Camptothecin analogues and their use

Abstract

The present application discloses a novel compound, and a pharmaceutical composition comprising the compound. Specifically, it relates to camptothecin analogs, pharmaceutically acceptable salts thereof, compositions comprising the camptothecin analogs, and their use in the prevention and / or treatment of diseases, particularly as therapeutic agents in the treatment of cancer.

Description

Technical Field

[0001] This invention relates to the medical field, disclosing novel compounds or pharmaceutically acceptable salts thereof. Specifically, it discloses camptothecin analogues, methods for their preparation, pharmaceutically acceptable salts thereof, compositions comprising camptothecin analogues, and their uses in the prevention and / or treatment of diseases. Background Technology

[0002] Camptothecin is a plant-based anticancer drug, appearing as pale yellow needle-like crystals. It is extracted from the camptotheca tree, which is distributed in central and southwestern China. Camptothecin has good efficacy against gastrointestinal and head and neck cancers, but it causes hematuria as a side effect in a small number of patients. After its discovery, researchers extracted and isolated several natural camptothecin derivatives, including 10-methoxycamptothecin, 9-methoxycamptothecin, and hydroxycamptothecin. Among them, hydroxycamptothecin exhibits stronger anticancer activity than camptothecin, showing significant efficacy against liver and head and neck cancers with fewer side effects. Subsequently, extensive research focused on the structural modification of camptothecin to obtain camptothecin derivatives with stronger antitumor activity, elucidating the effects of different substituents and substitution sites on its antitumor activity.

[0003] Camptothecin drugs have developed into an important class of anti-tumor drugs, with derivatives such as irinotecan, topotecan, and beloteccan already available. However, current camptothecin drugs and formulations suffer from poor in vivo metabolic stability and acquired resistance. These issues remain challenges in the development of camptothecin drugs. Currently, a large number of novel camptothecin drugs are in clinical trials, with the hope of achieving further breakthroughs in drug stability, drug targeting, or anti-tumor activity. Summary of the Invention

[0004] This application provides a novel camptothecin analogue, including its stereoisomers, tautomers, pharmaceutically acceptable salts, deuterated compounds, or solvates. The camptothecin analogue of this application is prepared via a simple and efficient synthetic route and possesses excellent physicochemical properties and biological activities, such as good stability, safety, and antitumor activity.

[0005] In a first aspect, this application provides a compound of Formula I or a stereoisomer thereof, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, or a solvate thereof.

[0006]

[0007] in:

[0008] R1 and R2 are each independently selected from hydrogen, hydroxyl, amino, halogen, and C. 1-5 Alkyl, C 3-5 cycloalkyl, C1-5 Alkoxy, C 3-5 Cycloalkyloxy group; wherein the alkyl, alkoxy, cycloalkyl, or cycloalkyloxy group may be selectively substituted with 1-3 halogen atoms;

[0009] Or R1, R2, along with the carbon atoms they are attached to, form C. 5-8 Heterocyclic rings;

[0010] R3 is selected from methyl, ethyl, propyl, isopropyl, C4 alkyl, and C5 alkyl, and R3 can be selectively substituted with 1-3 halogen atoms;

[0011] R4 is selected from C 1-5 Alkyl hydroxyl, C 1-5 Alkylamino, C 3-8 Cycloalkylhydroxyl, C 3-8 Cycloalkylamino, C 1-5 Alkyl mercapto, C 3-8 Cycloalkyl mercapto, C 3-8 Heterocyclic alkyl hydroxyl, C 3-8 Heterocyclic alkylamino, C 3-8 Heterocyclic alkyl mercapto, C 3-8 Heterocyclic alkyl C 1-5 Alkyl hydroxyl, C 3-8 Heterocyclic alkyl C 1-5 Alkylamino, C 3-8 Heterocyclic alkyl C 1-5 Alkyl mercapto, -NH-C 1-5 Alkyl hydroxyl, -N(R5)-C 1-5 Alkyl hydroxyl, -NH-C 3-8 Cycloalkylhydroxyl, -N(R5)-C 3-8 Cycloalkylhydroxyl, -NH-C 3-8 cycloalkyl C 1-5 Alkyl hydroxyl, -N(R5)-C 3-8 cycloalkyl C 1-5 Alkyl hydroxyl groups, wherein the alkyl, cycloalkyl, or heterocycloalkyl groups may be selectively substituted with 1-3 R5 groups;

[0012] R5 is selected from halogens, C 1-5 Alkyl, C 2-5 alkynyl group, C 1-5 Alkoxy, C 1-5 Oxyalkyl, C 6-14 Aryl, C 3-8 Cycloalkyl, wherein the alkyl, cycloalkyl, alkoxy, or aryl group can be selectively substituted with 1-3 halogen atoms, or two R5 groups together with the carbon atom in which they reside form a C group. 3-8 Carbon rings;

[0013] X is selected from O or S;

[0014] m1 and m2 are each independently selected from 0, 1, 2, 3, and 4.

[0015] In some embodiments, R1 and R2 are each independently selected from hydrogen, hydroxyl, amino, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, C4 alkyl, C5 alkyl, cyclopropane, cyclobutane, cyclopentane, methoxy, ethoxy, propoxy, isopropoxy, C4 alkoxy, C5 alkoxy, C 3-4 Cycloalkyloxy, C 4-5 Cycloalkyloxy groups; wherein the methyl, ethyl, propyl, isopropyl, alkyl, methoxy, ethoxy, propoxy, isopropoxy, alkoxy, cyclopropane, cyclobutane, cyclopentane, and cycloalkyloxy groups may be optionally substituted with 1-3 fluorine, chlorine, bromine, or iodine groups;

[0016] Alternatively, R1 and R2, together with the carbon atoms they are attached to, form C. 5-6 Heterocyclic or C 7-8 Heterocyclic rings;

[0017] In some embodiments, R1 and R2 are each independently selected from hydrogen, hydroxyl, amino, fluorine, chlorine, methyl, ethyl, propyl, cyclopropane, cyclobutane, methoxy, ethoxy, propoxy, C 3-4 Cycloalkyloxy, C 4-5 Cycloalkyloxy groups; the methyl, ethyl, propyl, cyclopropane, cyclobutane, methoxy, ethoxy, propoxy, and cycloalkyloxy groups may optionally be replaced by 1-3 fluorine, chlorine, bromine, or iodine groups;

[0018] Alternatively, R1 and R2, together with the carbon atoms they are attached to, form C. 5-6 Heterocyclic rings.

[0019] In some embodiments, R1 is selected from methyl, chlorine, cyclopropane, methoxy, and difluoromethyl; and R2 is selected from hydrogen, fluorine, and chlorine.

[0020] Alternatively, when R1 and R2 together with the carbon atoms they are attached to form a heterocycle, the portions attached to R1 and R2 are selected from the following groups: -OCH2O-, -O(CH2)2O-.

[0021] In some embodiments, R3 is selected from methyl, ethyl, propyl, and R3 can be selectively replaced by 1-3 fluorine, chlorine, bromine, or iodine molecules.

[0022] In some embodiments, R3 is selected from methyl or ethyl, and R3 may be selectively replaced by 1-3 fluorine or chlorine molecules.

[0023] In some embodiments, R3 is a methyl group.

[0024] In some embodiments, R4 is selected from methyl hydroxy, ethyl hydroxy, propyl hydroxy, isopropyl hydroxy, C4 alkyl hydroxy, C5 alkyl hydroxy, methyl amino, ethyl amino, propyl amino, C4 alkyl amino, C5 alkyl amino, C 3-4 Cycloalkylhydroxyl, C 5-6 Cycloalkylhydroxyl, C 7-8 Cycloalkylhydroxyl, C 3-4 Cycloalkylamino, C 5-6 Cycloalkylamino, C 7-8 Cycloalkylamino, methyl mercapto, ethyl mercapto, propyl mercapto, isopropyl mercapto, C4 alkyl mercapto, C5 alkyl mercapto, C 3-4 Cycloalkyl mercapto, C 5-6 Cycloalkyl mercapto, C 7-8 Cycloalkyl mercapto, C 3-4 Heterocyclic alkyl hydroxyl, C 5-6 Heterocyclic alkyl hydroxyl, C 7-8 Heterocyclic alkyl hydroxyl, C 3-4 Heterocyclic alkylamino, C 5-6 Heterocyclic alkylamino, C 7-8 Heterocyclic alkylamino, C 3-4 Heterocyclic alkyl mercapto, C 5-6 Heterocyclic alkyl mercapto, C 7-8 Heterocyclic alkyl mercapto, C 3-4 Heterocyclic alkyl C 1-5 Alkyl hydroxyl, C 5-6 Heterocyclic alkyl C 1-5 Alkyl hydroxyl, C 7-8 Heterocyclic alkyl C 1-5 Alkyl hydroxyl, C 3-8 Heterocyclic alkyl methyl hydroxy, C 3-8 Heterocyclic alkyl ethyl hydroxy, C 3-8 Heterocyclic alkylpropyl hydroxy, C 3-8 Heterocyclic alkyl isopropyl hydroxy, C 3-8 Heterocyclic alkyl C4 alkyl hydroxyl, C 3-8 Heterocyclic alkyl C5 alkyl hydroxyl, C 3-4 Heterocyclic alkyl C 1-5 Alkylamino, C 5-6 Heterocyclic alkyl C 1-5 Alkylamino, C 7-8 Heterocyclic alkyl C 1-5 Alkylamino, C 3-8 Heterocyclic alkyl methyl amino, C 3-8 Heterocyclic alkyl ethylamino, C 3-8 Heterocyclic alkylpropylamino, C 3-8 Heterocyclic alkyl isopropylamino, C 3-8 Heterocyclic alkyl C4 alkylamino, C 3-8 Heterocyclic alkyl C5 alkylamino, C 3-4Heterocyclic alkyl C 1-5 Alkyl mercapto, C 5-6 Heterocyclic alkyl C 1-5 Alkyl mercapto, C 7-8 Heterocyclic alkyl C 1-5 Alkyl mercapto, C 3-8 Heterocyclic alkyl methyl mercapto, C 3-8 Heterocyclic alkyl ethyl mercapto, C 3-8 Heterocyclic alkylpropyl mercapto, C 3-8 Heterocyclic alkyl isopropyl mercapto, C 3-8 Heterocyclic alkyl C4 alkyl mercapto, C 3-8 Heterocyclic alkyl C5 alkyl mercapto, -NH-methylhydroxy, -NH-ethylhydroxy, -NH-propylhydroxy, -NH-isopropylhydroxy, -NH-C4 alkylhydroxy, -NH-C5 alkylhydroxy, -N(R5)-methylhydroxy, -N(R5)-ethylhydroxy, -N(R5)-propylhydroxy, -N(R5)-isopropylhydroxy, -N(R5)-C4 alkylhydroxy, -N(R5)-C5 alkylhydroxy, -NH-C 3-4 Cycloalkylhydroxyl, -NH-C 5-6 Cycloalkylhydroxyl, -NH-C 7-8 Cycloalkylhydroxyl, -N(R5)-C 3-4 Cycloalkylhydroxyl, -N(R5)-C 5-6 Cycloalkylhydroxyl, -N(R5)-C 7-8 Cycloalkylhydroxyl, -NH-C 3-4 Heterocyclic alkyl C 1-5 Alkyl hydroxyl, -NH-C 5-6 Heterocyclic alkyl C 1-5 Alkyl hydroxyl, -NH-C 7-8 Heterocyclic alkyl C 1-5 Alkyl hydroxyl, -NH-C 3-8 Heterocyclic alkyl methyl hydroxyl, -NH-C 3-8 Heterocyclic alkyl ethyl hydroxyl, -NH-C 3-8 Heterocyclic alkylpropyl hydroxyl, -NH-C 3-8 Heterocyclic alkyl isopropyl hydroxyl, -NH-C 3-8 Heterocyclic alkyl C4 alkyl hydroxyl, -NH-C 3-8 Heterocyclic alkyl C5 alkyl hydroxyl, -N(R5)-C 3-4 Heterocyclic alkyl C 1-5 Alkyl hydroxyl, -N(R5)-C 5-6 Heterocyclic alkyl C 1-5 Alkyl hydroxyl, -N(R5)-C 7-8 Heterocyclic alkyl C 1-5 Alkyl hydroxyl, -N(R5)-C 3-8 Heterocyclic alkyl methyl hydroxyl, -N(R5)-C 3-8Heterocyclic alkyl ethyl hydroxy, -N(R5)-C 3-8 Heterocyclic alkylpropyl hydroxyl, -N(R5)-C 3-8 Heterocyclic alkyl isopropyl hydroxy, -N(R5)-C 3-8 Heterocyclic alkyl C4 alkyl hydroxyl, -N(R5)-C 3-8 Heterocyclic alkyl C5 alkyl hydroxyl, wherein the methyl, ethyl, propyl, isopropyl, alkyl, cycloalkyl, heterocyclic alkyl may be optionally replaced by 1-3 R5s.

[0025] In some embodiments, R5 is selected from fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, C4 alkyl, C5 alkyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, pentyynyl, methoxy, ethoxy, propoxy, C4 alkoxy, C5 alkoxy, methoxy, methoxymethyl, methoxyethyl, methoxypropyl, methoxyethoxymethyl, phenyl, naphthyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, wherein the methyl, ethyl, propyl, isopropyl, alkyl, alkyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, and cyclooctane may optionally be replaced by 1-3 fluorine, chlorine, bromine, or iodine molecules.

[0026] In some implementations, the two R5 atoms, together with the carbon atom they are attached to, form C. 3-8 Carbon ring.

[0027] In some implementations, the two R5 atoms, together with the carbon atom they are attached to, form C. 3-4 Carbon ring, C 5-6 Carbon ring, C 7-8 Carbon ring.

[0028] In some embodiments, R4 is selected from methyl hydroxy, ethyl hydroxy, propyl hydroxy, isopropyl hydroxy, cyclopropane hydroxy, C4 cycloalkyl hydroxy, C6 cycloalkyl hydroxy, methyl amino, methyl mercapto, ethyl mercapto, isopropyl mercapto, cyclopropyl mercapto, -NH-ethyl hydroxy, -N(R5)-ethyl hydroxy, C4 heterocyclic alkyl hydroxy, C4 heterocyclic alkyl methyl hydroxy, -NH-cyclobutane hydroxy, -N(R5)-cyclobutane hydroxy, wherein the methyl, ethyl, propyl, isopropyl, alkyl, cycloalkyl, and heterocyclic alkyl groups may be selectively replaced by 1-3 R5 groups;

[0029] In some embodiments, R5 is selected from cyclopropane, methyl, fluorine, 1-propynyl, 2-butynyl, methoxymethyl, methoxyethyl, phenyl, and cyclobutane, wherein the methyl, ethyl, cyclopropane, and cyclobutane may be optionally substituted with 1-3 fluorine or chlorine molecules.

[0030] In some implementations, R4 is selected from...

[0031] In some implementations, m1 is selected from 0, 1, 2, 3.

[0032] In some implementations, m1 is selected from 0, 1, 2.

[0033] In some implementations, m1 is selected from 0 and 1.

[0034] In some implementations, m2 is selected from 0, 1, 2, 3.

[0035] In some implementations, m2 is selected from 0, 1, and 2.

[0036] In some implementations, m2 is selected from 1 and 2.

[0037] In a second aspect of this application, the compound or its stereoisomer, tautomer, pharmaceutically acceptable salt, deuterated compound, or solvate according to the first aspect of this application is characterized in that the compound has a structure shown in formula II-1, II-2, II-3, or II-4.

[0038]

[0039] The meanings of R1, R2, R4, and m2 are as defined above.

[0040] In some embodiments, the compounds having the structures shown in Formula I, II-1, II-2, II-3, or II-4 are selected from:

[0041]

[0042]

[0043]

[0044] In a third aspect of this application, the compound or its stereoisomer, tautomer, pharmaceutically acceptable salt, deuterated compound, or solvate according to the first aspect of this application is characterized in that the compound has a structure shown in formula III-1, III-2, III-3, or III-4.

[0045]

[0046] The meanings of R4 and m2 are as defined above.

[0047] In some embodiments, the compounds having the structure shown in formula III-1, III-2, III-3, or III-4 are selected from:

[0048]

[0049]

[0050]

[0051] In a fourth aspect, this application provides a pharmaceutical composition comprising at least one of the aforementioned compounds, or a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a deuterated compound thereof, or a solvate thereof.

[0052] In some embodiments, the pharmaceutical composition comprises one or more pharmaceutically acceptable excipients or carriers.

[0053] In a fifth aspect, this application provides the use of at least one of the aforementioned compounds or at least one of the aforementioned pharmaceutical compositions in the preparation of a medicament for the prevention or treatment of a disease.

[0054] In some implementations, the disease is a tumor.

[0055] In a sixth aspect of this application, this application provides the use of at least one of the aforementioned compounds or at least one of the aforementioned pharmaceutical compositions in the preparation of a medicament for the prevention or treatment of diseases related to tumor cell proliferation.

[0056] In a seventh aspect of this application, this application provides at least one of the aforementioned compounds or at least one of the aforementioned pharmaceutical compositions for the treatment or prevention of disease.

[0057] In some implementations, the disease is a tumor.

[0058] In an eighth aspect, this application provides a method for treating or preventing a disease, comprising administering to a subject in need a therapeutically effective amount of at least one of the aforementioned compounds, or a stereoisomer thereof, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, or a solvate thereof, or at least one of the aforementioned pharmaceutical compositions.

[0059] In some implementations, the disease is a tumor.

[0060] In a ninth aspect of this application, this application provides a method for inhibiting the proliferation of cancer cells, comprising contacting the cells with an effective amount of at least one of the aforementioned compounds, or a stereoisomer thereof, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, or a solvate thereof, or at least one of the aforementioned pharmaceutical compositions.

[0061] In a tenth aspect, this application provides a method for preparing a compound of Formula I or its stereoisomers, tautomers, pharmaceutically acceptable salts, deuterated compounds, or solvates thereof, comprising the following steps:

[0062] Compound Ia reacts with compound Ib to give compound Ic. Compound Ic is treated under hydroxyl protection conditions to give compound Id. Compound Id is treated under thiolation conditions to give compound Ie. Compound Ie is treated under protecting group removal conditions to give compound I.

[0063]

[0064] The meanings of R1, R2, R3, R4, X, m1, and m2 are as defined above, and PG1 and PG2 are protecting groups.

[0065] In some embodiments, the protecting groups PG1 and PG2 are each independently selected from trimethylsilyl (TMS-), triethylsilyl (TES-), triisopropylsilyl (TIPS-), tert-butyldimethylsilyl (TBDMS-), tert-butyldiphenylsilyl (TBDPS-), benzyl (Bn-), p-methoxybenzyl (PMB-), 2,4-dimethoxybenzyl (DMB-), 2-tetrahydropyranyl (THP-), methoxymethyl (MOM-), 2-(trimethylsilyl)ethoxymethyl (SEM-), allyl (Allyl-), and acetyl (Ac-).

[0066] In some embodiments, the protecting groups PG1 and PG2 are each independently selected from trimethylsilyl (TMS-), triethylsilyl (TES-), triisopropylsilyl (TIPS-), tert-butyldimethylsilyl (TBDMS-), tert-butyldiphenylsilyl (TBDPS-), benzyl (Bn-), p-methoxybenzyl (PMB-), and 2,4-dimethoxybenzyl (DMB-).

[0067] In some embodiments, the protecting groups PG1 and PG2 are each independently selected from triisopropylsilyl (TIPS-), tert-butyldimethylsilyl (TBDMS-), tert-butyldiphenylsilyl (TBDPS-), benzyl (Bn-), and p-methoxybenzyl (PMB-).

[0068] In some embodiments, the protecting groups PG1 and PG2 are each independently selected from tert-butyldimethylsilyl (TBDMS-) and tert-butyldiphenylsilyl (TBDPS-).

[0069] In some embodiments, the compound represented by Formula I is selected from:

[0070]

[0071] Attached Figure Description

[0072] Figure 1 The results of compound 1 inhibiting the proliferation of HT29 cells Detailed Implementation

[0073] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention.

[0074] definition

[0075] Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings. When a trademark name is used herein, unless the context otherwise indicates, the trademark name includes the product formulation, generic medicine, and active ingredient of the product for which the trademark name is used.

[0076] In this article, the term "alkoxy" includes -O- (alkyl), which consists of an alkyl group and an oxygen atom. Examples include methoxy (CH3O-), ethoxy (C2H5O-), and propoxy (C3H7O-).

[0077] The term "cycloalkyloxy" includes -O- (cycloalkyl), consisting of a cycloalkyl group and an oxygen atom. For example, cyclopropyloxy. Cyclobutoxy

[0078] The term "alkyl mercapto" refers to -alkyl-SH. Examples include methyl mercapto (-CH2 SH), ethyl mercapto (-CH2CH2SH, -CH(SH)CH3), propyl mercapto (-CH2CH2CH2SH, -CH2CH(SH)CH3, -CH(SH)CH2CH3), and isopropyl mercapto. C4 alkyl mercapto (-CH2CH2CH2CH2SH, ).

[0079] The term "cycloalkyl mercapto" refers to -cycloalkyl-SH, where at least one hydrogen atom of the cycloalkyl group is replaced by an SH group. For example, cyclopropane mercapto. Cyclobutane mercapto

[0080] The term "alkylhydroxyl" refers to -alkyl-OH. Examples include methyl hydroxyl (-CH2OH), ethyl hydroxyl (-CH2CH2OH, -CH(OH)CH3), propyl hydroxyl (-CH2CH2CH2OH, -CH(OH)CH2CH3, -CH2CH(OH)CH3), and isopropyl hydroxyl. C4 alkyl hydroxyl group (-CH2CH2CH2CH2OH, ).

[0081] The term "cycloalkylhydroxyl" refers to -cycloalkyl-OH, where at least one hydrogen atom of the cycloalkyl group is replaced by an OH group. For example, cyclopropane hydroxyl. Cyclobutane hydroxyl

[0082] The term "alkylamino" refers to -alkyl-NH2. Examples include methylamino (-CH2NH2), ethylamino (-CH2CH2NH2, -CH(NH2)CH3), propylamino (-CH2CH2CH2NH2, -CH2CH(NH2)CH3, -CH(NH2)CH2CH3), and isopropylamino.

[0083] The term "cycloalkylamino" refers to -cycloalkyl-NH2, wherein at least one hydrogen atom of the cycloalkyl group is replaced by an amino group. For example, cyclopropaneamino. ), cyclobutane amino

[0084] The term "oxyalkyl group" refers to a group in which an alkyl skeleton is replaced by one or more alkoxy groups, such as methoxymethyl (CH2OCH2-), methoxyethyl (CH2OCH2CH2-), methoxyethoxymethyl (CH2OCH2CH2OCH2-), etc.

[0085] The term "aryl" refers to a monocyclic, bicyclic, or tricyclic aromatic hydrocarbon group having 6 to 14 carbon atoms in its ring moiety. When the "aryl" is bicyclic or tricyclic, each ring is an aromatic ring. The two rings of a bicyclic or tricyclic aryl group can be linked in various ways, including bridging, fusion, and helicaling. Examples include phenyl and naphthyl groups, each of which can be substituted.

[0086] The terms “heterocyclic,” “heterocyclic,” or “heterocyclic group” are used interchangeably and refer to substituted and unsubstituted 5-8 member monocyclic or bicyclic groups, wherein at least one ring has at least one heteroatom (O, S, or N), and the heteroatom-containing ring preferably has one, two, or three heteroatoms selected from O, S, and N.

[0087] The terms "PG1" or "PG2" refer to protecting groups. Examples include: trimethylsilyl (TMS-), triethylsilyl (TES-), triisopropylsilyl (TIPS-), tert-butyldimethylsilyl (TBDMS-), tert-butyldiphenylsilyl (TBDPS-), benzyl (Bn-), p-methoxybenzyl (PMB-), 2,4-dimethoxybenzyl (DMB-), 2-tetrahydropyranyl (THP-), methoxymethyl (MOM-), 2-(trimethylsilyl)ethoxymethyl (SEM-), allyl (Allyl-), and acetyl (Ac-).

[0088] The term "pharmaceutically acceptable salt" refers to the salts of the compounds of this invention, which are safe and effective when used in mammals and possess the desired biological activity. For example, the acidic group in the compounds of this invention forms a salt with a base; non-limiting examples include sodium, potassium, calcium, or magnesium salts. Alternatively, the basic group in the compounds of this invention can form a salt with an acid; non-limiting examples include hydrochloride, hydrobromide, hydroiodide, sulfate, hydrogen sulfate, citrate, acetate, succinate, ascorbate, oxalate, nitrate, phosphate, hydrogen phosphate, dihydrogen phosphate, salicylate, hydrogen citrate, tartrate, maleate, fumarate, formate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, and p-toluenesulfonate.

[0089] The term "solvent" refers to a pharmaceutically usable solvate formed by the compounds of the present invention with one or more solvent molecules, non-limiting examples of which include water, ethanol, acetonitrile, isopropanol, DMSO, and ethyl acetate.

[0090] The term "stereoisomer" refers to compounds with the same molecular formula in which atoms or substituents are connected in the same order but arranged in different spaces. It is a phenomenon of isomerism in organic chemistry.

[0091] The term "tautomer" refers to two isomers containing heteroatoms (such as nitrogen, oxygen, or sulfur atoms) whose structural differences lie only in the migration of protons and corresponding double bonds. These two isomers coexist in an equilibrium system and transform into each other at a fairly high rate. A typical example is keto-enol tautomerism.

[0092] The term "deuterated compound" refers to the structure formed when one or more hydrogen atoms in the compound of the present invention are replaced by deuterium atoms.

[0093] In this invention, "substituted" or "replaced by" means that any one or more hydrogen atoms on a specified atom or group are selectively substituted by a specified group, provided that the substitution does not exceed the normal valence state of the specified atom. Furthermore, if a specified atom or group is substituted by multiple specified groups, the multiple specified groups may be the same or different.

[0094] In this invention, "optionally" means that it can be selected or not.

[0095] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0096] The term "excipient" refers to any additive in a pharmaceutical preparation other than the active pharmaceutical ingredient. Excipients include, but are not limited to: ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffering substances such as phosphates, glycerol, sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, beeswax, lanolin, etc.

[0097] The term "carrier" refers to a system that can alter the way drugs enter the body and their distribution within the body, control the rate of drug release, and deliver drugs to target organs. Drug carrier release and targeting systems can reduce drug degradation and loss, decrease side effects, and improve bioavailability. For example, high-molecular-weight surfactants, due to their unique amphiphilic structure, can self-assemble to form various forms of aggregates, preferably such as micelles, microemulsions, gels, liquid crystals, and vesicles. These aggregates have the ability to encapsulate drug molecules while also exhibiting good membrane permeability, making them excellent drug carriers.

[0098] The term "treatment" generally refers to achieving a desired pharmacological and / or physiological effect. This effect can be preventative, based on the complete or partial prevention of the disease or its symptoms; and / or therapeutic, based on the partial or complete stabilization or cure of the disease and / or side effects resulting from the disease. As used herein, "treatment" encompasses any treatment of a patient's disease, including: (a) prevention of disease or symptoms occurring in a patient who is susceptible to the disease or its symptoms but has not yet been diagnosed with the disease; (b) suppression of the symptoms of the disease, i.e., prevention of its progression; or (c) relief of the symptoms of the disease, i.e., causing the disease or its symptoms to regress.

[0099] The term "subject" includes humans or non-human animals. Exemplary human subjects include people with a disease (such as the disease described herein) (referred to as patients) or normal individuals. The term "non-human animal" in this invention includes all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock, and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0100] The term "effective amount" refers to the amount that effectively achieves the desired therapeutic or preventative effect at the necessary dose and time. The "therapeutic effective amount" of the compounds of this invention may vary depending on factors such as an individual's disease state, age, sex, weight, and the compound's ability to elicit the desired response in the individual. Therapeutic effective amount also encompasses the amount in which the beneficial therapeutic effect of the compound outweighs any toxic or harmful consequences. "Preventative effective amount" refers to the amount that effectively achieves the desired preventative effect at the necessary dose and time. Typically, but not necessarily, the preventative effective amount will be lower than the therapeutic effective amount because the preventative dose is administered to the subject before or in the early stages of the disease. In the case of cancer, the therapeutically effective amount of the drug may reduce the number of cancer cells; shrink tumor volume; inhibit (i.e., slow down, preferably stop) the infiltration of cancer cells into surrounding organs; inhibit (i.e., slow down, preferably stop) tumor metastasis; inhibit tumor growth to some extent; and / or alleviate one or more symptoms associated with cancer to some extent.

[0101] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Test methods in the following embodiments that do not specify specific conditions are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise stated, all percentages, proportions, ratios, or parts are by weight.

[0102] Example 1: Preparation of Compound 1

[0103]

[0104] Step 1:

[0105] To a solution of compound 1a (1000 mg, 13.14 mmol) in N,N-dimethylformamide (20 mL), N,N-diisopropylethylamine (5942 mg, 45.99 mmol) was added. The reaction mixture was cooled to 0 °C, followed by the addition of tert-butyldiphenylchlorosilane (7947 mg, 28.91 mmol). The reaction mixture was stirred overnight at room temperature. After the reaction was complete, water (30 mL) was added to quench the reaction mixture, followed by extraction with ethyl acetate (50 mL x 3), washing with saturated brine, drying over anhydrous sodium sulfate, filtration, concentration of the filtrate, and purification by column chromatography (petroleum ether:ethyl acetate = 20:1) to obtain 1b (3415 mg).

[0106] Step 2:

[0107] A heptane solution of boron trichloride (51.96 mL, 51.96 mmol, 1 mol / L) was added to a three-necked flask, and nitrogen gas was purged three times. The reaction solution was cooled to 0°C, and then a 1,2-dichloroethane solution of compound 1c (5000 mg, 39.97 mmol) (5 mL) was slowly added dropwise. After the addition was complete, the reaction solution was cooled to room temperature and reacted for 0.5 hours. Subsequently, the reaction solution was cooled to 0°C, and chloroacetonitrile (5129.9 mg, 67.95 mmol), aluminum trichloride (10613.1 mg, 43.96 mmol), and 1,2-dichloroethane (50 mL) were added sequentially. After the addition was complete, the reaction solution was heated to 95°C and the reaction was continued at this temperature for 48 hours. After the reaction was complete, the reaction solution was cooled to 0°C, and 10 mL of 2 mol / L dilute hydrochloric acid solution was added. The reaction solution was heated to 95°C and the reaction was continued for 0.5 hours. Subsequently, the reaction solution was cooled to room temperature, and water (50 mL) was added to quench the reaction. The solution was extracted with dichloromethane (50 mL * 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain 1 d (3780 mg), ESI-MS (m / z): 202.1 [M + H]. + .

[0108] Step 3:

[0109] To a toluene (30 mL) solution of compound 1d (1200 mg, 5.95 mmol) and compound 1e (1492.1 mg, 5.67 mmol), pyridinium p-toluenesulfonate (427.4 mg, 1.70 mmol) was added, followed by purging with nitrogen three times. The reaction mixture was then heated to 100 °C and reacted at this temperature for 72 hours. After the reaction was complete, the reaction mixture was concentrated and purified by column chromatography (dichloromethane:methanol = 20:1) to give 1f (2.05 g), ESI-MS (m / z): 429.1 [M+H]. + .

[0110] Step 4:

[0111] Hexamethylenetetramine (1.0 g, 7.46 mmol) was added to a solution of compound 1f (1.6 g, 3.73 mmol) in N,N-dimethylformamide (20 mL) and ethanol (20 mL), and nitrogen was purged three times. The reaction mixture was then incubated overnight at 90 °C. After the reaction was complete, the solution was cooled to room temperature, and 2 mol / L hydrochloric acid (1 mL) was added. The reaction was continued at room temperature for 0.5 hours. The solution was then concentrated and purified by reversed-phase column chromatography (methanol: 0.1% formic acid aqueous solution = 0–50%) to give 1 g (400 mg). ESI-MS (m / z): 410.0 [M+H] + .

[0112] Step 5:

[0113] To a solution of compound 1 g (400 mg, 0.98 mmol) and compound 1b (737.5 mg, 1.17 mmol) in N,N-dimethylformamide (5 mL), N,N-diisopropylethylamine (378.7 mg, 2.93 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate (482.9 mg, 1.27 mmol) were added, and the reaction mixture was allowed to react overnight at room temperature. After the reaction was complete, the reaction mixture was quenched with water (20 mL), extracted with dichloromethane (30 mL * 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (dichloromethane:ethyl acetate = 1:1) to give 1 h (325 mg), ESI-MS (m / z): 706.3 [M + H). + .

[0114] Step 6:

[0115] A 10 mL solution of pyridine containing 1 h (325 mg, 0.46 mmol) was purged with nitrogen three times. Tert-butyldimethylsilyltrifluoromethanesulfonate (1.06 mL, 4.60 mmol) was then added, and the reaction mixture was incubated overnight at 80 °C. After the reaction was complete, the reaction mixture was concentrated, diluted with 20 mL of water, extracted with ethyl acetate (50 mL x 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography (dichloromethane:ethyl acetate = 5:1) to give 1 i (241 mg).

[0116] Step 7:

[0117] A 4 mL solution of compound 1i (100 mg, 0.12 mmol) in toluene was purged with nitrogen three times. Lawson's reagent (49.3 mg, 0.12 mmol) was then added, and the reaction mixture was incubated at 100 °C for 4 hours. After the reaction was complete, the reaction solution was concentrated and purified by column chromatography (dichloromethane:ethyl acetate = 5:1) to give 1j (60 mg), ESI-MS (m / z): 836.1 [M+H]. + .

[0118] Step 8:

[0119] To a solution of compound 1j (50 mg, 0.06 mmol) in dichloromethane (2 mL), 2 mL of trifluoroacetic acid was added, and the reaction mixture was allowed to react at room temperature for 24 hours. After the reaction was complete, the reaction mixture was concentrated and purified by reversed-phase column chromatography (acetonitrile: 0.05% ammonium bicarbonate aqueous solution = 0–35%) to give compound 1 (11 mg), ESI-MS (m / z): 484.2 [M+H). + . 1H NMR (400MHz, DMSO-d6) δ10.54(s,1H),8.42(d,J=8.2Hz,1H),7.91(d,J=10.8Hz,1H),7.32(s,1H),6.52(s,1H),6. 07(t,J=5.5Hz,1H),5.50-5.36(m,6H),4.29(d,J=5.3Hz,2H),2.51(s,3H),1.95-1.78(m,2H),0.96-0.79(m,3H).

[0120] Example 2: Preparation of Compound 2

[0121]

[0122] Step 1:

[0123] Imidazole (576.6 mg, 8.47 mmol) was added to an N,N-dimethylformamide (8 mL) solution of compound 2a (1 g, 8.47 mmol), and the mixture was stirred at room temperature for 10 minutes. Then, tert-butyldiphenylchlorosilane (2.3 g, 8.47 mmol) was added dropwise under ice bath conditions. After the addition was complete, the reaction mixture was stirred overnight at room temperature. After the reaction was complete, 20 mL of water was added to quench the reaction, followed by extraction with ethyl acetate (50 mL * 2), washing with saturated brine, drying over anhydrous sodium sulfate, filtering, and concentrating the filtrate to obtain crude product 2b (2 g), which was used directly in the next reaction step.

[0124] Step 2:

[0125] Lithium hydroxide (235.6 mg, 5.61 mmol) was added fractionally to a mixed solution of compound 2b (2 g, 5.61 mmol) in methanol (10 mL) and tetrahydrofuran (10 mL). After the addition was complete, the reaction solution was stirred at room temperature for 2 hours. After the reaction was complete, the pH was adjusted to approximately 6 with 1 mol / L hydrochloric acid solution. The reaction solution was concentrated and purified by reversed-phase column chromatography (acetonitrile: 0.1% formic acid aqueous solution = 0:100%-35%:65%) to give 2c (1 g), ESI-MS (m / z): 327.3 [MH]. - .

[0126] Step 3:

[0127] To a solution of 1 g (200 mg, 0.49 mmol) of compound 2c in 5 mL of N,N-dimethylformamide, add compound 2c (214.0 mg, 0.49 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate (278.6 mg, 0.73 mmol), and N,N-diisopropylethylamine (0.26 mL, 1.47 mmol). The reaction mixture was stirred overnight at room temperature. After the reaction was complete, 10 mL of water was added to quench the reaction, followed by extraction with dichloromethane (20 mL * 3), washing with saturated brine, drying over anhydrous sodium sulfate, filtration, concentration of the filtrate, and purification by column chromatography (dichloromethane:ethyl acetate = 1:1) to give compound 2d (320 mg), ESI-MS (m / z): 720.2 [M + H]. + .

[0128] Step 4:

[0129] To a pyridine (6 mL) solution of compound 2d (350 mg, 0.49 mmol), tert-butyldimethoxytrifluoromethanesulfonate (1.12 mL, 4.86 mmol) was added, and the reaction mixture was stirred overnight at 80 °C. After the reaction was complete, the reaction mixture was concentrated, diluted with 20 mL of water, extracted with ethyl acetate (30 mL * 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography (dichloromethane:methanol = 10:1) to give 2e (126 mg), ESI-MS (m / z): 834.1 [M + H]. + .

[0130] Step 5:

[0131] Lawson's reagent (48.5 mg, 0.12 mmol) was added to a toluene (3 mL) solution of compound 2e (100 mg, 0.12 mmol), and the reaction mixture was stirred at 100 °C for 3 hours. After the reaction was complete, the reaction solution was concentrated and purified by column chromatography (dichloromethane:ethyl acetate = 4:1) to give 2f (56 mg), ESI-MS (m / z): 850.9 [M+H). + .

[0132] Step 6:

[0133] To a solution of compound 2f (46 mg, 0.05 mmol) in dichloromethane (2 mL), 2 mL of trifluoroacetic acid was added. The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the solution was concentrated and purified by reversed-phase column chromatography (acetonitrile: 0.05% ammonium bicarbonate aqueous solution = 0:100%-30%:70%) to give compound 2 (9 mg), ESI-MS (m / z): 498.3 [M+H). + . 1H NMR (400MHz, DMSO-d6) δ10.57(s,1H),8.31(d,J=8.1Hz,1H),7.92(d,J=10.8Hz,1H),7.32(s,1H),6.51(s,1H),5.47-5.29(m ,6H),4.71(t,J=4.9Hz,1H),3.81-3.69(m,2H),2.78(t,J=6.5Hz,2H),2.51(s,3H),1.95-1.77(m,2H),0.87(t,J=7.3Hz,3H).

[0134] Example 3: Preparation of Compound 3

[0135]

[0136] Step 1:

[0137] To a solution of compound 3a (2 g, 16.18 mmol) in dichloromethane (20 mL), tert-butyldimethylchlorosilane (2.6 g, 16.99 mmol) and triethylamine (6.73 mL, 48.54 mmol) were added. The reaction mixture was stirred overnight at room temperature. After the reaction was complete, 20 mL of water was added to quench the reaction, followed by extraction with dichloromethane (50 mL * 3), washing with saturated brine, drying over anhydrous sodium sulfate, filtering, and concentrating the filtrate to obtain 3b (3 g). ESI-MS (m / z): 202.3 [M + H] + .

[0138] Step 2:

[0139] To a solution of 1 g (50 mg, 0.12 mmol) of compound 3b in N,N-dimethylformamide (2 mL), N,N'-thiocarbonyldiimidazole (22.9 mg, 0.13 mmol) was added, and the reaction mixture was stirred at room temperature for 30 minutes. Then, a solution of compound 3b (49.2 mg, 0.24 mmol) in N,N-dimethylformamide (1 mL) was added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was then cooled to 0 °C and trifluoroacetic acid (0.5 mL, 6.54 mmol) was added. The reaction mixture was then cooled to room temperature and stirred for another 1 hour. After the reaction was complete, the reaction mixture was purified by reversed-phase column chromatography (acetonitrile: 0.05% ammonium bicarbonate aqueous solution = 0:100%-35%:65%) to give compound 3 (15 mg), ESI-MS (m / z): 539.2 [M+H]. + . 1H NMR (400MHz, DMSO-d6) δ8.43(d,J=8.1Hz,1H),8.14(t,J=5.6Hz,1H),7.90(d,J=10 .8Hz,1H),7.32(s,1H),6.50(s,1H),5.43(s,2H),5.37(s,2H),5.28(d,J=5.4Hz,2 H),4.81(t,J=5.3Hz,1H),4.05(t,J=8.8Hz,2H),3.85-3.73(m,2H),3.56(t,J=5.8 Hz,2H),2.73-2.61(m,1H),2.51(s,3H),1.95-1.79(m,2H),0.87(t,J=7.3Hz,3H).

[0140] Example 4: Preparation of Compound 4

[0141]

[0142] Step 1:

[0143] To a solution of 1 g (100 mg, 0.24 mmol) of compound N,N-dimethylformamide (2 mL), N,N'-thiocarbonyldiimidazole (45.7 mg, 0.26 mmol) was added, and the reaction mixture was stirred at room temperature for 30 minutes. Then, a solution of 2-(tert-butyldimethylsiloxy)ethylamine (85.6 mg, 0.49 mmol) in N,N-dimethylformamide (1 mL) was added, and the reaction mixture was stirred at room temperature for 1 hour. The mixture was then cooled to 0 °C, and trifluoroacetic acid (0.5 mL, 6.54 mmol) was added. The reaction mixture was then stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was purified by reversed-phase column chromatography (acetonitrile: 0.05% ammonium bicarbonate aqueous solution = 0:100%-35%:65%) to give compound 4 (50 mg), ESI-MS (m / z): 513.0 [M+H]. + . 1 H NMR (400MHz, DMSO-d6) δ8.34(d,J=8.2Hz,1H),8.18(s,1H),7.94-7.82(m,2H),7.32(s,1H),6.50(s,1H),5.42(s,2H),5. 37(s,2H),5.33(d,J=4.9Hz,2H),4.80(s,1H),3.62-3.41(m,4H),2.51(s,3H),1.93-1.77(m,2H),0.87(t,J=7.3Hz,3H).

[0144] Example 5: Preparation of Control Compound 1

[0145]

[0146] Control compound 1 was prepared according to the method described in patent WO2020219287A1.

[0147] Example 6: Evaluation of cell proliferation inhibition activity

[0148] 6.1 Evaluation of HT-29 cell proliferation inhibitory activity

[0149] Cell plating: Collect HT29 cells (gifted by Chengdu Microchip Biotechnology Co., Ltd.), take 20uL for counting, and resuspend HT29 cells to 8E4 / mL; add 50uL / well (4000 cells / well) to a 96-well plate according to the arrangement, and incubate overnight at 37℃ with 5% CO2.

[0150] Drug addition treatment: Compound 1 was serially diluted 5-fold to 2x working concentrations (100000nM, 20000nM, 4000nM, 800nM, 160nM, 32nM, 6.4nM, 1.28nM, 0.256nM, 0.0512nM, 0.00041nM, 0.00008nM, 0.0000164nM, 0.0000033nM, 0.0000007nM, 0.0000001nM, 0.00000003nM, 0nM); each concentration of drug dilution was added at 50 μL / well (2 replicates) to a 96-well cell culture plate that had been cultured overnight, and cultured at 37°C and 5% CO2 for 72 h.

[0151] Assay: Remove the 96-well cell culture plate, add 10 μL of CCK-8 solution to each well, and incubate at 37°C with 5% CO2 for 4 h. Measure the absorbance at 450 nm and calculate the IC50 value for cell proliferation inhibition. 50 The results are shown in Table 1 and... Figure 1 .

[0152] Table 1 Evaluation of HT-29 cell proliferation inhibition activity

[0153] 1 0.053

[0154] The results show that the IC50 of compound 1 is... 50 The value was 0.053 nM, indicating that compound 1 had a significant inhibitory effect on the proliferation of HT-29 cells.

[0155] 6.2 Evaluation of the inhibitory activities of SK-OV-3, SK-HEP-1, HepG2, LS1034 and RKO cells on cell proliferation

[0156] Following the method described in section 6.1, cell plating, drug treatment, and detection were performed. The results are shown in Table 2.

[0157] Table 2 Evaluation of the cell proliferation inhibitory activities of SK-OV-3, SK-HEP-1, HepG2, LS1034 and RKO cells

[0158] Compound 1 4.79 31.5 24.44 3.64 3.39 Compound 2 4.70 39 36.9 4.79 4.17 Reference compound 1 27.26 184 295.1 26.11 19.36

[0159] The results show that the IC values ​​of compounds 1 and 2 of the present invention are [missing information]. 50 The values ​​were much lower than those of the control compound 1, indicating that compounds 1 and 2 all had good inhibitory activity against the proliferation of SK-OV-3, SK-HEP-1, HepG2, LS1034 and RKO cells, and their inhibitory activity was significantly better than that of the control compound 1.

[0160] Experimental results show that the compounds of this application (such as compound 1 and compound 2) have significant inhibitory effects on tumor cells (such as HT-29, SK-OV-3, SK-HEP-1, HepG2, LS1034, and RKO cells), and their proliferation inhibitory activity is significantly better than that of control compound 1.

[0161] This invention has been illustrated through various specific embodiments. However, those skilled in the art will understand that this invention is not limited to the specific embodiments, and various modifications or variations can be made within the scope of this invention. Furthermore, the various technical features mentioned throughout this specification can be combined with each other without departing from the spirit and scope of this invention. Such modifications and variations are all within the scope of this invention.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof, （I）， in: R1 is methyl; R2 is fluorine; R3 is ethyl; R4 is selected from , , ; X is O; m1 is 0; m2 is 1.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, The compound is selected from: 。 3. A pharmaceutical composition comprising the compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients or carriers.

4. Use of the compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 3, in the preparation of a medicament for the prevention or treatment of a disease, said disease being human colorectal adenocarcinoma, human ovarian adenocarcinoma, human hepatic adenocarcinoma, or human liver cancer.

5. A method for inhibiting cancer cell proliferation in vitro, comprising contacting the cells with an effective amount of at least one compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, or at least one pharmaceutical composition of claim 3, wherein the cancer cells are human colorectal adenocarcinoma cells, human ovarian adenocarcinoma cells, human hepatic adenocarcinoma cells, or human hepatocellular carcinoma cells.

6. A method for preparing a compound of Formula I or a pharmaceutically acceptable salt thereof, comprising the following steps: Compound Ia reacts with compound Ib to give compound Ic. Compound Ic is treated under hydroxyl protection conditions to give compound Id. Compound Id is treated under thiolation conditions to give compound Ie. Compound Ie is treated under protecting group removal conditions to give compound I. in, The meanings of R1, R2, R3, R4, X, m1, and m2 are as defined in claim 1, PG1 and PG2 are protecting groups, and each of PG1 and PG2 is independently tert-butyldiphenylsilyl.

7. The method according to claim 6, characterized in that, The compounds represented by Formula I are selected from: 。

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