Compound for treating oxaliplatin drug-resistant tumors, and preparation method, composition and application thereof

Abstract

The invention relates to a 1, 1 '-binaphthyl-2, 2'-diamine platinum oxide for treating oxaliplatin drug-resistant tumors, and a pharmaceutical composition and an application of the 1, 1 '-binaphthyl-2, 2'-diamine platinum oxide. The 1, 1 '-binaphthyl-2, 2'-diamine platinum oxide has a structure as shown in a formula (I): # imgabs0, and the 1, 1 '-binaphthyl-2, 2'-diamine platinum oxide can effectively inhibit proliferation of oxaliplatin drug-resistant tumor cells and can be used for preparing potential drugs for treating oxaliplatin drug-resistant tumors.

Description

Technical Field

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

[0002] Tumor drug resistance refers to the tolerance of tumor cells to anti-tumor drugs, resulting in a significant decline in the therapeutic effect of the anti-tumor drugs used, the regrowth of the tumor, and the deterioration and loss of control of the patient's condition. Tumor drug resistance is one of the main reasons for the failure of clinical chemotherapy and is also a major problem that needs to be solved and overcome urgently in the process of new drug development.

[0003] There is no established rule on how to overcome tumor drug resistance, because of the complexity of tumor drug resistance mechanisms, the heterogeneity of tumor cells, and the evolving immune escape mechanism. Tumor heterogeneity refers to the molecular biological or genetic changes in the daughter cells of a tumor during its growth process after multiple divisions and proliferations, resulting in differences in various aspects such as the growth rate, invasive ability, drug sensitivity, and prognosis of the tumor (Dagogo-Jack, I et al., Nat Rev Clin Oncol 2018, 15, 81-94). This heterogeneity difference causes the same tumor to become less sensitive and more drug-resistant to the same drug or different drugs at different stages of development. Tumor evolutionary immune escape refers to the stress factors formed by tumors in response to the stimulation of therapeutic drugs during treatment, which initiate multiple adaptive mechanisms to escape the recognition and attack of the immune system stimulated by the drugs and generate drug resistance. The molecular mechanisms of drug resistance formed by tumors during treatment currently known 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, 6) changes in cell proliferation patterns, etc. (Cree IA et al., BMC Cancer. 2017, 5, 17(1)).

[0004] Platinum-based anti-tumor drugs are one of the most widely used drugs in clinical practice. Representative platinum-based anti-cancer drugs include the first-generation cisplatin, the second-generation carboplatin and nedaplatin, etc., and the third-generation oxaliplatin. Cisplatin and carboplatin are used alone or in combination and are widely used clinically to treat 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 anti-cancer drug, oxaliplatin is widely used clinically to treat various cancers such as colorectal cancer, liver cancer, esophageal cancer, gastric cancer, and biliary tract malignancies, and is also the main therapeutic drug for the first-line chemotherapy regimen for advanced colorectal cancer.

[0005] Given the importance of platinum drugs in clinical applications, extensive research has been carried out in the biomedical field on the resistance problem of the most widely used first-generation cisplatin, and some solutions to overcome cisplatin resistance have been discovered (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 below, it has been found that after cisplatin develops resistance in lung cancer treatment, the second-generation carboplatin with the same chelating ligand (NH3) also loses sensitivity due to cross-resistance. However, nedaplatin, which also has the NH3 chelating ligand, remains effective against cisplatin-resistant lung cancer (does not develop resistance) (Wang H et al., Oncology Letters, 2016, 11, 2566-2572). As the third-generation oxaliplatin, there is no cross-resistance with cisplatin, and tumor cells remain sensitive (not resistant) to oxaliplatin after cisplatin develops resistance. On the contrary, after tumor cells develop resistance to oxaliplatin, the first-generation cisplatin and the second-generation carboplatin will also develop resistance and lose sensitivity at the same time, so they cannot be used to replace oxaliplatin for clinical treatment.

[0006] It can be seen that the therapeutic effect of platinum drugs on tumors and their selectivity for tumors 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). There is no specific rule or structure-activity relationship rule to follow regarding whether a platinum drug with a specific structure has the potential to overcome tumor resistance (Wang H et al., Oncology Letters, 2016, 11, 2566-2572).

[0007]

[0008] Oxaliplatin is mainly used in the first-line and second-line treatment of colorectal cancer in clinical practice. According to the NCCN treatment guidelines for colon cancer released by the National Comprehensive Cancer Network (NCCN) in 2020, oxaliplatin plays a very important role in the first (first-line) chemotherapy of advanced colon cancer. The combined chemotherapy drug regimens containing oxaliplatin mainly include: FOLFOX (fluorouracil, calcium folinate, oxaliplatin), CAPOX (capecitabine, oxaliplatin), FOLFOXIRI (fluorouracil, calcium folinate, irinotecan, oxaliplatin). With the emergence of oxaliplatin-resistant tumors, since the first-generation and second-generation platinum anticancer drugs cannot replace oxaliplatin to achieve an ideal clinical treatment effect on colorectal cancer, there are currently no other platinum drugs that have been successfully developed clinically to replace oxaliplatin after colorectal cancer patients develop resistance to oxaliplatin. SUMMARY OF THE INVENTION

[0009] In order to overcome the currently urgent problem of clinical resistance to oxaliplatin and obtain a new generation of platinum complexes that can effectively inhibit and kill oxaliplatin-resistant tumor cells, the present invention conducts modifications and extensive screening processes from various aspects, including [1] screening for changing the leaving ligand structure of oxaliplatin, [2] screening for introducing new chiral chelating ligands, [3] screening for aryl-substituted chiral ethylenediamine chelating ligands, and [4] screening for biphenyldiamine chelating ligands. Finally, it is designed and discovered that the platinum oxide with 1,1'-binaphthalene-2,2'-diamine as the chelating ligand in the present invention has the property of resisting oxaliplatin resistance, thus completing the present invention.

[0010]

[0011] In view of this, on the one hand, a 1,1'-binaphthalene-2,2'-diamine platinum oxide represented by formula (I) or a pharmaceutically acceptable salt thereof is provided.

[0012]

[0013] Wherein:

[0014] The two R1s are the same or different (preferably the same) and are selected from C1-C 25 linear or branched alkanoyl groups (wherein the number of carbon atoms includes the carbonyl carbon atom), C3-C 25 linear or branched unsaturated hydrocarbon acyl groups (preferably enoyl groups, where the number of carbon atoms includes the carbonyl carbon atom), substituted or unsubstituted C 6-10 aryl-C 1-25 linear or branched alkanoyl groups (where the number of carbon atoms includes the carbonyl carbon atom), or substituted or unsubstituted C 6-10 aryl-C 3-25 linear or branched unsaturated hydrocarbon acyl groups (preferably enoyl groups, where the number of carbon atoms includes the carbonyl carbon atom);

[0015] As the "C1-C 25 linear or branched alkanoyl group", examples include acetyl, propionyl, isopropyl, pentanoyl, pivaloyl, hexanoyl, octanoyl, decanoyl, 2,2-dimethyloctanoyl, lauroyl, myristoyl, palmitoyl, stearoyl, behenoyl, or lignoceroyl, preferably acetyl, octanoyl, myristoyl, or stearoyl.

[0016] As the "C3-C 25 linear or branched unsaturated hydrocarbon acyl group", examples include oleoyl, linoleoyl, or arachidonyl, more preferably oleoyl.

[0017] As the "substituted or unsubstituted C6-10 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-chain unsaturated hydrocarbon acyl", wherein the C 6-10 The aryl is preferably phenyl, and the substituents are selected from C 1-10 Alkyl, C 1-10 Alkoxy, hydroxyl, and halogen; said "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-chain unsaturated hydrocarbon acyl" may include, for example, benzoyl, salicyl, 3-hydroxybenzoyl, 4-hydroxybenzoyl, anisoyl, m-hydroxybenzoyl, vanilloyl, veratroyl, 3,5-dimethoxybenzoyl, cinnamoyl, galloyl, syringoyl, or 3,4,5-trimethoxybenzoyl, preferably benzoyl or cinnamoyl.

[0018] Or two R1s together form a group with the following structure:

[0019]

[0020] Or two R1s together form a group with the structure of formula (II);

[0021]

[0022] In formula (II), A is selected from the following sugar substituents, and the anomeric configuration at the 1-position of the sugar substituent is α or β or both coexist,

[0023]

[0024] Preferably, in formula (II), A is selected from the following sugar substituents, and the anomeric configuration at the 1-position of the sugar substituent is α or β or both coexist,

[0025]

[0026] Preferably, A is selected from the following monosaccharide substituents, and the anomeric configuration at the 1-position of the monosaccharide substituent is α or β or both coexist,

[0027]

[0028] Two R2s are the same or different (preferably the same), and are selected from a hydrogen atom, a hydroxyl group, C 1-10 Straight-chain or branched-chain alkyl, or C 1-10 Straight-chain or branched-chain alkoxy; as "C 1-10 Straight-chain or branched-chain alkyl and C1-10 "Straight-chain or branched-chain alkoxy", examples thereof include 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, a hydroxyl group, a methyl group, or a methoxy group;

[0029] The two R3s are the same or different (preferably the same) and are selected from a hydrogen atom, C 1-10 Straight-chain or branched-chain alkyl, and C 3-6 Cycloalkyl; as "C 1-10 Straight-chain or branched-chain alkyl", examples thereof include methyl, ethyl, n-propyl, isopropyl, n-pentyl, neopentyl, n-hexyl, n-octyl, n-decyl, preferably methyl; as "C 3-6 Cycloalkyl", examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. R3 is preferably a hydrogen atom or a methyl group.

[0030] Preferably, in the 1,1'-binaphthalene-2,2'-diamine platinum oxide represented by the formula (I) or a pharmaceutically acceptable salt thereof, the 1,1'-binaphthalene-2,2'-diamine group therein is a racemic 1,1'-binaphthalene-2,2'-diamine group, or the 1,1'-binaphthalene-2,2'-diamine platinum oxide represented by the formula (I) is the (R)-1,1'-binaphthalene-2,2'-diamine platinum oxide represented by the following formula (III), or is the (S)-1,1'-binaphthalene-2,2'-diamine platinum oxide represented by the following formula (IV), wherein the definitions of R1, R2, and R3 are the same as above.

[0031]

[0032] Preferably, the following compound or a pharmaceutically acceptable salt thereof

[0033]

[0034]

[0035]

[0036]

[0037]

[0038]

[0039]

[0040]

[0041] On the other hand, a pharmaceutical composition is provided, which comprises the 1,1'-binaphthalene-2,2'-diamine platinum oxide shown in the above formula (I), or a pharmaceutically acceptable salt thereof and optionally a pharmaceutically acceptable excipient.

[0042] Optionally, the pharmaceutically acceptable excipient is selected from: fillers, disintegrants, lubricants, glidants, effervescent agents, flavoring agents, preservatives, solubilizers, cosolvents, antioxidants, photodegradation inhibitors, pH regulators, emulsifiers, local anesthetics, complexing agents, non-aqueous solvents, coating materials or other excipients.

[0043] 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, polyvinylpyrrolidone, and sodium carboxymethylcellulose; the disintegrant includes one or more of starch, crospovidone, croscarmellose sodium, and effervescent disintegrants; 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 para-aminobenzoate, and cyclodextrin;

[0044] Optionally, the administration routes of the pharmaceutical composition include: oral administration (e.g., oral cavity), parenteral administration (e.g., intramuscular, intravenous or subcutaneous), rectal administration (e.g., suppository), or hepatic artery administration;

[0045] Optionally, under continuous treatment, it is administered in the form of a single unit dose or in the form of multiple-dose treatment;

[0046] Optionally, the pharmaceutical composition is in the form of an oil emulsion or a dispersant, which is combined with a lipophilic salt such as pamoic acid, or in the form of a biodegradable sustained-release composition for intravenous or intramuscular injection or hepatic artery administration;

[0047] Optionally, the pharmaceutical composition can be made into solid oral preparations (such as tablets, capsules, granules, dispersible tablets, enteric-coated tablets and capsules, etc.), liquid oral preparations (such as oral liquids, syrups, suspensions, etc.), or injections;

[0048] Optionally, the injection includes: lipid microspheres, aqueous injections, large volume infusions, or freeze-dried powder injections.

[0049] On the other hand, the use of the 1,1'-binaphthalene-2,2'-diamine platinum oxide shown in the above formula (I), or a pharmaceutically acceptable salt thereof, or the above pharmaceutical composition as an anti-tumor agent for preventing and / or treating tumors; and its use in the preparation of a drug for preventing and / or treating tumors.

[0050] On the other hand, a method for preventing or treating tumors is provided, which includes administering to an individual in need a prophylactically or therapeutically effective amount of the 1,1'-binaphthalene-2,2'-diamine platinum oxide represented by the above formula (I) or a pharmaceutically acceptable salt thereof, or the above pharmaceutical composition.

[0051] Preferably, the tumors are 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 tumors are lung cancer, ovarian cancer, liver cancer, or colorectal cancer; preferably, the tumors are drug-resistant tumors; preferably, the drug-resistant tumors are platinum-based anticancer drug-resistant tumors; preferably, the platinum-based anticancer drug-resistant tumors are cisplatin, carboplatin, or oxaliplatin-resistant tumors; preferably, the platinum-based anticancer drug-resistant tumors are oxaliplatin-resistant tumors.

[0052] In the structural formula herein, "*" represents the connecting site.

[0053] The 1,1'-binaphthalene-2,2'-diamine platinum oxide represented by the above formula (I), or a pharmaceutically acceptable salt thereof or the above pharmaceutical composition can be used alone or in combination with one or more other active drugs ("second active compounds"). They can be administered separately, including sequentially or simultaneously, or can be included in the same pharmaceutical composition for administration.

[0054] Examples of the above second active compounds include one or more of the following substances: 5-fluorouracil, irinotecan, floxuridine, tegafur-uracil, capecitabine, gemcitabine, clofarabine, temozolomide, folinate, paclitaxel, doxorubicin, etc.

[0055] The 1,1'-binaphthalene-2,2'-diamine platinum oxide represented by the above formula (I), or a pharmaceutically acceptable salt thereof includes their racemates, optical isomers, or isotope-labeled substances, which can exist in the form of amorphous, crystalline, solvate (such as hydrate), inclusion compound, etc.

[0056] The 1,1'-binaphthalene-2,2'-diamine platinum oxide represented by the above formula (I), or a pharmaceutically acceptable salt thereof can exist in the form of isotope tracing or enrichment, containing one or more atoms, and the atomic weight or mass number of these atoms is different from the atomic weight or mass number of the atoms found in the largest amount in nature. The isotope can be a radioactive or non-radioactive isotope. 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, 14C, 15 N, 18 O, 32 P, 35 S, 18 F, 36 Cl and 125 I. Compounds containing these and / or other isotopes of these atoms are within the scope of the 1,1'-binaphthalene-2,2'-diamine platinum oxide shown in the above formula (I), or a pharmaceutically acceptable salt thereof.

[0057] The 1,1'-binaphthalene-2,2'-diamine platinum oxide shown in the above formula (I), or a pharmaceutically acceptable salt thereof, includes mixtures of optical isomers in any proportion. The compound of formula (I) may contain one or more asymmetric carbon atoms, and may exist in the form of enantiomerically pure enantiomers, such as a mixture of enantiomers of a racemate, enantiomerically pure diastereoisomers, a mixture of diastereoisomers, a racemate of diastereoisomers or a mixture of racemates of diastereoisomers. The 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).

[0058] On the other hand, there is provided a method for preparing the 1,1'-binaphthalene-2,2'-diamine platinum oxide shown in the above formula (I), or a pharmaceutically acceptable salt thereof.

[0059] General synthetic method A: It includes 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 the 1,1'-binaphthalene-2,2'-diamine platinum oxide shown in formula (Ⅰ);

[0060]

[0061] The preparation method of the compound of formula (V) is prepared according to the general methods known in the literature (Chemistry - A European Journal, 2016, vol. 22, #43, p. 15468 - 15474).

[0062] General synthetic method B: It includes 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 the 1,1'-binaphthalene-2,2'-diamine platinum oxide shown in formula (Ⅰ);

[0063]

[0064] The preparation method of the compound of formula (VI) is prepared according to the general methods known in the literature (Chemistry - A European Journal, 2016, vol. 22, #43, p. 15468 - 15474).

[0065] General synthetic method C: It includes the step of reacting a compound of formula (VII) with a compound R1 - OH or OH - R1 - R1 - OH or their salts to prepare the 1,1'-binaphthalene-2,2'-diamine platinum oxide shown in formula (I);

[0066]

[0067] The preparation method of the compound of formula (VII) is prepared according to the general methods known in the literature (Inorganica Chimica Acta, 1991, vol. 179, p. 281 - 288).

[0068] In the above reaction formula, X is selected from halogen atoms (preferably chlorine atom or bromine atom); the definitions of R1, R2 and R3 are the same as above; 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.

[0069] 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, it is carried out at room temperature or heated to 40 - 100 °C in a light - protected environment; preferably, the reaction is carried out under the condition of pH 7 - 9; preferably, an aqueous solution of an inorganic base 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.

[0070] When preparing the platinum oxide of 1,1'-binaphthalene-2,2'-diamine shown in formula (I) by the above different methods, the reaction is generally carried out in a solvent environment after nitrogen replacement. Depending on the different target products, the reaction time required has a relatively wide range. Depending on the properties of different reactants, it generally takes 1 hour to 30 days to complete. In more cases, it takes 2 - 10 hours, and when longer, it takes 15 days to complete. Many methods can be used to purify the product obtained in the above reaction. For example, the mixture after the reaction is completed can first be filtered to remove the possible precipitates formed, then concentrated by vacuum distillation, and then an organic solvent is added to precipitate the desired target product. Organic solvents that are miscible with water are generally selected, such as alcohol solvents (such as methanol, ethanol, propanol, butanol, or isopropanol, etc.), or ether solvents that are partially miscible with water (such as diethyl ether, methyl tert-butyl ether, tetrahydrofuran, ethylene glycol diethyl ether, or ethylene glycol dimethyl ether, etc.). Then the obtained precipitate is collected, for example, by filtration, and further washed with the above solvents to obtain the desired target product. Chromatographic methods or the like can also be used to purify and refine the target product obtained in the above reaction. For example, ion exchange resins or preparative liquid chromatography are used. Liquid chromatography separation and purification are generally carried out using methanol and water as the mobile phase. Detailed implementation mode

[0071] The present invention will be described in detail below through examples. The provided examples are only used for exemplary illustration of the present invention and do not limit the scope of the present invention in any way. In the following examples, unless otherwise specified, the test 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 the disclosed methods.

[0072] Example

[0073] Example 1: Preparation of Compound 1

[0074]

[0075] Prepared by using the general synthesis method A.

[0076] 2 mmol of 1,1'-binaphthalene-2,2'-diamine dichloroplatinum and 2 equivalents of silver acetate (668 mg, 4 mmol) were suspended in 20 mL of N,N-dimethylformamide at room temperature. After nitrogen replacement, it was stirred at room temperature for 12 hours under light-shielded conditions. The formed silver iodide precipitate was filtered through a glass sand core funnel, and the solvent was removed from the filtrate under reduced pressure to obtain an oily crude product. Dichloromethane was added and stirred to precipitate a grayish-white solid product. The product solid was further washed with dichloromethane and ether to obtain the target product Compound 1 (yield 75%).

[0077] 11H NMR (600 MHz, Methanol-d4) δ 8.11 (d, J = 8.8 Hz, 2H), 8.02 (d, J = 8.3 Hz, 2H), 7.74 (d, J = 8.7 Hz, 2H), 7.49 (t, J = 7.3 Hz, 2H), 7.32 - 7.27 (m, 2H), 7.04 (d, J = 8.6 Hz, 2H), 1.95 (s, 6H).

[0078] Example 2: Preparation of Compound 2

[0079]

[0080] Prepared by the general synthetic method A, the same method as in Example 1. Yield: 80%.

[0081] 1 1H NMR (600 MHz, Methanol-d4) δ 8.11 (d, J = 8.8 Hz, 2H), 8.01 (d, J = 8.3 Hz, 2H), 7.75 (d, J = 8.8 Hz, 2H), 7.47 (t, J = 7.6 Hz, 2H), 7.25 (t, J = 7.7 Hz, 2H), 7.02 (d, J = 8.6 Hz, 2H), 1.93 (s, 6H).

[0082] Example 3: Preparation of Compound 3

[0083]

[0084] Prepared by the general synthetic method A, the same method as in Example 1. Yield: 82%.

[0085] 1 1H NMR (600 MHz, Methanol-d4) δ 8.13 (d, J = 8.8 Hz, 2H), 8.03 (d, J = 8.3 Hz, 2H), 7.75 (d, J = 8.8 Hz, 2H), 7.49 (t, J = 7.6 Hz, 2H), 7.28 (t, J = 7.7 Hz, 2H), 7.04 (d, J = 8.6 Hz, 2H), 1.94 (s, 6H).

[0086] Example 4: Preparation of Compound 4

[0087]

[0088] Prepared by the general synthetic method A, the same method as in Example 1. Yield: 70%.

[0089] 11H NMR (600 MHz, Methanol-d4) δ 8.13 (d, J = 8.8 Hz, 2H), 8.03 (d, J = 8.3 Hz, 2H), 7.91 (m, 4H), 7.75 (d, J = 8.8 Hz, 2H), 7.49 (t, J = 7.6 Hz, 2H), 7.41 (m, 2H), 7.33 (m, 4H), 7.28 (t, J = 7.7 Hz, 2H), 7.04 (d, J = 8.6 Hz, 2H).

[0090] Example 5: Preparation of Compound 5

[0091]

[0092] Prepared by the general synthetic method A, the same method as in Example 1. Yield: 68%.

[0093] 1 1H NMR (600 MHz, Methanol-d4) δ 8.14 (d, J = 8.8 Hz, 2H), 8.04 (d, J = 8.3 Hz, 2H), 7.90 (m, 4H), 7.75 (d, J = 8.8 Hz, 2H), 7.49 (t, J = 7.6 Hz, 2H), 7.41 (m, 2H), 7.32 (m, 4H), 7.27 (t, J = 7.7 Hz, 2H), 7.04 (d, J = 8.6 Hz, 2H).

[0094] Example 6: Preparation of Compound 6

[0095]

[0096] Prepared by the general synthetic method A, the same method as in Example 1. Yield: 72%.

[0097] 1 1H NMR (600 MHz, Methanol-d4) δ 8.15 (d, J = 8.8 Hz, 2H), 8.05 (d, J = 8.3 Hz, 2H), 7.91 (m, 4H), 7.76 (d, J = 8.8 Hz, 2H), 7.49 (t, J = 7.6 Hz, 2H), 7.43 (m, 2H), 7.33 (m, 4H), 7.28 (t, J = 7.7 Hz, 2H), 7.03 (d, J = 8.6 Hz, 2H).

[0098] Example 7: Preparation of Compound 7

[0099]

[0100] Prepared by the general synthetic method A, the same method as in Example 1. Yield: 72%.

[0101] 1 H NMR(600 MHz, Methanol-d4) δ 8.12 (d, J = 8.8 Hz, 2H), 8.02 (d, J = 8.3 Hz, 2H), 7.76 (d, J = 8.8 Hz, 2H), 7.65 (m, 4H), 7.48 (t, J = 7.6 Hz, 2H), 7.45 (m, 8H), 7.27 (t, J = 7.7 Hz, 2H), 7.04 (d, J = 8.6 Hz, 2H), 6.56 (m, 2H).

[0102] Example 8: Preparation of Compound 8

[0103]

[0104] Prepared by the general synthetic method A, the same method as in Example 1. Yield: 77%.

[0105] 1 H NMR(600 MHz, Methanol-d4) δ 8.14 (d, J = 8.8 Hz, 2H), 8.03 (d, J = 8.3 Hz, 2H), 7.77 (d, J = 8.8 Hz, 2H), 7.65 (m, 4H), 7.48 (t, J = 7.6 Hz, 2H), 7.45 (m, 8H), 7.28 (t, J = 7.7 Hz, 2H), 7.06 (d, J = 8.6 Hz, 2H), 6.56 (m, 2H).

[0106] Example 9: Preparation of Compound 9

[0107]

[0108] Prepared by the general synthetic method A, the same method as in Example 1. Yield: 73%.

[0109] 1 H NMR(600 MHz, Methanol-d4) δ 8.13 (d, J = 8.8 Hz, 2H), 8.01 (d, J = 8.3 Hz, 2H), 7.75 (d, J = 8.8 Hz, 2H), 7.63 (m, 4H), 7.46 (t, J = 7.6 Hz, 2H), 7.43 (m, 8H), 7.26 (t, J = 7.7 Hz, 2H), 7.07 (d, J = 8.6 Hz, 2H), 6.54 (m, 2H).

[0110] Example 10: Preparation of Compound 10

[0111]

[0112] Prepared by the same method as in Example 1 using the general synthetic method A. Yield: 73%.

[0113] 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).

[0114] Example 11: Preparation of Compound 11

[0115]

[0116] Prepared by the same method as in Example 1 using the general synthetic method A. Yield: 79%.

[0117] 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).

[0118] Example 12: Preparation of Compound 12

[0119]

[0120] Prepared by the same method as in Example 1 using the general synthetic method A. Yield: 82%.

[0121] 1 H 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).

[0122] Example 13: Preparation of Compound 13

[0123]

[0124] Prepared by the same method as Example 1 using the general synthetic method A. The yield is 80%.

[0125] 1 H NMR(600MHz,CDCl3)δδ8.05(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).

[0126] Example 14: Preparation of Compound 14

[0127]

[0128] Prepared by the same method as Example 1 using the general synthetic method A. The yield is 85%.

[0129] 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).

[0130] Example 15: Preparation of Compound 15

[0131]

[0132] Prepared by the same method as Example 1 using the general synthetic method A. The yield is 88%.

[0133] 11H NMR (600 MHz, 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 = 8.6 Hz, 2H), 2.37 (m, 4H), 1.65 (m, 4H), 1.50 - 1.40 (m, 40H), 0.89 (m, 6H).

[0134] Example 16: Preparation of Compound 16

[0135]

[0136] Prepared by the general synthetic method A, the same method as in Example 1. Yield: 82%.

[0137] 1 1H NMR (600 MHz, Methanol-d4) δ 8.14 (d, J = 8.8 Hz, 2H), 8.04 (d, J = 8.2 Hz, 2H), 7.73 (d, J = 8.7 Hz, 2H), 7.50 (t, J = 7.0 Hz, 2H), 7.31 (t, J = 7.7 Hz, 2H), 7.03 (d, J = 8.5 Hz, 2H), 2.30 (m, 4H), 1.60 (m, 4H), 1.42 - 1.10 (m, 56H), 0.88 (m, 6H).

[0138] Example 17: Preparation of Compound 17

[0139]

[0140] Prepared by the general synthetic method A, the same method as in Example 1. Yield: 80%.

[0141] 1 1H NMR (600 MHz, Methanol-d4) δ 8.13 (d, J = 8.8 Hz, 2H), 8.04 (d, J = 8.2 Hz, 2H), 7.71 (d, J = 8.7 Hz, 2H), 7.50 (t, J = 7.0 Hz, 2H), 7.32 (t, J = 7.7 Hz, 2H), 7.01 (d, J = 8.5 Hz, 2H), 2.31 (m, 4H), 1.60 (m, 4H), 1.42 - 1.10 (m, 56H), 0.88 (m, 6H).

[0142] Example 18: Preparation of Compound 18

[0143]

[0144] Prepared by the same method as Example 1 using the general synthetic method A. The yield was 77%.

[0145] 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=7.0Hz,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).

[0146] Example 19: Preparation of Compound 19

[0147] 19

[0149] Prepared by the same method as Example 1 using the general synthetic method A. The yield was 70%.

[0150] 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).

[0151] Example 20: Preparation of Compound 20

[0152]

[0153] Prepared by the same method as Example 1 using the general synthetic method A. The yield was 67%.

[0154] 11H NMR (600 MHz, Methanol-d4) δ 8.13 (d, J = 8.8 Hz, 2H), 8.02 (d, J = 8.3 Hz, 2H), 7.74 (d, J = 8.8 Hz, 2H), 7.45 (t, J = 7.6 Hz, 2H), 7.25 (t, J = 7.7 Hz, 2H), 7.03 (d, J = 8.6 Hz, 2H), 5.34 (m, 4H), 2.35 (m, 4H), 1.63 (m, 4H), 1.42 - 1.10 (m, 40H), 0.89 (m, 6H).

[0155] Example 21: Preparation of Compound 21

[0156]

[0157] Prepared by the general synthetic method A, the same method as in Example 1. Yield: 65%.

[0158] 1 1H NMR (600 MHz, Methanol-d4) δ 8.14 (d, J = 8.8 Hz, 2H), 8.01 (d, J = 8.3 Hz, 2H), 7.75 (d, J = 8.8 Hz, 2H), 7.46 (t, J = 7.6 Hz, 2H), 7.27 (t, J = 7.7 Hz, 2H), 7.05 (d, J = 8.6 Hz, 2H), 5.36 (m, 4H), 2.37 (m, 4H), 1.65 (m, 4H), 1.42 - 1.10 (m, 40H), 0.89 (m, 6H).

[0159] Example 22: Preparation of Compound 22

[0160]

[0161] To a suspension of (R / S)-1,1'-Binaphthalene-2,2'-diamine dichloroplatinum (200 mg, 0.36 mmol) in 4 mL of methanol and 3 mL of deionized water at room temperature was added silver sulfate (113 mg, 0.36 mmol), 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 centrifugation, the supernatant was collected, freeze-dried using a freeze dryer, and separated by semi-preparative high performance liquid chromatography to obtain 165 mg of the final product, a yellow solid, with a yield of 80%.

[0162] 11H NMR (600 MHz, Methanoll-d4) δ 8.15 (dd, J = 12.0, 8.7 Hz, 1H), 8.05 (dd, J = 8.2, 3.9 Hz, 1H), 7.97 (d, J = 8.3 Hz, 1H), 7.93 (dd, J = 7.9, 4.4 Hz, 1H), 7.70 (dd, J = 8.5, 5.0 Hz, 1H), 7.57 - 7.49 (m, 2H), 7.35 - 7.25 (m, 2H), 7.02 (t, J = 9.2 Hz, 2H).

[0163] Example 23: Preparation of Compound 23

[0164]

[0165] At room temperature, silver sulfate (113 mg, 0.36 mmol) was added to a suspension of (R)-1,1'-binaphthalene-2,2'-diamine dichloroplatinum (200 mg, 0.36 mmol) in 4 mL of methanol and 3 mL of deionized water, and the reaction mixture was heated to 60 °C under nitrogen protection and kept overnight in the dark. After the reaction was completed, the precipitate was removed by centrifugation, the supernatant was collected, freeze-dried using a freeze dryer, and separated by semi-preparative high performance liquid chromatography to obtain 155 mg of the final product, a yellow solid, with a yield of 75%.

[0166] 1 1H NMR (600 MHz, Methanol-d4) δ 8.15 (dd, J = 12.0, 8.7 Hz, 1H), 8.05 (dd, J = 8.2, 3.9 Hz, 1H), 7.97 (d, J = 8.3 Hz, 1H), 7.93 (dd, J = 7.9, 4.4 Hz, 1H), 7.70 (dd, J = 8.5, 5.0 Hz, 1H), 7.57 - 7.49 (m, 2H), 7.34 - 7.29 (m, 2H), 7.02 (t, J = 9.2 Hz, 2H).

[0167] Example 24: Preparation of Compound 24

[0168]

[0169] At room temperature, silver sulfate (113 mg, 0.36 mmol) was added to a suspension of (S)-1,1'-binaphthalene-2,2'-diamine dichloroplatinum (200 mg, 0.36 mmol) in 4 mL of methanol and 3 mL of deionized water, and the reaction mixture was heated to 60 °C under nitrogen protection and kept overnight in the dark. After the reaction was completed, the precipitate was removed by centrifugation, the supernatant was collected, freeze-dried using a freeze dryer, and separated by semi-preparative high performance liquid chromatography to obtain 155 mg of the final product, a yellow solid, with a yield of 75%.

[0170] 1 H NMR(600MHz, Methanol-d4) δ 8.15 (dd, J = 12.4, 8.7 Hz, 1H), 8.05 (dd, J = 8.4, 3.2 Hz, 1H), 8.00 - 7.94 (m, 1H), 7.94 - 7.90 (m, 1H), 7.70 (d, J = 8.7 Hz, 1H), 7.53 (dt, J = 13.8, 7.4 Hz, 2H), 7.32 (dt, J = 14.0, 7.3 Hz, 2H), 7.02 (t, J = 9.3 Hz, 2H).

[0171] Example 25: Preparation of Compound 25

[0172]

[0173] (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). Subsequently, silver nitrate (1.12 g, 6.57 mmol) was added to the above reaction solution, and the mixture was stirred for 0.5 h under light protection. The precipitate was separated by filtration, washed twice with water and once with absolute ethanol, and dried in vacuo at 40 °C to obtain a white solid product (721 mg, 60.0%).

[0174] (2) At room temperature, silver glycolate (105 mg, 0.57 mmol) prepared in step (1) was added to a suspension of 1,1'-binaphthalene-2,2'-diamine dichloroplatinum (300 mg, 0.55 mmol) in 6 mL of methanol and 4 mL of deionized water. 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 centrifugation, and the supernatant was collected. Sodium hydroxide solution was added dropwise to the supernatant at room temperature until the pH value of the solution was 7. Subsequently, the mixture was heated to 40 °C and stirred for 4 h. 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, an orange solid.

[0175] 1 H NMR(600MHz, Methanol-d4) δ 8.12 (dd, J = 8.7, 4.2 Hz, 2H), 8.03 (d, J = 8.2 Hz, 2H), 7.72 (dd, J = 20.0, 8.7 Hz, 2H), 7.48 (q, J = 6.8 Hz, 2H), 7.30 (t, J = 7.6 Hz, 2H), 7.02 (t, J = 8.7 Hz, 2H), 4.11 - 3.97 (m, 2H).

[0176] Example 26: Preparation of Compound 26

[0177]

[0178] Prepared by the general synthetic method A, the same method as in Example 25. Yield: 51%.

[0179] 1 H NMR (600 MHz, Methanol-d4) δ 8.13 (dd, J = 8.7, 4.2 Hz, 2H), 8.03 (d, J = 8.2 Hz, 2H), 7.72 (dd, J = 20.0, 8.7 Hz, 2H), 7.48 (q, J = 6.8 Hz, 2H), 7.30 (t, J = 7.6 Hz, 2H), 7.02 (t, J = 8.7 Hz, 2H), 4.12 - 3.95 (m, 2H).

[0180] Example 27: Preparation of Compound 27

[0181]

[0182] Prepared by the general synthetic method A, the same method as in Example 25. Yield: 51%.

[0183] 1 H NMR (600 MHz, Methanol-d4) δ 8.14 (dd, J = 8.7, 4.2 Hz, 2H), 8.04 (d, J = 8.2 Hz, 2H), 7.72 (dd, J = 20.0, 8.7 Hz, 2H), 7.48 (q, J = 6.8 Hz, 2H), 7.30 (t, J = 7.6 Hz, 2H), 7.02 (t, J = 8.7 Hz, 2H), 4.15 - 3.95 (m, 2H).

[0184] Example 28: Preparation of Compound 28

[0185]

[0186] Sodium pyrophosphate decahydrate (730 mg, 1.64 mmol) was added to a suspension of (R / S)-1,1'-binaphthalene-2,2'-diamine dichloroplatinum (300 mg, 0.55 mmol) in 4 mL of methanol and 10 mL of deionized water at room temperature, and the reaction mixture was heated to 40 °C under nitrogen protection and stirred for 15 hours in the dark. 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 153 mg of the final product, an orange solid.

[0187] 11H NMR (600 MHz, D2O) δ 8.16 (d, J = 8.8 Hz, 2H), 7.91 (d, J = 8.3 Hz, 2H), 7.84 (d, J = 8.7 Hz, 2H), 7.21 (t, J = 7.5 Hz, 2H), 6.78 (t, J = 7.6 Hz, 2H), 6.69 (d, J = 8.5 Hz, 2H).

[0188] Example 29: Preparation of Compound 29

[0189]

[0190] Prepared by the general synthetic method A in the same manner as in Example 28. Yield: 50%.

[0191] 1 1H NMR (600 MHz, D2O) δ 8.17 (d, J = 8.8 Hz, 2H), 7.92 (d, J = 8.3 Hz, 2H), 7.86 (d, J = 8.7 Hz, 2H), 7.23 (t, J = 7.5 Hz, 2H), 6.79 (t, J = 7.6 Hz, 2H), 6.70 (d, J = 8.5 Hz, 2H).

[0192] Example 30: Preparation of Compound 30

[0193]

[0194] Prepared by the general synthetic method A in the same manner as in Example 28. Yield: 50%.

[0195] 1 1H NMR (600 MHz, D2O) δ 8.15 (d, J = 8.8 Hz, 2H), 7.90 (d, J = 8.3 Hz, 2H), 7.85 (d, J = 8.7 Hz, 2H), 7.22 (t, J = 7.5 Hz, 2H), 6.80 (t, J = 7.6 Hz, 2H), 6.71 (d, J = 8.5 Hz, 2H).

[0196] Example 31: Preparation of Compound 31

[0197]

[0198] At room temperature, silver oxalate (110 mg, 0.36 mmol) was added to a suspension of (R / S)-1,1'-binaphthalene-2,2'-diamine dichloroplatinum (200 mg, 0.36 mmol) in 4 mL of methanol and 3 mL of deionized water. 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 centrifugation, the supernatant was collected, freeze-dried using a freeze dryer, and separated by semi-preparative high performance liquid chromatography to obtain 143 mg of the final product, a yellow solid.

[0199] 1 H NMR (600 MHz, Methanol-d4) δ 8.12 (d, J = 8.8 Hz, 2H), 8.02 (d, J = 8.3 Hz, 2H), 7.66 (d, J = 8.7 Hz, 2H), 7.48 (t, J = 7.6 Hz, 2H), 7.30 (t, J = 7.7 Hz, 2H), 7.04 (d, J = 8.6 Hz, 2H).

[0200] Example 32: Preparation of Compound 32

[0201]

[0202] Prepared by the general synthetic method A, the same method as in Example 31. The yield was 75%.

[0203] 1 H NMR (600 MHz, Methanol-d4) δ 8.11 (d, J = 8.8 Hz, 2H), 8.02 (d, J = 8.3 Hz, 2H), 7.76 (d, J = 8.8 Hz, 2H), 7.48 (t, J = 7.6 Hz, 2H), 7.27 (t, J = 7.7 Hz, 2H), 7.05 (d, J = 8.6 Hz, 2H).

[0204] Example 33: Preparation of Compound 33

[0205]

[0206] Prepared by the general synthetic method A, the same method as in Example 31. The yield was 77%.

[0207] 1 H NMR (600 MHz, Methanol-d4) δ 8.12 (d, J = 8.8 Hz, 2H), 8.03 (d, J = 8.3 Hz, 2H), 7.77 (d, J = 8.8 Hz, 2H), 7.49 (t, J = 7.6 Hz, 2H), 7.27 (t, J = 7.7 Hz, 2H), 7.06 (d, J = 8.6 Hz, 2H).

[0208] Example 34: Preparation of Compound 34

[0209]

[0210] (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). Subsequently, silver nitrate (1.18 g, 6.93 mmol) was 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%).

[0211] (2) At room temperature, silver 1,1-cyclobutanedicarboxylate (130 mg, 0.36 mmol) was added to a suspension of (R / S)-1,1'-binaphthalene-2,2'-diamine dichloroplatinum (200 mg, 0.36 mmol) in 4 mL of methanol and 3 mL of deionized water. 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 centrifugation, the supernatant was collected, freeze-dried using a freeze dryer, and separated by semi-preparative high performance liquid chromatography to obtain 100 mg of the final product, a yellow solid.

[0212] 1 H NMR (400 MHz, Methanol-d4) δ 8.13 (d, J = 8.7 Hz, 2H), 8.03 (d, J = 8.2 Hz, 2H), 7.73 (d, J = 8.8 Hz, 2H), 7.50 (ddd, J = 8.1, 6.8, 1.2 Hz, 2H), 7.31 (ddd, J = 8.3, 6.8, 1.3 Hz, 2H), 7.03 (dd, J = 8.6, 1.1 Hz, 2H), 2.84 (td, J = 7.6, 2.7 Hz, 4H), 1.86 - 1.80 (m, 2H).

[0213] Example 35: Preparation of Compound 35

[0214]

[0215] Prepared by the general synthetic method A, the same method as in Example 34. Yield 47%.

[0216] 11H NMR(600MHz, Methanol-d4) δ 7.85 (d, J = 8.8 Hz, 2H), 7.80 (d, J = 6.9 Hz, 2H), 7.28 (d, J = 8.8 Hz, 2H), 7.20 (ddd, J = 8.1, 6.6, 1.2 Hz, 2H), 7.12 (ddd, J = 8.3, 6.7, 1.3 Hz, 2H), 6.92 (d, J = 8.4 Hz, 2H), 2.50 (t, J = 8.0 Hz, 4H), 2.05 - 2.00 (m, 2H).

[0217] Example 36: Preparation of Compound 36

[0218]

[0219] Prepared by the general synthetic method A, the same method as in Example 34. Yield: 45%.

[0220] 1 1H NMR(600MHz, Methanol-d4) δ 8.13 (d, J = 8.7 Hz, 2H), 8.03 (d, J = 8.3 Hz, 2H), 7.73 (d, J = 8.7 Hz, 2H), 7.50 (ddd, J = 8.1, 6.8, 1.1 Hz, 2H), 7.31 (ddd, J = 8.3, 6.8, 1.3 Hz, 2H), 7.03 (d, J = 8.6 Hz, 2H), 2.49 (t, J = 8.0 Hz, 4H), 2.02 - 1.96 (m, 2H).

[0221] Example 37: Preparation of Compound 37

[0222]

[0223] Prepared by the general synthetic method A, the same method as in Example 34. Yield: 50%.

[0224] 1 1H NMR(600MHz, Methanol-d4) δ 7.85 (d, J = 8.8 Hz, 2H), 7.79 (d, J = 6.9 Hz, 2H), 7.28 (d, J = 8.8 Hz, 2H), 7.20 (ddd, J = 8.1, 6.6, 1.2 Hz, 2H), 7.13 (ddd, J = 8.3, 6.7, 1.3 Hz, 2H), 6.92 (d, J = 8.4 Hz, 2H), 2.90 (s, 6H), 2.53 (t, J = 8.0 Hz, 4H), 2.05 (p, J = 8.0 Hz, 2H).

[0225] Example 38: Preparation of Compound 38

[0226]

[0227] Prepared by the same method as Example 34 using the general synthetic method A. The yield was 53%.

[0228] 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=8.1,6.6,1.2Hz,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).

[0229] Example 39: Preparation of Compound 39

[0230]

[0231] Prepared by the same method as Example 34 using the general synthetic method A. The yield was 57%.

[0232] 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=8.1,6.6,1.2Hz,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).

[0233] Example 40: Preparation of Compound 40

[0234]

[0235] (1) Preparation of Diethyl 2-acetoxypropanedioate:

[0236]

[0237] Diethyl malonate (1.6 g) and lead(IV) tetraacetate (4.3 g) were separately placed in glacial acetic acid (20 mL), heated and dissolved at 100 °C under nitrogen protection. Then diethyl malonate was transferred to the lead(IV) tetraacetate solution, and the temperature was subsequently raised to 105 °C and stirred for 3 hours. The solvent was removed by rotary evaporation. Water (20 mL) was added to the residue, and it was extracted four times with diethyl ether (20 mL). The organic phases were combined, washed successively 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).

[0238] 1 H NMR (600 MHz, CDCl3) δ 5.47 (s, 1H), 4.28 - 4.22 (m, 4H), 2.18 (s, 3H), 1.27 (t, J = 7.2 Hz, 6H)

[0239] (2) Preparation of diethyl 2 - hydroxy - malonate:

[0240]

[0241] 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. It was stirred at room temperature for 5 hours. The solvent was removed by rotary evaporation. Water (5 mL) was added to the residue, and it was separated by liquid - liquid extraction. 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 a colorless oily product (1.4 g).

[0242] 1 H NMR (600 MHz, CDCl3) δ 4.68 (s, 1H), 4.31 - 4.25 (m, 4H), 1.29 (t, J = 7.2 Hz, 6H).

[0243] (3) Preparation of diethyl 1 - O-(2,3,4,6 - tetra - O - acetyl - D - glucopyranoside) - malonate:

[0244]

[0245] 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, displace the air in the flask with nitrogen, and slowly add boron trifluoride ether solution (98%, 1.3 mL) under nitrogen protection. Stir the reaction mixture at 0 °C for 15 minutes, then slowly warm to room temperature and react at room temperature for 5 hours. Monitor the end point of the reaction by TLC. After the reaction is complete, add dichloromethane (50 mL) and water (50 mL), extract and separate the layers. Collect the organic phase and wash it successively with water (2×100 mL), saturated sodium bicarbonate aqueous solution (2×100 mL), and saturated sodium chloride (1×100 mL). Dry it over anhydrous sodium sulfate and evaporate the solvent to dryness using a rotary evaporator. The obtained crude product is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain a light yellow viscous liquid product (1.5 g).

[0246] 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).

[0247] (4) Preparation of disodium 1 - O - (2,3,4,6 - tetraacetyl - D - glucoside) - malonate:

[0248]

[0249] Dissolve the product from the previous step, diethyl 1 - O - (2,3,4,6 - tetraacetyl - D - glucoside) - malonate (506 mg), in 4.5 mL of methanol. Dissolve sodium hydroxide (280 mg) in 1.5 mL of water and add it to the reaction solution at 0 °C, then warm to 60 °C and react for 2 hours. Monitor the end point of the reaction by TLC. After the reaction is complete, cool the reaction solution to room temperature. Wash the precipitated solid with methanol / water solution (volume ratio 3:1, 5×1 mL), and dry it to obtain 310 mg of a pale yellow solid crude product, which is directly used in the next step of the reaction.

[0250] 11H NMR (600 MHz, D2O) δ 4.43 (s, 1H), 4.38 (d, J = 7.8 Hz, 1H), 3.80 (d, J = 12.0 Hz, 1H), 3.65 (dd, J = 12.5, 4.9 Hz, 1H), 3.43 (t, J = 9.0 Hz, 1H), 3.39 - 3.30 (m, 3H).

[0251] (5) Preparation of Compound 40:

[0252] Dissolve the crude product of 1 - O - (2,3,4,6 - tetra - O - acetyl - D - glucopyranoside) - disodium malonate (119 mg) in 2 mL of water. Under nitrogen protection, dissolve (R / S) - 1,1'-binaphthalene - 2,2'-diamine platinum nitrate (219 mg, 0.36 mmol) in 4 mL of methanol, add it to the above reaction solution, adjust the pH to 7.0 with sodium hydroxide solution, and then raise the temperature to 60 °C and react for 2 hours. After the reaction is completed, use a centrifuge to remove the precipitate, collect the supernatant, freeze - dry it with a freeze - dryer, and separate it by semi - preparative high - performance liquid chromatography to obtain 100 mg of the final product, a yellow solid.

[0253] 1 1H NMR (600 MHz, Methanol - d4) δ 8.14 (dd, J = 8.7, 3.5 Hz, 2H), 8.04 (d, J = 8.3 Hz, 2H), 7.77 (dd, J = 17.2, 8.7 Hz, 2H), 7.50 (t, J = 7.5 Hz, 2H), 7.30 (dd, J = 8.3, 7.0 Hz, 2H), 7.02 (dd, J = 8.5, 3.9 Hz, 2H), 5.58 (s, 1H), 4.53 (d, J = 7.3 Hz, 1H), 3.88 - 3.81 (m, 1H), 3.65 (dd, J = 12.0, 5.2 Hz, 1H), 3.50 - 3.30 (m, 4H).

[0254] Example 41: Preparation of Compound 41

[0255]

[0256] Prepared by the general synthetic method B, the same method as in Example 40. The yield is 52%.

[0257] 11H NMR (600 MHz, Methanol-d4) δ 8.13 (dd, J = 8.7, 3.5 Hz, 2H), 8.04 (d, J = 8.3 Hz, 2H), 7.77 (dd, J = 17.2, 8.7 Hz, 2H), 7.51 (t, J = 7.5 Hz, 2H), 7.30 (dd, J = 8.3, 7.0 Hz, 2H), 7.02 (dd, J = 8.5, 3.9 Hz, 2H), 5.58 (s, 1H), 4.52 (d, J = 7.3 Hz, 1H), 3.88 - 3.81 (m, 1H), 3.65 (dd, J = 12.0, 5.2 Hz, 1H), 3.50 - 3.30 (m, 4H).

[0258] Example 42: Preparation of Compound 42

[0259]

[0260] Prepared by the general synthetic method B, in the same manner as in Example 40. Yield: 56%.

[0261] 1 1H NMR (600 MHz, Methanol-d4) δ 8.13 (dd, J = 8.7, 3.5 Hz, 2H), 8.04 (d, J = 8.3 Hz, 2H), 7.77 (dd, J = 17.2, 8.7 Hz, 2H), 7.51 (t, J = 7.5 Hz, 2H), 7.30 (dd, J = 8.3, 7.0 Hz, 2H), 7.02 (dd, J = 8.5, 3.9 Hz, 2H), 5.56 (s, 1H), 4.52 (d, J = 7.3 Hz, 1H), 3.90 - 3.80 (m, 1H), 3.62 (dd, J = 12.0, 5.2 Hz, 1H), 3.70 - 3.30 (m, 4H).

[0262] Example 43: Preparation of Compound 43

[0263]

[0264] (1) Preparation of silver malonate:

[0265] 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 mixed solution 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 in vacuo in the dark to obtain a white solid product (1.48 g, 96.7%).

[0266] (2) Preparation of Compound 43:

[0267] At room temperature, silver malonate (110 mg, 0.36 mmol) was added to a suspension of (R / S)-1,1'-binaphthalene-2,2'-diamine dichloroplatinum (200 mg, 0.36 mmol) in 4 mL of methanol and 3 mL of deionized water. 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 centrifugation, the supernatant was collected, freeze-dried using a freeze dryer, and separated by semi-preparative high performance liquid chromatography to obtain 105 mg of the final product, a yellow solid.

[0268] 1 H NMR (400 MHz, Methanol-d4) δ 8.13 (d, J = 8.8 Hz, 2H), 8.02 (d, J = 8.2 Hz, 2H), 7.74 (d, J = 8.7 Hz, 2H), 7.48 (ddd, J = 8.2, 6.8, 1.1 Hz, 2H), 7.30 (ddd, J = 8.3, 6.8, 1.3 Hz, 2H), 7.03 (d, J = 8.5 Hz, 2H), 3.51 (s, 2H).

[0269] Example 44: Preparation of Compound 44

[0270]

[0271] Prepared by the general synthetic method A, the same method as in Example 43. The yield was 57%.

[0272] 1 H NMR (400 MHz, Methanol-d4) δ 8.14 (d, J = 8.8 Hz, 2H), 8.04 (d, J = 8.2 Hz, 2H), 7.74 (d, J = 8.7 Hz, 2H), 7.50 (ddd, J = 8.2, 6.8, 1.1 Hz, 2H), 7.31 (ddd, J = 8.3, 6.8, 1.3 Hz, 2H), 7.02 (d, J = 8.5 Hz, 2H), 3.49 (s, 2H).

[0273] Example 45: Preparation of Compound 45

[0274]

[0275] Prepared by the general synthetic method A, the same method as in Example 43. The yield was 60%.

[0276] 11H NMR (600 MHz, Methanol-d4) δ 8.14 (d, J = 8.8 Hz, 2H), 8.04 (d, J = 8.2 Hz, 2H), 7.74 (d, J = 8.7 Hz, 2H), 7.50 (t, J = 7.5 Hz, 2H), 7.30 (ddd, J = 8.3, 6.7, 1.2 Hz, 2H), 7.02 (d, J = 8.6 Hz, 2H), 3.49 (s, 2H).

[0277] Example 46: Preparation of Compound 46

[0278]

[0279] Prepared by the general synthetic method A in the same manner as in Example 31. Yield: 67%.

[0280] 1 1H NMR (600 MHz, Methanol-d4) δ 8.12 (d, J = 8.8 Hz, 2H), 8.02 (d, J = 8.3 Hz, 2H), 7.76 (d, J = 8.8 Hz, 2H), 7.48 (t, J = 7.6 Hz, 2H), 7.27 (t, J = 7.7 Hz, 2H), 7.04 (d, J = 8.6 Hz, 2H), 2.45 (s, 6H).

[0281] Example 47: Preparation of Compound 47

[0282]

[0283] Prepared by the general synthetic method A in the same manner as in Example 31. Yield: 72%.

[0284] 1 1H NMR (600 MHz, Methanol-d4) δ 8.11 (d, J = 8.8 Hz, 2H), 8.02 (d, J = 8.3 Hz, 2H), 7.76 (d, J = 8.8 Hz, 2H), 7.48 (t, J = 7.6 Hz, 2H), 7.27 (t, J = 7.7 Hz, 2H), 7.05 (d, J = 8.6 Hz, 2H), 2.45 (s, 6H).

[0285] Example 48: Preparation of Compound 48

[0286]

[0287] Prepared by the general synthetic method A in the same manner as in Example 31. Yield: 70%.

[0288] 11H NMR (600 MHz, Methanol-d4) δ 8.12 (d, J = 8.8 Hz, 2H), 8.03 (d, J = 8.3 Hz, 2H), 7.77 (d, J = 8.8 Hz, 2H), 7.49 (t, J = 7.6 Hz, 2H), 7.27 (t, J = 7.7 Hz, 2H), 7.06 (d, J = 8.6 Hz, 2H), 2.45 (s, 6H).

[0289] Example 49: Preparation of Compound 49

[0290]

[0291] (1) Preparation of N,N'-([1,1'-Binaphthalene]-2,2'-diyl)diacetamide:

[0292] Add (R / S)-1,1'-Biphenyl-2,2'-diamine (1 g, 3.52 mmol) and dichloromethane (20 mL) to a 50 mL two-necked round-bottom flask, and then add acetic anhydride (1.16 mL, 12.31 mmol). Stir the reaction mixture at room temperature for 12 hours under nitrogen protection, and monitor the reaction by TLC. After the reaction is completed, extract the reaction solution with dichloromethane, combine the organic layers, wash with water, dry over anhydrous sodium sulfate, and concentrate in vacuo. The residue is purified by silica gel column chromatography (dichloromethane / methanol = 25 / 1) to obtain a white solid product (1.21 g, 93.5%).

[0293] 1 1H NMR (600 MHz, CDCl3) δ 8.36 (d, J = 9.0 Hz, 2H), 8.05 (d, J = 9.0 Hz, 2H), 7.95 (d, J = 8.2 Hz, 2H), 7.46 (ddd, J = 8.1, 6.8, 1.2 Hz, 2H), 7.28 (ddd, J = 8.2, 6.7, 1.2 Hz, 2H), 7.03 (dd, J = 8.5, 1.2 Hz, 2H), 6.90 (s, 2H), 1.83 (s, 6H).

[0294] (2) Preparation of N,N'-(6,6'-Dibromo-[1,1'-binaphthalene]-2,2'-diyl)diacetamide:

[0295] The product from the previous step (500 mg, 1.36 mmol) was dissolved in a solution of N,N-dimethylformamide (10 mL). N-Bromosuccinimide (NBS, 532 mg, 2.99 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was quenched with 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 an orange solid product (650 mg, 90.4%).

[0296] 1 1H NMR (600 MHz, CDCl3) δ 8.34 (d, J = 9.0 Hz, 2H), 8.11 (d, J = 2.0 Hz, 2H), 7.96 (d, J = 9.0 Hz, 2H), 7.35 (dd, J = 9.0, 2.0 Hz, 2H), 6.91 - 6.83 (m, 4H), 1.85 (s, 6H).

[0297] (3) Preparation of N,N'-6,6'-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-binaphthalene]-2,2'-diacetamide:

[0298] In a reaction flask, bis(pinacolato)diboron (720 mg, 2.83 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (500 mg, 0.43 mmol), potassium acetate (372 mg, 3.80 mmol), and dry 1,4-dioxane solution (15 mL) were added. After purging with nitrogen 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 protection. 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, the solvent was removed by rotary evaporation, and purification was carried out by silica gel column chromatography (dichloromethane / methanol = 40 / 1) to give an orange solid product (302 mg, 51.3%).

[0299] 1 1H NMR (400 MHz, CDCl3) δ 8.46 (s, 2H), 8.40 (d, J = 9.0 Hz, 2H), 8.09 (d, J = 8.9 Hz, 2H), 7.61 (d, J = 9.7 Hz, 2H), 6.98 (d, J = 8.4 Hz, 2H), 6.88 (s, 2H), 1.81 (s, 6H), 1.36 (s, 24H).

[0300] (4) Preparation of N,N'-(6,6'-dihydroxy-[1,1'-binaphthalene]-2,2'-diyl)diacetamide:

[0301] Dissolve the product from the previous step (120 mg, 0.19 mmol) in tetrahydrofuran (2 mL). Dissolve ammonium chloride (10 mg, 0.19 mmol) in 1 mL of water and add it to the above solution. Then, dropwise add aqueous hydrogen peroxide solution (0.5 mL) at 0 °C and stir at room temperature for 15 hours. After the reaction is complete, slowly add sodium sulfite solution to quench the reaction, and extract with ethyl acetate (3 × 3 mL). Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purify by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain a brown solid (53 mg, 68.8%).

[0302] 1 H NMR (600 MHz, Methanol-d4) δ 7.80 (d, J = 8.8 Hz, 2H), 7.63 (d, J = 8.8 Hz, 2H), 7.21 (d, J = 2.5 Hz, 2H), 6.91 (d, J = 9.1 Hz, 2H), 6.85 (dd, J = 9.1, 2.5 Hz, 2H), 1.76 (s, 6H).

[0303] (5) Preparation of 2,2'-diamino-[1,1'-binaphthalene]-6,6'-diol:

[0304] Dissolve the product from the previous step (100 mg, 0.25 mmol) in a mixed solution of ethanol (1 mL) and water (1 mL). Dropwise add concentrated hydrochloric acid (0.5 mL) at room temperature, and then reflux and stir for 2 hours. After the reaction is completed, evaporate the ethanol. Add saturated sodium carbonate solution to the residue and adjust the pH to 10 to precipitate a white product (50 mg, 63.3%).

[0305] 1 H NMR (400 MHz, DMSO-d6) δ 9.14 (s, 2H), 7.54 (d, J = 8.8 Hz, 2H), 7.12 (d, J = 8.8 Hz, 2H), 7.03 (d, J = 2.4 Hz, 2H), 6.80 - 6.63 (m, 4H), 4.27 (s, 4H).

[0306] (6) Preparation of 2,2'-diamino-[1,1'-binaphthalene]-6,6'-diol dichloroplatinum(II):

[0307] At room temperature, potassium tetrachloroplatinate (394 mg, 0.95 mmol) and 5 mL of deionized water were added to a 25 mL flask, stirred and filtered to remove insoluble substances. (R)-2,2'-Diamino-[1,1'-binaphthalene]-6,6'-diol (300 mg, 0.95 mmol) was dispersed in 5 mL of methanol and added to the above solution. The reaction mixture was stirred overnight at 40 °C under nitrogen protection to form a yellow precipitate. The precipitate was filtered and washed successively with cold water, and then dried under vacuum to obtain a yellow solid (394 mg, 71.2%).

[0308] (7) Preparation of Compound 49:

[0309] Prepared by the general synthetic method A, the same method as in Example 34. The yield was 48%.

[0310] 1 H NMR (400 MHz, Methanol-d4) δ 7.89 (dd, J = 8.8, 4.5 Hz, 2H), 7.64 (dd, J = 15.2, 8.8 Hz, 2H), 7.26 (s, 2H), 6.91 (s, 4H), 2.50 (t, J = 8.0 Hz, 4H), 1.95 - 2.10 (m, 2H).

[0311] Example 50: Preparation of Compound 50

[0312]

[0313] Prepared by the general synthetic method A, the same method as in Example 34. The yield was 52%.

[0314] 1 H NMR (400 MHz, Methanol-d4) δ 7.89 (dd, J = 8.8, 4.5 Hz, 2H), 7.63 (dd, J = 15.2, 8.8 Hz, 2H), 7.25 (s, 2H), 6.91 (s, 4H), 2.50 (t, J = 8.0 Hz, 4H), 1.95 - 2.10 (m, 2H).

[0315] Example 51: Preparation of Compound 51

[0316]

[0317] Prepared by the general synthetic method A, the same method as in Example 34. The yield was 55%.

[0318] 11H NMR (400 MHz, Methanol-d4) δ 7.87 (dd, J = 8.8, 4.5 Hz, 2H), 7.61 (dd, J = 15.2, 8.8 Hz, 2H), 7.23 (s, 2H), 6.90 (s, 4H), 2.50 (t, J = 8.0 Hz, 4H), 1.95 - 2.10 (m, 2H).

[0319] Example 52: Preparation of Compound 52

[0320]

[0321] Prepared by the general synthetic method B, in the same manner as in Example 40. Yield: 50%.

[0322] 1 1H NMR (600 MHz, Methanol-d4) δ 8.14 (dd, J = 8.7, 3.5 Hz, 2H), 8.04 (d, J = 8.3 Hz, 2H), 7.77 (dd, J = 17.2, 8.7 Hz, 2H), 7.50 (t, J = 7.5 Hz, 2H), 7.30 (dd, J = 8.3, 7.0 Hz, 2H), 7.02 (dd, J = 8.5, 3.9 Hz, 2H), 5.58 (s, 1H), 4.53 (d, J = 7.3 Hz, 1H), 3.88 - 3.81 (m, 1H), 3.65 (dd, J = 12.0, 5.2 Hz, 1H), 3.50 - 3.30 (m, 4H), 2.89 (s, 6H).

[0323] Example 53: Preparation of Compound 53

[0324]

[0325] Prepared by the general synthetic method B, in the same manner as in Example 40. Yield: 47%.

[0326] 1 1H NMR (600 MHz, Methanol-d4) δ 8.13 (dd, J = 8.7, 3.5 Hz, 2H), 8.04 (d, J = 8.3 Hz, 2H), 7.77 (dd, J = 17.2, 8.7 Hz, 2H), 7.51 (t, J = 7.5 Hz, 2H), 7.30 (dd, J = 8.3, 7.0 Hz, 2H), 7.02 (dd, J = 8.5, 3.9 Hz, 2H), 5.58 (s, 1H), 4.52 (d, J = 7.3 Hz, 1H), 3.88 - 3.81 (m, 1H), 3.65 (dd, J = 12.0, 5.2 Hz, 1H), 3.50 - 3.30 (m, 4H), 2.90 (s, 6H).

[0327] Example 54: Preparation of Compound 54

[0328]

[0329] Prepared by the general synthetic method B, in the same manner as in Example 40. Yield: 45%.

[0330] 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),2.90(s,6H).

[0331] Example 55: Preparation of Compound 55

[0332]

[0333] The crude product of disodium 1-O-(2,3,4,6-tetraacetyl-D-galactopyranoside) malonate (119 mg) was dissolved in 2 mL of water. Under nitrogen protection, (R)-1,1'-binaphthalene-2,2'-diamine platinum nitrate (219 mg) was dissolved in 4 mL of methanol and added to the above reaction solution. The pH was adjusted to 7 with sodium hydroxide solution, and then the temperature was raised to 60 °C and reacted for 2 hours. After the reaction was completed, the precipitate was removed by centrifugation, the supernatant was collected, freeze-dried by a freeze dryer, and separated by semi-preparative high performance liquid chromatography to obtain 135 mg of the final product, a yellow solid. Yield: 49%.

[0334] 1H NMR(600MHz, Methanol-d4) δ 8.10 (dd, J = 8.8, 5.7 Hz, 2H), 8.02 (d, J = 8.2 Hz, 2H), 7.76 (dd, J = 24.0, 8.7 Hz, 2H), 7.50 (t, J = 7.5 Hz, 2H), 7.28 (t, J = 6.8 Hz, 2H), 7.00 (t, J = 7.7 Hz, 2H), 5.59 (s, 1H), 4.47 (d, J = 7.7 Hz, 1H), 3.77 (d, J = 3.5 Hz, 1H), 3.71 (d, J = 7.0 Hz, 2H), 3.69 - 3.65 (m, 1H), 3.56 - 3.47 (m, 2H).

[0335] Example 56: Preparation of Compound 56

[0336]

[0337] Prepared by the general synthetic method B, in the same manner as in Example 40. Yield: 42%.

[0338] 1 H NMR(600MHz, Methanol-d4) δ 8.14 (dd, J = 8.8, 5.7 Hz, 2H), 8.04 (d, J = 8.2 Hz, 2H), 7.75 (dd, J = 24.0, 8.7 Hz, 2H), 7.50 (t, J = 7.5 Hz, 2H), 7.30 (t, J = 6.8 Hz, 2H), 7.01 (t, J = 7.7 Hz, 2H), 5.59 (s, 1H), 4.47 (d, J = 7.7 Hz, 1H), 3.77 (d, J = 3.5 Hz, 1H), 3.71 (d, J = 7.0 Hz, 2H), 3.69 - 3.65 (m, 1H), 3.56 - 3.47 (m, 2H).

[0339] Example 57: Preparation of Compound 57

[0340]

[0341] Prepared by the general synthetic method B, in the same manner as in Example 40. Yield: 40%.

[0342] 11H NMR (600 MHz, Methanol-d4) δ 8.14 (t, J = 7.4 Hz, 2H), 8.04 (d, J = 8.3 Hz, 2H), 7.75 (dd, J = 25.9, 8.6 Hz, 2H), 7.50 (t, J = 7.6 Hz, 2H), 7.30 (t, J = 7.7 Hz, 2H), 7.02 (t, J = 7.1 Hz, 2H), 5.59 (s, 1H), 4.43 (td, J = 27.0, 25.7, 7.5 Hz, 1H), 3.78 (d, J = 17.4 Hz, 2H), 3.74 - 3.62 (m, 2H), 3.48 (d, J = 6.8 Hz, 2H).

[0343] Example 58: Preparation of Compound 58

[0344]

[0345] The crude product of disodium 1-O-(2,3,4,6-tetraacetyl-D-mannopyranoside)-malonate (119 mg) was dissolved in 2 mL of water. Under nitrogen protection, (R)-1,1'-binaphthalene-2,2'-diamine platinum nitrate (219 mg) was dissolved in 4 mL of methanol and added to the above reaction solution. The pH was adjusted to 7 with sodium hydroxide solution, and then the temperature was raised to 60 °C and reacted for 2 hours. After the reaction was completed, the precipitate was removed by centrifugation, the supernatant was collected, freeze-dried with a freeze dryer, and separated by semi-preparative high performance liquid chromatography to obtain 50 mg of the final product, a yellow solid.

[0346] 1 1H NMR (600 MHz, Methanol-d4) δ 8.14 (dd, J = 8.8, 6.4 Hz, 2H), 8.03 (d, J = 8.5 Hz, 2H), 7.77 (d, J = 8.8 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.53 - 7.47 (m, 2H), 7.35 - 7.26 (m, 2H), 7.02 (dd, J = 8.1, 2.6 Hz, 2H), 5.51 (s, 1H), 4.91 (d, J = 1.7 Hz, 1H), 4.05 (dd, J = 3.5, 1.7 Hz, 1H), 3.95 (dd, J = 8.8, 3.5 Hz, 1H), 3.89 (dd, J = 11.7, 1.9 Hz, 1H), 3.74 (dd, J = 11.6, 5.3 Hz, 1H), 3.67 - 3.58 (m, 2H).

[0347] Example 59: Preparation of Compound 59

[0348]

[0349] Prepared by the same method as Example 40 using General Synthesis Method B. Yield: 20%.

[0350] 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).

[0351] Example 60: Preparation of Compound 60

[0352]

[0353] Prepared by the same method as Example 40 using General Synthesis Method B. Yield: 23%.

[0354] 1 H NMR(600MHz,Methanol-d4)δ8.14(dd,J=8.9,2.2Hz,2H),8.04(d,J=8.3Hz,2H),7.74(dd,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=9.0,3.5Hz,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).

[0355] Example 61: Preparation of Compound 61

[0356]

[0357] Prepared by the same method as Example 58 using General Synthesis Method B. Yield: 25%.

[0358] 1 H NMR (400 MHz, Methanol-d4) δ 7.87 (dd, J = 9.1, 4.2 Hz, 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, 4.8 Hz, 1H), 3.43 - 3.33 (m, 2H).

[0359] Example 62: Preparation of Compound 62

[0360]

[0361] Prepared by the general synthetic method B, in the same manner as Example 58. Yield: 27%.

[0362] 1 H NMR (400 MHz, Methanol-d4) δ 7.89 (dd, J = 9.1, 4.2 Hz, 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, 4.8 Hz, 1H), 3.43 - 3.33 (m, 2H).

[0363] Example 63: Preparation of Compound 63

[0364]

[0365] Prepared by the general synthetic method B, in the same manner as Example 58. Yield: 27%.

[0366] 1 H NMR (400 MHz, Methanol-d4) δ 7.89 (dd, J = 8.8, 3.9 Hz, 2H), 7.71 - 7.57 (m, 2H), 7.26 (s, 2H), 6.91 (s, 4H), 5.56 (d, J = 2.0 Hz, 1H), 4.51 (dd, J = 16.3, 6.4 Hz, 1H), 3.90 - 3.80 (m, 1H), 3.67 (td, J = 11.1, 10.7, 4.8 Hz, 1H), 3.43 - 3.33 (m, 2H).

[0367] Example 64: Preparation of Compound 64

[0368]

[0369] Prepared by the same method as in Example 58 using General Synthetic Method B. Yield: 31%.

[0370] 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).

[0371] Example 65: Preparation of Compound 65

[0372]

[0373] Prepared by the same method as in Example 58 using General Synthetic Method B. Yield: 29%.

[0374] 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),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).

[0375] Example 66: Preparation of Compound 66

[0376]

[0377] Prepared by the same method as in Example 58 using General Synthetic Method B. Yield: 33%.

[0378] 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).

[0379] Example 67: Preparation of Compound 67

[0380]

[0381] Prepared by the same method as in Example 58 using General Synthetic Method B. Yield: 33%.

[0382] 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=23.7Hz,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).

[0383] Example 68: Preparation of Compound 68

[0384]

[0385] Prepared by the same method as in Example 58 using General Synthetic Method B. Yield: 33%.

[0386] 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=23.7Hz,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).

[0387] Example 69: Preparation of Compound 69

[0388]

[0389] Prepared by the same method as in Example 58 using General Synthetic Method B. Yield: 33%.

[0390] 11H NMR (400 MHz, Methanol-d4) δ 7.89 (dd, J = 8.8, 4.0 Hz, 2H), 7.63 (dd, J = 18.8, 8.8 Hz, 2H), 7.26 (s, 2H), 6.94 - 6.88 (m, 4H), 5.45 (s, 1H), 5.00 (d, J = 1.8 Hz, 1H), 4.06 (dd, J = 3.5, 1.7 Hz, 1H), 3.93 (dd, J = 9.0, 3.5 Hz, 1H), 3.90 - 3.53 (m, 4H).

[0391] Example 70: Preparation of Compound 70

[0392]

[0393]

[0394] At room temperature, silver sulfate (227 mg, 0.73 mmol) was added to a suspension of (R)-1,1'-binaphthalene-2,2'-diamine dichloroplatinum (400 mg, 0.73 mmol) in 10 mL of methanol and 10 mL of deionized water. The reaction mixture was heated to 45 °C under nitrogen protection and stirred in the dark for two days. After the reaction was completed, the precipitate was removed by centrifugation, and the supernatant was collected. Phosphonoacetic acid (102 mg, 0.73 mmol) and barium sulfate (230 mg, 0.73 mmol) were added to the supernatant, and the mixture was further heated to 40 °C and stirred for 18 hours. After the reaction was completed, the precipitate was removed by centrifugation, and the supernatant was filtered through a nylon microporous membrane and freeze-dried. The final product, an orange-red solid (244 mg), was obtained by semi-preparative high performance liquid chromatography.

[0395] 1 1H NMR (600 MHz, Methanol-d4) δ 8.11 (dd, J = 8.8, 5.6 Hz, 2H), 8.02 (dd, J = 8.1, 3.2 Hz, 2H), 7.82 (d, J = 8.7 Hz, 1H), 7.71 (d, J = 8.7 Hz, 1H), 7.48 (tt, J = 7.0, 1.3 Hz, 2H), 7.31 - 7.24 (m, 2H), 7.00 (t, J = 9.5 Hz, 2H), 2.90 (dd, J = 19.1, 14.0 Hz, 1H), 2.78 (dd, J = 17.2, 14.0 Hz, 1H).

[0396] Example 71: Preparation of Compound 71

[0397]

[0398] Prepared by the same method as in Example 70 using the general synthetic method A. Yield: 53%.

[0399] 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).

[0400] Example 72: Preparation of Compound 72

[0401]

[0402] Prepared by the same method as in Example 70 using the general synthetic method A. Yield: 56%.

[0403] 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).

[0404] Example 73: Preparation of Compound 73

[0405]

[0406] Prepared by the same method as in Example 31 using the general synthetic method A. Yield: 70%.

[0407] 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).

[0408] Example 74: Preparation of Compound 74

[0409]

[0410] Prepared by the general synthetic method A, the same method as in Example 31. The yield is 70%.

[0411] 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).

[0412] Example 75: Preparation of Compound 75

[0413]

[0414] Prepared by the general synthetic method A, the same method as in Example 31. The yield is 76%.

[0415] 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).

[0416] Example 76: Preparation of Compound 76

[0417]

[0418] Prepared by the general synthetic method A, the same method as in Example 49. The yield is 76%.

[0419] 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).

[0420] Example 77: Preparation of Compound 77

[0421]

[0422] Prepared by the general synthetic method A, the same method as in Example 49. The yield is 77%.

[0423] 1 H NMR(400 MHz, Methanol-d4) δ 7.87 (dd, J = 8.8, 6.9 Hz, 4H), 7.16 (d, J = 8.8 Hz, 2H), 7.03 (dd, J = 8.8, 2.6 Hz, 2H), 6.65 (d, J = 2.6 Hz, 2H), 3.60 (s, 6H), 2.50 (t, J = 8.0 Hz, 4H), 1.95 - 2.10 (m, 2H).

[0424] Example 78: Preparation of Compound 78

[0425]

[0426]

[0427] Prepared by the general synthetic method A, the same method as in Example 49. Yield: 75%.

[0428] 1 H NMR(400 MHz, Methanol-d4) δ 7.89 (dd, J = 8.8, 6.9 Hz, 4H), 7.17 (d, J = 8.8 Hz, 2H), 7.06 (dd, J = 8.8, 2.6 Hz, 2H), 6.67 (d, J = 2.6 Hz, 2H), 3.63 (s, 6H), 2.52 (t, J = 8.0 Hz, 4H), 1.95 - 2.15 (m, 2H).

[0429] Example 79: Preparation of Compound 79

[0430]

[0431] Prepared by the general synthetic method A, the same method as in Example 31. Yield: 75%.

[0432] 1 H NMR(600 MHz, Methanol-d4) δ 8.12 (d, J = 8.8 Hz, 2H), 8.02 (d, J = 8.3 Hz, 2H), 7.76 (d, J = 8.8 Hz, 2H), 7.48 (t, J = 7.6 Hz, 2H), 7.27 (t, J = 7.7 Hz, 2H), 7.04 (d, J = 8.6 Hz, 2H), 2.89 (s, 6H).

[0433] Example 80: Preparation of Compound 80

[0434]

[0435] Prepared by the same method as in Example 31 using the general synthetic method A. The yield was 77%.

[0436] 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),2.90(s,6H).

[0437] Example 81: Preparation of Compound 81

[0438]

[0439]

[0440] Prepared by the same method as in Example 31 using the general synthetic method A. The yield was 73%.

[0441] 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),2.90(s,6H).

[0442] Example 82: Preparation of Compound 82

[0443]

[0444] Prepared by the same method as in Example 55 using the general synthetic method B. The yield was 41%.

[0445] 11H NMR (600 MHz, Methanol-d4) δ 8.14 (dd, J = 8.8, 5.7 Hz, 2H), 8.04 (d, J = 8.2 Hz, 2H), 7.75 (dd, J = 24.0, 8.7 Hz, 2H), 7.50 (t, J = 7.5 Hz, 2H), 7.30 (t, J = 6.8 Hz, 2H), 7.01 (t, J = 7.7 Hz, 2H), 5.59 (s, 1H), 4.47 (d, J = 7.7 Hz, 1H), 3.77 (d, J = 3.5 Hz, 1H), 3.71 (d, J = 7.0 Hz, 2H), 3.69 - 3.65 (m, 1H), 3.56 - 3.47 (m, 2H), 2.91 (s, 6H).

[0446] Example 83: Preparation of Compound 83

[0447]

[0448] Prepared by the general synthetic method B in the same manner as in Example 55. Yield: 44%.

[0449] 1 1H NMR (600 MHz, Methanol-d4) δ 8.14 (dd, J = 8.8, 5.7 Hz, 2H), 8.04 (d, J = 8.2 Hz, 2H), 7.75 (dd, J = 24.0, 8.7 Hz, 2H), 7.50 (t, J = 7.5 Hz, 2H), 7.30 (t, J = 6.8 Hz, 2H), 7.01 (t, J = 7.7 Hz, 2H), 5.59 (s, 1H), 4.47 (d, J = 7.7 Hz, 1H), 3.77 (d, J = 3.5 Hz, 1H), 3.71 (d, J = 7.0 Hz, 2H), 3.69 - 3.65 (m, 1H), 3.56 - 3.47 (m, 2H), 2.90 (s, 6H).

[0450] Example 84: Preparation of Compound 84

[0451]

[0452] Prepared by the general synthetic method B in the same manner as in Example 55. Yield: 44%.

[0453] 11H NMR (600 MHz, Methanol-d4) δ 8.14 (t, J = 7.4 Hz, 2H), 8.04 (d, J = 8.3 Hz, 2H), 7.75 (dd, J = 25.9, 8.6 Hz, 2H), 7.50 (t, J = 7.6 Hz, 2H), 7.30 (t, J = 7.7 Hz, 2H), 7.02 (t, J = 7.1 Hz, 2H), 5.59 (s, 1H), 4.43 (td, J = 27.0, 25.7, 7.5 Hz, 1H), 3.78 (d, J = 17.4 Hz, 2H), 3.74 - 3.62 (m, 2H), 3.48 (d, J = 6.8 Hz, 2H), 2.90 (s, 6H).

[0454] Example 85: Preparation of Reference Compound 1

[0455]

[0456] Prepared by the general synthetic method B, in the same manner as in Example 40. Yield: 73%.

[0457] The crude product of 1-O-(2,3,4,6-tetraacetyl-D-glucoside)-disodium malonate (429 mg) was dissolved in 3 mL of water. Under nitrogen protection, trans-(1R,2R)-cyclohexanediamine platinum nitrate (570 mg, 1.31 mmol) was dissolved in 4 mL of water and added to the above reaction solution. The pH was adjusted to 7.0 with sodium hydroxide solution, and then the temperature was raised to 60 °C and reacted for 2 hours. After the reaction was completed, the precipitate was removed by centrifugation, the supernatant was collected, freeze-dried using a freeze dryer, and separated by semi-preparative high performance liquid chromatography to obtain 565 mg of the final product, a white solid. Yield: 73%.

[0458] 1 1H NMR (600 MHz, D2O) δ 5.86 (s, 1H), 4.65 (d, J = 7.7 Hz, 1H), 3.92 (d, J = 12.3 Hz, 1H), 3.77 - 3.73 (m, 1H), 3.53 - 3.43 (m, 4H), 2.39 (dd, J = 5.3, 3.7 Hz, 2H), 2.04 (d, J = 11.3 Hz, 2H), 1.57 (d, J = 9.7 Hz, 2H), 1.34 - 1.26 (m, 2H), 1.15 (t, J = 10.1 Hz, 2H).

[0459] Example 86: Preparation of Reference Compound 2

[0460]

[0461] Prepared in the same manner as in Example 85. Yield: 30%.

[0462] 1 1H NMR (600 MHz, D2O) δ 5.97 (s, 1H), 4.67 (d, J = 7.0 Hz, 1H), 3.99 (d, J = 2.5 Hz, 1H), 3.90 - 3.82 (m, 2H), 3.79 - 3.72 (m, 3H), 2.47 (dd, J = 5.2, 3.7 Hz, 2H), 2.11 (d, J = 11.3 Hz, 2H), 1.64 (d, J = 9.1 Hz, 2H), 1.37 (dd, J = 7.7, 3.4 Hz, 2H), 1.22 (t, J = 10.4 Hz, 2H).

[0463] Example 87: Preparation of Reference Compound 3

[0464]

[0465] Prepared by the same method as in Example 85. Yield: 49%.

[0466] 1 1H NMR (600 MHz, D2O) δ 5.83 (s, 1H), 5.09 (d, J = 1.5 Hz, 1H), 4.21 (dd, J = 3.4, 1.7 Hz, 1H), 4.06 (dd, J = 9.4, 3.5 Hz, 1H), 3.99 (dd, J = 12.0, 1.8 Hz, 1H), 3.83 (dd, J = 12.0, 6.3 Hz, 1H), 3.81 - 3.76 (m, 1H), 3.73 (t, J = 9.7 Hz, 1H), 2.50 - 2.41 (m, 2H), 2.09 (dd, J = 12.3, 10.6 Hz, 2H), 1.65 - 1.60 (m, 2H), 1.41 - 1.26 (m, 2H), 1.25 - 1.11 (m, 2H).

[0467] Example 88: Preparation of Reference Compound 4

[0468]

[0469] Prepared by the same method as in Example 85. Yield: 40%.

[0470] 11H NMR (600 MHz, D2O) δ 5.83 (s, 1H), 4.63 (d, J = 7.8 Hz, 1H), 3.90 (d, J = 12.5 Hz, 1H), 3.76 - 3.70 (m, 1H), 3.49 - 3.42 (m, 4H), 2.37 (d, J = 8.9 Hz, 2H), 2.02 (d, J = 11.4 Hz, 2H), 1.55 (d, J = 8.9 Hz, 2H), 1.28 (dd, J = 22.1, 10.4 Hz, 2H), 1.13 (t, J = 10.3 Hz, 2H).

[0471] Example 89: Preparation of Reference Compound 5

[0472]

[0473] Prepared by the same method as in Example 85. Yield: 43%.

[0474] 1 1H NMR (600 MHz, DMSO-d6) δ 6.10 (d, J = 9.6 Hz, 1H), 6.00 (d, J = 10.4 Hz, 1H), 5.41 (t, J = 9.1 Hz, 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 = 7.7 Hz, 1H), 3.60 - 3.47 (m, 3H), 3.33 (dd, J = 13.0, 7.0 Hz, 2H), 2.17 - 2.02 (m, 2H), 1.80 (s, 2H), 1.44 (s, 2H), 1.21 (d, J = 9.8 Hz, 2H), 1.02 - 0.96 (m, 2H).

[0475] Example 90: Preparation of Reference Compound 6

[0476]

[0477] Prepared by the same method as in Example 85. Yield: 35%.

[0478] 1 1H NMR (600 MHz, D2O) δ 5.82 (s, 1H), 5.10 (s, 1H), 4.24 - 4.19 (m, 1H), 4.06 (dd, J = 9.3, 3.4 Hz, 1H), 3.98 (d, J = 11.5 Hz, 2H), 1.63 (d, J = 11.6 Hz, 2H), 1.41 - 1.28 (m, 2H), 1.25 - 1.13 (m, 2H).

[0479] Example 91: Preparation of Reference Compound 7

[0480]

[0481] Prepared by the general synthesis method B, in the same manner as in Example 40. Yield: 26%.

[0482] Dissolve the crude product of 1-O-(2,3,4,6-tetraacetyl-D-glucoside)-disodium malonate (178 mg) in 2 mL of water. Under nitrogen protection, dissolve (R)-3-aminopiperidine platinum sulfate (145 mg, 0.55 mmol) in 2 mL of water, add it to the above reaction solution, adjust the pH to 8.0 with barium hydroxide solution, then raise the temperature to 35 °C and react for 4 hours. After the reaction is completed, use a centrifuge to remove the precipitate, collect the supernatant, freeze-dry it with a freeze dryer, and separate it by semi-preparative high performance liquid chromatography to obtain 51 mg of the final product, a white solid. Yield: 26%.

[0483] 1 H NMR (600 MHz, D2O) δ 5.80, 5.75 (s, 1H), 4.62 (s, 1H), 3.88 (d, J = 12.4 Hz, 1H), 3.70 (d, J = 8.4 Hz, 1H), 3.49 - 3.36 (m, 4H), 3.34 - 3.23 (m, 1H), 3.18 - 3.09 (m, 1H), 3.05 (d, J = 11.1 Hz, 1H), 2.94 (s, 1H), 2.60 - 2.43 (m, 2H), 1.86 - 1.75 (m, 2H), 1.65 (d, J = 12.2 Hz, 1H).

[0484] Example 91: Preparation of Reference Compound 8

[0485]

[0486] Prepared in the same manner as in Example 85. Yield: 21%.

[0487] 1 H NMR (600 MHz, D2O) δ 5.82, 5.79 (s, 1H), 4.64 (dd, J = 13.8, 7.7 Hz, 1H), 3.89 (d, J = 12.1 Hz, 1H), 3.71 (dd, J = 11.3, 6.5 Hz, 1H), 3.51 - 3.40 (m, 4H), 3.36 - 3.23 (m, 1H), 3.16 (t, J = 14.8 Hz, 1H), 3.06 (d, J = 10.9 Hz, 1H), 2.96 (s, 1H), 2.62 - 2.45 (m, 2H), 1.88 - 1.77 (m, 2H), 1.66 (d, J = 12.5 Hz, 1H).

[0488] Example 92: Preparation of Reference Compound 9

[0489]

[0490] Prepared by the same method as in Example 85. Yield: 35%.

[0491] 1 H NMR (600 MHz, D2O) δ 5.86 (s, 0.3H), 5.80 (s, 0.7H), 4.70 (d, J = 8.0 Hz, 1H), 3.98 (d, J = 12.4 Hz, 1H), 3.84 - 3.78 (m, 2H), 3.58 - 3.47 (m, 4H), 3.30 - 3.21 (m, 3H), 2.45 (d, J = 10.4 Hz, 1H), 2.14 - 3.03 (m, 2H).

[0492] Example 93: Preparation of Reference Compound 10

[0493]

[0494] Prepared by the same method as in Example 85. Yield: 41%.

[0495] 1 H NMR (600 MHz, D2O) δ 5.89 (s, 0.5H), 5.84 (s, 0.5H), 4.73 (d, J = 7.7 Hz, 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).

[0496] Example 94: Preparation of Reference Compound 11

[0497]

[0498] Prepared by the same method as in Example 40 using General Synthetic Method B. Yield: 31%.

[0499] Dissolve the crude product of 1-O-(2,3,4,6-tetraacetyl-D-glucoside)-disodium malonate (109 mg) in 2 mL of water. Under nitrogen protection, dissolve trans-(1R,2R)-1,2-diphenylethylenediamine platinum dinitrate (178 mg, 0.33 mmol) in 4 mL of methanol, add it to the above reaction solution, adjust the pH to 7.0 with sodium hydroxide solution, and then raise the temperature to 60 °C and react for 2 hours. After the reaction is completed, use a centrifuge to remove the precipitate, collect the supernatant, freeze-dry it with a freeze dryer, and separate it by semi-preparative high-performance liquid chromatography to obtain 71 mg of the final product, a yellow solid. The yield is 31%.

[0500] 1 H NMR (600 MHz, DMSO-d6) δ 7.30 - 7.26 (m, 4H), 7.18 - 7.14 (m, 6H), 6.86 (d, J = 7.2 Hz, 1H), 6.71 (d, J = 7.5 Hz, 1H), 6.14 (t, J = 9.8 Hz, 1H), 5.97 (t, J = 9.8 Hz, 1H), 5.45 (s, 1H), 5.36 (s, 1H), 5.06 - 5.03 (m, 2H), 4.84 (d, J = 4.7 Hz, 1H), 4.23 (d, J = 7.9 Hz, 1H), 3.95 - 3.86 (m, 2H), 3.76 (dd, J = 11.4, 2.8 Hz, 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).

[0501] Example 95: Preparation of Reference Compound 12

[0502]

[0503] Prepared by the same method as in Example 85. The yield is 23%.

[0504] 1 H NMR (400 MHz, DMSO-d6) δ 7.27 (d, J = 6.0 Hz, 4H), 7.15 (d, J = 6.4 Hz, 6H), 6.84 (d, J = 8.4 Hz, 1H), 6.64 (d, J = 7.7 Hz, 1H), 6.13 - 6.05 (m, 2H), 5.41 (s, 1H), 5.22 (s, 1H), 4.83 - 4.75 (m, 2H), 4.54 (s, 1H), 4.16 (d, J = 7.5 Hz, 1H), 3.91 (d, J = 6.3 Hz, 2H), 3.65 - 3.48 (m, 4H), 3.33 - 3.31 (m, 1H).

[0505] Example 96: Preparation of Reference Compound 13

[0506]

[0507] Prepared by the same method as in Example 85. Yield: 26%.

[0508] 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).

[0509] Example 97: Preparation of Reference Compound 14

[0510]

[0511] Prepared by the same method as in Example 85. Yield: 35%.

[0512] 1 H 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).

[0513] Example 98: Preparation of Reference Compound 15

[0514]

[0515] Prepared by the same method as in Example 85. Yield: 21%.

[0516] 1 H NMR (600 MHz, DMSO-d6) δ 7.27 (d, J = 7.8 Hz, 4H), 7.18 - 7.14 (m, 6H), 6.89 - 6.79 (m, 1H), 6.75 - 6.65 (m, 1H), 6.10 (t, J = 10.2 Hz, 1H), 5.96 (t, J = 10.1 Hz, 1H), 5.42 (s, 1H), 4.79 (s, 2H), 4.50 (s, 1H), 4.18 (d, J = 7.8 Hz, 1H), 3.90 (dt, J = 6.7, 3.9 Hz, 2H), 3.60 (s, 1H), 3.58 - 3.54 (m, 2H), 3.43 - 3.34 (m, 3H).

[0517] Example 99: Preparation of Reference Compound 16

[0518]

[0519] Prepared by the same method as in Example 85. Yield: 29%.

[0520] 1 H NMR (600 MHz, DMSO-d6) δ 7.27 - 7.24 (m, 4H), 7.17 - 7.13 (m, 6H), 6.72 (d, J = 7.4 Hz, 1H), 6.63 - 6.53 (m, 1H), 6.01 (dd, J = 9.1, 6.4 Hz, 2H), 5.24 (s, 1H), 4.76 (d, J = 1.2 Hz, 1H), 4.69 (s, 2H), 4.54 (d, J = 3.0 Hz, 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 = 9.2 Hz, 1H), 3.55 (dd, J = 11.0, 4.6 Hz, 1H), 3.48 (t, J = 9.3 Hz, 1H), 3.41 - 3.38 (m, 1H).

[0521] Example 100: Preparation of Reference Compound 17

[0522]

[0523] Prepared by the same method as in Example 85. Yield: 17%.

[0524] 11H NMR (400 MHz, D2O) δ 7.56 - 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).

[0525] Example 101: Preparation of Reference Compound 18

[0526]

[0527] Prepared by the same method as in Example 85. Yield: 14%.

[0528] 1 1H NMR (400 MHz, D2O) δ 7.54 - 7.39 (m, 6H), 7.37 - 7.30 (m, 2H), 5.92 (d, J = 6.8 Hz, 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).

[0529] Example 102: Preparation of Reference Compound 19

[0530]

[0531] Prepared by the same method as in Example 85. Yield: 15%.

[0532] 1 1H NMR (400 MHz, D2O) δ 7.53 - 7.37 (m, 6H), 7.36 - 7.26 (m, 2H), 5.73 (d, J = 12.3 Hz, 1H), 4.98 (d, J = 1.7 Hz, 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).

[0533] Test Example

[0534] Test Example 1: Construction of Drug - Resistant Cell Line

[0535] (1) Cell Culture

[0536] Human colorectal cancer cells HT29 and oxaliplatin-resistant HT29 / Oxa were cultured in RPMI-1640 medium supplemented with 10% fetal bovine serum in an incubator at 37°C with 5% CO2. 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 an incubator at 37°C with 5% CO2.

[0537] (2) Construction of drug-resistant cell lines

[0538] The drug concentration gradient increment method was used to construct an oxaliplatin-resistant tumor cell line. The specific experimental procedure was as follows: In the initial stage, using the half-inhibitory concentration of oxaliplatin for non-resistant cells as the starting concentration, the cells were treated with the drug in culture for 48 hours. Then, the culture supernatant was discarded, and fresh drug-free culture medium was added for continued culture. After the cells resumed normal growth, they were digested and passaged. Repeated drug stimulation, medium replacement, and passage 3 times could obtain primary drug-resistant cells. On this basis, with a 1.25-fold increase in drug concentration each time as the benchmark, the drug concentration was gradually increased until the half-inhibitory concentration of the induced drug-resistant cells was increased to more than 5 times that of non-resistant cells to obtain the target drug-resistant cell line. Before subsequent biological tests, the drug-resistant tumor cells were washed with PBS to remove the drug and cultured and passaged 3 times in drug-free culture medium. Compared with non-resistant HT29 cells, the 50% cell inhibitory concentration IC 50 increased by 53 times, and the drug resistance coefficient was 53.

[0539] Using the same method, the cisplatin-resistant cell line A549 / Cis of human lung cancer cells A549 was prepared. Compared with non-resistant A549 cells, the 50% cell inhibitory concentration IC 50 increased by 10 times, and this value was defined as the drug resistance coefficient of tumor cells to the drug.

[0540] Experimental Example 2: Anticancer efficacy of tumor cells in vitro

[0541] (1) Test method:

[0542]

Cytotoxicity test

[0543] The cytotoxicity experiment was tested by the MTT method.

[0544] Collect tumor cells in the logarithmic growth phase, adjust the cell suspension concentration, add 100 μL of cell suspension to each well of a 96-well flat-bottom plate, with a plating density of approximately 10,000 - 100,000 cells / well (fill the edge wells with sterile PBS). Incubate at 5% CO2 and 37 °C until the cells adhere. Add drug solutions with different concentration gradients, 100 μL per well, and set 4 replicate wells. Incubate under the conditions of 5% CO2 and 37 °C for 72 hours, and observe under an inverted microscope. Add the prepared MTT solution (5 mg / ml) to the 96-well plate, 20 μL per well, mix well, incubate at 37 °C and 5% CO2 for 4 h, then discard the liquid in the plate. Add 150 μL of DMSO to each well, shake for 3 minutes, transfer to a microplate reader and measure the OD value (optical density value) at 490 nm. Set a control group in the experiment, that is, do not add the active ingredient to be tested under the same above conditions, and finally obtain the OD value measured at 490 nm for the tumor cells.

[0545]

Half maximal inhibitory concentration, IC 50

[0546] 1) Cell survival rate (%) = (OD value of the drug treatment group / OD value of the control group) × 100. Repeat the experiment for 4 groups at each drug concentration, and calculate the average OD value to obtain the cell survival rate.

[0547] 2) Calculate the cell survival rate at each drug concentration and plot it against the drug concentration. Use this to judge the efficacy of different drug concentrations in inhibiting tumor cell proliferation.

[0548] 3) The drug concentration corresponding to a cell survival rate of 50% of the control group is the half maximal inhibitory concentration of the drug against tumor cells, that is, the IC 50 value of the drug.

[0549]

Drug resistance coefficient

[0550] The drug resistance coefficient refers to the multiple by which the half maximal inhibitory concentration of a drug against drug-resistant cells is increased compared to that against non-drug-resistant cells. Calculate according to the following formula:

[0551] Drug resistance coefficient (RI) = IC of drug-resistant cells 50 / IC of non-drug-resistant cells 50 (2) Experimental results:

[0552] Reference compounds and their anti-drug resistance test results against drug-resistant cells:

[0553]

[0554]

[0555] Table 1 Anti-cisplatin resistance and anti-oxaliplatin resistance experimental results of reference compounds 1 - 6 (IC 50Value, unit: micromole)

[0556]

[0557] The results in Table 1 show that the novel platinum oxides derived from oxaliplatin chelating ligands (chiral cyclohexanediamine) do not produce cross-resistance against cells after cisplatin resistance, but show strong resistance similar to oxaliplatin against tumor cells after oxaliplatin resistance.

[0558]

[0559] Table 2 Anti-cisplatin resistance and anti-oxaliplatin resistance experimental results of reference compounds 7-10 (IC 50 Value, unit: micromole)

[0560]

[0561] The results in Table 2 show that the novel platinum oxides derived from different chiral cyclic propanediamine chelating ligands do not produce cross-resistance against cells after cisplatin resistance and show certain resistance against tumor cells after oxaliplatin resistance.

[0562]

[0563] Table 3 Anti-cisplatin resistance and anti-oxaliplatin resistance experimental results of reference compounds 11-16 (IC 50 Value, unit: micromole)

[0564]

[0565] The results in Table 3 show that the novel platinum oxides derived from different chiral diphenylethylenediamine chelating ligands do not produce cross-resistance against cells after cisplatin resistance, but show resistance similar to oxaliplatin against tumor cells after oxaliplatin resistance.

[0566]

[0567] Table 4 Anti-cisplatin resistance and anti-oxaliplatin resistance experimental results of reference compounds 17-19 (IC 50 Value, unit: micromole)

[0568]

[0569] The results in Table 4 show that the novel sugar-conjugated platinum oxides derived from 1,1'-biphenyl-2,2'-diamine as the chelating ligand lose their anti-tumor efficacy against oxaliplatin-sensitive colorectal cancer cells and colorectal cancer tumor cells after oxaliplatin resistance.

[0570] Table 5 Pharmacodynamic experimental results of 1,1'-binaphthalene-2,2'-diamine platinum oxide against oxaliplatin-resistant tumors (human colon cancer HT29 / Oxa) (IC 50 value, unit: micromole)

[0571]

[0572]

[0573] The results showed that 1,1'-binaphthalene-2,2'-diamine platinum oxide in the examples had equal or even stronger inhibitory effects on oxaliplatin-resistant and non-resistant tumor cells.

[0574] Test Example 3: Antitumor effect of drug combination

[0575] (1) Test method:

[0576]

Tumor cells

[0577] Human lung cancer (A549), human ovarian cancer (SKOV3), human liver cancer (Hep3B), human colorectal cancer (HT29)

[0578]

Cytotoxicity test

[0579] The cytotoxicity experiment was tested by the MTT method.

[0580] Collect tumor cells in the logarithmic phase, adjust the cell suspension concentration, add 100 μL of cell suspension to each well of a 96-well flat-bottom plate, and the plating density is about 10,000 - 100,000 cells / well (the edge wells are filled with sterile PBS). Incubate at 5% CO2, 37 °C until the cells adhere. Add drug solutions with different concentration gradients, 100 μL per well, and set 4 replicate wells. Incubate at 5% CO2, 37 °C for 72 hours, and observe under an inverted microscope. Add the prepared MTT solution (5 mg / ml) to the 96-well plate, 20 μL per well, mix well, incubate at 37 °C, 5% CO2 for 4 h, then discard the liquid in the plate, add 150 μL of DMSO to each well, shake for 3 minutes, transfer to an enzyme-linked immunosorbent assay (ELISA) reader and detect the OD value (optical density value) at 490 nm. A control group was set up in the experiment, that is, the tested active ingredient was not added under the same conditions as above, and finally the OD value of the tumor cells was detected at 490 nm.

[0581] Cell survival rate (%) = (OD value of the drug treatment group / OD value of the control group) × 100.

[0582]

Combined effect

[0583] Combined effect (%) = {

(Cell survival rate of the drug in the example - Cell survival rate after combination) + (Cell survival rate of the combined component - Cell survival rate after combination)

[0584] (2) Experimental results:

[0585] Table 6 Experimental results of the combined effect of Compound 1

[0586]

[0587]

[0588] In the table: ◎ indicates that the combined effect > 300%; ○ indicates that the combined effect is between 100% and 300%. Table 7 Experimental results of the combined effect of Compound 3

[0589]

[0590] In the table: ◎ indicates that the combined effect > 300%; ○ indicates that the combined effect is between 100% and 300%. Table 8 Experimental results of the combined effect of Compound 33

[0591]

[0592]

[0593] In the table: ◎ indicates that the combined effect > 300%; ○ indicates that the combined effect is between 100% and 300%. Table 9 Experimental results of the combined effect of Compound 37

[0594]

[0595] In the table: ◎ indicates that the combined effect > 300%; ○ indicates that the combined effect is between 100% and 300%. Table 10 Experimental results of the combined effect of Compound 51

[0596]

[0597]

[0598] In the table: ◎ indicates that the combined effect > 300%; ○ indicates that the combined effect is between 100% and 300%. Table 11 Experimental results of the combined effect of Compound 55

[0599]

[0600] In the table: ◎ indicates that the combined effect > 300%; ○ indicates that the combined effect is between 100% and 300%. Table 12 Experimental results of the combined effect of Compound 66

[0601]

[0602] In the table: ◎ indicates that the combined effect > 300%; ○ indicates that the combined effect is between 100% and 300%. Experimental results of the combined effect of Compound 69 in Table 13

[0603]

[0604] In the table: ◎ indicates that the combined effect > 300%; ○ indicates that the combined effect is between 100% and 300%. Experimental results of the combined effect of Compound 71 in Table 14

[0605]

[0606] In the table: ◎ indicates that the combined effect > 300%; ○ indicates that the combined effect is between 100% and 300%. Experimental results of the combined effect of Compound 77 in Table 15

[0607]

[0608]

[0609] In the table: ◎ indicates that the combined effect > 300%; ○ indicates that the combined effect is between 100% and 300%. Experimental results of the combined effect of Compound 80 in Table 16

[0610]

[0611] In the table: ◎ indicates that the combined effect > 300%; ○ indicates that the combined effect is between 100% and 300%. Experimental results of the combined effect of Compound 83 in Table 17

[0612]

[0613]

[0614] In the table: ◎ indicates that the combined effect > 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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