Preparation for and use of 7-hydroxylamine-substituted alkyl camptothecin derivatives

Abstract

The present invention relates to the field of medicines, and specifically provides a series of 7-hydroxylamine-substituted alkyl camptothecin derivatives, a preparation method therefor and a use thereof. The compound has a structure represented by formula (I), the definition of each group in the formula is detailed in the description, and the compound has good anti-cancer activity.

Description

Preparation and application of 7-alkyl camptothecin derivatives substituted with hydroxylamine structure

[0001] This application claims priority to Chinese patent application No. 2024100249681, 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 specifically provides a series of alkyl camptothecin derivatives substituted with 7-hydroxylamine structures and their preparation methods and applications. Background Art

[0003] Camptothecin and its derivatives have inhibitory activity against topoisomerase Top1, particularly against Top1-DNA complexes. Camptothecin has significant therapeutic effects on gastric cancer, esophageal cancer, lung cancer, bladder cancer, and other cancers, making it a broad-spectrum anti-tumor drug. The camptothecin derivatives 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. The main drawbacks of camptothecin anti-tumor drugs are their toxicity, poor solubility, and the development of drug resistance in tumor cells. Summary of the Invention

[0004] The present invention provides a series of 7-alkyl camptothecin derivatives substituted with a hydroxylamine structure. The 7-alkyl camptothecin derivatives substituted with a hydroxylamine structure contain a hydroxylamine structure. Such derivatives substituted with an oxygen atom on the N atom exhibit weak alkalinity, can reduce the hepatotoxicity of the compound in the body, improve metabolic stability and cell membrane penetration ability, and help improve anti-tumor activity.

[0005] In one aspect of the present invention, there is provided a compound of formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof:

[0006] Where,

[0007] R1 and R2 are each independently selected from hydrogen, fluorine and C 1-3 Alkyl, or R1, R2 and the carbon atom to which they are connected together form an oxygen-containing heterocyclic group;

[0008] M is selected from -NH-O- and -O-NH-;

[0009] N is selected from 0, 1, 2 and 3;

[0010] R3 is selected from hydrogen, C 1-3 Alkyl or C 3-6 Cycloalkyl.

[0011] In one embodiment, R1 and R2 are each independently selected from hydrogen, fluoro and methyl.

[0012] In one embodiment, R1, R2 and the carbon atom to which they are attached together form a heterocyclic group containing 1 or 2 oxygen atoms as ring atoms.

[0013] In one embodiment, R1, R2 and the carbon atom to which they are attached together form

[0014] In one embodiment, R1 is hydrogen, R2 is hydrogen;

[0015] R1 is fluorine, R2 is fluorine;

[0016] R1 is methyl, R2 is fluorine, or

[0017] R1, R2 and the carbon atom to which they are connected together form

[0018] In one embodiment, R3 is selected from C 1-3 alkyl.

[0019] In one embodiment, R3 is methyl.

[0020] In one embodiment, the compound of formula (I) has the structure shown in the following formula (IA):

[0021] Wherein, R1, R2, and R3 are the same as those in the compound of formula (I);

[0022] Preferably, R1 is hydrogen, R2 is hydrogen;

[0023] R1 is fluorine, R2 is fluorine;

[0024] R1 is methyl, R2 is fluorine, or

[0025] R1, R2 and the carbon atom to which they are connected together form

[0026] R3 is methyl.

[0027] In one embodiment, the compound of formula (I) has the structure shown in the following formula (IB):

[0028] Wherein, R1, R2, and R3 are the same as those in the compound of formula (I);

[0029] Preferably, R1 is hydrogen, R2 is hydrogen;

[0030] R1 is fluorine, R2 is fluorine;

[0031] R1 is methyl, R2 is fluorine, or

[0032] R1, R2 and the carbon atom to which they are connected together form

[0033] R3 is methyl.

[0034] In one embodiment, the compound of formula (I) has the structure shown in the following formula (IC):

[0035] Wherein, R1, R2, and R3 are the same as those in the compound of formula (I);

[0036] Preferably, R1 is hydrogen, R2 is hydrogen;

[0037] R1 is fluorine, R2 is fluorine;

[0038] R1 is methyl, R2 is fluorine, or

[0039] R1, R2 and the carbon atom to which they are connected together form

[0040] R3 is methyl.

[0041] The present invention provides the following compounds, stereoisomers or pharmaceutically acceptable salts thereof:

[0042] Another aspect of the present invention provides a method for preparing the above compound, which is selected from the following synthetic routes:

[0043] Synthesis Route 1:

[0044] The compound of formula (1-1) undergoes a substitution reaction with the compound of formula (1-2) to obtain a compound of formula (1-3);

[0045] The compound of formula (1-3) is subjected to removal of the Y group to obtain the compound of formula 1.

[0046] Synthesis route 2:

[0047] The compound of formula (2-1) and the compound of formula (2-2) undergo reductive amination reaction to obtain the compound of formula (2);

[0048] Wherein, R1, R2, and R3 are the same as those in the compound of formula (I);

[0049] X is selected from halogen, preferably bromine;

[0050] Y is selected from amino protecting groups, preferably p-methoxybenzyl

[0051] In one embodiment, R3 is C1-3 Alkyl, the preparation of the compound includes one or more selected from the following synthetic routes:

[0052] A substitution reaction is carried out using the corresponding 7-haloalkyl camptothecin and the corresponding O-alkylhydroxylamine;

[0053] Reductive amination reaction is carried out using the corresponding camptothecin-7-alkylaldehyde and the corresponding O-alkylhydroxylamine;

[0054] It is obtained by Mitsunobu reaction of the corresponding camptothecin-7-alkyl alcohol and the corresponding N-Boc-N-alkyl-hydroxylamine;

[0055] The substitution reaction is carried out using the corresponding 7-haloalkyl camptothecin and the corresponding N-Boc-N-alkyl-hydroxylamine.

[0056] The corresponding 7-haloalkyl camptothecin has the structure shown in the following formula (II):

[0057] Wherein, R1, R2, and n are as defined above;

[0058] X is selected from halogen.

[0059] The corresponding camptothecin-7 alkyl aldehyde has the structure shown in the following formula (III):

[0060] Wherein, R1, R2, and n are defined as above.

[0061] The corresponding camptothecin-7 alkyl alcohol has the structure shown in the following formula (IV):

[0062] Wherein, R1, R2, and n are defined as above.

[0063] Another aspect of the present invention provides a pharmaceutical composition comprising the aforementioned compound, its stereoisomers or pharmaceutically acceptable salts; and a pharmaceutically acceptable carrier.

[0064] Another aspect of the present invention provides use of the aforementioned compound, its stereoisomer or pharmaceutically acceptable salt, or the aforementioned pharmaceutical composition in the preparation of an anti-tumor drug.

[0065] In one embodiment, the tumor is selected from solid tumors, more preferably one or more selected from breast cancer, esophageal cancer, gastric cancer and lung cancer.

[0066] In one embodiment, the compound is capable of inhibiting tumor growth.

[0067] Another aspect of the present invention provides a method for treating cancer, comprising the step of administering the aforementioned compound, its stereoisomer or pharmaceutically acceptable salt, or the aforementioned pharmaceutical composition to a patient in need thereof.

[0068] In one embodiment, the cancer is selected from one or more of breast cancer, esophageal cancer, gastric cancer, and lung cancer. DETAILED DESCRIPTION

[0069] I. Definition

[0070] 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.

[0071] As used herein and unless otherwise indicated, the term "about" or "approximately" means within plus or minus 10% of a given value or range. Where an integer is required, the term means within plus or minus 10% of a given value or range, rounded up or down to the nearest integer.

[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 described in this application 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 containing asymmetric carbon atoms in this application 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 this application.

[0075] The small molecule drugs used in this application also include tautomers, which are formed when a single bond is exchanged with an adjacent double bond accompanied by the migration of a proton.

[0076] The numerical ranges herein refer to the individual integers within the given range. For example, “C 1-3 " means that the group may have 1 carbon atom, 2 carbon atoms or 3 carbon atoms; "C 3-6 ” means that the group can have 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms.

[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 1-5 R, the group may be optionally substituted with up to 5 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 "halogen" as used herein refers to fluorine, chlorine, bromine, and iodine.

[0079] The term "alkyl" as used herein 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 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl.

[0080] The term "heterocyclyl" or "heterocycloalkyl" as used herein refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2), but excluding the ring portion of -OO-, -OS- or -SS-, the remaining ring atoms are carbon.

[0081] The term "substituted" used herein refers to one or more hydrogen atoms in a group, preferably up to 5, more preferably 1-3 hydrogen atoms that are independently replaced by the substituents of corresponding number. It goes without saying that substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible replacement without paying too much effort. For example, amino or hydroxyl groups with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (such as olefinic) bond.

[0082] The term "pharmaceutically acceptable salt" as used herein refers to a salt formed between a corresponding amine compound and an inorganic acid or 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.

[0083] The term "pharmaceutical composition" as used herein refers to a composition comprising the compound described herein 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.

[0084] The medicament or pharmaceutical composition of the present application can be administered orally, topically, parenterally or mucosally (e.g., buccally, by inhalation or rectally) in a dosage unit formulation containing a conventional non-toxic pharmaceutically acceptable carrier. It is generally desirable to use the oral route. The active agent can be administered orally in the form of capsules, tablets, etc. (see Remington: The Science and Practice of Pharmacy, 20th Edition).

[0085] For oral administration in the form of tablets or capsules, the active drug component can be mixed with non-toxic, pharmaceutically acceptable excipients such as binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, sucrose, glucose, mannitol, sorbitol and other reducing and non-reducing sugars, microcrystalline cellulose, calcium sulfate or dibasic calcium phosphate); lubricants (e.g., magnesium stearate, talc or silica, stearic acid, sodium stearyl fumarate, glyceryl behenate, calcium stearate, etc.); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate), coloring and flavoring agents, gelatin, sweeteners, natural and synthetic gums (such as acacia, tragacanth or alginates), buffer salts, carboxymethylcellulose, polyethylene glycol, waxes, etc. For oral administration in liquid form, the drug component can be combined with a non-toxic, pharmaceutically acceptable inert carrier (e.g., ethanol, glycerol, water), an anti-settling agent (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats), an emulsifier (e.g., lecithin or gum arabic), a non-aqueous carrier (e.g., almond oil, oily esters, ethanol or fractionated vegetable oils), a preservative (e.g., methyl or propyl p-hydroxybenzoate or sorbic acid), etc. Stabilizers such as antioxidants (BHA, BHT, propyl citric acid, sodium ascorbate, citric acid) can also be added to stabilize the dosage form.

[0086] The tablet comprising the active compound can be coated by methods well known in the art. The composition of the present application comprising the compound of formula (I) as the active compound can also be introduced into beads, microspheres or microcapsules, for example, constructed from polyglycolic acid / lactic acid (PGLA). The preparation of liquid for oral administration can take the form of, for example, solution, syrup, emulsion or suspension or they can be presented as a dry product reconstituted with water or other suitable excipients before use. The preparation for oral administration can be suitably formulated so that the active compound is controlled or released in a delayed manner.

[0087] The term "patient" refers to an animal, preferably a mammal, more preferably a human.

[0088] 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.

[0089] As used herein, the term "treating," ...

[0090] As used herein, 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.

[0091] II. Examples

[0092] 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.

[0093] 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.

[0094] The raw materials and equipment used in the specific embodiments of the present invention are all known products and are obtained by purchasing commercial products.

[0095] Example 1: 7-(N-methoxy)aminomethylcamptothecin (1)

[0096] 7-Hydroxymethylcamptothecin (5 g, 12.4 mmol), 50% aqueous hydrobromic acid (100 mL) and concentrated sulfuric acid (1 mL) were added to the reaction flask, stirred and heated to 125°C for 2 h, cooled to room temperature, poured into ice water, filtered and dried to obtain 7-bromomethylcamptothecin 1a (2.5 g, yield 26%); LCMS: [M+H] + 441.05 (theoretical value 440.04).

[0097] 7-Bromomethylcamptothecin 1a (1.20 g, 2.72 mmol), DMF (15 mL) and N-methoxy-(4-methoxybenzyl)amine (909.62 mg, 5.44 mmol) were added to the reaction flask. The reaction solution was stirred and heated to 55°C for 16 h. The reaction solution was poured into ice water, and the precipitated solid was filtered and purified by reverse phase column chromatography to obtain 7-(N-methoxy-N-(4-methoxyphenyl)aminomethylcamptothecin 1b (700 mg, yield 44.3%); LCMS: [M+H] + 528.32 (theoretical value 527.21).

[0098] 7-(N-methoxy-N-(4-methoxyphenyl)aminomethylcamptothecin (700 mg, 1.33 mmol), DCM (10 mL) and methanesulfonic acid (10 mL) were added to the reaction flask, heated to 40°C and stirred for 96 h, concentrated, and saturated aqueous sodium bicarbonate solution was added to adjust the pH to 7. The precipitated solid product was filtered to obtain 7-(N-methoxy)aminomethylcamptothecin 1 (500 mg, yield 84.1%); LCMS: [M+H] + 408.25 (theoretical value 407.15); 1 H NMR (600MHz, DMSO-d6) δ8.33(d,J=8.6Hz,1H),8.13(d,J=8.5Hz,1H),7.82(dd,J=8.3,6.5Hz,1H),7.69(ddd,J=8.3,6.7,1.5Hz,1H),7.33(s,1H),7 .24(t,J=5.8Hz,1H),5.43(d,J=2.1Hz,2H),5.34(s,2H),4.54(d,J=5.6Hz ,1H),3.29(s,2H),2.35(s,3H),1.92-1.84(m,2H),0.89(t,J=7.2Hz,3H); 13C NMR (151MHz, DMSO) δ172.95,157.27,152.34,150.53,148.91,146.05,140.26,130.44,130.03,1 29.96,127.92,127.61,125.26,119.54,97.20,72.87,65.74,61.50,50.49,49.19,49.07,30.79.

[0099] Example 2: 7-(N-methoxy)aminomethyl-10,11-methylenedioxycamptothecin (2)

[0100] 7-Hydroxymethyl-10,11-methylenedioxycamptothecin (2.5 g, 5.90 mmol), 48% aqueous hydrobromic acid solution (477.76 mg, 5.90 mmol, 60 mL) and concentrated sulfuric acid (1 mL) were added to the reaction flask at 0°C and stirred for 30 min at 0°C. The mixture was poured into ice water, filtered and dried to obtain a brown solid product, 7-bromomethyl-10,11-methylenedioxycamptothecin 2a (1.7 g, 46.2% yield); LCMS: [M+H] + 485.20 (theoretical value 484.03).

[0101] 7-Bromomethyl-10,11-methylenedioxycamptothecin 2a (1.7 g, 2.73 mmol) and N-methoxy-(4-methoxybenzyl)amine (1.07 g, 6.37 mmol) were added to the reaction flask. The reaction solution was stirred at 55°C for 8 h, poured into ice water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to obtain 7-(N-methoxy-N-(4-methoxyphenyl)aminomethyl-10,11-methylenedioxycamptothecin 2b (1.1 g, yield 55.5%); LCMS: [M+H] + 572.28 (theoretical value 571.20); 1 H NMR (500MHz, DMSO-d6) δ7.52(s,1H),7.47(s,1H),7.35(d,J=8.6Hz,2H),7.23(s,1H),6.94(d,J=8.6Hz,2H),6.29(s,2H) ,5.42(s,2H),5.19(s,2H),4.26(s,2H),4.00(s,2H),3.76(s,3H),2.80(s,3H),1.96-1.78(m,2H),0.89(t,J=7.3Hz,3H).

[0102] 7-(N-methoxy-N-(4-methoxyphenyl)aminomethyl-10,11-methylenedioxycamptothecin 2b (1 g, 1.75 mmol) and trifluoroacetic acid (50 mL) were added to the reaction flask, and the reaction solution was stirred at 40°C overnight, concentrated, and purified by silica gel column chromatography to obtain 7-(N-methoxy)aminomethyl-10,11-methylenedioxycamptothecin 2 (260 mg, yield 32.3%); LCMS: [M+H] + 452.34 (theoretical value 451.14); 1 H NMR (500MHz, DMSO-d6) δ7.66(s,1H),7.50(d,J=3.0Hz,1H),7.24(s,1H),6.49(s,1H),6.29(d,J=2.4Hz,2H),5.42(d ,J=1.7Hz,2H),5.27(s,2H),4.44(d,J=3.7Hz,2H),3.30(s,3H),1.87(dp,J=17.2,7.1Hz,2H),0.89(t,J=7.3Hz,3H); 13 C NMR (126MHz, DMSO) δ173.00,157.28,151.35,150.59,149.86,149.23,147.71,146.49,138.83,128. 94,125.24,118.60,105.69,103.10,100.62,96.39,72.88,65.71,61.53,50.42,49.54,30.70,8.26.

[0103] Example 3: 7-(N-methoxy)aminomethyl-10,11-difluorocamptothecin (3)

[0104] 7-Hydroxymethyl-10,11-difluorocamptothecin (6 g, 14.45 mmol), 48% aqueous hydrobromic acid solution (150 mL) and concentrated sulfuric acid (1 mL) were added to the reaction flask. The reaction solution was stirred and heated to 125°C for 1.5 h, then poured into water. The precipitated solid was filtered and dried to obtain 7-bromomethyl-10,11-difluorocamptothecin 3a (4.5 g, yield 62%); LCMS: [M+H] + 477.09,[M+3] + 479.04 (theoretical value 476.02).

[0105] 7-Bromomethyl-10,11-difluorocamptothecin 3a (4.5 g, 4.70 mmol), DMF (80 mL), and N-methoxy-(4-methoxybenzyl)amine (1.58 g, 9.41 mmol) were added to the reaction flask, stirred and heated to 50°C for 4 h, poured into water, extracted with DCM, washed with saturated brine, dried over anhydrous magnesium sulfate, and purified by silica gel column chromatography to obtain a yellow solid product 7-(N-methoxy-N-(4-methoxyphenyl)aminomethyl-10,11-difluorocamptothecin 3b (1.6 g, yield 58.4%); LCMS: [M+H] + 564.17 (theoretical value 563.19).

[0106] 7-(N-methoxy-N-(4-methoxyphenyl)aminomethyl-10,11-difluorocamptothecin 3b (120 mg, 212.56 μmol) was dissolved in methanesulfonic acid (702.74 mg, 10.63 mmol, 3 mL). The reaction mixture was reacted at 40°C for 120 h. Saturated aqueous sodium bicarbonate solution was added, and the precipitated solid was filtered and purified by silica gel column chromatography to obtain a yellow solid product, 7-(N-methoxy)aminomethyl-10,11-difluorocamptothecin 3 (45 mg, yield 47.2%). LCMS: [M+H] + 444.64 (theoretical value 443.13); 1 H NMR(500MHz, DMSO-d6)δ8.36(dd,J=12.4,8.7Hz,1H),8.16(dd,J=11.5,8.0Hz,1H),7.31(s,1H),6.53(s,1H),5.43(s,2H),5.35(s,2H),4.5 3(s,2H),3.30(s,3H),1.87(ddt,J=16.9,14.1,7.1Hz,2H),1.39-1.26(m,2H),1.28-1.19(m,5H),0.87(dt,J=21.6,7.2Hz,3H),0.84(s,1H); 13C NMR (126MHz, DMSO-d6) δ174.96,172.87,157.15,153.14,153.12,152.92,152.79,150.91,150.78,15 0.45,148.92,148.79,146.47,146.38,145.56,140.71,140.67,130.46,125.25,125.18,124.79,124 .71,119.90,116.19,116.07,112.10,111.95,97.39,72.81,65.71,61.51,50.48,49.33,34.95,34.12,31.75,31.60,30.77,30.28,29.88,29.48,29.36,29.20,29.16,29.01,24.95,22.55,14.40,8.21.

[0107] Example 4: 7-(N-(Methoxy)amino)methyl-10-methyl-11-fluorocamptothecin (4)

[0108] 7-Hydroxymethyl-10-methyl-11-fluorocamptothecin (4 g, 9.72 mmol), 48% aqueous hydrobromic acid (30 mL) and concentrated sulfuric acid (0.9 mL) were added to the reaction flask at 0°C and the reaction was continued with stirring at 125°C for 30 min. The mixture was poured into ice water, the precipitated solid was filtered and dried to obtain a brown solid product, 7-bromomethyl-10-methyl-11-fluorocamptothecin 4a (5.5 g, yield 84%); LCMS: [M+H] + 473.26 (theoretical value 472.04).

[0109] 7-Bromomethyl-10-methyl-11-fluorocamptothecin 4a (5.5 g, 11.60 mmol), DMF (50 mL) and N-methoxy-(4-methoxybenzyl)amine (3.90 g, 23.19 mmol) were added to the reaction flask. The reaction solution was stirred at 55°C for 6 h, poured into ice water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to obtain 7-(N-methoxy-N-(4-methoxyphenyl)aminomethyl-10-methyl-11-fluorocamptothecin 4b (1.91 g, yield 27.3%); LCMS: [M+H] + 560.24 (theoretical value 559.21); 1H NMR (500MHz, DMSO-d6) δ8.00(d,J=8.3Hz,1H),7.85(d,J=10.7Hz,1H),7.42-7.36(m,2H),7.31(s,1H),7.01-6.93(m,2H),5.44(s,2H),5.29( s,2H),4.34(t,J=9.9Hz,2H),4.03(s,2H),3.77(s,3H),2.85(s,3H),2.44(s,3H),1.87(ddt,J=17.3,14.0,7.1Hz,2H),0.89(t,J=7.3Hz,3H).

[0110] 7-(N-methoxy-N-(4-methoxyphenyl)aminomethyl-10-methyl-11-fluorocamptothecin 4b (1.9 g, 3.39 mmol) was dissolved in methanesulfonic acid (20 mL), and the reaction mixture was reacted at 40°C for 168 h. Saturated aqueous sodium bicarbonate solution was added, and the precipitated solid was filtered and purified by silica gel column chromatography to obtain a yellow solid product, 7-(N-methoxy)aminomethyl-10-methyl-11-fluorocamptothecin 4 (390 mg, yield 24.9%); LCMS: [M+H] + 440.08 (theoretical value 439.15); 1 H NMR (500MHz, DMSO-d6) δ8.22(d,J=8.2Hz,1H),7.80(d,J=10.7Hz,1H),7.29(s,1H),7.23(t,J=5.7Hz,1H),6.52(s,1H),5.4 2(s,2H),5.27(s,2H),4.51(d,J=5.6Hz,2H),3.30(s,3H),2.47(s,3H),1.87(dh,J=21.4,7.2Hz,2H),0.90(t,J=7.3Hz,3H); 13 C NMR (126MHz, DMSO) δ172.91,162.24,157.18,152.52,150.46,148.92,145.83,139.90,129.45,127. 58,127.19,124.77,119.55,112.71,97.18,72.84,65.72,55.37,50.43,49.20,30.77,15.67,8.24.

[0111] Example 5: 7-(N-(Methoxy)amino)ethylcamptothecin (5)

[0112] In a 100 mL round-bottom flask at 0°C, camptothecin (1 g, 2.86 mmol) and FeSO4·7H2O (795.78 mg, 2.86 mmol) were dissolved in H2O (32.5 mL). H2SO4 (17.5 mL) and 1,3-propylene glycol (10.59 g, 137.39 mmol, 10.06 mL) were added, and 35% aqueous hydrogen peroxide (97.36 mg, 2.86 mmol, 87.71 μL) was added dropwise. The reaction was continued at 0°C for 3 h, then poured into ice water. The solid product was filtered and purified on a normal phase silica gel column to give 7-(2-hydroxy)ethylcamptothecin 5a as a pale yellow powder (345 mg, 29% yield); LCMS: [M+1] + 393.43 (calculated: 392.41); 1 H NMR (500MHz, DMSO-d6) δ8.23(d,J=8.4Hz,1H),8.13(d,J=8.4Hz,1H),7.81(t,J=7.6Hz,1H),7.67(t,J=7.6Hz,1H),7.31( s,1H),5.43(s,2H),5.25(s,2H),3.81(t,J=6.3Hz,3H),3.35(t,J=6.4Hz,2H),1.98-1.80(m,2H),0.90(t,J=7.3Hz,3H).

[0113] To a 250 mL round-bottom flask at 25°C was added 5a (345 mg, 0.833 mmol) dissolved in DMSO (20 mL) and DCM (6 mL). The mixture was stirred and cooled in an ice bath, and Dess-Martin periodinane (706 mg, 1.666 mmol) was added. The ice bath was removed and the reaction was stirred at room temperature for 3 hours. Water (100 mL) was added and the mixture was extracted with dichloromethane (100 mL x 3). The DCM organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 7-(N-(methoxy)amino)ethylcamptothecin 5b (291 mg, 0.74 mmol, 85% yield) as a brown viscous solid. The solid was used in the next step without purification. LCMS: [M+H] + 391.23 (calculated: 390.40).

[0114] To the reaction flask were added 5b (200 mg, 0.512 mmol), EtOH (5 mL), (O-methyl)hydroxylamine hydrochloride (100.2 mg, 1.2 mmol) and sodium acetate (100.8 mg, 1.2 mmol), stirred at room temperature for 6 hours, acetic acid (15 mL) and sodium cyanoborohydride (94.5 mg, 1.5 mmol), reacted at room temperature for 2 hours, water (100 mL) 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). The collected solution was freeze-dried to give the product 5,7-(N-methoxy)aminoethylcamptothecin as a light yellow powdery solid (80 mg, yield 37%); LCMS: [M+1] + 422.23 (calculated value: 421.45); 1 H NMR (500MHz, DMSO-d6) δ8.28(d,J=8.5Hz,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),6.72-6 .44(m,1H),5.45(s,2H),5.36(s,2H),3.54(s,3H),3.46-3.41(m,2H),3.29(t,J=7.3Hz,2H),1.92-1.85(m,2H),0.88(d,J=7.4Hz,3H).

[0115] Example 6: 7-(N-methoxy)aminoethyl-10,11-methylenedioxycamptothecin (6)

[0116] Under ice bath, water (25 mL), 75% dilute sulfuric acid (25 mL), and 1,3-propylene glycol (25 mL) were added to a 250 mL three-necked eggplant-shaped flask in sequence. After stirring, 10,11-methylenedioxycamptothecin (10 g, 25.5 mmol) was added and dissolved with stirring. Ferrous sulfate heptahydrate (14.17 g, 51 mmol) was added and stirred. 30% aqueous hydrogen peroxide solution (28.9 g, 0.25 mol) was slowly added dropwise. The temperature was maintained below 10°C and stirred for 10 min. The reaction solution was quenched by adding ice water. The precipitated solid was filtered and the filter cake was rinsed once with ethanol. The filter cake was directly mixed with silica gel and methanol and purified by silica gel column chromatography to obtain an off-white solid product, 7-(2-hydroxy)ethyl-10,11-methylenedioxycamptothecin 6a (2.2 g, 19.8% yield); LCMS: [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).

[0117] To a 100 mL single-necked eggplant-shaped flask were added 7-(2-hydroxy)ethyl-10,11-methylenedioxycamptothecin (400 mg, 0.9 mmol), DCM (20 mL), and DMSO (20 mL) in sequence. After stirring, Dess-Martin periodinane (971.9 mg, 2.3 mmol) was added and the mixture was reacted for 10 min. Water (50 mL) was added and the mixture was extracted with DCM (3 x 100 mL). The organic phases were separated and combined, washed with saturated sodium chloride, dried over anhydrous sodium, filtered, and concentrated to obtain a brownish-yellow solid crude product 6b, 10,11-methylenedioxycamptothecin-7-acetaldehyde, which was directly used in the next reaction without purification; LCMS: [M+1]. + 435.59 (calculated: 434.40).

[0118] At room temperature, the above 10,11-methylenedioxycamptothecin-7-acetaldehyde 6b (crude product) and ethanol (8 mL) were added to the reaction flask and stirred evenly. Sodium acetate (755.4 mg, 0.9 mmol) and hydroxylamine hydrochloride (789 mg, 0.9 mmol) were then added and stirred for 1 h. Acetic acid (24 mL) and sodium cyanoborohydride (1.16 g, 18 mmol) were then added to the reaction solution in sequence. The mixture was stirred for 1 h. Water (100 mL) was added to the reaction solution, and the mixture was extracted twice with DCM, washed with water, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated to give the product 7-(N-methoxy)aminoethyl-10,11-methylenedioxycamptothecin 6 (320 mg, total yield of two steps 76%); LCMS: [M+1] + 466.18 (calculated value: 465.46); 1H NMR (500MHz, DMSO-d6) δ7.54(s,1H),7.46(s,1H),7.22(s,1H),6.49(s,1H),6.28(d,J=2.7Hz,2H),5.42(d,J=2.6Hz,2H),5 .15(s,2H),3.45(s,3H),3.22(t,J=7.1Hz,2H),3.12(t,J=7.1Hz,2H),1.87(dh,J=22.0,7.4Hz,2H),0.89(t,J=7.3Hz,3H); 13 CNMR(126MHz,DMSO-d6)δ173.00,157.27,151.26,150.57,149.75,149.35,147.50,146.82,128.54,1 24.84,118.45,105.94,103.09,99.76,96.34,72.87,65.72,61.10,50.24,50.17,30.74,28.00,8.26.

[0119] Example 7: 7-(N-methoxy)aminoethyl-10,11-difluorocamptothecin (7)

[0120] In a 500mL three-necked reaction flask at 0°C, 10,11-difluorocamptothecin (3g, 7.37mmol), H2O (75mL) and 1,3-propylene glycol (62.07g, 626.45mmol, 58.95mL) were added, and then 75% H2SO4 (36.14g, 368.50mmol, 75mL) was added. At 0°C, ferrous sulfate heptahydrate (2.34g, 8 .40mmol), then 30% H2O2 aqueous solution (215.59mg, 6.34mmol, 194.23μL) was added dropwise, and stirring was continued at 0℃ for 4h. The reaction solution was poured into 2L ice water and allowed to stand for 16h. The precipitated solid was filtered and dried to obtain 7-(2-hydroxy)ethyl-10,11-difluorocamptothecin 7a (1.8g, yield 54.1%); LCMS: [M+1] + 429.31 (theoretical value 428.39).

[0121] In a 100 mL three-necked reaction flask, 7-(2-hydroxy)ethyl-10,11-difluorocamptothecin (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, and water (50 mL) was added. The mixture was extracted with DCM (3 x 100 mL), washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a brownish-yellow solid crude product 7b, 10,11-difluorocamptothecin-7-acetaldehyde, which was used directly in the next reaction without purification; LCMS: [M+1] + 427.16 (theoretical value 426.38).

[0122] 10,11-Difluorocamptothecin-7-acetaldehyde (50 mg, 111.27 μmol), DMSO (6 mL) and DCM (4 mL) were added to a 100 mL reaction bottle, and then (O-methyl)hydroxylamine hydrochloride (23.38 mg, 333.81 μmol) was added. The mixture was stirred at 25 °C for 1 h. NaBH3CN (13.98 mg, 222.54 μmol) and glacial acetic acid (33.41 mg, 556.35 μmol) were added and stirred at 25 °C for 16 h. The reaction solution was concentrated and purified by C18 Spherical 20-35um 100A Purification was performed on a 120 g reverse phase column using acetonitrile and 0.1% TFA aqueous solution as mobile phases B2 and A2, respectively. HPLC preparation method (monitoring at 254 nm and 214 nm wavelengths): 2 mL of the sample DMF solution was injected into the reverse phase column. The DMF solvent was flushed out over 5 min (mobile phase ratio A2:B2 = 95:5). The acetonitrile ratio was then increased to 10% over 90 min (mobile phase ratio from A2:B2 = 95:5 to A2:B2 = 90:10). The acetonitrile ratio was then maintained at 10% and the column was flushed for 30 min to flush out the product, yielding 7-(N-methoxy)aminoethyl-10,11-difluorocamptothecin 7 (13.5 mg, yield 26.5%). LCMS: [M+1] + 458.20 (theoretical value 457.43); 1 H NMR(600MHz,DMSO-d6)δ8.35-8.25(m,1H),8.21-8.13(m,1H),7.31(s,1H),6.53(s,1H),5.44(s,2H),5.30( s,2H),3.42(s,2H),3.16(t,J=6.5Hz,2H),1.87(dq,J=14.1,6.8Hz,2H),1.23(s,3H),0.88(t,J=7.2Hz,3H).

[0123] Example 8: 7-(N-methoxy)aminoethyl-10-methyl-11-fluorocamptothecin (8)

[0124] In a 100 mL three-necked flask, water (2.5 mL), 75% sulfuric acid (2.5 mL), 1,3-propylene glycol (2.5 mL), 10-methyl-11-fluorocamptothecin (500 mg, 1.3 mmol) and ferrous sulfate heptahydrate (722.8 mg, 2.6 mmol) were added, stirred and dissolved, and then cooled to 0°C. 30% H2O2 aqueous solution (1.7 g, 26 mmol) was added dropwise. The temperature was maintained at about 15°C and the reaction was allowed to react for 1 h. The reaction solution was poured into water, filtered and dried to obtain 7-(2-hydroxy)ethyl-10-methyl-11-fluorocamptothecin 8a (311 mg, yield 39.8%); LCMS: [M+1] + 425.35 (calculated: 424.41).

[0125] 7-(2-Hydroxy)ethyl-10-methyl-11-fluorocamptothecin (300 mg, 0.7 mmol) was added to a 100 mL single-necked bottle and dissolved in DCM / DMSO (1:1, 30 mL). Dess-Martin periodinane (742 mg, 1.75 mmol) was added and reacted at room temperature for 10 min. The mixture was 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 10-methyl-11-fluorocamptothecin-7-acetaldehyde 8b (280 mg, crude yield 95%), which was used directly in the next step without purification; LCMS: [M+1] + 423.35 (calculated: 422.41).

[0126] The above-mentioned 10-methyl-11-fluorocamptothecin-7-acetaldehyde 8b (150 mg, 0.35 mmol) was added to a 100 mL single-necked bottle and dissolved in EtOH (4 mL). (O-methyl)hydroxylamine hydrochloride (292 mg, 3.5 mmol) and sodium acetate (287 mg, 3.5 mmol) were added with stirring. The mixture was reacted at room temperature for 30 min. Sodium cyanoborohydride (287 mg, 53 mmol) was added to the reaction solution, followed by glacial acetic acid (12 mL). The mixture was stirred at room temperature for 1 h, and water (12 mL) was added. The mixture was extracted with DCM, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, purified by C18 reverse phase column, and lyophilized to obtain the product 7-(N-methoxy)aminoethyl-10-methyl-11-fluorocamptothecin as a yellow solid product 8 (10 mg, yield 6.8%); LCMS: [M+1] + 454.45 (calculated: 453.47); 1H NMR(500MHz,DMSO-d6)δ8.18(d,J=8.3Hz,1H),7.85(d,J=10.8Hz,1H),7.30(s,1H),6.52(s,1H),5.43(s,2H), 5.27(s,2H),3.28-3.40(s,6H),3.17(t,J=6.9Hz,2H),2.51(s,3H),2.03-1.78(m,2H),0.88(t,J=7.3Hz,3H).

[0127] Example 9: 7-(N-methoxy)aminopropyl-10,11-methylenedioxycamptothecin (9)

[0128] Under ice bath cooling, purified water (12.5 mL), 75% dilute sulfuric acid (12.5 mL), and 1,4-butanediol (12.5 mL) were added to a 100 mL three-necked flask in sequence. After stirring evenly, 10,11-methylenedioxycamptothecin (5 g, 12.7 mmol) was added, stirred and dissolved (internal temperature ~10 ° C), and ferrous sulfate heptahydrate (7.4 g, 26.6 mmol) was added. After stirring evenly, 30 % H2O2 aqueous solution (14.5 g, 127.9 mmol), the reaction was stirred at below 10°C for 10 min, the reaction solution was quenched by adding ice water, filtered, and the filter cake was rinsed once with ethanol. The filter cake was directly mixed with silica gel and methanol and purified by silica gel column chromatography to obtain a light yellow solid product 9a, 7-(3-hydroxy)propyl-10,11-methylenedioxycamptothecin (1.56 g, yield 27%); LCMS: [M+1] + 451.6 (calculated: 450.45).

[0129] To a 100 mL single-necked eggplant-shaped flask, 7-(3-hydroxy)propyl-10,11-methylenedioxycamptothecin 9a (400 mg, 0.89 mmol), 20 mL of DCM, and 20 mL of DMSO were added in sequence. After stirring, Dess-Martin periodinane (753 mg, 1.78 mmol) was added and the mixture was stirred at room temperature for 10 min. The reaction solution was added to water (10 mL) and extracted with DCM (3 x 50 mL). The organic phases were separated and combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated to give a brown-yellow solid crude product 9b, which was directly used in the next reaction without purification; LCMS: [M+1]. + 449.27 (calculated: 448.43).

[0130] At room temperature, ethanol (10 mL) was added to the above 9b, followed by sodium acetate (1.09 g, 13.3 mmol) and (O-methyl)hydroxylamine hydrochloride (924.2 mg, 13.3 mmol), and the mixture was stirred for 1 h. 24 mL of acetic acid and sodium cyanoborohydride (1.11 g, 17.7 mmol) were added, and the reaction was stirred for 1 h. Water (100 mL) was added to the reaction solution, and the mixture was extracted with DCM (2 x 50 mL). The organic phase was washed once with water and once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, and purified by reverse preparative method to give 7-(N-methoxy)aminopropyl-10,11-methylenedioxycamptothecin 9 (120 mg, 13% yield); LCMS: [M+1] + 480.31 (calculated value: 479.49); 1 H NMR(500MHz,DMSO-d6)δ7.61(s,1H),7.47(s,1H),7.22(s,1H),6.28(d,J=2.6Hz,2H),5.41(d,J=2.7Hz,2H), 5.14(s,2H),3.72(s,3H),3.29(t,J=7.2Hz,2H),3.17-3.09(m,2H),1.93-1.83(m,4H),0.88(t,J=7.3Hz,3H).

[0131] Test Example 1: Inhibition of tumor cell growth activity

[0132] 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 esophageal cancer cells TE12 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 in culture medium to 10,000 nM, 2,000 nM, 400 nM, 80 nM, 16 nM, 3.2 nM, 0.64 nM, and 0.13 nM, and 2 μL of the diluted compound was added to each well of the 96-well cell culture plate. Triplicate wells were set up for each concentration. A negative control without compound was added, and a blank control was added with 2 μL of the dilution per well. Dxd was tested at the same concentration as a positive control for screening. After addition, the plate was returned to a 37°C, 5% CO2 incubator for an additional 72 hours. After incubation, the plate was removed, the culture medium was aspirated, and 100 μL of culture medium containing 10% CCK-8 was added to each well. The plate was 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 Values ​​(Table 1).

[0133] The structural formula of Dxd is

[0134] For IC 50 Values, where “++++” means 10nM>IC 50 ; “+++” means 100nM>IC 50 ≥10nM; “++” indicates 500nM>IC 50 ≥100nM; “+” indicates 1000nM>IC 50 ≥500μM.

[0135] Table 1: IC values ​​of compounds for inhibiting tumor cell growth 50 (nM) value

[0136] The compounds of the embodiments provided by the present invention all have a good inhibitory effect on the growth of cancer cells and have significant anti-cancer activity.

[0137] 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. A compound of formula (I), its stereoisomers or pharmaceutically acceptable salts: Wherein, R1 and R2 are each independently selected from hydrogen, fluorine and C 1-3 alkyl, or R1 and R2 together with the carbon atom to which they are attached form an oxygen-containing heterocyclic group; M is selected from -NH-O- and -O-NH-; n is selected from 0, 1, 2, and 3; R3 is selected from hydrogen, C 1-3 alkyl or C 3-6 cycloalkyl.

2. The compound according to claim 1, wherein R1 and R2 are each independently selected from hydrogen, fluorine and methyl, or R1, R2 and the carbon atom to which they are attached together form Preferably, R1 is hydrogen and R2 is hydrogen; R1 is fluorine and R2 is fluorine; R1 is methyl and R2 is fluorine, or R1, R2 together with the carbon atom to which they are attached form 3. The compound according to claim 1 or 2, wherein, R3 is selected from C 1-3 alkyl, more preferably methyl.

4. The compound according to any one of claims 1-3, wherein, The compound of formula (I) has the structure shown in the following formula (IA): Wherein, R1, R2, and R3 are each defined in the same manner as the compound of formula (I); Preferably, R1 is hydrogen and R2 is hydrogen; R1 is fluorine and R2 is fluorine; R1 is methyl and R2 is fluorine, or R1, R2 and the carbon atom to which they are attached together form R3 is methyl.

5. The compound according to any one of claims 1-3, wherein, The compound of formula (I) has the structure shown in the following formula (IB): Wherein, R1, R2, and R3 are each defined in the same manner as the compound of formula (I); Preferably, R1 is hydrogen and R2 is hydrogen; R1 is fluorine and R2 is fluorine; R1 is methyl and R2 is fluorine, or R1, R2 together with the carbon atom to which they are attached form R3 is methyl.

6. The compound according to any one of claims 1 - 3, wherein The compound of formula (I) has the structure shown in the following formula (IC): Wherein, R1, R2, and R3 are each defined in the same manner as the compound of formula (I); Preferably, R1 is hydrogen and R2 is hydrogen; R1 is fluorine and R2 is fluorine; R1 is methyl and R2 is fluorine, or R1, R2 together with the carbon atom to which they are attached form R3 is methyl.

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

8. The method for preparing the compound according to any one of claims 1-7, which is selected from the following synthetic routes: Synthesis Route 1: The compound of formula (1-1) reacts with the compound of formula (1-2) by a substitution reaction to obtain the compound of formula (1-3); The compound of formula (1-3) eliminates the Y group to obtain the compound of formula 1; Synthesis Route 2: The compound of formula (2-1) reacts with the compound of formula (2-2) by reductive amination to obtain the compound of formula (2); Wherein, R1, R2, and R3 are each defined in the same manner as the compound of formula (I); X is selected from halogens, preferably bromine; Y is selected from amino protecting groups, preferably p-methoxybenzyl.

9. A pharmaceutical composition, which comprises the compound according to any one of claims 1-7, its stereoisomers or pharmaceutically acceptable salts; and a pharmaceutically acceptable carrier.

10. Use of the compound according to any one of claims 1-7, its stereoisomers or pharmaceutically acceptable salts, or the pharmaceutical composition according to claim 9 in the preparation of an anti-tumor drug; Preferably, the tumor is selected from solid tumors, more preferably one or more of breast cancer, esophageal cancer, gastric cancer, and lung cancer.

11. A method for treating cancer, which comprises the step of administering to a patient in need the compound according to any one of claims 1-7, its stereoisomers or pharmaceutically acceptable salts, or the pharmaceutical composition according to claim 9; Preferably, the cancer is selected from one or more of breast cancer, esophageal cancer, gastric cancer, and lung cancer.