12-Substituted camptothecin derivatives and their uses

Abstract

The present invention provides a 12-substituted camptothecin derivative and its uses, belonging to the technical field of medicine. The 12-substituted camptothecin derivative provided by the present invention, or its stereoisomers and pharmaceutically acceptable salts, has the structure shown in formula (I). By introducing a methylenedioxy group at the 10,11-positions and different substituents at the 12-position on the basis of the traditional camptothecin structure, camptothecin derivatives with excellent anti-tumor activity can be obtained. The obtained 12-substituted camptothecin derivative has clear structural characteristics, is convenient to synthesize, and the purification method is simple and fast. It can be used to prepare drugs for preventing or treating cancer and has broad application prospects.

Description

Technical Field

[0001] The present invention belongs to the technical field of medicine, and particularly relates to a novel class of camptothecin derivatives and their uses. Background Art

[0002] Camptothecin derivatives are regarded as one of the three major discoveries of anti-cancer drugs in the 1990s, showing broad-spectrum anti-tumor activity and great research and application value. The early camptothecin compounds have the mechanism of action of forming a ternary complex with Top I and DNA, blocking DNA replication and transcription, and having disadvantages such as low selectivity and large toxic and side effects. With the development of technology, molecularly targeted anti-tumor drugs have become a research hotspot in recent years. Such 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 anti-tumor candidate compounds is a problem to be solved in this field. Summary of the Invention

[0003] The present invention provides a 12-substituted camptothecin derivative and its uses. By introducing a methylenedioxy group at the 10,11-position and different substituents at the 12-position on the basis of the traditional camptothecin structure, camptothecin derivatives with excellent anti-tumor activity can be obtained.

[0004] To achieve the above object, the present invention provides a 12-substituted camptothecin derivative, or its stereoisomer and pharmaceutically acceptable salt, having the structure shown in formula (I):

[0005]

[0006] In the formula, R is a halogen or a ring structure, wherein:

[0007] When R is a halogen, it is selected from any one of F, Cl, Br, and I;

[0008] When R is a ring structure, it is selected from any one of a substituted or unsubstituted benzene ring, a substituted or unsubstituted pyridine ring, a substituted or unsubstituted furan ring, a substituted or unsubstituted thiophene ring, a substituted or unsubstituted pyrazole ring, a substituted or unsubstituted indole ring, a substituted or unsubstituted oxazole ring, and a substituted or unsubstituted naphthalene ring.

[0009] Preferably, when the R ring structure is selected from any one of a substituted benzene ring, a substituted pyridine ring, a substituted furan ring, a substituted thiophene ring, a substituted pyrazole ring, a substituted indole ring, a substituted oxazole ring, and a substituted naphthalene ring, the substituent is selected from any one of a halogen, a cyano group, a trifluoromethyl group, a trifluoromethoxy group, a nitro group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted ester group, a substituted or unsubstituted aryl group, a substituted or unsubstituted pyrrolidinyl group, and a substituted or unsubstituted piperidinyl group;

[0010] The substitution is mono-substitution or multi-substitution.

[0011] Preferably, when the R ring structure is a substituted or unsubstituted benzene ring, R in formula (I) is selected from any one of the following groups:

[0012]

[0013] Preferably, when the R ring structure is selected from any one of a substituted or unsubstituted pyridine ring, a substituted or unsubstituted furan ring, a substituted or unsubstituted thiophene ring, a substituted or unsubstituted pyrazole ring, a substituted or unsubstituted indole ring, a substituted or unsubstituted oxazole ring, and a substituted or unsubstituted naphthalene ring, R in formula (I) is selected from any one of the following groups:

[0014]

[0015] The present invention also provides a use of the compound according to any one of the above technical solutions in the preparation of a drug for preventing and / or treating cancer.

[0016] Preferably, the compound is selected from at least one of I-1, I-8, I-9, I-15, and I-32 - I-39.

[0017] Preferably, the cancer is selected from at least one of lung cancer, colon cancer, liver cancer, prostate cancer, leukemia, and breast cancer.

[0018] The present invention also provides an antibody-drug conjugate ADC or a polypeptide-drug conjugate PDC, using the compound according to any one of the above technical solutions as the highly active drug small molecule part in the drug.

[0019] Compared with the prior art, the advantages and positive effects of the present invention are as follows:

[0020] The 12 - substituted camptothecin derivatives provided by the present invention can obtain camptothecin derivatives with excellent anti - tumor activity by introducing a methylenedioxy group at the 10,11 - position and different substituents at the 12 - position on the basis of the traditional camptothecin structure. The obtained 12 - substituted camptothecin derivatives have clear structural characteristics, are convenient to synthesize, and the purification method is simple and fast. They can be used to prepare drugs for preventing or treating cancer and have broad application prospects. Brief Description of the Drawings

[0021] Figure 1 It is a simple schematic diagram of the synthesis route of the compound provided by the embodiment of the present invention;

[0022] Figures 2A - 2D It is the inhibition rates of the compounds I - 1 - I - 39 provided by the embodiment of the present invention on HepG2, A549, HCT116 and MCF - 7 cell lines at 1 μM respectively. Detailed Embodiments

[0023] The technical solutions in the embodiments of the present invention will be described clearly and completely below. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all of them. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts belong to the scope of protection of the present invention.

[0024] Unless otherwise specified, the scientific and technical terms used herein shall have the meanings commonly understood by those of ordinary skill in the art. However, the following terms have the following definitions:

[0025] "Cancer" refers to a large class of various diseases characterized by the uncontrolled growth of abnormal cells in 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 through the lymphatic system or bloodstream. Another equivalent description of "treating cancer" in the present invention is "treating tumors" or "anti - cancer" or "anti - tumor".

[0026] Cancer is a disorder of uncontrolled cell growth that interferes with the normal function of body organs and systems. A subject with cancer is a subject with objectively measurable cancer cells present in the subject's body. A subject at risk of developing cancer is a subject who is prone to developing cancer (e.g., based on family history, genetic predisposition), a subject exposed to radiation or other cancer - causing agents.

[0027] The compounds of the present invention can be used to treat various cancers or subjects 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, gastric cancer, liver cancer, esophageal cancer, kidney cancer, throat 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, biliary tract 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 lymphoma and non-Hodgkin lymphoma); melanoma; neuroblastoma; oral cancer (such as lip, tongue, mouth, and pharynx); retinoblastoma; rhabdomyosarcoma; respiratory system cancer; sarcoma; uterine cancer; urinary system cancer; and other cancers and sarcomas.

[0028] The present invention will be further described in detail below in conjunction with examples.

[0029] The present invention synthesized and tested a series of structurally novel camptothecin derivatives with a methylenedioxy group introduced at the 10,11-positions of the parent ring and different substituents introduced at the 12-position. Examples of such compounds are shown in Table 1 below:

[0030]

[0031] Table 1

[0032]

[0033]

[0034] Figure 1 A simplified synthesis route diagram of the above compounds is shown. The following will be described in conjunction with specific examples:

[0035] Example 1 Preparation of 20(S)-12-bromo-10,11-methylenedioxycamptothecin (Compound I-1)

[0036] Under nitrogen protection, compound D (0.97 g, 4 mmol) and compound 5′(S)-1,5-dioxo-(5′-ethyl-5′-hydroxy-2′H,5′H,6′H-6-oxopyran)-[3′,4′,f]-Δ were added to a 100 mL eggplant-shaped flask 6(8)-Tetrahydroindolizine (1.06 g, 4 mmol) was dissolved in toluene (50 mL), and then p-toluenesulfonic acid (0.16 g, 0.8 mmol) was added. The mixture was refluxed and stirred for 12 h. After the reaction was completed as detected by TLC, it was washed with water and extracted three times with ethyl acetate. Column chromatography was performed using a dichloromethane:methanol (100:1) system to obtain 1.06 g of a yellow powdery solid with a yield of 60%. mp > 250 °C; MS (ESI) m / z ESI + 471.01 [M+H] + ; 1 H NMR (500 MHz, TFA / DMSO) δ 9.23 (s, 1H), 8.65 (s, 1H), 7.65 (s, 1H), 6.61 (s, 2H), 6.01 (d, J = 17.2 Hz, 1H), 5.83 (s, 2H), 5.67 (d, J = 17.2 Hz, 1H), 2.22 (q, J = 7.5 Hz, 2H), 1.22 (t, J = 7.5 Hz, 3H). 13 C NMR (125 MHz, tfa) δ 175.76, 157.27, 152.14, 150.71, 141.99, 140.87, 138.85, 136.06, 130.92, 129.96, 129.94, 122.71, 105.73, 105.26, 103.62, 89.45, 74.14, 66.34, 51.43, 31.16, 5.76.

[0037] Example 2 Preparation of 20(S)-12-(3,5-bis(trifluoromethyl)phenyl)-10,11-methylenedioxycamptothecin (Compound I-2)

[0038] In a 50 mL two-necked flask, compound 1 (0.37 g, 0.8 mmol), 3,5-bis(trifluoromethyl)phenylboronic acid (0.48 g, 1.6 mmol), and cesium fluoride (0.27 mg, 1.6 mmol) were added. After purging with nitrogen three times, tetrakis(triphenylphosphine)palladium (0.09 g, 0.08 mmol) was added. Toluene, ethanol, and water (9.2 mL, 1.9 mL, 3.2 mL) were added in sequence, and nitrogen was purged 6 times. The mixture was refluxed and stirred for 8 h. After the reaction was completely detected by TLC, the solvent was removed by rotary evaporation and concentrated. Column chromatography was performed using dichloromethane:methanol (10:1) to obtain 0.28 g of a yellow powdery solid with a yield of 60%. mp > 250 °C; MS (ESI) m / z ESI + 605.11 [M+H] + ; 11H NMR (500 MHz, DMSO-d6) δ 8.51 (d, J = 11.0 Hz, 3H), 8.18 (s, 1H), 7.59 (s, 1H), 7.02 (s, 1H), 6.33 (d, J = 14.7 Hz, 3H), 5.37 (d, J = 3.5 Hz, 2H), 5.21 (s, 2H), 1.80 (dp, J = 32.6, 7.2 Hz, 2H), 0.82 (t, J = 7.3 Hz, 3H). 13 13C NMR (125 MHz, dmso) δ 173.13, 157.25, 150.29, 150.22, 149.71, 148.82, 146.09, 143.67, 135.33, 132.42, 131.29, 130.25, 129.99, 129.34, 126.41, 125.03, 122.86, 121.54, 118.76, 113.67, 104.34, 103.56, 96.42, 72.61, 65.59, 50.65, 30.60, 7.85.

[0039] Example 3 Preparation of 20(S)-12-(4-trifluoromethylphenyl)-10,11-methylenedioxycamptothecin (Compound I-3)

[0040] Replace 3,5-bis(trifluoromethyl)phenylboronic acid in the procedure of Example 2 with 4-trifluorophenylboronic acid, and use the same required raw materials, reagents and preparation method as in Example 2. 0.30 g of gray powdery solid can be prepared, with a yield of 63%. mp > 250 °C; MS (ESI) m / z ESI + 537.12 [M+H] + ; 1 1H NMR (500 MHz, TFA / DMSO) δ 9.25 (s, 1H), 8.13–8.03 (m, 3H), 7.87 (d, J = 7.9 Hz, 2H), 7.71 (s, 1H), 6.51 (d, J = 5.4 Hz, 2H), 5.96 (d, J = 17.2 Hz, 1H), 5.81 (s, 2H), 5.62 (d, J = 17.2 Hz, 1H), 2.12 (q, J = 7.6 Hz, 2H), 1.12 (t, J = 7.4 Hz, 3H). 13 13C NMR (125 MHz, tfa) δ 175.97, 156.38, 152.27, 141.48, 140.49, 139.19, 136.76, 130.62, 130.20, 129.69, 126.94, 126.91, 122.23, 105.31, 104.64, 104.07, 73.74, 66.24, 51.37, 31.09, 5.65.

[0041] Example 4 Preparation of 20(S)-12-(4-fluorophenyl)-10,11-methylenedioxycamptothecin (Compound I-4)

[0042] Replace 3,5-bis(trifluoromethyl)phenylboronic acid in the procedure of Example 2 with 4-fluorophenylboronic acid, and use the remaining required raw materials, reagents and preparation methods as in the procedure of Example 2. A gray powdery solid (0.32 g) can be prepared with a yield of 67%. mp > 250 °C; MS(ESI) m / z ESI + 487.12 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 8.46 (s, 1H), 7.76–7.68 (m, 2H), 7.49 (s, 1H), 7.36 (td, J = 8.9, 1.9 Hz, 2H), 6.98 (d, J = 1.7 Hz, 1H), 6.42 (d, J = 1.7 Hz, 1H), 6.25 (s, 2H), 5.37 (s, 2H), 5.16 (s, 2H), 1.80 (q, J = 7.3 Hz, 2H), 0.86–0.73 (m, 3H). 13 C NMR (125 MHz, dmso) δ 172.75, 163.02, 157.24, 150.61, 150.07, 149.11, 148.62, 146.55, 144.53, 133.64, 133.58, 130.99, 129.20, 128.91, 126.43, 118.49, 116.72, 115.21, 115.03, 103.12, 102.94, 96.02, 72.88, 65.68, 30.80, 8.33.

[0043] Example 5 Preparation of 20(S)-12-(3-fluorophenyl)-10,11-methylenedioxycamptothecin (Compound I-5)

[0044] Replace 3,5-bis(trifluoromethyl)phenylboronic acid in the procedure of Example 2 with 3-fluorophenylboronic acid, and use the remaining required raw materials, reagents and preparation methods as in the procedure of Example 2. A gray powdery solid (0.32 g) can be prepared with a yield of 67%. mp > 250 °C; MS(ESI) m / z ESI + 487.12 [M+H] + ; 11H NMR (500 MHz, TFA / DMSO) δ 9.24 (s, 1H), 8.15 (s, 1H), 7.79 (q, J = 7.3 Hz, 1H), 7.70 (s, 1H), 7.54–7.46 (m, 2H), 7.42 (d, J = 8.4 Hz, 1H), 6.53 (d, J = 4.5 Hz, 2H), 5.98 (d, J = 17.2 Hz, 1H), 5.81 (s, 2H), 5.64 (d, J = 17.2 Hz, 1H), 2.14 (q, J = 7.5 Hz, 2H), 1.13 (t, J = 7.5 Hz, 3H). 13 13C NMR (125 MHz, tfa) δ 176.07, 164.69, 158.04, 156.22, 152.32, 150.87, 140.35, 139.19, 136.90, 132.05, 129.66, 128.09, 125.78, 122.17, 105.26, 104.78, 103.85, 73.74, 66.26, 51.38, 31.10, 5.66, 5.66.

[0045] Example 6 Preparation of 20(S)-12-(2,4-difluorophenyl)-10,11-methylenedioxycamptothecin (Compound I-6)

[0046] Replace 3,5-bis(trifluoromethyl)phenylboronic acid in the procedure of Example 2 with 2,4-difluorophenylboronic acid, and use the same other required raw materials, reagents and preparation method as in the procedure of Example 2. 0.30 g of a gray powdery solid can be prepared, with a yield of 61%. mp > 250 °C; MS (ESI) m / z ESI + 505.11 [M+H] + ; 1 1H NMR (500 MHz, TFA / DMSO) δ 9.23 (s, 1H), 8.14 (d, J = 6.2 Hz, 1H), 7.70 (s, 2H), 7.26 (d, J = 34.9 Hz, 2H), 6.50 (d, J = 13.8 Hz, 2H), 5.96 (d, J = 17.1 Hz, 1H), 5.80 (s, 2H), 5.62 (d, J = 17.2 Hz, 1H), 2.12 (q, J = 7.7 Hz, 2H), 1.12 (q, J = 8.2 Hz, 3H). 13 13C NMR (125 MHz, tfa) δ 158.03, 157.09, 152.24, 150.86, 141.47, 140.37, 139.20, 137.22, 130.16, 129.64, 122.15, 105.33, 104.23, 73.70, 66.23, 51.35, 31.06, 5.62.

[0047] Example 7 Preparation of 20(S)-12-(3,4-difluorophenyl)-10,11-methylenedioxycamptothecin (Compound I-7)

[0048] Replace 3,5-bis(trifluoromethyl)phenylboronic acid in the procedure of Example 2 with 3,4-difluorophenylboronic acid, and use the same required raw materials, reagents and preparation method as in the procedure of Example 2. 0.31 g of a gray powdery solid can be prepared with a yield of 64%. mp > 250 °C; MS(ESI) m / z ESI + 505.11 [M+H] + ; 1 H NMR(500 MHz, TFA / DMSO) δ 9.21 (d, J = 4.5 Hz, 1H), 8.13 (d, J = 4.4 Hz, 1H), 7.68 (d, J = 4.5 Hz, 1H), 7.61–7.35 (m, 3H), 6.50 (d, J = 4.5 Hz, 2H), 5.95 (dd, J = 17.1, 4.5 Hz, 1H), 5.79 (d, J = 4.5 Hz, 2H), 5.61 (dd, J = 16.8, 4.6 Hz, 1H), 2.20–2.01 (m, 2H), 1.21–0.98 (m, 3H). 13 C NMR(125 MHz, tfa) δ 176.03, 162.37, 158.02, 156.39, 152.22, 150.81, 140.40, 139.15, 136.90, 130.16, 129.61, 126.91, 122.20, 119.60, 119.45, 119.29, 119.14, 117.63, 117.59, 105.28, 104.78, 103.98, 73.71, 66.23, 51.36, 31.10, 5.63.

[0049] Example 8 Preparation of 20(S)-12-(4-cyanophenyl)-10,11-methylenedioxycamptothecin (Compound I-8)

[0050] Replace 3,5-bis(trifluoromethyl)phenylboronic acid in the procedure of Example 2 with 4-cyanophenylboronic acid, and use the same required raw materials, reagents and preparation method as in the procedure of Example 2. 0.28 g of a gray powdery solid can be prepared with a yield of 50%. mp > 250 °C; MS(ESI) m / z ESI + 494.13 [M+H] + ; 11H NMR (500 MHz, DMSO-d6) δ 8.47 (d, J = 9.9 Hz, 1H), 8.03–7.98 (m, 2H), 7.91 (d, J = 8.0 Hz, 2H), 7.54 (s, 1H), 6.96 (s, 1H), 6.41 (s, 1H), 6.27 (s, 2H), 5.38 (d, J = 13.8 Hz, 2H), 5.17 (d, J = 8.3 Hz, 2H), 1.80 (q, J = 7.3 Hz, 2H), 0.82 (d, J = 7.3 Hz, 3H). 13 13C NMR (125 MHz, DMSO-D6) δ 132.69, 132.69, 132.67, 132.21, 132.17, 132.17, 119.49, 118.72, 115.94, 110.82, 104.04, 103.38, 96.20, 72.96, 65.78, 50.59, 30.93, 8.42.

[0051] Example 9 Preparation of 20(S)-12-(4-hydroxyphenyl)-10,11-methylenedioxycamptothecin (Compound I-9)

[0052] Using 4-hydroxyphenylboronic acid to replace 3,5-bis(trifluoromethyl)phenylboronic acid in the procedure of Example 2, with the remaining required raw materials, reagents and preparation method being the same as those in the procedure of Example 2, 0.28 g of a gray powdery solid was prepared, with a yield of 53%. mp > 250 °C; MS (ESI) m / z ESI + 485.13 [M+H] + ; 1 1H NMR (600 MHz, DMSO-d6) δ 8.44 (s, 1H), 7.63 (d, J = 7.9 Hz, 2H), 7.47–7.41 (m, 3H), 6.95 (s, 1H), 6.41 (s, 1H), 6.22 (d, J = 3.0 Hz, 2H), 5.35 (s, 2H), 5.29 (t, J = 5.8 Hz, 1H), 5.15 (s, 2H), 4.59 (d, J = 6.1 Hz, 2H), 3.27 (s, 1H), 1.77 (q, J = 7.4 Hz, 2H), 0.80 (t, J = 7.3 Hz, 3H). 13 13C NMR (150 MHz, DMSO-D6) δ 131.44, 126.34, 118.54, 118.54, 117.99, 104.38, 104.00, 103.90, 103.03, 103.03, 102.92, 96.08, 73.00, 65.77, 63.37, 50.57, 30.87, 8.43, 8.43.

[0053] Preparation of Example 10 20(S)-12-(4-pyridyl)-10,11-methylenedioxycamptothecin (Compound I-10)

[0054] Replace 3,5-bis(trifluoromethyl)phenylboronic acid in the procedure of Example 2 with 4-pyridylboronic acid. For the remaining required raw materials, reagents, and preparation methods, follow the procedure of Example 2. A gray powdery solid of 0.13 g can be prepared, with a yield of 28%. mp > 250 °C; MS(ESI) m / z ESI + 469.13 [M+H] + ; 1 H NMR(500 MHz, Chloroform-d) δ 8.81(s, 2H), 8.24(s, 1H), 7.75(s, 2H), 7.32(s, 1H), 7.23(s, 1H), 6.23(d, J = 12.0 Hz, 2H), 5.73(d, J = 16.2 Hz, 1H), 5.26(d, J = 11.1 Hz, 2H), 1.87(dq, J = 14.5, 7.4 Hz, 2H), 1.01(t, J = 7.4 Hz, 3H). 13 C NMR(126 MHz, tfa) δ 175.94, 162.41, 156.29, 152.15, 150.82, 140.56, 139.08, 136.40, 134.09, 134.09, 132.18, 132.10, 128.99, 128.89, 125.99, 122.25, 105.38, 104.77, 104.36, 73.65, 66.18, 51.30, 31.07, 5.60.

[0055] Preparation of Example 11 20(S)-12-(2-furyl)-10,11-methylenedioxycamptothecin (Compound I-11)

[0056] Replace 3,5-bis(trifluoromethyl)phenylboronic acid in the procedure of Example 2 with 2-furylboronic acid. For the remaining required raw materials, reagents, and preparation methods, follow the procedure of Example 2. A gray powdery solid of 0.16 g can be prepared, with a yield of 34%. mp > 250 °C; MS(ESI) m / z ESI + 459.11 [M+H] + ; 11H NMR (500 MHz, DMSO-d6) δ 8.44 (s, 1H), 7.90 (s, 1H), 7.65 (d, J = 2.9 Hz, 1H), 7.43 (s, 1H), 7.22 (d, J = 1.7 Hz, 1H), 6.82 (dt, J = 3.6, 1.9 Hz, 1H), 6.50 (s, 1H), 6.34 (s, 2H), 5.40 (s, 2H), 5.18 (s, 2H), 1.86 (q, J = 7.8 Hz, 2H), 0.96–0.80 (m, 3H). 13 13C NMR (150 MHz, DMSO-D6) δ 118.71, 113.88, 112.29, 108.18, 103.25, 103.01, 96.24, 73.01, 65.82, 50.66, 30.97, 8.41.

[0057] Example 12 Preparation of 20(S)-12-(4-nitrophenyl)-10,11-methylenedioxycamptothecin (Compound I-12)

[0058] Replace 3,5-bis(trifluoromethyl)phenylboronic acid in the procedure of Example 2 with 4-nitrophenylboronic acid, and use the remaining required raw materials, reagents and preparation method as in the procedure of Example 2 to prepare 0.29 g of a gray powdery solid with a yield of 63%. mp > 250 °C; MS(ESI) m / z ESI + 513.12 [M+H] + ; 1 1H NMR (500 MHz, DMSO-d6) δ 8.53 (s, 1H), 8.38 (d, J = 8.5 Hz, 2H), 8.01 (d, J = 8.5 Hz, 2H), 7.59 (s, 1H), 6.99 (s, 1H), 6.41 (s, 1H), 6.29 (s, 2H), 5.38 (s, 2H), 5.20 (s, 2H), 1.80 (q, J = 7.3 Hz, 2H), 0.82 (t, J = 7.3 Hz, 3H). 13 13C NMR (125 MHz, tfa) δ 176.08, 158.07, 156.43, 152.24, 150.90, 148.78, 141.96, 140.74, 139.17, 136.52, 134.27, 131.88, 131.88, 130.49, 129.73, 125.09, 125.08, 122.40, 122.39, 105.57, 104.96, 104.64, 73.71, 66.29, 51.43, 31.15, 5.68.

[0059] Preparation of Example 13 20(S)-12-(3-fluorophenyl)-10,11-methylenedioxycamptothecin (Compound I-13)

[0060] Replace 3,5-bis(trifluoromethyl)phenylboronic acid in the steps of Example 2 with 3-fluorophenylboronic acid, and use the same required raw materials, reagents, and preparation methods as in the steps of Example 2. 0.27 g of a gray powdery solid can be prepared, with a yield of 57%. mp > 250 °C; MS(ESI) m / z ESI + 537.12 [M+H] + ; 1 H NMR(600 MHz, TFA) δ 9.18 (s, 1H), 8.11 (s, 1H), 7.82–7.71 (m, 1H), 7.70–7.59 (m, 2H), 7.32 (t, J = 6.2 Hz, 2H), 6.46 (d, J = 4.5 Hz, 2H), 5.90 (d, J = 17.1 Hz, 1H), 5.74 (s, 2H), 5.57 (d, J = 17.1 Hz, 1H), 2.11–1.99 (m, 2H), 1.08 (t, J = 7.4 Hz, 3H). 13 C NMR(150 MHz, TFA) δ 176.10, 161.34, 158.10, 156.46, 152.26, 150.91, 141.78, 140.63, 139.19, 136.70, 134.23, 130.40, 129.12, 129.04, 122.21, 105.50, 104.38, 73.78, 66.32, 51.43, 31.21, 5.72, -3.23.

[0061] Preparation of Example 14 20(S)-12-(3-methylenephenol)-10,11-methylenedioxycamptothecin (Compound I-14)

[0062] Replace 3,5-bis(trifluoromethyl)phenylboronic acid in the steps of Example 2 with 3-methylenephenolboronic acid, and use the same required raw materials, reagents, and preparation methods as in the steps of Example 2. 0.29 g of a gray powdery solid can be prepared, with a yield of 60%. mp > 250 °C; MS(ESI) m / z ESI + 485.13 [M+H] + ; 11H NMR (600 MHz, TFA) δ 9.19 (s, 1H), 8.08 (s, 1H), 7.85–7.78 (m, 2H), 7.78–7.69 (m, 2H), 7.65 (s, 1H), 6.46 (d, J = 3.2 Hz, 2H), 5.92 (d, J = 17.1 Hz, 1H), 5.76 (s, 2H), 5.64 (s, 2H), 5.58 (d, J = 17.1 Hz, 1H), 2.09 (q, J = 7.3 Hz, 2H), 1.08 (t, J = 7.4 Hz, 3H). 13 13C NMR (150 MHz, TFA) δ 176.13, 158.08, 156.31, 152.32, 150.91, 140.36, 139.23, 134.16, 132.19, 130.13, 128.98, 127.94, 105.29, 104.83, 103.90, 73.75, 66.28, 51.40, 31.12, 5.67.

[0063] Example 15 Preparation of 20(S)-12-(3,4,5-trifluorophenyl)-10,11-methylenedioxycamptothecin (Compound I-15)

[0064] Using 3,4,5-trifluorophenylboronic acid instead of 3,5-bis(trifluoromethyl)phenylboronic acid in the procedure of Example 2, with the rest of the required raw materials, reagents and preparation method the same as in the procedure of Example 2, a gray powdery solid of 0.31 g can be prepared, with a yield of 65%. mp > 250 °C; MS (ESI) m / z ESI + 523.10 [M+H] + ; 1 1H NMR (600 MHz, TFA) δ 9.17 (s, 1H), 8.00 (s, 1H), 7.91 (s, 1H), 7.87 (d, J = 4.6 Hz, 1H), 7.64 (s, 1H), 6.44 (d, J = 3.0 Hz, 2H), 5.88 (d, J = 17.1 Hz, 1H), 5.73 (s, 2H), 5.54 (d, J = 17.1 Hz, 1H), 2.05 (q, J = 7.4 Hz, 2H), 1.05 (t, J = 7.4 Hz, 3H). 13 13C NMR (150 MHz, TFA) δ 176.09, 156.46, 152.37, 150.86, 141.50, 140.55, 139.21, 136.89, 133.46, 130.82, 129.76, 127.61, 127.43, 126.93, 105.39, 104.65, 104.12, 73.78, 66.29, 51.45, 31.14, 5.67.

[0065] Example 16 Preparation of 20(S)-12-(3-fluoro-4-cyanophenyl)-10,11-methylenedioxycamptothecin (Compound I-16)

[0066] Replace 3,5-bis(trifluoromethyl)phenylboronic acid in the procedure of Example 2 with 3-fluoro-4-cyanophenylboronic acid, and use the remaining required raw materials, reagents and preparation method as in the procedure of Example 2. 0.31 g of gray solid powder can be prepared, with a yield of 65%. mp > 250 °C; MS(ESI) m / z ESI+512.12 [M+H] + ; 1 H NMR(600 MHz, TFA) δ 9.18(s, 1H), 8.07(s, 1H), 8.04(dd, J = 7.9, 6.3 Hz, 1H), 7.69–7.62(m, 3H), 6.45(d, J = 6.7 Hz, 2H), 5.88(d, J = 17.1 Hz, 1H), 5.73(s, 2H), 5.54(d, J = 17.1 Hz, 1H), 2.05(q, J = 7.5 Hz, 2H), 1.04(t, J = 7.4 Hz, 3H). 13 C NMR(151 MHz, TFA) δ 176.05, 156.34, 152.18, 150.88, 142.15, 140.79, 139.14, 136.24, 135.29, 130.61, 129.67, 127.22, 127.20, 119.01, 105.64, 104.86, 73.74, 66.27, 51.40, 31.18, 5.69.

[0067] Example 17 Preparation of 20(S)-12-(3,4-dimethoxyphenyl)-10,11-methylenedioxycamptothecin (Compound I-17)

[0068] Replace 3,5-bis(trifluoromethyl)phenylboronic acid in the procedure of Example 2 with 3,4-dimethoxyphenylboronic acid, and use the remaining required raw materials, reagents and preparation method as in the procedure of Example 2. 0.26 g of gray powdery solid can be prepared, with a yield of 53%. mp > 250 °C; MS(ESI) m / z ESI + 529.15 [M+H] + ; 11H NMR (600 MHz, ) δ 9.15 (s, 1H), 8.07 (s, 1H), 7.61 (s, 1H), 7.32–7.21 (m, 3H), 6.44 (d, J = 9.3 Hz, 2H), 5.90 (d, J = 17.1 Hz, 1H), 5.74 (s, 2H), 5.56 (d, J = 17.0 Hz, 1H), 4.11 (s, 3H), 4.02 (s, 3H), 2.09–2.00 (m, 2H), 1.05 (t, J = 7.4 Hz, 3H). 13 13C NMR (150 MHz, TFA) δ 176.27, 156.25, 152.39, 151.03, 150.29, 141.24, 140.27, 139.33, 137.31, 129.76, 123.98, 122.15, 119.33, 105.18, 104.74, 103.55, 73.72, 66.29, 55.41, 54.92, 51.45, 31.10, 5.67.

[0069] Example 18 Preparation of 20(S)-12-(3-nitrophenyl)-10,11-methylenedioxycamptothecin (Compound I-18)

[0070] Using 3-nitrophenylboronic acid instead of 3,5-bis(trifluoromethyl)phenylboronic acid in the procedure of Example 2, with the remaining required raw materials, reagents, and preparation method the same as in the procedure of Example 2, a gray powdery solid (0.28 g) can be prepared, with a yield of 63%. mp > 250 °C; MS (ESI) m / z ESI + 514.12 [M + H] + ; 1 1H NMR (600 MHz, TFA) δ 9.22 (s, 1H), 8.61 (dd, J = 8.4, 2.3 Hz, 1H), 8.58 (d, J = 2.0 Hz, 1H), 8.10 (d, J = 7.6 Hz, 1H), 8.03 (s, 1H), 7.98 (t, J = 8.0 Hz, 1H), 7.69 (s, 1H), 6.47 (d, J = 2.9 Hz, 2H), 5.90 (d, J = 17.1 Hz, 1H), 5.77 (s, 2H), 5.56 (d, J = 17.1 Hz, 1H), 2.09–2.01 (m, 2H), 1.05 (t, J = 7.4 Hz, 3H). 1313C NMR (150 MHz, TFA) δ 176.18, 156.74, 152.25, 151.04, 148.76, 140.68, 139.21, 137.39, 131.52, 128.85, 125.63, 122.37, 105.56, 104.61, 73.68, 66.30, 51.43, 31.17, 5.71.

[0071] Example 19 Preparation of 20(S)-12-phenyl-10,11-methylenedioxycamptothecin (Compound I-19)

[0072] Using phenylboronic acid instead of 3,5-bis(trifluoromethyl)phenylboronic acid in the procedure of Example 2, with the remaining required raw materials, reagents, and preparation method the same as in the procedure of Example 2, 0.27 g of a gray powdery solid can be prepared, with a yield of 61%. mp > 250 °C; MS (ESI) m / z ESI + 469.13 [M+H] + ; 1 1H NMR (600 MHz, TFA) δ 9.15 (s, 1H), 8.03 (s, 1H), 7.72 (dd, J = 5.2, 1.9 Hz, 3H), 7.61 (d, J = 4.7 Hz, 3H), 6.43 (d, J = 7.1 Hz, 2H), 5.89 (d, J = 17.1 Hz, 1H), 5.73 (s, 2H), 5.55 (d, J = 17.1 Hz, 1H), 2.05 (q, J = 7.5 Hz, 2H), 1.04 (t, J = 7.4 Hz, 3H). 13 13C NMR (150 MHz, TFA) δ 176.13, 156.20, 152.44, 150.90, 140.22, 139.31, 130.98, 130.22, 129.87, 126.12, 105.16, 104.66, 103.51, 73.83, 66.30, 51.43, 31.12, 5.69.

[0073] Example 20 Preparation of 20(S)-12-(3-furan)-10,11-methylenedioxycamptothecin (Compound I-20)

[0074] Using 3-furanboronic acid instead of 3,5-bis(trifluoromethyl)phenylboronic acid in the procedure of Example 2, with the remaining required raw materials, reagents, and preparation method the same as in the procedure of Example 2, 0.16 g of a gray powdery solid can be prepared, with a yield of 34%. mp > 250 °C; MS (ESI) m / z ESI + 456.11 [M+H] + ; 11H NMR (600 MHz, TFA) δ 9.12 (s, 1H), 8.18 (s, 1H), 7.77 (dd, J = 9.3, 1.7 Hz, 1H), 7.56 (s, 1H), 6.76 (d, J = 1.9 Hz, 1H), 6.45 (d, J = 3.7 Hz, 2H), 5.89 (d, J = 17.0 Hz, 1H), 5.72 (s, 2H), 5.55 (d, J = 17.1 Hz, 1H), 4.29 (q, J = 7.2 Hz, 1H), 2.19 (s, 1H), 2.08 (q, J = 7.4 Hz, 2H), 1.07 (t, J = 7.3 Hz, 3H). 13 13C NMR (151 MHz, TFA) δ 176.07, 158.10, 156.31, 152.42, 150.92, 145.50, 140.30, 139.26, 137.31, 134.19, 132.28, 130.09, 129.09, 129.00, 105.29, 104.69, 103.46, 73.90, 66.33, 62.79, 51.50, 31.18, 19.16, 12.00, 5.73.

[0075] Example 21 Preparation of 20(S)-12-(3,4,5-trimethoxyphenyl)-10,11-methylenedioxycamptothecin (Compound I-21)

[0076] Replace 3,5-bis(trifluoromethyl)phenylboronic acid in the procedure of Example 2 with 3,4,5-trimethoxyphenylboronic acid, and use the same raw materials, reagents and preparation method as in the procedure of Example 2. A gray powdery solid (0.23 g) can be prepared with a yield of 45%. mp > 250 °C; MS (ESI) m / z ESI + 558.16 [M + H] + ; 1 1H NMR (600 MHz, TFA) δ 9.15 (s, 1H), 8.01 (s, 1H), 7.61 (s, 1H), 6.45 (d, J = 4.4 Hz, 2H), 5.89 (d, J = 17.1 Hz, 1H), 5.73 (s, 2H), 5.54 (d, J = 17.0 Hz, 1H), 4.15 (s, 3H), 4.00 (s, 6H), 2.08–2.00 (m, 2H), 1.04 (t, J = 7.3 Hz, 3H). 1313C NMR (151 MHz, TFA) δ 176.30, 158.17, 156.04, 154.12, 154.11, 152.41, 151.09, 141.30, 140.47, 139.20, 137.97, 136.84, 130.18, 129.73, 123.52, 122.27, 105.32, 104.53, 103.87, 73.57, 66.25, 66.25, 60.92, 60.92, 55.75, 55.74, 51.53, 51.53, 31.08, 5.64.

[0077] Example 22 Preparation of 20(S)-12-(3-methoxyphenyl)-10,11-methylenedioxycamptothecin (Compound I-22)

[0078] Replace 3,5-bis(trifluoromethyl)phenylboronic acid in the procedure of Example 2 with 3-methoxyphenylboronic acid, and use the same required raw materials, reagents and preparation method as in the procedure of Example 2. 0.22 g of a gray powdery solid can be prepared, with a yield of 48%. mp > 250 °C; MS(ESI) m / z ESI + 499.14 [M + H] + ; 1 1H NMR (600 MHz, TFA) δ 9.16 (s, 1H), 8.07 (s, 1H), 7.72 (t, J = 8.2 Hz, 1H), 7.62 (s, 1H), 7.37 (dd, J = 8.6, 2.5 Hz, 1H), 7.31 (dd, J = 4.4, 2.4 Hz, 2H), 6.45 (d, J = 6.6 Hz, 2H), 5.91 (d, J = 17.1 Hz, 1H), 5.75 (s, 2H), 5.57 (d, J = 17.1 Hz, 1H), 4.10 (s, 3H), 2.10–2.03 (m, 2H), 1.06 (t, J = 7.4 Hz, 3H). 13 13C NMR (150 MHz, TFA) δ 176.11, 158.07, 156.40, 152.26, 150.93, 141.56, 140.46, 139.22, 136.85, 136.24, 134.93, 134.17, 132.27, 132.19, 130.24, 129.68, 129.08, 128.99, 126.01, 122.25, 105.35, 104.86, 104.11, 73.73, 66.28, 51.40, 31.15, 5.69.

[0079] Example 23 Preparation of 20(S)-12-(3-thienyl)-10,11-methylenedioxycamptothecin (Compound I-23)

[0080] Replace 3,5-bis(trifluoromethyl)phenylboronic acid in the procedure of Example 2 with 3-thiopheneboronic acid. The remaining required raw materials, reagents, and preparation method are the same as those in the procedure of Example 2, and 0.13 g of a gray powdery solid can be prepared with a yield of 32%. mp > 250 °C; MS(ESI) m / z ESI+475.09 [M+H] + ; 1 H NMR(600 MHz, TFA) δ 9.16(s, 1H), 8.13(d, J = 2.2 Hz, 1H), 7.79(d, J = 4.9 Hz, 1H), 7.60(d, J = 2.2 Hz, 1H), 7.42(dd, J = 4.9, 2.6 Hz, 1H), 6.47(dd, J = 6.6, 2.2 Hz, 2H), 5.92(dd, J = 17.1, 2.3 Hz, 1H), 5.75(s, 2H), 5.58(d, J = 17.0 Hz, 1H), 2.10(q, J = 7.4 Hz, 2H), 1.09(t, J = 7.4 Hz, 3H). 13 C NMR(150 MHz, TFA) δ 176.05, 158.13, 156.11, 152.50, 150.90, 141.02, 140.24, 139.33, 137.30, 130.06, 129.74, 128.86, 127.57, 125.50, 122.23, 108.05, 105.25, 104.55, 104.55, 103.42, 73.96, 66.35, 51.49, 31.18, 5.75.

[0081] Example 24 Preparation of 20(S)-12-(5-(2-fluoro)pyridyl)-10,11-methylenedioxycamptothecin (Compound I-24)

[0082] Replace 3,5-bis(trifluoromethyl)phenylboronic acid in the procedure of Example 2 with 2-fluoro-5-pyridylboronic acid. The remaining required raw materials, reagents, and preparation method are the same as those in the procedure of Example 2, and 0.16 g of a gray powdery solid can be prepared with a yield of 38%. mp > 250 °C; MS(ESI) m / zESI + 488.12 [M+H] + ; 11H NMR (600 MHz, TFA) δ 9.15 (s, 1H), 8.91 (d, J = 2.5 Hz, 1H), 8.66 (ddd, J = 8.8, 6.3, 2.5 Hz, 1H), 8.01 (s, 1H), 7.76–7.56 (m, 2H), 6.45 (d, J = 2.5 Hz, 2H), 5.88 (d, J = 17.1 Hz, 1H), 5.72 (s, 2H), 5.54 (d, J = 17.1 Hz, 1H), 2.05 (q, J = 7.4 Hz, 2H), 1.05 (t, J = 7.4 Hz, 3H). 13 13C NMR (150 MHz, TFA) δ 176.11, 156.87, 151.92, 151.15, 145.44, 142.78, 140.32, 139.59, 137.16, 130.56, 129.58, 124.03, 122.21, 105.65, 105.26, 104.86, 73.67, 66.27, 51.37, 31.19, 5.70.

[0083] Example 25 Preparation of 20(S)-12-(2-fluoro-4-methoxyphenyl)-10,11-methylenedioxycamptothecin (Compound I-25)

[0084] Replace 3,5-bis(trifluoromethyl)phenylboronic acid in Step 2 of Example 2 with 2-fluoro-4-methoxyphenylboronic acid, and use the remaining required raw materials, reagents, and preparation method as in Step 2 of Example 2. A gray powdery solid of 0.27 g can be prepared, with a yield of 58%. mp > 250 °C; MS (ESI) m / z ESI+ 501.14 [M + H] + ; 1 1H NMR (600 MHz, TFA) δ 9.15 (s, 1H), 8.08 (s, 1H), 7.61 (s, 1H), 7.51–7.44 (m, 1H), 7.32 (d, J = 7.8 Hz, 1H), 7.24 (d, J = 10.7 Hz, 1H), 6.47–6.37 (m, 2H), 5.89 (d, J = 17.1 Hz, 1H), 5.73 (s, 2H), 5.55 (d, J = 17.1 Hz, 1H), 2.55 (s, 3H), 2.05 (s, 2H), 1.04 (q, J = 7.5, 7.0 Hz, 3H). 1313C NMR (151 MHz, TFA) δ 176.23, 159.57, 158.10, 156.94, 152.35, 145.83, 141.30, 140.21, 137.37, 131.69, 130.03, 129.72, 126.49, 122.08, 106.78, 105.23, 103.89, 73.78, 66.28, 51.39, 31.07, 19.66, 5.67.

[0085] Example 26 Preparation of 20(S)-12-(3-cyanophenyl)-10,11-methylenedioxycamptothecin (Compound I-26)

[0086] Using 3-cyanophenylboronic acid instead of 3,5-bis(trifluoromethyl)phenylboronic acid in the procedure of Example 2, with the other required raw materials, reagents and preparation method being the same as those in the procedure of Example 2, 0.28 g of a gray powdery solid was obtained with a yield of 60%. mp > 250 °C; MS(ESI) m / z ESI + 494.13 [M+H] + ; 1 1H NMR (600 MHz, TFA) δ 9.20 (s, 1H), 8.10–8.05 (m, 3H), 8.03 (dt, J = 8.0, 1.5 Hz, 1H), 7.93 (t, J = 7.8 Hz, 1H), 7.67 (s, 1H), 6.46 (d, J = 6.3 Hz, 2H), 5.91 (d, J = 17.2 Hz, 1H), 5.76 (s, 2H), 5.57 (d, J = 17.0 Hz, 1H), 2.07 (q, J = 7.5 Hz, 2H), 1.07 (t, J = 7.4 Hz, 3H). 13 13C NMR (150 MHz, TFA) δ 176.13, 156.68, 152.24, 150.94, 141.94, 140.68, 139.19, 136.79, 135.96, 134.37, 131.26, 130.45, 129.73, 128.70, 122.40, 105.53, 105.07, 104.55, 73.74, 66.30, 51.42, 31.19, 5.72.

[0087] Example 27 Preparation of 20(S)-12-(3-methylphenyl)-10,11-methylenedioxycamptothecin (Compound I-27)

[0088] Replace 3,5-bis(trifluoromethyl)phenylboronic acid in the procedure of Example 2 with 3-methylphenylboronic acid. The other required raw materials, reagents, and preparation method are the same as those in the procedure of Example 2. 0.21 g of a gray powdery solid can be prepared, with a yield of 51%. mp > 250 °C; MS(ESI) m / z ESI + 483.15 [M+H] + ; 1 H NMR(600 MHz, TFA) δ 9.11(s, 1H), 8.01(s, 1H), 7.57(d, J = 4.7 Hz, 2H), 7.51(d, J = 7.8 Hz, 1H), 7.41(s, 1H), 7.35(d, J = 7.5 Hz, 1H), 6.40(d, J = 8.0 Hz, 2H), 5.87(d, J = 17.1 Hz, 1H), 5.70(s, 2H), 5.53(d, J = 17.0 Hz, 1H), 2.49(s, 3H), 2.03(q, J = 7.5 Hz, 2H), 1.02(t, J = 7.3 Hz, 4H). 13 C NMR(151 MHz, TFA) δ 176.11, 158.11, 156.32, 152.36, 150.91, 141.35, 140.38, 140.38, 139.29, 138.01, 137.08, 134.21, 131.30, 130.51, 129.11, 129.02, 124.48, 122.23, 105.26, 104.73, 103.80, 66.31, 51.43, 31.15, 5.71.

[0089] Preparation of 20(S)-12-(4-methylphenyl)-10,11-methylenedioxycamptothecin (Compound I-28) in Example 28

[0090] Replace 3,5-bis(trifluoromethyl)phenylboronic acid in the procedure of Example 2 with 4-methylphenylboronic acid. The other required raw materials, reagents, and preparation method are the same as those in the procedure of Example 2. 0.21 g of a gray powdery solid can be prepared, with a yield of 53%. mp > 250 °C; MS(ESI) m / z ESI + 483.15 [M+H] + ; 11H NMR (600 MHz, TFA) δ 9.19 (s, 1H), 8.11 (s, 1H), 7.65 (s, 1H), 7.60 (d, J = 7.8 Hz, 2H), 7.55 (d, J = 7.7 Hz, 2H), 6.48 (d, J = 7.3 Hz, 2H), 5.96 (d, J = 17.1 Hz, 1H), 5.78 (s, 2H), 5.61 (d, J = 17.1 Hz, 1H), 2.61 (s, 3H), 2.12 (q, J = 7.5 Hz, 2H), 1.11 (t, J = 7.4 Hz, 3H). 13 13C NMR (150 MHz, TFA) δ 176.15, 156.22, 152.47, 151.03, 142.36, 141.11, 140.16, 139.43, 137.41, 130.93, 129.76, 122.97, 122.15, 105.10, 104.70, 103.36, 73.89, 66.36, 51.45, 31.19, 19.67, 5.75.

[0091] Example 29 Preparation of 20(S)-12-(3-(N,N-dimethyl)phenyl)-10,11-methylenedioxycamptothecin (Compound I-29)

[0092] Replace 3,5-bis(trifluoromethyl)phenylboronic acid in Step 2 of Example 2 with 3-(N,N-dimethyl)phenylboronic acid, and use the same raw materials, reagents and preparation methods as in Step 2 of Example 2. 0.19 g of 20(S)-10,11-methylenedioxy-12-(3-(N,N-dimethyl)phenyl)camptothecin gray powdery solid can be prepared, with a yield of 49%. mp > 250 °C; MS(ESI) m / z ESI + 512.17 [M+H] + ; 1 1H NMR (600 MHz, TFA) δ 9.25 (s, 1H), 8.16 (s, 1H), 8.08 (d, J = 9.8 Hz, 2H), 8.01 (t, J = 7.0 Hz, 2H), 7.73 (s, 1H), 6.52 (d, J = 9.6 Hz, 2H), 5.97 (d, J = 17.1 Hz, 1H), 5.81 (s, 2H), 5.62 (d, J = 17.1 Hz, 1H), 3.67 (s, 6H), 2.12 (q, J = 7.4 Hz, 2H), 1.12 (t, J = 7.4 Hz, 3H). 1313C NMR (150 MHz, TFA) δ 156.53, 152.19, 142.95, 142.30, 140.74, 139.28, 136.72, 133.44, 132.99, 130.73, 130.60, 129.84, 123.18, 121.61, 105.58, 105.29, 104.83, 73.70, 66.36, 51.39, 47.19, 31.26, 5.76.

[0093] Example 30 Preparation of 20(S)-12-(4-(N,N-dimethyl)phenyl)-10,11-methylenedioxycamptothecin (Compound I-30)

[0094] Using 4-(N,N-dimethyl)phenylboronic acid instead of 3,5-bis(trifluoromethyl)phenylboronic acid in the procedure of Example 2, with the remaining required raw materials, reagents, and preparation method the same as in the procedure of Example 2, a gray powdery solid (0.23 g) can be prepared, with a yield of 51%. mp > 250 °C; MS (ESI) m / z ESI+ 512.17 [M+H] + ; 1 1H NMR (600 MHz, TFA) δ 9.21 (s, 1H), 8.16 (s, 1H), 7.97 (s, 4H), 7.68 (s, 1H), 6.45 (d, J = 2.5 Hz, 2H), 5.92 (d, J = 17.1 Hz, 1H), 5.76 (s, 2H), 5.58 (d, J = 17.1 Hz, 1H), 3.65 (s, 6H), 2.08 (q, J = 7.4 Hz, 2H), 1.08 (t, J = 7.4 Hz, 3H). 13 13C NMR (150 MHz, TFA) δ 176.24, 156.71, 152.09, 151.31, 143.12, 140.54, 140.54, 139.25, 139.25, 136.71, 133.61, 133.61, 130.95, 130.50, 129.74, 121.75, 110.03, 105.65, 105.49, 104.66, 73.68, 66.28, 51.32, 47.10, 31.22, 5.76.

[0095] Example 31 Preparation of 20(S)-12-(4-methoxyphenyl)-10,11-methylenedioxycamptothecin (Compound I-31)

[0096] Replace 3,5-bis(trifluoromethyl)phenylboronic acid in the procedure of Example 2 with 4-methoxyphenylboronic acid, and use the same required raw materials, reagents and preparation method as in the procedure of Example 2. 0.22 g of gray powdery solid can be prepared with a yield of 48%. mp > 250 °C; MS(ESI) m / z ESI + 499.14[M+H] + ; 1 H NMR(600 MHz, TFA) δ 9.17(s, 1H), 8.08(s, 1H), 7.63(s, 1H), 7.62(s, 2H), 7.37(d, J = 8.4 Hz, 2H), 6.45(d, J = 8.4 Hz, 2H), 5.93(d, J = 17.1 Hz, 1H), 5.76(s, 2H), 5.58(d, J = 17.1 Hz, 1H), 4.15(s, 3H), 2.09(q, J = 7.5 Hz, 2H), 1.08(t, J = 7.4 Hz, 3H). 13 C NMR(150 MHz, TFA) δ 176.21, 160.28, 156.36, 152.40, 150.97, 141.20, 140.22, 139.35, 137.42, 131.80, 129.80, 122.18, 119.53, 115.85, 114.96, 113.08, 105.14, 104.79, 103.48, 73.81, 66.32, 55.02, 51.43, 31.16, 5.70.

[0097] Preparation of 20(S)-12-(2-thienyl)-10,11-methylenedioxycamptothecin (Compound I-32), Example 32

[0098] Replace 3,5-bis(trifluoromethyl)phenylboronic acid in the procedure of Example 2 with 2-thienylboronic acid, and use the same required raw materials, reagents and preparation method as in the procedure of Example 2. 0.15 g of gray powdery solid can be prepared with a yield of 32%. mp > 250 °C; MS(ESI) m / z ESI + 475.09[M+H] + ; 1 H NMR(600 MHz, TFA) δ 9.16(s, 1H), 8.15(d, J = 14.0 Hz, 1H), 7.69(t, J = 10.1 Hz, 2H), 7.55(s, 1H), 7.43(t, J = 3.9 Hz, 1H), 6.51–6.41(m, 3H), 5.92(d, J = 16.1 Hz, 1H), 5.76(s, 2H), 5.59(t, J = 13.8 Hz, 1H), 2.09(q, J = 7.4 Hz, 2H), 1.09(t, J = 7.3 Hz, 3H).13 CNMR(151MHz,TFA)δ156.79,152.36,150.96,141.26,140.33,139.24,137.61,134.07,133.99,132.05,130.29,129.65,128.68,124.87,105.42,103.92,73.89,66.33,51.45,31.17,5.73

[0099] Example 33 Preparation of 20(S)-12-(3-(1-methyl)pyrazol)-10,11-methylenedioxy camptothecin (Compound I-33)

[0100] Replace 3,5-bis(trifluoromethyl)phenylboronic acid in the procedure of Example 2 with 3-boronic acid-(1-methyl)pyrazole, and use the same raw materials, reagents and preparation method as in the procedure of Example 2. 0.17 g of gray powder solid can be prepared, with a yield of 36%. mp > 250 °C; MS(ESI) m / z ESI + 472.13[M+H] + ; 1 H NMR(500MHz,TFA)δ9.81(s,1H),9.46(s,1H),9.33(s,1H),8.86(s,1H),8.34(s,1H),7.16(d,J = 3.8Hz,2H),6.59(d,J = 17.1Hz,1H),6.40(d,J = 7.4Hz,1H),6.26(d,J = 17.1Hz,1H),5.15(s,2H),2.96(s,3H),2.80(p,J = 8.1,7.3Hz,2H),1.79(t,J = 7.4Hz,3H). 13 C NMR(125MHz,tfa)δ181.56,176.61,157.46,152.24,151.74,140.50,138.70,138.43,136.70,131.08,129.99,122.71,106.21,105.93,105.49,99.84,74.43,66.87,38.99,31.80,19.17,6.35.

[0101] Example 34 Preparation of 20(S)-12-(4-(3,5-dimethyl)oxazole)-10,11-methylenedioxy camptothecin (Compound I-34)

[0102] Replace 3,5-bis(trifluoromethyl)phenylboronic acid in the procedure of Example 2 with 4-boronic acid-(3,5-dimethyl)oxazole, and use the remaining required raw materials, reagents, and preparation methods as in the procedure of Example 2. 0.20 g of a gray powdery solid can be prepared, with a yield of 43%. mp > 250 °C; MS(ESI) m / z ESI + 488.14 [M+H] + ; 1 H NMR(500 MHz, TFA / DMSO) δ 9.26 (d, J = 2.2 Hz, 1H), 8.15 (s, 1H), 7.82–7.67 (m, 2H), 6.55 (dd, J = 6.0, 3.5 Hz, 2H), 5.94 (d, J = 17.2 Hz, 1H), 5.79 (s, 2H), 5.60 (d, J = 17.1 Hz, 1H), 2.53 (d, J = 15.1 Hz, 3H), 2.41 (d, J = 15.8 Hz, 3H), 2.11 (tt, J = 11.3, 7.6, 6.8 Hz, 2H), 1.12 (q, J = 8.0 Hz, 3H). 13 C NMR(125 MHz, tfa) δ 176.04, 172.10, 158.06, 152.14, 151.05, 142.39, 141.04, 139.07, 137.52, 134.13, 132.23, 130.86, 129.73, 128.93, 122.54, 105.73, 105.26, 104.86, 104.78, 98.78, 73.57, 66.20, 51.38, 31.07, 10.08, 8.69, 5.62, -3.32.

[0103] Preparation of 20(S)-12-(5-(2-cyano)pyridine)-10,11-methylenedioxycamptothecin (Compound I-35) in Example 35

[0104] Replace 3,5-bis(trifluoromethyl)phenylboronic acid in the procedure of Example 2 with 5-boronic acid-2-cyanopyridine, and use the remaining required raw materials, reagents, and preparation methods as in the procedure of Example 2. 0.17 g of a gray powdery solid can be prepared, with a yield of 36%. mp > 250 °C; MS(ESI) m / z ESI + 495.12 [M+H] + ; 11H NMR (500 MHz, TFA) δ 9.60 (s, 1H), 9.13 (s, 1H), 8.96–8.88 (m, 1H), 8.51 (d, J = 6.8 Hz, 1H), 8.08 (s, 1H), 7.73 (s, 1H), 6.52 (s, 2H), 5.96 (d, J = 16.9 Hz, 1H), 5.78 (s, 2H), 5.62 (d, J = 16.7 Hz, 1H), 2.14 (d, J = 8.0 Hz, 2H), 1.13 (d, J = 7.2 Hz, 3H). 13 13C NMR (125 MHz, tfa) δ 176.02, 156.00, 151.49, 151.38, 149.90, 144.99, 144.12, 140.92, 138.88, 137.79, 132.38, 131.20, 130.50, 129.22, 128.57, 121.57, 106.08, 105.84, 105.45, 104.47, 73.82, 66.22, 51.42, 31.16, 5.74.

[0105] Example 36 Preparation of 20(S)-12-(3-fluoro-4-hydroxyphenyl)-10,11-methylenedioxycamptothecin (Compound I-36)

[0106] Replace 3,5-bis(trifluoromethyl)phenylboronic acid in the procedure of Example 2 with 3-fluoro-4-hydroxyphenylboronic acid, and use the remaining required raw materials, reagents and preparation methods as in the procedure of Example 2 to obtain 0.21 g of a gray powdery solid, with a yield of 45%. mp > 250 °C; MS (ESI) m / z ESI + 503.12 [M+H] + ; 1 1H NMR (500 MHz, TFA) δ 9.20 (s, 1H), 8.15 (s, 1H), 7.66 (s, 1H), 7.50–7.36 (m, 3H), 6.49 (d, J = 4.6 Hz, 2H), 5.95 (d, J = 17.1 Hz, 1H), 5.79 (s, 2H), 5.61 (d, J = 17.1 Hz, 1H), 2.12 (q, J = 7.4 Hz, 2H), 1.11 (t, J = 7.3 Hz, 3H). 1313C NMR (125 MHz, tfa) δ 176.10, 158.05, 156.35, 152.26, 150.91, 144.66, 141.32, 140.24, 139.19, 137.13, 130.04, 129.64, 127.05, 122.12, 119.62, 119.07, 105.18, 104.89, 103.69, 73.68, 66.23, 51.37, 31.12, 5.63.

[0107] Example 37 Preparation of 20(S)-12-(4-hydroxyphenyl)-10,11-methylenedioxycamptothecin (Compound I-37)

[0108] Using 4-hydroxyphenylboronic acid instead of 3,5-bis(trifluoromethyl)phenylboronic acid in the procedure of Example 2, with the remaining required raw materials, reagents, and preparation method the same as in the procedure of Example 2, 0.18 g of a gray powder solid can be prepared, with a yield of 39%. mp > 250 °C; MS (ESI) m / z ESI + 485.13 [M+H] + ; 1H NMR (500 MHz, TFA / DMSO) δ 9.88 (s, 1H), 8.79 (s, 1H), 8.34 (s, 1H), 8.29 (d, J = 7.9 Hz, 2H), 8.05 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 4.9 Hz, 2H), 6.64 (d, J = 17.1 Hz, 1H), 6.46 (d, J = 7.6 Hz, 2H), 6.29 (d, J = 17.1 Hz, 1H), 3.02 (s, 2H), 2.80 (q, J = 7.4 Hz, 2H), 1.79 (t, J = 7.2 Hz, 2H). 13 13C NMR (125 MHz, tfa) δ 176.73, 156.97, 153.03, 151.57, 141.73, 140.82, 139.87, 138.05, 132.53, 130.56, 130.39, 120.13, 105.80, 105.30, 104.08, 74.40, 66.90, 52.04, 31.75, 19.23, 6.32.

[0109] Example 38 Preparation of 20(S)-12-(3-hydroxyphenyl)-10,11-methylenedioxycamptothecin (Compound I-38)

[0110] Replace 3,5-bis(trifluoromethyl)phenylboronic acid in the procedure of Example 2 with 3-hydroxyphenylboronic acid. The other required raw materials, reagents, and preparation method are the same as those in the procedure of Example 2. 0.20 g of a gray powdery solid can be prepared with a yield of 42%. mp > 250 °C; MS(ESI) m / z ESI + 485.13 [M+H] + ; 1 H NMR(500 MHz, TFA) δ 9.59 (s, 1H), 8.51 (s, 1H), 8.08 (d, J = 20.9 Hz, 2H), 7.85–7.63 (m, 2H), 6.95–6.83 (m, 2H), 6.35 (d, J = 17.1 Hz, 1H), 6.17 (d, J = 7.7 Hz, 1H), 6.00 (d, J = 17.1 Hz, 1H), 2.73 (s, 1H), 2.51 (q, J = 7.3 Hz, 2H), 1.50 (t, J = 7.3 Hz, 2H), 0.97 (d, J = 16.9 Hz, 3H). 13 C NMR(125 MHz, tfa) δ 176.46, 156.47, 155.64, 152.74, 151.38, 141.58, 140.59, 140.58, 139.56, 137.37, 132.19, 130.05, 128.15, 123.75, 122.50, 105.59, 105.18, 104.02, 74.09, 66.62, 51.74, 31.50, 18.92, 6.06.

[0111] Example 39 Preparation of 20(S)-12-(4-(2-hydroxy)pyridine)-10,11-methylenedioxycamptothecin (Compound I-39)

[0112] Replace 3,5-bis(trifluoromethyl)phenylboronic acid in the procedure of Example 2 with 2-hydroxy-4-boronic acid pyridine. The other required raw materials, reagents, and preparation method are the same as those in the procedure of Example 2. 0.10 g of a gray powdery solid can be prepared with a yield of 21%. mp > 250 °C; MS(ESI) m / z ESI+486.13 [M+H] + ; 11H NMR (500 MHz, TFA / DMSO) δ 9.09 (s, 1H), 8.85 (d, J = 6.1 Hz, 1H), 8.38 (d, J = 6.1 Hz, 1H), 8.22 (s, 1H), 8.13 (s, 1H), 7.74 (s, 1H), 6.56 (d, J = 8.2 Hz, 2H), 5.99 (d, J = 17.0 Hz, 1H), 5.79 (s, 2H), 5.65 (d, J = 17.0 Hz, 1H), 2.18 (q, J = 7.5 Hz, 2H), 1.17 (t, J = 7.5 Hz, 3H). 13 13C NMR (125 MHz, tfa) δ 176.02, 159.51, 155.19, 152.58, 152.49, 151.36, 151.29, 144.95, 141.85, 141.70, 138.10, 138.02, 130.48, 128.96, 125.21, 121.23, 114.62, 107.63, 106.48, 105.45, 104.06, 74.00, 66.25, 51.46, 31.09, 5.73.

[0113] Example 40 Testing of the in vitro anti-tumor activity of the compounds of the present invention

[0114] Using methods well-known to those skilled in the art, we tested the growth inhibitory effects of the compounds of the present invention on various tumor cell lines to demonstrate their anti-tumor activities. The selected tumor cell lines included: A549 cells (human non-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), Jurkat (human leukemia cells).

[0115] As Figures 2A - 2D shown, compared with doxorubicin and FL118, most of the compounds of the present invention showed good cell inhibitory activities. Compounds I-1, I-8, I-9, I-15, I-32 - I-39 were selected to test their IC 50 values. The results are shown in Table 2: Among them, the IC 50 values of most compounds for HCT-116 and MCF-7 cells were greater than 10 μM, and no obvious anti-tumor cell proliferation effect was shown, while certain anti-tumor activities were shown against HepG2, A549, LNCaP and Jurkat cell lines. The IC 50 values of Compound I-34 for HepG2, A549, LNCaP and Jurkat could reach 90 nM, 30 nM, 80 nM and 70 nM, and the IC for HCT-116 and MCF-750 It can also reach 4.76 μM and 1.00 μM, indicating that the 12-position modified FL118 derivative is selective for tumor cell lines.

[0116] Table 2 IC of the compounds against HCT116 cells, HepG2 cells, MCF-7 cells, A549 cells, LNCaP cells and Jurkat cells 50

[0117]

[0118] The above in vitro tests show that the compounds of the present invention have significant anti-tumor activity and can be used to prepare drugs for preventing or treating cancer.

Claims

1. A 12 - substituted camptothecin derivative, or a pharmaceutically acceptable salt thereof, has the structure shown in formula (I): （I） In the formula, R is a halogen or a ring structure, wherein: When R is a halogen, it is selected from any one of F, Br, and I; When R is a ring structure, it is selected from any one of a substituted or unsubstituted pyridine ring, a substituted or unsubstituted furan ring, a substituted or unsubstituted thiophene ring, a substituted or unsubstituted pyrazole ring, a substituted or unsubstituted indole ring, a substituted or unsubstituted oxazole ring, and a substituted or unsubstituted naphthalene ring. The substituents of the substitution are selected from any one of a halogen, a cyano group, a trifluoromethyl group, a trifluoromethoxy group, a nitro group, or an unsubstituted alkyl group; the substitution is mono - substitution or multi - substitution; or R is selected from any one of the following groups: 。 2. The 12-position substituted camptothecin derivative according to claim 1, wherein When the R ring structure is selected from any one of a substituted or unsubstituted pyridine ring, a substituted or unsubstituted furan ring, a substituted or unsubstituted thiophene ring, a substituted or unsubstituted pyrazole ring, a substituted or unsubstituted indole ring, a substituted or unsubstituted oxazole ring, and a substituted or unsubstituted naphthalene ring, R in formula (I) is selected from any one of the following groups: 。 3. Use of the 12 - substituted camptothecin derivative according to claim 1 or 2 in the preparation of a drug for preventing and / or treating cancer.

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

5. An antibody-drug conjugate (ADC) or a polypeptide-drug conjugate (PDC), characterized in that, Using the 12 - substituted camptothecin derivative according to claim 1 or 2 as a highly active drug small molecule part in a drug.

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