A halichondrin b analog

Abstract

A compound as shown in the following formula (I) and its racemate, stereoisomer, tautomer, isotopically labeled, nitroxide, solvate, polymorph or pharmaceutically acceptable salt thereof, the compound is an analogue of eribulin, has good anticancer activity, can overcome multiple drug resistance and maintain high cytotoxicity.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical compounds, and in particular relates to a halichondrin B analogue, a synthesis method of the compound and its application in the medical field. Background Art

[0002] Halichondrin B is a natural product from the marine environment, originally isolated from the sea sponge Halichondria okadai and found to possess excellent in vitro and in vivo antitumor activity. In 1992, the Kishi group reported the first total synthesis of Halichondrin B. The route involved three Nozaki–Hiyama–Kishi coupling reactions and multiple convergent synthesis steps, ultimately yielding only microgram quantities of the product (Thomas D. Aicher et al. J. Am. Chem. Soc. 1992, 114, 8, 3162–3164). The scarcity of natural sources and the difficulty of chemical synthesis have limited the development of Halichondrin B as an anticancer drug. Consequently, chemists have designed and synthesized a series of simplified Halichondrin B analogs. Among them, Eribulin, developed by Eisai, is one of the most successful structurally modified products; it retains the macrocyclic lactone core of the C1-C30 portion where the activity of halichondrin B is exerted, removes the polyether unit of the C37-C54 portion, and replaces the lactone bond with a more stable keto group (Murray J. Towle et al. Cancer Res. 2001, 114, 3, 1013–1021).

[0003]

[0004] Eribulin exerts a potent tumor cell-killing effect by inhibiting microtubule synthesis. However, compared with traditional microtubule inhibitors such as vinblastine and colchicine, it has a different mechanism of action: 1) Eribulin inhibits the growth phase of microtubules without affecting the shortening phase, sequestering tubulin into nonfunctional aggregates; 2) Eribulin disrupts the mitotic spindle, leading to an irreversible arrest of cell division at the G2 / M cycle; 3) Eribulin also exhibits non-cytotoxic effects in vivo, including vascular remodeling and reversal of the epithelial-mesenchymal transition of tumor cells (Nicholas F. Dybdal-Hargreaves et al. Clin. Cancer Res. 2015, 21, 11, 2445–2452). In November 2010, eribulin mesylate (trade name Halaven) received FDA approval in the United States for the treatment of metastatic breast cancer; in January 2016, it was also approved for the treatment of unresectable or metastatic liposarcoma.

[0005] Although eribulin possesses excellent anticancer activity and a wide therapeutic window, the presence of a primary amino group at position C35 in its structure makes it a suitable substrate for P-glycoprotein (P-gp). This significantly limits the use of eribulin in cancer patients with the MDR1 phenotype. Tumor multidrug resistance (MDR) refers to the phenomenon in which tumor cells, after developing resistance to a specific chemotherapy drug, also develop cross-resistance to other, unexperienced drugs of different structures and types. The mechanisms of MDR are diverse and complex, with the most intensively studied theory linking MDR to overexpression of P-glycoprotein (P-gp) in tumor cells (MDR1 phenotype). P-gp is a transmembrane transporter that functions as a drug efflux pump, expelling hydrophobic drugs from cells, reducing drug accumulation within tumor cells, leading to weakened or lost cytotoxicity, and the development of drug resistance. S. Narayan et al. discovered that by modifying the C33 hydroxyl group and C34 amino group of eribulin and then further substituting them, a series of derivatives that can partially overcome MDR while maintaining high cytotoxicity can be obtained (Sridhar Narayan et al. Bioorg. Med. Chem. Lett. 2011, 21, 6, 1639-1643). However, this paper is limited to substitutions at these limited sites and does not completely overcome the MDR problem. Summary of the Invention

[0006] To address the problems existing in the prior art, the present invention, based on the structure of eribulin, designs and synthesizes a series of aromatic or heteroaryl-substituted derivatives that can completely overcome multidrug resistance while maintaining high cytotoxic potency. The present invention also relates to a method for preparing these compounds from eribulin under efficient and mild conditions.

[0007] Specifically, the present invention provides a compound represented by the following formula (I) and its racemate, stereoisomer, tautomer, isotope-labeled substance, nitrogen oxide, solvate, polymorph or pharmaceutically acceptable salt:

[0008]

[0009] X, Y and Z are independently selected from the group consisting of: N, O, C-A2;

[0010] A1 and A2 are the same or different and are independently selected from H, -C(O)Ra, -OC(O)Ra, the following groups optionally substituted with one, two or more Rb: C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C12 cycloalkyl, C6-C14 aryl, 3-14 membered heterocyclyl and 5-14 membered heteroaryl; or, A1, A2 and the carbon atom to which they are attached together constitute a C3-C8 cycloalkyl, C6-C14 aryl, 3-14 membered heterocyclyl, or 5-14 membered heteroaryl group optionally substituted with one, two or more Rb;

[0011] Ra is selected from: H, OH, NH2, -NR1R2 or C1~C6 alkyl, C1~C6 alkoxy optionally substituted by one, two or more Rc;

[0012] Rb is selected from the group consisting of halogen, -CN, -NO2, -N3, oxo (=O), -NH2, -NR1R2, -NR1(CO)R2, -OH, -OR1, -O(CO)R1, -SH, -SR1, -SO2R1, -SO3H, -SO3R1, -OSO2R1, and -OSi(R 1)2 R2; or

[0013] Rb is selected from: C1-C6 alkyl, C1-C6 alkoxy, C6-C14 aryl, 5-14 membered heteroaryl, optionally substituted by one, two or more Rc; D1 and D2 are independently selected from H, halogen, -OH and C1-C6 alkoxy; or,

[0014] D1 and D2 together form oxo (=O); or,

[0015] D1, D2 and the carbon atom to which they are connected together form an oxime group -C=N-OR3;

[0016] R1, R2 and R3 are the same or different and are independently selected from the group consisting of: H, C1-C6 alkyl, C6-C10 aryl, (CH2) 1-3 C6-C10 aryl;

[0017] wherein Rc is selected from the group consisting of: halogen, -OH, -NH2, C1-C6 alkyl optionally substituted with halogen, -OH, -NH2, C1-C6 alkoxy, C6-C10 aryl;

[0018] n is an integer between 0 and 3.

[0019] According to an embodiment of the present invention, wherein X is N, O or C-A2; Y is N or O; and Z is N, O or C-A2.

[0020] According to an embodiment of the present invention, wherein D1 and D2 together constitute oxo (=O), n is 1.

[0021] According to an embodiment of the present invention, the compound of formula (I) has a structure shown by formula (II) or formula (III):

[0022]

[0023] Wherein, the definition of A1 is as described above in formula (I). Further, A1 is selected from the following groups optionally substituted by one, two or more Rb:

[0024] (1) C1-C6 alkyl, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, and n-hexyl;

[0025] (2) C3-C6 cycloalkyl, such as cyclopropyl, cyclobutyl, and cyclopentyl;

[0026] (3) -C(O)Ra, wherein Ra is selected from C1-C6 alkyl, C1-C6 alkoxy; preferably -C(O)OCH3;

[0027] (4) C6-C14 aryl, such as phenyl or naphthyl optionally substituted by C1-C6 alkyl, C1-C6 alkoxy, or halogen;

[0028] (5) C2-C12 alkenyl, preferably C3-C6 alkenyl; for example, vinyl, allyl, n-butenyl, isobutenyl, 1-butylene, 2-butylene, 1-pentylene, 2-pentylene, 3-pentylene, piperyl, isoprenyl, cyclopentenyl, 1-hexylene, 2-hexylene, 3-hexylene, 4-hexylene, 1,3-hexylene and 2,4-hexylene;

[0029] (6) C2-C12 alkynyl, such as ethynyl and propargyl;

[0030] (7) 3- to 7-membered heterocyclic groups, such as oxirane, glycidyl, oxetanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydrothienyl, oxazolidinyl, isoxazolidinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, isothiazolidinyl, epoxyhexyl, piperidinyl, piperazinyl, and morpholinyl; preferably, 5- to 6-membered heterocyclic groups, such as tetrahydrofuranyl, tetrahydropyrrolyl, epoxyhexyl, and piperidinyl; more preferably, tetrahydropyrrolyl and piperidinyl;

[0031] (8) 5- to 10-membered heteroaryl, such as furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, pyridinyl, indolyl, quinolyl, isoquinolyl, triazolyl, pyrimidinyl, pyrazinyl or purinyl; more preferably, pyridinyl and indolyl;

[0032] The Rb are the same or different and are independently selected from: halogen, -CN, -NO2, -NH2, -NR1R2, -OH, -OR1, -O(CO)R1, -SH, -SR1, -SO2R1; or,

[0033] Rb are independently selected from: C1~C6 alkyl, C1~C6 alkoxy optionally substituted by one, two or more Rc, wherein Rc is independently selected from: halogen, -OH, -NH2, C1~C6 alkyl, C1~C6 alkoxy.

[0034] In a specific embodiment of the present invention, examples of A1 in formula (II) or formula (III) include but are not limited to the following groups: -CH3, -CH2OH, -CH2CH2OH, -C(OH)(CH3)2, -C(O)H, -COOH, -C(O)NH2, -C(O)OCH3, -C(O)OC2H5, -C2H5, -CH2NH2, -C2H5NH2, -C2H5N(CH3)2,

[0035] wherein G1, G2 and G3 are the same or different and are independently selected from halogen, -OH, -OCH3, -NH2, -N(CH3)2, -CH3, -CH2OH, -CH2NH2 and -CH(CH3)2.

[0036] According to an embodiment of the present invention, the compound of formula (I) has a structure shown in formula (IV):

[0037]

[0038] Wherein, A1 and A2 are as defined above in formula (I). Further, A1 and A2 are the same or different and are independently selected from the following groups optionally substituted by one, two or more Rb:

[0039] (1) Hydrogen atom;

[0040] (2) C1-C6 alkyl, preferably C1-C4 alkyl; for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl;

[0041] (3) C3-C6 cycloalkyl, such as cyclopropyl, cyclobutyl, and cyclopentyl;

[0042] (4) C6-C14 aryl, such as phenyl or naphthyl;

[0043] Alternatively, A1, A2 and the carbon atom to which they are attached together form the following group optionally substituted by one, two or more Rb:

[0044] (1) A1, A2 and the carbon atoms to which they are connected together form a C4-C6 cycloalkyl group; preferably, a C5-C6 cycloalkyl group, such as a cyclohexenyl group;

[0045] (2) A1, A2 and the carbon atom to which they are attached together form a C6-C14 aryl group; preferably, phenyl or naphthyl;

[0046] (3) A1, A2 and the carbon atom to which they are attached together form a 5- to 14-membered heteroaryl group; for example, furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, pyridyl, indolyl, quinolyl, isoquinolyl, triazolyl, pyrimidinyl, pyrazinyl or purinyl; preferably, pyridyl and indolyl;

[0047] Wherein, the Rb are the same or different and are independently selected from: halogen, -CN, -NO2, NH2, -NR1R2, -OH, -OR1, -O(CO)R1, SH, -SR1, -SO2R1; or,

[0048] Rb are independently selected from: C1-C6 alkyl, C1-C6 alkoxy, optionally substituted by one, two or more Rc, wherein Rc is independently selected from: halogen, hydroxyl, NH2, C1-C6 alkyl, C1-C6 alkoxy.

[0049] In a specific embodiment of the present invention, in the formula (IV), examples of A1 and A2 include but are not limited to the following groups:

[0050] H, -CH3, -CH2OH, -CH2CH2OH, -C(O)H, -COOH, -C(O)NH2, -C(O)CH3, -C(O)C2H5, -OC(O)C2H5, -CH2NH2, -CH2CH2NH2, -CH2CH2N(CH3)2,

[0051]

[0052] wherein G1, G2 and G3 are the same or different and are independently selected from halogen, -OH, -OCH3, -NH2, -N(CH3)2, -CH2OH and -CH2NH2.

[0053] In a specific embodiment of the present invention, in the formula (IV), A1, A2 and the carbon atoms to which they are connected together form the following cyclic structure:

[0054]

[0055] wherein G1, G2 and G3 are the same or different and are independently selected from halogen, -OH, -OCH3, -NH2, -N(CH3)2, -CH2OH and -CH2NH2.

[0056] In a specific embodiment of the present invention, the compound of formula (I) is selected from the following specific compounds:

[0057]

[0058]

[0059] Where ER is the following formula: The present invention also provides a method for preparing a compound represented by formula (II), which comprises the steps of cyclizing formula (II-3) to obtain formula (II):

[0060]

[0061] According to the preparation method of the above formula (II) of the present invention, it further comprises the step of oxidizing the compound of formula (II-2) to obtain the compound of formula (II-3):

[0062]

[0063] According to the preparation method of the above formula (II) of the present invention, it further comprises the step of condensing the formula (II-1) with the carboxylic acid A1-C(O)OH to obtain the formula (II-2):

[0064]

[0065] The present invention also provides a method for preparing a compound represented by formula (III), which comprises the steps of cyclizing formula (III-3) to obtain formula (III):

[0066]

[0067] According to the preparation method of the above formula (III) of the present invention, it further comprises the step of oxidizing formula (III-2) to obtain formula (III-3):

[0068]

[0069] According to the preparation method of the above formula (III) of the present invention, it further comprises the step of condensing the formula (III-1) with the carboxylic acid A1-C(O)OH to obtain the formula (III-2):

[0070]

[0071] Specifically, the method for preparing the compound represented by formula (II) or formula (III) of the present invention is as shown in Scheme 1:

[0072]

[0073] Wherein, A1 is the same as defined above,

[0074] Step 1: Carboxylic acid A1-C(O)OH reacts with β-amino alcohol (II-1 or III-1) in the presence of a condensing agent and a base to generate the corresponding β-hydroxyamide (II-2 or III-2); for example, the condensing agent is DCC, EDCI, CDI, HATU, HBTU, PyBOP or PyAOP, preferably PyAOP; the base can be an inorganic base or an organic base, for example, sodium carbonate, potassium carbonate, sodium ethoxide, potassium tert-butoxide, diisopropylethylamine (DIPEA), triethylamine (TEA), pyridine (Py) or 4-lutidine (DMAP), preferably diisopropylethylamine (DIPEA);

[0075] Step 2: The obtained β-hydroxyamide undergoes an oxidation reaction, converting the hydroxyl group into a carbonyl group to produce compound II-3 or III-3; for example, the oxidation reaction can be a Swern oxidation, a Dess-Martin oxidation, or a variant thereof;

[0076] Step 3: Compound II-3 or III-3 undergoes a cyclization reaction to produce compound II or III. Preferably, the cyclization reaction occurs in the presence of triphenylphosphine, an activator, and a base, wherein the activator is iodine (I2), hexachloroethane ((CCl3)2), or 1,2-dibromotetrachloroethane ((CBrCl2)2), preferably 1,2-dibromotetrachloroethane; and the base is sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, potassium tert-butoxide, diisopropylethylamine (DIPEA), triethylamine (TEA), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), pyridine (Py), or 4-lutidine (DMAP), preferably diisopropylethylamine (DIPEA).

[0077] In the synthesis method, raw material II-1 is eribulin, and raw material III-1 is an impurity in the eribulin synthesis process. Raw materials II-1 and III-1 were prepared by the present inventors with reference to the method disclosed in the relevant literature (Brian C. Austad et al. Synlett 2013, 24, 3, 333-337).

[0078] The present invention also provides a method for preparing a compound represented by formula (IV), which comprises the step of cyclizing formula (IV-4) to obtain (IV): Wherein A1 and A2 in formula (IV) are as defined above, with the proviso that they do not form an aryl or heteroaryl group together with the carbon atom to which they are attached.

[0079] According to the method for preparing the compound represented by the above formula (IV) of the present invention, it further comprises the step of oxidizing the compound represented by formula (IV-3) to obtain the compound represented by formula (IV-4):

[0080]

[0081] According to the method for preparing the compound represented by the above formula (IV) of the present invention, it further comprises the step of condensing formula (IV-1) and formula (IV-2) to obtain formula (IV-3):

[0082]

[0083] Furthermore, in the preparation of formula (IV) of the present invention, A1 and A2 are defined as above, provided that they do not form an aryl or heteroaryl group with the carbon atom to which they are attached, and the method is shown in Scheme 2:

[0084]

[0085] Wherein, A1 and A2 are the same as above definitions,

[0086] Step 1: Carboxylic acid (IV-1) reacts with β-amino alcohol (IV-2) in the presence of a condensing agent and a base to generate the corresponding amide IV-3. For example, the condensing agent is DCC, EDCI, CDI, HATU, HBTU, PyBOP or PyAOP, preferably PyAOP; the base is an inorganic base or an organic base, such as sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, potassium tert-butoxide, diisopropylethylamine (DIPEA), triethylamine (TEA), pyridine (Py) or 4-lutidine (DMAP), preferably diisopropylethylamine (DIPEA);

[0087] Step 2: Compound IV-3 undergoes an oxidation reaction, converting the hydroxyl group to a carbonyl group to produce β-carbonyl amide IV-4. For example, the oxidation reaction can be a Swern oxidation, a Dess-Martin oxidation, or a variant thereof;

[0088] Step 3: Compound IV-4 undergoes a cyclization reaction to produce compound IV. The cyclization reaction occurs in the presence of triphenylphosphine, an activator, and a base. For example, the activator is iodine (I2), hexachloroethane ((CCl3)2), or 1,2-dibromotetrachloroethane ((CBrCl2)2), preferably 1,2-dibromotetrachloroethane; the base is an inorganic base or an organic base, such as sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, potassium tert-butoxide, diisopropylethylamine (DIPEA), triethylamine (TEA), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), pyridine (Py), or 4-lutidine (DMAP), preferably diisopropylethylamine (DIPEA).

[0089] The present invention also provides a method for preparing a compound represented by formula (IV), which comprises the step of cyclizing formula (IV-6) to obtain (IV): Wherein A1 and A2 in formula (IV) together with the carbon atom to which they are connected form the aforementioned aryl or heteroaryl group.

[0090] According to the method for preparing the compound represented by the above formula (IV) of the present invention, it further comprises the step of condensing formula (IV-1) and (IV-5) to obtain formula (IV-6):

[0091]

[0092] Furthermore, in the present invention, when A1 and A2 in formula (IV) together with the carbon atom to which they are connected constitute the aforementioned aryl or heteroaryl group, the preparation method is shown in Scheme 3:

[0093]

[0094] Among them, A1 and A2 together with the carbon atoms to which they are connected form a C4-C6 aromatic ring.

[0095] Step 1: Carboxylic acid (IV-1) reacts with compound (IV-5) in the presence of a condensing agent and a base to produce compound IV-6. For example, the condensing agent is DCC, EDCI, CDI, HATU, HBTU, PyBOP or PyAOP, preferably PyAOP; the base is an inorganic base or an organic base, such as sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, potassium tert-butoxide, diisopropylethylamine (DIPEA) or triethylamine (TEA), preferably diisopropylethylamine (DIPEA);

[0096] Step 2: Compound IV-6 undergoes a cyclization reaction to produce Compound IV. The cyclization reaction occurs in the presence of triphenylphosphine, an activator, and / or a base. For example, the activator is iodine (I2), hexachloroethane ((CCl3)2), 1,2-dibromotetrachloroethane ((CBrCl2)2), diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), or dipiperidine azodicarbonyl (ADDP), preferably 1,2-dibromotetrachloroethane and diethyl azodicarboxylate (DEAD); the base is an inorganic base or an organic base, such as sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, potassium tert-butoxide, diisopropylethylamine (DIPEA), triethylamine (TEA), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), pyridine (Py), or 4-lutidine (DMAP), preferably diisopropylethylamine (DIPEA).

[0097] In the synthesis method, raw material IV-1 is an impurity in the synthesis process of eribulin, and was prepared by the present inventors with reference to the method disclosed in the relevant literature (Sridhar Narayan et al. Bioorg. Med. Chem. Lett. 2011, 21, 6, 1630-1633).

[0098] According to the preparation method of the present invention, in the above schemes 1, 2, and 3, when A1 and / or A2 have an amino group (-NH2) or a hydroxyl group (-OH), the method further comprises: protecting the amino group or hydroxyl group before step 1, and a deprotection step after all steps.

[0099] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of at least one of the compound represented by formula (I), its racemate, tautomer, isotope-labeled substance, nitrogen oxide, solvate, polymorph or pharmaceutically acceptable salt thereof.

[0100] According to an embodiment of the present invention, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.

[0101] According to an embodiment of the present invention, the pharmaceutical composition may further contain one or more other therapeutic agents.

[0102] The present invention also provides a method for treating cancer, comprising administering to a patient a preventive or therapeutically effective amount of at least one of the compound represented by formula (I), its racemate, tautomer, isotope-labeled substance, nitrogen oxide, solvate, polymorph, or pharmaceutically acceptable salt thereof.

[0103] The present invention also provides the use of at least one of the compound represented by formula (I), its racemate, tautomer, isotope-labeled substance, nitrogen oxide, solvate, polymorph or pharmaceutically acceptable salt thereof in the preparation of a drug.

[0104] According to an embodiment of the present invention, the use may be use in preparing anticancer drugs.

[0105] According to an embodiment of the present invention, the cancer includes but is not limited to breast cancer, ovarian cancer, cervical cancer, uterine cancer, endometrial cancer, prostate cancer, kidney cancer, urethral cancer, bladder cancer, liver cancer, gastric cancer, salivary gland cancer, esophageal cancer, thyroid cancer, melanoma, glioma, neuroblastoma, sarcoma, lung cancer, colon cancer, rectal cancer, colorectal cancer, leukemia, lymphoma, bone cancer, pancreatic cancer and skin cancer.

[0106] Beneficial effects

[0107] The compound of the present invention, as an analogue of eribulin, has good anti-cancer effect, and the compound of the present invention can overcome multidrug resistance and maintain high cytotoxicity.

[0108] Definitions and Explanations of Terms

[0109] Unless otherwise indicated, the definitions of groups and terms in this specification and claims, including definitions used as examples, exemplary definitions, preferred definitions, definitions in tables, and definitions of specific compounds in the Examples, may be arbitrarily combined and coupled with one another. The group definitions and compound structures resulting from such combinations and couplings should be understood to be within the scope of this specification and / or claims.

[0110] Unless otherwise indicated, numerical ranges recited in this specification and claims are equivalent to reciting at least each specific integer value therein. For example, the numerical range "1-14" is equivalent to reciting each integer value in the numerical range "1-14", namely, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14.

[0111] The term "optional" (or "optionally", "optionally") in the general formula definitions of this application means the case of being substituted by zero, one or more substituents, for example, "optionally substituted by one, two or more R" means that it may not be substituted by R (unsubstituted) or may be optionally substituted by one, two or more R.

[0112] "More" means three or more.

[0113] The term "C1-C12 alkyl" is understood to mean straight-chain and branched alkyl groups having 1 to 12 carbon atoms, "C1-C8 alkyl" means straight-chain and branched alkyl groups having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, and "C1-C6 alkyl" means straight-chain and branched alkyl groups having 1, 2, 3, 4, 5, or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, or the like, or isomers thereof.

[0114] The term "C1-C12 alkoxy" is to be understood as "C1-C12 alkyl-O-", wherein C1-C12 alkyl is as defined above.

[0115] “C2-C12 alkenyl” is understood to mean preferably a straight or branched monovalent hydrocarbon radical containing one or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms, more preferably a “C2-C8 alkenyl”. “C2-C8 alkenyl” is understood to mean preferably a straight or branched monovalent hydrocarbon radical containing one or more double bonds and having 2, 3, 4, 5, 6, 7 or 8 carbon atoms, for example, having 2, 3, 4, 5 or 6 carbon atoms (i.e., C2-C6 alkenyl), having 2 or 3 carbon atoms (i.e., C2-C3 alkenyl). It will be appreciated that where the alkenyl group contains more than one double bond, the double bonds may be separated or conjugated. The alkenyl group is, for example, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)-pent-1-enyl, (Z)-pent-1-enyl, hex-5-enyl, yl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl, (Z)-1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut- 1-ethylprop-1-enyl, 1-propylvinyl, and 1-isopropylvinyl.

[0116] The term "C 2-12“Alkynyl” is understood as meaning a linear or branched monovalent hydrocarbon radical which contains one or more triple bonds and has 2 to 12 carbon atoms, preferably a “C2-C6-alkynyl” radical. The term “C2-C6-alkynyl” is understood as preferably meaning a linear or branched monovalent hydrocarbon radical which contains one or more triple bonds and has 2, 3, 4, 5, 6 carbon atoms, in particular 2 or 3 carbon atoms (“C2-C3-alkynyl”). Such alkynyl radicals are, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, -ynyl, 1-methylbut-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1-methylpent-4-ynyl, 2-methylpent-3-ynyl, 1-methylpent-3-ynyl, 4-methylpent-2-ynyl, 1-methylpent-2-ynyl, 4-methylpent-1-ynyl, 3-methylpent-1 ...2-ynyl, 4-methylpent-1-ynyl, 3-methylpent-1-ynyl, 2-methylpent-4-ynyl, 1-methylpent-4-ynyl, 2-methylpent-3-ynyl, 1-methylpent-3-ynyl, 4-methylpent-2-ynyl, In some embodiments, the alkynyl group is ethynyl, prop-1-ynyl or prop-2-ynyl.

[0117] The term "C3-12 cycloalkyl" should be understood as a saturated or partially saturated monovalent monocyclic, bicyclic (such as condensed ring, bridged ring, spiro ring) or tricyclic non-aromatic hydrocarbon group having 3 to 12 carbon atoms, preferably a "C3-C10 cycloalkyl" and more preferably a "C3-C8 cycloalkyl". The term "C3-C12 cycloalkyl" should be understood as a saturated or partially saturated monovalent monocyclic, bicyclic (such as bridged ring, spiro ring) or tricyclic hydrocarbon group having 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms, wherein the carbon atoms are all single bond chains or partially single bond, partially double bond and / or triple bond chains. The C3-12 cycloalkyl group can be a monocyclic hydrocarbon group, such as C 3-10The present invention further comprises a monocyclic alkyl, monocyclic alkenyl, or monocyclic alkynyl such as cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl, or a bicyclic hydrocarbon group such as borneol, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, 2,7-diazaspiro[3,5]nonyl, 2,6-diazaspiro[3,4]octyl, or a tricyclic hydrocarbon group such as adamantyl.

[0118] The term "C3-C12 cycloalkyl" is understood to mean a saturated monovalent monocyclic, bicyclic (e.g., fused, bridged, or spirocyclic) or tricyclic alkyl group having 3 to 12 carbon atoms, preferably a "C3-C10 cycloalkyl group," and more preferably a "C3-C8 cycloalkyl group." The term "C3-C12 cycloalkyl" is understood to mean a saturated monovalent monocyclic, bicyclic (e.g., bridged, or spirocyclic) or tricyclic alkyl group having 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms, wherein the carbon atoms are all single-bonded. The C3-C12 cycloalkyl group may be a monocyclic alkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic alkyl group, such as borneol, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, 2,7-diazaspiro[3,5]nonyl, 2,6-diazaspiro[3,4]octyl, or a tricyclic hydrocarbon group, such as adamantyl.

[0119] The term "C6-C14 aryl" is understood to preferably mean a monovalent aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring (e.g., fused, bridged, or spiro) having 6 to 14 carbon atoms, which may be a single aromatic ring or a fused polyaromatic ring, preferably a "C6-C10 aryl". The term "C6-C14 aryl" is understood to preferably mean a monovalent aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring ("C6-C14 aryl") having 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms, in particular a ring having 6 carbon atoms ("C6 aryl"), such as phenyl or biphenyl, or a ring having 10 carbon atoms ("C10 aryl"), such as naphthyl, or a ring having 13 carbon atoms ("C13 aryl"), such as fluorenyl, or a ring having 14 carbon atoms ("C14 aryl"), such as anthracenyl. When the C6-C20 aryl group is substituted, it may be monosubstituted or polysubstituted. There is no limitation on the substitution position, and for example, it may be substituted at the ortho, para or meta position.

[0120] The term "5- to 14-membered heteroaryl" is understood to include monovalent monocyclic, bicyclic (e.g. fused, bridged, spiro) or tricyclic aromatic ring systems having 5 to 14 ring atoms and containing 1 to 5 heteroatoms independently selected from N, O and S, having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 5 or 6 or 9 or 10 carbon atoms, and containing 1 to 5, preferably 1 to 3, heteroatoms each independently selected from N, O and S, and, in addition, in each case may be benzo-fused. In particular, the heteroaryl group is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl and the like and benzo derivatives thereof, such as benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like and benzo derivatives thereof, such as quinolyl, quinazolinyl, isoquinolyl and the like; or acininyl, indolizinyl, purinyl and the like and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl and the like. When the 5- to 14-membered heteroaryl group is linked to other groups to form the compounds of the present invention, the linking may be to a carbon atom on the 5- to 14-membered heteroaryl ring or to a heteroatom on the 5- to 14-membered heteroaryl ring. When the 5- to 14-membered heteroaryl group is substituted, it may be monosubstituted or polysubstituted. Furthermore, there is no limitation on the substitution site; for example, a hydrogen atom linked to a carbon atom on the heteroaryl ring may be substituted, or a hydrogen atom linked to a heteroatom on the heteroaryl ring may be substituted.

[0121] The term "3-14 membered heterocyclyl" means a saturated or unsaturated monovalent monocyclic, bicyclic or polycyclic non-aromatic hydrocarbon ring containing carbon atoms and 1-5 heteroatoms independently selected from N, O and S, with a total number of atoms constituting the ring being 3 to 14, and wherein there are no shared non-localized n electrons (aromaticity) between the ring carbons or heteroatoms. The term "3-12 membered heterocyclyl" means a saturated or unsaturated monovalent monocyclic or bicyclic non-aromatic hydrocarbon ring containing 1-5 heteroatoms independently selected from N, O and S; the term "3-10 membered heterocyclyl" means a saturated or unsaturated monovalent monocyclic or bicyclic hydrocarbon ring containing 1-5, preferably 1-3, heteroatoms selected from N, O and S, and also includes "3-6 membered heterocyclyl", "4-6 membered heterocyclyl" and "5-6 membered heterocyclyl". When all the ring atoms of the heterocyclic group are linked by single bonds, it forms a saturated heterocyclic group. When the heterocyclic group has 1, 2, 3 or more alkenyl groups or alkynyl groups, but does not make the heterocyclic group form an aromatic ring, it is respectively referred to as "heterocycloalkenyl" and "heterocycloalkynyl", such as "3-6 heterocycloalkenyl" and "3-6 heterocycloalkynyl". The heterocyclic group can be linked to the rest of the molecule through any carbon atom among the carbon atoms that do not form an acetylenic bond or a nitrogen atom (if present). In particular, the heterocyclic group may include, but is not limited to, a 3-membered ring, an oxiranyl group, a cyclonitroethane group; a 4-membered ring, such as an azetidinyl group, an azetidinyl group, an oxetane group, an oxetane group; a 5-membered ring, such as a tetrahydrofuranyl group, a dihydrofuranyl group, a dioxolyl group, a pyrrolidinyl group, a dihydroimidazolyl group, an imidazolidinyl group, a dihydropyrazolyl group, a pyrazolidinyl group, a pyrrolinyl group, an oxazolinyl group, an oxazolidinyl group, a thiazolinyl group, a thiazolidinyl group; or a 6-membered ring, such as a pyranyl group, a tetrahydropyranyl group, a thiopyranyl group, a dihydropyrimidinyl group, a piperidinyl group, a morpholinyl group, a dithianyl group, a thiomorpholinyl group, a piperazinyl group or a trithianyl group; or a 7-membered ring, such as a diazepanyl group, a diazepanyl group. Optionally, the heterocyclic group may be a fused ring, a bridged ring or a spirocyclic ring. The heterocyclic group may be bicyclic, such as, but not limited to, hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl. The nitrogen-containing ring may be partially unsaturated, i.e., it may contain one, two, or more double bonds, such as, but not limited to, 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl, or 4H-[1,4]thiazinyl, 5H,6H,8H-[1,2,4]triazolo[4,3-a]pyrazinyl. The heterocyclic group may be fused to the above-mentioned 4-membered, 5-membered, 6-membered, or 7-membered rings, such as 2,3-dihydrobenzofuran, benzopyran, 1,2-dihydroquinazoline, 3,4-dihydroquinazoline, and the like.

[0122] The term "spirocyclic" refers to a ring system in which two rings share one ring atom.

[0123] The term "fused ring" refers to a ring system in which two rings share two ring atoms.

[0124] The term "bridged ring" refers to a ring system in which two rings share three or more ring atoms.

[0125] The term "halogen" refers to fluorine, chlorine, bromine and iodine.

[0126] "Halo" means substituted with one or more halogens.

[0127] It will be appreciated by those skilled in the art that the compounds of formula (I) may exist in the form of various pharmaceutically acceptable salts. If these compounds have a basic center, they may form acid addition salts; if these compounds have an acidic center, they may form base addition salts; if these compounds contain both an acidic center (e.g., a carboxyl group) and a basic center (e.g., an amino group), they may also form internal salts.

[0128] The compounds of the present invention may exist in the form of solvates (e.g., hydrates), wherein the compounds of the present invention contain a polar solvent as a structural element of the crystal lattice of the compound, in particular water, methanol or ethanol. The amount of polar solvent, in particular water, may be present in a stoichiometric or non-stoichiometric ratio.

[0129] Depending on their molecular structure, the compounds of the present invention may be chiral and therefore may exist in various enantiomeric forms. Thus, these compounds may exist in racemic or optically active forms. The compounds of the present invention encompass isomers or mixtures or racemates in which each chiral carbon is in the R or S configuration. The compounds of the present invention or their intermediates can be separated into enantiomeric compounds by chemical or physical methods known to those skilled in the art, or used in this form for synthesis.

[0130] The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, the compounds may be labeled with radioactive isotopes, such as deuterium ( 2 H), tritium ( 3 H), iodine-125( 125 I) or C-14( 14 C) All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention. In some embodiments of the present invention, H is deuterium or tritium.

[0131] The term "patient" refers to any animal including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, and most preferably humans.

[0132] The term "therapeutically effective amount" refers to that amount of an active compound or drug that will elicit the biological or medical response that a researcher, veterinarian, physician, or other clinician is seeking in a tissue, system, animal, individual, or human, and includes one or more of the following: (1) prevents disease, e.g., prevents a disease, disorder, or condition in an individual who is susceptible to the disease, disorder, or condition but who is not yet experiencing or developing the pathology or symptoms of the disease. (2) inhibits disease, e.g., inhibits the disease, disorder, or condition (i.e., prevents further development of the pathology and / or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder, or condition. (3) alleviates disease, e.g., alleviates the disease, disorder, or condition (i.e., reverses the pathology and / or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder, or condition. DETAILED DESCRIPTION

[0133] The technical solutions of the present invention will be further described in detail below with reference to specific examples. It should be understood that the following examples are merely illustrative of and explain the present invention, and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are included in the scope of protection intended by the present invention. If specific conditions are not specified in the examples, they are carried out according to conventional conditions or conditions recommended by the manufacturer. Reagents or instruments used without indicating the manufacturer are all conventional products that can be obtained commercially. The separation or purification of the compounds can be carried out by preparative thin layer chromatography or silica gel column chromatography. In the present invention, GF 254 (1.0 mm) thin layer chromatography preparative plates are used in preparative thin layer chromatography; 200-300 mesh silica gel is used as the carrier for silica gel column chromatography. In the present invention, thin layer chromatography (TLC) is used for reaction monitoring using thin layer chromatography silica gel plates.

[0134] Example 1. Preparation of compound XY-141-105-1

[0135]

[0136] Step 1: To a 5 mL dry round-bottom flask, add glacial acetic acid (4.1 μL, 68.5 μmol), PyAOP (35.7 mg, 68.5 μmol), DIPEA (23.8 μL, 137 μmol), and 1.5 mL of anhydrous dichloromethane (DCM). Stir at room temperature for 15 min. Then, add eribulin (10 mg, 13.7 μmol) to the reaction mixture, and continue stirring at room temperature for 3 h. Monitor the reaction by TLC. Once the reaction is complete, concentrate the reaction mixture under reduced pressure. The crude product is purified by silica gel column chromatography to obtain 10.2 mg of acetamide XY-141-103-1 (yield 96.5%); ESI-MS (m / z): 772.73 [M+H] + .

[0137] Step 2: To a 5 mL, dry, nitrogen-protected round-bottom flask, add 27.4 μL of anhydrous oxalyl chloride and 1 mL of anhydrous dichloromethane. Cool to -78°C with dry ice / acetone. Add 0.5 mL of a dimethyl sulfoxide-dichloromethane solution (containing 46.0 μL of dimethyl sulfoxide) dropwise to the reaction mixture, and stir at this temperature for 30 minutes. Then, add acetamide XY-141-103-1 (10.2 mg, 13.2 μmol) prepared in the first step to the reaction mixture, and continue stirring at this temperature for 2 hours. Next, add 282 μL of DIPEA to the reaction mixture, and continue stirring at this temperature for 30 minutes. Monitor the reaction by TLC. Upon completion, quench the reaction mixture with an equal volume of saturated ammonium chloride solution and return to room temperature. Extract the aqueous phase with dichloromethane, and combine the organic phases and dry over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography to obtain 8.6 mg of compound XY-141-104-1 (yield 84.6%); ESI-MS (m / z): 770.66 [M+H] + .

[0138] Step 3: XY-141-104-1 (8.6 mg, 11.2 μmol), triphenylphosphine (11 mg, 41.9 μmol), DIPEA (96 μL, 551 μmol), and 1,2-dibromotetrachloroethane (13.7 mg, 42.0 μmol) were dissolved in 3 mL of anhydrous dichloromethane and reacted at room temperature overnight. The reaction was monitored by TLC. After completion, the reaction solution was directly concentrated under reduced pressure. The crude product was initially purified by silica gel column chromatography and then purified by preparative thin-layer chromatography to obtain 6.4 mg of the product XY-141-105-1 (yield 76.2%); ESI-MS (m / z): 752.66 [M+H] + .

[0139] Example 2. Preparation of compound XY-141-106-1

[0140]

[0141] A similar procedure to Example 1 was used, except that benzoic acid was used instead of glacial acetic acid in the first step; and in the third step, the reaction was heated under reflux for 5 h instead of overnight at room temperature. The molar ratios of the various materials remained unchanged. 6.2 mg of the product XY-141-106-1 was obtained (total yield of 55.4% over three steps); ESI-MS (m / z): 814.68 [M+H] + .

[0142] Example 3. Preparation of Compound XY-141-140-3

[0143]

[0144] A similar procedure to Example 1 was used, except that 2-isopropylbenzoic acid was used as the starting material in the first step instead of glacial acetic acid. In the third step, the reaction was heated under reflux for 5 h instead of overnight at room temperature. The molar ratios of the various materials remained unchanged. 2.1 mg of the product XY-141-140-3 was obtained (total yield of 21.6% over three steps); ESI-MS (m / z): 856.77 [M+H] + .

[0145] Example 4. Preparation of Compound XY-141-140-4

[0146]

[0147] A similar procedure to Example 1 was used, except that 2-methoxybenzoic acid was used as the starting material in the first step instead of glacial acetic acid. In the third step, the reaction was heated under reflux for 72 h instead of overnight at room temperature. The molar ratios of the various materials remained unchanged. 3.2 mg of the product XY-141-140-4 was obtained (total yield of 27.6% over three steps); ESI-MS (m / z): 844.86 [M+H] + .

[0148] Example 5. Preparation of Compound XY-141-140-5

[0149]

[0150] A similar procedure to Example 1 was used, except that 3-methoxybenzoic acid was used as the starting material in the first step instead of glacial acetic acid. In the third step, the reaction was heated under reflux for 72 h instead of overnight at room temperature. The molar ratios of the various materials remained unchanged. 3.8 mg of the product XY-141-140-5 was obtained (total yield of 32.7% over three steps); ESI-MS (m / z): 844.83 [M+H] + .

[0151] Example 6. Preparation of Compound XY-141-140-6

[0152]

[0153] A similar procedure to Example 1 was used, except that 4-methoxybenzoic acid was used instead of glacial acetic acid in the first step; and in the third step, the reaction was performed at room temperature for 72 h instead of overnight. The molar ratios of the various materials remained unchanged. 2.1 mg of the product XY-141-140-6 was obtained (total yield of 18.1% over three steps); ESI-MS (m / z): 844.85 [M+H] + .

[0154] Example 7. Preparation of Compound XY-141-156-1

[0155]

[0156] A similar procedure to Example 1 was used, except that 2-fluorobenzoic acid was used instead of glacial acetic acid in the first step; and in the third step, the overnight reaction at room temperature was replaced with a 5-h heating reflux reaction. The molar ratios of the various materials remained unchanged. The product XY-141-156-1 (59.6% total yield over three steps) was obtained. ESI-MS (m / z): 832.90 [M+H] + .

[0157] Example 8. Preparation of Compound XY-141-145-1

[0158]

[0159] A similar procedure to Example 1 was used, except that 3-fluorobenzoic acid was used as the starting material in the first step instead of glacial acetic acid. In the third step, the reaction was heated under reflux for 5 h instead of overnight at room temperature. The molar ratios of the various materials remained unchanged. 3.7 mg of the product XY-141-145-1 was obtained (total yield of 32.5% over three steps); ESI-MS (m / z): 832.81 [M+H] + .

[0160] Example 9. Preparation of Compound XY-141-145-2

[0161]

[0162] A similar procedure to Example 1 was used, except that 4-fluorobenzoic acid was used instead of glacial acetic acid in the first step; and in the third step, the reaction was heated under reflux for 5 h instead of overnight at room temperature. The molar ratios of the various materials remained unchanged. 3.2 mg of the product XY-141-145-2 was obtained (total yield of 28.1% over three steps); ESI-MS (m / z): 832.83 [M+H] + .

[0163] Example 10. Preparation of Compound XY-145-044

[0164]

[0165] A similar procedure to Example 1 was used, except that pyridine-3-carboxylic acid was used as the starting material in the first step instead of glacial acetic acid. In the third step, the reaction was heated under reflux for 7 h instead of overnight at room temperature. The molar ratios of the various materials remained unchanged. 2.0 mg of product XY-145-044 was obtained (total yield of 24.3% over three steps); ESI-MS (m / z): 815.71 [M+H] + .

[0166] Example 11. Preparation of Compound XY-145-043

[0167]

[0168] A similar procedure to Example 1 was used, except that pyridine-4-carboxylic acid was used as the starting material in the first step instead of glacial acetic acid. In the third step, the reaction was heated under reflux for 7 h instead of overnight at room temperature. The molar ratios of the various materials remained unchanged. 2.4 mg of product XY-145-043 was obtained (total yield of 33.6% over three steps); ESI-MS (m / z): 815.74 [M+H] + .

[0169] Example 12. Preparation of Compound XY-145-159

[0170]

[0171] A similar procedure to Example 1 was used, except that 5-methylpyridine-3-carboxylic acid was used as the starting material in the first step instead of glacial acetic acid. In the third step, the reaction was heated under reflux overnight instead of at room temperature. The molar ratios of the various materials remained unchanged. 1.7 mg of product XY-145-159 was obtained (total yield of 38.7% over three steps); ESI-MS (m / z): 829.82 [M+H] + .

[0172] Example 13. Preparation of Compound XY-145-155

[0173]

[0174] A similar procedure to Example 1 was used, except that pyrimidine-5-carboxylic acid was used as the starting material in the first step instead of glacial acetic acid. In the third step, the reaction was heated under reflux overnight instead of at room temperature. The molar ratios of the various materials remained unchanged. 1.8 mg of product XY-145-155 was obtained (total yield of 32.9% over three steps); ESI-MS (m / z): 816.84 [M+H] + .

[0175] Example 14. Preparation of Compound XY-145-174

[0176]

[0177] A similar procedure to Example 1 was used, except that 1-methyl-1H-imidazole-5-carboxylic acid was used instead of glacial acetic acid in the first step. In the third step, the reaction was performed at 50°C with a sealed tube instead of at room temperature overnight. The molar ratios of the various materials remained unchanged. 3.3 mg of product XY-145-174 was obtained (total yield of 53.4% ​​over three steps); ESI-MS (m / z): 818.87 [M+H] +

[0178] Example 15. Preparation of Compound XY-142-152

[0179]

[0180] A similar procedure to Example 1 was used, except that 3-hydroxyisovaleric acid was used as the starting material in the first step instead of glacial acetic acid; the molar ratios of the materials remained unchanged. 1.2 mg of product XY-142-152 was obtained (total yield of 24.0% over three steps); ESI-MS (m / z): 810.73 [M+H] + .

[0181] Example 16. Preparation of Compound XY-141-131-1

[0182]

[0183] The first three steps were similar to those in Example 1, except that in the first step, N-fluorenylmethoxycarbonyl-3(S)-aminobutyric acid was used as the starting material instead of glacial acetic acid. In the third step, the overnight reaction at room temperature was replaced with a 6-h heating under reflux. The molar ratios of the various materials remained unchanged. 2.2 mg of compound XY-141-130-2 was prepared (total yield of 15.5% over three steps); ESI-MS (m / z): 1017.87 [M+H] + .

[0184] Step 4: Compound XY-141-130-2 (2.2 mg, 2.2 μmol) was dissolved in 0.5 mL of anhydrous tetrahydrofuran solution, and 0.2 mL of diethylamine was added. The mixture was stirred at room temperature for 6 h. The reaction was monitored by TLC. After the reaction was complete, the solvent was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain 0.8 mg of compound XY-141-131-1 (yield 47.0%); ESI-MS (m / z): 795.81 [M+H] + .

[0185] Example 17. Preparation of Compound XY-141-153-1

[0186]

[0187] A similar method to Example 1 was used, but in the first step, Compound III-1 was used instead of Eribulin as the starting material, and the molar ratio of each material remained unchanged. 1.1 mg of product XY-141-153-1 was prepared (total yield of 21.6% over three steps); ESI-MS (m / z): 752.87 [M+H] + .

[0188] Example 18. Preparation of Compound XY-141-123-1

[0189]

[0190] Step 1: To a 5 mL dry round-bottom flask, compound IV-1 (10 mg, 14.0 μmol), PyAOP (29.2 mg, 56.0 μmol), DIPEA (146 μL, 838 μmol), and 1.0 mL of anhydrous dichloromethane (DCM) were added. Stir at room temperature for 15 min. DL-aminopropanol (4.2 mg, 56.0 μmol) was then added to the reaction mixture, and stirring was continued at room temperature for 3 h. The reaction was monitored by TLC. After completion, the reaction mixture was directly concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain 6.4 mg of compound XY-141-119-1 (yield 59.3%); ESI-MS (m / z): 772.71 [M+H] + .

[0191] Step 2: To a 5 mL, dry, nitrogen-protected round-bottom flask, add 27.4 μL of oxalyl chloride and 0.5 mL of anhydrous dichloromethane. Cool to -80°C with dry ice / acetone. Add 1 mL of anhydrous dimethyl sulfoxide (DMSO)-dichloromethane solution (containing 46.0 μL of anhydrous DMSO) dropwise to the reaction mixture, and stir at this temperature for 30 minutes. Then, add compound XY-141-119-1 (6.4 mg, 8.3 μmol) prepared in Step 1 to the reaction mixture, and continue stirring at this temperature for 2 hours. Next, add 282 μL of DIPEA to the reaction mixture, continue stirring at this temperature for 30 minutes, and then warm to room temperature. Monitor the reaction by TLC. Upon completion, quench the reaction mixture with an equal volume of saturated ammonium chloride solution and return to room temperature. Extract the aqueous phase with dichloromethane, and combine the organic phases and dry over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain 6.5 mg of crude compound XY-141-121-1; ESI-MS (m / z): 770.78 [M+H] + .

[0192] Step 3: Dissolve the crude product of compound XY-141-121-1 (6.5 mg), triphenylphosphine (11 mg, 41.9 μmol), DIPEA (96 μL, 551 μmol), and 1,2-dibromotetrachloroethane (13.7 mg, 42.0 μmol) in 3 mL of anhydrous dichloromethane and allow to react overnight at room temperature. Monitor the reaction by TLC. Once the reaction is complete, concentrate the reaction mixture under reduced pressure. The crude product is initially purified by silica gel column chromatography and then by preparative thin-layer chromatography to obtain 2.4 mg of product XY-141-123-1 (38.7% yield over two steps); ESI-MS (m / z): 752.64 [M+H] + .

[0193] Example 19. Preparation of Compound XY-141-124-1

[0194]

[0195] A similar procedure to Example 18 was used, except that DL-phenylglycinol was substituted for DL-aminopropanol in the first step. In the third step, the overnight reaction at room temperature was replaced with a 5-h reflux reaction. The molar ratios of the various materials remained unchanged. 1.6 mg of the product XY-141-12-1 was obtained (total yield of 14.0% over three steps). ESI-MS (m / z): 814.77 [M+H] + .

[0196] Example 20. Preparation of Compound XY-141-143-1

[0197]

[0198] XY-141-143-1

[0199] The first three steps were similar to those in Example 18, except that (R)-2-amino-3-[(tert-butyldimethylsilyl)oxy]-1-propanol was used as the starting material in the first step instead of DL-aminopropanol. In the third step, the overnight reaction at room temperature was replaced with a 6-h heating under reflux. The molar ratios of the various materials remained unchanged. 2.7 mg of compound XY-141-140-1 was prepared (total yield of 21.9% over three steps); ESI-MS (m / z): 882.88 [M+H] + .

[0200] Step 4: Compound XY-141-140-1 (2.7 mg, 3.1 μmol) was dissolved in 0.5 mL of anhydrous tetrahydrofuran solution, 5 μL of acetic acid and 25 μL of tetrabutylammonium fluoride (1.0 M in tetrahydrofuran solution) were added, and the mixture was stirred at room temperature for 6 h. The reaction was monitored by TLC. After the reaction was complete, an equal volume of saturated sodium bicarbonate solution was added to the reaction solution to quench the reaction and return it to room temperature. The aqueous phase was extracted with dichloromethane, and the organic phases were combined and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography to obtain 1.1 mg of compound XY-141-143-1 (yield 52.4%); ESI-MS (m / z): 678.71 [M+H] + .

[0201] Example 21. Preparation of Compound XY-141-147-1

[0202]

[0203] A similar procedure to Example 18 was used, except that isopropanolamine was used as the starting material in the first step instead of DL-aminopropanol. In the third step, the reaction was heated under reflux for 2 h instead of overnight at room temperature. The molar ratios of the various materials remained unchanged. 4.6 mg of the product XY-141-147-1 was obtained (total yield of 44.7% over three steps); ESI-MS (m / z): 752.82 [M+H] + .

[0204] Example 22. Preparation of Compound XY-141-147-2

[0205]

[0206] A similar procedure to Example 18 was used, except that 2-amino-1-phenylethanol was substituted for DL-aminopropanol in the first step. In the third step, the overnight reaction at room temperature was replaced with a 5-h heating under reflux. The molar ratios of the various materials remained unchanged. 2.1 mg of the product XY-141-147-2 was obtained (total yield of 18.8% over three steps). ESI-MS (m / z): 814.77 [M+H] + .

[0207] Example 23. Preparation of Compound XY-141-160-1

[0208]

[0209] A similar procedure to Example 18 was used, except that 3-amino-2-butanol was substituted for DL-aminopropanol in the first step. In the third step, the overnight reaction at room temperature was replaced with a 10-h reflux reaction. The molar ratios of the various materials remained unchanged. 3.1 mg of the product XY-141-160-1 was obtained (total yield of 58% over three steps); ESI-MS (m / z): 766.81 [M+H] + .

[0210] Example 24. Preparation of Compound XY145-047

[0211]

[0212] Step 1: Compound IV-1 (5 mg, 7.0 μmol), PyAOP (14.6 mg, 28.0 μmol), DIPEA (73 μL, 419 μmol), and 1.0 mL of anhydrous dichloromethane (DCM) were added to a 5 mL dry round-bottom flask. Stir at room temperature for 15 min. Then, o-aminophenol (3.8 mg, 35.0 μmol) was added to the reaction solution, and stirring was continued at room temperature for 3 h. The reaction was monitored by TLC. After the reaction was complete, the reaction solution was directly concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography to obtain 3.5 mg of compound XY-145-046 (yield 62%); ESI-MS (m / z): 806.76 [M+H] + .

[0213] Step 2: To a 5 mL dry round-bottom flask, compound XY-145-046 (3.0 mg, 3.7 μmol), triphenylphosphine (26.8 mg, 74.0 μmol), and 1 mL of anhydrous tetrahydrofuran (THF) were added. Stir at room temperature for 3 h and monitor the reaction by TLC. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography to obtain 2.0 mg of compound XY-145-047 (yield 66%); ESI-MS (m / z): 788.74 [M+H] + .

[0214] Example 25. Preparation of Compound XY-141-158-1

[0215]

[0216] A similar procedure to Example 24 was used, except that 2-amino-3-methoxyphenol was substituted for o-aminophenol in the first step; the molar ratios of the materials remained unchanged. 2.1 mg of the product XY-141-158-1 was obtained (total yield of 36.8% for two steps); ESI-MS (m / z): 818.80 [M+H] + .

[0217] Example 26. Preparation of Compound XY-141-158-2

[0218]

[0219] A similar procedure to Example 24 was used, except that 2-amino-4-methoxyphenol was substituted for o-aminophenol in the first step; the molar ratios of the materials remained unchanged. 2.3 mg of product XY-141-158-2 was obtained (total yield for two steps: 40.3%); ESI-MS (m / z): 818.86 [M+H] + .

[0220] Example 27. Preparation of Compound XY-145-071

[0221]

[0222] A similar procedure to Example 24 was used, except that 2-amino-3-fluorophenol was substituted for o-aminophenol in the first step; the molar ratios of the materials remained unchanged. 1.4 mg of product XY-145-071 was obtained (total yield for two steps: 31.5%); ESI-MS (m / z): 806.71 [M+H] + .

[0223] Example 28. Preparation of Compound XY-145-069

[0224]

[0225] A similar procedure to Example 24 was used, except that 2-amino-4-fluorophenol was substituted for o-aminophenol in the first step; the molar ratios of the materials remained unchanged. 1.7 mg of product XY-145-069 was obtained (total yield for two steps: 28.7%); ESI-MS (m / z): 806.70 [M+H] + .

[0226] Example 29. Preparation of Compound XY-145-075

[0227]

[0228] A similar procedure to Example 24 was used, except that 2-amino-5-fluorophenol was substituted for o-aminophenol in the first step; the molar ratios of the materials remained unchanged. 1.1 mg of product XY-145-075 was obtained (total yield for two steps: 23.2%); ESI-MS (m / z): 806.81 [M+H] + .

[0229] Example 30. Preparation of Compound XY-145-087

[0230]

[0231] A similar procedure to Example 24 was used, except that 2-amino-6-fluorophenol was substituted for o-aminophenol in the first step; the molar ratios of the materials remained unchanged. 1.2 mg of product XY-145-087 was obtained (total yield for two steps: 29.1%); ESI-MS (m / z): 806.79 [M+H] + .

[0232] Example 31. Preparation of Compound XY-145-048

[0233]

[0234] A similar procedure to Example 24 was used, except that in the first step, 2-amino-4-tert-butyldiphenylsilyloxymethylphenol was substituted for o-aminophenol; the molar ratios of the materials remained unchanged. 3.0 mg of product was obtained (total yield for two steps, 47%); ESI-MS (m / z): 1056.84 [M+H] + . Step 3: In a 5 mL dry round-bottom flask, add the compound (3.0 mg, 2.85 μmol), TBAF (6 μL, 1N in THF, 6 μmol) and 1 mL of anhydrous tetrahydrofuran (THF). Stir at room temperature for 3 h and monitor the reaction by TLC. After the reaction is complete, saturated ammonium chloride is added to quench the reaction, and the mixture is extracted with ethyl acetate. The organic phase is concentrated under reduced pressure. The crude product is purified by preparative thin-layer chromatography to obtain 1.8 mg of compound XY-145-048 (yield 64%); ESI-MS (m / z): 818.72 [M+H] + .

[0235] Example 32. Preparation of Compound XY-145-103

[0236]

[0237] Step 1: To a 5 mL dry round-bottom flask, compound IV-1 (5 mg, 7.0 μmol), PyAOP (14.6 mg, 28.0 μmol), DIPEA (73 μL, 419 μmol), and 1.0 mL of anhydrous dichloromethane (DCM) were added. Stir at room temperature for 15 min. 2-Amino-3-hydroxypyridine (3.9 mg, 35.0 μmol) was then added to the reaction mixture, and stirring was continued at room temperature for 3 h. The reaction was monitored by TLC. After completion, the reaction mixture was directly concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain 3.8 mg of compound XY-145-100 (yield 67.4%); ESI-MS (m / z): 807.80 [M+H] + .

[0238] Step 2: To a 5 mL dry round-bottom flask, compound XY-145-100 (3.0 mg, 3.7 μmol), DIPEA (26.8 μL, 148 μmol), 1,2-dibromotetrachloroethane (24.2 mg, 74.0 μmol), and 2 mL of anhydrous dichloromethane were added and allowed to react at room temperature overnight. The reaction was monitored by TLC. Upon completion, the reaction solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain 2.3 mg of compound XY-145-103 (yield 33.0%); ESI-MS (m / z): 789.86 [M+H] + .

[0239] Example 33. Preparation of Compound XY-145-102

[0240]

[0241] A similar procedure to Example 32 was used, except that 3-amino-4-hydroxypyridine was substituted for 2-amino-3-hydroxypyridine in the first step; the molar ratios of the materials remained unchanged. 1.6 mg of product was obtained (total yield for two steps: 33.7%); ESI-MS (m / z): 789.86 [M+H] + .

[0242] Example 34. Preparation of Compound XY-145-115

[0243]

[0244] A similar procedure to Example 32 was used, except that 4-amino-3-hydroxypyridine was used as the starting material in the first step instead of 2-amino-3-hydroxypyridine; the molar ratios of the materials remained unchanged. 1.5 mg of product was obtained (total yield for two steps: 19%); ESI-MS (m / z): 789.88 [M+H] + .

[0245] Example 35. Preparation of Compound XY-145-116

[0246]

[0247] A similar procedure to Example 32 was used, except that 3-amino-2-hydroxypyridine was substituted for 2-amino-3-hydroxypyridine in the first step; the molar ratios of the materials remained unchanged. 2.2 mg of product was obtained (total yield for two steps: 27.3%); ESI-MS (m / z): 789.89 [M+H] + .

[0248] Example 36. Inhibition of tumor cell growth by test compounds

[0249] The cells used for evaluation included human breast cancer MCF-7 cells, human ovarian cancer cells SKOV-3, human colon cancer cells COLO205, human colorectal adenocarcinoma cells HCT-15, docetaxel-resistant human lung adenocarcinoma cells A549 / DR, and wild-type human lung adenocarcinoma cells A549. Cell growth inhibition assays were performed using CCK-8 reagent according to the kit instructions and National Cancer Institute (NCI) standard methods.

[0250] MCF-7, SKOV-3, and COLO205 cells were purchased from ATCC; HCT-15, A549, and A549 / DR cells were purchased from Nanjing Kebai Biotechnology Co., Ltd., and the CCK-8 kit was purchased from Beibo Biotechnology. DMEM, RPMI-1640, and fetal bovine serum were purchased from Gibco. MCF-7, SKOV-3, COLO205, and HCT-15 cell lines were cultured in DMEM high-glucose medium supplemented with 10% FBS and 0.01 mg / mL insulin; A549 cell lines were cultured in RPMI-1640 supplemented with 10% FBS; and A549 / DR cell lines were cultured in RPMI-1640 supplemented with 10% FBS and 50 nM docetaxel. All cells were maintained at 37°C with 5% CO2 and passaged.

[0251] When the cell density of MCF-7, SKOV-3, COLO205, HCT-15, A549, and A549 / DR cells reaches 90%, digest and centrifuge, discard the supernatant, add an appropriate amount of culture medium, mix thoroughly, and count the cells. After preparing the cell suspension, gently mix it thoroughly and add 100 μL to each well. Plate the cells at the appropriate cell density, filling the edge wells with sterile PBS. Place the seeded 96-well plate in an incubator and incubate until the cell monolayer completely fills the 96-well flat-bottom plate. Treat with different drugs for the desired duration. Aspirate the drug-containing culture medium and add CCK-8 solution to each well. Incubate for another 4 hours before terminating the culture. Measure the absorbance of each well at 450 nm using a microplate reader. Data were calculated using the formula: Inhibition rate (%) = [(Ac - As) / (Ac - Ab)] × 100, where As = absorbance of the experimental wells (absorbance of the wells containing cells, culture medium, CCK-8, and the test compound); Ab = absorbance of the blank wells (absorbance of the wells containing culture medium and CCK-8); and Ac = absorbance of the control wells (absorbance of the wells containing cells, culture medium, and CCK-8). Experiments were repeated three times. The results are shown in Tables 1 and 2.

[0252] Table 1

[0253]

[0254]

[0255] Table 2

[0256]

[0257]

[0258] The above is an exemplary description of the implementation methods of the technical solution of the present invention. It should be understood that the scope of protection of the present invention is not limited to the above implementation methods. Any modifications, equivalent substitutions, improvements, etc. made by those skilled in the art within the spirit and principles of the present invention shall be included in the scope of protection of the claims of this application.

Claims

1. A compound represented by the following formula (II) or formula (III), its racemate, stereoisomer, tautomer or pharmaceutically acceptable salt thereof: ; in, A1 is independently selected from H, -C(O)Ra, -OC(O)Ra, the following groups optionally substituted by one, two or more Rb: C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C12 cycloalkyl, C6-C14 aryl, 3-14 membered heterocyclic group and 5-14 membered heteroaryl, wherein the 3-14 membered heterocyclic group is composed of carbon atoms and 1-5 heteroatoms independently selected from N, O and S, the total number of atoms constituting the ring is 3-14, and there are no shared non-localized n electrons between the ring carbons or heteroatoms, i.e., it is not aromatic; Ra is selected from: H, -OH, -NH2, -NR1R2 or C1~C6 alkyl, C1~C6 alkoxy optionally substituted by one, two or more Rc; Rb is selected from the group consisting of halogen, -CN, -NO2, -N3, oxo (=O), -NH2, -NR1R2, -NR1(CO)R2, -OH, -OR1, -O(CO)R1, -SH, -SR1, -SO2R1, -SO3H, -SO3R1, -OSO2R1, and -OSi(R 1)2 R2; or Rb is selected from: C1~C6 alkyl, C1~C6 alkoxy, C6~C14 aryl, 5-14 membered heteroaryl, optionally substituted by one, two or more Rc; R1 and R2 are the same or different and are independently selected from the group consisting of: H, C1~C6 alkyl, C6~C10 aryl, (CH2) 1-3 C6~C10 aryl; Rc is selected from the group consisting of halogen, -OH, -NH2, C1-C6 alkyl optionally substituted with halogen, -OH, -NH2, C1-C6 alkoxy, and C6-C10 aryl.

2. The compound represented by formula (II) or formula (III) according to claim 1, its racemate, stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein A1 is selected from the following groups optionally substituted by one, two or more Rb: (1) C1~C6 alkyl; (2) C3~C6 cycloalkyl; (3) -C(O)Ra, wherein Ra is selected from C1-C6 alkyl and C1-C6 alkoxy; (4) C6~C14 aryl; (5) C2~C12 alkenyl; (6) C2~C12 alkynyl; (7) 3- to 7-membered heterocyclic group; (8) 5-10 membered heteroaryl; The Rb are the same or different and are independently selected from: halogen, -CN, -NO2, -NH2, -NR1R2, -OH, -OR1, -O(CO)R1, -SH, -SR1, -SO2R1; or, Rb are independently selected from: C1~C6 alkyl, C1~C6 alkoxy, optionally substituted by one, two or more Rc, wherein Rc is independently selected from: halogen, -OH, -NH2, C1~C6 alkyl, C1~C6 alkoxy.

3. The compound represented by formula (II) or formula (III) according to claim 1, its racemate, stereoisomer, tautomer or pharmaceutically acceptable salt thereof, A1 is selected from the following groups: -CH3, -CH2OH, -CH2CH2OH, -C(OH)(CH3) 2、 -C(O)H, -COOH, -C(O)NH2, -C(O)OCH3, -C(O)OC2H5, -C2H5, -CH2NH2, -C2H5NH2, -C2H5N(CH3)2, 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ;in, G1, G2 and G3 are the same or different and are independently selected from halogen, -OH, -OCH3, -NH2, -N(CH3)2, -CH3, -CH2OH, -CH2NH2 and -CH(CH3)2.

4. A compound represented by the following formula (IV), its racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof: ； in, A1 and A2 are the same or different and are independently selected from H, -C(O)Ra, -OC(O)Ra, the following groups optionally substituted with one, two or more Rb: C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C12 cycloalkyl, C6-C14 aryl, 3-14 membered heterocyclyl and 5-14 membered heteroaryl; Alternatively, A1, A2 and the carbon atom to which they are attached together form a C3-C8 cycloalkyl, C6-C14 aryl, 3-14 membered heterocyclyl, or 5-14 membered heteroaryl group, which is optionally substituted with one, two or more Rb; The 3- to 14-membered heterocyclic group is composed of carbon atoms and 1-5 heteroatoms independently selected from N, O, and S, with a total number of atoms constituting the ring being 3 to 14, and wherein there are no shared delocalized n electrons between the ring carbons or heteroatoms, i.e., it is not aromatic; Ra is selected from: H, -OH, -NH2, -NR1R2 or C1~C6 alkyl, C1~C6 alkoxy optionally substituted by one, two or more Rc; Rb is selected from the group consisting of halogen, -CN, -NO2, -N3, oxo (=O), -NH2, -NR1R2, -NR1(CO)R2, -OH, -OR1, -O(CO)R1, -SH, -SR1, -SO2R1, -SO3H, -SO3R1, -OSO2R1, and -OSi(R 1)2 R2; or Rb is selected from: C1~C6 alkyl, C1~C6 alkoxy, C6~C14 aryl, 5-14 membered heteroaryl, optionally substituted by one, two or more Rc; R1 and R2 are the same or different and are independently selected from the group consisting of: H, C1~C6 alkyl, C6~C10 aryl, (CH2) 1-3 C6~C10 aryl; Rc is selected from the group consisting of halogen, -OH, -NH2, C1-C6 alkyl optionally substituted with halogen, -OH, -NH2, C1-C6 alkoxy, and C6-C10 aryl.

5. The compound of formula (IV) according to claim 4, its racemate, stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein A1 and A2 are the same or different and are independently selected from the following groups optionally substituted with one, two or more Rb: (1) Hydrogen atom; (2) C1~C6 alkyl; (3) C3~C6 cycloalkyl; (4) C6~C14 aryl; Alternatively, A1, A2 and the carbon atom to which they are attached together form the following group optionally substituted by one, two or more Rb: (1) A1, A2 and the carbon atoms to which they are connected together form a C4~C6 cyclic hydrocarbon group; (2) A1, A2 and the carbon atoms to which they are connected together form a C6~C14 aromatic group; (3) A1, A2 and the carbon atom to which they are connected together form a 5- to 14-membered heteroaryl group; in, The Rb are the same or different and are independently selected from: halogen, -CN, -NO2, NH2, -NR1R2, -OH, -OR1, -O(CO)R1, -SH, -SR1, -SO2R1; or, Rb are independently selected from: C1~C6 alkyl, C1~C6 alkoxy, optionally substituted by one, two or more Rc, wherein Rc is independently selected from: halogen, hydroxyl, NH2, C1~C6 alkyl, C1~C6 alkoxy.

6. The compound of formula (IV) according to claim 4, its racemate, stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein in formula (IV), A1 and A2 are selected from the following groups: H, -CH3, -CH2OH, -CH2CH2OH, -C(O)H, -COOH, -C(O)NH2, -C(O)CH3, -C(O)C2H5, -OC(O)C2H5, -CH2NH2, -CH2CH2NH2, -CH2CH2N(CH3)2, 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ;in, G1, G2 and G3 are the same or different and are independently selected from halogen, -OH, -OCH3, -NH2, -N(CH3)2, -CH2OH and -CH2NH2.

7. The compound of formula (IV) according to claim 4, its racemate, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein in formula (IV), A1, A2, and the carbon atom to which they are connected together form the following cyclic structure: 、 、 、 、 、 ， 、 、 、 、 、 、 、 、 、 、 、 、 ； in, G1, G2 and G3 are the same or different and are independently selected from halogen, -OH, -OCH3, -NH2, -N(CH3)2, -CH2OH and -CH2NH2.

8. A compound selected from the group consisting of: a racemate, a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , where ER is the following formula: .

9. A method for preparing a compound of formula (II), comprising the step of cyclizing formula (II-3) to obtain formula (II): , wherein formula (II) is as defined in claim 1.

10. The method for preparing the compound of formula (II) according to claim 9, further comprising the step of oxidizing the compound of formula (II-2) to obtain the compound of formula (II-3): 。 11. The method for preparing the compound of formula (II) according to claim 10, further comprising the step of condensing the compound of formula (II-1) with a carboxylic acid A1-C(O)OH to obtain the compound of formula (II-2): 。 12. A method for preparing a compound of formula (III), comprising the step of cyclizing formula (III-3) to obtain formula (III): , wherein formula (III) is as defined in claim 1.

13. The method for preparing the compound of formula (III) according to claim 12, further comprising the step of oxidizing the compound of formula (III-2) to obtain the compound of formula (III-3): 。 14. The method for preparing the compound of formula (III) according to claim 13, further comprising the step of condensing the compound of formula (III-1) with a carboxylic acid A1-C(O)OH to obtain the compound of formula (III-2): 。 15. A method for preparing a compound represented by formula (IV), comprising: (1) Steps for cyclizing (IV-4) to obtain (IV): , wherein formula (IV) is as defined in claim 4, provided that A1 and A2 do not form a C6-C14 aryl group or a 5-14 membered heteroaryl group together with the carbon atom to which they are attached; Alternatively, it comprises the following steps: (2) Steps for cyclization of formula (IV-6) to obtain (IV): , wherein formula (IV) is as defined in claim 4, with the proviso that A1 and A2 together with the carbon atom to which they are attached form a C6-C14 aryl group or a 5-14 membered heteroaryl group.

16. The method for preparing the compound of formula (IV) according to claim 15, further comprising the step of oxidizing the compound of formula (IV-3) to obtain the compound of formula (IV-4): 。 17. The method for preparing the compound of formula (IV) according to claim 16, further comprising the step of condensing formula (IV-1) and formula (IV-2) to obtain formula (IV-3): 。 18. The method for preparing the compound of formula (IV) according to claim 15, further comprising the step of condensing formula (IV-1) and (IV-5) to obtain formula (IV-6): 。 19. A pharmaceutical composition comprising a therapeutically effective amount of at least one of the compound of claim 1, claim 4 or claim 8, its racemate, tautomer or pharmaceutically acceptable salt thereof.

20. Use of at least one of the compound according to claim 1 or claim 4 or claim 8, its racemate, tautomer or pharmaceutically acceptable salt thereof in the preparation of a medicament for treating breast cancer, ovarian cancer, lung cancer or colon cancer.

21. Use of at least one of the compound according to claim 1 or claim 4 or claim 8, its racemate, tautomer or pharmaceutically acceptable salt thereof in the preparation of a medicament for treating colorectal cancer.

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