Compound for treating oxaliplatin-resistant tumors, preparation method therefor, composition and use thereof

Abstract

A 1,1'-binaphthyl-2,2'-diamine platinum oxide for treating oxaliplatin-resistant tumors, a pharmaceutical composition thereof and the use thereof. The 1,1'-binaphthyl-2,2'-diamine platinum oxide has a structure shown as formula (I). The 1,1'-binaphthyl-2,2'-diamine platinum oxide can effectively inhibit the proliferation of oxaliplatin-resistant tumor cells and thus can be used for preparing potential drugs for treating oxaliplatin-resistant tumors.

Description

Compound for treating oxaliplatin-resistant tumors, preparation method thereof, composition and use thereof Technical Field

[0001] The present invention relates to 1,1'-binaphthyl-2,2'-diamine platinum oxide for treating oxaliplatin-resistant tumors, a preparation method thereof, a pharmaceutical composition thereof and use thereof. Background Art

[0002] Tumor resistance occurs when tumor cells develop tolerance to anti-cancer drugs, leading to a significant decrease in the effectiveness of the drugs used and subsequent tumor re-growth, worsening the patient's condition and causing it to spiral out of control. Tumor resistance is a major cause of chemotherapy failure and a significant challenge that must be addressed and overcome in the development of new drugs.

[0003] There are no established rules for overcoming tumor drug resistance. This is due to the complexity of tumor resistance mechanisms, the heterogeneity of tumor cells, and their evolving immune escape mechanisms. Tumor heterogeneity refers to the molecular or genetic changes that occur in daughter cells during tumor growth, after multiple divisions and proliferations. This leads to differences in tumor growth rate, invasiveness, drug sensitivity, and prognosis (Dagogo-Jack, I et al., Nat Rev Clin Oncol 2018, 15, 81-94). This heterogeneity can cause the same tumor to develop decreased sensitivity and increased resistance to the same or different drugs at different stages of its development. Tumor evolutionary immune escape refers to the process by which tumors, in response to stressors created by therapeutic drugs during treatment, initiate multiple adaptive mechanisms to evade recognition and attack by the immune system, resulting in drug resistance. The molecular mechanisms by which tumors develop drug resistance during treatment are currently known to include: 1) mutations in drug targets, 2) enhanced drug efflux mechanisms, 3) expression of drug detoxification mechanisms, 4) reduced susceptibility to tumor cell apoptosis, 5) enhanced tumor DNA damage repair mechanisms, and 6) changes in cell proliferation patterns (Cree IA et al., BMC Cancer. 2017, 5, 17(1)).

[0004] Platinum-based anticancer drugs are the most widely used class of drugs in clinical practice. Representative platinum-based anticancer drugs include first-generation cisplatin, second-generation carboplatin and nedaplatin, and third-generation oxaliplatin. Cisplatin and carboplatin, used alone or in combination, are widely used in the clinical treatment of lung cancer, ovarian cancer, head and neck cancer, esophageal cancer, breast cancer, cervical cancer, malignant lymphoma, bone cancer, bladder cancer, prostate cancer, and reproductive system malignancies. As a third-generation platinum-based anticancer drug, oxaliplatin is widely used in the clinical treatment of various cancers, including colorectal cancer, liver cancer, esophageal cancer, gastric cancer, and biliary tract malignancies. It is also the main therapeutic agent in the first-line chemotherapy regimen for advanced colorectal cancer.

[0005] Given the importance of platinum drugs in clinical applications, the biopharmaceutical field has conducted extensive research on the resistance to the most widely used first-generation cisplatin, and has discovered some solutions to overcome cisplatin resistance (see, for example, Gabano E et al., J Biol Inorg Chem 2013, 18, 791-801; BH et al., Metallomics 2018, 10, 323-336). As shown in the figure below, studies have found that after cisplatin develops resistance in lung cancer, second-generation carboplatin with the same chelating ligand (NH3) also loses sensitivity due to cross-resistance. However, nedaplatin, which also has an NH3 chelating ligand, remains effective against cisplatin-resistant lung cancer (does not develop resistance) (Wang H et al., Oncology Letters, 2016, 11, 2566-2572). Oxaliplatin, a third-generation drug, does not have cross-resistance with cisplatin, and tumor cells that have become resistant to cisplatin remain sensitive to oxaliplatin (do not develop resistance). Conversely, after tumor cells develop resistance to oxaliplatin, first-generation cisplatin and second-generation carboplatin also develop resistance and lose sensitivity, and therefore cannot replace oxaliplatin in clinical treatment.

[0006] It can be seen that the therapeutic effect of platinum drugs on tumors and their tumor selectivity are jointly determined by the structural characteristics of the chelating ligand (nitrogen-containing ligand) and the leaving ligand (the group that forms a covalent bond with Pt). Whether a platinum drug with a specific structure has the potential to overcome tumor resistance has no specific rules or structure-activity relationship rules to follow (Wang H et al., Oncology Letters, 2016, 11, 2566-2572).

[0007] Oxaliplatin is primarily used clinically for the first-line and second-line treatment of colorectal cancer. According to the 2020 National Comprehensive Cancer Network (NCCN) guidelines for the treatment of colorectal cancer, oxaliplatin plays a very important role in the first-line chemotherapy of advanced colorectal cancer. Combination chemotherapy regimens containing oxaliplatin mainly include: FOLFOX (fluorouracil, leucovorin, oxaliplatin), CAPOX (capecitabine, oxaliplatin), and FOLFOXIRI (fluorouracil, leucovorin, irinotecan, oxaliplatin). With the emergence of oxaliplatin-resistant tumors, since first- and second-generation platinum-based anticancer drugs cannot replace oxaliplatin to achieve the ideal clinical therapeutic effect for colorectal cancer, no other platinum-based drugs have been successfully developed in the clinic to replace oxaliplatin after colorectal cancer patients develop resistance to oxaliplatin. Summary of the Invention

[0008] In order to overcome the current urgent problem of oxaliplatin resistance in clinical practice and obtain a new generation of platinum complexes that can effectively inhibit and kill oxaliplatin-resistant tumor cells, the present invention respectively carries out modifications and a large number of screening processes from various aspects such as [1] changing the screening of oxaliplatin leaving ligand structure, [2] introducing the screening of new chiral chelating ligands, [3] screening of aromatic substituted chiral ethylenediamine chelating ligands, and [4] screening of diphenyl diamine chelating ligands. Finally, it is designed and discovered that the platinum oxide with 1,1'-binaphthyl-2,2'-diamine as the chelating ligand of the present invention has the characteristics of resisting oxaliplatin resistance, thereby completing the present invention.

[0009] In view of this, on the one hand, a 1,1'-binaphthyl-2,2'-diamine platinum oxide or a pharmaceutically acceptable salt thereof represented by formula (I) is provided.

[0010] in:

[0011] Two R1 are the same or different (preferably the same), selected from C1-C 25 Straight-chain or branched alkanoyl (wherein the number of carbon atoms includes the carbonyl carbon atom), C3-C 25 Straight-chain or branched unsaturated hydrocarbon acyl (preferably alkenoyl, wherein the number of carbon atoms includes the carbonyl carbon atom), substituted or unsubstituted C 6-10 Aryl-C 1-25 Straight-chain or branched alkanoyl (wherein the number of carbon atoms includes the carbonyl carbon atom), or substituted or unsubstituted C 6-10 Aryl-C 3-25 a straight-chain or branched unsaturated hydrocarbon acyl group (preferably an alkenoyl group, wherein the number of carbon atoms includes the carbonyl carbon atom);

[0012] As "C1-C 25 Examples of the “straight-chain or branched-chain alkanoyl group” include acetyl, n-propionyl, isopropionyl, n-valeryl, pivaloyl, n-hexanoyl, n-octanoyl, n-decanoyl, 2,2-dimethyloctanoyl, lauroyl, myristoyl, palmitoyl, stearoyl, behenoyl, and lignoceryl groups, with acetyl, n-octanoyl, myristoyl, and stearoyl groups being preferred.

[0013] As "C3-C 25 Examples of the “straight-chain or branched unsaturated hydrocarbon acyl group” include oleoyl, linoleoyl, and arachidonic acid, with oleoyl being more preferred.

[0014] As "substituted or unsubstituted C 6-10 Aryl-C 1-25 Straight chain or branched chain alkanoyl and substituted or unsubstituted C 6-10 Aryl-C 3-25 Straight-chain or branched unsaturated hydrocarbon acyl group", wherein C 6-10 Aryl is preferably phenyl, wherein the substituent is selected from C 1-10 Alkyl, C 1-10 Alkoxy, hydroxy, and halogen; the "substituted or unsubstituted C 6-10 Aryl-C 1-25 Straight chain or branched chain alkanoyl and substituted or unsubstituted C 6-10 Aryl-C 3-25 Examples of the “straight-chain or branched unsaturated hydrocarbon acyl group” include benzoyl, salicyl, 3-hydroxybenzoyl, 4-hydroxybenzoyl, anisyl, m-hydroxybenzoyl, vanillyl, veratroloyl, 3,5-dimethoxybenzoyl, cinnamoyl, galloyl, syringoyl, and 3,4,5-trimethoxybenzoyl, preferably benzoyl or cinnamoyl.

[0015] Or two R1 together form a group of the following structure:

[0016] Or two R1 together form a group of formula (II);

[0017] In formula (II), A is selected from the following sugar substituents, wherein the 1-end isomer of the sugar substituent is α or β or both,

[0018] Preferably, in formula (II), A is selected from the following sugar substituents, wherein the 1-end isomer of the sugar substituent is α or β or both,

[0019] Preferably, A is selected from the following monosaccharide substituents, wherein the 1-end isomer of the monosaccharide substituent is α or β or both,

[0020] Two R2 are the same or different (preferably the same), selected from hydrogen atoms, hydroxyl groups, C 1-10 Straight chain or branched chain alkyl, or C 1-10 Straight-chain or branched alkoxy; as "C 1-10 Straight or branched alkyl and C 1-10 "Straight-chain or branched alkoxy" may be, for example, methyl, methoxy, ethyl, n-propyl, isopropyl, n-pentyl, neopentyl, n-hexyl, n-octyl, or n-decyl, preferably methyl or methoxy. R2 is preferably a hydrogen atom, hydroxyl, methyl or methoxy;

[0021] Two R3 are the same or different (preferably the same), selected from hydrogen atoms, C 1-10 Straight or branched alkyl, and C 3-6 Cycloalkyl; as "C 1-10 As "straight chain or branched chain alkyl", for example, methyl, ethyl, n-propyl, isopropyl, n-pentyl, neopentyl, n-hexyl, n-octyl, n-decyl can be mentioned, preferably methyl; as "C 3-6 Examples of the "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. R3 is preferably a hydrogen atom or a methyl group.

[0022] Preferably, in the 1,1'-binaphthyl-2,2'-diamine platinum oxide represented by formula (I), or a pharmaceutically acceptable salt thereof, the 1,1'-binaphthyl-2,2'-diamine group is a racemic 1,1'-binaphthyl-2,2'-diamine group, or the 1,1'-binaphthyl-2,2'-diamine platinum oxide represented by formula (I) is (R)-1,1'-binaphthyl-2,2'-diamine platinum oxide represented by the following formula (III), or is (S)-1,1'-binaphthyl-2,2'-diamine platinum oxide represented by the following formula (IV), wherein R1, R2, and R3 are as defined above.

[0023] The following compounds or pharmaceutically acceptable salts thereof are preferred:

[0024] In another aspect, a pharmaceutical composition is provided, comprising 1,1'-binaphthyl-2,2'-diamine platinum oxide represented by the above formula (I), or a pharmaceutically acceptable salt thereof, and optional pharmaceutically acceptable excipients.

[0025] Optionally, the pharmaceutically acceptable excipients are selected from: fillers, disintegrants, lubricants, glidants, effervescent agents, flavoring agents, preservatives, solubilizers, cosolvents, antioxidants, anti-photolysis agents, pH regulators, emulsifiers, local analgesics, chelating agents, non-aqueous solvents, coating materials or other excipients.

[0026] Optionally, among the pharmaceutically acceptable excipients, the filler includes one or more of lactose, mannitol, and calcium carbonate; the binder includes one or more of sucrose, starch, povidone, and sodium carboxymethyl cellulose; the disintegrant includes one or more of starch, cross-linked povidone, cross-linked sodium carboxymethyl cellulose, and an effervescent disintegrant; the non-aqueous solvent includes one or more of iodized oil, soybean oil, castor oil, and peanut oil; the solubilizer includes one or more of Tween 80, Tween 60, and poloxamer 68; and the cosolvent includes one or more of sodium benzoate, sodium salicylate, sodium p-aminobenzoate, and cyclodextrin.

[0027] Optionally, the administration of the pharmaceutical composition includes oral administration (e.g., buccal administration), parenteral administration (e.g., intramuscular, intravenous, or subcutaneous administration), rectal administration (e.g., suppository), or hepatic artery administration;

[0028] Optionally, administration is performed under continuous therapy, in a single unit dosage form, or in a multiple dosage treatment form;

[0029] Alternatively, the pharmaceutical composition is in the form of an oil emulsion or dispersion in combination with a lipophilic salt such as pamoic acid, or in the form of a biodegradable sustained-release composition for intravenous or intramuscular administration or hepatic artery administration;

[0030] Optionally, the pharmaceutical composition can be prepared into a solid oral preparation (such as tablets, capsules, granules, dispersible tablets, enteric-coated tablets and capsules, etc.), a liquid oral preparation (such as oral liquid, syrup, suspension, etc.), or an injection;

[0031] Optionally, the injection includes: lipid microspheres, water injection, large infusion, or freeze-dried powder injection.

[0032] On the other hand, provided are the use of 1,1'-binaphthyl-2,2'-diamine platinum oxide represented by the above formula (I), or a pharmaceutically acceptable salt thereof, or the above pharmaceutical composition as an antitumor agent for preventing and / or treating tumors; and the use thereof in the preparation of a drug for preventing and / or treating tumors.

[0033] In another aspect, a method for preventing or treating tumors is provided, comprising administering to an individual in need thereof an effective amount of 1,1'-binaphthyl-2,2'-diamineplatinum oxide represented by formula (I) or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition.

[0034] Preferably, the tumor is selected from human lung cancer, human colorectal cancer, human head and neck cancer, human prostate cancer, human breast cancer, human ovarian cancer, human cervical cancer, human leukemia, human lymphoma, human skin cancer, human pancreatic cancer, human liver cancer, human bladder cancer, human esophageal cancer, human gastric cancer, human multiple myeloma, human male genital cancer or human bone cancer; preferably, the tumor is lung cancer, ovarian cancer, liver cancer, or colorectal cancer; preferably, the tumor is a drug-resistant tumor; preferably, the drug-resistant tumor is a platinum anticancer drug-resistant tumor; preferably, the platinum anticancer drug-resistant tumor is a cisplatin, carboplatin, or oxaliplatin-resistant tumor; preferably, the platinum anticancer drug-resistant tumor is an oxaliplatin-resistant tumor.

[0035] In the structural formula herein, “*” represents a connection site.

[0036] The 1,1'-binaphthyl-2,2'-diamine platinum oxide of formula (I), or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described above can be used alone or in combination with one or more other active pharmaceutical ingredients ("second active compounds"). They can be administered separately, including sequentially or simultaneously, or they can be included in the same pharmaceutical composition for administration.

[0037] Examples of the second active compound include one or more of the following: 5-fluorouracil, irinotecan, floxuridine, tegafuridine, capecitabine, gemcitabine, clofarabine, temozolomide, folinate, paclitaxel, doxorubicin, and the like.

[0038] The 1,1'-binaphthyl-2,2'-diamine platinum oxide represented by the above formula (I), or its pharmaceutically acceptable salt includes their racemates, optical isomers, or isotope-labeled substances, which may exist in the form of amorphous, crystalline, solvate (such as hydrate), inclusion compound, etc.

[0039] The 1,1'-binaphthyl-2,2'-diamine platinum oxide of formula (I) or a pharmaceutically acceptable salt thereof may be present in an isotopically traced or enriched form, containing one or more atoms whose atomic weight or mass number differs from the atomic weight or mass number of the largest atom found in nature. Isotopes may be radioactive or non-radioactive. Isotopes of atoms such as hydrogen, carbon, phosphorus, sulfur, fluorine, chlorine, and iodine include, but are not limited to: 2 H, 3 H, 13 C, 14 C,15 N, 18 O, 32 P, 35 S, 18 F, 36 Cl and 125 I. Compounds containing other isotopes of these and / or other atoms are within the scope of the 1,1'-binaphthyl-2,2'-diamine platinum oxide represented by the above formula (I), or a pharmaceutically acceptable salt thereof.

[0040] 1,1'-binaphthyl-2,2'-diamine platinum oxide shown in the above formula (I), or its pharmaceutically acceptable salt includes a mixture of optical isomers in any ratio. The compound of formula (I) may contain one or more asymmetric carbon atoms, and its existence form may be an optically pure enantiomer, such as an enantiomeric mixture of a racemate, an optically pure diastereomer, a diastereomeric mixture, a racemate of a diastereomer, or a mixture of a racemate of a diastereomer. An optically active form can be obtained by, for example, resolution of a racemate, asymmetric synthesis, or asymmetric chromatography (chromatography using a chiral adsorbent or eluent).

[0041] In another aspect, a method for preparing the 1,1'-binaphthyl-2,2'-diamine platinum oxide represented by the above formula (I) or a pharmaceutically acceptable salt thereof is provided.

[0042] General synthetic method A: comprising the step of reacting a compound of formula (VI) with a compound R1-OH or OH-R1-R1-OH or a salt thereof to prepare 1,1'-binaphthyl-2,2'-diamine platinum oxide represented by formula (I);

[0043] The preparation method of the compound of formula (V) is prepared according to a general method known in the literature (Chemistry-A European Journal, 2016, vol. 22, #43, p. 15468-15474).

[0044] General synthetic method B: comprising the step of reacting a compound of formula (VI) with a compound R1-OH or OH-R1-R1-OH or a salt thereof to prepare 1,1'-binaphthyl-2,2'-diamine platinum oxide represented by formula (I);

[0045] The preparation method of the compound of formula (VI) is prepared according to a general method known in the literature (Chemistry-A European Journal, 2016, vol. 22, #43, p. 15468-15474).

[0046] General synthetic method C: comprising the step of reacting a compound of formula (VII) with a compound R1-OH or OH-R1-R1-OH or a salt thereof to prepare 1,1'-binaphthyl-2,2'-diamine platinum oxide represented by formula (I);

[0047] The preparation method of the compound of formula (VII) can be prepared according to a general method known in the literature (Inorganica Chimica Acta, 1991, vol. 179, p. 281-288).

[0048] In the above reaction formula, X is selected from a halogen atom (preferably a chlorine atom or a bromine atom); R1, R2 and R3 are as defined above; and the salts of the compounds R1-OH and OH-R1-R1-OH are each independently selected from their silver salts, sodium salts, potassium salts or barium salts.

[0049] Preferably, in method A, method B, or method C, the reaction is carried out in deionized water or distilled water, N,N-dimethylformamide, methanol, ethanol, isopropanol, butanol, or a mixed solvent of water and the above solvents, or a mixed solvent of dichloromethane and the above solvents; preferably, the reaction is carried out at room temperature or heated to 40-100° C. in a light-proof environment; preferably, the reaction is carried out at pH 7-9; preferably, the pH of the reaction solution is adjusted to 7-9 using an inorganic base aqueous solution; preferably, the inorganic base includes sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, lithium hydroxide, or barium hydroxide.

[0050] When preparing 1,1'-binaphthyl-2,2'-diamine platinum oxide represented by formula (I) using the above-mentioned different methods, the reaction is generally carried out in a nitrogen-purged solvent environment. The reaction time range varies depending on the target product. Depending on the properties of the reactants, the reaction generally takes from 1 hour to 30 days to complete. More often, it takes 2-10 hours, and sometimes as long as 15 days. The product obtained from the above reaction can be purified by various methods. For example, the mixture after the reaction is completed can be filtered to remove any precipitate, then concentrated by vacuum distillation, and then an organic solvent is added to precipitate the desired target product. Generally, a water-miscible organic solvent is selected, such as an alcohol (e.g., methanol, ethanol, propanol, butanol, or isopropanol), or an ether (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, ethylene glycol diethyl ether, or ethylene glycol dimethyl ether). The resulting precipitate is then collected, for example, by filtration, and further washed with the above-mentioned solvent to obtain the desired target product. The target product obtained in the above reaction can also be purified and refined by chromatography or other methods, such as ion exchange resins or preparative liquid chromatography. Liquid chromatography separation and purification is generally performed using methanol and water as the mobile phase. DETAILED DESCRIPTION

[0051] The present invention is described in detail below by way of examples. The examples provided are intended only to illustrate the present invention and are not intended to limit the scope of the present invention in any way. In the following examples, unless otherwise specified, the experimental methods used are conventional methods, and the raw materials and reagents used can be purchased from chemical or biological reagent companies or prepared according to published methods.

[0052] Example

[0053] Example 1: Preparation of Compound 1

[0054] Prepared using General Synthesis Method A.

[0055] 2mmol of 1,1'-binaphthyl-2,2'-diaminedichloroplatinum and 2 equivalents of silver acetate (668mg, 4mmol) were suspended in 20mL of N,N-dimethylformamide at room temperature. After nitrogen replacement, the mixture was stirred at room temperature for 12 hours in the dark. The formed silver iodide precipitate was filtered using a glass frit funnel, and the filtrate was decompressed to remove the solvent to obtain an oily crude product. Dichloromethane was added and stirred to precipitate an off-white solid product. The product solid was further washed with dichloromethane and ether to obtain the target product compound 1 (yield 75%).

[0056] 1 H NMR (600MHz, Methanol-d4) δ8.11(d,J=8.8Hz,2H),8.02(d,J=8.3Hz,2H),7.74(d,J=8. 7Hz,2H),7.49(t,J=7.3Hz,2H),7.32-7.27(m,2H),7.04(d,J=8.6Hz,2H),1.95(s,6H).

[0057] Example 2: Preparation of Compound 2

[0058] The compound was prepared by the same method as in Example 1 using General Synthesis Method A. The yield was 80%.

[0059] 1 H NMR (600MHz, Methanol-d4) δ8.11(d,J=8.8Hz,2H),8.01(d,J=8.3Hz,2H),7.75(d,J=8.8 Hz,2H),7.47(t,J=7.6Hz,2H),7.25(t,J=7.7Hz,2H),7.02(d,J=8.6Hz,2H),1.93(s,6H).

[0060] Example 3: Preparation of Compound 3

[0061] The compound was prepared by the same method as in Example 1 using General Synthesis Method A. The yield was 82%.

[0062] 1 H NMR (600MHz, Methanol-d4) δ8.13(d,J=8.8Hz,2H),8.03(d,J=8.3Hz,2H),7.75(d,J=8.8 Hz,2H),7.49(t,J=7.6Hz,2H),7.28(t,J=7.7Hz,2H),7.04(d,J=8.6Hz,2H),1.94(s,6H).

[0063] Example 4: Preparation of Compound 4

[0064] The compound was prepared by the same method as in Example 1 using General Synthesis Method A. The yield was 70%.

[0065] 1 H NMR (600MHz, Methanol-d4) δ8.13(d,J=8.8Hz,2H),8.03(d,J=8.3Hz,2H),7.91(m,4H),7.75(d,J=8.8 Hz,2H),7.49(t,J=7.6Hz,2H),7.41(m,2H),7.33(m,4H),7.28(t,J=7.7Hz,2H),7.04(d,J=8.6Hz,2H).

[0066] Example 5: Preparation of Compound 5

[0067] The compound was prepared by the same method as in Example 1 using General Synthesis Method A. The yield was 68%.

[0068] 1 H NMR (600MHz, Methanol-d4) δ8.14(d,J=8.8Hz,2H),8.04(d,J=8.3Hz,2H),7.90(m,4H),7.75(d,J=8.8 Hz,2H),7.49(t,J=7.6Hz,2H),7.41(m,2H),7.32(m,4H),7.27(t,J=7.7Hz,2H),7.04(d,J=8.6Hz,2H).

[0069] Example 6: Preparation of Compound 6

[0070] The compound was prepared by the same method as in Example 1 using General Synthesis Method A. The yield was 72%.

[0071] 1 H NMR (600MHz, Methanol-d4) δ8.15(d,J=8.8Hz,2H),8.05(d,J=8.3Hz,2H),7.91(m,4H),7.76(d,J=8.8 Hz,2H),7.49(t,J=7.6Hz,2H),7.43(m,2H),7.33(m,4H),7.28(t,J=7.7Hz,2H),7.03(d,J=8.6Hz,2H).

[0072] Example 7: Preparation of Compound 7

[0073] The compound was prepared by the same method as in Example 1 using General Synthesis Method A. The yield was 72%.

[0074] 1 H NMR (600MHz, Methanol-d4) δ8.12(d,J=8.8Hz,2H),8.02(d,J=8.3Hz,2H),7.76(d,J=8.8Hz,2H),7.65 (m,4H),7.48(t,J=7.6Hz,2H),7.45(m,8H),7.27(t,J=7.7Hz,2H),7.04(d,J=8.6Hz,2H),6.56(m,2H).

[0075] Example 8: Preparation of Compound 8

[0076] The compound was prepared by the same method as in Example 1 using General Synthesis Method A. The yield was 77%.

[0077] 1 H NMR (600MHz, Methanol-d4) δ8.14(d,J=8.8Hz,2H),8.03(d,J=8.3Hz,2H),7.77(d,J=8.8Hz,2H),7.65 (m,4H),7.48(t,J=7.6Hz,2H),7.45(m,8H),7.28(t,J=7.7Hz,2H),7.06(d,J=8.6Hz,2H),6.56(m,2H).

[0078] Example 9: Preparation of Compound 9

[0079] The compound was prepared by the same method as in Example 1 using General Synthesis Method A. The yield was 73%.

[0080] 1 H NMR (600MHz, Methanol-d4) δ8.13(d,J=8.8Hz,2H),8.01(d,J=8.3Hz,2H),7.75(d,J=8.8Hz,2H),7.63 (m,4H),7.46(t,J=7.6Hz,2H),7.43(m,8H),7.26(t,J=7.7Hz,2H),7.07(d,J=8.6Hz,2H),6.54(m,2H).

[0081] Example 10: Preparation of Compound 10

[0082] The compound was prepared by the same method as in Example 1 using General Synthesis Method A. The yield was 73%.

[0083] 1 H NMR (600MHz, Methanol-d4) δ8.12(d,J=8.8Hz,2H),8.02(d,J=8.3Hz,2H),7.76(d,J=8.8Hz,2H),7.48(t, J=7.6Hz,2H),7.27(t,J=7.7Hz,2H),7.04(d,J=8.6Hz,2H),2.20(m,4H),1.44-1.20(m,20H),0.85(m,6H).

[0084] Example 11: Preparation of Compound 11

[0085] The compound was prepared by the same method as in Example 1 using General Synthesis Method A. The yield was 79%.

[0086] 1 H NMR (600MHz, Methanol-d4) δ8.14(d,J=8.8Hz,2H),8.03(d,J=8.3Hz,2H),7.76(d,J=8.8Hz,2H),7.49(t, J=7.6Hz,2H),7.29(t,J=7.7Hz,2H),7.05(d,J=8.6Hz,2H),2.21(m,4H),1.44-1.20(m,20H),0.85(m,6H).

[0087] Example 12: Preparation of Compound 12

[0088] The compound was prepared by the same method as in Example 1 using General Synthesis Method A. The yield was 82%.

[0089] 1H NMR (600MHz, Methanol-d4) δ8.12(d,J=8.8Hz,2H),8.03(d,J=8.3Hz,2H),7.75(d,J=8.8Hz,2H),7.50(t, J=7.6Hz,2H),7.30(t,J=7.7Hz,2H),7.06(d,J=8.6Hz,2H),2.22(m,4H),1.44-1.20(m,20H),0.85(m,6H).

[0090] Example 13: Preparation of Compound 13

[0091] The compound was prepared by the same method as in Example 1 using General Synthesis Method A. The yield was 80%.

[0092] 1 H NMR (600MHz, CDCl3) δ 8.05 (d, J = 8.8 Hz, 2H), 8.01 ( d, J = 8.3 Hz, 2H), 7.82 ( d, J = 8.8 Hz, 2H), 7.46 ( t, J = 7.6 Hz ,2H),7.30-7.20(m,2H),7.11(d,J=8.6Hz,2H),2.37(m,4H),1.65(m,4H),1.50-1.40(m,40H),0.89(m,6H).

[0093] Example 14: Preparation of Compound 14

[0094] The compound was prepared by the same method as in Example 1 using General Synthesis Method A. The yield was 85%.

[0095] 1 H NMR (600MHz, CDCl3) δ8.06(d,J=8.8Hz,2H),8.00(d,J=8.3Hz,2H),7.80(d,J=8.8Hz,2H),7.46(t,J=7.6Hz ,2H),7.30-7.20(m,2H),7.11(d,J=8.6Hz,2H),2.37(m,4H),1.65(m,4H),1.50-1.40(m,40H),0.89(m,6H).

[0096] Example 15: Preparation of Compound 15

[0097] The compound was prepared by the same method as in Example 1 using General Synthesis Method A. The yield was 88%.

[0098] 1H NMR (600MHz, CDCl3) δ8.05(d,J=8.8Hz,2H),8.01(d,J=8.3Hz,2H),7.82(d,J=8.8Hz,2H),7.46(t,J=7.6Hz ,2H),7.30-7.20(m,2H),7.11(d,J=8.6Hz,2H),2.37(m,4H),1.65(m,4H),1.50-1.40(m,40H),0.89(m,6H).

[0099] Example 16: Preparation of Compound 16

[0100] The compound was prepared by the same method as in Example 1 using General Synthesis Method A. The yield was 82%.

[0101] 1 H NMR (600MHz, Methanol-d4) δ8.14(d,J=8.8Hz,2H),8.04(d,J=8.2Hz,2H),7.73(d,J=8.7Hz,2H),7.50(t,J=7.0H z,2H),7.31(t,J=7.7Hz,2H),7.03(d,J=8.5Hz,2H),2.30(m,4H),1.60(m,4H),1.42-1.10(m,56H),0.88(m,6H).

[0102] Example 17: Preparation of Compound 17

[0103] The compound was prepared by the same method as in Example 1 using General Synthesis Method A. The yield was 80%.

[0104] 1 H NMR (600MHz, Methanol-d4) δ8.13(d,J=8.8Hz,2H),8.04(d,J=8.2Hz,2H),7.71(d,J=8.7Hz,2H),7.50(t,J=7.0H z,2H),7.32(t,J=7.7Hz,2H),7.01(d,J=8.5Hz,2H),2.31(m,4H),1.60(m,4H),1.42-1.10(m,56H),0.88(m,6H).

[0105] Example 18: Preparation of Compound 18

[0106] The compound was prepared by the same method as in Example 1 using General Synthesis Method A. The yield was 77%.

[0107] 1 H NMR (600MHz, Methanol-d4) δ8.13(d,J=8.8Hz,2H),8.06(d,J=8.2Hz,2H),7.70(d,J=8.7Hz,2H),7.47(t,J=7.0H z,2H),7.30(t,J=7.7Hz,2H),7.00(d,J=8.5Hz,2H),2.33(m,4H),1.62(m,4H),1.42-1.10(m,56H),0.89(m,6H).

[0108] Example 19: Preparation of Compound 19

[0109] The compound was prepared by the same method as in Example 1 using General Synthesis Method A. The yield was 70%.

[0110] 1 H NMR (600MHz, Methanol-d4) δ8.12(d,J=8.8Hz,2H),8.02(d,J=8.3Hz,2H),7.76(d,J=8.8Hz,2H),7.48(t,J=7.6Hz,2H) ,7.27(t,J=7.7Hz,2H),7.04(d,J=8.6Hz,2H),5.36(m,4H),2.36(m,4H),1.64(m,4H),1.42-1.10(m,40H),0.89(m,6H).

[0111] Example 20: Preparation of Compound 20

[0112] The compound was prepared by the same method as in Example 1 using General Synthesis Method A. The yield was 67%.

[0113] 1 H NMR (600MHz, Methanol-d4) δ8.13(d,J=8.8Hz,2H),8.02(d,J=8.3Hz,2H),7.74(d,J=8.8Hz,2H),7.45(t,J=7.6Hz,2H) ,7.25(t,J=7.7Hz,2H),7.03(d,J=8.6Hz,2H),5.34(m,4H),2.35(m,4H),1.63(m,4H),1.42-1.10(m,40H),0.89(m,6H).

[0114] Example 21: Preparation of Compound 21

[0115] The compound was prepared by the same method as in Example 1 using General Synthesis Method A. The yield was 65%.

[0116] 1 H NMR (600MHz, Methanol-d4) δ8.14(d,J=8.8Hz,2H),8.01(d,J=8.3Hz,2H),7.75(d,J=8.8Hz,2H),7.46(t,J=7.6Hz,2H) ,7.27(t,J=7.7Hz,2H),7.05(d,J=8.6Hz,2H),5.36(m,4H),2.37(m,4H),1.65(m,4H),1.42-1.10(m,40H),0.89(m,6H).

[0117] Example 22: Preparation of Compound 22

[0118] To a suspension of (R / S)-1,1'-binaphthyl-2,2'-diaminedichloroplatinum (200 mg, 0.36 mmol) in 4 mL of methanol and 3 mL of deionized water was added silver sulfate (113 mg, 0.36 mmol) at room temperature. The reaction mixture was heated to 60°C under nitrogen and stirred overnight in the dark. After the reaction was complete, the precipitate was removed using a centrifuge, and the supernatant was collected, lyophilized using a freeze dryer, and separated by semi-preparative HPLC to obtain 165 mg of the final product as a yellow solid in an 80% yield.

[0119] 1 H NMR(600MHz,Methanoll-d4)δ8.15(dd,J=12.0,8.7Hz,1H),8.05(dd,J=8.2,3.9Hz,1H),7.97(d,J=8.3Hz,1H),7.9 3(dd,J=7.9,4.4Hz,1H),7.70(dd,J=8.5,5.0Hz,1H),7.57-7.49(m,2H),7.35-7.25(m,2H),7.02(t,J=9.2Hz,2H).

[0120] Example 23: Preparation of Compound 23

[0121] To a suspension of (R)-1,1'-binaphthyl-2,2'-diaminedichloroplatinum (200 mg, 0.36 mmol) in 4 mL of methanol and 3 mL of deionized water was added silver sulfate (113 mg, 0.36 mmol) at room temperature. The reaction mixture was heated to 60°C under nitrogen and maintained in the dark overnight. After the reaction was complete, the precipitate was removed using a centrifuge, and the supernatant was collected, lyophilized using a freeze dryer, and separated by semi-preparative HPLC to obtain 155 mg of the final product as a yellow solid in a 75% yield.

[0122] 1 H NMR (600MHz, Methanol-d4) δ8.15(dd,J=12.0,8.7Hz,1H),8.05(dd,J=8.2,3.9Hz,1H),7.97(d,J=8.3Hz,1H),7.9 3(dd,J=7.9,4.4Hz,1H),7.70(dd,J=8.5,5.0Hz,1H),7.57-7.49(m,2H),7.34-7.29(m,2H),7.02(t,J=9.2Hz,2H).

[0123] Example 24: Preparation of Compound 24

[0124] Silver sulfate (113 mg, 0.36 mmol) was added to a suspension of (S)-1,1'-binaphthyl-2,2'-diaminedichloroplatinum (200 mg, 0.36 mmol) in 4 mL of methanol and 3 mL of deionized water at room temperature. The reaction mixture was heated to 60°C under nitrogen and maintained in the dark overnight. After the reaction was completed, the precipitate was removed using a centrifuge, and the supernatant was collected, lyophilized using a freeze dryer, and separated by semi-preparative HPLC to obtain 155 mg of the final product as a yellow solid in a 75% yield.

[0125] 1 H NMR (600MHz, Methanol-d4) δ8.15 (dd, J=12.4, 8.7Hz, 1H), 8.05 (dd, J=8.4, 3.2Hz, 1H), 8.00-7.94 (m, 1H), 7.94-7. 90(m,1H),7.70(d,J=8.7Hz,1H),7.53(dt,J=13.8,7.4Hz,2H),7.32(dt,J=14.0,7.3Hz,2H),7.02(t,J=9.3Hz,2H).

[0126] Example 25: Preparation of Compound 25

[0127] (1) Sodium hydroxide (263 mg, 6.57 mmol) was dissolved in 3 mL of water and added to a solution of glycolic acid (500 mg, 6.57 mmol) in water (5 mL). Silver nitrate (1.12 g, 6.57 mmol) was then added to the reaction mixture and stirred in the dark for 0.5 h. The precipitate was isolated by filtration, washed twice with water and once with anhydrous ethanol, and dried in vacuo at 40°C to obtain a white solid product (721 mg, 60.0%).

[0128] (2) Silver glycolate (105 mg, 0.57 mmol) prepared in step (1) was added to a suspension of 1,1'-binaphthyl-2,2'-diaminedichloroplatinum (300 mg, 0.55 mmol) in 6 mL of methanol and 4 mL of deionized water at room temperature, and the reaction mixture was heated to 60°C under nitrogen protection and stirred overnight in the dark. After the reaction was completed, the precipitate was removed by centrifuge, and the supernatant was collected. Sodium hydroxide solution was added dropwise to the supernatant at room temperature until the pH value of the solution reached 7. The solution was then heated to 40°C and stirred for 4 hours. After the reaction was completed, the reaction solution was filtered through a nylon microporous membrane, freeze-dried using a freeze dryer, and separated by semi-preparative high performance liquid chromatography to obtain 152 mg of the final product as an orange solid.

[0129] 1 H NMR (600MHz, Methanol-d4) δ8.12(dd,J=8.7,4.2Hz,2H),8.03(d,J=8.2Hz,2H),7.72(dd,J=20.0, 8.7Hz,2H),7.48(q,J=6.8Hz,2H),7.30(t,J=7.6Hz,2H),7.02(t,J=8.7Hz,2H),4.11-3.97(m,2H).

[0130] Example 26: Preparation of Compound 26

[0131] The compound was prepared by the same method as Example 25 using General Synthesis Method A. The yield was 51%.

[0132] 1 H NMR (600MHz, Methanol-d4) δ8.13(dd,J=8.7,4.2Hz,2H),8.03(d,J=8.2Hz,2H),7.72(dd,J=20.0, 8.7Hz,2H),7.48(q,J=6.8Hz,2H),7.30(t,J=7.6Hz,2H),7.02(t,J=8.7Hz,2H),4.12-3.95(m,2H).

[0133] Example 27: Preparation of Compound 27

[0134] The compound was prepared by the same method as Example 25 using General Synthesis Method A. The yield was 51%.

[0135] 1 H NMR (600MHz, Methanol-d4) δ8.14(dd,J=8.7,4.2Hz,2H),8.04(d,J=8.2Hz,2H),7.72(dd,J=20.0, 8.7Hz,2H),7.48(q,J=6.8Hz,2H),7.30(t,J=7.6Hz,2H),7.02(t,J=8.7Hz,2H),4.15-3.95(m,2H).

[0136] Example 28: Preparation of Compound 28

[0137] To a suspension of (R / S)-1,1'-binaphthyl-2,2'-diaminedichloroplatinum (300 mg, 0.55 mmol) in 4 mL of methanol and 10 mL of deionized water was added sodium pyrophosphate decahydrate (730 mg, 1.64 mmol) at room temperature. The reaction mixture was heated to 40°C under nitrogen and stirred in the dark for 15 hours. After completion of the reaction, the reaction mixture was filtered through a nylon microporous membrane and lyophilized using a freeze dryer. Semi-preparative HPLC was used to obtain 153 mg of the final product as an orange solid.

[0138] 1 H NMR (600MHz, D2O) δ8.16(d,J=8.8Hz,2H),7.91(d,J=8.3Hz,2H),7.84(d,J=8. 7Hz, 2H), 7.21 (t, J = 7.5Hz, 2H), 6.78 (t, J = 7.6Hz, 2H), 6.69 (d, J = 8.5Hz, 2H).

[0139] Example 29: Preparation of Compound 29

[0140] The compound was prepared by the same method as Example 28 using General Synthesis Method A. The yield was 50%.

[0141] 1 H NMR (600MHz, D2O) δ8.17(d,J=8.8Hz,2H),7.92(d,J=8.3Hz,2H),7.86(d,J=8. 7Hz,2H),7.23(t,J=7.5Hz,2H),6.79(t,J=7.6Hz,2H),6.70(d,J=8.5Hz,2H).

[0142] Example 30: Preparation of Compound 30

[0143] The compound was prepared by the same method as Example 28 using General Synthesis Method A. The yield was 50%.

[0144] 1 H NMR (600MHz, D2O) δ8.15(d,J=8.8Hz,2H),7.90(d,J=8.3Hz,2H),7.85(d,J=8. 7Hz,2H),7.22(t,J=7.5Hz,2H),6.80(t,J=7.6Hz,2H),6.71(d,J=8.5Hz,2H).

[0145] Example 31: Preparation of Compound 31

[0146] Silver oxalate (110 mg, 0.36 mmol) was added to a suspension of (R / S)-1,1'-binaphthyl-2,2'-diaminedichloroplatinum (200 mg, 0.36 mmol) in 4 mL of methanol and 3 mL of deionized water at room temperature. The reaction mixture was heated to 60°C under nitrogen and stirred overnight in the dark. After the reaction was complete, the precipitate was removed using a centrifuge, and the supernatant was collected, lyophilized using a freeze dryer, and separated by semi-preparative HPLC to yield 143 mg of the final product as a yellow solid.

[0147] 1 H NMR (600MHz, Methanol-d4) δ8.12(d,J=8.8Hz,2H),8.02(d,J=8.3Hz,2H),7.66(d, J=8.7Hz,2H),7.48(t,J=7.6Hz,2H),7.30(t,J=7.7Hz,2H),7.04(d,J=8.6Hz,2H).

[0148] Example 32: Preparation of Compound 32

[0149] The compound was prepared by the same method as Example 31 using General Synthesis Method A. The yield was 75%.

[0150] 1 H NMR(600MHz,Methanol-d4)δ8.11(d,J=8.8Hz,2H),8.02(d,J=8.3Hz,2H),7.76(d, J=8.8Hz,2H),7.48(t,J=7.6Hz,2H),7.27(t,J=7.7Hz,2H),7.05(d,J=8.6Hz,2H).

[0151] Example 33: Preparation of Compound 33

[0152] The compound was prepared by the same method as Example 31 using General Synthesis Method A. The yield was 77%.

[0153] 1 H NMR (600MHz, Methanol-d4) δ8.12(d,J=8.8Hz,2H),8.03(d,J=8.3Hz,2H),7.77(d, J=8.8Hz,2H),7.49(t,J=7.6Hz,2H),7.27(t,J=7.7Hz,2H),7.06(d,J=8.6Hz,2H).

[0154] Example 34: Preparation of Compound 34

[0155] (1) Sodium hydroxide (277 mg, 6.93 mmol) was dissolved in 3 mL of water and added to a solution of 1,1-cyclobutanedicarboxylic acid (500 mg, 3.47 mmol) in water (5 mL). Silver nitrate (1.18 g, 6.93 mmol) was then added. The reaction mixture was stirred for 1 hour in the dark. The precipitate was separated by filtration, washed with water and ethanol, and dried in vacuo in the dark to obtain a white solid product (1.18 g, 95.1%).

[0156] (2) Silver 1,1-cyclobutanedicarboxylate (130 mg, 0.36 mmol) was added to a suspension of (R / S)-1,1'-binaphthyl-2,2'-diaminedichloroplatinum (200 mg, 0.36 mmol) in 4 mL of methanol and 3 mL of deionized water at room temperature. The reaction mixture was heated to 60°C under nitrogen and stirred overnight in the dark. After the reaction was completed, the precipitate was removed by centrifuge, and the supernatant was collected, freeze-dried, and separated by semi-preparative HPLC to obtain 100 mg of the final product as a yellow solid.

[0157] 1 H NMR (400MHz, Methanol-d4) δ8.13(d,J=8.7Hz,2H),8.03(d,J=8.2Hz,2H),7.73(d,J=8.8Hz,2H),7.50(ddd,J=8.1,6.8,1 .2Hz,2H),7.31(ddd,J=8.3,6.8,1.3Hz,2H),7.03(dd,J=8.6,1.1Hz,2H),2.84(td,J=7.6,2.7Hz,4H),1.86-1.80(m,2H).

[0158] Example 35: Preparation of Compound 35

[0159] The compound was prepared by the same method as Example 34 using General Synthesis Method A. The yield was 47%.

[0160] 1 H NMR (600MHz, Methanol-d4) δ7.85(d,J=8.8Hz,2H),7.80(d,J=6.9Hz,2H),7.28(d,J=8.8Hz,2H),7.20(ddd,J=8.1, 6.6,1.2Hz,2H),7.12(ddd,J=8.3,6.7,1.3Hz,2H),6.92(d,J=8.4Hz,2H),2.50(t,J=8.0Hz,4H),2.05-2.00(m,2H).

[0161] Example 36: Preparation of Compound 36

[0162] The compound was prepared by the same method as Example 34 using General Synthesis Method A. The yield was 45%.

[0163] 1 H NMR (600MHz, Methanol-d4) δ8.13(d,J=8.7Hz,2H),8.03(d,J=8.3Hz,2H),7.73(d,J=8.7Hz,2H),7.50(ddd,J=8.1, 6.8,1.1Hz,2H),7.31(ddd,J=8.3,6.8,1.3Hz,2H),7.03(d,J=8.6Hz,2H),2.49(t,J=8.0Hz,4H),2.02-1.96(m,2H).

[0164] Example 37: Preparation of Compound 37

[0165] The compound was prepared by the same method as Example 34 using General Synthesis Method A. The yield was 50%.

[0166] 1H NMR (600MHz, Methanol-d4) δ7.85(d,J=8.8Hz,2H),7.79(d,J=6.9Hz,2H),7.28(d,J=8.8Hz,2H),7.20(ddd,J=8.1,6.6,1.2 Hz,2H),7.13(ddd,J=8.3,6.7,1.3Hz,2H),6.92(d,J=8.4Hz,2H),2.90(s,6H),2.53(t,J=8.0Hz,4H),2.05(p,J=8.0Hz,2H).

[0167] Example 38: Preparation of Compound 38

[0168] The compound was prepared by the same method as Example 34 using General Synthesis Method A. The yield was 53%.

[0169] 1 H NMR (600MHz, Methanol-d4) δ7.83(d,J=8.8Hz,2H),7.76(d,J=6.9Hz,2H),7.25(d,J=8.8Hz,2H),7.16(ddd,J=8.1,6.6,1.2 Hz,2H),7.10(ddd,J=8.3,6.7,1.3Hz,2H),6.90(d,J=8.4Hz,2H),2.90(s,6H),2.50(t,J=8.0Hz,4H),2.05(p,J=8.0Hz,2H).

[0170] Example 39: Preparation of Compound 39

[0171] The compound was prepared by the same method as Example 34 using General Synthesis Method A. The yield was 57%.

[0172] 1 H NMR (600MHz, Methanol-d4) δ7.87(d,J=8.8Hz,2H),7.79(d,J=6.9Hz,2H),7.26(d,J=8.8Hz,2H),7.19(ddd,J=8.1,6.6,1.2 Hz,2H),7.13(ddd,J=8.3,6.7,1.3Hz,2H),6.91(d,J=8.4Hz,2H),2.91(s,6H),2.50(t,J=8.0Hz,4H),2.05(p,J=8.0Hz,2H).

[0173] Example 40: Preparation of Compound 40

[0174] (1) Preparation of diethyl 2-acetoxymalonate:

[0175] Diethyl malonate (1.6 g) and lead (IV) tetraacetate (4.3 g) were placed in glacial acetic acid (20 mL) and heated to 100° C. under nitrogen to dissolve. Diethyl malonate was then transferred to the lead (IV) tetraacetate solution, and the temperature was then raised to 105° C. and stirred for 3 hours. The solvent was removed by rotary evaporation, and water (20 mL) was added to the residue. The mixture was extracted four times with diethyl ether (20 mL). The organic phases were combined and washed sequentially with saturated sodium bicarbonate solution (20 mL) and 25% sodium sulfate solution (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a light yellow oily product (1.7 g).

[0176] 1 H NMR (600MHz, CDCl3) δ5.47 (s, 1H), 4.28-4.22 (m, 4H), 2.18 (s, 3H), 1.27 (t, J = 7.2Hz, 6H)

[0177] (2) Preparation of diethyl 2-hydroxymalonate:

[0178] The product from the previous step (2.2 g) was dissolved in ethanol (5 mL), and concentrated sulfuric acid solution (1 mL) was added dropwise. The mixture was stirred at room temperature for 5 hours. The solvent was removed by rotary evaporation, and water (5 mL) was added to the residue. The mixture was separated, and the aqueous phase was extracted with diethyl ether (3×5 mL). The combined organic phases were washed with saturated sodium bicarbonate solution (10 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 9 / 1) to obtain the product as a colorless oil (1.4 g).

[0179] 1 H NMR (600MHz, CDCl3) δ4.68 (s, 1H), 4.31-4.25 (m, 4H), 1.29 (t, J = 7.2Hz, 6H).

[0180] (3) Preparation of 1-O-(2,3,4,6-tetraacetyl-D-glucoside)-diethyl malonate:

[0181] Dissolve 1,2,3,4,6-O-pentaacetyl-D-glucose (2.7 g) in 15 mL of dry dichloromethane. Add the product from the previous step (3.1 g) at room temperature. Cool to 0°C, replace the air in the flask with nitrogen, and slowly add a 98% ethereal solution of boron trifluoride (1.3 mL) dropwise under nitrogen. Stir the reaction solution at 0°C for 15 minutes, then slowly warm to room temperature. Allow to react at room temperature for 5 hours, monitoring the reaction endpoint by TLC. After completion, add dichloromethane (50 mL) and water (50 mL). Extract the layers, collect the organic phase, and wash sequentially with water (2 × 100 mL), saturated aqueous sodium bicarbonate (2 × 100 mL), and saturated sodium chloride (1 × 100 mL). Dry over anhydrous sodium sulfate, and evaporate the solvent to dryness on a rotary evaporator. The crude product is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to yield the product (1.5 g) as a light yellow viscous liquid.

[0182] 1 H NMR (600MHz, CDCl3) δ5.22(t,J=9.4Hz,1H),5.13-5.07(m,2H),4.77(s,1H),4.74(d,J=7.9Hz,1H),4.30 -4.20(m,5H),4.11(dd,J=12.3,2.4Hz,1H),3.70(m,1H),2.08(s,3H),2.08(s,3H),2.02(s,3H),2.01(s,3H),1.28(m,6H).

[0183] (4) Preparation of 1-O-(2,3,4,6-tetraacetyl-D-glucoside)-malonic acid disodium salt:

[0184] The product of the previous step, 1-O-(2,3,4,6-tetraacetyl-D-glucoside)-malonic acid diethyl ester (506 mg), was dissolved in 4.5 mL of methanol. Sodium hydroxide (280 mg) was dissolved in 1.5 mL of water and added to the reaction solution at 0°C, and then the temperature was raised to 60°C for 2 hours. The reaction end point was monitored by TLC. After the reaction was completed, the reaction solution was cooled to room temperature, and the precipitated precipitate was washed with methanol / water solution (volume ratio, 3:1, 5×1 mL) and dried to obtain 310 mg of a crude product as a light yellow solid, which was used directly in the next step.

[0185] 1H NMR (600MHz, D2O) δ4.43 (s, 1H), 4.38 (d, J = 7.8Hz, 1H), 3.80 (d, J = 12.0Hz, 1H), 3.65 (dd, J = 12.5, 4.9Hz, 1H), 3.43 (t, J = 9.0Hz, 1H), 3.39-3.30 (m, 3H).

[0186] (5) Preparation of Compound 40:

[0187] The crude product of 1-O-(2,3,4,6-tetraacetyl-D-glucoside)-malonic acid disodium salt (119 mg) was dissolved in 2 mL of water. Under nitrogen protection, (R / S)-1,1'-binaphthyl-2,2'-diamine platinum nitrate (219 mg, 0.36 mmol) was dissolved in 4 mL of methanol and added to the above reaction solution. The pH was adjusted to 7.0 with sodium hydroxide solution, and the temperature was raised to 60°C for 2 hours. After the reaction was completed, the precipitate was removed by centrifuge, and the supernatant was collected and freeze-dried using a freeze dryer. 100 mg of the final product was separated by semi-preparative high-performance liquid chromatography to obtain a yellow solid.

[0188] 1 H NMR (600MHz, Methanol-d4) δ8.14(dd,J=8.7,3.5Hz,2H),8.04(d,J=8.3Hz,2H),7.77(dd,J=17.2,8.7Hz,2H),7.50(t,J=7.5Hz,2H),7.30(dd,J=8. 3,7.0Hz,2H),7.02(dd,J=8.5,3.9Hz,2H),5.58(s,1H),4.53(d,J=7.3Hz ,1H),3.88-3.81(m,1H),3.65(dd,J=12.0,5.2Hz,1H),3.50-3.30(m,4H).

[0189] Example 41: Preparation of Compound 41

[0190] The compound was prepared by the same method as Example 40 using General Synthesis Method B. The yield was 52%.

[0191] 1H NMR (600MHz, Methanol-d4) δ8.13(dd,J=8.7,3.5Hz,2H),8.04(d,J=8.3Hz,2H),7.77(dd,J=17.2,8.7Hz,2H),7.51(t,J=7.5Hz,2H),7.30(dd,J=8. 3,7.0Hz,2H),7.02(dd,J=8.5,3.9Hz,2H),5.58(s,1H),4.52(d,J=7.3Hz ,1H),3.88-3.81(m,1H),3.65(dd,J=12.0,5.2Hz,1H),3.50-3.30(m,4H).

[0192] Example 42: Preparation of Compound 42

[0193] The compound was prepared by the same method as Example 40 using General Synthesis Method B. The yield was 56%.

[0194] 1 H NMR (600MHz, Methanol-d4) δ8.13(dd,J=8.7,3.5Hz,2H),8.04(d,J=8.3Hz,2H),7.77(dd,J=17.2,8.7Hz,2H),7.51(t,J=7.5Hz,2H),7.30(dd,J=8. 3,7.0Hz,2H),7.02(dd,J=8.5,3.9Hz,2H),5.56(s,1H),4.52(d,J=7.3Hz ,1H),3.90-3.80(m,1H),3.62(dd,J=12.0,5.2Hz,1H),3.70-3.30(m,4H).

[0195] Example 43: Preparation of Compound 43

[0196] (1) Preparation of silver malonate:

[0197] A solution of malonic acid (500 mg, 4.81 mmol), triethylamine (1.34 mL, 9.62 mmol) and ethanol (20 mL) was added dropwise to silver nitrate (1.64 g, 9.62 mmol) dissolved in a mixture of ethanol and acetonitrile (volume ratio, 10 / 1, 30 mL). The reaction solution was stirred in the dark for 2 hours. The precipitate was separated by filtration, washed twice with ethanol and petroleum ether, and dried under vacuum in the dark to give a white solid product (1.48 g, 96.7%).

[0198] (2) Preparation of compound 43:

[0199] Silver malonate (110 mg, 0.36 mmol) was added to a suspension of (R / S)-1,1'-binaphthyl-2,2'-diaminedichloroplatinum (200 mg, 0.36 mmol) in 4 mL of methanol and 3 mL of deionized water at room temperature. The reaction mixture was heated to 60°C under nitrogen and stirred overnight in the dark. After the reaction was complete, the precipitate was removed using a centrifuge, and the supernatant was collected, lyophilized using a freeze dryer, and separated by semi-preparative HPLC to yield 105 mg of the final product as a yellow solid.

[0200] 1 H NMR (400MHz, Methanol-d4) δ8.13(d,J=8.8Hz,2H),8.02(d,J=8.2Hz,2H),7.74(d,J=8.7Hz,2H),7.4 8(ddd,J=8.2,6.8,1.1Hz,2H),7.30(ddd,J=8.3,6.8,1.3Hz,2H),7.03(d,J=8.5Hz,2H),3.51(s,2H).

[0201] Example 44: Preparation of Compound 44

[0202] The compound was prepared by the same method as Example 43 using General Synthesis Method A. The yield was 57%.

[0203] 1 H NMR (400MHz, Methanol-d4) δ8.14(d,J=8.8Hz,2H),8.04(d,J=8.2Hz,2H),7.74(d,J=8.7Hz,2H),7.5 0(ddd,J=8.2,6.8,1.1Hz,2H),7.31(ddd,J=8.3,6.8,1.3Hz,2H),7.02(d,J=8.5Hz,2H),3.49(s,2H).

[0204] Example 45: Preparation of Compound 45

[0205] The compound was prepared by the same method as Example 43 using General Synthesis Method A. The yield was 60%.

[0206] 1H NMR (600MHz, Methanol-d4) δ8.14(d,J=8.8Hz,2H),8.04(d,J=8.2Hz,2H),7.74(d,J=8.7Hz,2H ),7.50(t,J=7.5Hz,2H),7.30(ddd,J=8.3,6.7,1.2Hz,2H),7.02(d,J=8.6Hz,2H),3.49(s,2H).

[0207] Example 46: Preparation of Compound 46

[0208] The compound was prepared by the same method as Example 31 using General Synthesis Method A. The yield was 67%.

[0209] 1 H NMR (600MHz, Methanol-d4) δ8.12(d,J=8.8Hz,2H),8.02(d,J=8.3Hz,2H),7.76(d,J=8.8 Hz,2H),7.48(t,J=7.6Hz,2H),7.27(t,J=7.7Hz,2H),7.04(d,J=8.6Hz,2H),2.45(s,6H).

[0210] Example 47: Preparation of Compound 47

[0211] The compound was prepared by the same method as Example 31 using General Synthesis Method A. The yield was 72%.

[0212] 1 H NMR (600MHz, Methanol-d4) δ8.11(d,J=8.8Hz,2H),8.02(d,J=8.3Hz,2H),7.76(d,J=8.8 Hz,2H),7.48(t,J=7.6Hz,2H),7.27(t,J=7.7Hz,2H),7.05(d,J=8.6Hz,2H),2.45(s,6H).

[0213] Example 48: Preparation of Compound 48

[0214] The compound was prepared by the same method as Example 31 using General Synthesis Method A. The yield was 70%.

[0215] 1H NMR (600MHz, Methanol-d4) δ8.12(d,J=8.8Hz,2H),8.03(d,J=8.3Hz,2H),7.77(d,J=8.8 Hz,2H),7.49(t,J=7.6Hz,2H),7.27(t,J=7.7Hz,2H),7.06(d,J=8.6Hz,2H),2.45(s,6H).

[0216] Example 49: Preparation of Compound 49

[0217] (1) Preparation of N,N'-([1,1'-binaphthyl]-2,2'-diyl) diacetamide:

[0218] To a 50 mL two-necked round-bottom flask, (R / S)-1,1'-biphenyl-2,2'-diamine (1 g, 3.52 mmol) and dichloromethane (20 mL) were added, followed by acetic anhydride (1.16 mL, 12.31 mmol). The reaction mixture was stirred at room temperature under nitrogen for 12 hours, and the reaction progress was monitored by TLC. After completion of the reaction, the reaction solution was extracted with dichloromethane, and the combined organic layers were washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 25 / 1) to yield the product as a white solid (1.21 g, 93.5%).

[0219] 1 H NMR (600MHz, CDCl3) δ8.36(d,J=9.0Hz,2H),8.05(d,J=9.0Hz,2H),7.95(d,J=8.2Hz,2H),7.46(ddd,J=8.1 ,6.8,1.2Hz,2H),7.28(ddd,J=8.2,6.7,1.2Hz,2H),7.03(dd,J=8.5,1.2Hz,2H),6.90(s,2H),1.83(s,6H).

[0220] (2) Preparation of N,N'-(6,6'-dibromo-[1,1'-binaphthyl]-2,2'-diyl) diacetamide:

[0221] The product from the previous step (500 mg, 1.36 mmol) was dissolved in a solution of N,N-dimethylformamide (10 mL), and N-bromosuccinimide (NBS, 532 mg, 2.99 mmol) was added and stirred at room temperature overnight. The reaction solution was quenched with a 10% aqueous sodium thiosulfate solution (10 mL), and the aqueous layer was extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 25 / 1) to give the product as an orange solid (650 mg, 90.4%).

[0222] 1 H NMR (600MHz, CDCl3) δ8.34(d,J=9.0Hz,2H),8.11(d,J=2.0Hz,2H),7.96(d,J=9.0Hz,2H),7.35(dd,J=9.0,2.0Hz,2H),6.91-6.83(m,4H),1.85(s,6H).

[0223] (3) Preparation of N,N'-6,6'-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-binaphthyl]-2,2'-diacetamide:

[0224] To a reaction flask were added pinacol diboronate (720 mg, 2.83 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (500 mg, 0.43 mmol), potassium acetate (372 mg, 3.80 mmol), and a dry 1,4-dioxane solution (15 mL). After nitrogen was purged three times, the product from the previous step (500 mg, 0.95 mmol) was added, and the suspension was heated at 90°C overnight under nitrogen. After completion of the reaction, the crude product was quenched with water (20 mL) and diluted with dichloromethane (30 mL). The organic phase was washed with water (3 × 30 mL) and brine (1 × 30 mL), dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. Purification was performed by silica gel column chromatography (dichloromethane / methanol = 40 / 1) to yield the product as an orange solid (302 mg, 51.3%).

[0225] 1 H NMR (400MHz, CDCl3) δ8.46 (s, 2H), 8.40 (d, J = 9.0Hz, 2H), 8.09 (d, J = 8.9Hz, 2H), 7. 61(d,J=9.7Hz,2H),6.98(d,J=8.4Hz,2H),6.88(s,2H),1.81(s,6H),1.36(s,24H).

[0226] (4) Preparation of N,N'-(6,6'-dihydroxy-[1,1'-binaphthyl]-2,2'-diyl) diacetamide:

[0227] The product from the previous step (120 mg, 0.19 mmol) was dissolved in tetrahydrofuran (2 mL). Ammonium chloride (10 mg, 0.19 mmol) was dissolved in 1 mL of water and added to the solution. Aqueous hydrogen peroxide (0.5 mL) was then added dropwise at 0°C and stirred at room temperature for 15 hours. After completion of the reaction, sodium sulfite solution was slowly added to quench the mixture, followed by extraction with ethyl acetate (3 x 3 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification was performed by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to afford a brown solid (53 mg, 68.8%).

[0228] 1 H NMR(600MHz,Methanol-d4)δ7.80(d,J=8.8Hz,2H),7.63(d,J=8.8Hz,2H),7.21( d,J=2.5Hz,2H),6.91(d,J=9.1Hz,2H),6.85(dd,J=9.1,2.5Hz,2H),1.76(s,6H).

[0229] (5) Preparation of 2,2'-diamino-[1,1'-binaphthyl]-6,6'-diol:

[0230] The product from the previous step (100 mg, 0.25 mmol) was dissolved in a mixture of ethanol (1 mL) and water (1 mL). Concentrated hydrochloric acid (0.5 mL) was added dropwise at room temperature, followed by stirring at reflux for 2 hours. After the reaction, the ethanol was removed, and saturated sodium carbonate solution was added to the residue to adjust the pH to 10, resulting in the precipitation of a white product (50 mg, 63.3%).

[0231] 1 H NMR (400MHz, DMSO-d6) δ9.14(s,2H),7.54(d,J=8.8Hz,2H),7.12(d,J=8.8Hz,2H),7.03(d,J=2.4Hz,2H),6.80-6.63(m,4H),4.27(s,4H).

[0232] (6) Preparation of 2,2'-diamino-[1,1'-binaphthyl]-6,6'-dioldichloroplatinum(II):

[0233] Potassium tetrachloroplatinate (394 mg, 0.95 mmol) and 5 mL of deionized water were added to a 25 mL flask at room temperature, stirred, and filtered to remove insoluble matter. (R)-2,2'-diamino-[1,1'-binaphthyl]-6,6'-diol (300 mg, 0.95 mmol) was dispersed in 5 mL of methanol and added to the above solution. The reaction solution was stirred at 40°C under nitrogen overnight to form a yellow precipitate. The precipitate was filtered, washed with cold water, and then dried under vacuum to obtain a yellow solid (394 mg, 71.2%).

[0234] (7) Preparation of Compound 49:

[0235] The compound was prepared by the same method as Example 34 using General Synthesis Method A. The yield was 48%.

[0236] 1 H NMR (400MHz, Methanol-d4) δ7.89(dd,J=8.8,4.5Hz,2H),7.64(dd,J=15.2,8.8Hz,2H),7.26(s,2H),6.91(s,4H),2.50(t,J=8.0Hz,4H),1.95-2.10(m,2H).

[0237] Example 50: Preparation of Compound 50

[0238] The compound was prepared by the same method as Example 34 using General Synthesis Method A. The yield was 52%.

[0239] 1 H NMR (400MHz, Methanol-d4) δ7.89(dd,J=8.8,4.5Hz,2H),7.63(dd,J=15.2,8.8Hz,2H),7.25(s,2H),6.91(s,4H),2.50(t,J=8.0Hz,4H),1.95-2.10(m,2H).

[0240] Example 51: Preparation of Compound 51

[0241] The compound was prepared by the same method as Example 34 using General Synthesis Method A. The yield was 55%.

[0242] 1H NMR (400MHz, Methanol-d4) δ7.87(dd,J=8.8,4.5Hz,2H),7.61(dd,J=15.2,8.8Hz,2H),7.23(s,2H),6.90(s,4H),2.50(t,J=8.0Hz,4H),1.95-2.10(m,2H).

[0243] Example 52: Preparation of Compound 52

[0244] The compound was prepared by the same method as Example 40 using General Synthesis Method B. The yield was 50%.

[0245] 1 H NMR (600MHz, Methanol-d4) δ8.14(dd,J=8.7,3.5Hz,2H),8.04(d,J=8.3Hz,2H),7.77(dd,J=17.2,8.7Hz,2H),7.50(t,J=7.5Hz,2H),7.30(dd,J=8.3,7.0 Hz,2H),7.02(dd,J=8.5,3.9Hz,2H),5.58(s,1H),4.53(d,J=7.3Hz,1H),3.8 8-3.81(m,1H),3.65(dd,J=12.0,5.2Hz,1H),3.50-3.30(m,4H),2.89(s,6H).

[0246] Example 53: Preparation of Compound 53

[0247] The compound was prepared by the same method as Example 40 using General Synthesis Method B. The yield was 47%.

[0248] 1 H NMR (600MHz, Methanol-d4) δ8.13(dd,J=8.7,3.5Hz,2H),8.04(d,J=8.3Hz,2H),7.77(dd,J=17.2,8.7Hz,2H),7.51(t,J=7.5Hz,2H),7.30(dd,J=8.3,7.0 Hz,2H),7.02(dd,J=8.5,3.9Hz,2H),5.58(s,1H),4.52(d,J=7.3Hz,1H),3.8 8-3.81(m,1H),3.65(dd,J=12.0,5.2Hz,1H),3.50-3.30(m,4H),2.90(s,6H).

[0249] Example 54: Preparation of Compound 54

[0250] The compound was prepared by the same method as Example 40 using General Synthesis Method B. The yield was 45%.

[0251] 1 H NMR (600MHz, Methanol-d4) δ8.13(dd,J=8.7,3.5Hz,2H),8.04(d,J=8.3Hz,2H),7.77(dd,J=17.2,8.7Hz,2H),7.51(t,J=7.5Hz,2H),7.30(dd,J=8.3,7.0 Hz,2H),7.02(dd,J=8.5,3.9Hz,2H),5.56(s,1H),4.52(d,J=7.3Hz,1H),3.9 0-3.80(m,1H),3.62(dd,J=12.0,5.2Hz,1H),3.70-3.30(m,4H),2.90(s,6H).

[0252] Example 55: Preparation of Compound 55

[0253] Dissolve the crude product (119 mg) of 1-O-(2,3,4,6-tetraacetyl-D-galactopyranoside)-malonic acid disodium salt in 2 mL of water. Under nitrogen, dissolve (R)-1,1'-binaphthyl-2,2'-diamine platinum nitrate (219 mg) in 4 mL of methanol. Add the resulting mixture to the reaction mixture, adjust the pH to 7 with sodium hydroxide solution, and heat to 60°C for 2 hours. After the reaction is complete, remove the precipitate using a centrifuge, collect the supernatant, freeze-dry it, and separate it using semi-preparative HPLC to yield 135 mg of the final product as a yellow solid. The yield is 49%.

[0254] 1 H NMR (600MHz, Methanol-d4) δ8.10(dd,J=8.8,5.7Hz,2H),8.02(d,J=8.2Hz,2H),7.76(dd,J=24.0,8.7Hz,2H),7.50(t,J=7.5Hz,2H),7.28(t,J=6.8H z,2H),7.00(t,J=7.7Hz,2H),5.59(s,1H),4.47(d,J=7.7Hz,1H),3.77(d, J=3.5Hz,1H),3.71(d,J=7.0Hz,2H),3.69-3.65(m,1H),3.56-3.47(m,2H).

[0255] Example 56: Preparation of Compound 56

[0256] The compound was prepared by the same method as Example 40 using General Synthesis Method B. The yield was 42%.

[0257] 1 H NMR (600MHz, Methanol-d4) δ8.14(dd,J=8.8,5.7Hz,2H),8.04(d,J=8.2Hz,2H),7.75(dd,J=24.0,8.7Hz,2H),7.50(t,J=7.5Hz,2H),7.30(t,J=6.8H z,2H),7.01(t,J=7.7Hz,2H),5.59(s,1H),4.47(d,J=7.7Hz,1H),3.77(d, J=3.5Hz,1H),3.71(d,J=7.0Hz,2H),3.69-3.65(m,1H),3.56-3.47(m,2H).

[0258] Example 57: Preparation of Compound 57

[0259] The compound was prepared by the same method as Example 40 using General Synthesis Method B. The yield was 40%.

[0260] 1 H NMR (600MHz, Methanol-d4) δ8.14(t,J=7.4Hz,2H),8.04(d,J=8.3Hz,2H),7.75(dd,J=25.9,8.6Hz,2H),7.50(t,J=7.6Hz,2H),7.30(t,J=7.7Hz ,2H),7.02(t,J=7.1Hz,2H),5.59(s,1H),4.43(td,J=27.0,25.7,7.5Hz ,1H),3.78(d,J=17.4Hz,2H),3.74-3.62(m,2H),3.48(d,J=6.8Hz,2H).

[0261] Example 58: Preparation of Compound 58

[0262] The crude product of 1-O-(2,3,4,6-tetraacetyl-D-mannoside)-malonic acid disodium salt (119 mg) was dissolved in 2 mL of water. Under nitrogen, (R)-1,1'-binaphthyl-2,2'-diamine platinum nitrate (219 mg) was dissolved in 4 mL of methanol and added to the reaction solution. The pH was adjusted to 7 with sodium hydroxide solution, and the temperature was raised to 60°C for 2 hours. After the reaction was completed, the precipitate was removed by centrifuge, and the supernatant was collected and freeze-dried using a freeze dryer. 50 mg of the final product was separated by semi-preparative high-performance liquid chromatography to obtain a yellow solid.

[0263] 1 H NMR (600MHz, Methanol-d4) δ8.14(dd,J=8.8,6.4Hz,2H),8.03(d,J=8.5Hz,2H),7.77(d,J=8.8Hz,1H),7.71(d,J=8.8Hz,1H),7.53 -7.47(m,2H),7.35-7.26(m,2H),7.02(dd,J=8.1,2.6Hz,2H),5.51(s,1H),4.91(d,J=1.7Hz,1H),4.05(dd,J=3.5,1. 7Hz, 1H), 3.95 (dd, J=8.8, 3.5Hz, 1H), 3.89 (dd, J=11.7, 1.9Hz, 1H), 3.74 (dd, J=11.6, 5.3Hz, 1H), 3.67-3.58 (m, 2H).

[0264] Example 59: Preparation of Compound 59

[0265] The compound was prepared by the same method as Example 40 using General Synthesis Method B. The yield was 20%.

[0266] 1 H NMR (600MHz, Methanol-d4) δ8.13(dd,J=8.8,6.4Hz,2H),8.01(d,J=8.5Hz,2H),7.75(d,J=8.8Hz,1H),7.71(d,J=8.8Hz,1H),7.53 -7.47(m,2H),7.35-7.26(m,2H),7.02(dd,J=8.1,2.6Hz,2H),5.51(s,1H),4.91(d,J=1.7Hz,1H),4.05(dd,J=3.5,1. 7Hz, 1H), 3.95 (dd, J=8.8, 3.5Hz, 1H), 3.89 (dd, J=11.7, 1.9Hz, 1H), 3.74 (dd, J=11.6, 5.3Hz, 1H), 3.67-3.58 (m, 2H).

[0267] Example 60: Preparation of Compound 60

[0268] The compound was prepared by the same method as Example 40 using General Synthesis Method B. The yield was 23%.

[0269] 1H NMR(600MHz, Methanol-d4)δ8.14(dd,J=8.9,2.2Hz,2H),8.04(d,J=8.3Hz,2H),7.74(d d,J=25.1,8.7Hz,2H),7.52-7.47(m,2H),7.37-7.26(m,2H),7.02(dd,J=8.5,1.1Hz,2H ),5.45(s,1H),5.00(d,J=1.8Hz,1H),4.06(dd,J=3.5,1.7Hz,1H),3.93(dd,J=9.0,3.5 Hz,1H),3.77(dd,J=11.7,1.8Hz,1H),3.65(dt,J=11.4,5.6Hz,1H),3.62-3.53(m,2H).

[0270] Example 61: Preparation of Compound 61

[0271] The compound was prepared by the same method as Example 58 using General Synthesis Method B. The yield was 25%.

[0272] 1 H NMR(400MHz, Methanol-d4)δ7.87(dd,J=9.1,4.2Hz,2H),7.70-7.55(m,2H),7.26(s,2H),6.90(s,4H) ,5.57(s,1H),4.60-4.45(m,1H),3.89-3.79(m,1H),3.65(dd,J=12.1,4.8Hz,1H),3.43-3.33(m,2H).

[0273] Example 62: Preparation of Compound 62

[0274] The compound was prepared by the same method as Example 58 using General Synthesis Method B. The yield was 27%.

[0275] 1 H NMR(400MHz, Methanol-d4)δ7.89(dd,J=9.1,4.2Hz,2H),7.70-7.57(m,2H),7.26(s,2H),6.91(s,4H) ,5.57(s,1H),4.58-4.45(m,1H),3.89-3.79(m,1H),3.65(dd,J=12.1,4.8Hz,1H),3.43-3.33(m,2H).

[0276] Example 63: Preparation of Compound 63

[0277] The compound was prepared by the same method as Example 58 using General Synthesis Method B. The yield was 27%.

[0278] 1 H NMR (400MHz, Methanol-d4) δ7.89 (dd, J=8.8, 3.9Hz, 2H), 7.71-7.57 (m, 2H), 7.2 6(s,2H),6.91(s,4H),5.56(d,J=2.0Hz,1H),4.51(dd,J=16.3,6.4Hz,1H),3.90 -3.80(m,1H),3.67(td,J=11.1,10.7,4.8Hz,1H),3.43 -3.33(m,2H).

[0279] Example 64: Preparation of Compound 64

[0280] The compound was prepared by the same method as Example 58 using General Synthesis Method B. The yield was 31%.

[0281] 1 H NMR (400MHz, Methanol-d4) δ7.89 (dd, J=8.8, 4.0Hz, 2H), 7.61 (dd, J=18.8, 8.8Hz, 2H), 7.26 (s, 2H), 6 .95-6.85(m,4H),5.57(s,1H),4.43(d,J=7.6Hz,1H),3.80-3.65(m,4H),3.48(dt,J=9.6,5.3Hz,2H).

[0282] Example 65: Preparation of Compound 65

[0283] The compound was prepared by the same method as Example 58 using General Synthesis Method B. The yield was 29%.

[0284] 1 H NMR (400MHz, Methanol-d4) δ7.89 (dd, J=8.8, 4.5Hz, 2H), 7.64 (dd, J=15.2, 8.8Hz, 2H), 7.26 (s, 2 H),6.91(s,4H),5.59(s,1H),4.46(dd,J=17.4,7.7Hz,1H),3.81-3.63(m,4H),3.56-3.44(m,2H).

[0285] Example 66: Preparation of Compound 66

[0286] The compound was prepared by the same method as Example 58 using General Synthesis Method B. The yield was 33%.

[0287] 1 H NMR (400MHz, Methanol-d4) δ7.89 (dd, J=8.8, 4.0Hz, 2H), 7.63 (dd, J=18.8, 8.8Hz, 2H), 7.26 (s, 2H), 6 .94-6.88(m,4H),5.58(s,1H),4.44(d,J=7.6Hz,1H),3.78-3.65(m,4H),3.48(dt,J=9.6,5.3Hz,2H).

[0288] Example 67: Preparation of Compound 67

[0289] The compound was prepared by the same method as Example 58 using General Synthesis Method B. The yield was 33%.

[0290] 1 H NMR(400MHz, Methanol-d4)δ7.88(dd,J=8.8,2.9Hz,2H),7.70-7.55(m,2H),7.26(s,2H),6.91(s,4H),5.48(d,J=23.7 Hz,1H),4.93(dd,J=32.7,1.7Hz,1H),4.05(td,J=4.1,3.3,1.8Hz,1H),3.95(td,J=6.2,3.0Hz,1H),3.90-3.55(m,4H).

[0291] Example 68: Preparation of Compound 68

[0292] The compound was prepared by the same method as Example 58 using General Synthesis Method B. The yield was 33%.

[0293] 1 H NMR (400MHz, Methanol-d4) δ7.89(dd,J=8.8,2.9Hz,2H),7.69-7.57(m,2H),7.26(s,2H),6.91(s,4H),5.48(d,J=23.7 Hz,1H),4.95(dd,J=32.7,1.7Hz,1H),4.06(td,J=4.1,3.3,1.8Hz,1H),3.95(td,J=6.2,3.0Hz,1H),3.91-3.54(m,4H).

[0294] Example 69: Preparation of Compound 69

[0295] The compound was prepared by the same method as Example 58 using General Synthesis Method B. The yield was 33%.

[0296] 1 H NMR (400MHz, Methanol-d4) δ7.89 (dd, J=8.8, 4.0Hz, 2H), 7.63 (dd, J=18.8, 8.8Hz, 2H), 7.26 (s, 2H), 6.94 -6.88(m,4H),5.45(s,1H),5.00(d,J=1.8Hz,1H),4.06(dd,J=3.5,1.7Hz,1H),3.93(dd,J=9.0,3.5Hz,1H),3.90-3.53(m,4H).

[0297] Example 70: Preparation of Compound 70

[0298] To a suspension of (R)-1,1'-binaphthyl-2,2'-diaminedichloroplatinum (400 mg, 0.73 mmol) in 10 mL of methanol and 10 mL of deionized water was added silver sulfate (227 mg, 0.73 mmol) at room temperature. The reaction mixture was heated to 45°C under nitrogen and stirred in the dark for two days. After the reaction was complete, the precipitate was removed by centrifuge, and the supernatant was collected. Phosphorylacetic acid (102 mg, 0.73 mmol) and barium sulfate (230 mg, 0.73 mmol) were added to the supernatant. The mixture was heated to 40°C and stirred for 18 hours. After the reaction was complete, the precipitate was removed by centrifuge, and the supernatant was filtered through a nylon microporous membrane and freeze-dried using a freeze dryer. 244 mg of the final product was obtained as an orange-red solid using semi-preparative HPLC.

[0299] 1 H NMR (600MHz, Methanol-d4) δ8.11(dd,J=8.8,5.6Hz,2H),8.02(dd,J=8.1,3.2Hz,2H),7.82(d,J=8.7Hz,1H),7.71(d,J=8.7Hz,1H), 7.48(tt,J=7.0,1.3Hz,2H),7.31-7.24(m,2H),7.00(t,J=9.5Hz,2H),2.90(dd,J=19.1,14.0Hz,1H),2.78(dd,J=17.2,14.0Hz,1H).

[0300] Example 71: Preparation of Compound 71

[0301] The compound was prepared by the same method as Example 70 using General Synthesis Method A. The yield was 53%.

[0302] 1 H NMR (600MHz, Methanol-d4) δ8.10(dd,J=8.8,5.6Hz,2H),8.01(dd,J=8.1,3.2Hz,2H),7.81(d,J=8.7Hz,1H),7.70(d,J=8.7Hz,1H), 7.45(tt,J=7.0,1.3Hz,2H),7.35-7.20(m,2H),7.00(t,J=9.5Hz,2H),2.88(dd,J=19.1,14.0Hz,1H),2.76(dd,J=17.2,14.0Hz,1H).

[0303] Example 72: Preparation of Compound 72

[0304] The compound was prepared by the same method as Example 70 using General Synthesis Method A. The yield was 56%.

[0305] 1 H NMR (600MHz, Methanol-d4) δ8.11(dd,J=8.8,3.3Hz,2H),8.01(dd,J=8.3,3.1Hz,2H),7.79(dd,J=57.6,8.7Hz,2H),7.47(q,J= 6.8Hz,2H),7.25(dt,J=15.4,7.7Hz,2H),6.99(t,J=9.0Hz,2H),2.90(dd,J=19.0,14.0Hz,1H),2.79(dd,J=17.3,14.0Hz,1H).

[0306] Example 73: Preparation of Compound 73

[0307] The compound was prepared by the same method as Example 31 using General Synthesis Method A. The yield was 70%.

[0308] 1 H NMR (600MHz, Methanol-d4) δ7.77(d,J=8.7Hz,2H),7.71(d,J=8.2Hz,2H),7.11-7.06(m,4H),6.88(s,2H),2.26(s,6H).

[0309] Example 74: Preparation of Compound 74

[0310] The compound was prepared by the same method as Example 31 using General Synthesis Method A. The yield was 70%.

[0311] 1 H NMR (600MHz, Methanol-d4) δ7.80 (d, J = 8.7Hz, 2H), 7.73 (d, J = 8.2Hz, 2H), 7.11-7.05 (m, 4H), 6.90 (s, 2H), 2.26 (s, 6H).

[0312] Example 75: Preparation of Compound 75

[0313] The compound was prepared by the same method as Example 31 using General Synthesis Method A. The yield was 76%.

[0314] 1 H NMR (600MHz, Methanol-d4) δ7.81 (d, J = 8.7Hz, 2H), 7.73 (d, J = 8.2Hz, 2H), 7.11-7.05 (m, 4H), 6.90 (s, 2H), 2.27 (s, 6H).

[0315] Example 76: Preparation of Compound 76

[0316] The compound was prepared by the same method as Example 49 using General Synthesis Method A. The yield was 76%.

[0317] 1 H NMR (400MHz, Methanol-d4) δ7.85 (dd, J=8.8, 6.9Hz, 4H), 7.14 (d, J=8.8Hz, 2H), 7.00 (dd, J=8 .8,2.6Hz,2H),6.61(d,J=2.6Hz,2H),3.60(s,6H),2.50(t,J=8.0Hz,4H),1.95-2.10(m,2H).

[0318] Example 77: Preparation of Compound 77

[0319] The compound was prepared by the same method as Example 49 using General Synthesis Method A. The yield was 77%.

[0320] 1H NMR (400MHz, Methanol-d4) δ7.87 (dd, J=8.8, 6.9Hz, 4H), 7.16 (d, J=8.8Hz, 2H), 7.03 (dd, J=8 .8,2.6Hz,2H),6.65(d,J=2.6Hz,2H),3.60(s,6H),2.50(t,J=8.0Hz,4H),1.95-2.10(m,2H).

[0321] Example 78: Preparation of Compound 78

[0322] The compound was prepared by the same method as Example 49 using General Synthesis Method A. The yield was 75%.

[0323] 1 H NMR (400MHz, Methanol-d4) δ7.89 (dd, J=8.8, 6.9Hz, 4H), 7.17 (d, J=8.8Hz, 2H), 7.06 (dd, J=8 .8,2.6Hz,2H),6.67(d,J=2.6Hz,2H),3.63(s,6H),2.52(t,J=8.0Hz,4H),1.95-2.15(m,2H).

[0324] Example 79: Preparation of Compound 79

[0325] The compound was prepared by the same method as Example 31 using General Synthesis Method A. The yield was 75%.

[0326] 1 H NMR (600MHz, Methanol-d4) δ8.12(d,J=8.8Hz,2H),8.02(d,J=8.3Hz,2H),7.76(d,J=8.8 Hz,2H),7.48(t,J=7.6Hz,2H),7.27(t,J=7.7Hz,2H),7.04(d,J=8.6Hz,2H),2.89(s,6H).

[0327] Example 80: Preparation of Compound 80

[0328] The compound was prepared by the same method as Example 31 using General Synthesis Method A. The yield was 77%.

[0329] 1H NMR (600MHz, Methanol-d4) δ8.11(d,J=8.8Hz,2H),8.02(d,J=8.3Hz,2H),7.76(d,J=8.8 Hz,2H),7.48(t,J=7.6Hz,2H),7.27(t,J=7.7Hz,2H),7.05(d,J=8.6Hz,2H),2.90(s,6H).

[0330] Example 81: Preparation of Compound 81

[0331] The compound was prepared by the same method as Example 31 using General Synthesis Method A. The yield was 73%.

[0332] 1 H NMR (600MHz, Methanol-d4) δ8.12(d,J=8.8Hz,2H),8.03(d,J=8.3Hz,2H),7.77(d,J=8.8 Hz,2H),7.49(t,J=7.6Hz,2H),7.27(t,J=7.7Hz,2H),7.06(d,J=8.6Hz,2H),2.90(s,6H).

[0333] Example 82: Preparation of Compound 82

[0334] The compound was prepared by the same method as Example 55 using General Synthesis Method B. The yield was 41%.

[0335] 1 H NMR (600MHz, Methanol-d4) δ8.14(dd,J=8.8,5.7Hz,2H),8.04(d,J=8.2Hz,2H),7.75(dd,J=24.0,8.7Hz,2H),7.50(t,J=7.5Hz,2H),7.30(t,J=6.8Hz,2H), 7.01(t,J=7.7Hz,2H),5.59(s,1H),4.47(d,J=7.7Hz,1H),3.77(d,J=3.5Hz,1 H),3.71(d,J=7.0Hz,2H),3.69-3.65(m,1H),3.56-3.47(m,2H),2.91(s,6H).

[0336] Example 83: Preparation of Compound 83

[0337] The compound was prepared by the same method as Example 55 using General Synthesis Method B. The yield was 44%.

[0338] 1 H NMR (600MHz, Methanol-d4) δ8.14(dd,J=8.8,5.7Hz,2H),8.04(d,J=8.2Hz,2H),7.75(dd,J=24.0,8.7Hz,2H),7.50(t,J=7.5Hz,2H),7.30(t,J=6.8Hz,2H), 7.01(t,J=7.7Hz,2H),5.59(s,1H),4.47(d,J=7.7Hz,1H),3.77(d,J=3.5Hz,1 H), 3.71 (d, J = 7.0Hz, 2H), 3.69-3.65 (m, 1H), 3.56-3.47 (m, 2H), 2.90 (s, 6H).

[0339] Example 84: Preparation of Compound 84

[0340] The compound was prepared by the same method as Example 55 using General Synthesis Method B. The yield was 44%.

[0341] 1 H NMR (600MHz, Methanol-d4) δ8.14(t,J=7.4Hz,2H),8.04(d,J=8.3Hz,2H),7.75(dd,J=25.9,8.6Hz,2H),7.50(t,J=7.6Hz,2H),7.30(t,J=7.7Hz,2H), 7.02(t,J=7.1Hz,2H),5.59(s,1H),4.43(td,J=27.0,25.7,7.5Hz,1H),3.7 8(d,J=17.4Hz,2H),3.74-3.62(m,2H),3.48(d,J=6.8Hz,2H),2.90(s,6H).

[0342] Example 85: Preparation of Reference Compound 1

[0343] The compound was prepared by the same method as Example 40 using General Synthesis Method B. The yield was 73%.

[0344] Dissolve the crude product (429 mg) of 1-O-(2,3,4,6-tetraacetyl-D-glucoside)-malonic acid disodium salt in 3 mL of water. Under nitrogen, dissolve trans-(1R,2R)-cyclohexanediamine platinum nitrate (570 mg, 1.31 mmol) in 4 mL of water and add the resulting mixture to the reaction mixture. Adjust the pH to 7.0 with sodium hydroxide solution, then heat the mixture to 60°C and react for 2 hours. After the reaction is complete, remove the precipitate using a centrifuge, collect the supernatant, freeze-dry it, and separate it using semi-preparative HPLC to yield 565 mg of the final product as a white solid. The yield is 73%.

[0345] 1 H NMR(600MHz,D2O)δ5.86(s,1H),4.65(d,J=7.7Hz,1H),3.92(d,J=12.3Hz,1H),3.77-3.73(m,1H),3.53-3.43(m,4H), 2.39(dd,J=5.3,3.7Hz,2H),2.04(d,J=11.3Hz,2H),1.57(d,J=9.7Hz,2H),1.34-1.26(m,2H),1.15(t,J=10.1Hz,2H).

[0346] Example 86: Preparation of Reference Compound 2

[0347] Prepared by the same method as Example 85. Yield 30%.

[0348] 1 H NMR(600MHz,D2O)δ5.97(s,1H),4.67(d,J=7.0Hz,1H),3.99(d,J=2.5Hz,1H),3.90-3.82(m,2H),3.79-3.72(m,3H),2.47( dd,J=5.2,3.7Hz,2H),2.11(d,J=11.3Hz,2H),1.64(d,J=9.1Hz,2H),1.37(dd,J=7.7,3.4Hz,2H),1.22(t,J=10.4Hz,2H).

[0349] Example 87: Preparation of Reference Compound 3

[0350] Prepared by the same method as Example 85. Yield 49%.

[0351] 1H NMR(600MHz,D2O)δ5.83(s,1H),5.09(d,J=1.5Hz,1H),4.21(dd,J=3.4,1.7Hz,1 H),4.06(dd,J=9.4,3.5Hz,1H),3.99(dd,J=12.0,1.8Hz,1H),3.83(dd,J=12.0, 6.3Hz,1H),3.81-3.76(m,1H),3.73(t,J=9.7Hz,1H),2.50-2.41(m,2H),2.09(d d,J=12.3,10.6Hz,2H),1.65-1.60(m,2H),1.41-1.26(m,2H),1.25-1.11(m,2H).

[0352] Example 88: Preparation of Reference Compound 4

[0353] Prepared by the same method as Example 85. Yield 40%.

[0354] 1 H NMR(600MHz,D2O)δ5.83(s,1H),4.63(d,J=7.8Hz,1H),3.90(d,J=12.5Hz,1H),3.76-3.70(m,1H),3.49-3.42(m,4H),2.3 7(d,J=8.9Hz,2H),2.02(d,J=11.4Hz,2H),1.55(d,J=8.9Hz,2H),1.28(dd,J=22.1,10.4Hz,2H),1.13(t,J=10.3Hz,2H).

[0355] Example 89: Preparation of Reference Compound 5

[0356] Prepared by the same method as Example 85. Yield 43%.

[0357] 1H NMR(600MHz,DMSO-d6)δ6.10(d,J=9.6Hz,1H),6.00(d,J=10.4Hz,1H),5.41(t,J=9.1Hz,1H), 5.31(s,2H),5.06(s,1H),4.77(s,1H),4.71(s,1H),4.47(s,1H),4.15(d,J=7.7Hz,1H),3.60 -3.47(m,3H),3.33(dd,J=13.0,7.0Hz,2H),2.17-2.02(m,2H),1.80(s,2H),1.44(s,2H),1.21(d,J=9.8Hz,2H),1.02-0.96(m,2H).

[0358] Example 90: Preparation of Reference Compound 6

[0359] Prepared by the same method as Example 85. Yield 35%.

[0360] 1 H NMR(600MHz,D2O)δ5.82(s,1H),5.10(s,1H),4.24-4.19(m,1H),4.06(dd,J=9.3,3.4Hz,1H),3.98(d,J=11.5Hz,2H),1.63(d,J=11.6Hz,2H),1.41 -1.28(m,2H),1.25-1.13(m,2H).

[0361] Example 91: Preparation of Reference Compound 7

[0362] The compound was prepared by the same method as Example 40 using General Synthesis Method B. The yield was 26%.

[0363] Dissolve the crude product (178 mg) of 1-O-(2,3,4,6-tetraacetyl-D-glucoside)-malonic acid disodium salt in 2 mL of water. Under nitrogen, dissolve (R)-3-aminopiperidinium platinum sulfate (145 mg, 0.55 mmol) in 2 mL of water and add the resulting mixture to the reaction mixture. Adjust the pH to 8.0 with barium hydroxide solution, then heat the mixture to 35°C and react for 4 hours. After the reaction is complete, remove the precipitate using a centrifuge, collect the supernatant, freeze-dry it, and separate it using semi-preparative HPLC to yield 51 mg of the final product as a white solid. The yield is 26%.

[0364] 1H NMR(600MHz,D2O)δ5.80,5.75(s,1H),4.62(s,1H),3.88(d,J=12.4Hz,1H),3.70(d,J=8.4Hz,1H),3.49 -3.36(m,4H),3.34-3.23(m,1H),3.18-3.09(m,1H),3.05(d,J=11.1Hz,1H) ,2.94(s,1H),2.60-2.43(m,2H),1.86-1.75(m,2H),1.65(d,J=12.2Hz,1H).

[0365] Example 91: Preparation of Reference Compound 8

[0366] Prepared by the same method as Example 85. Yield 21%.

[0367] 1 H NMR(600MHz,D2O)δ5.82,5.79(s,1H),4.64(dd,J=13.8,7.7Hz,1H),3.89(d,J=12.1Hz,1H),3.71(dd,J=11.3,6.5Hz,1H),3.51 -3.40(m,4H),3.36-3.23(m,1H),3.16(t,J=14.8Hz,1H),3.06(d,J=10.9Hz,1 H), 2.96 (s, 1H), 2.62-2.45 (m, 2H), 1.88-1.77 (m, 2H), 1.66 (d, J = 12.5Hz, 1H).

[0368] Example 92: Preparation of Reference Compound 9

[0369] Prepared by the same method as Example 85. Yield 35%.

[0370] 1 H NMR (600MHz, D2O) δ5.86 (s, 0.3H), 5.80 (s, 0.7H), 4.70 (d, J = 8.0Hz, 1H), 3.98 (d, J = 12.4Hz, 1H), 3.84 -3.78(m,2H),3.58-3.47(m,4H),3.30-3.21(m,3H),2.45(d,J=10.4Hz,1H),2.14 -3.03(m,2H).

[0371] Example 93: Preparation of Reference Compound 10

[0372] Prepared by the same method as Example 85. Yield 41%.

[0373] 1 H NMR(600MHz,D2O)δ5.89(s,0.5H),5.84(s,0.5H),4.73(d,J=7.7Hz,1H),4.01-3.99(m,1H),3.89-3.81(m,2H),3.60-3.58(m,1H),3.55 -3.51(m,3H),3.32-3.21(m,3H),2.50-2.44(m,1H),2.18-2.05(m,2H).

[0374] Example 94: Preparation of Reference Compound 11

[0375] The compound was prepared by the same method as Example 40 using General Synthesis Method B. The yield was 31%.

[0376] Dissolve the crude product (109 mg) of 1-O-(2,3,4,6-tetraacetyl-D-glucoside)-malonic acid disodium salt in 2 mL of water. Under nitrogen, dissolve trans-(1R,2R)-1,2-diphenylethylenediamine platinum dinitrate (178 mg, 0.33 mmol) in 4 mL of methanol. Add the solution to the reaction mixture, adjust the pH to 7.0 with sodium hydroxide solution, and heat to 60°C for 2 hours. After the reaction is complete, remove the precipitate using a centrifuge, collect the supernatant, freeze-dry it, and separate it by semi-preparative HPLC to obtain 71 mg of the final product as a yellow solid. The yield is 31%.

[0377] 1 H NMR(600MHz,DMSO-d6)δ7.30-7.26(m,4H),7.18-7.14(m,6H),6.86(d,J=7.2Hz,1H),6.71(d ,J=7.5Hz,1H),6.14(t,J=9.8Hz,1H),5.97(t,J=9.8Hz,1H),5.45(s,1H),5.36(s,1H),5.06 -5.03(m,2H),4.84(d,J=4.7Hz,1H),4.23(d,J=7.9Hz,1H),3.95-3.86(m,2H),3.76(dd,J=1 1.4,2.8Hz,1H),3.47-3.43(m,1H),3.19-3.16(m,1H),3.14-3.06(m,2H),3.04-3.01(m,1H).

[0378] Example 95: Preparation of Reference Compound 12

[0379] Prepared by the same method as Example 85. Yield: 23%.

[0380] 1 H NMR (400MHz, DMSO-d6) δ7.27(d,J=6.0Hz,4H),7.15(d,J=6.4Hz,6H),6.84(d,J=8.4Hz,1H),6.64(d,J=7.7Hz,1H),6.13-6.05(m,2H),5.4 1(s,1H),5.22(s,1H),4.83-4.75(m,2H),4.54(s,1H),4.16(d,J=7.5Hz,1H),3.91(d,J=6.3Hz,2H),3.65-3.48(m,4H),3.33-3.31(m,1H).

[0381] Example 96: Preparation of Reference Compound 13

[0382] Prepared by the same method as Example 85. Yield: 26%.

[0383] 1 H NMR(600MHz, DMSO-d6)δ7.25(d,J=6.6Hz,4H),7.17-7.12(m,6H),6.71(dd,J=13.1,9.1Hz,2H),6.04-5.92(m,2H),5.29(s,1H),4.79-4.72(m, 3H),4.63(s,1H),4.49(s,1H),3.93-3.82(m,2H),3.74(s,1H),3.67-3. 62(m,2H),3.57-3.51(m,1H),3.47(t,J=9.4Hz,1H),3.40-3.36(m,1H).

[0384] Example 97: Preparation of Reference Compound 14

[0385] Prepared by the same method as Example 85. Yield 35%.

[0386] 1H NMR (600MHz, DMSO-d6) δ7.29-7.24(m,4H),7.17-7.12(m,6H),6.86(d,J=7.3Hz,1H),6.70(d,J =7.5Hz,1H),6.14(t,J=10.0Hz,1H),5.96(t,J=9.8Hz,1H),5.43(s,1H),5.35(s,1H),5.03(dd, J=26.0,4.6Hz,2H),4.84(s,1H),4.21(d,J=7.8Hz,1H),3.93-3.84(m,2H),3.78-3.71(m,1H),3 .43(dt,J=11.1,5.4Hz,1H),3.16(td,J=8.7,4.5Hz,1H),3.12-3.05(m,2H),3.02-2.98(m,1H).

[0387] Example 98: Preparation of Reference Compound 15

[0388] Prepared by the same method as Example 85. Yield 21%.

[0389] 1 H NMR(600MHz,DMSO-d6)δ7.27(d,J=7.8Hz,4H),7.18-7.14(m,6H),6.89 -6.79(m,1H),6.75-6.65(m,1H),6.10(t,J=10.2Hz,1H),5.96(t,J=10.1Hz,1H),5.42(s,1H),4.79(s,2H),4.5 0(s,1H),4.18(d,J=7.8Hz,1H),3.90(dt,J=6.7,3.9Hz,2H),3.60(s,1H),3.58-3.54(m,2H),3.43-3.34(m,3H).

[0390] Example 99: Preparation of Reference Compound 16

[0391] Prepared by the same method as Example 85. Yield 29%.

[0392] 1H NMR(600MHz,DMSO-d6)δ7.27-7.24(m,4H),7.17-7.13(m,6H),6.72(d,J=7.4Hz,1H),6.6 3-6.53(m,1H),6.01(dd,J=9.1,6.4Hz,2H),5.24(s,1H),4.76(d,J=1.2Hz,1H),4.69(s, 2H),4.54(d,J=3.0Hz,1H),4.43(s,1H),3.91-3.85(m,2H),3.74(s,1H),3.67(d,J=10.4 Hz,1H),3.63(d,J=9.2Hz,1H),3.55(dd,J=11.0,4.6Hz,1H),3.48(t,J=9.3Hz,1H),3.41 -3.38(m,1H).

[0393] Example 100: Preparation of Reference Compound 17

[0394] Prepared by the same method as Example 85. Yield 17%.

[0395] 1 H NMR (400MHz, D2O) δ7.56 -7.38(m,6H),7.33(s,2H),5.87(s,1H),4.67-4.62(m,1H),3.96-3.87(m,1H),3.79-3.71(m,1H),3.61-3.33(m,4H).

[0396] Example 101: Preparation of Reference Compound 18

[0397] Prepared by the same method as Example 85. Yield 14%.

[0398] 1 H NMR(400MHz,D2O)δ7.54-7.39(m,6H),7.37 -7.30(m,2H),5.92(d,J=6.8Hz,1H),4.63-4.58(m,1H),3.96-3.90(m,1H),3.86-3.76(m,2H),3.72-3.68(m,3H).

[0399] Example 102: Preparation of Reference Compound 19

[0400] Prepared by the same method as Example 85. Yield 15%.

[0401] 1H NMR(400MHz,D2O)δ7.53-7.37(m,6H),7.36-7.26(m,2H),5.73(d,J=12.3Hz,1H),4.98(d, J=1.7Hz,1H),4.17-4.15(m,1H),4.03-3.99(m,1H),3.98-3.82(m,1H),3.78-3.63(m,3H).

[0402] Test example

[0403] Experimental Example 1: Construction of drug-resistant cell lines

[0404] (1) Cell culture

[0405] Human colorectal cancer cells HT29 and oxaliplatin-resistant HT29 / Oxa were cultured in RPMI-1640 medium supplemented with 10% fetal bovine serum in a 5% CO2, 37°C incubator. Human lung cancer cells A549 and cisplatin-resistant human lung cancer cells A549 / Cis were cultured in RPMI-1640 medium supplemented with 10% fetal bovine serum in a 5% CO2, 37°C incubator.

[0406] (2) Construction of drug-resistant cell lines

[0407] The drug concentration gradient method was used to construct an oxaliplatin-resistant tumor cell line. The specific experimental process is as follows: In the initial stage, the half-inhibitory concentration of non-resistant cells to oxaliplatin was used as the starting concentration, and the cells were cultured with drugs for 48 hours. The culture supernatant was discarded, and fresh culture medium without drugs was added to continue culturing. After the cells resumed normal growth, they were digested and passaged. The drug stimulation, fluid change, and passage were repeated 3 times to obtain primary resistant cells. On this basis, the drug concentration was gradually increased with a 1.25-fold increase in drug concentration each time as the benchmark, until the half-inhibitory concentration of the induced resistant cells increased to more than 5 times that of the non-resistant cells, so as to obtain the target resistant cell line. Before subsequent biological tests, the resistant tumor cells were washed with PBS to remove the drug, cultured in a culture medium without drugs, and passaged 3 times. Compared with the non-resistant HT29 cells, the oxaliplatin-resistant human colorectal cancer HT29 / Oxa cells obtained based on the above method had a 50% cell inhibition concentration IC 50 It increased by 53 times, and the drug resistance coefficient was 53.

[0408] The same method was used to prepare the cisplatin-resistant cell line A549 / Cis of human lung cancer cells A549. The 50% inhibitory concentration IC 50 It increased by 10 times, and this value is defined as the drug resistance coefficient of tumor cells.

[0409] Experimental Example 2: In vitro anticancer efficacy of tumor cells

[0410] (1) Test method:

[0411]

Cytotoxicity test

[0412] The cytotoxicity experiment was tested using the MTT assay.

[0413] Tumor cells were harvested in the logarithmic phase and the cell suspension concentration was adjusted. 100 μL of the cell suspension was added to each well of a 96-well flat-bottom plate, with a plating density of approximately 10,000-100,000 cells / well (edge ​​wells were filled with sterile PBS). The plates were incubated at 37°C with 5% CO₂ until the cells adhered. A gradient of drug solutions was added at 100 μL per well, with four replicates. The plates were incubated at 37°C with 5% CO₂ for 72 hours and observed under an inverted microscope. 20 μL of the prepared MTT solution (5 mg / mL) was added to each well of the 96-well plate, mixed thoroughly, and incubated at 37°C with 5% CO₂ for 4 hours. The plate contents were then discarded, and 150 μL of DMSO was added to each well. The plates were shaken for 3 minutes, and the OD (optical density) was measured at 490 nm using a microplate reader. A control group was prepared under the same conditions, without the active ingredient being added. The OD values ​​of the tumor cells were measured at 490 nm.

[0414] [half inhibitory concentration, IC 50 】:

[0415] 1) Cell viability (%) = (OD value of drug-treated group / OD value of control group) × 100. The above experiment for each drug concentration was repeated 4 times, and the average OD value was used to calculate the cell viability.

[0416] 2) Calculate the cell survival rate at each drug concentration and plot this against drug concentration to determine the efficacy of different drug concentrations in inhibiting tumor cell proliferation.

[0417] 3) The drug concentration corresponding to the cell survival rate of 50% of the control group is the half-maximal inhibitory concentration of the drug on tumor cells, that is, the IC 50 value.

[0418]

Drug resistance coefficient

[0419] The drug resistance coefficient refers to the half-inhibitory concentration of the drug on drug-resistant cells, which is the multiple of the increase compared with non-resistant cells. It is calculated according to the following formula: Drug resistance coefficient (RI) = IC of drug-resistant cells 50 / Non-resistant cell IC 50

[0420] (2) Experimental results:

[0421] Reference compounds and their anti-resistance test results against drug-resistant cells:

[0422] Table 1 Anti-cisplatin resistance and anti-oxaliplatin resistance experimental results of reference compounds 1-6 (IC 50 Value, unit: micromolar)

[0423] The results in Table 1 show that the new platinum oxides derived from the oxaliplatin chelating ligand (chiral cyclohexanediamine) do not produce cross-resistance to cisplatin-resistant cells, but show strong resistance similar to oxaliplatin to oxaliplatin-resistant tumor cells.

[0424] Table 2 Anti-cisplatin resistance and anti-oxaliplatin resistance experimental results of reference compounds 7-10 (IC 50 Value, unit: micromolar)

[0425] The results in Table 2 show that the new platinum oxides derived from different chiral cyclic propylenediamine chelating ligands do not produce cross-resistance to cisplatin-resistant cells, and show a certain degree of resistance to oxaliplatin-resistant tumor cells.

[0426] Table 3 Anti-cisplatin resistance and anti-oxaliplatin resistance experimental results of reference compounds 11-16 (IC 50 Value, unit: micromolar)

[0427] The results in Table 3 indicate that the novel platinum oxides derived from diphenylethylenediamine chelating ligands of different chirality do not produce cross-resistance to cisplatin-resistant cells, but exhibit similar resistance to oxaliplatin to oxaliplatin-resistant tumor cells.

[0428] Table 4 Anti-cisplatin resistance and anti-oxaliplatin resistance experimental results of reference compounds 17-19 (IC 50 Value, unit: micromolar)

[0429] The results in Table 4 show that the novel sugar-coupled platinum oxide derived from 1,1'-biphenyl-2,2'-diamine as a chelating ligand loses its anti-tumor efficacy against oxaliplatin-sensitive colorectal cancer cells and oxaliplatin-resistant colorectal cancer cells.

[0430] Table 5 Pharmacological efficacy results of 1,1'-binaphthyl-2,2'-diamine platinum oxide against oxaliplatin-resistant tumors (human colon cancer HT29 / Oxa) (IC 50 Value, unit: micromolar)

[0431] The results showed that the 1,1'-binaphthyl-2,2'-diamine platinum oxide in the examples had the same or even stronger inhibitory effect on oxaliplatin-resistant and non-resistant tumor cells.

[0432] Test Example 3: Anti-tumor effect of drug combination

[0433] (1) Test method:

[0434] Tumor cells:

[0435] Human lung cancer (A549), human ovarian cancer (SKOV3), human liver cancer (Hep3B), human colorectal cancer (HT29)

[0436]

Cytotoxicity test

[0437] The cytotoxicity experiment was tested using the MTT assay.

[0438] Tumor cells were harvested in the logarithmic phase and the cell suspension concentration was adjusted. 100 μL of the cell suspension was added to each well of a 96-well flat-bottom plate, with a plating density of approximately 10,000-100,000 cells / well (edge ​​wells were filled with sterile PBS). The plates were incubated at 37°C with 5% CO₂ until the cells adhered. A gradient of drug solutions was added at 100 μL per well, with four replicates. The plates were incubated at 37°C with 5% CO₂ for 72 hours and observed under an inverted microscope. 20 μL of the prepared MTT solution (5 mg / mL) was added to each well of the 96-well plate, mixed thoroughly, and incubated at 37°C with 5% CO₂ for 4 hours. The plate contents were then discarded, and 150 μL of DMSO was added to each well. The plates were shaken for 3 minutes, and the OD (optical density) was measured at 490 nm using a microplate reader. A control group was prepared under the same conditions, without the active ingredient being added. The OD values ​​of the tumor cells were measured at 490 nm.

[0439] Cell survival rate (%) = (OD value of drug-treated group / OD value of control group) × 100.

[0440] [Combination effect]: Combination effect (%) = {[(cell survival rate of the example drug - cell survival rate after combination) + (cell survival rate of the combination component - cell survival rate after combination)] / (cell survival rate of the example drug - cell survival rate of the combination component)} X 100

[0441] (2) Experimental results:

[0442] Table 6 Experimental results of the combined effect of compound 1 In the table: ◎ indicates that the combined effect is >300%; ○ indicates that the combined effect is between 100% and 300%

[0443] Table 7 Experimental results of the combined effect of compound 3 In the table: ◎ indicates that the combined effect is >300%; ○ indicates that the combined effect is between 100% and 300%

[0444] Table 8 Experimental results of the combined effect of compound 33 In the table: ◎ indicates that the combined effect is >300%; ○ indicates that the combined effect is between 100% and 300%

[0445] Table 9 Experimental results of the combined effect of compound 37 In the table: ◎ indicates that the combined effect is >300%; ○ indicates that the combined effect is between 100% and 300%

[0446] Table 10 Experimental results of the combined effect of compound 51 In the table: ◎ indicates that the combined effect is >300%; ○ indicates that the combined effect is between 100% and 300%

[0447] Table 11 Experimental results of the combined effect of compound 55 In the table: ◎ indicates that the combined effect is >300%; ○ indicates that the combined effect is between 100% and 300%

[0448] Table 12 Experimental results of the combined effect of compound 66 In the table: ◎ indicates that the combined effect is >300%; ○ indicates that the combined effect is between 100% and 300%

[0449] Table 13 Experimental results of the combined effect of compound 69 In the table: ◎ indicates that the combined effect is >300%; ○ indicates that the combined effect is between 100% and 300%

[0450] Table 14 Experimental results of the combined effect of compound 71 In the table: ◎ indicates that the combined effect is >300%; ○ indicates that the combined effect is between 100% and 300%

[0451] Table 15 Experimental results of the combined effect of compound 77 In the table: ◎ indicates that the combined effect is >300%; ○ indicates that the combined effect is between 100% and 300%

[0452] Table 16 Experimental results of the combined effect of compound 80 In the table: ◎ indicates that the combined effect is >300%; ○ indicates that the combined effect is between 100% and 300%

[0453] Table 17 Experimental results of the combined effect of compound 83 In the table: ◎ indicates that the combined effect is >300%; ○ indicates that the combined effect is between 100% and 300%

Claims

1. 1,1'-binaphthyl-2,2'-diamine platinum oxide represented by formula (I), or a pharmaceutically acceptable salt thereof, in: Two R1 are the same or different and are selected from C1-C 25 Straight chain or branched chain alkanoyl, C3-C 25 Straight-chain or branched unsaturated hydrocarbon acyl (preferably alkenoyl), substituted or unsubstituted C 6-10 Aryl-C 1-25 Straight chain or branched chain alkanoyl, or substituted or unsubstituted C 6-10 Aryl-C 3-25 A straight-chain or branched unsaturated hydrocarbon acyl group (preferably an alkenoyl group) wherein the substitution C 6-10 Aryl-C 1-25 Straight chain or branched chain alkanoyl and substituted C 6-10 Aryl-C 3-25 The aryl group in the straight-chain or branched unsaturated hydrocarbon acyl group is preferably a phenyl group, and the aryl substituent is selected from C 1-10 Alkyl, C 1-10 Alkoxy, hydroxyl and halogen; preferably, the C1-C 25 The straight-chain or branched alkanoyl group is acetyl, n-propionyl, isopropionyl, n-valeryl, pivaloyl, n-hexanoyl, n-octanoyl, n-decanoyl, 2,2-dimethyloctanoyl, lauroyl, myristoyl, palmitoyl, stearoyl, behenoyl, or lignoceryl, more preferably acetyl, n-octanoyl, myristoyl, or stearoyl; preferably, the C3-C 25 The straight-chain or branched unsaturated hydrocarbon acyl group is oleoyl, linoleoyl, or arachidonic acid, more preferably oleoyl; preferably, the substituted or unsubstituted C 6-10 Aryl-C 1-25 Straight chain or branched chain alkanoyl and substituted or unsubstituted C 6-10 Aryl-C 3-25 The straight-chain or branched unsaturated hydrocarbon acyl group is benzoyl, cinnamoyl, salicyl, 3-hydroxybenzoyl, 4-hydroxybenzoyl, anisyl, m-hydroxybenzoyl, vanillyl, veratryl, 3,5-dimethoxybenzoyl, galloyl, syringoyl, or 3,4,5-trimethoxybenzoyl, preferably benzoyl or cinnamoyl; or Two R1 together form a group of the following structure: or Two R1 together form a group of formula (II); In formula (II), A is selected from the following sugar substituents, wherein the 1-end isomer of the sugar substituent is α or β or both: Preferably, in formula (II), A is selected from the following sugar substituents, wherein the 1-end isomer of the sugar substituent is α or β or both: The two R2 are the same or different (preferably the same), selected from hydrogen atoms, hydroxyl groups, C 1-10 Straight or branched chain alkyl, or C 1-10 Straight or branched alkoxy; preferably, the C 1-10 Straight chain and branched alkyl or C 1-10 The straight-chain or branched alkoxy group is selected from methyl, methoxy, ethyl, n-propyl, isopropyl, n-pentyl, neopentyl, n-hexyl, n-octyl, and n-decyl, more preferably methyl or methoxy; Two R3 are the same or different (preferably the same), selected from hydrogen atoms, C 1-10 Straight or branched alkyl, and C 3-6 Cycloalkyl; preferably, the C 1-10 The straight-chain or branched alkyl group is methyl, ethyl, n-propyl, isopropyl, n-pentyl, neopentyl, n-hexyl, n-octyl, or n-decyl, more preferably methyl; preferably, the C 3-6 The cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

2. The 1,1'-binaphthyl-2,2'-diamine platinum oxide represented by formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: The 1,1'-binaphthyl-2,2'-diamine group in the 1,1'-binaphthyl-2,2'-diamine platinum oxide of formula (I) is a racemic 1,1'-binaphthyl-2,2'-diamine group, or the 1,1'-binaphthyl-2,2'-diamine platinum oxide of formula (I) is a (R)-1,1'-binaphthyl-2,2'-diamine platinum oxide of formula (III) below, or the 1,1'-binaphthyl-2,2'-diamine platinum oxide of formula (I) is a (S)-1,1'-binaphthyl-2,2'-diamine platinum oxide of formula (IV) below, wherein R1, R2, and R3 are defined as in claim 1, 3. The 1,1'-binaphthyl-2,2'-diamine platinum oxide represented by formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: The two R1 are the same, or the two R1 together form a group selected from the group represented by formula (i) to formula (vii), or the two R1 together form a group of formula (II), wherein A in formula (II) is selected from the following monosaccharide substituents, wherein the 1-end isomer of the monosaccharide substituent is α or β or both, Two R2 are the same and are selected from hydrogen atom, hydroxyl group, methyl group, and methoxy group; Two R3 are the same and are selected from a hydrogen atom and a methyl group.

4. The 1,1'-binaphthyl-2,2'-diamine platinum oxide of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the 1,1'-binaphthyl-2,2'-diamine platinum oxide of formula (I) is selected from the following compounds:

5. A method for preparing the 1,1'-binaphthyl-2,2'-diamine platinum oxide of formula (I) as described in any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, comprising: Method A, Method B, or Method C, The method A comprises the steps of reacting a compound of formula (V) with a compound R1-OH or OH-R1-R1-OH or a salt thereof to prepare 1,1'-binaphthyl-2,2'-diamine platinum oxide of formula (I); The method B comprises the steps of reacting the compound of formula (VI) with the compound R1-OH or OH-R1-R1-OH or their salts to prepare 1,1'-binaphthyl-2,2'-diamine platinum oxide represented by formula (I); The method C comprises the step of reacting the compound of formula (VII) with the compound R1-OH or OH-R1-R1-OH or a salt thereof to prepare 1,1'-binaphthyl-2,2'-diamine platinum oxide represented by formula (I); wherein X is selected from a halogen atom (preferably a chlorine atom or a bromine atom); R1, R2 and R3 are defined as in any one of claims 1 to 4; the salts of the compounds R1-OH and OH-R1-R1-OH are each independently selected from their silver salts, sodium salts, potassium salts or barium salts; Preferably, in method A, method B, or method C, the reaction is carried out in deionized water or distilled water, N,N-dimethylformamide, methanol, ethanol, isopropanol, butanol, or a mixed solvent of water and the above solvents, or a mixed solvent of dichloromethane and the above solvents; preferably, the reaction is carried out at room temperature or heated to 40-100° C. in a light-proof environment; preferably, the reaction is carried out at pH 7-9; preferably, an inorganic base aqueous solution is used to adjust the pH of the reaction solution to 7-9; preferably, the inorganic base includes sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, lithium hydroxide, or barium hydroxide.

6. A pharmaceutical composition comprising 1,1'-binaphthyl-2,2'-diamine platinum oxide or a pharmaceutically acceptable salt thereof represented by formula (I) according to any one of claims 1 to 4 and optional pharmaceutically acceptable excipients, Optionally, the pharmaceutically acceptable excipient is selected from the group consisting of fillers, disintegrants, lubricants, glidants, effervescent agents, preservatives, solubilizers, cosolvents, antioxidants, anti-photolysis agents, pH regulators, emulsifiers, local analgesics, chelating agents, non-aqueous solvents, coating materials or other excipients; Optionally, among the pharmaceutically acceptable excipients, the filler includes one or more of lactose, mannitol, and calcium carbonate; the binder includes one or more of sucrose, starch, povidone, and sodium carboxymethyl cellulose; the disintegrant includes one or more of starch, cross-linked povidone, cross-linked sodium carboxymethyl cellulose, and effervescent disintegrant; the local analgesic includes one or more of benzyl alcohol, chlorobutanol, procaine hydrochloride, and lidocaine; the non-aqueous solvent includes one or more of iodized oil, soybean oil, castor oil, and peanut oil; the solubilizer includes one or more of Tween 80, Tween 60, and poloxamer 68; the cosolvent includes one or more of sodium benzoate, sodium salicylate, sodium p-aminobenzoate, and cyclodextrin; Optionally, the administration method of the pharmaceutical composition includes: Oral administration (e.g., buccal), parenteral administration (e.g., intramuscular, intravenous, or subcutaneous), rectal administration (e.g., suppository), or hepatic artery administration; Optionally, the pharmaceutical composition is in the form of an oil emulsion or dispersion, such as containing a lipophilic salt such as pamoic acid, or in the form of a biodegradable sustained release composition for intravenous or intramuscular administration or hepatic artery administration; Optionally, the pharmaceutical composition is a solid oral preparation (such as tablets, capsules, granules, dispersible tablets, enteric-coated tablets and capsules, etc.), a liquid oral preparation (such as oral liquid, syrup, suspension, etc.), or an injection; Optionally, the injection includes: lipid microspheres, water injection, large infusion, or freeze-dried powder injection.

7. Use of 1,1'-binaphthyl-2,2'-diamine platinum oxide or a pharmaceutically acceptable salt thereof represented by formula (I) as described in any one of claims 1 to 4, or the pharmaceutical composition as described in claim 6 in the preparation of a medicament for preventing and / or treating tumors; preferably, the tumor is selected from human lung cancer, human colorectal cancer, human head and neck cancer, human prostate cancer, human breast cancer, human ovarian cancer, human cervical cancer, human leukemia, human lymphoma, human skin cancer, human pancreatic cancer, human liver cancer, human bladder cancer, human esophageal cancer, human gastric cancer, human multiple myeloma, human male genital cancer or human bone cancer; preferably, the tumor is lung cancer, ovarian cancer, liver cancer, or colorectal cancer; preferably, the tumor is a drug-resistant tumor; preferably, the drug-resistant tumor is a platinum anticancer drug-resistant tumor; preferably, the platinum anticancer drug-resistant tumor is a cisplatin, carboplatin, or oxaliplatin-resistant tumor; preferably, the platinum anticancer drug-resistant tumor is an oxaliplatin-resistant tumor.

8. The use according to claim 7, wherein The 1,1'-binaphthyl-2,2'-diamine platinum oxide or its pharmaceutically acceptable salt represented by formula (I), or the pharmaceutical composition is used alone or in combination with at least one or more of the following anti-tumor agents: 5-fluorouracil, irinotecan, floxuridine, tegafluuracil, capecitabine, gemcitabine, clofarabine, temozolomide, folinate, paclitaxel, and doxorubicin.

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