Polycyclic ketone compounds, their preparation methods, pharmaceutical compositions and applications

Abstract

The present application relates to a kind of polycyclic polyketone compounds and its preparation method, pharmaceutical composition and application, the chemical structure type of the polycyclic polyketone compound is different from existing anti-osteosarcoma chemotherapy drug, it is compound with brand-new structure, while inventor finds that the polycyclic polyketone compound has significant anti-osteosarcoma cell 143B and U2OS activity by experiment, the anti-osteosarcoma activity of part compound is better than positive control drug, the result further indicates that the polycyclic polyketone compound of the present application can significantly inhibit the growth of osteosarcoma, and it is expected to develop into a new type of anti-osteosarcoma drug, can be used for treating osteosarcoma and the disease caused by bone and joint pain and lung disease.Further, the synthesis route of the polycyclic polyketone compound used in the present application is efficient and simple, and has good raw material economy.

Description

Technical Field

[0001] This application relates to the field of pharmaceutical technology, and in particular to a polycyclic polyketide compound and its preparation method, pharmaceutical composition and application. Background Technology

[0002] Osteosarcoma, also known as osteoblastoma, originates from primitive mesenchymal cells and is the most common primary malignant bone tumor in children and adolescents. To date, the main treatments for osteosarcoma are chemotherapy and surgery. Chemotherapy remains the most commonly used method. Since the 1970s, doxorubicin, cisplatin, methotrexate, and ifosfamide have been the main drugs for treating osteosarcoma, increasing the 5-year survival rate of osteosarcoma patients to approximately 70%. However, current treatments for osteosarcoma still face the following problems: (1) severe adverse drug reactions; (2) drug resistance and poor efficacy. In the past 20 years, although levofolinic acid calcium injection and mivastatin have been approved by the US FDA and Europe respectively, they still suffer from the aforementioned problems. Therefore, developing new osteosarcoma treatments is of great significance. Summary of the Invention

[0003] Therefore, it is necessary to provide a polycyclic polyketide compound, its preparation method, pharmaceutical composition, and application. The polycyclic polyketide compound can significantly inhibit the growth of osteosarcoma and can be used to treat osteosarcoma and the bone and joint pain and lung diseases it causes.

[0004] The technical solution of this application is as follows:

[0005] A first aspect of the present invention provides a polycyclic polyketide compound having the structure shown in formula (I) or a pharmaceutically acceptable salt thereof or an enantiomer thereof:

[0006]

[0007] in,

[0008] X is selected from oxygen or -CH2;

[0009] n is an integer between 0 and 2;

[0010] R 1 R 2 R 3 R 4 R 5 R 6 and R 7 Each is independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C4 haloalkyl, halogen, hydroxyl or hydrogen.

[0011] In one embodiment, R1 R 2 R 3 R 4 R 5 R 6 and R 7 Each is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl, n-hexyl, isohexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, n-pentoxy, isopentoxy, n-hexoxy, isohexyloxy, fluoromethyl, chloromethyl, bromomethyl, iodomethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2-chloroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 1-fluoropropyl, 2-chloropropyl, 3-fluoropropyl, 3-chloropropyl, 1-fluorobutyl, 1-chlorobutyl, 4-fluorobutyl, fluorine, chlorine, bromine, iodine, hydroxyl, or hydrogen.

[0012] In one embodiment, X is selected from -CH2;

[0013] R 1 R 2 R 3 R 4 R 5 R 6 and R 7 Each is independently selected from C1-C3 alkyl, C1-C3 alkoxy, halogen, hydroxyl or hydrogen.

[0014] In one embodiment, the polycyclic polyketide compound is selected from any one of compounds 1-20:

[0015]

[0016] A second aspect of the present invention provides a method for preparing the polycyclic polyketide compound as described above, comprising the following steps:

[0017] Compound Ia and compound Ib react under the action of a first base to prepare compound Ic;

[0018] Compound Ic reacts with a first oxidizing agent to prepare compound Id;

[0019] Compound Id undergoes debenzylation and demethylation reactions in the presence of a Lewis acid to prepare compound Ie;

[0020] Compound Ie reacts with a second oxidizing agent to prepare compound If;

[0021] Compound If reacts with compound Ig under the action of a second base to prepare a polyepoxyanthracene compound having the structure shown in formula (I);

[0022] Among them, R 1 R 2 R 3 R 4 R 5 R 6 R 7 X and n are as defined above;

[0023]

[0024] In one embodiment, the preparation of compound Ic includes the following steps:

[0025] Compound Ia, compound Ib, the first base and the first solvent were mixed and reacted at a temperature of -78℃ to -50℃ for 1 h to 4 h.

[0026] Wherein, the first base is at least one selected from n-butyllithium and tert-butyllithium; and / or

[0027] The first solvent is at least one of tetrahydrofuran and diethyl ether; and / or

[0028] The molar ratio of compound Ia, compound Ib and the first base is 1:(1-3):(1-3).

[0029] In one embodiment, the preparation of compound Id includes the following steps:

[0030] Compound Ic, a second solvent, and a first oxidant are mixed and reacted at a temperature of 0°C to 30°C for 0.5 h to 12 h; wherein the second solvent is at least one selected from dichloromethane, 1,2-dichloroethane, and acetone; and / or

[0031] The first oxidant is at least one of manganese dioxide, Des Martin reagent, and Jones reagent; and / or

[0032] The molar ratio of compound Ic to the first oxidant is 1:(1-20).

[0033] In one embodiment, the preparation of compound Ie includes the following steps:

[0034] Compound Id, the third solvent, and the Lewis acid were mixed and reacted at a temperature of 0℃ to 30℃ for 1h to 5h.

[0035] The third solvent is at least one selected from dichloromethane and 1,2-dichloroethane; and / or

[0036] The Lewis acid is at least one of boron tribromide and boron trichloride; and / or

[0037] The molar ratio of compound Id to Lewis acid is 1:(3-20).

[0038] In one embodiment, the preparation of compound If includes the following steps:

[0039] Compound Ie, the fourth solvent, and the second oxidant were mixed and reacted at a temperature of 0℃ to 30℃ for 1h to 12h.

[0040] The fourth solvent is at least one selected from diethyl ether, acetonitrile, ethylene glycol dimethyl ether, and dichloromethane; and / or

[0041] The second oxidizing agent is at least one of silver oxide, [bis(trifluoroacetoxy)iodide]benzene, bislauroyl peroxide, and di-tert-butyl peroxide; and / or

[0042] The molar ratio of the compound Ie and the second oxidant is 1:(1-5).

[0043] In one embodiment, the reaction of compound If with compound Ig under alkaline conditions includes the following steps:

[0044] The compound If, the fifth solvent, and the second base are mixed and reacted at a temperature of 0℃~30℃ for 6h~12h.

[0045] The fifth solvent is at least one selected from methanol, ethanol, dichloromethane, and 1,2-dichloroethane; and / or

[0046] The second base is at least one of triethylamine and N,N-diisopropylethylamine; and / or

[0047] The molar ratio of the compound If, the compound Ig, and the second base is 1:(1-3):(1-3).

[0048] A third aspect of the invention provides a pharmaceutical composition comprising, as described above, a polycyclic ketone compound or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

[0049] A fourth aspect of the invention provides the use of the polycyclic ketone compound as described above or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described above, in the preparation of a medicament for treating osteosarcoma.

[0050] A fifth aspect of the invention provides the use of the polycyclic ketone compound as described above or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described above, in the preparation of a medicament for treating osteosarcoma-induced bone and joint pain and lung disease.

[0051] Compared with the prior art, this application has the following beneficial effects:

[0052] This application provides a polycyclic polyketide compound or a pharmaceutically acceptable salt thereof. The chemical structure of the polycyclic polyketide compound differs from that of existing anti-osteosarcoma chemotherapy drugs, representing a novel structure. Furthermore, the inventors have experimentally discovered that the polycyclic polyketide compound exhibits significant anti-osteosarcoma cell 143B and U2OS activity, with some compounds showing superior anti-osteosarcoma activity compared to the positive control drug. This result further indicates that the polycyclic polyketide compound of this application can significantly inhibit the growth of osteosarcoma and holds promise for development into a novel anti-osteosarcoma drug that can be used to treat osteosarcoma and related bone and joint pain, lung disease, and other related illnesses.

[0053] Furthermore, the synthetic route for polycyclic ketone compounds used in this application is efficient and concise, while also exhibiting good raw material economy. Detailed Implementation

[0054] The present application will be further described in detail below with reference to specific embodiments. The present application can be implemented in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided to provide a more thorough and complete understanding of the disclosure of this application.

[0055] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the application.

[0056] Unless otherwise stated or in case of contradiction, the terms or phrases used herein shall have the following meanings:

[0057] In this document, the term "alkyl" refers to a monovalent residue formed by the loss of a hydrogen atom from a saturated hydrocarbon containing a primary (normal) carbon atom, a secondary carbon atom, a tertiary carbon atom, a quaternary carbon atom, or a combination thereof. Phrases containing this term, such as "C1-C6 alkyl," refer to alkyl groups containing 1 to 6 carbon atoms, and each occurrence can be independently C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl. Suitable examples include, but are not limited to: methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(C H3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (- CH2CH2CH(CH3)2), 2-methyl-1-butyl(-CH2CH(CH3)CH2CH3), 1-hexyl(-CH2CH2CH2CH2CH2CH3), 2-hexyl(-CH(CH3)CH2CH2CH2CH3), 3-hexyl(-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl(-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl(-CH(CH3)CH( CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3 and octyl (-(CH2)7CH3).

[0058] In this article, the term "haloalkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group with a specific number of carbon atoms, wherein hydrogen atoms are replaced by halogen atoms. For example, C1-C4 haloalkyl groups include, but are not limited to, fluoromethyl, chloromethyl, bromomethyl, iodomethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2-chloroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 1-fluoropropyl, 2-chloropropyl, 3-fluoropropyl, 3-chloropropyl, 1-fluorobutyl, 1-chlorobutyl, 4-fluorobutyl, etc.

[0059] In this article, the term "alkoxy" refers to a straight-chain or branched saturated aliphatic hydrocarbon group having a specific number of carbon atoms and an oxygen atom. For example, C1-C6 haloalkyl groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, n-pentoxy, isopentoxy, n-hexyloxy, and isohexyloxy.

[0060] In this article, "pharmaceutically acceptable" means those ligands, materials, compositions, and / or dosage forms that are suitable for administration to patients within the bounds of reasonable medical judgment and that are commensurate with a reasonable benefit / risk ratio.

[0061] In this document, "pharmaceutically acceptable salt" refers to a salt formed by any compound in the indicated structure with an acid or base that is suitable for use as a drug. Pharmaceutically acceptable salts include both inorganic and organic salts. One class of salts is the salt formed by the compound of this application with an acid. Acids suitable for salt formation include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, and naphthalenesulfonic acid; and amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid. Another type of salt is the salt formed by the compound of this application with a base. Suitable bases for forming salts include, but are not limited to: alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., magnesium or calcium salts), ammonium salts (such as lower alkanol ammonium salts and other pharmaceutically acceptable amine salts), such as methylamine salts, ethylamine salts, propylamine salts, dimethylamine salts, trimethylamine salts, diethylamine salts, triethylamine salts, tert-butylamine salts, ethylenediamine salts, hydroxyethylamine salts, dihydroxyethylamine salts, trihydroxyethylamine salts, and amine salts formed from morpholine, piperazine, and lysine, respectively.

[0062] In this document, "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition, or medium, such as liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials. As used herein, the term "pharmaceutically acceptable carrier" includes buffers compatible with drug administration, sterile water for injection, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents and absorption delay agents, and the like. Each carrier must be "pharmaceutically acceptable" in the sense of compatibility with other components in the formulation and harmlessness to the patient. Suitable examples include, but are not limited to: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch, potato starch and substituted or unsubstituted β-cyclodextrins; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth gum; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn... Rice oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffer; (21) other non-toxic compatible substances used in pharmaceutical formulations.

[0063] In this article, "composition" can refer to a combination of multiple substances, or more specifically, a combination of substances used together, or a mixture formed by combining substances.

[0064] In this article, "one or more" refers to any one, two or more of the listed items.

[0065] In this document, the optional range of "and / or", "or / and", and "and / or" includes any one of two or more of the related listed items, as well as any and all combinations of the related listed items, including any two related listed items, any more related listed items, or a combination of all the related listed items.

[0066] In this document, terms such as “further,” “even further,” and “especially” are used to describe the purpose and indicate differences in content, but should not be construed as limiting the scope of protection of this application.

[0067] In this document, terms such as "first aspect," "second aspect," "third aspect," and "fourth aspect" are used for descriptive purposes only and should not be construed as indicating or implying relative importance or quantity, nor should they be construed as implicitly specifying the importance or quantity of the indicated technical features. Furthermore, terms such as "first," "second," "third," and "fourth" serve only as a non-exhaustive enumeration and should be understood as not constituting a closed limitation on quantity. Therefore, a feature specified as "first" or "second" may explicitly or implicitly include at least one of that feature. In the description of this application, "multiple" means at least two, such as two, three, etc., unless otherwise explicitly specified. In the description of this application, "several" means at least one, such as one, two, etc., unless otherwise explicitly specified.

[0068] In this application, numerical ranges are referred to as continuous unless otherwise specified, and include the minimum and maximum values ​​of the range, as well as every value between the minimum and maximum values. Furthermore, when the range refers to integers, it includes every integer between the minimum and maximum values ​​of the range. Additionally, when multiple ranges are provided to describe a feature or characteristic, the ranges may be merged. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all subranges to which they are incorporated.

[0069] Unless otherwise specified, the percentage content mentioned in this application refers to mass percentage for solid-liquid mixtures and solid-phase-solid mixtures, and volume percentage for liquid-phase-liquid mixtures.

[0070] Unless otherwise specified, all percentage concentrations mentioned in this application refer to the final concentration. The final concentration refers to the proportion of the added component in the system after the addition of that component.

[0071] Unless otherwise specified, the temperature parameters in this application may be either constant temperature treatment or treatment within a certain temperature range. The constant temperature treatment allows temperature fluctuations within the precision range controlled by the instrument. Fluctuations are permitted within ranges such as ±5℃, ±2℃, ±1℃, ±0.5℃, ±0.4℃, ±0.3℃, ±0.2℃, and ±0.1℃.

[0072] A first aspect of the present invention provides a polycyclic polyketide compound having the structure shown in formula (I) or a pharmaceutically acceptable salt thereof or an enantiomer thereof:

[0073]

[0074] in,

[0075] X is selected from oxygen or -CH2;

[0076] n is an integer between 0 and 2;

[0077] R 1 R 2 R 3 R 4 R 5 R 6 and R 7 Each is independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C4 haloalkyl, halogen, hydroxyl or hydrogen.

[0078] In one embodiment, R 1 R 2 R 3 R 4 R 5 R 6 and R 7 Each is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl, n-hexyl, isohexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, n-pentoxy, isopentoxy, n-hexoxy, isohexyloxy, fluoromethyl, chloromethyl, bromomethyl, iodomethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2-chloroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 1-fluoropropyl, 2-chloropropyl, 3-fluoropropyl, 3-chloropropyl, 1-fluorobutyl, 1-chlorobutyl, 4-fluorobutyl, fluorine, chlorine, bromine, iodine, hydroxyl, or hydrogen.

[0079] In one embodiment, X is selected from -CH2;

[0080] R 1 R 2 R 3 R 4 R 5 R 6 and R 7 Each is independently selected from C1-C3 alkyl, C1-C3 alkoxy, halogen, hydroxyl or hydrogen.

[0081] In one embodiment, the polycyclic polyketide compound is selected from any one of compounds 1-20:

[0082]

[0083] A second aspect of the present invention provides a method for preparing the polycyclic polyketide compound as described above, comprising the following steps:

[0084] Compound Ia and compound Ib react under the action of a first base to prepare compound Ic;

[0085] Compound Ic reacts with a first oxidizing agent to prepare compound Id;

[0086] Compound Id undergoes debenzylation and demethylation reactions in the presence of a Lewis acid to prepare compound Ie;

[0087] Compound Ie reacts with a second oxidizing agent to prepare compound If;

[0088] Compound If reacts with compound Ig under the action of a second base to prepare a polyepoxyanthracene compound having the structure shown in formula (I);

[0089] Among them, R 1 R 2 R 3 R 4 R 5 R 6 R 7 X and n are as defined above;

[0090]

[0091] In some of these examples, the preparation of compound Ic includes the following steps:

[0092] Compound Ia, compound Ib, the first base, and the first solvent were mixed and reacted at a temperature of -78℃ to -50℃ for 1 to 4 hours.

[0093] In one specific example, the first base is at least one of n-butyllithium and tert-butyllithium.

[0094] In one specific example, the first solvent is at least one of tetrahydrofuran and diethyl ether.

[0095] In one specific example, the molar ratio of compound Ia, compound Ib, and the first base is 1:(1-3):(1-3). It is understood that the molar ratio of compound Ia, compound Ib, and the first base includes, but is not limited to, 1:1:1, 1:2:1, 1:3:1, 1:1:2, and 1:1:3.

[0096] In some of these examples, the preparation of compound Id includes the following steps:

[0097] Compound Ic, the second solvent, and the first oxidant were mixed and reacted at a temperature of 0℃ to 30℃ for 0.5h to 12h.

[0098] In one specific example, the second solvent is at least one of dichloromethane, 1,2-dichloroethane, and acetone.

[0099] In one specific example, the first oxidant is at least one of manganese dioxide, Des Martin reagent, and Jones reagent.

[0100] In one specific example, the molar ratio of compound Ic to the first oxidant is 1:(1 to 20). It is understood that the molar ratio of compound Ic to the first oxidant includes, but is not limited to, 1:1, 1:5, 1:10, and 1:20.

[0101] In some of these examples, the preparation of compound Ie includes the following steps:

[0102] Compound Id, a third solvent, and a Lewis acid are mixed and reacted at a temperature of 0°C to 30°C for 1 to 5 hours.

[0103] In one specific example, the third solvent is at least one of dichloromethane and 1,2-dichloroethane.

[0104] In one specific example, the Lewis acid is at least one of boron tribromide and boron trichloride.

[0105] In one specific example, the molar ratio of compound Id to the Lewis acid is 1:(3 to 20). It will be understood that the molar ratio of compound Id to the Lewis acid includes, but is not limited to, 1:3, 1:5, 1:10, 1:15, and 1:20.

[0106] In some of these examples, the preparation of compound If includes the following steps:

[0107] Compound Ie, the fourth solvent, and the second oxidant were mixed and reacted at a temperature of 0℃ to 30℃ for 1h to 12h.

[0108] In one specific example, the fourth solvent is at least one of diethyl ether, acetonitrile, ethylene glycol dimethyl ether, and dichloromethane.

[0109] In one specific example, the second oxidant is at least one of silver oxide, [bis(trifluoroacetoxy)iodide]benzene, bislauroyl peroxide, and di-tert-butyl peroxide.

[0110] In one specific example, the molar ratio of compound Ie to the second oxidant is 1:(1 to 5). It is understood that the molar ratio of compound Ie to the second oxidant includes, but is not limited to, 1:1, 1:2, 1:3, 1:4, and 1:5.

[0111] In some of these examples, the reaction of compound If with compound Ig under alkaline conditions includes the following steps:

[0112] The compound If, the fifth solvent, and the second base are mixed and reacted at a temperature of 0℃ to 30℃ for 6h to 12h.

[0113] In one specific example, the fifth solvent is at least one of methanol, ethanol, dichloromethane, and 1,2-dichloroethane.

[0114] In one specific example, the second base is at least one of triethylamine and N,N-diisopropylethylamine.

[0115] In one specific example, the molar ratio of compound If, compound Ig, and the second base is 1:(1-3):(1-3). It is understood that the molar ratio of compound If, compound Ig, and the second base includes, but is not limited to, 1:1:1, 1:2:1, 1:3:1, 1:1:2, and 1:1:3.

[0116] A third aspect of the invention provides a pharmaceutical composition comprising, as described above, a polycyclic ketone compound or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

[0117] A fourth aspect of the invention provides the use of the polycyclic ketone compound as described above or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described above, in the preparation of a medicament for treating osteosarcoma.

[0118] A fifth aspect of the invention provides the use of the polycyclic ketone compound as described above or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described above, in the preparation of a medicament for treating osteosarcoma-induced bone and joint pain and lung disease.

[0119] The following detailed description is provided in conjunction with specific embodiments. Unless otherwise specified, all raw materials used in the following embodiments are commercially available; all instruments used are commercially available; and all processes involved are conventionally selected by those skilled in the art unless otherwise specified.

[0120] The following are specific examples.

[0121] Example 1

[0122]

[0123] Step 1: Under argon protection and at -78°C, compound b (2.24 g, 10 mmol, 1 eq.) was added to 50 mL of anhydrous tetrahydrofuran solution, followed by the slow addition of n-butyllithium (1.6 M in THF, 6.25 mL, 10 mmol, 1 eq.) and stirring at -78°C for 1 h. Subsequently, compound a (1.38 g, 10 mmol, 1 eq.) was slowly added and stirred for 1 h. The reaction was then quenched with water, and the reaction solution was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to give compound c (3.39 g, 70% yield).

[0124] Compound C: 1 H NMR (400MHz, CDCl3) δ7.43–7.20(m,11H),6.58(m,3H),6.48(s,1H),5.08(s,2H),5.01(s,2H),3.61(s,3H),3.50(s,3H),2.30(s,3H),2.19(s,3H); 13 C NMR (100MHz, CDCl3) δ157.4,154.4,150.80,136.9,130.4,129.4,129.3,128.5,1 27.9,127.5,120.4,112.2,106.0,70.8,67.8,60.1,55.8,16.4,11.8; HR-ESI-MS m / z 485.2325[M+H] + .

[0125] Step 2: Under argon protection and at 0°C, compound c (121 mg, 0.25 mmol, 1 eq.) was added to 5 mL of anhydrous dichloromethane solution, followed by the slow addition of manganese dioxide (435 mg, 0.25 mmol, 20 eq.), and the mixture was stirred at 30°C for 12 h. Subsequently, the reaction was quenched with saturated sodium sulfite aqueous solution, and the reaction solution was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to obtain compound d (72.3 mg, yield 62%).

[0126] Compound d: 1 H NMR (400MHz, CDCl3) δ7.25(m,11H),6.57(m,3H),5.02(s,4H),3.60(s,3H),3.39(s,3H),2.33(s,3H),2.20(s,3H); 13C NMR (100MHz, CDCl3) δ196.0,157.3,154.1,151.3,136.8,133.3,131.6,131.0,130.8 ,128.3,127.6,127.1,122.6,112.2,105.6,70.4,60.0,56.4,16.8,13.0; HR-ESI-MS m / z 483.2169[M+H] + .

[0127] Step 3: Under argon protection and at 0°C, compound d (482 mg, 1 mmol, 1 eq.) was added to 10 mL of anhydrous dichloromethane solution, followed by the slow addition of boron tribromide (1 M in CH2Cl2, 3 mL, 1 mmol, 3 eq.) and stirring at 0°C for 1 h. Subsequently, the reaction was quenched with saturated sodium bicarbonate aqueous solution, and the reaction solution was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to give compound e (216 mg, yield 75%).

[0128] Compound e: 1 H NMR (400MHz, CD3OD) δ7.49(m,1H),7.33(dd,J=8.0,1.6Hz,1H),6.99(dd,J=8.4,0.6Hz,1H),6.82(m,1H),2.25(s,3H),2.01(s,3H); 13 C NMR (100MHz, CD3OD) δ204.8,162.4,146.7,145.8,136.4,133.2,128.1,124.5,122.8,120.7,118.8,117.3,114.8,15.7,12.0; HR-ESI-MS m / z 275.0918[M+H] + .

[0129] Step 4: Under argon protection and at 0°C, compound e (288 mg, 1 mmol, 1 eq.) was added to 10 mL of anhydrous diethyl ether solution, followed by the addition of silver oxide (231 mg, 1 mmol, 1 eq.) and stirring at 0°C for 1 h. Subsequently, the reaction was quenched with saturated sodium sulfite aqueous solution, and the reaction solution was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to give compound f (165.9 mg, yield 61%).

[0130] Compound f:1 H NMR (400MHz, CDCl3) δ13.20 (s, 1H), 11.34 (s, 1H), 7.39 (t, J = 8.3Hz, 1H), 6.82 ( s,1H),6.63(d,J=8.2Hz,1H),6.57(d,J=8.3Hz,1H),2.13(s,3H),1.60(s,3H); 13 C NMR (100MHz, CDCl3) δ191.3,162.8,137.8,136.3,135.8,132.8,131.8,130.4,126.8,126.0,122.4,119.6,118.8,26.4,16.4; HR-ESI-MS m / z 273.0759[M+H] + .

[0131] Step 5: Under argon protection and at 0°C, compound f (272 mg, 1 mmol, 1 eq.) was added to 10 mL of anhydrous methanol solution, followed by N,N-diisopropylethylamine (129 mg, 1 mmol, 1 eq.) and compound g (144 mg, 1 mmol, 1 eq.), and the mixture was stirred at 0°C for 12 h. Subsequently, the reaction was quenched with saturated ammonium chloride aqueous solution, and the reaction solution was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to give compound 1 (158.1 mg, yield 38%).

[0132] Compound 1: 1 H NMR (400MHz, CDCl3) δ11.58 (s, 1H), 7.79 (t, J = 11.0Hz, 1H), 7.69–7.59 (m, 1H), 7.42(dd,J=20.8,13.0Hz,3H), 6.62(d,J=8.1Hz,2H), 3.87(dd,J=31.6,15.2Hz, 1H),3.34(dd,J=25.7,16.3Hz,1H),3.07(d,J=17.8Hz,1H),2.81(t,J=17.0Hz,1 H),2.24(dd,J=17.4,6.5Hz,2H),1.46(d,J=21.5Hz,3H),0.88(d,J=9.7Hz,3H); 13C NMR (100MHz, CDCl3) δ205.7,204.3,200.0,192.9,163.2,156.8,152.1,138.7,136.2,135.2,128.4, 126.0,124.5,111.4,108.5,106.7,79.8,60.6,50.8,49.6,41.9,41.2,36.8,18.6,14.3; HR-ESI-MS m / z 417.1334[M+H] + .

[0133] Example 2

[0134] The preparation method of Example 2 is basically the same as that of Example 1, the main difference being that in the fifth step reaction, compound h is used instead of compound g in Example 1 to prepare compound 2; that is:

[0135]

[0136] Under argon protection and at 0°C, compound f (272 mg, 1 mmol, 1 eq.) was added to 10 mL of anhydrous ethanol solution, followed by the addition of triethylamine (303 mg, 3 mmol, 3 eq.) and compound h (486 mg, 3 mmol, 3 eq.), and the mixture was stirred at 0°C for 6 h. The reaction was then quenched with saturated ammonium chloride aqueous solution, and the reaction solution was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to give compound 2 (91.1 mg, yield 21%).

[0137] Compound 2: 1 H NMR (400MHz, CDCl3) δ11.53(s,1H),7.99(m,1H),7.45(t,J=8.3Hz,1H),6.82(t,J=8.3Hz,1H),6.65(m,3H),4.55(d,J=12.6Hz,1H),4.19(dd, J=49.4,9.9Hz,1H),3.33(t,J=20.1Hz,1H),2.72(d,J=14.7Hz,1H),2.23(d,J=20.2Hz,1H),1.97(d,J=14.8Hz,1H),1.48(s,3H),1.29(s,3H); 13C NMR (100MHz, CDCl3) δ204.7,199.1,192.4,190.4,163.1,156.4,138.9,130.8,130.6,111.6,111.2,11 0.9,108.6,106.9,104.9,104.7,79.9,73.4,59.8,53.5,50.6,46.3,43.8,30.7,19.0,14.4; HR-ESI-MS m / z435.1240[M+H] + .

[0138] Example 3

[0139] The preparation method of Example 3 is basically the same as that of Example 1, the main difference being that in the fifth step reaction, compound i is used instead of compound g in Example 1 to prepare compound 3; that is:

[0140]

[0141] Under argon protection and at 0°C, compound f (27.2 mg, 0.1 mmol, 1 eq.) was added to 2 mL of anhydrous dichloromethane solution, followed by N,N-diisopropylethylamine (19.4 mg, 0.15 mmol, 1.5 eq.) and compound i (26.7 mg, 0.15 mmol, 1.5 eq.), and the mixture was stirred at 30°C for 8 h. The reaction was then quenched with saturated ammonium chloride aqueous solution, and the reaction solution was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to give compound 3 (20.2 mg, yield 45%).

[0142] Compound 3: 1 H NMR (400MHz, CDCl3) δ11.57(s,1H),7.77–7.61(m,1H),7.44(q,J=8.3Hz,3H),6.59(dd,J=31.7,8.3Hz,2H),3.80(d,J =20.1Hz,1H),3.29(d,J=18.1Hz,1H),3.05(d,J=18.0Hz,1H),2.82(d,J=14.8Hz,1H),2.29–2.18(m,2H),1.49(s,3H); 13CNMR(100MHz, CDCl3)δ204.2,199.7,192.7,163.2,156.7,153.4,143.0,138.8,133.7,129.3,126.2,1 25.6,111.5,108.5,106.7,79.8,60.5,53.4,50.8,49.9,41.5,41.1,36.7,29.7,18.5,14.3; HR-ESI-MS m / z451.0946[M+H] + .

[0143] Example 4

[0144] The preparation method of Example 4 is basically the same as that of Example 1, the main difference being that in the fifth step reaction, compound j is used instead of compound g in Example 1 to prepare compound 4; that is:

[0145]

[0146] Under argon protection and at 0°C, compound f (27.2 mg, 0.1 mmol, 1 eq.) was added to 2 mL of anhydrous 1,2-dichloroethane solution, followed by N,N-diisopropylethylamine (19.4 mg, 0.15 mmol, 1.5 eq.) and compound j (44.2 mg, 0.2 mmol, 2 eq.), and the mixture was stirred at 20°C for 8 h. The reaction was then quenched with saturated ammonium chloride aqueous solution, and the reaction solution was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to give compound 4 (21.2 mg, yield 43%).

[0147] Compound 4: 1 H NMR (400MHz, CDCl3) δ11.54(s,1H),7.59(m,3H),7.43(t,J=8.3Hz,1H),6.61(d,J=8.3Hz,2H),3.76(d,J=20.1Hz,1H),3. 48(s,1H),3.28(d,J=18.1Hz,1H),3.04(d,J=18.1Hz,1H),2.80(d,J=14.8Hz,1H),2.23(m,2H),1.47(s,3H),0.85(s,3H); 13CNMR(100MHz, CDCl3)δ204.5,204.1,199.8,192.7,163.1,156.7,153.5,138.8,134.0,132.1,131.9 ,129.3,125.6,111.5,108.5,106.7,79.8,60.5,50.8,49.8,41.4,41.1,36.6,18.5,14.3; HR-ESI-MS m / z495.0439[M+H] + .

[0148] Example 5

[0149]

[0150] Step 1: Under argon protection and at -78°C, compound b (672 mg, 3 mmol, 3 eq.) was added to 15 mL of anhydrous diethyl ether solution, followed by slow addition of tert-butyllithium (1.3 M in pentane, 2.3 mL, 3 mmol, 3 eq.) and stirring at -78°C for 1 h. Subsequently, compound a (138 mg, 1 mmol, 1 eq.) was slowly added, and the mixture was heated to -50°C and stirred for 3 h. The reaction was then quenched with water, and the reaction solution was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to give compound c (392 mg, yield 81%).

[0151] Step 2: Under argon protection and at 0°C, compound c (121 mg, 0.25 mmol, 1 eq.) was added to 2.5 mL of anhydrous 1,2-dichloroethane solution. Subsequently, Dys-Martin reagent (106 mg, 2.5 mmol, 1 eq.) was slowly added, along with an appropriate amount of sodium bicarbonate, and the mixture was stirred at 0°C for 1.5 h. The reaction was then quenched with saturated sodium sulfite aqueous solution, and the reaction solution was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to give compound d (86.7 mg, yield 72%).

[0152] Step 3: Under argon protection and at 0°C, compound d (48.2 mg, 0.1 mmol, 1 eq.) was added to 2 mL of anhydrous 1,2-dichloroethane solution, followed by the slow addition of boron trichloride (1 M in CH2Cl2, 2 mL, 2 mmol, 20 eq.) and stirring at 30°C for 5 h. The reaction was then quenched with saturated sodium bicarbonate solution, and the reaction mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated NaCl solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to give compound e (10.1 mg, yield 35%).

[0153] Step 4: Under argon protection and at 0°C, compound e (28.8 mg, 0.1 mmol, 1 eq.) was added to 2 mL of anhydrous acetonitrile solution, followed by the addition of [bis(trifluoroacetoxy)iodo]benzene (46 mg, 0.2 mmol, 2 eq.) and stirring at 30°C for 3 h. Subsequently, the reaction was quenched with saturated sodium sulfite aqueous solution, and the reaction solution was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to give compound f (10.1 mg, yield 37%).

[0154] Step 5: Under argon protection and at 0°C, compound f (27.2 mg, 0.1 mmol, 1 eq.) was added to 2 mL of anhydrous ethanol solution, followed by triethylamine (30.3 mg, 0.3 mmol, 3 eq.) and compound k (43.2 mg, 0.3 mmol, 3 eq.), and the temperature was raised to 30°C. After stirring for 6 h, the reaction was quenched with saturated ammonium chloride aqueous solution, and the reaction solution was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to give compound 5 (11.6 mg, yield 27%).

[0155] Compound 5: 1 H NMR (400MHz, CDCl3) δ11.57(s,1H),7.93(d,J=7.8Hz,1H),7.44(dd,J=22.5,7.9Hz,2H),7.33(d,J=7.5Hz,1H),7.17(d,J=7.5Hz ,1H),6.60(d,J=8.3Hz,2H),4.05(d,J=20.5Hz,1H),2.94(s,2H),2.34(m,4H),2.04(d,J=13.9Hz,1H),1.45(s,3H),1.22(s,3H); 13C NMR (100MHz, CDCl3) δ205.3,200.8,198.3,193.1,163.3,156.8,142.5,138.9,134.2,132.5,128.5,12 8.5,127.4,111.5,108.7,107.0,79.5,60.3,52.5,45.9,44.2,33.3,32.0,24.8,19.2,14.2; HR-ESI-MS m / z 431.1489[M+H] + .

[0156] Example 6

[0157] The preparation method of Example 6 is basically the same as that of Example 5, the main difference being that in the fifth step reaction, compound 1 is used instead of compound k in Example 5 to prepare compound 6; that is:

[0158]

[0159] Under argon protection and at 0°C, compound f (27.2 mg, 0.1 mmol, 1 eq.) was added to 2 mL of anhydrous methanol / dichloromethane (v / v 1:1; 2 mL) solution, followed by N,N-diisopropylethylamine (25.8 mg, 0.2 mmol, 2 eq.) and compound l (26.4 mg, 0.15 mmol, 1.5 eq.), and the temperature was raised to 25°C. After stirring for 10 h, the reaction was quenched with saturated ammonium chloride aqueous solution, and the reaction solution was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to give compound 6 (22.8 mg, yield 51%).

[0160] Compound 6: 1 H NMR (400MHz, CDCl3) δ11.57(s,1H),8.00(m,1H),7.44(t,J=8.2Hz,1H),7.02(t,J=8.0Hz,1H),6.88(d,J=8.5Hz,1H ),6.61(d,J=7.9Hz,2H),4.05(d,J=20.4Hz,1H),2.96(s,2H),2.36(m,4H),2.05(m,1H),1.47(s,3H),1.23(s,3H); 13C NMR (100MHz, CDCl3) δ205.0,200.5,196.7,192.9,163.2,156.7,138.8,131.7,131.6,115.3,115.1,11 4.9,114.7,111.4,108.5,106.8,79.6,60.2,52.3,45.7,44.1,33.3,31.8,24.9,19.1,14.1; HR-ESI-MS m / z 449.1395[M+H] + .

[0161] Example 7

[0162] The preparation method of Example 7 is basically the same as that of Example 5, the main difference being that in the fifth step reaction, compound m is used instead of compound k in Example 5 to prepare compound 7; that is:

[0163]

[0164] Under argon protection and at 0°C, compound f (27.2 mg, 0.1 mmol, 1 eq.) was added to 2 mL of anhydrous methanol / 1,2-dichloroethane (v / v 1:1; 2 mL) solution, followed by N,N-diisopropylethylamine (25.8 mg, 0.2 mmol, 2 eq.) and compound m (17.4 mg, 0.1 mmol, 1 eq.), and the temperature was raised to 20°C. After stirring for 7 h, the reaction was quenched with saturated ammonium chloride aqueous solution, and the reaction solution was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to give compound 7 (17.4 mg, yield 39%).

[0165] Compound 7: 1 H NMR (400MHz, CDCl3) δ11.59(s,1H),7.90(d,J=8.7Hz,1H),7.42(t,J=8.3Hz,1H),6.76(dd,J=8.7, 2.4Hz,1H),6.60(m,3H),2.89(m,2H),2.29(m,4H),2.00(m,4.6Hz,2H),1.46(s,3H),1.22(s,3H); 13C NMR (100MHz, CDCl3) δ205.3,200.8,198.3,193.1,163.3,162.7,156.8,142.5,138.9,134.2,132.5,12 8.5,127.4,111.5,108.7,107.0,79.5,60.3,52.5,45.9,44.2,33.3,32.0,24.8,19.2,14.2; HR-ESI-MS m / z 447.1438[M+H] + .

[0166] Example 8

[0167] The preparation method of Example 8 is basically the same as that of Example 5, the main difference being that in the fifth step reaction, compound n is used instead of compound k in Example 5 to prepare compound 8; that is:

[0168]

[0169] Under argon protection and at 0°C, compound f (27.2 mg, 0.1 mmol, 1 eq.) was added to 2 mL of anhydrous methanol / dichloromethane (v / v 1:1; 2 mL) solution, followed by N,N-diisopropylethylamine (25.8 mg, 0.2 mmol, 2 eq.) and compound n (18.8 mg, 0.1 mmol, 1 eq.), and the temperature was raised to 30°C. After stirring for 12 h, the reaction was quenched with saturated ammonium chloride aqueous solution, and the reaction solution was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to give compound 8 (30.8 mg, yield 67%).

[0170] Compound 8: 1 H NMR (400MHz, CDCl3) δ11.65(s,1H),7.95(d,J=8.8Hz,1H),7.44(t,J=8.3Hz,1H),6.88(dd,J=8.8,2.0Hz,1H ),6.62(m,3H),4.13(m,2H),3.85(s,3H),2.94(m,2H),2.40(m,3H),2.04(m,1H),1.47(s,3H),1.23(s,3H); 13C NMR (100MHz, CDCl3) δ205.3,200.8,196.7,193.1,164.2,163.2,156.8,144.9,138.7,130.9,125.8,114. 0,112.1,111.4,108.5,79.6,60.3,55.5,52.5,45.5,44.2,33.6,32.1,29.7,25.2,19.2,14.1; HR-ESI-MS m / z 461.1595[M+H] + .

[0171] Example 9

[0172] The preparation method of Example 9 is basically the same as that of Example 5, the main difference being that in the fifth step reaction, compound O is used instead of compound K in Example 5 to prepare compound 9; that is:

[0173]

[0174] Under argon protection and at 0°C, compound f (27.2 mg, 0.1 mmol, 1 eq.) was added to 2 mL of anhydrous methanol / dichloromethane (v / v 1:1; 2 mL) solution, followed by N,N-diisopropylethylamine (38.7 mg, 0.3 mmol, 3 eq.) and compound o (28.2 mg, 0.15 mmol, 1.5 eq.), and the temperature was raised to 30°C. After stirring for 12 h, the reaction was quenched with saturated ammonium chloride aqueous solution, and the reaction solution was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to give compound 9 (33.6 mg, yield 73%).

[0175] Compound 9: 1 H NMR (400MHz, CDCl3) δ11.59(s,1H),7.44(dd,J=10.7,5.5Hz,2H),7.07(m,2H),6.61(t,J=9.4Hz,2H),4.06(d,J=20.5Hz,1H),3 .84(s,3H),2.92(dd,J=10.0,5.1Hz,2H),2.42(d,J=2.6Hz,2H),2.29(d,J=20.5Hz,1H),2.03(m,1H),1.48(s,3H),1.25(s,3H); 13CNMR(100MHz, CDCl3)δ205.2,200.7,198.0,193.0,163.2,158.8,156.7,138.8,134.9,133.0,129.7,122.7,1 11.4,110.1,108.5,106.9,79.6,60.2,55.5,52.4,45.7,44.2,33.1,32.0,29.7,23.9,19.1,14.1; HR-ESI-MS m / z 461.1597[M+H] + .

[0176] Example 10

[0177] The preparation method of Example 10 is basically the same as that of Example 5, the main difference being that in the fifth step reaction, compound p is used instead of compound k in Example 5 to prepare compound 10; that is:

[0178]

[0179] Under argon protection and at 0°C, compound f (27.2 mg, 0.1 mmol, 1 eq.) was added to 2 mL of anhydrous methanol / dichloromethane (v / v 1:1; 2 mL) solution, followed by N,N-diisopropylethylamine (38.7 mg, 0.3 mmol, 3 eq.) and compound p (28.8 mg, 0.15 mmol, 1.5 eq.), and the temperature was raised to 30°C. After stirring for 12 h, the reaction was quenched with saturated ammonium chloride aqueous solution, and the reaction solution was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to give compound 10 (31.6 mg, yield 68%).

[0180] Compound 10: 1 H NMR (400MHz, CDCl3) δ11.55(s,1H),7.91(d,J=7.9Hz,1H),7.58(d,J=7.8Hz,1H),7.45(t,J=8.3Hz,1H),7.32(t,J=7.9Hz,1H) ,6.63(d,J=8.3Hz,2H),4.06(d,J=20.5Hz,1H),3.15(m,1H),3.88(m,1H),2.35(m,4H),2.10(m,1H),1.48(s,3H),1.27(s,3H); 13CNMR(100MHz, CDCl3)δ205.1,200.5,196.8,192.8,163.2,156.6,139.7,138.9,134.5,133.9,133.8,128. 0,127.2,111.5,108.6,106.9,79.6,56.0,52.1,45.0,44.1,32.3,30.6,29.7,22.7,19.1,13.9; HR-ESI-MS m / z 465.1097[M+H] + .

[0181] Example 11

[0182] The preparation method of Example 11 is basically the same as that of Example 5, the main difference being that in the fifth step reaction, compound q is used instead of compound k in Example 5 to prepare compound 11; that is:

[0183]

[0184] Under argon protection and at 0°C, compound f (27.2 mg, 0.1 mmol, 1 eq.) was added to 2 mL of anhydrous methanol / dichloromethane (v / v 1:1; 2 mL) solution, followed by N,N-diisopropylethylamine (38.7 mg, 0.3 mmol, 3 eq.) and compound q (28.8 mg, 0.15 mmol, 1.5 eq.), and the temperature was raised to 30°C. After stirring for 12 h, the reaction was quenched with saturated ammonium chloride aqueous solution, and the reaction solution was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to give compound 11 (30.6 mg, yield 66%).

[0185] Compound 11: 1 H NMR (400MHz, CDCl3) δ11.57(s,1H),7.91(d,J=8.4Hz,1H),7.44(t,J=8.3Hz,1H),7.30(m,1H),7.21(s,1H),6.62(dd,J=8 .2,4.0Hz,2H),4.03(d,J=20.5Hz,1H),2.96(dd,J=9.4,4.8Hz,2H),2.36(m,4H),2.06(m,1H),1.48(s,3H),1.23(s,3H); 13CNMR(100MHz, CDCl3)δ205.0,200.4,197.1,192.9,163.2,156.7,143.9,140.6,138.8,130.8,130.0,12 8.3,127.9,111.5,108.6,106.8,79.6,60.2,52.3,45.8,44.1,33.3,31.8,24.6,19.1,14.1; HR-ESI-MS m / z 465.1099[M+H] + .

[0186] Example 12

[0187] The preparation method of Example 12 is basically the same as that of Example 5, the main difference being that in the fifth step reaction, compound r is used instead of compound k in Example 5 to prepare compound 12; that is:

[0188]

[0189] Under argon protection and at 0°C, compound f (27.2 mg, 0.1 mmol, 1 eq.) was added to 2 mL of anhydrous methanol / dichloromethane (v / v 1:1; 2 mL) solution, followed by N,N-diisopropylethylamine (38.7 mg, 0.3 mmol, 3 eq.) and compound r (35.4 mg, 0.15 mmol, 1.5 eq.), and the temperature was raised to 30°C. After stirring for 12 h, the reaction was quenched with saturated ammonium chloride aqueous solution, and the reaction solution was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to give compound 12 (29.5 mg, yield 58%).

[0190] Compound 12: 1 H NMR (400MHz, CDCl3) δ11.57(s,1H),7.82(d,J=8.4Hz,1H),7.44(m,3H),6.62(dd,J=8.1,4.7Hz,2H),4. 02(d,J=20.5Hz,1H),2.96(dd,J=10.2,4.8Hz,2H),2.36(m,4H),2.06(m,1H),1.48(s,3H),1.23(s,3H); 13C NMR (100MHz, CDCl3) δ205.0,200.4,197.4,192.9,163.2,156.6,144.0,138.8,131.4,131.2,130.9,13 0.0,129.5,111.5,108.6,106.8,79.6,60.2,52.3,45.8,44.1,33.3,31.7,24.5,19.1,14.1; HR-ESI-MS m / z509.0598[M+H] + .

[0191] Example 13

[0192] The preparation method of Example 13 is basically the same as that of Example 5, the main difference being that in the fifth step reaction, compound s is used instead of compound k in Example 5 to prepare compound 13; that is:

[0193]

[0194] Under argon protection and at 0°C, compound f (27.2 mg, 0.1 mmol, 1 eq.) was added to 2 mL of anhydrous methanol / dichloromethane (v / v 1:1; 2 mL) solution, followed by N,N-diisopropylethylamine (38.7 mg, 0.3 mmol, 3 eq.) and compound s (35.4 mg, 0.15 mmol, 1.5 eq.), and the temperature was raised to 30°C. After stirring for 12 h, the reaction was quenched with saturated ammonium chloride aqueous solution, and the reaction solution was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to give compound 13 (31.0 mg, yield 61%).

[0195] Compound 13: 1 H NMR (400MHz, CDCl3) δ11.55(s,1H),7.96(d,J=7.9Hz,1H),7.76(d,J=7.9Hz,1H),7.46(t,J=8.3Hz,1H),7.26(dd,J=15.4,7.4Hz, 1H),6.63(d,J=8.3Hz,2H),4.06(d,J=20.5Hz,1H),3.12(m,1H),2.87(m,1H),2.37(m,4H),2.09(m,1H),1.48(s,3H),1.27(s,3H); 13C NMR (100MHz, CDCl3) δ205.1,200.5,196.8,192.8,163.2,156.6,141.3,138.9,137.8,134.0,128.4,127.9 ,124.4,111.5,108.6,106.9,79.6,60.0,52.1,44.9,44.1,32.3,30.8,29.7,25.6,19.1,13.9; HR-ESI-MS m / z 509.0591[M+H] + .

[0196] Example 14

[0197]

[0198] Step 1: Under argon protection and at -78°C, compound b (488 mg, 2 mmol, 2 eq.) was added to 15 mL of anhydrous diethyl ether solution, followed by the slow addition of tert-butyllithium (1.3 M in pentane, 1.54 mL, 2 mmol, 2 eq.) and stirring at -78°C for 1 h. Subsequently, compound ta (152 mg, 1 mmol, 1 eq.) was slowly added, and the mixture was heated to -65°C and stirred for 2 h. The reaction was then quenched with water, and the reaction solution was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to give compound tc (358.6 mg, yield 72%).

[0199] Step 2: Under argon protection and at 5°C, compound tc (124.5 mg, 0.25 mmol, 1 eq.) was added to 2.5 mL of anhydrous acetone solution. Subsequently, Jones' reagent (1.8 M in H₂O, 139 μL, 0.5 mmol, 1.1 eq.) was slowly added, and the mixture was stirred at 5°C for 0.5 h. The reaction was then quenched with saturated sodium sulfite aqueous solution, and the reaction solution was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to give compound td (9.92 mg, yield 8%).

[0200] Step 3: Under argon protection and at 0°C, compound td (48.2 mg, 0.1 mmol, 1 eq.) was added to 2 mL of anhydrous dichloromethane solution, followed by the slow addition of trichloroboron bromide (1 M in CH2Cl2, 1 mL, 1 mmol, 10 eq.) and stirring at 20°C for 3 h. Subsequently, the reaction was quenched with saturated sodium bicarbonate aqueous solution, and the reaction solution was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to give compound te (13.9 mg, yield 46%).

[0201] Step 4: Under argon protection and at 0°C, compound te (30.2 mg, 0.1 mmol, 1 eq.) was added to 2 mL of anhydrous ethylene glycol dimethyl ether solution, followed by the addition of dilauroyl peroxide (19.95 mg, 0.5 mmol, 5 eq.) and a catalytic amount of copper acetate. The temperature was raised to 20°C. After stirring for 5 h, the reaction was quenched with saturated sodium sulfite aqueous solution. The reaction solution was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to obtain compound tf (4.0 mg, yield 14%).

[0202] Step 5: Under argon protection and at 0°C, compound qf (28.6 mg, 0.1 mmol, 1 eq.) was added to 2 mL of anhydrous methanol / dichloromethane (v / v 1:1; 2 mL) solution, followed by N,N-diisopropylethylamine (32.25 mg, 0.25 mmol, 2.5 eq.) and compound k (23.7 mg, 0.15 mmol, 1.5 eq.), and the temperature was raised to 20°C. After stirring for 10 h, the reaction was quenched with saturated ammonium chloride aqueous solution, and the reaction solution was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to give compound 14 (27.8 mg, yield 61%).

[0203] Compound 14: 1H NMR (400MHz, CDCl3) δ11.57(s,1H),7.93(d,J=7.8Hz,1H),7.44(dd,J=22.5,7.9Hz,1H),7.33(d,J=7.5Hz,1H),7.17(d,J=7.5Hz,1H),6 .60(d,J=8.3Hz,2H),4.05(d,J=20.5Hz,1H),2.94(m,2H),2.40(m,3H),2.30(s,3H),2.26(d,J=20.6Hz,1H),1.45(s,3H),1.22(s,3H); 13 C NMR (100MHz, CDCl3) δ205.5,201.1,198.3,192.4,163.1,156.6,151.3,151.3,142.5,134.2,132.5,128.5 ,127.5,112.0,109.6,105.0,79.7,60.3,52.5,45.9,44.3,33.3,32.0,24.9,22.7,19.3,14.2; HR-ESI-MS m / z 445.1646[M+H] + .

[0204] Example 15

[0205]

[0206] Step 1: Under argon protection and at -78°C, compound b (366 mg, 1.5 mmol, 1.5 eq.) was added to 15 mL of anhydrous diethyl ether solution, followed by the slow addition of n-butyllithium (1.6 M in hexane, 0.938 mL, 1.5 mmol, 1.5 eq.) and stirring at -78°C for 1 h. Subsequently, compound a (152 mg, 1 mmol, 1 eq.) was slowly added, and the mixture was heated to -60°C and stirred for 1.5 h. The reaction was then quenched with water, and the reaction solution was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to give compound c (251.7 mg, yield 52%).

[0207] Step 2: Under argon protection and at 0°C, compound c (124.5 mg, 0.25 mmol, 1 eq.) was added to 2.5 mL of anhydrous dichloromethane solution. Subsequently, Desmond reagent (318 mg, 0.75 mmol, 3 eq.) and 63 mg of anhydrous sodium bicarbonate were slowly added, and the temperature was raised to 25°C. After stirring for 6 h, the reaction was quenched with saturated sodium sulfite aqueous solution, and the reaction solution was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to give compound d (97.6 mg, yield 81%).

[0208] Step 3: Under argon protection and at 0°C, compound d (48.2 mg, 0.1 mmol, 1 eq.) was added to 2 mL of anhydrous dichloromethane solution, followed by the slow addition of trichloroboron (1 M in CH2Cl2, 0.5 mL, 0.5 mmol, 5 eq.) and stirring at 20°C for 4 h. The reaction was then quenched with saturated sodium bicarbonate aqueous solution, and the reaction mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to give compound e (18.7 mg, yield 65%).

[0209] Step 4: Under argon protection and at 0°C, compound e (30.2 mg, 0.1 mmol, 1 eq.) was added to 5 mL of anhydrous dichloromethane solution, followed by di-tert-butyl peroxide (43.8 mg, 0.3 mmol, 3 eq.) and a catalytic amount of copper acetate. The temperature was raised to 25°C. After stirring for 8 h, the reaction was quenched with saturated sodium sulfite aqueous solution. The reaction solution was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to give compound f (6.8 mg, yield 25%).

[0210] Step 5: Under argon protection and at 0°C, compound f (28.6 mg, 0.1 mmol, 1 eq.) was added to 2 mL of anhydrous methanol / dichloromethane (v / v 1:1; 2 mL) solution, followed by N,N-diisopropylethylamine (32.25 mg, 0.25 mmol, 2.5 eq.) and compound u (24 mg, 0.15 mmol, 1.5 eq.), and the temperature was raised to 25°C. After stirring for 12 h, the reaction was quenched with saturated ammonium chloride aqueous solution, and the reaction solution was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to give compound 12 (32.4 mg, yield 75%).

[0211] Compound 15: 1 H NMR (400MHz, CDCl3) δ11.58(s,1H),7.95(d,J=7.9Hz,1H),7.52(dd,J=20.5,12.7H z,1H),7.45(t,J=8.2Hz,1H),7.09(t,J=7.5Hz,1H),6.97(d,J=8.4Hz,1H),4.53(d, J=12.5Hz,1H),4.18(dd,J=42.9,9.8Hz,1H),3.40(d,J=20.1Hz,1H),2.71(d,J=14. 8Hz,1H),2.23(d,J=20.2Hz,1H),2.02(t,J=14.6Hz,1H),1.48(s,3H),1.27(s,3H); 13 C NMR (100MHz, CDCl3) δ204.8,199.3,192.5,191.8,163.1,161.0,156.5,138.9,137.0,128.0,122.3, 120.7,118.0,111.6,108.6,106.9,79.9,72.9,59.9,50.6,46.4,43.9,30.8,19.0,14.4; HR-ESI-MS m / z433.1285[M+H] + .

[0212] Example 16

[0213] The preparation method of Example 16 is basically the same as that of Example 15, the main difference being that in the fifth step reaction, compound v is used instead of compound u in Example 15 to prepare compound 16; that is:

[0214]

[0215] Under argon protection and at 0°C, compound f (28.6 mg, 0.1 mmol, 1 eq.) was added to 2 mL of anhydrous methanol / dichloromethane (v / v 1:1; 2 mL) solution, followed by N,N-diisopropylethylamine (32.25 mg, 0.25 mmol, 2.5 eq.) and compound v (26.7 mg, 0.15 mmol, 1.5 eq.), and the temperature was raised to 25°C. After stirring for 12 h, the reaction was quenched with saturated ammonium chloride aqueous solution, and the reaction solution was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to give compound 16 (28.8 mg, yield 64%).

[0216] Compound 16: 1 H NMR (400MHz, CDCl3) δ11.55(s,1H),7.77(m,1H),7.42(t,J=8.2Hz,1H),7.11(dd,J=16.4,8.2Hz,2H),6.60(d,J=8.1Hz,2H),3.80 (d,J=20.0Hz,1H),3.27(d,J=18.1Hz,1H),3.03(d,J=18.1Hz,1H),2.81(d,J=14.7Hz,1H),2.21(m,2H),1.47(s,3H),0.85(s,3H); 13 C NMR (100MHz, CDCl3) δ204.3,203.8,199.9,192.8,163.3,156.9,155.1,138.9,131.7,127.2,117.1 ,113.0,111.6,108.6,106.8,79.9,60.7,50.9,50.1,41.8,41.3,36.9,29.8,18.6,14.4; HR-ESI-MS m / z 451.1188[M+H] + .

[0217] Example 17

[0218] The preparation method of Example 17 is basically the same as that of Example 15, the main difference being that in the fifth step reaction, compound w is used instead of compound u in Example 15 to prepare compound 17; that is:

[0219]

[0220] Under argon protection and at 0°C, compound f (28.6 mg, 0.1 mmol, 1 eq.) was added to 2 mL of anhydrous methanol / dichloromethane (v / v 1:1; 2 mL) solution, followed by N,N-diisopropylethylamine (32.25 mg, 0.25 mmol, 2.5 eq.) and compound w (29.1 mg, 0.15 mmol, 1.5 eq.), and the temperature was raised to 25°C. After stirring for 12 h, the reaction was quenched with saturated ammonium chloride aqueous solution, and the reaction solution was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to give compound 17 (31.2 mg, yield 67%).

[0221] Compound 17: 1 H NMR (400MHz, CDCl3) δ11.54(s,1H),7.87(d,J=8.5Hz,1H),7.43(t,J=8.3Hz,1H),7.04(m,2H),6.61(t,J=7.6Hz,2H),4.53(d,J=12.6Hz,1H),4. 23(d,J=12.5Hz,1H),3.33(d,J=20.1Hz,1H),2.70(d,J=14.8Hz,1H),2.21(d,J=20.2Hz,1H),1.95(d,J=14.8Hz,1H),1.46(s,3H),1.24(s,3H); 13 C NMR (100MHz, CDCl3) δ204.7,199.2,192.5,190.9,163.3,161.4,156.5,143.3,139.0,129.3,123.4, 119.5,118.3,111.8,108.8,107.0,80.0,73.4,59.9,50.7,46.6,44.0,30.8,19.1,14.5; HR-ESI-MS m / z467.0892[M+H] + .

[0222] Example 18

[0223] The preparation method of Example 18 is basically the same as that of Example 15, the main difference being that in the fifth step reaction, compound x is used instead of compound u in Example 15 to prepare compound 18; that is:

[0224]

[0225] Under argon protection and at 0°C, compound f (28.6 mg, 0.1 mmol, 1 eq.) was added to 2 mL of anhydrous methanol / dichloromethane (v / v 1:1; 2 mL) solution, followed by N,N-diisopropylethylamine (32.25 mg, 0.25 mmol, 2.5 eq.) and compound x (35.7 mg, 0.15 mmol, 1.5 eq.), and the temperature was raised to 25°C. After stirring for 12 h, the reaction was quenched with saturated ammonium chloride aqueous solution, and the reaction solution was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to give compound 18 (36.2 mg, yield 71%).

[0226] Compound 18: 1 H NMR (400MHz, CDCl3) δ11.53(s,1H),7.78(d,J=8.5Hz,1H),7.43(t,J=8.3Hz,1H),7.20(m,2H),6.60(dd,J=8.0,5.9Hz,2H),4.52(d,J=12.6Hz,1H) ,4.22(d,J=12.6Hz,1H),3.31(d,J=20.2Hz,1H),2.68(d,J=14.8Hz,1H), 2.20(d,J=20.2Hz,1H),1.94(d,J=14.8Hz,1H),1.45(s,3H),1.23(s,3H); 13 C NMR (100MHz, CDCl3) δ204.7,199.2,192.5,191.1,163.3,161.2,156.5,139.0,131.9,129.3,126.3, 121.4,119.8,111.8,108.8,107.0,80.0,73.3,59.9,50.7,46.6,44.0,30.8,19.1,14.5; HR-ESI-MS m / z511.0387[M+H] + .

[0227] Example 19

[0228] The preparation method of Example 19 is basically the same as that of Example 15, the main difference being that in the fifth step reaction, compound y is used instead of compound u in Example 15 to prepare compound 19; that is:

[0229]

[0230] Under argon protection and at 0°C, compound f (28.6 mg, 0.1 mmol, 1 eq.) was added to 2 mL of anhydrous methanol / dichloromethane (v / v 1:1; 2 mL) solution, followed by N,N-diisopropylethylamine (32.25 mg, 0.25 mmol, 2.5 eq.) and compound y (25.8 mg, 0.15 mmol, 1.5 eq.), and the temperature was raised to 25°C. After stirring for 12 h, the reaction was quenched with saturated ammonium chloride aqueous solution, and the reaction solution was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to give compound 19 (15.5 mg, yield 35%).

[0231] Compound 19: 1 H NMR (400MHz, CDCl3) δ11.68 (s, 1H), 7.43 (m, 2H), 7.31 (m, 1H), 7.12 (d, J = 7.5Hz, 1H) ,6.64(d,J=8.4Hz,1H),6.59(d,J=8.2Hz,1H),3.35(d,J=20.2Hz,1H),2.72(s,1H), 2.67(d,J=14.3Hz,1H),2.53(m,1H),2.36(d,J=14.3Hz,1H),2.23(d,J=20.2Hz,1H) ,2.04(dd,J=14.0,8.4Hz,1H),1.89(m,2H),1.69(m,1H),1.47(s,3H),1.11(s,3H); 13 C NMR (100MHz, CDCl3) δ211.8,205.0,199.9,193.3,163.2,156.7,140.9,138.7,136.5,131.6,128.5,127.2 ,126.4,111.4,108.4,106.9,79.5,60.5,52.9,50.5,43.5,32.3,31.2,30.1,21.2,19.2,14.3; HR-ESI-MS m / z 445.1649[M+H] + .

[0232] Example 20

[0233] The preparation method of Example 20 is basically the same as that of Example 15, the main difference being that in the fifth step reaction, compound z is used instead of compound g in Example 1 to prepare compound 20; that is:

[0234]

[0235] Under argon protection and at 0°C, compound f (27.2 mg, 0.1 mmol, 1 eq.) was added to 2 mL of anhydrous 1,2-dichloroethane solution, followed by N,N-diisopropylethylamine (19.4 mg, 0.15 mmol, 1.5 eq.) and compound z (44.2 mg, 0.2 mmol, 2 eq.), and the mixture was stirred at 20°C for 8 h. The reaction was then quenched with saturated ammonium chloride aqueous solution, and the reaction solution was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography to give compound 20 (21.2 mg, yield 43%).

[0236] Compound 20: 1 H NMR (400MHz, CDCl3) δ11.52(s,1H),7.97(m,1H),7.45(t,J=8.3Hz,1H),6.82(t,J=8.3Hz,1H),6.63(m,3H),4.55(d,J=12.6Hz,1H),4.18(dd, J=49.4,9.9Hz,1H),3.35(t,J=20.1Hz,1H),2.73(d,J=14.7Hz,1H),2.25(d,J=20.2Hz,1H),1.97(d,J=14.8Hz,1H),1.49(s,3H),1.28(s,3H); 13 C NMR (100MHz, CDCl3) δ204.5,199.3,192.4,190.4,163.6,156.4,139.5,130.8,130.6,112.3,111.2,11 0.9,108.6,106.9,104.9,104.4,79.9,73.4,60.2,53.5,50.6,46.3,43.8,30.7,19.0,14.4; HR-ESI-MS m / z485.1206[M+H] + .

[0237] Compounds 1-20 obtained in Examples 1-20 were subjected to in vitro anti-osteosarcoma activity tests as polycyclic polyketides, as detailed below:

[0238] I. Experimental Materials and Methods

[0239] (1) Cell line

[0240] Osteosarcoma cell lines 143B and U2OS were purchased from the American Type Culture Collection (ATCC).

[0241] (2) Preparation methods of main reagents

[0242] RPMI-1640 culture medium: Dissolve RPMI-1640 medium solid and NaHCO3 (2.0g) in 100mL of double-distilled water, adjust the pH to 7.2-7.4 with concentrated hydrochloric acid, filter with a sterile filter and filter membrane, take 5mL for bacterial testing, and after ensuring sterility, add 100mL of serum and 10mL of double antibiotic solution, and dispense into small vials (FBS content is 10%), and store at 4℃ for later use.

[0243] (3) Phosphate Buffered Solution (PBS)

[0244] Weigh 1.56g Na2HPO4·12H2O, 8.00g NaCl, 0.20g K2HPO4 and 0.20g KCl and dissolve them in 900mL of double-distilled water. Adjust the pH to about 7.4, add double-distilled water to 1000mL, dispense into containers, autoclave, and store at 4℃ for later use.

[0245] (4) MTT solution

[0246] Weigh 250 mg of MTT solid and dissolve it in 50 mL of PBS. Filter to remove bacteria and store at 4 °C in the dark for later use.

[0247] (5) Cell Culture

[0248] At 37°C, RPMI-1640 medium containing U2OS or 143B cell lines in 10% FBS was placed in a 5% (v / v) CO2 cell culture incubator. When the cells reached approximately 80% confluence, the medium was removed, the cells were washed with PBS, and a certain amount of trypsin was added for digestion. Once the adherent cells became rounded, medium was added again to stop the digestion, and the cells were centrifuged. After resuspending the cells in the medium, an appropriate amount of the cell suspension was passaged. All cells used in each passage and experiment were logarithmically growing cells.

[0249] (6) Cell proliferation activity experiment

[0250] Osteosarcoma cells (143B, U2OS) in good growth condition and in the logarithmic growth phase were collected, digested, centrifuged, and resuspended. They were then incubated with 1×10⁻⁶ cells. 4Cells were seeded at a density of [number] cells / well in 96-well plates and incubated overnight at 37°C, 5% CO2, and 95% humidity. Then, different concentrations of polycyclic ketone compounds or the positive control cisplatin were added, and assays were performed at different time points (24h, 48h, and 72h). 20 μL of MTT was added to each well, and the plates were incubated for 2–4 h. The supernatant was discarded, and 100 μL of LDMSO was added to each well. The plates were shaken for 3 minutes using a microplate reader to ensure complete dissolution of the crystal violet. The absorbance of each well was measured using an automated microplate reader (wavelength 570 nm), with a reference wavelength of 630 nm. The OD values ​​of each well were read. The average absorbance values ​​for each group were calculated. Survival curves were plotted to determine the IC50 effect of polycyclic ketone compounds on cell proliferation at different time points and concentrations. 50 value.

[0251] II. Experimental Results

[0252] The experimental results are summarized in Table 1. The data in the table show that polycyclic ketone compounds 1-20 have significant anti-osteosarcoma cell 143B and U2OS activities. In particular, compounds 4 and 19 have better anti-osteosarcoma activities than the positive control drug, indicating that polycyclic ketone compounds have the potential to treat osteosarcoma.

[0253] Table 1

[0254]

[0255] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0256] The embodiments described above are merely illustrative of several implementation methods of this application, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the patent application. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of this application, and these all fall within the protection scope of this application. Therefore, the protection scope of this patent application should be determined by the appended claims, and the specification can be used to interpret the content of the claims.

Claims

1. A polycyclic polyketide compound having a structure as shown in formula (I) or a pharmaceutically acceptable salt thereof or an enantiomer thereof: wherein, X is selected from oxygen or -CH 2; n is an integer from 0 to 2; X is selected from -CH 2; the polycyclic polyketide compound is selected from any one of compounds 1-20: comprising the following steps: reacting compound Ia with compound Ib under the action of a first base to prepare compound Ic; reacting compound Ic with a first oxidizing agent to prepare compound Id; de-benzylating and de-methylating compound Id under the action of a Lewis acid to prepare compound Ie; reacting compound Ie with a second oxidizing agent to prepare compound If; reacting compound If with compound Ig under the action of a second base to prepare a polycyclic oxyanthracene compound having a structure as shown in formula (I); the preparation of compound Ic comprises the following steps: mixing compound Ia, compound Ib, a first base and a first solvent, and reacting at a temperature of -78 ℃ to -50 ℃ for 1 h to 4 h; wherein, the first base is at least one of n-butyllithium and tert-butyllithium; and / or the first solvent is at least one of tetrahydrofuran and diethyl ether; and / or the molar ratio of compound Ia, compound Ib and the first base is 1: (1-3) : (1-3). the preparation of compound Id comprises the following steps: mixing compound Ic, a second solvent and a first oxidizing agent, and reacting at a temperature of 0 ℃ to 30 ℃ for 0.5 h to 12 h; wherein, the second solvent is at least one of dichloromethane, 1, 2-dichloroethane and acetone; and / or the first oxidizing agent is at least one of manganese dioxide, des-martin reagent and Jones reagent; and / or the molar ratio of compound Ic and the first oxidizing agent is 1: (1-20). the preparation of compound Ie comprises the following steps: mixing compound Id, a third solvent and a Lewis acid, and reacting at a temperature of 0 ℃ to 30 ℃ for 1 h to 5 h; wherein, the third solvent is at least one of dichloromethane and 1, 2-dichloroethane; and / or the Lewis acid is at least one of boron tribromide and boron trichloride; and / or the molar ratio of compound Id and the Lewis acid is 1: (3-20). the preparation of compound If comprises the following steps: mixing compound Ie, a fourth solvent and a second oxidizing agent, and reacting at a temperature of 0 ℃ to 30 ℃ for 1 h to 12 h; wherein, the fourth solvent is at least one of diethyl ether, acetonitrile, ethylene glycol dimethyl ether and dichloromethane; and / or the second oxidizing agent is at least one of silver oxide, [bis (trifluoroacetoxy) iodine] benzene, peroxide bis-lauric acid and di-tert-butyl peroxide; and / or the molar ratio of compound Ie and the second oxidizing agent is 1: (1-5). the reaction of compound If with compound Ig under basic conditions comprises the following steps: mixing compound If, a fifth solvent and a second base, and reacting at a temperature of 0 ℃ to 30 ℃ for 6 h to 12 h; wherein, the fifth solvent is at least one of methanol, ethanol, dichloromethane and 1, 2-dichloroethane; and / or ​ ​ ​ R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are each independently selected from C1-C6alkyl, C1-C6alkoxy, C1-C4haloalkyl, halogen, hydroxyl, or hydrogen.

2. The polycyclic polyketide compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are each independently selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, n-pentyl, i-pentyl, n-hexyl, i-hexyl, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy, n-pentoxy, i-pentoxy, n-hexoxy, i-hexoxy, fluoromethyl, chloromethyl, bromomethyl, iodomethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2-chloroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 1-fluoropropyl, 2-chloropropyl, 3-fluoropropyl, 3-chloropropyl, 1-fluorobutyl, 1-chlorobutyl, 4-fluorobutyl, fluorine, chlorine, bromine, iodine, hydroxyl, or hydrogen.

3. The polycyclic polyketide compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein ​ R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are each independently selected from the group consisting of C1-C3alkoxy, halogen or hydrogen.

4. The polycyclic polyketide compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein ​ 5. A method for producing the polycyclic polyketide compound according to any one of claims 1 to 4, characterized by, ​ ​ ​ ​ ​ ​ wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X and n are as defined in any one of claims 1 to 4; 6. The process for preparing a polycyclic polyketide compound according to claim 5, wherein ​ ​ ​ ​ ​ 7. The process for preparing a polycyclic polyketide compound according to claim 5, wherein ​ ​ ​ ​ ​ 8. The process for preparing a polycyclic polyketide compound according to claim 5, wherein ​ ​ ​ ​ ​ 9. The process for preparing a polycyclic polyketide compound according to claim 5, wherein ​ ​ ​ ​ ​ 10. The process for preparing a polycyclic polyketide compound according to claim 5, wherein ​ ​ ​ the second base is at least one of triethylamine and N,N-diisopropylethylamine; and / or the molar ratio of the compound If, the compound Ig and the second base is 1:(1-3):(1-3).

11. A pharmaceutical composition, characterized by, The polycyclic polyketide compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4; and a pharmaceutically acceptable carrier.

12. Use of the polycyclic polyketide compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, or the pharmaceutical composition according to claim 11, for the manufacture of a medicament for treating osteosarcoma.

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