Camptothecin derivatives substituted at the 7- and 20-positions and uses thereof

Abstract

The application provides a 7-position and 20-position substituted camptothecin derivative and application thereof, and belongs to the technical field of medicines. The 7-position and 20-position substituted camptothecin derivative provided by the application, or a stereoisomer and a pharmaceutically acceptable salt thereof has a structure shown in formula (I) or formula (II). By introducing a methylenedioxy group at 10, 11-positions and introducing different substituent groups at 7-positions or 20-positions through 1, 2, 3-triazole on the basis of a traditional camptothecin structure, a camptothecin derivative with excellent antitumor activity can be obtained. The obtained 7-position and 20-position substituted camptothecin derivative has clear structural characteristics, is convenient to synthesize, and is simple, fast and convenient to purify, and can be used for preparing a medicine for preventing or treating cancer, and has a wide application prospect.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a novel class of camptothecin derivatives with 7- and 20-position substitutions and their uses. Background Technology

[0002] Camptothecin derivatives are hailed as one of the three major discoveries in anticancer drugs in the 1990s, demonstrating broad-spectrum antitumor activity and significant research and application value. Early camptothecin compounds acted by forming a ternary complex with Top I and DNA, blocking DNA replication and transcription, but suffered from low selectivity and significant toxicity. With technological advancements, molecularly targeted antitumor drugs have become a research hotspot in recent years. These drugs can selectively act on signal transduction pathways related to tumor cell differentiation and proliferation. Therefore, how to use camptothecin as a lead compound and modify its structure to develop more efficient and less toxic antitumor candidate compounds is a pressing problem in this field. Summary of the Invention

[0003] This invention provides camptothecin derivatives with 7- and 20-position substitutions and their uses. By introducing methylenedioxy groups at the 10 and 11-positions and introducing different substituent groups at the 7- or 20-positions via 1, 2, 3-triazoles on the basis of the traditional camptothecin structure, camptothecin derivatives with excellent antitumor activity can be obtained.

[0004] To achieve the above objectives, the present invention provides a camptothecin derivative, or its stereoisomers and pharmaceutically acceptable salts, substituted at the 7- and 20-positions, having the structure shown in formula (I) or formula (II):

[0005]

[0006] Formula (I) Formula (II)

[0007] In the formula, R represents a benzyl structure, a chain alkyl structure, or a heterocyclic structure, wherein:

[0008] When R is a benzyl structure, it is a benzyl structure with no substitution, monosubstituted or polysubstituted on the benzene ring;

[0009] When R is a chain alkyl structure, the end of the chain alkyl structure may be unsubstituted or substituted, and the substitution may be monosubstituted or polysubstituted.

[0010] When R is a heterocyclic structure, the heterocyclic ring can be unsubstituted, monosubstituted, or polysubstituted.

[0011] The stereoisomers include: conformational isomers, optical isomers (such as enantiomers and diastereomers), and geometric isomers (such as cis-trans isomers). These isomers or combinations thereof may exist as racemic mixtures, individual enantiomers, individual diastereomers, mixtures of diastereomers, or cis or trans isomers.

[0012] The pharmaceutically acceptable salts referred to are salts formed by the reaction of the above-mentioned compounds with inorganic acids, organic acids, alkali metals, or alkaline earth metals. These salts include (but are not limited to): (1) salts formed with the following inorganic acids: such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; (2) salts formed with the following organic acids: such as acetic acid, lactic acid, citric acid, succinic acid, fumaric acid, gluconic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, oxalic acid, succinic acid, tartaric acid, maleic acid, or arginine; (3) other salts, including those formed with alkali metals or alkaline earth metals (such as sodium, potassium, calcium, or magnesium). It can be in the form of salts, ammonium salts or water-soluble amine salts (such as N-methylglucosamine salt), lower alkanol ammonium salts and other pharmaceutically acceptable amine salts (such as methylamine salt, ethylamine salt, propylamine salt, dimethylamine salt, trimethylamine salt, diethylamine salt, triethylamine salt, tert-butylamine salt, ethylenediamine salt, hydroxyethylamine salt, dihydroxyethylamine salt, trihydroxyethylamine salt, and amine salts formed from morpholine, piperazine, lysine, respectively), or other conventional "prodrug" forms.

[0013] Furthermore, the present invention also provides precursors to the above-mentioned compounds, wherein the precursors, when taken by an appropriate method, are metabolized or chemically reacted in the patient's body to transform into compounds of the general formula included in the present invention, as well as salts or solutions of the compounds. Precursors to the compounds include, but are not limited to, carboxylic acid esters, carbonates, phosphate esters, nitrate esters, sulfate esters, sulfone esters, sulfoxide esters, amino compounds, carbamates, azo compounds, phosphoramides, glucosides, ethers, acetals, etc.

[0014] Preferably, when R is a benzyl structure and there are substituents on the benzene ring, the substituents are selected from any one of halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted ester, substituted or unsubstituted ether, substituted or unsubstituted aryl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted amino, and substituted or unsubstituted hydroxyl.

[0015] Preferably, when R is a benzyl structure without substitution, monosubstituted or polysubstituted on the benzene ring, R in formula (I) is selected from any of the following groups:

[0016] .

[0017] Preferably, when R is a benzyl structure with no substitution, monosubstituted or polysubstituted on the benzene ring, R in formula (II) is selected from any of the following groups:

[0018] .

[0019] Preferably, when the chain alkyl structure has a substituent at the end, the substituent is selected from any one of halogen, substituted or unsubstituted oxygen atom, substituted or unsubstituted nitrogen atom, substituted or unsubstituted alkyl group, or substituted or unsubstituted saturated heterocyclic group.

[0020] Preferably, when R is a chain alkyl structure with an unsubstituted or substituted end, R in formula (I) is selected from any of the following groups:

[0021] .

[0022] Preferably, when R is a chain alkyl structure with an unsubstituted or substituted end, R in formula (II) is selected from any of the following groups:

[0023] .

[0024] The present invention also provides the use of camptothecin derivatives with 7- and 20-position substitutions according to any of the above technical solutions in the preparation of drugs for the prevention and / or treatment of cancer.

[0025] Preferably, the compound is selected from at least one of I-3 ~ I-8, I-10, I-11, I-13 ~ I-18, I-20 ~ I-22, I-24, I-25, I-45 ~ I-49 and II-2 ~ II-5.

[0026] Preferably, the cancer is selected from at least one of lung cancer, colon cancer, liver cancer, prostate cancer, leukemia, and breast cancer.

[0027] The present invention also provides an antibody-drug conjugate (ADC) or a peptide-drug conjugate (PDC), wherein the camptothecin derivative with 7- and 20-position substitution as described in any of the above technical solutions is used as the highly active small molecule part of the drug.

[0028] Compared with the prior art, the advantages and positive effects of the present invention are as follows:

[0029] The 7- and 20-substituted camptothecin derivatives provided by this invention are obtained by introducing methylenedioxy groups at the 10 and 11 positions and different substituent groups at the 7- or 20- positions via 1,2,3-triazoles, based on the traditional camptothecin structure. These derivatives exhibit excellent antitumor activity. The resulting 7- and 20-substituted camptothecin derivatives have clear structural characteristics, are convenient to synthesize, and are simple and rapid to purify. They can be used to prepare drugs for the prevention or treatment of cancer and have broad application prospects. Attached Figure Description

[0030] Figure 1 A simplified synthetic route diagram of the compound of formula (I) provided in the embodiments of the present invention;

[0031] Figure 2 A simplified synthetic route diagram of the compound of formula (II) provided in the embodiments of the present invention;

[0032] Figure 3 The inhibition rate of compound I-3-I-49 provided in the embodiments of the present invention against A549 cell line at 1 µM;

[0033] Figure 4 The inhibition rate of compound II-2-II-7 provided in the embodiments of the present invention against A549 cell line at 1 µM;

[0034] Figure 5 The inhibition rates of some of the I-series and II-series compounds provided in this embodiment of the invention on the NCI-H446 cell line at 1 µM. Detailed Implementation

[0035] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0036] Unless otherwise stated, the scientific and technical terms used herein shall have the meanings commonly understood by one of ordinary skill in the art. However, the following terms shall have the following definitions:

[0037] "Cancer" refers to a broad class of diseases characterized by the uncontrolled growth of abnormal cells within the body. Uncontrolled cell division and growth lead to the formation of malignant tumors or cells that invade adjacent tissues and can also metastasize to distant parts of the body via the lymphatic system or bloodstream. In this invention, another equivalent description of "treating cancer" is "treating tumors," "anti-cancer," or "anti-tumor."

[0038] Cancer is an uncontrolled growth of cells that impairs the normal function of the body's organs and systems. A subject with cancer is one with objectively measurable amounts of cancer cells present in their body. Subjects at risk of developing cancer are those who are predisposed to cancer (e.g., based on family history or genetic predisposition), or those exposed to radiation or other carcinogenic agents.

[0039] The compounds of this invention can be used to treat subjects with a variety of cancers or at risk of developing cancer. Examples of such cancers include breast cancer, prostate cancer, lung cancer, ovarian cancer, cervical cancer, skin cancer, melanoma, colon cancer, stomach cancer, liver cancer, esophageal cancer, kidney cancer, pharyngeal cancer, thyroid cancer, pancreatic cancer, testicular cancer, brain cancer, bone cancer, and blood cancers (such as leukemia, chronic lymphocytic leukemia), etc. Other cancers include, but are not limited to, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain and central nervous system (CNS) cancer, cervical cancer, choriocarcinoma, colorectal cancer, connective tissue cancer, digestive system cancer, endometrial cancer, esophageal cancer, eye cancer, head and neck cancer, intraepithelial neoplasia, laryngeal cancer, lung cancer (small cell, large cell), lymphoma (including Hodgkin's lymphoma and non-Hodgkin's lymphoma); melanoma; neuroblastoma; oral cancer (e.g., lip, tongue, mouth and pharynx); retinoblastoma; rhabdomyosarcoma; respiratory system cancer; sarcoma; uterine cancer; urinary system cancer; and other cancers and sarcomas.

[0040] As an example of tumor treatment, compared to untreated subjects, a therapeutically effective amount or dose of the drug preferably inhibits cell growth or tumor growth by at least about 20%, more preferably at least about 40%, even more preferably at least about 60%, and still more preferably at least about 80%. In the most preferred embodiment, a therapeutically effective amount or dose of the drug completely inhibits cell growth or tumor growth, i.e., preferably inhibits cell growth or tumor growth by 100%. The ability of the compound to inhibit tumor growth can be evaluated in animal model systems, which can predict efficacy in human tumors. Alternatively, this property of the composition can be assessed by testing the compound's ability to inhibit cell growth, such inhibition being measured in vitro using assays known to those skilled in the art. In other preferred embodiments of the invention, tumor regression can be observed and last for at least about 20 days, more preferably at least about 40 days, or even more preferably at least about 60 days.

[0041] "Treatment" for a subject refers to any type of intervention or treatment performed on the subject with the aim of reversing, reducing, improving, inhibiting, slowing down or preventing the occurrence, progression, development, severity or recurrence of symptoms, complications, symptoms or biochemical indicators related to the disease.

[0042] The present invention will be further described in detail below with reference to the embodiments.

[0043] The compound of formula (I) provided by this invention is prepared by the following method, and the simplified synthetic route is shown in the figure below. Figure 1 As shown, it includes the following steps:

[0044] Starting with 10,11-methylenedioxycamptothecin (FL118), in FeSO4 In the presence of 7H2O and 30% H2O2, chloroacetaldehyde undergoes a Minisci reaction in 75% H2SO4 solution to give intermediate I-1; subsequently, it undergoes a nucleophilic substitution reaction with propargylamine in dry DMF to give intermediate I-2; finally, intermediate I-2 reacts with various substituted azides in CuSO4. A Click reaction was carried out in DCM:H2O (1:1) under the catalysis of 5H2O and VcNa to give compounds I-3 to I-49 with 7-position substitution.

[0045] The compound of formula (II) provided by this invention was prepared by the following method, and the simplified synthetic route is shown in the figure below. Figure 2 As shown, it includes the following steps:

[0046] Starting with 10,11-methylenedioxycamptothecin (FL118), it reacts with 3-bromopropyne in dry DMF under the action of a strong base NaH to give intermediate II-1; subsequently, it undergoes a Click reaction with various substituted azides to give compounds II-2 to II-7 with 20-position substitution.

[0047] Based on the above methods, a series of novel camptothecin derivatives were prepared by introducing methylenedioxy groups at the 10 and 11-positions of the parent ring, and by introducing different substituents at the 7- or 20-position via 1, 2, 3-triazoles. Examples of R in this class of compounds are shown in Table 1 below:

[0048]

[0049] Formula (I) Formula (II)

[0050] Table 1

[0051]

[0052] The following examples illustrate this:

[0053] Example 120 ( S Preparation of 7-chloromethyl-10,11-methylenedioxycamptothecin (compound I-1)

[0054] In a 250 mL three-necked flask, 10,11-methylenedioxycamptothecin (FL118) (1.57 g, 4 mmol), chloroacetaldehyde (0.63 g, 8 mmol), ferrous sulfate (1.8 g, 6.4 mmol), and 75% sulfuric acid solution (50 mL) were added. The mixture was stirred at room temperature for 30 min, then 30% hydrogen peroxide (8 mL) was added, and the reaction was continued with stirring. After the reaction was confirmed to be complete by TLC, 150 mL of water was added, and the mixture was extracted three times with DCM. The organic phase was dried over anhydrous MgSO4, filtered, and the filtrate was concentrated under reduced pressure to remove the filtrate. The residue was purified by column chromatography to give 1.1 g of a yellow solid compound I-1, with a yield of 40%. mp 237-238℃. 1 H NMR (400 MHz, DMSO- d 6) d 7.77 – 7.74 (m, 1H), 7.55 (s, 1H), 7.24 (s, 1H), 6.50 (s, 1H), 6.32 (s, 2H), 5.42 (s, 2H), 5.35 (s, 2H), 5.29 (s, 2H), 1.86 (s, 2H), 0.88 (s, 3H). ESI-MS(m / z): 441.08 [M+H] + .

[0055] Example 220 ( S Preparation of 7-(2-propargylamino)methyl 10,11-methylenedioxycamptothecin (compound I-2)

[0056] Intermediate I-1 (1.8 g, 4 mmol), propargylamine (1.1 g, 20 mmol), and dried DMF (20 mL) were added sequentially to a 100 mL round-bottom flask. The mixture was stirred at room temperature for 2 h. After the reaction was confirmed to be complete by TLC, the mixture was poured into water and extracted three times with DCM. The organic phase was washed with saturated brine and dried over anhydrous MgSO4. The mixture was filtered, concentrated under reduced pressure to remove the filtrate, and the residue was purified by column chromatography to obtain 1.0 g of yellow solid I-2, with a yield of 55%. 1 H NMR (400 MHz, DMSO- d 6) d7.63 (s, 1H), 7.47 (s, 1H), 7.23 (s, 1H), 6.48 (s, 1H), 6.27 (d, J = 2.5Hz, 2H), 5.41 (s, 2H), 5.24 (s, 2H), 4.20 (s, 2H), 3.40 (d, J = 2.4 Hz, 2H), 3.22 (s, 1H), 1.87 (h, J = 7.1 Hz, 2H), 0.89 (t, J = 7.3 Hz, 4H). 13 C NMR (100MHz, DMSO- d 6) δ 173.00, 157.27, 151.25, 150.57, 150.03, 149.07, 147.61,146.52, 140.12, 128.29, 125.04, 118.53, 105.69, 103.06, 100.63, 96.30, 83.23,74.74, 72.88, 65.73, 50.39, 46.41, 37.75, 30.73, 8.26. ESI-MS (m / z), 460.14[M+H] + .

[0057] Example 37 - ((((1-Benzyl-1) H Preparation of -1,2,3-triazol-4-yl)methyl)amino)methyl)-10,11-methylenedioxycamptothecin (compound I-3)

[0058] In a 50 mL round-bottom flask, benzyl bromide (1.3 mmol) and sodium azide (52 mg, 1.3 mmol) dissolved in 6 mL DMSO were added sequentially. The mixture was stirred at room temperature for 4 h until TLC analysis showed the disappearance of the starting material. The mixture was then poured into water, extracted three times with dichloromethane, washed with saturated brine, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to obtain benzyl azide, which could be used without further purification.

[0059] In a 100 mL round-bottom flask, intermediate I-2 (50 mg, 0.11 mmol), benzyl azide (29.3 mg, 0.22 mmol), copper sulfate pentahydrate (68.6 mg, 0.275 mmol), sodium ascorbate (54.5 mg, 0.275 mmol), and 10 mL of DCM:H2O (1:1) were added sequentially. The mixture was stirred at room temperature for 12 h. After the reaction was complete as detected by TLC, the mixture was extracted three times with DCM, and the organic phase was washed with saturated brine. The organic phase was dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to remove the filtrate. The residue was purified by column chromatography to obtain 21.3 mg of yellow solid I-3, with a yield of 33%. mp>250℃. 1 H NMR (400 MHz, DMSO- d 6) d 8.00 (s, 1H), 7.69 (d, J = 3.9 Hz, 1H), 7.50 (d, J = 1.7 Hz, 1H), 7.39 – 7.30 (m, 3H),7.30 – 7.26 (m, 2H), 7.24 (s, 1H), 6.48 (s, 1H), 6.28 (s, 2H), 5.57 (s, 2H),5.42 (s, 2H), 5.31 (s, 2H), 4.31 – 4.14 (m, 2H), 3.87 (s, 2H), 1.99 (s, 1H),1.91 – 1.82 (m, 2H), 0.88 (d, J = 7.3 Hz, 3H). 13 C NMR (100 MHz, DMSO- d 6) d 185.44, 173.03, 162.79, 130.12, 129.33, 129.24, 128.87, 128.79, 128.58,128.40, 72.88, 53.66, 53.27, 36.26, 35.58, 31.76, 31.24, 30.63, 29.55, 29.50,29.45, 29.34, 29.30, 29.21, 29.17, 29.05, 27.02, 25.58, 22.57, 14.43, 8.25.HRMS: m / z [M+H] ＋ calcd for C 32 H 29N6O6,593.2143; found, 593.2138.

[0060] Example 47 - (((((1-4-methoxy)benzyl-1 H Preparation of -1,2,3-triazol-4-yl)methyl)amino)methyl)-10,11-methylenedioxycamptothecin (compound I-4)

[0061] Replacing benzyl bromo with 4-methoxybenzyl bromide in the steps of Example 3, while using the same raw materials, reagents, and preparation methods as in Example 3, yielded a yellow solid I-4 (24.4 mg) with a yield of 36%. mp > 250°C. 1 H NMR (400MHz, DMSO- d 6) d 7.93 (s, 1H), 7.64 (d, J = 3.8 Hz, 1H), 7.48 (d, J = 1.8 Hz,1H), 7.28 – 7.20 (m, 3H), 6.93 – 6.88 (m, 2H), 6.48 (s, 1H), 6.27 (d, J = 2.2Hz, 2H), 5.47 (s, 2H), 5.42 (s, 2H), 5.25 (d, J = 4.8 Hz, 2H), 4.19 (s, 2H), 4.09 (q, J = 5.3 Hz, 2H), 3.84 (s, 2H), 3.72 (s, 3H), 3.17 (d, J = 5.2 Hz, 5H),1.92 – 1.82 (m, 2H), 0.88 (t, J = 7.3 Hz, 3H). 13 C NMR (100 MHz, DMSO- d 6) d173.03, 159.54, 157.28, 151.23, 150.55, 150.06, 149.09, 147.62, 146.55,129.96, 128.50, 128.21, 125.00, 123.04, 118.50, 114.57, 105.70, 103.02,100.74, 96.27, 72.88, 65.73, 55.59, 52.74, 50.50, 49.07, 47.43, 44.65, 30.70,8.25. HRMS: m / z [M+H] ＋ calcd for C 33 H 31 N6O7,623.2176; found, 623.2254.

[0062] Example 57 - (((((1-4-methyl)benzyl-1 H Preparation of -1,2,3-triazol-4-yl)methyl)amino)methyl)-10,11-methylenedioxycamptothecin (compound I-5)

[0063] Replacing benzyl bromide in the steps of Example 3 with 4-methylbenzyl bromide, and using the same raw materials, reagents, and preparation methods as in Example 3, yielded a yellow solid I-5 (22.6 mg) with a yield of 34%. mp>250℃. 1 H NMR (400 MHz, DMSO- d 6) d 7.94 (s, 1H), 7.61 (s, 1H), 7.46 (s, 1H), 7.22 (s, 1H), 7.17 (d, J =3.3 Hz, 4H), 6.49 (s, 1H), 6.27 (d, J = 2.5 Hz, 2H), 5.50 (s, 2H), 5.42 (s,2H), 5.22 (s, 2H), 4.17 (s, 2H), 3.83 (s, 2H), 2.26 (s, 3H), 1.87 (p, J = 7.0Hz, 2H), 0.88 (q, J = 6.3, 5.4 Hz, 3H). 13 C NMR (100 MHz, DMSO- d 6) d173.02,157.26, 151.22, 150.54, 150.03, 149.06, 147.59, 146.88, 146.53, 140.70,137.84, 133.59, 129.73, 128.37, 128.11, 124.96, 123.19, 118.50, 105.67,103.03, 100.67, 96.25, 72.88, 65.73, 53.00, 50.49, 47.45, 44.66, 30.72,21.15, 8.26. HRMS: m / z [M+H] ＋ calcd for C 33 H 31 N6O6,607.2300; found, 623.2304.

[0064] Example 67 - (((((1-4-fluoro)benzyl-1) H Preparation of -1,2,3-triazol-4-yl)methyl)amino)methyl)-10,11-methylenedioxycamptothecin (compound I-6)

[0065] Replacing benzyl bromobromo with 4-fluorobenzyl bromide in the steps of Example 3, and using the same raw materials, reagents, and preparation methods as in Example 3, yielded a yellow solid I-6 (17.00 mg) with a yield of 25%. mp 238-239℃. 1 H NMR (400MHz, DMSO- d 6) d 8.00 (s, 1H), 7.64 (s, 1H), 7.47 (s, 1H), 7.36 (dd, J = 8.4, 5.4 Hz, 2H), 7.20 (dd, J = 14.8, 6.2 Hz, 3H), 6.49 (s, 1H), 6.31 – 6.23 (m,2H), 5.56 (s, 2H), 5.42 (s, 2H), 5.24 (d, J = 6.3 Hz, 2H), 4.19 (s, 2H), 3.86(s, 2H), 1.90 – 1.79 (m, 2H), 0.88 (t, J = 7.5 Hz, 3H). 13 C NMR (100 MHz, DMSO- d 6) d 171.94, 162.44, 160.02, 156.20, 150.16, 149.47, 148.97, 148.02, 146.54, 145.45, 131.82, 131.79, 129.59, 129.51, 129.04, 127.14, 123.91, 122.28, 117.44, 115.07, 114.86, 104.61, 101.96, 99.64, 95.20, 71.80, 64.65, 51.31, 49.41, 46.29, 43.53, 29.63, 28.47, 28.41, 28.22, 25.95, 7.18. HRMS: m / z [M+H] + calcd for C 32 H 28 FN6O6,611.2049; found, 611.2051.

[0066] Example 77 - (((((1-4-nitro)benzyl-1 H Preparation of -1,2,3-triazol-4-yl)methyl)amino)methyl)-10,11-methylenedioxycamptothecin (compound I-7)

[0067] Replacing benzyl bromo with 4-nitrobenzyl bromide in the steps of Example 3, and using the same raw materials, reagents, and preparation methods as in Example 3, yielded a yellow solid I-7 (27.55 mg) with a yield of 39%. mp 244-245℃. 1 H NMR (400MHz, DMSO- d 6) d 8.25 (s, 1H), 8.22 (s, 1H), 8.09 (s, 1H), 7.63 (s, 1H), 7.51(s, 1H), 7.49 (s, 1H), 7.46 (s, 1H), 7.23 (s, 1H), 6.50 (s, 1H), 6.27 (d, J =2.5 Hz, 2H), 5.76 (s, 2H), 5.42 (s, 2H), 5.24 (s, 2H), 4.20 (s, 2H), 3.88 (s,2H), 1.86 (p, J = 7.0 Hz, 2H), 0.88 (t, J = 7.3 Hz, 3H).13 C NMR (100 MHz, DMSO- d 6) d 173.02, 157.26, 151.23, 150.56, 150.05, 149.08, 147.66, 147.59, 146.51, 144.11, 130.12, 129.36, 128.21, 124.96, 124.39, 123.91, 118.50, 105.68, 103.04, 100.71, 96.29, 72.88, 65.71, 52.29, 50.51, 47.36, 44.59, 35.59, 31.75, 30.70, 29.55, 29.49, 29.30, 29.04, 27.02, 25.58, 22.56, 14.42, 8.25.HRMS: m / z [M+H] ＋ calcd for C 32 H 28 N7O8,638.1994; found, 638.1979.

[0068] Example 87 - (((((1-4-cyano)benzyl-1 H Preparation of -1,2,3-triazol-4-yl)methyl)amino)methyl)-10,11-methylenedioxycamptothecin (compound I-8)

[0069] Replacing benzyl bromo with 4-cyanobenzyl bromide in the steps of Example 3, and using the same raw materials, reagents, and preparation methods as in Example 3, yielded a yellow solid I-8 (22.38 mg) with a yield of 33%. mp 247-248℃. 1 H NMR (400MHz, DMSO- d 6) d 8.07 (s, 1H), 7.85 (d, J = 8.0 Hz, 2H), 7.66 (s, 1H), 7.49 (s,1H), 7.42 (d, J = 8.0 Hz, 2H), 7.23 (s, 1H), 6.49 (s, 1H), 6.28 (d, J= 2.0 Hz,2H), 5.70 (s, 2H), 5.42 (s, 2H), 5.28 (s, 2H), 4.21 (s, 2H), 3.88 (s, 2H),1.90 – 1.83 (m, 2H), 0.88 (s, 3H). 13 C NMR (100 MHz, DMSO- d 6) d 173.03, 157.29, 151.25, 150.57, 150.09, 149.12, 147.64, 146.57, 142.12, 133.21, 129.05, 125.04, 119.04, 118.52, 111.33, 105.74, 103.04, 100.74, 96.30, 72.88, 65.73, 50.52, 32.01, 31.75, 30.69, 29.90, 29.49, 29.16, 29.04, 27.02, 22.56, 14.42, 8.25. HRMS: m / z [M+H] + calcd for C 32 H 28 N7O6,618.2096; found, 618.2096.

[0070] Example 97 - (((((1-2-fluoro)benzyl-1) H Preparation of -1,2,3-triazol-4-yl)methyl)amino)methyl)-10,11-methylenedioxycamptothecin (compound I-9)

[0071] Replacing benzyl bromobromo with 2-fluorobenzyl bromide in the steps of Example 3, and using the same raw materials, reagents, and preparation methods as in Example 3, yielded a yellow solid I-9 (19.14 mg) with a yield of 28%. mp 238-239℃. 1 H NMR (400MHz, DMSO- d 6) d 8.00 (s, 1H), 7.63 (d, J = 2.5 Hz, 1H), 7.46 (d, J = 1.4 Hz,1H), 7.45 – 7.37 (m, 1H), 7.33 – 7.26 (m, 1H), 7.25 – 7.18 (m, 3H), 6.50 (s,1H), 6.28 (d,J = 2.5 Hz, 2H), 5.64 (s, 2H), 5.45 – 5.38 (m, 2H), 5.30 – 5.17(m, 2H), 4.20 (s, 2H), 3.87 (s, 2H), 1.92 – 1.83 (m, 2H), 1.18 (s, 1H), 0.89(t, J = 7.3 Hz, 3H). 13 C NMR (100 MHz, DMSO- d 6) d 173.04, 161.72, 159.27, 157.25,151.25, 150.55, 150.01, 149.11, 147.58, 146.48, 131.08, 125.33, 125.30,124.95, 123.34, 118.52, 116.17, 115.96, 105.67, 103.06, 100.69, 96.29, 72.88,65.72, 50.50, 47.25, 47.22, 30.66, 14.43, 8.27. HRMS: m / z [M+H] ＋ calcd forC 32 H 28 FN6O6,611.2049; found, 611.2052.

[0072] Example 107 - (((((1-4-chloro)benzyl-1) H Preparation of -1,2,3-triazol-4-yl)methyl)amino)methyl)-10,11-methylenedioxycamptothecin (compound I-10)

[0073] Replacing benzyl bromobromo with 4-chlorobenzyl bromobromo in the steps of Example 3, and using the same raw materials, reagents, and preparation methods as in Example 3, yielded a yellow solid I-10 (28.45 mg) with a yield of 41%. mp>250℃. 1 H NMR (400 MHz, DMSO- d 6) d 8.00 (s, 1H), 7.65 (s, 1H), 7.48 (s, 1H), 7.43 (d, J = 8.1 Hz, 2H),7.32 (s, 2H), 7.23 (s, 1H), 6.49 (s, 1H), 6.28 (d,J = 2.1 Hz, 2H), 5.57 (s,2H), 5.42 (s, 2H), 5.26 (s, 2H), 4.19 (s, 2H), 3.85 (s, 2H), 1.90 – 1.82 (m,2H), 0.87 (d, J = 7.3 Hz, 3H). 13 C NMR (100 MHz, DMSO- d 6) d 173.03, 162.78,157.29, 151.23, 150.56, 150.08, 149.10, 147.63, 146.58, 135.63, 134.13,133.24, 130.26, 129.21, 125.03, 118.50, 105.72, 103.03, 100.74, 96.27, 72.88,65.73, 52.37, 50.49, 40.63, 30.70, 29.78, 29.55, 29.49, 29.05, 8.25. HRMS: m / z [M+H] + calcd for C 32 H 28 ClN6O6,627.1753; found, 627.1763.

[0074] Example 117-(((((1-4-trifluoromethoxy)benzyl-1 H Preparation of -1,2,3-triazol-4-yl)methyl)amino)methyl)-10,11-methylenedioxycamptothecin (compound I-11)

[0075] Replacing benzyl bromo with 4-trifluoromethoxybenzyl bromide in the steps of Example 3, and using the same raw materials, reagents, and preparation methods as in Example 3, yielded a yellow solid I-11 (17.38 mg) with a yield of 23%. mp 243-244℃. 1 HNMR (400 MHz, DMSO- d 6) d 8.04 (s, 1H), 7.67 (s, 1H), 7.49 (s, 1H), 7.39 (d, J=7.8 Hz, 5H), 6.49 (s, 1H), 6.27 (s, 2H), 5.62 (s, 2H), 5.42 (s, 2H), 5.28 (s,2H), 4.36 – 4.14 (m, 2H), 3.87 (s, 2H), 1.86 (s, 2H), 0.89 – 0.85 (m, 3H). 13 CNMR (100 MHz, DMSO- d 6) d 173.03, 157.28, 151.25, 150.57, 150.10, 149.16,148.48, 147.65, 146.56, 130.35, 130.12, 121.80, 119.22, 118.52, 107.37,105.75, 103.05, 100.77, 96.30, 72.88, 65.71, 50.51, 31.75, 30.67, 29.49,29.17, 29.04, 27.02, 22.57, 8.25. HRMS: m / z [M+H] + calcd for C 33 H 28 N6O6,677.1966;found, 677.1753.

[0076] Example 127-(((((1-4-hydroxybutyl)-1 H Preparation of -1,2,3-triazol-4-yl)methyl)amino)methyl)-10,11-methylenedioxycamptothecin (compound I-12)

[0077] Replacing benzyl bromo with 4-bromobutyl-1-ol in the steps of Example 3, and using the same raw materials, reagents, and preparation methods as in Example 3, yielded a yellow solid I-12 (19.88 mg), with a yield of 31%. mp 182-183℃. 1 H NMR (600 MHz, DMSO-) d 6) d7.93 (s, 1H), 7.65 (s, 1H), 7.45 (s, 1H), 7.19 (s, 2H), 6.46 (s, 1H), 6.24 (s, 2H), 5.37 (s, 2H), 5.27 (s, 2H), 4.44 (s, 1H), 4.28(s, 2H), 3.35 (s, 2H), 1.94 (s, 2H), 1.82 – 1.74 (m, 4H), 1.43 – 1.38 (m,2H), 1.31 (s, 2H), 0.82 (s, 3H). 13 C NMR (150 MHz, DMSO- d 6) d 174.81, 173.08,157.34, 150.63, 150.14, 147.72, 118.59, 117.86, 105.78, 103.11, 100.88,100.00, 96.38, 72.94, 60.49, 49.72, 35.63, 31.81, 30.72, 29.78, 29.34, 29.25,29.10, 27.16, 27.08, 25.63, 22.62, 14.48, 8.31. HRMS: m / z [M+H] ＋ calcd forC 29 H 30 N6O7,575.2176; found, 575.2178.

[0078] Example 137-(((((1-4-bromo)benzyl-1 H Preparation of -1,2,3-triazol-4-yl)methyl)amino)methyl)-10,11-methylenedioxycamptothecin (compound I-13)

[0079] Replacing benzyl bromobromo with 4-bromobenzyl bromo in the steps of Example 42, and using the same raw materials, reagents, and preparation methods as in Example 42, yielded a yellow solid II-13 (18.06 mg) with a yield of 24%. mp>250℃. 1 H NMR (400MHz, DMSO- d 6) δ 8.00 (s, 1H), 7.63 (d, J= 11.4 Hz, 1H), 7.58 – 7.41 (m, 3H), 7.25 – 7.18 (m, 3H), 6.47 (d, J = 11.8 Hz, 1H), 6.29 – 6.21 (m, 2H), 5.62 –5.48 (m, 2H), 5.40 (d, J = 10.0 Hz, 2H), 5.24 (d, J = 9.7 Hz, 2H), 4.19 (s,2H), 3.85 (s, 2H), 1.84 (dd, J = 13.2, 7.0 Hz, 2H), 0.86 (d, J = 7.5 Hz, 3H). 13 CNMR (100 MHz, DMSO- d 6) δ 171.94, 156.20, 150.16, 149.48, 148.98, 148.02,146.54, 145.47, 134.97, 131.06, 129.48, 129.04, 127.14, 123.92, 122.41,120.71, 117.43, 104.62, 101.96, 99.65, 95.20, 71.80, 64.65, 54.31, 49.43,46.30, 43.53, 29.62, 25.94, 21.48, 13.34, 7.18. HRMS: m / z [M+H] ＋ calcd forC 32 H 28 BrN6O6,673.1228; found, 673.1227.

[0080] Example 147 - (((((1-4-trifluoromethyl)benzyl-1 H Preparation of -1,2,3-triazol-4-yl)methyl)amino)methyl)-10,11-methylenedioxycamptothecin (compound I-14)

[0081] Replacing benzyl bromide in the step of Example 3 with 4-trifluoromethylbenzyl bromide, and using the same raw materials, reagents, and preparation methods as in Example 3, yielded a pale yellow solid I-14 (23.35 mg) with a yield of 32%. mp 246-247℃. 1 HNMR (400 MHz, DMSO-d 6) d 8.05 (s, 1H), 7.76 (s, 1H), 7.74 (s, 1H), 7.67 (s,1H), 7.48 (d, J = 3.6 Hz, 2H), 7.45 (s, 1H), 6.48 (s, 1H), 6.27 (d, J = 1.9 Hz,2H), 5.70 (s, 2H), 5.42 (s, 2H), 5.29 (s, 2H), 4.22 (s, 2H), 3.87 (s, 2H),1.86 (p, J = 7.0 Hz, 2H), 0.88 (d, J = 7.3 Hz, 3H). 13 C NMR (100 MHz, DMSO- d 6) d 171.97, 156.20, 150.16, 149.48, 148.99, 148.02, 146.54, 145.47, 140.27,129.04, 128.10, 127.87, 127.78, 127.17, 125.10, 125.06, 123.94, 122.67,117.41, 104.62, 101.94, 99.68, 95.21, 71.80, 64.62, 51.42, 49.46, 43.53,29.55, 7.16. HRMS: m / z [M+H] ＋ calcd for C 33 H 28 F3N6O6,661.2017; found, 661.2023.

[0082] Example 157-(((((1-3-fluoro)benzyl-1 H Preparation of -1,2,3-triazol-4-yl)methyl)amino)methyl)-10,11-methylenedioxycamptothecin (compound I-15)

[0083] Replacing benzyl bromotribenzyl with 3-fluorobromotribenzyl in the steps of Example 3, and using the same raw materials, reagents, and preparation methods as in Example 3, yielded a yellow solid I-15 (24.56 mg) with a yield of 37%. mp>250℃. 1 H NMR (400 MHz, DMSO- d6) d 8.06 (s, 1H), 7.64 (d, J = 5.5 Hz, 1H), 7.51 – 7.37 (m, 2H), 7.23 (s, 1H), 7.19 – 7.08 (m, 3H), 6.52 (s, 1H), 6.28 (d, J = 2.5 Hz, 2H), 5.61 (s,2H), 5.42 (s, 2H), 5.27 (s, 2H), 4.22 (s, 2H), 3.89 (s, 2H), 1.89 – 1.82 (m,2H), 0.88 (t, J = 7.3 Hz, 3H). 13 C NMR (100 MHz, DMSO- d 6) d 173.04, 163.80, 161.37, 157.27, 151.26, 150.55, 150.05, 149.12, 147.61, 146.52, 139.34, 139.26, 131.36, 131.28, 125.00, 124.41, 124.38, 118.52, 115.50, 115.33, 115.11, 105.70, 103.06, 100.74, 96.30, 72.88, 65.72, 52.49, 50.54, 44.54, 30.65, 8.26. HRMS: m / z [M+H] ＋ calcd for C 32 H 28 FN6O6,611.2049; found, 611.2058.

[0084] Example 167 - (((((1-4-bromo-3-fluoro)benzyl-1 H Preparation of -1,2,3-triazol-4-yl)methyl)amino)methyl)-10,11-methylenedioxycamptothecin (compound I-16)

[0085] Replacing benzyl bromobromo with 3-fluoro-4-bromobenzyl bromo in the steps of Example 3, and using the same raw materials, reagents, and preparation methods as in Example 3, yielded a yellow solid I-16 (25.20 mg) with a yield of 33%. mp > 250°C. 1 H NMR (400MHz, DMSO- d 6) d 8.05 (s, 1H), 7.72 (t, J = 7.8 Hz, 1H), 7.65 (s, 1H), 7.48 (s,1H), 7.35 (dd, J = 9.7, 2.0 Hz, 1H), 7.24 (s, 1H), 7.06 (dd, J = 8.3, 2.0 Hz,1H), 6.48 (s, 1H), 6.28 (d, J = 2.1 Hz, 2H), 5.60 (s, 2H), 5.45 – 5.39 (m,2H), 5.28 (s, 2H), 4.23 (s, 2H), 3.89 (s, 2H), 1.87 (s, 2H), 0.88 (d, J = 7.3Hz, 3H). 13 C NMR (100 MHz, DMSO- d 6) d 173.04, 159.83, 157.27, 151.25, 150.56,150.05, 149.12, 147.61, 146.51, 138.88, 138.81, 134.40, 126.08, 126.04,124.99, 118.52, 116.91, 116.68, 108.23, 108.03, 105.69, 103.06, 100.72,96.30, 72.88, 65.72, 52.00, 50.53, 30.66, 8.26. HRMS: m / z [M+H] ＋ calcd forC 32 H 27 BrFN6O6,691.1134; found, 691.1127.

[0086] Example 177-(((((1-3-bromo)benzyl-1 H Preparation of -1,2,3-triazol-4-yl)methyl)amino)methyl)-10,11-methylenedioxycamptothecin (compound I-17)

[0087] Replacing benzyl bromobromo with 3-bromobenzyl bromo in the steps of Example 3, and using the same raw materials, reagents, and preparation methods as in Example 3, yielded a yellow solid I-17 (26.09 mg) with a yield of 35%. mp>250℃.1 H NMR (400 MHz, DMSO- d 6) d 8.05 (s, 1H), 7.66 (s, 1H), 7.53 (s, 2H), 7.48 (d, J = 3.4 Hz, 1H), 7.32 (d, J = 7.7 Hz, 1H), 7.28 (s, 1H), 7.23 (s, 1H), 6.51 (s, 1H), 6.28 (d, J = 2.0 Hz, 2H), 5.59 (s, 2H), 5.42 (s, 2H), 5.28 (s, 2H), 4.20 (s, 2H), 3.86(s, 2H), 1.90 – 1.83 (m, 2H), 0.89 (d, J = 7.3 Hz, 3H). 13 C NMR (100 MHz, DMSO- d 6) d 171.96, 156.19, 150.16, 149.46, 148.98, 148.02, 146.53, 145.47, 138.18,130.37, 130.34, 130.05, 126.35, 123.93, 122.52, 121.19, 117.42, 104.62,101.95, 99.66, 95.20, 71.80, 64.64, 55.41, 51.25, 49.44, 46.32, 43.53, 29.58,17.95, 7.18. HRMS: m / z [M+H] ＋ calcd for C 32 H 28 BrN6O6,673.1228; found, 673.1232.

[0088] Example 187-(((((1-3-methyl)benzyl-1 H Preparation of -1,2,3-triazol-4-yl)methyl)amino)methyl)-10,11-methylenedioxycamptothecin (compound I-18)

[0089] Replacing benzyl bromide in the steps of Example 3 with 3-methylbenzyl bromide, and using the same raw materials, reagents, and preparation methods as in Example 3, yielded a yellow solid I-18 (22.23 mg) with a yield of 33%. mp 236-237℃. 1 H NMR (400 MHz, DMSO-) d 6) d 7.99 (s, 1H), 7.67 (d, J = 3.9 Hz, 1H), 7.49 (d, J = 1.9Hz, 1H), 7.24 (d, J = 4.0 Hz, 2H), 7.13 (d, J = 2.4 Hz, 2H), 7.07 (d, J = 7.7Hz, 1H), 6.51 (s, 1H), 6.28 (d, J = 2.0 Hz, 2H), 5.52 (s, 2H), 5.42 (s, 2H),5.29 (s, 2H), 4.21 (s, 2H), 3.86 (s, 2H), 2.27 (s, 3H), 1.90 – 1.84 (m, 2H),0.88 (t, J = 7.3 Hz, 3H). 13 C NMR (100 MHz, DMSO- d 6) d 171.96, 156.20, 150.18, 149.47, 149.00, 148.04, 146.55, 145.47, 137.34, 135.40, 129.03, 128.13, 128.08, 128.05, 127.87, 127.11, 124.39, 123.95, 117.43, 104.64, 101.96, 99.70, 95.21, 71.80, 64.63, 55.40, 52.12, 49.47, 43.49, 29.56, 20.29, 17.95, 7.17. HRMS: m / z [M+H] ＋ calcd for C 33 H 31 N6O6,607.2300; found, 607.2299.

[0090] Example 197 - (((((1-2-bromo)benzyl-1 H Preparation of -1,2,3-triazol-4-yl)methyl)amino)methyl)-10,11-methylenedioxycamptothecin (compound I-19)

[0091] Replacing benzyl bromo with 2-bromobenzyl bromo in the steps of Example 3, and using the same raw materials, reagents, and preparation methods as in Example 3, yielded a yellow solid I-19 (19.14 mg), with a yield of 29%. mp 240-241℃. 1 H NMR (400MHz, DMSO- d 6) d 7.97 (s, 1H), 7.68 (dd, J = 7.9, 1.3 Hz, 1H), 7.66 – 7.60 (m,1H), 7.46 (s, 1H), 7.40 (d, J = 1.3 Hz, 1H), 7.30 (td, J = 7.7, 1.8 Hz, 1H), 7.23 (d, J = 1.2 Hz, 1H), 7.11 (dd, J = 7.6, 1.8 Hz, 1H), 6.49 (s, 1H), 6.27(d, J = 2.3 Hz, 2H), 5.65 (s, 2H), 5.42 (s, 2H), 5.25 (s, 2H), 4.20 (s, 2H), 3.89 (s, 2H), 1.91 – 1.83 (m, 2H), 1.34 (s, 1H), 0.88 (t, J = 7.3 Hz, 3H). 13 CNMR (100 MHz, DMSO- d 6) d 173.02, 157.27, 151.28, 150.55, 150.05, 149.15,147.63, 146.50, 135.43, 133.35, 130.82, 130.79, 128.76, 124.99, 123.27,118.54, 105.72, 103.06, 100.74, 96.31, 72.88, 65.72, 53.33, 50.54, 30.69,14.43, 8.26. HRMS: m / z [M+H]＋ calcd for C 32 H 28 BrN6O6,673.1228; found, 673.1230.

[0092] Example 207 - (((((1-2-cyano)benzyl-1) H Preparation of -1,2,3-triazol-4-yl)methyl)amino)methyl)-10,11-methylenedioxycamptothecin (compound I-20)

[0093] Replacing benzyl bromo with 2-cyanobenzyl bromide in the steps of Example 3, and using the same raw materials, reagents, and preparation methods as in Example 3, yielded a yellow solid I-20 (24.79 mg) with a yield of 37%. mp > 250°C. 1 H NMR (400MHz, DMSO- d 6) d 8.07 (s, 1H), 7.91 (d, J = 7.7 Hz, 1H), 7.72 (s, 1H), 7.65 –7.52 (m, 2H), 7.49 – 7.45 (m, 1H), 7.32 (d, J = 7.8 Hz, 1H), 7.22 (d, J = 2.8Hz, 1H), 6.51 (s, 1H), 6.38 – 6.11 (m, 2H), 5.79 (s, 2H), 5.42 (s, 2H), 5.25(s, 2H), 4.19 (s, 2H), 3.89 (s, 2H), 1.92 – 1.75 (m, 2H), 0.88 (t, J = 7.4 Hz, 3H). 13 C NMR (150 MHz, DMSO- d 6) d 173.09, 157.32, 151.31, 150.60, 150.09,149.17, 147.65, 146.56, 139.49, 134.39, 133.86, 129.77, 129.66, 125.03,118.57, 117.53, 105.73, 103.11, 100.77, 96.36, 72.94, 65.78, 56.55, 51.44,50.57, 44.55, 30.74, 19.08, 8.31. HRMS: m / z [M+H] ＋ calcd for C 33 H 28 N7O6,618.2096;found, 618.2100.

[0094] Example 217 - (((((1-3-cyano)benzyl-1 H Preparation of -1,2,3-triazol-4-yl)methyl)amino)methyl)-10,11-methylenedioxycamptothecin (compound I-21)

[0095] Replacing benzyl bromo with 3-cyanobenzyl bromide in the steps of Example 3, and using the same raw materials, reagents, and preparation methods as in Example 3, yielded a yellow solid I-21 (25.94 mg) with a yield of 38%. mp > 250°C. 1 H NMR (400MHz, DMSO- d 6) d 8.08 (s, 1H), 7.82 (d, J = 2.2 Hz, 2H), 7.60 (d, J = 2.3 Hz,3H), 7.47 (s, 1H), 7.38 – 7.27 (m, 2H), 7.22 (s, 1H), 6.51 (s, 1H), 6.28 (d, J = 2.4 Hz, 2H), 5.76 (s, 1H), 5.65 (s, 2H), 5.59 (s, 1H), 5.42 (s, 2H), 5.24(s, 2H), 4.20 (s, 2H), 3.87 (s, 2H), 3.61 (s, 1H), 1.86 (hept, J = 7.1 Hz, 2H), 0.88 (t, J = 7.3 Hz, 3H). 13 C NMR (100 MHz, DMSO- d 6) d171.96, 156.19, 150.17, 149.47, 148.96, 148.02, 146.52, 145.44, 137.09, 135.63, 132.24, 131.33, 130.99, 129.49, 128.13, 127.11, 122.62, 117.84, 117.44, 111.04, 104.61, 101.96, 99.63, 95.21, 71.80, 64.65, 55.41, 54.32, 51.15, 46.30, 29.59, 17.96, 7.18. HRMS: m / z [M+H] + calcd for C 33 H 28 N7O6,618.2096; found,618.2094.

[0096] Example 227 - (((((1-3-nitro)benzyl-1 H Preparation of -1,2,3-triazol-4-yl)methyl)amino)methyl)-10,11-methylenedioxycamptothecin (compound I-22)

[0097] Replacing benzyl bromo with 3-nitrobenzyl bromide in the steps of Example 3, and using the same raw materials, reagents, and preparation methods as in Example 3, yielded a yellow solid I-22 (28.20 mg) with a yield of 40%. mp > 250°C. 1 H NMR (400MHz, DMSO- d 6) d 8.27 – 8.16 (m, 2H), 8.11 (s, 1H), 7.79 – 7.63 (m, 3H), 7.47(s, 1H), 7.38 – 7.28 (m, 1H), 7.22 (s, 1H), 6.51 (s, 1H), 6.27 (d, J = 2.1 Hz,2H), 5.76 (s, 2H), 5.42 (s, 2H), 5.27 (s, 2H), 4.22 (s, 2H), 3.90 (s, 2H),2.54 (s, 1H), 1.99 (s, 1H), 1.86 (p, J = 7.0 Hz, 2H), 0.88 (d, J = 7.4 Hz, 3H). 13C NMR (150 MHz, DMSO- d 6) d 173.08, 162.84, 157.32, 151.32, 150.61, 150.12,149.20, 148.38, 147.69, 146.56, 138.76, 135.16, 130.95, 129.26, 128.25,125.06, 123.61, 123.25, 118.58, 72.94, 65.76, 56.55, 52.20, 50.58, 36.31,31.30, 30.72, 27.08, 19.07, 14.48, 8.31. HRMS: m / z [M+H] ＋ calcd for C 32 H 28 N7O8,638.1994; found, 638.1990.

[0098] Example 237 - (((((1-4-benzyloxy)benzyl-1 H Preparation of -1,2,3-triazol-4-yl)methyl)amino)methyl)-10,11-methylenedioxycamptothecin (compound I-23)

[0099] Replacing benzyl bromide with 4-benzyloxybenzyl bromide in the steps of Example 3, and using the same raw materials, reagents, and preparation methods as in Example 3, yielded a yellow solid I-23 (28.93 mg) with a yield of 38%. mp > 250°C. 1 H NMR (600MHz, DMSO- d 6) d 7.92 (s, 1H), 7.59 (s, 1H), 7.42 (s, 1H), 7.36 (s, 2H), 7.32(s, 2H), 7.26 (d, J = 7.3 Hz, 1H), 7.20 (s, 2H), 6.95 (s, 2H), 6.46 (s, 1H), 6.23 (s, 2H), 5.43 (s, 2H), 5.37 (s, 2H), 5.19 (s, 2H), 5.03 (s, 2H), 4.14(s, 2H), 3.80 (s, 2H), 1.86 – 1.77 (m, 2H), 1.21 – 1.13 (m, 2H), 0.83 (t, J=7.3 Hz, 3H). 13 C NMR (150 MHz, DMSO- d 6) d 173.07, 158.66, 157.32, 151.29,150.61, 150.09, 149.14, 147.66, 146.58, 130.01, 128.94, 128.82, 128.34,128.15, 125.05, 118.56, 115.50, 105.74, 103.10, 100.79, 96.34, 72.94, 69.71,65.78, 52.78, 50.55, 44.65, 30.75, 8.32. HRMS: m / z [M+H] ＋ calcd for C 34 H 33 N6O6,699.2562; found, 699.2581.

[0100] Example 247 - (((((1-2-nitro)benzyl-1 H Preparation of -1,2,3-triazol-4-yl)methyl)amino)methyl)-10,11-methylenedioxycamptothecin (compound I-24)

[0101] Replacing benzyl bromo with 2-nitrobenzyl bromide in the steps of Example 3, and using the same raw materials, reagents, and preparation methods as in Example 3, yielded a yellow solid I-24 (29.83 mg) with a yield of 43%. mp > 250°C. 1 H NMR (500MHz, DMSO- d 6) d 8.18 – 8.12 (m, 1H), 8.05 (s, 1H), 7.75 (d, J = 1.4 Hz, 1H), 7.65 (d, J = 2.2 Hz, 1H), 7.63 (s, 1H), 7.48 (s, 1H), 7.23 (s, 1H), 7.00 (s,1H), 6.52 (s, 1H), 6.28 (d, J= 2.8 Hz, 2H), 5.96 (s, 2H), 5.43 (s, 2H), 5.26(s, 2H), 4.23 (s, 2H), 3.92 (s, 2H), 1.92 – 1.84 (m, 2H), 0.89 (t, J = 7.3 Hz, 3H). 13 C NMR (125 MHz, DMSO- d 6) d 173.03, 157.25, 151.24, 150.53, 150.02,149.09, 147.92, 147.58, 146.49, 134.87, 131.61, 130.20, 129.99, 129.21,128.19, 125.52, 124.97, 124.34, 118.51, 105.68, 103.05, 100.71, 96.29, 72.88,65.72, 50.52, 50.29, 47.25, 44.52, 35.58, 30.66, 8.27. HRMS: m / z [M+H] + calcdfor C 32 H 28 N7O8,638.1994; found, 638.1989.

[0102] Example 257-(((((1-3,4-dimethoxy)benzyl-1 H Preparation of -1,2,3-triazol-4-yl)methyl)amino)methyl)-10,11-methylenedioxycamptothecin (compound I-25)

[0103] Replacing benzyl bromide in the steps of Example 3 with 3,4-dimethoxybenzyl bromide, and using the same raw materials, reagents, and preparation methods as in Example 3, yielded a yellow solid I-25 (28.20 mg) with a yield of 40%. mp>250℃. 1 H NMR (400 MHz, DMSO-) d 6) d 7.95 (s, 1H), 7.63 (s, 1H), 7.47 (s, 1H), 7.23 (s, 1H),7.00 (d, J = 2.0 Hz, 1H), 6.91 (s, 1H), 6.83 (dd, J= 8.2, 2.0 Hz, 1H), 6.49(s, 1H), 6.27 (d, J = 2.4 Hz, 2H), 5.46 (s, 2H), 5.42 (s, 2H), 5.24 (s, 2H), 4.19 (s, 2H), 3.85 (s, 2H), 3.72 (d, J = 1.8 Hz, 6H), 2.55 (s, 1H), 1.91 –1.84 (m, 2H), 1.34 (s, 0H), 0.89 (t, J = 7.3 Hz, 3H). 13 C NMR (100 MHz, DMSO- d 6) d 173.02, 157.26, 151.22, 150.55, 150.03, 149.20, 149.13, 149.07, 147.59,146.52, 128.71, 124.96, 123.09, 121.00, 118.50, 112.46, 112.32, 105.68,103.04, 100.69, 96.27, 72.88, 65.72, 55.97, 55.94, 53.12, 50.51, 47.40,44.63, 30.70, 8.26. HRMS: m / z [M+H] + calcd for C 34 H 33 N6O8,653.2354; found,653.2349.

[0104] Example 267 - (((((1-3,4,5-trimethoxy)benzyl-1 H Preparation of -1,2,3-triazol-4-yl)methyl)amino)methyl)-10,11-methylenedioxycamptothecin (compound I-26)

[0105] Replacing benzyl bromide in the steps of Example 3 with 3,4,5-trimethoxybenzyl bromide, and using the same raw materials, reagents, and preparation methods as in Example 3, yielded a yellow solid I-26 (26.64 mg) with a yield of 36%. mp > 250°C. 1 HNMR (400 MHz, DMSO- d 6) d8.02 (s, 1H), 7.64 (s, 1H), 7.47 (s, 1H), 7.23 (s,1H), 6.69 (s, 2H), 6.49 (s, 1H), 6.27 (d, J = 2.3 Hz, 2H), 5.47 (s, 2H), 5.42(s, 2H), 5.26 (s, 2H), 4.21 (s, 2H), 3.85 (s, 2H), 3.73 (s, 6H), 3.62 (s,3H), 1.90 – 1.83 (m, 2H), 1.24 (d, J = 4.6 Hz, 2H), 0.89 (t, J = 7.3 Hz, 3H). 13 CNMR (100 MHz, DMSO- d 6) d 173.02, 157.26, 153.46, 151.22, 150.56, 150.06,149.08, 147.59, 146.52, 137.73, 131.89, 128.20, 124.97, 123.23, 118.49,106.16, 105.68, 103.04, 100.69, 96.27, 72.89, 65.72, 60.42, 56.35, 53.50,50.54, 47.43, 44.62, 30.69, 22.56, 8.26. HRMS: m / z [M+H] ＋ calcd for C 34 H 35 N6O9,683.2460; found, 683.2449.

[0106] Example 277-(((((1-3-methoxy)benzyl-1 H Preparation of -1,2,3-triazol-4-yl)methyl)amino)methyl)-10,11-methylenedioxycamptothecin (compound I-27)

[0107] Replacing benzyl bromo with 3-methoxybenzyl bromide in the steps of Example 3, and using the same raw materials, reagents, and preparation methods as in Example 3, yielded a yellow solid I-27 (19.65 mg) with a yield of 29%. mp > 250°C. 1 H NMR (400 MHz, DMSO-) d 6) d 8.02 (s, 1H), 7.64 (s, 1H), 7.47 (s, 1H), 7.28 – 7.22 (m,2H), 6.89 (d, J = 1.7 Hz, 2H), 6.82 (d, J = 7.6 Hz, 1H), 6.50 (s, 1H), 6.31 –6.25 (m, 2H), 5.54 (s, 2H), 5.42 (s, 2H), 5.26 (s, 2H), 4.22 (s, 2H), 3.89(s, 2H), 3.72 (s, 3H), 2.54 (s, 2H), 1.89 – 1.84 (m, 2H), 0.89 (d, J = 7.3 Hz, 3H). 13 C NMR (125 MHz, DMSO- d 6) d 185.40, 172.98, 159.84, 157.21, 151.34,150.54, 150.02, 149.25, 147.65, 146.38, 137.91, 130.36, 124.96, 120.42,118.59, 114.16, 113.86, 105.71, 103.12, 100.75, 96.35, 72.86, 65.70, 55.53,53.15, 50.58, 30.66, 29.15, 22.55, 14.42, 8.25. HRMS: m / z [M+H] ＋ calcd forC 33 H 31 N6O7,623.2249; found, 623.2256.

[0108] Example 287-(((((1-3-chloro)benzyl-1 H Preparation of -1,2,3-triazol-4-yl)methyl)amino)methyl)-10,11-methylenedioxycamptothecin (compound I-28)

[0109] Replacing benzyl bromobromo with 3-chlorobenzyl bromobromo in the steps of Example 3, and using the same raw materials, reagents, and preparation methods as in Example 3, yielded a yellow solid I-28 (11.23 mg) with a yield of 18%. mp 236-237℃. 1H NMR (400MHz, DMSO- d 6) d 8.08 (s, 1H), 7.64 (d, J = 14.5 Hz, 1H), 7.48 (s, 1H), 7.43 –7.35 (m, 3H), 7.25 – 7.20 (m, 2H), 6.50 (s, 1H), 6.27 (d, J = 3.0 Hz, 2H),5.60 (s, 2H), 5.42 (s, 2H), 5.27 (s, 2H), 4.22 (s, 2H), 3.90 (s, 2H), 1.93 –1.80 (m, 2H), 1.34 (s, 1H), 0.89 (d, J = 7.3 Hz, 3H). 13 C NMR (100 MHz, DMSO- d 6) d 173.01, 157.26, 151.30, 150.56, 150.05, 149.17, 147.63, 146.47, 138.98,133.71, 131.17, 128.53, 128.27, 127.07, 124.99, 118.56, 105.70, 103.08,100.73, 96.33, 72.88, 65.73, 52.42, 50.55, 44.38, 32.01, 30.70, 29.16, 22.56,14.42, 8.26. HRMS: m / z [M+H] ＋ calcd for C 32 H 28 ClN6O6,627.1753; found, 627.1742.

[0110] Example 297 - (((((1-2-chloro)benzyl-1) H Preparation of -1,2,3-triazol-4-yl)methyl)amino)methyl)-10,11-methylenedioxycamptothecin (compound I-29)

[0111] Replacing benzyl bromobromo with 2-chlorobenzyl bromobromo in the steps of Example 3, and using the same raw materials, reagents, and preparation methods as in Example 3, yielded a yellow solid I-29 (15.48 mg) with a yield of 22%. mp 240-241℃. 1H NMR (400MHz, DMSO- d 6) d 7.98 (s, 1H), 7.62 (s, 1H), 7.51 (dd, J = 7.2, 1.9 Hz, 1H),7.46 (s, 1H), 7.39 – 7.33 (m, 2H), 7.22 (s, 1H), 7.17 (dd, J = 7.1, 2.3 Hz,1H), 6.49 (s, 1H), 6.27 (d, J = 2.5 Hz, 2H), 5.67 (s, 2H), 5.42 (s, 2H), 5.23(s, 2H), 4.19 (s, 2H), 3.88 (s, 2H), 1.92 – 1.79 (m, 2H), 1.34 (s, 1H), 0.87(d, J = 7.3 Hz, 3H). 13 C NMR (100 MHz, DMSO- d 6) d 173.02, 157.26, 151.27, 150.55,150.04, 149.13, 147.62, 146.49, 133.83, 133.00, 130.81, 130.64, 130.07,128.21, 124.97, 118.54, 105.70, 103.06, 100.71, 96.30, 72.88, 65.73, 50.98,50.52, 44.46, 40.41, 30.70, 8.25. HRMS: m / z [M+H] ＋ calcd for C 32 H 28 ClN6O6,627.1753; found, 627.1740.

[0112] Example 307-(((((1-hydroxyethyl)benzyl-1 H Preparation of -1,2,3-triazol-4-yl)methyl)amino)methyl)-10,11-methylenedioxycamptothecin (compound I-30)

[0113] Replacing benzyl bromoethanol in the steps of Example 3 with the other required raw materials, reagents, and preparation methods are the same as in Example 3, yielding a yellow solid I-30 (11.23 mg) with a yield of 18%. mp 168-169℃. 1 H NMR (400MHz, DMSO- d 6) d 8.00 (s, 1H), 7.73 (s, 1H), 7.51 (s, 1H), 7.25 (s, 1H), 6.50(s, 1H), 6.29 (d, J = 1.5 Hz, 2H), 5.42 (s, 2H), 5.33 (d, J = 4.7 Hz, 2H), 5.10(t, J = 5.4 Hz, 1H), 4.39 (s, 2H), 3.76 (d, J = 5.4 Hz, 2H), 2.03 – 1.93 (m,2H), 1.85 (dp, J = 14.1, 7.0 Hz, 2H), 0.88 (s, 3H). 13 C NMR (150 MHz, DMSO- d 6) d 174.83, 173.05, 157.32, 150.66, 150.15, 130.17, 125.13, 72.93, 65.77, 64.28,60.41, 59.98, 52.71, 35.62, 32.07, 31.79, 30.71, 29.95, 29.61, 29.34, 29.24,29.08, 27.12, 25.63, 22.61, 14.49, 8.32. HRMS: m / z [M+H] ＋ calcd for C 27 H 27 N6O7,547.1936; found, 547.1921.

[0114] Example 317-(((((1-2-methyl)benzyl-1 H Preparation of -1,2,3-triazol-4-yl)methyl)amino)methyl)-10,11-methylenedioxycamptothecin (compound I-31)

[0115] Replacing benzyl bromide in the steps of Example 3 with 2-methylbenzyl bromide, and using the same raw materials, reagents, and preparation methods as in Example 3, yielded a yellow solid I-31 (15.48 mg) with a yield of 22%. mp 240-241℃. 1 H NMR (400 MHz, DMSO-) d 6) d 7.88 (s, 1H), 7.61 (q, J = 2.2 Hz, 1H), 7.48 – 7.43 (m,1H), 7.24 – 7.20 (m, 3H), 7.17 (d, J = 2.7 Hz, 1H), 7.04 (d, J = 7.3 Hz, 1H), 6.49 (s, 1H), 6.27 (d, J = 2.7 Hz, 2H), 5.57 (s, 2H), 5.41 (s, 2H), 5.22 (s,2H), 4.18 (s, 2H), 3.86 (s, 2H), 2.28 (s, 3H), 1.99 (dd, J = 9.4, 6.7 Hz, 1H),1.90 – 1.79 (m, 2H), 0.89 (d, J = 7.3 Hz, 3H). 13 C NMR (100 MHz, DMSO- d 6) d 173.02, 157.26, 151.26, 150.55, 150.03, 149.12, 147.61, 146.48, 136.74,134.64, 130.86, 129.07, 128.72, 126.72, 124.95, 118.53, 105.69, 103.07,100.68, 96.29, 72.88, 65.73, 51.38, 50.50, 44.50, 30.70, 19.09, 8.26. HRMS: m / z [M+H] ＋ calcd for C 33 H 31 N6O6,607.2300; found, 607.2303.

[0116] Example 327 - (((((1-Cyclobutylmethyl)benzyl-1 HPreparation of -1,2,3-triazol-4-yl)methyl)amino)methyl)-10,11-methylenedioxycamptothecin (compound I-32)

[0117] Replacing benzyl bromo in the step of Example 3 with 1-bromomethylcyclobutane, and using the same raw materials, reagents, and preparation methods as in Example 3, yielded a yellow solid I-32 (20.22 mg) with a yield of 32%. mp 246-247℃. 1 HNMR (600 MHz, DMSO- d 6) d 7.85 (s, 1H), 7.59 (s, 1H), 7.42 (s, 1H), 7.18 (s,1H), 6.42 (s, 1H), 6.23 (s, 2H), 5.37 (s, 2H), 5.19 (s, 2H), 4.29 (d, J = 7.4Hz, 2H), 4.16 (s, 2H), 3.83 (s, 2H), 2.68 (dt, J = 15.1, 7.6 Hz, 1H), 1.92(dt, J = 7.4, 3.7 Hz, 2H), 1.86 – 1.76 (m, 4H), 1.73 – 1.66 (m, 2H), 0.84 (t, J = 7.3 Hz, 3H). 13 C NMR (150 MHz, DMSO- d 6) d 173.04, 157.32, 151.30, 150.59, 150.11, 149.15, 147.69, 146.59, 134.20, 128.30, 125.04, 123.31, 118.58, 105.75, 103.69, 103.09, 100.76, 99.24, 96.91, 96.31, 94.25, 81.43, 76.81, 74.96, 72.94, 71.70, 65.80, 54.49, 50.54, 47.35, 44.65, 35.60, 30.82, 25.55, 18.07, 8.30. HRMS: m / z [M+H] + calcd for C 30 H 31N6O6,571.2300; found, 571.2286.

[0118] Example 337-(((((1-2-trifluoromethyl)benzyl-1 H Preparation of -1,2,3-triazol-4-yl)methyl)amino)methyl)-10,11-methylenedioxycamptothecin (compound I-33)

[0119] Replacing benzyl bromide in the step of Example 3 with 2-trifluoromethylbenzyl bromide, and using the same raw materials, reagents, and preparation methods as in Example 3, yielded a yellow solid I-33 (28.64 mg) with a yield of 39%. mp 245-246℃. 1 HNMR (600 MHz, DMSO- d 6) d 7.97 (s, 1H), 7.75 (d, J = 7.7 Hz, 1H), 7.65 – 7.61(m, 2H), 7.52 (t, J = 7.6 Hz, 1H), 7.43 (s, 1H), 7.18 (s, 1H), 7.06 (d, J = 7.7Hz, 1H), 6.46 (s, 1H), 6.23 (s, 2H), 5.72 (s, 2H), 5.37 (s, 2H), 5.24 (s,2H), 4.17 (s, 2H), 3.86 (s, 2H), 1.97 – 1.92 (m, 1H), 1.85 – 1.79 (m, 2H), 0.83 (s, 3H). 13 C NMR (150 MHz, DMSO- d 6) d 173.07, 157.33, 151.30, 150.60,150.12, 149.16, 147.68, 146.59, 133.72, 130.53, 130.16, 129.33, 128.25,126.67, 125.07, 118.57, 105.76, 103.09, 100.00, 96.35, 72.94, 65.78, 32.07,29.95, 14.48, 8.30. HRMS: m / z [M+H] ＋ calcd for C 33 H 28F3N6O6,661.2017; found,661.2017.

[0120] Example 347 - (((((1-3-trifluoromethyl)benzyl-1) H Preparation of -1,2,3-triazol-4-yl)methyl)amino)methyl)-10,11-methylenedioxycamptothecin (compound I-34)

[0121] Replacing benzyl bromide in the steps of Example 3 with 3-trifluoromethylbenzyl bromide, and using the same raw materials, reagents, and preparation methods as in Example 3, yielded a yellow solid I-34 (32.36 mg) with a yield of 42%. mp>250℃. 1 H NMR (500 MHz, DMSO-) d 6) d 8.12 (s, 1H), 7.77 – 7.67 (m, 2H), 7.67 – 7.55 (m, 3H), 7.48 (s, 1H), 7.23 (s, 1H), 6.52 (s, 1H), 6.28 (d, J = 2.7 Hz, 2H), 5.72 (s,2H), 5.43 (s, 2H), 5.28 (s, 2H), 4.23 (s, 2H), 3.91 (s, 2H), 2.00 (dd, J =12.5, 6.8 Hz, 1H), 1.87 (dt, J = 17.9, 7.0 Hz, 2H), 0.88 (d, J = 7.3 Hz, 3H). 13 CNMR (125 MHz, DMSO- d 6) d 173.02, 157.25, 151.24, 150.54, 150.03, 149.10,147.59, 146.49, 138.03, 132.51, 130.43, 125.33, 124.98, 118.51, 105.68,103.05, 100.71, 96.29, 72.88, 65.71, 52.44, 50.53, 44.52, 31.62, 30.66,30.29, 29.48, 29.18, 22.57, 14.44, 8.27. HRMS: m / z [M+H] ＋ calcd for C33 H 28 F3N6O6,661.2017; found, 661.2019.

[0122] Example 357-(((((1-2-trifluoromethoxy)benzyl-1 H Preparation of -1,2,3-triazol-4-yl)methyl)amino)methyl)-10,11-methylenedioxycamptothecin (compound I-35)

[0123] Replacing benzyl bromo with 2-trifluoromethoxybenzyl bromide in the steps of Example 3, and using the same raw materials, reagents, and preparation methods as in Example 3, yielded a yellow solid I-35 (32.78 mg) with a yield of 45%. mp > 250°C. 1 H NMR (600 MHz, DMSO-) d 6) d 7.97 (s, 1H), 7.61 (s, 1H), 7.47 – 7.43 (m, 2H), 7.40 –7.35 (m, 2H), 7.23 (d, J = 7.6 Hz, 1H), 7.18 (s, 1H), 6.46 (s, 1H), 6.23 (s,2H), 5.62 (s, 2H), 5.37 (s, 2H), 5.24 (s, 2H), 4.17 (s, 2H), 3.88 (s, 2H),1.94 (d, J = 9.1 Hz, 1H), 1.82 (dd, J = 14.5, 7.3 Hz, 2H), 0.82 (d, J = 6.6 Hz, 3H). 13 C NMR (150 MHz, DMSO- d 6) d 173.08, 157.32, 150.61, 150.12, 147.69,146.77, 130.94, 130.94, 128.83, 128.38, 125.94, 125.05, 121.46, 121.10,105.76, 99.99, 96.36, 72.93, 65.78, 50.59, 48.01, 30.73, 22.62, 8.31. HRMS: m / z [M+H] ＋ calcd for C 33 H28 F3N6O7,677.1966; found, 677.1964.

[0124] Example 367-(((((1-3-trifluoromethoxy)benzyl-1 H Preparation of -1,2,3-triazol-4-yl)methyl)amino)methyl)-10,11-methylenedioxycamptothecin (compound I-36)

[0125] Replacing benzyl bromo with 3-trifluoromethoxybenzyl bromide in the steps of Example 3, and using the same raw materials, reagents, and preparation methods as in Example 3, yielded a yellow solid I-36 (27.96 mg) with a yield of 38%. mp 227-228℃. 1 HNMR (600 MHz, DMSO- d 6) d 8.04 (s, 1H), 7.59 (s, 1H), 7.45 (d, J = 29.5 Hz, 2H),7.29 (s, 2H), 7.23 (s, 1H), 7.18 (s, 1H), 6.46 (s, 1H), 6.23 (s, 2H), 5.61(s, 2H), 5.37 (s, 2H), 5.22 (s, 2H), 4.17 (s, 2H), 3.84 (s, 2H), 1.85 – 1.72 (m, 2H), 0.85 – 0.82 (m, 3H). 13 C NMR (150 MHz, DMSO- d 6) d 173.07, 157.32,151.30, 150.60, 150.10, 149.16, 148.95, 148.94, 147.66, 146.56, 139.36,131.37, 127.41, 121.05, 120.92, 118.57, 105.74, 103.10, 100.76, 96.34, 72.94,65.77, 52.39, 50.58, 30.74, 22.61, 8.31. HRMS: m / z [M+H] ＋ calcd for C 33 H 28 F3N6O7,677.1966; found, 677.1957.

[0126] Example 377-(((((1-hydroxypropyl)benzyl-1 H Preparation of -1,2,3-triazol-4-yl)methyl)amino)methyl)-10,11-methylenedioxycamptothecin (compound I-37)

[0127] Replacing benzyl bromopropane-1-ol with benzyl bromopropane in the steps of Example 3, and using the same raw materials, reagents, and preparation methods as in Example 3, yielded a yellow solid I-37 (11.23 mg) with a yield of 18%. mp 168-169℃. 1 H NMR (600 MHz, DMSO-) d 6) d 7.93 (s, 1H), 7.65 (s, 1H), 7.45 (s, 1H), 7.19 (s, 2H), 6.46 (s, 1H), 6.24 (s, 2H), 5.37 (s, 2H), 5.27 (s, 2H), 4.44 (s, 1H), 4.28(s, 2H), 3.35 (s, 2H), 1.94 (s, 2H), 1.82 – 1.74 (m, 4H), 1.43 – 1.38 (m,2H), 0.82 (s, 3H). 13 C NMR (150 MHz, DMSO- d 6) d 174.81, 173.08, 157.34, 151.34,150.63, 150.14, 149.20, 147.72, 146.61, 118.59, 117.86, 105.78, 103.11,100.00, 96.38, 72.94, 65.77, 60.49, 50.62, 49.72, 35.63, 31.81, 29.51, 27.08,25.63, 22.62, 14.48, 8.31. HRMS: m / z [M+H] ＋ calcd for C 28 H 28 N6O7,561.2119; found,561.2120.

[0128] Example 387-(((((1-2,3-difluoro)benzyl-1 H Preparation of -1,2,3-triazol-4-yl)methyl)amino)methyl)-10,11-methylenedioxycamptothecin (compound I-38)

[0129] Replacing benzyl bromo2-difluorobromo2- with benzyl bromo2- in the steps of Example 3, and using the same raw materials, reagents, and preparation methods as in Example 3, yielded a yellow solid I-38 (24.32 mg) with a yield of 35%. mp > 250°C. 1 H NMR (600MHz, DMSO- d 6) d 8.01 (s, 1H), 7.60 (s, 1H), 7.39 (td, J = 10.8, 9.6, 5.9 Hz,2H), 7.18 (s, 1H), 7.10 (s, 1H), 6.46 (s, 1H), 6.23 (s, 2H), 5.53 (s, 2H),5.37 (s, 2H), 5.22 (s, 2H), 4.17 (s, 2H), 3.84 (s, 2H), 1.98 (s, 1H), 1.86 –1.77 (m, 2H), 1.29 (s, 1H), 0.85 – 0.82 (m, 3H). 13 C NMR (150 MHz, DMSO- d 6) d 173.07, 157.32, 151.30, 150.61, 150.10, 149.16, 149.01, 148.93, 148.85,147.67, 146.57, 125.56, 125.05, 118.57, 118.47, 118.36, 117.90, 117.79,105.74, 103.09, 100.78, 100.00, 96.35, 65.77, 52.05, 50.58, 30.74, 22.62,14.48, 8.31. HRMS: m / z [M+H] ＋ calcd for C 32 H 27 F2N6O6,629.1955; found, 629.1951.

[0130] Example 397 - (((((1-2, 3, 4-trifluoro)benzyl-1 H Preparation of -1,2,3-triazol-4-yl)methyl)amino)methyl)-10,11-methylenedioxycamptothecin (compound I-39)

[0131] Replacing benzyl bromo2-trifluorobromo2- with benzyl bromo2- in the steps of Example 3, and using the same raw materials, reagents, and preparation methods as in Example 3, yielded a yellow solid I-39 (30.08 mg) with a yield of 42%. mp > 250°C. 1 H NMR (600 MHz, DMSO-) d 6) d 8.02 (s, 1H), 7.60 (s, 1H), 7.42 (s, 1H), 7.26 (s, 2H), 7.18 (s, 1H), 6.46 (s, 1H), 6.23 (s, 2H), 5.53 (s, 2H), 5.37 (s, 2H), 5.23(s, 2H), 4.18 (s, 2H), 3.83 (s, 2H), 1.95 (dt, J = 14.0, 6.5 Hz, 1H), 1.85 –1.78 (m, 2H), 1.29 (s, 1H), 0.84 (d, J = 10.0 Hz, 3H). 13 C NMR (150 MHz, DMSO- d 6) d 173.09, 157.32, 151.29, 150.61, 150.12, 149.16, 147.68, 146.59, 133.69,125.06, 118.57, 113.62, 105.75, 103.09, 100.78, 96.35, 95.24, 72.94, 65.77,51.82, 50.59, 32.07, 30.74, 29.95, 22.61, 14.48, 8.31. HRMS: m / z [M+H] ＋ calcdfor C 32 H 26 F3N6O6,647.1860; found, 647.1852.

[0132] Example 407-(((((1-2,3-dimethyl)benzyl-1 H Preparation of -1,2,3-triazol-4-yl)methyl)amino)methyl)-10,11-methylenedioxycamptothecin (compound I-40)

[0133] Replacing benzyl bromide in the steps of Example 3 with 2,3-dimethylbenzyl bromide, and using the same raw materials, reagents, and preparation methods as in Example 3, yielded a yellow solid I-40 (28.4 mg) with a yield of 42%. mp>250℃. 1 H NMR (600 MHz, DMSO-) d 6) d 7.95 (s, 1H), 7.63 (s, 1H), 7.44 (s, 1H), 7.19 (s, 1H),7.08 – 7.04 (m, 2H), 6.97 (d, J = 6.9 Hz, 1H), 6.46 (s, 1H), 6.27 – 6.22 (m,2H), 5.43 (s, 2H), 5.37 (s, 3H), 5.26 (s, 2H), 4.23 (s, 2H), 3.90 (s, 2H),2.12 (s, 6H), 1.95 (dd, J = 12.2, 7.4 Hz, 1H), 1.86 – 1.79 (m, 2H), 0.84 (d, J = 8.4 Hz, 3H). 13 C NMR (150 MHz, DMSO- d 6) d 173.07, 157.32, 151.36, 150.61,150.14, 147.72, 146.55, 137.08, 133.86, 130.29, 129.68, 126.00, 125.07,118.62, 105.79, 103.14, 100.84, 96.38, 72.94, 65.78, 53.16, 50.64, 40.47,30.74, 22.62, 19.84, 19.56, 14.48, 8.31. HRMS: m / z [M+H] ＋ calcd for C 34 H 33 N6O6,621.2456 found, 621.2450.

[0134] Example 417 - (((((1-Cyclopropylmethyl)benzyl-1 H Preparation of -1,2,3-triazol-4-yl)methyl)amino)methyl)-10,11-methylenedioxycamptothecin (compound I-41)

[0135] Replacing benzyl bromo in the step of Example 3 with 1-bromomethylcyclopropane, and using the same raw materials, reagents, and preparation methods as in Example 3, yielded a yellow solid I-41 (17.53 mg), with a yield of 29%. mp 243-244℃. 1 HNMR (600 MHz, DMSO- d 6) d 7.96 (s, 1H), 7.64 (s, 1H), 7.44 (s, 1H), 7.18 (s,1H), 6.46 (s, 1H), 6.24 (s, 2H), 5.37 (s, 2H), 5.23 (s, 2H), 4.23 – 4.17 (m,1H), 4.14 (s, 2H), 3.84 (s, 1H), 1.94 (s, 1H), 1.89 – 1.77 (m, 2H), 1.25 (s,2H), 0.83 (s, 3H), 0.49 (s, 2H), 0.35 (s, 2H). 13 C NMR (150 MHz, DMSO- d 6) d 173.09, 157.33, 151.32, 150.61, 150.12, 149.17, 147.70, 146.61, 125.10,118.57, 105.76, 103.10, 100.86, 96.34, 72.93, 65.78, 54.15, 50.58, 40.46,35.63, 31.81, 30.72, 27.13, 25.63, 22.62, 14.49, 11.88, 8.31, 4.22. HRMS: m / z [M+H] ＋ calcd for C 29 H 29 N6O6,557.2143; found, 557.2148.

[0136] Example 427 - (((((1-cyclopentylmethyl)benzyl-1 H Preparation of -1,2,3-triazol-4-yl)methyl)amino)methyl)-10,11-methylenedioxycamptothecin (compound I-42)

[0137] Replacing benzyl bromo in the step of Example 3 with 1-bromomethylcyclopentane, and using the same raw materials, reagents, and preparation methods as in Example 3, yielded a yellow solid I-42 (23.52 mg) with a yield of 37%. mp > 250 °C. 1 H NMR (600 MHz, DMSO-) d 6) d 7.98 (s, 1H), 7.49 (s, 1H), 7.23 (s, 2H), 6.50 (s, 1H), 6.28 (s, 2H), 5.63 (s, 2H), 5.41 (s, 2H), 5.31 (d, J = 5.3 Hz, 2H), 4.25 –4.23 (m, 2H), 4.13 (t, J = 6.1 Hz, 2H), 4.05 – 4.03 (m, 2H), 3.98 – 3.96 (m,4H), 2.03 – 1.98 (m, 1H), 1.86 (dt, J = 15.2, 7.1 Hz, 2H), 1.57 – 1.52 (m,8H), 0.87 (s, 3H). 13 C NMR (150 MHz, DMSO- d 6) d 172.99, 169.76, 167.51, 132.23,132.13, 129.19, 73.40, 72.93, 65.01, 64.28, 43.58, 30.60, 30.50, 30.31,30.05, 28.89, 25.04, 23.76, 22.93, 19.08, 14.43, 14.06, 14.04, 11.33, 8.31.HRMS: m / z [M+H] + calcd for C 31 H 33 N6O6,585.2456; found, 585.2456.

[0138] Example 437-(((((1-cyclohexylmethyl)benzyl-1 H Preparation of -1,2,3-triazol-4-yl)methyl)amino)methyl)-10,11-methylenedioxycamptothecin (compound I-43)

[0139] Replacing benzyl bromo in the step of Example 3 with 1-bromomethylcyclohexane, and using the same raw materials, reagents, and preparation methods as in Example 3, yielded a yellow solid I-43 (26.49 mg) with a yield of 40%. mp > 250°C. 1 H NMR (500 MHz, DMSO-) d 6) d 7.93 (s, 1H), 7.61 (s, 1H), 7.46 (s, 1H), 7.23 (s, 1H), 6.53 (s, 1H), 6.28 (d, J = 3.7 Hz, 2H), 5.42 (s, 2H), 5.23 (s, 2H), 4.26 –4.15 (m, 3H), 3.88 (s, 2H), 1.88 (dd, J = 10.8, 7.2 Hz, 2H), 1.77 (s, 1H),1.70 – 1.63 (m, 2H), 1.61 (s, 1H), 1.48 (d, J = 12.9 Hz, 2H), 1.37 – 1.21 (m,4H), 1.21 – 1.07 (m, 4H), 0.89 (t, J = 7.4 Hz, 3H). 13 C NMR (125 MHz, DMSO- d 6) d 173.03, 157.23, 151.21, 150.52, 149.98, 149.06, 147.54, 146.47, 124.92,123.68, 118.50, 105.64, 103.05, 100.65, 96.27, 72.88, 65.72, 55.52, 50.51,44.64, 38.60, 32.02, 30.67, 30.23, 26.21, 25.50, 8.28. HRMS: m / z [M+H] ＋ calcdfor C 32 H 35 N6O6,599.2613; found, 599.2610.

[0140] Example 447-(((((1-2-morpholinoethyl)benzyl-1 HPreparation of -1,2,3-triazol-4-yl)methyl)amino)methyl)-10,11-methylenedioxycamptothecin (compound I-44)

[0141] Replacing benzyl bromo in the step of Example 3 with 4-(2-bromoethyl)morpholine, and using the same raw materials, reagents, and preparation methods as in Example 3, yielded a pale yellow solid I-44 (22.69 mg), with a yield of 34%. mp 176-177℃. 1 HNMR (400 MHz, DMSO- d 6) d 7.96 (s, 1H), 7.70 (s, 1H), 7.50 (s, 1H), 7.24 (s,1H), 6.49 (s, 1H), 6.29 (s, 2H), 5.42 (s, 2H), 5.32 (d, J = 5.7 Hz, 2H), 4.45(s, 2H), 4.24 (s, 2H), 3.86 (s, 2H), 3.51 (t, J = 4.6 Hz, 4H), 2.69 (t, J = 8.3Hz, 2H), 2.00 (d, J = 8.0 Hz, 2H), 1.90 – 1.83 (m, 2H), 0.87 (s, 3H). 13 C NMR (150 MHz, DMSO-) d 6) d 174.88, 173.08, 171.80, 157.33, 150.64, 150.15, 138.80,134.79, 130.18, 101.33, 101.00, 97.91, 96.66, 72.93, 66.59, 65.76, 57.83,53.47, 35.63, 31.80, 30.71, 29.60, 29.54, 29.34, 29.26, 29.21, 29.09, 27.07,22.62, 14.46, 8.31. HRMS: m / z [M+H] ＋ calcd for C 31 H 33 N7O7,616.2514; found,616.2501.

[0142] Example 457-(((((1-2-piperidinylethyl)benzyl-1 H Preparation of -1,2,3-triazol-4-yl)methyl)amino)methyl)-10,11-methylenedioxycamptothecin (compound I-45)

[0143] Replacing benzyl bromodiphenyl ether with 1-(2-bromoethyl)piperidine in the steps of Example 3, and using the same raw materials, reagents, and preparation methods as in Example 3, yielded a pale yellow solid I-45 (21.68 mg) with a yield of 32%. mp 186-187℃. 1 HNMR (400 MHz, DMSO- d 6) d 8.08 (s, 1H), 7.71 (s, 1H), 7.51 (s, 1H), 7.24 (s,1H), 6.50 (s, 1H), 6.32 – 6.25 (m, 2H), 5.42 (s, 2H), 5.32 (s, 2H), 4.46 –3.99 (m, 4H), 3.17 (d, J = 4.9 Hz, 2H), 2.38 – 2.30 (m, 2H), 2.06 – 1.91 (m,2H), 1.87 (q, J = 7.3 Hz, 2H), 1.44 (dd, J = 20.6, 13.6 Hz, 4H), 1.17 (s, 4H), 0.88 (t, J = 7.3 Hz, 3H), 0.77 (d, J = 8.1 Hz, 2H). 13 C NMR (100 MHz, DMSO- d 6) d 171.92, 156.19, 150.29, 149.51, 149.03, 148.19, 146.62, 145.42, 129.04,123.96, 117.52, 104.70, 102.04, 99.75, 95.30, 71.80, 64.64, 49.51, 49.50,34.51, 30.67, 29.61, 28.47, 28.41, 28.22, 28.08, 27.96, 25.94, 24.50, 21.48,13.34, 7.18. HRMS: m / z [M+H] ＋calcd for C 32 H 36 N7O6,614.2722; found, 614.2707.

[0144] Example 467-((((((1-2-pyrrolidine-1-yl)-ethyl)-1 H Preparation of -1,2,3-triazol-4-yl)methyl)amino)methyl)-10,11-methylenedioxycamptothecin (compound I-46)

[0145] Replacing benzyl bromo in the step of Example 3 with 1-(2-bromoethyl)pyrrolidine, and using the same raw materials, reagents, and preparation methods as in Example 3, yielded a yellow solid I-46 (13.42 mg) with a yield of 20%. mp 176-177℃. 1 HNMR (400 MHz, DMSO- d 6) d 8.02 (s, 1H), 7.70 (s, 1H), 7.50 (s, 1H), 7.24 (s,1H), 6.49 (s, 1H), 6.29 (s, 2H), 5.42 (s, 2H), 5.29 (s, 2H), 4.56 (s, 2H),4.25 (s, 2H), 3.91 (s, 2H), 1.99 (dt, J = 13.6, 6.9 Hz, 4H), 1.89 – 1.83 (m,2H), 1.73 (s, 4H), 1.45 (t, J = 7.4 Hz, 4H), 0.85 (s, 3H). 13 C NMR (100 MHz, DMSO- d 6) d 173.01, 157.28, 151.30, 150.58, 150.10, 149.17, 146.54, 130.12,125.05, 118.54, 105.75, 103.07, 100.82, 96.34, 72.88, 65.71, 53.77, 50.56,35.59, 31.75, 30.68, 29.55, 29.49, 29.30, 29.16, 29.04, 27.02, 25.58, 23.39,22.56, 14.42. HRMS: m / z [M+H] ＋calcd for C 31 H 34 N7O6,600.2565; found, 600.2558.

[0146] Example 477-(((((1-2-4-methylpiperazin-1-yl)ethyl-1) H Preparation of -1,2,3-triazol-4-yl)methyl)amino)methyl)-10,11-methylenedioxycamptothecin (compound I-47)

[0147] Replacing benzyl bromo in the step of Example 3 with 1-(2-bromoethyl)-4-methylpiperazine, and using the same raw materials, reagents, and preparation methods as in Example 3, yielded a yellow solid I-47 (10.77 mg) with a yield of 16%. mp 166-167℃. 1 H NMR (400 MHz, DMSO- d 6) d 8.09 (d, J = 7.9 Hz, 1H), 7.76 (s, 1H), 7.66 (s,1H), 7.30 (s, 1H), 7.27 – 7.20 (m, 2H), 6.71 – 6.60 (m, 2H), 6.32 (d, J = 8.1Hz, 1H), 5.42 (s, 1H), 5.32 (t, J = 5.0 Hz, 2H), 4.49 (s, 1H), 4.11 (d, J = 5.3Hz, 2H), 3.17 (d, J = 4.9 Hz, 5H), 2.73 (s, 2H), 2.67 (s, 2H), 2.00 (d, J = 8.0Hz, 6H), 1.46 (d, J = 7.9 Hz, 4H), 0.85 (s, 3H). 13 C NMR (150 MHz, DMSO- d 6) d174.82, 152.61, 139.66, 130.17, 129.75, 129.32, 128.28, 128.15, 127.93,126.76, 124.85, 124.63, 123.66, 123.27, 120.48, 64.29, 44.28, 41.71, 35.62,34.96, 34.20, 31.81, 30.92, 29.55, 29.22, 29.10, 27.13, 27.08, 25.63, 25.02,22.62, 14.48. HRMS: m / z [M+H] ＋ calcd for C 32 H 37 N8O6,629.2831; found, 629.2836.

[0148] Example 487-(((((1-2-dimethylamino)ethyl-1 H Preparation of -1,2,3-triazol-4-yl)methyl)amino)methyl)-10,11-methylenedioxycamptothecin (compound I-48)

[0149] 2-bromo- N , N 1-Dimethylethane-1-amine replaces benzyl bromide in the step of Example 3. The other required raw materials, reagents, and preparation methods are the same as in Example 3. A yellow solid I-48 (15.50 mg) can be prepared with a yield of 25%. mp 166-167℃. 1 H NMR (400 MHz, DMSO- d 6) d 8.14 (s, 1H), 7.73 (s, 1H), 7.52 (s, 1H),7.25 (s, 1H), 6.51 (s, 1H), 6.30 (s, 2H), 5.42 (s, 2H), 5.35 (s, 3H), 4.63(s, 2H), 4.35 (s, 2H), 4.03 (s, 2H), 3.18 – 3.08 (m, 2H), 2.43 (s, 6H), 2.04– 1.95 (m, 2H), 0.89 (d, J = 7.2 Hz, 3H). 13 C NMR (150 MHz, DMSO- d 6) d174.86,173.05, 157.31, 150.65, 150.14, 147.77, 146.51, 130.18, 125.12, 118.68,105.82, 103.20, 96.47, 72.93, 65.76, 50.67, 40.44, 35.63, 31.80, 30.71,29.60, 29.34, 29.26, 29.09, 27.07, 25.64, 22.62, 14.48, 8.32.HRMS: m / z [M+H] ＋ calcd for C 29 H 31 N7O6,574.2409; found, 574.2403.

[0150] Example 497-(((((1-2-Diethylamino)ethyl-1 H Preparation of -1,2,3-triazol-4-yl)methyl)amino)methyl)-10,11-methylenedioxycamptothecin (compound I-49)

[0151] 2-azide- N , N Replacing benzyl bromo in the step of Example 3 with diethylethane-1-amine, and using the same raw materials, reagents, and preparation methods as in Example 3, yielded a yellow solid I-49 (18.71 mg) with a yield of 28%. mp 206-207℃. 1 H NMR (400 MHz, DMSO- d 6) d 8.51 (s, 1H), 7.86 (s, 1H), 7.60 (s, 1H), 7.28 (s, 1H), 6.35 (s, 2H), 5.44 (d, J = 7.4 Hz, 4H), 4.96 (d, J = 6.9 Hz, 2H), 4.80 (s, 2H), 4.61 (s, 2H), 3.65 (d, J = 6.8 Hz, 2H), 3.19 (dd, J = 14.6, 7.6Hz, 5H), 1.87 (p, J = 7.0 Hz, 2H), 1.46 (s, 1H), 1.23 (s, 6H), 0.88 (t, J= 7.3Hz, 3H). 13 C NMR (150 MHz, DMSO- d 6) d 172.97, 157.24, 151.87, 150.70, 149.93,148.00, 146.16, 130.13, 127.40, 125.05, 106.00, 103.50, 100.90, 96.76, 72.88,65.91, 50.17, 48.98, 47.23, 44.66, 31.78, 31.78, 30.68, 29.57, 29.07, 27.04,25.61, 22.58, 14.37, 8.85, 8.23. HRMS: m / z [M+H] ＋ calcd for C 31 H 35 N7O6,602.2722;found, 602.2708.

[0152] Example 5010, 11-methylenedioxycamptothecin-20 ( S Preparation of 1-propyne (compound II-1)

[0153] In a 100 mL three-necked flask, 1.57 g (4 mmol) and NaH (0.144 g, 6 mmol), and 20 mL of dry DMF were added sequentially. The mixture was stirred at 0 °C for 30 min, and then 0.177 g (6 mmol) of 3-bromopropyne was added. After the addition was complete, the reaction mixture was moved to room temperature and stirred for another 2 h. After the reaction was confirmed to be complete by TLC, the reaction mixture was slowly poured into ice water to quench the reaction. The aqueous phase was extracted three times with DCM, and the organic phases were combined and dried over anhydrous MgSO4. The mixture was filtered, concentrated under reduced pressure to remove the filtrate, and the residue was purified by silica gel column chromatography (DCM: MeOH = 200: 1) to give 1.02 g of yellow solid (II-1), with a yield of 59%. 1 HNMR (400 MHz, DMSO- d 6) d 8.54 (s, 1H), 7.51 (s, 1H), 7.46 (s, 1H), 7.19 (s,1H), 6.52 (s, 1H), 6.29 (d, J = 2.5 Hz, 2H), 5.40 (d, J= 9.3 Hz, 2H), 3.96 –3.75 (m, 2H), 3.30 (d, J = 4.8 Hz, 1H), 2.56 (dt, J = 9.1, 2.5 Hz, 2H), 1.87(d, J = 28.0 Hz, 2H), 0.85 (t, J = 7.3 Hz, 3H). 13 C NMR (100 MHz, DMSO- d 6) d 172.90, 162.77, 158.03, 152.21, 150.72, 149.38, 147.83, 146.75, 133.77,129.29, 126.28, 120.07, 105.47, 103.87, 103.15, 96.12, 78.72, 74.39, 72.72,72.54, 65.62, 36.25, 31.24, 8.20. MS-ESI (m / z): 431.12 [M + H] + .

[0154] Example 5110, 11-methylenedioxy-20 ( S )- O -((1-benzyl-1 H Preparation of 1,2,3-triazol-4-yl)-methyl)camptothecin (compound II-2)

[0155] Intermediate II-1 (43 mg, 0.1 mmol), benzyl azide (26.6 mg, 0.2 mmol), copper sulfate pentahydrate (62.5 mg, 0.25 mmol), sodium ascorbate (49.53 mg, 0.25 mmol), and 10 mL of DCM:H2O (1:1) were added sequentially to a 100 mL round-bottom flask. The mixture was stirred at room temperature for 12 h. After the reaction was complete as detected by TLC, the mixture was extracted three times with DCM, and the organic phase was washed with saturated brine. The organic phase was dried over anhydrous MgSO4, filtered, and the filtrate was removed by rotary evaporation. The residue was purified by column chromatography to give a yellow solid II-2 (21.3 mg), with a yield of 33%. mp>250℃. 1 H NMR (400 MHz, DMSO- d 6) d8.22 (s,1H), 7.44 (s, 1H), 7.41 (s, 1H), 7.35 (s, 1H), 7.27 – 7.21 (m, 3H), 7.07 (s,1H), 6.78 (dd, J = 6.5, 3.0 Hz, 2H), 6.49 (s, 1H), 6.27 (d, J = 2.4 Hz, 2H), 6.00 (d, J = 2.4 Hz, 1H), 5.42 (d, J = 8.6 Hz, 2H), 5.34 (s, 2H), 3.99 (d, J =5.7 Hz, 1H), 3.71 (d, J = 3.3 Hz, 1H), 1.93 – 1.77 (m, 2H), 0.86 (t, J = 7.3Hz, 3H). 13 C NMR (100 MHz, DMSO- d 6) d 171.93, 156.80, 150.73, 149.14, 148.77,147.93, 146.15, 145.06, 139.85, 135.46, 130.46, 129.45, 127.95, 127.11,126.23, 124.80, 123.07, 118.41, 104.25, 102.67, 101.96, 95.07, 71.66, 64.78,61.09, 54.31, 51.58, 29.75, 24.67, 7.13. HRMS: m / z [M+H] ＋ calcd for C 31 H 26 N5O6,564.1878; found, 564.1863.

[0156] Example 5210, 11-methylenedioxy-20 ( S )- O -(((1-4-methoxybenzyl)-1 H Preparation of 1,2,3-triazol-4-yl)methoxy)camptothecin (compound II-3)

[0157] Replacing benzyl azide in the step of Example 51 with 1-(azidomethyl)-4-methoxybenzene, and using the same raw materials, reagents, and preparation methods as in Example 51, yielded a yellow solid II-3 (28.93 mg) with a yield of 38%. mp 236-237℃. 1 H NMR (400 MHz, DMSO- d 6) d 8.19 (s, 1H), 7.44 (s, 1H), 7.36 (d, J =7.5 Hz, 2H), 7.08 (s, 1H), 6.78 (s, 4H), 6.50 (s, 1H), 6.27 (s, 2H), 6.00(dd, J = 5.9, 3.3 Hz, 1H), 5.46 (d, J = 16.3 Hz, 1H), 5.41 (s, 1H), 5.26 (d, J =2.1 Hz, 2H), 3.98 (dd, J = 14.6, 5.9 Hz, 1H), 3.74 (s, 3H), 3.69 (dd, J = 14.9, 3.6 Hz, 1H), 2.00 (dt, J = 13.8, 6.9 Hz, 1H), 1.85 (p, J = 7.1 Hz, 2H), 0.85(d, J = 7.5 Hz, 3H). 13 C NMR (100 MHz, DMSO- d 6) d 173.01, 159.29, 157.88, 151.81,150.22, 149.85, 149.03, 147.23, 146.13, 140.90, 131.58, 128.93, 128.35,125.88, 123.85, 119.52, 114.38, 105.32, 103.74, 103.05, 96.18, 72.77, 65.87,62.17, 55.57, 52.25, 30.85, 25.77, 22.56, 8.20. HRMS: m / z [M+H] ＋ calcd forC 32 H 28N5O7,594.1983; found, 594.1975.

[0158] Example 5310, 11-methylenedioxy-20 ( S )- O -(((1-4-methylbenzyl)-1 H Preparation of -1,2,3-triazol-4-yl)methoxy)camptothecin (compound II-4)

[0159] Replacing the benzyl azide in step 51 with 1-(azidomethyl)-4-methylbenzene, and using the same raw materials, reagents, and preparation methods as in Example 51, yielded a yellow solid II-4 (28.93 mg) with a yield of 38%. mp>250℃. 1 H NMR (400 MHz, DMSO- d 6) d 8.16 (s, 1H), 7.44 (s, 1H), 7.37 (s, 1H), 7.31 (s, 1H), 7.08 (s, 1H), 7.03 (d, J = 7.7 Hz, 2H), 6.75 – 6.68 (m, 2H), 6.47 (s,1H), 6.28 (d, J = 2.2 Hz, 2H), 5.99 (dd, J = 5.7, 3.4 Hz, 1H), 5.42 (d, J = 8.9Hz, 2H), 5.29 (s, 2H), 3.96 (dd, J = 14.6, 5.9 Hz, 1H), 3.71 (dd, J = 14.6, 3.4Hz, 1H), 2.26 (s, 3H), 1.85 (s, 2H), 0.87 (t, J = 7.3 Hz, 3H). 13 C NMR (100 MHz, DMSO- d 6) d172.97, 157.89, 151.80, 150.25, 149.87, 149.01, 147.25, 146.13,141.00, 137.52, 133.47, 131.57, 130.48, 129.57, 127.42, 127.31, 125.86,123.96, 119.51, 105.35, 103.74, 103.04, 96.19, 72.74, 65.86, 62.17, 52.54,30.89, 25.79, 21.09, 8.21.HRMS: m / z [M+H] ＋ calcd for C 32 H 28 N5O6,578.2034; found,578.2026.

[0160] Example 5410, 11-methylenedioxy-20 ( S )- O -(((1-4-Fluorobenzyl)-1 H Preparation of -1,2,3-triazol-4-yl)methoxy)camptothecin (compound II-5)

[0161] Replacing benzyl azide in step 51 with 1-(azidomethyl)-4-fluorobenzene, and using the same raw materials, reagents, and preparation methods as in Example 51, yielded a yellow solid II-5 (22.23 mg) with a yield of 38%. mp 228-229℃. 1 H NMR (400 MHz, DMSO- d 6) d 8.25 (s, 1H), 7.47 – 7.36 (m, 3H), 7.11 –7.02 (m, 3H), 6.93 – 6.83 (m, 2H), 6.53 (s, 1H), 6.27 (d, J = 2.8 Hz, 2H), 6.00 (dd, J = 5.6, 3.2 Hz, 1H), 5.43 (d, J = 11.1 Hz, 2H), 5.32 (d, J = 2.7 Hz,2H), 4.12 – 3.95 (m, 1H), 3.66 (dd, J= 14.6, 3.2 Hz, 1H), 1.92 – 1.77 (m,2H), 0.86 (t, J = 7.3 Hz, 3H). 13 C NMR (100 MHz, DMSO- d 6) d 171.95, 162.17, 159.75, 156.77, 150.74, 149.08, 148.75, 147.95, 146.13, 145.03, 139.84, 131.70, 131.67, 130.46, 129.47, 129.03, 128.58, 128.49, 124.81, 122.94, 118.44, 114.86, 114.64, 104.22, 102.66, 101.97, 95.03, 71.67, 64.79, 61.07, 50.81, 29.74, 24.67, 7.12. HRMS: m / z [M+H] + calcd for C 31 H 25 FN5O6,582.1783;found, 582.1771.

[0162] Example 5510, 11-methylenedioxy-20 ( S )- O -(((1-4-bromobenzyl)-1 H Preparation of 1,2,3-triazol-4-yl)methoxy)camptothecin (compound II-6)

[0163] Replacing benzyl azide in step 51 with 1-(azidomethyl)-4-fluorobenzene, and using the same raw materials, reagents, and preparation methods as in Example 51, yielded a yellow solid II-6 (22.87 mg) with a yield of 36%. mp 236-237℃. 1 H NMR (400 MHz, DMSO- d 6) d 8.26 (s, 1H), 7.50 – 7.35 (m, 5H), 7.07 (s,1H), 6.80 – 6.62 (m, 2H), 6.51 (s, 1H), 6.28 (s, 2H), 6.01 (d, J = 2.2 Hz, 1H), 5.43 (d, J= 12.9 Hz, 2H), 5.32 (d, J = 6.0 Hz, 2H), 4.05 (dd, J = 14.6, 5.6 Hz, 1H), 3.67 (dd, J = 14.6, 3.3 Hz, 1H), 1.93 – 1.78 (m, 2H), 0.86 (t, J =7.4 Hz, 3H). 13 C NMR (100 MHz, DMSO- d 6) δ 173.04, 157.88, 151.85, 150.19,149.86, 149.04, 147.20, 146.11, 141.01, 136.01, 131.89, 131.50, 130.56,129.52, 125.90, 124.16, 121.42, 119.54, 105.27, 103.77, 103.07, 96.14, 72.76,65.87, 62.16, 51.93, 30.79, 29.46, 25.66, 8.22. HRMS: m / z [M+H] ＋ calcd forC 31 H 25 BrN5O6,644.0962; found, 644.0967.

[0164] Example 5610, 11-methylenedioxy-20 ( S )- O -(((1-4-bromobenzyl)-1 H Preparation of -1,2,3-triazol-4-yl)methoxy)camptothecin (compound II-7)

[0165] Replacing benzyl azide in step 51 with 1-(azidomethyl)-4-chlorobenzene, and using the same raw materials, reagents, and preparation methods as in Example 51, yielded a yellow solid II-7 (21.88 mg) with a yield of 37%. mp>250℃. 1 H NMR (600 MHz, DMSO- d 6) d 8.21 (s, 1H), 7.37 (d, J= 12.4 Hz, 2H), 7.34 (s,1H), 7.25 – 7.21 (m, 2H), 7.01 (s, 1H), 6.75 (s, 2H), 6.48 (s, 1H), 6.23 (d, J = 3.9 Hz, 2H), 5.99 – 5.93 (m, 1H), 5.46 – 5.35 (m, 2H), 5.35 – 5.24 (m, 2H), 4.00 (dd, J = 14.7, 5.6 Hz, 1H), 3.62 (dd, J = 14.7, 3.2 Hz, 1H), 1.88 – 1.73 (m, 2H), 0.83 – 0.80 (m, 3H). 13 C NMR (150 MHz, DMSO- d 6) d 173.06, 157.93,151.89, 150.25, 149.90, 149.09, 147.26, 146.16, 141.05, 135.63, 132.96,131.55, 130.60, 129.31, 129.02, 125.95, 124.18, 119.60, 105.33, 103.81,103.11, 96.19, 72.81, 65.94, 62.20, 51.95, 30.89, 25.77, 8.27. HRMS: m / z [M+H] ＋ calcd for C 31 H 25 ClN5O6,598.1488; found, 598.1484.

[0166] Example 57: In vitro antitumor activity test of the compounds of the present invention

[0167] Using methods known to those skilled in the art, we tested the growth inhibition of the compounds of this invention on various tumor cell lines to demonstrate their antitumor activity. The selected tumor cell lines included: A549 cells (human non-small cell lung cancer cell line), NCI-H446 (human small cell lung cancer cell line), HCT-116 cells (human colorectal adenocarcinoma cells), MCF-7 cells (human breast cancer cells), HepG2 cells (human liver cancer cells), LNCaP cells (human prostate cancer cells), and Jurkat (human leukemia cells).

[0168] First, we tested the inhibition rate of 1 µM of the I and II series compounds involved in this invention on the A549 cell line, such as... Figure 3 , 4 As shown, most of the I-series compounds involved in this invention exhibit better cell inhibitory activity compared to doxorubicin and FL118. At a concentration of 1 µM, compounds I-3 ~ I-8, I-10, I-11, I-13 ~ I-18, I-20 ~ I-22, I-24, I-25, and I-45 ~ I-49 showed inhibition rates of more than 73.5% against A549, which is higher than that of the positive control drug doxorubicin (70.94%) and FL118 (73.38%). The inhibition rates of compounds I-9, I-12, I-19, I-23, and I-26 ~ I-44 were all below 70%. The inhibition rates of compounds II-2 ~ II-5 were all above 81%, which is better than that of the positive control drug doxorubicin and FL118. Compounds II-6 and II-7 showed poor inhibitory effects, with inhibition rates below 50%.

[0169] Furthermore, the cytotoxicity of compounds I-3 ~ I-8, I-10, I-11, I-13 ~ I-18, I-20 ~ I-22, I-24, I-25, I-45 ~ I-49, and II-2 ~ II-5 against small cell lung cancer NCI-H446 at a concentration of 1 µM was determined using the MTT assay. The results are as follows: Figure 5 As shown, most of the compounds in the I series exhibited cytotoxic activity against NCI-H446 cells comparable to the positive control drugs doxorubicin and FL118, while compounds II-2 to II-5 showed lower activity against NCI-H446 cells than the positive control drugs doxorubicin and FL118.

[0170] To further determine the in vitro antitumor activity of compounds I-3 ~ I-8, I-10, I-11, I-13 ~ I-18, I-20 ~ I-22, I-24, I-25, I-45 ~ I-49, and II-2 ~ II-5, human non-small cell lung cancer cells A549, human colon cancer cells HCT-116, small cell lung cancer cells NCI-H446, human breast cancer cells MCF-7, human liver cancer cells HepG2, human prostate cancer cells LNCaP, and human leukemia cells Jurkat were selected to test their inhibitory IC50 on tumor cells. 50The values ​​were tested using the SRB method. As shown in Table 2, most of the tested compounds exhibited antitumor cell proliferation activity at the nM level. In particular, compounds I-22 and I-45, modified at the 7-position, showed excellent antiproliferative activity against these three cell lines, especially against NCI-H446 cells, with inhibitory activities 806.4 and 4031.8 times that of FL118, respectively. In addition, I-16, I-17, and I-20 also showed strong cytotoxic activity against the NCI-H446 cell line, with inhibitory activities comparable to FL118.

[0171] Table 2 shows the IC50 values ​​of the compounds against A549, HCT116, and NCI-H446 cell lines. 50

[0172]

[0173] The above in vitro tests show that the compounds of the present invention have significant antitumor activity and can be used to prepare drugs for the prevention and / or treatment of cancer.

Claims

1. A 7- and 20-substituted camptothecin derivative, or a stereoisomer and a pharmaceutically acceptable salt thereof, having a structure represented by Formula (I) or Formula (II): Formula (I) Formula (II) wherein R is selected from any one of the following groups: Formula (I) wherein R is selected from any one of the following groups: Formula (II) Formula (II) Formula (I) wherein R is selected from any one of the following groups: Formula (II) wherein R is selected from any one of the following groups: 。 2. Use of the 7- and 20-substituted camptothecin derivative according to claim 1 for the manufacture of a medicament for the prevention and / or treatment of cancer.

3. Use according to claim 2, characterized in that, The cancer is selected from at least one of lung cancer, colon cancer, liver cancer, prostate cancer, leukemia, and breast cancer.

4. An antibody-drug conjugate (ADC) or a polypeptide-drug conjugate (PDC) characterized in that, The 7- and 20-substituted camptothecin derivative according to claim 1 is used as a high-activity small-molecule drug moiety in a medicament.

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