0018] This invention provides a compound of general formula I or a stereoisomer thereof, a solvate, a hydrate, a prodrug, a stable isotopic derivative, and a pharmaceutically acceptable salt thereof: ; in: X is selected from , , and ; R1 is selected from H, D, hydroxyl, halogen, nitro, cyano, amino, mercapto, amide, carboxyl, -C(O)O-alkyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the amino, mercapto, amide, carboxyl, -C(O)O-alkyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted by one or more groups selected from H, D, hydroxyl, halogen, nitro, cyano, amino, mercapto, and aryl; R2 and R3 are each independently selected from H, D, hydroxyl, halogen, nitro, cyano, amino, mercapto, amide, carboxyl, -C(O)O-alkyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups, wherein the amino, mercapto, amide, carboxyl, -C(O)O-alkyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted by one or more groups selected from H, D, hydroxyl, halogen, nitro, cyano, amino, mercapto, and aryl groups; R4 and R5 are each independently selected from H, D, hydroxyl, halogen, nitro, cyano, amino, mercapto, amide, carboxyl, -C(O)O-alkyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups, wherein the amino, mercapto, amide, carboxyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted by one or more groups selected from H, D, hydroxyl, halogen, nitro, cyano, amino, mercapto, and aryl groups; R6 is selected from H, D, hydroxyl, halogen, nitro, cyano, amino, mercapto, carboxyl, -C(O)O-alkyl, and amide, wherein the amino, mercapto, carboxyl, -C(O)O-alkyl, and amide groups are optionally substituted by one or more R7 groups; Each time R7 appears, it is independently selected from H, D, hydroxyl, halogen, nitro, cyano, amino, mercapto, amide, carboxyl, -C(O)O-alkyl, alkyl, alkenyl, and alkynyl, wherein the amino, mercapto, amide, carboxyl, -C(O)O-alkyl, alkyl, alkenyl, and alkynyl groups are optionally substituted by one or more R8 groups. Alternatively, two R7s and the atoms attached thereto form a heteroaryl and a heterocyclic group, which are optionally substituted by one or more R8s; Each time R8 appears, it is independently selected from H, D, hydroxyl, halogen, nitro, cyano, amino, mercapto, amide, carboxyl, -C(O)O-alkyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the amino, mercapto, amide, carboxyl, -C(O)O-alkyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl are optionally substituted by one or more R9; Each time R9 appears, it is independently selected from H, D, hydroxyl, halogen, nitro, cyano, amino, mercapto, amide, carboxyl, -C(O)O-alkyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the amino, mercapto, amide, carboxyl, -C(O)O-alkyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted by one or more groups selected from H, D, hydroxyl, halogen, nitro, cyano, amino, mercapto, amide, carboxyl, -C(O)O-alkyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups.

[0019] In some embodiments, the present invention provides compounds of general formula II or their stereoisomers, solvates, hydrates, prodrugs, stable isotopic derivatives, and pharmaceutically acceptable salts: ; in: R1 is selected from alkyl groups, which are optionally substituted by one or more groups selected from H, D, hydroxyl, halogen, nitro, cyano, amino, mercapto, and aryl.

[0020] In some embodiments, R1 is selected from C 1-6 Alkyl, the C 1-6 Alkyl groups are optionally separated by one or more H and C. 6-10 Aryl group substitution.

[0021] In some embodiments, R1 is selected from methyl, ethyl, propyl, and butyl, wherein the methyl group is optionally substituted with one or more groups selected from H and phenyl.

[0022] In some embodiments, R1 is selected from methyl, ethyl, propyl, butyl, and... .

[0023] In some embodiments, the present invention provides compounds of general formula III or their stereoisomers, solvates, hydrates, prodrugs, stable isotopic derivatives, and pharmaceutically acceptable salts: ; in: R2 and R3 are each independently selected from alkyl and alkenyl groups, which are optionally substituted by one or more groups selected from H, D, hydroxyl, halogen, nitro, cyano, amino, mercapto, and aryl.

[0024] In some implementations, R2 and R3 are each independently selected from C. 1-6 Alkyl and C 2-6 alkenyl, the C 1-6 Alkyl and C 2-6 Alkenyl groups are optionally separated by one or more groups selected from H and C. 6-10 Aryl group substitution.

[0025] In some embodiments, R2 and R3 are each independently selected from methyl, ethyl, propyl, butyl, and allyl, wherein the methyl group is optionally substituted with one or more groups selected from H and phenyl.

[0026] In some embodiments, R2 and R3 are each independently selected from methyl, ethyl, propyl, butyl, allyl, and .

[0027] In some embodiments, the present invention provides compounds of general formula IV or their stereoisomers, solvates, hydrates, prodrugs, stable isotopic derivatives, and pharmaceutically acceptable salts: ; in: R4 and R5 are each independently selected from alkyl groups, which are optionally substituted by one or more groups selected from H, D, hydroxyl, halogen, nitro, cyano, amino, mercapto, and aryl.

[0028] In some implementations, R4 and R5 are each independently selected from C. 1-6 alkyl.

[0029] In some embodiments, R4 and R5 are each independently selected from ethyl, propyl, and butyl.

[0030] In some embodiments, the present invention provides compounds of general formula V or their stereoisomers, solvates, hydrates, prodrugs, stable isotopic derivatives, and pharmaceutically acceptable salts: ; in: R6 is selected from -C(O)O-alkyl and amide groups, wherein the amide group is optionally substituted by one or more R7 groups; Each time R7 appears, it is independently selected from H and alkyl groups, and the alkyl group is optionally substituted by one or more R8 groups; Alternatively, two R7s and the atoms attached to them can form a heterocyclic group, which may optionally be substituted by one or more R8s; Each time R8 appears, it is independently selected from H, alkyl, aryl, and alkoxy, and the alkyl group is optionally substituted by one or more R9s; Each time, the R9 is independently selected from H and aryl, the aryl group optionally being substituted by one or more H, halogens and alkoxy groups.

[0031] In some implementations, R6 is selected from -C(O)OC 1-6 Alkyl and amide groups, wherein the amide group is optionally substituted with one or more R7 groups.

[0032] In some embodiments, R6 is selected from -C(O)O-CH3 and an amide group, wherein the amide group is optionally substituted with one or more R7 groups.

[0033] In some implementations, each time R7 appears, it is independently selected from H and C. 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with one or more R8 groups.

[0034] In some embodiments, each of the R7s is independently selected from H, methyl, ethyl, isopropyl, and sec-butyl, wherein the methyl and ethyl groups are optionally substituted with one or more R8s.

[0035] In some embodiments, two R7s and the atoms attached thereto form a 3-10 membered heterocyclic group, which is optionally substituted by one or more R8s.

[0036] In some embodiments, two R7s and the atoms attached thereto form a 3-7 membered heterocyclic group containing 1-4 heteroatoms selected from N, O, and S, and the 3-7 membered heterocyclic group is optionally substituted by one or more R8s.

[0037] In some embodiments, the two R7s and the atoms attached thereto form azacyclobutyl, tetrahydropyrrole, piperidinyl, and morpholinyl, wherein the piperidinyl is optionally substituted by one or more R8s.

[0038] In some implementations, each occurrence of R8 is independently selected from H and C. 1-6 Alkyl, C 6-10 Aryl and C 1-6 Alkoxy, the C 1-6 The alkyl group may optionally be substituted with one or more R9s.

[0039] In some implementations, each occurrence of R8 is independently selected from H and C. 1-3 Alkyl, C 6-10 Aryl and C 1-3 Alkoxy, the C 1-3 The alkyl group may optionally be substituted with one or more R9s.

[0040] In some embodiments, each of the R8s is independently selected from H, methyl, phenyl, and methoxy, and the methyl group is optionally substituted by one or more R9s.

[0041] In some implementations, each occurrence of R9 is independently selected from H and C. 6-10 Aryl, the C 6-10 The aryl group is optionally reacted with one or more H, halogens and C. 1-6 Alkyl-substituted.

[0042] In some implementations, each occurrence of R9 is independently selected from H and C. 6-10 Aryl, the C 6-10 The aryl group is optionally reacted with one or more H, halogens and C. 1-3 Alkyl-substituted.

[0043] In some embodiments, each of the R9s is independently selected from H and phenyl, wherein the phenyl is optionally substituted with one or more H, F and methoxy groups.

[0044] In some embodiments, the present invention provides compounds of formula VI or their stereoisomers, solvates, hydrates, prodrugs, stable isotopic derivatives, and pharmaceutically acceptable salts: ; in: Each time R7 appears, it is independently selected from H and alkyl groups, and the alkyl group is optionally substituted by one or more R8 groups; Alternatively, two R7s and the atoms attached to them can form a heterocyclic group, which may optionally be substituted by one or more R8s; Each time R8 appears, it is independently selected from H, alkyl, aryl, and alkoxy, and the alkyl group is optionally substituted by one or more R9s; Each time, the R9 is independently selected from H and aryl, the aryl group optionally being substituted by one or more H, halogens and alkoxy groups.

[0045] In some implementations, each time R7 appears, it is independently selected from H and C. 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with one or more R8 groups.

[0046] In some embodiments, each of the R7s is independently selected from H, methyl, ethyl, isopropyl, and sec-butyl, wherein the methyl and ethyl groups are optionally substituted with one or more R8s.

[0047] In some embodiments, two R7s and the atoms attached thereto form a 3-10 membered heterocyclic group, which is optionally substituted by one or more R8s.

[0048] In some embodiments, two R7s and the atoms attached thereto form a 3-7 membered heterocyclic group containing 1-4 heteroatoms selected from N, O, and S, and the 3-7 membered heterocyclic group is optionally substituted by one or more R8s.

[0049] In some embodiments, the two R7s and the atoms attached thereto form azacyclobutyl, tetrahydropyrrole, piperidinyl, and morpholinyl, wherein the piperidinyl is optionally substituted by one or more R8s.

[0050] In some implementations, each occurrence of R8 is independently selected from H and C. 1-6 Alkyl, C 6-10 Aryl and C 1-6 Alkoxy, the C 1-6 The alkyl group may optionally be substituted with one or more R9s.

[0051] In some implementations, each occurrence of R8 is independently selected from H and C. 1-3 Alkyl, C 6-10 Aryl and C 1-3 Alkoxy, the C 1-3 The alkyl group may optionally be substituted with one or more R9s.

[0052] In some embodiments, each of the R8s is independently selected from H, methyl, phenyl, and methoxy, and the methyl group is optionally substituted by one or more R9s.

[0053] In some implementations, each occurrence of R9 is independently selected from H and C. 6-10Aryl, the C 6-10 The aryl group is optionally reacted with one or more H, halogens and C. 1-6 Alkyl-substituted.

[0054] In some implementations, each occurrence of R9 is independently selected from H and C. 6-10 Aryl, the C 6-10 The aryl group is optionally reacted with one or more H, halogens and C. 1-3 Alkyl-substituted.

[0055] In some embodiments, each of the R9s is independently selected from H and phenyl, wherein the phenyl is optionally substituted with one or more H, F and methoxy groups.

[0056] In some embodiments, each of the R7s is independently selected from H, methyl, ethyl, isopropyl, sec-butyl, ... and .

[0057] In some implementations, two R7 atoms and the atoms attached to them form , , , , , , , and .

[0058] In some embodiments, the present invention provides a compound or its stereoisomer, solvate, hydrate, prodrug, stable isotope derivative, or pharmaceutically acceptable salt, said compound being any of the following: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , .

[0059] In some embodiments, the present invention provides a compound or its stereoisomer, solvate, hydrate, prodrug, stable isotope derivative, or pharmaceutically acceptable salt, said compound being any of the following: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , .

[0060] This disclosure also provides a pharmaceutical composition comprising a therapeutically effective amount of the aforementioned compound or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0061] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg to 1000 mg.

[0062] In some embodiments, the pharmaceutical composition contains 0.01%-99.99% of the aforementioned compound based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1%-99.9% of the aforementioned compound. In some embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound. In some embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound. In some embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compound.

[0063] In some embodiments, the pharmaceutical composition contains 0.01% to 99.99% pharmaceutically acceptable carriers, diluents, or excipients based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1% to 99.9% pharmaceutically acceptable carriers, diluents, or excipients. In some embodiments, the pharmaceutical composition contains 0.5% to 99.5% pharmaceutically acceptable carriers, diluents, or excipients. In some embodiments, the pharmaceutical composition contains 1% to 99% pharmaceutically acceptable carriers, diluents, or excipients. In some embodiments, the pharmaceutical composition contains 2% to 98% pharmaceutically acceptable carriers, diluents, or excipients.

[0064] All compounds disclosed herein, as well as mixtures and compositions comprising compounds of the present invention, can be administered to a living organism via any route of administration. Routes of administration may include oral, intravenous, intramuscular, subcutaneous, rectal, vaginal, sublingual, nasal, oral, ophthalmic, or local or systemic transdermal administration.

[0065] All compounds disclosed herein, as well as mixtures and compositions containing compounds of the present invention, can be formulated into single doses containing the active compounds of the present invention, as well as carriers, excipients, etc. The dosage forms can be tablets, capsules, injections, granules, powders, suppositories, pills, creams, pastes, gels, powders, oral solutions, inhalers, suspensions, dry suspensions, patches, lotions, etc. These dosage forms may contain commonly used pharmaceutical ingredients, such as diluents, absorbents, wetting agents, binders, disintegrants, colorants, pH adjusters, antioxidants, antibacterial agents, isotonic adjusters, anti-adhesives, etc. In some embodiments, the single dose includes, but is not limited to, 1 mg, 1.25 mg, 2.5 mg, 5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, etc. The compounds of the present invention, or their stereoisomers or pharmaceutically acceptable salts thereof, in doses of 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, and 500 mg.

[0066] Suitable formulations for the aforementioned dosage forms are available from publicly available sources, such as Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins, 2006, and Rowe, Raymond C. Handbook of Pharmaceutical Excipients, Chicago, Pharmaceutical Press, 2005. Therefore, those skilled in the art can readily prepare them.

[0067] Depending on the nature and severity of the disease suffered by different individuals, the patient's age, sex, weight, route of administration, and other factors, different dosages can be selected. The dosage of the compound of the present invention can be from 0.01 to 500 mg / kg daily, preferably 1-100 mg / kg daily, and can be administered once or multiple times. Examples of daily dosages include, but are not limited to, 0.01-500 mg, 0.01-400 mg, 0.01-300 mg, 0.01-200 mg, 0.01-100 mg, 0.01-50 mg, 0.1-500 mg, 0.1-400 mg, 0.1-300 mg, 0.1-200 mg, 0.1-100 mg, 1-500 mg, 1-400 mg, 1-300 mg, 1-2 00mg, 1-125mg, 1-100mg, 1-80mg, 1-60mg, 1-50mg, 1-40mg, 1-25mg, 1-20mg, 5-500mg, 5-400mg , 5-300mg, 5-250mg, 5-200mg, 5-150mg, 5-125mg, 5-100mg, 5-90mg, 5-70mg, 5-80mg, 5-60mg, 5- 50mg, 5-40mg, 5-30mg, 5-25mg, 5-20mg, 10-500mg, 10-450mg, 10-400mg, 10-300mg, 10-250mg, 10-200mg, 10-150mg, 10-125mg, 10-100mg, 10-90mg, 10-80mg, 10-70mg, 10-60mg, 10-50mg, 10- 40mg, 10-30mg, 10-20mg; 20-500mg, 20-400mg, 20-350mg, 20-300mg, 20-250mg, 20-200mg, 20-1 50mg, 20-125mg, 20-100mg, 20-90mg, 20-80mg, 20-70mg, 20-60mg, 20-50mg, 20-40mg, 20-30mg.

[0068] This disclosure also provides the use of the aforementioned compounds or their stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts or the aforementioned pharmaceutical compositions in the preparation of medicaments for the treatment and / or prevention of liver fibrosis.

[0069] Terminology Explanation: Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0070] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms, and more preferably an alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-Dimethylpentyl, 2,2-Dimethylpentyl, 3,3-Dimethylpentyl, 2-Ethylpentyl, 3-Ethylpentyl, n-Octyl, 2,3-Dimethylhexyl, 2,4-Dimethylhexyl, 2,5-Dimethylhexyl, 2,2-Dimethylhexyl, 3,3-Dimethylhexyl, 4,4-Dimethylhexyl, 2-Ethylhexyl, 3-Ethylhexyl, 4-Ethylhexyl, 2-Methyl-2-Ethylpentyl, 2-Methyl-3-Ethylpentyl, n-Nonyl, 2-Methyl-2-Ethylhexyl, 2-Methyl-3-Ethylhexyl, 2,2-Diethylpentyl, n-Decyl, 3,3-Diethylhexyl, 2,2-Diethylhexyl, and their various branched isomers, etc. More preferably, lower alkyl groups containing 1 to 6 carbon atoms are used. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. Alkyl groups can be substituted or unsubstituted, and when substituted, they can be substituted at any usable connection point. The substituents are preferably independently selected independently from one or more substituents chosen from the following: D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0071] The term "alkylene" refers to a saturated straight-chain or branched aliphatic hydrocarbon group, which is a residue derived from a parent alkane by removing two hydrogen atoms from the same carbon atom or two different carbon atoms. It is a straight-chain or branched group containing 1 to 20 carbon atoms, preferably containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, more preferably alkylene containing 1 to 6 carbon atoms. Non-limiting examples of alkylene include, but are not limited to, methylene (-CH2-), 1,1-ethylene (-CH(CH3)-), 1,2-ethylene (-CH2CH2)-, 1,1-propylene (-CH(CH2CH3)-), 1,2-propylene (-CH2CH(CH3)-), 1,3-propylene (-CH2CH2CH2-), 1,4-butylene (-CH2CH2CH2CH2-), etc. The alkylene group can be substituted or unsubstituted, and when substituted, it can be substituted at any usable connection point. The substituent is preferably independently selected independently from one or more substituents selected from alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclic alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkoxy, heterocyclic alkoxy, cycloalkylthio, heterocyclic alkylthio, and oxo.

[0072] The term "alkenyl" refers to an alkyl compound containing at least one carbon-carbon double bond in its molecule, wherein the definition of alkyl is as described above. Alkenyl groups can be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl substituents.

[0073] The term "alkynyl" refers to an alkyl compound containing at least one carbon-carbon triple bond in its molecule, wherein the definition of alkyl is as described above. The alkynyl group can be substituted or unsubstituted; when substituted, the substituent is preferably one or more of the following groups, independently selected from alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl substituents.

[0074] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 (e.g., 3, 4, 5, 6, 7, and 8) carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups.

[0075] The term "spirocyclic ring" refers to a 5- to 20-membered polycyclic group that shares a single carbon atom (called a spiro atom) between the rings, and may contain one or more double bonds. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered). Spirocyclic alkyl groups are classified as monospirocyclic, bispirocyclic, or polyspirocyclic based on the number of shared spiro atoms between the rings, with monospirocyclic and bispirocyclic alkyl groups being preferred. More preferably, they are 3 / 5-membered, 3 / 6-membered, 4 / 4-membered, 4 / 5-membered, 4 / 6-membered, 5 / 5-membered, or 5 / 6-membered monospirocyclic alkyl groups. Non-limiting examples of spirocyclic alkyl groups include: .

[0076] The term "fused ring" refers to a 5- to 20-membered polycyclic carbon group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds. Preferably, it is 6 to 14-membered, more preferably 7 to 10-membered (e.g., 7, 8, 9, or 10-membered). Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused cycloalkyl groups, preferably bicyclic or tricyclic, more preferably 3 / 4-membered, 3 / 5-membered, 3 / 6-membered, 4 / 4-membered, 4 / 5-membered, 4 / 6-membered, 5 / 4-membered, 5 / 5-membered, 5 / 6-membered, 6 / 3-membered, 6 / 4-membered, 6 / 5-membered, and 6 / 6-membered bicyclic alkyl groups. Non-limiting examples of fused cycloalkyl groups include: .

[0077] The term "bridging ring" refers to a 5- to 20-membered polycyclic carbon group in which any two rings share two non-directly bonded carbon atoms, and may contain one or more double bonds. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered). Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridging cycloalkyl groups, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridging cycloalkyl groups include:

[0078] The cycloalkyl ring comprises a cycloalkyl group (including monocyclic, spirocyclic, fused, and bridged rings) fused to an aryl, heteroaryl, or heterocyclic alkyl ring as described above, wherein the ring attached to the parent structure is a cycloalkyl group. Non-limiting examples include... , , etc.; preferred and .

[0079] The cycloalkyl group can be substituted or unsubstituted, and when substituted, it can be substituted at any usable connection point. The substituent is preferably selected independently from one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl.

[0080] The term "alkoxy" refers to -O-(alkyl) and -O-(cycloalkyl), where alkyl and cycloalkyl are defined as described above. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, and butoxy. Alkoxy groups can be optionally substituted or unsubstituted, and when substituted, they are preferably one or more of the following groups, independently selected from D atoms, halogens, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclic oxy groups, hydroxyl groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups.

[0081] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic substituent comprising 3 to 20 ring atoms, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the sulfur may optionally be oxidized (i.e., forming sulfoxide or sulfone), but excluding the -OO-, -OS-, or -SS- ring moiety, and the remaining ring atoms are carbon. Preferably, it comprises 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) ring atoms, wherein 1 to 4 (e.g., 1, 2, 3, and 4) are heteroatoms; more preferably, it comprises 3 to 8 ring atoms (e.g., 3, 4, 5, 6, 7, and 8), wherein 1 to 3 (e.g., 1, 2, and 3) are heteroatoms; even more preferably, it comprises 3 to 6 ring atoms, wherein 1 to 3 are heteroatoms; most preferably, it comprises 5 or 6 ring atoms, wherein 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and homopiperazinyl. Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups.

[0082] The term "spiroheterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group in which one or more ring atoms share a single atom (called a spiro atom), wherein the sulfur may optionally be oxidized (i.e., forming a sulfoxide or sulfone), and the remaining ring atoms are carbon. It may contain one or more double bonds. Preferably, it is 6 to 14-membered, more preferably 7 to 10-membered (e.g., 7, 8, 9, or 10-membered). Spiroheterocyclic groups are classified into monospirocyclic, bispirocyclic, or polyspirocyclic groups according to the number of shared spiro atoms between rings, with monospirocyclic and bispirocyclic groups being preferred. More preferably, it is a 3 / 5-membered, 3 / 6-membered, 4 / 4-membered, 4 / 5-membered, 4 / 6-membered, 5 / 5-membered, or 5 / 6-membered monospirocyclic group. Non-limiting examples of spirocyclic groups include: .

[0083] The term "fused heterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system. One or more rings may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the sulfur may optionally be oxidized (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered). Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, and 6-membered / 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

[0084] and .

[0085] The term "bridged heterocyclic group" refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two non-directly connected atoms. It may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the sulfur may optionally be oxidized (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered). Depending on the number of rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include: .

[0086] The heterocyclic ring comprises a heterocyclic group (including monocyclic, spirocyclic, fused heterocyclic, and bridged heterocyclic rings) fused to an aryl, heteroaryl, or cycloalkyl ring as described above, wherein the ring connected to the parent structure is a heterocyclic group, and non-limiting examples include: and wait.

[0087] The heterocyclic group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is preferably selected independently from one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclicoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl.

[0088] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic) group having a conjugated π-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl ring comprises an aryl ring fused to a heteroaryl, heterocyclic, or cycloalkyl ring as described above, wherein the ring attached to the parent structure is an aryl ring, and non-limiting examples include: and .

[0089] The aryl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable linker. The substituent is preferably independently selected independently from one or more substituents chosen from halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclic oxy groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups. The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 10-membered (e.g., 5, 6, 7, 8, 9, or 10-membered), more preferably 5- or 6-membered, such as furanyl, thiophene, pyridinyl, pyrroleyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc. The heteroaryl ring comprises a heteroaryl group fused to an aryl, heterocyclic, or cycloalkyl ring as described above, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples include: and .

[0090] The heteroaryl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is preferably selected independently from one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl.

[0091] The aforementioned cycloalkyl, heterocyclic, aryl, and heteroaryl groups include residues derived from removing one hydrogen atom from a parent ring atom, or residues derived from removing two hydrogen atoms from the same or two different ring atoms of the parent, namely "divalent cycloalkyl", "divalent heterocyclic", "aryl", and "heteroaryl".

[0092] The term "halogenated alkyl" refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined above.

[0093] The term "hydroxyalkyl" refers to an alkyl group that is replaced by one or more hydroxyl groups, wherein the alkyl group is as defined above.

[0094] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0095] The term "hydroxyl group" refers to -OH.

[0096] The term "amino" refers to -NH2.

[0097] The term "nitro" refers to -NO2.

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

[0099] The term "thiol" refers to -SH.

[0100] The term "amide group" refers to -NH-CO-.

[0101] The term "carboxyl group" refers to -C(O)OH.

[0102] The term "substituted" refers to one or more hydrogen atoms in a group, preferably up to five, more preferably one to three hydrogen atoms, that are independently substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0103] In the chemical structure of the compounds described in this disclosure, the bond " "No configuration specified, i.e., key" "can be " "or" , or both contain " "and" "Two configurations. Bond" " indicates a single configuration, which is " "or" In the chemical structure of the compounds described in this disclosure, the bond " "No configuration is specified, which means it can be Z configuration or E configuration, or both configurations at the same time."

[0104] "Optional" or "optionally" means that the event or environment described below may but does not have to occur, and the description includes the possibility or absence of the event or environment. For example, "optionally alkyl-substituted heterocyclic group" means that the alkyl group may but does not have to be present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.

[0105] The term "stereoisomer" refers to compounds that have the same chemical structure but whose atoms or groups are arranged differently in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric (cis / trans) isomers, and hindered isomers, etc.

[0106] The term "isotope derivative" refers to compounds whose structure differs only in the presence of one or more isotope-enriched atoms. For example, compounds having the structure disclosed herein, using "deuterium" or "tritium" instead of hydrogen, or using... 18 F-fluorine labeling ( 18 F isotopes) can be used instead of fluorine, or... 11 C-, 13 C-, or 14 C-enriched carbon ( 11 C-, 13 C-, or 14 C-carbon labeling; 11 C-, 13 C-, or 14 Compounds in which carbon atoms are replaced by C-isotopes are within the scope of this disclosure. Such compounds can be used as analytical tools or probes in, for example, biological assays, or as in vivo diagnostic imaging tracers for diseases, or as tracers for pharmacodynamic, pharmacokinetic, or receptor studies. The various deuterated forms of compounds disclosed herein refer to compounds in which each available hydrogen atom bonded to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize deuterated forms of compounds by referring to relevant literature. Commercially available deuteration starting materials can be used in the preparation of deuterated forms of compounds, or they can be synthesized using conventional techniques with deuteration reagents, including but not limited to deuterated boranes, trideuterated borane tetrahydrofuran solutions, deuterated lithium aluminum hydride, deuterated iodoethane, and deuterated iodomethane. Deuterated compounds generally retain activity comparable to undeuterated compounds, and better metabolic stability can be achieved when deuterated at certain specific sites, resulting in certain therapeutic advantages.

[0107] The term "pharmaceutically acceptable salt" means that the compounds of the present invention exist in the form of their pharmaceutical salts, including acid addition salts and base addition salts. Pharmaceutically acceptable salts are described in SMBerge's description of pharmaceutically acceptable salts in J. Pharmaceutical Sciences (Vol. 66: 1-19, 1977). In the present invention, a pharmaceutically acceptable non-toxic acid addition salt means a salt formed by the compounds of the present invention with an organic or inorganic acid, including but not limited to hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, nitric acid, perchloric acid, acetic acid, oxalic acid, maleic acid, fumaric acid, tartaric acid, benzenesulfonic acid, methanesulfonic acid, salicylic acid, succinic acid, citric acid, lactic acid, propionic acid, benzoic acid, p-toluenesulfonic acid, malic acid, etc. Pharmaceutically acceptable non-toxic base addition salts refer to salts formed by the compounds of this invention with organic or inorganic bases, including but not limited to alkali metal salts, such as lithium, sodium, or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; and organic base salts, such as ammonium salts or N-containing organic bases. + (C 1-6 Alkyl)4 salt.

[0108] The term "solvent" refers to the physical combination of a compound of this disclosure with one or more, preferably one to three, solvent molecules, whether organic or inorganic. This physical combination includes hydrogen bonds. In some cases, such as when one or more, preferably one to three, solvent molecules are incorporated into the lattice of a crystalline solid, the solvate will be separated. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.

[0109] The term "hydrate" refers to the case where the solvent in the aforementioned term "solvent" is water.

[0110] The term "prodrug" refers to a compound that can be converted in the body to produce an active drug substance under physiological conditions, such as through hydrolysis in the blood.

[0111] The term "pharmaceutical composition" refers to a mixture containing one or more of the compounds described herein or their physiologically / pharmacologically acceptable salts or prodrugs, along with other chemical components, such as physiologically / pharmacologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and the exertion of its biological activity.

[0112] The terms involved in this invention have been defined above. Those skilled in the art can also understand the above terms in conjunction with the prior art. The following is a further description based on the content of this invention and the definition of the terms.

[0113] The following examples further describe the preparation of the compounds and pharmaceutically acceptable salts described in this disclosure, but these examples are not intended to limit the scope of this disclosure.

[0114] Experimental methods in the embodiments of this disclosure that do not specify specific conditions are generally performed under conventional conditions or as recommended by the raw material or product manufacturer. Reagents whose specific source is not specified are commercially available conventional reagents.

[0115] First, the reactions in the examples are generally carried out under nitrogen protection.

[0116] Furthermore, the intermediates and final products were separated and purified using chromatographic columns, preparative chromatographic plates, and the ISCO rapid preparative chromatography system. The chromatographic columns were packed with silica gel (300-400 mesh), manufactured by Shanghai Titan Technology Co., Ltd.; the preparative chromatographic plates were manufactured by Yantai Jiangyou Silica Gel Development Co., Ltd.; and the ISCO columns (particle size 40-63 µm, 60 Å) were manufactured by Changzhou Santai Technology Co., Ltd.

[0117] Furthermore, the LC-MS system used was a Waters ACQUITY Arc equipped with a QDaDetector. A Waters XBridge C18 column (2.1 × 50 mm, 3.5 µm) was used. Mass spectrometry (MS) employed an ESI source, indicating only the molecular weight M of the parent molecule, typically reporting [M+H]. + The injection volume was determined by the sample concentration; the flow rate was 1.2 mL / min; HPLC peak values ​​were recorded and read using UV-Vis wavelengths at 220 nm and 254 nm. The mobile phases were an ultrapure aqueous solution of 0.01% formic acid (mobile phase A) and an acetonitrile solution of 0.01% formic acid (mobile phase B). Gradient elution conditions are shown in Tables 1 and 2 below:

[0118] Table 1: Gradient elution conditions 1 Time (min) <![CDATA[A(H2O,0.01%HCOOH)]]> <![CDATA[B(CH3CN,0.01%HCOOH)]]> 0.0-0.3 95-85 5-15 0.3-3.2 85-20 15-80 3.2-3.8 20-5 80-95 3.8-3.81 5-95 95-5 3.81-4.0 95 5

[0119] Table 2: Gradient elution conditions 2 Time (min) <![CDATA[A(H2O,0.01%HCOOH)]]> <![CDATA[B(CH3CN,0.01%HCOOH)]]> 0.00-5.90 95-5 5-95 5.90-5.91 5-95 95-5 5.91-6.00 95 5

[0120] Furthermore, the NMR spectrum was used Varian 400MHz nuclear magnetic resonance spectrometer Data is obtained using CDCl3 or DMSO-d6 as solvents, and chemical shifts are reported in ppm. The various peaks are described as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet). Coupling constants are expressed in Hz.

[0121] Example

[0122] Example 1 Preparation of Compound I-1

[0123] A commercially available starting material, compound A (3.0 g, 5.22 mmol), was dissolved in 100 mL of dichloromethane (DCM) to prepare a homogeneous solution. Then, under ice bath conditions, DSS-Martin reagent (3.3 g, 7.83 mmol) was slowly added dropwise while stirring to ensure the reaction temperature remained stable within the ice bath range. The reaction was continued with stirring for 5 hours, during which the process was monitored (e.g., by TLC) to ensure complete reaction. After the reaction was complete, 100 mL of petroleum ether was added to the reaction system, resulting in the formation of a white solid precipitate. The resulting mixture was filtered, and the filter cake was collected. The filter cake was washed with petroleum ether to remove residual impurities. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel column chromatography to finally obtain compound I-1 as a colorless oily substance (2.6 g, yield: 87%).

[0124] 1 H NMR (300 MHz, Chloroform-d) δ 8.85 (d, J = 5.5 Hz, 1H), 5.83 (dp,J = 9.7, 1.1 Hz, 1H), 5.71 (dq, J = 9.7, 0.9 Hz, 1H), 5.02 (d, J = 0.9 Hz,2H), 4.39 (ddt, J = 7.2, 5.0, 0.9 Hz, 1H), 3.53 (tt, J = 7.3, 5.3 Hz, 1H), 2.56 – 2.27 (m, 6H), 1.97 – 1.36 (m, 11H), 1.08 (d, J = 6.5 Hz, 3H), 0.90 –0.79 (m, 21H), 0.05 (d, J = 5.6 Hz, 12H).

[0125] MS (ESI, m / z): 595.39 [M+Na] + .

[0126] Example 2 Preparation of compound I-2

[0127] Compound I-1 (2.6 g, 4.54 mmol) was dissolved in 100 mL of anhydrous tetrahydrofuran (THF) to prepare a homogeneous solution. Diethylmethylphosphonoacetate (1.1 g, 4.99 mmol) was added to the solution at room temperature, followed by the slow addition of sodium hydride (NaH, 199 mg, 4.99 mmol) in portions, and the mixture was stirred vigorously. The system temperature was maintained in an ice bath range, and the reaction was stirred continuously for 2 hours. After the reaction was complete, the reaction mixture was poured into 100 mL of ice water to quench any unreacted sodium hydride. The mixture was then extracted with ethyl acetate (100 mL × 2), and the organic phases were combined. The combined organic phases were washed with a saturated sodium chloride solution to remove water-soluble impurities, and then dried over anhydrous sodium sulfate. After drying, the sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure to remove the solvent, yielding the crude product. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (volume ratio 20:1) as eluent, and compound I-2 was finally obtained as a colorless oil (2.7 g, yield: 95%).

[0128] 1 H NMR (300 MHz, Chloroform-d) δ 8.85 (d, J = 5.5 Hz, 1H), 5.83 (dp,J = 9.7, 1.1 Hz, 1H), 5.71 (dq, J = 9.7, 0.9 Hz, 1H), 5.02 (d, J = 0.9 Hz,2H), 4.39 (ddt, J = 7.2, 5.0, 0.9 Hz, 1H), 3.53 (tt, J = 7.3, 5.3 Hz, 1H), 2.56 – 2.27 (m, 6H), 1.97 – 1.36 (m, 11H), 1.08 (d, J = 6.5 Hz, 3H), 0.90 –0.79 (m, 21H), 0.05 (d, J = 5.6 Hz, 12H).

[0129] MS (ESI, m / z): 651.42 [M+Na] + .

[0130] Example 3 Preparation of compound I-3

[0131] Compound I-2 (2.7 g, 4.29 mmol) was dissolved in a mixture of water and methanol (50 mL:50 mL, volume ratio) to prepare a homogeneous reaction system. Sodium hydroxide (0.52 g, 12.88 mmol) was added to the solution, and the mixture was stirred at 50°C for 6 hours. After the reaction was complete, the reaction mixture was acidified to neutral with 1 M hydrochloric acid to quench any remaining basic reagent and adjust the pH. The organic phases were then extracted with dichloromethane (50 mL × 3) and combined. The combined organic layers were washed with a saturated sodium chloride solution to remove water-soluble impurities and dried with anhydrous sodium sulfate. After drying, the mixture was filtered, and the filtrate was concentrated under reduced pressure to remove the solvent, yielding product I-3 as a colorless oil (2.5 g, yield: 95%).

[0132] 1 H NMR (300 MHz, DMSO-d6) δ 11.19 (s, 1H), 6.36 (dd, J = 16.0, 6.1Hz, 1H), 5.92 – 5.78 (m, 2H), 5.72 (dq, J = 9.7, 1.0 Hz, 1H), 5.00 (d, J =1.2 Hz, 2H), 4.16 (ddt, J = 6.9, 5.0, 0.9 Hz, 1H), 3.53 (tt, J = 7.3, 5.1 Hz, 1H), 2.71 (ddt, J = 15.0, 5.3, 0.9 Hz, 1H), 2.56 – 2.28 (m, 5H), 1.90 (ddd, J= 14.3, 7.2, 5.1 Hz, 1H), 1.79 – 1.39 (m, 9H), 1.29 (dtd, J = 12.5, 6.2, 4.5Hz, 1H), 0.96 (d, J = 6.5 Hz, 3H), 0.90 – 0.79 (m, 21H), 0.05 (d, J = 5.6 Hz, 12H).

[0133] MS (ESI, m / z): 637.41 [M+Na] + .

[0134] Example 4 Preparation of compound D1

[0135] Compound I-2 (0.33 mmol) was dissolved in 10 mL of anhydrous tetrahydrofuran (THF) to prepare a homogeneous reaction system under an inert gas (argon) atmosphere. The system was placed in an ice bath for cooling, and 0.85 mL of 1 M methyl magnesium bromide solution was slowly added dropwise while stirring at this temperature for 1 hour to ensure homogeneous reaction. Subsequently, the ice bath was removed, and the reaction system was gradually heated to room temperature and stirred for 5 hours to promote complete reaction. After the reaction was complete, the reaction mixture was slowly poured into 20 mL of saturated ammonium chloride solution to quench the reaction, followed by extraction with ethyl acetate (20 mL × 3), and the organic layers were combined. The combined organic phases were washed with saturated sodium chloride solution to remove water-soluble impurities and then dried with anhydrous sodium sulfate. After drying, the mixture was filtered, and the filtrate was concentrated under reduced pressure to remove the solvent, yielding compound I-6-1.

[0136] The obtained compound I-6-1 (0.12 mmol) was dissolved in 10 mL of anhydrous methanol, and p-toluenesulfonic acid (0.03 mmol) was added under argon protection. The mixture was stirred at room temperature for 5 hours. After the reaction was complete, the mixture was poured into 20 mL of saturated sodium bicarbonate aqueous solution, and the product was extracted with dichloromethane (30 mL × 3). The organic layers were combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography to finally obtain the target compound D1. (D1), dichloromethane / methanol (20 / 1, v / v), white solid, yield 64%.

[0137] 1H NMR (400 MHz, ) δ 6.20 (d, J = 11.2 Hz, 1H), 5.98 (d, J = 11.2 Hz,1H), 5.51 – 5.32 (m, 2H), 5.22 (d, J = 2.4 Hz, 1H), 4.88 (d, J = 4.8 Hz, 1H), 4.76 (d, J = 3.0 Hz, 1H), 4.56 (d, J = 3.7 Hz, 1H), 4.36 (s, 1H), 4.19 (dt, J= 9.1, 4.4 Hz, 1H), 3.99 (dt, J = 9.1, 4.0 Hz, 1H), 2.85 – 2.72 (m, 1H), 2.40– 2.33 (m, 1H), 2.17 (dd, J = 13.5, 5.7 Hz, 1H), 1.98 (dq, J = 22.5, 12.6,10.5 Hz, 4H), 1.82 – 1.74 (m, 1H), 1.63 (qt, J = 8.2, 4.8 Hz, 4H), 1.51 –1.16 (m, 5H), 1.13 (d, J = 2.0 Hz, 6H), 0.99 (d, J = 6.6 Hz, 3H), 0.52 (s,3H).

[0138] 13 C NMR (101 MHz, Chloroform-d) δ 147.60, 142.93, 135.57, 133.20,133.07, 124.87, 117.10, 111.78, 70.74, 70.69, 66.81, 56.36, 56.24, 45.88,45.20, 42.81, 40.34, 39.78, 29.91, 29.79, 29.05, 27.59, 26.91, 23.55, 22.20,20.65, 12.29.

[0139] HR-MS (ESI, m / z): 423.28697[M+Na] + . HPLC Purity: 99.6% (Rt: 2.96min).

[0140] Example 5 Preparation of compound D2

[0141] Replace the Grignard reagent with ethyl magnesium bromide (1 M, 0.85 mL), and proceed as in D1. (D2), dichloromethane / methanol (20 / 1, v / v), white solid, yield 51%.

[0142] 1 H NMR (400 MHz, DMSO-d6) δ 6.20 (d, J = 11.2 Hz, 1H), 5.98 (d, J =11.2 Hz, 1H), 5.36 (dd, J = 15.5, 8.6 Hz, 1H), 5.27 – 5.11 (m, 2H), 4.88 (d,J = 4.8 Hz, 1H), 4.82 – 4.72 (m, 1H), 4.56 (d, J = 3.7 Hz, 1H), 4.19 (dt, J =9.3, 4.5 Hz, 1H), 3.97 (d, J = 10.9 Hz, 2H), 2.87 – 2.72 (m, 1H), 2.40 – 2.27(m, 1H), 2.17 (dd, J = 13.6, 5.6 Hz, 1H), 2.07 – 1.88 (m, 3H), 1.80 (dt, J =11.2, 5.0 Hz, 1H), 1.73 – 1.56 (m, 4H), 1.50 – 1.13 (m, 12H), 1.00 (d, J =6.6 Hz, 3H), 0.76 (td, J = 7.4, 2.0 Hz, 7H), 0.53 (s, 3H).

[0143] 13 C NMR (101 MHz, Chloroform-d) δ 147.58, 143.06, 135.18, 132.95,132.79, 124.96, 117.07, 111.82, 75.29, 70.81, 66.86, 56.39, 56.21, 45.86,45.22, 42.81, 40.36, 33.25, 29.06, 27.98, 26.92, 23.58, 22.29, 21.10, 12.27,7.95, 7.83.

[0144] HR-MS (ESI, m / z): 451.31827[M+Na] + . HPLC Purity: 99.8% (Rt: 2.97min).

[0145] Example 6 Preparation of compound D3

[0146] Replace the Grignard reagent in the reaction with allyl magnesium bromide (1 M, 0.85 mL), and proceed as in D1. (D3), dichloromethane / methanol (20 / 1, v / v), white solid, yield 64%.

[0147] 1 H NMR (400 MHz, DMSO-d6) δ 6.20 (d, J = 11.2 Hz, 1H), 5.98 (d, J =11.2 Hz, 1H), 5.83 – 5.73 (m, 2H), 5.40 – 5.22 (m, 3H), 5.05 – 4.94 (m, 4H), 4.87 (s, 1H), 4.80 – 4.70 (m, 1H), 4.56 (d, J = 3.7 Hz, 1H), 4.42 (s, 1H), 4.19 (dt, J = 9.1, 4.5 Hz, 1H), 3.99 (dp, J = 9.2, 4.6, 4.0 Hz, 1H), 2.84 –2.74 (m, 1H), 2.36 (dd, J = 13.8, 3.5 Hz, 1H), 2.17 (dd, J = 10.5, 6.3 Hz, 4H), 1.97 (dt, J = 27.5, 11.3 Hz, 3H), 1.79 (dt, J = 11.0, 5.0 Hz, 1H), 1.64(ddd, J = 12.4, 8.9, 3.4 Hz, 4H), 1.47 – 1.20 (m, 7H), 0.98 (s, 3H), 0.52 (s,3H).

[0148] 13C NMR (101 MHz, Chloroform-d) δ 147.60, 142.97, 135.60, 133.77,133.67, 133.00, 132.52, 124.91, 118.71, 117.10, 111.80, 73.26, 70.80, 66.83,56.36, 56.13, 45.86, 45.62, 45.57, 45.23, 42.82, 40.35, 40.21, 29.04, 27.95,26.91, 23.56, 22.29, 20.98, 12.27.

[0149] HR-MS (ESI, m / z): 475.31827[M+Na] + . HPLC Purity: 99.4% (Rt: 2.89min).

[0150] Example 7 Preparation of compound D4

[0151] Replace the Grignard reagent with benzyl magnesium bromide (1M, 0.85 mL), and proceed as in D1. (D4), dichloromethane / methanol (20 / 1, v / v), white solid, yield 69%.

[0152] 1H NMR (400 MHz, DMSO-d6) δ 7.28 – 7.12 (m, 10H), 6.18 (d, J = 11.2Hz, 1H), 5.95 (d, J = 11.2 Hz, 1H), 5.32 – 5.18 (m, 2H), 5.06 (dd, J = 15.4,8.5 Hz, 1H), 4.88 (d, J = 4.8 Hz, 1H), 4.80 – 4.69 (m, 1H), 4.56 (d, J = 3.7Hz, 1H), 4.40 (s, 1H), 4.19 (dt, J = 9.2, 4.6 Hz, 1H), 3.98 (dh, J = 6.3, 3.4Hz, 1H), 2.75 (d, J = 10.1 Hz, 4H), 2.39 – 2.31 (m, 1H), 2.16 (dd, J = 13.6,5.6 Hz, 1H), 1.82 (tt, J = 18.4, 4.0 Hz, 4H), 1.68 – 1.54 (m, 3H), 1.47 –1.36 (m, 1H), 1.33 – 0.98 (m, 6H), 0.90 – 0.71 (m, 4H), 0.42 (s, 3H).

[0153] 13 C NMR (101 MHz, Chloroform-d) δ 147.62, 143.06, 136.99, 136.89,135.51, 132.93, 132.25, 130.92, 130.78, 128.00, 127.82, 126.40, 124.95,117.04, 111.83, 77.24, 74.97, 70.83, 66.84, 56.29, 48.04, 45.80, 45.25,42.88, 40.29, 40.05, 29.04, 27.77, 23.54, 22.12, 20.42, 12.15.

[0154] HR-MS (ESI, m / z): 575.34957[M+Na]+. HPLC Purity: 99.9% (Rt: 3.13min).

[0155] Example 8 Preparation of compound D5

[0156] The reaction reagent was changed from methyl magnesium bromide to ethyl magnesium bromide (1M, 0.85 mL), and the reaction temperature was adjusted to 50 °C. The rest of the preparation method was the same as in D1. (D5), dichloromethane / methanol (20 / 1, v / v), white solid, yield 55%.

[0157] 1 H NMR (400 MHz, ) δ 6.19 (d, J = 11.2 Hz, 1H), 5.99 (d, J = 11.2 Hz, 1H), 5.23 (dd, J = 3.0, 1.5 Hz, 1H), 4.89 (d, J = 4.8 Hz, 1H), 4.79 – 4.71(m, 1H), 4.56 (s, 1H), 4.19 (dt, J = 9.0, 4.6 Hz, 1H), 3.99 (d, J = 4.5 Hz,1H), 2.84 – 2.75 (m, 1H), 2.45 – 2.28 (m, 3H), 2.17 (dd, J = 13.5, 5.6 Hz, 1H), 2.06 (dd, J = 16.3, 10.1 Hz, 1H), 2.01 – 1.71 (m, 6H), 1.63 (tt, J =8.9, 3.3 Hz, 3H), 1.58 – 1.08 (m, 9H), 0.92 (d, J = 7.3 Hz, 3H), 0.76 (d, J =7.1 Hz, 6H), 0.53 (s, 3H).

[0158] 13 C NMR (101 MHz, Chloroform-d) δ 212.46, 147.61, 142.82, 133.18,124.81, 117.18, 111.78, 77.24, 70.70, 66.81, 56.43, 54.14, 54.07, 45.96,45.17, 42.79, 42.67, 40.59, 37.81, 36.51, 36.26, 29.08, 27.59, 26.91, 25.65,25.63, 23.58, 22.16, 13.17, 12.15, 12.00, 7.92.

[0159] HR-MS (ESI, m / z): 451.3177[M+Na] +. HPLC Purity: 99.9% (Rt: 3.02min).

[0160] Example 9 Preparation of compound D6

[0161] Replace the Grignard reagent with methylmagnesium bromide (1M, 0.85 mL), and proceed as in D1. (D6), dichloromethane / methanol (20 / 1, v / v), white solid, yield 57%.

[0162] 1 H NMR (400 MHz, DMSO-d6) δ 6.20 (d, J = 11.2 Hz, 1H), 5.99 (d, J =11.1 Hz, 1H), 5.35 (dd, J = 15.4, 8.4 Hz, 1H), 5.28 – 5.17 (m, 2H), 4.85 (d,J = 4.8 Hz, 1H), 4.76 (d, J = 3.0 Hz, 1H), 4.53 (s, 1H), 4.19 (dt, J = 9.1,4.5 Hz, 1H), 3.98 (d, J = 8.3 Hz, 2H), 2.85 – 2.75 (m, 1H), 2.37 (dd, J =14.6, 3.2 Hz, 1H), 2.17 (dd, J = 13.6, 5.7 Hz, 1H), 2.07 – 1.90 (m, 3H), 1.80 (dt, J = 11.0, 5.0 Hz, 1H), 1.71 – 1.56 (m, 4H), 1.46 – 1.19 (m, 14H), 0.99(d, J = 6.6 Hz, 3H), 0.83 (t, J = 6.9 Hz, 6H), 0.52 (s, 3H).

[0163] 113C NMR (101 MHz, Chloroform-d) δ 147.69, 142.92, 134.39, 133.58,133.08, 124.86, 117.11, 111.72, 74.92, 70.76, 66.80, 56.37, 56.23, 45.84,45.25, 43.66, 43.63, 42.86, 40.36, 40.25, 29.04, 27.92, 23.56, 22.31, 21.04,16.90, 16.78, 14.64, 14.62, 12.25.

[0164] HR-MS (ESI, m / z):479.34957[M+Na] + . HPLC Purity: 99.5% (Rt: 2.90 min).

[0165] Example 10 Preparation of compound D7

[0166] Replace the Grignard reagent with methylmagnesium bromide (1M, 0.85ml), and adjust the reaction temperature to 50℃. The rest of the preparation method is the same as in D1. (D7) Dichloromethane / methanol (20 / 1, v / v), white solid, yield 64%.

[0167] 1H NMR (400 MHz, ) δ 6.19 (d, J = 11.2 Hz, 1H), 5.99 (d, J = 11.3 Hz, 1H), 5.23 (dd, J = 3.0, 1.5 Hz, 1H), 4.90 – 4.88 (m, 1H), 4.76 (d, J = 3.1Hz, 1H), 4.56 (d, J = 3.5 Hz, 1H), 4.23 – 4.12 (m, 1H), 3.98 (d, J = 4.6 Hz, 1H), 2.80 (d, J = 10.7 Hz, 1H), 2.39 (q, J = 6.9 Hz, 3H), 2.20 – 2.15 (m,1H), 2.04 – 1.94 (m, 5H), 1.79 (dd, J = 12.2, 5.9 Hz, 2H), 1.64 – 1.61 (m,1H), 1.45 (d, J = 7.2 Hz, 2H), 1.35 – 1.25 (m, 9H), 1.11 (s, 2H), 0.86 – 0.75 (m, 13H), 0.52 (s, 3H).

[0168] 13 C NMR (101 MHz, Chloroform-d) δ 211.82, 147.66, 142.90, 133.08,124.88, 117.15, 111.75, 70.75, 66.86, 56.42, 54.21, 45.96, 45.35, 45.25,43.14, 42.85, 40.59, 36.73, 35.56, 35.26, 29.09, 27.57, 23.59, 22.17, 20.53,17.29, 14.22, 13.81, 13.27, 12.02.

[0169] HR-MS (ESI, m / z): 413.30337[M+H]+. HPLC Purity: 99.8% (Rt: 2.85 min).

[0170] Example 11 Preparation of compound D8

[0171] Replace the Grignard reagent with butyl magnesium bromide (1M, 0.85 mL), and proceed as in D1. (D8), dichloromethane / methanol (20 / 1, v / v), white solid, yield 59%.

[0172] 1 H NMR (400 MHz, DMSO-d6) δ 6.20 (d, J = 11.2 Hz, 1H), 5.98 (d, J =11.2 Hz, 1H), 5.34 (dd, J = 15.5, 8.5 Hz, 1H), 5.27 – 5.15 (m, 2H), 4.87 (d,J = 4.8 Hz, 1H), 4.76 (dd, J = 3.0, 1.3 Hz, 1H), 4.56 (d, J = 3.7 Hz, 1H), 4.19 (dt, J = 9.1, 4.6 Hz, 1H), 3.99 (d, J = 1.9 Hz, 2H), 2.83 – 2.74 (m,1H), 2.41 – 2.31 (m, 1H), 2.17 (dd, J = 13.6, 5.7 Hz, 1H), 2.06 – 1.90 (m,3H), 1.79 (dt, J = 11.0, 5.1 Hz, 1H), 1.64 (td, J = 12.2, 10.5, 5.8 Hz, 4H), 1.47 – 1.17 (m, 18H), 0.99 (d, J = 6.6 Hz, 3H), 0.87 – 0.80 (m, 6H), 0.52 (s, 3H).

[0173] 13 C NMR (101 MHz, Chloroform-d) δ 147.71, 142.85, 134.44, 133.63,133.16, 124.81, 117.14, 111.71, 74.87, 70.71, 66.77, 56.38, 56.25, 45.82,45.23, 42.86, 40.96, 40.92, 40.35, 40.27, 40.01, 29.04, 27.92, 25.84, 25.71,23.56, 23.19, 22.29, 21.04, 14.14, 14.12, 12.26.

[0174] HR-MS (ESI, m / z): 507.38087[M+Na]+ . HPLC Purity: 98.5% (Rt: 3.12min).

[0175] Example 12 Preparation of compound D9

[0176] Replace the Grignard reagent with methylmagnesium bromide (1M, 0.85ml), and adjust the reaction temperature to 50℃. The rest of the preparation method is the same as in D1. (D9) Dichloromethane / methanol (20 / 1, v / v), white solid, yield 52%.

[0177] 1 H NMR (400 MHz, DMSO-d6) δ 6.19 (d, J = 11.2 Hz, 1H), 5.99 (d, J =11.2 Hz, 1H), 5.23 (dd, J = 3.0, 1.5 Hz, 1H), 4.89 (d, J = 4.8 Hz, 1H), 4.76(dd, J = 3.0, 1.3 Hz, 1H), 4.56 (d, J = 3.8 Hz, 1H), 4.19 (dt, J = 9.1, 4.6Hz, 1H), 3.99 (dh, J = 6.5, 3.5 Hz, 1H), 2.83 – 2.75 (m, 1H), 2.45 – 2.30 (m,4H), 2.17 (dd, J = 13.5, 5.6 Hz, 1H), 2.05 (dd, J = 16.0, 10.1 Hz, 1H), 1.95 (q, J = 11.7, 10.4 Hz, 3H), 1.79 (ddt, J = 11.7, 6.6, 3.9 Hz, 2H), 1.62 (ddt,J = 15.5, 10.1, 4.9 Hz, 3H), 1.49 – 1.32 (m, 7H), 1.28 – 1.08 (m, 10H), 0.88– 0.81 (m, 7H), 0.76 (d, J = 6.6 Hz, 3H), 0.52 (s, 3H).

[0178] 13C NMR (101 MHz, Chloroform-d) δ 211.99, 147.67, 142.85, 133.16,124.83, 117.16, 111.72, 70.70, 66.83, 56.42, 54.20, 45.96, 45.21, 43.14,42.83, 40.59, 36.73, 35.82, 32.66, 29.71, 29.08, 27.57, 25.97, 23.58, 22.86,22.37, 22.17, 14.09, 13.90, 13.25, 12.03.HR-MS (ESI, m / z): 485.3983[M+H]+.HPLC Purity: 98.5% (Rt: 2.96 min).

[0179] Example 13 Preparation of compound D10

[0180] Compound I-3 (0.16 mmol) was dissolved in 30 mL of dichloromethane (DCM). Triethylamine (33 mg, 0.32 mmol), dimethylamine (0.19 mmol), and HATU (25 mg, 0.24 mmol) were added sequentially at room temperature and mixed thoroughly. The reaction mixture was then stirred at room temperature for 6 hours.

[0181] After the reaction was complete, the reaction mixture was slowly poured into 30 mL of 1 M citric acid aqueous solution to remove unreacted amines and byproducts. Subsequently, extraction was performed with dichloromethane (50 mL × 3), and the organic layers were combined. The combined organic phases were washed with saturated sodium chloride aqueous solution to remove water-soluble impurities. The washed organic solution was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent, yielding compound I-4-1.

[0182] The obtained compound I-4-1 (0.13 mmol) was dissolved in 10 mL of anhydrous methanol, and p-toluenesulfonic acid (0.03 mmol) was added. Under argon protection, the reaction mixture was stirred at room temperature for 5 hours. After the reaction was complete, the mixture was poured into 20 mL of saturated sodium bicarbonate aqueous solution, followed by extraction with dichloromethane (30 mL × 3). The organic layers were combined. The combined organic phases were washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the solvent, and then purified by silica gel column chromatography to finally obtain the target compound D10. (D10), dichloromethane / methanol (20 / 1, v / v), white solid, 50% yield.

[0183] 1 H NMR (400 MHz, DMSO-d6) δ 6.54 – 6.47 (m, 1H), 6.35 (d, J = 15.0Hz, 1H), 6.20 (d, J = 11.2 Hz, 1H), 5.99 (d, J = 11.2 Hz, 1H), 5.23 (dd, J =3.1, 1.5 Hz, 1H), 4.88 (d, J = 4.7 Hz, 1H), 4.76 (dd, J = 3.0, 1.3 Hz, 1H), 4.57 (d, J = 3.8 Hz, 1H), 4.19 (dt, J = 9.0, 4.6 Hz, 1H), 3.99 (dt, J = 9.0,4.1 Hz, 1H), 3.02 (s, 3H), 2.85 (s, 4H), 2.39 – 2.26 (m, 2H), 2.17 (dd, J =13.6, 5.7 Hz, 1H), 2.03 – 1.90 (m, 2H), 1.82 – 1.75 (m, 1H), 1.63 (tq, J =10.4, 6.6, 4.8 Hz, 4H), 1.40 (ddt, J = 16.3, 8.8, 4.2 Hz, 4H), 1.26 – 1.20(m, 2H), 1.05 (d, J = 6.5 Hz, 3H), 0.54 (s, 3H).

[0184] 13 C NMR (101 MHz, Chloroform-d) δ 167.19, 151.57, 147.74, 142.30,133.53, 124.60, 117.88, 117.36, 111.69, 70.61, 66.69, 56.14, 55.44, 46.02,45.20, 42.86, 40.28, 40.24, 37.38, 35.72, 28.99, 27.51, 23.49, 22.27, 19.75,12.33.

[0185] HR-MS (ESI, m / z): 436.28103[M+Na] + . HPLC Purity: 98.0% (Rt: 3.99min).

[0186] Example 14 Preparation of compound D11

[0187] The dimethylamine in the reaction was replaced with diethylamine (0.19 mmol), and the rest of the method was the same as for the preparation of D10. (D11), dichloromethane / methanol (20 / 1, v / v), white solid, yield 47%.

[0188] 1 H NMR (400 MHz, DMSO-d6) δ 6.52 (dd, J = 14.8, 9.1 Hz, 1H), 6.31 –6.17 (m, 2H), 5.99 (d, J = 11.2 Hz, 1H), 5.23 (dd, J = 3.0, 1.5 Hz, 1H), 4.86(d, J = 4.7 Hz, 1H), 4.76 (d, J = 3.0 Hz, 1H), 4.54 (d, J = 3.7 Hz, 1H), 4.19(d, J = 4.3 Hz, 1H), 3.99 (s, 1H), 3.32 (s, 4H), 2.86 – 2.77 (m, 1H), 2.40 –2.23 (m, 2H), 2.17 (dd, J = 13.4, 5.6 Hz, 1H), 2.04 – 1.91 (m, 2H), 1.79 (dd,J = 12.3, 6.5 Hz, 1H), 1.66 (d, J = 11.1 Hz, 4H), 1.54 – 1.32 (m, 5H), 1.25 (d, J = 5.4 Hz, 1H), 1.06 (tt, J = 14.7, 7.1 Hz, 9H), 0.55 (s, 3H).

[0189] 13 C NMR (101 MHz, Chloroform-d) δ 166.21, 151.41, 147.65, 142.57,133.26, 124.78, 118.21, 117.27, 111.78, 77.23, 70.76, 66.79, 56.17, 55.47,46.05, 45.23, 42.84, 42.18, 40.86, 40.32, 40.30, 29.01, 27.57, 23.52, 22.29,19.78, 14.90, 13.21, 12.33.

[0190] HR-MS (ESI, m / z):464.31410[M+Na] + . HPLC Purity: 96.9% (Rt: 4.77 min).

[0191] Example 15 Preparation of compound D12

[0192]

[0193] The dimethylamine in the reaction was replaced with diisobutylamine (0.19 mmol), and the rest of the method was the same as for the preparation of D10. (D12), dichloromethane / methanol (20 / 1, v / v), white solid, yield 51%.

[0194] 1 H NMR (400 MHz, DMSO-d6) δ 6.49 (dd, J = 14.8, 9.0 Hz, 1H), 6.34 (d,J = 14.9 Hz, 1H), 6.20 (d, J = 11.1 Hz, 1H), 5.99 (d, J = 11.1 Hz, 1H), 5.29– 5.19 (m, 1H), 4.87 (d, J = 4.7 Hz, 1H), 4.76 (d, J = 3.1 Hz, 1H), 4.56 (d,J = 3.7 Hz, 1H), 4.19 (dt, J = 9.1, 4.5 Hz, 1H), 3.99 (tt, J = 5.9, 3.1 Hz,1H), 3.25 – 3.01 (m, 4H), 2.85 – 2.75 (m, 1H), 2.40 – 2.26 (m, 2H), 2.17 (dd,J = 13.6, 5.7 Hz, 1H), 1.95 (dp, J = 20.6, 8.0, 6.8 Hz, 3H), 1.88 – 1.75 (m,2H), 1.69 – 1.54 (m, 4H), 1.41 (dt, J = 24.1, 11.1 Hz, 4H), 1.29 – 1.14 (m,2H), 1.04 (d, J = 6.5 Hz, 3H), 0.82 (ddd, J = 12.3, 6.7, 2.9 Hz, 12H), 0.55 (s, 3H). 2.9 Hz, 12H), 0.55 (s, 3H).

[0195] 13C NMR (101 MHz, Chloroform-d) δ 167.16, 151.02, 147.66, 142.63,133.20, 124.82, 118.58, 117.24, 111.79, 70.79, 66.80, 56.16, 55.97, 55.54,54.46, 46.05, 45.26, 42.86, 40.35, 40.29, 29.71, 29.02, 28.77, 27.59, 26.92,23.53, 22.30, 20.32, 20.18, 20.17, 19.73, 12.33.

[0196] HR-MS (ESI, m / z): 498.3928[M+H]+. HPLC Purity: 99.2% (Rt: 5.94 min).

[0197] Example 16 Preparation of compound D13

[0198] The dimethylamine in the reaction was replaced with dibenzylamine (0.19 mmol), and the rest of the method was the same as for the preparation of D10. (D13), dichloromethane / methanol (20 / 1, v / v), white solid, yield 61%.

[0199] 1H NMR (400 MHz, DMSO-d6) δ 7.40 – 7.17 (m, 10H), 6.65 (dd, J = 14.8,9.0 Hz, 1H), 6.39 (d, J = 14.9 Hz, 1H), 6.19 (d, J = 11.2 Hz, 1H), 5.97 (d, J= 11.2 Hz, 1H), 5.23 (dd, J = 3.0, 1.5 Hz, 1H), 4.87 (d, J = 4.8 Hz, 1H),4.75 (dd, J = 3.0, 1.3 Hz, 1H), 4.67 – 4.46 (m, 5H), 4.19 (dt, J = 9.1, 4.5Hz, 1H), 3.98 (tt, J = 6.4, 3.0 Hz, 1H), 2.84 – 2.74 (m, 1H), 2.40 – 2.29 (m,1H), 2.26 – 2.13 (m, 2H), 2.00 – 1.86 (m, 2H), 1.82 – 1.72 (m, 1H), 1.63 (tt,J = 8.6, 4.0 Hz, 3H), 1.54 – 1.25 (m, 7H), 1.12 (dt, J = 15.0, 7.2 Hz, 1H),1.00 (d, J = 6.6 Hz, 3H), 0.48 (s, 3H).

[0200] 13 C NMR (101 MHz, Chloroform-d) δ 167.65, 153.05, 147.62, 142.59,137.44, 136.81, 133.21, 128.89, 128.59, 128.43, 127.61, 127.40, 126.58,124.82, 117.95, 117.25, 111.81, 70.78, 66.81, 56.14, 55.39, 49.96, 48.61,46.05, 45.23, 42.85, 40.34, 40.26, 29.01, 27.47, 23.50, 22.27, 19.68, 12.31.

[0201] HR-MS (ESI, m / z): 566.3628[M+H] + . HPLC Purity: 98.6% (Rt: 4.93 min).

[0202] Example 17 Preparation of compound D14

[0203] The dimethylamine in the reaction was replaced with isopropylamine (0.19 mmol), and the rest of the method was the same as for the preparation of D10. (D14), dichloromethane / methanol (20 / 1, v / v), white solid, yield 52%.

[0204] 1 H NMR (300 MHz, DMSO-d6) δ 7.73 (d, J = 7.6 Hz, 1H), 6.53 – 6.44 (m,1H), 6.20 (d, J = 11.2 Hz, 1H), 5.99 (d, J = 11.1 Hz, 1H), 5.78 (d, J = 15.3Hz, 1H), 5.23 (dd, J = 3.1, 1.5 Hz, 1H), 4.88 (d, J = 4.7 Hz, 1H), 4.82 –4.69 (m, 1H), 4.56 (d, J = 3.7 Hz, 1H), 4.18 (d, J = 5.4 Hz, 1H), 3.98 (s,1H), 3.92 – 3.83 (m, 1H), 2.80 (d, J = 13.5 Hz, 1H), 2.37 (d, J = 13.2 Hz, 1H), 2.24 – 2.12 (m, 2H), 2.02 – 1.91 (m, 2H), 1.78 (dd, J = 11.9, 6.2 Hz,1H), 1.64 (s, 4H), 1.46 – 1.34 (m, 4H), 1.28 – 1.18 (m, 2H), 1.06 (dd, J =6.6, 1.5 Hz, 9H), 0.54 (s, 3H).

[0205] 13C NMR (75 MHz, Chloroform-d) δ 165.36, 149.72, 147.63, 142.58,133.23, 124.82, 121.65, 117.27, 111.83, 70.79, 66.82, 56.15, 55.49, 46.05,45.26, 42.85, 41.31, 40.30, 39.82, 29.71, 29.01, 27.53, 23.51, 22.87, 22.27,19.66, 12.29.

[0206] HR-MS (ESI, m / z): 428.3156[M+H] + . HPLC Purity: 97.3% (Rt: 3.82 min).

[0207] Example 18 Preparation of compound D21

[0208] The dimethylamine in the reaction was replaced with bis(2-methoxyethyl)amine (0.19 mmol), and the rest of the method was the same as that used for the preparation of D10. (D21), dichloromethane / methanol (20 / 1, v / v), white solid, yield 51%.

[0209] 1H NMR (400 MHz, ) δ 6.51 (dd, J = 14.9, 9.0 Hz, 1H), 6.35 (d, J =15.0 Hz, 1H), 6.20 (d, J = 11.2 Hz, 1H), 5.99 (d, J = 11.2 Hz, 1H), 5.23 (dd,J = 3.1, 1.5 Hz, 1H), 4.87 (d, J = 4.7 Hz, 1H), 4.76 (dd, J = 3.0, 1.3 Hz,1H), 4.56 (d, J = 3.7 Hz, 1H), 4.19 (dt, J = 8.9, 4.5 Hz, 1H), 3.98 (tt, J =6.2, 3.3 Hz, 1H), 3.58 – 3.37 (m, 8H), 3.24 (d, J = 5.5 Hz, 6H), 2.86 – 2.75(m, 1H), 2.39 – 2.22 (m, 2H), 2.17 (dd, J = 13.5, 5.6 Hz, 1H), 2.03 – 1.92(m, 2H), 1.79 (dt, J = 11.2, 5.1 Hz, 1H), 1.63 (qd, J = 8.5, 4.0 Hz, 4H),1.39 (dtd, J = 30.8, 11.7, 10.5, 4.5 Hz, 4H), 1.31 – 1.12 (m, 2H), 1.04 (s,3H), 0.54 (s, 3H).

[0210] 13 C NMR (75 MHz, Chloroform-d) δ 167.25, 151.78, 147.70, 142.43,133.39, 124.69, 118.21, 117.31, 111.71, 77.27, 71.25, 71.12, 70.67, 66.73,59.10, 58.78, 56.16, 55.44, 52.21, 48.84, 47.19, 46.04, 45.21, 42.89, 40.30,29.69, 29.00, 27.55, 25.14, 23.51, 22.29, 20.12, 19.73, 13.59, 12.32.

[0211] HR-MS (ESI, m / z): 502.3674[M+H] +. HPLC Purity: 98.3% (Rt: 4.06 min).

[0212] Example 19 Preparation of compound D22

[0213] The dimethylamine in the reaction was replaced with aziridine (0.19 mmol), and the rest of the method was the same as for the preparation of D10. (D22), dichloromethane / methanol (20 / 1, v / v), white solid, yield 58%.

[0214] 1 H NMR (400 MHz, DMSO-d6) δ 6.48 (dd, J = 15.2, 9.1 Hz, 1H), 6.20 (d,J = 11.2 Hz, 1H), 5.98 (d, J = 11.2 Hz, 1H), 5.87 (d, J = 15.2 Hz, 1H), 5.23(dd, J = 3.0, 1.5 Hz, 1H), 4.88 (d, J = 4.7 Hz, 1H), 4.76 (dd, J = 2.9, 1.3Hz, 1H), 4.56 (d, J = 3.7 Hz, 1H), 4.17 (dt, J = 15.1, 5.9 Hz, 3H), 3.98 (dh,J = 6.4, 3.4 Hz, 1H), 3.86 (t, J = 7.7 Hz, 2H), 2.86 – 2.75 (m, 1H), 2.39 –2.31 (m, 1H), 2.29 – 2.11 (m, 4H), 2.02 – 1.91 (m, 2H), 1.79 (dt, J = 11.0,5.2 Hz, 1H), 1.62 (dtd, J = 22.1, 9.3, 4.8 Hz, 4H), 1.47 – 1.22 (m, 6H), 1.04(d, J = 6.5 Hz, 3H), 0.53 (s, 3H).

[0215] 13C NMR (75 MHz, Chloroform-d) δ 166.42, 150.74, 147.68, 142.47,133.34, 124.74, 117.31, 116.21, 111.76, 70.73, 66.77, 56.14, 55.36, 50.04,47.88, 46.04, 45.23, 42.86, 40.30, 40.17, 29.00, 27.53, 23.51, 22.27, 19.74,15.30, 12.32.

[0216] HR-MS (ESI, m / z): 426.2998[M+H] + . HPLC Purity: 99.1% (Rt: 4.11 min).

[0217] Example 20 Preparation of compound D23

[0218] The dimethylamine in the reaction was replaced with tetrahydropyrrole (0.19 mmol), and the rest of the method was the same as for the preparation of D10. (D23), dichloromethane / methanol (20 / 1, v / v), white solid, yield 55%.

[0219] 1H NMR (400 MHz, ) δ 6.53 (dd, J = 15.0, 9.1 Hz, 1H), 6.23 – 6.12 (m,2H), 5.99 (d, J = 11.2 Hz, 1H), 5.22 (d, J = 1.4 Hz, 1H), 4.88 (d, J = 4.7Hz, 1H), 4.76 (dd, J = 3.0, 1.3 Hz, 1H), 4.56 (d, J = 3.8 Hz, 1H), 4.19 (dt,J = 8.9, 4.6 Hz, 1H), 3.98 (tt, J = 6.5, 3.2 Hz, 1H), 3.48 (t, J = 6.8 Hz,2H), 3.31 (t, J = 6.8 Hz, 2H), 2.88 – 2.74 (m, 1H), 2.41 – 2.22 (m, 2H), 2.17 (dd, J = 13.5, 5.7 Hz, 1H), 2.08 – 1.70 (m, 8H), 1.64 (ddd, J = 12.6, 8.5,3.5 Hz, 4H), 1.54 – 1.16 (m, 5H), 1.05 (d, J = 6.5 Hz, 3H), 0.54 (s, 3H).

[0220] 13 C NMR (75 MHz, Chloroform-d) δ 165.16, 151.10, 147.70, 142.49,133.35, 124.73, 119.35, 117.30, 111.73, 70.71, 66.76, 56.16, 55.41, 46.53,46.04, 45.86, 45.23, 42.87, 40.30, 40.21, 29.01, 27.56, 26.12, 24.33, 23.52,22.28, 19.79, 12.33.

[0221] HR-MS (ESI, m / z):440.3156[M+H] + . HPLC Purity: 99.8% (Rt: 4.43 min).

[0222] Example 21 Preparation of compound D24

[0223] The dimethylamine in the reaction was replaced with piperidine (0.19 mmol), and the rest of the method was the same as for the preparation of D10. (D24), dichloromethane / methanol (15 / 1, v / v), white solid, yield 57%.

[0224] 1 H NMR (400 MHz, DMSO-d6) δ 6.51 – 6.44 (m, 1H), 6.38 (d, J = 15.0Hz, 1H), 6.20 (d, J = 11.2 Hz, 1H), 5.99 (d, J = 11.2 Hz, 1H), 5.23 (dd, J =3.0, 1.5 Hz, 1H), 4.88 (d, J = 4.8 Hz, 1H), 4.76 (dd, J = 3.0, 1.2 Hz, 1H), 4.56 (s, 1H), 4.19 (dt, J = 9.2, 4.6 Hz, 1H), 3.98 (t, J = 4.9 Hz, 1H), 3.51– 3.41 (m, 4H), 2.86 – 2.76 (m, 1H), 2.38 – 2.26 (m, 2H), 2.17 (dd, J = 13.5,5.7 Hz, 1H), 2.01 – 1.92 (m, 2H), 1.79 (dd, J = 12.1, 6.1 Hz, 1H), 1.66 –1.54 (m, 6H), 1.49 – 1.34 (m, 9H), 1.26 – 1.22 (m, 1H), 1.05 (d, J = 6.5 Hz,3H), 0.54 (s, 3H).

[0225] 13 C NMR (75 MHz, Chloroform-d) δ 165.85, 151.20, 147.69, 142.47,133.37, 124.71, 118.08, 117.30, 111.73, 77.27, 70.69, 66.75, 56.16, 55.49,46.89, 46.03, 45.22, 43.11, 42.86, 40.30, 29.01, 27.54, 26.62, 25.55, 24.65,23.52, 22.28, 19.75, 12.32.

[0226] HR-MS (ESI, m / z): 454.3311[M+H] +. HPLC Purity: 99.5% (Rt: 4.83 min).

[0227] Example 22 Preparation of compound D25

[0228] The dimethylamine in the reaction was replaced with morpholine (0.19 mmol), and the rest of the method was the same as for the preparation of D10. (D25), dichloromethane / methanol (15 / 1, v / v), white solid, yield 49%.

[0229] 1 H NMR (400 MHz, DMSO-d6) δ 6.56 (dd, J = 14.9, 8.9 Hz, 1H), 6.39 (d,J = 14.9 Hz, 1H), 6.20 (d, J = 11.2 Hz, 1H), 5.99 (d, J = 11.2 Hz, 1H), 5.22(d, J = 2.4 Hz, 1H), 4.88 (d, J = 4.8 Hz, 1H), 4.76 (d, J = 3.0 Hz, 1H), 4.56(d, J = 3.7 Hz, 1H), 4.19 (dt, J = 9.3, 4.5 Hz, 1H), 3.98 (d, J = 5.6 Hz,1H), 3.61 – 3.42 (m, 8H), 2.86 – 2.75 (m, 1H), 2.38 – 2.25 (m, 2H), 2.17 (dd,J = 13.6, 5.7 Hz, 1H), 2.02 – 1.91 (m, 2H), 1.82 – 1.73 (m, 1H), 1.68 – 1.55(m, 4H), 1.47 – 1.35 (m, 4H), 1.25 (d, J = 5.9 Hz, 2H), 1.05 (d, J = 6.6 Hz,3H), 0.54 (s, 3H).

[0230] 13C NMR (101 MHz, Chloroform-d) δ 165.98, 152.53, 147.65, 142.46,133.31, 124.76, 117.31, 117.08, 111.79, 70.75, 66.79, 56.13, 55.42, 46.06,45.23, 42.86, 40.36, 40.29, 29.71, 29.01, 27.56, 23.50, 22.28, 19.68, 12.34.

[0231] HR-MS (ESI, m / z): 456.3105[M+H] + . HPLC Purity: 99.9% (Rt: 3.80 min).

[0232] Example 23 Preparation of compound D26

[0233]

[0234] The dimethylamine in the reaction was replaced with 4-methylpiperidine (0.19 mmol), and the rest of the method was the same as for the preparation of D10. (D26), dichloromethane / methanol (15 / 1, v / v), white solid, yield 50%.

[0235] 1H NMR (400 MHz, DMSO-d6) δ 6.50 – 6.35 (m, 2H), 6.20 (d, J = 11.1Hz, 1H), 5.99 (d, J = 11.2 Hz, 1H), 5.23 (dd, J = 3.1, 1.5 Hz, 1H), 4.88 (d,J = 4.8 Hz, 1H), 4.80 – 4.70 (m, 1H), 4.56 (d, J = 3.8 Hz, 1H), 4.37 (d, J =13.0 Hz, 1H), 4.19 (dt, J = 9.0, 4.5 Hz, 1H), 4.09 – 3.94 (m, 2H), 2.97 (t, J= 13.0 Hz, 1H), 2.84 – 2.76 (m, 1H), 2.56 (d, J = 12.6 Hz, 1H), 2.40 – 2.25(m, 2H), 2.17 (dd, J = 13.5, 5.7 Hz, 1H), 2.02 – 1.90 (m, 2H), 1.79 (dt, J =11.2, 5.1 Hz, 1H), 1.71 – 1.52 (m, 7H), 1.48 – 1.34 (m, 4H), 1.25 (d, J = 5.7Hz, 2H), 1.04 (d, J = 6.5 Hz, 3H), 0.97 (d, J = 13.6 Hz, 2H), 0.90 (d, J =6.2 Hz, 3H), 0.54 (s, 3H).

[0236] 13 C NMR (101 MHz, Chloroform-d) δ 165.80, 151.27, 151.14, 147.66,142.54, 133.28, 124.77, 118.18, 118.03, 117.27, 111.76, 70.74, 66.78, 56.16,55.49, 46.16, 46.04, 45.23, 42.86, 42.48, 40.30, 34.79, 33.77, 31.21, 29.71,29.02, 27.55, 23.52, 22.29, 21.75, 19.75, 12.33.

[0237] HR-MS (ESI, m / z): 468.3469[M+H] +. HPLC Purity: 99.7% (Rt: 5.29 min).

[0238] Example 24 Preparation of compound D27

[0239] The dimethylamine in the reaction was replaced with 4-phenylpiperidine (0.19 mmol), and the rest of the method was the same as that used for the preparation of D10. (D27), dichloromethane / methanol (15 / 1, v / v), white solid, yield 60%.

[0240] 1 H NMR (400 MHz, DMSO-d6) δ 7.34 – 7.18 (m, 5H), 6.56 – 6.41 (m, 2H), 6.20 (d, J = 11.2 Hz, 1H), 5.99 (d, J = 11.1 Hz, 1H), 5.23 (dd, J = 3.1, 1.5Hz, 1H), 4.88 (d, J = 4.7 Hz, 1H), 4.76 (dd, J = 2.7, 1.3 Hz, 1H), 4.57 (d, J= 3.8 Hz, 2H), 4.19 (dt, J = 9.5, 4.6 Hz, 2H), 3.98 (q, J = 4.7 Hz, 1H), 3.10(t, J = 13.1 Hz, 1H), 2.84 – 2.73 (m, 2H), 2.65 (t, J = 12.5 Hz, 1H), 2.34(ddd, J = 17.0, 11.6, 5.5 Hz, 2H), 2.17 (dd, J = 13.5, 5.7 Hz, 1H), 2.02 –1.91 (m, 2H), 1.79 (dt, J = 11.1, 5.2 Hz, 3H), 1.68 – 1.58 (m, 4H), 1.51 –1.35 (m, 6H), 1.25 (d, J = 5.7 Hz, 2H), 1.05 (s, 3H), 0.55 (s, 3H).

[0241] 13C NMR (101 MHz, Chloroform-d) δ 165.92, 151.70, 147.67, 145.26,142.54, 133.29, 128.59, 126.77, 126.51, 124.79, 118.02, 117.29, 111.78,70.76, 66.80, 56.17, 55.49, 46.48, 46.06, 45.25, 42.93, 42.87, 40.36, 40.31,34.05, 32.85, 29.71, 29.03, 27.59, 23.53, 22.31, 19.76, 12.35.

[0242] HR-MS (ESI, m / z):530.3628[M+H] + . HPLC Purity: 99.4% (Rt: 5.50 min).

[0243] Example 25 Preparation of compound D28

[0244] The dimethylamine in the reaction was replaced with 3,5-dimethylpiperidine (0.19 mmol), and the rest of the method was the same as that for the preparation of D10. (D28), dichloromethane / methanol (15 / 1, v / v), white solid, yield 64%.

[0245] 1H NMR (400 MHz, DMSO-d6) δ 6.43 (td, J = 13.5, 11.9, 6.3 Hz, 2H),6.20 (d, J = 11.1 Hz, 1H), 5.98 (d, J = 11.2 Hz, 1H), 5.23 (dd, J = 3.0, 1.5Hz, 1H), 4.88 (d, J = 4.7 Hz, 1H), 4.78 – 4.71 (m, 1H), 4.57 (d, J = 3.7 Hz,1H), 4.39 (s, 1H), 4.19 (dt, J = 9.0, 4.5 Hz, 1H), 4.08 – 3.85 (m, 2H), 2.84– 2.75 (m, 1H), 2.45 (d, J = 12.2 Hz, 1H), 2.40 – 2.27 (m, 2H), 2.17 (dd, J =13.5, 5.7 Hz, 1H), 2.06 – 1.91 (m, 3H), 1.83 – 1.73 (m, 2H), 1.64 (dt, J =13.4, 6.6 Hz, 4H), 1.41 (tdd, J = 18.0, 11.0, 7.1 Hz, 7H), 1.25 (d, J = 5.7Hz, 2H), 1.04 (s, 3H), 0.89 – 0.81 (m, 6H), 0.54 (s, 3H).

[0246] 13 C NMR (101 MHz, Chloroform-d) δ 165.69, 150.99, 147.64, 142.65,133.17, 124.85, 118.03, 117.24, 111.81, 70.80, 66.82, 56.18, 55.49, 53.05,49.17, 46.05, 45.26, 42.86, 42.51, 40.35, 40.30, 39.51, 32.22, 30.97, 29.71,29.02, 27.57, 23.53, 22.29, 19.78, 19.17, 19.09, 12.34.

[0247] HR-MS (ESI, m / z):482.3628[M+H] + . HPLC Purity: 99.1% (Rt: 5.88 min).

[0248] Example 26 Preparation of compound D29

[0249] The dimethylamine in the reaction was replaced with 0.19 mmol of 4-(4-fluorobenzyl)piperidine, and the rest of the method was the same as that used for the preparation of D10. (D29), dichloromethane / methanol (15 / 1, v / v), white solid, yield 70%.

[0250] 1 H NMR (400 MHz, DMSO-d6) δ 7.24 – 7.08 (m, 4H), 6.52 – 6.35 (m, 2H), 6.20 (d, J = 11.2 Hz, 1H), 5.98 (d, J = 11.1 Hz, 1H), 5.23 (s, 1H), 4.88 (d,J = 4.8 Hz, 1H), 4.76 (s, 1H), 4.57 (d, J = 3.8 Hz, 1H), 4.42 – 4.34 (m, 1H), 4.18 (d, J = 7.1 Hz, 1H), 4.08 – 3.96 (m, 2H), 2.92 (t, J = 12.9 Hz, 1H),2.80 (d, J = 13.1 Hz, 1H), 2.39 – 2.24 (m, 2H), 2.17 (dd, J = 13.7, 5.6 Hz,1H), 2.02 – 1.91 (m, 2H), 1.83 – 1.52 (m, 9H), 1.41 (dq, J = 26.0, 15.0, 12.6Hz, 5H), 1.29 – 1.17 (m, 2H), 1.16 – 0.75 (m, 6H), 0.54 (s, 3H).

[0251] 13C NMR (101 MHz, Chloroform-d) δ 165.82, 162.59, 160.16, 151.48,147.67, 142.53, 135.56, 133.30, 130.40, 130.33, 124.77, 117.92, 117.28,115.16, 114.95, 111.76, 70.74, 66.79, 56.15, 55.48, 46.04, 45.23, 42.87,42.36, 42.12, 40.30, 38.42, 32.62, 31.68, 29.71, 29.02, 27.55, 23.52, 22.29, 19.74, 12.33.

[0252] HR-MS (ESI, m / z):562.3690[M+H] + . HPLC Purity: 98.9% (Rt: 5.91 min).

[0253] Example 27 Preparation of compound D30

[0254] The dimethylamine in the reaction was replaced with 4-(4-methoxybenzyl)piperidine (0.19 mmol), and the rest of the method was the same as for the preparation of D10. (D30), dichloromethane / methanol (15 / 1, v / v), white solid, yield 68%.

[0255] 1H NMR (400 MHz, DMSO-d6) δ 7.13 – 7.04 (m, 2H), 6.88 – 6.80 (m, 2H),6.48 (dd, J = 14.9, 8.8 Hz, 1H), 6.37 (d, J = 15.0 Hz, 1H), 6.20 (d, J = 11.2Hz, 1H), 5.99 (d, J = 11.1 Hz, 1H), 5.31 – 5.17 (m, 1H), 4.88 (d, J = 4.7 Hz,1H), 4.75 (s, 1H), 4.57 (d, J = 3.7 Hz, 1H), 4.37 (d, J = 12.9 Hz, 1H), 4.19(dt, J = 9.3, 4.8 Hz, 1H), 4.08 – 3.92 (m, 2H), 3.72 (s, 3H), 2.92 (t, J =12.7 Hz, 1H), 2.84 – 2.74 (m, 1H), 2.44 (d, J = 7.0 Hz, 2H), 2.38 – 2.22 (m,2H), 2.17 (dd, J = 13.6, 5.7 Hz, 1H), 2.04 – 1.89 (m, 2H), 1.82 – 1.75 (m,1H), 1.73 – 1.53 (m, 7H), 1.51 – 1.32 (m, 5H), 1.32 – 1.09 (m, 2H), 1.07 –0.91 (m, 5H), 0.54 (s, 3H).

[0256] 13 C NMR (101 MHz, Chloroform-d) δ 165.80, 157.90, 151.34, 147.66,142.58, 133.24, 132.06, 129.97, 124.80, 118.09, 117.27, 113.68, 111.77,70.76, 66.80, 56.16, 55.49, 55.27, 46.05, 45.25, 42.87, 42.41, 42.06, 40.30,38.53, 32.68, 31.75, 29.02, 27.56, 23.53, 22.29, 19.75, 12.34.

[0257] HR-MS (ESI, m / z): 574.3892[M+H]+ . HPLC Purity: 97.8% (Rt: 6.33 min).

[0258] Example 28 Preparation of compound D15

[0259] Compound I-1 (0.33 mmol) was dissolved in 10 mL of anhydrous tetrahydrofuran (THF) to prepare a homogeneous reaction system under an inert gas (argon) atmosphere. The system was placed in an ice bath for cooling, and 0.85 mL of 1 M methyl magnesium bromide solution was slowly added dropwise while stirring at this temperature for 1 hour to ensure homogeneous reaction. Subsequently, the ice bath was removed, and the reaction system was gradually heated to room temperature and stirred for another 5 hours to promote complete reaction. After the reaction was complete, the reaction mixture was slowly poured into 20 mL of saturated ammonium chloride solution to quench the reaction, followed by extraction with ethyl acetate (20 mL × 3), and the organic layers were combined. The combined organic phases were washed with saturated sodium chloride solution to remove water-soluble impurities and then dried with anhydrous sodium sulfate. After drying, the mixture was filtered, and the filtrate was concentrated under reduced pressure to remove the solvent, yielding compound I-5-1.

[0260] The obtained compound I-5-1 (0.12 mmol) was dissolved in 10 mL of anhydrous methanol, and p-toluenesulfonic acid (0.03 mmol) was added under argon protection. The mixture was stirred at room temperature for 5 hours. After the reaction was complete, the mixture was poured into 20 mL of saturated sodium bicarbonate aqueous solution, and the product was extracted with dichloromethane (30 mL × 3). The organic layers were combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography to finally obtain the target compound D15. (D15), dichloromethane / methanol (20 / 1, v / v), white solid, yield 64%.

[0261] 1H NMR (400 MHz, DMSO-d6) δ 6.20 (d, J = 11.1 Hz, 1H), 5.99 (d, J =11.2 Hz, 1H), 5.23 (d, J = 3.0 Hz, 1H), 4.88 (d, J = 4.7 Hz, 1H), 4.76 (d, J= 3.0 Hz, 1H), 4.56 (d, J = 3.7 Hz, 1H), 4.25 – 4.14 (m, 1H), 4.09 – 3.94 (m,2H), 3.72 (p, J = 6.4 Hz, 1H), 2.86 – 2.74 (m, 1H), 2.37 (dd, J = 13.5, 3.5Hz, 1H), 1.53 – 1.12(m, 7H), 1.00 (d, J = 6.3 Hz, 3H), 0.83 (d, J = 6.7 Hz, 3H), 0.50 (s, 3H).

[0262] 13 C NMR (101 MHz, Chloroform-d) δ 147.58, 143.05, 132.96, 124.98,117.09, 111.88, 70.89, 69.22, 66.85, 56.19, 53.23, 45.80, 45.28, 42.84,42.16, 40.49, 29.08, 27.17, 23.58, 22.23, 21.51, 11.93, 11.43.

[0263] HR-MS (ESI, m / z): 361.2372[M+H] + . HPLC Purity: 99.2% (Rt: 3.82 min).

[0264] Example 29 Preparation of compound D16

[0265] Using compound I-1 (0.33 mmol) as the starting material, the Grignard reagent was replaced with ethyl magnesium bromide (1 M, 0.85 mL), and the rest of the method was the same as that used for D15. (D16), dichloromethane / methanol (20 / 1, v / v), white solid, yield 71%.

[0266] 1 H NMR (400 MHz, DMSO-d6) δ 6.20 (d, J = 11.2 Hz, 1H), 5.99 (d, J =11.2 Hz, 1H), 5.23 (d, J = 3.0 Hz, 1H), 4.88 (d, J = 4.7 Hz, 1H), 4.76 (d, J= 3.0 Hz, 1H), 4.56 (d, J = 3.7 Hz, 1H), 4.19 (dt, J = 9.1, 4.3 Hz, 1H), 4.07(d, J = 5.6 Hz, 1H), 4.01 – 3.89 (m, 1H), 2.86 – 2.73 (m, 1H), 2.37 (dd, J =13.6, 3.4 Hz, 1H), 2.17 (dd, J = 13.5, 5.7 Hz, 1H), 1.94 (dq, J = 16.1, 9.7,8.9 Hz, 3H), 1.77 (dt, J = 12.0, 6.8 Hz, 1H), 1.63 (q, J = 9.2, 8.3 Hz, 4H), 1.53 – 1.11 (m, 9H), 0.91 – 0.71 (m, 6H), 0.51 (s, 3H).

[0267] 13 C NMR (101 MHz, Chloroform-d) δ 147.59, 143.09, 132.94, 124.99,117.07, 111.86, 75.18, 70.87, 66.85, 56.24, 53.00, 45.80, 45.27, 42.83,40.49, 40.17, 29.09, 28.20, 27.22, 23.59, 22.20, 11.94, 11.60, 10.89.

[0268] HR-MS (ESI, m / z): 375.2886[M+H] + . HPLC Purity: 99.6% (Rt: 4.13 min).

[0269] Example 30 Preparation of compound D17

[0270] It was obtained by deprotection of compound I-2 (0.33 mmol), using the same method as in Example 28 for deprotection of compound I-5-1 to obtain compound D15. (D17), dichloromethane / methanol (20 / 1, v / v), white solid, yield 74%.

[0271] 1 H NMR (400 MHz, ) δ 6.77 (dd, J = 15.6, 9.1 Hz, 1H), 6.20 (d, J =11.2 Hz, 1H), 5.98 (d, J = 11.2 Hz, 1H), 5.83 (d, J = 15.6 Hz, 1H), 5.23 (dd,J = 3.1, 1.5 Hz, 1H), 4.88 (d, J = 4.8 Hz, 1H), 4.75 (dd, J = 3.1, 1.3 Hz,1H), 4.56 (d, J = 3.8 Hz, 1H), 4.21 – 4.14 (m, 1H), 3.99 (dt, J = 6.5, 3.1Hz, 1H), 3.64 (s, 3H), 2.85 – 2.77 (m, 1H), 2.39 – 2.29 (m, 2H), 2.17 (dd, J= 13.5, 5.7 Hz, 1H), 1.96 (dd, J = 14.0, 9.6 Hz, 2H), 1.81 – 0.54 (s, 3H).

[0272] 13C NMR (101 MHz, Chloroform-d) δ 167.49, 154.81, 147.59, 142.52,133.22, 124.83, 118.73, 117.30, 111.87, 70.82, 66.85, 56.11, 55.33, 51.44,46.11, 45.25, 42.83, 40.28, 40.00, 29.01, 27.38, 23.49, 22.28, 19.41, 12.32.

[0273] HR-MS (ESI, m / z): 401.2682[M+H] + . HPLC Purity: 97.9% (Rt: 5.21 min).

[0274] Example 31 Preparation of compound D18

[0275] Using compound I-1 (0.33 mmol) as the starting material, the Grignard reagent was replaced with propyl magnesium bromide (1 M, 0.85 mL), and the rest of the method was the same as that used for D15. (D18), dichloromethane / methanol (20 / 1, v / v), white solid, yield 53%.

[0276] 1H NMR (400 MHz, DMSO-d6) δ 6.20 (d, J = 11.2 Hz, 1H), 6.00 (d, J =11.2 Hz, 1H), 5.22 (d, J = 2.3 Hz, 1H), 4.81 (dd, J = 37.6, 3.9 Hz, 2H), 4.54(d, J = 3.7 Hz, 1H), 4.23 – 4.14 (m, 1H), 4.07 – 3.95 (m, 2H), 3.46 (q, J =6.7, 6.2 Hz, 1H), 2.80 (dd, J = 12.5, 4.1 Hz, 1H), 2.37 (dd, J = 13.6, 3.5Hz, 1H), 2.17 (dd, J = 13.5, 5.8 Hz, 1H), 1.94 (dt, J = 16.1, 11.8 Hz, 3H), 1.79 (dt, J = 11.6, 5.2 Hz, 1H), 1.64 (t, J = 10.0 Hz, 4H), 1.46 – 1.17 (m,10H), 0.91 – 0.78 (m, 6H), 0.50 (s, 3H).

[0277] 13 C NMR (75 MHz, Chloroform-d) δ 147.58, 142.97, 133.11, 124.86,117.10, 111.82, 73.33, 70.74, 66.79, 56.22, 53.03, 45.79, 45.18, 42.80,40.60, 40.48, 37.68, 29.08, 27.19, 23.59, 22.21, 19.68, 14.19, 11.94, 11.71.

[0278] HR-MS (ESI, m / z): 389.3042[M+H]+. HPLC Purity: 98.5% (Rt: 4.55 min).

[0279] Example 32 Preparation of compound D19

[0280] Using compound I-1 (0.33 mmol) as the starting material, the Grignard reagent was replaced with butyl magnesium bromide (1 M, 0.85 mL), and the rest of the method was the same as that used for D15. (D19), dichloromethane / methanol (20 / 1, v / v), white solid, yield 61%.

[0281] 1 H NMR (400 MHz, DMSO-d6) δ 6.20 (d, J = 11.1 Hz, 1H), 6.00 (d, J =11.2 Hz, 1H), 5.23 (dd, J = 3.1, 1.4 Hz, 1H), 4.86 (d, J = 4.8 Hz, 1H), 4.80– 4.70 (m, 1H), 4.54 (d, J = 3.8 Hz, 1H), 4.25 – 4.16 (m, 1H), 4.00 (dd, J =12.1, 4.5 Hz, 2H), 3.48 – 3.41 (m, 1H), 2.80 (dd, J = 12.0, 4.1 Hz, 1H), 2.37(dd, J = 13.7, 3.6 Hz, 1H), 2.17 (dd, J = 13.5, 5.8 Hz, 1H), 2.02 – 1.88 (m,3H), 1.79 (dt, J = 11.5, 5.2 Hz, 1H), 1.69 – 1.57 (m, 4H), 1.46 – 1.14 (m,12H), 0.90–0.79 (m, 6H), 0.50 (s, 3H).

[0282] 13 C NMR (75 MHz, Chloroform-d) δ 147.60, 143.02, 133.04, 124.92,117.09, 111.84, 77.24, 73.60, 70.79, 66.81, 56.22, 53.02, 45.79, 45.21,42.81, 40.56, 40.48, 35.18, 29.08, 28.70, 27.20, 23.58, 22.81, 22.20, 14.11,11.94, 11.67.

[0283] HR-MS (ESI, m / z): 403.3202[M+H]+. HPLC Purity: 98.3% (Rt: 5.06 min).

[0284] Example 33 Preparation of compound D20

[0285] Using compound I-1 (0.33 mmol) as the starting material, the Grignard reagent was replaced with benzylmagnesium bromide (1 M, 0.85 mL), and the rest of the method was the same as that for the preparation of D15. (D20), dichloromethane / methanol (20 / 1, v / v), white solid, yield 57%.

[0286] 1 H NMR (400 MHz, DMSO-d6) δ 7.29 – 7.15 (m, 5H), 6.18 (d, J = 11.1Hz, 1H), 5.97 (d, J = 11.2 Hz, 1H), 5.21 (d, J = 2.3 Hz, 1H), 4.84 (s, 1H), 4.74 (d, J = 3.0 Hz, 1H), 4.53 (d, J = 3.7 Hz, 1H), 4.27 (d, J = 5.8 Hz, 1H), 4.18 (dt, J = 9.2, 4.6 Hz, 1H), 3.98 (td, J = 5.9, 2.9 Hz, 1H), 3.73 (q, J =6.6 Hz, 1H), 2.80 – 2.67 (m, 2H), 2.56 (d, J = 5.8 Hz, 1H), 2.36 (dd, J =13.7, 3.6 Hz, 1H), 2.16 (dd, J = 13.7, 5.6 Hz, 1H), 1.99 – 1.77 (m, 4H), 1.63(dq, J = 14.6, 8.5, 7.7 Hz, 4H), 1.35 (ddt, J = 25.5, 18.2, 12.2 Hz, 5H), 1.08 (q, J = 7.1, 6.3 Hz, 1H), 0.92 (d, J = 6.6 Hz, 3H), 0.42 (s, 3H). 13C NMR (101 MHz, Chloroform-d) δ 147.60, 142.99, 139.37, 133.04,129.24, 128.58, 126.35, 124.91, 117.09, 111.81, 74.61, 70.77, 66.82, 56.19,53.07, 45.80, 45.20, 42.81, 42.09, 40.54, 40.47, 29.08, 27.16, 23.60, 22.18,12.12, 11.92.

[0287] HR-MS (ESI, m / z): 437.3044[M+H]+. HPLC Purity: 99.6% (Rt: 4.46 min).

[0288] Example 34 Determination of VDR affinity of the compounds of the present invention Following the instructions of the Polarscreen Vitamin D Receptor Competitor Assay kit (catalog number: A15907), the test compound was diluted to a final concentration of 1 μM with the specified solvent. The compound solution was mixed with the fluorescent VDR ligand and VDR protein, and placed in a 384-well black opaque plate. The mixture was incubated at room temperature in the dark for 3 hours. After incubation, the fluorescence polarization intensity of each well was measured using a multi-functional microplate reader (Tecan brand) at an excitation wavelength of 535 nm and an emission wavelength of 590 nm. The experimental results are shown in Table 1.

[0289] Calcipotriol was included as a positive control in each batch of experiments, and the blank group served as a control group without the compound. The VDR affinity of the samples was calculated using the following formula: Affinity ratio (%) = (blank group - drug-treated group) / (blank group - positive control group) × 100%.

[0290] Table 1. VDR affinity of the compounds of the present invention

[0291] Pharmacodynamic data show that the compounds of this invention have high affinity for the VDR receptor. Specifically, compounds D11, D13, and D22 exhibit relatively superior affinity compared to the known control compound calcipotriol. These results indicate that the compounds provided by this invention demonstrate strong receptor affinity in VDR competitive binding experiments and possess the potential for further development into vitamin D receptor modulators.

[0292] Example 35: Selectivity of the compounds of the present invention for the VDR and TGFβ / SMAD3 signaling pathways This embodiment aims to evaluate the selectivity of the compounds of the present invention for the VDR and TGFβ / SMAD3 signaling pathways. Specifically, the agonistic activity of the compounds on the VDR pathway was characterized by measuring CYP24A1, and the inhibitory activity of the TGFβ / SMAD3 signaling pathway was characterized by measuring Serpine 1 expression. The test results are as follows: Figure 1 As shown.

[0293] The specific experimental steps are as follows: (1) RNA extraction Adjust the cell suspension density to 1×10 5 Cells / mL were seeded into 24-well cell culture plates, with 500 μL of cell suspension in each well. The plates were then incubated at 37°C and 5% CO2 for 24 h. The original culture medium was removed, and 500 μL of 1640 complete culture medium (to a final compound concentration of 0.5 μM) was added to each well.

[0294] After culture, discard the supernatant, wash twice with pre-chilled PBS, add 200 μL of Trizol to each well to lyse the cells, transfer the Trizol containing cells to a 1.5 mL RNase-free EP tube, add 40 μL of chloroform to each tube, vortex for 30 s to completely emulsify the mixture, incubate at 4 °C for 10 min, and after separation, centrifuge at 4 °C and 12000 rpm for 15 min. After centrifugation, transfer the colorless aqueous phase to a new 1.5 mL RNA-free EP tube, add an equal volume of pre-chilled isopropanol, vortex to mix, incubate at 4 °C for 20 min, and centrifuge at 4 °C and 12000 rpm for 10 min. Discard the supernatant; RNA will form a white gel-like precipitate at the bottom of the tube. Add 200 μL of 75% ethanol, invert and gently tap the EP tube to suspend the precipitate, incubate for 3-5 min, and centrifuge at 4 °C and 12000 rpm for 5-10 min. Slowly aspirate the liquid with a pipette, air dry for 5-10 minutes, then add 40 μL of DEPC water and mix thoroughly. Perform RNA quantification to determine the amount of template added for subsequent reverse transcription. An OD260 / 280 ratio between 1.8 and 2.2 meets the experimental requirements.

[0295] (2) Reverse transcription RNA was reverse transcribed to obtain cDNA according to the instructions of the HiScript II Q RT SuperMix for qPCR (+ gDNA wiper Mix) reverse transcription kit. This kit is a two-step qPCR kit. The 4×gDNA wiper Mix in the kit removes residual genomic DNA, ensuring the reliability of subsequent quantification results. The 4×gDNA wiper Mix was thoroughly mixed, and the reaction solution was prepared according to Table 2.

[0296] Table 2

[0297] Gently mix with a pipette and remove air bubbles by centrifugation. Set the PCR thermal cycler program to 42°C for 2 min. After the program is complete, add 4 μL of 5×HiScript II qRT SuperMix II directly to the reaction tube and mix well. Set the PCR thermal cycler program to 50°C for 15 min and 85°C for 5 sec to perform the reverse transcription reaction.

[0298] (3) RT-qPCR RT-qPCR of cDNA was performed according to the Hieff® qPCR SYBR Green Master Mix (High Rox Plus) instructions. Table 3 shows the premix components required for each RT-qPCR well. Depending on the number of samples, different gene RT-qPCR premixes were added to 1.5 mL RNase-free EP tubes and gently mixed with a pipette.

[0299] Table 3

[0300] The obtained RT-qPCR premixes of different genes were aliquoted into RT-qPCR plates at 9 μL per well, and 1 μL of cDNA was added. Each sample was tested in triplicate. As shown in Table 4, the parameters of the real-time quantitative PCR instrument were set, and amplification and melting curve analysis were performed using the built-in ΔΔCt program in the software.

[0301] Table 4

[0302] β-actin was used as an internal reference gene, and the Control group was used as a control sample. The relative gene expression was calculated as follows: Relative Expression = 2 -ΔΔCt , in, ΔCt = Ct (target gene) - Ct (internal reference gene), ΔΔCt = ΔCt (experimental sample) - ΔCt (control sample).

[0303] The primer pairs used are shown in Table 5.

[0304] Table 5

[0305] Example 36: Selectivity of the compounds of the present invention for the VDR and TGFβ / SMAD3 signaling pathways This embodiment aims to evaluate the inhibitory activity of the compounds of the present invention on the synthesis of hepatic stellate cell activation markers type I collagen (COL1) and α-smooth muscle actin (α-SMA).

[0306] The specific experimental steps are as follows: (1) Extraction of total cell protein: Adjust the density of the cell suspension to 1×10⁻⁶ 5 LX-2 cells were seeded at a density of 2 mL / mL into 6-well cell culture plates, with each well containing 2 mL of cell suspension. The plates were incubated at 37°C and 5% CO2 for 24 h. After seeding LX-2 cells, three wells were left untreated as negative controls. The remaining wells were incubated with 5 ng / mL TGF-β1 for 24 h to induce LX-2 activation. The supernatant was then discarded. Fresh culture medium was added to the three activated wells, and D11 and D13 media were added to the remaining wells to a final concentration of 25 μM. The plates were then returned to the cell culture incubator and incubated at 37°C and 5% CO2. After incubation, the supernatant was discarded, and the cells were washed once with pre-cooled PBS. 200 μL of RIPA lysis buffer (with pre-added protease inhibitors) was added to each well, and the plates were incubated at 4°C for 5 min. Cells were pipetted several times to ensure complete lysis. All lysis buffer was scraped from the wells and transferred to 1.5 mL EP tubes. The plates were centrifuged at 10000-14000 g for 3-5 min, and the supernatant was collected.

[0307] (2) BCA quantification and protein concentration adjustment: The protein concentration of the lysis buffer was determined according to the instructions of the Beyotime BCA protein concentration assay kit. Based on the BCA determination results, the concentration of each sample was adjusted to be consistent using RIPA lysis buffer.

[0308] (3) Protein denaturation: Take the protein solution and add SDS-PAGE protein loading buffer containing reducing agent at a ratio of 1 μL of 5x protein loading buffer per 4 μL of protein sample. Heat at 100°C for 10 min to fully denature the protein sample for subsequent experiments.

[0309] (4) Western Blot experimental protocol: 1) Electrophoresis: Proteins were separated using a 15-well Hepes-Tris 4%~20% high-resolution precast gel. 15 μL of denatured protein sample and protein marker were added to each well of the gel, maintaining a consistent loading volume. Electrophoresis was performed at a constant voltage of 120 V. Electrophoresis was stopped when the blue dye at the very tip of the gel reached near the bottom.

[0310] 2) Transfer: For wet transfer, weigh 14.4 g of glycine and 2 g of Tris 3.0 g, dissolve them in deionized water, add 200 mL of methanol, and finally add deionized water to prepare 1000 mL of transfer buffer. Pre-cool the buffer on ice. Perform the transfer clamp operation in the transfer buffer and install it in the transfer tank. Using a constant current of 350 mAh under ice bath conditions, transfer the protein to a 0.22 μm PVDF membrane for 90 min. After the transfer step, immerse the PVDF membrane in Ponceau S staining solution and agitate for 3-5 min or longer for staining. After confirming good protein transfer, wash the PVDF membrane 2-3 times with TBS buffer for 5 min each time to remove the Ponceau S staining solution.

[0311] 3) Blocking: Weigh 2 g of skim milk powder and 0.2 g of bovine serum albumin. Place the PVDF membrane in Western blotting buffer and block at 37°C for 1 h in a shaker at 50 rpm (60 rpm). Then, wash the PVDF membrane three times with TBS buffer (TBST solution) containing 0.05% Tween-20, 5 min each time. Cut the PVDF membrane according to the protein marker to obtain the desired protein band.

[0312] 4) Primary antibody incubation: Dilute the antibody using Western blotting buffer according to the antibody dilution ratio recommended in the antibody instructions to obtain a primary antibody solution. Immerse the band in the corresponding primary antibody solution and incubate overnight at 4 °C by rotation. After the primary antibody incubation step, recover the primary antibody solution and wash the band three times with TBST solution for 5 min each time.

[0313] 5) Secondary antibody incubation: Dilute the antibody using Western blotting buffer according to the antibody dilution ratio recommended in the antibody instructions to obtain the secondary antibody solution. Immerse the band in the corresponding secondary antibody solution and incubate at 37°C for 1 h in a shaker at 60 rpm. Rinse the band 5 times with TBST solution for 5 min each time.

[0314] 6) Mix equal volumes of solutions A and B according to the ECL chemiluminescence solution instructions and vortex to mix thoroughly. Then immerse the strip in the mixture for 1 min, and immediately perform chemiluminescence imaging using a Tanon 5200. Analyze the strip grayscale values ​​using ImageJ.

[0315] See the experimental results. Figures 2 to 4 Pharmacological studies showed that the compounds of this invention exhibited good inhibitory effects on the synthesis of type I collagen and α-smooth muscle actin, markers of hepatic stellate cell activation, in vitro. Specifically, compounds D11 and D13 showed anti-type I collagen and α-smooth muscle actin synthesis activities close to those of the positive control calcipotriol. Compound D13, in particular, demonstrated the best inhibitory ability on HSC activation, suggesting its strong potential for in vitro anti-hepatic fibrosis.

[0316] Example 37: Establishment of an animal model of liver fibrosis and evaluation of the in vivo efficacy of the compounds of this invention.

[0317]

Experimental Methods

[0318] Specimen processing Mouse liver tissue was harvested, cut into approximately 4mm × 4mm cubes, and fixed in 4% paraformaldehyde solution for 24 hours. After fixation, the tissues were routinely dehydrated, embedded in paraffin, and serially sectioned to a thickness of 5 μm. Hematoxylin-eosin (HE) staining and Masson's trichrome staining were performed to observe pathological changes and collagen fiber deposition in the liver tissue. Whole blood samples were collected, and serum was separated by centrifugation at 12,000 rpm for 10 minutes at 4°C. Serum calcium levels were measured using a commercial kit manufactured by Rayto (Shenzhen, China).

[0319]

Experimental Results

[0320] It should be understood that the above embodiments are exemplary and are not intended to encompass all possible implementations included in the claims. Various modifications and changes can be made to the above embodiments without departing from the scope of this disclosure. Similarly, the various technical features of the above embodiments can be arbitrarily combined to form other embodiments of the present invention that may not be explicitly described. Therefore, the above embodiments only illustrate several implementations of the present invention and do not limit the scope of protection of this patent.

Claims

1. A compound of general formula I or a stereoisomer thereof, solvate, hydrate, prodrug, stable isotopic derivative thereof, or pharmaceutically acceptable salt thereof: ； in: X is selected from , , and ; R1 is selected from H, D, hydroxyl, halogen, nitro, cyano, amino, mercapto, amide, carboxyl, -C(O)O-alkyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the amino, mercapto, amide, carboxyl, -C(O)O-alkyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted by one or more groups selected from H, D, hydroxyl, halogen, nitro, cyano, amino, mercapto, and aryl; R2 and R3 are each independently selected from H, D, hydroxyl, halogen, nitro, cyano, amino, mercapto, amide, carboxyl, -C(O)O-alkyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups, wherein the amino, mercapto, amide, carboxyl, -C(O)O-alkyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted by one or more groups selected from H, D, hydroxyl, halogen, nitro, cyano, amino, mercapto, and aryl groups; R4 and R5 are each independently selected from H, D, hydroxyl, halogen, nitro, cyano, amino, mercapto, amide, carboxyl, -C(O)O-alkyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups, wherein the amino, mercapto, amide, carboxyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted by one or more groups selected from H, D, hydroxyl, halogen, nitro, cyano, amino, mercapto, and aryl groups; R6 is selected from H, D, hydroxyl, halogen, nitro, cyano, amino, mercapto, carboxyl, -C(O)O-alkyl, and amide, wherein the amino, mercapto, carboxyl, -C(O)O-alkyl, and amide groups are optionally substituted by one or more R7 groups; Each time R7 appears, it is independently selected from H, D, hydroxyl, halogen, nitro, cyano, amino, mercapto, amide, carboxyl, -C(O)O-alkyl, alkyl, alkenyl, and alkynyl, wherein the amino, mercapto, amide, carboxyl, -C(O)O-alkyl, alkyl, alkenyl, and alkynyl groups are optionally substituted by one or more R8 groups. Alternatively, two R7s and the atoms attached thereto form a heteroaryl and a heterocyclic group, which are optionally substituted by one or more R8s; Each time R8 appears, it is independently selected from H, D, hydroxyl, halogen, nitro, cyano, amino, mercapto, amide, carboxyl, -C(O)O-alkyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the amino, mercapto, amide, carboxyl, -C(O)O-alkyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl are optionally substituted by one or more R9; Each time R9 appears, it is independently selected from H, D, hydroxyl, halogen, nitro, cyano, amino, mercapto, amide, carboxyl, -C(O)O-alkyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the amino, mercapto, amide, carboxyl, -C(O)O-alkyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted by one or more groups selected from H, D, hydroxyl, halogen, nitro, cyano, amino, mercapto, amide, carboxyl, -C(O)O-alkyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups.

2. The compound of general formula I according to claim 1, or its stereoisomers, solvates, hydrates, prodrugs, stable isotopic derivatives, and pharmaceutically acceptable salts, characterized in that, The compound has the structure of Formula II: ； in: R1 is selected from alkyl groups, which are optionally substituted by one or more groups selected from H, D, hydroxyl, halogen, nitro, cyano, amino, mercapto, and aryl. Preferably, R1 is selected from C 1-6 Alkyl, the C 1-6 Alkyl groups are optionally separated by one or more H and C. 6-10 Aryl group substitution; More preferably, R1 is selected from methyl, ethyl, propyl and butyl, wherein the methyl group is optionally substituted with one or more groups selected from H and phenyl; Most preferably, R1 is selected from methyl, ethyl, propyl, butyl, and... .

3. The compound of general formula I according to claim 1 or 2, or its stereoisomers, solvates, hydrates, prodrugs, stable isotopic derivatives, and pharmaceutically acceptable salts, characterized in that, The compound has the structure of Formula III: ； in: R2 and R3 are each independently selected from alkyl and alkenyl groups, which are optionally substituted by one or more groups selected from H, D, hydroxyl, halogen, nitro, cyano, amino, mercapto, and aryl. Preferably, R2 and R3 are each independently selected from C 1-6 Alkyl and C 2-6 alkenyl, the C 1-6 Alkyl and C 2-6 Alkenyl groups are optionally separated by one or more groups selected from H and C. 6-10 Aryl group substitution; More preferably, R2 and R3 are each independently selected from methyl, ethyl, propyl, butyl and allyl, wherein the methyl group is optionally substituted by one or more groups selected from H and phenyl; Most preferably, R2 and R3 are each independently selected from methyl, ethyl, propyl, butyl, allyl, and .

4. The compound of general formula I according to any one of claims 1-3, or its stereoisomers, solvates, hydrates, prodrugs, stable isotopic derivatives, and pharmaceutically acceptable salts thereof, characterized in that, The compound has the structure of formula IV: ； in: R4 and R5 are each independently selected from alkyl groups, which are optionally substituted by one or more groups selected from H, D, hydroxyl, halogen, nitro, cyano, amino, mercapto, and aryl. Preferably, R4 and R5 are each independently selected from C. 1-6 alkyl; More preferably, R4 and R5 are each independently selected from ethyl, propyl and butyl.

5. The compound of general formula I according to any one of claims 1-4, or its stereoisomers, solvates, hydrates, prodrugs, stable isotopic derivatives, and pharmaceutically acceptable salts thereof, characterized in that, The compound has the structure of formula V: ； in: R6 is selected from -C(O)O-alkyl and amide groups, wherein the amide group is optionally substituted by one or more R7 groups; Preferably, R6 is selected from -C(O)OC 1-6 Alkyl and amide groups, wherein the amide group is optionally substituted with one or more R7 groups; More preferably, R6 is selected from -C(O)O-CH3 and an amide group, wherein the amide group is optionally substituted by one or more R7 groups; Each time R7 appears, it is independently selected from H and alkyl groups, and the alkyl group is optionally substituted by one or more R8 groups; Preferably, each time R7 appears, it is independently selected from H and C. 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with one or more R8 groups; More preferably, each of the R7s is independently selected from H, methyl, ethyl, isopropyl, and sec-butyl, wherein the methyl and ethyl groups are optionally substituted by one or more R8s; Alternatively, two R7s and the atoms attached to them can form a heterocyclic group, which may optionally be substituted by one or more R8s; Preferably, the two R7s and the atoms attached thereto form a 3-10 membered heterocyclic group, which is optionally substituted by one or more R8s; More preferably, the two R7s and the atoms attached thereto form a 3-7 membered heterocyclic group, the 3-7 membered heterocyclic group containing 1-4 heteroatoms selected from N, O and S, the 3-7 membered heterocyclic group being optionally substituted by one or more R8s; Most preferably, the two R7s and the atoms attached thereto form a nitrogen-containing heterocyclic butyl, tetrahydropyrrole, piperidinyl, and morpholinyl, wherein the piperidinyl is optionally substituted by one or more R8s; Each time R8 appears, it is independently selected from H, alkyl, aryl, and alkoxy, and the alkyl group is optionally substituted by one or more R9s; Preferably, each time R8 appears, it is independently selected from H and C. 1-6 Alkyl, C 6-10 Aryl and C 1-6 Alkoxy, the C 1-6 The alkyl group is optionally substituted with one or more R9s; More preferably, each time R8 appears, it is independently selected from H and C. 1-3 Alkyl, C 6-10 Aryl and C 1-3 Alkoxy, the C 1-3 The alkyl group is optionally substituted with one or more R9s; Most preferably, each of the R8s is independently selected from H, methyl, phenyl, and methoxy, and the methyl group is optionally substituted by one or more R9s; Each time R9 appears, it is independently selected from H and aryl, wherein the aryl group is optionally substituted by one or more H, halogen and alkoxy groups; Preferably, each time R9 appears, it is independently selected from H and C. 6-10 Aryl, the C 6-10 The aryl group is optionally reacted with one or more H, halogens and C. 1-6 Alkyl substitution; More preferably, each time R9 appears, it is independently selected from H and C. 6-10 Aryl, the C 6-10 The aryl group is optionally reacted with one or more H, halogens and C. 1-3 Alkyl substitution; Most preferably, each of the R9s is independently selected from H and phenyl, wherein the phenyl is optionally substituted by one or more H, F and methoxy groups.

6. The compound of general formula I according to any one of claims 1-5, or its stereoisomers, solvates, hydrates, prodrugs, stable isotopic derivatives, and pharmaceutically acceptable salts thereof, characterized in that, The compound has the structure of formula VI: ； Wherein, R7 is as described in any one of claims 1-5.

7. The compound of general formula I according to any one of claims 1-6, or its stereoisomers, solvates, hydrates, prodrugs, stable isotopic derivatives, and pharmaceutically acceptable salts thereof, characterized in that, Each time R7 appears, it is independently selected from H, methyl, ethyl, isopropyl, sec-butyl, ... and ; Or two R7 atoms and the atoms attached to them form , , , , , , , and .

8. A compound or its stereoisomers, solvates, hydrates, prodrugs, stable isotopic derivatives, and pharmaceutically acceptable salts, characterized in that, The compound is any one of the following: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ； Preferably, the compound is any one of the following: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 9. A pharmaceutical composition comprising a therapeutically effective amount of the compound or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts according to any one of claims 1-8, and one or more pharmaceutically acceptable carriers, diluents or excipients.

10. The use of the compound or stereoisomer thereof, solvate, hydrate, prodrug, stable isotope derivative and pharmaceutically acceptable salt, or the pharmaceutical composition according to any one of claims 1-8 in the preparation of a medicament for the treatment and / or prevention of liver fibrosis.

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