Polycyclic polyketone compound as well as preparation method, pharmaceutical composition and application thereof

Abstract

The invention relates to a polycyclic polyketone compound as well as a preparation method, a pharmaceutical composition and application thereof. The chemical structure type of the polycyclic polyketone compound is different from that of an existing anti-osteosarcoma chemotherapeutic drug, and the polycyclic polyketone compound is a compound with a brand new structure. Meanwhile, through experiments, the inventor finds that the polycyclic polyketone compound has remarkable activity of resisting osteosarcoma cells 143B and U2OS, the osteosarcoma resisting activity of part of the compound is superior to that of a positive control drug, and the result further shows that the polycyclic polyketone compound can remarkably inhibit growth of osteosarcoma; the compound is expected to be developed into a novel anti-osteosarcoma medicine, and can be used for treating osteosarcoma and bone joint pain, lung diseases and other diseases caused by osteosarcoma. Furthermore, the synthetic route of the polycyclic polyketone compound is efficient and simple, and meanwhile, the method has good raw material economy.

Description

Technical Field

[0001] The present application relates to the field of medical technology, and in particular to a polycyclic polyketone compound, a preparation method thereof, a pharmaceutical composition and application thereof. Background Art

[0002] Osteosarcoma, also known as osteogenic sarcoma, originates from primitive mesenchymal cells and is the most common tumor in the spectrum of primary malignant bone tumors in children and adolescents. To date, the main treatments for osteosarcoma are chemotherapy and surgery. Among them, chemotherapy is still the most commonly used method for treating osteosarcoma. Since the 1970s, doxorubicin, cisplatin, methotrexate and ifosfamide have been used as the main drugs for the treatment of osteosarcoma, which can increase the 5-year survival rate of osteosarcoma patients to about 70%. However, the current treatment of osteosarcoma still has the following problems: (1) serious adverse drug reactions; (2) drugs are prone to drug resistance and the effect is poor. In the past 20 years, although osteosarcoma treatment drugs levofloxacin calcium injection and mivastatin have been approved for marketing by the US FDA and Europe, respectively, they still have the above problems. Therefore, it is of great significance to develop new osteosarcoma treatment drugs. Summary of the invention

[0003] Based on this, it is necessary to provide a polycyclic polyketone compound and a preparation method, a pharmaceutical composition and application thereof, wherein the polycyclic polyketone compound can significantly inhibit the growth of osteosarcoma and can be used to treat osteosarcoma and diseases such as bone and joint pain and lung disease caused by it.

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

[0005] In a first aspect of the present invention, there is provided a polycyclic polyketone compound having a structure as shown in the following 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 from 0 to 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-pentyloxy, isopentyl, n-hexyl, isohexyl, 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 polyketone compound is selected from any one of compounds 1-20:

[0015]

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

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

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

[0019] Compound Id is subjected to debenzylation and demethylation reactions under the action of Lewis acid to prepare compound Ie;

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

[0021] Compound If reacts with compound Ig under the action of a second base to prepare a polycyclic oxygenated anthracene compound having a structure as 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 comprises the following steps:

[0025] Compound Ia, compound Ib, a first base and a first solvent are mixed, and reacted at a temperature of -78°C to -50°C for 1h to 4h;

[0026] Wherein, the first base is at least one of n-butyl lithium and tert-butyl lithium; and / or

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

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

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

[0030] Mixing compound Ic, a second solvent and a first oxidant, and reacting them at a temperature of 0°C to 30°C for 0.5h to 12h; wherein the second solvent is at least one of dichloromethane, 1,2-dichloroethane and acetone; and / or

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

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

[0033] In one embodiment, the preparation of compound 1e comprises the following steps:

[0034] Compound Id, a third solvent and a Lewis acid are mixed, and reacted at a temperature of 0° C. to 30° C. for 1 h to 5 h;

[0035] Wherein, the third solvent is at least one of 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 the compound Id to the Lewis acid is 1:(3-20).

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

[0039] Mixing compound Ie, the fourth solvent and the second oxidant, and reacting at a temperature of 0° C. to 30° C. for 1 h to 12 h;

[0040] Wherein, the fourth solvent is at least one of diethyl ether, acetonitrile, ethylene glycol dimethyl ether and dichloromethane; and / or

[0041] The second oxidant is at least one of silver oxide, [bis(trifluoroacetoxy)iodo]benzene, dilauroyl peroxide and di-tert-butyl peroxide; and / or

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

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

[0044] Mixing the compound If, the fifth solvent and the second base, and reacting at a temperature of 0° C. to 30° C. for 6 h to 12 h;

[0045] Wherein, the fifth solvent is at least one of 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] The third aspect of the present invention provides a pharmaceutical composition, comprising the polycyclic polyketide compound or a pharmaceutically acceptable salt thereof as described above; and a pharmaceutically acceptable carrier.

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

[0050] The fifth aspect of the present invention provides the use of the polycyclic polyketide compound or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described above, in the preparation of a drug for treating bone and joint pain and lung disease caused by osteosarcoma.

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

[0052] The present application provides a polycyclic polyketone compound or a pharmaceutically acceptable salt thereof. The chemical structure type of the polycyclic polyketone compound is different from that of existing anti-osteosarcoma chemotherapy drugs and is a compound with a completely new structure. At the same time, the inventors have found through experiments that the polycyclic polyketone compound has significant anti-osteosarcoma cell 143B and U2OS activity, and the anti-osteosarcoma activity of some compounds is better than that of the positive control drug. This result further shows that the polycyclic polyketone compound of the present application can significantly inhibit the growth of osteosarcoma and is expected to be developed into a new type of anti-osteosarcoma drug, which can be used to treat osteosarcoma and diseases such as bone and joint pain and lung disease caused by it.

[0053] Furthermore, the synthesis route of the polycyclic polyketone compounds adopted in the present application is efficient and simple, and has good raw material economy. DETAILED DESCRIPTION

[0054] The present application will be further described in detail below in conjunction with specific embodiments. The present application can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the disclosure of the present application more thoroughly understood.

[0055] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which this application belongs. The terms used herein in the specification of this application are only for the purpose of describing specific embodiments and are not intended to limit this application.

[0056] Unless otherwise specified or incompatible herewith, the terms and phrases used herein shall have the following meanings:

[0057] Herein, 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, or a secondary carbon atom, or a tertiary carbon atom, or a quaternary carbon atom, or a combination thereof. Phrases containing this term, for example, "C1-C6 alkyl" refers to an alkyl group containing 1 to 6 carbon atoms, and each occurrence can be independently C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, 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( 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] As used herein, the term "haloalkyl" refers to a straight or branched saturated aliphatic hydrocarbon group having a specific number of carbon atoms, wherein the hydrogen atoms are replaced by halogen atoms. For example, C1 to 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, and the like.

[0059] Herein, the term "alkoxy" refers to a straight or branched saturated aliphatic hydrocarbon group having a specific number of carbon atoms and an oxygen atom. For example, C1-C6 haloalkyl includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, n-pentoxy, isopentoxy, n-hexoxy, isohexoxy, etc.

[0060] As used herein, "pharmaceutically acceptable" refers to those ligands, materials, compositions, and / or dosage forms that are suitable for administration to a patient within the scope of sound medical judgment and commensurate with a reasonable benefit / risk ratio.

[0061] Herein, "pharmaceutically acceptable salt" refers to a salt suitable for use as a drug formed by any compound in the structure shown and an acid or base. Pharmaceutically acceptable salts include inorganic salts and organic salts. Among them, one type of salt is a salt formed by the compound of the present application and an acid. Acids suitable for forming salts 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 a salt formed by a compound of the present application and a base. Suitable bases for forming salts include but are not limited to alkali metal salts (such as sodium salts or potassium salts), alkaline earth metal salts (such as magnesium salts or calcium salts), ammonium salts (such as lower alkanolammonium salts and other pharmaceutically acceptable amine salts), for example, 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] As used herein, "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. As used herein, the language "pharmaceutically acceptable carrier" includes buffers, sterile water for injection, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are compatible with drug administration. Each carrier must be "pharmaceutically acceptable" in the sense of being compatible with the other ingredients in the formulation and not harmful 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 carboxymethylcellulose, ethylcellulose and cellulose acetate; (4) powdered tragacanth; (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 starch, etc. 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] Herein, a "composition" may be a combination of multiple substances, and further, may be used in combination, or may be a mixture of the combination.

[0064] As used herein, "one or more" refers to any one, any two, or any two or more of the listed items.

[0065] Herein, the optional scope of "and / or", "or / and", and "and / or" includes any one of two or more relevant listed items, and also includes any and all combinations of the relevant listed items, wherein said any and all combinations include any two relevant listed items, any more relevant listed items, or a combination of all relevant listed items.

[0066] Herein, "further", "further", "particularly" and the like are used for descriptive purposes to indicate differences in content, but should not be construed as limiting the scope of protection of this application.

[0067] Herein, "first aspect", "second aspect", "third aspect", "fourth aspect", etc. are used for descriptive purposes only and cannot be understood as indicating or implying relative importance or quantity, nor can they be understood as implicitly indicating the importance or quantity of the indicated technical features. In addition, "first", "second", "third", "fourth", etc. only serve the purpose of non-exhaustive enumeration and description, and it should be understood that they do not constitute a closed limitation on quantity. Therefore, the features defined as "first" and "second" may explicitly or implicitly include at least one of the features. In the description of the present application, the meaning of "multiple" is at least two, such as two, three, etc., unless otherwise clearly and specifically defined. In the description of the present application, the meaning of "several" is at least one, such as one, two, etc., unless otherwise clearly and specifically defined.

[0068] In this application, when it comes to numerical ranges, unless otherwise specified, the above numerical ranges are deemed to be continuous and include the minimum and maximum values ​​of the range, as well as each value between such minimum and maximum values. Further, when a range refers to an integer, each integer between the minimum and maximum values ​​of the range is included. In addition, when multiple ranges are provided to describe features or characteristics, the ranges can be merged. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all subranges included therein.

[0069] The percentage contents involved in this application, unless otherwise specified, refer to mass percentage for solid-liquid mixing and solid-solid mixing, and refer to volume percentage for liquid-liquid mixing.

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

[0071] The temperature parameters in this application, unless otherwise specified, allow both constant temperature treatment and treatment within a certain temperature range. The constant temperature treatment allows the temperature to fluctuate within the accuracy range controlled by the instrument. Fluctuations within the range of ±5°C, ±2°C, ±1°C, ±0.5°C, ±0.4°C, ±0.3°C, ±0.2°C, and ±0.1°C are allowed.

[0072] In a first aspect of the present invention, there is provided a polycyclic polyketone compound having a structure as shown in the following 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 from 0 to 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-pentyloxy, isopentyl, n-hexyl, isohexyl, 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 polyketone compound is selected from any one of compounds 1-20:

[0082]

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

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

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

[0086] Compound Id is subjected to debenzylation and demethylation reactions under the action of Lewis acid to prepare compound Ie;

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

[0088] Compound If reacts with compound Ig under the action of a second base to prepare a polycyclic oxygenated anthracene compound having a structure as 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 examples, the preparation of compound Ic includes the following steps:

[0092] Compound Ia, compound Ib, a first base and a first solvent are mixed and reacted at a temperature of -78°C to -50°C for 1 h to 4 h.

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

[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 the compound Ia, the compound Ib and the first base is 1:(1-3):(1-3). It can be understood that the molar ratio of the compound Ia, the compound Ib and the first base includes but is not limited to 1:1:1, 1:2:1, 1:3:1, 1:1:2, 1:1:3.

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

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

[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, Dess-Martin reagent, and Jones reagent.

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

[0101] In some examples, the preparation of compound 1e includes the following steps:

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

[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 the compound Id to the Lewis acid is 1:(3-20). It can be understood that the molar ratio of the compound Id to the Lewis acid includes but is not limited to 1:3, 1:5, 1:10, 1:15, 1:20.

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

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

[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)iodo]benzene, dilauroyl peroxide and di-tert-butyl peroxide.

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

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

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

[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 the compound If, the compound Ig and the second base is 1:(1-3):(1-3). It can be understood that the molar ratio of the compound If, the compound Ig and the second base includes but is not limited to 1:1:1, 1:2:1, 1:3:1, 1:1:2, 1:1:3.

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

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

[0118] The fifth aspect of the present invention provides the use of the polycyclic polyketide compound or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described above, in the preparation of a drug for treating bone and joint pain and lung disease caused by osteosarcoma.

[0119] The following is further described in conjunction with specific embodiments. The raw materials involved in the following specific embodiments, unless otherwise specified, can all be commercially available; the instruments used, unless otherwise specified, can all be commercially available; the processes involved, unless otherwise specified, are all routinely selected by those skilled in the art.

[0120] The following are specific embodiments.

[0121] Example 1

[0122]

[0123] Step 1: Under argon protection and -78°C, compound b (2.24 g, 10 mmol, 1 eq.) was added to 50 mL of anhydrous tetrahydrofuran solution, followed by slow addition of n-butyl lithium (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. Water was then added to quench the reaction, and the reaction solution was extracted 3 times with ethyl acetate. The organic phases were combined, washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure. The crude product was separated and purified by silica gel column chromatography to obtain 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 0°C, compound c (121 mg, 0.25 mmol, 1 eq.) was added to 5 mL of anhydrous dichloromethane solution, followed by slow addition of manganese dioxide (435 mg, 0.25 mmol, 20 eq.), and stirred at 30°C for 12 h. Subsequently, a saturated aqueous sodium sulfite solution was added to quench the reaction, and the reaction solution was extracted 3 times with ethyl acetate. The organic phases were combined, washed with a saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure. The crude product was separated and purified by silica gel column chromatography to obtain compound d (72.3 mg, 62% yield).

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

[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 0°C, compound e (288 mg, 1 mmol, 1 eq.) was added to 10 mL of anhydrous ether solution, followed by the addition of silver oxide (231 mg, 1 mmol, 1 eq.) and stirred at 0°C for 1 h. Subsequently, a saturated aqueous sodium sulfite solution was added to quench the reaction, and the reaction solution was extracted with ethyl acetate 3 times. The organic phases were combined, washed with a saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure. The crude product was separated and purified by silica gel column chromatography to obtain compound f (165.9 mg, 61% yield).

[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 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 stirred at 0°C for 12 h. Subsequently, a saturated aqueous solution of ammonium chloride was added to quench the reaction, and the reaction solution was extracted 3 times with ethyl acetate. The organic phases were combined, washed with a saturated aqueous solution of NaCl, dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure. The crude product was separated and purified by silica gel column chromatography to obtain compound 1 (158.1 mg, 38% yield).

[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, except that in the fifth step, compound h is used instead of compound g in Example 1 to prepare compound 2; that is:

[0135]

[0136] Under argon protection and 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 stirred at 0°C for 6 h. Subsequently, a saturated aqueous solution of ammonium chloride was added to quench the reaction, and the reaction solution was extracted 3 times with ethyl acetate. The organic phases were combined, washed with a saturated aqueous solution of NaCl, dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure. The crude product was separated and purified by silica gel column chromatography to obtain compound 2 (91.1 mg, with a yield of 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, except that in the fifth step, compound i is used instead of compound g in Example 1 to prepare compound 3; that is:

[0140]

[0141] Under argon protection and 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 stirred at 30°C for 8 h. Subsequently, saturated aqueous ammonium chloride solution was added to quench the reaction, and the reaction solution was extracted 3 times with ethyl acetate. The organic phases were combined, washed with saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure. The crude product was separated and purified by silica gel column chromatography to obtain compound 3 (20.2 mg, 45% yield).

[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, except that in the fifth step, compound j is used instead of compound g in Example 1 to prepare compound 4; that is:

[0145]

[0146] Under argon protection and 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 stirred at 20°C for 8 h. Subsequently, saturated aqueous ammonium chloride solution was added to quench the reaction, and the reaction solution was extracted 3 times with ethyl acetate. The organic phases were combined, washed with saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure. The crude product was separated and purified by silica gel column chromatography to obtain compound 4 (21.2 mg, 43% yield).

[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 -78°C, compound b (672 mg, 3 mmol, 3 eq.) was added to 15 mL of anhydrous ether solution, followed by slow addition of tert-butyl lithium (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 stirred at -50°C for 3 h. Water was then added to quench the reaction, and the reaction solution was extracted 3 times with ethyl acetate. The organic phases were combined, washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure. The crude product was separated and purified by silica gel column chromatography to obtain compound c (392 mg, 81% yield).

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

[0152] Step 3: Under argon protection and 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 slow addition of boron trichloride (1 M in CH2Cl2, 2 mL, 2 mmol, 20 eq.) and the temperature was raised to 30°C and stirred for 5 h. Subsequently, a saturated aqueous sodium bicarbonate solution was added to quench the reaction, and the reaction solution was extracted with ethyl acetate three times. The organic phases were combined, washed with a saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure. The crude product was separated and purified by silica gel column chromatography to obtain compound e (10.1 mg, 35% yield).

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

[0154] Step 5: Under argon protection and 0°C, compound f (27.2 mg, 0.1 mmol, 1 eq.) was added to 2 mL of anhydrous ethanol solution, followed by the addition of 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, a saturated aqueous solution of ammonium chloride was added to quench the reaction, and the reaction solution was extracted with ethyl acetate 3 times. The organic phases were combined, washed with a saturated aqueous solution of NaCl, dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure. The crude product was separated and purified by silica gel column chromatography to obtain compound 5 (11.6 mg, with a yield of 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, except that in the fifth step, compound 1 is used instead of compound k in Example 5 to prepare compound 6; that is:

[0158]

[0159] Under argon protection and 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 the addition of 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, a saturated aqueous solution of ammonium chloride was added to quench the reaction, and the reaction solution was extracted with ethyl acetate three times. The organic phases were combined, washed with a saturated aqueous solution of NaCl, dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure. The crude product was separated and purified by silica gel column chromatography to obtain 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, except that in the fifth step, compound m is used instead of compound k in Example 5 to prepare compound 7; that is:

[0163]

[0164] Under argon protection and 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 the addition of 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, a saturated aqueous solution of ammonium chloride was added to quench the reaction, and the reaction solution was extracted with ethyl acetate three times. The organic phases were combined, washed with a saturated aqueous solution of NaCl, dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure. The crude product was separated and purified by silica gel column chromatography to obtain compound 7 (17.4 mg, 39% yield).

[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, except that in the fifth step, compound n is used instead of compound k in Example 5 to prepare compound 8; that is:

[0168]

[0169] Under argon protection and 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 the addition of 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, a saturated aqueous solution of ammonium chloride was added to quench the reaction, and the reaction solution was extracted with ethyl acetate three times. The organic phases were combined, washed with a saturated aqueous solution of NaCl, dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure. The crude product was separated and purified by silica gel column chromatography to obtain 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, compound o is used instead of compound k in Example 5 to prepare compound 9; namely:

[0173]

[0174] Under argon protection and 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 the addition of 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, a saturated aqueous solution of ammonium chloride was added to quench the reaction, and the reaction solution was extracted with ethyl acetate three times. The organic phases were combined, washed with a saturated aqueous solution of NaCl, dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure. The crude product was separated and purified by silica gel column chromatography to obtain 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, except that in the fifth step, compound p is used instead of compound k in Example 5 to prepare compound 10; that is:

[0178]

[0179] Under argon protection and 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 the addition of 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, a saturated aqueous solution of ammonium chloride was added to quench the reaction, and the reaction solution was extracted with ethyl acetate three times. The organic phases were combined, washed with a saturated aqueous solution of NaCl, dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure. The crude product was separated and purified by silica gel column chromatography to obtain 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] Embodiment 11

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

[0183]

[0184] Under argon protection and 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 the addition of 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, a saturated aqueous solution of ammonium chloride was added to quench the reaction, and the reaction solution was extracted with ethyl acetate three times. The organic phases were combined, washed with a saturated aqueous solution of NaCl, dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure. The crude product was separated and purified by silica gel column chromatography to obtain 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, except that in the fifth step, compound r is used instead of compound k in Example 5 to prepare compound 12; that is:

[0188]

[0189] Under argon protection and 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 the addition of 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, a saturated aqueous solution of ammonium chloride was added to quench the reaction, and the reaction solution was extracted with ethyl acetate three times. The organic phases were combined, washed with a saturated aqueous solution of NaCl, dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure. The crude product was separated and purified by silica gel column chromatography to obtain 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] Embodiment 13

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

[0193]

[0194] Under argon protection and 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 the addition of 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, a saturated aqueous solution of ammonium chloride was added to quench the reaction, and the reaction solution was extracted with ethyl acetate three times. The organic phases were combined, washed with a saturated aqueous solution of NaCl, dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure. The crude product was separated and purified by silica gel column chromatography to obtain 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] Embodiment 14

[0197]

[0198] Step 1: Under argon protection and -78°C, compound b (488 mg, 2 mmol, 2 eq.) was added to 15 mL of anhydrous ether solution, followed by slow addition of tert-butyl lithium (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. Water was then added to quench the reaction, and the reaction solution was extracted 3 times with ethyl acetate. The organic phases were combined, washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure. The crude product was separated and purified by silica gel column chromatography to obtain compound tc (358.6 mg, with a yield of 72%).

[0199] Step 2: Under argon protection and 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 stirred at 5°C for 0.5 h. Saturated aqueous sodium sulfite solution was then added to quench the reaction, and the reaction solution was extracted 3 times with ethyl acetate. The organic phases were combined, washed with saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure. The crude product was separated and purified by silica gel column chromatography to obtain compound td (9.92 mg, 8% yield).

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

[0201] Step 4: Under argon protection and 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 dilauroyl peroxide (19.95 mg, 0.5 mmol, 5 eq.) and a catalytic amount of copper acetate, and the temperature was raised to 20°C. After stirring for 5 h, a saturated aqueous sodium sulfite solution was added to quench the reaction, and the reaction solution was extracted 3 times with ethyl acetate. The organic phases were combined, washed with a saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure. The crude product was separated and purified by silica gel column chromatography to obtain compound tf (4.0 mg, yield 14%).

[0202] Step 5: Under argon protection and 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 the addition of 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, a saturated aqueous solution of ammonium chloride was added to quench the reaction, and the reaction solution was extracted with ethyl acetate three times. The organic phases were combined, washed with a saturated aqueous solution of NaCl, dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure. The crude product was separated and purified by silica gel column chromatography to obtain 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] Embodiment 15

[0205]

[0206] Step 1: Under argon protection and -78°C, compound b (366 mg, 1.5 mmol, 1.5 eq.) was added to 15 mL of anhydrous ether solution, followed by slow addition of n-butyl lithium (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 stirred at -60°C for 1.5 h. Water was then added to quench the reaction, and the reaction solution was extracted 3 times with ethyl acetate. The organic phases were combined, washed with a saturated aqueous solution of NaCl, dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure. The crude product was separated and purified by silica gel column chromatography to obtain compound c (251.7 mg, with a yield of 52%).

[0207] Step 2: Under argon protection and 0°C, compound c (124.5 mg, 0.25 mmol, 1 eq.) was added to 2.5 mL of anhydrous dichloromethane solution. Subsequently, Dess-Martin 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, a saturated aqueous sodium sulfite solution was added to quench the reaction, and the reaction solution was extracted 3 times with ethyl acetate. The organic phases were combined, washed with a saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure. The crude product was separated and purified by silica gel column chromatography to obtain compound d (97.6 mg, with a yield of 81%).

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

[0209] Step 4: Under argon protection and 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, and the temperature was raised to 25°C. After stirring for 8 h, a saturated aqueous sodium sulfite solution was added to quench the reaction, and the reaction solution was extracted 3 times with ethyl acetate. The organic phases were combined, washed with a saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure. The crude product was separated and purified by silica gel column chromatography to obtain compound f (6.8 mg, yield 25%).

[0210] Step 5: Under argon protection and 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 the addition of 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, a saturated aqueous solution of ammonium chloride was added to quench the reaction, and the reaction solution was extracted with ethyl acetate three times. The organic phases were combined, washed with a saturated aqueous solution of NaCl, dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure. The crude product was separated and purified by silica gel column chromatography to obtain 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, except that in the fifth step, compound v is used instead of compound u in Example 15 to prepare compound 16; that is:

[0214]

[0215] Under argon protection and 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 the addition of 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, a saturated aqueous solution of ammonium chloride was added to quench the reaction, and the reaction solution was extracted with ethyl acetate three times. The organic phases were combined, washed with a saturated aqueous solution of NaCl, dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure. The crude product was separated and purified by silica gel column chromatography to obtain 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] Embodiment 17

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

[0219]

[0220] Under argon protection and 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 the addition of 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, a saturated aqueous solution of ammonium chloride was added to quench the reaction, and the reaction solution was extracted with ethyl acetate three times. The organic phases were combined, washed with a saturated aqueous solution of NaCl, dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure. The crude product was separated and purified by silica gel column chromatography to obtain 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] Embodiment 18

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

[0224]

[0225] Under argon protection and 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 the addition of 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, a saturated aqueous solution of ammonium chloride was added to quench the reaction, and the reaction solution was extracted with ethyl acetate three times. The organic phases were combined, washed with a saturated aqueous solution of NaCl, dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure. The crude product was separated and purified by silica gel column chromatography to obtain 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] Embodiment 19

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

[0229]

[0230] Under argon protection and 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 the addition of 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, a saturated aqueous solution of ammonium chloride was added to quench the reaction, and the reaction solution was extracted with ethyl acetate three times. The organic phases were combined, washed with a saturated aqueous solution of NaCl, dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure. The crude product was separated and purified by silica gel column chromatography to obtain compound 19 (15.5 mg, 35% yield).

[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] Embodiment 20

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

[0234]

[0235] Under argon protection and 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 stirred at 20°C for 8 h. Subsequently, saturated aqueous ammonium chloride solution was added to quench the reaction, and the reaction solution was extracted 3 times with ethyl acetate. The organic phases were combined, washed with saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure. The crude product was separated and purified by silica gel column chromatography to obtain compound 20 (21.2 mg, 43% yield).

[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 prepared in Examples 1 to 20 were tested for in vitro anti-osteosarcoma activity of polycyclic polyketide compounds, as follows:

[0238] 1. Experimental Materials and Methods

[0239] (1) Cell lines

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

[0241] (2) Preparation method of main reagents

[0242] RPMI-1640 culture medium: RPMI-1640 culture medium solid and NaHCO3 (2.0 g) were dissolved in 100 mL of double distilled water, concentrated hydrochloric acid was added to adjust the pH to 7.2-7.4, and filtered with a sterilized filter and filter membrane. 5 mL was taken for bacteria testing. After ensuring sterility, 100 mL of serum and 10 mL of double antibody solution were added, and the solution was divided into small bottles (FBS content was 10%) and stored at 4°C for later use.

[0243] (3) Phosphate buffered saline (PBS)

[0244] Weigh 1.56 g Na2HPO4·12H2O, 8.00 g NaCl, 0.20 g K2HPO4 and 0.20 g KCl and dissolve them in 900 mL double distilled water. Adjust the pH to about 7.4, add double distilled water to 1000 mL, divide and sterilize by high pressure, and store at 4°C for later use.

[0245] (4) MTT solution

[0246] Weigh MTT solid (250 mg) and dissolve it in PBS (50 mL), filter and sterilize it, and store it at 4°C in the dark for future use.

[0247] (5) Cell culture

[0248] At 37°C, RPMI-1640 medium containing 10% FBS of cell line U2OS or 143B was placed in a cell culture incubator with 5% (V / V) CO2. When the cells were attached to the wall and confluent to about 80%, the medium was removed, washed with PBS, and a certain amount of trypsin was added for digestion. When the attached cells became round, the medium was added, the digestion was terminated and centrifuged. After the medium was resuspended, an appropriate amount of cell suspension was taken for subculture. The cells used for each subculture and experiment were logarithmically growing cells.

[0249] (6) Cell proliferation activity assay

[0250] Osteosarcoma cells (143B, U2OS) in good growth state and in logarithmic growth phase were digested, centrifuged and resuspended. 4Cells were seeded in a 96-well plate at a density of 100 cells / well and cultured overnight in an incubator at 37°C, 5% CO2, and 95% humidity. Next, different concentrations of polycyclic polyketide compounds or positive control drug cisplatin were added, and the plates were tested at different time points (24h, 48h, and 72h). 20μL of MTT was added to each well, and the culture was continued for 2-4h. The supernatant was discarded, and 100μL of DMSO was added to each well. The plates were shaken for 3 minutes using a micro-oscillator to ensure that the crystal violet was completely dissolved. The absorbance of each well was detected using an automatic microplate reader (wavelength 570nm), and a reference wavelength of 630nm was used. The OD value of each well was read. The average absorbance value of each group was calculated. The IC value of polycyclic polyketide compounds on cell proliferation at different time points and concentrations was determined by drawing survival curves. 50 value.

[0251] 2. Experimental Results

[0252] The experimental results are summarized in Table 1. From the data in the table, it can be seen that polycyclic polyketide compounds 1-20 have significant anti-osteosarcoma cell 143B and U2OS activity, especially compound 4 and compound 19 have better anti-osteosarcoma activity than the positive control drug, indicating that polycyclic polyketide compounds have the potential to treat osteosarcoma.

[0253] Table 1

[0254]

[0255] The technical features of the above-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the technical features in the above-described 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 above-described embodiments only express several implementation methods of the present application, and the descriptions thereof are relatively specific and detailed, but they cannot be construed as limiting the scope of the patent application. It should be pointed out that, for a person of ordinary skill in the art, several variations and improvements can be made without departing from the concept of the present application, and these all belong to the protection scope of the present application. Therefore, the protection scope of the patent application shall be subject to the attached claims, and the description may be used to interpret the content of the claims.

Claims

1. A polycyclic polyketone compound having a structure as shown in the following formula (I) or a pharmaceutically acceptable salt or an enantiomer thereof: in, X is selected from oxygen or -CH2; n is an integer from 0 to 2; 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.

2. The polycyclic polyketide compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: 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-pentyloxy, isopentyl, n-hexyl, isohexyl, 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, characterized in that: X is selected from -CH2; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 Each is independently selected from C1-C3 alkoxy, halogen or hydrogen.

4. The polycyclic polyketone compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The polycyclic polyketone compound is selected from any one of compounds 1-20:

5. A method for preparing a polycyclic polyketone compound according to any one of claims 1 to 4, characterized in that: The following steps are involved: Compound Ia reacts with compound Ib under the action of a first base to prepare compound Ic; Compound Ic reacts with a first oxidant to prepare compound Id; Compound Id is subjected to debenzylation and demethylation reactions under the action of Lewis acid to prepare compound Ie; Compound Ie reacts with a second oxidant to prepare compound If; Compound If reacts with compound Ig under the action of a second base to prepare a polycyclic oxygenated anthracene compound having a structure as shown in formula (I); Among them, 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 method for preparing the polycyclic polyketone compound according to claim 5, characterized in that: The preparation of compound Ic comprises the following steps: Compound Ia, compound Ib, a first base and a first solvent are mixed, and reacted at a temperature of -78°C to -50°C for 1h to 4h; Wherein, the first base is at least one of n-butyl lithium and tert-butyl lithium; and / or The first solvent is at least one of tetrahydrofuran and diethyl ether; and / or The molar ratio of the compound Ia, the compound Ib and the first base is 1:(1-3):(1-3).

7. The method for preparing the polycyclic polyketone compound according to claim 5, characterized in that: The preparation of compound Id comprises the following steps: Compound Ic, the second solvent and the 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 of dichloromethane, 1,2-dichloroethane and acetone; and / or The first oxidant is at least one of manganese dioxide, Dess-Martin reagent, and Jones reagent; and / or The molar ratio of the compound Ic to the first oxidant is 1:(1-20).

8. The method for preparing the polycyclic polyketone compound according to claim 5, characterized in that: The preparation of compound 1e comprises the following steps: Compound Id, a third solvent and a Lewis acid are mixed, and reacted at a temperature of 0° C. to 30° C. 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 the compound Id to the Lewis acid is 1:(3-20).

9. The method for preparing the polycyclic polyketone compound according to claim 5, characterized in that: The preparation of compound If comprises the following steps: Mixing compound Ie, the fourth solvent and the second oxidant, and reacting at a temperature of 0° C. to 30° C. 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 oxidant is at least one of silver oxide, [bis(trifluoroacetoxy)iodo]benzene, dilauroyl peroxide and di-tert-butyl peroxide; and / or The molar ratio of the compound Ie to the second oxidant is 1:(1-5).

10. The method for preparing the polycyclic polyketone compound according to claim 5, characterized in that: The reaction of compound If with compound Ig under alkaline conditions comprises the following steps: Mixing the compound If, the fifth solvent and the second base, and reacting at a temperature of 0° C. to 30° C. for 6 h to 12 h; Wherein, the fifth solvent is at least one of methanol, ethanol, dichloromethane and 1,2-dichloroethane; and / or 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 in that The invention comprises the polycyclic polyketone 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, in the preparation of a medicament for treating osteosarcoma.

13. 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, in the preparation of a medicament for treating bone and joint pain and lung disease caused by osteosarcoma.

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