A benzene ring-containing tripeptide compound, a preparation method, a composition and an application thereof

Abstract

The application belongs to the field of pharmaceutical chemistry, and discloses a benzene ring-containing tripeptide compound, a preparation method, a composition and application thereof, the tripeptide compound is a compound of formula I or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, a co-crystal, a solvate, a metabolite, a prodrug or any mixture of two or more thereof, and a preparation method, a pharmaceutical composition and a pharmaceutical preparation of the tripeptide compound, and an application of the compound as a preventive or therapeutic drug for triple-negative breast cancer.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry, specifically relating to a benzene-containing tripeptide compound, its preparation method, composition, and application. Background Technology

[0002] Breast cancer is one of the most common malignant tumors among women worldwide, with triple-negative breast cancer (TNBC) accounting for approximately 15% to 20% of all breast cancers. Because it is negative for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), TNBC is insensitive to endocrine therapy and anti-HER2 targeted therapy. It is characterized by its high invasiveness, tendency to metastasize, high recurrence rate, and extremely poor prognosis, making it the most challenging subtype of breast cancer to treat.

[0003] Currently, chemotherapy remains the primary treatment for triple-negative breast cancer (TNBC), including anthracyclines, taxanes, and platinum-based drugs. However, these treatments generally suffer from low response rates, significant side effects, easy development of drug resistance, and limited long-term survival benefits. In recent years, immune checkpoint inhibitors, PARP inhibitors, and ADCs have made some progress in TNBC treatment, but they still have limitations such as a limited patient population benefiting from their drugs, frequent drug resistance, and poor safety and tolerability. Clinically, there is still an urgent need for novel small molecule drugs with novel structures, clear mechanisms, and definite efficacy.

[0004] In basic and preclinical drug development for triple-negative breast cancer (TNBC), the MDA MB 231 cell line is one of the most widely used and representative cell models. Derived from human TNBC tissue, this cell line exhibits typical TNBC molecular phenotypes and biological characteristics, including high proliferation, high invasion, high migration, and a high susceptibility to epithelial-mesenchymal transition (EMT). It also demonstrates inherent resistance to many conventional chemotherapeutic drugs, effectively mimicking the malignant biological behavior and clinical drug resistance characteristics of human TNBC. Therefore, it is widely used for in vitro efficacy evaluation of small molecule compounds, target validation, signaling pathway research, and exploration of anti-tumor mechanisms. Consequently, small molecule compounds that can potently inhibit the proliferation of MDA MB 231 cells and block their malignant progression have significant theoretical and clinical translational value for developing next-generation TNBC therapeutics.

[0005] However, existing drugs often have limited inhibitory effects on MDA MB 231 cells, failing to achieve significant and sustained proliferation inhibition at low concentrations, and are frequently accompanied by poor selectivity and high toxicity. Therefore, developing novel small molecules with highly efficient and specific proliferative inhibitory activity against MDA MB 231 cells holds promise for providing a more effective and safer treatment strategy for triple-negative breast cancer, meeting current unmet clinical needs. Summary of the Invention

[0006] The purpose of this invention is to provide a benzene-containing tripeptide compound, its preparation method, composition, and application.

[0007] To achieve the objectives of this invention, the following implementation scheme is provided: In one embodiment, the present invention provides a benzene-containing tripeptide compound or its stereoisomers, tautomers, pharmaceutically acceptable salts, polymorphs, cocrystals, solvates, metabolites, prodrugs, or any mixture of two or more thereof, wherein the tripeptide compound is a compound of Formula I:

[0008] In the formula, R1 is selected from hydrogen, deuterium, halogen, cyano, C1-C6 alkyl, C3-C7 cycloalkyl, 3-7 membered heterocyclic, C2-C6 alkenyl, C2-C6 ynyl, C6-C 14 aryl and 5-14 membered heteroaryl, wherein the C1-C6 alkyl, C3-C7 cycloalkyl, 3-7 membered heterocyclic, C2-C6 alkenyl, C2-C6 alkynyl, C6-C 14 The aryl and 5-14 heteroaryl groups are each optionally bounded by one or more R groups. f replace; R2 and R3 are each independently selected from hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 14 Aryl, 3-8 membered heterocyclic and 5-14 membered heteroaryl, -C(O)R a SO2R b The C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 14 Aryl, 3-8 membered heterocyclic and 5-14 membered heteroaryl are each optionally bound by one or more R f replace; Alternatively, R1 and R2 together with the nitrogen and carbon atoms they are attached to form a 4-7 membered heterocyclic group, which is optionally surrounded by one or more R atoms. f replace; Alternatively, R2 and R3 together with the nitrogen atom they are attached to form a 4-7 membered heterocyclic group, which is optionally surrounded by one or more R atoms. f replace; R a and R b Each is independently selected from C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 14 Aryl and 5-14 membered heteroaryl, the C6-C 14The aryl group and the 5-14 membered heteroaryl group are each optionally fused with a C3-C7 cycloalkyl group or a 5-10 membered heterocyclic group, wherein the C1-C6 alkyl group, C3-C7 cycloalkyl group, C6-C7 cycloalkyl group, and C1-C7 cycloalkyl group are respectively fused with a C3-C7 cycloalkyl group or a C1-C7 cycloalkyl group. 14 Aryl, 5-14 membered heteroaryl and 5-10 membered heterocyclic are each optionally bounded by one or more R f replace; R f Independently selected from hydrogen, deuterium, hydroxyl, halogen, oxo, CN, NO2, SiR c R d R e C(O)R g CO2R g NR h SO2R j S(O)R j SO2R j C(O) NR h R i SO2NR h R i NR h R i NR h C(O)R g C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C3-C7 cycloalkyl, C1-C6 alkoxy, C1-C6 alkoxy, C6-C 14 aryl, 5-14 membered heteroaryl and 3-8 membered heterocyclic groups, wherein the C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C3-C7 cycloalkyl, C1-C6 alkoxy, C6-C 14 Aryl, 5-14 membered heteroaryl and 3-8 membered heterocyclic group are each optionally bounded by one or more R L replace; R g Independently selected from hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 14 Aryl and 5-14 heteroaryl groups; R j Independently selected from C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 14 Aryl and 5-14 heteroaryl groups; R h and R i Each is independently selected from hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, and 4-7 membered heterocyclic groups, or, R h and R i Together with the nitrogen atom it is attached to, it forms a 4-7 membered heterocyclic group; R L Independently selected from hydrogen, deuterium, halogen, hydroxyl, CN, C(O)Rm NR n R o C(O)NR n R o NR n C(O)R m SiR c R d R e C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C3-C7 cycloalkyl, C1-C6 alkoxy, C6-C 14 Aryl, 5-14 membered heteroaryl and 3-8 membered heterocyclic; R c R d R e Each is independently selected from C1-C6 alkyl or phenyl groups; R m Independently selected from hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 14 Aryl and 5-14 membered heteroaryl; R n and R o Each is independently selected from hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 14 aryl and 5-14 heteroaryl, or, R n and R o Together with the nitrogen atom it is attached to, it forms a 4-7 membered heterocyclic group.

[0009] In some embodiments, the tripeptide compound or its stereoisomers, tautomers, pharmaceutically acceptable salts, polymorphs, cocrystals, solvates, metabolites, prodrugs, or any mixture of two or more thereof, compounds of Formula I, R1 is selected from hydrogen, C1-C6 alkyl, C6-C 14 Aryl, 3-7 membered heterocyclic groups, wherein the C1-C6 alkyl, C6-C 14 Aryl and 3-7 membered heterocyclic groups are each optionally surrounded by one or more R f replace; R2 and R3 are each independently selected from hydrogen and C1-C6 alkyl groups, wherein the C1-C6 alkyl group is affected by one or more R... f replace; Or R 1 and R 2 Together with the nitrogen and carbon atoms to which it is attached, it forms a 4-7 membered heterocyclic group, which is then bonded by one or more R atoms. f replace; Or R 2 and R 3Together with the nitrogen atom to which it is attached, it forms a 4-7 membered heterocyclic group, which is then bonded by one or more R atoms. f replace; R f Independently selected from hydrogen, deuterium, hydroxyl, C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 alkoxy, C6-C 14 aryl, 5-14 membered heteroaryl and 3-8 membered heterocyclic, wherein the C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 alkoxy, C6-C 14 Aryl, 5-14 membered heteroaryl and 3-8 membered heterocyclic group are each optionally bounded by one or more R L replace; R L Independently selected from hydrogen, deuterium, halogen, hydroxyl, C1-C6 alkyl, CN, SiR c R d R e C(O)R m NR n R o C(O)NR n R o NR n C(O)R m and 3-8 membered heterocyclic groups; R c R d R e Each is independently selected from C1-C6 alkyl and phenyl groups; R m Independently selected from hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 14 Aryl and 5-14 membered heteroaryl; R n and R o Each is independently selected from hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 14 aryl and 5-14 heteroaryl, or, R n and R o Together with the nitrogen atom it is attached to, it forms a 4-7 membered heterocyclic group.

[0010] In a preferred embodiment, the benzene-containing tripeptide compound of the present invention, or its stereoisomers, tautomers, pharmaceutically acceptable salts, polymorphs, cocrystals, solvates, metabolites, prodrugs, or any mixture of two or more thereof, wherein the tripeptide compound is a compound having the formula shown in Formula II,

[0011] R1 is selected from hydrogen, C1-C6 alkyl, C6-C 14Aryl, the C1-C6 alkyl, C6-C 14 Each aryl group is optionally bounded by one or more R f replace; R2 is selected from hydrogen and C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are optionally replaced by one or more R2 groups. f replace; Alternatively, R1 and R2 together with the nitrogen and carbon atoms they are attached to form a 4-7 membered heterocyclic group, which is optionally surrounded by one or more R atoms. f replace; R f Independently selected from hydrogen, deuterium, hydroxyl, C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 14 aryl, 5-14 heteroaryl, wherein the C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 14 Aryl and 5-14 heteroaryl groups are each optionally bounded by one or more R groups. L replace; R L Independently selected from hydrogen, deuterium, halogen, hydroxyl, C1-C4 alkyl, CN, SiR c R d R e C(O)R m NR n R o C(O)NR n R o NR n C(O)R m and 3-8 membered heterocyclic groups; R c R d R e Each is independently selected from C1-C6 alkyl and phenyl groups.

[0012] In some embodiments, the present invention comprises a benzene-containing tripeptide compound or its stereoisomers, tautomers, pharmaceutically acceptable salts, polymorphs, cocrystals, solvates, metabolites, prodrugs, or any mixture of two or more thereof, wherein the compound of formula II structure, R1 is selected from hydrogen, phenyl, and C1-C6 alkyl, wherein the C1-C6 alkyl group is reacted with one or more R1 groups. f replace; R2 is selected from hydrogen and C1-C6 alkyl groups, wherein the C1-C6 alkyl group is reacted with one or more R f replace; R f Independently selected from hydrogen, hydroxyl, and C1-C4 alkyl, wherein the C1-C4 alkyl group is separated by one or more R L replace; RL Independently selected from hydrogen, hydroxyl, C1-C4 alkyl and SiR c R d R e ; R c R d R e Each is independently selected from C1-C6 alkyl and phenyl groups.

[0013] In some embodiments, the present invention comprises a benzene-containing tripeptide compound or its stereoisomers, tautomers, pharmaceutically acceptable salts, polymorphs, cocrystals, solvates, metabolites, prodrugs, or any mixture of two or more thereof, wherein the compound of formula II, wherein, R1 is selected from hydrogen, phenyl, and C1-C4 alkyl, wherein the C1-C4 alkyl is optionally surrounded by one or more R f replace; R2 is selected from hydrogen, methyl, ethyl, and propyl, wherein the methyl, ethyl, or propyl group is reacted with one or more R2 groups. f replace; Alternatively, R1 and R2 together with the nitrogen and carbon atoms they are attached to form a 4-6 membered heterocyclic group, which is optionally surrounded by one or more R atoms. f replace; R f Independently selected from hydrogen, hydroxyl, and C1-C3 alkyl, wherein the C1-C3 alkyl group is separated by one or more R L replace; R L Independently selected from hydrogen, hydroxyl, methyl, ethyl and SiR c R d R e ; R c R d R e Each is an independent C1-C3 alkyl group.

[0014] In one specific embodiment, the benzene-containing tripeptide compound of the present invention, or its stereoisomers, tautomers, pharmaceutically acceptable salts, polymorphs, cocrystals, solvates, metabolites, prodrugs, or any mixture of two or more thereof, is selected from the compounds shown below:

[0015] .

[0016] This invention provides specific examples of compounds having the structure of Formula I or Formula II, including: 1. (S)-2-[(R)-3-(2-fluorophenyl)-2-(2-methylaminoacetamido)propionamido]-3-methyl-3-((triethylsilyl)oxy)methyl butyrate; 2. Methyl (S)-2-[(R)-3-(2-fluorophenyl)-2-((S)-2-(methylamino)propionylamino)propionylamino]-3-methyl-3-(triethylsiloxy)butyrate; 3. Methyl (S)-2-[(R)-3-(2-fluorophenyl)-2-[(S)-4-methyl-2-(methylamino)pentanoylamino]propionylamino]-3-methyl-3-triethylsiloxybutyrate; 4. (S)-2-[(R)-3-(2-fluorophenyl)-2-((S)-1-methylpiperidine-2-formylamino)propionylamino]-3-methyl-3-(triethylsiloxy)butyrate methyl ester; 5. Methyl (S)-2-[(R)-2-((S)-2-dimethylaminopropionylamino)-3-(2-fluorophenyl)propionylamino]-3-methyl-3-(triethylsiloxy)butyrate; 6. (S)-2-[(R)-2-((S)-3,3-dimethyl-2-methylaminobutyrylamino)-3-(2-fluorophenyl)propionylamino]-3-methyl-3-(triethylsiloxy)butyrate methyl ester; 7. Methyl (S)-2-[(R)-3-(2-fluorophenyl)-2-[(S)-3-hydroxy-2-(methylamino)propionylamino]propionylamino]-3-methyl-3-(triethylsiloxy)butyrate; 8. Methyl (S)-2-[(R)-3-(2-fluorophenyl)-2-[(S)-2-(methylamino)-2-phenylacetamido]propamido]-3-methyl-3-[(triethylsilyl)oxy]butyrate; 9. (S)-2-[(R)-3-(2-fluorophenyl)-2-((S)-3-methyl-2-methylaminobutyrylamino)propionylamino]-3-methyl-3-(triethylsiloxy)butyrate methyl ester; 10. (5R,6S,9R,12S)-3,3-diethyl-9-(2-fluorobenzyl)-5-methyl-6-(methylamino)-7,10-dioxo-12-(2-triethylsiloxypropyl-2-yl)-4-oxa-8,11-diaza-3-silazadecan-13-olate; 11. (S)-2-[(R)-3-(2-fluorophenyl)-2-((S)-1-methylpyrrolidine-2-formamide)propionamide]-3-methyl-3-(triethylsiloxy)butyrate methyl ester; 12. Methyl (S)-2-[(R)-2-[(2S,3S)-2-dimethylamino-3-methylpentanoylamino]-3-(2-fluorophenyl)propionylamino]-3-methyl-3-(triethylsiloxy)butyrate; 13. Methyl (S)-2-[(R)-3-(2-fluorophenyl)-2-[(S)-1-methylazacyclobutane-2-formylamino]propionylamino]-3-methyl-3-(triethylsiloxy)butyrate.

[0017] In one embodiment, the present invention provides a method for preparing a benzene-containing tripeptide compound, the synthetic route of which is as follows: , In the formula, PG is the protecting group; the definitions of R1 and R2 are the same as those mentioned above. The method includes the following steps: Step 1: Compound SM-1 and compound SM-2 are subjected to an acid-amine condensation reaction in the presence of a condensing agent to generate compound IM-1; Step 2: Compound IM-1 is deprotected under alkaline or acidic conditions to generate compound IM-2; Step 3: Compound IM-2 and compound SM-3 undergo an acid-amine condensation reaction in the presence of a condensing agent to generate compound IM-3; Step 4: Compound IM-3 is reacted with triethylsilyltrifluoromethanesulfonate or triethylchlorosilane to form compound I.

[0018] In another embodiment, a pharmaceutical composition is provided comprising a benzene-containing tripeptide compound or its stereoisomers, tautomers, pharmaceutically acceptable salts, polymorphs, cocrystals, solvates, metabolites, prodrugs, or any mixture of two or more thereof, and one or more pharmaceutically acceptable carriers or pharmaceutical excipients.

[0019] The benzene-containing tripeptide compound is a compound represented by Formula I or Formula II, and the definitions of R1, R2 and R3 are the same as those previously defined.

[0020] In some embodiments, a pharmaceutical formulation of the present invention comprises a benzene-containing tripeptide compound or a pharmaceutically acceptable salt, ester, solvate, isomer, any crystal form or racemate thereof, metabolite form thereof, or mixture thereof as an active ingredient. The formulation is a solid, semi-solid, liquid, or gaseous formulation, wherein the benzene-containing tripeptide compound is a compound represented by Formula I or Formula II, and the definitions of R1, R2, and R3 are the same as those defined above.

[0021] In one embodiment, the present invention provides the use of a benzene-containing tripeptide compound or a pharmaceutically acceptable salt, ester, solvate, isomer, any crystal form or racemate thereof, metabolite form thereof, or mixture thereof, in the manufacture of a medicament for the treatment or prevention of triple-negative breast cancer.

[0022] Technical effects of the invention: The compounds of the present invention exhibit excellent inhibitory activity against MDA-MB-231 cells and possess superior properties such as good physicochemical properties (e.g., solubility, physical and / or chemical stability), good pharmacokinetic properties (e.g., good bioavailability, appropriate blood concentration, half-life and duration of action), and good safety (low toxicity, e.g., low cardiotoxicity, low hepatotoxicity, and / or fewer side effects, and a wide therapeutic window). Detailed Implementation

[0023] The following embodiments are provided to describe the present invention in more detail. However, these embodiments are provided only to help further understand the present invention and are not intended to limit the present invention. Those skilled in the art should understand that equivalent substitutions or corresponding improvements made to the content of the present invention still fall within the protection scope of the present invention.

[0024] General terms and definitions Unless otherwise defined, the terms used herein have the same meaning as commonly understood by those skilled in the art. The technical intent used herein refers to technology commonly understood in the art, including variations or equivalent substitutions that are obvious to those skilled in the art. While the following terms are readily understood by those skilled in the art, they are set forth below to better explain the invention.

[0025] The term "isomer" refers to compounds that have the same molecular weight due to having the same number and type of atoms, but different spatial arrangements or configurations of atoms.

[0026] The term "stereoisomer" (or "optical isomer") refers to a stable isomer that, due to having at least one chiral element (including a chiral center, chiral axis, chiral plane, etc.), has a perpendicular asymmetric plane, thereby enabling the rotation of plane-polarized light. Since the compounds of the present invention (or pharmaceutically acceptable salts thereof) comprise asymmetric carbon atoms, they can exist as a single stereoisomer, a racemic mixture, or a mixture of enantiomers and diastereomers. These compounds can be monomorphic compounds, mixtures of racemic mixtures, or mixtures of a single stereoisomer enriched with other enantiomers and / or diastereomers.

[0027] The term "tautomer" (or "tautomer form") refers to structural isomers with different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium can be achieved in the tautomer. For example, proton tautomers (or proton transfer tautomers) include (but are not limited to) interconversions via proton transfer, such as keto-enol isomerization, imine-enamine isomerization, amide-imine alcohol isomerization, etc. Unless otherwise stated, all tautomer forms of the compounds of this invention are within the scope of this invention.

[0028] The term "pharmaceutically acceptable salt" refers to a salt of the compound of the present invention that is substantially non-toxic to organisms. Pharmaceutically acceptable salts generally include (but are not limited to) salts formed by the reaction of the compound of the present invention with a pharmaceutically acceptable inorganic acid / organic acid / acidic amino acid or inorganic base / organic base / basic amino acid; such salts are also known as acid addition salts or base addition salts.

[0029] The term "polymorph" (or "polymorphic form") refers to the solid crystalline form of a compound or complex. Those skilled in the art can obtain polymorphs of molecules using many known methods. These methods include (but are not limited to) melt recrystallization, melt cooling, solvent recrystallization, desolvation, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, and sublimation. Furthermore, well-known techniques can be used to detect, classify, and identify polymorphs, including (but not limited to) differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), X-ray powder diffraction (XRPD), single-crystal X-ray diffraction (SCXRD), solid-state nuclear magnetic resonance (NMR), infrared spectroscopy (IR), Raman spectroscopy, and scanning electron microscopy (SEM). This invention covers all possible crystalline forms or polymorphs of the compounds of this invention, which can be a single polymorph or a mixture of multiple polymorphs in any proportion.

[0030] The term "eutectic" refers to a multi-component molecular crystal complex formed in the solid state by spontaneous association of two or more chemically independent pure components through non-covalent intermolecular interactions (including hydrogen bonds, van der Waals forces, π-π stacking interactions, dipole interactions, etc.) without the breaking or formation of ionic or covalent bonds. Each component of the complex retains its original chemical molecular structure, without proton transfer or salt bond formation, and the components are regularly arranged in the same lattice system with a fixed stoichiometric ratio. This is distinct from physical mixtures, solvates, and polymorphs, and possesses inherent characteristics such as melting point, solubility, dissolution characteristics, physicochemical stability, and powder properties that differ from those of the individual components.

[0031] The term "solvent" refers to a substance formed by the combination of a compound of the present invention (or a pharmaceutically acceptable salt thereof) with at least one solvent molecule through non-covalent intermolecular forces. Common solvates include (but are not limited to) hydrates (including hemihydrates, monohydrates, dihydrates, trihydrates, etc.), ethanol compounds, acetone compounds, etc. The compounds of the present invention may exist in the form of solvates (preferably hydrates), containing a polar solvent (particularly water, methanol, or ethanol) as a lattice structure element. The amount of polar solvent (particularly water) may be present in stoichiometric or non-stoichiometric form.

[0032] The term "metabolite" refers to a derivative compound formed after the compounds of the present invention are metabolized, for example, by reactions such as oxidation, reduction, hydrolysis, amidation, deamidation, esterification, or enzymatic hydrolysis. The present invention covers all possible metabolite forms of the compounds of the present invention, i.e., substances formed in the body of an individual administering the compounds of the present invention. Metabolites of the compounds can be identified using techniques known in the art, and their activity can be characterized experimentally.

[0033] The term "prodrug" refers to a derived compound that, upon administration to an individual, can directly or indirectly provide the compounds of the present invention. Particularly preferred derived compounds or prodrugs are those that, upon administration to an individual, can improve the bioavailability of the compounds of the present invention (e.g., facilitate absorption into the bloodstream) or promote the delivery of the parent compound to its site of action (e.g., the lymphatic system). Unless otherwise indicated, all prodrug forms of the compounds of the present invention are within the scope of the present invention. Furthermore, the present invention also covers compounds of the present invention containing protecting groups. In any process of preparing the compounds of the present invention, protection of sensitive or reactive groups on any relevant molecule may be necessary and / or desired, thereby forming a form of chemical protection for the compounds of the present invention. This can be achieved by conventional protecting groups. These protecting groups can be removed at appropriate subsequent stages using methods known in the art.

[0034] The terms “including,” “comprising,” “having,” “containing,” or “involving,” and their other variations herein, are inclusive or open-ended and do not exclude other unlisted elements or method steps.

[0035] The term "halogenated" or "halogenated" is defined as including F, Cl, Br, or I.

[0036] The term "alkyl" is defined as a straight-chain or branched saturated aliphatic hydrocarbon group. In some embodiments, the alkyl group has 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms, and more preferably 1 to 4 carbon atoms. For example, as used herein, the term "C1-C6 alkyl" refers to a linear or branched group with 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, or n-hexyl). The term "C1-C4 alkyl" refers to a linear or branched aliphatic hydrocarbon chain with 1 to 4 carbon atoms (i.e., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl). In this invention, the "alkyl" is optionally replaced by one or more (such as one to three) suitable substituents such as halogens (in which case the group is referred to as "haloalkyl") (e.g., -CF3, -C2F5, -CHF2, -CH2F, -CH2CF3, -CH2Cl or -CH2CH2CF3, etc.).

[0037] The term “cycloalkyl” refers to a monocyclic or polycyclic (e.g., bicyclic) saturated or partially unsaturated aliphatic monovalent hydrocarbon group (e.g., monocyclic cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, etc.; or bicyclic cycloalkyl, including fused ring, bridged ring or spiro ring, such as decahydronaphthyl, bicyclic [2.2.1]heptyl, spiro [4.5]decyl, etc.).

[0038] The term "heterocyclic alkyl" refers to a monocyclic or polycyclic (e.g., bicyclic) saturated or partially unsaturated aliphatic monovalent hydrocarbon group having one or more carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) and one or more (e.g., 1, 2, 3, or 4) segments each independently selected from O, S, S(=O), S(=O)₂, and NR (R represents a hydrogen atom or substituent, such as alkyl or cycloalkyl). The ring system in a heterocyclic alkyl group can be a fused ring, a bridged ring, or a spirocyclic system. If the valence requirements are met, a heterocyclic alkyl group can be linked to other groups (or segments) through any carbon atom or heteroatom in the ring.

[0039] The term "alkenyl" refers to a hydrocarbon group containing at least one carbon-carbon double bond. Alkenyl groups can be straight-chain or branched.

[0040] The term "alkynyl" refers to a hydrocarbon group containing at least one carbon-carbon triple bond. Alynyl groups can be straight-chain or branched.

[0041] The term "aryl" refers to a monocyclic or fused-ring aromatic group with a conjugated π-electron system that is entirely carbon. For example, as used herein, the term "C6-C" is used in the following context. 10 "Aryl" refers to an aromatic group containing 6 to 10 carbon atoms, such as phenyl or naphthyl. The aryl group is optionally substituented by one or more (such as 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, C). 1-6 Alkyl groups, etc., are substituted.

[0042] The term "heteroaryl" refers to a monocyclic or polycyclic aromatic ring system containing at least one heteroatom, which may be the same or different (the heteroatom is, for example, oxygen, nitrogen, or sulfur), and, in some cases, may be benzo-fused. In some embodiments, the heteroaryl group has 3 to 18 cyclic atoms, preferably 5 to 10. In particular, the heteroaryl group is selected from thiophene, furanyl, pyrrole, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiazolyl, etc., and their benzo-derived derivatives; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and their benzo-derived derivatives.

[0043] The term "substitution" refers to the replacement of one or more (e.g., 1, 2, 3, or 4) hydrogen atoms on a specified atom by a selected group, provided that the substitution does not exceed the normal valence of the specified atom in its current state and the substitution forms a stable compound. The number of substituted groups selected is permitted only when such a combination forms a stable compound.

[0044] If a substituent is described as “each independently selected”, then each substituent may be the same as or different from another (other) substituent. The term “one or more” means one or more under reasonable conditions, such as two, three, four, five, or ten.

[0045] The term "protecting group" refers to a chemical group that has the following characteristics: 1) It can react with corresponding functional groups to form protected groups; 2) The protected group will be stable under the reaction conditions; 3) Functional groups can be released by removing them from the protected groups.

[0046] In addition, groups not defined herein follow their usual definitions. Pharmaceutically acceptable salts of the compounds of this invention include their acid addition salts and base addition salts. Examples include salts formed from alkali metals, alkaline earth metals, ammonium, alkylammonium, etc., and salts formed with inorganic or organic acids. These salts can be listed as sodium salts, potassium salts, calcium salts, ammonium salts, aluminum salts, triethylammonium salts, acetates, propionates, butyrates, formates, trifluoroacetates, maleates, tartrates, citrates, stearates, succinates, ethylsuccinates, lactobionates, gluconates, glucohepanoates, benzoates, methanesulfonates, ethanesulfonates, 2-hydroxyethanesulfonates, benzenesulfonates, p-toluenesulfonates, lauryl sulfates, malates, aspartate salts, glutamates, adipates, tris(hydroxymethyl)aminomethane salts, salts formed with cysteine, salts formed with N-acetylcysteine, hydrochlorides, hydrobromide salts, phosphates, sulfates, hydroiodates, nicotinate salts, oxalates, picrates, thiocyanates, undecanoates, salts formed with acrylic acid polymers, and salts formed with carboxyl vinyl polymers, etc.

[0047] The compounds of the present invention can exist as solvates (preferably hydrates), wherein the compounds of the present invention contain a polar solvent, particularly, for example, water, methanol, or ethanol, as a structural element of the lattice of the compound. The amount of the polar solvent, particularly water, can be stoichiometric or non-stoichiometric.

[0048] The scope of this invention also includes metabolites of the compounds of this invention, i.e., substances formed in the body when the compounds of this invention are administered. Such products can be generated, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic hydrolysis, etc., of the administered compound. Therefore, this invention includes metabolites of the compounds of this invention, including compounds obtained by methods that expose the compounds of this invention to mammals for a time sufficient to produce their metabolites.

[0049] The present invention further includes, within its scope, prodrugs of the compounds of the present invention, which are certain derivatives of the compounds of the present invention that may themselves have little or no pharmacological activity, and which, when administered to or onto the body, can be converted, for example, by hydrolysis and cleavage into the compounds of the present invention having the desired activity. Typically, such prodrugs are functional group derivatives of the compounds that are readily converted in vivo into the desired therapeutically active compounds.

[0050] This invention also covers compounds of the invention containing protecting groups. In any process of preparing the compounds of the invention, protection of sensitive or reactive groups on any relevant molecule may be necessary and / or desired, thereby forming a form of chemical protection for the compounds of the invention.

[0051] The technical solution of the present invention will be further illustrated below through specific embodiments. Unless otherwise stated, the pharmaceuticals, reagents, materials, instruments, etc., described in the following embodiments can all be obtained through conventional commercial means.

[0052] The meanings of the abbreviations in the conventional synthesis methods and in the examples and intermediate synthesis examples are shown in Table 1 below.

[0053] Table 1. Meaning of abbreviations used in this article

[0054] The structures of the compounds described in the following examples were confirmed by nuclear magnetic resonance (1H-NMR) and / or liquid chromatography-mass spectrometry (LC-MS).

[0055] The nuclear magnetic resonance (¹H-NMR) measurements were performed using a Bruker 400MHz NMR spectrometer. The solvents used were deuterated methanol (CD3OD), deuterated chloroform (CDCl3), or hexadeuterated dimethyl sulfoxide (DMSO-d6), and the internal standard was tetramethylsilane (TMS). The abbreviations used in the nuclear magnetic resonance (NMR) data in the following examples have the following meanings: s: singlet, d: doublet, t: triplet, q: quartet, dd: double doublet, qd: quartet doublet, ddd: double double doublet, ddt: double double triplet, dddd: double double double doublet, m: multiplet, br: broad, J: coupling constant, Hz: Hertz, δ: chemical shift. All chemical shift (δ) values ​​are given in parts per million (ppm). High-performance liquid chromatography-tandem mass spectrometry (HPLC-MS) was performed using a Shimadzu LC-2050C chromatograph and a Shimadzu LCMS-2050 mass spectrometer. Unless otherwise specified, the general separation conditions were as follows: Shim pack Scepter C18-120 (4.6 mm × 150 mm × 3.0 μm) column; column temperature: 40℃; flow rate: 1.0 mL / min; detection wavelength: 190 / 220 / 254 nm; mobile phase A: 0.05% formic acid aqueous solution; mobile phase B: 100% acetonitrile; elution gradient: (0-2 min: 70% A, 30% B; 6 min: 20% A, 80% B; 9 min: 5% A, 95% B); mass spectrometry scan range: ±100~1000 Da.

[0056] Column chromatography uses 200-300 mesh silica gel (Sichuan Buster Fine Chemical Co., Ltd.) as the stationary phase. The eluent system (but not limited to) is a petroleum ether / ethyl acetate system and a dichloromethane / methanol system. The volume ratio of the two solvents can be adjusted according to the polarity of the compounds to be separated. Unless otherwise stated, the reaction temperature in the following examples is room temperature (20–30°C).

[0057] Unless otherwise stated, the reagents used in the following examples were purchased from companies such as SANN Chemical Technology (Shanghai) Co., Ltd., Shanghai BIDE Pharmaceutical Technology Co., Ltd., and Shanghai Haohong Biomedical Technology Co., Ltd.

[0058] Preparation of related intermediate compounds: Intermediate a1: Methyl(S)-2-amino-3-methyl-3-((triethylsilyl)oxy)butyrate

[0059] Step 1: Methyl (S)-2-((tert-Butoxycarbonyl)amino)-3-hydroxy-3-methylbutyrate (a1-2) Compound a1-1 ((S)-2-((tert-Butoxycarbonyl)amino)-3-hydroxy-3-methylbutyric acid) (CAS No. 102507-13-1, source: commercially obtained) (10.0 g) was added to a mixed solution of methanol (100 mL) and toluene (100 mL). Under ice bath conditions, 2 mol / L trimethylsilyldiazomethane (107 mL) was added dropwise, and the reaction was carried out overnight at room temperature. After the reaction was completed, the solution was concentrated to dryness under reduced pressure to obtain compound a1-2. The crude product did not require purification and was used for the next step in 100% yield.

[0060] Step 2: Methyl (S)-2-amino-3-methyl-3-((triethylsilyl)oxy)butyrate (a1) Compound a1-2 (8.0 g) was added to dichloromethane (80 mL), and 2,6-lutidine (41.6 g) and TESOTf (51.2 g) were added sequentially under ice bath conditions. The reaction was carried out overnight at room temperature. After the reaction was completed, the reaction was quenched with sodium bicarbonate aqueous solution, and the mixture was extracted with dichloromethane. The extract was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain compound a1 (7.6 g), with a yield of 90.0%.

[0061] MS m / z (ESI): 262.2 [M+H] + Intermediate b1: Methyl(S)-2-((R)-2-amino-3-(2-fluorophenyl)propionylamino)-3-methyl-3-((triethylsiloxy)butyrate)

[0062] Step 1: Methyl(S)-2-((R)-2-((tert-butoxycarbonyl)amino)-3-(2-fluorophenyl)propamido)-3-methyl-3-((triethylsiloxy)oxy)butyrate Compound b1-1 ((R)-2-((tert-Butoxycarbonyl)amino)-3-(2-fluorophenyl)propionic acid) (CAS No. 114873-10-8, source: commercially obtained) (5.0 g) was added to dichloromethane (100 mL), and HATU (8.1 g) was added under ice bath conditions. After stirring for 30 min, DIPEA (4.6 g) and compound a1 (4.6 g) were added sequentially, and the reaction was continued under ice bath conditions for 2 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the concentrate was separated by silica gel column chromatography to obtain compound b1-2 (9.1 g) in 97.8% yield.

[0063] MS m / z (ESI): 527.3 [M+H] + Step 2: Methyl(S)-2-((R)-2-amino-3-(2-fluorophenyl)propionylamino)-3-methyl-3-((triethylsiloxy)butyrate) Compound b1-2 (9.1 g) was added to dichloromethane (100 mL), and 2,6-lutidine (22.0 g) and TESOTf (27.4 g) were added sequentially under ice bath conditions. The reaction was continued under ice bath conditions for 4 h. After the reaction was completed, the reaction was quenched with sodium bicarbonate aqueous solution, concentrated under reduced pressure, and the concentrate was separated by silica gel column chromatography to give compound b1 (6.1 g), with a yield of 83.6%.

[0064] MS m / z (ESI): 427.2 [M+H] + Example 1: Methyl(S)-2-((R)-3-(2-fluorophenyl)-2-(2-(methylamino)acetamido)propionylamino)-3-methyl-3-((triethylsiloxy)oxy)butyrate (1)

[0065] Step 1: Methyl(9R,12S)-9-(2-fluorobenzyl)-2,2,5-trimethyl-4,7,10-trioxo-12-(2-((triethylsiloxy)prop-2-yl)-3-oxa-5,8,11-triazatridecane-13-ester (1-2) Compound b1 (100.0 mg) was added to dichloromethane (5 ml), HATU was added under ice bath conditions, and the mixture was stirred for 30 min. Then, DIPEA (59.3 mg) and compound 1-1 (44.3 mg) were added sequentially, and the reaction was continued under ice bath conditions for 2 h. After the reaction was completed, the mixture was concentrated under reduced pressure, and the concentrate was separated by silica gel column chromatography to give compound 1-2 (96.0 mg), with a yield of 69.8%.

[0066] MS m / z (ESI): 598.3 [M+H] + Step 2: Methyl(S)-2-((R)-3-(2-fluorophenyl)-2-(2-(methylamino)acetamido)propionylamino)-3-methyl-3-((triethylsiloxy)oxy)butyrate (1) Compounds 1-2 (96.0 mg) were added to dichloromethane (5 mL), and 2,6-lutidine (300.0 mg) and TESOTf (300.0 mg) were added sequentially under ice bath conditions. The reaction was continued under ice bath conditions for 2 h. After the reaction was completed, the reaction was quenched with sodium bicarbonate aqueous solution, concentrated under reduced pressure, and the concentrate was separated by liquid phase to give compound 1 (56.3 mg), with a yield of 70.5%.

[0067] 1 H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 8.2 Hz, 1H), 7.25 – 7.14 (m,2H), 7.08 – 6.96 (m, 2H), 6.87 (d, J = 8.9 Hz, 1H), 4.81 - 4.72(m, 1H), 4.37(d, J= 9.0 Hz, 1H), 3.68 (s, 3H), 3.29 – 3.17 (m, 2H), 3.16 – 2.99 (m, 2H), 2.29 (s, 3H), 1.33 (s, 3H), 1.15 (s, 3H), 0.92 (t, J = 7.9 Hz, 9H), 0.55 (q, J = 7.9 Hz, 6H).

[0068] MS m / z (ESI): 498.3 [M+H] + Example 2, Methyl(2S)-2-((2R)-3-(2-fluorophenyl)-2-(2-(methylamino)propamido)propamido)-3-methyl-3-((triethylsilyl)oxy)butyrate (2)

[0069] Step 1: (6S,9R,12S)-9-(2-fluorobenzyl)-2,2,5,6-tetramethyl-4,7,10-trioxo-12-(2-((triethylsilyl)oxy)prop-2-yl)-3-oxa-5,8,11-triazatridecane-13-olate (2-2) Following the preparation method of compounds 1-2, compound 2-2 (99.8 mg) was obtained with a yield of 71.0%.

[0070] MS m / z (ESI): 612.3 [M+H] + Step 2: Methyl(2S)-2-((2R)-3-(2-fluorophenyl)-2-(2-(methylamino)propamido)propamido)-3-methyl-3-((triethylsilyl)oxy)butyrate (2) Following the preparation method of compound 1, compound 2 (60.1 mg) was obtained in a yield of 71.8%.

[0071] 1 H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 8.0 Hz, 1H), 7.26 – 7.16 (m,2H), 7.09 – 6.94 (m, 3H), 4.76 – 4.66(m, 1H), 4.38 (d, J = 8.9 Hz, 1H), 3.68(s, 3H), 3.24 (dd, J= 14.3, 5.5 Hz, 1H), 3.08 (dd, J = 14.3, 9.7 Hz, 1H), 2.96(q, J = 7.0 Hz, 1H), 2.13 (s, 3H), 1.34 (s, 3H), 1.26 (s, 3H), 1.17 (s, 3H),0.92 (t, J = 7.9 Hz, 9H), 0.56 (q, J = 7.9 Hz, 6H).

[0072] MS m / z (ESI): 512.3 [M+H] + Example 3: Methyl (2S)-2-((2R)-3-(2-fluorophenyl)-2-(4-methyl-2-(methylamino)pentamido)propamido)-3-methyl-3-((triethylsilyl)oxy)butyrate (3)

[0073] Step 1: (9R,12S)-9-(2-fluorobenzyl)-6-isobutyl-2,2,5-trimethyl-4,7,10-trioxo-12-(2-((triethylsilyl)oxy)prop-2-yl)-3-oxa-5,8,11-triazatridecane-13-olate (3-2) Following the preparation method of compounds 1-2, compound 3-2 (95.6 mg) was obtained with a yield of 63.5%.

[0074] MS m / z (ESI): 654.4 [M+H] + Step 2: (2S)-2-((2R)-3-(2-fluorophenyl)-2-(4-methyl-2-(methylamino)pentamido)propamido)-3-methyl-3-((triethylsilyl)oxy)butyrate (3) Following the preparation method of compound 1, compound 3 (59.0 mg) was obtained with a yield of 72.9%.

[0075] 1 H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 7.9 Hz, 1H), 7.26 – 7.15 (m,2H), 7.10 – 6.93 (m, 3H), 4.76 – 4.65(m, 1H), 4.38 (d, J= 8.9 Hz, 1H), 3.67(s, 3H), 3.23 (dd, J = 14.3, 5.5 Hz, 1H), 3.08 (dd, J = 14.3, 9.7 Hz, 1H), 2.85(dd, J = 9.6, 4.2 Hz, 1H), 2.09 (s, 3H), 1.62 – 1.50 (m, 3H), 1.33 (s, 3H), 1.16 (s, 3H), 0.96 – 0.86 (m, 15H), 0.56 (q, J = 7.9 Hz, 6H).

[0076] MS m / z (ESI): 554.3 [M+H] + Example 4: Methyl 2-((R)-3-(2-fluorophenyl)-2-((S)-1-methylpiperidin-2-carbamoyl)propamido)-3-methyl-3-((triethylsilyl)oxy)butyrate (4)

[0077] Following the preparation methods of compounds 1-2, compound 4 (388.6 mg) was obtained with a yield of 70.4%.

[0078] 1 H NMR (400 MHz, CDCl3) δ 7.29 – 7.15 (m, 2H), 7.10 – 6.89 (m, 4H), 4.77 – 4.68 (m, 1H), 4.39 (d, J = 8.9 Hz, 1H), 3.68 (s, 3H), 3.25 (dd, J = 14.4, 5.5 Hz, 1H), 3.07 (dd, J = 14.4, 10.0 Hz, 1H), 2.89 - 2.78(m, 1H), 2.39 (dd, J = 11.3, 3.4 Hz, 1H), 1.98 – 1.86 (m, 2H), 1.79 (s, 3H), 1.65 – 1.36 (m, 5H), 1.34 (s, 3H), 1.16 (s, 3H), 0.93 (t, J = 7.9 Hz, 9H), 0.56 (q, J = 7.9 Hz, 6H).

[0079] MS m / z (ESI): 551.3 [M+H] + Example 5: Methyl (S)-2-((R)-2-((S)-2-(dimethylamino)propamido)-3-(2-fluorophenyl)propamido)-3-methyl-3-((triethylsilyl)oxy)butyrate (5)

[0080] Following the preparation methods of compounds 1-2, compound 5 (367.0 mg) was obtained with a yield of 69.8%.

[0081] 1 H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 8.2 Hz, 1H), 7.26 – 7.15 (m,2H), 7.10 – 6.85 (m, 3H), 4.77 – 4.66(m, 1H), 4.38 (d, J = 8.9 Hz, 1H), 3.67(s, 3H), 3.23 (dd, J = 14.3, 5.7 Hz, 1H), 3.06 (dd, J = 14.2, 9.5 Hz, 1H), 2.82(q, J = 7.0 Hz, 1H), 2.11 (s, 6H), 1.33 (s, 3H), 1.20 – 1.15 (m, 6H), 0.92 (t, J = 7.9 Hz, 9H), 0.55 (q, J = 7.9 Hz, 6H).

[0082] MS m / z (ESI): 525.3 [M+H] + Example 6: Methyl (S)-2-((R)-2-(S)-3,3-dimethyl-2-(methylamino)butamido)-3-(2-fluorophenyl)propamido)3-methyl-3-((triethylsilyl)oxy)butyrate (6)

[0083] Step 1: (9R,12S)-6-(tert-butyl)-9-(2-fluorobenzyl)-2,2,5-trimethyl-4,7,10-trioxo-12-(2-((triethylsilyl)oxy)prop-2-yl)-3-oxa-5,8,11-triazatridecane-13-olate (6-2) Following the preparation method of compounds 1-2, compound 6-2 (288.0 mg) was obtained in a yield of 88.0%.

[0084] MS m / z (ESI): 654.4 [M+H] + Step 2: (S)-2-((R)-2-(S)-3,3-dimethyl-2-(methylamino)butamido)-3-(2-fluorophenyl)propamido)3-methyl-3-((triethylsilyl)oxy)butyrate (6) Following the preparation method of compound 1, compound 6 (201.5 mg) was obtained with a yield of 82.7%.

[0085] 1 H NMR (400 MHz, CDCl3) δ 7.40 (d, J = 7.6 Hz, 1H), 7.28 – 7.11 (m,2H), 7.10 – 6.89 (m, 3H), 4.84 – 4.68(m, 1H), 4.39 (d, J = 8.8 Hz, 1H), 3.64(s, 3H), 3.20 (dd, J = 14.3, 5.9 Hz, 1H), 3.09 (dd, J = 14.3, 9.5 Hz, 1H), 2.50(s, 1H), 2.01 (s, 3H), 1.32 (s, 3H), 1.14 (s, 3H), 0.97 – 0.77 (m, 18H), 0.55(q, J = 7.9 Hz, 6H).

[0086] MS m / z (ESI): 554.3 [M+H] + Example 7: Methyl (2S)-2-((2R)-2-(3-(benzyloxy)-2-(methylamino)propamido)-3-(2-fluorophenyl)propamido)-3-methyl-3-((triethylsilyl)oxy)butyrate (7)

[0087] Step 1: Methyl(9R,12S)-6-((benzyloxy)methyl)-9-(2-fluorobenzyl)-2,2,5-trimethyl-4,7,10-trioxo-12-(2-(triethylsilyl)oxy)propyl-2-yl)-3-oxa-5,8,11-triazatridecane-13-ester (7-2) Following the preparation method of compounds 1-2, compound 7-2 (80.0 mg) was obtained with a yield of 37.9%.

[0088] MS m / z (ESI): 718.4 [M+H] + Step 2: (2S)-2-((2R)-2-(3-(benzyloxy)-2-(methylamino)propamido)-3-(2-fluorophenyl)propamido)-3-methyl-3-((triethylsilyl)oxy)methyl butyrate (7-3) Following the preparation method of compound 1, compound 7-3 (68.0 mg) was obtained in 99.0% yield.

[0089] MS m / z (ESI): 618.3 [M+H] + Step 3: (2S)-2-((2R)-2-(3-(benzyloxy)-2-(methylamino)propamido)-3-(2-fluorophenyl)propamido)-3-methyl-3-((triethylsilyl)oxy)methyl butyrate (7) Compound 7-3 (68 mg) was added to methanol (10 mL), followed by diisopropylamine (50 mg) and palladium hydroxide on carbon (50 mg). Hydrogen gas was introduced under normal pressure, and the reaction was carried out overnight at 55 °C. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the preparative liquid phase was separated to obtain compound 7 (9.4 mg), with a yield of 16.2%.

[0090] 1 H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 8.2 Hz, 1H), 7.47 (d, J = 9.1 Hz,1H), 7.26 – 7.16 (m, 2H), 7.10 – 6.97 (m, 2H), 4.78 – 4.66(m, 1H), 4.39 (d, J = 9.1 Hz, 1H), 4.00 (dd, J = 11.4, 3.4 Hz, 1H), 3.73 – 3.63 (m, 4H), 3.25 (dd, J= 14.4, 5.4 Hz, 1H), 3.08 (dd, J = 14.4, 10.1 Hz, 1H), 2.90 (t, J = 3.8 Hz,1H), 2.25 (s, 3H), 1.35 (s, 3H), 1.23 (s, 3H), 0.94 (t, J = 7.9 Hz, 9H), 0.59(q, J = 7.9 Hz, 6H).

[0091] MS m / z (ESI): 528.3 [M+H] + Example 8: Methyl 2-((R)-3-(2-fluorophenyl)-2-((S)-2-(methylamino)-2-phenylacetamido)propamido)-3-methyl-3-((triethylsilyl)oxy)butyrate (8)

[0092] Step 1: (9R,12S)-9-(2-fluorobenzyl)-2,2,5-trimethyl-4,7,10-trioxo-6-phenyl-12-(2-((triethylsilyl)oxy)prop-2-yl)-3-oxa-5,8,11-triazatridecane-13-olate (8-2) Following the preparation method of compounds 1-2, compound 8-2 (550.0 mg) was obtained in a yield of 81.6%.

[0093] MS m / z (ESI): 674.4 [M+H] + Step 2: 2-((R)-3-(2-fluorophenyl)-2-((S)-2-(methylamino)-2-phenylacetamido)propamido)-3-methyl-3-((triethylsilyl)oxy)butyrate (8) Following the preparation method of compound 1, compound 8 (350.0 mg) was obtained with a yield of 74.3%.

[0094] 1 H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 7.8 Hz, 1H), 7.33 – 7.25 (m,5H), 7.24 – 7.16 (m, 2H), 7.07 – 6.95 (m, 2H), 6.73 (d, J= 8.8 Hz, 1H), 4.78- 4.66(m, 1H), 4.36 (d, J = 8.8 Hz, 1H), 3.96 (s, 1H), 3.59 (s, 3H), 3.23 (dd, J = 14.2, 5.7 Hz, 1H), 3.08 (dd, J = 14.2, 9.2 Hz, 1H), 2.22 (s, 3H), 1.22 (s,3H), 0.97 (s, 3H), 0.90 (t, J = 7.9 Hz, 9H), 0.53 (q, J = 7.9 Hz, 6H).

[0095] MS m / z (ESI): 574.3 [M+H] + Example 9: (S)-2-[(R)-3-(2-fluorophenyl)-2-((S)-3-methyl-2-methylaminobutyrylamino)propionylamino]-3-methyl-3-(triethylsiloxy)butyrate (9)

[0096] Step 1: (6S,9R,12S)-9-(2-fluorobenzyl)-6-isopropyl-2,2,5-trimethyl-4,7,10-trioxo-12-[2-(triethylsiloxy)prop-2-yl]-3-oxa-5,8,11-triazatridecane-13-methyl ester (9-2) Following the preparation method of compounds 1-2, compound 9-2 (120.0 mg) was obtained with a yield of 92.4%.

[0097] MS m / z (ESI): 640.4 [M+H] + Step 2: (S)-2-[(R)-3-(2-fluorophenyl)-2-[(S)-3-methyl-2-(methylamino)butamido]propamido]-3-methyl-3-(triethylsiloxy)butyrate (9) Following the preparation method of compound 1, compound 9 (78.0 mg) was obtained in a yield of 82.3%.

[0098] 1 H NMR (400 MHz, CDCl3) δ 7.75 (t, J= 8.8 Hz, 1H), 7.34 – 7.26 (m,1H), 7.20 (dd, J = 13.3, 6.1 Hz, 1H), 7.10 – 6.93 (m, 3H), 4.98 – 4.88 (m,1H), 4.38 (d, J = 8.8 Hz, 1H), 3.68 (s, 3H), 3.36 – 3.20 (m, 2H), 3.06 – 3.00(m, 1H), 2.37 (s, 3H), 2.10 – 1.99 (m, 1H), 1.34 (s, 3H), 1.18 (s, 3H), 0.95–0.85 (m, 15H), 0.60–0.54 (m, 6H).

[0099] MS m / z (ESI): 540.3 [M+H] + Example 10: (5R,6S,9R,12S)-3,3-diethyl-9-(2-fluorobenzyl)-5-methyl-6-(methylamino)-7,10-dioxo-12-[2-(triethylsiloxy)prop-2-yl]-4-oxa-8,11-diaza-3-silazadecan-13-olate (10)

[0100] Step 1: (6S,9R,12S)-9-(2-fluorobenzyl)-6-[(R)-1-hydroxyethyl]-2,2,5-trimethyl-4,7,10-trioxo-12-[2-(triethylsiloxy)prop-2-yl]-3-oxa-5,8,11-triazatridecane-13-methyl ester (10-2) Following the preparation method of compounds 1-2, compound 10-2 (64.0 mg) was obtained in a yield of 46.6%.

[0101] Step 2: (5R,6S,9R,12S)-3,3-diethyl-9-(2-fluorobenzyl)-5-methyl-6-(methylamino)-7,10-dioxo-12-[2-(triethylsiloxy)prop-2-yl]-4-oxa-8,11-diaza-3-silazadecan-13-methyl ester (10) Following the preparation method of compound 1, compound 10 (32.0 mg) was obtained in a yield of 75.6%.

[0102] 1 H NMR (400 MHz, Chloroform- d ) δ 7.80 (d, J = 8.6 Hz, 1H), 7.25 – 7.16(m, 2H), 7.07 – 6.96 (m, 2H), 6.85 (d, J = 8.9 Hz, 1H), 4.75 (td, J = 8.9, 6.0Hz, 1H), 4.40 (d, J = 8.9 Hz, 1H), 3.67 (s, 4H), 3.21 (dd, J = 14.2, 6.0 Hz, 1H), 3.02 (dd, J = 14.1, 9.1 Hz, 1H), 2.76 (d, J = 6.0 Hz, 1H), 2.38 (s, 3H), 1.33 (s, 3H), 1.15 (s, 3H), 1.01 (d, J = 6.3 Hz, 3H), 0.92 (td, J = 7.9, 5.6Hz, 18H), 0.55 (q, J = 7.9 Hz, 12H).

[0103] MS m / z (ESI): 656.4 [M+H] + Example 11: Methyl (S)-2-[(R)-3-(2-fluorophenyl)-2-[(S)-1-methylpyrrolidine-2-formamido]propamido]-3-methyl-3-(triethylsiloxy)butyrate (11)

[0104] Step 1: Following the preparation methods of compounds 1-2, compound 11 (230.0 mg) was obtained with a yield of 92.7%.

[0105] 1 H NMR (400 MHz, Chloroform- d ) δ 7.80 (d, J = 8.1 Hz, 1H), 7.30 – 7.16(m, 2H), 7.13 – 6.96 (m, 3H), 4.70 (ddd,J = 10.1, 8.1, 5.2 Hz, 1H), 4.40 (d, J = 8.9 Hz, 1H), 3.69 (s, 3H), 3.25 (dd, J = 14.4, 5.3 Hz, 1H), 3.19 – 3.01 (m,2H), 2.81 (s, 1H), 2.31 (d, J = 9.8 Hz, 1H), 2.24 – 2.06 (m, 4H), 1.93 – 1.82(m, 1H), 1.35 (s, 3H), 1.21 (s, 3H), 0.93 (t, J = 7.9 Hz, 9H), 0.57 (q, J = 7.9Hz, 6H).

[0106] MS m / z (ESI): 538.3 [M+H] + Example 12: Methyl (S)-2-[(R)-2-[(2S,3S)-2-(dimethylamino)-3-methylpentamido]-3-(2-fluorophenyl)propamido]-3-methyl-3-(triethylsiloxy)butyrate (12)

[0107] Step 1: (6S,9R,12S)-6-[(S)-sec-butyl]-9-(2-fluorobenzyl)-2,2,5-trimethyl-4,7,10-trioxo-12-[2-(triethylsiloxy)prop-2-yl]-3-oxa-5,8,11-triazatridecane-13-methyl ester (12-2) Following the preparation method of compounds 1-2, compound 12-2 (330 mg) was obtained with a yield of 93.8%.

[0108] MS m / z (ESI): 654.4 [M+H] + Step 2: (S)-2-[(R)-3-(2-fluorophenyl)-2-[(2S,3S)-3-methyl-2-(methylamino)pentamido]propamido]-3-methyl-3-(triethylsiloxy)butyrate (12-3) Following the preparation method of compound 1, compound 12-3 (270 mg) was obtained in 85.5% yield.

[0109] MS m / z (ESI): 554.3 [M+H] + Step 3: (S)-2-[(R)-2-[(2S,3S)-2-(dimethylamino)-3-methylpentamido]-3-(2-fluorophenyl)propamido]-3-methyl-3-(triethylsiloxy)butyrate (12) 12-3 (250 mg, 0.45 mmol) was dissolved in 10 mL of THF, followed by the addition of paraformaldehyde (27 mg, 0.91 mmol) and acetic acid (2.7 mg, 0.045 mmol). After stirring for 1 hour, sodium triacetoxyborohydride was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was quenched with 10 mL of water, and then 10 mL of EA was added. After thorough stirring, the mixture was separated into aqueous and organic phases. The aqueous phase was extracted once with EA, and the organic phases were combined and washed once with water. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated, and the residue was separated by preparative liquid chromatography to give compound 12 (105 mg), with a yield of 39.6%.

[0110] 1 H NMR (400 MHz, Chloroform- d ) δ 7.26 – 7.16 (m, 2H), 7.09 – 6.97 (m,2H), 6.89 (t, J = 7.7 Hz, 2H), 4.77 (td, J = 8.5, 6.6 Hz, 1H), 4.38 (d, J = 8.8Hz, 1H), 3.67 (s, 3H), 3.24 – 3.03 (m, 2H), 2.48 (d, J = 5.7 Hz, 1H), 2.09 (s,6H), 1.83 – 1.70 (m, 1H), 1.52 (ddd, J = 13.0, 7.4, 5.3 Hz, 1H), 1.32 (s, 3H), 1.24 – 1.12 (m, 4H), 1.00 – 0.84 (m, 12H), 0.75 (d, J = 6.7 Hz, 3H), 0.56 (q, J = 7.9 Hz, 6H).

[0111] MS m / z (ESI): 568.4 [M+H] + Example 13: Methyl (S)-2-[(R)-3-(2-fluorophenyl)-2-[(S)-1-methylazacyclobutane-2-formamido]propamido]-3-methyl-3-(triethylsiloxy)butyrate (13)

[0112] Step 1: Following the preparation methods of compounds 1-2, compound 13 (65.0 mg) was obtained with a yield of 84.4%.

[0113] 1 H NMR (400 MHz, Chloroform- d ) δ 7.85 (d, J = 8.9 Hz, 1H), 7.28 (dd, J = 7.5, 1.9 Hz, 1H), 7.23 – 7.17 (m, 1H), 7.10 – 7.01 (m, 2H), 6.83 (d, J = 8.9Hz, 1H), 4.78 (td, J = 9.3, 5.4 Hz, 1H), 4.40 (d, J = 9.1 Hz, 1H), 3.69 (s,3H), 3.41 – 3.29 (m, 2H), 3.14 – 3.04 (m, 1H), 2.89 (td, J = 8.7, 6.9 Hz, 1H),2.30 (s, 3H), 2.23 – 2.09 (m, 1H), 1.65 – 1.58 (m, 1H), 1.42 (d, J = 4.8 Hz,1H), 1.34 (s, 3H), 1.18 (s, 3H), 0.92 (t, J = 7.9 Hz, 9H), 0.55 (qd, J = 7.9, 2.6 Hz, 6H).

[0114] MS m / z (ESI): 524.3 [M+H] + Biological evaluation: The present invention will be further described and explained below through experimental examples, but these experimental examples are not intended to limit the scope of the present invention.

[0115] Experimental Example 1: Investigating the anti-proliferative effect of a compound in the tumor cell line MDA-MB-231 using in vitro cell activity assays. 1. Reagents and instruments used in cell viability experiments (1) MDA-MB-231 cells, Wuhan Pronosei Life Science Technology Co., Ltd.; (2) Cell Counting Kit-8 (CCK-8) cell viability assay kit (Selleck-B34302); (3) SpectraMax M5e reader, Molecular Devices.

[0116] 2. Cell lines and culture methods are shown in Table 2.

[0117] Table 2. Cell lines and culture methods

[0118] The tumor cell lines were cultured in a CO2-free incubator at 37ºC according to the culture conditions shown in Table 2 above. Cells were passaged periodically, and cells in the logarithmic growth phase were used for plating.

[0119] 3. Experimental Methods (1) The cells seeded in 96-well plates were cultured overnight. When the confluence of cells reached about 70%-80%, different concentrations of drugs were added and cultured for 48 hours. Three replicates were set up for each drug-treated group (the cells were cultured in complete culture medium throughout this process).

[0120] (2) Preparation of CCK-8 working solution: Mix CCK-8 solution with serum-free culture medium at a ratio of 1:9.

[0121] (3) Add 100 µL of CCK-8 working solution to each well and place in a constant temperature incubator at 37℃ for 1-4 h.

[0122] (4) Once the solution of the negative control group turns orange-yellow, remove the cell culture plate and detect the absorbance value at a wavelength of 450 nm to calculate the survival rate (%).

[0123] 4. Data Analysis The cell viability of the detected compound is calculated using the following formula: Cell viability (%) = [A (Drug+) – A (Black)] / [A (Drug-) – A (Black)] x 100%, where A (Drug+): OD value of experimental wells containing cells, CCK8, and the compound; A (Drug-): OD value of control wells containing only cells and CCK8, without the compound; A (Black): OD value of blank wells containing only culture medium and CCK8, without cells. Cell viability at different compound concentrations was calculated in Excel, and then graphs were plotted and relevant parameters, including minimum cell viability, maximum cell viability, and IC50, were calculated using GraphPad Prism software. 50 .

[0124] 5. Test results, see Table 3.

[0125] Table 3. Results of experiments on the inhibitory effect of compounds on the proliferation of MDA-MB-231 cells.

[0126] Therefore, it can be seen that the compounds of the present invention have good inhibitory effects on the proliferation of MDA-MB-231 cells, especially compounds 3, 6, 8 and 9, which show stronger inhibitory activity.

Claims

1. A benzene ring containing tripeptide compound or its stereoisomer, tautomer, pharmaceutically acceptable salt, polymorph, co-crystal, solvate, metabolite, prodrug or any mixture of two or more thereof, characterized in that, The tripeptide compound is the compound shown in Formula I: In the formula, R1 is selected from hydrogen, deuterium, halogen, cyano, C1-C6 alkyl, C3-C7 cycloalkyl, 3-7 membered heterocyclic, C2-C6 alkenyl, C2-C6 ynyl, C6-C 14 aryl and 5-14 membered heteroaryl, wherein the C1-C6 alkyl, C3-C7 cycloalkyl, 3-7 membered heterocyclic, C2-C6 alkenyl, C2-C6 alkynyl, C6-C 14 The aryl and 5-14 heteroaryl groups are each optionally bounded by one or more R groups. f replace; R2 and R3 are each independently selected from hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 14 Aryl, 3-8 membered heterocyclic and 5-14 membered heteroaryl, -C(O)R a SO2R b The C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 14 Aryl, 3-8 membered heterocyclic and 5-14 membered heteroaryl are each optionally bound by one or more R f replace; Alternatively, R1 and R2 together with the nitrogen and carbon atoms they are attached to form a 4-7 membered heterocyclic group, which is optionally surrounded by one or more R atoms. f replace; or R2and R3together with the nitrogen atom to which they are attached form a 4-7 membered heterocyclyl group optionally substituted with one or more R f substituents; R a and R b Each is independently selected from C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 14 Aryl and 5-14 membered heteroaryl, the C6-C 14 The aryl group and the 5-14 membered heteroaryl group are each optionally fused with a C3-C7 cycloalkyl group or a 5-10 membered heterocyclic group, wherein the C1-C6 alkyl group, C3-C7 cycloalkyl group, C6-C7 cycloalkyl group, and C1-C7 cycloalkyl group are respectively fused with a C3-C7 cycloalkyl group or a C1-C7 cycloalkyl group. 14 Aryl, 5-14 membered heteroaryl and 5-10 membered heterocyclic are each optionally bounded by one or more R f replace; R f Independently selected from hydrogen, deuterium, hydroxyl, halogen, oxo, CN, NO2, SiR c R d R e C(O)R g CO2R g NR h SO2R j S(O)R j SO2R j C(O) NR h R i SO2NR h R i NR h R i NR h C(O)R g C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C3-C7 cycloalkyl, C1-C6 alkoxy, C1-C6 alkoxy, C6-C 14 aryl, 5-14 membered heteroaryl and 3-8 membered heterocyclic groups, wherein the C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C3-C7 cycloalkyl, C1-C6 alkoxy, C6-C 14 Aryl, 5-14 membered heteroaryl and 3-8 membered heterocyclic group are each optionally bounded by one or more R L replace; R g Independently selected from hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 14 Aryl and 5-14 heteroaryl groups; R j Independently selected from C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 14 Aryl and 5-14 heteroaryl groups; R h and R i Each is independently selected from hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, and 4-7 membered heterocyclic groups, or, R h and R i Together with the nitrogen atom it is attached to, it forms a 4-7 membered heterocyclic group; R L Independently selected from hydrogen, deuterium, halogen, hydroxyl, CN, C(O)R m NR n R o C(O)NR n R o NR n C(O)R m SiR c R d R e C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C3-C7 cycloalkyl, C1-C6 alkoxy, C6-C 14 Aryl, 5-14 membered heteroaryl and 3-8 membered heterocyclic; R c , R d , R e each independently is selected from the group consisting of Ci-C6-alkyl, phenyl; R m Independently selected from hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 14 Aryl and 5-14 membered heteroaryl; R n and R o Each is independently selected from hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 14 aryl and 5-14 heteroaryl, or R n and R o Together with the nitrogen atom it is attached to, it forms a 4-7 membered heterocyclic group.

2. The tripeptide compound or its stereoisomer, tautomer, pharmaceutically acceptable salt, polymorph, co-crystal, solvate, metabolite, prodrug or any mixture of two or more thereof as claimed in claim 1, wherein, The compound represented by Formula I R1 is selected from hydrogen, C1-C6 alkyl, C6-C 14 Aryl, 3-7 membered heterocyclic groups, wherein the C1-C6 alkyl, C6-C 14 Aryl and 3-7 membered heterocyclic groups are each optionally surrounded by one or more R f replace; R2 and R3 are each independently selected from hydrogen and C1-C6 alkyl groups, wherein the C1-C6 alkyl group is affected by one or more R... f replace; Alternatively, R1 and R2 together with the nitrogen and carbon atoms they are attached to form a 4-7 membered heterocyclic group, which is then atomized by one or more R atoms. f replace; or R2and R3together with the nitrogen atom to which they are attached form a 4-7 membered heterocyclyl group, said 4-7 membered heterocyclyl group being substituted by one or more R f substituents; R f Independently selected from hydrogen, deuterium, hydroxyl, C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 alkoxy, C6-C 14 aryl, 5-14 membered heteroaryl and 3-8 membered heterocyclic, wherein the C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 alkoxy, C6-C 14 Aryl, 5-14 membered heteroaryl and 3-8 membered heterocyclic group are each optionally bounded by one or more R L replace; R L Independently selected from hydrogen, deuterium, halogen, hydroxyl, C1-C6 alkyl, CN, SiR c R d R e C(O)R m NR n R o C(O)NR n R o NR n C(O)R m and 3-8 membered heterocyclic groups; R c , R d , R e each independently is selected from the group consisting of Ci-C6-alkyl and phenyl; R m Independently selected from hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 14 Aryl and 5-14 membered heteroaryl; R n and R o Each is independently selected from hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 14 aryl and 5-14 heteroaryl, or, R n and R o Together with the nitrogen atom it is attached to, it forms a 4-7 membered heterocyclic group.

3. The tripeptide compound according to claim 1, or its stereoisomers, tautomers, pharmaceutically acceptable salts, polymorphs, cocrystals, solvates, metabolites, prodrugs, or any mixture of two or more thereof, characterized in that, The tripeptide compound is the compound shown in Formula II. R1 is selected from hydrogen, C1-C6 alkyl, C6-C 14 Aryl, the C1-C6 alkyl, C6-C 14 Each aryl group is optionally bounded by one or more R f replace; R2is selected from hydrogen and C1-C6alkyl, said C1-C6alkyl optionally substituted with one or more R f substituted; or R1and R2together with the nitrogen and carbon atom to which they are attached form a 4-7 membered heterocyclyl group, optionally substituted with one or more R f substituents; R f Independently selected from hydrogen, deuterium, hydroxyl, C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 14 aryl, 5-14 heteroaryl, wherein the C1-C6 alkyl, C3-C7 cycloalkyl, C6-C 14 Aryl and 5-14 heteroaryl groups are each optionally bounded by one or more R groups. L replace; R L Independently selected from hydrogen, deuterium, halogen, hydroxyl, C1-C4 alkyl, CN, SiR c R d R e C(O)R m NR n R o C(O)NR n R o NR n C(O)R m and 3-8 membered heterocyclic groups; R c , R d , R e each independently is selected from the group consisting of Ci-C6-alkyl and phenyl.

4. The tripeptide compound according to claim 3, or its stereoisomers, tautomers, pharmaceutically acceptable salts, polymorphs, cocrystals, solvates, metabolites, prodrugs, or any mixture of two or more thereof, characterized in that, The compound represented by Formula II R1is selected from hydrogen, phenyl and C1-C6alkyl, said C1-C6alkyl being substituted by one or more R f substituted; R2is selected from hydrogen and Ci-C6alkyl, said Ci-C6alkyl being substituted by one or more R f substituted; Alternatively, R1 and R2 together with the nitrogen and carbon atoms they are attached to form a 4-6 membered heterocyclic group, which is optionally surrounded by one or more R atoms. f replace; R f independently selected from hydrogen, hydroxyl, and C1-C4alkyl, said C1-C4alkyl being substituted with one or more R L substituents; R L independently selected from hydrogen, hydroxyl, C1-C4alkyl, and SiR c R d R e ; R c R d R e Each is independently selected from C1-C6 alkyl and phenyl groups.

5. The tripeptide compound or its stereoisomer, tautomer, pharmaceutically acceptable salt, polymorph, co-crystal, solvate, metabolite, prodrug or any mixture of two or more thereof, according to claims 1-4, characterized in that, The compound represented by Formula II R1is selected from hydrogen, phenyl and C1-C4alkyl, said C1-C4alkyl optionally being substituted by one or more R f substituted; R2is selected from hydrogen, methyl and ethyl, said methyl or ethyl being substituted by one or more R f substituted; Alternatively, R1 and R2 together with the nitrogen and carbon atoms they are attached to form a 4-6 membered heterocyclic group, which is optionally surrounded by one or more R atoms. f replace; R f Independently selected from hydrogen, hydroxyl, and C1-C3 alkyl, wherein the C1-C3 alkyl group is separated by one or more R L replace; R L Independently selected from hydrogen, hydroxyl, methyl, ethyl and SiR c R d R e ; R c , R d , R e each independently is C1-C3 alkyl.

6. The tripeptide compound according to claim 3, or its stereoisomers, tautomers, pharmaceutically acceptable salts, polymorphs, cocrystals, solvates, metabolites, prodrugs, or any mixture of two or more thereof, characterized in that, Selected from the following compounds: 。 7. A method for preparing the tripeptide compound according to any one of claims 1-6, characterized in that, Its synthetic route is as follows: ， In the formula, PG is the protecting base; the definitions of R1 and R2 are the same as those in claim 1 or 3. The method includes the following steps: Step 1: Compounds SM-1 and SM-2 undergo an acid-amine condensation reaction in the presence of a condensing agent to generate compound IM-1; Step 2: Remove the protecting group from compound IM-1 under alkaline or acidic conditions to generate IM-2; Step 3: Compounds IM-2 and SM-3 undergo an acid-amine condensation reaction in the presence of a condensing agent to generate compound IM-3; Step 4: Compound IM-3 is reacted with triethylsilyltrifluoromethanesulfonate or triethylchlorosilane to generate compound I.

8. A pharmaceutical composition, characterized by, The compound comprises any one of the tripeptide compounds of claims 1 to 6, or stereoisomers, tautomers, pharmaceutically acceptable salts, polymorphs, cocrystals, solvates, metabolites, prodrugs, or any mixture of two or more thereof, and one or more pharmaceutically acceptable carriers or pharmaceutical excipients.

9. A pharmaceutical preparation, characterized in that, The formulation comprises, as an active ingredient, any of the tripeptide compounds of claims 1 to 6 or their pharmaceutically acceptable salts, esters, solvates, isomers, any crystal forms or racemates thereof, their metabolite forms, or mixtures thereof, and the formulation is a solid, semi-solid, liquid, or gaseous formulation.

10. The use of the compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt, ester, solvate, isomer, any crystal form or racemate thereof, metabolite form thereof, or mixture thereof, in the manufacture of a medicament for the treatment or prevention of triple-negative breast cancer.

11. Use of the pharmaceutical composition of claim 8 in the manufacture of a medicament for the treatment or prevention of triple-negative breast cancer.

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