Preparation and use of 7-fluoroalkyl substituted camptothecin derivative

Abstract

The present invention relates to the field of medicines, and in particular to a 7-fluoroalkyl substituted camptothecin derivative compound, and a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a preparation method therefor, and a use thereof in the field of anti-tumor. The camptothecin derivative compound is used as an anti-tumor drug, and has the advantages of high activity, low toxicity, stable metabolism.

Description

Preparation and application of 7-fluoroalkyl substituted camptothecin derivatives

[0001] This application claims priority to Chinese patent application No. 2024100287414, filed on January 8, 2024, and cites the full text of the aforementioned Chinese patent application. Technical Field

[0002] The present invention relates to the field of medicine, and in particular to the preparation and application of a series of 7-fluoroalkyl-substituted camptothecin derivatives. Background Art

[0003] Camptothecin and its derivatives inhibit topoisomerase Top1, particularly the Top1-DNA complex. Camptothecin has demonstrated significant therapeutic efficacy against gastric, esophageal, lung, and bladder cancers, making it a broad-spectrum anti-tumor agent. The camptothecin derivatives irinotecan and topotecan have been approved in many countries for the treatment of various cancers. Belotecan, another camptothecin derivative, has been approved in South Korea for the treatment of SCLC and ovarian cancer. The development of new camptothecin-based drugs is essential and has broad potential applications. Summary of the Invention

[0004] The object of the present invention is to provide a 7-fluoroalkyl-substituted aminomethylcamptothecin derivative, which has the advantages of high activity, low toxicity, and metabolic stability as an anti-tumor drug.

[0005] In one aspect of the present invention, there are provided compounds of formula (I), pharmaceutically acceptable salts thereof and stereoisomers thereof:

[0006] Where,

[0007] R1 and R2 are each independently selected from hydrogen, fluorine, and methyl; or

[0008] R1, R2 and the carbon atom to which they are connected together form

[0009] X1 is selected from hydrogen, C1-C3 alkyl;

[0010] X2 is selected from substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, wherein the C1-C8 alkyl and C3-C6 cycloalkyl include at least one fluorine atom substituent;

[0011] n is selected from 1, 2 or 3;

[0012] The term "substituted" refers to the substitution of 1, 2, 3 or 4 hydrogen atoms in a group by substituents independently selected from the group consisting of deuterium, halogen, -halogen substituted or unsubstituted C1-6 Alkyl, -halogen substituted or unsubstituted C 3-6 Cycloalkyl, deuterium-substituted or unsubstituted C 1-6 Alkyl, deuterium substituted or unsubstituted C 3-6 Cycloalkyl.

[0013] In one embodiment, X1 is selected from hydrogen, methyl, ethyl, propyl or isopropyl;

[0014] In one embodiment, X1 is hydrogen.

[0015] In one embodiment, X2 is selected from 1, 2 or 3 fluorine-substituted C1-C8 alkyl groups; further selected from 1, 2 or 3 fluorine-substituted C1-C6 alkyl groups.

[0016] In one embodiment, X2 is selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl includes 1, 2 or 3 fluorine atom substituents.

[0017] In one embodiment, X2 is selected from substituted or unsubstituted C1-C6 alkyl groups, wherein the C1-C6 alkyl groups include 1, 2 or 3 fluorine atom substituents.

[0018] In one embodiment, X2 is selected from substituted or unsubstituted C3-C6 cycloalkyl groups, said C3-C6 cycloalkyl groups including 1, 2 or 3 fluorine atom substituents.

[0019] In one embodiment, X2 is selected from an ethyl group, wherein the ethyl group includes 1, 2, or 3 fluorine atom substituents, and the ethyl group is further substituted with 1 or 2 methyl groups. Such fluorine-substituted ethylamines can significantly reduce the basicity of the substituted amine, reduce the hepatotoxicity of the compound in vivo, improve metabolic stability and cell membrane penetration ability, and contribute to enhanced anti-tumor activity.

[0020] In one embodiment, X2 is selected from -CH2-CF3, -CH(CH3)-CF3 or -C(CH3)2-CF3.

[0021] In one embodiment, X2 is selected from

[0022] In one embodiment, R1 is selected from hydrogen, fluorine, methyl; R2 is selected from hydrogen, fluorine; or

[0023] R1, R2 and the carbon atom to which they are connected together form

[0024] In one embodiment, R1 is hydrogen; R2 is hydrogen; or

[0025] R1 is fluorine; R2 is fluorine; or

[0026] R1 is methyl; R2 is fluorine; or

[0027] R1, R2 and the carbon atom to which they are connected together form

[0028] In another aspect of the present invention, there is provided a compound of formula (II), a pharmaceutically acceptable salt thereof and a stereoisomer thereof:

[0029] wherein R1, R2, and n are the same as those of the compound of formula (I);

[0030] Furthermore, in formula (II), R1 and R2 are each independently selected from hydrogen, fluorine, and methyl; or

[0031] R1, R2 and the carbon atom to which they are connected together form

[0032] R3 and R4 are each independently selected from hydrogen, fluorine, substituted or unsubstituted C1-C6 alkyl; or

[0033] R3, R4 and the carbon atom to which they are connected together form a C3-C6 cycloalkyl group;

[0034] n is selected from 1, 2 or 3, preferably 1 or 2;

[0035] m is selected from 1 or 2;

[0036] y is selected from 1 or 2, preferably 2;

[0037] The term "substituted" refers to the substitution of 1, 2, 3 or 4 hydrogen atoms in a group by substituents independently selected from the group consisting of deuterium, halogen, -halogen substituted or unsubstituted C 1-6 Alkyl, -halogen substituted or unsubstituted C 3-6 Cycloalkyl, deuterium-substituted or unsubstituted C 1-6 Alkyl, deuterium substituted or unsubstituted C 3-6 Cycloalkyl.

[0038] In another aspect of the present invention, there is provided a compound of formula (III), a pharmaceutically acceptable salt thereof and a stereoisomer thereof:

[0039] Wherein, R1, R2, and n are the same as those of the compound of formula (I);

[0040] L is selected from substituted or unsubstituted C1-C6 alkyl;

[0041] The term "substituted" refers to the substitution of 1, 2, 3 or 4 hydrogen atoms in a group by substituents independently selected from the group consisting of deuterium, halogen, -halogen substituted or unsubstituted C 1-6alkyl.

[0042] In one embodiment, L is selected from -CH2-, -CH(CH3)-, or -CH(CH3)2-.

[0043] In one embodiment, R1 is selected from hydrogen, fluorine, methyl; R2 is selected from hydrogen, fluorine; or

[0044] R1, R2 and the carbon atom to which they are connected together form

[0045] In one embodiment, R1 is hydrogen; R2 is hydrogen; or

[0046] R1 is fluorine; R2 is fluorine; or

[0047] R1 is methyl; R2 is fluorine; or

[0048] R1, R2 and the carbon atom to which they are connected together form

[0049] In one embodiment, the compound is selected from the following compounds represented by formula (II-1), formula (II-2), formula (II-3) or formula (II-4):

[0050] wherein R3, R4, n, m, and y are the same as those in the compound of formula (II).

[0051] In one embodiment, R3 and R4 are each independently selected from hydrogen, fluorine, substituted or unsubstituted C1-C6 alkyl; or

[0052] R3, R4 and the carbon atom to which they are connected together form a C3-C6 cycloalkyl group.

[0053] In one embodiment, R3 and R4 are each independently selected from hydrogen, fluorine, and substituted or unsubstituted C1-C3 alkyl.

[0054] In one embodiment, R3 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl.

[0055] In one embodiment, R3 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or hexyl; preferably hydrogen or methyl.

[0056] In one embodiment, R4 is selected from hydrogen or fluorine; more preferably fluorine.

[0057] Preferably, y is 2.

[0058] The present invention provides the following compounds, their pharmaceutically acceptable salts and stereoisomers:

[0059] In another aspect of the present invention, a method for preparing the aforementioned compound is provided, which comprises the step of performing a reductive amination reaction using a 7-formylcamptothecin derivative and a corresponding fluorine-substituted amine.

[0060] In one embodiment, the 7-formylcamptothecin derivative is selected from Any one of .

[0061] In one embodiment, the corresponding fluorine-substituted amine refers to at least one compound selected from the group consisting of compounds having the following structures, equivalents thereof, and pharmaceutically acceptable salts thereof:

[0062] Wherein, X1, X2, R3, R4, m, n, y, and L are as defined above.

[0063] In one embodiment, the corresponding fluoro-substituted amine is selected from

[0064] In another aspect of the present invention, a pharmaceutical composition is provided, comprising the above-mentioned compound, a pharmaceutically acceptable salt or a stereoisomer thereof, and a pharmaceutically acceptable excipient.

[0065] In another aspect of the present invention, there is provided a use of the above-mentioned compound, its pharmaceutically acceptable salt, its stereoisomer or the above-mentioned pharmaceutical composition in the preparation of a drug for treating cancer.

[0066] In another aspect of the present invention, a method for treating cancer is provided, comprising the step of administering the above compound, its pharmaceutically acceptable salt, its stereoisomer or the above pharmaceutical composition to a subject.

[0067] In one embodiment, the amount of the compound, its pharmaceutically acceptable salt, its stereoisomer or the pharmaceutical composition administered is a therapeutically effective amount.

[0068] In one embodiment, the cancer is selected from solid tumors.

[0069] In one embodiment, the cancer is selected from one or more of esophageal cancer, gastric cancer, lung cancer, and breast cancer. DETAILED DESCRIPTION

[0070] I. Definition

[0071] Unless otherwise indicated, scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. Furthermore, the relevant terms and laboratory procedures used herein are those widely used in the relevant fields and routine procedures. To facilitate a better understanding of the present invention, definitions and explanations of relevant terms are provided below.

[0072] In the description herein, references to “some embodiments,” “some implementation schemes,” or “some implementation plans” describe a subset of all possible embodiments, but it will be understood that “some embodiments” may be the same subset or different subsets of all possible embodiments and may be combined with each other without conflict.

[0073] As used herein and unless otherwise specified, the terms "comprises," "includes," "has," "contains," and their grammatical equivalents should generally be understood as open-ended and non-limiting, e.g., not excluding other unlisted elements or steps.

[0074] The compounds of the present invention may be asymmetric, for example, having one or more stereoisomers. Unless otherwise indicated, all stereoisomers are included, such as enantiomers and diastereomers. The stereoisomers include geometric isomers (such as cis, trans structures) and optical isomers (such as enantiomers), and therapeutic substances composed of monomers, racemates, racemic mixtures and pharmaceutically acceptable salts thereof. The compounds of the present invention containing asymmetric carbon atoms can be isolated in optically pure form or racemic form. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral raw materials or chiral reagents. Racemates, diastereomers, and enantiomers are all included within the scope of the present disclosure.

[0075] As used herein, numerical ranges refer to each integer in the given range. For example, "C1-C8" means that the group can have 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms; "C3-C6" means that the group can have 3, 4, 5, or 6 carbon atoms.

[0076] The term "substituted" refers to the replacement of any one or more hydrogen atoms on a particular atom or group with a substituent, provided that the valence of the particular atom or group is normal and the substituted compound is stable. Unless otherwise specified, the type and number of substituents may be any chemically feasible.

[0077] When any variable (such as R n) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 1-4 R, the group may be optionally substituted with up to 4 R, with each occurrence of R being an independent choice. Furthermore, combinations of substituents and / or variants thereof are permissible only if such combinations result in stable compounds.

[0078] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, and most preferably an alkyl group containing 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl , 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, and various branched-chain isomers thereof. More preferably, it is a lower alkyl group containing 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment.

[0079] Refers to the chemical bond connection.

[0080] The term "pharmaceutically acceptable salt" refers to a salt formed between a corresponding amine compound and an inorganic acid or an organic acid, or a salt formed between a corresponding carboxylic acid compound and an alkali metal or alkaline earth metal, or a salt formed with an organic amine. Inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like; organic acids include, but are not limited to, acetic acid, propionic acid, butyric acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, oxalic acid, succinic acid, lactic acid, citric acid, succinic acid, gluconic acid, maleic acid, fumaric acid, tartaric acid, and the like; alkali metal or alkaline earth metal salts include, but are not limited to, sodium, potassium, calcium, and magnesium salts; and organic amine salts include, but are not limited to, salts composed of ammonia, methylamine, ethylamine, propylamine, isopropylamine, dimethylamine, diethylamine, trimethylamine, triethylamine, tert-butylamine, ethylenediamine, ethanolamine, diethanolamine, triethanolamine, morpholine, piperidine, piperazine, and amino acids.

[0081] The drugs or pharmaceutical compositions of the present disclosure can be administered orally, topically, parenterally, or mucosally (e.g., buccally, by inhalation, or rectally) in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers. It is generally desirable to use the oral route. The active agent can be administered orally in the form of capsules, tablets, and the like.

[0082] The term "treating" includes inhibiting, alleviating, preventing or eliminating one or more symptoms or side effects associated with the disease, condition or disorder being treated.

[0083] The term "inhibit" is used relative to a control. One skilled in the art will readily determine the appropriate control for each experiment. For example, a reduced response in a subject or cell treated with a compound is compared to a response in a subject or cell not treated with the compound.

[0084] The term "pharmaceutical composition" means a composition comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable ingredient selected from the following depending on the mode of administration and the nature of the dosage form, including but not limited to: carriers, diluents, adjuvants, excipients, preservatives, fillers, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants, dispersants, temperature-sensitive materials, temperature regulators, adhesives, stabilizers, suspending agents, etc.

[0085] The term "effective amount" or "therapeutically effective amount" refers to a non-toxic but sufficient amount of a drug or medicament that can achieve the desired effect. In embodiments of the present invention, when a patient is treated according to the present invention, the amount of a given drug depends on many factors, such as a specific dosage regimen, the type of disease or condition and its severity, the uniqueness (e.g., body weight) of the patient or host in need of treatment, but, according to specific surrounding circumstances, including, for example, the specific drug, route of administration, the condition to be treated, and the patient or host to be treated, the dosage can be conventionally determined by methods known in the art. Typically, with respect to the dosage used for adult treatment, the dosage is typically in the range of 0.02-5000 mg / day, for example, about 1-1500 mg / day. The desired dosage can be conveniently expressed as a single dose, or simultaneously administered (or in a short period of time) or in divided doses at appropriate intervals, such as two, three, four, or more divided doses per day. It will be appreciated by those skilled in the art that, although the above-mentioned dosage range has been given, the specific effective amount can be appropriately adjusted according to the patient's condition and in conjunction with the physician's diagnosis.

[0086] The term "subject" refers to a mammal being evaluated for treatment and / or treated. In one embodiment, the mammal is a human. The term "subject" includes, but is not limited to, individuals with cancer, individuals with autoimmune diseases, individuals with pathogenic infections, and the like. The subject can be human, but also includes other mammals, particularly mammals that can be used as laboratory models of human diseases, such as mice, rats, and the like.

[0087] II. Examples

[0088] In order to make the purpose, technical solutions and advantages of the present invention clearer, the present invention will be further described in detail below. The described embodiments should not be regarded as limiting the present invention. All other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention.

[0089] Before further explaining the embodiments of the present invention in detail, the nouns and terms involved in the embodiments of the present invention are explained. The nouns and terms involved in the embodiments of the present invention are subject to the following interpretations.

[0090] The raw materials and equipment used in the specific embodiments of the present disclosure are all known products and are obtained by purchasing commercially available products.

[0091] Example 1: 7-(N-(2',2',2'-trifluoroethyl)amine)methylcamptothecin (1)

[0092] Camptothecin (10 g, 28.62 mmol), methanol (330 mL), and water (275 mL) were added to a reaction flask. 75% sulfuric acid (275 mL) was added dropwise with stirring, followed by FeSO4·7H2O (7.96 g, 28.62 mmol). 30% aqueous H2O2 solution (440.00 mL) was added dropwise with stirring. The reaction mixture was stirred at room temperature for 18 hours, poured into ice water, and the solid product was filtered and dried to obtain 7-hydroxymethylcamptothecin 1a (7 g, yield 51.57%); LCMS: [M+1] + 379.12 (theoretical value: 378.12), which was used directly in the next reaction without purification.

[0093] 1a (9.5 g, 25.04 mmol), sodium bicarbonate (8.41 g, 100.16 mmol) and DCM (190 mL) were added to a reaction flask. The mixture was cooled in an ice bath and stirred. Dess-Martin periodinane (15.93 g, 37.56 mmol) was added. The mixture was stirred at room temperature overnight and poured into water. The precipitated solid product was filtered and dried to obtain 1b, camptothecin-7-carboxaldehyde (9 g, 76% yield); [M+1] + 377.21 (theoretical value: 376.11), which was used directly in the next reaction without purification.

[0094] 1b (1.5 g, 4.0 mmol), 2,2,2-trifluoroethylamine (1.18 g, 11.9 mmol), DCM (60 mL), and NaBH3CN (0.75 g, 11.9 mmol) were added to the reaction flask. The reaction solution was stirred at room temperature for 3 hours, concentrated, and purified by silica gel column chromatography to obtain the product 7-(N-(2',2',2'-trifluoroethyl)amino)methylcamptothecin 1 (376 mg, yield 20%, HPLC 98.5%); LCMS: [M+1] + 460.39 (theoretical value 459.43); 1 H NMR (500MHz, DMSO-d6) δ8.44(d,J=8.5Hz,1H),8.27-8.18(m,1H),7.91(ddd,J=8.3,6.8,1.3Hz,1H),7.79(ddd,J=8.3,6.8,1.3Hz ,1H),7.37(s,1H),5.59(s,2H),5.50-5.36(m,3H),4.76(s,3H),4.07(q,J=9.6Hz,2H),1.96-1.85(m,2H),0.90(t,J=7.3Hz,3H).

[0095] Example 2: 7-(N-(S)-(1',1',1'-trifluoropropyl-2'-)amine)methylcamptothecin (2)

[0096] 1b (2 g, 5.3 mmol), (S)-1,1,1-trifluoropropan-2-amine (2.38 g, 15.9 mmol, 2.07 mL), DCM / DMSO (4:1, 20 mL) and NaBH3CN (1 g, 15.9 mmol) were added to the reaction flask. The reaction solution was stirred at room temperature for 2 hours, concentrated, and purified by silica gel column chromatography to obtain the product 7-(N-(S)-(1',1',1'-trifluoroethyl)amino)methylcamptothecin 2 (900 mg, yield 31.5%, HPLC 95%); LCMS: [M+H] + 474.60 (theoretical value 473.45); 1 H NMR(500MHz,DMSO-d6)δ8.33(dd,J=8.6,1.4Hz,1H),8.15(dd,J=8.5,1.3Hz,1H),7.83(dd d,J=8.3,6.8,1.3Hz,1H),7.70(ddd,J=8.3,6.8,1.3Hz,1H),7.33(s,1H),6.53(s,1H),5. 43(s,2H),5.36(d,J=1.7Hz,2H),4.47(d,J=13.7Hz,1H),4.38(d,J=13.7Hz,1H),3.53(p, J=7.3Hz,1H),1.88(dh,J=21.5,7.2Hz,2H),1.27(d,J=6.7Hz,3H),0.90(t,J=7.3Hz,3H); 13 CNMR(126MHz,DMSO-d6)δ172.96,157.26,152.61,150.48,148.89,146.04,141.67,130.41,130.07,129.33,128.93,1 27.89,127.24,126.68,125.11,119.51,97.07,72.86,65.74,54.83,50.49,45.81,30.78,14.52,14.50,14.48,8.24.

[0097] Example 3: 7-(N-(R)-(1',1',1'-trifluoropropyl-2'-)amine)methylcamptothecin (3)

[0098] 1b (200 mg, 530 μmol), (R)-1,1,1-trifluoropropan-2-amine (181.40 mg, 1.21 mmol), DCM / DMSO (4:1, 10 mL), and NaBH3CN (100 mg, 1.59 mmol) were added to a reaction flask. The reaction solution was stirred at room temperature for 2 hours, concentrated, and purified by silica gel column chromatography to obtain the product 7-(N-(R)-(1',1',1'-trifluoroethyl)amino)methylcamptothecin 3 (40 mg, yield 15%, HPLC 97%); LCMS: [M+H] + 474.60 (theoretical value 473.45); 1 H NMR (500MHz, DMSO-d6) δ8.34(d,J=8.5Hz,1H),8.17(d,J=8.5Hz,1H),7.85(t,J=8.5Hz,1H),7.72(t,J=8.5,1H),7.35(s,3H),5.46(s,2H),5.38 (s,2H),4.50(d,J=13.6Hz,1H),4.40(d,J=13.7Hz,1H),3.55(p,J=7.2Hz,2H),1.99-1.83(m,2H),1.30(d,J=6.7Hz,3H),0.92(t,J=7.3Hz,3H); 13 C NMR (126MHz, DMSO-d6) δ172.94,157.25,152.60,150.49,148.88,146.03,141.47,130.41,130.06,129.38,128.84,127.89, 127.24,126.59,125.12,119.51,97.09,72.87,65.74,55.29,55.07,54.85,54.63,50.50,45.75,30.80,14.41,12.46,8.24.

[0099] Example 4: 7-(N-(2'-trifluoromethylpropane-2'-)amine)methylcamptothecin (4)

[0100] 1b (400 mg, 1.06 mmol), 2-trifluoromethylpropan-2-amine hydrochloride (520.13 mg, 3.18 mmol), DCM (24 mL), DMSO (4 mL), and NaBH3CN (200 mg, 3.18 mmol) were added to a reaction flask. The reaction solution was stirred at room temperature for 3 hours, concentrated, and purified by silica gel column chromatography to obtain the product 7-(N-(2-trifluoromethylpropan-2-)amine)methylcamptothecin 4 (42 mg, yield 7.5%, HPLC 94%); LCMS: [M+H]+ 488.28 (theoretical value 487.48); 1 HNMR (500MHz, DMSO-d6) δ8.30(d,J=8.4Hz,1H),8.17(d,J=8.3Hz,1H),7.86(ddd,J=8.4,6.6,1.3Hz,1H),7.74(ddd,J=8.4,6.7,1.3 Hz,1H),7.34(s,1H),5.43(d,J=14.0Hz,4H),4.42(s,2H),1.89(ddt,J=17.9,14.1,7.1Hz,2H),1.41(s,6H),0.89(t,J=7.3Hz,3H).

[0101] Example 5: 7-(N-(2',2',2'-trifluoroethyl)amine)methyl-10,11-methylenedioxycamptothecin (5)

[0102] 6-Nitropiperonal (25 g, 127.46 mmol) and methanol (250 mL) were added to the reaction flask and dissolved. 10% Pd / C (2.49 g, 23.37 mmol) was added and the reaction mixture was stirred under a hydrogen balloon for 16 h. The mixture was filtered and concentrated to give product 5a (20 g, 116.76 mmol, yield 91.60%, HPLC 97%); LCMS: [M+1] + 166.91 (theoretical value 165.04).

[0103] The tricyclic intermediate 5b (26.51 g, 100.31 mmol), toluene (200 mL), 5a (20 g, 120.37 mmol) and PPTS (10.08 g, 40.12 mmol) were added to the reaction flask. The reaction solution was heated to 110°C with stirring for 16 h, concentrated under reduced pressure, and acetone (50 mL) was added. The precipitated solid was filtered, washed with methanol, and dried to give 5c (33 g, yield 80.29%, HPLC 96%); LCMS: [M+1] + 393.39 (theoretical value 392.37); 1H NMR(500MHz,DMSO-d6)δ8.46(s,1H),7.51(s,2H),7.26(s,1H),6.28(s,2H),5 .42(s,2H),5.22(s,2H),1.87(qd,J=14.7,7.3Hz,2H),0.89(t,J=7.4Hz,3H).

[0104] A reaction flask was charged with 5c (11 g, 27.96 mmol), methanol (330 mL), H2O (275 mL), H2SO4 (75%) (2.74 g, 27.96 mmol, 275 mL), and FeSO4·7H2O (8.8 g, 31.65 mmol). A 30% aqueous solution of H2O2 (55.50 g, 1.63 mol, 50 mL) was slowly added dropwise to the reaction mixture at 0°C. The reaction mixture was stirred at room temperature for 16 h. H2O (500 mL) was added, and the solid product was filtered, washed with acetonitrile and methyl tert-butyl ether, and dried to give the brown solid product 5d (8.3 g, yield 63.10%, HPLC 94%); LCMS: [M+1] + 423.39 (theoretical value 422.39); 1 H NMR(500MHz,DMSO-d6)δ7.39(s,1H),7.34(s,1H),7.22(s,1H),6.25(d,J=5.2Hz,2H),5.45 -5.35(m,2H),5.12(s,2H),5.04(s,2H),1.94-1.80(m,J=7.1Hz,2H),0.90(t,J=7.2Hz,3H).

[0105] 5d (5 g, 11.81 mmol), DCM (100 mL), and DMSO (20 mL) were added to the reaction flask. Dess-Martin periodinane (10.02 g, 23.62 mmol) was added dropwise at 0°C with stirring. The reaction mixture was stirred at room temperature for 16 h, concentrated under reduced pressure, and purified by silica gel column chromatography to give a yellow solid product 5e (2.7 g, yield 49.92%, HPLC 92%); LCMS: [M+1] + 421.36 (theoretical value 420.38) was used directly in the next reaction.

[0106] 5e (2.7 g, 6.41 mmol), 2,2,2-trifluoroethylamine (2.60 g, 19.22 mmol, 2.09 mL), DCM (60 mL), DMSO (10 mL) and NaBH3CN (1.21 g, 19.22 mmol) were added to the reaction flask. The reaction solution was stirred at room temperature for 3 h, concentrated under reduced pressure, and purified by silica gel column chromatography to give a yellow solid product 5 (1.5 g, yield 42.70%, HPLC 95%); LCMS: [M+1] + 504.28 (theoretical value 503.43); 1 H NMR(500MHz,DMSO-d6)δ7.66(s,1H),7.50(s,1H),7.24(s,1H),6.48(s,1H),6.29(d,J=2.3Hz,2H),5.42(s,2H),5.29(s,2H),4 .27(d,J=6.6Hz,2H), 3.40(dd,J=10.2,7.2Hz,2H), 3.09(p,J=7.0Hz,1H), 1.86(dh,J=21.5,7.3Hz,2H), 0.88(t,J=7.3Hz,3H).

[0107] Example 6: 7-(N-(S)-(1',1',1'-trifluoropropyl-2'-)amino)methyl-10,11-methylenedioxycamptothecin (6)

[0108] 5e (0.85 g, 1.21 mmol), (S)-1,1,1-trifluoroisopropylamine (352.27 mg, 2.42 mmol), DCM (40 mL), and DMSO (10 mL) were added to the reaction flask and stirred for 30 min. NaBH3CN (114.09 mg, 1.82 mmol) was added and the reaction was continued at room temperature with stirring for 2 h. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography to give a solid product 6 (0.54 g, yield 77%, HPLC 95%); LCMS [M+H] + 518.2 (theoretical value 517.15); 1H NMR(600MHz,DMSO-d6)δ7.67(s,1H),7.50(s,1H),7.24(s,1H),6.49(s,1H),6.2 9(d,J=2.1Hz,2H),5.42(s,2H),5.31(d,J=3.7Hz,2H),4.35(dd,J=13.6,5.9Hz, 1H), 4.24 (dd, J=13.4, 7.8Hz, 1H), 3.49 (h, J=7.3Hz, 1H), 2.80 (q, J=7.1Hz, 1H), 1.87(m,J=21.6,14.0,7.2Hz,2H), 1.25(d,J=6.7Hz,3H), 0.88(t,J=7.3Hz,3H).

[0109] Example 7: 7-(N-(R)-(1',1',1'-trifluoropropyl-2'-)amino)methyl-10,11-methylenedioxycamptothecin (7)

[0110] 5e (500 mg, 1.19 mmol), (R)-1,1,1-trifluoropropan-2-amine (201.27 mg, 1.35 mmol), DCM (8 mL), and DMSO (2 mL) were added to the reaction flask and stirred for 30 min. NaBH3CN (111.85 mg, 1.78 mmol) was added and the reaction was continued at room temperature with stirring for 2 h. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography to give a solid product 7 (200 mg, 30% yield, HPLC 94%); LCMS: [M+H] + 518.26 (theoretical value 517.46); 1 H NMR(500MHz,DMSO-d6)δ7.68(s,1H),7.50(s,1H),7.24(s,1H),6.48(s,1H),6.2 9(d,J=2.6Hz,2H),5.42(s,2H),5.32(d,J=4.1Hz,2H),4.35(dd,J=13.5,5.8Hz,1 H),4.24(dd,J=13.5,7.8Hz,1H),3.49(h,J=7.5Hz,1H),2.80(q,J=7.1Hz,1H),1 .86(ddq,J=21.3,14.3,7.2Hz,2H), 1.25(d,J=6.8Hz,3H), 0.88(t,J=7.3Hz,3H).

[0111] Example 8: 7-(N-(2'-trifluoromethylpropane-2'-)amine)methyl-10,11-methylenedioxycamptothecin (8)

[0112] 5e (200 mg, 474.63 μmol), 2-trifluoromethylpropan-2-amine (116.45 mg, 711.95 μmol), DCM (8 mL), and DMSO (2 mL) were added to the reaction flask and stirred for 30 min. NaBH3CN (44.74 mg, 711.95 μmol) was added and the reaction was continued with stirring at room temperature for 2 h. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography to give a solid product 7 (200 mg, yield 7.5%, HPLC 95%); LCMS: [M+H] + 532.28 (theoretical value 531.49); 1 H NMR (600MHz, DMSO-d6) δ7.62(s,1H),7.52(s,1H),7.25(s,1H),6.49(s,1H),6.30(d,J=1.9Hz,2H),5.42(s,2H ), 5.35 (s, 2H), 4.26 (s, 2H), 2.84 (s, 1H), 1.93-1.81 (m, 3H), 1.36 (s, 6H), 1.24 (s, 1H), 0.88 (t, J = 7.3Hz, 3H).

[0113] Example 9: 7-(N-(2',2',2'-trifluoroethyl)amino)methyl-10,11-difluorocamptothecin (9)

[0114] 2-Nitro-4,5-difluorobenzaldehyde (13.6 g, 86.01 mmol), PPTS (196.49 g, 781.89 mmol) and tricyclic intermediate 5b (20.58 g, 77.89 mmol) were added to a reaction flask. The reaction solution was heated to 130°C with stirring for 1 h, cooled to room temperature, and methanol (100 mL) was added. The mixture was stirred at room temperature overnight, and the precipitated solid was filtered and dried to give a brown solid 9c (23 g, yield 71.76%, HPLC 94%); LCMS: [M+H] + 385.20 (theoretical value 384.09) was used directly in the next reaction.

[0115] 9c (15 g, 38.93 mmol), methanol (450 mL), and H2O (325 mL) were added to the reaction flask. 75% H2SO4 (3.82 g, 38.93 mmol, 325 mL) and FeSO4·7H2O (10.82 g, 38.93 mmol) were added dropwise at 0°C with stirring. 30% H2O2 aqueous solution (83.25 g, 2.45 mol, 75 mL) was slowly added dropwise to the reaction mixture at 0°C. The reaction mixture was stirred at room temperature for 16 h. H2O (650 mL) was added, and the solid product was filtered, washed with acetonitrile and methyl tert-butyl ether, and dried to give a brown solid product 9d (10 g, 40.20% yield); LCMS: [M+1] + 415.24 (theoretical value 414.36).

[0116] 9d (6 g, 14.45 mmol), DCM (120 mL) and DMSO (20 mL) were added to the reaction flask. Dess-Martin periodinane (12.25 g, 28.89 mmol) was added dropwise at 0°C with stirring. The reaction mixture was stirred at room temperature for 16 h, poured into water, and the precipitated solid product was filtered and dried to give 9e (9 g, yield 52.76%); LCMS: [M+1] + 413.35 (theoretical value 412.35).

[0117] 9e (1 g, 2.42 mmol), 2,2,2-trifluoroethylamine hydrochloride (983.54 mg, 7.26 mmol), DCM (30 mL), DMSO (5 mL), and NaBH3CN (0.6 g, 9.62 mmol) were added to the reaction flask. The reaction solution was stirred at room temperature for 3 h, concentrated under reduced pressure, and purified by silica gel column chromatography to give a yellow solid product 9 (440 mg, yield 35.17%, HPLC 96%); LCMS: [M+1] + 496.26 (theoretical value 495.41); 1 H NMR (500MHz, DMSO-d6) δ8.30(dd,J=12.3,8.7Hz,1H),8.10(dd,J=11.4,8.0Hz,1H),7.28(s,1H),6.52(s,1H),5.41(s,2H),5.29(s, 2H), 4.33 (d, J = 6.5Hz, 2H), 3.42 (dd, J = 10.5, 7.5Hz, 2H), 3.17 (p, J = 7.0Hz, 1H), 1.87 (dh, J = 14.3, 7.2Hz, 2H), 0.89 (t, J = 7.3Hz, 3H).

[0118] Example 10: 7-(N-(S)-(1',1',1'-trifluoropropyl-2'-)amino)methyl-10,11-difluorocamptothecin (10)

[0119] 9e (1.5 g, 3.64 mmol), (S)-1,1,1-trifluoropropan-2-amine hydrochloride (1.63 g, 10.92 mmol), DCM (50 mL), DMSO (8 mL) and NaBH3CN (686 mg, 10.92 mmol) were added to the reaction flask. The reaction solution was stirred at room temperature for 2 h. Saturated aqueous NaHCO3 solution (50 mL) was added, and the solid product was filtered and purified by silica gel column chromatography to give a solid product 10 (500 mg, yield 27%, HPLC 97%); LCMS: [M+H] + 510.26 (theoretical value 509.14); 1 H NMR(500MHz,DMSO-d6)δ8.28(dd,J=12.3,8.7Hz,1H),8.10(dd,J=11.4,8.0H z,1H),7.28(s,1H),6.51(s,1H),5.41(s,2H),5.28(s,2H),4.40(dd,J=14.0, 5.9Hz, 1H), 4.28 (dd, J=14.0, 7.5Hz, 1H), 3.51 (q, J=7.3Hz, 1H), 2.87 (q, J=7. 1Hz, 1H), 1.87 (p, J = 7.2Hz, 2H), 1.26 (d, J = 6.8Hz, 3H), 0.88 (t, J = 7.3Hz, 3H); 13 C NMR (126MHz, DMSO-d6) δ172.87,157.11,153.27,150.42,146.43,146.34,145.47,141.83,129.68,124.77, 124.70,119.88,116.17,116.04,111.88,111.73,97.29,72.80,65.71,54.94,54.72,50.38,46.03,30.81.

[0120] Example 11: 7-(N-(R)-(1',1',1'-trifluoropropyl-2'-)amino)methyl-10,11-difluorocamptothecin (11)

[0121] 9e (500 mg, 1.21 mmol), (R)-1,1,1-trifluoropropan-2-amine hydrochloride (410.36 mg, 2.74 mmol), DCM (8 mL), DMSO (2 mL) and NaBH3CN (228.05 mg, 3.63 mmol) were added to the reaction flask. The reaction solution was stirred at room temperature for 2 h. Saturated aqueous NaHCO3 solution (50 mL) was added, and the solid product was filtered and purified by silica gel column chromatography to give a yellow solid product 11 (150 mg, yield 23.08%, HPLC 95%); LCMS: [M+H] + 510.43 (theoretical value 509.43); 1 H NMR(600MHz,DMSO-d6)δ8.30(dd,J=12.3,8.7Hz,1H),8.12(dd,J=11.4,8.0Hz,1H),7.29( s,1H),6.53(s,1H),5.42(s,2H),5.30(d,J=6.2Hz,2H),4.41(dd,J=13.9,5.9Hz,1H),4.2 8(dd,J=13.9,7.6Hz,1H),3.50(h,J=7.3Hz,1H),2.88(td,J=7.5,5.9Hz,1H),1.87(dp,J= 21.4,7.1Hz,2H),1.27(d,J=6.8Hz,3H),1.21(q,J=5.2,4.4Hz,1H),0.89(t,J=7.3Hz,3H); 13 C NMR(151MHz,DMSO-d6)δ172.86,157.12,153.28,153.27,152.65,152.54,150.97,150.86,150.63,150.53, 150.44,148.97,148.87,146.42,146.34,145.50,141.83,141.79,130.50,130.08,129.71,128.63,126.76, 124.88,124.80,124.74,119.86,116.15,116.04,111.91,111.78,97.30,72.80,65.70,55.10,54.91,54.73,54.54,50.40,46.03,31.73,30.80,29.48,29.28,29.19,29.02,26.99,25.57,22.54,14.42,14.41,8.19.

[0122] Example 12: 7-(N-(2'-trifluoromethylpropane-2'-)amine)methyl-10,11-difluorocamptothecin (12)

[0123] 9e (350 mg, 846.74 μmol), 2-trifluoromethylisopropylamine hydrochloride (15.50 mg, 2.54 mmol), DCM (18 mL), DMSO (3 mL) and NaBH3CN (159.63 mg, 2.54 mmol) were added to the reaction flask. The reaction solution was stirred at room temperature for 3 h. Saturated aqueous NaHCO3 solution (50 mL) was added, and the solid product was filtered and purified by silica gel column chromatography to give a yellow solid product 12 (140 mg, 29.00% yield); LCMS: [M+H] + 524.30 (theoretical value 523.46); 1 H NMR (600MHz, DMSO-d6) δ8.23(dddt,J=56.2,11.0,8.1,2.5Hz,2H),7.32(t,J=1.2Hz,1H),6.54(s,1H),5.50-5.28(m,4H ), 4.33 (d, J = 7.3Hz, 2H), 2.94 (t, J = 7.4Hz, 1H), 1.87 (ddp, J = 21.4, 14.5, 7.3Hz, 2H), 1.37 (s, 6H), 0.88 (t, J = 7.3Hz, 3H).

[0124] Example 13: 7-(N-(2',2',2,-trifluoroethyl)amine)methyl-10-methyl-11-fluorocamptothecin (13)

[0125] A solution of hydroxylamine sulfate (444.0 g, 2.4 mol), anhydrous sodium sulfate (494.0 g, 3.5 mol) and trichloroacetaldehyde hydrate (65.0 g, 519.4 mmol) in water (1600 mL) was added to the reaction flask and dissolved by stirring. 3-Fluoro-4-methylaniline (65.0 g, 438.8 mmol) and 1N HCl (550.0 mL) were added and stirred. The mixture was heated to 45°C with stirring for 2 h, then heated to 75°C for 1 h. The mixture was cooled, the precipitated solid was filtered, and dried to give 13a (96 g, yield 94%, HPLC 95%); LCMS: [M+H] + 197.20 (theoretical value 196.06); 1H NMR(300MHz,DMSO-d6)δ2.08(d,J=1.0Hz,3H),7.12(t,J=8.8Hz,1H),7.25(dd ,J=2.1,8.2Hz,1H),7.36(dd,J=1.6,12.4Hz,1H),10.18(s,1H),12.11(s,1H).

[0126] 98% concentrated sulfuric acid (1200 mL) and 13a (96 g, 438.0 mmol) were added to the reaction flask, stirred and heated to 80°C for 4 h, cooled to room temperature, poured into ice water (2400 mL), and the precipitated solid was filtered, washed with water several times, and dried (60°C) to obtain intermediate 13b (85 g, yield 94%, HPLC 98%); LCMS: [M+H] + 180.01 (theoretical value 179.04); 1 H NMR (500MHz, CDCl3) δ7.70-7.65 (m, 2H), 7.48 (d, J = 7.9Hz, 2H), 2.28 (s, 5H).

[0127] To the reaction flask were added 13b (85.0 g, 420.5 mmol), KOH (29.0 g, 685.3 mmol), KCl (97.8 g, 1300 mmol) and water (1700.0 mL). 30% H2O2 aqueous solution (85.0 g) was added dropwise with stirring at 0°C. The mixture was stirred at room temperature overnight. The pH was adjusted to 4-6 with 4N HCl under ice cooling. The precipitated solid was filtered and dried at 48°C for 16 h to give 13c (48.5 g, yield 60.4%, HPLC 95%); LCMS: [M+H] + 170.10 (theoretical value 169.05); 1 H NMR (400MHz, DMSO-d6) δ 87.55 (d, J = 8.2 Hz, 1H), 6.34 (d, J = 12.1 Hz, 1H), 2.02 (s, 3H).

[0128] Lithium aluminum hydride (14.9 g, 382.0 mmol) and dry THF (100.0 mL) were added to the reaction flask, stirred and cooled to 0°C, and a solution of 13c (26.0 g, 152.8 mmol) in THF (400.0 mL) was added. The reaction solution was stirred at room temperature for 3 h, quenched with a small amount of saturated aqueous Na2SO4, filtered, and the filtrate was concentrated. Water was added and the product was extracted with ethyl acetate, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to give the product 13d (22.1 g, yield 92.9%, HPLC 94%) as a light yellow liquid; LCMS: [M+H] +156.11 (theoretical value 155.07); 1 H NMR (600MHz, DMSO-d6) δ66.90 (d, J = 9.0 Hz, 1H), 4.98 (s, 2H), 4.95 (t, J = 5.6 Hz, 1H), 4.32 (d, J = 5.1 Hz, 2H), 2.05 (s, 3H).

[0129] 13d (22.1 g, 141.0 mmol), DCM (450.0 mL) and manganese dioxide (59.0 g, 707.0 mmol) were added to the reaction flask. The reaction solution was stirred at room temperature for 16 h, filtered, washed with DCM, and the filtrate was concentrated to give 13e (21.0 g, yield 87%); LCMS: [M+H] + 154.10 (theoretical value 153.06); 1 H NMR (400MHz, CDCl3) δ9.75 (s, 1H), 7.27 (d, J = 8.3Hz, 1H), 6.29 (d, J = 11.5Hz, 1H), 6.12 (s, 2H), 2.17 (s, 3H).

[0130] 13e (21.0 g, 136.2 mmol), tricyclic intermediate 5b (36.0 g, 136.2 mmol), PPTS (13.8 g, 136.22 mmol) and toluene (600.0 mL) were added to the reaction flask and heated to 110°C with stirring overnight. After cooling to room temperature, MeOH (400.0 mL) was added and stirred at room temperature for 2 h. The precipitated solid was filtered to give 13f (38.5 g, yield 72%, HPLC 97%); LCMS: [M+H] + 381.3 (theoretical value 380.12); 1 H NMR (500MHz, DMSO-d6) δ8.60(s,1H),8.03(d,J=8.3Hz,1H),7.86(d,J=10.9Hz,1H),7.31(s,1H),6.52(s ,1H),5.42(s,2H),5.22(s,2H),2.47(s,3H),1.87(ddt,J=17.2,14.1,7.1Hz,2H),0.89(t,J=7.3Hz,3H).

[0131] 13f (30.0 g, 78.7 mmol), CH3OH (450.0 mL) and H2O (375.0 mL) were added to the reaction flask, cooled to 0°C, and 75% H2SO4 (375.0 mL) was added dropwise, maintaining the temperature below 10°C. Ferrous sulfate hydrate (22.0 g, 78.7 mmol) and 30% H2O2 (160.0 mL) were added with stirring at 0°C. Stirring was continued at room temperature for 16 h, and the mixture was poured into ice water (6.0 L). The precipitated solid was filtered, washed with acetonitrile, and dried to give 13g (18.2 g, 56% yield, HPLC 97%); LCMS: [M+H] + 411.1, (theoretical value 410.13); 1 H NMR (500MHz, DMSO-d6) δ8.14(d,J=8.2Hz,1H),7.88(d,J=10.7Hz,1H),7.32(s,1H),5.49(s,1H),5.43(s,2H), 5.39(s,2H),5.26(s,2H),3.17(s,1H),1.87(qd,J=14.6,14.2,7.0Hz,3H),1.24(s,2H),0.89(t,J=7.3Hz,3H).

[0132] 13g (14.0g, 34.0mmol), sodium bicarbonate (11.4g, 136.1mmol), DCM (260.0mL) and DMSO (45.0mL), Dess-Martin periodinane (28.9g, 67.9mmol) were added to the reaction flask. The reaction solution was stirred at room temperature for 16h. The reaction solution was concentrated, water was added, and the precipitated solid was filtered and dried to obtain 13h (21.3g, yield 77%); LCMS: [M+H] + 409.34 (theoretical value 408.11); 1 H NMR (600MHz, CDCl3) δ11.00(s,1H),8.90(d,J=7.7Hz,1H),7.95(d,J=10.3Hz,1H),7.31(s,1 H), 6.56 (s, 1OH), 5.44 (s, 2H), 5.42 (s, 2H), 2.48 (s, 3H), 1.88 (m, 2H), 0.89 (t, J = 7.4Hz, 8H).

[0133] 13h (5 g, 9.77 mmol), 2,2,2-trifluoroethylamine (3.97 g, 29.31 mmol, 3.19 mL), DCM (80 mL) and DMSO (20 mL) were added to the reaction flask and stirred at room temperature for 30 min. NaBH3CN (1.84 g, 29.31 mmol) was added and stirring was continued at room temperature for 2 h. The mixture was concentrated and saturated aqueous NaHCO3 solution was added. The precipitated solid was filtered and purified by silica gel column chromatography to give a light yellow solid product 13 (1.1 g, yield 21.72%, HPLC 95%); LCMS: [M+H] + 492.22 (theoretical value 491.44); 1 H NMR (500MHz, DMSO-d6) δ8.28(d,J=8.2Hz,1H),7.87(d,J=10.7Hz,1H),7.32(s,1H),6.53(s,1H),5.44(s,2H),5.36(s,2H),4.40(d, J=6.7Hz,2H),3.44(td,J=10.1,7.0Hz,2H),3.18(p,J=6.9Hz,1H),2.50(s,3H),1.88(dp,J=18.3,7.1Hz,2H),0.89(t,J=7.3Hz,3H); 13 C NMR (126MHz, DMSO) δ172.95,161.26,157.25,152.95,150.48,149.07,145.93,141.14,128.99,127.86,127.49, 127.27,124.54,119.53,112.91,112.74,97.12,72.84,65.73,50.50,49.84,49.60,47.30,30.73,15.73,8.22.

[0134] Example 14: 7-(N-(S)-(1',1',1'-trifluoropropyl-2'-)amine)methyl-10-methyl-11-fluorocamptothecin (14)

[0135] 13h (5.0 g, 12.2 mmol), (S)-1,1,1-trifluoropropan-2-amine hydrochloride (5.5 g, 36.6 mmol), DMSO (45.0 mL), DCM (260.0 mL), and NaBH3(CN) (2.3 g, 36.6 mmol) were added to the reaction flask. The reaction solution was stirred at room temperature for 3 h, concentrated, and H2O (100.0 mL) was added. The solid product was filtered and purified by silica gel column chromatography to obtain a yellow solid product 14 (2.1 g, yield 65.2%, HPLC 96%). LCMS: [M+H]+ 506.30 (theoretical value 505.47); 1 HNMR(500MHz,DMSO-d6)δ8.30(d,J=8.3Hz,1H),7.88(d,J=10.7Hz,1H),7.32(s,1H),6.52(s,1H),5.44(s,2H),5.39(s,2H),4.48(dd,J=13.8,6.1Hz ,1H),4.38(dd,J=13.9,7.7Hz,1H),3.59-3.46(m,1H),2.89(q,J=7.2Hz,1 H), 1.88 (dp, J = 19.1, 7.1 Hz, 2H), 1.44-1.12 (m, 6H), 0.88 (t, J = 7.3 Hz, 3H).

[0136] Example 15: 7-(N-(R)-(1',1',1'-trifluoropropyl-2'-)amino)methyl-10-methyl-11-fluorocamptothecin (15)

[0137] 13h (0.6 g, 1.47 mmol), (R)-1,1,1-trifluoropropyl-2-amine (639.87 mg, 4.40 mmol), DCM (15 mL) and DMSO (3 mL) were added to the reaction flask and stirred at room temperature for 1 h. NaBH3CN (276.30 mg, 4.40 mmol) was added and stirred at room temperature for 2 h. The mixture was concentrated and saturated aqueous sodium bicarbonate solution was added. The precipitated solid was filtered and purified by silica gel column chromatography to give a light yellow solid product 15 (0.2 g, yield 26%, HPLC 96%); LCMS: [M+H] + 506.21 (theoretical value 505.47); 1 H NMR(500MHz,DMSO-d6)δ8.34-8.26(m,1H),7.88(d,J=10.8Hz,1H),7.32(s,1 H),6.52(s,1H),5.44(s,2H),5.39(d,J=2.4Hz,2H),4.48(dd,J=13.8,6.1Hz, 1H), 4.37 (dd, J=13.8, 7.8Hz, 1H), 3.53 (h, J=7.3Hz, 1H), 2.89 (q, J=7.2Hz, 1H ), 1.87 (dh, J = 21.3, 7.2 Hz, 2H), 1.27 (d, J = 6.8 Hz, 3H), 0.88 (t, J = 7.3 Hz, 3H).

[0138] Example 16: 7-(N-(2'-trifluoromethylpropane-2'-)amine)methyl-10-methyl-11-fluorocamptothecin (16)

[0139] 13h (100 mg, 244.87 μmol), 2-trifluoromethylpropyl-2-amine hydrochloride (120.16 mg, 734.61 μmol), DMSO (1.0 mL) and DCM (5.0 mL) were added to the reaction flask and stirred at room temperature for 30 min. NaBH3CN (46.16 mg, 734.61 μmol) was added and stirring continued at room temperature overnight. Saturated aqueous sodium bicarbonate solution was added and the precipitated solid was filtered and purified by silica gel column chromatography to give a light yellow solid product 16 (40 mg, yield 32%, HPLC 95%); LCMS: [M+H] + 520.20 (theoretical value 519.18); 1 H NMR (500MHz, DMSO-d6) δ8.25(d,J=8.4Hz,1H),7.90(d,J=10.9Hz,1H),7.33(s,1H),6.52(s,1H),5.43(d,J=7.8Hz, 4H), 4.38 (d, J = 7.4Hz, 2H), 2.94 (t, J = 7.4Hz, 1H), 1.88 (dq, J = 14.3, 7.0Hz, 2H), 1.38 (s, 6H), 0.88 (t, J = 7.3Hz, 3H).

[0140] Example 17: 7-(N-(2',2',2'-trifluoroethyl)amine)ethylcamptothecin (17)

[0141] Camptothecin (1 g, 2.86 mmol) and FeSO4·7H2O (795.78 mg, 2.86 mmol) were dissolved in H2O (32.5 mL) in a 100 mL round-bottom flask at 0°C. H2SO4 (17.5 mL), 1,3-propylene glycol (10.59 g, 137.39 mmol, 10.06 mL), and 35% hydrogen peroxide (97.36 mg, 2.86 mmol, 87.71 μL) were then carefully added. The mixture was stirred and dissolved. The reaction was continued at 0°C for 3 h. The reaction solution was poured into 1 L of ice-water, and the precipitated solid was filtered, dissolved in methanol, and purified by silica gel column chromatography. The product was concentrated to give 17a as a light yellow powder (345 mg, 29.11% yield); LCMS: [M+1] + 393.43 (calculated: 392.41).

[0142] At 25°C, the above-prepared 17a (345 mg, 0.833 mmol) was dissolved in DMSO (20 mL) and DCM (6 mL) in a 250 mL round-bottom flask. Dess-Martin periodinane (706 mg, 1.666 mmol) was added at 0°C. The reaction was continued at 25°C for 3 hours. Water (100 mL) was added and the mixture was extracted with dichloromethane (100 mL x 3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a brown viscous solid 17b (291 mg, 85% yield); LCMS: [M+H] + 391.23 (calculated: 390.40).

[0143] The above-prepared 17b (200 mg, 0.512 mmol) was dissolved in EtOH (5 mL), and 2,2,2-trifluoroethylamine hydrochloride (162.64 mg, 1.2 mmol, HCl salt) and sodium acetate (100.8 mg, 1.2 mmol) were added and stirred at room temperature for 6 hours. Acetic acid (15 mL) and sodium cyanoborohydride (94.5 mg, 1.5 mmol) were added and reacted at room temperature for 2 hours. Water was added and the mixture was extracted with dichloromethane (100 mL x 4). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified on a reverse phase C18 column (ACN / 0.1% TFA aqueous solution) to obtain the product 17 as a light yellow powdery solid (18 mg, 7.4% yield); LCMS: [M+1] + 474.38 (calculated value 473.45); 1 H NMR (500MHz, DMSO-d6) δ8.32(dd,J=8.5,1.3Hz,1H),8.22(dd,J=8.5,1.2Hz,1H),7.90(ddd,J=8.3,6.8,1.3Hz,1H),7.80(ddd,J=8.3,6.8,1 .3Hz,1H),7.36(s,1H),6.55(s,1H),5.46(s,2H),5.38(s,2H),3.51(s,2H),1.89(ddt,J=17.8,14.1,7.2Hz,2H),0.88(q,J=8.6,7.9Hz,3H).

[0144] Example 18: 7-(N-(S)-(1',1',1'-trifluoropropyl-2'-)amine)ethylcamptothecin (18)

[0145] 17b (200 mg, 0.512 mmol) was dissolved in EtOH (5 mL), and (S)-1,1,1-trifluoropropane-2-amine (179.4 mg, 1.2 mmol, HCl salt) and sodium acetate (100.8 mg, 1.2 mmol) were added. The mixture was stirred at room temperature for 6 hours. Acetic acid (15 mL) and sodium cyanoborohydride (94.5 mg, 1.5 mmol) were added and allowed to react at room temperature for 2 hours. Water was added and the mixture was extracted with dichloromethane (100 mL x 4). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified on a reverse phase C18 column (ACN / 0.1% TFA in water). The collected solution was freeze-dried to give the product 18 as a light yellow powdery solid (12 mg, 5% yield); LCMS: [M+1] + 488.68 (calculated value 487.48); 1 H NMR (500MHz, DMSO-d6) δ8.32(dd,J=8.5,1.4Hz,1H),8.20(dd,J=8.5,1.2Hz,1H),7.88(ddd,J=8.3,6.8,1.3Hz,1H),7.85-7.72(m,1H),7.35(s, 1H),6.62-6.46(m,1H),5.46(s,2H),5.38(d,J=2.1Hz,2H),3.13(d,J=3 2.0Hz,2H),1.94-1.84(m,2H),1.27-1.21(m,3H),0.89(t,J=7.3Hz,3H).

[0146] Example 19: 7-(N-(R)-(1',1',1'-trifluoropropyl-2'-)amine)ethylcamptothecin (19)

[0147] 17b (200 mg, 0.512 mmol) was dissolved in EtOH (5 mL), and (R)-1,1,1-trifluoro-2-propylamine (179.4 mg, 1.2 mmol, HCl salt) and sodium acetate (100.8 mg, 1.2 mmol) were added. The mixture was stirred at room temperature for 6 hours. Acetic acid (15 mL) and sodium cyanoborohydride (94.5 mg, 1.5 mmol) were added and allowed to react at room temperature for 2 hours. Water was added and the mixture was extracted with dichloromethane (100 mL x 4). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified on a reverse phase C18 column (ACN / 0.1% TFA in water). The collected solution was freeze-dried to obtain the product 19 as a light yellow powdery solid (8 mg, 3% yield); LCMS: [M+1] + 488.75 (calculated value 487.48); 1H NMR (500MHz, DMSO-d6) δ8.32(d,J=8.4Hz,1H),8.20(d,J=8.4Hz,1H),7.88(t,J=7.6Hz,1H),7.77(t,J=7.7Hz,1H),7.35(s,1H),6.54(s,1 H), 5.42 (d, J = 37.4Hz, 4H), 3.41-3.38 (m, 2H), 3.20-3.00 (m, 2H), 1.89 (dt, J = 18.1, 7.0Hz, 2H), 1.33-1.17 (m, 4H), 0.89 (t, J = 7.3Hz, 3H).

[0148] Example 20: 7-(N-(2'-trifluoromethylpropane-2'-)amine)ethylcamptothecin (20)

[0149] 17b (200 mg, 0.512 mmol) was dissolved in EtOH (5 mL), and 1,1,1-trifluoro-2-methyl-2-propylamine (196.2 mg, 1.2 mmol, HCl salt) and sodium acetate (100.8 mg, 1.2 mmol) were added. The mixture was stirred at room temperature for 6 hours. Acetic acid (15 mL) and sodium cyanoborohydride (94.5 mg, 1.5 mmol) were added and the reaction was allowed to react at room temperature for 2 hours. Water was added and the mixture was extracted with dichloromethane (100 mL x 4). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified on a reverse phase C18 column (ACN / 0.1% TFA in water). The collected solution was freeze-dried to give the product 20 as a light yellow powdery solid (10 mg, 4% yield); LCMS: [M+1] + 502.45 (calculated value 501.51); 1 H NMR (500MHz, DMSO-d6) δ8.32(d,J=8.6Hz,1H),8.20(dd,J=8.5,1.2Hz,1H),7.92-7.84(m,1H),7.79-7.68(m,1H),7.36(s,1H),5.69(s,1 H), 5.46 (d, J = 13.2Hz, 4H), 3.60-3.55 (m, 2H), 3.19-3.02 (m, 2H), 1.89 (dt, J = 16.6, 7.1Hz, 2H), 1.29-1.12 (m, 6H), 0.90 (t, J = 7.3Hz, 3H).

[0150] Example 21: 7-(N-(2',2',2'-trifluoroethyl)amine)ethyl-10-methyl-11-fluorocamptothecin (21)

[0151] In a 500 mL three-necked flask, 25 mL of deionized water was added, and 25 mL of 75% sulfuric acid was slowly added dropwise under ice bath. Then, 25 mL of 1,3-propylene glycol, 13f (5.0 g, 13.1 mmol), and ferrous sulfate heptahydrate (7.2 mg, 26.2 mmol) were added. After the reaction solution became clear, it was cooled to 0°C and 30% aqueous H2O2 solution (17 g, 260 mmol) was added dropwise. The reaction was stirred and maintained at <15°C for 30 min. The reaction solution was poured into water, and the precipitated solid was filtered, dried, and purified by silica gel column chromatography to obtain product 21a (2.3 g, 33.4% yield); LCMS: [M+1] + 425.35 (calculated: 424.41).

[0152] In a 100 mL three-necked flask, 21a (300 mg, 0.7 mmol) was added and dissolved in a DCM / DMSO (1:1, 30 mL) mixture. Dess-Martin periodinane (742 mg, 1.75 mmol) was then added and reacted at room temperature for 10 min. The reaction solution was poured into ice water and extracted with DCM (50 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and spin-dried to give product 21b (280 mg, 94% yield). The crude product was used directly in the next step without purification; LCMS: [M+1] + 423.35 (calculated: 422.41).

[0153] 21b (280 mg, 0.66 mmol) was dissolved in EtOH (5 mL) in a 100 mL single-necked bottle. Trifluoroethylamine hydrochloride (1.43 g, 10.6 mmol) and sodium acetate (869.5 mg, 10.6 mmol) were added with stirring. The mixture was reacted at room temperature for 30 min. Sodium cyanoborohydride (999 mg, 15.9 mmol) was added to the reaction solution, followed by 15 mL of glacial acetic acid. The mixture was stirred at room temperature for 1 h. Water (10 mL) was added and the mixture was extracted with DCM (20 mL*3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, purified by reverse phase preparative purification, and lyophilized to give the product 21 as a yellow solid (9 mg, 3% yield); LCMS: [M+1] + 506.31 (calculated value: 505.47); 1 H NMR(500MHz,DMSO-d6)δ8.22(d,J=7.2Hz,1H),7.88(d,J=10.5Hz,1H),7.31(s,1H),6.53(s,1H) ,5.44(s,2H),5.32(s,2H),3.14(s,7H),2.51(s,3H),2.00-1.72(m,2H),0.88(t,J=6.5Hz,3H).

[0154] Example 22: 7-(N-(S)-(1',1',1'-trifluoropropyl-2'-)amine)ethyl-10-methyl-11-fluorocamptothecin (22)

[0155] 21b (200 mg, 0.47 mmol) was dissolved in EtOH (2 mL) in a 100 mL single-necked bottle. (S)-1,1,1-trifluoroisopropylamine hydrochloride (702.8 mg, 4.7 mmol) and sodium acetate (385.5 mg, 4.7 mmol) were added with stirring. The mixture was reacted at room temperature for 30 min. Sodium cyanoborohydride (443 mg, 7.05 mmol) was added, followed by 6 mL of glacial acetic acid. The mixture was stirred at room temperature for 1 h. Water (15 mL) was added and the mixture was extracted with DCM (20 mL*3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, purified by reverse phase preparative purification, and lyophilized to give the product 22 (18 mg, 7.3% yield) as a yellow solid; LCMS: [M+1] + 520.51 (calculated value: 519.5); 1 H NMR (500MHz, DMSO-d6) δ8.16(d,J=8.1Hz,1H),7.81(d,J=10.7Hz,1H),7.28(s,1H),6.52(s,1H),5.43(s,2H),5.23(s,2H),3.94-3. 65(m,2H),3.40-3.30(m,2H),3.10(d,J=32.8Hz,2H),2.48(s,3H),1.98-1.77(m,2H),1.24(d,J=6.1Hz,2H),0.89(t,J=7.3Hz,3H).

[0156] Example 23: 7-(N-(R)-(1',1',1'-trifluoropropyl-2'-)amine)ethyl-10-methyl-11-fluorocamptothecin (23)

[0157] 21b (200 mg, 0.47 mmol) was dissolved in EtOH (2 mL) in a 100 mL single-necked bottle. (R)-1,1,1-trifluoroisopropylamine hydrochloride (702.8 mg, 4.7 mmol) and sodium acetate (385.5 mg, 4.7 mmol) were added with stirring. The reaction was allowed to react at room temperature for 30 min. Sodium cyanoborohydride (443 mg, 7.05 mmol) and 6 mL of glacial acetic acid were added. The mixture was stirred at room temperature for 1 h. Water (15 mL) was added and the mixture was extracted with DCM (20 mL*3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, purified by reverse phase preparative purification, and lyophilized to give the product 23 (14 mg, 5.7% yield) as a yellow solid; LCMS: [M+1] +520.51 (calculated value: 519.5); 1 H NMR(500MHz,DMSO-d6)δ8.20(d,J=8.1Hz,1H),7.86(d,J=10.8Hz,1H),7.30(s,1H),6.53(s,1H),5.44(s,2H),5.29(s,2H) ,3.89-3.46(m,4H),3.11(d,J=35.2Hz,2H),2.51(s,3H),2.03-1.76(m,2H),1.24(d,J=5.4Hz,3H),0.88(t,J=7.2Hz,3H).

[0158] Example 24: 7-(N-(2'-trifluoromethylpropane-2'-)amine)ethyl-10-methyl-11-fluorocamptothecin (24)

[0159] 21b (200 mg, 0.47 mmol) was added to a 100 mL single-necked bottle and dissolved in EtOH (2 mL). 2,2,2-Trifluoro-1,1-dimethylethylamine hydrochloride (768.7 mg, 4.7 mmol) and sodium acetate (385.5 mg, 4.7 mmol) were added with stirring. The mixture was reacted at room temperature for 30 min. Sodium cyanoborohydride (443 mg, 7.05 mmol) was added, followed by 6 mL of glacial acetic acid. The mixture was stirred at room temperature for 1 h. Water (15 mL) was added and the mixture was extracted with DCM (20 mL*3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, purified by reverse phase preparative purification, and lyophilized to obtain the yellow solid product 24 (19 mg, 7.6% yield); LCMS: [M+1] + 534.3 (calculated: 533.52); 1 H NMR (500MHz, DMSO-d6) δ8.15(d,J=7.8Hz,1H),7.79(d,J=10.7Hz,1H),7.28(s,1H),6.51(s,1H),5.43(s,2H),5.22 (s,2H),3.30-3.15(m,2H),3.00-2.96(m,2H),2.48(s,3H),2.00-1.80(m,2H),1.09(s,6H),0.89(t,J=7.0Hz,3H).

[0160] Example 25: 7-(N-(2',2',2'-trifluoroethyl)amine)ethyl-10,11-difluorocamptothecin (25)

[0161] To a 500 mL three-necked reaction flask were added 9c (3 g, 7.37 mmol), H2O (75 mL), and 1,3-propylene glycol (62.07 g, 626.45 mmol, 58.95 mL). H2SO4 (75%) (36.14 g, 368.50 mmol, 75 mL) was then added. Ferrous sulfate heptahydrate (2.34 g, 8.40 mmol) was added at 0°C, followed by a 30% aqueous H2O2 solution (215.59 mg, 6.34 mmol, 194.23 μL) dropwise. The mixture was stirred at 0°C for 4 h. The reaction mixture was poured into 2 L of ice water and allowed to stand for 16 h. The precipitated solid was filtered and dried to afford 25a (1.8 g, 54.11% yield); LCMS: [M+1] + 429.31 (calculated value 428.39);

[0162] In a 100 mL three-necked reaction flask, 25a (1 g, 2.22 mmol), DMSO (20 mL), and DCM (14 mL) were added, followed by Dess-Martin periodinane (1.88 g, 4.44 mmol). The mixture was stirred at 25°C for 4 h. The reaction solution was poured into ice water and extracted with DCM (50 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and spin-dried to give the product 25b (320 mg, 33.8% yield). The crude product was used directly in the next step without purification; LCMS: [M+1] + 427.16. (Calculated value 426.38).

[0163] To a 100 mL single-necked reaction vial was added 25b (50 mg, 111.27 μmol), DMSO (6.00 mL), and DCM (4.00 mL), followed by 2,2,2-trifluoroethylamine (40.74 mg, 333.81 μmol, 32.72 μL). The mixture was stirred at 25°C for 1 h. NaBH3CN (13.98 mg, 222.54 μmol) and acetic acid (33.41 mg, 556.35 μmol) were then added. The mixture was stirred at 25°C for 16 h, concentrated, and purified using a C18 Spherical 20-35 μm 100A 120 g reverse phase column. The product was collected and lyophilized to afford 25 (19.41 mg, 32.76% yield); LCMS: [M+1] + 510.15 (calculated value 509.43); 1H NMR(600MHz,DMSO-d6)δ8.47-8.29(m,1H),8.23-8.04(m,1H),7.29(s,1H),6.53(s,1H),5.43(s, 2H), 5.29 (s, 2H), 2.97 (s, 2H), 2.71 (s, 1H), 1.87 (dq, J = 14.1, 7.0Hz, 2H), 0.88 (t, J = 7.1Hz, 3H).

[0164] Example 26: 7-(N-(R)-(1',1',1'-trifluoropropyl-2'-)amino)ethyl-10,11-difluorocamptothecin (26)

[0165] In a 10 mL reaction vial, 25b (15 mg, 33.38 μmol), 1,4-dioxane (1 mL) and DCM (1 mL) were added. A solution of (2R)-1,1,1-trifluoro-2-propylamine (4.99 mg, 33.38 μmol) in dichloromethane (1 mL) and DIPEA (8.63 mg, 66.76 μmol, 11.63 μL) was added to the reaction solution and stirred for 10 min. NaBH3CN (4.20 mg, 66.76 μmol) and acetic acid (4.01 mg, 66.76 μmol) were added and stirred at 25°C for 2 h. The mixture was concentrated and 1 mL of DMF was added. The reaction mixture was purified by chromatography on a C18 Spherical 20-35 μm 100A HPLC column. 20 g of the product was purified by reverse-phase column chromatography using acetonitrile (HPLC grade) and 0.1% TFA aqueous solution as mobile phases B2 and A2, respectively, using the HPLC preparation method (monitoring at 254 nm and 214 nm wavelengths). The product was collected and lyophilized to obtain product 26 (5 mg, 27.41% yield); LCMS: [M+1] + 524.23 (calculated value 523.46); 1 H NMR(500MHz,DMSO-d6)δ8.46-8.37(m,1H),8.25-8.16(m,1H),7.31(s,1H),6.54(s,1H), 5.45(s,2H),5.37(s,2H),5.33(s,1H),2.19(t,J=7.3Hz,4H),1.12(s,3H),0.85(s,3H).

[0166] Example 27: 7-(N-(S)-(1',1',1'-trifluoropropyl-2'-)amine)ethyl-10,11-difluorocamptothecin (27)

[0167] In a 100 mL single-necked reaction vial, 25b (50 mg, 111.27 μmol), DMSO (6.02 mL) and DCM (4.01 mL) were added, followed by (2S)-1,1,1-trifluoro-2-propylamine (15.14 mg, 111.27 μmol, 13.19 μL). The mixture was stirred at 25°C for 1 h, followed by the addition of NaBH3CN (13.98 mg, 222.54 μmol) and acetic acid (33.41 mg, 556.35 μmol). The mixture was stirred at 25°C for 16 h, concentrated, and purified by a C18 Spherical 20-35 μm 100A. Purification was performed on a 120 g reverse phase column using acetonitrile (HPLC grade) and 0.1% TFA aqueous solution as mobile phases B2 and A2, respectively, using the HPLC preparation method (monitored at 254 nm and 214 nm wavelengths). The product was collected and lyophilized to obtain product 27 (10.45 mg, 17.94% yield); LCMS: [M+1] + 524.33 (calculated value 523.46); 1 H NMR(600MHz,DMSO-d6)δ8.37(s,1H),8.20(s,1H),7.32(s,1H),6.54(s,1H),5.44(s,2H),5.35( s, 2H), 3.08 (d, J = 49.6Hz, 2H), 1.87 (dd, J = 14.2, 7.2Hz, 2H), 1.21 (s, 3H), 0.88 (t, J = 7.1Hz, 3H).

[0168] Example 28: 7-(N-(S)-(1',1',1'-trifluoropropyl-2'-)amine)ethyl-10,11-methylenedioxycamptothecin (28)

[0169] In a 1000 mL round-bottom flask at 0°C, water (361.65 mL), 5c (5 g, 12.71 mmol), FeSO4·7H2O (11.31 g, 40.67 mmol), and 1,3-propylene glycol (28.9 g, 381.3 mmol) were added sequentially. After stirring, concentrated sulfuric acid (180.82 mL) was slowly added dropwise, followed by 30% hydrogen peroxide (5.82 g, 171.45 mmol). The mixture was reacted at 0°C for 3 h, poured into 3 L of ice-water, and the precipitated solid was filtered and purified by silica gel column chromatography to give intermediate 28a as a light yellow powder (1.67 g, 28.53% yield); MS: [M+1] + 437.32 (calculated value: 436.42); 1H NMR(500MHz,DMSO-d6)δ7.64(s,1H),7.52(s,1H),7.28(s,1H),6.54(s,1H),6.33(s,2H),5.47(s,2H),5.25(s,2H),3 .82(d,J=6.4Hz,1H), 3.29(t,J=5.9Hz,2H), 1.92(p,J=7.8,7.4Hz,2H), 1.75(d,J=6.4Hz,1H), 0.94(t,J=7.3Hz,3H).

[0170] To a reaction flask were added 28a (800 mg, 1.83 mmol), DMSO (50 mL) and DCM (35 mL), and Dess-Martin periodinane (1.55 g, 3.66 mmol). The mixture was stirred at room temperature for 1 h, and water (100 mL) was added. The mixture was extracted with dichloromethane (100 mL x 3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give intermediate 28b as a brown viscous solid (796.31 mg, 90% yield), which was used directly in the next step without purification; LCMS: [M+H] + 435.33 (calculated: 434.40).

[0171] To a 100 mL reaction bottle was added 28b (950 mg, 1.4 mmol), DCM (10 mL), DMSO (4 mL), and (S)-1,1,1-trifluoropropane-2-amine (780 mg, 7 mmol) in sequence at room temperature. The mixture was stirred at room temperature for 60 min. Sodium cyanoborohydride (130 mg, 2.1 mmol) was added and the mixture was stirred for 2 h. The mixture was concentrated and purified by silica gel column chromatography to give the product 28 (600 mg, 80% yield); LCMS: [M+1] + 532.03 (calculated: 531.49); 1 H NMR(600MHz,DMSO-d6)δ7.55(s,1H),7.41(s,1H),7.20(s,1H),6.48(s,1H),6.27(d,J=3.4Hz,2H),5.54-5.33(m,2H), 5.09(s,2H),3.34(s,2H),3.23-3.06(m,2H),2.90(m,2H),1.95-1.80(m,2H),1.14(d,J=6.7Hz,3H),0.94-0.83(m,3H); 13C NMR(150MHz,DMSO-d6)δ172.98,157.26,151.20,150.54,149.62,149.29,147.47,146.78,140.98,128.35,127.78(d,J =280Hz),124.84,118.41,105.83,103.05,99.83,96.32,72.86,65.73,54.45,50.29,47.31,31.28,30.79,14.68,8.24.

[0172] Example 29: 7-(N-(R)-(1',1',1'-trifluoropropyl-2'-)amino)ethyl-10,11-methylenedioxycamptothecin (29)

[0173] To a 10 mL single-necked eggplant-shaped flask at 25°C were added 28b (30 mg, 69.06 μmol), DCM (2 mL), DMSO (2 mL), and (R)-1,1,1-trifluoro-2-propylamine (78.1 mg, 0.69 mmol) in sequence. The mixture was stirred at room temperature for 30 min. Sodium cyanoborohydride (13 mg, 207.2 μmol) was added and the mixture was stirred for 2 h. The mixture was concentrated and purified by silica gel column chromatography to give a brown solid product 29 (10 mg, 27.2% yield); LCMS: [M+1] + 532.53 (calculated: 531.49); 1 H NMR (500MHz, DMSO-d6) δ7.68(s,1H),7.55(s,1H),7.26(s,1H),6.32(s,2H),5.44(d,J=1.3Hz,2H),5.31(d,J=3.0Hz,2H),3.47(d,J=16 .4Hz,1H),3.37-3.24(m,2H),3.19(s,1H),1.87(dp,J=19.0,7.2Hz,2H),1.36(d,J=6.8Hz,3H),0.89(q,J=7.9,7.4Hz,3H),0.87(s,1H).

[0174] Test Example 1: Inhibition of tumor cell growth activity

[0175] Human esophageal cancer cells OE33, human breast cancer cells MDA-MB-231, human gastric cancer cells NCI-N87, human lung cancer cells NCI-H1975, and human breast cancer cells SK-BR-3 were cultured in RPMI1640 (Cellmax) containing 10% fetal bovine serum (Cellmax). Tumor cells in the exponential growth phase were diluted with culture medium to 1×10 5cells / mL, 100 μL was added to each well of a 96-well cell culture plate and returned to a 37°C, 5% CO2 incubator for overnight incubation. The next day, the compound was diluted to 10,000 nM, 2,000 nM, 400 nM, 80 nM, 16 nM, 3.2 nM, 0.64 nM, and 0.13 nM using culture medium, and 2 μL of the diluted compound was added to each well of the 96-well cell culture plate. Three replicates were set for each concentration. For the negative control and blank control groups without compound addition, 2 μL of the dilution was added to each well. After addition, the plates were returned to a 37°C, 5% CO2 incubator and incubated for an additional 72 hours. After incubation, the cell culture plates were removed, the culture medium was aspirated, and 100 μL of culture medium containing 10% CCK-8 was added to each well. The plates were incubated at 37°C for 3 hours. After incubation, remove the culture plate, protect from light, and place it in an ELISA plate. Select 630 nm as the reference wavelength and 450 nm as the measurement wavelength to measure the absorbance. Based on the absorbance value, use the four-parameter regression in GraphPad to calculate the IC 50 Value (Table 1). Dxd was used as the positive control drug, and its structural formula is

[0176] The exemplary compounds of the present invention have good inhibitory activity against cancer cells such as OE33, MDA-MB-231, NCI-N87, NCI-H1975, and SK-B-3. The inhibitory activity IC 50 The values ​​were all less than 500nM, and the IC values ​​of some compounds against these cancer cells were 50 Below 100nM, further below 50nM or 10nM, or even below 1nM. 50 Value, where "++++" indicates IC 50 ≤10nM; “+++” means 10nM<IC 50 ≤100nM; “++” means 100nM<IC 50 ≤500nM; “+” indicates 500nM<IC 50 ≤1000nM.

[0177] Table 1: IC values ​​of compounds for inhibiting tumor cell growth 50 (nM) value

[0178] Note: “-” means not tested.

[0179] The foregoing descriptions of specific exemplary embodiments of the present invention are for purposes of illustration and description. These descriptions are not intended to limit the invention to the precise forms disclosed, and it is apparent that many variations and modifications are possible in light of the foregoing teachings. The exemplary embodiments have been selected and described for the purpose of explaining the specific principles of the invention and their practical application, thereby enabling those skilled in the art to realize and utilize a variety of exemplary embodiments of the invention and various options and modifications. The scope of the invention is intended to be defined by the claims and their equivalents.

Claims

1. Compounds of formula (I), their pharmaceutically acceptable salts and their stereoisomers: In the formula, R1 and R2 are each independently selected from hydrogen, fluorine, methyl; or R1, R2 together with the carbon atom to which they are attached form X1 is selected from hydrogen, C1-C3 alkyl; X2 is selected from substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, and the C1-C8 alkyl and C3-C6 cycloalkyl each contain at least one fluorine atom substituent; n is selected from 1, 2 or 3; The "substitution" means that 1, 2, 3 or 4 hydrogen atoms in the group are each independently substituted by substituents selected from the group consisting of: deuterium, halogen, halogen-substituted or unsubstituted C 1-6 alkyl, halogen-substituted or unsubstituted C 3-6 cycloalkyl, deuterium-substituted or unsubstituted C 1-6 alkyl, deuterium-substituted or unsubstituted C 3-6 cycloalkyl.

2. The compound according to claim 1, wherein, X1 is hydrogen.

3. The compound according to claim 1 or 2, wherein X2 is selected from C1-C8 alkyl substituted with 1, 2 or 3 fluorines; Preferably, X2 is selected from -CH2-CF3, -CH(CH3)-CF3 or -C(CH3)2-CF3.

4. Compounds of formula (II) or formula (III), their pharmaceutically acceptable salts and their stereoisomers: In formula (II), R1 and R2 are each independently selected from hydrogen, fluorine, methyl; or R1, R2 together with the carbon atom to which they are attached form R3 and R4 are each independently selected from hydrogen, fluorine, substituted or unsubstituted C1-C6 alkyl; or R3 and R4 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl; n is selected from 1, 2 or 3; m is selected from 1 or 2, and y is selected from 1 or 2; The term "substituted" means that 1, 2, 3 or 4 hydrogen atoms in the group are each independently replaced by substituents selected from the group consisting of: deuterium, halogen, -halogen-substituted or unsubstituted C 1-6 alkyl, -halogen-substituted or unsubstituted C 3-6 cycloalkyl, -deuterium-substituted or unsubstituted C 1-6 alkyl, -deuterium-substituted or unsubstituted C 3-6 cycloalkyl; In formula (III), R1, R2 and n are each defined as in the compound of formula (I); L is selected from substituted or unsubstituted C1-C6 alkyl; The term "substituted" means that 1, 2, 3 or 4 hydrogen atoms in the group are each independently substituted by a substituent selected from the group consisting of deuterium, halogen, halogen-substituted or unsubstituted C 1-6 alkyl.

5. The compound according to claim 4, wherein, The compound is selected from the compounds represented by the following formula (II-1), formula (II-2), formula (II-3) or formula (II-4): In the formula, R3, R4, n, m, y are each defined as in the compound of formula (II).

6. The compound according to claim 4 or 5, wherein R3 is selected from hydrogen, substituted or unsubstituted C1-C6 alkyl; preferably hydrogen or methyl; Preferably, R4 is selected from hydrogen or fluorine; more preferably fluorine; Preferably, y is 2.

7. The following compounds, their pharmaceutically acceptable salts and their stereoisomers:

8. A method for preparing the compound according to any one of claims 1-7, which comprises the step of performing reductive amination reaction using a 7-formyl camptothecin derivative and a corresponding fluorine-substituted amine; The 7-formylcamptothecin derivative is selected from any one of; The corresponding fluorine-substituted amine is selected from at least one of the following compounds: Among them, X1, X2, R3, R4, m, n, y, L are defined as above; Preferably, the corresponding fluorine-substituted amine is selected from 9. A pharmaceutical composition, which comprises the compound according to any one of claims 1-8, its pharmaceutically acceptable salt, its stereoisomer and pharmaceutically acceptable excipients.

10. Use of the compound according to any one of claims 1-8, its pharmaceutically acceptable salt, its stereoisomer or the pharmaceutical composition according to claim 9 in the preparation of a drug for treating cancer; Preferably, the cancer is selected from one or more of esophageal cancer, gastric cancer, lung cancer and breast cancer.

11. A method for treating cancer, which comprises the step of administering to a subject the compound according to any one of claims 1-8, its pharmaceutically acceptable salt, its stereoisomer or the pharmaceutical composition according to claim 9; Preferably, the cancer is selected from one or more of esophageal cancer, gastric cancer, lung cancer and breast cancer.