Preparation and application of 7-hydroxylamine structure-containing substituted alkyl camptothecin derivative

Abstract

The invention provides a series of 7-site hydroxylamine structure substituted alkyl camptothecin derivatives and a preparation method and application thereof, the compound has a structure shown in a formula (I), the definition of each group in the formula is shown in the specification, and the compound has good anticancer activity. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of medicine. Specifically, the present invention provides a series of alkyl camptothecin derivatives substituted with a hydroxylamine structure at the 7-position, and their preparation methods and applications. 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. The main defects of camptothecin anti-tumor drugs are their toxicity, poor solubility and the development of tumor cell resistance to them. Summary of the Invention

[0003] The present invention provides a series of alkyl camptothecin derivatives substituted with a hydroxylamine structure at the 7-position. The alkyl camptothecin derivatives substituted with a hydroxylamine structure at the 7-position contain a hydroxylamine structure. Such derivatives with an oxygen atom substitution on the N atom exhibit weak basicity, can reduce the hepatotoxicity of the compound in vivo, improve the metabolic stability and the cell membrane penetration ability, and contribute to improving the anti-tumor activity.

[0004] In one aspect of the present invention, there is provided a compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt:

[0005]

[0006] In the formula,

[0007] R 1 , R 2 are each independently selected from hydrogen, fluorine and C 1-3 alkyl, or R 1 , R 2 together with the carbon atom to which they are attached 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] R 3 is selected from hydrogen, C 1-3 alkyl or C 3-6 cycloalkyl.

[0011] In one embodiment, R 1 , R 2 are each independently selected from hydrogen, fluorine and methyl.

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

[0013] In one embodiment, R 1 and R 2 together with the carbon atom to which they are attached form

[0014] In one embodiment, R 1 is hydrogen, and R 2 is hydrogen;

[0015] R 1 is fluorine, and R 2 is fluorine;

[0016] R 1 is methyl, and R 2 is fluorine, or

[0017] R 1 and R 2 together with the carbon atom to which they are attached form

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

[0019] In one embodiment, R 3 is methyl.

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

[0021]

[0022] wherein R 1 , R 2 , and R 3 are each defined as in the compound of formula (I);

[0023] Preferably, R 1 is hydrogen, and R 2 is hydrogen;

[0024] R 1 is fluorine, and R 2 is fluorine;

[0025] R 1 is methyl, and R 2 is fluorine, or

[0026] R 1 and R 2The carbon atoms connected thereto together form

[0027] R 3 is methyl.

[0028] In one embodiment, the compound of formula (I) has the structure shown in the following formula (IB):

[0029]

[0030] wherein R 1 、R 2 、R 3 are each defined as in the compound of formula (I);

[0031] Preferably, R 1 is hydrogen and R 2 is hydrogen;

[0032] R 1 is fluorine and R 2 is fluorine;

[0033] R 1 is methyl and R 2 is fluorine, or

[0034] R 1 、R 2 and the carbon atom connected thereto together form R 3 is methyl.

[0035] In one embodiment, the compound of formula (I) has the structure shown in the following formula (IC):

[0036]

[0037] wherein R 1 、R 2 、R 3 are each defined as in the compound of formula (I);

[0038] Preferably, R 1 is hydrogen and R 2 is hydrogen;

[0039] R 1 is fluorine and R 2 is fluorine;

[0040] R 1 is methyl and R 2 is fluorine, or

[0041] R 1 、R 2 and the carbon atom connected thereto together form R 3is methyl.

[0042] The present invention provides the following compounds, their stereoisomers or pharmaceutically acceptable salts:

[0043]

[0044]

[0045] Another aspect of the present invention provides a method for preparing the above compounds, which is selected from the following synthetic routes:

[0046] Synthetic route 1:

[0047]

[0048] 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);

[0049] The compound of formula (1-3) is deprotected from the Y group to obtain the compound of formula 1.

[0050] Synthetic route 2:

[0051]

[0052] The compound of formula (2-1) reacts with the compound of formula (2-2) by reductive amination to obtain the compound of formula (2);

[0053] In the formula, R 1 , R 2 , R 3 are each defined in the same way as the compound of formula (I);

[0054] X is selected from halogen, preferably bromine;

[0055] Y is selected from amino protecting groups, preferably p-methoxybenzyl

[0056] In one embodiment, R 3 is C 1-3 alkyl, and the preparation of the compound includes one or more selected from the following synthetic routes:

[0057] Carry out a substitution reaction using the corresponding 7-haloalkyl camptothecin and the corresponding O-alkylhydroxylamine;

[0058] Carry out a reductive amination reaction using the corresponding camptothecin-7-alkyl aldehyde and the corresponding O-alkylhydroxylamine;

[0059] Obtained by carrying out a Mitsunobu reaction using the corresponding camptothecin-7-alkyl alcohol and the corresponding N-Boc-N-alkyl-hydroxylamine;

[0060] A substitution reaction is carried out using the corresponding 7-haloalkyl camptothecin and the corresponding N-Boc-N-alkyl-hydroxylamine.

[0061] The corresponding 7-haloalkyl camptothecin has the structure shown in the following formula (II):

[0062]

[0063] In the formula, R 1 , R 2 , and n are each defined as before;

[0064] X is selected from halogen.

[0065] The corresponding camptothecin-7-alkyl aldehyde has the structure shown in the following formula (III):

[0066]

[0067] In the formula, R 1 , R 2 , and n are each defined as before.

[0068] The corresponding camptothecin-7-alkyl alcohol has the structure shown in the following formula (IV):

[0069]

[0070] In the formula, R 1 , R 2 , and n are each defined as before. On the other hand, the present invention provides a pharmaceutical composition, which comprises the aforementioned compound, its stereoisomer or a pharmaceutically acceptable salt; and a pharmaceutically acceptable carrier.

[0071] On the other hand, the present invention provides the use of the aforementioned compound, its stereoisomer or a pharmaceutically acceptable salt, or the aforementioned pharmaceutical composition in the preparation of an anti-tumor drug.

[0072] In one embodiment, the tumor is selected from solid tumors, more preferably one or more of breast cancer, esophageal cancer, gastric cancer and lung cancer.

[0073] In one embodiment, the compound can inhibit tumor growth.

[0074] On the other hand, the present invention provides a method for treating cancer, which comprises administering the aforementioned compound, its stereoisomer or a pharmaceutically acceptable salt, or the aforementioned pharmaceutical composition to a patient in need. Detailed Description

[0075] I. Definitions

[0076] 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 procedures used herein are terms and conventional procedures widely used in the corresponding fields. Meanwhile, to better understand the present invention, definitions and explanations of relevant terms are provided below.

[0077] As used herein and unless otherwise stated, the term "about" or "approximately" means within plus or minus 10% of a given value or range. In cases 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.

[0078] In the description herein, reference to "some embodiments", "some embodiments" or "some implementation manners" describes a subset of all possible embodiments. However, it can be 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.

[0079] As used herein and unless otherwise stated, the terms "comprising", "including", "having", "containing", including their grammatical equivalents, should generally be understood as open-ended and non-restrictive, e.g., not excluding other unlisted elements or steps.

[0080] The compounds described in the present application can be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, 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 application can 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 application.

[0081] The small molecule drugs used in the present application also include tautomeric forms. Tautomeric forms result from the exchange of a single bond with an adjacent double bond along with the migration of a proton.

[0082] The numerical ranges herein refer to each integer within the given range. For example, "C 1-3 " means that the group can 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.

[0083] When any variable (such as Rn ) When it 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 - 5 Rs, the group may optionally be substituted by up to 5 Rs, and each R in each case has independent options. In addition, combinations of substituents and / or their variants are only permitted if such combinations result in stable compounds.

[0084] As used herein, the term “halogen” refers to fluorine, chlorine, bromine, and iodine.

[0085] As used herein, the term “alkyl” refers to saturated aliphatic hydrocarbon groups, which are straight - chain or branched - chain groups containing 1 to 20 carbon atoms, preferably alkyl groups containing 1 to 3 carbon atoms. Non - limiting examples include methyl, ethyl, n - propyl, and isopropyl.

[0086] As used herein, the term “heterocyclic group” or “heterocycloalkyl” refers to saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituents containing 3 to 20 ring atoms, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O) m (where m is an integer from 0 to 2), but does not include ring moieties of - O - O -, - O - S -, or - S - S -, and the remaining ring atoms are carbon.

[0087] As used herein, the term “substituted” means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 - 3 hydrogen atoms, are independently replaced by a corresponding number of substituents. 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) what substitutions are possible or impossible without undue effort. For example, an amino or hydroxyl group with a free hydrogen may be unstable when bonded to a carbon atom with an unsaturated (such as olefinic) bond.

[0088] As used herein, the term “pharmaceutically acceptable salt” refers to salts formed by corresponding amine compounds and inorganic acids or organic acids, or salts formed by corresponding carboxylic acid compounds and alkali metals or alkaline earth metals or organic amines. 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.

[0089] As used herein, the term "pharmaceutical composition" means a composition comprising a compound or a pharmaceutically acceptable salt thereof as described herein, and at least one pharmaceutically acceptable ingredient selected from the group consisting of, 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, thermosensitive materials, temperature regulators, adhesives, stabilizers, suspending aids, etc., depending on the mode of administration and the nature of the dosage form.

[0090] The drugs or pharmaceutical compositions of the present application can be administered orally, topically, parenterally or mucosally (e.g., sublingually, by inhalation or rectally) in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers. The oral route is generally preferred. The active agent can be administered orally in the form of capsules, tablets, etc. (see Remington: The Science and Practice of Pharmacy, 20th Edition).

[0091] For oral administration in the form of tablets or capsules, the active pharmaceutical ingredient can be combined with non-toxic, pharmaceutically acceptable excipients such as binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g., lactose, sucrose, glucose, mannitol, sorbitol and other reducing and non-reducing sugars, microcrystalline cellulose, calcium sulfate or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc or silica, stearic acid, sodium stearyl fumarate, behenin, calcium stearate, etc.); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate), coloring agents and flavoring agents, gelatin, sweeteners, natural and synthetic gums (such as gum arabic, tragacanth or alginates), buffer salts, carboxymethylcellulose, polyethylene glycol, waxes, etc. For oral administration in liquid form, the pharmaceutical ingredient can be combined with non-toxic, pharmaceutically acceptable inert carriers (e.g., ethanol, glycerol, water), anti-settling agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats), emulsifiers (e.g., lecithin or gum arabic), non-aqueous carriers (e.g., almond oil, esters of fatty acids, ethanol or fractionated vegetable oils), preservatives (e.g., methyl p-hydroxybenzoate or propyl p-hydroxybenzoate or sorbic acid), etc. Stabilizers such as antioxidants (BHA, BHT, propyl gallate, sodium ascorbate, citric acid) can also be added to stabilize the dosage form.

[0092] Tablets containing the active compound can be coated by methods well known in the art. The compositions of the present application containing the compound of formula I as the active compound can also be incorporated into beads, microspheres or microcapsules, for example, constructed from polyglycolic acid / lactic acid (PGLA). Liquid formulations for oral administration can take the form of, for example, solutions, syrups, emulsions or suspensions or they can be presented as dry products to be reconstituted with water or other suitable excipients before use. Formulations for oral administration can be suitably formulated to provide controlled or delayed release of the active compound.

[0093] The term "patient" refers to an animal, preferably a mammal, more preferably a human.

[0094] 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, for example about 1 - 1500 mg / day. The required dosage can conveniently be presented as a single dose, or as simultaneous doses (or within a short period of time) or as divided doses at appropriate intervals, for example 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 circumstances of the patient in combination with the physician's diagnosis.

[0095] As used in this application, 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.

[0096] The use of the term "inhibit" as used in this application 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.

[0097] II. Examples

[0098] 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 regarded as limiting the present invention. All other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the scope of protection of the present invention.

[0099] 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 applicable to the following explanations.

[0100] The raw materials and equipment used in the specific embodiments of the present invention are all known products and are obtained by purchasing commercially available products.

[0101] Example 1: 7-(N-Methoxy)aminomethyl camptothecin (1)

[0102]

[0103] Add 7-hydroxymethyl camptothecin (5 g, 12.4 mmol), 50% aqueous hydrobromic acid solution (100 mL) and concentrated sulfuric acid (1 mL) into a reaction flask, stir and heat to 125 °C for reaction for 2 h, cool to room temperature, pour into ice water, filter to precipitate a solid, and dry to obtain 7-bromomethyl camptothecin 1a (2.5 g, yield 26%); LCMS: [M+H] + 441.05 (theoretical value 440.04).

[0104] Add 7-bromomethyl camptothecin (1.20 g, 2.72 mmol), DMF (15 ml) and N-methoxy-(4-methoxybenzyl)amine (909.62 mg, 5.44 mmol) into a reaction flask, stir the reaction solution, heat to 55 °C for reaction for 16 h, pour into ice water, filter to precipitate a solid, and purify by reverse column chromatography to obtain 7-(N-methoxy-N-(4-methoxyphenyl)aminomethyl camptothecin 1b (700 mg, yield 44.3%); LCMS: [M+H] + 528.32 (theoretical value 527.21).

[0105] Add 7-(N-methoxy-N-(4-methoxyphenyl)aminomethyl camptothecin (700 mg, 1.33 mmol), DCM (10 mL) and methanesulfonic acid (10 mL) into a reaction flask, heat to 40 °C and stir for reaction for 96 h, concentrate, add saturated aqueous sodium bicarbonate solution to adjust the pH to ~7, filter to precipitate a solid product to obtain 7-(N-methoxy)aminomethyl camptothecin 1 (500 mg, yield 84.1%); LCMS: [M+H] + 408.25 (theoretical value 407.15); 1 H NMR (600 MHz, DMSO-d 6)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); 13 C NMR(151MHz,DMSO)δ172.95,157.27,152.34,150.53,148.91,146.05,140.26,130.44,130.03,129.96,127.92,127.61,125.26,119.54,97.20,72.87,65.74,61.50,50.49,49.19,49.07,30.79.

[0106] Example 2: 7-(N-Methoxy)aminomethyl-10,11-methylenedioxycamptothecin (2)

[0107]

[0108] Add 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) to the reaction flask at 0 °C, continue to stir the reaction at 0 °C for 30 min, pour it into ice water, filter to precipitate the solid, dry to obtain the brown solid product 7-bromomethyl-10,11-methylenedioxycamptothecin 2a (1.7 g, yield 46.2%); LCMS: [M+H] + 485.20 (theoretical value 484.03).

[0109] Add 7-bromomethyl-10,11-methylenedioxycamptothecin (1.7 g, 2.73 mmol) and N-methoxy-(4-methoxybenzyl)amine (1.07 g, 6.37 mmol) to the reaction flask, stir the reaction solution at 55 °C for 8 h, pour it into ice water, extract with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, and purify 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 1H NMR (500 MHz, DMSO-d 6 ) δ 7.52 (s, 1H), 7.47 (s, 1H), 7.35 (d, J = 8.6 Hz, 2H), 7.23 (s, 1H), 6.94 (d, J = 8.6 Hz, 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 = 7.3 Hz, 3H).

[0110] 7-(N-Methoxy-N-(4-methoxyphenyl)aminomethyl)-10,11-methylenedioxycamptothecin ((1 g, 1.75 mmol) and trifluoroacetic acid (50 mL) were added to a reaction flask. The reaction mixture 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 1H NMR (500 MHz, DMSO-d 6 ) δ 7.66 (s, 1H), 7.50 (d, J = 3.0 Hz, 1H), 7.24 (s, 1H), 6.49 (s, 1H), 6.29 (d, J = 2.4 Hz, 2H), 5.42 (d, J = 1.7 Hz, 2H), 5.27 (s, 2H), 4.44 (d, J = 3.7 Hz, 2H), 3.30 (s, 3H), 1.87 (dp, J = 17.2, 7.1 Hz, 2H), 0.89 (t, J = 7.3 Hz, 3H); 13 13C NMR (126 MHz, DMSO) δ 173.00, 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.

[0111] Example 3: 7-(N-Methoxy)aminomethyl-10,11-difluorocamptothecin (3)

[0112]

[0113] Add 7-hydroxymethyl-10,11-difluorocamptothecin (6 g, 14.45 mmol), 48% aqueous hydrobromic acid solution (150 mL) and concentrated sulfuric acid (1 mL) to the reaction flask. Stir and heat the reaction solution to 125 °C for 1.5 h, pour it into water, filter to precipitate a solid, and dry 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).

[0114] Add 7-bromomethyl-10,11-difluorocamptothecin (4.5 g, 4.70 mmol), DMF (80 mL), N-methoxy-(4-methoxybenzyl)amine (1.58 g, 9.41 mmol) to the reaction flask. Stir and heat to 50 °C for 4 h, pour it into water, extract with DCM, wash with saturated brine, dry over anhydrous magnesium sulfate, and purify by silica gel column chromatography to obtain the 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).

[0115] Dissolve 7-(N-methoxy-N-(4-methoxyphenyl)aminomethyl)-10,11-difluorocamptothecin (120 mg, 212.56 μmol) in methanesulfonic acid (702.74 mg, 10.63 mmol, 3 mL). React the reaction solution at 40 °C for 120 h, add saturated aqueous sodium bicarbonate solution, filter to precipitate a solid, and purify by silica gel column chromatography to obtain the 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 (500 MHz, DMSO-d 6 ) δ 8.36 (dd, J = 12.4, 8.7 Hz, 1H), 8.16 (dd, J = 11.5, 8.0 Hz, 1H), 7.31 (s, 1H), 6.53 (s, 1H), 5.43 (s, 2H), 5.35 (s, 2H), 4.53 (s, 2H), 3.30 (s, 3H), 1.87 (ddt, J = 16.9, 14.1, 7.1 Hz, 2H), 1.39 - 1.26 (m, 2H), 1.28 - 1.19 (m, 5H), 0.87 (dt, J = 21.6, 7.2 Hz, 3H), 0.84 (s, 1H); 1313C NMR (126 MHz, DMSO) δ 174.96, 172.87, 157.15, 153.14, 153.12, 152.92, 152.79, 150.91, 150.78, 150.45, 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.

[0116] Example 4: 7-(N-(methoxy)amino)methyl-10-methyl-11-fluorocamptothecin (4)

[0117]

[0118] At 0 °C, 7-hydroxymethyl-10-methyl-11-fluorocamptothecin (4 g, 9.72 mmol), 48% aqueous hydrobromic acid solution (30 mL) and concentrated sulfuric acid (0.9 mL) were added to a reaction flask. The reaction was continued by stirring at 125 °C for 30 min, then poured into ice water. The precipitated solid was filtered, 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).

[0119] 7-Bromomethyl-10-methyl-11-fluorocamptothecin (5.5 g, 11.60 mmol), DMF (50 mL) and N-methoxy-(4-methoxybenzyl)amine (3.90 g, 23.19 mmol) were added to a reaction flask. The reaction solution was stirred at 55 °C for 6 h, then 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); 1 1H NMR (500 MHz, DMSO-d 6)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).

[0120] 7-(N - Methoxy - N-(4 - methoxyphenyl)aminomethyl - 10 - methyl - 11 - fluorocamptothecin (1.9 g, 3.39 mmol) was dissolved in methanesulfonic acid (20 mL). The reaction solution was reacted at 40 °C for 168 h. Saturated aqueous sodium bicarbonate was added, and the precipitated solid was filtered and purified by silica gel column chromatography to obtain the 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 - d 6 )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),5.42(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.

[0121] Example 5: 7-(N-(Methoxy)amine)ethyl camptothecin (5)

[0122]

[0123] At 0 °C, in a 100 mL round-bottom flask, 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), H 2 SO 4 (17.5 mL) and 1,3-propanediol (10.59 g, 137.39 mmol, 10.06 mL) were added. 35% hydrogen peroxide (97.36 mg, 2.86 mmol, 87.71 μL) was added dropwise, and the reaction was continued at 0 °C for 3 hours. It was poured into ice water, the solid product was filtered, and purified by normal-phase silica gel column chromatography to obtain the pale yellow powdery solid product 7-(2-hydroxy)ethyl camptothecin 5a (345 mg, yield 29%); LCMS: [M+1] + 393.43 (calculated value: 392.41); 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.23 (d, J = 8.4 Hz, 1H), 8.13 (d, J = 8.4 Hz, 1H), 7.81 (t, J = 7.6 Hz, 1H), 7.67 (t, J = 7.6 Hz, 1H), 7.31 (s, 1H), 5.43 (s, 2H), 5.25 (s, 2H), 3.81 (t, J = 6.3 Hz, 3H), 3.35 (t, J = 6.4 Hz, 2H), 1.98 - 1.80 (m, 2H), 0.90 (t, J = 7.3 Hz, 3H).

[0124] At 25 °C, 5a (345 mg, 0.833 mmol) was added to a 250 mL round-bottom flask dissolved in DMSO (20 mL) and DCM (6 mL). Under stirring and cooling in an ice bath, 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 it 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 obtain 7-(N-(methoxy)amine)ethyl camptothecin 5b (291 mg, 0.74 mmol, yield 85%) as a brown viscous solid, which was used for the next reaction without purification; LCMS: [M+H] + 391.23 (calculated value: 390.40).

[0125] Add 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) to a reaction flask, stir at room temperature for 6 hours, add acetic acid (15 mL) and sodium cyanoborohydride (94.5 mg, 1.5 mmol), react at room temperature for 2 hours, add water (100 mL), extract with dichloromethane (100 mL x 4), combine the organic phases, dry over anhydrous magnesium sulfate, filter, concentrate the filtrate under reduced pressure, concentrate, purify by reverse-phase C18 column (ACN / 0.1% aqueous TFA solution), freeze-dry the collected solution to obtain a pale yellow powdery solid product 5,7-(N-methoxy)aminoethyl camptothecin (80 mg, yield 37%); LCMS: [M+1] + 422.23 (calculated: 421.45); 1 H NMR (500 MHz, DMSO-d 6 ) δ8.28 (d, J = 8.5 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), 6.72 - 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 = 7.3 Hz, 2H), 1.92 - 1.85 (m, 2H), 0.88 (d, J = 7.4 Hz, 3H).

[0126] Example 6: 7-(N-methoxy)aminoethyl-10,11-methylenedioxy camptothecin (6)

[0127]

[0128] Under an ice bath, add water (25 mL), 75% dilute sulfuric acid (25 mL), 1,3-propanediol (25 mL) to a 250 mL three-necked eggplant-shaped flask in sequence. After stirring evenly, add 10,11-methylenedioxy camptothecin (10 g, 25.5 mmol), stir and dissolve, add ferrous sulfate heptahydrate (14.17 g, 51 mmol), stir evenly, slowly dropwise add 30% hydrogen peroxide (28.9 g, 0.25 mol), maintain the temperature below 10 °C and stir for 10 min. Quench the reaction solution into ice water, filter to precipitate a solid, wash the filter cake with ethanol once, directly mix the filter cake with silica gel and methanol, purify by silica gel column chromatography to obtain a white solid product 7-(2-hydroxy)ethyl-10,11-methylenedioxy camptothecin 6a (2.2 g, yield 19.8%); LCMS: [M+1] +437.32 (Calculated value: 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).

[0129] To a 100 mL single-necked eggplant-shaped flask, 7-(2-hydroxy)ethyl-10,11-methylenedioxycamptothecin (400 mg, 0.9 mmol), DCM (20 mL) and DMSO (20 mL) were added successively. After stirring evenly, Dess-Martin Periodinane (971.9 mg, 2.3 mmol), a Dess-Martin oxidant, was added. The reaction was carried out for 10 min, water (50 mL) was added, and extraction was performed with DCM (3 x 100 mL). After liquid separation, the organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product of 6b, 10,11-methylenedioxycamptothecin-7-acetaldehyde, a yellowish-brown solid, which was directly used in the next step without purification; LCMS: [M+1] + 435.59 (Calculated value: 434.40).

[0130] At room temperature, the above-mentioned 10,11-methylenedioxycamptothecin-7-acetaldehyde (crude product) and ethanol (8 mL) were added to a reaction flask and stirred evenly. Then, sodium acetate (755.4 mg, 0.9 mmol) and hydroxylamine hydrochloride (789 mg, 0.9 mmol) were added, and the mixture was stirred for 1 h. Then, acetic acid (24 mL) and sodium cyanoborohydride (1.16 g, 18 mmol) were successively added to the reaction solution, and the reaction was stirred for 1 h. Water (100 mL) was added to the reaction solution, and extraction was performed twice with DCM, followed by washing with water, washing with saturated sodium chloride, drying over anhydrous sodium sulfate, and concentrating to obtain 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); 1 H NMR (500 MHz, DMSO-d 6)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-d 6 )δ173.00,157.27,151.26,150.57,149.75,149.35,147.50,146.82,128.54,124.84,118.45,105.94,103.09,99.76,96.34,72.87,65.72,61.10,50.24,50.17,30.74,28.00,8.26.

[0131] Example 7: 7-(N-Methoxy)aminoethyl-10,11-difluorocamptothecin (7)

[0132]

[0133] At 0 °C, into a 500 mL three-necked reaction flask, add 10,11-difluorocamptothecin (3 g, 7.37 mmol), H 2 O (75 mL) and 1,3-propanediol (62.07 g, 626.45 mmol, 58.95 mL), then add 75% H 2 SO 4 (36.14 g, 368.50 mmol, 75 mL). At 0 °C, add ferrous sulfate heptahydrate (2.34 g, 8.40 mmol), and then dropwise add 30% H 2 O 2 aqueous solution (215.59 mg, 6.34 mmol, 194.23 μL). Continue to stir at 0 °C for 4 h. Pour the reaction solution into 2 L of ice water, let it stand for 16 h, filter the precipitated solid, and after drying, obtain 7-(2-hydroxy)ethyl-10,11-difluorocamptothecin 7a (1.8 g, yield 54.1%); LCMS: [M+1] + 429.31 (theoretical value 428.39).

[0134] 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. Then Dess-Martin Periodinane (1.88 g, 4.44 mmol) was added, and the mixture was stirred at 25 °C for 4 h. Water (50 mL) was added, and the mixture was extracted with DCM (3 x 100 mL), washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude yellowish-brown solid, 10,11-difluorocamptothecin-7-acetaldehyde (7b), which was directly used in the next reaction without purification; LCMS: [M+1] + 427.16 (theoretical value 426.38).

[0135] In a 100 ml reaction flask, 10,11-difluorocamptothecin-7-acetaldehyde (50 mg, 111.27 μmol), DMSO (6 mL), and DCM (4 mL) were added. Then (O-methyl)hydroxylamine hydrochloride (23.38 mg, 333.81 μmol) was added, and the mixture was stirred at 25 °C for 1 h. NaBH 3 CN (13.98 mg, 222.54 μmol) and glacial acetic acid (33.41 mg, 556.35 μmol) were added, and the mixture was stirred at 25 °C for 16 h. The reaction solution was concentrated and purified using a C18 Spherical 20 - 35um 100A 120 g reverse column. Acetonitrile and 0.1% TFA aqueous solution were used as mobile phases B2 and A2 respectively in the HPLC preparation method (monitored at 254 nm and 214 nm wavelengths): 2 ml of the sample DMF solution was injected into the reverse column, and the DMF solvent was flushed out using 5 min (mobile phase ratio A2:B2 = 95:5). Then the acetonitrile ratio was increased to 10% within 90 min (mobile phase ratio from A2:B2 = 95:5 to A2:B2 = 90:10). Then the acetonitrile ratio was maintained at 10% and the column was flushed for another 30 min to elute the product, obtaining 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 (600 MHz, DMSO-d 6 ) δ 8.35 - 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 = 6.5 Hz, 2H), 1.87 (dq, J = 14.1, 6.8 Hz, 2H), 1.23 (s, 3H), 0.88 (t, J = 7.2 Hz, 3H).

[0136] Example 8: 7-(N-Methoxy)aminoethyl-10-methyl-11-fluorocamptothecin (8)

[0137]

[0138] Add water (2.5 mL), 75% sulfuric acid (2.5 mL), 1,3-propanediol (2.5 mL), 10-methyl-11-fluorocamptothecin (500 mg, 1.3 mmol) and ferrous sulfate heptahydrate (722.8 mg, 2.6 mmol) to a 100 mL three-necked flask. After stirring and dissolving, cool to 0 °C, and add dropwise 30% H 2 O 2 (1.7 g, 26 mmol). Maintain the temperature at about 15 °C and react for 1 h. Pour the reaction solution into water, filter and dry to obtain 7-(2-hydroxy)ethyl-10-methyl-11-fluorocamptothecin 8a (311 mg, yield 39.8%); LCMS: [M+1] + 425.35 (calculated value: 424.41).

[0139] Add 7-(2-hydroxy)ethyl-10-methyl-11-fluorocamptothecin (300 mg, 0.7 mmol) to a 100 ml single-necked flask, dissolve it with DCM / DMSO (1:1, 30 mL), add Dess-Martin Periodinane (742 mg, 1.75 mmol), react at room temperature for 10 min, extract with DCM (50 ml x 3). Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate and evaporate to dryness to obtain 10-methyl-11-fluorocamptothecin-7-acetaldehyde 8b (280 mg, crude yield 95%), which is directly used in the next step without purification; LCMS: [M+1] + 423.35 (calculated value: 422.41).

[0140] Add the above 10-methyl-11-fluorocamptothecin-7-acetaldehyde (150 mg, 0.35 mmol) dissolved in EtOH (4 mL) to a 100 mL single-necked flask. Stir and add (O-methyl)hydroxylamine hydrochloride (292 mg, 3.5 mmol) and sodium acetate (287 mg, 3.5 mmol). React at room temperature for 30 min. Add sodium cyanoborohydride (287 mg, 53 mmol) to the reaction solution, then add glacial acetic acid (12 mL). Stir at room temperature for 1 h, add water (12 mL), extract with DCM, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate, purify by C18 reverse-phase column, and lyophilize 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 value: 453.47); 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.18 (d, J = 8.3 Hz, 1H), 7.85 (d, J = 10.8 Hz, 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 = 6.9 Hz, 2H), 2.51 (s, 3H), 2.03 - 1.78 (m, 2H), 0.88 (t, J = 7.3 Hz, 3H).

[0141] Example 9: 7-(N-Methoxy)aminopropyl-10,11-methylenedioxycamptothecin (9)

[0142]

[0143] Under ice bath cooling, purified water (12.5 mL), 75% dilute sulfuric acid (12.5 mL), and 1,4-butanediol (12.5 mL) were successively added to a 100 mL three-necked flask. After stirring evenly, 10,11-methylenedioxycamptothecin (5 g, 12.7 mmol) was added. After stirring and dissolving (internal temperature ~10 °C), ferrous sulfate heptahydrate (7.4 g, 26.6 mmol) was added. After stirring evenly, 30% hydrogen peroxide (14.5 g, 127.9 mmol) was slowly added dropwise. The reaction was stirred at a temperature below 10 °C for 10 min. The reaction solution was quenched by adding it to ice water, filtered by suction, the filter cake was rinsed once with ethanol, and the filter cake was directly mixed with silica gel and methanol for sample preparation. It was purified by silica gel column chromatography to obtain a pale yellow solid product 9a, 7-(3-hydroxy)propyl-10,11-methylenedioxycamptothecin (1.56 g, yield 27%); LCMS: [M + 1] + 451.6 (Calculated value: 450.45).

[0144] 7-(3-Hydroxy)propyl-10,11-methylenedioxycamptothecin (400 mg, 0.89 mmol), 20 mL of DCM and 20 mL of DMSO were successively added to a 100 mL single-necked eggplant-shaped flask. After stirring evenly, Dess-Martin Periodinane oxidant (753 mg, 1.78 mmol) was added. The reaction 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 layers were separated, the organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to obtain a crude brown-yellow solid 9b, which was directly used in the next step without purification; LCMS: [M + 1] + 449.27 (Calculated value: 448.43).

[0145] At room temperature, ethanol (10 mL) was added to the above-mentioned 9b, followed by sodium acetate (1.09 g, 13.3 mmol) and (O-methyl) hydroxylamine hydrochloride (924.2 mg, 13.3 mmol). The mixture was stirred for 1 h, then 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 it was extracted with DCM (2 x 50 mL). The organic phase was washed once with water and once with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated, and purified by reverse preparation to obtain 7-(N-methoxy) aminopropyl-10,11-methylenedioxycamptothecin 9 (120 mg, yield 13%); LCMS: [M+1] + 480.31 (calculated value: 479.49); 1 HNMR (500 MHz, DMSO-d 6 ) δ 7.61 (s, 1H), 7.47 (s, 1H), 7.22 (s, 1H), 6.28 (d, J = 2.6 Hz, 2H), 5.41 (d, J = 2.7 Hz, 2H), 5.14 (s, 2H), 3.72 (s, 3H), 3.29 (t, J = 7.2 Hz, 2H), 3.17 - 3.09 (m, 2H), 1.93 - 1.83 (m, 4H), 0.88 (t, J = 7.3 Hz, 3H).

[0146] Test Example 1: Inhibitory activity against tumor cell growth

[0147] 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 esophageal cancer cells TE12, 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 added to a 96-well cell culture plate at 100 μL per well, and then placed back in an incubator at 37 °C with 5% CO 2 overnight. The next day, the compound was diluted with the medium to 10000 nM, 2000 nM, 400 nM, 80 nM, 16 nM, 3.2 nM, 0.64 nM, 0.13 nM, and 2 μL of the diluted compound was added to the 96-well cell culture plate at each concentration, with 3 replicates for each concentration. 2 μL of the diluent was added to the negative control wells without the compound and the blank control wells. Dxd was detected at the same concentration as the positive control for screening. After adding the samples, it was placed back in an incubator at 37 °C with 5% CO 2Continue to incubate in the incubator for 72 h. After incubation, take out the cell culture plate, aspirate and discard the culture medium in the plate with a pipette, add 100 μL of culture medium containing 10% CCK-8 to each well, and incubate at 37 °C for 3 h. After incubation, take out the culture plate, keep it away from light, place it in an ELISA plate, select 630 nm as the reference wavelength and 450 nm as the measurement wavelength to measure the absorbance. According to the absorbance value, use four-parameter regression in GraphPad to calculate the IC 50 value (Table 1).

[0148] For the IC 50 value, where "++++" means 10 nM > IC 50 ; "+++" means 100 nM > IC 50 ≥ 10 nM; "++" means 500 nM > IC 50 ≥ 100 nM; "+" means 1000 nM > IC 50 ≥ 500 μM.

[0149] Table 1: IC 50 (nM) values of the compounds inhibiting the growth of tumor cells

[0150]

[0151] The example compounds provided by the present invention all have good inhibitory effects on the growth of cancer cells and have significant anti-cancer activities.

[0152] The foregoing description of the specific exemplary embodiments of the present invention is for the purposes of illustration and exemplification. These descriptions are not intended to limit the invention to the precise forms disclosed, and obviously, many changes and variations are possible in light of the above teaching. The purpose of selecting and describing the exemplary embodiments is to explain the specific principles of the present invention and its practical applications, so that those skilled in the art can implement and utilize the various different exemplary embodiments of the present invention as well as various different selections and changes. The scope of the present invention is intended to be defined by the claims and their equivalents.

Claims

1. A compound of formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof: In the formula, 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; 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 connected together form Preferably, R1 is hydrogen and R2 is hydrogen; R1 is fluorine, R2 is fluorine; R1 is methyl, R2 is fluorine, or R1, R2 and the carbon atom to which they are connected together form 3. The compound according to claim 1, wherein R3 is selected from C 1-3 The alkyl group is more preferably a methyl group.

4. The compound according to claim 1, wherein The compound of formula (I) has the structure shown in the following formula (IA): In the formula, R1, R2, and R3 are defined as the compound of formula (I); Preferably, R1 is hydrogen and R2 is hydrogen; R1 is fluorine, R2 is fluorine; R1 is methyl, R2 is fluorine, or R1, R2 and the carbon atom to which they are connected together form R3 is methyl.

5. The compound according to claim 1, wherein The compound of formula (I) has the structure shown in the following formula (IB): In the formula, R1, R2, and R3 are defined as the compound of formula (I); Preferably, R1 is hydrogen and R2 is hydrogen; R1 is fluorine, R2 is fluorine; R1 is methyl, R2 is fluorine, or R1, R2 and the carbon atom to which they are connected together form R3 is methyl.

6. The compound according to claim 1, wherein The compound of formula (I) has the structure shown in the following formula (IC): In the formula, R1, R2, and R3 are defined as the compound of formula (I); Preferably, R1 is hydrogen and R2 is hydrogen; R1 is fluorine, R2 is fluorine; R1 is methyl, R2 is fluorine, or R1, R2 and the carbon atom to which they are connected together form R3 is methyl.

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

8. A method for preparing a compound according to any one of claims 1 to 7, which is selected from the following synthetic routes: Synthetic route 1: The compound of formula (1-1) and the compound of formula (1-2) undergo substitution reaction to obtain a compound of formula (1-3); The compound of formula (1-3) is freed from the Y group to obtain a compound of formula 1; Synthesis route 2: The compound of formula (2-1) is subjected to a reductive amination reaction with the compound of formula (2-2) to obtain the compound of formula (2; In the formula, R1, R2, and R3 are defined as the compound of formula (I); X is selected from halogen, preferably bromine; Y is selected from amino protecting groups, preferably p-methoxybenzyl.

9. A pharmaceutical composition comprising the compound according to any one of claims 1 to 7, its stereoisomer or pharmaceutically acceptable salt; and a pharmaceutically acceptable carrier.

10. Use of the compound according to any one of claims 1 to 7, its stereoisomer or pharmaceutically acceptable salt, 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 selected from breast cancer, esophageal cancer, gastric cancer and lung cancer.

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