An antitumor macrolide polymer and a preparation method and application thereof

Abstract

The present application relates to the field of polymer chemistry and biomedical technology, and particularly relates to a macrocyclic lactone polymer shown in formula (I) which is used for preventing or treating hyperproliferative diseases, including liver cancer, leukemia, breast cancer, colon adenocarcinoma, gastric cancer, lung cancer, Barrett's esophageal cancer, cervical cancer, pancreatic cancer, endometrial cancer, bone cancer, lymphoma, kidney cancer, brain cancer, nerve cancer, nasopharyngeal cancer, oral cancer, bladder cancer, colorectal cancer and melanoma, and has the potential to be developed into a new type of antitumor drug.

Description

Technical Field

[0001] This invention belongs to the field of polymer chemistry and biomedical technology, specifically relating to a macrocyclic lactone polymer, a composition, its preparation method and application, wherein the compound or composition has the use of inhibiting tumor proliferation activity and can be used to prevent or treat hyperproliferative diseases. Background Technology

[0002] Brefeldin A (BFA) is a macrolide fungal metabolite. It was isolated in 1958 by Singleton et al. from *Penicillium decumbens* (Singleton, VL et al.). Nature (1958, 181, 1072-1073), whose absolute configuration was determined in 1971 by Weber et al. through single crystal, CD, and asymmetric synthesis (Weber, HPet, al.). Helv. Chim. Acta , 1971, 54 (2763-2766). However, BFA is not suitable for clinical use due to its undesirable pharmacokinetic properties (low bioavailability, poor water solubility, low plasma exposure, short plasma half-life, and high toxicity) (Sausville, EA et al.). Cancer. J. Sci. Am. 1996, 2 (52-58). To date, there are no reports on BFA derivatives that can effectively improve pharmacokinetic properties, or other properties such as increasing solubility and reducing toxicity.

[0003] In recent years, nanomedicines have attracted increasing scientific attention due to their significant advantages, such as improved drug solubility, prolonged drug circulation time, and enhanced drug accumulation at tumor sites through enhanced permeability and retention (EPR). Targeted nanomedicines have become an effective means of treating cancer, and to date, several nanomedicines have been used clinically and commercially for the treatment of certain diseases. Therefore, to overcome the aforementioned shortcomings, structural modification of BFA by coupling it with hydrophilic polymer segments via linkers has gained attention, with the aim of finding compounds that can maintain high antitumor activity while possessing favorable pharmacokinetic properties for clinical application. Summary of the Invention

[0004] The following is a summary description of some aspects of the invention and is not intended to limit it. These aspects and other parts are described in more detail below. All references in this specification are incorporated herein by reference in their entirety. In the event of any discrepancy between the disclosure in this specification and the cited references, the disclosure in this specification shall prevail.

[0005] This invention provides a novel class of macrolide derivatives for the prevention or treatment of proliferative diseases, such as liver cancer, leukemia, breast cancer, colonic adenocarcinoma, gastric cancer, lung cancer, Bartholin's esophagus cancer, cervical cancer, pancreatic cancer, endometrial cancer, bone cancer, lymphoma, kidney cancer, brain cancer, neurogenic cancer, nasopharyngeal carcinoma, oral cancer, bladder cancer, colorectal cancer, and melanoma. The compounds of this invention are stable and have good safety profiles. They can significantly increase the content of macrolides (BFA) in mammals (increasing plasma Cmax and plasma exposure), greatly improving the problem of unsatisfactory in vivo efficacy caused by the undesirable pharmacokinetic properties of BFAs, thus possessing good prospects for clinical application.

[0006] The present invention also provides methods for preparing these compounds, pharmaceutical compositions comprising these compounds, and methods for treating the aforementioned diseases in mammals, particularly humans, using these compounds or compositions.

[0007] Specifically, the present invention relates to a macrocyclic lactone polymer, characterized in that it is a compound of formula (I) or a stereoisomer, geometric isomer, tautomer, nitride, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt, or prodrug thereof.

[0008] (I),

[0009] Where R1 and R2 are each independently H or R1 and R2 cannot both be H; L is selected from disulfide bonds, two-carbon bonds, hydrazone bonds, polypeptides, and glucuronides.

[0010] Z is Y is selected from polyethylene glycol, polyvinylpyrrolidone, polyoxazoline, polyacrylic acid, polyethyleneimine, chitosan, dextran, hyaluronic acid, hydroxyethyl cellulose and their functional derivatives; G is selected from folic acid, RGD peptide, RGD-derived polypeptide, LyP-1, vasoactive intestinal peptide VIP, penetrating peptide F3 or is not present.

[0011] In some embodiments, Y is selected from mPEG-NH2, mPEG-COOH, mPEG-acetic acid, mPEG-succinic acid, mPEG-glutaric acid, mPEG-succinic acid, mPEG-glutaramide acid, mPEG-OH, mPEG-SH, mPEG-maleimide, mPEG-Br, mPEG-CHO, mPEG-propylene oxide, mPEG-alkynyl, mPEG-silane, mPEG-CH2-COOH, mPEG-benzaldehyde, mPEG-nitrobenzene, mPEG-dopamine, mPEG-isocyanate, mPEG-biotin, mPEG-folic acid, mPEG-glycerol, mPEG-N3, mPEG-succinimide ester, mPEG-succinimide carbonate, mPEG-succinimide acetate, mPEG-succinimide succinate, mPEG-succinimide glutarate, mPEG-succinamide succinimide ester, mPEG-glutaramide succinimide ester mPEG-succinimide propionate, mPEG-succinimide butyrate, mPEG-succinimide valerate, COOH-mPEG-COOH, acetic acid-mPEG-acetic acid, succinic acid-mPEG-succinic acid, glutaric acid-mPEG-glutaric acid, succinamide acid-mPEG-succinamide acid, glutaramide acid-mPEG-glutaramide acid, NH2-mPEG-NH2, SH-mPEG-SH, maleimide-mPEG-maleimide, succinimide carbonate-mPEG-succinimide carbonate, succinimide acetate-mPEG-succinimide acetate, succinimide succinate-mPEG-succinimide succinate, succinimide glutarate-mPEG-succinimide glutarate, succinamide succinimide ester-mPEG-succinamide succinimide ester Glutaramide succinimide ester (mPEG-glutaramide succinimide ester), succinimide propionate (mPEG-succinimide propionate), succinimide butyrate (mPEG-succinimide butyrate), succinimide valerate (mPEG-succinimide valerate), N3-mPEG-N3, alkynyl-mPEG-alkynyl, silane-mPEG-silane, CHO-mPEG-CHO, isocyanate-mPEG-isocyanate, biotin-mPEG-biotin, folic acid-mPEG-folic acid, benzaldehyde-mPEG-benzaldehyde, nitrobenzene-mPEG-nitrobenzene, silane-mPEG-silane, succinimide ester (mPEG-succinimide ester), ethylene oxide-mPEG-propylene oxide, DNP-mPEG-DNP, OH-mPEG-OH NH2-mPEG-DNP, NH2-mPEG-mannose,NH2-mPEG-SH, NH2-mPEG-maleimide, NH2-mPEG-N3, NH2-mPEG-phospholipid, NH2-mPEG-folic acid, NH2-mPEG-alkynyl, NH2-mPEG-acrylamide, NH2-mPEG-silane, NH2-mPEG-biotin, NH2-mPEG-mercaptopyridine, NH2-mPEG-tert-butyl ester, NH2-mPEG-DNP, NH2-mPEG-COOH, NH2-mPEG-OH, NH2-mPEG-CHO, COOH-mPEG-SH, COOH-mPEG-maleimide, COOH-mPEG-N3, COOH-mPEG-alkynyl, COOH-mPEG-mercaptopyridine, COOH-mPEG-biotin, COOH-mPEG-silane, COOH-mPEG-acrylamide, COOH-mPEG-folic acid COOH-mPEG-succinimide ester, COOH-mPEG-OH, COOH-mPEG-DNP, COOH-mPEG-Br, COOH-mPEG-CHO, COOH-mPEG-COOMe, COOH-mPEG-tert-butyl ester, SH-mPEG-OH, SH-mPEG-N3, SH-mPEG-alkynyl, SH-mPEG-mercaptopyridine, SH-mPEG-biotin, SH-mPEG-silane, SH-mPEG-phospholipid, SH-mPEG-folic acid, SH-mPEG-mannose, OH-mPEG-succinimide ester, OH-mPEG-acrylamide, OH-mPEG-mercaptopyridine, OH-mPEG-silane, OH-mPEG-maleimide, OH-mPEG-phospholipid, OH-mPEG-folic acid, OH-mPEG-CHO, OH-mPEG-DNP, OH-mPEG-Br, OH-mPEG-Biotin, OH-mPEG-Alkyne, OH-mPEG-T-butyl Acetate, OH-mPEG-N3, Maleimide-mPEG-N3, Maleimide-mPEG-Alkyne, Maleimide-mPEG-Silane, Maleimide-mPEG-Folic Acid, N3-mPEG-Alkyne, N3-mPEG-Acrylamide, N3-mPEG-Mercaptopyridine, N3-mPEG-Biotin, N3-mPEG-Silane, N3-mPEG-Folic Acid, N3-mPEG-T-butyl Acetate, Polyvinylpyrrolidone, Polyoxazoline, Polyacrylic Acid, Polyethyleneimine, Chitosan, Dextran, Hyaluronic Acid, Hydroxyethylcellulose, RGD-mPEG-NH2, RGD-mPEG-COOH, RGD-mPEG-SH, RGD-mPEG-N3,RGD-mPEG-folate, cRGD-mPEG-NH2, cRGD-mPEG-COOH, cRGD-mPEG-SH,cRGD-mPEG-N3, cRGD-mPEG-folate, iRGD-mPEG-NH2, iRGD-mPEG-COOH, iRGD-mPEG-SH,iRGD-mPEG-N3, iRGD-mPEG-folate. ,

[0012] In some embodiments, the molecular weight of the polymer is between 300 and 20,000.

[0013] In some embodiments, the present invention relates to structures or stereoisomers thereof, nitrides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof, but is by no means limited to these compounds:

[0014] .

[0015] On the other hand, the present invention relates to a pharmaceutical composition comprising the compounds disclosed herein.

[0016] In some embodiments, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable excipient, carrier, adjuvant, solvent, or combination thereof.

[0017] Optionally, the excipient is selected from diluents, fillers, binders, disintegrants, lubricants, flow aids, granulators, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, flavor masking agents, colorants, anti-caking agents, humectants, chelating agents, plasticizers, thickeners, antioxidants, preservatives, stabilizers, surfactants, or buffers.

[0018] Optionally, the carrier is selected from disintegrants, controlled-release polymers, lubricants, diluents, or colorants.

[0019] On the other hand, the present invention relates to the use of the compounds or pharmaceutical compositions disclosed herein in the preparation of a medicament for the prevention or treatment of hyperproliferative diseases in mammals, including humans; wherein the hyperproliferative diseases include liver cancer, leukemia, breast cancer, colon adenocarcinoma, gastric cancer, lung cancer, Bartholin's esophagus cancer, cervical cancer, pancreatic cancer, endometrial cancer, bone cancer, lymphoma, kidney cancer, brain cancer, neurogenic cancer, nasopharyngeal carcinoma, oral cancer, bladder cancer, colorectal cancer, and melanoma.

[0020] Biological test results show that the compounds provided by this invention can inhibit tumor proliferation.

[0021] Any embodiment of any aspect of the present invention can be combined with other embodiments, provided that they do not contradict each other. Furthermore, any technical feature in any embodiment of any aspect of the present invention can be applied to the same technical feature in other embodiments, provided that they do not contradict each other.

[0022] The foregoing description only outlines certain aspects of the invention, but is not limited to these aspects. These and other aspects will be described in more detail below.

[0023] Detailed Description of the Invention

[0024] Definitions and general terms

[0025] Certain embodiments of the invention will now be described in detail, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover all alternatives, modifications, and equivalents, all of which are included within the scope of the invention as defined in the claims. Those skilled in the art will recognize that many similar or equivalent methods and materials can be used to practice the invention. The invention is by no means limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ from or contradict this application (including, but not limited to, defined terminology, application of terminology, described techniques, etc.), this application shall prevail.

[0026] It should be further appreciated that certain features of the invention, for clarity, have been described in multiple independent embodiments, but may also be provided in combination in a single embodiment. Conversely, various features of the invention, for brevity, have been described in a single embodiment, but may also be provided individually or in any suitable sub-combination.

[0027] Unless otherwise stated, all technical terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art. All patents and publications related to this invention are incorporated herein by reference in their entirety.

[0028] Unless otherwise stated, the following definitions shall apply as used herein. For the purposes of this invention, chemical elements are consistent with the CAS edition of the periodic table and the Handbook of Chemistry and Physics, 75th edition, 1994. Furthermore, general principles of organic chemistry can be found in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

[0029] Unless otherwise stated or there is a clear conflict in the context, the articles “a,” “an,” and “described” as used herein are intended to include “at least one” or “one or more.” Therefore, these articles as used herein refer to articles for one or more (i.e., at least one) objects. For example, “a component” refers to one or more components, meaning that more than one component may be considered for use or adoption in the implementation of the described embodiments.

[0030] As used in this invention, the term "test subject" refers to an animal. Typical animals are mammals. Test subjects also include, for example, primates (e.g., humans, males or females), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In some embodiments, the test subject is a primate. In other embodiments, the test subject is a human.

[0031] As used in this invention, the term "patient" refers to a person (including adults and children) or other animal. In some embodiments, "patient" refers to a person.

[0032] The term "comprising" is an open-ended expression, meaning it includes the contents specified in this invention, but does not exclude other aspects.

[0033] "Stereoisomers" are compounds that have the same chemical structure but whose atoms or groups are arranged differently in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis / trans) isomers, and hindered isomers, etc.

[0034] "Chirality" refers to molecules that have the property that they cannot be superimposed on their mirror image; while "chirality" refers to molecules that can be superimposed on their mirror image.

[0035] "Enantiomers" refer to two non-overlapping but mirror-image isomers of a compound.

[0036] A diastereomer is a stereoisomer that has two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties, and reactivity. Mixtures of diastereomers can be separated by high-resolution analytical procedures such as electrophoresis and chromatography, for example, HPLC.

[0037] The stereochemical definitions and rules used in this invention generally follow those of S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds,” John Wiley & Sons, Inc., New York, 1994.

[0038] Many organic compounds exist in an optically active form, meaning they possess the ability to rotate the plane of plane-polarized light. When describing optically active compounds, the prefixes D and L are used. R and S To indicate the absolute configuration of a molecule with respect to one or more chiral centers. Prefix d and l Or (+) and (−) are symbols used to specify the rotation of plane-polarized light caused by a compound, where (−) or l This indicates that the compound is levorotatory. The prefix is ​​(+) or... d The compound is dextrorotatory. A specific stereoisomer is an enantiomer, and a mixture of such isomers is called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in the chemical reaction.

[0039] Any asymmetric atom (e.g., carbon, etc.) in the compounds disclosed in this invention can exist in racemic or enantiomerically enriched forms, for example ( R )-、( S )-or( R, S The asymmetric atom exists in a configuration form. In some implementations, the asymmetric atoms are in ( R )-or( S - In terms of configuration, it has at least 50% enantiomer excess, at least 60% enantiomer excess, at least 70% enantiomer excess, at least 80% enantiomer excess, at least 90% enantiomer excess, at least 95% enantiomer excess, or at least 99% enantiomer excess.

[0040] Depending on the choice of starting materials and method, the compounds of this invention can exist as one or a mixture of possible isomers, such as racemic mixtures and diastereomers (depending on the number of asymmetric carbon atoms). Optically active ( R )-or( S The )-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be E or Z configurations; if the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituents may be cis or trans configurations.

[0041] Any mixture of stereoisomers obtained can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physicochemical properties of the components, for example, by chromatography and / or fractional crystallization.

[0042] Racemates of any resulting end product or intermediate can be separated into optical enantiomers using known methods, such as by separating the salts of their diastereomers. Racemate products can also be separated by chiral chromatography, such as high-performance liquid chromatography (HPLC) using chiral adsorbents. In particular, enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2 ndEd. Robert E. Gawley, Jeffrey Aubé, Elsevier, Oxford, UK, 2012); Eliel, EL Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SH Tables of Resolving Agents and Optical Resolutions p.268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972); ChiralSeparation Techniques: A Practical Approach (Subramanian, G. Ed., Wiley-VCHVerlag GmbH&Co. KGaA, Weinheim, Germany, 2007).

[0043] As described in this invention, the compounds of this invention may optionally be substituted with one or more substituents, such as the general formula compounds above, or as the specific examples, subclasses, and a class of compounds included in this invention.

[0044] Additionally, it should be noted that, unless otherwise explicitly stated, the descriptive terms “each…independently is”, “…each…independently is”, and “…independently is” used in this invention are interchangeable and should be interpreted broadly. They can mean that the specific options expressed by the same symbols in different groups do not affect each other, or that the specific options expressed by the same symbols in the same group do not affect each other.

[0045] The term "prodrug" as used in this invention refers to the conversion of a compound into the compound represented by formula (I) in vivo. Such conversion is influenced by the hydrolysis of the prodrug in the blood or its enzymatic conversion into the parent structure in the blood or tissues. The prodrug compounds of this invention can be esters; among existing inventions, esters that can serve as prodrugs include phenyl esters and aliphatic (C1-C1) esters. 24Esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, one compound in this invention contains a hydroxyl group, meaning it can be acylated to yield a prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a parent hydroxyl group. A complete discussion of prodrugs can be found in the following literature: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACS Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al. , Prodrugs: Design and ClinicalApplications, Nature Reviews Drug Discovery ,2008, 7, 255-270, and SJHecker et al. , Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry ,2008, 51, 2328-2345.

[0046] "Metabolic products" refer to the products obtained from the metabolism of a specific compound or its salt in vivo. The metabolites of a compound can be identified using techniques known in the art, and their activity can be characterized by experimental methods as described in this invention. Such products can be obtained by administering the compound through oxidation, reduction, hydrolysis, acylation, deacylation, esterification, defatting, enzymatic cleavage, etc. Accordingly, this invention includes the metabolites of compounds, including metabolites produced by sufficiently exposing the compounds of this invention to mammals for a period of time.

[0047] The term "pharmaceutically acceptable salt" as used in this invention refers to the organic and inorganic salts of the compounds of this invention. Pharmaceutically acceptable salts are well-known in the field, as described in references such as SM Berge. et al.The text describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19. These include, but are not limited to, inorganic acid salts formed by reactions with amino groups, such as hydrochlorides, hydrobroms, phosphates, sulfates, and perchlorates, and organic acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or other methods described in the literature, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, transbutenedioic acid, glucono-p-gluconate, glyceryl phosphate, gluconate, hemisulfate, heptanate, hexanoate, hydroiodate, 2-hydroxy-ethanesulfonate, lacturonate, lactate, laurate, lauryl sulfate, malate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pyruvate, pectinate, persulfate, 3-phenylpropionate, picrate, pentanoate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts obtained by means of appropriate bases include alkali metals, alkaline earth metals, ammonium, and nitrogen. + (C 1-4 Salts of alkyl groups (4). This invention also contemplates quaternary ammonium salts formed from any compound containing an N group. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts, and amine cations resistant to the formation of equilibrium ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C 1-8 Sulfonates and aromatic sulfonates.

[0048] In this invention, "solvent" refers to an association formed by one or more solvent molecules with the compound of this invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association formed when the solvent molecules are water.

[0049] When the solvent is water, the term "hydrate" may be used. In some embodiments, one molecule of the compound of the present invention may bind to one water molecule, such as a monohydrate; in other embodiments, one molecule of the compound of the present invention may bind to more than one water molecule, such as a dihydrate; and in still other embodiments, one molecule of the compound of the present invention may bind to fewer than one water molecule, such as a hemihydrate. It should be noted that the hydrates of the present invention retain the bioavailability of the non-hydrated form of the compound.

[0050] The term "solubility" as used in this invention refers to the mass of solute that dissolves in 100g of solvent at a given temperature to reach saturation. For solubility testing, please refer to the following literature: (ZHU Shang-bin, et al. Preparation, characterization, and physicochemical properties of arbutinphospholipid complex[J]. Chinese Traditional and Herbal Drugs.2020:1-10).

[0051] As used herein, the term "treatment" for any disease or condition refers to anything that can slow, interrupt, prevent, control, or stop the progression of the disease or condition, but does not necessarily mean the complete disappearance of all symptoms of the disease or condition. It also includes preventative treatment of said symptoms, particularly in patients susceptible to such diseases or disorders. In some embodiments, "treatment" refers to improving the disease or condition (i.e., slowing, preventing, or alleviating the development of the disease or at least one of its clinical symptoms). In other embodiments, "treatment" refers to alleviating or improving at least one bodily parameter, including bodily parameters that may not be perceptible to the patient. In still other embodiments, "treatment" refers to regulating the disease or condition physically (e.g., stabilizing perceptible symptoms) or physiologically (e.g., stabilizing bodily parameters), or both. In still other embodiments, "treatment" refers to preventing or delaying the onset, occurrence, or worsening of the disease or condition.

[0052] As used herein, the terms "therapeutic effective amount" or "therapeutic effective dose" refer to the amount of the compound of the present invention capable of eliciting a biological or medical response in an individual (e.g., reducing or inhibiting enzyme or protein activity, or improving symptoms, alleviating symptoms, slowing or delaying disease progression, or preventing disease, etc.). In one non-limiting embodiment, the term "therapeutic effective amount" refers to the amount that, when administered to an individual, is effective in: (1) at least partially alleviating, inhibiting, preventing, and / or improving tumor proliferation. In another embodiment, the term "therapeutic effective amount" refers to the amount of the compound of the present invention that, when administered to cells, organs, non-cellular biological substances, or media, is effective in at least partially reducing or inhibiting tumor proliferation.

[0053] As used herein, the term "composition" refers to a product comprising a specified amount of a specified ingredient, or any product directly or indirectly produced by a combination of specified amounts of a specified ingredient. In the context of pharmaceutical compositions, this term includes products comprising an active ingredient (single or multiple) and an inert ingredient (single or multiple) constituting a carrier, as well as any product directly or indirectly produced by mixing, compounding, or aggregating any two or more ingredients, or by decomposing one or more ingredients, or by other types of reactions or interactions of one or more ingredients. Therefore, pharmaceutical compositions of the present invention include any compositions prepared by mixing the compounds of the present invention with a pharmaceutically acceptable carrier.

[0054] The compounds disclosed in this invention may contain asymmetric or chiral centers, and therefore may exist in different stereoisomeric forms. This invention aims to include all stereoisomeric forms of the compounds shown in formula (I), including but not limited to diastereomers, enantiomers, transasterisomers, and geometric (or conformational) isomers, as well as mixtures thereof such as racemic mixtures, as part of this invention.

[0055] In the structures disclosed in this invention, when the stereochemistry of any particular chiral atom is not specified, all stereoisomers of that structure are considered within the scope of this invention and are included in this invention as disclosed compounds. When the stereochemistry is indicated by a solid wedge or dashed line representing a particular configuration, the stereoisomers of that structure are thus clearly defined.

[0056] The compound shown in formula (I) may exist in different tautomer forms, and all such tautomers are included within the scope of this invention.

[0057] The compound shown in formula (I) may exist in the form of a salt. In one embodiment, the salt refers to a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" means that the substance or composition must be chemically and / or toxicologically compatible with other components comprising the formulation and / or the mammals treated therewith. In another embodiment, the salt is not necessarily a pharmaceutically acceptable salt and may be an intermediate used for the preparation and / or purification of the compound shown in formula (I) and / or for the isolation of enantiomers of the compound shown in formula (I).

[0058] Pharmaceutically usable acid addition salts can be formed by the reaction of the compounds disclosed in this invention with inorganic or organic acids, such as acetates, aspartates, benzoates, benzenesulfonates, bromides / hydrobromoates, bicarbonates / carbonates, hydrogen sulfates / sulfates, camphor sulfonates, chlorides / hydrochlorides, theophylline salts, citrates, ethanedisulfonates, fumarates, gluconate, gluconate, glucuronide, hippurate, hydroiodide / iodide, hydroxyethyl sulfonate, lactates, lacturonide, lauryl sulfate, malates, maleates, malonates, mandelates, methanesulfonates, methyl sulfates, naphthates, naphthalenesulfonates, nicotinates, nitrates, stearates, oleates, oxalates, palmitates, pyrates, phosphates / hydrogen phosphates / dihydrogen phosphates, polygalactosates, propions, stearates, succinates, sulfosalicylates, tartrates, toluenesulfonates, and trifluoroacetates.

[0059] Pharmaceutical alkali addition salts can be formed by the reaction of the compounds disclosed in this invention with inorganic or organic bases.

[0060] Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from Groups I to XII of the periodic table. In some embodiments, the salt is derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium, and magnesium salts.

[0061] Organic bases from which salts can be derived include primary, secondary, and tertiary amines. Substituted amines include naturally occurring substituted amines, cyclic amines, and basic ion exchange resins. Some organic amines include, for example, isopropylamine, benzathine penicillin, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0062] The pharmaceutically acceptable salts of the present invention can be synthesized using conventional chemical methods from a parent compound, a basic or acidic moiety. Generally, these salts can be prepared by reacting the free acidic form of these compounds with a stoichiometric amount of a suitable base (such as hydroxides, carbonates, bicarbonates, etc. of Na, Ca, Mg, or K), or by reacting the free basic form of these compounds with a stoichiometric amount of a suitable acid. These reactions are typically carried out in water or an organic solvent or a mixture thereof. Generally, in suitable cases, a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is required. Other lists of suitable salts can be found in, for example, “Remington’s Pharmaceutical Sciences”, 20th edition, Mack Publishing Company, Easton, Pa., (1985); and “Handbook of Pharmaceutical Salts: Properties, Selection, and Use”, Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0063] Furthermore, the compounds disclosed in this invention, including their salts, can also be obtained in their hydrated form or in the form containing their solvents (e.g., ethanol, DMSO, etc.) for their crystallization. The compounds disclosed in this invention can inherently or by design form solvates with pharmaceutically acceptable solvents (including water); therefore, this invention is intended to include both solvated and unsolvated forms of the compounds disclosed in this invention.

[0064] Any structural formulas provided in this invention are intended to represent both the unenriched and isotopically enriched forms of these compounds. Isotopically enriched compounds have the structures described by the general formulas provided in this invention, except that one or more atoms are replaced by atoms having a chosen atomic weight or mass number. Exemplary isotopes that may be introduced into the compounds of this invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as... 2 H, 3 H, 11 C 13 C 14 C 15 N、 17 O、 18 O、 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I.

[0065] On the other hand, the compounds described in this invention include isotopically enriched compounds as defined in this invention, for example, compounds containing radioactive isotopes, such as... 3 H, 14 C and 18 Those compounds of F, or those containing non-radioactive isotopes, such as 2 H and 13 Compounds containing C. Compounds enriched in this type of isotope can be used for metabolic studies (using...). 14 C) Reaction kinetic studies (using, for example) 2 H or 3 H) Detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) which includes the determination of drug or substrate tissue distribution, may be used in the patient's radiotherapy. 18 F-enriched compounds are particularly desirable for PET or SPECT studies. The isotopically enriched compounds of formula (I) can be prepared using conventional techniques familiar to those skilled in the art, or by replacing the previously used unlabeled reagent with a suitable isotopically labeled reagent, as described in the examples and preparation procedures of this invention.

[0066] In addition, heavier isotopes, especially deuterium (i.e., 2 Substitution with H or D can provide certain therapeutic advantages resulting from increased metabolic stability. For example, this may lead to an increased half-life in vivo, a reduced dose requirement, or an improved therapeutic index. It should be understood that deuterium in this invention is considered a substituent in the compound represented by formula (I). The concentration of such heavier isotopes, particularly deuterium, can be defined using an isotope enrichment factor. As used in this invention, the term "isotope enrichment factor" refers to the ratio between the isotopic abundance of the specified isotope and its native abundance. If the substituents of the compounds of the present invention are designated as deuterium, the compounds have an isotopic enrichment factor of at least 3500 (52.5% deuterium doping at each designated deuterium atom), at least 4000 (60% deuterium doping), at least 4500 (67.5% deuterium doping), at least 5000 (75% deuterium doping), at least 5500 (82.5% deuterium doping), at least 6000 (90% deuterium doping), at least 6333.3 (95% deuterium doping), at least 6466.7 (97% deuterium doping), at least 6600 (99% deuterium doping), or at least 6633.3 (99.5% deuterium doping) with respect to each designated deuterium atom. Pharmaceutically applicable solvates of the present invention include those in which the crystallization solvent can be isotopically substituted, such as D2O, acetone, etc. d 6 DMSO- d 6 Those solvates.

[0067] On the other hand, the present invention provides a pharmaceutical composition comprising the compounds of the present invention. In one embodiment, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable carrier, excipient, adjuvant, solvent, or combination thereof. In another embodiment, the pharmaceutical composition may be a liquid, solid, semi-solid, gel, or spray formulation.

[0068] Pharmaceutical compositions, formulations and administration of the compounds of the present invention

[0069] The present invention provides a pharmaceutical composition comprising compounds disclosed herein, such as those listed in the examples; and pharmaceutically acceptable excipients, carriers, adjuvants, solvents, or combinations thereof.

[0070] This invention provides a method for treating, preventing, or improving diseases or conditions, comprising administering a safe and effective amount of a combination drug comprising the compounds disclosed in this invention and one or more therapeutically active agents. The combination drug comprises one or more drugs for the prevention or treatment of diseases including liver cancer, leukemia, breast cancer, colon adenocarcinoma, gastric cancer, lung cancer, Bartholin's esophagus cancer, cervical cancer, pancreatic cancer, endometrial cancer, bone cancer, lymphoma, kidney cancer, brain cancer, neurogenic cancer, nasopharyngeal carcinoma, oral cancer, bladder cancer, colorectal cancer, and melanoma, wherein the active ingredient of the drug is different from the compounds disclosed in this invention.

[0071] Drugs for the prevention or treatment of liver cancer, leukemia, breast cancer, colon adenocarcinoma, gastric cancer, lung cancer, Bartholin's esophagus cancer, cervical cancer, pancreatic cancer, endometrial cancer, bone cancer, lymphoma, kidney cancer, brain cancer, neurogenic cancer, nasopharyngeal carcinoma, oral cancer, bladder cancer, colorectal cancer, and melanoma include, but are not limited to: aromatase inhibitors, topoisomerase I inhibitors, topoisomerase II inhibitors, microtubule activators, alkylating agents, histone deacetylase inhibitors, compounds that induce cell differentiation, cyclooxygenase inhibitors, MMP inhibitors, Mtor inhibitors, antitumor antimetabolites, platinum compounds, compounds that target / reduce the activity of protein or lipid phosphokinases and other anti-angiogenic compounds, antiproliferative antibodies, heparanase inhibitors, Ras oncogenic inhibitors, telomerase inhibitors, proteasome inhibitors, or any combination thereof.

[0072] The dosage of the active ingredient in the compositions of this invention can be varied; however, the amount of the active ingredient must be such that a suitable dosage form is available. The active ingredient can be administered to patients (animals and humans) requiring this treatment at a dosage that provides optimal pharmaceutical efficacy. The chosen dosage depends on the desired therapeutic effect, the route of administration, and the duration of treatment. The dosage will vary from patient to patient, depending on the nature and severity of the disease, the patient's weight, the patient's specific diet, concomitant medications, and other factors that will be recognized by those skilled in the art. The dosage range is generally from about 0.5 mg to 1.0 g per patient per day, and can be administered as a single or multiple dose. In one embodiment, the dosage range is from about 0.5 mg to 500 mg per patient per day; in another embodiment, it is from about 0.5 mg to 200 mg per patient per day; and in yet another embodiment, it is from about 5 mg to 50 mg per patient per day.

[0073] It should also be recognized that certain compounds of the present invention may be present in free form and used for treatment, or, if appropriate, in the form of their pharmaceutically acceptable derivatives. Pharmaceutically acceptable derivatives include pharmaceutically acceptable prodrugs, salts, esters, salts of these esters, or any other adducts or derivatives that, when administered to a patient in need, directly or indirectly provide the compounds of the present invention or their metabolites or residues.

[0074] The pharmaceutical or pharmaceutical composition disclosed in this invention can be prepared and packaged in bulk form, wherein a safe and effective amount of the compound represented by formula (I) can be extracted and then administered to the patient in powder or syrup form. Typically, the drug is administered to the patient at a dose level between 0.0001 and 10 mg / kg body weight daily to achieve an effective effect. Alternatively, the pharmaceutical composition disclosed in this invention can be prepared and packaged in unit dosage forms, wherein each physically discrete unit contains a safe and effective amount of the compound represented by formula (I). When prepared in unit dosage forms, the pharmaceutical composition disclosed in this invention typically contains, for example, 0.5 mg to 1 g, or 1 mg to 700 mg, or 5 mg to 100 mg of the compound disclosed in this invention.

[0075] When the pharmaceutical composition of the present invention contains one or more other active ingredients in addition to the compound of the present invention, the weight ratio of the compound of the present invention to the second active ingredient can vary and depends on the effective dose of each ingredient. Typically, the effective dose of each ingredient is used. Therefore, for example, when the compound of the present invention is mixed with another pharmaceutical agent, the weight ratio of the compound of the present invention to the other pharmaceutical agent is typically in the range of about 1000:1 to about 1:1000, for example, about 200:1 to about 1:200. Mixtures of the compound of the present invention with other active ingredients are generally also within the above range, but in each case, the effective dose of each active ingredient should be used.

[0076] As used in this invention, "pharmaceuticalally acceptable excipient" refers to a pharmaceutically acceptable material, mixture, or solvent related to the consistency of the dosage form or pharmaceutical composition. Each excipient must be compatible with the other components of the pharmaceutical composition when mixed to avoid interactions that would significantly reduce the efficacy of the compounds disclosed in this invention when administered to a patient, and interactions that would result in a pharmaceutically unacceptable pharmaceutical composition. Furthermore, each excipient must be pharmaceutically acceptable, for example, having sufficiently high purity.

[0077] Suitable pharmaceutically acceptable excipients vary depending on the specific dosage form chosen. Furthermore, pharmaceutically acceptable excipients can be selected based on their specific function in the composition. For example, certain pharmaceutically acceptable excipients may be selected that contribute to the production of a uniform dosage form. Certain pharmaceutically acceptable excipients may be selected that contribute to the production of a stable dosage form. Certain pharmaceutically acceptable excipients may be selected that facilitate the carrying or transport of the compounds disclosed in this invention from one organ or part of the body to another organ or part of the body when administered to a patient. Certain pharmaceutically acceptable excipients may be selected that enhance patient compliance.

[0078] Suitable pharmaceutically acceptable excipients include the following types: diluents, fillers, binders, disintegrants, lubricants, flow aids, granulators, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, flavor masking agents, colorants, anti-caking agents, humectants, chelating agents, plasticizers, thickeners, antioxidants, preservatives, stabilizers, surfactants, and buffers. Those skilled in the art will recognize that some pharmaceutically acceptable excipients can provide more than one function and offer alternative functions, depending on the amount of that excipient present in the formulation and the other excipients present in the formulation.

[0079] Those skilled in the art possess the knowledge and skills to select appropriate amounts of suitable pharmaceutically acceptable excipients for use in this invention. Furthermore, numerous resources are available to those skilled in the art describing pharmaceutically acceptable excipients and for selecting suitable ones. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).

[0080] Various carriers for formulating pharmaceutically acceptable compositions and known techniques for their preparation are disclosed in Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. DB Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JCBoylan, 1988–1999, Marcel Dekker, New York, the contents of which are incorporated herein by reference. The use of any conventional carrier medium, except for those incompatible with the compounds of the invention (e.g., producing any adverse biological effects or otherwise interacting harmfully with any other component in the pharmaceutically acceptable composition), is covered within the scope of this invention.

[0081] The pharmaceutical compositions disclosed in this invention are prepared using techniques and methods known to those skilled in the art. Descriptions of some commonly used methods in the art can be found in Remington's Pharmaceutical Sciences (Mack Publishing Company).

[0082] Therefore, on the other hand, the present invention relates to a process for preparing pharmaceutical compositions comprising the compounds disclosed herein and pharmaceutically acceptable excipients, carriers, adjuvants, solvents, or combinations thereof, wherein the process includes mixing various components. Pharmaceutical compositions comprising the compounds disclosed herein can be prepared by mixing, for example, at ambient temperature and atmospheric pressure.

[0083] The compounds disclosed in this invention are generally formulated into dosage forms suitable for administration to patients via desired routes. For example, dosage forms include those suitable for the following routes of administration: (1) oral administration, such as tablets, capsules, sac tablets, pills, lozenges, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets, and sachets; (2) parenteral administration, such as sterile solutions, suspensions, and reconstituted powders; (3) transdermal administration, such as transdermal patches; (4) rectal administration, such as suppositories; (5) inhalation, such as aerosols, solutions, and dry powders; and (6) topical administration, such as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels.

[0084] In one embodiment, the compound disclosed in this invention can be formulated into an oral dosage form. In another embodiment, the compound disclosed in this invention can be formulated into an inhaled dosage form. In yet another embodiment, the compound disclosed in this invention can be formulated into a nasal dosage form. In still another embodiment, the compound disclosed in this invention can be formulated into a transdermal dosage form. In still another embodiment, the compound disclosed in this invention can be formulated into a topical dosage form.

[0085] The pharmaceutical compositions provided by this invention can be provided as compressed tablets, formulated tablets, chewable tablets, instant tablets, recompressed tablets, or enteric-coated tablets, sugar-coated tablets, or film-coated tablets. Enteric-coated tablets are compressed tablets coated with a substance resistant to gastric acid but dissolving or disintegrating in the intestine, thereby preventing the active ingredient from contacting the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which helps to mask unpleasant tastes or odors and prevents tablet oxidation. Film-coated tablets are compressed tablets covered with a thin layer or film of a water-soluble substance. Film coatings include, but are not limited to, hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coatings possess the same general properties as sugar coatings. Recompressed tablets are compressed tablets prepared through more than one compression cycle, including multilayer tablets and compressed-coated or dry-coated tablets.

[0086] Tablet dosage forms can be prepared from an active ingredient in powder, crystalline, or granular form, alone or in combination with one or more carriers or excipients described in this invention, including binders, disintegrants, controlled-release polymers, lubricants, diluents, and / or colorants. Flavoring agents and sweeteners are particularly useful in the formation of chewable tablets and lozenges.

[0087] The pharmaceutical compositions provided by this invention can be provided in soft or hard capsules, which can be prepared from gelatin, methylcellulose, starch, or calcium alginate. The hard gelatin capsules, also known as dry-filled capsules (DFC), consist of two segments, one inserted into the other, thus completely encapsulating the active ingredient. Soft elastic capsules (SEC) are soft, spherical shells, such as gelatin shells, which are plasticized by the addition of glycerol, sorbitol, or similar polyols. Soft gelatin shells may contain preservatives to prevent microbial growth. Suitable preservatives are those described in this invention, including methylparaben and propylparaben, and sorbic acid. Liquid, semi-solid, and solid dosage forms provided by this invention can be encapsulated in capsules. Suitable liquid and semi-solid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils, or triglycerides. Capsules containing such solutions can be prepared as described in U.S. Patents US Pat. Nos. 4,328,245; 4,409,239, and 4,410,545. The capsules may also be coated as is known to those skilled in the art, thereby improving or maintaining the dissolution of the active ingredients.

[0088] The pharmaceutical compositions provided by this invention can be provided in liquid and semi-solid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups. Emulsions are two-phase systems in which one liquid is completely dispersed in another liquid in the form of small spheres; they can be oil-in-water or water-in-oil. Emulsions may include pharmaceutically acceptable non-aqueous liquids and solvents, emulsifiers, and preservatives. Suspensions may include pharmaceutically acceptable suspending agents and preservatives. Aqueous alcoholic solutions may include pharmaceutically acceptable acetals, such as di(lower alkyl) acetals of lower alkyl aldehydes, such as acetaldehyde diethyl acetal; and water-soluble solvents having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs are clear, sweet aqueous alcoholic solutions. Syrups are concentrated aqueous solutions of sugars such as sucrose and may also contain preservatives. For liquid dosage forms, for example, solutions in polyethylene glycol may be diluted with a sufficient amount of a pharmaceutically acceptable liquid carrier, such as water, for precise and convenient administration.

[0089] Other useful liquid and semi-solid dosage forms include, but are not limited to, those containing the active ingredients provided by this invention and secondary mono- or poly-alkylene glycols, said mono- or poly-alkylene glycols including: 1,2-dimethoxymethane, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, tetraethylene glycol dimethyl ether, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750 refer to the approximate average molecular weight of polyethylene glycol. These formulations may further include one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarin, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates.

[0090] When appropriate, oral dosage units can be microencapsulated. They can also be formulated into compositions for prolonged or sustained release, for example, by coating or embedding particulate material in polymers, waxes, or the like.

[0091] The oral pharmaceutical compositions provided by this invention can also be provided in the form of liposomes, micelles, microspheres, or nanosystems. Micellar dosage forms can be prepared using the methods described in US Pat. No. 6,350,458.

[0092] The pharmaceutical compositions provided by this invention can be provided in non-effervescent or effervescent granules and powders for recombination into liquid dosage forms. Pharmaceutically acceptable carriers and excipients used in non-effervescent granules or powders may include diluents, sweeteners, and wetting agents. Pharmaceutically acceptable carriers and excipients used in effervescent granules or powders may include organic acids and carbon dioxide sources.

[0093] Colorants and flavorings can be used in all of the above dosage forms.

[0094] The compounds disclosed in this invention can also be combined with soluble polymers used as targeted drug carriers. Such polymers include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropyl methacrylamide-phenol, polyhydroxyethyl asparagine-phenol, or palmitoyl residue-substituted polyoxyethylene polylysine. Furthermore, the compounds disclosed in this invention can be combined with a class of biodegradable polymers used to achieve controlled drug release, such as crosslinked or amphiphilic block copolymers of polylactic acid, polyε-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyran, polycyanoacrylates, and hydrogels.

[0095] The pharmaceutical compositions provided by this invention can be formulated into immediate or modified release dosage forms, including delayed-release, sustained-release, pulsatile, controlled-release, targeted-release, and programmed-release forms.

[0096] The pharmaceutical compositions provided by this invention can be formulated with other active ingredients that do not impair the intended therapeutic effect, or with substances that complement the intended effect.

[0097] The pharmaceutical compositions provided by this invention can be administered parenterally via injection, infusion, or implantation for local or systemic drug delivery. Parenterial delivery methods used in this invention include intravenous, intra-arterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, intrasynovial, and subcutaneous administration.

[0098] The pharmaceutical compositions provided by this invention can be formulated into any dosage form suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and solid forms suitable for preparation as solutions or suspensions in liquids prior to injection. Such dosage forms can be prepared according to conventional methods known to those skilled in the art of pharmaceutical science (see Remington: The Science and Practice of Pharmacy, ibid.).

[0099] Pharmaceutical compositions intended for parenteral administration may include one or more pharmaceutically acceptable carriers and excipients, including, but not limited to, aqueous carriers, water-miscible carriers, non-aqueous carriers, antimicrobial agents or preservatives that inhibit microbial growth, stabilizers, solubilizers, isotonic agents, buffers, antioxidants, local anesthetics, suspending agents and dispersants, wetting agents or emulsifiers, complexing agents, multivalent chelating agents or chelating agents, antifreeze agents, cryoprotectants, thickeners, pH adjusters, and inert gases.

[0100] Suitable aqueous carriers include, but are not limited to: water, saline, physiological saline or phosphate-buffered saline (PBS), sodium chloride injection, Ringers injection, isotonic glucose injection, sterile water injection, glucose, and lactated Ringers injection. Non-aqueous carriers include, but are not limited to, non-volatile oils of plant origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oil, hydrogenated soybean oil, medium-chain triglycerides of coconut oil, and palm seed oil. Water-miscible carriers include, but are not limited to, ethanol, 1,3-butanediol, liquid polyethylene glycol (e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerol, etc. N 2-Methyl-2-pyrrolidone, N,N - Dimethylacetamide and dimethyl sulfoxide.

[0101] Suitable antimicrobial agents or preservatives include, but are not limited to, phenol, cresol, mercury, benzyl alcohol, chlorobutanol, methylparaben and propylparaben, thimerosal, benzalkonium chloride (e.g., benzyl chloride), methylparaben and propylparaben, and sorbic acid. Suitable isotonic agents include, but are not limited to, sodium chloride, glycerol, and glucose. Suitable buffers include, but are not limited to, phosphates and citrates. Suitable antioxidants are those described in this invention, including bisulfite and sodium metabisulfite. Suitable local anesthetics include, but are not limited to, procaine hydrochloride. Suitable suspending and dispersing agents are those described in this invention, including sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Suitable emulsifiers include those described in this invention, including polyoxyethylene dehydrated sorbitan monolaurate, polyoxyethylene dehydrated sorbitan monooleate 80, and triethanolamine oleate. Suitable multivalent chelating agents or chelating agents include, but are not limited to, EDTA. Suitable pH adjusters include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid. Suitable complexing agents include, but are not limited to, cyclodextrins, including α-cyclodextrin, β-cyclodextrin, hydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, and sulfobutyl ether 7-β-cyclodextrin (CAPTISOL). ® , CyDex, Lenexa, KS).

[0102] The pharmaceutical compositions provided by this invention can be formulated for single-dose or multiple-dose administration. The single-dose formulations are packaged in ampoules, vials, or syringes. The multiple-dose parenteral formulations must contain an antimicrobial agent at an antibacterial or antifungal concentration. All parenteral formulations must be sterile, as is known and practiced in the art.

[0103] In one embodiment, the pharmaceutical composition is provided as a ready-to-use sterile solution. In another embodiment, the pharmaceutical composition is provided as a sterile, dried, soluble product, including lyophilized powders and subcutaneous tablets, reconstituted with a carrier prior to use. In yet another embodiment, the pharmaceutical composition is formulated as a ready-to-use sterile suspension. In still another embodiment, the pharmaceutical composition is formulated as a sterile, dried, insoluble product reconstituted with a carrier prior to use. In yet another embodiment, the pharmaceutical composition is formulated as a ready-to-use sterile emulsion.

[0104] The pharmaceutical composition can be formulated as a suspension, solid, semi-solid, or thixotropic liquid for use as an implantable reservoir for drug delivery. In one embodiment, the pharmaceutical composition disclosed herein is dispersed in a solid internal matrix surrounded by an external polymeric membrane that is insoluble in body fluids but allows the active ingredient in the pharmaceutical composition to diffuse through.

[0105] Suitable internal matrices include polymethyl methacrylate, polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymer, silicone rubber, polydimethicone, silicone carbonate copolymer, hydrophilic polymers such as esters of acrylic acid and methacrylate, hydrogels, collagen, cross-linked polyvinyl alcohol, and partially hydrolyzed polyvinyl acetate.

[0106] Suitable external polymeric membranes include polyethylene, polypropylene, ethylene / propylene copolymer, ethylene / ethyl acrylate copolymer, ethylene / vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, chloroprene rubber, chlorinated polyethylene, polyvinyl chloride, copolymer of ethylene chloride and vinyl acetate, vinylidene chloride, ethylene and propylene, ionically crosslinked polymer polyethylene terephthalate, butyl rubber, chlorohydrin rubber, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol trimer, and ethylene / vinyloxyethanol copolymer.

[0107] On the other hand, the pharmaceutical compositions disclosed in this invention can be formulated into any dosage form suitable for inhalation administration to a patient, such as dry powder, aerosol, suspension, or solution composition. In one embodiment, the pharmaceutical compositions disclosed in this invention can be formulated into a dosage form suitable for inhalation administration to a patient as a dry powder. In yet another embodiment, the pharmaceutical compositions disclosed in this invention can be formulated into a dosage form suitable for inhalation administration to a patient via a nebulizer. Dry powder compositions delivered to the lungs by inhalation typically comprise a finely powdered compound disclosed in this invention and one or more pharmaceutically acceptable excipients in a finely powdered form. Pharmaceutically acceptable excipients particularly suitable for use as dry powders are known to those skilled in the art and include lactose, starch, mannitol, and mono-, di-, and polysaccharides. Fine powders can be prepared, for example, by micronization and grinding. Generally, size-reduced (e.g., micronized) compounds can be prepared by a D0 of about 1 to 10 micrometers. 50 Defined by values ​​(e.g., measured using laser diffraction).

[0108] Aerosols can be formulated by suspending or dissolving the compounds disclosed in this invention in a liquefied propellant. Suitable propellants include chlorinated hydrocarbons, hydrocarbons, and other liquefied gases. Representative propellants include: trichlorofluoromethane (propellant 11), dichlorofluoromethane (propellant 12), dichlorotetrafluoroethane (propellant 114), tetrafluoroethane (HFA-134a), 1,1-difluoroethane (HFA-152a), difluoromethane (HFA-32), pentafluoroethane (HFA-12), heptafluoropropane (HFA-227a), perfluoropropane, perfluorobutane, perfluoropentane, butane, isobutane, and pentane. Aerosols containing the compounds disclosed in this invention are typically administered to patients via metered-dose inhalers (MDIs). Such devices are known to those skilled in the art.

[0109] Aerosols may contain additional pharmaceutically acceptable excipients that can be used with MDIs, such as surfactants, lubricants, cosolvents, and other excipients, to improve the physical stability of the formulation, improve valve properties, improve solubility, or improve taste.

[0110] Pharmaceutical compositions suitable for transdermal delivery can be formulated as discontinuous patches intended to maintain close contact with the patient's epidermis for an extended period of time. For example, the active ingredient can be delivered from the patch via iontophoresis, as generally described in Pharmaceutical Research, 3(6), 318 (1986).

[0111] Pharmaceutical compositions suitable for topical administration can be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, or oils. For example, ointments, creams, and gels can be formulated with an aqueous or oil-based matrix and suitable thickeners and / or gelling agents and / or solvents. Such a matrix may include water, and / or oils such as liquid paraffin and vegetable oils (e.g., peanut oil or castor oil), or solvents such as polyethylene glycol. Thickeners and gelling agents used, depending on the nature of the matrix, include soft paraffin, aluminum stearate, cetearyl alcohol, polyethylene glycol, lanolin, beeswax, polycarboxylate, and cellulose derivatives, and / or glyceryl monostearate and / or nonionic emulsifiers.

[0112] Lotions can be formulated with a water or oil base and typically contain one or more emulsifiers, stabilizers, dispersants, suspending agents, or thickeners.

[0113] Topical powders can be shaped in the presence of any suitable powder matrix, such as talc, lactose, or starch. Drops can be formulated with an aqueous or non-aqueous matrix containing one or more dispersants, solubilizers, suspending agents, or preservatives.

[0114] Topical formulations can be administered by applying them to the affected area once or more daily; occlusive dressings covering the skin are preferred. Adhesive reservoir systems allow for continuous or prolonged administration.

[0115] Uses of the compounds and compositions of the present invention

[0116] The compounds or pharmaceutical compositions disclosed in this invention can be used to prepare treatments for the treatment, prevention, improvement, control or relief of hyperproliferative diseases in mammals, including humans.

[0117] Specifically, the compounds of the present invention can be used as drugs for the prevention or treatment of human overproliferative diseases, including liver cancer, leukemia, breast cancer, colon adenocarcinoma, gastric cancer, lung cancer, Bartholin's esophagus cancer, cervical cancer, pancreatic cancer, endometrial cancer, bone cancer, lymphoma, kidney cancer, brain cancer, neurogenic cancer, nasopharyngeal carcinoma, oral cancer, bladder cancer, colorectal cancer, and melanoma.

[0118] The compounds or compositions of the present invention may be applied to, but are by no means limited to, administering effective amounts of the compounds or compositions of the present invention to patients to prevent, treat or alleviate hyperproliferative diseases in mammals, including humans.

[0119] The compounds and pharmaceutical compositions of the present invention, in addition to their therapeutic benefits for humans, can also be used in veterinary treatment of mammals, including pets, introduced breeds of animals, and farm animals. Other examples of animals include horses, dogs, and cats. Herein, the compounds of the present invention include their pharmaceutically acceptable derivatives.

[0120] Treatment

[0121] In one embodiment, the treatment method disclosed in this invention includes administering a safe and effective amount of the compound of this invention or a pharmaceutical composition comprising the compound of this invention to a patient in need. Various embodiments of this invention disclose a method of treating the aforementioned diseases by administering a safe and effective amount of the disclosed compound of this invention or a pharmaceutical composition comprising the disclosed compound of this invention to a patient in need.

[0122] In one embodiment, the compounds disclosed in this invention or pharmaceutical compositions comprising the compounds disclosed in this invention can be administered via any suitable route of administration, including systemic and local administration. Systemic administration includes oral administration, parenteral administration, transdermal administration, and rectal administration. Typical parenteral administration refers to administration by injection or infusion, including intravenous, intramuscular, and subcutaneous injection or infusion. Local administration includes application to the skin, as well as intraocular, intravaginal, inhalation, and intranasal administration. In one embodiment, the compounds disclosed in this invention or pharmaceutical compositions comprising the compounds disclosed in this invention can be administered orally. In another embodiment, the compounds disclosed in this invention or pharmaceutical compositions comprising the compounds disclosed in this invention can be administered by inhalation. In yet another embodiment, the compounds disclosed in this invention or pharmaceutical compositions comprising the compounds disclosed in this invention can be administered intranasally.

[0123] In one embodiment, the disclosed compound or pharmaceutical composition comprising the disclosed compound may be administered once, or, depending on the dosing regimen, administered several times at different time intervals within a specified period. For example, administered once, twice, three times, or four times daily. In one embodiment, administered once daily. In another embodiment, administered twice daily. Administration may continue until the desired therapeutic effect is achieved or to maintain the desired therapeutic effect indefinitely. A suitable dosing regimen for the disclosed compound or pharmaceutical composition comprising the disclosed compound depends on the pharmacokinetic properties of the compound, such as dilution, distribution, and half-life, which can be determined by a person skilled in the art. Furthermore, a suitable dosing regimen for the disclosed compound or pharmaceutical composition comprising the disclosed compound includes the duration of administration, depending on factors within the knowledge and experience of a person skilled in the art, such as the disease being treated, the severity of the disease, the age and physical condition of the patient being treated, the patient's medical history, the nature of concurrent therapies, and the desired therapeutic effect. Such a person skilled in the art should also understand that adjustments to the dosing regimen may be required for individual patient responses to the dosing regimen, or for changes in individual patient needs over time.

[0124] The compounds disclosed in this invention can be administered simultaneously with, before, or after one or more other therapeutic agents. The compounds of this invention can be administered separately, or co-administered with, other therapeutic agents via the same or different routes of administration, in the form of a pharmaceutical composition.

[0125] For an individual weighing approximately 50-70 kg, the pharmaceutical compositions and combinations disclosed in this invention may be in unit dose form containing approximately 1-1000 mg, or approximately 1-500 mg, or approximately 1-250 mg, or approximately 1-150 mg, or approximately 0.5-100 mg, or approximately 1-50 mg of active ingredient. The therapeutically effective amount of the compound, pharmaceutical composition, or combination thereof depends on the individual's species, weight, age, individual condition, the disorder or disease being treated, or its severity. A physician, clinician, or veterinarian with common skills can readily determine the effective amount of each active ingredient required to prevent, treat, or inhibit the development of a disorder or disease.

[0126] The dosage characteristics cited above have been demonstrated in in vitro and in vivo studies using advantageous mammals (e.g., mice, rats, dogs, monkeys) or their isolated organs, tissues, and specimens. The compounds disclosed herein are intended for in vitro use in solution, such as aqueous solution, and may also be used in vivo in intestinal, parenteral, and especially intravenous forms, such as suspensions or aqueous solutions.

[0127] In one embodiment, the therapeutically effective dose of the compound disclosed in this invention is from about 0.1 mg to about 2,000 mg daily. The pharmaceutical composition thereof should provide a dose of the compound from about 0.1 mg to about 2,000 mg. In a particular embodiment, the prepared pharmaceutical dosage unit form can provide about 1 mg to about 2,000 mg, about 10 mg to about 1,000 mg, about 20 mg to about 500 mg, or about 25 mg to about 250 mg of the main active ingredient or a combination of the main ingredients in each dosage unit form. In a particular embodiment, the prepared pharmaceutical dosage unit form can provide about 10 mg, 20 mg, 25 mg, 50 mg, 100 mg, 250 mg, 500 mg, 1000 mg, or 2000 mg of the main active ingredient.

[0128] Furthermore, the compounds disclosed in this invention can be administered as prodrugs. In this invention, a "prodrug" of the disclosed compounds is a functional derivative of the disclosed compounds that, when administered to a patient, ultimately releases in vivo. When the disclosed compounds are administered as prodrugs, those skilled in the art can perform one or more of the following: (a) changing the in vivo onset time of the compound; (b) changing the in vivo duration of action of the compound; (c) changing the in vivo delivery or distribution of the compound; (d) changing the in vivo solubility of the compound; and (e) overcoming the side effects or other difficulties faced by the compound. Typical functional derivatives used to prepare prodrugs include variants of compounds that are chemically or enzymatically cleaved in vivo. These variants, including those for preparing phosphates, amides, esters, thioesters, carbonates, and carbamates, are well known to those skilled in the art.

[0129] General synthesis steps

[0130] Examples are listed below to describe the present invention. However, it should be understood that the present invention is not limited to these examples, but merely provides a method for practicing the present invention.

[0131] Generally, the compounds of the present invention can be prepared by the methods described herein, unless otherwise specified, wherein the substituents are defined as shown in formula (I). The following reaction schemes and examples are provided to further illustrate the content of the present invention.

[0132] Those skilled in the art will recognize that the chemical reactions described herein can be suitably used to prepare many other compounds of the present invention, and that other methods for preparing the compounds of the present invention are considered to be within the scope of the present invention. For example, the synthesis of those non-illustrative compounds according to the present invention can be successfully accomplished by those skilled in the art through modification methods, such as by appropriately protecting interfering groups, by utilizing other known reagents besides those described herein, or by making some conventional modifications to the reaction conditions. Furthermore, the reactions disclosed in this invention or the known reaction conditions are also generally accepted to be applicable to the preparation of other compounds of the present invention.

[0133] The examples described below are in Celsius unless otherwise stated. Reagents were purchased from commodity suppliers such as Aldrich Chemical Company, Arco Chemical Company, and Alfa Chemical Company and were not further purified before use unless otherwise stated. Common reagents were purchased from Shantou Xilong Chemical Plant, Guangdong Guanghua Chemical Reagent Plant, Guangzhou Chemical Reagent Plant, Tianjin Haoyuyu Chemical Co., Ltd., Tianjin Fuchen Chemical Reagent Plant, Wuhan Xinhuayuan Technology Development Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Haiyang Chemical Plant.

[0134] Anhydrous tetrahydrofuran, dioxane, toluene, and diethyl ether are obtained by reflux drying with metallic sodium. Anhydrous dichloromethane and chloroform are obtained by reflux drying with calcium hydride. Ethyl acetate, petroleum ether, and n-hexane... N,N -dimethylacetamide and N,N- Dimethylformamide is used after being dried with anhydrous sodium sulfate.

[0135] The following reactions are generally carried out under positive pressure of nitrogen or argon or with a drying tube attached to an anhydrous solvent (unless otherwise specified). All reaction flasks are sealed with suitable rubber stoppers, and the substrate is injected using a syringe. All glassware is dried.

[0136] The chromatographic column used was a silica gel column. The silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Plant.

[0137] Nuclear magnetic resonance (NMR) spectra were recorded using a Bruker 400 MHz or 600 MHz NMR spectrometer, with CDCl3 and DMSO as the resonants. d 6 CD3OD or acetone- d 6 The solvent is specified in ppm, with TMS (0 ppm) or chloroform (7.26 ppm) as the reference standard. When multiplets are observed, the following abbreviations will be used: s (singlet), d (doublet), t (triplet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets). The coupling constant is expressed in Hertz (Hz).

[0138] The determination conditions for low-resolution mass spectrometry (MS) data were as follows: Agilent 6120 quadrupole HPLC-M (column model: Zorbax SB-C18, 2.1 x 30 mm, 3.5 μm, 6 min, flow rate: 0.6 mL / min; mobile phase: 5% - 95% (CH3CN containing 0.1% formic acid) in (H2O containing 0.1% formic acid)), electrospray ionization (ESI), at 210 nm / 254 nm, with UV detection.

[0139] Compound purity was determined by high performance liquid chromatography (HPLC) using an Agilent 1260 HPLC system (column model: Agilent zorbax Eclipse Plus C18) and a DAD detector. The compound purity was finally calculated using the area normalization method.

[0140] The following abbreviations are used throughout this invention:

[0141] CDC13 deuterated chloroform

[0142] DMAP 4-Dimethylaminopyridine

[0143] DMSO- d 6 Deuterated dimethyl sulfoxide

[0144] g gram

[0145] h hours

[0146] min minutes

[0147] mmol millimole

[0148] M moles per liter

[0149] °C Celsius

[0150] MeCN, CH3CN acetonitrile

[0151] MeOH (methanol)

[0152] mL, ml

[0153] RT, rt, rt room temperature

[0154] eq equivalent

[0155] rpm (revolutions per minute)

[0156] Rt retention time

[0157] The following examples further illustrate the compounds, pharmaceutical compositions, and their applications provided by the present invention. Detailed Implementation

[0158] The following specific embodiments are used to further illustrate the present invention, but the present invention is by no means limited to these examples.

[0159] 1. 4,7-TBS-BFA (compound 1a)

[0160] BFA (1.0 mmol, 280.0 mg), TBSCl (6.0 mmol, 900.0 mg), and imidazole (18.0 mmol, 1224.0 mg) were dissolved in 5 mL of DMF and stirred at 50 °C for 2–4 h. After the reaction was completed by TLC, the mixture was cooled to room temperature and extracted three times with DCM / H2O. The organic phases were combined, concentrated under reduced pressure, and separated by normal-phase silica gel column chromatography to obtain a colorless oily solid compound 1a in >95% yield. 1 H NMR (400 MHz, CDCl3) d 7.29 (1H, dd, J = 15.5, 3.1Hz), 5.86(1H, dd, J = 15.5, 1.9 Hz), 5.62 (1H, m), 5.25 (1H, dd, J = 15.2, 9.6 Hz), 4.87(1H, m), 4.19 (1H, m), 4.01 (1H, ddd, J = 9.2, 3.1, 1.9 Hz), 2.25 (1H, m), 2.08−1.90 (4H,overlapped), 1.89−1.63 (4H, overlapped), 1.58−1.42 (3H,overlapped),1.25 (3H, d, J = 6.2 Hz), 0.92 (9H, s), 0.87 (9H, s), 0.03 (12H, overlapped). 13 CNMR (100 MHz, CDCl3) d166.6 (C=O), 152.7 (CH), 137.5 (CH), 129.4 (CH), 118.2(CH), 76.5 (CH), 73.0 (CH), 71.5(CH), 53.0 (CH), 43.9 (CH), 43.8 (CH2), 42.2(CH2), 34.2 (CH2), 32.0 (CH2), 26.9 (CH2), 26.0 (CH3× 6), 21.1 (CH3), 18.3(C), 18.2 (C), -4.0 (CH3), -4.6 (CH3), -4.6 (CH3), -4.7 (CH3).

[0161] 2. 4-TBS-BFA (compound 1b)

[0162] Compound 1a (0.94 mmol, 480 mg) was dissolved in 10 mL of HOAc: H2O: THF = 1: 1: 2 and stirred at 50–60 °C for 4–12 h. The reaction was monitored by TLC. The same treatment was performed to give compound 1b as a white solid, in 67% yield. 1 H NMR (400MHz, CDCl3) d 7.29 (1H, dd, J = 15.5, 3.2 Hz), 5.86 (1H, dd, J = 15.5, 1.9 Hz),5.64 (1H, m), 5.27 (dd, 1H, m, J = 15.2, 9.5 Hz), 4.88 (1H, m), 4.30 (1H, m), 4.03 (1H, ddd, J = 9.2, 3.2, 1.8 Hz), 2.31 (1H, m), 2.18 (1H, m), 2.07−1.95(3H, overlapped), 1.88−1.76 (2H, overlapped), 1.76−1.58 (3H, overlapped), 1.56−1.44 (2H, overlapped), 1.25 (3H, d, J =6.2 Hz), 0.92 (10H, s), 0.05 (3H, s), 0.01 (3H, s). 13 C NMR (100 MHz, CDCl3) d166.5 (C=O),152.5 (CH), 137.2 (CH),129.9 (CH), 118.3 (CH), 76.5 (CH), 72.7 (CH), 71.6 (CH), 53.0 (CH), 44.1(CH), 43.6 (CH2), 42.3 (CH2), 34.3 (CH2), 31.9 (CH2), 26.8 (CH2), 26.0 (CH3×3), 21.0 (CH3), 18.3 (C), -4.0 (CH3), -4.7 (CH3).

[0163] Example 1: Synthesis of 4-TBS-BFA-ss-OH (compound 1c):

[0164] Under nitrogen protection, compound 1b (50 mg) and 37.6 mg triphosgene were dissolved in 2 mL of anhydrous DCM. After stirring at room temperature for 10 min, 1 mL of DMAP (125 mg) in DCM solution was slowly added dropwise. Stirring continued for 30 min, followed by the slow addition of 1 mL of dihydroxyethyl disulfide (120 mg). m The reaction was carried out in a THF solution of L for 1 h (with appropriate heating). The reaction was basically complete as detected by TLC. The reaction was stopped, the reaction solution was concentrated, and the colorless oily solid compound 1c was obtained by normal phase silica gel column chromatography with a yield >95%. 1 H NMR (400 MHz, CDCl3) d 7.23 (1H, dd, J =15.5, 3.2 Hz), 5.85 (1H, dd, J =15.5, 1.8 Hz), 5.65 (1H, m), 5.22 (1H,dd, J = 15.1, 8.9 Hz), 5.03 (1H, m), 4.88(1H, m), 4.37 (2H, t, J = 6.8 Hz), 4.04 (1H, ddd, J = 9.5, 3.3, 1.8 Hz), 3.87(2H, q, J = 5.7 Hz), 2.94 (2H, t, J = 6.8 Hz), 2.88 (2H, t, J= 5.8 Hz), 2.27 (4H, overlapped), 1.98 (2H, overlapped), 1.82 (2H, overlapped), 1.66 (3H, overlapped), 1.51 (1H, m), 1.24 (3H, d, J = 6.2 Hz), 0.91 (10H, s). 0.05 (3H, s), 0.00 (3H, s); 13 C NMR (100 MHz, CDCl3) d 166.4, 154.6, 152.0, 136.3, 130.6, 118.6, 79.7, 76.3, 71.6, 65.6, 60.3, 53.0, 43.7, 41.8, 40.3, 39.3, 36.9, 34.2, 31.8, 29.8, 26.7, 26.0, 21.0, 18.2, -4.0, -4.8.

[0165] Example 2: Synthesis of 4-TBS-BFA-ss-COOH (compound 1d)

[0166] Approximately 40 mg of compound 1c and 16 mg of DMAP were dissolved in 2 mL of anhydrous DCM. The mixture was stirred at 35 °C for 5 min, and then 25 mg of glutaric anhydride was added. The mixture was stirred continuously for 2 h, and the reaction was confirmed to be complete by TLC. The reaction was then stopped, and the reaction solution was concentrated. The colorless oily solid compound 1d was obtained by reversed-phase silica gel column chromatography (MeCN-H2O) and HPLC (MeCN-H2O (1‰CF3COOH)), with a yield >95%. 1 H NMR (400 MHz, CDCl3) d 7.24 (1H, dd, J = 15.5, 3.2 Hz), 5.86 (1H, dd, J =15.5, 1.8 Hz), 5.65 (1H, m), 5.22 (1H, dd, J = 15.2, 8.9 Hz), 5.03 (1H, m), 4.88 (1H, m), 4.35 (4H, td, J = 6.6, 1.8 Hz), 4.04 (1H, ddd, J = 9.5, 3.3, 1.8Hz), 2.93 (4H, q, J= 6.4 Hz), 2.66 (4H, overlapped), 2.28 (3H, overlapped), 1.98 (2H, overlapped), 1.82 (2H, overlapped), 1.67 (3H, overlapped), 1.50 (1H, m), 1.24 (3H, d, J = 6.2 Hz), 0.91 (10H, s), 0.05 (3H, s), 0.00 (3H, s); 13 C NMR (100 MHz, CDCl3) d 172.1, 166.5, 154.6, 152.1, 136.3, 130.6, 118.5, 79.7, 76.4, 71.6, 65.6, 62.7, 53.0, 43.8, 40.3, 39.3, 37.3, 37.1, 34.3, 31.8, 26.7, 26.0, 21.0, 18.2, -4.0, -4.8.

[0167] Example 3: Synthesis of BFA-ss-COOH (compound 1e)

[0168] Approximately 50 mg of compound 1d was dissolved in 5 mL of a TFA-DCM (1:3) mixed solvent and stirred at 35 °C for 2 h. The reaction was confirmed to be complete by TLC. The reaction was then stopped, the reaction solution was concentrated, and the colorless oily liquid compound 1e was obtained by reversed-phase silica gel column chromatography (MeCN / MO-H2O) with a yield >67%. 1 H NMR (400 MHz, CDCl3) d 7.33 (1H, dd, J = 15.6, 3.0Hz), 5.90 (1H, d, J = 15.6 Hz), 5.70 (1H, m), 5.23 (1H, dd, J = 15.2, 9.1 Hz),5.04 (1H, m), 4.82 (1H, m), 4.43–4.26 (4H, m), 4.10 (1H,m), 3.02–2.87 (4H, q, J = 6.0 Hz), 2.71–2.58 (4H, q, J= 5.4, 4.3 Hz), 2.45–2.25 (3H, m), 2.00 (1H,m), 1.94–1.78 (4H, m), 1.77–1.62 (2H, m), 1.50 (1H, m), 1.24 (3H, d, J = 6.2Hz), 0.92 (1H, m); 13 C NMR (100 MHz, CDCl3) d 172.4, 166.7, 154.6, 151.8, 136.0,131.1, 117.7, 79.6, 75.8, 72.1, 65.6, 62.7, 52.0, 44.0,40.0, 38.7, 37.4,37.3, 34.2, 31.8, 29.0, 28.9, 26.7, 20.9; HRESIMS m / z 561.1836 [M + H] + (calcd.for [C 25 H 37 O 10 S2] + , 561.1823).

[0169] Example 4: BFA-ss-mPEG 2000 Synthesis of (Compound 1)

[0170] Compound 1e 50.0 mg, mPEG 2000 An appropriate amount of -NH2 (~50 mg) and EDCl 50.0 mg were dissolved in 3 mL of anhydrous DCM. The mixture was stirred at 35 °C for 2 h. The reaction was detected by TLC and stopped when it was complete. The reaction solution was concentrated and separated by gel column chromatography (MeOH / DCM, V / V = 1 / 1) to obtain a white solid compound 1 with a yield of 95%, which is readily soluble in DCM, H2O, and DMSO. 1 H NMR (400 MHz, CDCl3) d 7.30 (1H, m), 6.62 (1H, t, J = 5.6 Hz), 5.87 (1H, m), 5.69(1H, m), 5.21 (1H, m), 5.02 (1H, t, J = 5.1 Hz), 4.80 (1H, m), 4.40−4.25 (4H, overlapped), 4.06 (1H, d, J= 9.2 Hz), 3.90−3.55 (n H, overlapped), 3.51 (4H, overlapped), 3.41 (2H, m), 3.34 (3H, m), 2.96−2.87 (4H, overlapped), 2.63(2H, t, J = 6.9 Hz), 2.47 (3H, t, J = 6.4 Hz), 2.43−2.22 (5H, m), 1.98 (1H, m), 1.92−1.75 (4H, overlapped), 1.64 (2H, m), 1.49 (1H, m), 1.22 (3H, d, J = 5.6Hz), 0.90 (1H, m); 13 C NMR (100 MHz, CDCl3) d 172.8, 171.4, 166.2, 154.5, 151.8,136.0, 131.0, 117.7, 79.4, 77.2, 75.6, 72.0, 71.7, 70.8−70.5 (n C,overlapped), 70.2, 69.9, 65.5, 62.5,59.1, 52.0, 43.9, 40.0, 39.4, 38.7, 37.4,37.2, 34.2, 31.8, 30.7, 29.4, 26.7, 20.9.

[0171] Example 5: BFA-ss-mPEG 1000 Synthesis of (Compound 2)

[0172] The preparation and purification methods are the same as for compound 1. Compound 1e and MPEG 1000 -NH2 (2.0 mmol, 280.0 mg) was coupled to give compound 2, a white solid, in 92% yield. 1 H NMR (400 MHz, CDCl3) d 7.32 (1H, dd, J = 15.6, 3.1Hz), 6.84 (1H, t, J = 5.5 Hz), 5.89 (1H, dd, J = 15.6, 2.0 Hz), 5.69 (1H, m), 5.22 (1H, dd, J= 15.1, 9.1 Hz), 5.03 (1H, m), 4.82 (1H, dqd, J = 12.5, 6.2, 1.7Hz), 4.42−4.26 (4H, overlapped), 4.07 (1H, dt, J = 9.4, 2.4 Hz), 3.70−3.56 (nH, overlapped), 3.55−3.50 (4H, overlapped), 3.42 (2H, m), 3.35 (3H, s), 2.96−2.89 (4H, overlapped), 2.65 (2H, t, J = 6.7 Hz), 2.49 (2H, t, J = 6.9 Hz), 2.42−2.24 (6H, overlapped), 1.99 (1H, m), 1.93−1.76 (4H, overlapped), 1.68 (2H,m), 1.50 (1H, m), 1.23 (3H, d, J = 6.2 Hz), 0.90 (1H, m); 13 C NMR (100 MHz, CDCl3) d 172.7, 171.5, 166.2, 154.4, 151.7, 135.9, 130.9, 117.7, 79.3, 75.6,71.9, 71.6, 70.6−70.4 (n C, overlapped), 70.1, 69.9, 65.4, 62.4, 59.0, 51.9,43.9,39.9, 39.3, 38.6, 37.3, 37.1, 34.1, 31.8, 30.6, 29.4, 26.6, 20.8.

[0173] Example 6: BFA-ss-mPEG 350 Synthesis of (compound 3)

[0174] The preparation and purification methods are the same as for compound 1. Compound 1e and MPEG 350 -NH2 (2.0 mmol, 103.4 mg) was coupled to give compound 3, a white solid, in 93% yield. 1 H NMR (400 MHz, CDCl3) d 7.35 (1H, dd, J= 15.7, 3.1Hz), 6.93 (1H, q, J = 5.6 Hz), 5.92 (1H, dd, J = 15.6, 2.0 Hz), 5.72 (1H, m),5.25 (1H, dd, J = 15.2, 9.1 Hz), 5.06 (1H, m), 4.85 (1H, dqd, J = 12.5, 6.2, 1.8Hz), 4.44−4.29 (4H, overlapped), 4.10 (1H, dt, J = 9.4, 2.5 Hz), 3.72−3.60 (nH, overlapped), 3.58−3.53 (4H, overlapped), 3.44 (2H, m), 3.38 (3H, s), 2.99−2.92 (4H, overlapped),2.68 (2H, t, J = 7.3 Hz), 2.51 (2H, t, J = 6.9 Hz), 2.44−2.28 (4H, overlapped), 2.02 (1H, m), 1.96−1.80 (4H, overlapped), 1.71 (2H,m), 1.53 (1H, m), 1.26 (3H, d, J = 6.2 Hz), 0.94 (1H, m); 13 C NMR (100 MHz,CDCl3) d 172.8, 171.6, 166.3, 154.5, 151.7, 135.9, 131.0, 117.7, 79.4, 75.6,71.9, 71.7, 70.6−7,`0.3 (n C, overlapped), 70.1, 70.0, 65.4, 62.5, 59.0, 52.0,43.9,39.9, 39.3, 38.6, 37.4, 37.2, 34.1, 31.8, 30.6, 29.4, 26.7, 20.9.

[0175] Example 7: Synthesis of 4-TBS-BFA-cc-OH (Compound 4a)

[0176] The preparation and purification methods were the same as those for compound 1c. 4-TBS-BFA and 1,6-hexanediol (2.0 mmol, 280.0 mg) were reacted to give a colorless, oily liquid compound 4a in >95% yield. 1 H NMR (400 MHz, CDCl3) d 7.24 (1H, dd, J =15.6, 3.3 Hz), 5.85 (1H, dd, J = 15.5, 1.9 Hz), 5.64 (1H, m), 5.22 (1H, dd, J =15.2, 8.9 Hz), 5.00 (1H, m), 4.87 (1H, m), 4.10 (2H, t, J = 6.7 Hz), 4.03 (1H, ddd, J = 9.5, 3.3, 1.9 Hz), 3.62 (2H, t, J = 6.5 Hz), 2.38−2.18 (3H, overlapped),1.97 (2H, m), 1.81 (2H, m), 1.74−1.61 (5H, overlapped),1.60−1.46 (4H,overlapped), 1.42−1.35 (4H, overlapped),1.24 (3H, d, J = 6.2 Hz), 0.98−0.80(10H, overlapped), 0.04 (3H, d), -0.00 (3H, s); 13 C NMR (100 MHz, CDCl3) d 166.4,155.0, 152.1, 136.4, 130.5, 118.5, 79.1, 76.4, 71.5, 67.9, 62.8, 53.0, 43.8,40.3,39.2, 34.2, 32.7, 31.8, 28.8, 26.7, 25.9, 25.9, 25.9, 25.6, 25.5, 21.0,18.2,-4.1,-4.8.

[0177] Example 8: Synthesis of 4-TBS-BFA-cc-COOH (compound 4b)

[0178] The preparation and purification methods were the same as those for compound 1d. Compound 4a (35 mg) reacted with succinic anhydride (26 mg, 4.00 mmol) to give compound 4b, a colorless oily liquid, in 93% yield. 1 H NMR (400 MHz, CDCl3) d 7.25 (1H, dd, J =15.5, 3.2 Hz), 5.86 (1H, dd, J = 15.5, 1.8 Hz), 5.65 (1H, m), 5.22 (1H, dd, J =15.2, 8.9 Hz), 5.01 (1H, m), 4.88 (1H, m), 4.13−4.06 (4H, overlapped), 4.03(1H, ddd, J = 9.5, 3.3, 1.8 Hz), 2.70−2.58 (4H,overlapped), 2.38−2.18 (3H,overlapped), 1.99 (2H, m), 1.82 (2H, m), 1.74−1.58 (7H, overlapped), 1.51(1H, m), 1.43−1.33 (4H, overlapped), 1.24 (3H, d, J = 6.2 Hz), 0.98−0.84 (10H, overlapped), 0.04 (3H, s), 0.00 (3H, s); 13 C NMR (100 MHz, CDCl3) d 177.3, 172.3, 166.5, 155.0, 152.2, 136.4, 130.5, 118.5, 79.2, 76.4, 71.6, 67.9, 64.9, 53.0, 43.8, 40.3, 39.2, 34.2, 31.8, 29.1, 28.6, 28.5, 26.7, 26.0, 26.0, 26.0, 26.0, 25.6, 25.4, 21.0, 18.2, -4.0, -4.8.

[0179] Example 9: Synthesis of BFA-cc-COOH (compound 4c)

[0180] The preparation and purification methods were the same as for compound 1e. Deprotection of compound 4b (35 mg) yielded a colorless, oily liquid compound 4c, in 93% yield. 1H NMR (400 MHz, CDCl3) d 7.34 (1H, dd, J = 15.7, 3.1 Hz), 5.91 (1H,dd, J = 15.6, 1.9 Hz), 5.71 (1H, m), 5.26 (1H, m), 5.05 (1H, m), 4.85 (1H, m), 4.18−4.05 (5H, overlapped), 2.70−2.58 (4H, overlapped), 2.43−2.25 (3H,overlapped), 2.01 (1H, m), 1.95−1.79 (4H, overlapped), 1.78−1.59 (6H,overlapped), 1.53 (1H, m), 1.45−1.33 (4H, overlapped), 1.25 (3H, d, J = 6.2Hz), 0.94 (1H, m); 13 C NMR (100 MHz, CDCl3) d 172.5, 166.5, 155.1, 151.6, 136.0,131.1, 117.8, 79.1, 76.0, 72.0, 67.9, 64.8, 52.1, 44.1, 40.0, 38.8, 34.2,31.9, 29.2,28.6, 28.5, 26.8, 25.5, 25.4, 21.0. HRESIMS m / z 525.2687 [M + H] + (calcd. for [C 27 H 41 O 10 ] + , 525.2694).

[0181] Example 10: BFA-cc-mPEG 2000 Synthesis of (Compound 4)

[0182] Preparation and purification methods were the same as for compound 1. Compound 4c (35 mg) was coupled with mPEG. 2000 -NH2 (2.0 mmol, 280.0 mg) yielded a white solid compound 4 in 93% yield. 1 H NMR (400 MHz, CDCl3) d 7.29 (1H, dd, J= 3.1, 15.6 Hz), 6.65 (1H, t, J = 5.5 Hz), 5.86 (1H, dt, J = 2.0, 15.6 Hz), 5.67(1H, m), 5.20 (1H, dd, J = 9.1, 15.2 Hz), 4.99 (1H, m), 4.79 (1H, m), 4.12−3.98(6H, overlapped), 3.77 (1H, m), 3.52−3.48 (4H, overlapped), 3.44−3.46 (8H, overlapped), 3.33 (3H, s), 2.59 (2H, m), 2.45 (1H, m), 2.33 (1H, m), 2.25(1H, m), 2.02−1.92 (2H, overlapped),1.90−1.75 (3H, overlapped), 1.61 (3H, m),1.49 (1H, m), 1.40−1.30 (3H, overlapped), 1.20 (3H, d, J = 3.3 Hz), 0.90 (1H,m); 13 C NMR (100 MHz, CDCl3) d 172.9, 171.4, 166.1, 154.7, 151.8, 135.9, 130.7,117.5, 78.7, 75.4, 71.8, 71.5, 70.4 (nC),70.0, 69.8, 67.6, 67.6, 64.4, 58.9,51.8, 43.8, 39.8, 39.2, 38.5, 38.5, 34.0, 31.6, 30.6, 29.4, 28.4, 28.2, 26.5,25.4, 25.2, 20.7.

[0183] Example 11: Solubility Test

[0184] Test objective: To compare the solubility and stability differences between the compound of this invention and BFA.

[0185] Test method: 2 mg BFA and 20 mg of compounds 1, 3, 5, 9, 11 of the present invention were added to 2 mL of 5% solutol + 95% saline solvent, respectively. After sonication for 10 min and suspension for 5 min, the solubility of the compounds was observed and the sedimentation was observed after standing for 3 days. The stability of the solution was analyzed by HPLC.

[0186] The results showed that compounds 1, 3, 5, 9, and 11 of this invention were completely soluble in 5% solutol + 95% saline, remaining clear with no precipitation within 3 days, and the peak areas in HPLC analysis remained essentially consistent over 3 days. BFA, on the other hand, was insoluble, remaining turbid, and showed significant precipitation after 3 days. Compounds 1, 3, 5, 9, and 11 were completely soluble, remaining clear, but precipitation occurred within 3 days, resulting in a slight decrease in HPLC peak area; however, they could be re-dissolved after shaking. Therefore, the solubility of the compounds of this invention (greater than 10 mg / mL) is significantly higher than that of BFA (less than 1 mg / mL), demonstrating a significant advantage in drug delivery.

[0187] Example 12 Cell Proliferation Experiment

[0188] 1) Detection principle:

[0189] CCK-8 Assay: The CCK-8 assay is a highly sensitive, non-radioactive colorimetric method for determining the number of viable cells in cell proliferation or cytotoxicity assays. CCK-8 is bioreduced by intracellular dehydrogenases to produce an orange formazan dye that is soluble in cell culture medium, and the amount of formazan produced is directly proportional to the number of viable cells. The kit used in this method is tetrazolium salt −WST-8 (2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfonylbenzene)-2H-tetrazole monosodium salt), developed by Dojindo Chemical Research Institute. It can be reduced to a water-soluble formazan dye in the presence of the electron carrier 1-Methoxy PMS.

[0190] 2) Cell culture and preparation of test compounds

[0191] Human gastric cancer cells MGC-803 and SGC-7901, human colon cancer cells HCT116, HT-29, and SW480, human colorectal adenocarcinoma epithelial cells DLD1, human colon cancer cells COLO205, human orthotopic pancreatic adenocarcinoma cells BxPC-3, human bladder cancer cells BIU-87, pancreatic cancer cells PANC-1, and human breast cancer cells MCF7 were placed in a solution containing 10% FBS (fetal bovine serum), 100 U / ml penicillin, and 100 mCells were cultured in DMEM medium containing g / ml streptomycin. All cells were incubated in a cell culture incubator at 37°C and 5% CO2. The medium was changed every 3-5 days. After the cells reached 80% confluence, they were trypsinized, passaged, and kept in good logarithmic growth phase.

[0192] All samples to be tested were dissolved in DMSO.

[0193] 3) Detection method:

[0194] Cells in logarithmic growth phase were seeded at 5000 cells / well in 96-well plates and cultured for 24 h. Then, the test sample (final concentration as shown in the table) was added, with two replicates per sample. The amount of DMSO solvent did not exceed 2‰. After 72 h of drug treatment, 10 mg / well of DMSO was added to each well. m Incubate the sample with 1 μL of CCK-8 solution at 37°C for 1.5–3 hours. Measure the OD value at 450 nm using a microplate reader.

[0195] Inhibition rate (%) = (1 - [(OD) 450 Dosing port - OD 450 Blank hole) / (OD) 450 Reference Hole - OD 450 Blank hole) × 100%

[0196] The fitted IC was calculated using the log(inhibitor) vs. response – Variable slop analysis method in GraphPad Prism software. 50 value.

[0197] 4) Test results:

[0198] Table 1. Effects of the compounds of this invention on tumor cell proliferation.

[0199]

[0200] Note: "++++" in the table indicates IC 50 Values ​​less than 50 nM, “++” indicates IC 50 Values ​​between 50 and 100 nM, “++” indicates IC 50 Values ​​between 100 and 500 nM, with "+" indicating IC 50 The value is greater than 500 nM.

[0201] In vitro cell experiments revealed that the compounds of this invention exhibited strong cytotoxic activity against multiple cancer cell lines, showing superiority to BFA and the positive control drug doxorubicin to some extent. Most compounds also demonstrated significant selectivity, with particularly pronounced anti-proliferative inhibitory effects against human colon cancer cells and bladder cancer cells. Therefore, the compounds of this invention have promising potential applications in inhibiting tumor proliferation.

[0202] Example 13 Acute Toxicity Test

[0203] Experimental objective: To observe the toxic effects of intraperitoneal injection (ip.) of the compound in mice.

[0204] Experimental materials:

[0205] 1) Drug: The compounds of the present invention are prepared into appropriate concentrations for later use.

[0206] 2) Animals: Kunming mice, weighing 18-22g, male. Supplied by Jinan Pengyue Experimental Animal Breeding Co., Ltd., Animal License No.: SCXK (Lu 20140007).

[0207] Test method:

[0208] Kunming mice were randomly divided into groups of six based on body weight: a normal control group, high- and low-dose BFA groups (100 mg / kg and 50 mg / kg, respectively), and high- and low-dose groups of some compounds from this invention (based on the effective amount of BFA). After administration, the animals' behavior, mental state, feeding and drinking responses, and mortality were observed. After 14 days of continuous administration, all animals were weighed, sacrificed, dissected, and visually inspected for any abnormalities.

[0209] Results of intraperitoneal injection test:

[0210] a) Mice in the high-dose BFA group experienced a continuous decrease in body weight, indicating significant toxicity, and died on day 12 after administration. Mice in the low-dose group died on day 14 after administration.

[0211] (b) Animals treated with compounds 1, 3, 5, 9, and 11 of the present invention at both high and low doses showed good mental condition with no deaths. Furthermore, during administration, animals treated with the compounds of the present invention exhibited smoother fur compared to those treated with BFA. Autopsy results after 14 days showed no significant abnormalities in any organ during anatomical observation.

[0212] c) The weight of the animals in the drug-treated group was slightly lower than that of the normal control group, but the difference was not statistically significant.

[0213] The results showed that, compared with BFA, the compound of the present invention had a significant reduction in toxicity after administration to mice, and had a certain degree of attenuation effect.

[0214] Example 14 Pharmacokinetic Evaluation

[0215] Test method:

[0216] SD rats were weighed after a 15-hour overnight fast and randomly assigned to groups based on body weight. An appropriate amount of the test compound was accurately weighed and added to a final volume of 5% DMSO, 10% Solutol, and 85% Saline. The mixture was vortexed or sonicated to obtain a 4 mg / mL administration solution for intravenous injection. iv Then, venous blood was collected at time points 0, 0.083 (intravenous injection group only), 0.25, 0.5, 1.0, 2.0, 5.0, 7.0, and 24 hours, via jugular vein or other suitable methods. Approximately 0.20 mL of blood was collected per sample, anticoagulated with heparin sodium (6.25 μL 200 mM DDVP / tube). After collection, the samples were placed on ice and centrifuged within 2 hours (centrifugation conditions: 6800g, 6 minutes, 2–8°C). Collected plasma samples were stored at -70°C before analysis. Remaining plasma samples after analysis were stored at -20°C or -70°C until LC / MS / MS analysis. Quality control sample accuracy was evaluated simultaneously with sample analysis, with over 66% of the quality control samples required to have an accuracy between 80–120%. BLQ was recorded as 0 when plotting plasma drug concentration-time curves. When calculating pharmacokinetic parameters, the concentration before administration is calculated as 0; BLQs before Cmax (including "No peak") are calculated as 0; BLQs after Cmax (including "No peak") are not included in the calculation. Using blood concentration data of brefidobacterium A at different time points, WinNonlin is used to calculate pharmacokinetic parameters such as AUC(0-t), T1 / 2, Cmax, Tmax, and MRT.

[0217] The pharmacokinetic properties of the compounds of this invention were tested using the above methods.

[0218] Table 2. Pharmacokinetic activities of the compounds of this invention

[0219]

[0220] In summary, the compounds of this invention have achieved significant progress in reducing toxicity and increasing efficacy based on BFA, while also greatly improving solubility. Furthermore, the compounds of this application can inhibit the release of related inflammatory factors, and have further research value and broad development prospects in the treatment of sepsis.

[0221] Finally, it should be noted that there are other ways to implement this invention. Accordingly, the embodiments of the invention are described as examples, but are not limited to the content described herein, and may include modifications made within the scope of the invention or equivalent content added to the claims. All publications or patents cited in this invention are to be used as references in this invention.

Claims

1. A macrocyclic lactone polymer, characterized in that, The polymer is a compound of formula (I) or a stereoisomer, geometric isomer, tautomer, or pharmaceutically acceptable salt of a compound of formula (I). （I）, Where R1 and R2 are each independently H or R1 and R2 cannot both be H; L is selected from disulfide bonds, two-carbon bonds, hydrazone bonds, polypeptides, and glucuronides. Z is Y is polyethylene glycol; G is selected from folic acid, RGD peptide, RGD-derived polypeptide, LyP-1, vasoactive intestinal peptide VIP, penetrating peptide F3 or not present.

2. The macrocyclic lactone polymer according to claim 1, wherein, Y is selected from mPEG-NH2, mPEG-COOH, mPEG-acetic acid, mPEG-succinic acid, mPEG-glutaric acid, mPEG-succinamide acid, mPEG-glutaramide acid, mPEG-OH, mPEG-SH, mPEG-maleimide, mPEG-Br, mPEG-CHO, mPEG-propylene oxide, mPEG-alkynyl, mPEG-silane, mPEG-CH2-COOH, mPEG-benzaldehyde, mPEG-nitrobenzene, mPEG-dopamine, mPEG-isocyanate, mPEG-biotin, mPEG-folic acid, mPEG-glycerol, mPEG-N3, mPEG-succinimide ester, mPEG-succinimide carbonate, mPEG-succinimide acetate, mPEG-succinimide succinate, mPEG-succinimide glutarate, mPEG-succinamide succinimide ester, mPEG-glutaramide succinimide ester mPEG-succinimide propionate, mPEG-succinimide butyrate, mPEG-succinimide valerate, COOH-mPEG-COOH, acetic acid-mPEG-acetic acid, succinic acid-mPEG-succinic acid, glutaric acid-mPEG-glutaric acid, succinamide acid-mPEG-succinamide acid, glutaramide acid-mPEG-glutaramide acid, NH2-mPEG-NH2, SH-mPEG-SH, maleimide-mPEG-maleimide, succinimide carbonate-mPEG-succinimide carbonate, succinimide acetate-mPEG-succinimide acetate, succinimide succinate-mPEG-succinimide succinate, succinimide glutarate-mPEG-succinimide glutarate, succinamide succinimide ester-mPEG-succinamide succinimide ester Glutaramide succinimide ester (mPEG-glutaramide succinimide ester), succinimide propionate (mPEG-succinimide propionate), succinimide butyrate (mPEG-succinimide butyrate), succinimide valerate (mPEG-succinimide valerate), N3-mPEG-N3, alkynyl-mPEG-alkynyl, CHO-mPEG-CHO, isocyanate-mPEG-isocyanate, biotin-mPEG-biotin, folic acid-mPEG-folic acid, benzaldehyde-mPEG-benzaldehyde, nitrobenzene-mPEG-nitrobenzene, silane-mPEG-silane, succinimide ester (mPEG-succinimide ester), ethylene oxide-mPEG-propylene oxide, DNP-mPEG-DNP, OH-mPEG-OH, NH2-mPEG-mannose. NH2-mPEG-SH, NH2-mPEG-maleimide, NH2-mPEG-N3,NH2-mPEG-phospholipids, NH2-mPEG-folic acid, NH2-mPEG-alkynyl, NH2-mPEG-acrylamide, NH2-mPEG-silane, NH2-mPEG-biotin, NH2-mPEG-mercaptopyridine, NH2-mPEG-tert-butyl ester, NH2-mPEG-DNP, NH2-mPEG-COOH, NH2-mPEG-OH, NH2-mPEG-CHO, COOH-mPEG-SH, COOH-mPEG-maleimide, COOH-mPEG-N3, COOH-mPEG-alkynyl, COOH-mPEG-mercaptopyridine, COOH-mPEG-biotin, COOH-mPEG-silane, COOH-mPEG-acrylamide, COOH-mPEG-folic acid, COOH-mPEG-succinimide ester, COOH-mPEG-OH, COOH-mPEG-DNP, COOH-mPEG-Br, COOH-mPEG-CHO, COOH-mPEG-COOMe, COOH-mPEG-tert-butyl ester, SH-mPEG-OH, SH-mPEG-N3, SH-mPEG-alkynyl, SH-mPEG-mercaptopyridine, SH-mPEG-biotin, SH-mPEG-silane, SH-mPEG-phospholipid, SH-mPEG-folic acid, SH-mPEG-mannose, OH-mPEG-succinimide ester, OH-mPEG-acrylamide, OH-mPEG-mercaptopyridine, OH-mPEG-silane, OH-mPEG-maleimide, OH-mPEG-phospholipid, OH-mPEG-folic acid, OH-mPEG-CHO, OH-mPEG-DNP, OH-mPEG-Br, OH-mPEG-biotin, OH-mPEG-alkynyl, OH-mPEG-tert-butyl ester OH-mPEG-N3, maleimide-mPEG-N3, maleimide-mPEG-alkynyl, maleimide-mPEG-silane, maleimide-mPEG-folic acid, N3-mPEG-alkynyl, N3-mPEG-acrylamide, N3-mPEG-mercaptopyridine, N3-mPEG-biotin, N3-mPEG-silane, N3-mPEG-folic acid, N3-mPEG-tert-butyl acetate, RGD-mPEG-NH2, RGD-mPEG-COOH, RGD-mPEG-SH, RGD-mPEG-N3, RGD-mPEG-folic acid, cRGD-mPEG-NH2, cRGD-mPEG-COOH, cRGD-mPEG-SH, cRGD-mPEG-N3, cRGD-mPEG-folic acidiRGD-mPEG-NH2, iRGD-mPEG-COOH, iRGD-mPEG-SH, iRGD-mPEG-N3, iRGD-mPEG-Folic acid.

3. The macrocyclic lactone polymer according to claim 1, wherein, The molecular weight of the polymer is between 300 and 20,000.

4. The macrocyclic lactone polymer according to claim 1, characterized in that, Having one of the following structures or stereoisomers, or a pharmaceutically acceptable salt: 。 5. A pharmaceutical composition, characterized in that, It comprises the macrocyclic lactone polymer according to any one of claims 1-4.

6. The pharmaceutical composition according to claim 5, characterized in that, It further includes pharmaceutically acceptable excipients, carriers, adjuvants, solvents, or combinations thereof.

7. The pharmaceutical composition according to claim 6, wherein the excipient is selected from diluents, fillers, binders, disintegrants, lubricants, flow aids, granulators, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, flavor masking agents, colorants, anti-caking agents, humectants, chelating agents, plasticizers, thickeners, antioxidants, preservatives, stabilizers, surfactants, or buffers.

8. The pharmaceutical composition according to claim 6, wherein the carrier is selected from disintegrants, controlled-release polymers, lubricants, diluents, or colorants.

9. Use of the macrocyclic lactone polymer according to any one of claims 1-4 or the pharmaceutical composition according to any one of claims 5-8 in the preparation of a medicament for the prevention or treatment of hyperproliferative diseases in mammals, wherein the hyperproliferative diseases are breast cancer, colonic adenocarcinoma, gastric cancer, pancreatic cancer, colorectal cancer, or bladder cancer, and the mammals include humans.

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