Preparation and application of 7-fluoroalkyl substituted camptothecin derivative

Abstract

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

Description

Technical Field

[0001] The present invention relates to the field of medicine, and particularly to the preparation and application of a series of 7-fluoroalkyl-substituted camptothecin derivatives. Background Art

[0002] Camptothecin and its derivatives have inhibitory activity against topoisomerase Top1, especially strong inhibitory activity against the complex formed by Top1-DNA. Camptothecin has significant curative effects on gastric cancer, esophageal cancer, lung cancer, bladder cancer, etc., and is a broad-spectrum anti-tumor active drug. Among them, Irinotecan and Topotecan have been approved in many countries for the treatment of various cancers. Another camptothecin derivative, Belotecan, has been approved in South Korea for the treatment of SCLC and ovarian cancer. Developing new camptothecin drugs is necessary and has broad application value. Summary of the Invention

[0003] The purpose of the present invention is to provide a 7-fluoroalkyl-substituted aminomethyl camptothecin derivative, which has the advantages of high activity, low toxicity, and stable metabolism as an anti-tumor drug.

[0004] On the one hand, the present invention provides a compound of formula (I), its pharmaceutically acceptable salts, and its stereoisomers:

[0005]

[0006] In the formula,

[0007] R 1 , R 2 are each independently selected from hydrogen, fluorine, methyl; or

[0008] R 1 , R 2 together with the carbon atom to which they are attached form

[0009] X 1 is selected from hydrogen, C 1 -C 3 alkyl;

[0010] X 2 is selected from substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, and the C 1 -C 8 alkyl, C 3 -C 6 cycloalkyl includes at least one fluorine atom substituent;

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

[0012] 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 following group: tritium, halogen, halogen-substituted or unsubstituted C 1-6 alkyl, halogen-substituted or unsubstituted C 3-6 cycloalkyl, tritium-substituted or unsubstituted C 1-6 alkyl, tritium-substituted or unsubstituted C 3-6 cycloalkyl.

[0013] In one embodiment, X 1 is selected from hydrogen, methyl, ethyl, propyl or isopropyl;

[0014] In one embodiment, X 1 is hydrogen.

[0015] In one embodiment, X 2 is selected from 1, 2 or 3 fluorine-substituted C 1 -C 8 alkyl; further selected from 1, 2 or 3 fluorine-substituted C 1 -C 6 alkyl.

[0016] In one embodiment, X 2 is selected from substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, the C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl includes 1, 2 or 3 fluorine atom substituents.

[0017] In one embodiment, X 2 is selected from substituted or unsubstituted C 1 -C 6 alkyl, the C 1 -C 6 alkyl includes 1, 2 or 3 fluorine atom substituents.

[0018] In one embodiment, X 2 is selected from substituted or unsubstituted C 3 -C 6 cycloalkyl, the C 3 -C 6 cycloalkyl includes 1, 2 or 3 fluorine atom substituents.

[0019] In one embodiment, X 2Selected from ethyl groups, the ethyl groups include 1, 2 or 3 fluorine atom substituents, and the ethyl groups are further substituted by 1 or 2 methyl groups. Such ethylamines with fluorine atom substitution can significantly reduce the basicity of the substituted amines, reduce the hepatotoxicity of the compounds in vivo, improve the metabolic stability and the cell membrane penetration ability, and contribute to improving the anti-tumor activity.

[0020] In one embodiment, X 2 is selected from -CH 2 -CF 3 , -CH(CH 3 )-CF 3 or -C(CH 3 ) 2 -CF 3 .

[0021] In one embodiment, X 2 is selected from

[0022] In one embodiment, R 1 is selected from hydrogen, fluorine, methyl; R 2 is selected from hydrogen, fluorine; or

[0023] R 1 , R 2 and the carbon atom to which they are attached together form

[0024] In one embodiment, R 1 is hydrogen; R 2 is hydrogen; or

[0025] R 1 is fluorine; R 2 is fluorine; or

[0026] R 1 is methyl; R 2 is fluorine; or

[0027] R 1 , R 2 and the carbon atom to which they are attached together form

[0028] In another aspect of the present invention, there are provided compounds of formula (II), their pharmaceutically acceptable salts and their stereoisomers:

[0029]

[0030] wherein R 1 , R 2 , n are each defined as in the compound of formula (I);

[0031] Further, in formula (II), R 1 and R 2 are each independently selected from hydrogen, fluorine, methyl; or

[0032] R 1 and R 2 together with the carbon atom to which they are attached form

[0033] R 3 and R 4 are each independently selected from hydrogen, fluorine, substituted or unsubstituted C 1 -C 6 alkyl; or

[0034] R 3 and R 4 together with the carbon atom to which they are attached form C 3 -C 6 cycloalkyl;

[0035] n is selected from 1, 2 or 3, preferably 1 or 2;

[0036] m is selected from 1 or 2;

[0037] y is selected from 1 or 2, preferably 2;

[0038] The "substitution" means that 1, 2, 3 or 4 hydrogen atoms in the group are each independently substituted by substituents selected from the following group: 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.

[0039] In another aspect of the present invention, there is provided a compound of formula (III), a pharmaceutically acceptable salt thereof and a stereoisomer thereof:

[0040]

[0041] In the formula, R 1 and R 2 and n are each defined as in the compound of formula (I);

[0042] L is selected from substituted or unsubstituted C 1 -C 6 alkyl;

[0043] The "substitution" means that 1, 2, 3 or 4 hydrogen atoms in the group are each independently substituted by substituents selected from the following group: deuterium, halogen, -halogen-substituted or unsubstituted C 1-6 alkyl.

[0044] In one embodiment, L is selected from -CH 2 -, -CH(CH 3 )-, or -CH(CH 3 ) 2 -.

[0045] In one embodiment, R 1 is selected from hydrogen, fluorine, methyl; R 2 is selected from hydrogen, fluorine; or

[0046] R 1 and R 2 together with the carbon atom to which they are attached form

[0047] In one embodiment, R 1 is hydrogen; R 2 is hydrogen; or

[0048] R 1 is fluorine; R 2 is fluorine; or

[0049] R 1 is methyl; R 2 is fluorine; or

[0050] R 1 and R 2 together with the carbon atom to which they are attached form

[0051] In one embodiment, the compound is selected from the compounds represented by the following formula (II-1), formula (II-2), formula (II-3), or formula (II-4):

[0052]

[0053]

[0054] wherein R 3 , R 4 , n, m, and y are each defined as in the compound of formula (II).

[0055] In one embodiment, R 3 and R 4 are each independently selected from hydrogen, fluorine, substituted or unsubstituted C 1 -C 6 alkyl; or

[0056] R 3 and R 4 together with the carbon atom to which they are attached form C 3 -C 6 cycloalkyl.

[0057] In one embodiment, R 3 , R 4 are each independently selected from hydrogen, fluorine, substituted or unsubstituted C 1 -C 3 alkyl.

[0058] In one embodiment, R 3 is selected from hydrogen, substituted or unsubstituted C 1 -C 6 alkyl.

[0059] In one embodiment, R 3 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or hexyl; preferably hydrogen or methyl.

[0060] In one embodiment, R 4 is selected from hydrogen or fluorine; more preferably fluorine.

[0061] Preferably, y is 2.

[0062] The present invention provides the following compounds, their pharmaceutically acceptable salts and their stereoisomers:

[0063]

[0064]

[0065] Another aspect of the present invention provides a method for preparing the aforementioned compound, which comprises the step of performing a reductive amination reaction using a 7-formylcamptothecin derivative and a corresponding fluorine-substituted amine.

[0066] In one embodiment, the 7-formylcamptothecin derivative is selected from any one of among them.

[0067] In one embodiment, the corresponding fluorine-substituted amine refers to at least one selected from compounds having the following structures, their equivalents, and their pharmaceutically acceptable salts:

[0068]

[0069] Wherein, X 1 , X 2 , R 3 , R 4 , m, n, y, L are defined as above.

[0070] In one embodiment, the corresponding fluorine-substituted amine is selected from

[0071] In another aspect of the present invention, there is provided a pharmaceutical composition comprising the above compound, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, and a pharmaceutically acceptable excipient.

[0072] In another aspect of the present invention, there is provided the use of the above compound, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or the above pharmaceutical composition in the preparation of a medicament for treating cancer.

[0073] In another aspect of the present invention, there is provided a method for treating cancer, which comprises the step of administering the above compound, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or the above pharmaceutical composition to a subject.

[0074] In one embodiment, the dosage of the above compound, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or the above pharmaceutical composition is a therapeutically effective amount.

[0075] In one embodiment, the cancer is selected from solid tumors.

[0076] In one embodiment, the cancer is selected from one or more of esophageal cancer, gastric cancer, lung cancer and breast cancer. Detailed Description of the Invention

[0077] I. Definitions

[0078] In the present invention, unless otherwise specified, scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. Also, relevant terms and laboratory operation procedures used herein are terms and conventional procedures widely used in the corresponding fields. Meanwhile, for a better understanding of the present invention, definitions and explanations of relevant terms are provided below.

[0079] In the description herein, reference to "some embodiments", "some embodiments" or "some implementations" describes a subset of all possible embodiments, but it is understood that "some embodiments" can be the same subset or different subsets of all possible embodiments, and can be combined with each other without conflict.

[0080] As used herein and unless otherwise stated, the terms "comprising", "including", "having", "containing", including their grammatical equivalents, are generally to be understood as open-ended and non-restrictive, for example, not excluding other unlisted elements or steps.

[0081] The compounds of the present disclosure may be asymmetric, for example, having one or more stereoisomers. Unless otherwise specified, 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 the therapeutics are composed of monomers, racemates, racemic mixtures, and their pharmaceutically acceptable salts. Compounds containing asymmetric carbon atoms in the present disclosure may be isolated in optically pure form or in racemic form. The optically pure form can be resolved from the racemic mixture or synthesized by using chiral starting materials or chiral reagents. Racemates, diastereomers, and enantiomers are all included within the scope of the present disclosure.

[0082] The numerical ranges herein refer to each integer within the given range. For example, "C 1 -C 8 " means that the group may have 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms; "C 3 -C 6 " means that the group may have 3, 4, 5, or 6 carbon atoms.

[0083] The term "substituted" means that any one or more hydrogen atoms on a particular atom or group are replaced by a substituent, provided that the valence of the particular atom or group is normal and the resulting compound is stable. Unless otherwise specified, the type and number of substituents can be arbitrary based on what is chemically achievable.

[0084] When any variable (such as R n ) appears more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted by 1-4 R's, the group may optionally be substituted by up to 4 R's, and each R in each case has an independent option. In addition, combinations of substituents and / or their variants are only permitted if such combinations result in a stable compound.

[0085] The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight-chain 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 isomers thereof, etc. More preferably, it is a lower alkyl group containing 1 to 6 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, etc. The alkyl group can be substituted or unsubstituted. When substituted, the substituent can be substituted at any available point of attachment.

[0086] Refers to the chemical bond connection point.

[0087] The term "pharmaceutically acceptable salt" refers to a salt formed by the corresponding amine compound and an inorganic acid or an organic acid, or a salt formed by the corresponding carboxylic acid compound and an alkali metal or an alkaline earth metal or an organic amine. Among them, inorganic acids include but are not limited to hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, etc.; 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, etc.; alkali metal or alkaline earth metal salts include but are not limited to sodium, potassium, calcium, magnesium salts, etc.; 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, amino acids, etc.

[0088] The drugs or pharmaceutical compositions of the present disclosure can be administered orally, topically, parenterally or mucosally (e.g., sublingually, by inhalation or rectally) in dosage unit formulations comprising 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, etc.

[0089] The term "treatment" includes inhibiting, alleviating, preventing or eliminating one or more symptoms or side effects associated with the disease, disorder or condition being treated.

[0090] The use of the term "inhibit" is relative to a control. Those skilled in the art will readily determine the appropriate control for each experiment. For example, the reduced response in a subject or cell treated with a compound is compared with the response in a subject or cell not treated with the compound.

[0091] The term "pharmaceutical composition" means a composition comprising a compound or its pharmaceutically acceptable salt as described in the present disclosure, 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 aids, etc.

[0092] The term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of a drug or agent that is non-toxic but capable of achieving the desired effect. In embodiments of the present invention, when treating a patient according to the present invention, the amount of a given drug depends on many factors, such as the specific dosing regimen, the type and severity of the disease or disorder, the uniqueness of the subject or host to be treated (e.g., body weight), however, depending on the specific circumstances, including for example the specific drug employed, the route of administration, the disorder being treated, and the subject or host being treated, the dosage can be routinely determined by methods known in the art. Generally, for adult therapeutic use, the dosage typically ranges from 0.02 - 5000 mg / day, such as about 1 - 1500 mg / day. The required dosage can be conveniently presented as a single dose, or as divided doses administered simultaneously (or within a short period of time) or at appropriate intervals, such as two, three, four or more divided doses per day. Those skilled in the art will understand that, although the above dosage ranges are given, the specific effective amount can be appropriately adjusted according to the patient's condition in combination with the physician's diagnosis.

[0093] The term "subject" refers to a mammal being evaluated for treatment and / or being treated. In one embodiment, the mammal is a human. The term "subject" includes, but is not limited to, an individual with cancer, an individual with an autoimmune disease, an individual infected with a pathogen, etc. The subject can be a human, but also includes other mammals, especially mammals that can be used as laboratory models of human diseases, such as mice, rats, etc.

[0094] II. Examples

[0095] In order to make the objectives, 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 construed as limiting the present invention. All other embodiments obtained by those of ordinary skill in the art without creative efforts fall within the scope of protection of the present invention.

[0096] Before further elaborating on the embodiments of the present invention, the nouns and terms involved in the embodiments of the present invention are described. The nouns and terms involved in the embodiments of the present invention are subject to the following explanations.

[0097] The raw materials and equipment used in the specific embodiments of the present disclosure are known products and are obtained by purchasing commercially available products.

[0098] Example 1: 7-(N-(2’,2’,2’-trifluoroethyl)amino)methyl camptothecin (1)

[0099]

[0100] Add camptothecin (10 g, 28.62 mmol), methanol (330 mL) and water (275 mL) into a reaction flask. While stirring, add 75% sulfuric acid (275 mL) dropwise. Then add FeSO 4 ·7H 2 O (7.96 g, 28.62 mmol). While stirring, add H 2 O 2 (440.00 mL) dropwise. The reaction solution is continuously stirred at room temperature for 18 hours, poured into ice water, and the solid product is filtered and dried to obtain 7-hydroxymethylcamptothecin 1a (7 g, yield 51.57%); LCMS: [M+1] + 379.12 (theoretical value: 378.12), which is directly used for the next reaction without purification.

[0101] Add 1a (9.5 g, 25.04 mmol), sodium bicarbonate (8.41 g, 100.16 mmol) and DCM (190 mL) into a reaction flask. While cooling in an ice bath and stirring, add Dess-Martin Periodinane (15.93 g, 37.56 mmol). Stir at room temperature overnight, pour into water, filter the precipitated solid product, and dry to obtain 1b, camptothecin-7-carbaldehyde (9 g, yield 76%); [M+1] + 377.21 (theoretical value: 376.11), which is directly used for the next reaction without purification.

[0102] Add 1b (1.5 g, 4.0 mmol) and 2,2,2-trifluoroethylamine (1.18 g, 11.9 mmol), DCM (60 mL) and NaBH 3 CN (0.75 g, 11.9 mmol) into a reaction flask. The reaction solution is 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 (500 MHz, DMSO-d 6 ) δ8.44 (d, J = 8.5 Hz, 1H), 8.27 - 8.18 (m, 1H), 7.91 (ddd, J = 8.3, 6.8, 1.3 Hz, 1H), 7.79 (ddd, J = 8.3, 6.8, 1.3 Hz, 1H), 7.37 (s, 1H), 5.59 (s, 2H), 5.50 - 5.36 (m, 3H), 4.76 (s, 3H), 4.07 (q, J = 9.6 Hz, 2H), 1.96 - 1.85 (m, 2H), 0.90 (t, J = 7.3 Hz, 3H).

[0103] Example 2: 7-(N-(S)-(1’,1’,1’-trifluoropropan-2’-yl)amino)methylcamptothecin (2)

[0104]

[0105] 1b (2 g, 5.3 mmol) and (S)-1,1,1-trifluoropropan-2-amine (2.38 g, 15.9 mmol, 2.07 mL) were added to a reaction flask, along with DCM / DMSO (4:1, 20 mL) and NaBH 3 CN (1 g, 15.9 mmol). The reaction mixture 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 (500 MHz, DMSO-d 6 ) δ 8.33 (dd, J = 8.6, 1.4 Hz, 1H), 8.15 (dd, J = 8.5, 1.3 Hz, 1H), 7.83 (ddd, J = 8.3, 6.8, 1.3 Hz, 1H), 7.70 (ddd, J = 8.3, 6.8, 1.3 Hz, 1H), 7.33 (s, 1H), 6.53 (s, 1H), 5.43 (s, 2H), 5.36 (d, J = 1.7 Hz, 2H), 4.47 (d, J = 13.7 Hz, 1H), 4.38 (d, J = 13.7 Hz, 1H), 3.53 (p, J = 7.3 Hz, 1H), 1.88 (dh, J = 21.5, 7.2 Hz, 2H), 1.27 (d, J = 6.7 Hz, 3H), 0.90 (t, J = 7.3 Hz, 3H); 13 C NMR (126 MHz, DMSO) δ 172.96, 157.26, 152.61, 150.48, 148.89, 146.04, 141.67, 130.41, 130.07, 129.33, 128.93, 127.89, 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.

[0106] Example 3: 7-(N-(R)-(1’,1’,1’-trifluoropropan-2’-yl)amino)methylcamptothecin (3)

[0107]

[0108] 1b (200 mg, 530 μmol) and (R)-1,1,1-trifluoropropan-2-amine (181.40 mg, 1.21 mmol) were added to a reaction flask, along with DCM / DMSO (4:1, 10 mL) and NaBH 3 CN (100 mg, 1.59 mmol). The reaction mixture 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)amine)methylcamptothecin 3 (40 mg, yield 15%, HPLC 97%); LCMS: [M+H] + 474.60 (theoretical value 473.45); 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.34 (d, J = 8.5 Hz, 1H), 8.17 (d, J = 8.5 Hz, 1H), 7.85 (t, J = 8.5 Hz, 1H), 7.72 (t, J = 8.5, 1H), 7.35 (s, 3H), 5.46 (s, 2H), 5.38 (s, 2H), 4.50 (d, J = 13.6 Hz, 1H), 4.40 (d, J = 13.7 Hz, 1H), 3.55 (p, J = 7.2 Hz, 2H), 1.99 - 1.83 (m, 2H), 1.30 (d, J = 6.7 Hz, 3H), 0.92 (t, J = 7.3 Hz, 3H); 13 C NMR (126 MHz, DMSO-d6) δ 172.94, 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.

[0109] Example 4: 7-(N-(2’-trifluoromethylprop-2’-)amine)methylcamptothecin (4)

[0110]

[0111] 1b (400 mg, 1.06 mmol) and 2-trifluoromethylprop-2-amine hydrochloride (520.13 mg, 3.18 mmol) were added to a reaction flask, along with DCM (24 mL), DMSO (4 mL), NaBH 3CN (200 mg, 3.18 mmol), 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-yl)amino)methyl camptothecin 4 (42 mg, yield 7.5%, HPLC 94%); LCMS: [M+H]+ 488.28 (theoretical value 487.48); 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.30 (d, J = 8.4 Hz, 1H), 8.17 (d, J = 8.3 Hz, 1H), 7.86 (ddd, J = 8.4, 6.6, 1.3 Hz, 1H), 7.74 (ddd, J = 8.4, 6.7, 1.3 Hz, 1H), 7.34 (s, 1H), 5.43 (d, J = 14.0 Hz, 4H), 4.42 (s, 2H), 1.89 (ddt, J = 17.9, 14.1, 7.1 Hz, 2H), 1.41 (s, 6H), 0.89 (t, J = 7.3 Hz, 3H).

[0112] Example 5: 7-(N-(2’,2’,2’-trifluoroethyl)amino)methyl-10,11-methylenedioxy camptothecin (5)

[0113]

[0114] 6-Nitropiperonal (25 g, 127.46 mmol) and methanol (250 mL) were added to a reaction flask and dissolved. 10% Pd / C (2.49 g, 23.37 mmol) was added, and the reaction solution was stirred under a hydrogen balloon for 16 h, filtered and concentrated to obtain the product 5a (20 g, 116.76 mmol, yield 91.60%, HPLC 97%); LCMS: [M+1] + 166.91 (theoretical value 165.04).

[0115] 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 a reaction flask. The reaction solution was added dropwise with stirring to 110 °C and reacted for 16 h. It was concentrated under reduced pressure, acetone (50 ml) was added, the solid was filtered out, washed with methanol, and dried to obtain 5c (33 g, yield 80.29%, HPLC 96%); LCMS: [M+1] + 393.39 (theoretical value 392.37); 11H NMR (500 MHz, DMSO-d6) δ 8.46 (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, 7.3 Hz, 2H), 0.89 (t, J = 7.4 Hz, 3H).

[0116] 5c (11 g, 27.96 mmol), methanol (330 mL), H 2 O (275 mL), H 2 SO 4 (75%) (2.74 g, 27.96 mmol, 275 mL), and FeSO 4 ·7H 2 O (8.8 g, 31.65 mmol) were added to a reaction flask. At 0 °C, 30% aqueous H 2 O 2 solution (55.50 g, 1.63 mol, 50 mL) was slowly added dropwise to the reaction mixture. The reaction mixture was stirred at room temperature for 16 h, H 2 O (500 ml) was added, the solid product was filtered, washed with acetonitrile and methyl tert-butyl ether, and dried to obtain a brown solid product 5d (8.3 g, yield 63.10%, HPLC 94%); LCMS: [M + 1] + 423.39 (theoretical value 422.39); 1 1H NMR (500 MHz, DMSO-d 6 ) δ 7.39 (s, 1H), 7.34 (s, 1H), 7.22 (s, 1H), 6.25 (d, J = 5.2 Hz, 2H), 5.45 - 5.35 (m, 2H), 5.12 (s, 2H), 5.04 (s, 2H), 1.94 - 1.80 (m, J = 7.1 Hz, 2H), 0.90 (t, J = 7.2 Hz, 3H).

[0117] 5d (5 g, 11.81 mmol), DCM (100 mL), and DMSO (20 mL) were added to a reaction flask. At 0 °C with stirring, Dess-Martin periodinane (1,1-diacetoxy-3-oxo-1,2-benziodoxol-1-yl)acetate (10.02 g, 23.62 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 16 h, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain a yellow solid product 5e (2.7 g, yield 49.92%, HPLC 92%); LCMS: [M + 1] + 421.36 (theoretical value 420.38), which was directly used in the next step of the reaction.

[0118] 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 NaBH 3 CN (1.21 g, 19.22 mmol) were added to a reaction flask. The reaction mixture was stirred at room temperature for 3 h, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain the yellow solid product 5 (1.5 g, yield 42.70%, HPLC 95%); LCMS: [M+1] + 504.28 (theoretical value 503.43); 1 H NMR (500 MHz, DMSO-d 6 ) δ 7.66 (s, 1H), 7.50 (s, 1H), 7.24 (s, 1H), 6.48 (s, 1H), 6.29 (d, J = 2.3 Hz, 2H), 5.42 (s, 2H), 5.29 (s, 2H), 4.27 (d, J = 6.6 Hz, 2H), 3.40 (dd, J = 10.2, 7.2 Hz, 2H), 3.09 (p, J = 7.0 Hz, 1H), 1.86 (dh, J = 21.5, 7.3 Hz, 2H), 0.88 (t, J = 7.3 Hz, 3H).

[0119] Example 6: 7-(N-(S)-(1’,1’,1’-trifluoropropan-2’-yl)amino)methyl-10,11-methylenedioxycamptothecin (6)

[0120]

[0121] 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 a reaction flask. After stirring for 30 min, NaBH 3 CN (114.09 mg, 1.82 mmol) was added, and the reaction was continued to stir at room temperature for 2 h. After concentration under reduced pressure, the solid product 6 (0.54 g, yield 77%, HPLC 95%) was obtained by silica gel column chromatography; LCMS [M+H] + 518.2 (theoretical value 517.15); 1 H NMR (600 MHz, DMSO-d 6)δ 7.67 (s, 1H), 7.50 (s, 1H), 7.24 (s, 1H), 6.49 (s, 1H), 6.29 (d, J = 2.1 Hz, 2H), 5.42 (s, 2H), 5.31 (d, J = 3.7 Hz, 2H), 4.35 (dd, J = 13.6, 5.9 Hz, 1H), 4.24 (dd, J = 13.4, 7.8 Hz, 1H), 3.49 (h, J = 7.3 Hz, 1H), 2.80 (q, J = 7.1 Hz, 1H), 1.87 (m, J = 21.6, 14.0, 7.2 Hz, 2H), 1.25 (d, J = 6.7 Hz, 3H), 0.88 (t, J = 7.3 Hz, 3H).

[0122] Example 7: 7-(N-(R)-(1’,1’,1’-Trifluoropropan-2’-yl)amino)methyl-10,11-methylenedioxycamptothecin (7)

[0123]

[0124] 5e (500 mg, 1.19 mmol), (R)-1,1,1-trifluoropropan-2-amine (201.27 mg, 1.35 mmol), DCM (8 mL), DMSO (2 mL) were added to a reaction flask, stirred for 30 min, then NaBH 3 CN (111.85 mg, 1.78 mmol) was added, and the reaction was continued to stir at room temperature for 2 h. The solvent was concentrated under reduced pressure, and the solid product 7 (200 mg, yield 30%, HPLC 94%) was obtained by silica gel column chromatography; LCMS: [M + H] + 518.26 (theoretical value 517.46); 1 H NMR (500 MHz, DMSO-d 6 )δ 7.68 (s, 1H), 7.50 (s, 1H), 7.24 (s, 1H), 6.48 (s, 1H), 6.29 (d, J = 2.6 Hz, 2H), 5.42 (s, 2H), 5.32 (d, J = 4.1 Hz, 2H), 4.35 (dd, J = 13.5, 5.8 Hz, 1H), 4.24 (dd, J = 13.5, 7.8 Hz, 1H), 3.49 (h, J = 7.5 Hz, 1H), 2.80 (q, J = 7.1 Hz, 1H), 1.86 (ddq, J = 21.3, 14.3, 7.2 Hz, 2H), 1.25 (d, J = 6.8 Hz, 3H), 0.88 (t, J = 7.3 Hz, 3H).

[0125] Example 8: 7-(N-(2’-Trifluoromethylpropan-2’-yl)amino)methyl-10,11-methylenedioxycamptothecin (8)

[0126]

[0127] 5e (200 mg, 474.63 μmol), 2-trifluoromethylpropan-2-amine (116.45 mg, 711.95 μmol), DCM (8 mL), DMSO (2 mL) were added to the reaction flask, and the mixture was stirred for 30 min. Then NaBH 3 CN (44.74 mg, 711.95 μmol) was added, and the reaction was continued to stir at room temperature for 2 h. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the solid product 7 (200 mg, yield 7.5%, HPLC 95%); LCMS: [M+H] + 532.28 (theoretical value 531.49); 1 H NMR (600 MHz, DMSO-d 6 ) δ 7.62 (s, 1H), 7.52 (s, 1H), 7.25 (s, 1H), 6.49 (s, 1H), 6.30 (d, J = 1.9 Hz, 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 = 7.3 Hz, 3H).

[0128] Example 9: 7-(N-(2’,2’,2’-trifluoroethyl)amino)methyl-10,11-difluorocamptothecin (9)

[0129]

[0130] 2-Nitro-4,5-difluorobenzaldehyde (13.6 g, 86.01 mmol), PPTS (196.49 g, 781.89 mmol) and the tricyclic intermediate 5b (20.58 g, 77.89 mmol) were added to the reaction flask. The reaction mixture was heated to 130 °C with stirring for several hours, cooled to room temperature, methanol (100 mL) was added, and the mixture was stirred overnight at room temperature. The solid was filtered out, dried to obtain a brown solid 9c (23 g, yield 71.76%, HPLC 94%); LCMS: [M+H] + 385.20 (theoretical value 384.09), which was directly used for the next step reaction.

[0131] 9c (15 g, 38.93 mmol), methanol (450 mL), H 2 O (325 mL) were added to the reaction flask. At 0 °C and with stirring, 75% H 2 SO 4(3.82 g, 38.93 mmol, 325 mL) and FeSO 4 ·7H 2 O (10.82 g, 38.93 mmol). At 0 °C, 30% H 2 O 2 aqueous solution (83.25 g, 2.45 mol, 75 mL) was slowly added dropwise to the reaction solution. The reaction solution was stirred at room temperature for 16 h, H 2 O (650 ml) was added, the solid product was filtered, washed with acetonitrile and methyl tert-butyl ether, and dried to obtain a brown solid product 9d (10 g, yield 40.20%); LCMS: [M+1] + 415.24 (theoretical value 414.36).

[0132] 9d (6 g, 14.45 mmol), DCM (120 mL) and DMSO (20 mL) were added to the reaction flask. At 0 °C and with stirring, Dess-Martin oxidant (12.25 g, 28.89 mmol) was added dropwise. The reaction solution was stirred at room temperature for 16 h, poured into water, the precipitated solid product was filtered, and after drying, 9e (9 g, yield 52.76%) was obtained; LCMS: [M+1] + 413.35 (theoretical value 412.35).

[0133] 9e (1 g, 2.42 mmol), 2,2,2-trifluoroethylamine hydrochloride (983.54 mg, 7.26 mmol), DCM (30 mL), DMSO (5 mL) and NaBH 3 CN (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 obtain a yellow solid product 9 (440 mg, yield 35.17%, HPLC 96%); LCMS: [M+1] + 496.26 (theoretical value 495.41); 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.30 (dd, J = 12.3, 8.7 Hz, 1H), 8.10 (dd, J = 11.4, 8.0 Hz, 1H), 7.28 (s, 1H), 6.52 (s, 1H), 5.41 (s, 2H), 5.29 (s, 2H), 4.33 (d, J = 6.5 Hz, 2H), 3.42 (dd, J = 10.5, 7.5 Hz, 2H), 3.17 (p, J = 7.0 Hz, 1H), 1.87 (dh, J = 14.3, 7.2 Hz, 2H), 0.89 (t, J = 7.3 Hz, 3H).

[0134] Example 10: 7-(N-(S)-(1’,1’,1’-trifluoropropan-2’-yl)amino)methyl-10,11-difluorocamptothecin (10)

[0135]

[0136] 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 NaBH 3 CN (686 mg, 10.92 mmol) were added to a reaction flask. The reaction mixture was stirred at room temperature for 2 h. Saturated NaHCO 3 aqueous solution (50 mL) was added. The solid product was filtered and purified by silica gel column chromatography to obtain solid product 10 (500 mg, yield 27%, HPLC 97%); LCMS: [M+H] + 510.26 (theoretical value 509.14); 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.28 (dd, J = 12.3, 8.7 Hz, 1H), 8.10 (dd, J = 11.4, 8.0 Hz, 1H), 7.28 (s, 1H), 6.51 (s, 1H), 5.41 (s, 2H), 5.28 (s, 2H), 4.40 (dd, J = 14.0, 5.9 Hz, 1H), 4.28 (dd, J = 14.0, 7.5 Hz, 1H), 3.51 (q, J = 7.3 Hz, 1H), 2.87 (q, J = 7.1 Hz, 1H), 1.87 (p, J = 7.2 Hz, 2H), 1.26 (d, J = 6.8 Hz, 3H), 0.88 (t, J = 7.3 Hz, 3H); 13 C NMR (126 MHz, DMSO) δ 172.87, 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.

[0137] Example 11: 7-(N-(R)-(1’,1’,1’-trifluoropropan-2’-yl)amino)methyl-10,11-difluorocamptothecin (11)

[0138]

[0139] 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 NaBH 3 CN (228.05 mg, 3.63 mmol) were added to the reaction flask. The reaction mixture was stirred at room temperature for 2 h. Saturated NaHCO 3 aqueous solution (50 mL) was added, and the solid product was filtered. The product was purified by silica gel column chromatography to obtain a yellow solid product 11 (150 mg, yield 23.08%, HPLC 95%); LCMS: [M+H] + 510.43 (theoretical value 509.43); 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.30 (dd, J = 12.3, 8.7 Hz, 1H), 8.12 (dd, J = 11.4, 8.0 Hz, 1H), 7.29 (s, 1H), 6.53 (s, 1H), 5.42 (s, 2H), 5.30 (d, J = 6.2 Hz, 2H), 4.41 (dd, J = 13.9, 5.9 Hz, 1H), 4.28 (dd, J = 13.9, 7.6 Hz, 1H), 3.50 (h, J = 7.3 Hz, 1H), 2.88 (td, J = 7.5, 5.9 Hz, 1H), 1.87 (dp, J = 21.4, 7.1 Hz, 2H), 1.27 (d, J = 6.8 Hz, 3H), 1.21 (q, J = 5.2, 4.4 Hz, 1H), 0.89 (t, J = 7.3 Hz, 3H); 13 C NMR (151 MHz, DMSO) δ 172.86, 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.

[0140] Example 12: 7-(N-(2'-trifluoromethylpropan-2'-yl)amino)methyl-10,11-difluorocamptothecin (12)

[0141]

[0142] 9e (350 mg, 846.74 μmol), 2-trifluoromethylisopropylamine hydrochloride (15.50 mg, 2.54 mmol), DCM (18 mL), DMSO (3 mL) and NaBH 3 CN (159.63 mg, 2.54 mmol) were added to a reaction flask. The reaction mixture was stirred at room temperature for 3 h, and saturated NaHCO 3 aqueous solution (50 mL) was added. The solid product was filtered and purified by silica gel column chromatography to obtain the yellow solid product 12 (140 mg, yield 29.00%); LCMS: [M+H] + 524.30 (theoretical value 523.46); 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.23 (dddt, J = 56.2, 11.0, 8.1, 2.5 Hz, 2H), 7.32 (t, J = 1.2 Hz, 1H), 6.54 (s, 1H), 5.50 - 5.28 (m, 4H), 4.33 (d, J = 7.3 Hz, 2H), 2.94 (t, J = 7.4 Hz, 1H), 1.87 (ddp, J = 21.4, 14.5, 7.3 Hz, 2H), 1.37 (s, 6H), 0.88 (t, J = 7.3 Hz, 3H).

[0143] Example 13: 7-(N-(2',2',2,-trifluoroethyl)amino)methyl-10-methyl-11-fluorocamptothecin (13)

[0144]

[0145] Aqueous solution (1600 mL) of hydroxylamine sulfate (444.0 g, 2.4 mol), anhydrous sodium sulfate (494.0 g, 3.5 mol) and chloral hydrate (65.0 g, 519.4 mmol) was added to a reaction flask and stirred until dissolved. 3-Fluoro-4-methylaniline (65.0 g, 438.8 mmol) and 1N HCl (550.0 mL) were added, and the mixture was stirred and heated to 45 °C for 2 h, then heated to 75 °C for 1 h, cooled, and the precipitated solid was filtered. After drying, 13a (96 g, yield 94% yield, HPLC 5%) was obtained; LCMS: [M+H] + 197.20 (theoretical value 196.06); 1 H NMR (300 MHz, MSO-d6 1δ2.08 (d, J = 1.0 Hz, 3H), 7.12 (t, J = 8.8 Hz, 1H), 7.25 (dd, J = 2.1, 8.2 Hz, 1H), 7.36 (dd, J = 1.6, 12.4 Hz, 1H), 10.18 (s, 1H), 12.11 (s, 1H).

[0146] 98% sulfuric acid (1200 mL) and 13a (96 g, 438.0 mmol) were added to a reaction flask, stirred and heated to 80 °C for 4 h, cooled to room temperature, poured into ice water (2400 mL), the precipitated solid was filtered and 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 (500 MHz, CDCl 3 ) δ 7.70 - 7.65 (m, 2H), 7.48 (d, J = 7.9 Hz, 2H), 2.28 (s, 5H).

[0147] 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) were added to a reaction flask, and 30% H 2 O 2 aqueous solution (85.0 g) was added dropwise under stirring at 0 °C, stirred at room temperature overnight, adjusted to pH ~ 4 - 6 with 4N HCl under ice bath cooling, the precipitated solid was filtered and dried at 48 °C for 16 h to obtain 13c (48.5 g, yield 60.4%, HPLC 95%); LCMS: [M+H] + 170.10 (theoretical value 169.05); 1 H NMR (400 MHz, DMSO-d 6 ) δ 87.55 (d, J = 8.2 Hz, 1H), 6.34 (d, J = 12.1 Hz, 1H), 2.02 (s, 3H).

[0148] Lithium aluminum hydride (14.9 g, 382.0 mmol) and dry THF (100.0 mL) were added to a 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 mixture was stirred at room temperature for 3 h, and a small amount of saturated Na 2 SO 4Quench with aqueous solution, filter, concentrate the filtrate, add water, extract with ethyl acetate, wash with saturated sodium chloride, dry over anhydrous sodium sulfate, filter and concentrate to obtain a pale yellow liquid product 13d (22.1 g, yield 92.9%, HPLC 94%); LCMS: [M+H] + 156.11 (theoretical value 155.07); 1 H NMR (600 MHz, DMSO-d 6 ) δ 66.90 (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).

[0149] Add 13d (22.1 g, 141.0 mmol), DCM (450.0 mL) and manganese dioxide (59.0 g, 707.0 mmol) to the reaction flask, stir the reaction mixture at room temperature for 16 h, filter, wash with DCM, and concentrate the filtrate to obtain 13e (21.0 g, yield 87%); LCMS: [M+H] + 154.10 (theoretical value 153.06); 1 H NMR (400 MHz, CDCl 3 ) δ 9.75 (s, 1H), 7.27 (d, J = 8.3 Hz, 1H), 6.29 (d, J = 11.5 Hz, 1H), 6.12 (s, 2H), 2.17 (s, 3H).

[0150] Add 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) to the reaction flask, stir and heat to 110 °C and react overnight. Cool to room temperature, add MeOH (400.0 mL), stir at room temperature for 2 h, filter to precipitate a solid to obtain 13f (38.5 g, yield 72% yield, HPLC 97%); LCMS: [M+H] + 381.3 (theoretical value 380.12); 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.60 (s, 1H), 8.03 (d, J = 8.3 Hz, 1H), 7.86 (d, J = 10.9 Hz, 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, 7.1 Hz, 2H), 0.89 (t, J = 7.3 Hz, 3H).

[0151] Add 13f (30.0 g, 78.7 mmol), CH 3 OH (450.0 mL) and H 2 O (375.0 mL) to the reaction flask, cool to 0 °C, and add dropwise 75% H 2 SO 4 (375.0 mL). Maintain the temperature below 10 °C. While stirring at 0 °C, add ferrous sulfate hydrate (22.0 g, 78.7 mmol) and 30% H 2 O 2 (160.0 mL). Continue stirring at room temperature for 16 h. Pour the reaction mixture into ice water (6.0 L), filter the precipitated solid, wash with acetonitrile, and dry to obtain 13 g (18.2 g, yield 56%, HPLC 97% p); LCMS: [M+H] + 411.1, (theoretical value 410.13); 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.14 (d, J = 8.2 Hz, 1H), 7.88 (d, J = 10.7 Hz, 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, 7.0 Hz, 3H), 1.24 (s, 2H), 0.89 (t, J = 7.3 Hz, 3H).

[0152] Add 13 g (14.0 g, 34.0 mmol), sodium bicarbonate (11.4 g, 136.1 mmol), DCM (260.0 mL) and DMSO (45.0 mL), and Dess-Martin oxidation reagent (28.9 g, 67.9 mmol) to the reaction flask. Stir the reaction mixture at room temperature for 16 h. Concentrate the reaction mixture, add water, filter the precipitated solid, and dry to obtain 13h (21.3 g, yield 77%); LCMS: [M+H] + 409.34 (theoretical value 408.11); 1 H NMR (600 MHz, CDCl 3 ) δ 11.00 (s, 1H), 8.90 (d, J = 7.7 Hz, 1H), 7.95 (d, J = 10.3 Hz, 1H), 7.31 (s, 1H), 6.56 (s, 1OH), 5.44 (s, 2H), 5.42 (s, 2H), 2.48 (s, 3H), 1.88 (m, 2H), 0.89 (t, J = 7.4 Hz, 8H).

[0153] 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 a reaction flask and stirred at room temperature for 30 min. Then NaBH 3 CN (1.84 g, 29.31 mmol) was added, and the mixture was stirred at room temperature for another 2 h. The mixture was concentrated, saturated NaHCO 3 aqueous solution was added, and the precipitated solid was filtered. The product was purified by silica gel column chromatography to obtain a pale yellow solid 13 (1.1 g, yield 21.72%, HPLC 95%); LCMS: [M+H] + 492.22 (theoretical value 491.44); 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.28 (d, J = 8.2 Hz, 1H), 7.87 (d, J = 10.7 Hz, 1H), 7.32 (s, 1H), 6.53 (s, 1H), 5.44 (s, 2H), 5.36 (s, 2H), 4.40 (d, J = 6.7 Hz, 2H), 3.44 (td, J = 10.1, 7.0 Hz, 2H), 3.18 (p, J = 6.9 Hz, 1H), 2.50 (s, 3H), 1.88 (dp, J = 18.3, 7.1 Hz, 2H), 0.89 (t, J = 7.3 Hz, 3H); 13 CNMR (126 MHz, DMSO) δ 172.95, 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.

[0154] Example 14: 7-(N-(S)-(1’,1’,1’-trifluoropropan-2’-yl)amino)methyl-10-methyl-11-fluorocamptothecin (14)

[0155]

[0156] 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) and DCM (260.0 mL) were added to a reaction flask. NaBH 3 (CN) (2.3 g, 36.6 mmol) was added, and the reaction mixture was stirred at room temperature for 3 h. The mixture was concentrated, and H2 O(100.0 mL), filter the solid product, purify 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 H NMR (500 MHz, DMSO-d 6 ) δ8.30 (d, J = 8.3 Hz, 1H), 7.88 (d, J = 10.7 Hz, 1H), 7.32 (s, 1H), 6.52 (s, 1H), 5.44 (s, 2H), 5.39 (s, 2H), 4.48 (dd, J = 13.8, 6.1 Hz, 1H), 4.38 (dd, J = 13.9, 7.7 Hz, 1H), 3.59 - 3.46 (m, 1H), 2.89 (q, J = 7.2 Hz, 1H), 1.88 (dp, J = 19.1, 7.1 Hz, 2H), 1.44 - 1.12 (m, 6H), 0.88 (t, J = 7.3 Hz, 3H).

[0157] Example 15: 7-(N-(R)-(1’,1’,1’-trifluoropropan-2’-yl)amino)methyl-10-methyl-11-fluorocamptothecin (15)

[0158]

[0159] Add 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) to a reaction flask, stir at room temperature for 1 h, add NaBH 3 CN (276.30 mg, 4.40 mmol), continue to stir at room temperature for 2 h, concentrate, add saturated sodium bicarbonate aqueous solution, filter the precipitated solid, and purify by silica gel column chromatography to obtain a pale yellow solid product 15 (0.2 g, yield 26%, HPLC 96%); LCMS: [M+H] + 506.21 (theoretical value 505.47); 1 HNMR (500 MHz, DMSO-d 6)δ 8.34 - 8.26 (m, 1H), 7.88 (d, J = 10.8 Hz, 1H), 7.32 (s, 1H), 6.52 (s, 1H), 5.44 (s, 2H), 5.39 (d, J = 2.4 Hz, 2H), 4.48 (dd, J = 13.8, 6.1 Hz, 1H), 4.37 (dd, J = 13.8, 7.8 Hz, 1H), 3.53 (h, J = 7.3 Hz, 1H), 2.89 (q, J = 7.2 Hz, 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).

[0160] Example 16: 7-(N-(2'-Trifluoromethylpropan-2'-yl)amino)methyl-10-methyl-11-fluorocamptothecin (16)

[0161]

[0162] 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 a reaction flask, stirred at room temperature for 30 min, and NaBH 3 CN (46.16 mg, 734.61 μmol) was added, and the mixture was stirred 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 obtain the light yellow solid product 16 (40 mg, yield 32%, 9, HPLC 95%); LCMS: [M + H] + 520.20 (theoretical value 519.18); 1 H NMR (500 MHz, DMSO-d 6 )δ 8.25 (d, J = 8.4 Hz, 1H), 7.90 (d, J = 10.9 Hz, 1H), 7.33 (s, 1H), 6.52 (s, 1H), 5.43 (d, J = 7.8 Hz, 4H), 4.38 (d, J = 7.4 Hz, 2H), 2.94 (t, J = 7.4 Hz, 1H), 1.88 (dq, J = 14.3, 7.0 Hz, 2H), 1.38 (s, 6H), 0.88 (t, J = 7.3 Hz, 3H).

[0163] Example 17: 7-(N-(2',2',2'-Trifluoroethyl)amino)ethylcamptothecin (17)

[0164]

[0165] At 0 °C, camptothecin (1 g, 2.86 mmol) and FeSO 4 ·7H 2 O (795.78 mg, 2.86 mmol) were dissolved in H 2 O (32.5 mL), and then H 2 SO 4 (17.5 mL), 1,3 - propanediol (10.59 g, 137.39 mmol, 10.06 mL) and 35% hydrogen peroxide (97.36 mg, 2.86 mmol, 87.71 μL) were carefully added. The mixture was stirred and dissolved, and the reaction was continued at 0 °C for 3 hours. The reaction solution was poured into 1 L of ice - water, and the precipitated solid was filtered out, dissolved in methanol, purified by silica gel column chromatography, and concentrated to obtain a pale yellow powdery solid 17a (345 mg, yield 29.11%); LCMS: [M + 1] + 393.43 (calculated value: 392.41).

[0166] At 25 °C, in a 250 - ml round - bottom flask, the above - prepared 17a (345 mg, 0.833 mmol) was dissolved in DMSO (20 mL) and DCM (6 mL). At 0 °C, Dess - Martin Periodinane (706 mg, 1.666 mmol) was added, and the reaction was carried out 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, yield 85%); LCMS: [M + H] + 391.23 (calculated value: 390.40).

[0167] The above - prepared 17b (200 mg, 0.512 mmol) was dissolved in EtOH (5 mL), 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 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 carried out 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 by reverse - phase C18 column (ACN / 0.1% TFA aqueous solution) to obtain a pale yellow powdery solid product 17 (18 mg, yield 7.4%); LCMS: [M + 1] + 474.38 (calculated value 473.45); 1 H NMR (500 MHz, DMSO - d 6)δ8.32 (dd, J = 8.5, 1.3 Hz, 1H), 8.22 (dd, J = 8.5, 1.2 Hz, 1H), 7.90 (ddd, J = 8.3, 6.8, 1.3 Hz, 1H), 7.80 (ddd, J = 8.3, 6.8, 1.3 Hz, 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, 7.2 Hz, 2H),.88 (q, J = 8.6, 7.9 Hz, 3H).

[0168] Example 18: 7-(N-(S)-(1’,1’,1’-trifluoropropan-2’-)-amine)ethyl camptothecin (18)

[0169]

[0170] Dissolve 17b (200 mg, 0.512 mmol) in EtOH (5 mL), add (S)-1,1,1-trifluoropropan-2-amine (179.4 mg, 1.2 mmol, HCl salt) and sodium acetate (100.8 mg, 1.2 mmol), and stir at room temperature for 6 hours. Add acetic acid (15 mL) and sodium cyanoborohydride (94.5 mg, 1.5 mmol), and react at room temperature for 2 hours. Add water and extract with dichloromethane (100 mL x 4). Combine the organic phases, dry over anhydrous magnesium sulfate, filter, concentrate the filtrate under reduced pressure, purify by reverse-phase C18 column (ACN / 0.1% aqueous TFA solution), and lyophilize the collected fractions to obtain the product 18 as a pale yellow powdery solid (12 mg, yield 5%); LCMS: [M+1] + 488.68 (calculated value 487.48); 1 1H NMR (500 MHz, DMSO-d 6 )δ8.32 (dd, J = 8.5, 1.4 Hz, 1H), 8.20 (dd, J = 8.5, 1.2 Hz, 1H), 7.88 (ddd, J = 8.3, 6.8, 1.3 Hz, 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 = 2.1 Hz, 2H), 3.13 (d, J = 32.0 Hz, 2H), 1.94 - 1.84 (m, 2H), 1.27 - 1.21 (m, 3H), 0.89 (t, J = 7.3 Hz, 3H).

[0171] Example 19: 7-(N-(R)-(1’,1’,1’-trifluoropropan-2’-)-amine)ethyl camptothecin (19)

[0172]

[0173] Dissolve 17b (200 mg, 0.512 mmol) in EtOH (5 mL), add (R)-1,1,1-trifluoropropan-2-amine (179.4 mg, 1.2 mmol, HCl salt) and sodium acetate (100.8 mg, 1.2 mmol), and stir at room temperature for 6 hours. Add acetic acid (15 mL) and sodium cyanoborohydride (94.5 mg, 1.5 mmol), and react at room temperature for 2 hours. Add water and extract with dichloromethane (100 mL x 4). Combine the organic phases, dry over anhydrous magnesium sulfate, filter, concentrate the filtrate under reduced pressure, purify by reverse-phase C18 column (ACN / 0.1% aqueous TFA solution), freeze-dry the collected fractions to obtain the product 19 as a pale yellow powdery solid (8 mg, yield 3%); LCMS: [M+1] + 488.75 (calculated value 487.48); 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.32 (d, J = 8.4 Hz, 1H), 8.20 (d, J = 8.4 Hz, 1H), 7.88 (t, J = 7.6 Hz, 1H), 7.77 (t, J = 7.7 Hz, 1H), 7.35 (s, 1H), 6.54 (s, 1H), 5.42 (d, J = 37.4 Hz, 4H), 3.41 - 3.38 (m, 2H), 3.20 - 3.00 (m, 2H), 1.89 (dt, J = 18.1, 7.0 Hz, 2H), 1.33 - 1.17 (m, 4H), 0.89 (t, J = 7.3 Hz, 3H).

[0174] Example 20: 7-(N-(2'-trifluoromethylprop-2'-)amino)ethyl camptothecin (20)

[0175]

[0176] Dissolve 17b (200 mg, 0.512 mmol) in EtOH (5 mL), add 1,1,1-trifluoro-2-methylpropan-2-amine (196.2 mg, 1.2 mmol, HCl salt) and sodium acetate (100.8 mg, 1.2 mmol), and stir at room temperature for 6 hours. Add acetic acid (15 mL) and sodium cyanoborohydride (94.5 mg, 1.5 mmol), and react at room temperature for 2 hours. Add water and extract with dichloromethane (100 mL x 4). Combine the organic phases, dry over anhydrous magnesium sulfate, filter, concentrate the filtrate under reduced pressure, purify by reverse-phase C18 column (ACN / 0.1% aqueous TFA solution), and lyophilize the collected fractions to obtain a pale yellow powdery solid product 20 (10 mg, yield 4%); LCMS: [M+1] + 502.45 (calculated value 501.51); 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.32 (d, J = 8.6 Hz, 1H), 8.20 (dd, J = 8.5, 1.2 Hz, 1H), 7.92 - 7.84 (m, 1H), 7.79 - 7.68 (m, 1H), 7.36 (s, 1H), 5.69 (s, 1H), 5.46 (d, J = 13.2 Hz, 4H), 3.60 - 3.55 (m, 2H), 3.19 - 3.02 (m, 2H), 1.89 (dt, J = 16.6, 7.1 Hz, 2H), 1.29 - 1.12 (m, 6H), 0.90 (t, J = 7.3 Hz, 3H).

[0177] Example 21: 7-(N-(2’,2’,2’-trifluoroethyl)amine)ethyl-10-methyl-11-fluorocamptothecin (21)

[0178]

[0179] In a 500 ml three-necked flask, add 25 ml of deionized water, slowly drop 25 ml of 75% sulfuric acid under ice bath, then add 25 ml of 1,3-propanediol, 13f (5.0 g, 13.1 mmol) and ferrous sulfate heptahydrate (7.2 mg, 26.2 mmol). After the reaction solution becomes clear, cool to 0 °C and dropwise add 30% H 2 O 2 (17 g, 260 mmol), maintain the temperature at <15 °C and stir the reaction for 30 min. Pour the reaction solution into water, filter to precipitate the solid, dry, and purify by silica gel column chromatography to obtain product 21a (2.3 g, yield 33.4%); LCMS: [M+1] + 425.35 (calculated value: 424.41).

[0180] In a 100 mL three-necked flask, 21a (300 mg, 0.7 mmol) was added, dissolved in a mixed solution of DCM / DMSO (1:1, 30 mL), then Dess-Martin Periodinane (742 mg, 1.75 mmol) was added, and the reaction was carried out at room temperature for 10 min. The reaction solution was poured into ice water, extracted with DCM (50 ml x 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation to obtain the crude product of 21b (280 mg, yield 94%). The crude product was directly used in the next step without purification; LCMS: [M+1] + 423.35 (calculated value: 422.41).

[0181] In a 100 mL single-necked flask, 21b (280 mg, 0.66 mmol) was dissolved in EtOH (5 ml). Under stirring, trifluoroethylamine hydrochloride (1.43 g, 10.6 mmol) and sodium acetate (869.5 mg, 10.6 mmol) were added, and the reaction was carried out at room temperature for 30 min. Sodium cyanoborohydride (999 mg, 15.9 mmol) was added to the reaction solution, then 15 ml of glacial acetic acid was added, and 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 chromatography, and freeze-dried to obtain the yellow solid product 21 (9 mg, yield 3%); LCMS: [M+1] + 506.31 (calculated value: 505.47); 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.22 (d, J = 7.2 Hz, 1H), 7.88 (d, J = 10.5 Hz, 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 = 6.5 Hz, 3H).

[0182] Example 22: 7-(N-(S)-(1’,1’,1’-trifluoropropan-2’-yl)amino)ethyl-10-methyl-11-fluorocamptothecin (22)

[0183]

[0184] Dissolve 21b (200 mg, 0.47 mmol) in EtOH (2 mL) in a 100 mL single-necked flask. With stirring, add (S)-1,1,1-trifluoro-2-propanamine hydrochloride (702.8 mg, 4.7 mmol) and sodium acetate (385.5 mg, 4.7 mmol). React at room temperature for 30 min, then add sodium cyanoborohydride (443 mg, 7.05 mmol), followed by 6 mL of glacial acetic acid. Stir at room temperature for 1 h, add water (15 mL), extract with DCM (20 mL * 3). Combine the organic phases, wash the organic phases with saturated brine, dry over anhydrous sodium sulfate, concentrate, purify by reverse-phase preparation, and lyophilize to obtain the yellow solid product 22 (18 mg, yield 7.3%); LCMS: [M+1] + 520.51 (calculated: 519.5); 1 H NMR (500 MHz, DMSO) δ 8.16 (d, J = 8.1 Hz, 1H), 7.81 (d, J = 10.7 Hz, 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 = 32.8 Hz, 2H), 2.48 (s, 3H), 1.98 - 1.77 (m, 2H), 1.24 (d, J = 6.1 Hz, 2H), 0.89 (t, J = 7.3 Hz, 3H).

[0185] Example 23: 7-(N-(R)-(1’,1’,1’-Trifluoropropan-2’-yl)amino)ethyl-10-methyl-11-fluorocamptothecin (23)

[0186]

[0187] Dissolve 21b (200 mg, 0.47 mmol) in EtOH (2 mL) in a 100 mL single-necked flask. With stirring, add (R)-1,1,1-trifluoro-2-propanamine hydrochloride (702.8 mg, 4.7 mmol) and sodium acetate (385.5 mg, 4.7 mmol). React at room temperature for 30 min, then add sodium cyanoborohydride (443 mg, 7.05 mmol) and 6 mL of glacial acetic acid. Stir at room temperature for 1 h, add water (15 mL), extract with DCM (20 mL * 3). Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate, purify by reverse-phase preparation, and lyophilize to obtain the yellow solid product 23 (14 mg, yield 5.7%); LCMS: [M+1] + 520.51 (calculated: 519.5); 1 H NMR (500 MHz, DMSO-d 6)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).

[0188] Example 24: 7-(N-(2'-Trifluoromethylpropan-2'-)amine)ethyl-10-methyl-11-fluorocamptothecin (24)

[0189]

[0190] 21b (200 mg, 0.47 mmol) was dissolved in EtOH (2 ml) in a 100 mL single-necked flask. Under stirring, 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. The reaction was carried out at room temperature for 30 min. Sodium cyanoborohydride (443 mg, 7.05 mmol) was added, and then 6 ml of glacial acetic acid was 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 chromatography, and freeze-dried to obtain the yellow solid product 24 (19 mg, yield 7.6%); LCMS: [M + 1] + 534.3 (calculated value: 533.52); 1 1H NMR (500 MHz, DMSO-d 6 )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).

[0191] Example 25: 7-(N-(2',2',2'-Trifluoroethyl)amine)ethyl-10,11-difluorocamptothecin (25)

[0192]

[0193] 9c (3 g, 7.37 mmol) was added to a 500 ml three-necked reaction flask, H2 O (75 mL) and 1,3 - propanediol (62.07 g, 626.45 mmol, 58.95 mL), then add H 2 SO 4 (75%) (36.14 g, 368.50 mmol, 75 mL), add ferrous sulfate heptahydrate (2.34 g, 8.40 mmol) at 0 °C, then add 30% H 2 O 2 aqueous solution (215.59 mg, 6.34 mmol, 194.23 μL), stir at 0 °C for 4 h, pour the reaction solution into 2 L of ice water, let stand for 16 h, filter out the precipitated solid, dry to obtain 25a (1.8 g, yield 54.11%); LCMS: [M + 1] + 429.31 (calculated value 428.39);

[0194] Add 25a (1 g, 2.22 mmol), DMSO (20 mL) and DCM (14 mL) to a 100 ml three - necked reaction flask, then add Dess - Martin Periodinane (1.88 g, 4.44 mmol), stir at 25 °C for 4 h, pour the reaction solution into ice water, extract with DCM (50 ml x 3), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, rotary evaporate to obtain the crude product 25b (320 mg, yield 33.8%), which is directly used in the next step without purification; LCMS: [M + 1] + 427.16. (calculated value 426.38).

[0195] Add 25b (50 mg, 111.27 μmol), DMSO (6.00 mL) and DCM (4.00 mL) to a 100 ml single - necked reaction flask, then add 2,2,2 - trifluoroethanamine (40.74 mg, 333.81 μmol, 32.72 μL), stir at 25 °C for 1 h, add NaBH 3 CN (13.98 mg, 222.54 μmol) and acetic acid (33.41 mg, 556.35 μmol), stir at 25 °C for 16 h, concentrate, purify with a C18 Spherical 20 - 35um 100A 120 g reverse column, collect the product, lyophilize to obtain the product 25 (19.41 mg, yield 32.76%); LCMS: [M + 1] + 510.15 (calculated value 509.43); 1 H NMR (600 MHz, DMSO - d 6) δ 8.47 - 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, 7.0 Hz, 2H), 0.88 (t, J = 7.1 Hz, 3H).

[0196] Example 26: 7-(N-(R)-(1’,1’,1’-trifluoropropan-2’-amine)ethyl)-10,11-difluorocamptothecin (26)

[0197]

[0198] Add 25b (15 mg, 33.38 μmol), dioxane (1 mL) and DCM (1 mL) to a 10 mL reaction flask. Add a solution of (2R)-1,1,1-trifluoropropan-2-amine (4.99 mg, 33.38 μmol) in dichloromethane (1 mL) and DIPEA (8.63 mg, 66.76 μmol, 11.63 μL) to the reaction solution, stir for 10 min, add NaBH 3 CN (4.20 mg, 66.76 μmol) and acetic acid (4.01 mg, 66.76 μmol), stir at 25 °C for 2 h, concentrate, add 1 mL of DMF, purify by reverse column chromatography using a C18 Spherical 20 - 35 μm 100A 20 g column, with acetonitrile (HPLC grade) and 0.1% TFA aqueous solution as mobile phases B2 and A2 respectively, HPLC preparation method (monitoring at wavelengths of 254 nm and 214 nm), collect the product, lyophilize to obtain product 26 (5 mg, yield 27.41%); LCMS: [M + 1] + 524.23 (calculated value 523.46); 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.46 - 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 = 7.3 Hz, 4H), 1.12 (s, 3H), 0.85 (s, 3H).

[0199] Example 27: 7-(N-(S)-(1’,1’,1’-trifluoropropan-2’-amine)ethyl)-10,11-difluorocamptothecin (27)

[0200]

[0201] Add 25b (50 mg, 111.27 μmol), DMSO (6.02 mL) and DCM (4.01 mL) to a 100 mL single-neck reaction flask, then add (2S)-1,1,1-trifluoropropan-2-amine (15.14 mg, 111.27 μmol, 13.19 μL). Stir at 25 °C for 1 h, then add NaBH 3 CN (13.98 mg, 222.54 μmol) and acetic acid (33.41 mg, 556.35 μmol). Stir at 25 °C for 16 hr, concentrate, and purify using a C18 Spherical 20 - 35um 100A 120 g reverse column. Use acetonitrile (HPLC grade) and 0.1% aqueous TFA solution as mobile phases B2 and A2 respectively for HPLC preparation method (monitoring at 254 nm and 214 nm wavelengths). Collect the product, lyophilize to obtain product 27 (10.45 mg, yield 17.94%); LCMS: [M+1] + 524.33 (calculated value 523.46); 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.37 (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 = 49.6 Hz, 2H), 1.87 (dd, J = 14.2, 7.2 Hz, 2H), 1.21 (s, 3H), 0.88 (t, J = 7.1 Hz, 3H).

[0202] Example 28: 7-(N-(S)-(1’,1’,1’-trifluoropropan-2’-yl)amino)ethyl-10,11-methylenedioxycamptothecin (28)

[0203]

[0204] Under the condition of 0 °C, add water (361.65 mL), 5c (5 g, 12.71 mmol), FeSO 4 · 7 H 2 O (11.31 g, 40.67 mmol) and propane-1,3-diol (28.9 g, 381.3 mmol) to a 1000 mL round-bottom flask. After stirring evenly, slowly add concentrated sulfuric acid H 2 SO 4(180.82 mL), and finally 30% hydrogen peroxide (5.82 g, 171.45 mmol) was added dropwise. The reaction was carried out at 0 °C for 3 hours, then poured into 3 L of ice-water. The solid was filtered out and purified by silica gel column chromatography to obtain a pale yellow powdery solid intermediate 28a (1.67 g, yield 28.53%); MS: [M + 1] + 437.32 (calculated: 436.42); 1 H NMR (500 MHz, DMSO-d 6 ) δ 7.64 (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 = 6.4 Hz, 1H), 3.29 (t, J = 5.9 Hz, 2H), 1.92 (p, J = 7.8, 7.4 Hz, 2H), 1.75 (d, J = 6.4 Hz, 1H), 0.94 (t, J = 7.3 Hz, 3H).

[0205] 28a (800 mg, 1.83 mmol), DMSO (50 mL) and DCM (35 mL) were added to a reaction flask, and Dess-Martin periodinane (1.55 g, 3.66 mmol) was added. The mixture was stirred at room temperature for several hours, then water (100 mL) was added. It was extracted with dichloromethane (100 mL × 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 intermediate 28b (796.31 mg, yield 90%). It was directly used in the next step without purification; LCMS: [M + H] + 435.33 (calculated: 434.40).

[0206] At room temperature, 28b (950 mg, 1.4 mmol), DCM (10 mL), DMSO (4 mL), (S)-1,1,1-trifluoropropan-2-amine (780 mg, 7 mmol) were successively added to a 100 mL reaction flask. The mixture was stirred at room temperature for 60 min, then sodium cyanoborohydride (130 mg, 2.1 mmol) was added. The reaction was stirred for 2 h, concentrated, and purified by silica gel column chromatography to obtain product 28 (600 mg, yield 80%); LCMS: [M + 1] + 532.03 (calculated: 531.49); 1 H NMR (600 MHz, DMSO-d 6)δ 7.55 (s, 1H), 7.41 (s, 1H), 7.20 (s, 1H), 6.48 (s, 1H), 6.27 (d, J = 3.4 Hz, 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 = 6.7 Hz, 3H), 0.94 - 0.83 (m, 3H); 13 C NMR (150 MHz, DMSO) δ 172.98, 157.26, 151.20, 150.54, 149.62, 149.29, 147.47, 146.78, 140.98, 128.35, 127.78 (d, J = 280 Hz), 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.

[0207] Example 29: 7-(N-(R)-(1’,1’,1’-trifluoropropan-2’-yl)amino)ethyl-10,11-methylenedioxycamptothecin (29)

[0208]

[0209] At room temperature (25 °C), 28b (30 mg, 69.06 μmol), DCM (2 mL), DMSO (2 mL), and (R)-1,1,1-trifluoropropan-2-amine (78.1 mg, 0.69 mmol) were successively added to a 10 mL single-necked eggplant-shaped flask. The reaction was stirred at room temperature for 30 min, sodium cyanoborohydride (13 mg, 207.2 μmol) was added, and the reaction was stirred for 2 h. The mixture was concentrated and purified by silica gel column chromatography to obtain a yellowish-brown solid product 29 (10 mg, yield 27.2%); LCMS: [M + 1] + 532.53 (calculated: 531.49); 1 H NMR (500 MHz, DMSO-d 6)δ 7.68 (s, 1H), 7.55 (s, 1H), 7.26 (s, 1H), 6.32 (s, 2H), 5.44 (d, J = 1.3 Hz, 2H), 5.31 (d, J = 3.0 Hz, 2H), 3.47 (d, J = 16.4 Hz, 1H), 3.37 - 3.24 (m, 2H), 3.19 (s, 1H), 1.87 (dp, J = 19.0, 7.2 Hz, 2H), 1.36 (d, J = 6.8 Hz, 3H), 0.89 (q, J = 7.9, 7.4 Hz, 3H), 0.87 (s, 1H).

[0210] Test Example 1: Inhibitory Activity against Tumor Cell Growth

[0211] Human esophageal cancer cells OE33, human breast cancer cells MDA-MB-231, human gastric cancer cells NCI-N87, human lung cancer cells NCI-H1975, human breast cancer cells SK-BR-3, etc. were cultured in RPMI1640 (Cellmax) containing 10% fetal bovine serum (Cellmax). Tumor cells in the exponential growth phase were diluted with the medium to 1×10 5 cells / mL, and 100 μL per well was added to a 96-well cell culture plate, and then placed back in an incubator at 37°C with 5% CO 2 overnight. The next day, the compound was diluted to 10000 nM, 2000 nM, 400 nM, 80 nM, 16 nM, 3.2 nM, 0.64 nM, 0.13 nM with the medium, and 2 μL of the diluted compound per well was added to the 96-well cell culture plate. Three replicates were set for each concentration. 2 μL of the diluent was added to each well of the negative control without the compound and the blank control group. After adding the samples, it was placed back in an incubator at 37°C with 5% CO 2 and incubated for another 72 h. After incubation, the cell culture plate was taken out, and the medium in the plate was aspirated with a pipette. 100 μL of the medium containing 10% CCK-8 was added to each well and incubated at 37°C for 3 h. After incubation, the plate was taken out, protected from light, and placed in an enzyme-linked immunosorbent assay (ELISA) plate. 630 nm was selected as the reference wavelength and 450 nm as the measurement wavelength to measure the absorbance. According to the absorbance value, the IC 5 0 value was calculated using four-parameter regression in GraphPad (Table 1). Dxd was used as the positive control drug.

[0212] The exemplary compounds of the present invention have good inhibitory activity against cancer cells such as OE33, MDA-MB-231, NCI-N87, NCI-H1975, SK-B-3, etc. Their inhibitory activity IC 50 values against these cancer cells are all less than 500 nM. The inhibitory activity IC 50Less than 100 nM, further less than 50 nM or 10 nM, and even less than 1 nM. For IC 50 values, where "++++" indicates IC 50 ≤ 10 nM; "+++" indicates 10 nM < IC 50 ≤ 100 nM; "++" indicates 100 nM < IC 50 ≤ 500 nM; "+" indicates 500 nM < IC 50 ≤ 1000 nM.

[0213] Table 1: IC 50 (nM) values of the compounds inhibiting the growth of tumor cells

[0214]

[0215]

[0216] Note: "-" indicates not tested.

[0217] The foregoing description of the specific exemplary embodiments of the present invention is for purposes of illustration and exemplification. These descriptions are not intended to limit the invention to the precise forms disclosed, and it is apparent that many modifications and variations are possible in light of the above teachings. The purpose of selecting and describing the exemplary embodiments is to explain the specific principles of the invention and its practical applications, so that those skilled in the art can implement and utilize the various different exemplary embodiments of the invention, as well as various different selections and modifications. The scope of the invention is intended to be defined by the claims and their equivalents.

Claims

1. Compounds of formula (I), pharmaceutically acceptable salts thereof and stereoisomers thereof: In the formula, R1 and R2 are each independently selected from hydrogen, fluorine, and methyl; or R1, R2 and the carbon atom to which they are connected together 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, wherein the C1-C8 alkyl and C3-C6 cycloalkyl include at least one fluorine atom substituent; n is selected from 1, 2 or 3; The term "substituted" refers to the substitution of 1, 2, 3 or 4 hydrogen atoms in the 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.

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 1, 2 or 3 fluorine-substituted C1-C8 alkyl; Preferably, X2 is selected from -CH2-CF3, -CH(CH3)-CF3 or -C(CH3)2-CF3.

4. A compound of formula (II) or (III), a pharmaceutically acceptable salt thereof, and a stereoisomer thereof: In formula (II), R1 and R2 are each independently selected from hydrogen, fluorine, and methyl; or R1, R2 and the carbon atom to which they are connected together form R3 and R4 are each independently selected from hydrogen, fluorine, substituted or unsubstituted C1-C6 alkyl; or R3, R4 and the carbon atom to which they are connected together form a C3-C6 cycloalkyl group; n is selected from 1, 2 or 3; m is selected from 1 or 2, y is selected from 1 or 2; The term "substituted" refers to the substitution of 1, 2, 3 or 4 hydrogen atoms in the 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; In formula (III), R1, R2, and n are the same as those of the compound of formula (I); L is selected from substituted or unsubstituted C1-C6 alkyl; The term "substituted" refers to the substitution of 1, 2, 3 or 4 hydrogen atoms in the group by substituents independently 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 following compounds represented by formula (II-1), formula (II-2), formula (II-3) or formula (II-4): In the formula, R3, R4, n, m, and y are defined the same as those of 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 stereoisomers:

8. A method for preparing the compound according to any one of claims 1 to 7, comprising the step of carrying out a reductive amination reaction using a 7-formylcamptothecin derivative and a corresponding fluorine-substituted amine; The 7-formylcamptothecin derivative is selected from Any of the following: The corresponding fluorine-substituted amine is selected from at least one of the following compounds: in, X1, X2, R3, R4, m, n, y, and L are as defined above; Preferably, the corresponding fluorine-substituted amine is selected from 9. A pharmaceutical composition comprising the compound according to any one of claims 1 to 8, a pharmaceutically acceptable salt thereof, a stereoisomer thereof and a pharmaceutically acceptable excipient.

10. Use of the compound according to any one of claims 1 to 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.

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