Falcarine phthalide derivative, preparation thereof and application of Falcarine phthalide derivative in preparation of medicine for preventing and / or treating bone diseases

Abstract

The invention provides a Falcarinphthalide derivative, preparation thereof and application of the Falcarinphthalide derivative in preparation of medicines for preventing and / or treating bone diseases. The structural general formula of the Falcarinphthalide derivative is as shown in formula I in the specification. Experimental results show that the Falcarinphthalide derivative can significantly inhibit osteoclast differentiation, and is expected to be used for preparing novel drugs for preventing and / or treating osteoporosis, osteoporotic fracture, osteolysis, periprosthetic osteolysis, tumor bone metastasis, inflammatory bone loss, periodontitis inflammatory bone resorption and other bone diseases. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of medicine, and particularly to falkaline phthalide derivatives, their preparation and their application in the preparation of drugs for preventing and / or treating bone diseases. Background Art

[0002] The over-activation of osteoclasts can lead to the occurrence of a series of related bone diseases, including osteoporosis, osteoporotic fractures, osteolysis, periprosthetic osteolysis, tumor bone metastasis, inflammatory bone loss, and inflammatory bone resorption in periodontitis. The maintenance of normal bone metabolism depends on the balance between osteoblast-mediated bone formation and osteoclast-mediated bone resorption. When osteoclasts are overactive, this balance is disrupted, leading to the occurrence of bone metabolism imbalance-related diseases such as osteoporosis, osteoporotic fractures, osteolysis, periprosthetic osteolysis, tumor bone metastasis, inflammatory bone loss, and inflammatory bone resorption in periodontitis. These diseases are closely related to the over-activity of osteoclast function.

[0003] Osteoporosis is a systemic bone disease characterized by decreased bone mass and deterioration of bone microstructure, resulting in increased bone fragility and a predisposition to fracture. Its pathological cause is decreased bone formation and increased bone resorption, leading to an imbalance in bone metabolism. Osteoporotic fractures are the most serious complication of osteoporosis. Although the initiation and initial stages of osteoporotic fractures are similar to those of non-osteoporotic fractures, after eight weeks, osteoclast activity in osteoporotic fractures remains high, with robust bone resorption, insufficient collagen fiber formation, relatively low mineralization, and delayed new bone formation and callus maturation. Osteolysis is a bone disease characterized by the progressive dissolution, resorption, and loss of affected bone, as well as excessive lymphatic vessel formation within the bone tissue. Studies have shown that increased osteoclast number or activity is the primary cause of osteolysis. Osteolysis caused by wear particles around prostheses and the resulting aseptic loosening have become the most common long-term complications after hip and knee replacement surgery. During the development and progression of these complications, debris activates macrophages, leading to their aggregation and subsequent release of osteolytic factors such as TNF-α, IL-1, and IL-6. This increase in these factors leads to an increase in RANK, which in turn increases RANK and RANKL activation, resulting in abnormal osteoclast recruitment and activation, and a significant upregulation of bone resorption, leading to osteolysis. Periprosthetic osteolysis can cause micromotion of the prosthesis, further increasing wear and loosening. Tumor bone metastasis refers to the metastasis of malignant tumor cells to bone through hematogenous dissemination and localized growth, causing bone destruction. When tumor cells metastasize to bone, they disrupt the metabolic balance among bone cells, ultimately leading to overactivation of osteoclasts and enhanced bone resorption. This overactivation also releases growth factors, some of which can induce continued tumor growth within the bone. Inflammatory bone loss is primarily due to chronic, persistent inflammation, which activates osteoclasts and increases bone resorption, leading to bone loss. Numerous studies have demonstrated that HIV or active tuberculosis can increase serum levels of receptor activator of nuclear factor-κB ligand (RANKL) and the ratio of RANKL to osteoprotegerin (OPG), thereby activating osteoclast function, increasing bone resorption, and reducing bone mass. Periodontitis is a chronic inflammatory disease caused by oral bacteria. With persistent inflammation, periodontal tissues such as the gingiva, periodontal ligament, cementum, and alveolar bone are destroyed. During periodontal infection, bacterial endotoxins and various inflammatory factors induce osteoclast activation and proliferation, thereby inhibiting osteoblast activity, leading to an imbalance in alveolar bone metabolism and pathological alveolar bone resorption. Therefore, inhibiting excessive osteoclast differentiation and activity is an effective approach for treating bone diseases such as osteoporosis, osteoporotic fractures, osteolysis, periprosthetic osteolysis, tumor bone metastasis, inflammatory bone loss, and inflammatory bone resorption associated with periodontitis.

[0004] Currently, the main drugs for inhibiting osteoclast bone resorption mainly include bisphosphonates, calcitonins, estrogens, selective estrogen receptor modulators, RANKL inhibitors, etc. Although these drugs can prevent and treat osteoporosis and other diseases related to excessive osteoclast activation to a certain extent, they also have problems such as uncertain efficacy, adverse side effects, and high prices. Therefore, it is of great significance to find drugs for the prevention and treatment of bone diseases with a new structure and mechanism, definite efficacy, low toxicity and side effects, and easy access.

[0005] Falcarinphthalide is a new type of phthalide first isolated from Angelica sinensis, with a completely new carbon skeleton structure. Summary of the Invention

[0006] The object of the present invention is to provide a class of falcarinphthalide derivatives, their preparation methods, and their applications in the preparation of drugs for preventing and / or treating bone diseases.

[0007] The falcarinphthalide derivatives provided by the present invention have a structural general formula as shown in Formula I:

[0008]

[0009] Formula I

[0010] In the above Formula I, R1 can be selected from any one of alkenyl, substituted or unsubstituted aromatic groups; wherein, at least one H on at least one carbon atom of the substituted aromatic group is substituted by at least one of deuterium, tritium, hydroxyl group, halogen, C1-C6 straight-chain or branched-chain alkyl group, C1-C6 alkoxy group, and alkenyl group.

[0011] The structural formula of the alkenyl is as follows:

[0012] Among them, R2 is hydrogen, C1-C 12 straight-chain or branched-chain alkyl group;

[0013] Specifically, R2 is C1-C 10 straight-chain or branched-chain alkyl group; more specifically, R2 is C1-C8 straight-chain or branched-chain alkyl group; preferably, it is at least one of methyl, propyl, and heptyl.

[0014] The aromatic group can be at least one of phenyl, thiophenyl, and furyl.

[0015] The falcarinphthalide derivatives shown in Formula I are selected from any one of the following compounds. Compound 1 is a representative falcarinphthalide compound, named Falcarinphthalide A(1):

[0016]

[0017] In formula I, R1 is an alkenyl ( R2 is a C1-C 12 linear or branched alkyl), and the compound shown in formula I is prepared by a method comprising the following steps:

[0018] 1) Under the catalysis of bis(triphenylphosphine)palladium chloride and tetramethylethylenediamine, reacting the compound shown in formula A with R3-ZnI (R3 is a C1-C 12 linear or branched alkyl) to obtain the compound shown in formula B;

[0019]

[0020] 2) The compound shown in formula B is deprotected from the hydroxyl group in the presence of tetrabutylammonium fluoride to obtain the compound shown in formula I, wherein R1 is an alkenyl ( R2 is a C1-C 12 linear or branched alkyl);

[0021] Or, under the catalysis of Me2Zn, Cat.1o, and PO(Ph)3, reacting the compound shown in formula I' with the compound shown in formula a, and then deprotecting the hydroxyl group under the catalysis of tetrabutylammonium fluoride to obtain the compound shown in formula I, wherein R1 is an alkenyl ( R2 is a C1-C 12 linear or branched alkyl),

[0022]

[0023] In formula a, R4 is a C1-C 12 linear or branched alkyl.

[0024] In formula I, R1 is vinyl, and the compound shown in formula I is prepared by a method comprising the following steps: Under the catalysis of Me2Zn, Cat.1o, and PO(Ph)3, reacting the compound shown in formula I' with the compound shown in formula b, and then deprotecting the hydroxyl group under the catalysis of tetrabutylammonium fluoride to obtain the compound shown in formula I, wherein R1 is vinyl,

[0025]

[0026] In formula I, R1 is any one of a substituted or unsubstituted aromatic group, and the compound shown in formula I is prepared by a method comprising the following steps:

[0027] Under the catalysis of Me2Zn, Cat.1o, and PO(Ph)3, reacting the compound shown in formula I' with the compound shown in formula c, and then deprotecting the hydroxyl group under the catalysis of tetrabutylammonium fluoride to obtain the compound shown in formula I, wherein R1 is any one of a substituted or unsubstituted aromatic group,

[0028]

[0029] In formula c, R5 is any one of substituted or unsubstituted aryl groups.

[0030] The compound represented by formula I' is prepared by a method comprising the following steps:

[0031] 1) In diphenyl ether, the compound represented by formula d reacts with ligustilide to obtain the compound represented by formula e;

[0032]

[0033] 2) The compound represented by formula e is deprotected by TMS under the catalysis of tetrabutylammonium fluoride, and then under the catalysis of 2,6-dimethylpyridine, tert-butyldimethylsilyl trifluoromethanesulfonate is added for reaction to protect the group, obtaining the compound represented by formula I'.

[0034] The use of the falcarindiol phthalide derivative represented by formula I and the compound represented by formula 1' or the derivative obtained by removing the protecting group on the hydroxyl group of the compound represented by formula 1' in the preparation of a drug for inhibiting osteoclast formation also belongs to the protection scope of the present invention.

[0035] The drug for inhibiting osteoclast formation is a drug for preventing and / or treating bone diseases.

[0036] The bone disease is a bone disease caused by excessive activation of osteoclasts.

[0037] The bone diseases include osteoporosis, osteoporotic fractures, osteolysis, periprosthetic osteolysis, tumor bone metastasis, inflammatory bone loss, and inflammatory bone resorption in periodontitis, etc.

[0038] The present invention also provides a drug for preventing and / or treating bone diseases.

[0039] The drug for preventing and / or treating bone diseases contains the falcarindiol phthalide derivative represented by formula I or the compound represented by formula I' or the derivative obtained by removing the protecting group on the hydroxyl group of the compound represented by formula I'; further, it also includes an optional pharmaceutically acceptable excipient or carrier.

[0040] The present invention also provides a pharmaceutical composition, which comprises at least one or more of the above-mentioned falcarindiol phthalide derivatives and / or the compound represented by formula I' and / or the derivative obtained by removing the protecting group on the hydroxyl group of the compound represented by formula I'.

[0041] The present invention also provides a group of compounds, and their structures are as follows:

[0042]

[0043] The compound can be used as an intermediate for synthesizing falcarinphthalide derivatives represented by Formula I, can also be used for preventing and / or treating bone diseases, and can also be used as a drug for preventing and / or treating bone diseases; more specifically, it can also be used as a pharmaceutical composition for preventing and / or treating bone diseases.

[0044] The compound of the present invention is a falcarinphthalide derivative, and a total synthesis method and route thereof are constructed for the representative component falcarinphthalide A (Falcarinphthalide A(1)). Based on the total synthesis strategy, 16 falcarinphthalide derivatives are synthesized. Through activity tests, it is found that the representative compounds 1-5, 9, 11-13, and 17 have a significant effect on inhibiting osteoclast differentiation and are expected to be used for preventing and / or treating related bone diseases caused by overactivation of osteoclasts. BRIEF DESCRIPTION OF THE DRAWINGS

[0045] The drawings are used to provide a further understanding of the present invention, and constitute a part of the specification. Together with the embodiments of the present invention, they are used to explain the present invention and do not constitute a limitation to the present invention. In the drawings:

[0046] Figure 1 It is the total synthesis route diagram of falcarinphthalide A (Falcarinphthalide A(1)) in the present invention.

[0047] Figure 2 It is the CCK-8 experimental result of the representative compound in Example 2 of the present invention (compared with the DMSO group: **P < 0.01, ****P < 0.0001).

[0048] Figure 3 It is the osteoclast differentiation inhibitory activity of the representative compound in Example 3 of the present invention, and the distribution area of TRAP-stained cells in each well (NC: negative control group; C: Control group; compared with the Control group: *P < 0.05, **P < 0.01, ****P < 0.0001).

[0049] Figure 4 It is the observation and photographing under the microscope of the inhibition of RANKL-induced osteoclast formation by the representative compound in Example 3 of the present invention at concentrations of 1 μM, 5 μM, and 10 μM (NC: negative control group; C: Control group). DETAILED DESCRIPTION OF THE INVENTION

[0050] The following is a description of the preferred embodiments of the present invention with reference to the drawings. It should be understood that the preferred embodiments described herein are only used to illustrate and explain the present invention and are not used to limit the present invention.

[0051] For those without specific technologies or conditions indicated in the examples, they shall be in accordance with the technologies or conditions described in the literature in this field or in accordance with the product specifications. For reagents or instruments without the manufacturer indicated, they are all conventional products that can be obtained through regular channels.

[0052] In the following examples, ligustilide was isolated from Angelica sinensis according to the method described in the literature (Organic Letters. 2018, 20, 884 - 887; Chemical Communications, 2019, 55, 6221–6224.), and its structural formula is:

[0053]

[0054] Compound 1c used in the following examples was prepared by the following method:

[0055]

[0056] Under nitrogen protection, trimethylsilylacetylene (TMSA, 13.2 mL, 97.0 mmol) was added to toluene (48.0 mL) with stirring, and then diethylzinc (Et2Zn, 97.0 mL, 1.0 M in n - hexane, 97.0 mmol) was slowly added dropwise to the mixed solution. The mixture was refluxed at 120 °C for 2 h. After cooling to room temperature, (S)-1,1'-bi-2-naphthol ((S)-BINOL, 2.78 g, 9.7 mmol), diethyl ether (Et2O, 400 mL), and titanium isopropoxide (Ti(O i Pr)4, 6.91 mL, 24.0 mmol) were added successively, and the reaction was stirred at room temperature for 2 h. Then acrolein (1a, 1.6 mL, 24.0 mmol) was added to the reaction solution, and the reaction was stirred at room temperature for 16 h. After the reaction was completed, the reaction was quenched with water (300 mL) at 0 °C, filtered through a Celite pad, the aqueous phase was extracted twice with diethyl ether (500 mL) and three times, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (PE:EA = 10:1, V / V) to obtain a yellow oily liquid compound 1b (2.60 mg, purity 90%, yield 62.0%, ee% = 96%).

[0057] Physical and chemical parameters of compound 1b:

[0058]

[0059] 11H NMR (400 MHz, CDCl3) δ 5.95 (ddd, J = 17.0, 10.2, 5.3 Hz, 1H), 5.46 (brd, J = 17.1 Hz, 1H), 5.21 (brd, J = 10.2 Hz, 1H), 4.86 (brd, J = 5.3 Hz, 1H), 0.18 (s, 9H);

[0060] 13 13C NMR (101 MHz, CDCl3) δ 136.7, 116.5, 104.1, 91.1, 63.4, -0.2;

[0061] HRMS (ESI): m / z calcd. for C8H 15 OSi [M+H] + : 155.0892, found: 155.0899.

[0062]

[0063] Under nitrogen protection, compound 1b (15.00 g, 97.2 mmol) was placed in a 100 mL two-necked round-bottom flask, dissolved in acetone (300.0 mL), and then silver nitrate (AgNO3, 3.30 g, 19.4 mmol) and N-bromosuccinimide (NBS, 24.20 g, 13.6 mmol) were added successively. The reaction mixture was stirred at room temperature for 4 h. After the reaction was completed, the reaction solution was cooled to 0 °C, quenched with 300 mL of water. The aqueous phase was extracted three times with ether (2 × 400 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (PE:EA = 8:1 - 5:1, V / V) to obtain a yellow oily liquid compound 1c (13.5 g, purity 90%, yield 78.0%).

[0064] Physical and chemical parameters of compound 1c:

[0065]

[0066] 1 1H NMR (400 MHz, CDCl3) δ H 5.95 (ddd, J = 17.0, 10.1, 5.4, Hz, 1H), 5.47 (brd, J = 17.1 Hz, 1H), 5.25 (brd, J = 10.1 Hz, 1H), 4.90 (brd, 5.3 Hz, 1H);

[0067] 13 13C NMR (101 MHz, CDCl3) δ C136.2, 117.0, 78.8, 64.0, 46.9;

[0068] HRMS(ESI): m / z calcd. for C5H6 79 BrO[M + H] + : 160.9602, found: 160.9597.

[0069] Example 1, Synthesis of Compound 1

[0070] Step c:

[0071]

[0072] Under nitrogen protection and at 0 °C, cuprous chloride (CuCl, 2.95 g, 29.8 mM) and trimethylsilylacetylene (TMSA, 10.70 g, 109 mM) were added to a solution of n-butylamine (n-BuNH2, 200 mL, 30% aqueous solution) in dichloromethane (DCM, 300 mL). Compound 1c (16.00 g, 99.4 mM) was dissolved in dichloromethane (100 mL), and then it was slowly (30 min) added dropwise to the reaction mixture. The mixture was stirred at room temperature for 3.5 h. After the reaction was completed, the reaction was quenched with 300 mL of saturated ammonium chloride solution, extracted with dichloromethane, washed with saturated sodium chloride, and dried over anhydrous sodium sulfate. The product was separated and purified by silica gel column chromatography to obtain a brown oily compound, namely Compound 1d (9.00 g, 80% purity, 40% yield).

[0073] Physical and chemical parameters of Compound 1d:

[0074]

[0075] 1 H NMR (400 MHz, CDCl3) δ H 5.93 (ddd, J = 17.0, 10.0, 5.4 Hz, 1H), 5.47 (brd, J = 17.0 Hz, 1H), 5.25 (brd, J = 10.2 Hz, 1H), 4.92 (brd, J = 5.3 Hz, 1H), 0.19 (s, 9H);

[0076] 13 C NMR (101 MHz, CDCl3) δ C 135.7, 117.3, 88.4, 87.0, 76.0, 71.1, 63.4, -0.5;

[0077] HRMS(ESI): m / z calcd. for C 10 H 15OSi[M+H] + : 179.0892, found: 179.0888.

[0078] Step d:

[0079]

[0080] At room temperature, ligustilide (2.40 g, 12.0 mmol) was dissolved in diphenyl ether (Ph2O, 40 mL), and compound 1d (2.80 g, 14.9 mmol) was added thereto. The reaction was carried out at 200 °C under nitrogen for 3 hours. Subsequently, the reaction solution was cooled to room temperature, and the product was directly separated and purified by silica gel column chromatography to obtain a yellow oily compound, which was compound 1e (1.30 g, 90% purity, 40% yield).

[0081] Physical and chemical parameters of compound 1e:

[0082]

[0083] 1 H NMR (400 MHz, CDCl3) δ H 7.87 (d, J = 8.0 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), 6.58 (t, J = 7.7 Hz, 1H), 6.01 (ddd, J = 17.1, 10.1, 5.9 Hz, 1H), 5.83 (brd, J = 5.5 Hz, 1H), 5.44 (brd, J = 17.1 Hz, 1H), 5.23 (brd, J = 10.3 Hz, 1H), 2.50 (m, 2H), 1.57 (m, 2H), 1.01 (t, J = 7.3 Hz, 3H), 0.33 (s, 9H);

[0084] 13 C NMR (101 MHz, CDCl3) δ C 166.2, 152.1, 145.2, 138.8, 138.1, 126.6, 125.5, 124.1, 116.1, 114.4, 113.7, 108.9, 98.9, 72.6, 28.2, 22.6, 13.9, 1.0;

[0085] HRMS (ESI): m / z calcd. for C 20 H 25 O3Si[M+H] + : 341.1573, found: 341.1572.

[0086] Step e

[0087]

[0088] Compound 1e (17.80 g, 52.3 mM) was dissolved in tetrahydrofuran (THF, 178 mL), and tetrabutylammonium fluoride (TBAF, 1.0 M in THF, 52.3 mL, 52.3 mM) was added thereto. The mixture was stirred at room temperature for 3 hours. Subsequently, the reaction solution was poured into 300 mL of water for quenching, extracted with ethyl acetate, washed with saturated sodium chloride, and dried over anhydrous sodium sulfate. The product was separated and purified by silica gel column chromatography to obtain a yellow oily compound, which was compound 1f (10.50 g, 92% purity, 69% yield).

[0089] Physical and chemical parameters of compound 5:

[0090]

[0091] 1 H NMR (600 MHz, CDCl3) δ H 7.88 (d, J = 8.0 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 6.55 (t, J = 7.9 Hz, 1H), 6.01 (ddd, J = 17.1, 10.4, 5.5 Hz, 1H), 5.85 (brd, J = 5.6 Hz, 1H), 5.43 (brd, J = 17.1 Hz, 1H), 5.22 (brd, J = 10.4 Hz, 1H), 3.84 (s, 1H), 2.48 (m, 2H), 1.57 (m, 2H), 1.00 (t, J = 7.4 Hz, 3H);

[0092] 13 C NMR (151 MHz, CDCl3) δ C 166.1, 152.6, 145.1, 139.2, 138.1, 126.9, 125.9, 124.3, 116.1, 114.6, 112.6, 90.0, 77.9, 72.1, 28.2, 22.5, 13.8;

[0093] HRMS (ESI): m / z calcd. for C 17 H 17 O3 [M + H] + : 268.1178, found: 269.1189.

[0094] Step f

[0095]

[0096] Compound 5 (10.50 g, 39.1 mmol) was dissolved in dichloromethane (DCM, 200 mL). 2,6-Lutidine (8.38 g, 78.2 mmol) and tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf, 14.60 g, 58.7 mmol) were added at -70 °C, and the mixture was stirred at -70 °C for 3 hours. Subsequently, the reaction mixture was quenched by pouring it into 300 mL of saturated ammonium chloride solution, extracted with diethyl ether, washed with saturated sodium chloride, and dried over anhydrous sodium sulfate. The product was separated and purified by silica gel column chromatography to obtain a yellow oily compound, which is compound 1g (12.50 g, 95% purity, 79% yield).

[0097] Physical and chemical parameters of compound 1g:

[0098]

[0099] 1 H NMR (400 MHz, CDCl3) δ H 7.88 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 6.56 (t, J = 7.9 Hz, 1H), 5.92 (ddd, J = 17.0, 10.3, 4.8 Hz, 1H), 5.82 (brd, J = 4.6 Hz, 1H), 5.40 (brd, J = 17.0 Hz, 1H), 5.09 (brd, J = 10.2 Hz, 1H), 3.84 (s, 1H), 2.49 (m, 2H), 1.57 (m, 2H), 1.00 (t, J = 7.26 Hz, 3H), 0.90 (s, 9H), 0.09 (s, 3H), 0.02 (s, 3H);

[0100] 13 C NMR (101 MHz, CDCl3) δ C 166.1, 154.2, 145.2, 139.1, 139.0, 127.3, 125.8, 124.0, 114.2, 114.2, 111.8, 89.6, 78.1, 72.5, 28.2, 25.8, 22.5, 18.2, 13.8, -4.9, -5.0; HRMS (ESI): m / z calcd. for C 23 H 31 O3Si [M + H] + : 383.2042, found: 383.2044.

[0101]

[0102] Under nitrogen protection, triphenylphosphine oxide (PO(Ph)3, 1.18 g, 4.2 mmol), 2,6-bis[[(R)-2-[hydroxy(diphenyl)methyl]-1-pyrrolidinyl]methyl]-4-methylphenol (Cat.1o, 1.60 g, 2.6 mM) and Compound 1g (6.00 g, 15.7 mmol) were dissolved in toluene (150 mL). Dimethylzinc (Me2Zn, 1.0 M, 24 mL, 24.0 mmol) was added dropwise to the reaction solution, and the mixture was stirred at room temperature for half an hour. Subsequently, the reaction solution was cooled to -10 °C, and (Z)-3-iodoacrolein (1m, 3.43 g, 18.8 mM) was added dropwise to the reaction solution. The mixture was stirred at -10 to 10 °C for 24 hours. The reaction solution was poured into 100 mL of saturated ammonium chloride solution for quenching. After extraction with ethyl acetate, washing with saturated sodium chloride, and drying over anhydrous sodium sulfate, the product was separated and purified by silica gel column chromatography to obtain a yellow oily compound, which was Compound 1h (7.00 g, 95% purity, 69% yield).

[0103] Physical and chemical parameters of Compound 1h:

[0104]

[0105] 1 H NMR (400 MHz, CDCl3) δ H 7.86 (d, J = 8.1 Hz, 1H), 7.72 (d, J = 8.1 Hz, 1H), 6.63 (brd, J = 7.6 Hz, 1H), 6.56 (t, J = 7.5 Hz, 1H), 6.48 (t, J = 7.8 Hz, 1H), 5.89 (ddd, J = 17.0, 10.3, 5.2 Hz, 1H), 5.76 (brd, J = 5.1 Hz, 1H), 5.53 (brd, J = 7.4 Hz, 1H), 5.40 (brd, J = 17.0 Hz, 1H), 5.10 (brd, J = 10.2 Hz, 1H), 2.48 (m, 2H), 1.57 (m, 2H), 1.00 (t, J = 7.3 Hz, 3H), 0.90 (s, 9H), 0.09 (s, 3H), 0.01 (s, 3H); 13 C NMR (101 MHz, CDCl3) δ C 166.2, 153.5, 145.2, 139.3, 139.1, 138.7, 127.3, 125.6, 124.0, 114.4, 114.3, 111.9, 98.8, 84.6, 80.1, 72.7, 66.4, 28.3, 25.8, 22.6, 18.3, 13.9, -4.7, -4.9;

[0106] HRMS(ESI): m / z calcd. for C 26 H 34 IO4Si[M + H] + : 565.1271, found: 565.1261.

[0107] Step h

[0108]

[0109] Dissolve compound 1h (13.50 g, 23.9 mmol) in dichloromethane (DCM, 300 mL). Add 2,6 - lutidine (5.12 g, 47.8 mmol) and tert - butyldimethylsilyl trifluoromethanesulfonate (TBSOTf, 8.90 g, 35.9 mmol) at - 70 °C and stir at - 70 °C for 2 h. Then pour the reaction mixture into 100 mL of saturated ammonium chloride solution for quenching. After extraction with dichloromethane, washing with saturated sodium chloride, and drying over anhydrous sodium sulfate, the product was separated and purified by silica gel column chromatography to obtain a colorless oily compound, which is compound 1i (13.5 g, 95% purity, 82% yield).

[0110] Physical and chemical parameters of compound 1i:

[0111]

[0112] 1 H NMR (400 MHz, CDCl3) δ H 7.87 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 6.47 - 6.53 (m, 3H), 5.93 (ddd, J = 17.0, 10.3, 5.1 Hz, 1H), 5.81 (brd, J = 5.0 Hz, 1H), 5.50 (brd, J = 5.4 Hz, 1H), 5.43 (brd, J = 16.9 Hz, 1H), 5.09 (brd, J = 10.2 Hz, 1H), 2.49 (m, 2H), 1.59 (m, 2H), 1.02 (t, J = 7.3 Hz, 3H), 0.97 (s, 9H), 0.93 (s, 9H), 0.23 (s, 3H), 0.21 (s, 3H), 0.12 (s, 3H), 0.10 (s, 3H);

[0113] 13 C NMR (101 MHz, CDCl3) δ C166.3, 153.5, 145.4, 140.5, 139.2, 138.6, 127.2, 125.4, 124.0, 114.1, 112.3, 99.8, 82.3, 79.0, 72.6, 67.6, 28.3, 25.8, 25.7, 22.6, 18.3, 18.1, 11.0, -4.6, -4.8, -4.9;

[0114] HRMS(ESI): m / z calcd. for C 32 H 48 IO4Si2 [M + H] + : 679.2136, found: 679.2132.

[0115] Step i

[0116]

[0117] Under nitrogen protection, compound 1i (9.50 g, 14.0 mmol), bis(triphenylphosphine)palladium(II) chloride (Pd(PPh3)2, 0.98 g, 1.40 mmol), and tetramethylethylenediamine (TMEDA, 3.25 g, 28.0 mM) were dissolved in tetrahydrofuran (THF, 95 mL). n-Heptylzinc iodide (1k, 1.0 M in THF) (28 mL, 28.0 mmol) was added dropwise to the reaction solution, and the mixture was stirred at room temperature for 16 hours. Subsequently, the reaction was quenched with 100 mL of saturated ammonium chloride, extracted with ethyl acetate, washed with saturated sodium chloride, and dried over anhydrous sodium sulfate. The product was purified by silica gel column chromatography to obtain a colorless oily compound, namely compound 1j (6.80 g, 80% purity, 60% yield).

[0118] Physical and chemical parameters of compound 1j:

[0119]

[0120] 1 H NMR (400 MHz, CDCl3) δ H7.87 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 6.47 - 6.53 (m, 3H), 5.93 (ddd, J = 17.0, 10.3, 5.1 Hz, 1H), 5.81 (brd, J = 5.0 Hz, 1H), 5.50 (brd, J = 5.4 Hz, 1H), 5.43 (brd, J = 16.9 Hz, 1H), 5.09 (brd, J = 10.2 Hz, 1H), 2.49 (m, 2H), 1.59 (m, 2H), 1.02 (t, J = 7.3 Hz, 3H), 0.97 (s, 9H), 0.93 (s, 9H), 0.23 (s, 3H), 0.21 (s, 3H), 0.12 (s, 3H), 0.10 (s, 3H);

[0121] 13 C NMR (101 MHz, CDCl3) δ C 166.3, 153.5, 145.4, 140.5, 139.2, 138.6, 127.2, 125.4, 124.0, 114.1, 112.3, 99.8, 82.3, 79.0, 72.6, 67.6, 28.3, 25.8, 25.7, 22.6, 18.3, 18.1, 11.0, -4.6, -4.8, -4.9;

[0122] HRMS (ESI): m / z calcd. for C 32 H 48 IO4Si2 [M + H] + : 679.2136, found: 679.2132.

[0123] Step j

[0124]

[0125] Dissolve compound 1j (6.80 g, 80% purity, 10.4 mmol) in tetrahydrofuran (THF, 60 mL), and add tetrabutylammonium fluoride (TBAF, 1.0 M in THF, 20.8 mL, 20.8 mmol) thereto. Stir at room temperature for 4 hours. Subsequently, pour the reaction solution into 50 mL of water for quenching, extract with ethyl acetate, wash with saturated sodium chloride, and dry over anhydrous sodium sulfate. Then, separate and purify the product by silica gel column chromatography to obtain a yellow oily compound. Further separate and purify it using a chiral preparative column (separation conditions: chromatographic column: Chiralpak IG 5 μm 30 * 250 mm; mobile phase: n-hexane:isopropanol = 80:20, flow rate 30 mL / min; temperature: 30 °C; wavelength: 254 nm) to obtain a yellow oily compound Falcarinphthalide A (1) (2.53 g, 98.8% purity, 57% yield), and simultaneously obtain by-product 2 (25 mg, 98% purity). Physical and chemical parameters of compound 1:

[0126]

[0127] 1 H NMR (600 MHz, CDCl3) δ H 7.86 (d, J = 8.0 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 6.43 (t, J = 7.7 Hz, 1H), 5.95 (ddd, J = 17.1, 10.4, 5.8 Hz, 1H), 5.70 (m, 1H), 5.68 (m, 2H), 5.48 (d, J = 7.2 Hz, 1H), 5.42 (brd, J = 17.1 Hz, 1H), 5.20 (brd, J = 10.3 Hz, 1H), 2.47 (m, 2H), 2.18 (m, 2H), 1.56 (m, 2H), 1.42 (m, 2H), 1.31–1.22 (m, 8H), 1.00 (t, J = 7.4 Hz, 3H), 0.84 (t, J = 6.8 Hz, 3H);

[0128] 13 C NMR (151 MHz, CDCl3) δ C 166.6, 151.7, 145.0, 138.9, 137.9, 134.5, 128.0, 126.4, 125.7, 124.1, 116.2, 114.8, 113.1, 102.0, 78.8, 72.3, 58.8, 31.8, 29.3, 29.2, 29.1, 28.3, 27.8, 22.6, 22.5, 14.0, 13.9;

[0129] HRMS(ESI): m / z calcd. for C 27 H 35 O4[M + H] + : 423.2535, found: 423.2534.

[0130]

[0131] Physicochemical parameters of Compound 2:

[0132]

[0133] 1 H NMR(600 MHz, CDCl3) δ H 7.87 (d, J = 8.0 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 6.45 (t, J = 7.7 Hz, 1H), 5.96 (ddd, J = 17.1, 10.4, 5.8 Hz, 1H), 5.73 (m, 1H), 5.69 (m, 2H), 5.50 (d, J = 7.2 Hz, 1H), 5.44 (d, J = 17.0 Hz, 1H), 5.21 (d, J = 10.3 Hz, 1H), 2.47 (m, 2H), 2.18 (m, 2H), 1.56 (m, 2H), 1.42 (m, 2H), 1.31–1.22 (m, 8H), 1.00 (t, J = 7.4 Hz, 3H), 0.86 (t, J = 6.8 Hz, 3H);

[0134] 13 C NMR(101 MHz, CDCl3) δ C 166.3, 151.8, 145.2, 138.9, 138.1, 134.6, 128.0, 126.6, 125.6, 124.2, 116.2, 114.5, 113.2, 102.0, 79.0, 72.4, 58.9, 31.8, 29.4, 29.2, 29.1, 28.3, 27.8, 22.6, 22.5, 14.0, 13.8;

[0135] HRMS(ESI): C 27 H 35 O4[M + H] + : 423.2535, found: 423.2539.

[0136] Synthesis of Compounds 3 - 4

[0137]

[0138] Following the synthetic step g of Compound 1, 3c (186 mg, 1.02 mmol) was used to replace 1m to complete the reaction. After column chromatography, Compound 3a (329 mg, 0.58 mmol, yield 56.8%) was obtained.

[0139]

[0140] Following the synthetic step h of Compound 1, 3a (329 mg, 0.58 mmol) was used to replace 1h to complete the reaction. After column chromatography, Compound 3b (322 mg, 0.47 mmol, yield 81.9%) was obtained.

[0141]

[0142] Following the synthetic steps i - j of Compound 1, 3b (322 mg, 0.58 mmol) was used to replace 1i to complete the reaction. After column chromatography, the crude product Compound 3 (102 mg, 0.16 mmol, yield 33%) was obtained. Finally, Compound 3 and the by - product 4 were obtained by HPLC preparation.

[0143] Physical and chemical parameters of Compound 3:

[0144]

[0145] 1 H NMR (400 MHz, CDCl3) δ H 7.87 (d, J = 8.0 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 6.47 (t, J = 7.7 Hz, 1H), 5.97 (m, 2H), 5.73 (m, 2H), 5.42 (d, J = 17.2 Hz, 1H), 5.20 (m, 2H), 2.47 (m, 2H), 2.11 (m, 2H), 1.56 (m, 2H), 1.42 (m, 2H), 1.28 (m, 8H), 1.00 (t, J = 7.4 Hz, 3H), 0.88 (t, J = 6.8 Hz, 3H);

[0146] 13 C NMR (101 MHz, CDCl3) δ C 166.4, 151.7, 145.1, 138.8, 138.1, 135.3, 128.0, 126.6, 125.6, 124.2, 116.2, 114.6, 113.2, 101.5, 79.9, 72.3, 63.7, 32.0, 31.8, 29.2, 29.1, 28.9, 28.3, 22.6, 22.6, 14.1, 13.9;

[0147] HRMS(ESI): m / z calcd. for C 27 H 35 O4 [M + H] + : 423.2535, found: 423.2537.

[0148]

[0149] Physicochemical parameters of Compound 4:

[0150]

[0151] 1 H NMR (400 MHz, CDCl3) δ H 7.87 (d, J = 8.0 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 6.46 (t, J = 7.7 Hz, 1H), 5.98 (m, 2H), 5.74 (m, 2H), 5.42 (d, J = 17.0 Hz, 1H), 5.20 (m, 2H), 2.48 (m, 2H), 2.11 (m, 2H), 1.56 (m, 2H), 1.42 (m, 2H), 1.28 (m, 8H), 1.00 (t, J = 7.4 Hz, 3H), 0.88 (t, J = 6.8 Hz, 3H);

[0152] 13 C NMR (101 MHz, CDCl3) δ C 166.3, 151.7, 145.1, 138.8, 138.1, 135.4, 128.0, 126.7, 125.6, 124.3, 116.2, 114.5, 113.2, 101.4, 79.9, 72.4, 63.7, 32.0, 31.8, 29.2, 29.1, 28.9, 28.3, 22.6, 22.6, 14.1, 13.9;

[0153] HRMS(ESI): m / z calcd. for C 27 H 35 O4 [M + H] + : 423.2535, found: 423.2523.

[0154] Synthesis of Compounds 6 - 7

[0155]

[0156] The reaction procedure was the same as that of Step g of Compound 1, and 1a (44 mg, 0.79 mmol) was used instead of 1m to complete the reaction. After Step e, the crude product 6 (84 mg, 0.26 mmol, yield 32.9%) was obtained. The derivative 6 and the by-product 7 were obtained by HPLC preparation.

[0157] Physical and chemical parameters of Compound 6:

[0158]

[0159] 1 H NMR (400 MHz, CDCl3) δ H 7.87 (d, J = 8.0 Hz, 1H), 7.67 (d, J = 7.9 Hz, 1H), 6.42 (t, J = 7.8 Hz, 1H), 6.09 (ddd, J = 17.1, 10.2, 5.5 Hz, 1H), 5.94 (ddd, J = 17.1, 10.4, 5.8 Hz, 1H), 5.68 (d, J = 5.8 Hz, 1H), 5.57 (d, J = 17.1 Hz, 1H), 5.40 (d, J = 17.1 Hz, 1H), 5.35 (d, J = 10.2 Hz, 1H), 5.22 (m, 2H), 2.47 (m, 2H), 1.55 (m, 2H), 1.00 (t, J = 7.4 Hz, 3H);

[0160] 13 C NMR (101 MHz, CDCl3) δ C 166.6, 151.8, 144.9, 138.8, 137.9, 136.1, 126.4, 125.8, 124.1, 117.3, 116.3, 115.0, 112.8, 100.8, 80.0, 72.2, 63.7, 28.3, 22.4, 13.9;

[0161] HRMS (ESI): m / z calcd. for C 20 H 21 O4 [M + H] + : 325.1440, found: 325.1446.

[0162]

[0163] Physical and chemical parameters of Compound 7:

[0164]

[0165] 1 H NMR (400 MHz, CDCl3) δ H7.88 (d, J = 8.0 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), 6.46 (t, J = 7.8 Hz, 1H), 6.10 (ddd, J = 17.1, 10.3, 5.5 Hz, 1H), 6.00 (ddd, J = 17.1, 10.2, 5.8 Hz, 1H), 5.77 (d, J = 5.8 Hz, 1H), 5.58 (d, J = 17.0 Hz, 1H), 5.43 (d, J = 17.0 Hz, 1H), 5.37 (d, J = 10.2 Hz, 1H), 5.24 (m, 2H), 2.49 (m, 2H), 1.55 (m, 2H), 1.00 (t, J = 7.4 Hz, 3H);

[0166] 13 C NMR (101 MHz, CDCl3) δ C 166.2, 151.7, 145.1, 138.9, 138.1, 136.2, 126.7, 125.8, 124.3, 117.4, 116.3, 114.6, 113.1, 100.5, 80.4, 72.4, 63.8, 28.3, 22.5, 13.8;

[0167] HRMS (ESI): m / z calcd. for C 20 H 21 O4 [M + H] + : 325.1440, found: 325.1459.

[0168] Synthesis of Compound 8 - 9

[0169]

[0170] The reaction procedure was the same as that of Step g of Compound 1. Replace 1m with benzaldehyde (PhCHO, 21.2 mg, 0.2 mmol). After Step e, the crude product 9 (20 mg, 0.053 mmol, yield 26.5%) was obtained. Compound 9 and by - product 8 were obtained by HPLC preparation.

[0171]

[0172] Physical and chemical parameters of Compound 8:

[0173]

[0174] 1 H NMR (400 MHz, CDCl3) δ H7.83 (d, J = 8.1 Hz, 1H), 7.65 (d, J = 8.1 Hz, 1H), 7.59 (d, J = 7.6 Hz, 2H), 7.40 (m, 3H), 6.31 (t, J = 7.8 Hz, 1H), 5.93 (ddd, J = 17.0, 10.3, 5.5 Hz, 1H), 5.81 (s, 1H), 5.70 (d, J = 5.8 Hz, 1H), 5.30 (d, J = 17.3 Hz, 1H), 5.15 (d, J = 10.3 Hz, 1H), 2.38 (m, 2H), 1.42 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H); 13 13C NMR (100 MHz, CDCl3) δ C 167.9, 153.3, 146.4, 141.3, 140.3, 139.4, 130.3, 130.2, 128.0, 127.9, 127.2, 125.6, 117.8, 116.2, 114.4, 103.2, 81.9, 73.8, 66.6, 29.7, 23.8, 15.2;

[0175] HRMS (ESI): m / z calcd. for C 24 H 23 O4 [M + H] + : 375.1596, found: 375.1589.

[0176] Physical and chemical parameters of compound 9

[0177]

[0178] 1 1H NMR (400 MHz, CDCl3) δ H 7.84 (d, J = 8.0 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 7.2 Hz, 2H), 7.39 (m, 3H), 6.23 (t, J = 7.8 Hz, 1H), 5.93 (ddd, J = 17.0, 10.3, 5.5 Hz, 1H), 5.80 (s, 1H), 5.70 (d, J = 5.8 Hz, 1H), 5.35 (d, J = 17.3 Hz, 1H), 5.17 (d, J = 10.3 Hz, 1H), 2.33 (m, 2H), 1.34 (m, 2H), 0.88 (t, J = 7.3 Hz, 3H); 13 13C NMR (101 MHz, CDCl3) δ C168.0,153.3,146.3,141.3,140.3,139.3,130.3,130.1,127.9,127.8,127.2,125.5,117.7,116.5,114.4,103.3,81.7,73.7,66.6,29.7,23.7,15.2;

[0179] HRMS(ESI):m / z calcd.for C 24 H 23 O4[M+H] + :375.1596,found:375.1588.

[0180] Synthesis of Compound 10-11

[0181]

[0182] The reaction procedure was the same as that of step g of Compound 1. Crotonaldehyde (62.4 mg, 0.79 mmol) was used instead of 1m. After step e, crude product 11 (77 mg, 0.23 mmol, yield 29.1%) was obtained. Compound 11 and by-product 10 were obtained by HPLC preparation.

[0183]

[0184] Physical and chemical parameters of Compound 10:

[0185]

[0186] 1 H NMR(400MHz,CDCl3)δ H 7.84(d,J=8.0Hz,1H),7.66(d,J=8.0Hz,1H),6.42(t,J=7.8Hz,1H),5.93(m,2H),5.73(m,2H),5.41(dt,J=17.2,1.2Hz,1H),5.20(dt,J=10.2,1.1Hz,1H),5.17(d,J=6.4Hz,1H),2.47(m,2H),1.79(d,J=6.4Hz,3H),1.56(m,2H),1.00(t,J=7.3Hz,3H);

[0187] 13 C NMR(101MHz,CDCl3)δ C166.6, 151.7, 145.0, 138.8, 138.0, 129.9, 129.4, 126.5, 125.7, 124.1, 116.3, 114.8, 113.1, 101.6, 79.8, 72.3, 63.5, 28.3, 22.5, 17.6, 13.8;

[0188] HRMS(ESI): m / z calcd. for C 21 H 23 O4 [M + H] + : 339.1596, found: 339.1609.

[0189] Physicochemical parameters of compound 11:

[0190]

[0191] 1 H NMR (400 MHz, CDCl3) δ H 7.85 (d, J = 8.0 Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H), 6.43 (t, J = 7.8 Hz, 1H), 5.96 (m, 2H), 5.75 (m, 1H), 5.69 (d, J = 5.8 Hz, 1H), 5.41 (d, J = 17.2, 1H), 5.20 (d, J = 10.2, 1H), 5.15 (d, J = 6.5 Hz, 1H), 2.47 (m, 2H), 1.79 (d, J = 6.4 Hz, 3H), 1.56 (m, 2H), 1.00 (t, J = 7.3 Hz, 3H);

[0192] 13 C NMR (101 MHz, CDCl3) δ C 166.6, 151.7, 145.0, 138.8, 138.0, 129.8, 129.4, 126.4, 125.7, 124.1, 116.2, 114.9, 113.0, 101.6, 79.6, 72.2, 63.5, 28.3, 22.5, 17.5, 13.8;

[0193] HRMS(ESI): m / z calcd. for C 21 H 23 O4 [M + H] + : 339.1596, found: 339.1595.

[0194] Synthesis of compounds 12 - 13

[0195]

[0196] The reaction procedure was the same as that of Step g of Compound 1. Furfural (69 mg, 0.72 mmol) was used to replace 1m. After Step e, crude product 13 (109 mg, 0.30 mmol, yield 41.7%) was obtained. Compound 13 and by-product 12 were obtained by HPLC preparation.

[0197]

[0198] Physicochemical parameters of Compound 12:

[0199]

[0200] 1 H NMR (400 MHz, CDCl3) δ H 7.87 (d, J = 8.0 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.48 (m, 1H), 6.53 (d, J = 3.2 Hz, 1H), 6.43 (m, 2H), 5.96 (ddd, J = 17.0, 10.3, 5.9 Hz, 1H), 5.82 (s, 1H), 5.75 (d, J = 5.8 Hz, 1H), 5.38 (d, J = 17.1, 1H), 5.20 (d, J = 10.2, 1H), 2.45 (m, 2H), 1.53 (m, 2H), 0.97 (t, J = 7.3 Hz, 3H);

[0201] 13 C NMR (101 MHz, CDCl3) δ C 166.4, 152.0, 151.9, 145.0, 143.3, 139.0, 138.0, 126.6, 126.0, 124.3, 116.4, 114.9, 112.7, 110.7, 108.2, 99.0, 79.9, 72.4, 58.8, 28.4, 22.4, 13.9;

[0202] HRMS (ESI): m / z calcd. for C 22 H 21 O5 [M + H] + : 365.1389, found: 365.1385.

[0203] Physicochemical parameters of Compound 13:

[0204]

[0205] 1 H NMR (400 MHz, CDCl3) δH 7.86 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.46 (m, 1H), 6.51 (d, J = 3.2 Hz, 1H), 6.40 (m, 2H), 5.93 (ddd, J = 17.0, 10.3, 5.9 Hz, 1H), 5.80 (s, 1H), 5.68 (d, J = 5.8 Hz, 1H), 5.38 (d, J = 17.1, 1H), 5.18 (d, J = 10.4, 1H), 2.43 (m, 2H), 1.49 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H);

[0206] 13 13C NMR (101 MHz, CDCl3) δ C 166.7, 152.0, 151.9, 144.8, 143.1, 138.9, 137.8, 126.4, 126.0, 124.0, 116.3, 115.2, 112.5, 110.7, 108.1, 99.2, 79.6, 72.2, 58.7, 28.4, 22.4, 13.9;

[0207] HRMS (ESI): m / z calcd. for C 22 H 21 O5 [M + H] + : 365.1389, found: 365.1387.

[0208] Synthesis of Compound 14 - 15

[0209]

[0210] The reaction procedure was the same as that of Step g of Compound 1. Replace 1m with formylthiophene (88 mg, 0.79 mmol). After Step e, the crude product 15 (125 mg, 0.33 mmol, yield 41.7%) was obtained. Compound 15 and by - product 14 were obtained by HPLC preparation.

[0211]

[0212] Physical and chemical parameters of Compound 14:

[0213]

[0214] 1 1H NMR (400 MHz, Acetone - d6) δ H7.87 (m, 2H), 7.49 (d, J = 5.1 Hz, 1H), 7.27 (m, 1H), 7.04 (m, 1H), 6.56 (t, J = 7.8 Hz, 1H), 6.20 (s, 1H), 6.01 (ddd, J = 17.0, 10.3, 5.6 Hz, 1H), 5.85 (d, J = 5.2 Hz, 1H), 5.42 (d, J = 17.0, 1H), 5.09 (d, J = 10.4, 1H), 2.39 (m, 2H), 1.49 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H);

[0215] 13 C NMR (101 MHz, Acetone-d6) δ C 166.6, 155.3, 146.6, 140.9, 139.8, 128.7, 128.0, 127.1, 126.5, 126.4, 125.2, 115.5, 114.6, 114.4, 103.7, 80.2, 72.7, 61.4, 29.4, 23.6, 14.6;

[0216] HRMS (ESI): m / z calcd. for C 22 H 21 O4S [M + H] + : 381.1161, found: 381.1167. Physical and chemical parameters of Compound 15:

[0217]

[0218] 1 H NMR (400 MHz, Acetone-d6) δ H 7.88 (m, 2H), 7.50 (d, J = 5.1 Hz, 1H), 7.27 (m, 1H), 7.05 (m, 1H), 6.56 (t, J = 7.8 Hz, 1H), 6.20 (s, 1H), 6.02 (ddd, J = 17.0, 10.3, 5.6 Hz, 1H), 5.86 (d, J = 5.2 Hz, 1H), 5.43 (d, J = 17.0, 1H), 5.09 (d, J = 10.4, 1H), 2.39 (m, 2H), 1.49 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H);

[0219] 13 C NMR (101 MHz, Acetone-d6) δ C166.6, 155.2, 146.6, 146.6, 140.9, 139.8, 128.7, 128.0, 127.1, 126.5, 126.5, 125.2, 115.5, 114.6, 114.4, 103.7, 80.3, 72.7, 61.4, 29.4, 23.6, 14.6;

[0220] HRMS(ESI): m / z calcd. for C 22 H 21 O4S[M + H] + : 381.1161, found: 381.1168.

[0221] Synthesis of Compound 16 - 17

[0222]

[0223] The reaction procedure was the same as that of steps i - j of Compound 1. Zinc propyl iodide was used to replace 1k to complete the reaction, and the crude product 17 (105 mg, 0.29 mmol, yield 70.7%) was obtained. Compound 17 and by - product 16 were obtained by HPLC preparation.

[0224]

[0225] Physical and chemical parameters of Compound 16:

[0226]

[0227] 1 H NMR(600 MHz, CDCl3) δ H 7.87 (d, J = 8.0 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 6.46 (t, J = 7.8 Hz, 1H), 6.00 (ddd, J = 17.1, 10.3, 5.5 Hz, 1H), 5.77 (d, J = 5.8 Hz, 1H), 5.70 (m, 2H), 5.50 (d, J = 7.4 Hz, 1H), 5.44 (d, J = 17.0 Hz, 1H), 5.22 (d, J = 10.2 Hz, 1H), 2.48 (m, 2H), 2.18 (m, 2H), 1.56 (m, 2H), 1.47 (m, 2H), 1.00 (t, J = 7.4 Hz, 3H), 0.95 (t, J = 7.4 Hz, 3H);

[0228] 13 C NMR(151 MHz, CDCl3) δ C166.3, 151.7, 145.2, 138.9, 138.1, 134.4, 134.4, 128.2, 126.7, 125.6, 124.3, 116.2, 114.5, 114.4, 113.2, 101.8, 79.1, 72.4, 58.9, 29.8, 28.3, 22.6, 22.5, 13.9, 13.7;

[0229] HRMS(ESI): m / z calcd. for C 23 H 27 O4 [M + H] + : 367.1909, found: 367.1914.

[0230] Physicochemical parameters of Compound 17:

[0231]

[0232] 1 H NMR(400 MHz, CDCl3) δ H 7.84 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 6.42 (t, J = 7.8 Hz, 1H), 5.94 (ddd, J = 17.1, 10.3, 5.5 Hz, 1H), 5.68 (m, 3H), 5.48 (d, J = 6.2 Hz, 1H), 5.41 (d, J = 17.0 Hz, 1H), 5.20 (d, J = 10.4 Hz, 1H), 2.47 (m, 2H), 2.16 (m, 2H), 1.56 (m, 2H), 1.45 (m, 2H), 1.00 (t, J = 7.4 Hz, 3H), 0.93 (t, J = 7.4 Hz, 3H);

[0233] 13 C NMR(101 MHz, CDCl3) δ C 166.5, 151.8, 145.1, 138.8, 138.0, 134.1, 128.2, 126.5, 125.7, 124.1, 116.2, 114.7, 113.1, 102.0, 78.9, 72.6, 58.8, 29.7, 28.3, 22.5, 22.5, 13.9, 13.7;

[0234] HRMS(ESI): m / z calcd. for C 23 H 27 O4 [M + H] + : 367.1909, found: 367.1903.

[0235] Example 2. Activity Test of Representative Compounds

[0236] CCK-8 Cytotoxicity Assay

[0237] The cytotoxicity of representative compounds 1-5, 9, 11-13, and 17 against RAW264.7 cells was detected by the CCK-8 method. RAW264.7 cells (ATCC, USA) were cultured in α-MEM medium supplemented with 10% fetal bovine serum (FBS), penicillin (100 U / mL), and streptomycin (100 μg / mL) in a 37 °C, 5% CO2 cell incubator and passaged every three days. The cells used for the experiment were at passages 8-15. The RAW264.7 cells were seeded in a 96-well plate at a density of 3000 cells / well. After 24 hours of attachment, the test compounds (representative compounds 1-5, 9, 11-13, 17) were added. After incubation for 48 hours, the medium containing 10% CCK-8 was added, and the cells were incubated for 1 h. The OD value was measured at a wavelength of 450 nm using a microplate reader. The test results are shown in the following figure ( Figure 2 ). The results showed that compound 2 had no cytotoxicity at 5 μM, and the other compounds had no cytotoxicity at 10 μM.

[0238] Example 3. Experiment on Inhibiting Osteoclast Formation and TRAP Staining

[0239] Setting of Experimental Groups

[0240] (1) Normal control group (Normal, NC): Growth medium was added throughout the experiment.

[0241] (2) Induction control group (Control, C): Osteoclast induction medium was added during the differentiation and bone resorption stages.

[0242] (3) Drug treatment group: After culturing in the differentiation stage and induction medium for 4 days, the induction culture with the final concentration of the representative compound was added (the final concentrations of compounds 1-5, 9, 11-13, 17 were determined according to the CCK-8 experiment).

[0243] 1) When RAW264.7 cells (ATCC, Manassas, VA, USA) reached 80% confluence in growth medium α-MEM (containing 10% FBS, 1% P / S), they were seeded in a common 96-well plate at a density of 3000 cells / well, with 3 replicates for each concentration.

[0244] 2) After 24 hours of seeding, the medium was discarded. The induction group was added with osteoclast induction medium α-MEM (containing 100 ng / mL sRANKL, 30 ng / mL M-CSF, 10% FBS, 1% P / S) for osteoclast differentiation induction, and the corresponding drug solution was added simultaneously, marked as day 0 of osteoclast induction.

[0245] 3) On the 4th day of osteoclast induction, discard the culture medium, add 4% paraformaldehyde for fixation for 15 minutes, wash three times with distilled water, add the prepared Trap staining solution, incubate at 37 °C for 1 hour, wash three times with distilled water, and take pictures with an optical microscope.

[0246] 4) Data analysis: Quantify the cell area of Trap-positive multinucleated (nucleus ≥ 3) cells in different wells of different experimental groups through ImageJ ProPlus software, and use Prism Graphpad for statistical analysis and graphing.

[0247] Osteoclast activity test results

[0248] In this study, a RANKL-induced osteoclast differentiation induction model of RAW264.7 cells was used to test the activities of representative compounds 1-5, 9, 11-13, and 17 in inhibiting RANKL-induced osteoclast differentiation. RAW264.7( TIB-71) is a macrophage cell line of mice, derived from tumors induced by Abelson murine leukemia virus. RAW264.7 cells will differentiate into multinucleated osteoclasts after being induced by RANKL for about 4 days. Mature osteoclasts can adhere to the surface of the bone matrix to exert bone resorption activity and form bone resorption cavities. The effects of drugs on osteoclast differentiation were detected by co-culturing with compounds for 4 days while inducing osteoclast differentiation. The results showed that representative compounds 1-5, 9, 11-13, and 17 could significantly inhibit osteoclast differentiation, and the test results are shown in the following figure( Figure 3 、 4 ).

[0249] Obviously, those skilled in the art can make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if these modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalent technologies, the present invention is also intended to include these modifications and variations.

Claims

1. The Falcarindiol phthalide derivative represented by Formula I: In Formula I, R1 is selected from any one of alkenyl, substituted or unsubstituted aryl; Among them, In the substituted aryl, H on at least one carbon atom is substituted by at least one of deuterium, tritium, hydroxyl, halogen, C1-C6 straight-chain or branched alkyl, C1-C6 alkoxy, alkenyl.

2. The flupirtine derivative according to claim 1, characterized in that, The structural formula of the alkenyl is shown as follows: Among them, R2 is hydrogen, C1-C 12 linear or branched alkyl group.

3. The flupirtine derivative according to claim 1, wherein The aryl is at least one of phenyl, thienyl, furyl.

4. A method for preparing the compound shown in Formula I of claim 1, wherein, R1 is an alkenyl group, R2 is hydrogen, C1-C 12 a straight-chain or branched-chain alkyl group, It includes the following steps: 1) Under the catalysis of bis(triphenylphosphine)palladium chloride and tetramethylethylenediamine, the compound shown by formula A reacts with R3-ZnI (R3 is a C1-C 12 linear or branched alkyl) to obtain the compound shown by formula B; 2) The compound shown by formula B is deprotected from the hydroxyl group in the presence of tetrabutylammonium fluoride to obtain the compound shown by formula I, where R1 is an alkenyl, R2 is C1-C 12 a straight-chain or branched-chain alkyl group; Alternatively, in the presence of Me2Zn, Cat.1o, and PO(Ph)3, the compound represented by formula I’ reacts with the compound represented by formula a, and then the hydroxyl protecting group is removed under the catalysis of tetrabutylammonium fluoride to obtain the compound represented by formula I, wherein R1 is an alkenyl, R2 is a C1-C 12 linear or branched alkyl, In formula a, R4 is a C1-C 12 linear or branched alkyl group.

5. A method for preparing the compound shown in Formula I of claim 1, wherein, When R1 is vinyl, it includes the following steps: Under the catalysis of Me2Zn, Cat.1o, PO(Ph)3, the compound represented by Formula I’ reacts with the compound represented by Formula b, and then the hydroxyl protection is removed under the catalysis of tetrabutylammonium fluoride to obtain the compound represented by Formula I, where R1 is vinyl.

6. A method for preparing the compound represented by Formula I in claim 1, wherein, When R1 is any one of substituted or unsubstituted aryl, it includes the following steps: Under the catalysis of Me2Zn, Cat.1o, PO(Ph)3, the compound represented by Formula I’ reacts with the compound represented by Formula c, and then the hydroxyl protection is removed under the catalysis of tetrabutylammonium fluoride to obtain the compound represented by Formula I, where R1 is any one of substituted or unsubstituted aryl. In Formula c, R5 is any one of substituted or unsubstituted aryl.

7. The compound represented by Formula I’ in Claim 4 or the derivative obtained by removing the protecting group on the hydroxyl of the compound represented by Formula I’:

8. A group of compounds, whose structures are as follows:

9. The application of the Falcarindiol phthalide derivative described in any one of Claims 1-3, the compound represented by Formula I’ in Claim 4 or the derivative obtained by removing the protecting group on the hydroxyl of the compound represented by Formula I’, and the compound shown in Claim 8 in the preparation of a drug for inhibiting osteoclast formation. Specifically, the drug for inhibiting osteoclast formation is a drug for preventing and / or treating bone diseases.

10. The application according to claim 9, characterized in that, The bone disease is a bone disease caused by over-activation of osteoclasts; Specifically, the bone diseases include osteoporosis, osteoporotic fracture, osteolysis, periprosthetic osteolysis, tumor bone metastasis, inflammatory bone loss, and inflammatory bone resorption in periodontitis.

11. A drug for preventing and / or treating bone diseases, containing the Falcarindiol phthalide derivative described in any one of Claims 1-3, or the compound represented by Formula I’ in Claim 4, or the derivative obtained by removing the protecting group on the hydroxyl of the compound represented by Formula I’, or the compound shown in Claim 8.

12. The drug according to claim 11, wherein, It contains the Falcarindiol phthalide derivative described in any one of Claims 1-3, or the compound represented by Formula I’ in Claim 4, or the derivative obtained by removing the protecting group on the hydroxyl of the compound represented by Formula I’, or the compound shown in Claim 8; and optionally a pharmaceutically acceptable excipient or carrier.

13. A pharmaceutical composition, which contains at least one or more of the Falcarindiol phthalide derivative described in any one of Claims 1-3, and / or the compound represented by Formula I’ in Claim 4, and / or the derivative obtained by removing the protecting group on the hydroxyl of the compound represented by Formula I’, and / or the compound shown in Claim 8.

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