Eribulin derivative and antibody-drug conjugate thereof, and medical use thereof

Abstract

The present application relates to the technical field of medicines, and in particular to an eribulin derivative and an antibody-drug conjugate (ADC) thereof, and a medical use thereof. In the present application, a series of derivatives with good tumor suppression effects are synthesized by modifying eribulin, and have lower toxicity and a larger therapeutic window than that of eribulin; and then the the eribulin derivative and an antibody are made into an ADC by means of an appropriate linker, and the therapeutic efficiency of the eribulin derivative is improved using the targeting specificity of the antibody.

Description

ERIBULIN DERIVATIVE AND ANTIBODY-DRUG CONJUGATE THEREOF, AND MEDICAL USE THEREOF TECHNICAL FIELD

[0001] The present application relates to the field of medical technology, and specifically, to an eribulin derivative and an antibody-drug conjugate thereof, and a medical use thereof. BACKGROUND

[0002] Antibody-Drug Conjugates (ADCs) are therapeutic agents formed by conjugating, with small- molecule toxins (payloads) via linkers, antibodies specifically targeting relevant antigens, and have both a potent cytotoxic effect of small-molecule chemotherapeutic agents and a tumor-targeting property of antibody drugs. Once inside the body, ADC molecules can bind to antigens on surfaces of target cells via a targeting function of the antibodies, and release toxin molecules through chemical or enzymatic action to eliminate target cells. By virtue of their targeting property and intracellular drug release in tumor cells, the ADCs can bind precisely to tumors and reduce their impact on normal cells, thereby increasing local drug concentration, decreasing toxic and side effects on normal cells, and expanding a therapeutic window. The ADCs have broad application prospects in tumor therapy and have achieved some encouraging results in clinical research.

[0003] Early failures of the ADCs were mainly attributed to their toxicity. Some side effects of certain ADCs are similar to those caused by conventional cytotoxins used in chemotherapy, and sometimes, these side effects may be severe. First, these side effects are caused by the uncontrolled release of cytotoxic agents due to linker instability during systemic circulation. Second, these side effects are caused because immunoglobulin G1 (IgG1) isotypes of some ADCs may interact with Fc-γ receptors (Fc<com:Math><semantics>γ<annotation encoding="application / x-tex">\gamma< / annotation>< / semantics>< / com:Math>R), which may trigger target-independent, Fc<com:Math><semantics>γ<annotation encoding="application / x-tex">\gamma< / annotation>< / semantics>< / com:Math>R-mediated internalization in Fc<com:Math><semantics>γ<annotation encoding="application / x-tex">\gamma< / annotation>< / semantics>< / com:Math>R-positive cells. With such non-specific endocytosis (off-target toxicities), the antibodies exert toxic effects on these healthy cells, which are not intended targets of the ADCs. Other side effects are related to specificity (on-target toxicity) of the ADCs. According to statistical analysis, dose-limiting toxicity of ADCs is almost consistent with that of chemotherapeutic agents used as toxins (Cancer Cell 40, 14, 2022, 1257). The development of cytotoxicities for the ADCs becomes a complex task due to these factors.

[0004] Eribulin belongs to a class of inhibitors featuring tubulin polymerization and has a unique and novel use. Eribulin is a synthetic analog of halichondrin B. In 1986, Japanese scientists Hirata and Uemura isolated a polyether macrolide compound containing only C, H, and O atoms from a sponge (Halichondria okadai). They named this natural product with an extremely complex structure halichondrin B. Eribulin inhibits microtubule elongation and mitotic spindle formation to exert its antitumor activity, thereby inducing apoptosis. In addition, studies have revealed that eribulin has subnanomolar effects on both mitotic and non-mitotic processes in tumors and the tumor microenvironment. In November 2010, eribulin was first approved for use in treatment of patients with metastatic breast cancer in the United States. Currently, eribulin is approved for the treatment of breast cancer in more than 65 countries and regions in Europe, the Americas, and Asia. In addition, eribulin was first approved in the United States in January 2016 for the treatment of soft tissue sarcoma, and has been approved in 55 countries and regions ever since. In addition, in the United States and Japan, eribulin has been designated as an orphan drug for the treatment of soft tissue sarcoma. Five most common adverse reactions of eribulin are: decreased white blood cell count, decreased neutrophil count, elevated aspartate aminotransferase, elevated alanine aminotransferase, and anemia.

[0005] In the present application, a series of derivatives with good tumor suppression effects are synthesized by modifying eribulin, and have lower toxicity and a larger therapeutic window than that of eribulin; and then the eribulin derivative and an antibody are made into an ADC by means of an appropriate linker, and the therapeutic efficiency of the eribulin derivative is improved using the targeting specificity of the antibody. SUMMARY

[0006] To achieve the inventive objective of the present application, a first aspect of the present application provides an eribulin derivative, which is a compound of formula (I) or (II), or an isotope- labeled compound, an optical isomer, a geometric isomer, a tautomer, an isomer mixture, or a pharmaceutically acceptable salt thereof; [Image disponible dans le document PDF, Image available in the PDF document] Formula (I) Formula (II)

[0007] where:

[0008] A<com:Sub>1< / com:Sub> in formula (I) is selected from <com:Math><semantics>X3<annotation encoding="application / x-tex">X_3< / annotation>< / semantics>< / com:Math> <com:Math><semantics>X2<annotation encoding="application / x-tex">X_2< / annotation>< / semantics>< / com:Math> <com:Math><semantics>X1<annotation encoding="application / x-tex">X_1< / annotation>< / semantics>< / com:Math> <com:Math><semantics>X2<annotation encoding="application / x-tex">X_2< / annotation>< / semantics>< / com:Math> <com:Math><semantics>X1<annotation encoding="application / x-tex">X_1< / annotation>< / semantics>< / com:Math> <com:Math><semantics>X2<annotation encoding="application / x-tex">X_2< / annotation>< / semantics>< / com:Math> <com:Math><semantics>X1<annotation encoding="application / x-tex">X_1< / annotation>< / semantics>< / com:Math> <com:Math><semantics>X2<annotation encoding="application / x-tex">X_2< / annotation>< / semantics>< / com:Math> <com:Math><semantics>X1<annotation encoding="application / x-tex">X_1< / annotation>< / semantics>< / com:Math> <com:Math><semantics>X2<annotation encoding="application / x-tex">X_2< / annotation>< / semantics>< / com:Math> <com:Math><semantics>X1<annotation encoding="application / x-tex">X_1< / annotation>< / semantics>< / com:Math> <com:Math><semantics>X2<annotation encoding="application / x-tex">X_2< / annotation>< / semantics>< / com:Math> <com:Math><semantics>X1<annotation encoding="application / x-tex">X_1< / annotation>< / semantics>< / com:Math> <com:Math><semantics>X2<annotation encoding="application / x-tex">X_2< / annotation>< / semantics>< / com:Math> <com:Math><semantics>X1<annotation encoding="application / x-tex">X_1< / annotation>< / semantics>< / com:Math> <com:Math><semantics>X2<annotation encoding="application / x-tex">X_2< / annotation>< / semantics>< / com:Math> <com:Math><semantics>X1<annotation encoding="application / x-tex">X_1< / annotation>< / semantics>< / com:Math> <com:Math><semantics>X2<annotation encoding="application / x-tex">X_2< / annotation>< / semantics>< / com:Math> <com:Math><semantics>X1<annotation encoding="application / x-tex">X_1< / annotation>< / semantics>< / com:Math> <com:Math><semantics>X2<annotation encoding="application / x-tex">X_2< / annotation>< / semantics>< / com:Math> <com:Math><semantics>X1<annotation encoding="application / x-tex">X_1< / annotation>< / semantics>< / com:Math> <com:Math><semantics>X2<annotation encoding="application / x-tex">X_2< / annotation>< / semantics>< / com:Math> <com:Math><semantics>X1<annotation encoding="application / x-tex">X_1< / annotation>< / semantics>< / com:Math> <com:Math><semantics>X2<annotation encoding="application / x-tex">X_2< / annotation>< / semantics>< / com:Math> <com:Math><semantics>X1<annotation encoding="application / x-tex">X_1< / annotation>< / semantics>< / com:Math> <com:Math><semantics>X2<annotation encoding="application / x-tex">X_2< / annotation>< / semantics>< / com:Math> <com:Math><semantics>X1<annotation encoding="application / x-tex">X_1< / annotation>< / semantics>< / com:Math> <com:Math><semantics>X2<annotation encoding="application / x-tex">X_2< / annotation>< / semantics>< / com:Math> <com:Math><semantics>X2<annotation encoding="application / x-tex">X_2< / annotation>< / semantics>< / com:Math> <Formule mathématique disponible dans le document PDF, Math available in the PDF document>$X_$ [Image disponible dans le document PDF, Image available in the PDF document]

[0009] A<com:Sub>2< / com:Sub> in formula (II) is selected from [Image disponible dans le document PDF, Image available in the PDF document] ; each of ___ marked by * and ** is independently a single bond, a double bond, or an oxo bond (=O), and at least one of ____ is not a double bond;

[0010] R<com:Sub>1< / com:Sub> is selected from H, an alkyl group, a hydroxyl-substituted alkyl group, an alkyloxy- substituted alkyl group, an amino-substituted alkyl group, a haloalkyl group or a cyano-substituted alkyl group;

[0011] <com:Math><semantics>X1<annotation encoding="application / x-tex">X_1< / annotation>< / semantics>< / com:Math> is selected from CO-, -CH<com:Sub>2< / com:Sub>, -S(O)-, or -S(O)<com:Sub>2< / com:Sub>-;

[0012] <com:Math><semantics>X2<annotation encoding="application / x-tex">X_2< / annotation>< / semantics>< / com:Math> is selected from the direct bond, -O-, or -NR<com:Sub>1< / com:Sub>-;

[0013] X<com:Sub>3< / com:Sub> is selected from <com:Math><semantics>−(CR2R3)m1−NH2<annotation encoding="application / x-tex">-(CR_2R_3)_{m1}-NH_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−(CR2R3)m1−OH<annotation encoding="application / x-tex">-(CR_2R_3)_{m1}-OH< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−R4−(CR2R3)m2−NH2<annotation encoding="application / x-tex">-R_4-(CR_2R_3)_{m2}-NH_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−R4−(CR2R3)m2−NH2<annotation encoding="application / x-tex">-R_4-(CR_2R_3)_{m2}-NH_2< / annotation>< / semantics>< / com:Math> [Image disponible dans le document PDF, Image available in the PDF document] OH, or

[0014] <com:Math><semantics>Y1<annotation encoding="application / x-tex">Y_1< / annotation>< / semantics>< / com:Math> is selected from -(<com:Math><semantics>CR2R3<annotation encoding="application / x-tex">CR_2R_3< / annotation>< / semantics>< / com:Math>)<com:Sub>m1< / com:Sub>-NH<com:Sub>2< / com:Sub>, -(<com:Math><semantics>CR2R3<annotation encoding="application / x-tex">CR_2R_3< / annotation>< / semantics>< / com:Math>)<com:Sub>m1< / com:Sub>-OH, -R<com:Sub>4< / com:Sub>-(<com:Math><semantics>CR2R3<annotation encoding="application / x-tex">CR_2R_3< / annotation>< / semantics>< / com:Math>)<com:Sub>m2< / com:Sub>-NH<com:Sub>2< / com:Sub>, -R<com:Sub>4< / com:Sub>-(<com:Math><semantics>CR2R3<annotation encoding="application / x-tex">CR_2R_3< / annotation>< / semantics>< / com:Math>)<com:Sub>m2< / com:Sub>- [Image disponible dans le document PDF, Image available in the PDF document] OH, or

[0015] R<com:Sub>2< / com:Sub> and R<com:Sub>3< / com:Sub> are each independently selected from H, an alkyl group, a hydroxyl group, an alkyloxy group, an amino group, halogen, a cyano group, a hydroxyl-substituted alkyl group, an alkyloxy-substituted alkyl group, an amino-substituted alkyl group, a haloalkyl group, a cyano- substituted alkyl group, an alkyl group substituted by a substituted or unsubstituted carbon ring, an alkyl group substituted by a substituted or unsubstituted heterocyclic substituent, a substituted or unsubstituted carbon ring group or a substituted or unsubstituted heterocyclic group; and the substituted or unsubstituted carbon ring group and the substituted or unsubstituted heterocyclic group are optionally substituted by one or more substituents selected from an oxo group, the alkyl group, the hydroxyl group, the alkyloxy group, the amino group, halogen, the cyano group, the hydroxyl- substituted alkyl group, the alkyloxy-substituted alkyl group, the amino-substituted alkyl group, a haloalkyl group, and the cyano-substituted alkyl group;

[0016] R<com:Sub>4< / com:Sub> is selected from a substituted or unsubstituted carbon ring group or a substituted or unsubstituted heterocyclic group; and the substituted or unsubstituted carbon ring group and the substituted or unsubstituted heterocyclic group are optionally substituted by one or more substituents selected from an oxo group, the alkyl group, the hydroxyl group, the alkyloxy group, the amino group, halogen, the cyano group, the hydroxyl-substituted alkyl group, the alkyloxy-substituted alkyl group, the amino-substituted alkyl group, a haloalkyl group, and the cyano-substituted alkyl group;

[0017] ® ring is a substituted or unsubstituted heterocyclic group; and a ring of the heterocyclic group contains at least one -NH-, and the substitution refers to substitution with one or more substituents selected from an oxo group, the alkyl group, the alkyloxy group, halogen, the cyano group, the alkyloxy-substituted alkyl group, a haloalkyl group, and the cyano-substituted alkyl group;

[0018] A ring is the heterocyclic group; and a ring of the heterocyclic group contains at least one - NH-, and / or the heterocyclic group is substituted by the amino group, the hydroxyl group, the amino- substituted alkyl group, or the hydroxyl-substituted alkyl group, and the heterocyclic group is optionally substituted by one or more substituents selected from an oxo group, the alkyl group, the alkyloxy group, halogen, the cyano group, the alkyloxy-substituted alkyl group, a haloalkyl group, and the cyano-substituted alkyl group;

[0019] m1 is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and

[0020] m2 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0021] Specifically, the alkyl group is a <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C12<annotation encoding="application / x-tex">C_{12}< / annotation>< / semantics>< / com:Math> linear or branched alkyl group (for example, the number of carbon atoms is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12). The carbon ring group may be a saturated, partially unsaturated or completely unsaturated carbon ring group such as a cycloalkyl group, an aryl group, a cycloalkenyl group, a cycloalkynyl group, and an enyne ring group, and the number of carbon atoms may be 3 to 20 (for example, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20). The heterocyclic group may be a saturated, partially unsaturated or completely unsaturated heterocyclic group such as a heterocycloalkyl group or a heteroaryl group, the number of carbon atoms may be 3 to 20 (for example, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), and may contain 1, 2, 3, or 4 heteroatoms selected from N, O, and S.

[0022] In a group of embodiments, R<com:Sub>1< / com:Sub> is selected from H, the alkyl group, or a hydroxyl- substituted alkyl group, or preferably, is selected from H, a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl group, or a hydroxy- substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl group, or is more preferably selected from H, a C<com:Sub>1< / com:Sub>-C<com:Sub>4< / com:Sub> alkyl group, or a hydroxy-substituted C<com:Sub>1< / com:Sub>- C<com:Sub>4< / com:Sub> alkyl group; or specifically, can be selected from H, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a hydroxymethyl group, a hydroxyethyl group, a hydroxy-n-propyl group, and a hydroxyisopropyl group.

[0023] In a group of embodiments, <com:Math><semantics>X1<annotation encoding="application / x-tex">X_1< / annotation>< / semantics>< / com:Math> is selected from -CO- or -CH<com:Sub>2< / com:Sub>-.

[0024] In a group of embodiments, m1 is selected from 1, 2, 3, 4, 5, or 6; and m2 is selected from 0, 1, 2, 3, or 4.

[0025] In a group of embodiments, R<com:Sub>2< / com:Sub> and R<com:Sub>3< / com:Sub> are each independently selected from H, a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl group, a hydroxy group, a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyloxy group, a hydroxy-substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl group, a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyloxy-substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl group, a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl group substituted by a substituted or unsubstituted C<com:Sub>3< / com:Sub>-C<com:Sub>6< / com:Sub> cycloalkyl group, a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl group substituted by a substituted or unsubstituted 3- to 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms of N or O, a substituted or unsubstituted C<com:Sub>3< / com:Sub>-C<com:Sub>6< / com:Sub> cycloalkyl group, and a substituted or unsubstituted 3- to 6- membered heterocycloalkyl group containing 1 or 2 heteroatoms of N or O; and the substituted or unsubstituted C<com:Sub>3< / com:Sub>-C<com:Sub>6< / com:Sub> cycloalkyl group and the substituted or unsubstituted 3- to 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms of N or O are optionally substituted with one or more substituents selected from oxo, a <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl group, a hydroxy group, a <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyloxy group, a hydroxy-substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl group, and a <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyloxy-substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl group. Preferably, R<com:Sub>2< / com:Sub> and R<com:Sub>3< / com:Sub> are each independently selected from H, a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl group, a hydroxy group, a hydroxy-substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl group, a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl group substituted by a substituted or unsubstituted C<com:Sub>3< / com:Sub>-C<com:Sub>6< / com:Sub> cycloalkyl group, a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl group substituted by a substituted or unsubstituted 3- to 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms of N or O, a substituted or unsubstituted C<com:Sub>3< / com:Sub>-C<com:Sub>6< / com:Sub> cycloalkyl group, and a substituted or unsubstituted 3- to 6- membered heterocycloalkyl group containing 1 or 2 heteroatoms of N or O; and the substituted or unsubstituted C<com:Sub>3< / com:Sub>-C<com:Sub>6< / com:Sub> cycloalkyl group and the substituted or unsubstituted 3- to 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms of N or O are optionally substituted with one or more substituents selected from oxo, a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl group, a hydroxy group, and a hydroxy- substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl group.

[0026] In a group of embodiments, R<com:Sub>4< / com:Sub> is selected from a substituted or unsubstituted C<com:Sub>3< / com:Sub>-C<com:Sub>12< / com:Sub> monocyclic, fused, bicyclic, spiro or bridged cycloalkyl group, a substituted or unsubstituted 3- to 12-membered monocyclic, fused, bicyclic, spiro or bridged heterocycloalkyl group containing 1, 2, or 3 heteroatoms of N or O, a substituted or unsubstituted C<com:Sub>6< / com:Sub>-C<com:Sub>10< / com:Sub> aryl group, and a substituted or unsubstituted 5- to 10-membered heteroaryl group containing 1, 2, or 3 heteroatoms of N or O; and substitution means being substituted with one or more substituents selected from oxo, a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl group, a hydroxy group, a <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyloxy group, a hydroxy-substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl group, and a <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>- C<com:Sub>6< / com:Sub> alkyloxy-substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl group. Preferably, R<com:Sub>4< / com:Sub> is selected from a substituted or unsubstituted C<com:Sub>4< / com:Sub>-C<com:Sub>12< / com:Sub> monocyclic, fused, bicyclic, spiro or bridged cycloalkyl group, a substituted or unsubstituted 4- to 12-membered monocyclic, fused, bicyclic, spiro or bridged heterocycloalkyl group containing 1, 2, or 3 heteroatoms of N or O, a substituted or unsubstituted phenyl group, and a substituted or unsubstituted 5- to 10-membered heteroaryl group containing 1, 2, or 3 heteroatoms of N or O; and substitution means being substituted with one or more substituents selected from oxo and a <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl group.

[0027] In a group of embodiments, ® ring is a substituted or unsubstituted 3- to 12-membered monocyclic, fused, bicyclic, spiro or bridged heterocycloalkyl group containing 1, 2, or 3 heteroatoms of N or O, the heterocycloalkyl ring contains at least one -NH-, and substitution means being substituted with one or more substituents selected from oxo, a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl group, a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyloxy group, and a <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyloxy-substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl group.

[0028] In a group of embodiments, X<com:Sub>3< / com:Sub> is selected from -(CR<com:Sub>2< / com:Sub>R<com:Sub>3< / com:Sub>)<com:Sub>m1< / com:Sub>-NH<com:Sub>2< / com:Sub>, -(CR<com:Sub>2< / com:Sub>R<com:Sub>3< / com:Sub>)<com:Sub>m1< / com:Sub>-OH, -R<com:Sub>4< / com:Sub>- [Image disponible dans le document PDF, Image available in the PDF document] <com:Math><semantics>(CR2R3)m2<annotation encoding="application / x-tex">(CR_2R_3)_{m2}< / annotation>< / semantics>< / com:Math>-NH<com:Sub>2< / com:Sub>, -R<com:Sub>4< / com:Sub>-<com:Math><semantics>(CR2R3)m2<annotation encoding="application / x-tex">(CR_2R_3)_{m2}< / annotation>< / semantics>< / com:Math>-OH, or ® ring is a substituted or unsubstituted 4- to 12- membered monocyclic, fused, bicyclic, spiro or bridged heterocycloalkyl group containing 1, 2, or 3 heteroatoms of N or O, the substitution means being substituted with one or more substituents selected from oxo and a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl group; m1 is selected from 1, 2, 3, 4, 5, or 6; m2 is selected from 0, 1, 2, 3, 4, 5, or 6; R<com:Sub>2< / com:Sub> and R<com:Sub>3< / com:Sub> are each independently selected from H, a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl group, a hydroxy group, a hydroxy-substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl group, a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl group substituted by a substituted or unsubstituted C<com:Sub>3< / com:Sub>-C<com:Sub>6< / com:Sub> cycloalkyl group, and a substituted or unsubstituted C<com:Sub>3< / com:Sub>-C<com:Sub>6< / com:Sub> cycloalkyl group, where the substituted or unsubstituted C<com:Sub>3< / com:Sub>-C<com:Sub>6< / com:Sub> cycloalkyl group is optionally substituted with one or more substituents selected from oxo and a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl group; and R<com:Sub>4< / com:Sub> is selected from a C<com:Sub>4< / com:Sub>-C<com:Sub>12< / com:Sub> monocyclic, fused, bicyclic, spiro or bridged cycloalkyl group, a 4- to 12-membered monocyclic, fused, bicyclic, spiro or bridged heterocycloalkyl group containing 1, 2, or 3 heteroatoms of N or O, and a phenyl group. OH OH

[0029] More preferably, <com:Math><semantics>X3<annotation encoding="application / x-tex">X_3< / annotation>< / semantics>< / com:Math> is selected from the following groups: <com:Math><semantics>H2N1<annotation encoding="application / x-tex">H_2N_1< / annotation>< / semantics>< / com:Math> [Image disponible dans le document PDF, Image available in the PDF document] OH OH The Han see .

[0030] Most preferably, X<com:Sub>3< / com:Sub> is selected from the following groups: H<com:Sub>2< / com:Sub>N [Image disponible dans le document PDF, Image available in the PDF document]

[0031] In a group of embodiments, Y<com:Sub>1< / com:Sub> is selected from -(CR<com:Sub>2< / com:Sub>R<com:Sub>3< / com:Sub>)<com:Sub>m1< / com:Sub>-NH<com:Sub>2< / com:Sub>, -(CR<com:Sub>2< / com:Sub>R<com:Sub>3< / com:Sub>)<com:Sub>m1< / com:Sub>-OH, -R<com:Sub>4< / com:Sub>- <com:Math><semantics>(CR2R3)m2<annotation encoding="application / x-tex">(CR_2R_3)_{m2}< / annotation>< / semantics>< / com:Math>-NH<com:Sub>2< / com:Sub>, -R<com:Sub>4< / com:Sub>-<com:Math><semantics>(CR2R3)m2<annotation encoding="application / x-tex">(CR_2R_3)_{m2}< / annotation>< / semantics>< / com:Math>-OH, or <com:Math><semantics>(CR2R3)m2<annotation encoding="application / x-tex">(CR_2R_3)_{m2}< / annotation>< / semantics>< / com:Math>-OH, or <com:Math><semantics>(CR2R3)m2<annotation encoding="application / x-tex">(CR_2R_3)_{m2}< / annotation>< / semantics>< / com:Math>-NH<com:Sub>2< / com:Sub>, -R<com:Sub>4< / com:Sub>-<com:Math><semantics>(CR2R3)m2<annotation encoding="application / x-tex">(CR_2R_3)_{m2}< / annotation>< / semantics>< / com:Math>-OH, or membered monocyclic, fused, bicyclic, spiro or bridged heterocycloalkyl group containing 1, 2, or 3 heteroatoms of N or O, the substitution means being substituted with one or more substituents selected from oxo and a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl group; m1 is selected from 1, 2, 3, 4, 5, or 6; m2 is selected from 0, 1, 2, 3, 4, 5, or 6; R<com:Sub>2< / com:Sub> and R<com:Sub>3< / com:Sub> are each independently selected from H, a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl group, a hydroxy group, a hydroxy-substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl group, a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl group substituted by a substituted or unsubstituted C<com:Sub>3< / com:Sub>-C<com:Sub>6< / com:Sub> cycloalkyl group, and a substituted or unsubstituted C<com:Sub>3< / com:Sub>-C<com:Sub>6< / com:Sub> cycloalkyl group, where the substituted or unsubstituted C<com:Sub>3< / com:Sub>-C<com:Sub>6< / com:Sub> cycloalkyl group is optionally substituted with one or more substituents selected from oxo and a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl group; and R<com:Sub>4< / com:Sub> is selected from a C<com:Sub>4< / com:Sub>-C<com:Sub>12< / com:Sub> monocyclic, fused, bicyclic, spiro or bridged cycloalkyl group, a 4- to 12-membered monocyclic, fused, bicyclic, spiro or bridged heterocycloalkyl group containing 1, 2, or 3 heteroatoms of N or O, and a phenyl group.

[0032] Preferably, Y<com:Sub>1< / com:Sub> is selected from -(CR<com:Sub>2< / com:Sub>R<com:Sub>3< / com:Sub>)<com:Sub>m1< / com:Sub>-NH<com:Sub>2< / com:Sub> and -(CR<com:Sub>2< / com:Sub>R<com:Sub>3< / com:Sub>)<com:Sub>m1< / com:Sub>-OH, m1 is selected from 1, 2, 3, 4, 5, or 6, and R<com:Sub>2< / com:Sub> and R<com:Sub>3< / com:Sub> are each independently selected from H, a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl group, a hydroxy group, or a hydroxy-substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl group. [Image disponible dans le document PDF, Image available in the PDF document]

[0033] More preferably, <com:Math><semantics>Y1<annotation encoding="application / x-tex">Y_1< / annotation>< / semantics>< / com:Math> is selected from the following group:

[0034] In a group of embodiments, iring is a 3- to 12-membered monocyclic, fused, bicyclic, spiro or bridged heterocycloalkyl group containing 1, 2, or 3 heteroatoms of N or O, the heterocycloalkyl ring contains at least one -NH- and / or the heterocycloalkyl group is substituted with an amino group, a hydroxy group, an amino-substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl group, or a hydroxy-substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl group, and the heterocycloalkyl group is optionally substituted with one or more substituents selected from oxo, a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl group, a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyloxy group, or a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyloxy- substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl group.

[0035] In a group of embodiments, @ ring is a 4- to 12-membered monocyclic, fused, bicyclic, spiro or bridged heterocycloalkyl group containing 1, 2, or 3 heteroatoms of N or O, and the heterocycloalkyl ring contains at least one -NH- and / or the heterocycloalkyl group is substituted with an amino group, a hydroxy group, an amino-substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl group, or a hydroxy-substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl group. [Image disponible dans le document PDF, Image available in the PDF document]

[0036] More preferably, (a) is selected from the following groups: , [Image disponible dans le document PDF, Image available in the PDF document]

[0037] In a group of embodiments, <com:Math><semantics>A1<annotation encoding="application / x-tex">A_1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>A2<annotation encoding="application / x-tex">A_2< / annotation>< / semantics>< / com:Math> are selected from the following groups: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document]

[0038] A<com:Sub>2< / com:Sub> in formula (II) is alternatively selected from H<com:Sub>2< / com:Sub>N or HO . OH OH O <com:Math><semantics>H2N<annotation encoding="application / x-tex">H_2N< / annotation>< / semantics>< / com:Math> N<com:Br / >H Θ̈́Η,

[0039] Preferably, A<com:Sub>1< / com:Sub> and A<com:Sub>2< / com:Sub> are selected from the following groups: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document]

[0040] Specifically, the compound of formula (I) is one of the following: [Image disponible dans le document PDF, Image available in the PDF document] . . , , [Image disponible dans le document PDF, Image available in the PDF document] , , , , , [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] , , , , , 1 , , , , , [Image disponible dans le document PDF, Image available in the PDF document] 1.1 , , , , , [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] , , , , or

[0041] specifically, the compound of formula (II) is one of the following: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] , , , , [Image disponible dans le document PDF, Image available in the PDF document]

[0042] A second aspect of the present application provides an eribulin derivative, which is a compound of formula (I') or (II'), or an isotope-labeled compound, an optical isomer, a geometric isomer, a tautomer, an isomer mixture, or a pharmaceutically acceptable salt thereof; [Image disponible dans le document PDF, Image available in the PDF document]

[0043] where:

[0044] Q is a linker group capable of conjugating to an antibody or antigen-binding fragment;

[0045] L is a linker group that connects Q to <com:Math><semantics>A1<annotation encoding="application / x-tex">A_1< / annotation>< / semantics>< / com:Math>' or Q to <com:Math><semantics>A2<annotation encoding="application / x-tex">A_2< / annotation>< / semantics>< / com:Math>';

[0046] <com:Math><semantics>A1<annotation encoding="application / x-tex">A_1< / annotation>< / semantics>< / com:Math>' is a group formed by connecting <com:Math><semantics>A1<annotation encoding="application / x-tex">A_1< / annotation>< / semantics>< / com:Math> to L after removal of a hydrogen atom from -NH<com:Sub>2< / com:Sub>, - OH, -NH- on the chain, or -NH- on the ring of <com:Math><semantics>A1<annotation encoding="application / x-tex">A_1< / annotation>< / semantics>< / com:Math>;

[0047] A<com:Sub>2< / com:Sub>' is a group formed by connecting A<com:Sub>2< / com:Sub> to L after removal of a hydrogen atom from -NH<com:Sub>2< / com:Sub>, - OH, -NH- on the chain, or -NH- on the ring of A2; and

[0048] definitions of <com:Math><semantics>A1<annotation encoding="application / x-tex">A_1< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>A2<annotation encoding="application / x-tex">A_2< / annotation>< / semantics>< / com:Math>, *, and ** are the same as those in the foregoing formula (I) and formula <com:Math><semantics>(II)<annotation encoding="application / x-tex">(II)< / annotation>< / semantics>< / com:Math>.

[0049] In a group of embodiments, when <com:Math><semantics>X3<annotation encoding="application / x-tex">X_3< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>Y1<annotation encoding="application / x-tex">Y_1< / annotation>< / semantics>< / com:Math> are each independently selected from -(<com:Math><semantics>CR2R3<annotation encoding="application / x-tex">CR_2R_3< / annotation>< / semantics>< / com:Math>)<com:Sub>m1< / com:Sub>- <com:Math><semantics>NH2<annotation encoding="application / x-tex">NH_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−(CR2R3)m1−OH<annotation encoding="application / x-tex">-(CR_2R_3)_{m1}-OH< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−R4−(CR2R3)m2−NH2<annotation encoding="application / x-tex">-R_4-(CR_2R_3)_{m2}-NH_2< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>−R4−(CR2R3)m2−OH<annotation encoding="application / x-tex">-R_4-(CR_2R_3)_{m2}-OH< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>A1′<annotation encoding="application / x-tex">A_1'< / annotation>< / semantics>< / com:Math> is a group formed by connecting A<com:Sub>1< / com:Sub> to L after removal of the hydrogen atom from terminal -NH<com:Sub>2< / com:Sub> or terminal -OH of X<com:Sub>3< / com:Sub> or Y<com:Sub>1< / com:Sub>; and A<com:Sub>2< / com:Sub>' is a group formed by connecting A<com:Sub>2< / com:Sub> to L after removal of the hydrogen atom from the terminal -NH<com:Sub>2< / com:Sub> or terminal -OH of <com:Math><semantics>X3<annotation encoding="application / x-tex">X_3< / annotation>< / semantics>< / com:Math> or <com:Math><semantics>Y1<annotation encoding="application / x-tex">Y_1< / annotation>< / semantics>< / com:Math>; [Image disponible dans le document PDF, Image available in the PDF document]

[0050] when <com:Math><semantics>X3<annotation encoding="application / x-tex">X_3< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>Y1<annotation encoding="application / x-tex">Y_1< / annotation>< / semantics>< / com:Math> are each independently represents a group formed by connecting A<com:Sub>1< / com:Sub> to L after removal of the hydrogen atom of -NH- on the <com:Sup>®< / com:Sup> ring, and A2' represents a group formed by connecting A<com:Sub>2< / com:Sub> to L after removal of the hydrogen atom of -NH- on the <com:Sup>(B)< / com:Sup> ring; and [Image disponible dans le document PDF, Image available in the PDF document]

[0051] when <com:Math><semantics>A1<annotation encoding="application / x-tex">A_1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>A2<annotation encoding="application / x-tex">A_2< / annotation>< / semantics>< / com:Math> are each independently <com:Math><semantics>A1<annotation encoding="application / x-tex">A_1< / annotation>< / semantics>< / com:Math>' is a group formed by connecting A<com:Sub>1< / com:Sub> to L after removal of the hydrogen atom of -NH- on the or ring, or the hydrogen atom of -NH<com:Sub>2< / com:Sub> or -OH on the ing substituent, and A<com:Sub>2< / com:Sub>' is a group formed by connecting A<com:Sub>2< / com:Sub> to L after removal of the hydrogen atom of -NH- on the or -NH<com:Sub>2< / com:Sub> or -OH on the ing substituent.

[0052] Definitions of <com:Math><semantics>R1<annotation encoding="application / x-tex">R_1< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>X1<annotation encoding="application / x-tex">X_1< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>X2<annotation encoding="application / x-tex">X_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R2<annotation encoding="application / x-tex">R_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R3<annotation encoding="application / x-tex">R_3< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R4<annotation encoding="application / x-tex">R_4< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R4<annotation encoding="application / x-tex">R_4< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R5<annotation encoding="application / x-tex">R_5< / annotation>< / semantics>< / com:Math> ring, <com:Math><semantics>R4<annotation encoding="application / x-tex">R_4< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R5<annotation encoding="application / x-tex">R_5< / annotation>< / semantics>< / com:Math> ring, <com:Math><semantics>R5<annotation encoding="application / x-tex">R_5< / annotation>< / semantics>< / com:Math> ring, <com:Math><semantics>R6<annotation encoding="application / x-tex">R_6< / annotation>< / semantics>< / com:Math> ring, <com:Math><semantics>R7<annotation encoding="application / x-tex">R_7< / annotation>< / semantics>< / com:Math> ring, <com:Math><semantics>R8<annotation encoding="application / x-tex">R_8< / annotation>< / semantics>< / com:Math> ring, <com:Math><semantics>R8<annotation encoding="application / x-tex">R_8< / annotation>< / semantics>< / com:Math> ring, <com:Math><semantics>R8<annotation encoding="application / x-tex">R_8< / annotation>< / semantics>< / com:Math> ring, <com:Math><semantics>R8<annotation encoding="application / x-tex">R_8< / annotation>< / semantics>< / com:Math> ring, <com:Math><semantics>R8<annotation encoding="application / x-tex">R_8< / annotation>< / semantics>< / com:Math> ring, <com:Math><semantics>R8<annotation encoding="application / x-tex">R_8< / annotation>< / semantics>< / com:Math> ring, <com:Math><semantics>R8<annotation encoding="application / x-tex">R_8< / annotation>< / semantics>< / com:Math> ring, the foregoing formula (I) and formula (II).

[0053] In a group of embodiments, <com:Math><semantics>R1<annotation encoding="application / x-tex">R_1< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>H<annotation encoding="application / x-tex">H< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>A1<annotation encoding="application / x-tex">A_1< / annotation>< / semantics>< / com:Math>' is a group formed by connecting <com:Math><semantics>A1<annotation encoding="application / x-tex">A_1< / annotation>< / semantics>< / com:Math> to <com:Math><semantics>L<annotation encoding="application / x-tex">L< / annotation>< / semantics>< / com:Math> after removal of <com:Math><semantics>R1<annotation encoding="application / x-tex">R_1< / annotation>< / semantics>< / com:Math> from -NR<com:Sub>1< / com:Sub>-, and <com:Math><semantics>A2<annotation encoding="application / x-tex">A_2< / annotation>< / semantics>< / com:Math>' is a group formed by connecting <com:Math><semantics>A2<annotation encoding="application / x-tex">A_2< / annotation>< / semantics>< / com:Math> to L after removal of <com:Math><semantics>R1<annotation encoding="application / x-tex">R_1< / annotation>< / semantics>< / com:Math> from -NR<com:Sub>1< / com:Sub>-.

[0054] In a group of embodiments, L is -L<com:Sub>4< / com:Sub>-L<com:Sub>3< / com:Sub>-L<com:Sub>2< / com:Sub>-L<com:Sub>1< / com:Sub>-, and L<com:Sub>1< / com:Sub> is connected to A<com:Sub>1< / com:Sub>' or A<com:Sub>2< / com:Sub>', and L<com:Sub>4< / com:Sub> is connected to Q; [Image disponible dans le document PDF, Image available in the PDF document] and <com:Math><semantics>32<annotation encoding="application / x-tex">\frac{3}{2}< / annotation>< / semantics>< / com:Math> is a ligation site for ligating L<com:Sub>2< / com:Sub>;

[0056] L<com:Sub>2< / com:Sub> is a direct bond, an amino acid residue, or a short peptide chain formed by two or more amino acid residues (for example, 2 to 10 amino acid residues, optionally, a short peptide chain formed by 2, 3, 4, 5, 6, 7, 8, 9, and 10 amino acid residues), the amino acid residues are selected from natural or unnatural amino acid residues, the amino acid residue or short peptide chain has N-terminus for ligating L<com:Sub>3< / com:Sub> and C-terminus for ligating L<com:Sub>1< / com:Sub>, and L<com:Sub>2< / com:Sub> optionally contains one or more structures selected from formula (III-1) to formula (III-9): [Image disponible dans le document PDF, Image available in the PDF document] OH .

[0057] s is selected from 1, 2, 3, 4, 5, 6, 7, and 8, t is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12, and R<com:Sub>5< / com:Sub> is selected from H or a C<com:Sub>1< / com:Sub>-C<com:Sub>8< / com:Sub> alkyl group; or preferably, s is selected from 2, 3, 4, 5, and 6, t is selected from 4, 5, 6, 7, and 8, and R<com:Sub>5< / com:Sub> is selected from H or a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl group;

[0058] L<com:Sub>3< / com:Sub> is selected from a direct bond, <com:Math><semantics>−NR6−(CH2)r1−(CH2CH2O)r2−(CH2)r3−CO−<annotation encoding="application / x-tex">-NR_6-(CH_2)_{r1}-(CH_2CH_2O)_{r2}-(CH_2)_{r3}-CO-< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−O−(CH2)r1−<annotation encoding="application / x-tex">-O-(CH_2)_{r1}-< / annotation>< / semantics>< / com:Math> <com:Math><semantics>(CH2CH2O)r2−(CH2)r3−CO−<annotation encoding="application / x-tex">(CH_2CH_2O)_{r2}-(CH_2)_{r3}-CO-< / annotation>< / semantics>< / com:Math> <com:Math><semantics>•<annotation encoding="application / x-tex">\bullet< / annotation>< / semantics>< / com:Math> , <com:Math><semantics>−NR6−(CH2)r4−(OCH2CH2)r5−(CH2)r6−CO−<annotation encoding="application / x-tex">-NR_6-(CH_2)_{r4}-(OCH_2CH_2)_{r5}-(CH_2)_{r6}-CO-< / annotation>< / semantics>< / com:Math> <com:Math><semantics>•<annotation encoding="application / x-tex">\bullet< / annotation>< / semantics>< / com:Math> , or <com:Math><semantics>−O−(CH2)r4−(OCH2CH2)r5−(OCH2)r6−O<annotation encoding="application / x-tex">-O-(CH_2)_{r4}-(OCH_2CH_2)_{r5}-(OCH_2)_{r6}-O< / annotation>< / semantics>< / com:Math> <com:Math><semantics>(OCH2CH2)r5<annotation encoding="application / x-tex">(OCH_2CH_2)_{r5}< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>(CH2)r6<annotation encoding="application / x-tex">(CH_2)_{r6}< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>CO<annotation encoding="application / x-tex">CO< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>•<annotation encoding="application / x-tex">\bullet< / annotation>< / semantics>< / com:Math>; or L<com:Sub>3< / com:Sub> is selected from: [Image disponible dans le document PDF, Image available in the PDF document] or ected from 0, 1, 2, 3, 4, 5, or 6, r2 is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, r3 is selected from 1, 2, 3, 4, 5, or 6, r4 is selected from 1, 2, 3, 4, 5, or 6, r5 is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, r6 is selected from 0, 1, 2, 3, 4, 5, or 6, r7 is selected from 0, 1, 2, 3, 4, 5, or 6, r8 is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, r9 is selected from 1, 2, 3, 4, 5, or 6, r10 is selected from 1, 2, 3, 4, 5, or 6, W is selected from O or NR<com:Sub>6< / com:Sub>, R<com:Sub>6< / com:Sub> is selected from H or a C<com:Sub>1< / com:Sub>-C<com:Sub>8< / com:Sub> alkyl group, where • represents an attachment site to L2, and when • appears twice in the same L<com:Sub>3< / com:Sub> group, it means that L<com:Sub>2< / com:Sub> is attached at both sites; and preferably, r1 is selected from 0, 1, 2, 3, or 4; r2 is selected from 4, 5, 6, 7, or 8; r3 is selected from 1, 2, 3, or 4; r4 is selected from 1, 2, 3, or 4; r5 is selected from 4, 5, 6, 7, or 8; r6 is selected from 0, 1, 2, 3, or 4; r7 is selected from 0, 1, 2, 3, or 4; r8 is selected from 1, 2, 3, 4, 5, or 6; r9 is selected from 1, 2, 3, or 4; r10 is selected from 1, 2, 3, or 4; W is selected from O or NR<com:Sub>6< / com:Sub>; and R<com:Sub>6< / com:Sub> is selected from H or C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl group; and

[0060] L<com:Sub>4< / com:Sub> is selected from a direct bond, -CO-, -(CH<com:Sub>2< / com:Sub>)<com:Sub>p1< / com:Sub>-CO-, -(CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>O)<com:Sub>p2< / com:Sub>-(CH<com:Sub>2< / com:Sub>)<com:Sub>p3< / com:Sub>-CO-, -(CH<com:Sub>2< / com:Sub>)<com:Sub>p4< / com:Sub>- <com:Math><semantics>O−(CH2)p5−C(O)−<annotation encoding="application / x-tex">O-(CH_2)_{p5}-C(O)-< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NR7−(CH2)p1−CO−<annotation encoding="application / x-tex">-NR_7-(CH_2)_{p1}-CO-< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NR7−(CH2CH2O)p2−(CH2)p3−CO−<annotation encoding="application / x-tex">-NR_7-(CH_2CH_2O)_{p2}-(CH_2)_{p3}-CO-< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NR7−(CH2)p4−O−<annotation encoding="application / x-tex">-NR_7-(CH_2)_{p4}-O-< / annotation>< / semantics>< / com:Math> <com:Math><semantics>(CH2)p5−<annotation encoding="application / x-tex">(CH_2)_{p5}-< / annotation>< / semantics>< / com:Math> <com:Math><semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>< / com:Math>-, <com:Math><semantics>−O<annotation encoding="application / x-tex">-O< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>(CH2)p1<annotation encoding="application / x-tex">(CH_2)_{p1}< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>CO<annotation encoding="application / x-tex">CO< / annotation>< / semantics>< / com:Math>-, <com:Math><semantics>−O<annotation encoding="application / x-tex">-O< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>(CH2CH2O)p2<annotation encoding="application / x-tex">(CH_2CH_2O)_{p2}< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>(CH2)p3<annotation encoding="application / x-tex">(CH_2)_{p3}< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>CO<annotation encoding="application / x-tex">CO< / annotation>< / semantics>< / com:Math>-, and <com:Math><semantics>−O<annotation encoding="application / x-tex">-O< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>(CH2)p4<annotation encoding="application / x-tex">(CH_2)_{p4}< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>O<annotation encoding="application / x-tex">O< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>(CH2)p5<annotation encoding="application / x-tex">(CH_2)_{p5}< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>< / com:Math>-, <com:Math><semantics>p1<annotation encoding="application / x-tex">p1< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>p2<annotation encoding="application / x-tex">p2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>p3<annotation encoding="application / x-tex">p3< / annotation>< / semantics>< / com:Math>, p4, and p5 are each independently selected from 1, 2, 3, 4, 5, 6, 7, and 8, and R<com:Sub>7< / com:Sub> is selected from H or a C<com:Sub>1< / com:Sub>-C<com:Sub>8< / com:Sub> alkyl group, where -CO- is ligated to L<com:Sub>3< / com:Sub>; and preferably, p1 is selected from 1, 2, 3, 4, 5, and 6, p2 is selected from 1, 2, 3, and 4, p3 is selected from 1, 2, 3, and 4, p4 is selected from 1, 2, 3, and 4, p5 is selected from 1, 2, 3, and 4, and R<com:Sub>7< / com:Sub> is selected from H or a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl group.

[0061] In a group of embodiments, <com:Math><semantics>A1<annotation encoding="application / x-tex">A_1< / annotation>< / semantics>< / com:Math>' represents a group formed by connecting <com:Math><semantics>A1<annotation encoding="application / x-tex">A_1< / annotation>< / semantics>< / com:Math> to L after removal of the hydrogen atom from -NH<com:Sub>2< / com:Sub>, -NH- on the chain, or -NH- on the ring, and A<com:Sub>2< / com:Sub>' represents a group formed by connecting A<com:Sub>2< / com:Sub> to L after removal of the hydrogen atom from -NH<com:Sub>2< / com:Sub>, -NH- on the chain, or [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] or when A<com:Sub>1< / com:Sub>' represents a group formed by connecting A<com:Sub>1< / com:Sub> to L after removal of the hydrogen atom of -OH-, or A2' represents a group formed by connecting A<com:Sub>2< / com:Sub> to L after removal of the hydrogen atom of -OH-, L<com:Sub>1< / com:Sub> is [Image disponible dans le document PDF, Image available in the PDF document] selected from

[0062] In a group of embodiments, L<com:Sub>1< / com:Sub> is selected from a direct bond, `Z; N ◆ and [Image disponible dans le document PDF, Image available in the PDF document]

[0063] In a group of embodiments, L<com:Sub>2< / com:Sub> is an amino acid residue or a short peptide chain formed by 2 to 8 amino acid residues, and preferably, the amino acid residues are amino acid residues formed by amino acids selected from phenylalanine, alanine, glycine, valine, citrulline, leucine, isoleucine, tryptophan, tyrosine, histidine, lysine, serine, threonine, cysteine, glutamic acid, glutamine, aspartic acid, asparagine, methionine, and arginine, or more preferably, the amino acid residues are amino acid residues formed by amino acids selected from phenylalanine, alanine, glycine, valine, and citrulline.

[0064] In a group of embodiments, L<com:Sub>2< / com:Sub> optionally includes one or more structures selected from formula (III-1) and formula (III-9), or preferably, includes one or more structures selected from the [Image disponible dans le document PDF, Image available in the PDF document] following groups: where <com:Math><semantics>t=8<annotation encoding="application / x-tex">t=8< / annotation>< / semantics>< / com:Math>.

[0065] In a group of embodiments, L<com:Sub>2< / com:Sub> is selected from -NHGly<com:Sup>CO< / com:Sup>-, or selected from the following short peptide chains: -NHGly-Gly-Phe-Gly<com:Sup>CO< / com:Sup>-, -NHVal-Cit<com:Sup>CO< / com:Sup>-, -NHVal-Ala<com:Sup>CO< / com:Sup>-, -NHGly-Gly-Val-Ala<com:Sup>CO< / com:Sup>-, -NHGly-Gly-Val-Cit<com:Sup>CO< / com:Sup>-, -NHLys-Gly-Val-Ala<com:Sup>CO< / com:Sup>-, -NHLys-Gly-Val-Cit<com:Sup>CO< / com:Sup>-, and -NHGly-Val-Cit<com:Sup>CO< / com:Sup>-. In addition, L<com:Sub>2< / com:Sub> optionally contains one or more structures selected from formula (III-1) to formula (III- 9); or preferably, L<com:Sub>2< / com:Sub> optionally contains one or more structures selected from formula (III-1) and formula (III-9). [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document]

[0068] In a group of embodiments, L<com:Sub>3< / com:Sub> is selected from a direct bond, -NH-(CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>O)<com:Sub>r2< / com:Sub>- (CH<com:Sub>2< / com:Sub>)<com:Sub>r3< / com:Sub>- CO- <com:Math><semantics>♠<annotation encoding="application / x-tex">\spadesuit< / annotation>< / semantics>< / com:Math> , -NH-(CH<com:Sub>2< / com:Sub>)<com:Sub>r4< / com:Sub>-(OCH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>)<com:Sub>r5< / com:Sub>-CO- <com:Math><semantics>♠<annotation encoding="application / x-tex">\spadesuit< / annotation>< / semantics>< / com:Math> , -O-(CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>O)<com:Sub>r2< / com:Sub>-(CH<com:Sub>2< / com:Sub>)<com:Sub>r3< / com:Sub>-CO- <com:Math><semantics>♠<annotation encoding="application / x-tex">\spadesuit< / annotation>< / semantics>< / com:Math> or -O-(CH<com:Sub>2< / com:Sub>)<com:Sub>r4< / com:Sub>- (OCH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>)<com:Sub>r5< / com:Sub>-CO-♦; L<com:Sub>3< / com:Sub> is selected from [Image disponible dans le document PDF, Image available in the PDF document] or or r7 is 0, r2 is selected from 4, 5, 6, 7, or 8, r3 is selected from 1, 2, 3, or 4, r4 is selected from 1, 2, 3, or 4, r5 is selected from 4, 5, 6, 7, or 8, r8 is selected from 1, 2, 3, or 4, r9 is selected from 1, 2, 3, or 4, r10 is selected from 1, 2, 3, or 4, and W is NH; or preferably, L<com:Sub>3< / com:Sub> is selected from a direct bond, -O- <com:Math><semantics>(CH2CH2O)r2<annotation encoding="application / x-tex">(CH_2CH_2O)_{r2}< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>(CH2)r3<annotation encoding="application / x-tex">(CH_2)_{r3}< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>CO−Φ<annotation encoding="application / x-tex">CO-\Phi< / annotation>< / semantics>< / com:Math>, -NH-<com:Math><semantics>(CH2CH2O)r2<annotation encoding="application / x-tex">(CH_2CH_2O)_{r2}< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>(CH2)r3<annotation encoding="application / x-tex">(CH_2)_{r3}< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>CO−Φ<annotation encoding="application / x-tex">CO-\Phi< / annotation>< / semantics>< / com:Math>, and [Image disponible dans le document PDF, Image available in the PDF document] r2 is selected from 4, 5, 6, 7, or 8, r3 is 2, r8 is selected from 2, 3, or 4, r9 is 2, and r10 is 2.

[0071] In a group of embodiments, L<com:Sub>4< / com:Sub> is selected from the direct bond, -(CH<com:Sub>2< / com:Sub>)<com:Sub>p1< / com:Sub>-CO-, -(CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>O)<com:Sub>p2< / com:Sub>- <com:Math><semantics>(CH2)p3<annotation encoding="application / x-tex">(CH_2)_{p3}< / annotation>< / semantics>< / com:Math>-CO-, <com:Math><semantics>−(CH2)p4<annotation encoding="application / x-tex">-(CH_2)_{p4}< / annotation>< / semantics>< / com:Math>-O-<com:Math><semantics>(CH2)p5<annotation encoding="application / x-tex">(CH_2)_{p5}< / annotation>< / semantics>< / com:Math>-C(O)-, <com:Math><semantics>−NR7<annotation encoding="application / x-tex">-NR_7< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>(CH2)p1<annotation encoding="application / x-tex">(CH_2)_{p1}< / annotation>< / semantics>< / com:Math>-CO-, <com:Math><semantics>−NR7<annotation encoding="application / x-tex">-NR_7< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>(CH2CH2O)p2<annotation encoding="application / x-tex">(CH_2CH_2O)_{p2}< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>(CH2)p3<annotation encoding="application / x-tex">(CH_2)_{p3}< / annotation>< / semantics>< / com:Math>-CO-, or - NR<com:Sub>7< / com:Sub>-(CH<com:Sub>2< / com:Sub>)<com:Sub>p4< / com:Sub>-O-(CH<com:Sub>2< / com:Sub>)<com:Sub>p5< / com:Sub>-C(O)-, p1 is selected from 1, 2, 3, 4, 5, or 6, p2, p3, p4, and p5 are each independently selected from 1, 2, 3, or 4, and R<com:Sub>7< / com:Sub> is selected from H or a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl group. Preferably, L<com:Sub>4< / com:Sub> is selected from the following groups: the direct bond, -(CH<com:Sub>2< / com:Sub>)<com:Sub>p1< / com:Sub>-CO-, -(CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>O)<com:Sub>p2< / com:Sub>-(CH<com:Sub>2< / com:Sub>)<com:Sub>p3< / com:Sub>-CO-, <com:Math><semantics>−(CH2)p4−O−(CH2)p5−C(O)−<annotation encoding="application / x-tex">-(CH_2)_{p4}-O-(CH_2)_{p5}-C(O)-< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NR7−(CH2)p1−CO−<annotation encoding="application / x-tex">-NR_7-(CH_2)_{p1}-CO-< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NR7−(CH2CH2O)p2−(CH2)p3−CO−<annotation encoding="application / x-tex">-NR_7-(CH_2CH_2O)_{p2}-(CH_2)_{p3}-CO-< / annotation>< / semantics>< / com:Math>, or <com:Math><semantics>−NR7−(CH2)p4−CO−<annotation encoding="application / x-tex">-NR_7-(CH_2)_{p4}-CO-< / annotation>< / semantics>< / com:Math> O-(CH<com:Sub>2< / com:Sub>)<com:Sub>p5< / com:Sub>-C(O)-, p1 is selected from 3, 4, 5, or 6, p2, p3, p4, and p5 are each independently selected from 2 and 3, and R<com:Sub>7< / com:Sub> is H.

[0072] In a group of embodiments, Q is selected from a group containing a maleimide linker, a group containing a methanesulfonylpyrimidine linker, a group containing a methanesulfonylpyrimidinylthiazole linker, a group containing a methanesulfonylpyrimidinothiazole linker, a group containing a cycloenyne linker, or a group containing an oxime bond linker. [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] and

[0075] p1 is selected from 1, 2, 3, 4, 5, and 6, p2 is selected from 1, 2, 3, and 4, p3 is selected from 1, 2, 3, and 4, p4 is selected from 1, 2, 3, and 4, p5 is selected from 1, 2, 3, and 4, and R<com:Sub>7< / com:Sub> is selected from H or a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl group. Preferably, p1 is selected from 3, 4, 5, and 6; p2 is selected from 2 and 3; p3 is selected from 2 and 3; p4 is selected from 2 and 3; p5 is selected from 2 and 3; and R7 is selected from H. [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document]

[0077] Specifically, the formula (I') is one of the following: [Image disponible dans le document PDF, Image available in the PDF document] ^ 1 [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] -H [Image disponible dans le document PDF, Image available in the PDF document] n e [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document]

[0078] Specifically, the formula (II') is one of the following: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document]

[0079] A third aspect of the present application provides an antibody-drug conjugate, which is a compound of formula (I") or (II"), or an isotope-labeled compound, an optical isomer, a geometric isomer, a tautomer, an isomer mixture, or a pharmaceutically acceptable salt thereof; [Image disponible dans le document PDF, Image available in the PDF document]

[0080] where:

[0081] Ab is an antibody or an antigen-binding fragment;

[0082] L<com:Sub>5< / com:Sub> is a direct bond or a linking group connecting Ab and Q';

[0083] Q' is a group formed after Q is attached to Ab via L<com:Sub>5< / com:Sub>;

[0084] n is an integer or a decimal between 0 and 20, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 0 and a decimal between the foregoing integers; and

[0085] definitions of Q, L, A<com:Sub>1< / com:Sub>, A<com:Sub>2< / com:Sub>, *, and ** are the same as those in the foregoing formula (I') and formula (II').

[0086] In a group of embodiments, n is an integer or a decimal between 0 and 8. [Image disponible dans le document PDF, Image available in the PDF document]

[0087] In a group of embodiments, L<com:Sub>5< / com:Sub> is the direct bond or 75 / represents a ligation site for ligating Ab, and • indicates that Z<com:Sub>3< / com:Sub> is ligated to Q'; and Z<com:Sub>3< / com:Sub> is a click probe or a sulfhydryl group or a precursor thereof that can be ligated to Q' after reaction such as a metal-free click reaction, and preferably, Z<com:Sub>3< / com:Sub> is an azide group;

[0088] <com:Math><semantics>Z1<annotation encoding="application / x-tex">Z_1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>Z2<annotation encoding="application / x-tex">Z_2< / annotation>< / semantics>< / com:Math> are each independently selected from -C(O)NH-, -C(O)O-, -C(O)-, -OC(O)-, - NHC(O)-, -NH-, -O-, -OC(O)NH-, or -NHC(O)O-;

[0089] q<com:Sub>1< / com:Sub> is 0, 1, 2, 3, 4, 5, 6, 7, or 8;

[0090] q<com:Sub>2< / com:Sub> is 1, 2, 3, 4, 5, 6, 7, or 8;

[0091] q<com:Sub>3< / com:Sub> is 1, 2, 3, 4, 5, 6, 7, or 8; and

[0092] q<com:Sub>4< / com:Sub> is 1, 2, 3, 4, 5, 6, 7, or 8. [Image disponible dans le document PDF, Image available in the PDF document]

[0093] Preferably, L<com:Sub>5< / com:Sub> is the direct bond or or more preferably, L<com:Sub>5< / com:Sub> [Image disponible dans le document PDF, Image available in the PDF document] is the direct bond or

[0094] Preferably, <com:Math><semantics>Z1<annotation encoding="application / x-tex">Z_1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>Z2<annotation encoding="application / x-tex">Z_2< / annotation>< / semantics>< / com:Math> are each independently -C(O)NH-. [Image disponible dans le document PDF, Image available in the PDF document]

[0095] In a group of embodiments, Q' is selected from: [Image disponible dans le document PDF, Image available in the PDF document] <com:Math><semantics>•<annotation encoding="application / x-tex">\bullet< / annotation>< / semantics>< / com:Math> is a ligation site for ligating L<com:Sub>5< / com:Sub>, and <com:Math><semantics>∼><annotation encoding="application / x-tex">\stackrel{>}{\sim}< / annotation>< / semantics>< / com:Math> represents a ligation site for ligating L<com:Sub>4< / com:Sub>. [Image disponible dans le document PDF, Image available in the PDF document]

[0096] In a group of embodiments, L<com:Sub>5< / com:Sub>-Q' is selected from [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] where • is a ligation site for ligating Ab, and represents a ligation site for ligating L<com:Sub>4< / com:Sub>.

[0097] Preferably, L5-Q' is selected from [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] and [Image disponible dans le document PDF, Image available in the PDF document] or more preferably, <com:Math><semantics>Z1<annotation encoding="application / x-tex">Z_1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>Z2<annotation encoding="application / x-tex">Z_2< / annotation>< / semantics>< / com:Math> are each independently -C(O)NH-.

[0098] In a group of embodiments, Ab is selected from a mouse-derived antibody, a chimeric antibody, a humanized antibody, a fully human antibody, or an antigen-binding fragment thereof; and preferably, Ab is selected from anti-HER2 (ErbB2) antibody, anti-EGFR antibody, anti-B7-H3 antibody, anti-c- Met antibody, anti-HER3 (ErbB3) antibody, anti-HER4 (ErbB4) antibody, anti-ROR1 antibody, anti- CLDN6 antibody, anti-CLDN9 antibody, anti-CLDN18.2 antibody, anti-NaPi-2b antibody, anti-TNF- α antibody, anti-ENPP3 antibody, anti-DLL3 antibody, anti-CD20 antibody, anti-CD22 antibody, anti- CD28 antibody, anti-CD30 antibody, anti-CD33 antibody, anti-CD37 antibody, anti-CD38 antibody, anti-CD44 antibody, anti-CD45 antibody, anti-CD47 antibody, anti-CD48 antibody, anti-CD56 antibody, anti-CD70 antibody, anti-CD73 antibody, anti-CD98 antibody, anti-CD105 antibody, anti- CEA antibody, anti-EphA2 antibody, anti-MUCI antibody, anti-Lewis Y antibody, anti-VEGFR antibody, anti-GPNMB antibody, anti-Integrin antibody, anti-PSMA antibody, anti-Tenascin-C antibody, anti-SLC44A4 antibody, anti-CD79 antibody, anti-TROP-2 antibody, anti-CD79B antibody, anti-Mesothelin antibody, anti-Nectin-4 antibody, anti-TPBG antibody, or an antigen-binding fragment thereof.

[0099] Preferably, Ab is the anti-HER2 (ErbB2) antibody or the antigen-binding fragment thereof.

[00100] Preferably, Ab is selected from the monoclonal antibody or the antigen-binding fragment thereof, or preferably, selected from Trastuzumab, Cetuximab, Pertuzumab, Nimotuzumab, Enoblituzumab, Emibetuzumab, Inotuzumab, Pinatuzumab Vedotin, Brentuximab Vedotin, Gemtuzumab, Bivatuzumab, Lorvotuzumab, or an antigen-binding fragment thereof, or more preferably, Ab is selected from Trastuzumab or an antigen-binding fragment thereof.

[00101] In a group of embodiments, the formula (I") is one of the following: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] ٦ [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] n า n T-LA27AA-2 —'n [Image disponible dans le document PDF, Image available in the PDF document] _ n n า [Image disponible dans le document PDF, Image available in the PDF document] .1 [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] ---- [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] • [Image disponible dans le document PDF, Image available in the PDF document] 1 [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] Ab N N N N N N N N N N N N N N N N N N N [Image disponible dans le document PDF, Image available in the PDF document] _ T-LA31B [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] ___n [Image disponible dans le document PDF, Image available in the PDF document] I [Image disponible dans le document PDF, Image available in the PDF document] 1 [Image disponible dans le document PDF, Image available in the PDF document] .1 [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] .

[00102] preferably, Ab is the anti-HER2 (ErbB2) antibody or the antigen-binding fragment thereof, and more preferably, Ab is Trastuzumab or an antigen-binding fragment thereof.

[00103] In a group of embodiments, the formula (II") is one of the following: [Image disponible dans le document PDF, Image available in the PDF document] 1 [Image disponible dans le document PDF, Image available in the PDF document]

[00104] preferably, Ab is the anti-HER2 (ErbB2) antibody or the antigen-binding fragment thereof, and more preferably, Ab is Trastuzumab or an antigen-binding fragment thereof.

[00105] A fourth aspect of the present application provides an eribulin derivative, where the eribulin derivative is a compound shown below, or an isotope-labeled compound, an optical isomer, a geometric isomer, a tautomer, an isomer mixture, or a pharmaceutically acceptable salt thereof; [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document]

[00106] A fifth aspect of the present application provides an antibody-drug conjugate, where the antibody-drug conjugate is a compound shown below, or an isotope-labeled compound, an optical isomer, a geometric isomer, a tautomer, an isomer mixture, or a pharmaceutically acceptable salt thereof; [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] n [Image disponible dans le document PDF, Image available in the PDF document]

[00107] definitions of Ab and n are the same as those in the foregoing formula (I") and formula (II"). Preferably, Ab is the anti-HER2 (ErbB2) antibody or the antigen-binding fragment thereof, and more preferably, Ab is Trastuzumab or an antigen-binding fragment thereof.

[00108] A sixth aspect of the present application provides a pharmaceutical composition, including the foregoing eribulin derivative, antibody-drug conjugate, and one or more pharmaceutically acceptable carriers or excipients according to the present application.

[00109] A seventh aspect of the present application provides use of the foregoing eribulin derivative according to the present application in preparation of an antibody-drug conjugate.

[00110] An eighth aspect of the present application provides use of the foregoing eribulin derivative, antibody-drug conjugate, and pharmaceutical composition according to the present application in preparation of a medicament for treating tumors or cancers.

[00111] A ninth aspect of the present application provides a method for treating a tumor or cancer, including administering an effective dose of the foregoing eribulin derivative, antibody-drug conjugate, and pharmaceutical composition according to the present application to a subject in need thereof.

[00112] In a group of embodiments, the tumor or cancer is selected from a solid tumor or hematological tumor; preferably, the tumor or cancer is selected from a metastatic and recurrent tumor or cancer; and preferably, the tumor or cancer is selected from breast cancer, gastric cancer, colon cancer, pancreatic cancer, kidney cancer, ovarian cancer, lung cancer, soft tissue sarcoma, liposarcoma, non-small cell lung cancer, melanoma, head and neck cancer, cervical cancer, and prostate cancer, and may be specifically HER-2-positive breast cancer, triple-negative breast cancer, HER-2-positive triple-negative breast cancer, clear cell renal cell carcinoma, small cell lung cancer, non-small cell lung cancer, and large cell lung cancer.

[00113] In a group of embodiments, the tumor or cancer is selected from a cancer or tumor with high expression of HER2 (ErbB2) antibody.

[00114] In the present application, a series of derivatives with good tumor suppression effects are synthesized by modifying eribulin, and have lower toxicity and a larger therapeutic window than that of eribulin; and then the eribulin derivative and an antibody are made into an ADC by means of an appropriate linker, and the therapeutic efficiency of the eribulin derivative may be further improved using the targeting specificity of the antibody. BRIEF DESCRIPTION OF DRAWINGS

[00115] FIG. 1 is a tumor volume change curve 1 in a JIMT-1 breast cancer xenograft mouse model.

[00116] FIG. 2 is a weight change curve of rats after administration.

[00117] FIG. 3 is a tumor volume change curve 2 in a JIMT-1 breast cancer xenograft mouse model. DETAILED DESCRIPTION

[00118] Unless otherwise specified, all terms (including technical and scientific terms) used to disclose the present application have the same meanings as commonly understood by a person of ordinary skills in the art to which the present application belongs. The following definitions are used to better understand instructions in the present application. Herein, interpretation of the terms used in the present application is only intended to describe specific examples rather than limit the present application.

[00119] Features illustrated or described as a part of a groups of embodiments in the present application can be used in another embodiment to create still another embodiment.

[00120] The term "and / or" as used herein refers to a selection range that includes any one of the listed items among two or more related items, as well as any and all combinations of those listed items. These combinations include any two of the related items, any greater number of the related items, or all of the related items. In the present application, it should be understood that when at least three items are connected by "and / or", the technical solutions undoubtedly include technical solutions connected by logical "AND", and also undoubtedly include technical solutions connected by logical "OR". For example, "A and / or B" includes three parallel solutions: A, B, and both A and B. For another example, technical solutions of "A, B, C and / or D" include any one of A, B, C or D (namely, a technical solution connected by logical "OR"), and also include a combination of any one and all of A, B, C and D, that is, a combination of any two or three of A, B, C and D and a combination of four of A, B, C and D (namely, technical solutions connected by logical "AND").

[00121] The terms "comprise", "include", and "contain", as well as their variations, as used herein are synonymous, and are inclusive or open-ended, and do not exclude additional uncited members, elements, or method steps.

[00122] In the present application, a numerical range defined by endpoints includes all values and fractions within the range, as well as the cited endpoints.

[00123] In the present application, concentration values refer to values that may fluctuate within a certain range. For example, fluctuations may occur within the corresponding precision range. For instance, a value of <com:Math><semantics>2%<annotation encoding="application / x-tex">2\%< / annotation>< / semantics>< / com:Math> may allow fluctuations within <com:Math><semantics>±0.1%<annotation encoding="application / x-tex">\pm 0.1\%< / annotation>< / semantics>< / com:Math>. For larger values or values that do not require precise control, the meaning may include greater fluctuations. For example, a value of 100 mM may allow fluctuations within <com:Math><semantics>±1%<annotation encoding="application / x-tex">\pm 1\%< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>±2%<annotation encoding="application / x-tex">\pm 2\%< / annotation>< / semantics>< / com:Math>, etc. For molecular weight, the meaning may include fluctuations within <com:Math><semantics>±10%<annotation encoding="application / x-tex">\pm 10\%< / annotation>< / semantics>< / com:Math>.

[00124] In the present application, descriptions such as "multiple" and "various" refer to two or more than two, unless otherwise specified.

[00125] In the present application, technical features described in an open-ended manner encompass both closed technical solutions consisting of the listed features and open technical solutions that include the listed features.

[00126] In the present application, expressions such as "preferably", "more preferably", "most preferably", "specific", or "desirably" are used solely to describe embodiments or examples with better effects, and shall not be construed as limiting the scope of protection of the present application. In present application, "optionally", "optional" and "option" refer to "dispensable" or any one of two parallel solutions of "with" and "without". If "optional" appears multiple times in a technical solution, "optional" at each location is independent unless specific explanation is provided and there are contradictions or mutual constraints.

[00127] Eribulin derivatives in the present application include a compound of formula (I), a compound of formula (II), a compound of formula (I'), a compound of formula (II'), the compound of claim 44, isotope-labeled compounds of the compound of formula (I), the compound of formula (II), the compound of formula (I'), the compound of formula (II'), or the compound of claim 44, and optical isomers, geometric isomers, tautomers, or isomeric mixtures of the compound of formula (I), the compound of formula (II), the compound of formula (I'), the compound of formula (II'), or the compound of claim 44, or the isotope-labeled compounds thereof, as well as pharmaceutically acceptable salts of the various compounds mentioned above.

[00128] The antibody-drug conjugate in the present application include a compound of formula (I"), a compound of formula (II"), and the compound of claims 45 to 48, isotope-labeled compounds of the compound of formula (I"), the compound of formula (II"), or the compound of claims 45 to 48, and optical isomers, geometric isomers, tautomers, or isomeric mixtures of the compound of formula (I"), the compound of formula (II"), or the compound of claims 45 to 48, or the isotope-labeled compounds thereof, as well as pharmaceutically acceptable salts of the various compounds mentioned above.

[00129] The term "isotope-labeled compound" refers to a compound that is labeled with an isotope and that is obtained by substituting any atom in the compound with its isotopic atom. The present invention includes all pharmaceutically acceptable isotope-labeled compounds of the compound, where one or more atoms are substituted by an atom having the same atomic number as an atom usually found in nature but a different atomic mass or mass quantity. Examples of isotopes suitable for inclusion in the compound in the present application include isotopes of hydrogen, such as <com:Sup>2< / com:Sup>H(D) and <com:Sup>3< / com:Sup>H(T); isotopes of carbon, such as <com:Sup>11< / com:Sup>C, <com:Sup>13< / com:Sup>C, and <com:Sup>14< / com:Sup>C; isotopes of chlorine, such as <com:Sup>37< / com:Sup>Cl; isotopes of fluorine, such as <com:Sup>18< / com:Sup>F; isotopes of iodine such as <com:Sup>123< / com:Sup>I and <com:Sup>125< / com:Sup>I; isotopes of nitrogen such as <com:Sup>13< / com:Sup>N and <com:Sup>15< / com:Sup>N; isotopes of oxygen, such as <com:Sup>15< / com:Sup>O, <com:Sup>17< / com:Sup>O, and <com:Sup>18< / com:Sup>O; and isotopes of sulfur such as <com:Sup>35< / com:Sup>S. The isotope- labeled compound can generally be prepared by conventional techniques known to a person skilled in the art or by using a suitable isotope-labeled reagent in place of a previously used non-labeled reagent in a method analogous to that described in examples and preparations appended herein.

[00130] The term "optical isomer" means that when a compound has one or more chiral centers, each chiral center can have an R configuration or an S configuration, and various isomers formed by them are optical isomers. The optical isomers include all diastereoisomers, enantiomers, mesoforms, racemates, or mixtures thereof. For example, the optical isomer can be separated via a chiral chromatographic column or chiral synthesis.

[00131] The term "geometric isomer" means that when there is a double bond in the compound, the compound may have a cis isomer, a trans isomer, an E isomer, and a Z isomer. The geometric isomer includes a cis isomer, a trans isomer, an E isomer, a Z isomer, or a mixture thereof.

[00132] The term "tautomer" refers to an isomer generated due to rapid movement of a specific atom in a molecule between two positions. A person skilled in the art can understand that tautomers can transform into each other, and may is present together when an equilibrium state is reached in a specific state.

[00133] The compound in the present application may be present in a form of a pharmaceutically acceptable salt such as an acid addition salt and / or base addition salt of the compound of formula (I). Unless otherwise clarified, the "pharmaceutically acceptable salt" used herein includes acid addition salt or base addition salt that may be present in the compound in the present application. A suitable acid addition salt is formed by an acid that forms a non-toxic salt. Examples of the acid addition salt include, but are not limited to: acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate / carbonate, bisulfate / sulfate, borate, camphorsulfonate, citrate, cyclamate, edisylate, formate, fumarate, glucoheptonate, gluconate, glucuronic acid salt, hexafluorophosphate, 2-(4- hydroxybenzyl)benzoate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, 2- isethionate, lactate, malate, maleate, malonate, methanesulfonate, sulfate, methylsulfate, naphthalate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, phosphate / hydrogen phosphate / dihydrogen phosphate, pyroglutamate, glucarate, stearate, salicylate, tannate, tartrate, tosylate, and trifluoroacetate. A suitable acid addition base is formed by a base that forms a non-toxic salt. Examples of the base addition salt include, but are not limited to, aluminum, arginine, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, tromethamine, and zinc salt. Half-salts of acids and bases such as hemisulfate and hemicalcium salts may also be formed. For a review of suitable salts, refer to Handbook of Pharmaceutical Salts: Properties, Selection and Use (Stahl and Wermuth, Wiley-VCH, 2002). A method for preparing the pharmaceutically acceptable salt of the compound in the present application is known to a person skilled in the art.

[00134] Some compounds in the present application may is present in different crystalline or amorphous forms, and fall within the scope of the present application regardless of which form the compounds are in.

[00135] In the present application, the term "antibody" refers to an immunoglobulin, which is a tetrapeptide chain structure formed by bonding two identical heavy chains with two identical light chains through interchain disulfide bonds. Immunoglobulins have heavy chain constant regions with different amino acid compositions and sequences, and therefore, also have different antigenicities. Therefore, immunoglobulins can be divided into five categories, or isoforms of immunoglobulins, namely IgM, IgD, IgG, IgA, and IgE, and corresponding heavy chains thereof are <com:Math><semantics>μ<annotation encoding="application / x-tex">\mu< / annotation>< / semantics>< / com:Math> chain, <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> chain, <com:Math><semantics>γ<annotation encoding="application / x-tex">\gamma< / annotation>< / semantics>< / com:Math> chain, <com:Math><semantics>α<annotation encoding="application / x-tex">\alpha< / annotation>< / semantics>< / com:Math> chain, and <com:Math><semantics>ε<annotation encoding="application / x-tex">\varepsilon< / annotation>< / semantics>< / com:Math> chain respectively. The same type of Ig can be further divided into different subtypes based on a difference in amino acid compositions in hinge regions and the numbers and positions of disulfide bonds in heavy chains. For example, Ig can be divided into IgG1, IgG2, IgG3, and IgG4. Light chains are divided into <com:Math><semantics>κ<annotation encoding="application / x-tex">\kappa< / annotation>< / semantics>< / com:Math> chains or <com:Math><semantics>λ<annotation encoding="application / x-tex">\lambda< / annotation>< / semantics>< / com:Math> chains as per the difference in the constant regions. Each of the five types of Ig can include either the <com:Math><semantics>κ<annotation encoding="application / x-tex">\kappa< / annotation>< / semantics>< / com:Math> chains or <com:Math><semantics>λ<annotation encoding="application / x-tex">\lambda< / annotation>< / semantics>< / com:Math> chains. The sequences of about 110 amino acids near the N-termini of the heavy chain and light chain of the antibody may vary greatly and are referred to as variable regions (Fv regions). The rest amino acid sequences near the C-termini are relatively stable and are referred to as the constant regions. The variable region includes 3 hypervariable regions (HVRs) and 4 framework regions (FRs) with relatively conserved sequences. Specificity of the antibody is determined by the 3 hypervariable regions, also referred to as complementary-determining regions (CDRs). Each of a light chain variable region (LCVR) and a heavy chain variable region (HCVR) is composed of 3 CDR regions and 4 FR regions, and a sequence from the N-terminus to the C-terminus is as follows: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. 3 CDR regions of the light chain are LCDR1, LCDR2, and LCDR3. 3 CDR regions of the heavy chain are HCDR1, HCDR2, and HCDR3. The number and positions of CDR amino acid residues in the LCVR region and HCVR region of the antibody or antigen-binding fragment in the present application conform to the known Kabat numbering rule (LCDR1 to LCDR3 and HCDR2 and HCDR3) or the Kabat and Chothia numbering rules (HCDR1).

[00136] The term "antigen-binding fragment" refers to one or more fragments of an antibody that maintain an ability to bind specifically to the antigen. The antigen-binding ability of the antibody has been demonstrated by using a fragment of a full-length antibody. Examples of binding fragments included in the "antigen-binding fragment" include: (i) Fab fragment, a monovalent fragment consisting of VL, VH, CL, and CH domains; (ii) F(ab')2 fragments, including bivalent fragments of two Fab fragments bound by a disulfide bridge in the hinge region; (iii) F fragment consisting of VH and CH domains; (iv) Fv fragment consisting of VH and VL domains on a single arm of the antibody; (v) a single-domain or dAb fragment consisting of a VH domain; and (vi) a separated complementary- determining region (CDR) or (vii) a combination of two or more separated CDRs that can optionally be bound by a synthesized linker. In addition, although both VL and VH domains of the Fv fragment are encoded by separate genes, the VL and VH domains can be bound in a recombinant method through synthesized linkers, so that the VL and VH domains can generate a single protein chain (referred to as single-stranded Fv (scFv)) for pairing the VL and VH regions to form monovalent molecules. Such single-chain antibodies are incorporated into the term "antigen-binding fragment". Such antibody fragments are obtained through conventional techniques known to persons skilled in the art, and fragments are sifted out as per functions in the same manner as intact antibodies. Antigen- binding sites can be generated by recombinant DNA techniques, enzymatic reactions or chemical fragmentation of intact immunoglobulins. Antibodies can be different types of antibodies, for example, IgG (for example, IgG1, IgG2, IgG3, or IgG4 subtype), IgA1, IgA2, IgD, IgE, or IgM antibody.

[00137] The term "linker group" refers to a chemical structure fragment or bond that has one end linked to an antibody and another end linked to a toxin drug, which can also be linked to the antibody or toxin drug after linked to another linking group.

[00138] The term "antibody-drug conjugate (ADC)" means that an antibody or an antigen-binding fragment is linked to a biologically active toxin drug such as the eribulin derivative through the stable linking unit.

[00139] The term "short peptide" has a common meaning in the art and can refer to a compound formed by covalent linking of an amide bond (peptide bond) formed by condensation and dehydration of a carboxyl group of one amino acid molecule and an amino group of another amino acid molecule. The nomenclature for defining peptides is commonly used in the art, where an amino group at the N- terminus is on the left side and a carboxyl group at the C-terminus is on the right side. The short peptide chain in the present application refers to a peptide chain obtained by condensation and dehydration of two or more (for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) amino acids, with -NH- formed by the amino group at the N-terminus on the left side and -CO- formed by the carboxyl group at the C-terminus on the right side. For example, "-NHGly-Gly-Phe-Gly<com:Sup>CO< / com:Sup>-" represents a tetrapeptide chain formed by condensation of Gly, Gly, Phe, and Gly in sequence, with -NH- formed by the amino group of Gly at the N-terminus on the left side and -CO- formed by the carboxyl group of Gly at the C-terminus on the right side.

[00140] The term "amino acid residue" has a common meaning in the art and refers to a group formed by reaction of an amino acid (as a single amino acid or part of a peptide) and a peptide, another amino acid, or an amino acid residue. Usually, when the amino acid is ligated with another amino acid or the amino acid residue, water is eliminated, and remaining part of the amino acid is referred to as the amino acid residue.

[00141] The term "amino acid" has a common meaning in the art and can include both natural and unnatural amino acids. An abbreviation of the amino acid residue in the present invention is a standard 3-letter and / or 1-letter code for denoting one of 20 common amino acids in the art.

[00142] The amino acid residue or amino acid has isomeric forms, including L-type and D-type.

[00143] Examples of three-letter and single-letter codes of amino acids used in the present application and structures thereof are as follows: [Image disponible dans le document PDF, Image available in the PDF document]

[00144] In some substituents in the present application, " represents a linking site and " • " represents a linking site. For example, for <com:Math><semantics>3<annotation encoding="application / x-tex">^{3}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>4<annotation encoding="application / x-tex">^{4}< / annotation>< / semantics>< / com:Math> represents a linking site linked to <com:Math><semantics>A1′<annotation encoding="application / x-tex">A_1'< / annotation>< / semantics>< / com:Math> or <com:Math><semantics>A2′<annotation encoding="application / x-tex">A_2'< / annotation>< / semantics>< / com:Math>, and represents a linking site linked to L<com:Sub>2< / com:Sub>. The expression "-NH-CH<com:Sub>2< / com:Sub>-" means that the left side is connected to <com:Math><semantics>L2<annotation encoding="application / x-tex">L_2< / annotation>< / semantics>< / com:Math> via -NH-, and the right side is connected to <com:Math><semantics>A1<annotation encoding="application / x-tex">A_1< / annotation>< / semantics>< / com:Math>' or <com:Math><semantics>A2<annotation encoding="application / x-tex">A_2< / annotation>< / semantics>< / com:Math>' via -CH<com:Sub>2< / com:Sub>-.

[00145] Unless otherwise specified, "optional substitution" means that hydrogen on the substituted group is not substituted or one or more substitutable sites of the substituted group are independently subjected to substitution with a substituent. The substituent is independently selected from one or more of deuterium, an oxo group, halogen, an amino group, a hydroxyl group, a nitro group, a cyano group, a sulfhydryl group, an optionally substituted alkyl group, an optionally substituted alkyloxy group, an optionally substituted alkylthio group, an optionally substituted alkyl amino group, an optionally substituted carbon ring group, and an optionally substituted heterocyclic group; and the substituent on the alkyl group, the carbon ring group, and the heterocyclic group is selected from one or more of an oxo group, deuterium, halogen, an amino group, a hydroxyl group, a nitro group, a cyano group, a sulfhydryl group, an alkyl group, a haloalkyl group, an alkyloxy group, a hydroxyl- substituted alkyl group, an alkyloxyalkyl group, and the like. When the substituent is "oxo", this indicates that two hydrogen atoms on carbon at the same substitution site are substituted by oxygen atoms, or a heteroatom is bonded to oxygen, to form, for example, a nitrogen oxide with nitrogen bonded to oxygen or a sulfinyl group or sulfonyl group with sulfur bonded to oxygen. "Optional oxo" means that the hydrogen on the substituted group is not substituted, or two hydrogen atoms on carbon at the same substitution site are substituted by oxygen atoms, or a heteroatom is bonded to oxygen, to form, for example, a nitrogen oxide with nitrogen bonded to oxygen or a sulfinyl group or sulfonyl group with sulfur bonded to oxygen. The term "independently" means that when the number of substituents is greater than one, these substituents may be the same or different.

[00146] The term "oxygen bond" (=O) means that two hydrogen atoms on the bonded carbon atom are substituted by an oxygen atom to form a carbonyl group. [Image disponible dans le document PDF, Image available in the PDF document]

[00147] In the present application, " means that N forms a ing with another group [Image disponible dans le document PDF, Image available in the PDF document] bonded thereto; and " " means that <com:Math><semantics>X3<annotation encoding="application / x-tex">X_3< / annotation>< / semantics>< / com:Math> or <com:Math><semantics>Y1<annotation encoding="application / x-tex">Y_1< / annotation>< / semantics>< / com:Math> is a <Formule mathématique disponible dans le document PDF, Math available in the PDF document>$^{\textcircled{B}}$ ring that contains at least one -NH-.

[00148] The term "alkyl group" refers to a saturated aliphatic hydrocarbonyl group, which is a linear or branched group including 1 to 20 carbon atoms, or preferably, an alkyl group including 1 to 12 carbon atoms (the number of carbon atoms is between 1 and 12, and is specifically 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12), or more preferably, an alkyl group including 1 to 10 carbon atoms or most preferably 1-8 carbon atoms (namely, a C<com:Sub>1< / com:Sub>-C<com:Sub>8< / com:Sub> alkyl group, where the number of carbon atoms is 1-8, and is specifically 1, 2, 3, 4, 5, 6, 7, or 8) or 1-6 carbon atoms (namely, a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl group, where the number of carbon atoms is 1-6, and is specifically 1, 2, 3, 4, 5, or 6). Examples include, but are not limited to, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, a sec-butyl group, an n-amyl group, a neopentyl group, a 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group, 2-methylbutyl group, 3-methylbutyl group, an n-hexyl group, an n-heptyl group, an n-octyl group, 3-hexyl group, and 2-pentyl group.

[00149] The terms "alkyloxy group" refers to an alkyl group with -O-, and a definition of the alkyl group is the same as that in the foregoing description. Representative examples include, but are not limited to, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, 1-methyl butoxy group, 2-methyl butoxy group, or a tert-butoxy group.

[00150] The term "halogen" refers to F, Cl, Br, and I.

[00151] The terms "hydroxyl-substituted alkyl group", "alkyloxy-substituted alkyl group", "amino- substituted alkyl group", "haloalkyl group", "cyano-substituted alkyl group", "carbon ring-substituted alkyl group", and "heterocyclyl-substituted alkyl group" refer to substitution on an alkyl group with one or more hydroxyl groups, substitution on an alkyl group with one or more alkyloxy groups, substitution on an alkyl group with one or more amino groups, substitution on an alkyl group with one or more halogen atoms, substitution on an alkyl group with one or more cyano groups, substitution on an alkyl group with one or more carbon ring groups, and substitution on an alkyl group with one or more heterocyclic groups.

[00152] The term "carbon ring group" refers to a saturated, partially unsaturated or completely unsaturated carbon ring group such as a cycloalkyl group, an aryl group, a cycloalkenyl group, a cycloalkynyl group, and an enyne ring group, and may be monocyclic or polycyclic (for example, bicyclic or tricyclic), for example, single-ring, fused-ring, integrated-ring, spiro-ring, or bridged-ring. The number of carbon atoms may be 3 to 20 (for example, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20).

[00153] The term "cycloalkyl group" refers to a saturated monocyclic or polycyclic (for example, bicyclic or tricyclic) cyclic hydrocarbon substituent, including a single ring, a fused ring, an integrated ring, a spiro ring, a bridged ring, or the like. The cycloalkyl group can contain 3 to 20 carbon atoms (for example, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), preferably 3 to 15 carbon atoms, and more preferably, 3 to 12 carbon atoms. Non-limiting examples of the cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a [Image disponible dans le document PDF, Image available in the PDF document] cycloheptyl group, a cyclooctyl group, , and the like.

[00154] The term "aryl group" represents a monocyclic or bicyclic aromatic carbon ring system containing 6-10 carbon atoms, and examples of aryl groups include a phenyl group and a naphthalene group, for example, 1-naphthalene group, 2-naphthalene group, 3-naphthalene group, and 4- naphthalene group.

[00155] The term "heterocyclic group" refers to a saturated, partially unsaturated or completely unsaturated heterocyclic group such as a heterocycloalkyl group and heteroaryl group, and may be monocyclic or polycyclic (for example, bicyclic or tricyclic), for example, single-ring, fused-ring, integrated-ring, spiro-ring, or bridged-ring. The number of atoms can be 3 to 20 (for example, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), and can contain 1, 2, 3, or 4 heteroatoms selected from N, O, or S, for example, 1, 2, or 3 heteroatoms selected from N or O.

[00156] The term "heterocycloalkyl group" refers to a saturated monocyclic or polycyclic (for example, bicyclic or tricyclic) hydrocarbon substituent, including, a single-ring, fused-ring, integrated-ring, spiro-ring, or bridged-ring hydrocarbon substituent, which contains 3 to 20 ring atoms (for example, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), where one or more (for example, 1, 2, 3, or 4) ring atoms are heteroatoms selected from N, O, or S. Preferably, the hydrocarbon substituent contains 3 to 12 ring atoms (including 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms), where 1 to 3 ring atoms are heteroatoms (1, 2, or 3 heteroatoms), and the heteroatoms are selected from N, O or S. The heterocycloalkyl group can be 3- to 11-membered single-ring, fused- ring, integrated-ring, spiro-ring, or bridged-ring heterocycloalkyl group with selectively 1 or 2 N atoms, for example, 3- to 6-membered single-ring heterocycloalkyl group, 6- to 12-membered fused- ring heterocycloalkyl group, 6- to 12-membered integrated-ring heterocycloalkyl group, 6- to 12- membered spiro-ring heterocycloalkyl group, and 6- to 12-membered bridged-ring heterocycloalkyl group. Inclusive examples include a pyrrolidinyl group, an imidazolidinyl group, a tetrahydrofuran group, a piperidinyl group, a piperazine group, a tetrahydropyranyl group, an azacyclopropyl group, an oxacyclopropyl group, a thiacyclopropyl group, an azacyclobutyl group, an oxacyclobutyl group, a thiacyclobutyl group, oxacyclohexane, a morpholinyl group, a thiomorpholinyl group, a dioxane group, a dithiacyclohexyl group, an oxazolidinyl group, a thiazolidinyl group, a pyrazolidinyl group, imidazoline, tetrahydrofuran-1-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydropyran-1-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, piperidine-1-yl, piperidine-4-yl, [Image disponible dans le document PDF, Image available in the PDF document] HN.

[00157] The term "heteroaryl group" represents an aromatic monocyclic or multi-cyclic system containing a 5- to 10-membered structure, or preferably, a 5- to 8-membered structure or a 6- to 10- membered structure, or more preferably, a 5- to 6-membered structure, where one or more ring atoms are heteroatoms and other atoms are carbon atoms, heteroatoms are independently selected from O, N or S, and the number of heteroatoms is preferably 1, 2, 3 or 4. The heteroaryl group can be 5- or 6- membered aromatic monocyclic structure containing selectively 1 or 2 N, S, or O atoms, and can be 8- to 10-membered aromatic fused-ring structure containing selectively 1, 2, 3 or 4 N, S, or O atoms. Examples of heteroaryl groups include, but are not limited to, a furanyl group, a thienyl group, an oxazolyl group, a thiazolyl group, an isooxazolyl group, an oxadiazolyl group, a thiadiazolyl group, a pyrrolyl group, a pyrazolyl group, an imidazol group, a triazolyl group, a tetrazolyl group, a pyridinyl group, a pyrimidyl group, a pyrazinyl group, a pyridazinyl group, a thiodiazolyl group, a triazinyl group, a phtharazinyl group, a quinolinyl group, an isoquinolinyl group, a pteridinyl group, a purinyl group, an indolyl group, an isoindolyl group, an inazolyl group, a benzo-furanyl group, a benzo-thiophenyl group, a benzo-pyridinyl group, a benzo-pyrimidinyl group, a benzo-pyrazinyl group, a benzo-imidazol group, a benzo-phtharazinyl group, a pyrrolo [2,3-b]pyridinyl group, an imidazo[1,2-a]pyridinyl group, a pyrazolo[1,5-a]pyridinyl group, a pyrazolo[1,5-a]pyrimidinyl group, an imidazo[1,2-b]pyridazinyl group, a [1,2,4]triazolo[4,3-b] pyridazinyl group, a [1,2,4]triazolo[1,5-a]pyrimidinyl group and a [1,2,4]triazolo[1,5-a] pyridyl group, a pyridin-1-yl group, a pyridin-2-yl group, a pyridin-3-yl group, a pyridin-4-yl group, a quinolin-2-yl group, a quinolin-3-yl group, a quinolin-4-yl group, a quinolin-5-yl group, a quinolin- 6-yl group, a quinolin- 7-yl group, and a quinolin-8-yl group.

[00158] The term "fused-ring" means that two rings share two bonded ring atoms. For example, the H [Image disponible dans le document PDF, Image available in the PDF document]

[00159] The term "integrated-ring" means that two rings are bonded by a single bond. For example, the "integrated-ring" is a biphenyl group, a terphenyl group, , [Image disponible dans le document PDF, Image available in the PDF document] , and the like.

[00160] The term "spiro-ring" means that two rings share one ring atom. For example, the "spiro- [Image disponible dans le document PDF, Image available in the PDF document]

[00161] The term "bridged-ring" means that two rings share two indirectly linked ring atoms. For example, the "bridged-ring" is , and the like.

[00162] In the present application, number ranges related to the number of substituents, the number of carbon atoms, the number of ring atoms, the number of heteroatoms, and the number of groups represent enumerations of all integers within the range, and the range is only used as a simplified representation. For example, "1–4 substituents" represent 1, 2, 3, or 4 substituents; and "3–8 ring atoms" represent 3, 4, 5, 6, 7, or 8 ring atoms. Therefore, the number ranges related to the number of substituents, the number of carbon atoms, the number of ring atoms, the number of heteroatoms, and the number of groups also cover any one of its sub-ranges, and each sub-range is also construed as being disclosed in the present application.

[00163] The term "pharmaceutical composition" refers to a mixture containing one or more of the compounds in the present application and one or more pharmaceutically acceptable carriers or excipients. The pharmaceutical composition may not contain other active ingredients, or may further contain one or more other active ingredients. An objective of the pharmaceutical composition is to facilitate administration to the organism and facilitate absorption of the active components, thereby exerting biological activity.

[00164] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes, but is not limited to, any glidant, sweetener, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, emulsifier, disintegrant, binder, filler, antioxidant, fragrance, co-solvent, solubilizer, osmotic pressure regulator, and matrix fraction in semi-solid formulations of ointments and creams approved for use in humans or livestock by a relevant regulatory authority.

[00165] The pharmaceutical composition in the present application can be prepared into a liquid dosage form, a solid dosage form, or a semisolid dosage form. The liquid dosage form can be a solution (including a true solution and a colloid solution), an emulsion (including o / w type, w / o type and double emulsions), a suspension, an injection (including a water injection, a powder injection and an infusion), eye drops, nasal drops, a lotion, a liniments, and the like; the solid dosage form can be a tablet (including an ordinary tablet, an enteric-coated tablet, a buccal tablet, a dispersible tablet, a chewable tablet, an effervescent tablet and an orally disintegrating tablet), a capsule (including a hard capsule, a soft capsule and an enteric-coated capsule), granules, powder, pills, a suppository, films, patches, an aerosol, a spray, and the like; and the semisolid dosage form can be an ointment, a gel, a paste, and the like. The drug composition in the present application can be prepared into a common formulation or a sustained-release formulation, a controlled-release formulation, a targeted formulation and various particle delivery systems.

[00166] The term "subject" refers to any human or non-human organism that could potentially benefit from treatment with the compound in the present application. Exemplarily, a subject includes a human or a mammal at any age. Preferably, the subject is a human.

[00167] The term "treatment" includes treatment of a disease or a symptom in the mammal, especially the human, and includes: (a) inhibition of an infection, a disease or a symptom, that is, inhibition or delaying of development of the infection, the disease or the symptom; (b) relief of the infection, the disease or the symptom, that is, improvement of the disease or the symptom; and / or (c) cure of the infection, the disease or the symptom.

[00168] The term "prevention" includes a prophylactic therapy in the mammal, especially the human, to reduce occurrence possibility of the infection, the disease or the symptom. A patient can be selected for the prophylactic therapy based on a factor of an increased risk of infection or having a disease or a symptom compared to the general population. The "prevention" can include treatment of a subject who has not yet exhibited an infection or a clinical condition, and prevention of a second occurrence of the same or similar infection or clinical condition.

[00169] The "effective dose" refers to the amount of compound in the present application that is effective in treating or preventing cancers, inhibiting cancer cell proliferation, and / or reducing tumor volumes when administered alone or in combination.

[00170] The embodiments of the present application are described in detail below with reference to examples. It should be understood that these embodiments are merely used to describe the present application but not to limit the scope of the present application. A person skilled in the art can make various modifications and changes to the present application without departing from the scope or spirit of the present application. In the following examples, for a test method for which a specific condition is not specified, preferably, refer to the guidance provided in the present application, a test manual or a conventional condition in the art, another test method known in the art, or a condition recommended by a manufacturer.

[00171] In the following specific examples, a measurement parameter related to an ingredient may have a slight deviation within a weighing accuracy range unless otherwise specified. Parameters involving temperature and time may allow acceptable deviations resulting from instrument testing accuracy or operational precision.

[00172] In addition, some protective groups may be used in the present application to protect some functional groups from unnecessary reactions. Protective groups suitable for various functional groups and protection or deprotection conditions thereof have been widely known to persons skilled in the art. For example, Protective Groups in Organic Synthesis (T. W. Greene and G. M. Wuts, 3rd edition, Wiley, New York, 1999) and references in the book describe in detail protection or deprotection of a large number of protective groups.

[00173] Isolation and purification of compounds and intermediates are implemented through suitable methods and steps, for example, filtration, extraction, distillation, crystallization, column chromatography, preparative thin-layer chromatography, preparative high-performance liquid chromatography, or a combination of these methods based on specific needs. For specific use method, refer to examples described in the present application. Certainly, other similar isolation and purification methods can also be used. Conventional methods (including physical constants and spectral data) can be used for characterization.

[00174] Preparation Examples

[00175] Preparation Example 1: Preparation of PE-1 [Image disponible dans le document PDF, Image available in the PDF document]

[00176] Step 1: Preparation of tert-butyl 2-((4R,6R)-6-(2-((((9H-fluoren-9-yl)methoxy)carbonyl) amino)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate

[00177] Sodium bicarbonate (307 mg, 3.66 mmol, 2 eq) (dissolved in 3 mL of water) was added to a solution of tert-butyl 2-((4R,6R)-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate (500 mg, 1.83 mmol, 1.0 eq) and 2,5-dioxocyclopentyl (9H-fluoren-9-yl)methyl carbonate (615.17 mg, 1.83 mmol, 1.0 eq) in tetrahydrofuran (6 mL) at 0°C. After the addition, the mixture was allowed to react at 25°C for 16 hours. After LCMS showed the reaction ended, the reaction solution was diluted with water and extracted with ethyl acetate three times. The combined organic phases were washed with brine once, dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure to obtain the compound tert-butyl 2-((4R,6R)-6-(2-((((9H-fluoren-9-yl) methoxy)carbonyl)amino)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate as a yellow solid (988 mg, crude product, where the yield was not calculated).

[00178] Step 2: Preparation of (3R,5R)-7-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3,5- dihydroxyheptanoic acid

[00179] 10% hydrochloric acid (2 mL) was added to a solution of the compound tert-butyl 2- ((4R,6R)-6-(2-(((9H-fluoren-9-yl)methoxy)carbonyl)amino)ethyl)-2,2-dimethyl-1,3-dioxan-4- yl)acetate (111 mg, 90%, 0.20 mmol, 1 eq) in tetrahydrofuran (10 mL). After the addition, the reaction solution was allowed to react at 25°C for 2 hours, and the LCMS showed approximately 10% product. The reaction solution was purified by preparative high-performance liquid chromatography (preparative chromatograph manufacturer: ISCO, model: ISCO-R2, column: YMC-Triart Prep C18 <com:Math><semantics>250×30 mm×10μm<annotation encoding="application / x-tex">250 \times 30 \text{ mm} \times 10 \mu\text{m}< / annotation>< / semantics>< / com:Math>, mobile phase: water (0.225% FA, formic acid)—acetonitrile, with an elution ratio of acetonitrile increased from 39% to 69%), to afford the compound (3R,5R)-7-((((9H-fluoren- 9-yl)methoxy)carbonyl)amino)-3,5-dihydroxyheptanoic acid (17 mg, 21% yield).

[00180] LCMS (ESI): m / z, <com:Math><semantics>422[M+Na]+<annotation encoding="application / x-tex">422[M+Na]^+< / annotation>< / semantics>< / com:Math>. Rt = 1.662 min. <com:Sup>1< / com:Sup>H NMR (400 MHz, Chloroform-d) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 7.77 <com:Math><semantics>(d,J=7.6 Hz,2H),7.59(d,J=8.0 Hz,2H),7.41(t,J=7.4 Hz,2H),7.36−7.29(m,2H),5.09(s,2H),<annotation encoding="application / x-tex">(d, J = 7.6 \text{ Hz}, 2H), 7.59 (d, J = 8.0 \text{ Hz}, 2H), 7.41 (t, J = 7.4 \text{ Hz}, 2H), 7.36-7.29 (m, 2H), 5.09 (s, 2H),< / annotation>< / semantics>< / com:Math> <com:Math><semantics>4.48 (d, J=6.6 Hz, 2H),4.34−4.14 (m, 2H),3.88 (t, J=10.2 Hz, 1H),3.63−3.47 (m, 1H),3.17−3.06<annotation encoding="application / x-tex">4.48 \text{ (d, } J = 6.6 \text{ Hz, 2H)}, 4.34-4.14 \text{ (m, 2H)}, 3.88 \text{ (t, } J = 10.2 \text{ Hz, 1H)}, 3.63-3.47 \text{ (m, 1H)}, 3.17-3.06< / annotation>< / semantics>< / com:Math> (m, 1H), 2.52-2.55 (m, 3H).

[00181] Step 3: Preparation of (9H-fluoren-9-yl)methyl (3R,5R)-3,5-dihydroxy-7-(S)-2-hydroxy-3- (2S,5S,8S,11S,13R,15R,16aS,18R,19R,19aS,23R,24aS,25S,26aR,27S,28R,29aR,29bS)-19- methoxy-13-methyl-7,14-dimethylene-21-oxooctahydro-25H-2,27:5,8,15-trioxa-23,25-ethano-2,28- methano[3,2',3':5,6]pyran[4]

[00182] A solution of compound (3R,5R)-7-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3,5- dihydroxyheptanoic acid (2.9 mg, 7.26 μmol, 1.2 eq), eribulin mesylate (5 mg, 6.05 μmol, 1 eq), N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (HATU, 2.76 mg, 7.26 µmol, 1.2 eq), and N,N-diisopropylethylamine (2 µL, 12.11 µmol, 2 eq) in N,N- dimethylformamide (1 mL) was stirred in an ice bath for 5 minutes, then warmed to room temperature and stirred for 2 hours. LCMS showed the starting materials were completely consumed. The mixture was concentrated via an oil pump to afford (9H-fluoren-9-yl)methyl (3R,5R)-3,5-dihydroxy-7-(S)-2- hydroxy-3-(2S,5S,8S,11S,13R,15R,16aS,18R,19R,19aS,23R,24aS,25S,26aR,27S,28R,29aR,29bS)- 19-methoxy-13-methyl-7,14-dimethylene-21-oxooctahydro-25H-2,27:5,8,15-trioxa-23,25-ethano- 2,28-methano[3,2',3':5,6]pyran[4] (10.4 mg, crude product, where the yield was not calculated).

[00183] LCMS (ESI): m / z, 1133[M+Na]<com:Sup>+< / com:Sup>.

[00184] Step 4: Preparation of (3R,5R)-7-amino-3,5-dihydroxy-N-((S)-2-hydroxy-3-((2S,5S,8S,11S, 13R,15R,16aS,18R,19R,19aS,23R,24aS,25S,26aR,27S,28R,29aR,29bS)-19-methoxy-13-methyl- 7,14-dimethylene-21-oxooctahydro-25H-2,27,5,8,15-trioxa-23,25-ethoxy-2,28-methoxy[3,2- i]furo[2',3':5,6]pyrano[4,3-b][1,4]dioxepin-18-yl)propyl)heptanamide (PE-1)

[00185] 1,8-diazabicyclo[5.4.0]undec-7-ene (1.75 <com:Math><semantics>μ<annotation encoding="application / x-tex">\mu< / annotation>< / semantics>< / com:Math>L, 11.69 <com:Math><semantics>μ<annotation encoding="application / x-tex">\mu< / annotation>< / semantics>< / com:Math>mol, 3 eq) was added to a solution of (9H-fluoren-9-yl)methyl ((3R,5R)-3,5-dihydroxy-7-(((S)-2-hydroxy-3-((2S,5S,8S,11S,13R,15R, 16aS,18R,19R,19aS,23R,24aS,25S,26aR,27S,28R,29aR,29bS)-19-methoxy-13-methyl-7,14- dimethylene-21-oxooctahydro-25H-2,27:5,8,15-trioxa-23,25-ethano-2,28- methano[3,2',3':5,6]pyran[4] (10.4 mg, crude) in N,N-dimethylformamide (1 mL). The mixture was stirred in an ice bath for 5 minutes, then allowed to warm to room temperature and stirred for 2 hours. LCMS indicated that the starting materials were completely consumed. The resulting solution was purified by preparative high-performance liquid chromatography (preparative chromatograph manufacturer: Shimadzu, model LC-20AP, column: GS-120-10-C18AP, mobile phase: water (0.225%) HCOOH)—acetonitrile, with an elution ratio of water increased from 10% to 45%), to afford (3R,5R)- 7-amino-3,5- dihydroxy-N-((S)-2-hydroxy-3- ((2S,5S,8S,11S,13R,15R,16aS,18R,19R,19aS,23R,24aS,25S,26aR,27S,28R,29aR,29bS)-19- methoxy-13-methyl-7,14-dimethylene-21-oxooctahydro-25H-2,27,5,8,15-trioxa-23,25-ethoxy-2,28- methoxy[3,2-i]furo[2',3':5,6]pyrano[4,3-b][1,4]dioxepin-18-yl)propyl)heptanamide (1.05 mg, 24.2% yield).

[00186] LCMS (ESI): m / z, 889[M+H]<com:Sup>+< / com:Sup>.

[00187] <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-<com:Math><semantics>d6<annotation encoding="application / x-tex">d_6< / annotation>< / semantics>< / com:Math>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.40 (s, 1H), 7.80 (s, 1H), 5.08-4.97 (m, 2H), 4.79 (d, <com:Math><semantics>J=<annotation encoding="application / x-tex">J =< / annotation>< / semantics>< / com:Math> 30.8 Hz, 2H), 4.64 (dt, <com:Math><semantics>J=4.6<annotation encoding="application / x-tex">J = 4.6< / annotation>< / semantics>< / com:Math>, 2.6 Hz, 1H), 4.55 (t, <com:Math><semantics>J=4.2<annotation encoding="application / x-tex">J = 4.2< / annotation>< / semantics>< / com:Math> Hz, 1H), 4.26 (d, <com:Math><semantics>J=10.8<annotation encoding="application / x-tex">J = 10.8< / annotation>< / semantics>< / com:Math> Hz, 1H), 4.17 <com:Math><semantics>(td,J=10.2,4.2 Hz,1H),4.10(d,J=4.4 Hz,2H),4.02(s,1H),3.93(d,J=5.6 Hz,1H),3.84−3.67<annotation encoding="application / x-tex">(td, J = 10.2, 4.2 \text{ Hz}, 1\text{H}), 4.10 (d, J = 4.4 \text{ Hz}, 2\text{H}), 4.02 (s, 1\text{H}), 3.93 (d, J = 5.6 \text{ Hz}, 1\text{H}), 3.84-3.67< / annotation>< / semantics>< / com:Math> <com:Math><semantics>(m,4H),3.52(d,J=10.0Hz,4H),3.05(q,J=6.8Hz,4H),2.86−2.75(m,4H),2.28−2.20(m,6H),<annotation encoding="application / x-tex">(m, 4H), 3.52 (d, J = 10.0 Hz, 4H), 3.05 (q, J = 6.8 Hz, 4H), 2.86-2.75 (m, 4H), 2.28-2.20 (m, 6H),< / annotation>< / semantics>< / com:Math> <com:Math><semantics>2.13<annotation encoding="application / x-tex">2.13< / annotation>< / semantics>< / com:Math> (t, <com:Math><semantics>J=11.6<annotation encoding="application / x-tex">J = 11.6< / annotation>< / semantics>< / com:Math> Hz, 3H), <com:Math><semantics>2.06−1.82<annotation encoding="application / x-tex">2.06-1.82< / annotation>< / semantics>< / com:Math> (m, 10H), <com:Math><semantics>1.74−1.57<annotation encoding="application / x-tex">1.74-1.57< / annotation>< / semantics>< / com:Math> (m, 8H), <com:Math><semantics>1.55−1.39<annotation encoding="application / x-tex">1.55-1.39< / annotation>< / semantics>< / com:Math> (m, 6H), <com:Math><semantics>1.36−1.14<annotation encoding="application / x-tex">1.36-1.14< / annotation>< / semantics>< / com:Math> (m, 6H), <com:Math><semantics>1.04<annotation encoding="application / x-tex">1.04< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=6.4<annotation encoding="application / x-tex">J = 6.4< / annotation>< / semantics>< / com:Math> Hz, <com:Math><semantics>3<annotation encoding="application / x-tex">3< / annotation>< / semantics>< / com:Math>H).

[00188] Preparation Example 2: Preparation of Compound PE-2 [Image disponible dans le document PDF, Image available in the PDF document]

[00189] Step 1: Preparation of compound PE-2-c

[00190] A solution of eribulin mesylate (8 mg, 9.69 µmol, 1 eq), (((9H-fluoren-9-yl)methoxy) carbonyl)-L-serine (3.8 mg, 11.69 µmol, 1.2 eq), N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1- yl)uronium hexafluorophosphate (4.42 mg, 11.62 µmol, 1.2 eq), and N,N-diisopropylethylamine (3.2 μL, 19.37 μmol, 2 eq) in N,N-dimethylformamide (1 mL) was stirred in an ice bath for 5 minutes, then allowed to warm to room temperature and stirred for 2 hours. LCMS indicated that the starting materials were completely consumed. The mixture was concentrated via an oil pump to afford the crude product PE-2-c (19.4 mg, crude product, where the yield was not calculated).

[00191] LCMS(ESI): <com:Math><semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>1039[M+H]+<annotation encoding="application / x-tex">1039[M+H]^+< / annotation>< / semantics>< / com:Math>.

[00192] Step 2: Preparation of compound PE-2

[00193] 1,8-diazabicyclo[5.4.0]undec-7-ene (8.37 µL) was added to a solution of compound PE-2-c (crude, 19.4 mg) in N,N-dimethylformamide (1 mL) in an ice bath. The mixture was stirred in an ice bath for 5 minutes, then allowed to warm to room temperature and stirred for 2 hours. LCMS showed that the starting materials were completely consumed. The resulting mixture was purified by preparative reversed-phase HPLC (preparative chromatograph manufacturer: Shimadzu, model: LC- 20AP, column: GS-120-10-C18AP, mobile phase: water (0.225% HCOOH)-acetonitrile, with an elution ratio of acetonitrile increased from 30% to 60%), to afford compound PE-2 (3.11 mg, 39.4% yield, white solid).

[00194] LCMS(ESI): m / z, 817[M+H]<com:Sup>+< / com:Sup>.

[00195] <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-<com:Math><semantics>d6<annotation encoding="application / x-tex">d_6< / annotation>< / semantics>< / com:Math>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.25 (s, 1H), 7.92 (s, 1H), 5.03 (dd, <com:Math><semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics>< / com:Math> = 21.6, 2.6 Hz, 2H), <com:Math><semantics>4.84−4.74<annotation encoding="application / x-tex">4.84-4.74< / annotation>< / semantics>< / com:Math> (m, 2H), <com:Math><semantics>4.63<annotation encoding="application / x-tex">4.63< / annotation>< / semantics>< / com:Math> (dt, <com:Math><semantics>J=4.2<annotation encoding="application / x-tex">J = 4.2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>2.4<annotation encoding="application / x-tex">2.4< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>4.55<annotation encoding="application / x-tex">4.55< / annotation>< / semantics>< / com:Math> (t, <com:Math><semantics>J=4.2<annotation encoding="application / x-tex">J = 4.2< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>4.26<annotation encoding="application / x-tex">4.26< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=10.8<annotation encoding="application / x-tex">J = 10.8< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>4.17<annotation encoding="application / x-tex">4.17< / annotation>< / semantics>< / com:Math> (td, <com:Math><semantics>J=10.2<annotation encoding="application / x-tex">J = 10.2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>4.2<annotation encoding="application / x-tex">4.2< / annotation>< / semantics>< / com:Math> Hz, <com:Math><semantics>1H<annotation encoding="application / x-tex">1H< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>4.10<annotation encoding="application / x-tex">4.10< / annotation>< / semantics>< / com:Math> (q, <com:Math><semantics>J=4.8<annotation encoding="application / x-tex">J = 4.8< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>4.0<annotation encoding="application / x-tex">4.0< / annotation>< / semantics>< / com:Math> Hz, <com:Math><semantics>3H<annotation encoding="application / x-tex">3H< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>4.06−3.99<annotation encoding="application / x-tex">4.06-3.99< / annotation>< / semantics>< / com:Math> (m, <com:Math><semantics>1H<annotation encoding="application / x-tex">1H< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>3.83−3.67<annotation encoding="application / x-tex">3.83-3.67< / annotation>< / semantics>< / com:Math> (m, <com:Math><semantics>4H<annotation encoding="application / x-tex">4H< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>3.58−3.49<annotation encoding="application / x-tex">3.58-3.49< / annotation>< / semantics>< / com:Math> (m, 6H), <com:Math><semantics>3.19−2.99<annotation encoding="application / x-tex">3.19-2.99< / annotation>< / semantics>< / com:Math> (m, 6H), <com:Math><semantics>2.84<annotation encoding="application / x-tex">2.84< / annotation>< / semantics>< / com:Math> (dd, <com:Math><semantics>J=9.4<annotation encoding="application / x-tex">J = 9.4< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>1.8<annotation encoding="application / x-tex">1.8< / annotation>< / semantics>< / com:Math> Hz, <com:Math><semantics>1<annotation encoding="application / x-tex">1< / annotation>< / semantics>< / com:Math>H), <com:Math><semantics>2.80−2.70<annotation encoding="application / x-tex">2.80-2.70< / annotation>< / semantics>< / com:Math> (m, <com:Math><semantics>2<annotation encoding="application / x-tex">2< / annotation>< / semantics>< / com:Math>H), <com:Math><semantics>2.33−2.17<annotation encoding="application / x-tex">2.33-2.17< / annotation>< / semantics>< / com:Math> <com:Math><semantics>(m,6H),2.17−2.07(m,2H),2.05−1.95(m,2H),1.92(q,J=6.4,5.8Hz,4H),1.75−1.58(m,6H),1.48<annotation encoding="application / x-tex">(m, 6H), 2.17-2.07 (m, 2H), 2.05-1.95 (m, 2H), 1.92 (q, J = 6.4, 5.8 Hz, 4H), 1.75-1.58 (m, 6H), 1.48< / annotation>< / semantics>< / com:Math> <com:Math><semantics>(dtd,J=19.8,11.2,9.8,5.2Hz,3H),1.31(ddt,J=15.8,11.4,5.0Hz,3H),1.26−1.10(m,2H),1.06−1.06<annotation encoding="application / x-tex">(dtd, J = 19.8, 11.2, 9.8, 5.2 Hz, 3H), 1.31 (ddt, J = 15.8, 11.4, 5.0 Hz, 3H), 1.26-1.10 (m, 2H), 1.06-1.06< / annotation>< / semantics>< / com:Math> <com:Math><semantics>0.98(m,3H)<annotation encoding="application / x-tex">0.98 \, (m, 3H)< / annotation>< / semantics>< / com:Math>.

[00196] Preparation Example 3: Preparation of Compound PE-E2H [Image disponible dans le document PDF, Image available in the PDF document]

[00197] Step 1: Preparation of compound PE-E2H-a

[00198] Wet Pd / C (10 mg) was added to a solution of compound PE-E2K-a (for synthesis of the compound, refer to the preparation example of PE-E2K) (10 mg, 10.50 µmol, 1 eq) in MeOH (2 mL). The reaction solution was stirred at 25°C under hydrogen for 3 hours. LCMS analysis showed that the reaction ended. The mixture was filtered through Celite and concentrated under reduced pressure, then purified by preparative high-performance liquid chromatography (preparative chromatograph manufacturer: Orienda, model: BRIX-2860, column: Welch Xtimate C18 150 × 30 mm × 10 μm, mobile phase: water (0.225% FA)-acetonitrile, with an elution ratio of acetonitrile increased from 50% to 80%), to obtain the compound PE-E2H-a (7 mg, 69.85% yield) as a white solid. LCMS (ESI): m / z, 954.4[M+H]<com:Sup>+< / com:Sup>.

[00199] Step 2: Preparation of compound PE-E2H

[00200] Et<com:Sub>2< / com:Sub>NH (5.42 mg 73.36 μmol, 10 eq) was added to the solution of PE-E2H-a (7 mg, 7.34 μmol, 1 eq) in DMF (2 mL), the reaction solution was stirred at 25°C for 2 hours, and the LCMS showed that the starting materials were completely consumed. The mixture was purified by preparative high- performance liquid chromatography (preparative chromatograph manufacturer: Orienda, model: BRIX-2860, column: YMC-Triart Prep C18 150 × 30 mm × 10 μm, mobile phase: water (0.225%) FA)-acetonitrile, with an elution ratio of acetonitrile increased from 30% to 60%), to obtain PE-E2H <com:Math><semantics>(3.70 mg,52.03% yield)<annotation encoding="application / x-tex">(3.70 \text{ mg}, 52.03\% \text{ yield})< / annotation>< / semantics>< / com:Math> as a white solid. LCMS (ESI): m / z, <com:Math><semantics>732.4[M+H]+<annotation encoding="application / x-tex">732.4[M+H]^+< / annotation>< / semantics>< / com:Math>.

[00201] <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-<com:Math><semantics>d6<annotation encoding="application / x-tex">d_6< / annotation>< / semantics>< / com:Math>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.43 (s, 2H), 5.58 (d, <com:Math><semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics>< / com:Math> = 8.0 Hz, 3H), 4.81 (s, 1H), 4.74 <com:Math><semantics>(s,1H),4.62(t,J=4.4Hz,1H),4.56(t,J=4.4Hz,1H),4.26−4.15(m,2H),4.14−4.07(m,3H),3.89−1.00(m,2H),4.62(m,2H),4.14−4.07(m,2H),4.14−4.07(m,2H),4.14−4.07(m,2H),4.14−4.07(m,2H),4.14−4.07(m<annotation encoding="application / x-tex">(s, 1H), 4.62 (t, J = 4.4 Hz, 1H), 4.56 (t, J = 4.4 Hz, 1H), 4.26-4.15 (m, 2H), 4.14-4.07 (m, 3H), 3.89-1.00 (m, 2H), 4.62 (m, 2H), 4.14-4.07 (m, 2H), 4.14-4.07 (m, 2H), 4.14-4.07 (m, 2H), 4.14-4.07 (m, 2H), 4.14-4.07 (m< / annotation>< / semantics>< / com:Math> <com:Math><semantics>3.79 (m, 3H),3.75−3.68 (m, 2H),3.56 (s, 4H),3.27 (d, J=3.2 Hz, 6H),2.89−2.81 (m, 2H),2.70 (d, J=3.2 Hz, 6H)<annotation encoding="application / x-tex">3.79 \text{ (m, 3H)}, 3.75-3.68 \text{ (m, 2H)}, 3.56 \text{ (s, 4H)}, 3.27 \text{ (d, } J = 3.2 \text{ Hz, 6H)}, 2.89-2.81 \text{ (m, 2H)}, 2.70 \text{ (d, } J = 3.2 \text{ Hz, 6H)}< / annotation>< / semantics>< / com:Math> <com:Math><semantics>=7.2 Hz,1H,2.26−2.14 (m, 4H),2.05−1.84 (m, 7H),1.73−1.61 (m, 6H),1.51−1.44 (m, 2H),1.30−1.61 (m, 6H)<annotation encoding="application / x-tex">= 7.2 \text{ Hz}, 1\text{H}, 2.26-2.14 \text{ (m, 4H)}, 2.05-1.84 \text{ (m, 7H)}, 1.73-1.61 \text{ (m, 6H)}, 1.51-1.44 \text{ (m, 2H)}, 1.30-1.61 \text{ (m, 6H)}< / annotation>< / semantics>< / com:Math> 1.20 (m, 4H), 1.11-1.01 (m, 5H), 0.96-0.86 (m, 3H).

[00202] Preparation Example 4: Preparation of Compound PE-E2K [Image disponible dans le document PDF, Image available in the PDF document]

[00203] Step 1: Preparation of compound PE-E2K-a

[00204] NaHCO<com:Sub>3< / com:Sub> (6.13 mg, 72.64 µmol, 2 eq) and Fmoc-Osu (fluorenylmethyloxycarbonyl succinimide, 13.75 mg, 39.95 µmol, 1.1 eq) were added to the solution of the compound eribulin mesylate (30 mg, 36.32 µmol, 1 eq) in THF (2 mL) at 0°C and the reaction solution was stirred at 25°C for 2 hours. LCMS analysis showed that the reaction ended. The residue was purified by silica gel column chromatography (C18, ISCO, R-40g SepaFlash Silica Flash Column, eluent of 10%–75% water / CH<com:Sub>3< / com:Sub>CN, 100 mL / min) to afford PE-E2K-a (30 mg, 86.75% yield) as a colorless oil. LCMS <com:Math><semantics>(ESI)<annotation encoding="application / x-tex">(ESI)< / annotation>< / semantics>< / com:Math>: m / z, 952.6[M+H]<com:Sup>+< / com:Sup>.

[00205] Step 2: Preparation of compound PE-E2K-b

[00206] Potassium osmate dihydrate (490.97 μg, 1.58 μmol, 0.1 eq) and NaIO<com:Sub>4< / com:Sub> (67.73 mg, 315.08 μmol, 20 eq) were added to the solution of the compound PE-E2K-a (15 mg, 15.75 μmol, 1 eq) in THF (tetrahydrofuran, 3 mL) and water (1 mL) at 0°C and the reaction solution was stirred at 25°C for 2 hours. NaIO<com:Sub>4< / com:Sub> (67.73 mg, 315.08 μmol, 20 eq) was added to the reaction solution, the reaction solution was stirred overnight at room temperature, and the LCMS analysis showed that the reaction ended. The mixture (combined with the previous batch, 5 mg, small-scale test) was subjected to preparative high-performance liquid chromatography (preparative chromatograph manufacturer: Orienda, model: BRIX-2860, column: Synergi Max-RP 200 × 30mm × 10 μm, mobile phase: water (0.1% TFA)-acetonitrile, with an elution ratio of acetonitrile increased from 40% to 70%), to afford the product PE-E2K-b (16.60 mg, 82.68% yield) as a white solid. LCMS (ESI): m / z, 956.4[M+H]<com:Sup>+< / com:Sup>.

[00207] Step 3: Preparation of compound PE-E2K

[00208] Et<com:Sub>2< / com:Sub>NH (6.41 mg, 86.81 μmol, 5 eq) was added to the solution of PE-E2K-b (16.6 mg, 17.36 μmol, 1 eq) in DMF (2 mL), the reaction solution was stirred at 25°C for 1 hour, and the LCMS showed that the starting materials were completely consumed. The mixture was purified by preparative high-performance liquid chromatography (preparative chromatograph manufacturer: Orienda, model: BRIX-2860, column: Welch Xtimate C18 250 × 30 mm × 10 µm, mobile phase: water (0.1% TFA, trifluoroacetic acid)-acetonitrile, with an elution ratio of acetonitrile increased from 10% to 40%), to afford PE-E2K (7.50 mg, 58.86% yield) as a white solid.

[00209] LCMS (ESI): m / z, 734.3[M+H]<com:Sup>+< / com:Sup>. <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-<com:Math><semantics>d6<annotation encoding="application / x-tex">d_6< / annotation>< / semantics>< / com:Math>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 7.67 (s, 2H), 5.23 (s, 1H), 4.70-4.53 (m, 2H), 4.46-4.28 (m, 2H), 4.19-4.05 (m, 3H), 3.94-3.67 (m, 5H), 3.61-3.47 (m, 1H), 3.33-3.21 (m, 4H), 3.01-2.70 (m, 4H), 2.65-2.52 (m, 2H), 2.41-2.34 (m, 2H), 2.30-1.87 (m, 8H), 1.85- 1.10 (m, 14H), 0.97-0.90 (m, 2H).

[00210] Preparation Example 5: Preparation of Compounds PE-E4HB1 and PE-E4HS1 [Image disponible dans le document PDF, Image available in the PDF document]

[00211] Step 1: Preparation of compounds PE-E4H-a and PE-E4H-b

[00212] Wet Pd / C (10 mg) was added to a solution of compound PE-E2K-a (for synthesis of the compound, refer to the preparation example of PE-E2K) (10 mg, 10.50 µmol, 1 eq) in MeOH (2 mL). The reaction solution was stirred at 25°C under hydrogen overnight. LCMS analysis showed that the reaction ended. The mixture was filtered through Celite and concentrated under reduced pressure, then purified by preparative high-performance liquid chromatography (preparative chromatograph manufacturer: Orienda, model: BRIX-2860, column: YMC-Triart Prep C18 150 × 30 mm × 10 μm, mobile phase: water (0.225% FA)-acetonitrile, with an elution ratio of acetonitrile increased from 60% to 90%), to obtain products PE-E4H-a (7 mg, 69.7% yield, where LCMS (ESI): m / z, 954.4[M+H]<com:Sup>+< / com:Sup>) and PE-E4H-b (2.50 mg, 24.89% yield, where LCMS (ESI): m / z, 954.4[M+H]<com:Sup>+< / com:Sup>) as white solids.

[00213] Step 2: Preparation of compound PE-E4HB1

[00214] Et<com:Sub>2< / com:Sub>NH (5.41 mg 73.21 μmol, 10 eq) was added to the solution of PE-E4H-a (7 mg, 7.32 μmol, 1 eq) in DMF (2 mL), the reaction solution was stirred at 25°C for 2 hours, and the LCMS showed that the starting materials were completely consumed. The mixture was purified by preparative high- performance liquid chromatography (preparative chromatograph manufacturer: Orienda, model: BRIX-2860, column: YMC-Triart Prep C18 150 × 30 mm × 10 μm, mobile phase: water (0.225%) FA)-acetonitrile, with an elution ratio of acetonitrile increased from 20% to 50%), to obtain PE- E4HB1 (4.90 mg, 40.52% yield, dimethanesulfonate) as a white solid. LCMS (ESI): m / z, <com:Math><semantics>734.4[M+H]+<annotation encoding="application / x-tex">734.4[M+H]^{+}< / annotation>< / semantics>< / com:Math>.

[00215] <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-<com:Math><semantics>d6<annotation encoding="application / x-tex">d_6< / annotation>< / semantics>< / com:Math>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.41 (s, 6H), 5.42 (s, 1H), 5.26 (s, 1H), 4.95 (t, <com:Math><semantics>J=9.2<annotation encoding="application / x-tex">J = 9.2< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>4.62<annotation encoding="application / x-tex">4.62< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>4.11<annotation encoding="application / x-tex">4.11< / annotation>< / semantics>< / com:Math> (s, 2H), <com:Math><semantics>3.65<annotation encoding="application / x-tex">3.65< / annotation>< / semantics>< / com:Math> (t, <com:Math><semantics>J=9.0<annotation encoding="application / x-tex">J = 9.0< / annotation>< / semantics>< / com:Math> Hz, 3H), <com:Math><semantics>3.28<annotation encoding="application / x-tex">3.28< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=3.0<annotation encoding="application / x-tex">J = 3.0< / annotation>< / semantics>< / com:Math> Hz, 3H), <com:Math><semantics>2.79<annotation encoding="application / x-tex">2.79< / annotation>< / semantics>< / com:Math> (s, 14H), <com:Math><semantics>2.56<annotation encoding="application / x-tex">2.56< / annotation>< / semantics>< / com:Math> <Formule mathématique disponible dans le document PDF, Math available in the PDF document>$(d, J = 15.9 \text{ Hz}, 1H), 2.29 \text{ (s, 3H)}, 1.99-1.70 \text{ (m, 4H)}, 1.47 \text{ (s, 3H)}, 1.33-1.21 \text{ (m, 2H)}, 1.12 \text{ (t, } J = 7.2 \text{ (m, 2H)}, 1.12 \text{ (t, } J = 7.2 \text{ (m, 2H)}, 1.12 \text{ (m, 2H)}, 1.12 \text{ (m, 2H)}, 1.12 \text$ Hz, 19H), 1.07 (d, <com:Math><semantics>J=10.4<annotation encoding="application / x-tex">J = 10.4< / annotation>< / semantics>< / com:Math> Hz, 1H), 0.96-0.72 (m, 4H).

[00216] Step 3: Preparation of compound PE-E4HS1

[00217] Et<com:Sub>2< / com:Sub>NH (1.93 mg 26.15 μmol, 10 eq) was added to the solution of PE-E4H-b (2.50 mg, 2.61 μmol, 1 eq) in DMF (2 mL), the reaction solution was stirred at 25°C for 2 hours, and the LCMS showed that the starting materials were completely consumed. The mixture was purified by preparative high-performance liquid chromatography (preparative chromatograph manufacturer: Orienda, model: BRIX-2860, column: YMC-Triart Prep C18 150 × 30 mm × 10 µm, mobile phase: water (0.225% FA)-acetonitrile, with an elution ratio of acetonitrile increased from 20% to 50%), to obtain PE-E4HS1 (1.90 mg, 99.01% yield) as a white solid. LCMS (ESI): m / z, 734.4[M+H]<com:Sup>+< / com:Sup>.

[00218] Preparation Example 6: Preparation of Compound PE-5 [Image disponible dans le document PDF, Image available in the PDF document]

[00219] Step 1: Preparation of (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid

[00220] LiOH.H<com:Sub>2< / com:Sub>O (163.36 mg, 108.18 μL, 3.89 mmol, 4 eq) was added to a solution of (1R,2S, 5S)- methyl 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate hydrochloride (200 mg, 972.37 μmol, 1 eq) in THF (4 mL) and H<com:Sub>2< / com:Sub>O (4 mL), and the mixture was stirred at 25°C for 16 hours. The reaction was monitored by LCMS. The starting materials were completely consumed and a major product was generated. The pH was adjusted to 3–4 with HCl to afford a crude product 6,6-dimethyl-3-(1R,2S,5S)- azabicyclo[3.1.0]hexane-2-carboxylic acid, to be used directly in the next step (140 mg, where the yield was not calculated for the crude product). LCMS (ESI): m / z, 156[M+H]<com:Sup>+< / com:Sup>.

[00221] Step 2: Preparation of (1R,2S,5S)-3-(((9H-fluoren-9-yl)methoxy)carbonyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid

[00222] Fmoc-OSu (304.29 mg, 217.35 μL, 902.06 μmol, 1 eq) was added to a NaHCO<com:Sub>3< / com:Sub> solution (1 mL, adjusted to pH <com:Math><semantics>≥<annotation encoding="application / x-tex">\geq< / annotation>< / semantics>< / com:Math> 7) of 6,6-dimethyl-3-(1R,2S,5S)-azabicyclo[3.1.0]hexane-2-carboxylic acid (140 mg, 902.06 μmol, 1 eq). The mixture was stirred at 25°C for 5 hours. The reaction was monitored by LCMS. The starting material was completely consumed and the major product was formed. The mixture was extracted with ethyl acetate (EA, 5 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 3) and H<com:Sub>2< / com:Sub>O (5 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 2). The organic phases were then combined. The pH of the aqueous phase was adjusted to 3–4 with HCl, and the water layer was then extracted with EA (10 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 3). The organic layers were then combined and evaporated to dryness. The residue was purified by preparative high-performance liquid chromatography (preparative chromatograph manufacturer: Orienda, model: Lab311-DJ-R7, column: Welch Xtimate C18 250 <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 30mm <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 10 <com:Math><semantics>μ<annotation encoding="application / x-tex">\mu< / annotation>< / semantics>< / com:Math>m, mobile phase: water (0.225% HCOOH)— acetonitrile, with an elution ratio of acetonitrile increased from 39% to 69%). The product was lyophilized to afford the white solid product (1R,2S,5S)-3-(((9H-fluoren-9-yl) methoxy)carbonyl)- 6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (80 mg, 23.50% yield). LCMS (ESI): m / z, 400[M+Na]<com:Sup>+< / com:Sup>.

[00223] Step 3: Preparation of compound PE-5d

[00224] HATU (6.55 mg, 17.22 μmol, 1.3 eq) and DIPEA (N,N-diisopropylethylamine, 5.14 mg, 6.57 μL, 39.75 μmol, 3 eq) were added to a solution of eribulin mesylate (9.67 mg, 13.25 μmol, 1 eq) and (1R,2S,5S)-3-(((9H-fluoren-9-yl)methoxy)carbonyl)-6,6-dimethyl-3-azabicyclo[3.1.0] hexane-2- carboxylic acid (5 mg, 13.25 µmol, 1 eq) in DMF (5 mL) at 0°C. The mixture was stirred at 25°C for 16 hours. The reaction was monitored by LCMS. The starting material was completely consumed and the major product was formed. The residue was purified preparative high-performance liquid chromatography (preparative chromatograph manufacturer: ISCO, model: Lab311-DJ-R5, column: Phenomenex Luna C18 250 <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 30mm <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 10 <com:Math><semantics>μ<annotation encoding="application / x-tex">\mu< / annotation>< / semantics>< / com:Math>m, mobile phase: water (0.225% HCOOH)-acetonitrile, with an elution ratio of acetonitrile increased from 57% to 87%) and lyophilized to afford a compound PE-5d (12.50 mg, 86.61% yield) as a white solid. LCMS (ESI): m / z, 1011[M+Na]<com:Sup>+< / com:Sup>.

[00225] Step 4: Preparation of compound PE-5

[00226] DBU (1,8-diazabicyclo[5.4.0]undec-7-ene, 146.74 μg, 1.44e<com:Sup>-1< / com:Sup> μL, 963.90 nmol, 0.1 eq) was added to a solution of compound PE-5d (10.50 mg, 9.64 µmol, 1 eq) in DMF (2 mL). The mixture was stirred at 25°C for 1 hour. The reaction was monitored by LCMS. The starting material was completely consumed and the major product was formed. The residue was purified preparative high- performance liquid chromatography (preparative chromatograph manufacturer: ISCO, model: Lab311-DJ-R5, column: Phenomenex Luna C18 250 × 30mm × 10 µm, mobile phase: water (0.225%) HCOOH)-acetonitrile, with an elution ratio of acetonitrile increased from 30% to 60%) and lyophilized to obtain a compound PE-5 (1 mg, 11.96% yield, 100% purity) as a white solid.

[00227] LCMS (ESI): m / z, 867[M+H]<com:Sup>+< / com:Sup>. <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.25 (s, 1H), 8.02 (t, <com:Math><semantics>J=<annotation encoding="application / x-tex">J =< / annotation>< / semantics>< / com:Math> 5.9 Hz, 1H), 5.03 (d, <com:Math><semantics>J=21.3<annotation encoding="application / x-tex">J = 21.3< / annotation>< / semantics>< / com:Math> Hz, 2H), 4.83 (s, 1H), 4.76 (s, 2H), 4.64 (t, <com:Math><semantics>J=4.0<annotation encoding="application / x-tex">J = 4.0< / annotation>< / semantics>< / com:Math> Hz, 1H), 4.55 (t, <com:Math><semantics>J=4.0<annotation encoding="application / x-tex">J = 4.0< / annotation>< / semantics>< / com:Math> Hz, 1H), 4.55 (t, <com:Math><semantics>J=4.0<annotation encoding="application / x-tex">J = 4.0< / annotation>< / semantics>< / com:Math> Hz, 1H), 4.55 (t, <com:Math><semantics>J=4.0<annotation encoding="application / x-tex">J = 4.0< / annotation>< / semantics>< / com:Math> Hz, 1H), 4.55 (t, <com:Math><semantics>J=4.0<annotation encoding="application / x-tex">J = 4.0< / annotation>< / semantics>< / com:Math> Hz, 1H), 4.55 (t, <com:Math><semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics>< / com:Math> <com:Math><semantics>=4.3 Hz,1H,4.26 (d, J=10.8 Hz,1H),4.17 (td, J=10.2,4.1 Hz,1H),4.13−4.06 (m, 3H),4.01 (d, J=10.8 Hz,1Hz)<annotation encoding="application / x-tex">= 4.3 \text{ Hz}, 1\text{H}, 4.26 \text{ (d, } J = 10.8 \text{ Hz}, 1\text{H}), 4.17 \text{ (td, } J = 10.2, 4.1 \text{ Hz}, 1\text{H}), 4.13-4.06 \text{ (m, 3H)}, 4.01 \text{ (d, } J = 10.8 \text{ Hz}, 1\text{Hz})< / annotation>< / semantics>< / com:Math> <com:Math><semantics>J=9.4 Hz<annotation encoding="application / x-tex">J = 9.4 \text{ Hz}< / annotation>< / semantics>< / com:Math>, 1H), 3.77 (ddd, <com:Math><semantics>J=13.5<annotation encoding="application / x-tex">J = 13.5< / annotation>< / semantics>< / com:Math>, 10.1, 6.7 Hz, 2H), 3.69 (ddd, <com:Math><semantics>J=9.3<annotation encoding="application / x-tex">J = 9.3< / annotation>< / semantics>< / com:Math>, 5.6, 2.9 Hz, 1H), 3.52 (q, <com:Math><semantics>J=11.1,9.9 Hz,6H<annotation encoding="application / x-tex">J = 11.1, 9.9 \text{ Hz}, 6\text{H}< / annotation>< / semantics>< / com:Math>), 3.26 (s, 6H), 3.12 (dt, <com:Math><semantics>J=11.4,5.4 Hz,2H<annotation encoding="application / x-tex">J = 11.4, 5.4 \text{ Hz}, 2\text{H}< / annotation>< / semantics>< / com:Math>), 3.04 (dt, <com:Math><semantics>J=10.4,6.2 Hz,2H<annotation encoding="application / x-tex">J = 10.4, 6.2 \text{ Hz}, 2\text{H}< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>2.89−2.81<annotation encoding="application / x-tex">2.89 - 2.81< / annotation>< / semantics>< / com:Math> (m, 2H), <com:Math><semantics>2.61−2.55<annotation encoding="application / x-tex">2.61-2.55< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>2.33<annotation encoding="application / x-tex">2.33< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=14.7<annotation encoding="application / x-tex">J = 14.7< / annotation>< / semantics>< / com:Math> Hz, 2H), <com:Math><semantics>2.14<annotation encoding="application / x-tex">2.14< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=12.0<annotation encoding="application / x-tex">J = 12.0< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>2.07−12.0<annotation encoding="application / x-tex">2.07-12.0< / annotation>< / semantics>< / com:Math> 1.96 (m, 2H), 1.92 (q, <com:Math><semantics>J=6.2<annotation encoding="application / x-tex">J = 6.2< / annotation>< / semantics>< / com:Math>, 5.7 Hz, 4H), 1.66 (tq, <com:Math><semantics>J=13.4<annotation encoding="application / x-tex">J = 13.4< / annotation>< / semantics>< / com:Math>, 9.2, 6.5 Hz, 6H), 1.56-1.44 (m, 2H), <com:Math><semantics>1.41(d,J=7.1Hz,1H),1.38−1.26(m,3H),1.24−1.14(m,2H),1.03(d,J=6.5Hz,3H),0.98(s,6H).<annotation encoding="application / x-tex">1.41 (d, J = 7.1 Hz, 1H), 1.38-1.26 (m, 3H), 1.24-1.14 (m, 2H), 1.03 (d, J = 6.5 Hz, 3H), 0.98 (s, 6H).< / annotation>< / semantics>< / com:Math>

[00228] Preparation Example 7: Preparation of Compound PE-7 [Image disponible dans le document PDF, Image available in the PDF document]

[00229] Step 1: Preparation of (S)-2-((tert-butoxycarbonyl)amino)-3-((S)-2-oxopyrrolidin-3-yl) propanoic acid

[00230] Methyl (S)-2-((tert-butoxycarbonyl)amino)-3-((S)-3-oxopyrrolidin-3-yl)propanoate (300 mg, 1.0 eq) was dissolved in a mixture of tetrahydrofuran (3 mL) and water (3 mL). Lithium hydroxide monohydrate (132 mg, 3.0 eq) was added, and then the reaction mixture was stirred and allowed to react at 25°C for 3 hours. LCMS analysis showed that the reaction ended. Aftertreatment: The reaction solution was diluted with purified water (10 mL), neutralized with 1 M dilute hydrochloric acid to pH of 5, and extracted twice with a mixture of dichloromethane and methanol (10:1 by volume). The organic phases were combined, washed with saturated brine, dried, and then concentrated to obtain the crude product (S)-2-((tert-butoxycarbonyl)amino)-3-((S)-2-oxopyrrolidin -3-yl)propanoic acid, to be used directly in the next step.

[00231] LCMS: <com:Math><semantics>m / z=295.2<annotation encoding="application / x-tex">m / z = 295.2< / annotation>< / semantics>< / com:Math> [M+Na]<com:Sup>+< / com:Sup>; Rt = 0.761min.

[00232] Step 2: Preparation of compound PE-7-d

[00233] Eribulin mesylate (10 mg, 1.0 eq, ChemExpress) and (S)-2-((tert-butoxycarbonyl)amino)- 3- ((S)-2-oxopyrrolidin-3-yl)propanoic acid (3.73 mg, 1.0 eq) were dissolved in DMF (2 mL). DIPEA (6.79 μL, 3.0 eq) and HATU (6.77 mg, 1.3 eq) were added, and the reaction mixture was then stirred and allowed to react at 25°C for 16 hours. LCMS analysis showed that the starting material was completely consumed. Aftertreatment: The reaction solution was filtered, and the filtrate was subjected to preparative high-performance liquid chromatography (preparative chromatograph manufacturer: Orienda, model: BRIX-2860, column: Phenomenex Luna C18 250 × 30mm × 10 μm, mobile phase: water (0.225% HCOOH),-acetonitrile, with an elution ratio of water increased from 30% to 60%), to obtain compound PE-7-d (10 mg, 74% yield) as a white solid.

[00234] LCMS: <com:Math><semantics>m / z=984.5<annotation encoding="application / x-tex">m / z = 984.5< / annotation>< / semantics>< / com:Math> [M+H]<com:Sup>+< / com:Sup>; Rt = 2.040 min.

[00235] Step 3: Preparation of compound PE-7

[00236] Compound PE-7-d (10 mg, 1.0 eq) was dissolved in anhydrous dichloromethane (2 mL). Trifluoroacetic acid (280 µL) was added while cooled under an ice bath, and the mixture was warmed naturally to 25°C, stirred, and allowed to react for 16 hours. LCMS analysis showed that the starting material was completely consumed. Aftertreatment: The reaction solution was concentrated to dryness, and the residue was dissolved in DMF. The resulting mixture was then purified by preparative high-performance liquid chromatography (preparative chromatograph manufacturer: Orienda, model: BRIX-2860, column: Phenomenex Luna C18 250 × 50 mm × 10 µm, mobile phase: water (0.225% HCOOH)-acetonitrile, with an elution ratio of acetonitrile increased from 30% to 60%), to obtain compound PE-7 (5.68 mg, 79% yield) as a white solid. LCMS: <com:Math><semantics>m / z=884.5[M+H]+<annotation encoding="application / x-tex">m / z = 884.5 [M+H]^+< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>Rt=2.040 min.<annotation encoding="application / x-tex">Rt = 2.040 \text{ min.}< / annotation>< / semantics>< / com:Math>

[00237] <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-<com:Math><semantics>d6<annotation encoding="application / x-tex">d^6< / annotation>< / semantics>< / com:Math>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.05 (t, <com:Math><semantics>J=5.9<annotation encoding="application / x-tex">J = 5.9< / annotation>< / semantics>< / com:Math> Hz, 1H), 7.66 (s, 2H), 6.20 (d, <com:Math><semantics>J=3.0<annotation encoding="application / x-tex">J = 3.0< / annotation>< / semantics>< / com:Math> Hz, 1H), 5.95 (d, <com:Math><semantics>J=3.0<annotation encoding="application / x-tex">J = 3.0< / annotation>< / semantics>< / com:Math> Hz, 1H), 4.97-4.83 (m, 3H), 4.81 (s, 2H), 4.75 (s, 3H), 4.67-4.63 (m, 2H), 4.32 <com:Math><semantics>(dd,J=19.2,7.8 Hz,3H),4.06(q,J=6.8,6.3 Hz,1H),4.01(d,J=3.0 Hz,1H),3.88−3.75(m,3H),<annotation encoding="application / x-tex">(dd, J = 19.2, 7.8 \text{ Hz}, 3H), 4.06 (q, J = 6.8, 6.3 \text{ Hz}, 1H), 4.01 (d, J = 3.0 \text{ Hz}, 1H), 3.88-3.75 (m, 3H),< / annotation>< / semantics>< / com:Math> <com:Math><semantics>3.70 (dd, J=8.4,3.9 Hz, 3H),3.61 (d, J=4.6 Hz, 1H),3.21 (s, 4H),3.17−3.07 (m, 4H),2.98 (dd, J=4.6 Hz, 1H)<annotation encoding="application / x-tex">3.70 \text{ (dd, } J = 8.4, 3.9 \text{ Hz, 3H)}, 3.61 \text{ (d, } J = 4.6 \text{ Hz, 1H)}, 3.21 \text{ (s, 4H)}, 3.17-3.07 \text{ (m, 4H)}, 2.98 \text{ (dd, } J = 4.6 \text{ Hz, 1H)}< / annotation>< / semantics>< / com:Math> <com:Math><semantics>=9.3,2.1 Hz,1H,2.76 (dt,J=14.5,5.7 Hz,3H),2.35 (s, 1H),2.31−2.16 (m, 3H),2.13 (td, J=15.9,1.9)<annotation encoding="application / x-tex">= 9.3, 2.1 \text{ Hz}, 1\text{H}, 2.76 \text{ (dt}, J = 14.5, 5.7 \text{ Hz}, 3\text{H}), 2.35 \text{ (s, 1H)}, 2.31-2.16 \text{ (m, 3H)}, 2.13 \text{ (td, } J = 15.9, 1.9)< / annotation>< / semantics>< / com:Math> 15.4, 6.8 Hz, 1H), 1.96 (dd, <com:Math><semantics>J=5.8<annotation encoding="application / x-tex">J = 5.8< / annotation>< / semantics>< / com:Math>, 3.1 Hz, 1H), 1.96-1.89 (m, 1H), 1.89-1.81 (m, 2H), 1.76 (dt, <com:Math><semantics>J=<annotation encoding="application / x-tex">J =< / annotation>< / semantics>< / com:Math> <com:Math><semantics>8.4,4.2 Hz,2H),1.74−1.66 (m, 7H),1.69−1.61 (m, 1H),1.60 (d, J=8.2 Hz,3H),1.59−1.43 (m, 1H),<annotation encoding="application / x-tex">8.4, 4.2 \text{ Hz}, 2H), 1.74-1.66 \text{ (m, 7H)}, 1.69-1.61 \text{ (m, 1H)}, 1.60 \text{ (d, } J = 8.2 \text{ Hz}, 3H), 1.59-1.43 \text{ (m, 1H)},< / annotation>< / semantics>< / com:Math> <com:Math><semantics>1.42 (dd, J=11.1,5.1 Hz, 2H),1.31 (s, 2H),1.04 (d, J=6.3 Hz, 4H),0.94 (q, J=12.0 Hz, 1H).<annotation encoding="application / x-tex">1.42 \text{ (dd, } J = 11.1, 5.1 \text{ Hz, 2H)}, 1.31 \text{ (s, 2H)}, 1.04 \text{ (d, } J = 6.3 \text{ Hz, 4H)}, 0.94 \text{ (q, } J = 12.0 \text{ Hz, 1H)}.< / annotation>< / semantics>< / com:Math>

[00238] Preparation Example 8: Preparation of Compound PE-10 [Image disponible dans le document PDF, Image available in the PDF document]

[00239] Step 1: Preparation of compound PE-10b

[00240] Potassium carbonate (5.02 mg, 36.3 µmol, 3 eq) was added to a solution of eribulin mesylate (10 mg, 12.1 μmol, 1 eq) and bromoethanol (2.27 mg, 18.2 μmol, 1.5 eq) in N,N-dimethyl formamide (1.5 mL). The mixture was maintained in an oil bath at 25°C for 4 hours. LCMS indicated formation of the product. The mixture was filtered and the residue was purified by preparative high-performance liquid chromatography (preparative chromatograph manufacturer: Shimadzu, model: LC-20AP, column: Welch Xtimate C18 250 × 30mm × 10 μm, mobile phase: water (0.225% HCOOH)- acetonitrile, with an elution ratio of acetonitrile increased from 20% to 50%), to obtain PE-10b (7.8) mg, 73.5% yield). LCMS (ESI): <com:Math><semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>< / com:Math>, 774[M+H]<com:Sup>+< / com:Sup>.

[00241] Step 2: Preparation of compound PE-10c

[00242] N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (5.75 mg, 15.12 μmol, 1.5 eq) and N,N-diisopropylethylamine (3.33 μL, 20.16 μmol, 2 eq) were added to a solution of compound PE-10b (7.8 mg, 10.08 µmol, 1 eq) and (3R,5R)-7-((((9H-fluoren-9-yl) methoxy)carbonyl)amino)-3,5-dihydroxyheptanoic acid (4.83 mg, 12.09 µmol, 1.2 eq; for the synthesis of this intermediate, refer to the preparation example of PE-1) in N,N-dimethylformamide (2 mL). The mixture was stirred at room temperature for 2 hours. LCMS analysis showed complete consumption of the starting material. The mixture was concentrated under an oil pump to dryness to afford the crude product (22.5 mg, the yield not calculated for the crude product). LCMS (ESI): m / z, 1155[M+H]<com:Sup>+< / com:Sup>.

[00243] Step 3: Preparation of compound PE-10

[00244] 1,8-diazabicyclo[5.4.0]undec-7-ene (4.5 μL, 30.24 μmol, 3 eq) was added to a solution of compound PE-10c (22.5 mg, 51.7% purity, 10.08 µmol, 1 eq) in N,N-dimethylformamide (2 mL). The mixture was stirred at room temperature for 1 hour. LCMS analysis showed complete consumption of the starting material. After filtration, the residue was purified by preparative high- performance liquid chromatography (preparative chromatograph manufacturer: Shimadzu, model: LC-20AP, column: GS-120-10-C18AP, mobile phase: water (0.225% HCOOH)-acetonitrile, with an elution ratio of acetonitrile increased from 20% to 50%), to afford compound PE-10 (7.8 mg, 73.5%) yield) as a white solid.

[00245] LCMS (ESI): m / z, 933[M+H]<com:Sup>+< / com:Sup>. <com:Math><semantics>1<annotation encoding="application / x-tex">^{1}< / annotation>< / semantics>< / com:Math>H NMR (400 MHz, DMSO-<com:Math><semantics>d6<annotation encoding="application / x-tex">d_6< / annotation>< / semantics>< / com:Math>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.42 (s, 1H), 7.81 (s, 1H), <com:Math><semantics>5.06<annotation encoding="application / x-tex">5.06< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>5.00<annotation encoding="application / x-tex">5.00< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>4.84<annotation encoding="application / x-tex">4.84< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>4.76<annotation encoding="application / x-tex">4.76< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>4.64<annotation encoding="application / x-tex">4.64< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>4.56<annotation encoding="application / x-tex">4.56< / annotation>< / semantics>< / com:Math> (t, <com:Math><semantics>J=4.2<annotation encoding="application / x-tex">J = 4.2< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>4.26<annotation encoding="application / x-tex">4.26< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=4.2<annotation encoding="application / x-tex">J = 4.2< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>4.84<annotation encoding="application / x-tex">4.84< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>4.84<annotation encoding="application / x-tex">4.84< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>4.84<annotation encoding="application / x-tex">4.84< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>4.84<annotation encoding="application / x-tex">4.84< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>4.84<annotation encoding="application / x-tex">4.84< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>=10.4 Hz,1H,4.19 (d, J=13.2 Hz,1H),4.10 (d, J=4.8 Hz,3H),4.06−3.93 (m, 2H),3.85−3.64 (m, 2H)<annotation encoding="application / x-tex">= 10.4 \text{ Hz}, 1\text{H}, 4.19 \text{ (d, } J = 13.2 \text{ Hz}, 1\text{H}), 4.10 \text{ (d, } J = 4.8 \text{ Hz}, 3\text{H}), 4.06-3.93 \text{ (m, 2H)}, 3.85-3.64 \text{ (m, 2H)}< / annotation>< / semantics>< / com:Math> 5H), 3.51 (s, 6H), 3.27 (d, <com:Math><semantics>J=7.2<annotation encoding="application / x-tex">J = 7.2< / annotation>< / semantics>< / com:Math> Hz, 8H), 3.06 (s, 2H), 2.87-2.70 (m, 5H), 2.58 (d, <com:Math><semantics>J=16.2<annotation encoding="application / x-tex">J = 16.2< / annotation>< / semantics>< / com:Math> Hz, 1H), 2.34 (s, 1H), 2.24 (dd, <com:Math><semantics>J=16.8<annotation encoding="application / x-tex">J = 16.8< / annotation>< / semantics>< / com:Math>, 9.8 Hz, 5H), 2.14 (d, <com:Math><semantics>J=12.0<annotation encoding="application / x-tex">J = 12.0< / annotation>< / semantics>< / com:Math> Hz, 2H), 2.06-1.96 (m, 2H), 1.93 (s, 4H), 1.67 (t, <com:Math><semantics>J=12.2<annotation encoding="application / x-tex">J = 12.2< / annotation>< / semantics>< / com:Math> Hz, 6H), 1.50 (s, 6H), 1.35 (d, <com:Math><semantics>J=18.2<annotation encoding="application / x-tex">J = 18.2< / annotation>< / semantics>< / com:Math> Hz, 3H), 1.26-1.12 (m, 2H), 1.04 (d, <com:Math><semantics>J=18.2<annotation encoding="application / x-tex">J = 18.2< / annotation>< / semantics>< / com:Math> Hz, 3H), 1.26-1.12 (m, 2H), 1.04 (d, <com:Math><semantics>J=18.2<annotation encoding="application / x-tex">J = 18.2< / annotation>< / semantics>< / com:Math> Hz, 3H), 1.26-1.12 (m, 2H), 1.04 (d, <com:Math><semantics>J=18.2<annotation encoding="application / x-tex">J = 18.2< / annotation>< / semantics>< / com:Math> Hz, 3H), <com:Math><semantics>=6.4 Hz,3H<annotation encoding="application / x-tex">= 6.4 \text{ Hz}, 3\text{H}< / annotation>< / semantics>< / com:Math>).

[00246] Preparation Example 9: Preparation of Compound PE-12 [Image disponible dans le document PDF, Image available in the PDF document]

[00247] Step 1: Preparation of compound PE-12-a

[00248] N,N-diisopropylethylamine (1.5 µL, 9.08 µmol, 1.5 eq) and N-BOC-4-aminobenzene sulfonyl chloride (1.94 mg, 6.66 µmol, 1.1 eq) were added to a solution of eribulin mesylate (5 mg, 6.05 µmol, 1 eq) in dichloromethane (1 mL) under an ice bath. The mixture was stirred at room temperature for 2 hours. LCMS analysis showed complete consumption of the starting material. The mixture was concentrated under an oil pump to afford the crude product PE-12-a (13 mg, where the yield was not calculated for the crude product, and a theoretical mass was 9.6 mg).

[00249] LCMS (ESI): m / z, 1007[M+Na]<com:Sup>+< / com:Sup>.

[00250] Step 2: Preparation of compound PE-12

[00251] Trifluoroacetic acid (0.1 mL) was added to a solution of compound PE-12-a (7.68 mg, 4.84) μmol, 1 eq) in dichloromethane (1 mL) under an ice bath and the resulting mixture was stirred for 2 hours at room temperature. LCMS indicated that the starting materials were completely consumed. After being concentrated, the reaction solution was dissolved in N,N-dimethylformamide, the mixture was filtered, and the filtrate was purified by high-performance liquid chromatography (preparative chromatograph manufacturer: Orienda, model: BRIX-2860, column: Synergi Max-RP 250 × 40 mm × 10 μm, mobile phase: water (0.225% HCOOH)-acetonitrile, with an elution ratio of acetonitrile increased from 30% to 60%), to afford compound PE-12 (0.52 mg, 12.14% yield) as a white solid.

[00252] LCMS (ESI): m / z, 907[M+Na]<com:Sup>+< / com:Sup>.

[00253] Preparation Example 10: Preparation of Compound PE-16 [Image disponible dans le document PDF, Image available in the PDF document]

[00254] Step 1: Preparation of compound PE-16-a

[00255] N,N-diisopropylethylamine (2 µL, 12.11 µmol, 2 eq) and N,N,N',N'-tetramethyl-O-(7- azabenzotriazol-1-yl)uronium hexafluorophosphate (2.76 mg, 7.26 μmol, 1.2 eq) were added to the solution of eribulin mesylate (5 mg, 6.05 µmol, 1 eq) and 6-((tert-butoxycarbonyl)amino)spiro [3.3]heptane-2-carboxylic acid (1.85 mg, 7.26 µmol, 1.2 eq) in N,N-dimethylformamide (1 mL) under an ice bath, and then the reaction solution was stirred at room temperature for 2 hours. LCMS analysis showed complete consumption of the starting material. The reaction solution was purified by preparative high-performance liquid chromatography (preparative chromatograph manufacturer: Orienda, model: BRIX-2860, column: YMC-Triart Prep C18 150 × 30 mm × 10 μm, mobile phase: water (0.225% HCOOH)-acetonitrile, with an elution ratio of acetonitrile increased from 40% to 70%), to afford a product PE-16-a (4.60 mg, 78.5% yield) as a white solid.

[00256] LCMS (ESI): <com:Math><semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>< / com:Math>, 967[M+H]<com:Sup>+< / com:Sup>.

[00257] Step 2: Preparation of compound PE-16

[00258] Trifluoroacetic acid (0.1 mL) was added to a solution of compound PE-16-a (4.60 mg, 4.76 μmol, 1 eq) in dichloromethane (1 mL) under an ice bath. The mixture was then stirred at room temperature for 2 hours. LCMS analysis showed complete consumption of the starting material. The mixture was concentrated via an oil pump. The residue was purified by preparative high-performance liquid chromatography (preparative chromatograph manufacturer: Orienda, model: BRIX-2860, column: Welch Xtimate C18 250 × 30mm × 10 μm, mobile phase: water (0.225% HCOOH)- acetonitrile, with an elution ratio of acetonitrile increased from 30% to 60%), to obtain product PE- 16 (1.66 mg, 39.3% yield) as a white solid.

[00259] LCMS (ESI): <com:Math><semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>< / com:Math>, 867[M+H]<com:Sup>+< / com:Sup>.

[00260] Preparation Example 11: Preparation of Compound PE-18 [Image disponible dans le document PDF, Image available in the PDF document]

[00261] Step 1: Preparation of compound PE-18-a

[00262] N,N-diisopropylethylamine (4.69 mg, 6 <com:Math><semantics>μ<annotation encoding="application / x-tex">\mu< / annotation>< / semantics>< / com:Math>L, 36.32 <com:Math><semantics>μ<annotation encoding="application / x-tex">\mu< / annotation>< / semantics>< / com:Math>mol, 3 eq), 2-(7-azabenzotriazol)- N,N,N',N'-tetramethyluronium hexafluorophosphate (5.52 mg, 14.53 µmol, 1.2 eq) and 4-((tert- butoxycarbonyl)amino)bicyclo[2.2.1]heptane-1-carboxylic acid (2.55 mg, 10 µmol, 1 eq) were added sequentially to a solution of eribulin mesylate (10 mg, 12.11 µmol, 1 eq) in N,N-dimethylformamide (1 mL) at room temperature. The mixture was stirred at 20°C for 3 hours. LCMS analysis showed complete consumption of the starting material. The reaction solution was purified by preparative high-performance liquid chromatography (preparative chromatograph manufacturer: Orienda, model: BRIX-2860 (R1, 4, 5, 6, and 7), column: Phenomenex Luna C18 250 <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 50 mm <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 10 <com:Math><semantics>μ<annotation encoding="application / x-tex">\mu< / annotation>< / semantics>< / com:Math>m, mobile phase: water (0.225% HCOOH)-acetonitrile, with an elution ratio of acetonitrile increased from 30% to 60%) and lyophilized, to afford a product PE-18-a (6 mg, 6.20 µmol, 51% yield) as a white solid.

[00263] LCMS (ESI): <com:Math><semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>< / com:Math>, 967.6[M+H]<com:Sup>+< / com:Sup>.

[00264] Step 2: Preparation of compound PE-18

[00265] At room temperature, PE-18-a (6 mg, 6.20 µmol, 1 eq) was added to dichloromethane (1 mL) and trifluoroacetic acid (0.1 mL), and the mixture was stirred at 20°C for 1 hour. LCMS analysis showed that the reaction ended. The reaction solution was purified by preparative high-performance liquid chromatography (preparative chromatograph manufacturer: Orienda, model: BRIX-2860, column: Phenomenex Luna C18 250×50 mm×10 μm, mobile phase: water (0.225% HCOOH)- acetonitrile, with an elution ratio of water increased from 30% to 60%) and lyophilized, to afford a product PE-18 (3.09 mg, 3.38 µmol, 55% yield) as a white solid.

[00266] LCMS (ESI): m / z, 867.6[M+H]<com:Sup>+< / com:Sup>.

[00267] Preparation Example 12: Preparation of Compound PE-21A [Image disponible dans le document PDF, Image available in the PDF document]

[00268] Step 1: Preparation of compound 2-[(tert-butyldimethylsilyl)oxy]ethyl 4-nitrophenyl carbonate

[00269] DIPEA (6.60g, 8.44 mL, 51.04 mmol, 3 eq) was added to a solution of tert-butyldimethylsilyl ethanol (3g, 17.01 mmol, 1 eq) and bis(4-nitrophenyl) carbonate (10.35g, 6.90 mL, 34.03 mmol, 2 eq) in DMF (20 mL). The reaction solution was allowed to react at 25°C for 15 hours. LCMS analysis showed complete consumption of the starting material. The mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined and washed with water (20 mL × 2) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluents: petroleum ether: ethyl acetate = 5:1), to afford the compound 2-[(tert-butyldimethylsilyl)oxy]ethyl 4-nitrophenyl carbonate (4.52g, 77.73% yield) as a yellow oil. LCMS (ESI): m / z, 342[M+H]<com:Sup>+< / com:Sup>.

[00270] Step 2: Preparation of compound PE-21A-a

[00271] DIPEA (N,N-diisopropylethylamine, 1.42 mg, 1.81 µL, 10.96 µmol, 2 eq) was added to a solution of 2-((tert-butyldimethylsilyl)oxy)ethyl 4-nitrophenyl carbonate (2.25 mg, 6.58 µmol, 1.2 eq) and eribulin mesylate (4 mg, 5.48 µmol, 1 eq) in DMF (1 mL) at 0°C. The reaction mixture was allowed to react at 25°C for 15 hours. TLC indicated complete consumption of the starting material. The mixture was evaporated to dryness and used directly in the next step to afford the compound PE- 21A-a (5.11 mg, where the yield was not calculated for the crude product) as a brown oil. LCMS <com:Math><semantics>(ESI)<annotation encoding="application / x-tex">(ESI)< / annotation>< / semantics>< / com:Math>: m / z, 945[M+H]<com:Sup>+< / com:Sup>.

[00272] Step 3: Preparation of compound PE-21A

[00273] TFA (625 μg, 80 μL, 5.48 μmol, 1 eq) was added to a solution of PE-21A-a (5.11 mg, 5.48 µmol, 1 eq) in DCM (dichloromethane, 800 µL) at 0°C. The mixture was allowed to react at 0°C to 25°C for 2 hours. LCMS analysis showed complete consumption of the starting material. The reaction solution was purified by preparative high-performance liquid chromatography (preparative chromatograph manufacturer: Orienda, model: BRIX-2860, column: Welch Xtimate C18 150 × 30 mm <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 10 µm, mobile phase: water (0.225% HCOOH)-acetonitrile, with an elution ratio of acetonitrile increased from 30% to 60%), to afford compound PE-21A (600 µg, 13.38% yield, 100% purity) as a white solid. LCMS (ESI): <com:Math><semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>< / com:Math>, 840[M+Na]<com:Sup>+< / com:Sup>.

[00274] Preparation Example 13: Preparation of Compound PE-21B [Image disponible dans le document PDF, Image available in the PDF document]

[00275] Step 1: Preparation of compound (S)-1-((tert-butyldimethylsilyl)oxy)propan-2-ol

[00276] TBSCl (tert-butyldimethylsilyl chloride, 2.18g, 2.50 mL, 14.46 mmol, 1.1 eq) and imidazole (894.73 mg, 813.39 μL, 13.14 mmol, 1 eq) were added to a solution of (S)-propane-1,2- diol (1g, 13.14 mmol, 1 eq) in DCM (10 mL) at 0°C. After the addition, the reaction mixture was allowed to react at 25°C for 16 hours. The reaction solution was added into ice-cold aqueous sodium bicarbonate solution (60 mL) and the mixture was then stirred for 2 minutes and extracted with dichloromethane (60 mL × 3). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to afford the compound (S)-1-((tert- butyldimethylsilyl)oxy)propan-2-ol (2.30g, 91.94% yield) as a colorless oil.

[00277] <com:Sup>1< / com:Sup>H NMR (400 MHz, Chloroform-d) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 3.82-3.78 (m, 1H), 3.59-3.56 (m, 1H), 3.36-3.31 (m, 1H), 2.52 (brs, 1H), 1.11 (d, <com:Math><semantics>J=8.0<annotation encoding="application / x-tex">J = 8.0< / annotation>< / semantics>< / com:Math> Hz, 3H), 0.90 (s, 9H), 0.06 (s, 6H).

[00278] Step 2: Preparation of compound PE-21B-a

[00279] Bis(4-nitrophenyl) carbonate (2.43g, 1.62 mL, 8 mmol, 2 eq) and DIPEA (1.55g, 1.98 mL, 12 mmol, 3 eq) were added to a solution of (S)-1-((tert-butyldimethylsilyl)oxy)propan-2-ol (761.40 mg, 4 mmol, 1 eq) in DMF (10 mL) at 0°C. The reaction solution was allowed to react at 25°C for 16 hours. The LCMS showed that a new compound was generated. The reaction solution was evaporated to dryness, to afford the residue. The residue was purified by silica gel column chromatography (eluents: ethyl acetate / hexane = 1:30 to 1:15) to afford PE-21B-a (900 mg, 63.30% yield) as a pale yellow oil.

[00280] <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-<com:Math><semantics>d6<annotation encoding="application / x-tex">d^6< / annotation>< / semantics>< / com:Math>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.32 (d, <com:Math><semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics>< / com:Math> = 8.0 Hz, 2H), 7.51 (d, <com:Math><semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics>< / com:Math> = 8.0 Hz, 2H), 4.88- <com:Math><semantics>4.86 (m, 1H),3.78−3.66 (m, 2H),1.28 (d, J=8.0 Hz, 3H),0.86 (s, 9H),0.06 (s, 6H).<annotation encoding="application / x-tex">4.86 \text{ (m, 1H)}, 3.78-3.66 \text{ (m, 2H)}, 1.28 \text{ (d, } J = 8.0 \text{ Hz, 3H)}, 0.86 \text{ (s, 9H)}, 0.06 \text{ (s, 6H)}.< / annotation>< / semantics>< / com:Math>

[00281] Step 3: Preparation of compound PE-21B-b

[00282] Eribulin mesylate (5.66 mg, 6.85 μmol, 1 eq), DIPEA (2.66 mg, 3.40 μL, 20.55 μmol, 3 eq) and HOBt (1-hydroxybenzotriazole, 925.61 µg, 6.85 µmol, 1 eq) were added to a solution of compound PE-21B-a (2.43 mg, 6.85 µmol, 1 eq) in DMF (1 mL) at 0°C. The reaction solution was allowed to react at 25°C for 1 hour. The LCMS analysis showed that the reaction ended. The reaction solution was concentrated to afford the crude product PE-21B-b (7 mg, crude) as a yellow oil.

[00283] LCMS (ESI): <com:Math><semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>< / com:Math>, 968.7 [M+Na]<com:Sup>+< / com:Sup>, Rt = 2.46 min.

[00284] Step 4: Preparation of compound PE-21B

[00285] Trifluoroacetic acid (0.1 mL) was added to a solution of compound PE-21B-b (6.48 mg, 6.85) μmol, 1 eq) in DCM (1 mL) at room temperature. The reaction solution was allowed to react at 25°C for 1 hour. The LCMS analysis showed that the reaction ended. The reaction solution was concentrated, and the residue was purified by preparative high-performance liquid chromatography (preparative chromatograph manufacturer: Orienda, model: BRIX-2860, column: Welch Xtimate C18 <com:Math><semantics>150×30 mm×10 μm<annotation encoding="application / x-tex">150 \times 30 \text{ mm} \times 10 \text{ }\mu\text{m}< / annotation>< / semantics>< / com:Math>, mobile phase: water (0.225% HCOOH)-acetonitrile, with an elution ratio of acetonitrile increased from 30% to 60%) and lyophilized, to afford PE-21B (360 µg, 6.32% yield, 96.6% purity) as a white solid.

[00286] LCMS (ESI): <com:Math><semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>< / com:Math>, 854.5 [M+Na]<com:Sup>+< / com:Sup>, Rt = 2.153 min. HPLC: Rt = 5.683 min.

[00287] Preparation Example 14: Preparation of Compound PE-21C [Image disponible dans le document PDF, Image available in the PDF document]

[00288] Step 1: Preparation of compound PE-21C-a

[00289] NPC (4-nitrophenyl chloroformate, 2.68g, 8.81 mmol, 6 eq) and DIPEA (1.14g, 8.81 mmol, 6 eq) were added to a solution of 2-((tert-butyldiphenylsilyl)oxy)-1-cyclopropylethan-1-ol (500 mg, 1.47 mmol, 1 eq; for synthesis of the compound, refer to the Example of LA-31B) in DMF (20 mL). The reaction solution was stirred at room temperature for 2 hours. LCMS analysis showed that the reaction ended. The reaction solution was evaporated to dryness under reduced pressure. DCM (50 mL) and water (100 mL) were added to the mixture. The mixture was extracted with DCM (50 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 3). The organic phases were combined and washed with saturated brine (100 mL), dried over anhydrous Na<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub>, filtered, and evaporated to dryness. The residue was purified by silica gel column chromatography (eluents: ethyl acetate / petroleum ether = 0:1 to 1:5) to afford the product PE-21C-a (426 mg, 57.38% yield) as a colorless oil.

[00290] <com:Sup>1< / com:Sup>H NMR (400 MHz, CDCl<com:Sub>3< / com:Sub>) δ 8.29-8.25 (m, 2H), 7.72-7.68 (m, 4H), 7.46-7.37 (m, 6H), <com:Math><semantics>7.36−7.31<annotation encoding="application / x-tex">7.36-7.31< / annotation>< / semantics>< / com:Math> (m, 2H), <com:Math><semantics>4.34−4.27<annotation encoding="application / x-tex">4.34-4.27< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>3.91<annotation encoding="application / x-tex">3.91< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=5.6<annotation encoding="application / x-tex">J = 5.6< / annotation>< / semantics>< / com:Math> Hz, 2H), <com:Math><semantics>1.09−1.05<annotation encoding="application / x-tex">1.09-1.05< / annotation>< / semantics>< / com:Math> (m, 10H), <com:Math><semantics>0.64−0.49<annotation encoding="application / x-tex">0.64-0.49< / annotation>< / semantics>< / com:Math> (m, 3H), 0.29-0.21 (m, 1H).

[00291] Step 2: Preparation of compound PE-21C-b

[00292] DIPEA (4.69 mg, 36.32 μmol, 3 eq) and HOBT (1.64 mg, 12.11 μmol, 1 eq) were added to the solution of eribulin mesylate (10 mg, 12.11 µmol, 1 eq) and PE-21C-a (7.35 mg, 14.53 µmol, 1.2 eq) in DMF (2 mL), and the reaction solution was stirred for 2 hours at room temperature. LCMS analysis showed that the reaction ended. The reaction solution was evaporated to dryness under reduced pressure to afford the product PE-21C-b (13.27 mg, where the yield was not calculated for the crude product) as a colorless oil. LCMS (ESI): m / z, 1118.8[M+Na]<com:Sup>+< / com:Sup>, Rt=3.950 min.

[00293] Step 3: Preparation of compound PE-21C

[00294] Triethylamine trihydrofluoride (0.04 mL) was added to a solution of compound PE-21C-b (12.52 mg, crude) in DMF (2 mL) at 0°C. The reaction solution was stirred at 65°C for 2.5 hours. LCMS analysis showed complete consumption of the starting material. The mixture was purified by preparative high-performance liquid chromatography (preparative chromatograph manufacturer: Orienda, model: BRIX-2860-R6, column: Welch Xtimate C18 250 × 30mm × 10 µm, mobile phase: water (0.225% HCOOH)-acetonitrile, with an elution ratio of water increased from 30% to 60%), to afford PE-21C (4.2 mg, 42.87% yield) as a white solid. LCMS (ESI): m / z, 880.7[M+Na]<com:Sup>+< / com:Sup>, Rt=1.985 min.

[00295] <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-<com:Math><semantics>d6<annotation encoding="application / x-tex">d_6< / annotation>< / semantics>< / com:Math>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 6.93-6.79 (m, 1H), 5.10-4.96 (m, 2H), 4.87-4.49 (m, 5H), 4.33-3.98 (m, 6H), 3.86-3.64 (m, 3H), 3.57-3.42 (m, 4H), 3.26 (s, 6H), 3.02-2.54 (m, 7H), 2.35-1.82 (m, 12H), 1.78-0.86 (m, 17H), 0.51-0.18 (m, 4H).

[00296] Preparation Example 15: Preparation of Compound PE-21D [Image disponible dans le document PDF, Image available in the PDF document]

[00297] Step 1: Preparation of compound PE-21D-a

[00298] DIPEA (4.69 mg, 36.32 μmol, 3 eq) and HOBt (1.64 mg, 12.11 μmol, 1 eq) were added to the solution of eribulin mesylate (10 mg, 12.11 μmol, 1 eq) and PY-4Car2-b (5.82 mg, 15.74 μmol, 1.3 eq) in THF (20 mL), and the reaction solution was stirred for 2.5 hours at room temperature. LCMS analysis showed that the reaction ended. The reaction solution was evaporated to dryness under reduced pressure to afford the product PE-21D-a (11.60 mg, where the yield was not calculated for the crude product) as a colorless oil. LCMS (ESI): m / z, 960.9[M+H]<com:Sup>+< / com:Sup>, Rt=1.128min.

[00299] Step 2: Preparation of compound PE-21D

[00300] TFA (0.4 mL) was added to a solution of compound PE-21D-a (11.60 mg, crude) in DCM (2 mL) at 0°C. The reaction solution was stirred at room temperature for 2 hours. LCMS analysis showed complete consumption of the starting material. The reaction solution was evaporated to dryness under reduced pressure. The mixture was purified by preparative high-performance liquid chromatography (preparative chromatograph manufacturer: Orienda, model: BRIX-2860, column: Welch Xtimate C18 <com:Math><semantics>200×30 mm×10μm<annotation encoding="application / x-tex">200 \times 30 \text{ mm} \times 10 \mu\text{m}< / annotation>< / semantics>< / com:Math>, mobile phase: water (0.225% HCOOH)-acetonitrile, with an elution ratio of acetonitrile increased from 30% to 60%), to afford PE-21D (1.40 mg, 13.70% yield) as a white solid.

[00301] Preparation Example 16: Preparation of Compound PE-21DA [Image disponible dans le document PDF, Image available in the PDF document]

[00302] Step 1: Preparation of 1-{[(4-{[(tert-butoxy)carbonyl]amino}butoxy)carbonyl]oxy}-4- nitrobenzene

[00303] Bis(4-nitrophenyl) carbonate (642.98 mg, 428.65 μL, 2.11 mmol, 4 eq) and DIPEA (409.74 mg, 523.97 μL, 3.17 mmol, 6 eq) were added to a solution of 4-(Boc-amino)-1-butanol (100 mg, 528.40 μmol, 1 eq) in DMF (5 mL). The reaction solution was allowed to react at 33°C for 1 hour. LCMS analysis indicated the reaction ended. The residue was purified by silica gel column chromatography (C18, ISCO, R-120g SepaFlash Silica Flash Column, eluents: 10%–60% water / CH<com:Sub>3< / com:Sub>CN, 60 mL / min) to afford the compound 1-{[(4-{[(tert-butoxy)carbonyl]amino}butoxy) carbonyloxy\-4-nitrobenzene as a white solid (131 mg, 69.96% yield).

[00304] LCMS (ESI): m / z, 255[M-100+H]<com:Sup>+< / com:Sup>. <com:Sup>1< / com:Sup>H NMR (400 MHz, Chloroform-d) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.29 (d, <com:Math><semantics>J=9.1<annotation encoding="application / x-tex">J = 9.1< / annotation>< / semantics>< / com:Math> Hz, 2H), 7.39 (d, <com:Math><semantics>J=9.2<annotation encoding="application / x-tex">J = 9.2< / annotation>< / semantics>< / com:Math> Hz, 2H), 4.58 (s, 1H), 4.31 (t, <com:Math><semantics>J=6.5<annotation encoding="application / x-tex">J = 6.5< / annotation>< / semantics>< / com:Math> Hz, 2H), 3.19 (t, <com:Math><semantics>J=6.7<annotation encoding="application / x-tex">J = 6.7< / annotation>< / semantics>< / com:Math> Hz, 2H), 1.79 <com:Math><semantics>(dt,J=8.8,6.6 Hz,2H),1.66(d,J=7.3 Hz,2H),1.45(s,9H).<annotation encoding="application / x-tex">(dt, J = 8.8, 6.6 \text{ Hz}, 2H), 1.66 (d, J = 7.3 \text{ Hz}, 2H), 1.45 (s, 9H).< / annotation>< / semantics>< / com:Math>

[00305] Step 2: Preparation of compound PE-21DA-a

[00306] DIPEA (5.31 mg, 6.79 μL, 41.10 μmol, 3 eq) and HOBT (1.85 mg, 1.23 μL, 13.70 μmol, 1 eq) were added to a solution of 1-{[(4-{[(tert-butoxy)carbonyl]amino}butoxy)carbonyl]oxy}- 4- nitrobenzene (9.71 mg, 27.40 μmol, 2 eq) and eribulin mesylate (10 mg, 13.70 μmol, 1 eq) in THF (1 mL) at 0°C. The reaction solution was allowed to react at 35°C for 1 hour. LCMS then indicated complete consumption of the starting material. The mixture was evaporated to dryness and used directly in the next step. LCMS (ESI): m / z, 945[M+H]<com:Sup>+< / com:Sup>.

[00307] Step 3: Preparation of compound PE-21DA

[00308] At 0°C, TFA (614 mg, 400 µL, 5.39 mmol, 393.0275 eq) was added to a solution of PE- 21DA-a (12.95 mg, 13.70 µmol, 1 eq) in DCM (1 mL). The reaction solution was allowed to react at 0°C for 90 minutes. LCMS indicated complete consumption of the starting material. The reaction solution was evaporated to dryness to afford the crude product. The crude product was purified by preparative high-performance liquid chromatography (preparative chromatograph manufacturer: Shimadzu, model: LC-20AP, column: Phenomenex Luna C18 150 × 25 mm × 10 µm, mobile phase: water (0.225% HCOOH)-acetonitrile, with an elution ratio of acetonitrile increased from 20% to 50%) and lyophilized, to afford compound PE-21DA (4 mg, 34.55% yield, 95% purity) as a white solid.

[00309] LCMS (ESI): m / z, 845 [M+H]<com:Sup>+< / com:Sup>. <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) δ 8.42 (s, 1H), 6.97 (s, 1H), <com:Math><semantics>6.20 (d, J=3.0 Hz, 1H),5.95 (d, J=3.0 Hz, 1H),4.95 (s, 1H),4.87 (s, 1H),4.81 (s, 1H),4.75 (s, 1H)<annotation encoding="application / x-tex">6.20 \text{ (d, } J = 3.0 \text{ Hz, } 1\text{H)}, 5.95 \text{ (d, } J = 3.0 \text{ Hz, } 1\text{H)}, 4.95 \text{ (s, } 1\text{H)}, 4.87 \text{ (s, } 1\text{H)}, 4.81 \text{ (s, } 1\text{H)}, 4.75 \text{ (s, } 1\text{H)}< / annotation>< / semantics>< / com:Math> 1H), <com:Math><semantics>4.65<annotation encoding="application / x-tex">4.65< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>4.36−4.27<annotation encoding="application / x-tex">4.36-4.27< / annotation>< / semantics>< / com:Math> (m, 2H), <com:Math><semantics>4.07−3.99<annotation encoding="application / x-tex">4.07-3.99< / annotation>< / semantics>< / com:Math> (m, 2H), <com:Math><semantics>3.93<annotation encoding="application / x-tex">3.93< / annotation>< / semantics>< / com:Math> (t, <com:Math><semantics>J=6.4<annotation encoding="application / x-tex">J = 6.4< / annotation>< / semantics>< / com:Math> Hz, 2H), <com:Math><semantics>3.84−3.77<annotation encoding="application / x-tex">3.84-3.77< / annotation>< / semantics>< / com:Math> (m, 2H), <Formule mathématique disponible dans le document PDF, Math available in the PDF document>$3.70 \text{ (s, 3H)}, 3.60 \text{ (d, } J = 4.1 \text{ Hz, 3H)}, 3.52 \text{ (s, 5H)}, 3.21 \text{ (s, 5H)}, 3.02-2.91 \text{ (m, 4H)}, 2.78 \text{ (d, } J = 6.8 \text{ (d, } J = 6.8 \text{ (d, } J = 6.8 \text{ (d, } J = 6.8 \text{ (d, } J = 6.8 \text{ (d, } J = 6.8 \text$ Hz, 1H), 2.72 (q, <com:Math><semantics>J=7.6<annotation encoding="application / x-tex">J = 7.6< / annotation>< / semantics>< / com:Math>, 6.7 Hz, 3H), 2.67 (q, <com:Math><semantics>J=1.9<annotation encoding="application / x-tex">J = 1.9< / annotation>< / semantics>< / com:Math> Hz, 1H), 2.33 (dt, <com:Math><semantics>J=3.8<annotation encoding="application / x-tex">J = 3.8< / annotation>< / semantics>< / com:Math>, 1.9 Hz, 2H), 2.11 <com:Math><semantics>(dd,J=15.8,7.4 Hz,1H),1.90(dd,J=35.4,11.5 Hz,3H),1.77−1.67(m,4H),1.66−1.45(m,8H),<annotation encoding="application / x-tex">(dd, J = 15.8, 7.4 \text{ Hz}, 1H), 1.90 (dd, J = 35.4, 11.5 \text{ Hz}, 3H), 1.77-1.67 (m, 4H), 1.66-1.45 (m, 8H),< / annotation>< / semantics>< / com:Math> 1.31 (t, <com:Math><semantics>J=9.1<annotation encoding="application / x-tex">J = 9.1< / annotation>< / semantics>< / com:Math> Hz, 2H), 1.04 (d, <com:Math><semantics>J=6.4<annotation encoding="application / x-tex">J = 6.4< / annotation>< / semantics>< / com:Math> Hz, 3H).

[00310] Preparation Example 17: Preparation of Compound PE-21E [Image disponible dans le document PDF, Image available in the PDF document]

[00311] Step 1: Preparation of 5-[(tert-butyldimethylsilyl)oxy]pentyl 4-nitrophenyl carbonate

[00312] 5-[(tert-butyldimethylsilyl)oxy]-1-pentanol (218.41 mg, 1 mmol, 1 eq) was dissolved in DMF (3 mL). Then bis(4-nitrophenyl) carbonate (912.63 mg, 608.42 µL, 3 mmol, 3 eq) and DIPEA (387.72 mg, 495.81 μL, 3 mmol, 3 eq) were added. The reaction solution was allowed to react at 35°C for 3 hours. The LCMS showed that a new compound was generated. The reaction solution was diluted with water (50 mL) and extracted with dichloromethane (50 mL × 3). The organic phases were combined, washed with water (100 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE / EA (petroleum ether / ethyl acetate) = 93% / 7%) to afford 5-[(tert-butyldimethylsilyl)oxy]pentyl 4-nitrophenyl carbonate (330 mg, 86.05%) yield) as a pale yellow oil.

[00313] <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-<com:Math><semantics>d6<annotation encoding="application / x-tex">d_6< / annotation>< / semantics>< / com:Math>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.39-8.25 (m, 2H), 7.60-7.45 (m, 2H), 4.24 (t, J = 6.4 Hz, 2H), <com:Math><semantics>3.58<annotation encoding="application / x-tex">3.58< / annotation>< / semantics>< / com:Math> (t, <com:Math><semantics>J=6.4<annotation encoding="application / x-tex">J = 6.4< / annotation>< / semantics>< / com:Math> Hz, 2H), <com:Math><semantics>1.77−1.59<annotation encoding="application / x-tex">1.77-1.59< / annotation>< / semantics>< / com:Math> (m, 2H), <com:Math><semantics>1.60−1.45<annotation encoding="application / x-tex">1.60-1.45< / annotation>< / semantics>< / com:Math> (m, 2H), <com:Math><semantics>1.46−1.33<annotation encoding="application / x-tex">1.46-1.33< / annotation>< / semantics>< / com:Math> (m, 2H), <com:Math><semantics>0.85<annotation encoding="application / x-tex">0.85< / annotation>< / semantics>< / com:Math> (s, 9H), <com:Math><semantics>0.02<annotation encoding="application / x-tex">0.02< / annotation>< / semantics>< / com:Math> (s, <com:Math><semantics>6H<annotation encoding="application / x-tex">6H< / annotation>< / semantics>< / com:Math>).

[00314] Step 2: Preparation of compound PE-21E-c

[00315] 5-[(tert-butyldimethylsilyl)oxy]pentyl 4-nitrophenyl carbonate (5.57 mg, 14.53 μmol, 2 eq) was dissolved in THF (500 μL), the mixture was cooled to 0°C, and then eribulin mesylate (6 mg, 7.26 µmol, 1 eq) and DIPEA (2.82 mg, 3.60 µL, 21.79 µmol, 3 eq) were added. The reaction solution was allowed to react at 25°C for 36 hours. The LCMS analysis showed that the reaction ended. The reaction solution was concentrated to afford the crude product PE-21E-c (8 mg) as a yellow oil.

[00316] LCMS (ESI): <com:Math><semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>< / com:Math>, 974.6 [M+H]<com:Sup>+< / com:Sup>, Rt = 3.83 min.

[00317] Step 3: Preparation of compound PE-21E

[00318] PE-21E-c (8 mg, 8.21 μmol, 1 eq) was dissolved in DCM (500 μL), the mixture was cooled to 0°C, and then TFA (153.50 mg, 100 μL) was added. The reaction solution was allowed to react at 0°C for 30 minutes. The LCMS analysis showed that the reaction ended. The reaction solution was concentrated, and the residue was purified by preparative high-performance liquid chromatography (preparative chromatograph manufacturer: Orienda, model: BRIX-2860, column: Welch Xtimate C18 <com:Math><semantics>150×30mm×10μm<annotation encoding="application / x-tex">150 \times 30 \text{mm} \times 10 \mu \text{m}< / annotation>< / semantics>< / com:Math>, mobile phase: water (0.225% HCOOH)-acetonitrile, with an elution ratio of acetonitrile increased from 30% to 60%), to afford a white solid PE-21E (1.03 mg, 14.59% yield, 97.91% purity).

[00319] LCMS (ESI): <com:Math><semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>< / com:Math>, 882.6 [M+Na]<com:Sup>+< / com:Sup>, Rt = 2.208 min.

[00320] Preparation Example 18: Preparation of Compound PE-21EA [Image disponible dans le document PDF, Image available in the PDF document]

[00321] Step 1: Preparation of compound PE-21EA-a

[00322] Bis(4-nitrophenyl) carbonate (2.59g, 8.25 mmol, 3 eq) and DIPEA (2.15g, 16.51 mmol, 6 eq) were added to a solution of (9H-fluoren-9-yl)methyl (5-hydroxypentyl)carbamate (895 mg, 2.75 mmol, 1 eq) in DMF (10 mL). The reaction solution was stirred at 25°C for 1 hour. The LCMS showed that the product was generated. After concentration, the reaction solution was purified by silica gel column chromatography (eluents: petroleum ether / ethyl acetate = 0:100 to 40:60) and reversed-phase silica gel column chromatography (C18, ISCO, R-220g SepaFlash Silica Flash Column, eluents: water / CH<com:Sub>3< / com:Sub>CN, with an elution ratio of acetonitrile increased from 5% to 80%, flow rate: 80 mL / min) to afford PE-21EA-a (1.07g, 79.29% yield) as a white solid.

[00323] LCMS (ESI): <com:Math><semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>< / com:Math>, 491.3[M+H]<com:Sup>+< / com:Sup>.

[00324] Step 2: Preparation of compound PE-21EA-b

[00325] A solution of compound PE-21EA-a (32.07 mg, 65.37 µmol, 1.2 eq) in DMF (1 mL) was added to a solution of eribulin mesylate (45 mg, 54.48 µmol, 1 eq) and DIPEA (21.34 mg, 163.44 μmol, 3 eq) in DMF (1 mL) at 0°C. After the addition, the reaction solution was stirred at 25°C for 1 hour. LCMS analysis showed that the reaction ended. The reaction solution was filtered and the residue was then purified by preparative high-performance liquid chromatography (preparative chromatograph manufacturer: Oriento; model: BRIX-2860; column: Synergi Max-RP 200 × 30 mm <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 10 µm; mobile phase: water (0.225% FA)—acetonitrile, with an elution ratio of acetonitrile increased from 50% to 80%) and silica gel column chromatography (eluents: dichloromethane / tetrahydrofuran = 0:100 to 30:70) to afford PE-21EA-b (56.10 mg, 95.23% yield) as a white solid.

[00326] LCMS (ESI): m / z, 1103.8[M+Na]<com:Sup>+< / com:Sup>.

[00327] Step 3: Preparation of compound PE-21EA

[00328] Diethylamine (29 mg, 388.42 µmol, 10 eq) was added to the solution of compound PE-21EA- b (42 mg, 38.84 μmol, 1 eq) in DMF (3 mL) at 0°C. The reaction solution was stirred at 25°C for 1 hour. LCMS analysis showed that the reaction ended. The reaction solution was filtered and the residue was then purified by high-performance liquid chromatography (preparative chromatograph manufacturer: Oriento; model: BRIX-2860; column: Synergi Max-RP 200 × 30 mm × 10 μm; mobile phase: water (0.225% FA)—acetonitrile, with an elution ratio of acetonitrile increased from 20% to 50%) to afford PE-21EA (26.06 mg, 78.1% yield, 95% purity) as a white solid.

[00329] LCMS (ESI): m / z, 859.6[M+H]<com:Sup>+< / com:Sup>.

[00330] <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-<com:Math><semantics>d6<annotation encoding="application / x-tex">d_6< / annotation>< / semantics>< / com:Math>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.42 (s, 1H), 6.94 (t, <com:Math><semantics>J=5.9<annotation encoding="application / x-tex">J = 5.9< / annotation>< / semantics>< / com:Math> Hz, 1H), 5.05 (s, 1H), 4.99 (s, 1H), 4.83 (s, 1H), 4.75 (s, 1H), 4.63 (d, <com:Math><semantics>J=3.9<annotation encoding="application / x-tex">J = 3.9< / annotation>< / semantics>< / com:Math> Hz, 1H), 4.55 (t, <com:Math><semantics>J=4.2<annotation encoding="application / x-tex">J = 4.2< / annotation>< / semantics>< / com:Math> Hz, 1H), 4.26 (d, <com:Math><semantics>J=10.9<annotation encoding="application / x-tex">J = 10.9< / annotation>< / semantics>< / com:Math> Hz, 1H), 4.18 (dd, <com:Math><semantics>J=10.3<annotation encoding="application / x-tex">J = 10.3< / annotation>< / semantics>< / com:Math>, 4.2 Hz, 1H), 4.09 (d, <com:Math><semantics>J=5.0<annotation encoding="application / x-tex">J = 5.0< / annotation>< / semantics>< / com:Math> Hz, 2H), 4.02 (t, <com:Math><semantics>J=9.6<annotation encoding="application / x-tex">J = 9.6< / annotation>< / semantics>< / com:Math> Hz, 1H), 3.91 (t, <com:Math><semantics>J=10.3<annotation encoding="application / x-tex">J = 10.3< / annotation>< / semantics>< / com:Math>) <com:Math><semantics>=6.6 Hz,2H<annotation encoding="application / x-tex">= 6.6 \text{ Hz}, 2\text{H}< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>3.80 (s, 1H)<annotation encoding="application / x-tex">3.80 \text{ (s, 1H)}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>3.77−3.73 (m, 1H)<annotation encoding="application / x-tex">3.77 - 3.73 \text{ (m, 1H)}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>3.70 (s, 1H)<annotation encoding="application / x-tex">3.70 \text{ (s, 1H)}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>3.56 (s, 2H)<annotation encoding="application / x-tex">3.56 \text{ (s, 2H)}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>3.49 (d, J=10.7 Hz, 5H)<annotation encoding="application / x-tex">3.49 \text{ (d, } J = 10.7 \text{ Hz, 5H)}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>3.25<annotation encoding="application / x-tex">3.25< / annotation>< / semantics>< / com:Math> (s, 4H), <com:Math><semantics>2.94<annotation encoding="application / x-tex">2.94< / annotation>< / semantics>< / com:Math> (t, <com:Math><semantics>J=6.0<annotation encoding="application / x-tex">J = 6.0< / annotation>< / semantics>< / com:Math> Hz, 2H), <com:Math><semantics>2.84<annotation encoding="application / x-tex">2.84< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=9.6<annotation encoding="application / x-tex">J = 9.6< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>2.79−2.73<annotation encoding="application / x-tex">2.79 - 2.73< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>2.69<annotation encoding="application / x-tex">2.69< / annotation>< / semantics>< / com:Math> (q, <com:Math><semantics>J=6.5<annotation encoding="application / x-tex">J = 6.5< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>5.6 Hz<annotation encoding="application / x-tex">5.6 \text{ Hz}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>3H<annotation encoding="application / x-tex">3\text{H}< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>2.60−2.54 (m, 1H)<annotation encoding="application / x-tex">2.60 - 2.54 \text{ (m, 1H)}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>2.34−2.30 (m, 1H)<annotation encoding="application / x-tex">2.34 - 2.30 \text{ (m, 1H)}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>2.24 (t, J=14.7 Hz, 3H)<annotation encoding="application / x-tex">2.24 \text{ (t, } J = 14.7 \text{ Hz, 3H)}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>2.14 (d, J=12.0 Hz, J=12.0 Hz<annotation encoding="application / x-tex">2.14 \text{ (d, } J = 12.0 \text{ Hz, } J = 12.0 \text{ Hz}< / annotation>< / semantics>< / com:Math> 1H), <com:Math><semantics>2.04−1.95<annotation encoding="application / x-tex">2.04 - 1.95< / annotation>< / semantics>< / com:Math> (m, 2H), <com:Math><semantics>1.91<annotation encoding="application / x-tex">1.91< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=9.0<annotation encoding="application / x-tex">J = 9.0< / annotation>< / semantics>< / com:Math> Hz, 4H), <com:Math><semantics>1.71<annotation encoding="application / x-tex">1.71< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=11.4<annotation encoding="application / x-tex">J = 11.4< / annotation>< / semantics>< / com:Math> Hz, 2H), <com:Math><semantics>1.65<annotation encoding="application / x-tex">1.65< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=12.6<annotation encoding="application / x-tex">J = 12.6< / annotation>< / semantics>< / com:Math> Hz, 2H), <com:Math><semantics>1.50<annotation encoding="application / x-tex">1.50< / annotation>< / semantics>< / com:Math> (dd, <com:Math><semantics>J=14.7<annotation encoding="application / x-tex">J = 14.7< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>7.5<annotation encoding="application / x-tex">7.5< / annotation>< / semantics>< / com:Math> Hz, 5H), <com:Math><semantics>1.35−1.30<annotation encoding="application / x-tex">1.35 - 1.30< / annotation>< / semantics>< / com:Math> (m, 3H), <com:Math><semantics>1.26<annotation encoding="application / x-tex">1.26< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=12.9<annotation encoding="application / x-tex">J = 12.9< / annotation>< / semantics>< / com:Math> Hz, 2H), <com:Math><semantics>1.19−1.12<annotation encoding="application / x-tex">1.19 - 1.12< / annotation>< / semantics>< / com:Math> (m, 1H), 1.03 (d, <com:Math><semantics>J=6.6<annotation encoding="application / x-tex">J = 6.6< / annotation>< / semantics>< / com:Math> Hz, 3H), 0.94 (d, <com:Math><semantics>J=6.8<annotation encoding="application / x-tex">J = 6.8< / annotation>< / semantics>< / com:Math> Hz, 1H), 0.86 (d, <com:Math><semantics>J=6.9<annotation encoding="application / x-tex">J = 6.9< / annotation>< / semantics>< / com:Math> Hz, 1H), 0.84 – 0.80 (m, 2H).

[00331] Preparation Example 19: Preparation of Compound PE-21EMS [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document]

[00332] Step 1: Preparation of (S)-tert-butyldimethylsilyloxy-2-methylbutanol

[00333] Imidazole (65.37 mg, 960.15 µmol, 1 eq) and tert-butyldimethylsilyl chloride (159.19 mg, 1.06 mmol, 1.1 eq) were added to a solution of (4S)-1,4-pentanediol (100 mg, 960.15 µmol, 1 eq) in DCM (2 mL) at 0°C. The reaction solution was stirred at room temperature overnight. TLC analysis showed that the reaction ended. DCM (10 mL) and water (20 mL) were added to the mixture. The mixture was extracted with DCM (20 mL × 3). The organic phases were combined and washed with saturated brine (10 mL), dried over anhydrous Na<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub>, filtered, and evaporated to dryness, to afford (S)-tert-butyldimethylsilyloxy-2-methylbutanol (131 mg, 62.47% yield) as a colorless oil.

[00334] <com:Sup>1< / com:Sup>H NMR (400 MHz, CDCl<com:Sub>3< / com:Sub>) 3.93-3.58 (m, 3H), 1.59-1.42 (m, 4H), 1.30-1.09 (m, 3H), 0.95- 0.86 (m, 10H), 0.11-0.05 (m, 6H).

[00335] Step 2: Preparation of compound PE-21EMS-a

[00336] NPC (547.39 mg, 1.80 mmol, 3 eq) and DIPEA (465.10 mg, 594.76 μL, 3.60 mmol, 6 eq) were added to a solution of (S)-tert-butyldimethylsilyloxy-2-methylbutanol (131 mg, 599.79 μmol, 1 eq) in DMF (2 mL). The reaction solution was stirred at 35°C for 2 hours. LCMS analysis showed that the reaction ended. The reaction solution was evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (eluents: ethyl acetate / petroleum ether = 0:1 to 1:20) to afford the product PE-21EMS-a (112 mg, 48.69% yield) as a colorless oil.

[00337] <com:Sup>1< / com:Sup>H NMR (400 MHz, CDCl<com:Sub>3< / com:Sub>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.29 (d, <com:Math><semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics>< / com:Math> = 9.2 Hz, 2H), 7.42-7.36 (m, 2H), 5.03 – 4.89 (m, 1H), 3.74-3.60 (m, 2H), 1.85-1.58 (m, 4H), 1.45-1.33 (m, 3H), 0.95-0.86 (m, 9H), 0.10-0.02 (m, 6H).

[00338] Step 3: Preparation of compound PE-21EMS-b

[00339] DIPEA (4.69 mg, 36.32 μmol, 3 eq) and HOBT (1.64 mg, 12.11 μmol, 1 eq) were added to the solution of eribulin mesylate (10 mg, 12.11 μmol, 1 eq) and PE-21EMS-a (5.57 mg, 14.53 μmol, 1.2 eq) in DMF (2 mL), and the reaction solution was stirred for 2 hours at room temperature. LCMS analysis showed that the reaction ended. The reaction solution was evaporated to dryness under reduced pressure to afford the product PE-21EMS-b (11.80 mg, where the yield was not calculated for the crude product) as a colorless oil. LCMS (ESI): m / z, 1014.6[M+Na]<com:Sup>+< / com:Sup>, Rt=2.968 min.

[00340] Step 4: Preparation of compound PE-21EMS

[00341] Triethylamine trihydrofluoride (0.1 mL) was added to a solution of compound PE-21EMS- b (11.4 mg, crude) in DMF (2 mL). The reaction solution was stirred at 65°C for 2.5 hours. LCMS analysis showed complete consumption of the starting material. The mixture was purified by preparative high-performance liquid chromatography (preparative chromatograph manufacturer: Orienda, model: BRIX-2860-R6, column: Welch Xtimate C18 250 × 30 mm × 10 µm, mobile phase: water (0.225% HCOOH)-acetonitrile, with an elution ratio of acetonitrile increased from 30% to 60%), to afford PE-21EMS (5.10 mg, 50.68% yield) as a white solid. LCMS (ESI): m / z, 860.6[M+H]<com:Sup>+< / com:Sup>, Rt=2.038min.

[00342] <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-<com:Math><semantics>d6<annotation encoding="application / x-tex">d_6< / annotation>< / semantics>< / com:Math>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 6.96-6.80 (m, 1H), 5.02 (d, <com:Math><semantics>J=22.8<annotation encoding="application / x-tex">J = 22.8< / annotation>< / semantics>< / com:Math> Hz, 2H), 4.79 (d, <com:Math><semantics>J=22.8<annotation encoding="application / x-tex">J = 22.8< / annotation>< / semantics>< / com:Math> Hz, 2H), 4.79 (d, <com:Math><semantics>J=22.8<annotation encoding="application / x-tex">J = 22.8< / annotation>< / semantics>< / com:Math> Hz, 2H), 4.79 (d, <com:Math><semantics>J=22.8<annotation encoding="application / x-tex">J = 22.8< / annotation>< / semantics>< / com:Math> Hz, 2H), 4.79 (d, <com:Math><semantics>J=22.8<annotation encoding="application / x-tex">J = 22.8< / annotation>< / semantics>< / com:Math> Hz, 2H), 4.79 (d, <com:Math><semantics>J=<annotation encoding="application / x-tex">J =< / annotation>< / semantics>< / com:Math> 31.2 Hz, 2H), 4.67-4.50 (m, 3H), 4.44-4.36 (m, 1H), 4.29-3.64 (m, 10H), 3.61-3.39 (m, 5H), 3.25 (s, 6H), 2.99-2.53 (m, 7H), 2.36-1.88 (m, 11H), 1.78-1.10 (m, 17H), 1.06-0.92 (m, 4H).

[00343] Preparation Example 20: Preparation of Compound PE-21EMR [Image disponible dans le document PDF, Image available in the PDF document]

[00344] Step 1: Preparation of (R)-tert-butyldimethylsilyloxy-2-methylbutanol

[00345] Imidazole (32.68 mg, 480.08 µmol, 1 eq) and tert-butyldimethylsilyl chloride (79.59 mg, 528.08 μmol, 1.1 eq) were added to a solution of (4R)-1,4-pentanediol (50 mg, 480.08 μmol, 1 eq) in DCM (2 mL) at 0°C. The reaction solution was stirred at room temperature overnight. TLC analysis showed that the reaction ended. DCM (10 mL) and water (20 mL) were added to the mixture. The mixture was extracted with DCM (20 mL <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 3). The organic phases were combined and washed with saturated brine (10 mL), dried over anhydrous Na<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub>, filtered, and evaporated to dryness, to afford (R)-tert-butyldimethylsilyloxy-2-methylbutanol (84.40 mg, 80.49% yield) as a colorless oil.

[00346] <com:Sup>1< / com:Sup>H NMR (400 MHz, CDCl<com:Sub>3< / com:Sub>) 3.93-3.56 (m, 3H), 1.70-1.60 (m, 2H), 1.53-1.42 (m, 2H), 1.27- 1.11 (m, 3H), 0.94-0.82 (m, 10H), 0.11 (s, 3H), 0.08 (s, 3H).

[00347] Step 2: Preparation of compound PE-21EMR-a

[00348] NPC (352.67 mg, 1.16 mmol, 3 eq) and DIPEA (299.65 mg, 2.32 mmol, 6 eq) were added to a solution of (R)-tert-butyldimethylsilyloxy-2-methylbutanol (84.40 mg, 386.43 µmol, 1 eq) in DMF (2 mL). The reaction solution was stirred at 35°C for 2 hours. LCMS analysis showed that the reaction ended. The reaction solution was evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (eluents: ethyl acetate / petroleum ether <com:Math><semantics>=0.1<annotation encoding="application / x-tex">= 0.1< / annotation>< / semantics>< / com:Math> to 1:20) to afford the product PE-21EMR-a (40 mg, 26.99% yield) as a colorless oil.

[00349] <com:Sup>1< / com:Sup>H NMR (400 MHz, CDCl<com:Sub>3< / com:Sub>) δ 8.31-8.26 (m, 2H), 7.42-7.37 (m, 2H), 4.98-4.89 (m, 1H), 3.69-3.62 (m, 2H), 1.80-1.59 (m, 4H), 1.45-1.38 (m, 3H), 0.93-0.87 (m, 9H), 0.07 (s, 6H).

[00350] Step 3: Preparation of compound PE-21EMR-b

[00351] DIPEA (4.69 mg, 36.32 μmol, 3 eq) and HOBT (1.64 mg, 12.11 μmol, 1 eq) were added to the solution of eribulin mesylate (10 mg, 12.11 μmol, 1 eq) and PE-21EMR-a (6 mg, 15.64 μmol, 1.29 eq) in DMF (2 mL), and the reaction solution was stirred for 1 hour at room temperature. LCMS analysis showed that the reaction ended. The reaction solution was evaporated to dryness under reduced pressure to afford the product PE-21EMR-b (11.80 mg, where the yield was not calculated for the crude product) as a colorless oil. LCMS (ESI): m / z, 1014.6[M+Na]<com:Sup>+< / com:Sup>.

[00352] Step 4: Preparation of compound PE-21EMR

[00353] Triethylamine trihydrofluoride (0.1 mL) was added to a solution of compound PE-21EMR - b (11.8 mg, crude) in DMF (2 mL). The reaction solution was stirred at 60°C for 4 hours. LCMS analysis showed complete consumption of the starting material. The mixture was purified by preparative high-performance liquid chromatography (preparative chromatograph manufacturer: Orienda, model: BRIX-2860-R6, column: Welch Xtimate C18 250 × 30 mm × 10 μm, mobile phase: water (0.225% HCOOH)-acetonitrile, with an elution ratio of acetonitrile increased from 30% to 60%), to afford PE-21EMR (3.90 mg, 37.44% yield) as a white solid. LCMS (ESI): m / z, <com:Math><semantics>860.6[M+H]+<annotation encoding="application / x-tex">860.6[M+H]^{+}< / annotation>< / semantics>< / com:Math>.

[00354] <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-<com:Math><semantics>d6<annotation encoding="application / x-tex">d_6< / annotation>< / semantics>< / com:Math>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 6.93-6.81 (m, 1H), 5.02 (d, <com:Math><semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics>< / com:Math> = 22.8 Hz, 2H), 4.79 (d, <com:Math><semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics>< / com:Math> = 31.6 Hz, 2H), 4.68-4.49 (m, 3H), 4.43-4.35 (m, 1H), 4.31-3.63 (m, 9H), 3.62-3.37 (m, 6H), 3.30-3.23 (m, 6H), 2.96-2.55 (m, 7H), 2.35-1.89 (m, 11H), 1.77-1.08 (m, 17H), 1.07-0.92 (m, 4H).

[00355] Preparation Example 21: Preparation of Compound PE-21EK [Image disponible dans le document PDF, Image available in the PDF document]

[00356] Step 1: Preparation of compound PE-21EK-a

[00357] 5-[(tert-butyldimethylsilyl)oxy]pentyl 4-nitrophenyl carbonate (10 mg, 26.07 µmol, 1 eq; for the synthesis of the compound, refer to the preparation example of PE-21E) was dissolved in DMF (2 mL). Eribulin mesylate (80 mg, 289.38 μmol, 1 eq), DIPEA (10.11 mg, 99%, 12.93 μL, 78.22 μmol, 3 eq) and HOBt (3.52 mg, 99.96%, 2.35 μL, 26.07 μmol, 1 eq) were added. The reaction solution was stirred at 25°C for 2 hours. The LCMS showed that the product was generated. The reaction solution was subjected to preparative high-performance liquid chromatography to obtain a white solid product (15 mg, 59.04% yield).

[00358] Conditions of the preparative high-performance liquid chromatography (preparative chromatograph manufacturer: Orienda, model: BRIX-2860, column: Welch Xtimate C18 250 × 30 mm <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 10 µm, mobile phase: water (0.225% HCOOH)-acetonitrile, with an elution ratio of water increased from 65% to 95%.

[00359] LCMS (ESI): <com:Math><semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>< / com:Math>, 974.7[M+H]<com:Sup>+< / com:Sup>.

[00360] Step 2: Preparation of compound PE-21EK-b

[00361] Compound PE-22EK-a (10 mg, 10.26 µmol, 1 eq) was dissolved in DCM (3 mL), DMP (26.12 mg, 98%, 19.18 μL, 61.58 μmol, 6 eq) was added at 0°C, and finally, a catalytic amount of water (50 µL) was added. The reaction mixture was stirred at 25°C for 12 hours. LCMS analysis showed that the reaction ended. The reaction solution was evaporated to dryness, and the residue was dissolved in DMF (1 mL). The mixture was subjected to preparative high-performance liquid chromatography to afford a white solid product (3 mg, 30.06% yield).

[00362] The conditions of the preparative high-performance liquid chromatography were as follows:

[00363] preparative chromatograph manufacturer: Orienda, model: BRIX-2860, column: Welch Xtimate C18 150 <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 30 mm <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 10 µm, mobile phase: water (0.225% HCOOH)-acetonitrile, with an elution ratio of water increased from 65% to 95%.

[00364] LCMS (ESI): <com:Math><semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>< / com:Math>, 972.54[M+H]<com:Sup>+< / com:Sup>.

[00365] Step 3: Preparation of compound PE-21EK

[00366] Et3N.3HF (98.90 mg, 97%, 100 μL, 595.08 μmol, 192.8653 eq) was added to the solution of compound PE-21EK-b (3 mg, 3.09 µmol, 1 eq) in THF (1 mL) at 25°C, and the reaction solution was stirred at 25°C for 2 hours. LCMS analysis showed complete consumption of the starting material. The reaction solution was purified by high-performance liquid chromatography to afford the product (1.32 mg, 49.86% yield, 96% purity) as a white solid.

[00367] The conditions of the preparative high-performance liquid chromatography were as follows:

[00368] preparative chromatograph manufacturer: Orienda, model: BRIX-2860, column: YMC- Triart Prep C18 150 <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 30 mm <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 10 <com:Math><semantics>μ<annotation encoding="application / x-tex">\mu< / annotation>< / semantics>< / com:Math>m, mobile phase: water (0.225% HCOOH)-acetonitrile, with an elution ratio of acetonitrile increased from 30% to 60%.

[00369] LCMS (ESI): <com:Math><semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>< / com:Math>, 880.4[M+Na]<com:Sup>+< / com:Sup>.

[00370] <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-<com:Math><semantics>d6<annotation encoding="application / x-tex">d_6< / annotation>< / semantics>< / com:Math>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 7.29 (t, <com:Math><semantics>J=6.0<annotation encoding="application / x-tex">J = 6.0< / annotation>< / semantics>< / com:Math> Hz, 1H), 5.04 (d, <com:Math><semantics>J=11.1<annotation encoding="application / x-tex">J = 11.1< / annotation>< / semantics>< / com:Math> Hz, 2H), 4.83 (s, 1H), <com:Math><semantics>4.77−4.73<annotation encoding="application / x-tex">4.77-4.73< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>4.63<annotation encoding="application / x-tex">4.63< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=2.8<annotation encoding="application / x-tex">J = 2.8< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>4.55<annotation encoding="application / x-tex">4.55< / annotation>< / semantics>< / com:Math> (t, <com:Math><semantics>J=4.2<annotation encoding="application / x-tex">J = 4.2< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>4.37<annotation encoding="application / x-tex">4.37< / annotation>< / semantics>< / com:Math> (t, <com:Math><semantics>J=5.1<annotation encoding="application / x-tex">J = 5.1< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>4.26 (d, J=10.8 Hz, 1H),4.17 (td, J=10.2,4.2 Hz, 1H),4.10 (t, J=3.2 Hz, 2H),4.06−3.98 (m, 2H),<annotation encoding="application / x-tex">4.26 \text{ (d, } J = 10.8 \text{ Hz, } 1\text{H)}, 4.17 \text{ (td, } J = 10.2, 4.2 \text{ Hz, } 1\text{H)}, 4.10 \text{ (t, } J = 3.2 \text{ Hz, } 2\text{H)}, 4.06-3.98 \text{ (m, } 2\text{H)},< / annotation>< / semantics>< / com:Math> <com:Math><semantics>3.93<annotation encoding="application / x-tex">3.93< / annotation>< / semantics>< / com:Math> (t, <com:Math><semantics>J=6.7<annotation encoding="application / x-tex">J = 6.7< / annotation>< / semantics>< / com:Math> Hz, <com:Math><semantics>2H<annotation encoding="application / x-tex">2H< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>3.87−3.75<annotation encoding="application / x-tex">3.87-3.75< / annotation>< / semantics>< / com:Math> (m, <com:Math><semantics>3H<annotation encoding="application / x-tex">3H< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>3.71<annotation encoding="application / x-tex">3.71< / annotation>< / semantics>< / com:Math> (s, <com:Math><semantics>1H<annotation encoding="application / x-tex">1H< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>3.57−3.47<annotation encoding="application / x-tex">3.57-3.47< / annotation>< / semantics>< / com:Math> (m, <com:Math><semantics>2H<annotation encoding="application / x-tex">2H< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>3.23<annotation encoding="application / x-tex">3.23< / annotation>< / semantics>< / com:Math> (s, <com:Math><semantics>3H<annotation encoding="application / x-tex">3H< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>2.84<annotation encoding="application / x-tex">2.84< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics>< / com:Math> <com:Math><semantics>=9.2 Hz,1H,2.82−2.72 (m, 2H),2.71−2.65 (m, 2H),2.60 (dd, J=18.0,8.0 Hz,2H),2.29 (q, J=18.0,8.0 Hz,2H)<annotation encoding="application / x-tex">= 9.2 \text{ Hz}, 1\text{H}, 2.82-2.72 \text{ (m, 2H)}, 2.71-2.65 \text{ (m, 2H)}, 2.60 \text{ (dd, } J = 18.0, 8.0 \text{ Hz}, 2\text{H}), 2.29 \text{ (q, } J = 18.0, 8.0 \text{ Hz}, 2\text{H})< / annotation>< / semantics>< / com:Math> 18.7, 17.8 Hz, 5H), 2.18-1.84 (m, 8H), 1.68 (q, <com:Math><semantics>J=12.5<annotation encoding="application / x-tex">J = 12.5< / annotation>< / semantics>< / com:Math> Hz, 4H), 1.58-1.38 (m, 6H), 1.38-1.15 (m, 6H), <com:Math><semantics>1.00<annotation encoding="application / x-tex">1.00< / annotation>< / semantics>< / com:Math> (dd, <com:Math><semantics>J=22.6<annotation encoding="application / x-tex">J = 22.6< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>9.1<annotation encoding="application / x-tex">9.1< / annotation>< / semantics>< / com:Math> Hz, <com:Math><semantics>4<annotation encoding="application / x-tex">4< / annotation>< / semantics>< / com:Math>H).

[00371] Preparation Example 22: Preparation of Compound E2KO [Image disponible dans le document PDF, Image available in the PDF document]

[00372] Step 1: Preparation of compound PE-E2KO

[00373] Compound PE-E2K (30 mg, 0.04 mmol) was dissolved in N,N-dimethylformamide (2 mL), glycolic acid (7 mg, 0.08 mmol), 1-hydroxybenzotriazole (16 mg, 0.12 mmol) and 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide (23 mg, 0.12 mmol) were added at room temperature. The reaction solution was stirred at 30°C for 2 hours. The reaction solution was purified by preparative high-performance liquid chromatography (preparative chromatograph manufacturer: Oriento, model: BRIX-2860, column: phenomenex Luna C18 250×50 mm×10 µm, mobile phase: water (0.5% TFA)-acetonitrile, with an elution ratio of acetonitrile increased from 12% to 42%) and the eluate was lyophilized, to afford the product PE-E2KO (8.1 mg, 24.7%) as a white solid.

[00374] LCMS (ESI): <com:Math><semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>< / com:Math>, 792.5 [M+H]<com:Sup>+< / com:Sup>, Rt = 0.97 min.

[00375] <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-<com:Math><semantics>d6<annotation encoding="application / x-tex">d_{6}< / annotation>< / semantics>< / com:Math>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 7.51 (s, 1H), 4.64 (t, <com:Math><semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics>< / com:Math> = 4.4 Hz, 1H), 4.56 (s, 1H), 4.39 (s, 1H), 4.11 (d, <com:Math><semantics>J=1.6<annotation encoding="application / x-tex">J = 1.6< / annotation>< / semantics>< / com:Math> Hz, 4H), 3.79 (s, 6H), 3.55 (d, <com:Math><semantics>J=5.2<annotation encoding="application / x-tex">J = 5.2< / annotation>< / semantics>< / com:Math> Hz, 3H), 3.27 (d, <com:Math><semantics>J=3.2<annotation encoding="application / x-tex">J = 3.2< / annotation>< / semantics>< / com:Math> Hz, 2H), 3.25 (s, 3H), <com:Math><semantics>3.21−3.01<annotation encoding="application / x-tex">3.21 - 3.01< / annotation>< / semantics>< / com:Math> (m, 3H), <com:Math><semantics>2.89−2.61<annotation encoding="application / x-tex">2.89 - 2.61< / annotation>< / semantics>< / com:Math> (m, 4H), <com:Math><semantics>2.43−2.12<annotation encoding="application / x-tex">2.43 - 2.12< / annotation>< / semantics>< / com:Math> (m, 6H), <com:Math><semantics>1.95<annotation encoding="application / x-tex">1.95< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=17.2<annotation encoding="application / x-tex">J = 17.2< / annotation>< / semantics>< / com:Math> Hz, 5H), <com:Math><semantics>1.71−<annotation encoding="application / x-tex">1.71 -< / annotation>< / semantics>< / com:Math> 1.43 (m, 9H), 1.23 (s, 4H), 0.94 (d, <com:Math><semantics>J=6.4<annotation encoding="application / x-tex">J = 6.4< / annotation>< / semantics>< / com:Math> Hz, 3H).

[00376] Preparation Example 23: Preparation of Compound PE-21F [Image disponible dans le document PDF, Image available in the PDF document]

[00377] Step 1: Preparation of 6-((tert-butyldimethylsilyl)oxy)hexyl 4-nitrophenyl carbonate

[00378] 6-((tert-butyldimethylsilyl)oxy)hexan-1-ol (232.43 mg, 1 mmol, 1 eq) was dissolved in DMF (3 mL). Then bis(4-nitrophenyl) carbonate (912.63 mg, 608.42 μL, 3 mmol, 3 eq) and DIPEA (387.72 mg, 495.81 μL, 3 mmol, 3 eq) were added. The reaction solution was allowed to react at 35°C for 2 hours. The LCMS showed that a new compound was generated. The reaction solution was diluted with water (50 mL) and extracted with dichloromethane (50 mL × 3). The organic phases were combined, washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluents: <com:Math><semantics>PE / EA=95% / 5%<annotation encoding="application / x-tex">PE / EA = 95\% / 5\%< / annotation>< / semantics>< / com:Math>), to afford 6- ((tert-butyldimethylsilyl)oxy)hexyl 4-nitrophenyl carbonate (370 mg, 93.07% yield) as a yellow oil.

[00379] <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-<com:Math><semantics>d6<annotation encoding="application / x-tex">d_6< / annotation>< / semantics>< / com:Math>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.37-8.24 (m, 2H), 7.54 (dd, <com:Math><semantics>J=9.2<annotation encoding="application / x-tex">J = 9.2< / annotation>< / semantics>< / com:Math>, 1.6 Hz, 2H), 4.23 (t, <com:Math><semantics>J=6.4 Hz,2H,3.56 (t,J=6.4 Hz,2H),1.67 (t,J=7.2 Hz,2H),1.46 (t,J=6.4 Hz,2H),1.34 (dt,J=6.4 Hz,2Hz)<annotation encoding="application / x-tex">J = 6.4 \text{ Hz}, 2\text{H}, 3.56 \text{ (t}, J = 6.4 \text{ Hz}, 2\text{H}), 1.67 \text{ (t}, J = 7.2 \text{ Hz}, 2\text{H}), 1.46 \text{ (t}, J = 6.4 \text{ Hz}, 2\text{H}), 1.34 \text{ (dt}, J = 6.4 \text{ Hz}, 2\text{Hz})< / annotation>< / semantics>< / com:Math> <com:Math><semantics>=8.0,4.8 Hz,4H),0.84 (d,J=1.2 Hz,9H),0.01 (d,J=1.2 Hz,6H).<annotation encoding="application / x-tex">= 8.0, 4.8 \text{ Hz}, 4\text{H}), 0.84 \text{ (d}, J = 1.2 \text{ Hz}, 9\text{H}), 0.01 \text{ (d}, J = 1.2 \text{ Hz}, 6\text{H}).< / annotation>< / semantics>< / com:Math>

[00380] Step 2: Preparation of compound PE-21F-c

[00381] 6-((tert-butyldimethylsilyl)oxy)hexyl 4-nitrophenyl carbonate (9.63 mg, 24.21 µmol, 2 eq) was dissolved in THF (500 μL), the mixture was cooled to 0°C, and then eribulin mesylate (10 mg, 12.11 μmol, 1 eq) and DIPEA (4.69 mg, 6 μL, 36.32 μmol, 3 eq) were added. The reaction solution was allowed to react at 25°C for 16 hours. LCMS analysis showed that the reaction ended. The reaction solution was concentrated to afford the crude product of PE-21F-c (12 mg) as a yellow oil.

[00382] LCMS (ESI): <com:Math><semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>< / com:Math>, 988.7 [M+H]<com:Sup>+< / com:Sup>, Rt = 3.93 min.

[00383] Step 3: Preparation of compound PE-21F

[00384] Compound PE-21F-c (12 mg, 12.14 <com:Math><semantics>μ<annotation encoding="application / x-tex">\mu< / annotation>< / semantics>< / com:Math>mol, 1 eq) was dissolved in DCM (500 <com:Math><semantics>μ<annotation encoding="application / x-tex">\mu< / annotation>< / semantics>< / com:Math>L), the mixture was cooled to 0°C, and then TFA (153.50 mg, 100 μL) was added. The reaction solution was allowed to react at 0°C for 30 minutes. The LCMS analysis showed that the reaction ended. The reaction solution was concentrated, and the residue was purified by preparative high-performance liquid chromatography (preparative chromatograph manufacturer: Shimadzu, model: LC-20AP, column: Welch Xtimate C18 250 <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 40mm <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 10 <com:Math><semantics>μ<annotation encoding="application / x-tex">\mu< / annotation>< / semantics>< / com:Math>m, mobile phase: water (0.225% HCOOH)-acetonitrile, with an elution ratio of acetonitrile increased from 30% to 60%), to afford a white solid PE-21F (2.46 mg, 23.18% yield, 100% purity).

[00385] LCMS (ESI): <com:Math><semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>< / com:Math>, 874.6 [M+H]<com:Sup>+< / com:Sup>, Rt = 2.298 min.

[00386] Preparation Example 24: Preparation of Compound PE-21G [Image disponible dans le document PDF, Image available in the PDF document]

[00387] Step 1: Preparation of 3-((tert-butyldimethylsilyl)oxy)-1-cyclopropylpropan-1-ol

[00388] TBSCl (135.59 mg, 155.85 <com:Math><semantics>μ<annotation encoding="application / x-tex">\mu< / annotation>< / semantics>< / com:Math>L, 899.62 <com:Math><semantics>μ<annotation encoding="application / x-tex">\mu< / annotation>< / semantics>< / com:Math>mol, 1.1 eq) and imidazole (55.68 mg, 50.62 <com:Math><semantics>μ<annotation encoding="application / x-tex">\mu< / annotation>< / semantics>< / com:Math>L, 817.84 µmol, 1 eq) were added to a solution of 1-cyclopropylpropane-1,3-diol (95 mg, 817.84 µmol, 1 eq) in DCM (8 mL) at 0°C. After the addition, the mixture was allowed to react at 25°C for 16 hours. The reaction ended as indicated by NMR. The reaction solution was added into ice-cold aqueous sodium bicarbonate solution (60 mL) and the mixture was then stirred for 2 minutes and extracted with dichloromethane (<com:Math><semantics>60 mL×3<annotation encoding="application / x-tex">60 \text{ mL} \times 3< / annotation>< / semantics>< / com:Math>). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to afford the compound 3-((tert- butyldimethylsilyl)oxy)-1-cyclopropylpropan-1-ol (147 mg, 78.01% yield) as a colorless oil.

[00389] <com:Sup>1< / com:Sup>H NMR (400 MHz, Chloroform-d) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 3.96-3.87 (m, 1H), 3.80 (ddd, <com:Math><semantics>J=10.1,7.0,6.0<annotation encoding="application / x-tex">J = 10.1, 7.0, 6.0< / annotation>< / semantics>< / com:Math> Hz, 1H), 3.11 (dt, <com:Math><semantics>J=8.3<annotation encoding="application / x-tex">J = 8.3< / annotation>< / semantics>< / com:Math>, 5.8 Hz, 1H), 1.85-1.78 (m, 2H), 0.89 (s, 9H), 0.89-0.86 (m, 1H), 0.57-0.41 (m, 2H), <com:Math><semantics>0.41−0.33<annotation encoding="application / x-tex">0.41-0.33< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>0.21−0.13<annotation encoding="application / x-tex">0.21-0.13< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>0.07<annotation encoding="application / x-tex">0.07< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=2.9<annotation encoding="application / x-tex">J = 2.9< / annotation>< / semantics>< / com:Math> Hz, 6H).

[00390] Step 2: Preparation of compound PE-21G-a

[00391] Bis(4-nitrophenyl) carbonate (1.61g, 1.07 mL, 5.28 mmol, 4 eq) and DIPEA (1.02g, 1.31 mL, 7.92 mmol, 6 eq) were added to a solution of 3-((tert-butyldimethylsilyl)oxy)-1-cyclopropyl propan- 1-ol (304 mg, 1.32 mmol, 1 eq) in DMF (10 mL) at 0°C. The reaction solution was allowed to react at 33°C for 2 hours. The LCMS showed that a new compound was generated. The reaction solution was evaporated to dryness, to afford the residue. The residue was purified by silica gel column chromatography (eluents: ethyl acetate / hexane = 1:30 to 1:20) to afford PE-21G-a (257 mg, 49.25% yield) as a pale yellow oil.

[00392] <com:Sup>1< / com:Sup>H NMR (400 MHz, Chloroform-d) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.29-8.26 (m, 2H), 7.41-7.36 (m, 2H), 4.38 (ddd, <com:Math><semantics>J=<annotation encoding="application / x-tex">J =< / annotation>< / semantics>< / com:Math> 9.3, 7.8, 5.1 Hz, 1H), 3.81-3.69 (m, 2H), 2.11-1.92 (m, 2H), 1.18-1.06 (m, 1H), 0.88 (s, 9H), 0.67- <com:Math><semantics>0.55 (m, 3H),0.40−0.31 (m, 1H),0.05 (d, J=1.1 Hz, 6H).<annotation encoding="application / x-tex">0.55 \text{ (m, 3H)}, 0.40-0.31 \text{ (m, 1H)}, 0.05 \text{ (d, } J = 1.1 \text{ Hz, 6H)}.< / annotation>< / semantics>< / com:Math> The structure of the compound was further confirmed by 2D NMR spectroscopy.

[00393] Step 3: Preparation of compound PE-21G-b

[00394] Eribulin mesylate (10 mg, 12.11 μmol, 1 eq), DIPEA (4.69 mg, 6 μL, 36.32 μmol, 3 eq) and HOBt (1.64 mg, 1.09 μL, 12.11 μmol, 1 eq) were added to a solution of compound PE-21G-a (5.57 mg, 14.53 μmol, 2 eq) in DMF (1 mL) at 0°C. The reaction solution was allowed to react at 25°C for 16 hours. The LCMS analysis showed that the reaction ended. The reaction solution was concentrated to afford the crude product PE-21G-b (12 mg, crude) as a yellow oil.

[00395] LCMS (ESI): <com:Math><semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>< / com:Math>, 1008.6 [M+Na]<com:Sup>+< / com:Sup>, Rt = 2.430 min.

[00396] Step 4: Preparation of compound PE-21G

[00397] Triethylamine trihydrofluoride (78.45 mg, 79.33 <com:Math><semantics>μ<annotation encoding="application / x-tex">\mu< / annotation>< / semantics>< / com:Math>L, 486.65 <com:Math><semantics>μ<annotation encoding="application / x-tex">\mu< / annotation>< / semantics>< / com:Math>mol, 40 eq) was added to a solution of compound PE-21G-b (12 mg, 12.17 µmol, 1 eq) in THF (3 mL) at room temperature. The reaction solution was allowed to react at 60°C for 2 hours. The LCMS analysis showed that the reaction ended. The reaction solution was concentrated, and the residue was purified by preparative high-performance liquid chromatography (preparative chromatograph manufacturer: Orienda, model: BRIX-2860, column: Welch Xtimate C18 150 × 30 mm × 10 µm, mobile phase: water (0.225%) HCOOH)-acetonitrile, with an elution ratio of acetonitrile increased from 30% to 60%) and lyophilized, to afford PE-21G (3.77 mg, 35.53% yield, 95% purity) as a white solid.

[00398] LCMS (ESI): <com:Math><semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>< / com:Math>, 894.5 [M+Na]<com:Sup>+< / com:Sup>, Rt = 2.168 min.

[00399] <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-<com:Math><semantics>d6<annotation encoding="application / x-tex">d_6< / annotation>< / semantics>< / com:Math>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 6.86 (t, <com:Math><semantics>J=5.8<annotation encoding="application / x-tex">J = 5.8< / annotation>< / semantics>< / com:Math> Hz, 1H), 5.05 (s, 1H), 4.99 (s, 1H), 4.83 (s, 1H), <com:Math><semantics>4.75<annotation encoding="application / x-tex">4.75< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>4.63<annotation encoding="application / x-tex">4.63< / annotation>< / semantics>< / com:Math> (dt, <com:Math><semantics>J=4.3<annotation encoding="application / x-tex">J = 4.3< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>2.4<annotation encoding="application / x-tex">2.4< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>4.58−4.47<annotation encoding="application / x-tex">4.58-4.47< / annotation>< / semantics>< / com:Math> (m, 2H), <com:Math><semantics>4.39<annotation encoding="application / x-tex">4.39< / annotation>< / semantics>< / com:Math> (td, <com:Math><semantics>J=5.1<annotation encoding="application / x-tex">J = 5.1< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>3.3<annotation encoding="application / x-tex">3.3< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>4.26(d,J=10.9Hz,1H),4.22−4.05(m,5H),4.02(s,1H),3.84−3.65(m,3H),3.59−3.42(m,5H),3.26<annotation encoding="application / x-tex">4.26 (d, J = 10.9 Hz, 1H), 4.22-4.05 (m, 5H), 4.02 (s, 1H), 3.84-3.65 (m, 3H), 3.59-3.42 (m, 5H), 3.26< / annotation>< / semantics>< / com:Math> (s, 4H), <com:Math><semantics>3.01−2.89<annotation encoding="application / x-tex">3.01-2.89< / annotation>< / semantics>< / com:Math> (m, 2H), <com:Math><semantics>2.84<annotation encoding="application / x-tex">2.84< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=9.8<annotation encoding="application / x-tex">J = 9.8< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>2.72<annotation encoding="application / x-tex">2.72< / annotation>< / semantics>< / com:Math> (td, <com:Math><semantics>J=20.0<annotation encoding="application / x-tex">J = 20.0< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>18.2<annotation encoding="application / x-tex">18.2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>8.7<annotation encoding="application / x-tex">8.7< / annotation>< / semantics>< / com:Math> Hz, 2H), <com:Math><semantics>2.61−2.53<annotation encoding="application / x-tex">2.61-2.53< / annotation>< / semantics>< / com:Math> <com:Math><semantics>(m,1H),2.23(tt,J=29.1,12.9Hz,6H),1.96(d,J=34.1Hz,6H),1.81−1.58(m,7H),1.56−1.41(m,1H),2.23(tt,J=29.1,12.9Hz,6H),1.96(d,J=34.1Hz,6H),1.81−1.58(m,7H),1.56−1.41(m,1H),2.23(tt,J=<annotation encoding="application / x-tex">(m, 1H), 2.23 (tt, J = 29.1, 12.9 Hz, 6H), 1.96 (d, J = 34.1 Hz, 6H), 1.81-1.58 (m, 7H), 1.56-1.41 (m, 1H), 2.23 (tt, J = 29.1, 12.9 Hz, 6H), 1.96 (d, J = 34.1 Hz, 6H), 1.81-1.58 (m, 7H), 1.56-1.41 (m, 1H), 2.23 (tt, J =< / annotation>< / semantics>< / com:Math> 3H), 1.38-1.12 (m, 4H), 1.07-0.83 (m, 5H), 0.51-0.34 (m, 2H), 0.34-0.19 (m, 2H).

[00400] Preparation Example 25: Preparation of Compound PE-AL1 [Image disponible dans le document PDF, Image available in the PDF document]

[00401] Step 1: Preparation of compound PE-AL1-a

[00402] Acetic acid (2.76 mg, 99.5%, 2.64 µL, 45.79 µmol, 2 eq) was added to a solution of compound PE-AM1-b (for the synthesis of the compound, refer to the preparation example of PE- AM1) (16 mg, 22.89 μmol, 1 eq) and 3-N-(tert-butoxycarbonyl)aminocyclobutylamine (4.88 mg, 97%, 27.47 µmol, 1.2 eq) in 1,2-dichloroethane (1 mL). After stirring at 25°C for 20 minutes, sodium triacetoxyborohydride (9.90 mg, 98%, 45.79 µmol, 2 eq) was added to the reaction solution, and the mixture was stirred at 25°C for 40 minutes. LCMS analysis indicated the reaction ended. The reaction solution was added to water (20 mL) and extracted with ethyl acetate (10 mL×3). The organic phases were combined and washed with saturated brine (30 mL), anhydrous sodium sulfate was added for drying, and a resulting mixture was evaporated to dryness under reduced pressure to afford the compound PE-AL1-a (26 mg, crude product) as a white solid.

[00403] LCMS (ESI): <com:Math><semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>< / com:Math>, 855.6[M+H]<com:Sup>+< / com:Sup>.

[00404] Step 2: Preparation of compound PE-AL1

[00405] Trifluoroacetic acid (0.2 mL) was added to a solution of compound PE-AL1-a (19.58 mg, 22.90 µmol, 1 eq) in dichloromethane (1 mL) at 0°C. The mixture was stirred at 0°C for 1 hour. LCMS analysis indicated the reaction ended. The reaction solution was concentrated. The residue was then purified by preparative high-performance liquid chromatography (preparative chromatograph manufacturer: Shimadzu, model: LC-20AP, column: YMC-Triart Prep C18 150 × 30 mm × 10 μm, mobile phase: water (0.225% HCOOH)-acetonitrile, with an elution ratio of acetonitrile increased from 30% to 60%) and lyophilized, to afford compound PE-AL1 (0.93 mg, 5.38% yield) as a white solid.

[00406] LCMS (ESI): <com:Math><semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>< / com:Math>, 755.5[M+H]<com:Sup>+< / com:Sup>, 777.5[M+Na]<com:Sup>+< / com:Sup>.

[00407] <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-<com:Math><semantics>d6<annotation encoding="application / x-tex">d_6< / annotation>< / semantics>< / com:Math>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 6.20 (d, <com:Math><semantics>J=3.0<annotation encoding="application / x-tex">J = 3.0< / annotation>< / semantics>< / com:Math> Hz, 1H), 5.95 (d, <com:Math><semantics>J=3.0<annotation encoding="application / x-tex">J = 3.0< / annotation>< / semantics>< / com:Math> Hz, 1H), 4.96- <com:Math><semantics>4.94 (m, 1H),4.87 (s, 1H),4.81 (s, 1H),4.75 (s, 1H),4.34 (d, J=6.1 Hz, 1H),4.30 (d, J=9.6 Hz, 1H)<annotation encoding="application / x-tex">4.94 \text{ (m, 1H)}, 4.87 \text{ (s, 1H)}, 4.81 \text{ (s, 1H)}, 4.75 \text{ (s, 1H)}, 4.34 \text{ (d, } J = 6.1 \text{ Hz, 1H)}, 4.30 \text{ (d, } J = 9.6 \text{ Hz, 1H)}< / annotation>< / semantics>< / com:Math> 1H), <com:Math><semantics>4.10−4.04<annotation encoding="application / x-tex">4.10-4.04< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>4.01<annotation encoding="application / x-tex">4.01< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=2.6<annotation encoding="application / x-tex">J = 2.6< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>3.78<annotation encoding="application / x-tex">3.78< / annotation>< / semantics>< / com:Math> (dd, <com:Math><semantics>J=9.7<annotation encoding="application / x-tex">J = 9.7< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>2.7<annotation encoding="application / x-tex">2.7< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>3.68<annotation encoding="application / x-tex">3.68< / annotation>< / semantics>< / com:Math> (q, <com:Math><semantics>J=4.7<annotation encoding="application / x-tex">J = 4.7< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>3.7<annotation encoding="application / x-tex">3.7< / annotation>< / semantics>< / com:Math> Hz, 3H), 3.59 (dd, <com:Math><semantics>J=9.0<annotation encoding="application / x-tex">J = 9.0< / annotation>< / semantics>< / com:Math>, 4.6 Hz, 3H), 3.54-3.49 (m, 6H), 3.22 (s, 4H), 2.97 (d, <com:Math><semantics>J=7.1<annotation encoding="application / x-tex">J = 7.1< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>2.80−2.74<annotation encoding="application / x-tex">2.80-2.74< / annotation>< / semantics>< / com:Math> (m, 2H), <com:Math><semantics>2.67−2.62<annotation encoding="application / x-tex">2.67-2.62< / annotation>< / semantics>< / com:Math> (m, 3H), <com:Math><semantics>2.58−2.55<annotation encoding="application / x-tex">2.58-2.55< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>2.43<annotation encoding="application / x-tex">2.43< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=9.4<annotation encoding="application / x-tex">J = 9.4< / annotation>< / semantics>< / com:Math> Hz, 3H), <com:Math><semantics>2.32<annotation encoding="application / x-tex">2.32< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=4.6<annotation encoding="application / x-tex">J = 4.6< / annotation>< / semantics>< / com:Math> Hz, 1H), 2.25 (t, <com:Math><semantics>J=6.5<annotation encoding="application / x-tex">J = 6.5< / annotation>< / semantics>< / com:Math> Hz, 1H), 2.14-2.08 (m, 1H), 2.01-1.94 (m, 3H), 1.85 (dd, <com:Math><semantics>J=11.9<annotation encoding="application / x-tex">J = 11.9< / annotation>< / semantics>< / com:Math>, 4.3 Hz, 1H), 1.70 (dd, <com:Math><semantics>J=11.0<annotation encoding="application / x-tex">J = 11.0< / annotation>< / semantics>< / com:Math>, 6.4 Hz, 3H), 1.62 (dd, <com:Math><semantics>J=10.4<annotation encoding="application / x-tex">J = 10.4< / annotation>< / semantics>< / com:Math>, 5.0 Hz, 2H), 1.53 (d, <com:Math><semantics>J=7.1<annotation encoding="application / x-tex">J = 7.1< / annotation>< / semantics>< / com:Math> Hz, 2H), 1.48- 1.40 (m, 3H), 1.34-1.28 (m, 3H), 1.04 (d, <com:Math><semantics>J=6.5<annotation encoding="application / x-tex">J = 6.5< / annotation>< / semantics>< / com:Math> Hz, 3H), 0.97-0.91 (m, 1H), 0.85 (t, <com:Math><semantics>J=6.7<annotation encoding="application / x-tex">J = 6.7< / annotation>< / semantics>< / com:Math> Hz, 1H).

[00408] Preparation Example 26: Preparation of Compound PE-AL2 [Image disponible dans le document PDF, Image available in the PDF document]

[00409] Step 1: Preparation of compound PE-AL2-a

[00410] Acetic acid (2.76 mg, 99.5%, 2.64 <com:Math><semantics>μ<annotation encoding="application / x-tex">\mu< / annotation>< / semantics>< / com:Math>L, 45.79 <com:Math><semantics>μ<annotation encoding="application / x-tex">\mu< / annotation>< / semantics>< / com:Math>mol, 2 eq) was added to a solution of compound PE-AM1-b (for the synthesis of the compound, refer to the preparation example of PE- AM1) (16 mg, 22.89 µmol, 1 eq) and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (4.78 mg, 95%, 22.89 µmol, 1 eq) in 1,2-dichloroethane (1 mL). After stirring at 25°C for 20 minutes, sodium triacetoxyborohydride (9.90 mg, 98%, 45.79 µmol, 2 eq) was added to the reaction solution, and the mixture was stirred at 25°C for 40 minutes. LCMS analysis indicated the reaction ended. The reaction solution was added to water (20 mL) and extracted with ethyl acetate (10 mL×3). The organic phases were combined and washed with saturated brine (30 mL), anhydrous sodium sulfate was added for drying, and a resulting mixture was evaporated to dryness under reduced pressure to afford the compound PE-AL2-a (24 mg, crude product) as a white solid.

[00411] LCMS (ESI): <com:Math><semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>< / com:Math>, 881.6[M+H]<com:Sup>+< / com:Sup>, 903.6[M+Na]<com:Sup>+< / com:Sup>.

[00412] Step 2: Preparation of compound PE-AL2

[00413] Trifluoroacetic acid (0.2 mL) was added to a solution of compound PE-AL2-a (20.17 mg, 22.89 µmol, 1 eq) in dichloromethane (1 mL) at 0°C. The mixture was stirred at 25°C for 1 hour. LCMS analysis indicated the reaction ended. The reaction solution was concentrated. The residue was then purified by preparative high-performance liquid chromatography (preparative chromatograph manufacturer: Shimadzu, model: LC-20AP, column: Welch Xtimate C18 250 × 30mm × 10 μm, mobile phase: water (0.225% HCOOH)-acetonitrile, with an elution ratio of acetonitrile increased from 30% to 60%) and lyophilized, to afford compound PE-AL2 (2.32 mg, 12.98% yield) as a white solid.

[00414] LCMS (ESI): <com:Math><semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>< / com:Math>, 781.4[M+H]<com:Sup>+< / com:Sup>, 803.4[M+Na]<com:Sup>+< / com:Sup>.

[00415] <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-<com:Math><semantics>d6<annotation encoding="application / x-tex">d_6< / annotation>< / semantics>< / com:Math>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 6.20 (d, <com:Math><semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics>< / com:Math> = 3.0 Hz, 1H), 5.95 (d, <com:Math><semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics>< / com:Math> = 3.0 Hz, 1H), 4.95 (d, <com:Math><semantics>J=2.1 Hz<annotation encoding="application / x-tex">J = 2.1 \text{ Hz}< / annotation>< / semantics>< / com:Math>, 1H), 4.88-4.85 (m, 1H), 4.80 (s, 1H), 4.75 (s, 1H), 4.34 (d, <com:Math><semantics>J=6.3 Hz<annotation encoding="application / x-tex">J = 6.3 \text{ Hz}< / annotation>< / semantics>< / com:Math>, 1H), 4.29 (d, <com:Math><semantics>J=6.3 Hz<annotation encoding="application / x-tex">J = 6.3 \text{ Hz}< / annotation>< / semantics>< / com:Math>, 1H), 4.80 (s, 1H), 4.75 (s, 1H), 4.84 (d, <com:Math><semantics>J=6.3 Hz<annotation encoding="application / x-tex">J = 6.3 \text{ Hz}< / annotation>< / semantics>< / com:Math>, 1H), 4.29 (d, <com:Math><semantics>J=6.3 Hz<annotation encoding="application / x-tex">J = 6.3 \text{ Hz}< / annotation>< / semantics>< / com:Math>, 9.7 Hz, 1H), <com:Math><semantics>4.06<annotation encoding="application / x-tex">4.06< / annotation>< / semantics>< / com:Math> (t, <com:Math><semantics>J=6.6<annotation encoding="application / x-tex">J = 6.6< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>4.00<annotation encoding="application / x-tex">4.00< / annotation>< / semantics>< / com:Math> (t, <com:Math><semantics>J=2.5<annotation encoding="application / x-tex">J = 2.5< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>3.87<annotation encoding="application / x-tex">3.87< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=9.7<annotation encoding="application / x-tex">J = 9.7< / annotation>< / semantics>< / com:Math> Hz, 4H), <com:Math><semantics>3.78<annotation encoding="application / x-tex">3.78< / annotation>< / semantics>< / com:Math> (dd, <com:Math><semantics>J=<annotation encoding="application / x-tex">J =< / annotation>< / semantics>< / com:Math> 9.7, 2.7 Hz, 1H), 3.68 (dd, <com:Math><semantics>J=9.8<annotation encoding="application / x-tex">J = 9.8< / annotation>< / semantics>< / com:Math>, 5.9 Hz, 4H), 3.57 (dt, <com:Math><semantics>J=9.3<annotation encoding="application / x-tex">J = 9.3< / annotation>< / semantics>< / com:Math>, 5.0 Hz, 6H), 3.21 (s, 5H), 3.00-2.95 <com:Math><semantics>(m,2H),2.80−2.73(m,2H),2.66(dt,J=6.8,1.9Hz,1H),2.63−2.57(m,2H),2.56−2.54(m,1H),2.44<annotation encoding="application / x-tex">(m, 2H), 2.80-2.73 (m, 2H), 2.66 (dt, J = 6.8, 1.9 Hz, 1H), 2.63-2.57 (m, 2H), 2.56-2.54 (m, 1H), 2.44< / annotation>< / semantics>< / com:Math> <com:Math><semantics>(d,J=3.4 Hz,1H),2.33 (ddd,J=7.8,5.6,3.7 Hz,3H),2.24 (t,J=7.6 Hz,1H),2.14−2.08 (m, 1H),<annotation encoding="application / x-tex">(d, J = 3.4 \text{ Hz}, 1\text{H}), 2.33 \text{ (ddd}, J = 7.8, 5.6, 3.7 \text{ Hz}, 3\text{H}), 2.24 \text{ (t}, J = 7.6 \text{ Hz}, 1\text{H}), 2.14-2.08 \text{ (m, 1H)},< / annotation>< / semantics>< / com:Math> <com:Math><semantics>1.97−1.90 (m, 2H),1.85 (dd, J=12.0,3.9 Hz, 1H),1.71 (ddd, J=14.0,10.3,6.5 Hz, 4H),1.65−1.57<annotation encoding="application / x-tex">1.97-1.90 \text{ (m, 2H)}, 1.85 \text{ (dd, } J = 12.0, 3.9 \text{ Hz, 1H)}, 1.71 \text{ (ddd, } J = 14.0, 10.3, 6.5 \text{ Hz, 4H)}, 1.65-1.57< / annotation>< / semantics>< / com:Math> <com:Math><semantics>(m,3H),1.52−1.47(m,2H),1.45−1.39(m,2H),1.34−1.27(m,2H),1.04(d,<math>J=6.5Hz,3H),0.98−1.04(d,J=6.5Hz,3H)<annotation encoding="application / x-tex">(m, 3H), 1.52-1.47 (m, 2H), 1.45-1.39 (m, 2H), 1.34-1.27 (m, 2H), 1.04 (d, J = 6.5 Hz, 3H), 0.98-1.04 (d, J = 6.5 Hz, 3H)< / annotation>< / semantics>< / com:Math> 0.90 (m, 1H).

[00416] Preparation Example 27: Preparation of Compound PE-AL2H5 253128-27-7 1299493-24-5 [Image disponible dans le document PDF, Image available in the PDF document]

[00417] Acetic acid (2.76 mg, 99.5%, 2.64 µL, 45.79 µmol, 2 eq) was added to a solution of compound PE-AM1-b (for the synthesis of the compound, refer to the preparation example of PE- AM1) (16 mg, 22.89 μmol, 1 eq) and ammonia solution (3.85 mg, 25%, 27.47 μmol, 1.2 eq) in 1,2- dichloroethane (1 mL). After stirring at 25°C for 20 minutes, sodium triacetoxyborohydride (9.90 mg, 98%, 45.79 µmol, 2 eq) was added to the reaction solution, and the mixture was stirred at 25°C for 40 minutes. LCMS analysis indicated the reaction ended. The reaction solution was concentrated. The residue was then purified by preparative high-performance liquid chromatography (preparative chromatograph manufacturer: Shimadzu, model: LC-20AP, column: Welch Xtimate C18 250 × 30mm × 10 μm, mobile phase: water (0.225% HCOOH)-acetonitrile, with an elution ratio of acetonitrile increased from 30% to 60%) and lyophilized, to afford compound PE-AL2H5 (0.42 mg, 2.62% yield) as a white solid.

[00418] LCMS (ESI): <com:Math><semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>< / com:Math>, 700.2[M+H]<com:Sup>+< / com:Sup>, 722.2[M+Na]<com:Sup>+< / com:Sup>.

[00419] <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-d6) δ 5.06 (s, 1H), 4.98 (s, 1H), 4.83 (s, 1H), 4.76 (s, 1H), 4.63 <com:Math><semantics>(dt,J=4.6,2.4Hz,1H),4.55(t,J=4.2Hz,1H),4.26(d,J=10.8Hz,1H),4.18(dd,J=10.5,4.0)<annotation encoding="application / x-tex">(dt, J = 4.6, 2.4 Hz, 1H), 4.55 (t, J = 4.2 Hz, 1H), 4.26 (d, J = 10.8 Hz, 1H), 4.18 (dd, J = 10.5, 4.0)< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>4.10<annotation encoding="application / x-tex">4.10< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=4.8<annotation encoding="application / x-tex">J = 4.8< / annotation>< / semantics>< / com:Math> Hz, 3H), <com:Math><semantics>4.02<annotation encoding="application / x-tex">4.02< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>3.80<annotation encoding="application / x-tex">3.80< / annotation>< / semantics>< / com:Math> (t, <com:Math><semantics>J=10.1<annotation encoding="application / x-tex">J = 10.1< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>3.74−3.67<annotation encoding="application / x-tex">3.74-3.67< / annotation>< / semantics>< / com:Math> (m, 2H), <com:Math><semantics>3.48<annotation encoding="application / x-tex">3.48< / annotation>< / semantics>< / com:Math> (s, 5H), <com:Math><semantics>3.27<annotation encoding="application / x-tex">3.27< / annotation>< / semantics>< / com:Math> (s, <com:Math><semantics>2H<annotation encoding="application / x-tex">2H< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>3.26<annotation encoding="application / x-tex">3.26< / annotation>< / semantics>< / com:Math> (s, <com:Math><semantics>1H<annotation encoding="application / x-tex">1H< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>2.84<annotation encoding="application / x-tex">2.84< / annotation>< / semantics>< / com:Math> (dd, <com:Math><semantics>J=9.5<annotation encoding="application / x-tex">J = 9.5< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>1.9<annotation encoding="application / x-tex">1.9< / annotation>< / semantics>< / com:Math> Hz, <com:Math><semantics>1H<annotation encoding="application / x-tex">1H< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>2.74<annotation encoding="application / x-tex">2.74< / annotation>< / semantics>< / com:Math> (q, <com:Math><semantics>J=7.8<annotation encoding="application / x-tex">J = 7.8< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>6.9<annotation encoding="application / x-tex">6.9< / annotation>< / semantics>< / com:Math> Hz, <com:Math><semantics>2H<annotation encoding="application / x-tex">2H< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>2.67<annotation encoding="application / x-tex">2.67< / annotation>< / semantics>< / com:Math> (h, <com:Math><semantics>J=9.5<annotation encoding="application / x-tex">J = 9.5< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>2.67<annotation encoding="application / x-tex">2.67< / annotation>< / semantics>< / com:Math> (h, <com:Math><semantics>3.27<annotation encoding="application / x-tex">3.27< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>3.26<annotation encoding="application / x-tex">3.26< / annotation>< / semantics>< / com:Math> (s, <com:Math><semantics>3.27<annotation encoding="application / x-tex">3.27< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>3.26<annotation encoding="application / x-tex">3.26< / annotation>< / semantics>< / com:Math> (s, <com:Math><semantics>3.27<annotation encoding="application / x-tex">3.27< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>3.26<annotation encoding="application / x-tex">3.26< / annotation>< / semantics>< / com:Math> (s, <com:Math><semantics>3.27<annotation encoding="application / x-tex">3.27< / annotation>< / semantics>< / com:Math>) <com:Math><semantics>=2.3,1.9 Hz,1H),2.60−2.54 (m, 1H),2.36−2.06 (m, 6H),2.04−1.97 (m, 1H),1.96−1.87 (m, 3H),1.86−1.87 (m, 2H)<annotation encoding="application / x-tex">= 2.3, 1.9 \text{ Hz}, 1\text{H}), 2.60-2.54 \text{ (m, 1H)}, 2.36-2.06 \text{ (m, 6H)}, 2.04-1.97 \text{ (m, 1H)}, 1.96-1.87 \text{ (m, 3H)}, 1.86-1.87 \text{ (m, 2H)}< / annotation>< / semantics>< / com:Math> <com:Math><semantics>1.76 (m, 1H),1.76−1.61 (m, 4H),1.56−1.43 (m, 2H),1.33 (dd, J=29.9,18.2 Hz, 3H),1.23 (s, 2H),<annotation encoding="application / x-tex">1.76 \text{ (m, 1H)}, 1.76-1.61 \text{ (m, 4H)}, 1.56-1.43 \text{ (m, 2H)}, 1.33 \text{ (dd, } J = 29.9, 18.2 \text{ Hz, 3H)}, 1.23 \text{ (s, 2H)},< / annotation>< / semantics>< / com:Math> <com:Math><semantics>1.22−1.05<annotation encoding="application / x-tex">1.22-1.05< / annotation>< / semantics>< / com:Math> (m, 2H), <com:Math><semantics>1.03<annotation encoding="application / x-tex">1.03< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=6.5<annotation encoding="application / x-tex">J = 6.5< / annotation>< / semantics>< / com:Math> Hz, 2H), <com:Math><semantics>1.00−0.93<annotation encoding="application / x-tex">1.00-0.93< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>0.89−0.80<annotation encoding="application / x-tex">0.89-0.80< / annotation>< / semantics>< / com:Math> (m, 2H).

[00420] Preparation Example 28: Preparation of Compound PE-AL3 [Image disponible dans le document PDF, Image available in the PDF document]

[00421] Step 1: Preparation of compound PE-AL3-a

[00422] Acetic acid (2.76 mg, 45.79 µmol, 2 eq) was added to a solution of compound PE-AM1-b (16 mg, crude; for the synthesis of the compound, refer to the preparation example of PE-AM1) and tert-butyl N-2-azaspiro[3.3]hept-6-ylcarbamate (5.01 mg, 22.89 µmol, 1 eq) in DCE (1,2-dichloro ethane, 1 mL). The reaction solution was stirred at room temperature for 20 minutes. Sodium triacetoxyborohydride (9.90 mg, 45.79 µmol, 2 eq) was added to the reaction solution, and the reaction solution was stirred at room temperature for 40 minutes. LCMS analysis showed that the reaction ended. DCM (10 mL) and water (20 mL) were added to the mixture. The mixture was extracted with DCM (20 mL × 3). The organic phases were combined and washed with saturated brine (10 mL), dried over anhydrous Na<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub>, filtered, and evaporated to dryness, to afford the product PE-AL3-a (20.59 mg, where the yield was not calculated for the crude product) as a colorless oil. LCMS (ESI): <com:Math><semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>< / com:Math>, 895.6[M+H]<com:Sup>+< / com:Sup>.

[00423] Step 2: Preparation of compound PE-AL3

[00424] TFA (0.4 mL) was added to a solution of compound PE-AL3-a (20.49 mg, crude) in DCM (2 mL) at 0°C. The reaction solution was stirred at room temperature for half an hour. LCMS analysis showed complete consumption of the starting material. The mixture was evaporated to dryness under reduced pressure. The mixture was purified by preparative high-performance liquid chromatography (preparative chromatograph manufacturer: Orienda, model: BRIX-2860-R6, column: Welch Xtimate C18 250 <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 30 mm <com:Math><semantics>×<annotation encoding="application / x-tex">\times< / annotation>< / semantics>< / com:Math> 10 <com:Math><semantics>μ<annotation encoding="application / x-tex">\mu< / annotation>< / semantics>< / com:Math>m, mobile phase: water (0.225% HCOOH)- acetonitrile, with an elution ratio of acetonitrile increased from 20% to 50%), to obtain PE-AL3 (2.70 mg, 12.37% yield) as a white solid. LCMS (ESI): <com:Math><semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>< / com:Math>, 795.6[M+H]<com:Sup>+< / com:Sup>.

[00425] <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-<com:Math><semantics>d6<annotation encoding="application / x-tex">d_6< / annotation>< / semantics>< / com:Math>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.33 (s, 2H), 6.20 (d, <com:Math><semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics>< / com:Math> = 3.2 Hz, 1H), 5.95 (d, <com:Math><semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics>< / com:Math> = 3.2 Hz, 1H), <com:Math><semantics>4.95<annotation encoding="application / x-tex">4.95< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>4.89−4.72<annotation encoding="application / x-tex">4.89-4.72< / annotation>< / semantics>< / com:Math> (m, 4H), <com:Math><semantics>4.34<annotation encoding="application / x-tex">4.34< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=6.4<annotation encoding="application / x-tex">J = 6.4< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>4.29<annotation encoding="application / x-tex">4.29< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=9.6<annotation encoding="application / x-tex">J = 9.6< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>4.11−3.94<annotation encoding="application / x-tex">4.11-3.94< / annotation>< / semantics>< / com:Math> (m, 4H), <com:Math><semantics>3.80−3.75<annotation encoding="application / x-tex">3.80-3.75< / annotation>< / semantics>< / com:Math> (m, 3H), <com:Math><semantics>3.70<annotation encoding="application / x-tex">3.70< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=4.0<annotation encoding="application / x-tex">J = 4.0< / annotation>< / semantics>< / com:Math> Hz, 3H), <com:Math><semantics>3.33<annotation encoding="application / x-tex">3.33< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=3.6<annotation encoding="application / x-tex">J = 3.6< / annotation>< / semantics>< / com:Math> Hz, 3H), <com:Math><semantics>3.21<annotation encoding="application / x-tex">3.21< / annotation>< / semantics>< / com:Math> (s, 2H), <com:Math><semantics>3.18<annotation encoding="application / x-tex">3.18< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>3.16−3.11<annotation encoding="application / x-tex">3.16-3.11< / annotation>< / semantics>< / com:Math> (m, 3H), <com:Math><semantics>3.04<annotation encoding="application / x-tex">3.04< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=9.2<annotation encoding="application / x-tex">J = 9.2< / annotation>< / semantics>< / com:Math> Hz, 2H), <com:Math><semantics>2.99−2.92<annotation encoding="application / x-tex">2.99-2.92< / annotation>< / semantics>< / com:Math> (m, 2H), <com:Math><semantics>2.80−2.72<annotation encoding="application / x-tex">2.80-2.72< / annotation>< / semantics>< / com:Math> (m, 2H), <com:Math><semantics>2.69−2.58<annotation encoding="application / x-tex">2.69-2.58< / annotation>< / semantics>< / com:Math> (m, 3H), 2.39-2.27 (m, 6H), 2.15-2.06 (m, 2H), 1.97-1.81 (m, 4H), 1.75-1.54 (m, 7H), 1.52-1.39 (m, 4H), 1.35- <com:Math><semantics>1.27 (m, 2H),1.04 (d, J=6.4 Hz, 2H),1.01-0.88 (m, 2H).<annotation encoding="application / x-tex">1.27 \text{ (m, 2H)}, 1.04 \text{ (d, } J = 6.4 \text{ Hz, 2H)}, 1.01 \text{-} 0.88 \text{ (m, 2H)}.< / annotation>< / semantics>< / com:Math>

[00426] Preparation Example 29: Preparation of Compound PE-AL4 [Image disponible dans le document PDF, Image available in the PDF document]

[00427] Acetic acid (2.76 mg, 99.5%, 2.64 µL, 45.79 µmol, 2 eq) was added to a solution of compound PE-AM1-b (for the synthesis of the compound, refer to the preparation example of PE- AM1) (16 mg, 22.89 µmol, 1 eq) and 3-(hydroxymethyl)azetidine hydrochloride (3.50 mg, 97%, 27.47 µmol, 1.2 eq) in 1,2-dichloroethane (1 mL). After stirring at 25°C for 20 minutes, sodium triacetoxyborohydride (9.90 mg, 98%, 45.79 µmol, 2 eq) was added to the reaction solution, and the mixture was stirred at 25°C for 40 minutes. LCMS analysis indicated the reaction ended. The reaction solution was added to water (20 mL) and extracted with ethyl acetate (10 mL×3). The organic phases were combined and washed with saturated brine (30 mL), anhydrous sodium sulfate was added for drying, and a resulting mixture was evaporated to dryness under reduced pressure to afford the crude product. The crude product was purified by preparative high-performance liquid chromatography (preparative chromatograph manufacturer: Shimadzu, model: LC-20AP, column: Synergi Max-RP <com:Math><semantics>200×30mm×10μm<annotation encoding="application / x-tex">200 \times 30 \text{mm} \times 10 \mu \text{m}< / annotation>< / semantics>< / com:Math>, mobile phase: water (0.225% HCOOH)-acetonitrile, with an elution ratio of acetonitrile increased from 20% to 50%) and lyophilized, to afford compound PE-AL4 (0.59 mg, 3.35% yield) as a white solid.

[00428] LCMS (ESI): <com:Math><semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>< / com:Math>, 770.5[M+H]<com:Sup>+< / com:Sup>.

[00429] <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-<com:Math><semantics>d6<annotation encoding="application / x-tex">d_6< / annotation>< / semantics>< / com:Math>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 5.03 (dd, <com:Math><semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics>< / com:Math> = 18.1, 2.4 Hz, 2H), 4.83 (s, 1H), 4.75 (d, <com:Math><semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics>< / com:Math> = 1.7 Hz, 1H), 4.63 (dt, <com:Math><semantics>J=4.4<annotation encoding="application / x-tex">J = 4.4< / annotation>< / semantics>< / com:Math>, 2.5 Hz, 1H), 4.55 (t, <com:Math><semantics>J=4.3<annotation encoding="application / x-tex">J = 4.3< / annotation>< / semantics>< / com:Math> Hz, 1H), 4.26 (d, <com:Math><semantics>J=10.8<annotation encoding="application / x-tex">J = 10.8< / annotation>< / semantics>< / com:Math> Hz, 1H), 4.17 <com:Math><semantics>(td,J=10.3,4.2 Hz,1H),4.10(t,J=3.1 Hz,2H),4.03(d,J=10.3 Hz,1H),3.80(t,J=10.4 Hz,1H)<annotation encoding="application / x-tex">(td, J = 10.3, 4.2 \text{ Hz}, 1H), 4.10 (t, J = 3.1 \text{ Hz}, 2H), 4.03 (d, J = 10.3 \text{ Hz}, 1H), 3.80 (t, J = 10.4 \text{ Hz}, 1H)< / annotation>< / semantics>< / com:Math> 1H), 3.67 (td, <com:Math><semantics>J=6.6<annotation encoding="application / x-tex">J = 6.6< / annotation>< / semantics>< / com:Math>, 2.7 Hz, 1H), 3.61 (td, <com:Math><semantics>J=6.7<annotation encoding="application / x-tex">J = 6.7< / annotation>< / semantics>< / com:Math>, 3.3 Hz, 1H), 3.55-3.49 (m, 2H), 3.45 (d, <com:Math><semantics>J=6.7<annotation encoding="application / x-tex">J = 6.7< / annotation>< / semantics>< / com:Math> Hz, 2H), 3.26 (s, 3H), 3.22 (d, <com:Math><semantics>J=3.5<annotation encoding="application / x-tex">J = 3.5< / annotation>< / semantics>< / com:Math> Hz, 1H), 3.15 (s, 2H), 2.85-2.76 (m, 3H), 2.75-2.65 (m, 2H), <com:Math><semantics>2.60−2.52<annotation encoding="application / x-tex">2.60-2.52< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>2.42<annotation encoding="application / x-tex">2.42< / annotation>< / semantics>< / com:Math> (q, <com:Math><semantics>J=6.8<annotation encoding="application / x-tex">J = 6.8< / annotation>< / semantics>< / com:Math> Hz, 2H), <com:Math><semantics>2.35−2.31<annotation encoding="application / x-tex">2.35-2.31< / annotation>< / semantics>< / com:Math> (m, 3H), <com:Math><semantics>2.27−2.22<annotation encoding="application / x-tex">2.27-2.22< / annotation>< / semantics>< / com:Math> (m, 2H), <com:Math><semantics>2.19−2.09<annotation encoding="application / x-tex">2.19-2.09< / annotation>< / semantics>< / com:Math> (m, 2H), <com:Math><semantics>2.04−1.97<annotation encoding="application / x-tex">2.04-1.97< / annotation>< / semantics>< / com:Math> (m, 2H), <com:Math><semantics>1.92<annotation encoding="application / x-tex">1.92< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=2.9<annotation encoding="application / x-tex">J = 2.9< / annotation>< / semantics>< / com:Math> Hz, 3H), <com:Math><semantics>1.70−1.62<annotation encoding="application / x-tex">1.70-1.62< / annotation>< / semantics>< / com:Math> (m, 3H), <com:Math><semantics>1.54−1.44<annotation encoding="application / x-tex">1.54-1.44< / annotation>< / semantics>< / com:Math> (m, 4H), <com:Math><semantics>1.35−1.27<annotation encoding="application / x-tex">1.35-1.27< / annotation>< / semantics>< / com:Math> (m, 3H), 1.24 (d, <com:Math><semantics>J=3.3<annotation encoding="application / x-tex">J = 3.3< / annotation>< / semantics>< / com:Math> Hz, 3H), 1.20-1.13 (m, 1H), 1.03 (d, <com:Math><semantics>J=6.5<annotation encoding="application / x-tex">J = 6.5< / annotation>< / semantics>< / com:Math> Hz, 3H), 1.00-0.93 (m, 1H), 0.85 (t, <com:Math><semantics>J=3.3<annotation encoding="application / x-tex">J = 3.3< / annotation>< / semantics>< / com:Math> Hz, 3H), 1.00-0.93 (m, 1H), 0.85 (t, <com:Math><semantics>J=3.3<annotation encoding="application / x-tex">J = 3.3< / annotation>< / semantics>< / com:Math> Hz, 3H), 1.00-0.93 (m, 1H), 0.85 (t, <com:Math><semantics>J=3.3<annotation encoding="application / x-tex">J = 3.3< / annotation>< / semantics>< / com:Math> Hz, 3H), 1.00- 6.7 Hz, 1H).

[00430] Preparation Example 30: Preparation of Compound PE-AL5 [Image disponible dans le document PDF, Image available in the PDF document]

[00431] Acetic acid (2.76 mg, 99.5%, 2.64 µL, 45.79 µmol, 2 eq) was added to a solution of compound PE-AM1-b (for the synthesis of the compound, refer to the preparation example of PE- AM1) (16 mg, 22.89 μmol, 1 eq) and 5-(methylamino)pentan-1-ol (3.39 mg, 95%, 27.47 μmol, 1.2 eq) in 1,2-dichloroethane (1 mL). After stirring at 25°C for 20 minutes, sodium triacetoxy borohydride (9.90 mg, 98%, 45.79 µmol, 2 eq) was added to the reaction solution, and the mixture was stirred at 25°C for 40 minutes. LCMS analysis indicated the reaction ended. The reaction solution was concentrated. The residue was then purified by preparative high-performance liquid chromatography (preparative chromatograph manufacturer: Shimadzu, model: LC-20AP, column: Synergi Max-RP 200 × 30mm × 10 μm, mobile phase: water (0.225% HCOOH)-acetonitrile, with an elution ratio of acetonitrile increased from 20% to 50%) and lyophilized, to afford compound PE- AL5 (5.02 mg, 26.86% yield) as a white solid.

[00432] LCMS (ESI): <com:Math><semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>800.5[M+H]+<annotation encoding="application / x-tex">800.5[M+H]^+< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>822.5[M+Na]+<annotation encoding="application / x-tex">822.5[M+Na]^+< / annotation>< / semantics>< / com:Math>.

[00433] <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-<com:Math><semantics>d6<annotation encoding="application / x-tex">d_6< / annotation>< / semantics>< / com:Math>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 5.02 (d, <com:Math><semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics>< / com:Math> = 23.5 Hz, 2H), 4.83 (d, <com:Math><semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics>< / com:Math> = 6.3 Hz, 1H), 4.75 (s, 1H), <com:Math><semantics>4.66−4.61<annotation encoding="application / x-tex">4.66-4.61< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>4.55<annotation encoding="application / x-tex">4.55< / annotation>< / semantics>< / com:Math> (t, <com:Math><semantics>J=4.2<annotation encoding="application / x-tex">J = 4.2< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>4.26<annotation encoding="application / x-tex">4.26< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=10.5<annotation encoding="application / x-tex">J = 10.5< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>4.17<annotation encoding="application / x-tex">4.17< / annotation>< / semantics>< / com:Math> (td, <com:Math><semantics>J=10.3<annotation encoding="application / x-tex">J = 10.3< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>4.1<annotation encoding="application / x-tex">4.1< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>4.10<annotation encoding="application / x-tex">4.10< / annotation>< / semantics>< / com:Math> (q, <com:Math><semantics>J=4.2<annotation encoding="application / x-tex">J = 4.2< / annotation>< / semantics>< / com:Math> Hz, 3H), <com:Math><semantics>4.03<annotation encoding="application / x-tex">4.03< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>3.80<annotation encoding="application / x-tex">3.80< / annotation>< / semantics>< / com:Math> (t, <com:Math><semantics>J=10.8<annotation encoding="application / x-tex">J = 10.8< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>3.67<annotation encoding="application / x-tex">3.67< / annotation>< / semantics>< / com:Math> (t, <com:Math><semantics>J=7.5<annotation encoding="application / x-tex">J = 7.5< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>3.64−3.59<annotation encoding="application / x-tex">3.64-3.59< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>3.55−3.47<annotation encoding="application / x-tex">3.55-3.47< / annotation>< / semantics>< / com:Math> (m, 3H), <com:Math><semantics>3.27<annotation encoding="application / x-tex">3.27< / annotation>< / semantics>< / com:Math> (s, 4H), <com:Math><semantics>3.24−3.22<annotation encoding="application / x-tex">3.24-3.22< / annotation>< / semantics>< / com:Math> (m, 2H), <com:Math><semantics>3.19<annotation encoding="application / x-tex">3.19< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>2.84<annotation encoding="application / x-tex">2.84< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=9.6<annotation encoding="application / x-tex">J=9.6< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>2.78−2.67<annotation encoding="application / x-tex">2.78-2.67< / annotation>< / semantics>< / com:Math> (m, 2H), <com:Math><semantics>2.60−2.54<annotation encoding="application / x-tex">2.60-2.54< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Mat...

Claims

What is claimed is:

1. An eribulin derivative, which is a compound of formula (I) or (II), or an isotope-labeled compound, an optical isomer, a geometric isomer, a tautomer, an isomer mixture, or a pharmaceutically acceptable salt thereof; [Image disponible dans le document PDF, Image available in the PDF document] wherein: <com:Math><semantics>A1 in formula (I) is selected from X3→X2X1→N1,X3→X2X1→N1,X3→X2X1→N1,X3→N1,X1→N1,X2→N1,X3→N1,X2→N1,X3→N1,X3→N1<annotation encoding="application / x-tex">A_1 \text{ in formula (I) is selected from } X_3 \xrightarrow{X_2} X_1 \xrightarrow{N_1} , \ X_3 \xrightarrow{X_2} X_1 \xrightarrow{N_1} , \ X_3 \xrightarrow{X_2} X_1 \xrightarrow{N_1} , \ X_3 \xrightarrow{N_1} , \ X_1 \xrightarrow{N_1} , \ X_2 \xrightarrow{N_1} , \ X_3 \xrightarrow{N_1} , \ X_2 \xrightarrow{N_1} , \ X_3 \xrightarrow{N_1} , \ X_3 \xrightarrow{N_1}< / annotation>< / semantics>< / com:Math> [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] A<com:Sub>2< / com:Sub> in formula (II) is selected from , [Image disponible dans le document PDF, Image available in the PDF document] ; each of ___ marked by * and ** is independently a single bond, a double bond, or an oxo bond (=O), and at least one of ____ is not a double bond; R<com:Sub>1< / com:Sub> is selected from H, an alkyl group, a hydroxyl-substituted alkyl group, an alkyloxy- substituted alkyl group, an amino-substituted alkyl group, a haloalkyl group or a cyano-substituted alkyl group;p <com:Math><semantics>X1<annotation encoding="application / x-tex">X_1< / annotation>< / semantics>< / com:Math> is selected from CO-, -CH<com:Sub>2< / com:Sub>, -S(O)-, or -S(O)<com:Sub>2< / com:Sub>-; <com:Math><semantics>X2<annotation encoding="application / x-tex">X_2< / annotation>< / semantics>< / com:Math> is selected from the direct bond, -O-, or -NR<com:Sub>1< / com:Sub>-; <com:Math><semantics>X3<annotation encoding="application / x-tex">X_3< / annotation>< / semantics>< / com:Math> is selected from -(CR<com:Sub>2< / com:Sub>R<com:Sub>3< / com:Sub>)<com:Sub>m1< / com:Sub>-NH<com:Sub>2< / com:Sub>, -(CR<com:Sub>2< / com:Sub>R<com:Sub>3< / com:Sub>)<com:Sub>m1< / com:Sub>-OH, -R<com:Sub>4< / com:Sub>-(CR<com:Sub>2< / com:Sub>R<com:Sub>3< / com:Sub>)<com:Sub>m2< / com:Sub>-NH<com:Sub>2< / com:Sub>, -R<com:Sub>4< / com:Sub>-(CR<com:Sub>2< / com:Sub>R<com:Sub>3< / com:Sub>)<com:Sub>m2< / com:Sub>-OH, [Image disponible dans le document PDF, Image available in the PDF document] or <com:Math><semantics>Y1<annotation encoding="application / x-tex">Y_1< / annotation>< / semantics>< / com:Math> is selected from -<com:Math><semantics>(CR2R3)m1<annotation encoding="application / x-tex">(CR_2R_3)_{m1}< / annotation>< / semantics>< / com:Math>-NH<com:Sub>2< / com:Sub>, -<com:Math><semantics>(CR2R3)m1<annotation encoding="application / x-tex">(CR_2R_3)_{m1}< / annotation>< / semantics>< / com:Math>-OH, -R<com:Sub>4< / com:Sub>-<com:Math><semantics>(CR2R3)m2<annotation encoding="application / x-tex">(CR_2R_3)_{m2}< / annotation>< / semantics>< / com:Math>-NH<com:Sub>2< / com:Sub>, -R<com:Sub>4< / com:Sub>-<com:Math><semantics>(CR2R3)m2<annotation encoding="application / x-tex">(CR_2R_3)_{m2}< / annotation>< / semantics>< / com:Math>-OH, [Image disponible dans le document PDF, Image available in the PDF document] or R<com:Sub>2< / com:Sub> and R<com:Sub>3< / com:Sub> are each independently selected from H, an alkyl group, a hydroxyl group, an alkyloxy group, an amino group, halogen, a cyano group, a hydroxyl-substituted alkyl group, an alkyloxy- substituted alkyl group, an amino-substituted alkyl group, a haloalkyl group, a cyano- substituted alkyl group, an alkyl group substituted by a substituted or unsubstituted carbon ring, an alkyl group substituted by a substituted or unsubstituted heterocyclic substituent, a substituted or unsubstituted carbon ring group or a substituted or unsubstituted heterocyclic group; and the substituted or unsubstituted carbon ring group and the substituted or unsubstituted heterocyclic group are optionally substituted by one or more substituents selected from an oxo group, an alkyl group, a hydroxyl group, an alkyloxy group, an amino group, halogen, a cyano group, a hydroxyl- substituted alkyl group, an alkyloxy-substituted alkyl group, an amino-substituted alkyl group, a haloalkyl group, and a cyano- substituted alkyl group; R<com:Sub>4< / com:Sub> is selected from a substituted or unsubstituted carbon ring group or a substituted or unsubstituted heterocyclic group; and the substituted or unsubstituted carbon ring group and the substituted or unsubstituted heterocyclic group are optionally substituted by one or more substituents selected from an oxo group, an alkyl group, a hydroxyl group, an alkyloxy group, an amino group, halogen, a cyano group, a hydroxyl-substituted alkyl group, an alkyloxy-substituted alkyl group, an amino-substituted alkyl group, a haloalkyl group, and a cyano-substituted alkyl group; (B) ring is a substituted or unsubstituted heterocyclic group; and a ring of the heterocyclic group contains at least one -NH-, and the substitution refers to substitution with one or more substituents selected from an oxo group, an alkyl group, an alkyloxy group, halogen, a cyano group, an alkyloxy- substituted alkyl group, a haloalkyl group, and a cyano-substituted alkyl group; A ring is the heterocyclic group; and a ring of the heterocyclic group contains at least one - NH-, and / or the heterocyclic group is substituted by an amino group, a hydroxyl group, an amino- substituted alkyl group, or a hydroxyl-substituted alkyl group, and the heterocyclic group is optionally substituted by one or more substituents selected from an oxo group, an alkyl group, an alkyloxy group, halogen, a cyano group, an alkyloxy-substituted alkyl group, a haloalkyl group, and a cyano- substituted alkyl group; m1 is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and m2 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

2. The eribulin derivative of claim 1, wherein the alkyl group is a <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C12<annotation encoding="application / x-tex">C_{12}< / annotation>< / semantics>< / com:Math> linear or branched alkyl group; the carbon ring group is a saturated, partially unsaturated or completely unsaturated carbon ring group, and the number of carbon atoms is 3 to 20; and the heterocyclic group is a saturated, partially unsaturated or completely unsaturated heterocyclic group, containing 3 to 20 atoms and 1, 2, 3, or 4 heteroatoms selected from N, O, and S.

3. The eribulin derivative of claim 1 or 2, wherein <com:Math><semantics>R1<annotation encoding="application / x-tex">R_1< / annotation>< / semantics>< / com:Math> is selected from H, a <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl group, or a hydroxy-substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl group, or is preferably selected from H, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a hydroxymethyl group, a hydroxyethyl group, a hydroxy-n-propyl group, and a hydroxyisopropyl group; <com:Math><semantics>X1<annotation encoding="application / x-tex">X_1< / annotation>< / semantics>< / com:Math> is selected from -CO- and -CH<com:Sub>2< / com:Sub>-; R<com:Sub>2< / com:Sub> and R<com:Sub>3< / com:Sub> are each independently selected from H, a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl group, a hydroxy group, a C<com:Sub>1< / com:Sub>- <com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyloxy group, a hydroxy- substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl group, a <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyloxy-substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl group, a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl group substituted by a substituted or unsubstituted C<com:Sub>3< / com:Sub>-C<com:Sub>6< / com:Sub> cycloalkyl group, a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl group substituted by a substituted or unsubstituted 3- to 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms of N or O, a substituted or unsubstituted C<com:Sub>3< / com:Sub>-C<com:Sub>6< / com:Sub> cycloalkyl group, and a substituted or unsubstituted 3- to 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms of N or O; and the substituted or unsubstituted C<com:Sub>3< / com:Sub>-C<com:Sub>6< / com:Sub> cycloalkyl group and the substituted or unsubstituted 3- to 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms of N or O are optionally substituted with one or more substituents selected from oxo, a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl group, a hydroxy group, a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyloxy group, a hydroxy-substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl group, and a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyloxy-substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl group; R<com:Sub>4< / com:Sub> is selected from a substituted or unsubstituted C<com:Sub>3< / com:Sub>-C<com:Sub>12< / com:Sub> monocyclic, fused, bicyclic, spiro or bridged cycloalkyl group, a substituted or unsubstituted 3- to 12-membered monocyclic, fused, bicyclic, spiro or bridged heterocycloalkyl group containing 1, 2, or 3 heteroatoms of N or O, a substituted or unsubstituted <com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C10<annotation encoding="application / x-tex">C_{10}< / annotation>< / semantics>< / com:Math> aryl group, and a substituted or unsubstituted 5- to 10-membered heteroaryl group containing 1, 2, or 3 heteroatoms of N or O; and substitution means being substituted with one or more substituents selected from oxo, a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl group, a hydroxy group, a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyloxy group, a hydroxy- substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl group, and a <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyloxy-substituted <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl group; ® ring is a substituted or unsubstituted 3- to 12-membered monocyclic, fused, bicyclic, spiro or bridged heterocycloalkyl group containing 1, 2, or 3 heteroatoms of N or O, the heterocycloalkyl ring contains at least one -NH-, and substitution means being substituted with one or more substituents selected from oxo, a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl group, a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyloxy group, and a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyloxy- substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl group; [Image disponible dans le document PDF, Image available in the PDF document] or , ® ring is preferably a substituted or unsubstituted 4- to 12-membered monocyclic, fused, bicyclic, spiro or bridged heterocycloalkyl group containing 1, 2, or 3 heteroatoms of N or O, the substitution means being substituted with one or more substituents selected from oxo and a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl group; m1 is selected from 1, 2, 3, 4, 5, or 6; m2 is selected from 0, 1, 2, 3, 4, 5, or 6; R<com:Sub>2< / com:Sub> and R<com:Sub>3< / com:Sub> are each independently selected from H, a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl group, a hydroxy group, a hydroxy-substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl group, a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl group substituted by a substituted or unsubstituted C<com:Sub>3< / com:Sub>-C<com:Sub>6< / com:Sub> cycloalkyl group, and a substituted or unsubstituted C<com:Sub>3< / com:Sub>-C<com:Sub>6< / com:Sub> cycloalkyl group, wherein the substituted or unsubstituted C<com:Sub>3< / com:Sub>-C<com:Sub>6< / com:Sub> cycloalkyl group is optionally substituted with one or more substituents selected from oxo and a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl group; and R<com:Sub>4< / com:Sub> is selected from a C<com:Sub>4< / com:Sub>-C<com:Sub>12< / com:Sub> monocyclic, fused, bicyclic, spiro or bridged cycloalkyl group, a 4- to 12-membered monocyclic, fused, bicyclic, spiro or bridged heterocycloalkyl group containing 1, 2, or 3 heteroatoms of N or O, and a phenyl group; <com:Math><semantics>Y1<annotation encoding="application / x-tex">Y_1< / annotation>< / semantics>< / com:Math> is selected from -<com:Math><semantics>(CR2R3)m1<annotation encoding="application / x-tex">(CR_2R_3)_{m1}< / annotation>< / semantics>< / com:Math>-NH<com:Sub>2< / com:Sub>, -<com:Math><semantics>(CR2R3)m1<annotation encoding="application / x-tex">(CR_2R_3)_{m1}< / annotation>< / semantics>< / com:Math>-OH, -R<com:Sub>4< / com:Sub>-<com:Math><semantics>(CR2R3)m2<annotation encoding="application / x-tex">(CR_2R_3)_{m2}< / annotation>< / semantics>< / com:Math>-NH<com:Sub>2< / com:Sub>, -R<com:Sub>4< / com:Sub>-<com:Math><semantics>(CR2R3)m2<annotation encoding="application / x-tex">(CR_2R_3)_{m2}< / annotation>< / semantics>< / com:Math>-OH, [Image disponible dans le document PDF, Image available in the PDF document] or ring is preberably a substituted or unsubstituted 4- to 12-membered monocyclic, fused, bicyclic, spiro or bridged heterocycloalkyl group containing 1, 2, or 3 heteroatoms of N or O, the substitution means being substituted with one or more substituents selected from oxo and a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl group; m1 is selected from 1, 2, 3, 4, 5, or 6; m2 is selected from 0, 1, 2, 3, 4, 5, or 6; R<com:Sub>2< / com:Sub> and R<com:Sub>3< / com:Sub> are each independently selected from H, a <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl group, a hydroxy group, a hydroxy-substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl group, a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl group substituted by a substituted or unsubstituted C<com:Sub>3< / com:Sub>-C<com:Sub>6< / com:Sub> cycloalkyl group, and a substituted or unsubstituted C<com:Sub>3< / com:Sub>-C<com:Sub>6< / com:Sub> cycloalkyl group, wherein the substituted or unsubstituted C<com:Sub>3< / com:Sub>-C<com:Sub>6< / com:Sub> cycloalkyl group is optionally substituted with one or more substituents selected from oxo and a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl group; and R<com:Sub>4< / com:Sub> is selected from a C<com:Sub>4< / com:Sub>-C<com:Sub>12< / com:Sub> monocyclic, fused, bicyclic, spiro or bridged cycloalkyl group, a 4- to 12-membered monocyclic, fused, bicyclic, spiro or bridged heterocycloalkyl group containing 1, 2, or 3 heteroatoms of N or O, and a phenyl group; and / or ing is a 3- to 12-membered monocyclic, fused, bicyclic, spiro or bridged heterocycloalkyl group containing 1, 2, or 3 heteroatoms of N or O, the heterocycloalkyl ring contains at least one - NH- and / or the heterocycloalkyl group is substituted with an amino group, a hydroxy group, an amino-substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl group, or a hydroxy- substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl group, and the heterocycloalkyl group is optionally substituted with one or more substituents selected from oxo, a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl group, a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyloxy group, or a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyloxy-substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl group.

4. The eribulin derivative of claim 3, wherein R<com:Sub>2< / com:Sub> and R<com:Sub>3< / com:Sub> are each independently selected from H, a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl group, a hydroxy group, a hydroxy-substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl group, a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl group substituted by a substituted or unsubstituted C<com:Sub>3< / com:Sub>-C<com:Sub>6< / com:Sub> cycloalkyl group, a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl group substituted by a substituted or unsubstituted 3- to 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms of N or O, a substituted or unsubstituted C<com:Sub>3< / com:Sub>-C<com:Sub>6< / com:Sub> cycloalkyl group, and a substituted or unsubstituted 3- to 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms of N or O; and the substituted or unsubstituted C<com:Sub>3< / com:Sub>-C<com:Sub>6< / com:Sub> cycloalkyl group and the substituted or unsubstituted 3- to 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms of N or O are optionally substituted with one or more substituents selected from oxo, a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl group, a hydroxy group, and a hydroxy- substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl group; R<com:Sub>4< / com:Sub> is selected from a substituted or unsubstituted C<com:Sub>4< / com:Sub>-C<com:Sub>12< / com:Sub> monocyclic, fused, bicyclic, spiro or bridged cycloalkyl group, a substituted or unsubstituted 4- to 12-membered monocyclic, fused, bicyclic, spiro or bridged heterocycloalkyl group containing 1, 2, or 3 heteroatoms of N or O, a substituted or unsubstituted phenyl group, and a substituted or unsubstituted 5- to 10-membered heteroaryl group containing 1, 2, or 3 heteroatoms of N or O; and substitution means being substituted with one or more substituents selected from oxo and a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl group; OH OH <com:Math><semantics>H2N<annotation encoding="application / x-tex">H_2N< / annotation>< / semantics>< / com:Math> , <com:Math><semantics>H2N<annotation encoding="application / x-tex">H_2N< / annotation>< / semantics>< / com:Math> , , X<com:Sub>3< / com:Sub> is selected from the following groups: H<com:Sub>2< / com:Sub>N<com:Sup>7< / com:Sup> [Image disponible dans le document PDF, Image available in the PDF document] <com:Math><semantics>Y1<annotation encoding="application / x-tex">Y_1< / annotation>< / semantics>< / com:Math> is selected from -(CR<com:Sub>2< / com:Sub>R<com:Sub>3< / com:Sub>)<com:Sub>m1< / com:Sub>-NH<com:Sub>2< / com:Sub> and -(CR<com:Sub>2< / com:Sub>R<com:Sub>3< / com:Sub>)<com:Sub>m1< / com:Sub>-OH, m1 is selected from 1, 2, 3, 4, 5, or 6, and R<com:Sub>2< / com:Sub> and R<com:Sub>3< / com:Sub> are each independently selected from H, a C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl group, a hydroxy group, or a hydroxy-substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl group; and / or (A) ring is a 4- to 12-membered monocyclic, fused, bicyclic, spiro or bridged heterocycloalkyl group containing 1, 2, or 3 heteroatoms of N or O, and the heterocycloalkyl ring contains at least one -NH- and / or the heterocycloalkyl group is substituted with an amino group, a hydroxy group, an amino-substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl group, or a hydroxy-substituted C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl group.

5. The eribulin derivative of claim 4, wherein <com:Math><semantics>X3<annotation encoding="application / x-tex">X_3< / annotation>< / semantics>< / com:Math> is selected from the following groups: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] 6. The eribulin derivative of claim 1, wherein <com:Math><semantics>A1<annotation encoding="application / x-tex">A_1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>A2<annotation encoding="application / x-tex">A_2< / annotation>< / semantics>< / com:Math> are selected from the following groups: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] OH OH O <com:Math><semantics>H2N<annotation encoding="application / x-tex">H_2N< / annotation>< / semantics>< / com:Math> N H preferably, A<com:Sub>1< / com:Sub> and A<com:Sub>2< / com:Sub> are selected from the following groups: ÖH, [Image disponible dans le document PDF, Image available in the PDF document] ...

7. The eribulin derivative of claim 1, wherein the compound of formula (I) is one of the following: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] , , , , , [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] , , , , 4 , , , , , , , , [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] , , , , , , , , , , , , [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] , , , , , , , , , , specifically, the compound of formula (II) is one of the following: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] PE-O2K [Image disponible dans le document PDF, Image available in the PDF document] , , [Image disponible dans le document PDF, Image available in the PDF document] -H PE-E2KO , , [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] and 8. An eribulin derivative, which is a compound of formula (I') or (II'), or an isotope-labeled compound, an optical isomer, a geometric isomer, a tautomer, an isomer mixture, or a pharmaceutically acceptable salt thereof; [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] Q Formula (I') Formula (II') wherein: Q is a linker group capable of conjugating to an antibody or antigen-binding fragment; L is a linker group that connects Q to <com:Math><semantics>A1<annotation encoding="application / x-tex">A_1< / annotation>< / semantics>< / com:Math>' or Q to <com:Math><semantics>A2<annotation encoding="application / x-tex">A_2< / annotation>< / semantics>< / com:Math>'; A<com:Sub>1< / com:Sub>' is a group formed by connecting A<com:Sub>1< / com:Sub> to L after removal of a hydrogen atom from -NH<com:Sub>2< / com:Sub>, -OH, -NH- on the chain, or -NH- on the ring of <com:Math><semantics>A1<annotation encoding="application / x-tex">A_1< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>A2<annotation encoding="application / x-tex">A_2< / annotation>< / semantics>< / com:Math>' is a group formed by connecting <com:Math><semantics>A2<annotation encoding="application / x-tex">A_2< / annotation>< / semantics>< / com:Math> to L after removal of a hydrogen atom from -NH<com:Sub>2< / com:Sub>, -OH, -NH- on the chain, or -NH- on the ring of A<com:Sub>2< / com:Sub>; and definitions of A<com:Sub>1< / com:Sub>, A<com:Sub>2< / com:Sub>, *, and ** are the same as those in formula (I) and formula (II) of any one of claims 1 to 7.

9. The eribulin derivative of claim 8, wherein when <com:Math><semantics>X3<annotation encoding="application / x-tex">X_3< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>Y1<annotation encoding="application / x-tex">Y_1< / annotation>< / semantics>< / com:Math> are each independently selected from <com:Math><semantics>−(CR2R3)m1−NH2<annotation encoding="application / x-tex">-(CR_2R_3)_{m1}-NH_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−(CR2R3)m1−OH<annotation encoding="application / x-tex">-(CR_2R_3)_{m1}-OH< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−R4−(CR2R3)m2−NH2<annotation encoding="application / x-tex">-R_4-(CR_2R_3)_{m2}-NH_2< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>−R4−(CR2R3)m2−OH<annotation encoding="application / x-tex">-R_4-(CR_2R_3)_{m2}-OH< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>A1′<annotation encoding="application / x-tex">A_1'< / annotation>< / semantics>< / com:Math> is a group formed by connecting A<com:Sub>1< / com:Sub> to L after removal of the hydrogen atom from terminal -NH<com:Sub>2< / com:Sub> or terminal - OH of X<com:Sub>3< / com:Sub> or Y<com:Sub>1< / com:Sub>; and A<com:Sub>2< / com:Sub>' is a group formed by connecting A<com:Sub>2< / com:Sub> to L after removal of the hydrogen atom from the terminal -NH<com:Sub>2< / com:Sub> or terminal -OH of <com:Math><semantics>X3<annotation encoding="application / x-tex">X_3< / annotation>< / semantics>< / com:Math> or <com:Math><semantics>Y1<annotation encoding="application / x-tex">Y_1< / annotation>< / semantics>< / com:Math>; [Image disponible dans le document PDF, Image available in the PDF document] when <com:Math><semantics>X3<annotation encoding="application / x-tex">X_3< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>Y1<annotation encoding="application / x-tex">Y_1< / annotation>< / semantics>< / com:Math> are each independently , A<com:Sub>1< / com:Sub>' represents a group formed by connecting A<com:Sub>1< / com:Sub> to L after removal of the hydrogen atom of -NH- on the <com:Sup>®< / com:Sup> ring, and A2' represents a group formed by connecting A<com:Sub>2< / com:Sub> to L after removal of the hydrogen atom of -NH- on the <com:Sup>®< / com:Sup> ring; [Image disponible dans le document PDF, Image available in the PDF document] when <com:Math><semantics>A1<annotation encoding="application / x-tex">A_1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>A2<annotation encoding="application / x-tex">A_2< / annotation>< / semantics>< / com:Math> are each independently <com:Math><semantics>A1<annotation encoding="application / x-tex">A_1< / annotation>< / semantics>< / com:Math> is a group formed by connecting A<com:Sub>1< / com:Sub> to L after removal of the hydrogen atom of -NH- on the or ring, or the hydrogen atom of -NH<com:Sub>2< / com:Sub> or -OH on the ing substituent, and A<com:Sub>2< / com:Sub>' is a group formed by connecting A<com:Sub>2< / com:Sub> to L after removal of the hydrogen atom of -NH- on the or -NH<com:Sub>2< / com:Sub> or -OH on the ing substituent; and when <com:Math><semantics>R1<annotation encoding="application / x-tex">R_1< / annotation>< / semantics>< / com:Math> is H, <com:Math><semantics>A1<annotation encoding="application / x-tex">A_1< / annotation>< / semantics>< / com:Math>' is a group formed by connecting <com:Math><semantics>A1<annotation encoding="application / x-tex">A_1< / annotation>< / semantics>< / com:Math> to L after removal of <com:Math><semantics>R1<annotation encoding="application / x-tex">R_1< / annotation>< / semantics>< / com:Math> from -NR<com:Sub>1< / com:Sub>-, and <com:Math><semantics>A2<annotation encoding="application / x-tex">A_2< / annotation>< / semantics>< / com:Math>' is a group formed by connecting <com:Math><semantics>A2<annotation encoding="application / x-tex">A_2< / annotation>< / semantics>< / com:Math> to L after removal of <com:Math><semantics>R1<annotation encoding="application / x-tex">R_1< / annotation>< / semantics>< / com:Math> from -NR<com:Sub>1< / com:Sub>-.

10. The eribulin derivative of claim 8, wherein L is <com:Math><semantics>−L4−L3−L2−L1−<annotation encoding="application / x-tex">-L_4-L_3-L_2-L_1-< / annotation>< / semantics>< / com:Math>, and L<com:Sub>1< / com:Sub> is connected to A<com:Sub>1< / com:Sub>' or <com:Math><semantics>A2′<annotation encoding="application / x-tex">A_2'< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>L4<annotation encoding="application / x-tex">L_4< / annotation>< / semantics>< / com:Math> is connected to Q; [Image disponible dans le document PDF, Image available in the PDF document] or <com:Math><semantics>A2<annotation encoding="application / x-tex">A_2< / annotation>< / semantics>< / com:Math>', and represents an attachment site to <com:Math><semantics>L2<annotation encoding="application / x-tex">L_2< / annotation>< / semantics>< / com:Math>; and L<com:Sub>2< / com:Sub> is a direct bond, an amino acid residue, a short peptide chain formed by two or more amino acid residues, the amino acid residues are selected from natural or unnatural amino acid residues, the amino acid residue or short peptide chain has N-terminus attached to L<com:Sub>3< / com:Sub> and C-terminus attached to L<com:Sub>1< / com:Sub>, and L<com:Sub>2< / com:Sub> optionally contains one or more structures selected from formula (III-1) to formula (III-9): [Image disponible dans le document PDF, Image available in the PDF document] <com:Math><semantics>∼<annotation encoding="application / x-tex">\sim< / annotation>< / semantics>< / com:Math> <com:Math><semantics>∼<annotation encoding="application / x-tex">\sim< / annotation>< / semantics>< / com:Math> [Image disponible dans le document PDF, Image available in the PDF document] s is selected from 1, 2, 3, 4, 5, 6, 7, and 8, t is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12, and <com:Math><semantics>R5<annotation encoding="application / x-tex">R_5< / annotation>< / semantics>< / com:Math> is selected from H or a <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C8<annotation encoding="application / x-tex">C_8< / annotation>< / semantics>< / com:Math> alkyl group; L<com:Sub>3< / com:Sub> is selected from a direct bond, <com:Math><semantics>−NR6−(CH2)r1−(CH2CH2O)r2−(CH2)r3−CO−<annotation encoding="application / x-tex">-NR_6-(CH_2)_{r1}-(CH_2CH_2O)_{r2}-(CH_2)_{r3}-CO-< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−O−(CH2)r1−<annotation encoding="application / x-tex">-O-(CH_2)_{r1}-< / annotation>< / semantics>< / com:Math> <com:Math><semantics>(CH2CH2O)r2−(CH2)r3−CO−<annotation encoding="application / x-tex">(CH_2CH_2O)_{r2}-(CH_2)_{r3}-CO-< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NR6−(CH2)r4−(OCH2CH2)r5−(CH2)r6−CO−<annotation encoding="application / x-tex">-NR_6-(CH_2)_{r4}-(OCH_2CH_2)_{r5}-(CH_2)_{r6}-CO-< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−O−(CH2)r4−(OCH2CH2)r5−(CH2)r6−CO−<annotation encoding="application / x-tex">-O-(CH_2)_{r4}-(OCH_2CH_2)_{r5}-(CH_2)_{r6}-CO-< / annotation>< / semantics>< / com:Math> <com:Math><semantics>(CH2)r6<annotation encoding="application / x-tex">(CH_2)_{r6}< / annotation>< / semantics>< / com:Math>-CO-<com:Math><semantics>•<annotation encoding="application / x-tex">\bullet< / annotation>< / semantics>< / com:Math>, or ; or L<com:Sub>3< / com:Sub> is selected from: [Image disponible dans le document PDF, Image available in the PDF document] or elected from 0, 1, 2, 3, 4, 5, or 6, r2 is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, r3 is selected from 1, 2, 3, 4, 5, or 6, r4 is selected from 1, 2, 3, 4, 5, or 6, r5 is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, r6 is selected from 0, 1, 2, 3, 4, 5, or 6, r7 is selected from 0, 1, 2, 3, 4, 5, or 6, r8 is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, r9 is selected from 1, 2, 3, 4, 5, or 6, r10 is selected from 1, 2, 3, 4, 5, or 6, W is selected from O or NR<com:Sub>6< / com:Sub>, R<com:Sub>6< / com:Sub> is selected from H or a C<com:Sub>1< / com:Sub>-C<com:Sub>8< / com:Sub> alkyl group, wherein • represents an attachment site to <com:Math><semantics>L2<annotation encoding="application / x-tex">L_2< / annotation>< / semantics>< / com:Math>, and when <com:Math><semantics>•<annotation encoding="application / x-tex">\bullet< / annotation>< / semantics>< / com:Math> appears twice in the same <com:Math><semantics>L3<annotation encoding="application / x-tex">L_3< / annotation>< / semantics>< / com:Math> group, it means that L<com:Sub>2< / com:Sub> is attached at both sites; and L<com:Sub>4< / com:Sub> is selected from a direct bond, -CO-, -(CH<com:Sub>2< / com:Sub>)<com:Sub>p1< / com:Sub>-CO-, -(CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>O)<com:Sub>p2< / com:Sub>-(CH<com:Sub>2< / com:Sub>)<com:Sub>p3< / com:Sub>-CO-, -(CH<com:Sub>2< / com:Sub>)<com:Sub>p4< / com:Sub> - <com:Math><semantics>O−(CH2)p5−C(O)−<annotation encoding="application / x-tex">O-(CH_2)_{p5}-C(O)-< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NR7−(CH2)p1−CO−<annotation encoding="application / x-tex">-NR_7-(CH_2)_{p1}-CO-< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NR7−(CH2CH2O)p2−(CH2)p3−CO−<annotation encoding="application / x-tex">-NR_7-(CH_2CH_2O)_{p2}-(CH_2)_{p3}-CO-< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NR7−(CH2)p4−O−(CH2)p5−<annotation encoding="application / x-tex">-NR_7-(CH_2)_{p4}-O-(CH_2)_{p5}-< / annotation>< / semantics>< / com:Math> <com:Math><semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>< / com:Math>-, <com:Math><semantics>−O<annotation encoding="application / x-tex">-O< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>(CH2)p1<annotation encoding="application / x-tex">(CH_2)_{p1}< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>CO<annotation encoding="application / x-tex">CO< / annotation>< / semantics>< / com:Math>-, <com:Math><semantics>−O<annotation encoding="application / x-tex">-O< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>(CH2CH2O)p2<annotation encoding="application / x-tex">(CH_2CH_2O)_{p2}< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>(CH2)p3<annotation encoding="application / x-tex">(CH_2)_{p3}< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>CO<annotation encoding="application / x-tex">CO< / annotation>< / semantics>< / com:Math>-, and <com:Math><semantics>−O<annotation encoding="application / x-tex">-O< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>(CH2)p4<annotation encoding="application / x-tex">(CH_2)_{p4}< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>O<annotation encoding="application / x-tex">O< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>(CH2)p5<annotation encoding="application / x-tex">(CH_2)_{p5}< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>< / com:Math>-, <com:Math><semantics>p1<annotation encoding="application / x-tex">p1< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>p2<annotation encoding="application / x-tex">p2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>p3<annotation encoding="application / x-tex">p3< / annotation>< / semantics>< / com:Math>, p4, and p5 are each independently selected from 1, 2, 3, 4, 5, 6, 7, and 8, and R<com:Sub>7< / com:Sub> is selected from H or a <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C8<annotation encoding="application / x-tex">C_8< / annotation>< / semantics>< / com:Math> alkyl group, wherein -CO- is attached to <com:Math><semantics>L3<annotation encoding="application / x-tex">L_3< / annotation>< / semantics>< / com:Math>.

11. The eribulin derivative of claim 10, wherein <com:Math><semantics>A1<annotation encoding="application / x-tex">A_1< / annotation>< / semantics>< / com:Math> represents a group formed by connecting A<com:Sub>1< / com:Sub> to L after removal of the hydrogen atom from -NH<com:Sub>2< / com:Sub>, -NH- on the chain, or -NH- on the ring, and A<com:Sub>2< / com:Sub>' represents a group formed by connecting A<com:Sub>2< / com:Sub> to L after removal of the hydrogen atom from -NH<com:Sub>2< / com:Sub>, [Image disponible dans le document PDF, Image available in the PDF document] -NH- on the chain, or -NH- on the ring, and L<com:Sub>1< / com:Sub> is selected from a direct bond, [Image disponible dans le document PDF, Image available in the PDF document] when <com:Math><semantics>A1<annotation encoding="application / x-tex">A_1< / annotation>< / semantics>< / com:Math>' represents a group formed by connecting <com:Math><semantics>A1<annotation encoding="application / x-tex">A_1< / annotation>< / semantics>< / com:Math> to L after removal of the hydrogen atom of -OH-, or A<com:Sub>2< / com:Sub>' represents a group formed by connecting A<com:Sub>2< / com:Sub> to L after removal of the hydrogen atom [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] 12. The eribulin derivative of claim 10, wherein <com:Math><semantics>L1<annotation encoding="application / x-tex">L_1< / annotation>< / semantics>< / com:Math> is selected from the direct bond, [Image disponible dans le document PDF, Image available in the PDF document] anc L<com:Sub>2< / com:Sub> is an amino acid residue or a short peptide chain formed by 2 to 8 amino acid residues, and preferably, the amino acid residues are amino acid residues formed by amino acids selected from phenylalanine, alanine, glycine, valine, citrulline, leucine, isoleucine, tryptophan, tyrosine, histidine, lysine, serine, threonine, cysteine, glutamic acid, glutamine, aspartic acid, asparagine, methionine, and arginine, or more preferably, the amino acid residues are amino acid residues formed by amino acids selected from phenylalanine, alanine, glycine, valine, and citrulline; L<com:Sub>3< / com:Sub> is selected from the direct bond, <com:Math><semantics>−NH−(CH2CH2O)r2−(CH2)r3−CO−<annotation encoding="application / x-tex">-NH-(CH_2CH_2O)_{r2}-(CH_2)_{r3}-CO-< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NH−(CH2)r4−<annotation encoding="application / x-tex">-NH-(CH_2)_{r4}-< / annotation>< / semantics>< / com:Math> <com:Math><semantics>(OCH2CH2)r5−CO−Φ<annotation encoding="application / x-tex">(OCH_2CH_2)_{r5}-CO-\Phi< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−O−(CH2CH2O)r2−(CH2)r3−CO−Φ<annotation encoding="application / x-tex">-O-(CH_2CH_2O)_{r2}-(CH_2)_{r3}-CO-\Phi< / annotation>< / semantics>< / com:Math>, or <com:Math><semantics>−O−(CH2)r4−(OCH2CH2)r5−CO−Φ<annotation encoding="application / x-tex">-O-(CH_2)_{r4}-(OCH_2CH_2)_{r5}-CO-\Phi< / annotation>< / semantics>< / com:Math>; or L<com:Sub>3< / com:Sub> is selected from [Image disponible dans le document PDF, Image available in the PDF document] or or r7 is 0, r2 is selected from 4, 5, 6, 7, or 8, r3 is selected from 1, 2, 3, or 4, r4 is selected from 1, 2, 3, or 4, r5 is selected from 4, 5, 6, 7, or 8, r8 is selected from 1, 2, 3, or 4, r9 is selected from 1, 2, 3, or 4, r10 is selected from 1, 2, 3, or 4, and W is NH; and / or <com:Math><semantics>L4<annotation encoding="application / x-tex">L_4< / annotation>< / semantics>< / com:Math> is selected from the direct bond, <com:Math><semantics>−(CH2)p1−CO−<annotation encoding="application / x-tex">-(CH_2)_{p1}-CO_{-}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−(CH2CH2O)p2−(CH2)p3−CO−<annotation encoding="application / x-tex">-(CH_2CH_2O)_{p2}-(CH_2)_{p3}-CO_{-}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−(CH2)p4−O−<annotation encoding="application / x-tex">-(CH_2)_{p4}-O_{-}< / annotation>< / semantics>< / com:Math> <com:Math><semantics>(CH2)p5−C(O)−<annotation encoding="application / x-tex">(CH_2)_{p5}-C(O)-< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NR7−(CH2)p1−CO−<annotation encoding="application / x-tex">-NR_7-(CH_2)_{p1}-CO-< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NR7−(CH2CH2O)p2−(CH2)p3−CO−<annotation encoding="application / x-tex">-NR_7-(CH_2CH_2O)_{p2}-(CH_2)_{p3}-CO-< / annotation>< / semantics>< / com:Math>, or <com:Math><semantics>−NR7−(CH2)p4−O−(CH2)p5−CO−<annotation encoding="application / x-tex">-NR_7-(CH_2)_{p4}-O-(CH_2)_{p5}-CO-< / annotation>< / semantics>< / com:Math> C(O)-, p1 is selected from 1, 2, 3, 4, 5, or 6, p2, p3, p4, and p5 are each independently selected from 1, 2, 3, or 4, and <com:Math><semantics>R7<annotation encoding="application / x-tex">R_7< / annotation>< / semantics>< / com:Math> is selected from H or a <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl group; 13. The eribulin derivative of claim 12, wherein L<com:Sub>2< / com:Sub> optionally comprises one or more structures selected from formula (III-1) and formula (III-9), or preferably, comprises one or more structures [Image disponible dans le document PDF, Image available in the PDF document] selected from the following groups: wherein t=8; preferably, L<com:Sub>2< / com:Sub> is selected from -NHGly<com:Sup>CO< / com:Sup>-, or selected from the following short peptide chains: -NHGly-Gly-Phe-Gly<com:Sup>CO< / com:Sup>-, -NHVal-Cit<com:Sup>CO< / com:Sup>-, -NHVal- Ala<com:Sup>CO< / com:Sup>-, -NHGly-Gly-Val-Ala<com:Sup>CO< / com:Sup>-, -NHGly-Gly-Val- Cit<com:Sup>CO< / com:Sup>-, -NHLys-Gly-Val-Ala<com:Sup>CO< / com:Sup>-, -NHLys-Gly-Val- Cit<com:Sup>CO< / com:Sup>-, and -NHGly-Val-Cit<com:Sup>CO< / com:Sup>-; more preferably, L<com:Sub>2< / com:Sub> is selected from the following groups: [Image disponible dans le document PDF, Image available in the PDF document] , further preferably, L<com:Sub>2< / com:Sub> is selected from the following groups: [Image disponible dans le document PDF, Image available in the PDF document] 14. The eribulin derivative of claim 12, wherein L<com:Sub>3< / com:Sub> is selected from the direct bond, -O- <com:Math><semantics>(CH2CH2O)r2<annotation encoding="application / x-tex">(CH_2CH_2O)_{r2}< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>(CH2)r3<annotation encoding="application / x-tex">(CH_2)_{r3}< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>CO<annotation encoding="application / x-tex">CO< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>•<annotation encoding="application / x-tex">\bullet< / annotation>< / semantics>< / com:Math>, -NH-<com:Math><semantics>(CH2CH2O)r2<annotation encoding="application / x-tex">(CH_2CH_2O)_{r2}< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>(CH2)r3<annotation encoding="application / x-tex">(CH_2)_{r3}< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>CO<annotation encoding="application / x-tex">CO< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>•<annotation encoding="application / x-tex">\bullet< / annotation>< / semantics>< / com:Math>, and [Image disponible dans le document PDF, Image available in the PDF document] r2 is selected from 4, 5, 6, 7, or 8, r3 is 2, r8 is selected from 2, 3, or 4, r9 is 2, and r10 is 2; and / or L<com:Sub>4< / com:Sub> is selected from the following groups: the direct bond, -(CH<com:Sub>2< / com:Sub>)<com:Sub>p1< / com:Sub>-CO-, -(CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>O)<com:Sub>p2< / com:Sub>- <com:Math><semantics>(CH2)p3<annotation encoding="application / x-tex">(CH_2)_{p3}< / annotation>< / semantics>< / com:Math>-CO-, <com:Math><semantics>−(CH2)p4<annotation encoding="application / x-tex">-(CH_2)_{p4}< / annotation>< / semantics>< / com:Math>-O-<com:Math><semantics>−(CH2)p5<annotation encoding="application / x-tex">-(CH_2)_{p5}< / annotation>< / semantics>< / com:Math>-C(O)-, <com:Math><semantics>−NR7<annotation encoding="application / x-tex">-NR_7< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>−(CH2)p1<annotation encoding="application / x-tex">-(CH_2)_{p1}< / annotation>< / semantics>< / com:Math>-CO-, <com:Math><semantics>−NR7<annotation encoding="application / x-tex">-NR_7< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>−(CH2)p2<annotation encoding="application / x-tex">-(CH_2)_{p2}< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>−(CH2)p3<annotation encoding="application / x-tex">-(CH_2)_{p3}< / annotation>< / semantics>< / com:Math>-CO-, or - <com:Math><semantics>NR7−(CH2)p4−O−(CH2)p5−C(O)−<annotation encoding="application / x-tex">NR_7-(CH_2)_{p4}-O-(CH_2)_{p5}-C(O)-< / annotation>< / semantics>< / com:Math>, p1 is selected from 3, 4, 5, or 6, p2, p3, p4, and p5 are each independently selected from 2 and 3, and R<com:Sub>7< / com:Sub> is H.

15. The eribulin derivative of claim 8, wherein Q is selected from a group comprising a maleimide linker, a group comprising a mesylpyrimidine linker, a group comprising a mesylpyridothiazole linker, a group comprising a mesylpyrimidothiazole linker, a group comprising a cycloalkyne linker, or a group comprising an oxime bond linker, [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] 17. The eribulin derivative of claim 8, wherein formula (I') is one of the following: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] e e [Image disponible dans le document PDF, Image available in the PDF document] ... [Image disponible dans le document PDF, Image available in the PDF document] . . [Image disponible dans le document PDF, Image available in the PDF document] _ [Image disponible dans le document PDF, Image available in the PDF document] 1 II [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] 18. An antibody-drug conjugate, which is a compound of formula (I") or (II"), or an isotope- labeled compound, an optical isomer, a geometric isomer, a tautomer, an isomer mixture, or a pharmaceutically acceptable salt thereof; [Image disponible dans le document PDF, Image available in the PDF document] wherein: Ab is an antibody or an antigen-binding fragment; L<com:Sub>5< / com:Sub> is a direct bond or a linking group connecting Ab and Q'; Q' is a group formed after Q is attached to Ab via <com:Math><semantics>L5<annotation encoding="application / x-tex">L_5< / annotation>< / semantics>< / com:Math>; n is an integer or decimal between 0 and 20, or preferably, n is an integer or decimal between 0 and 8; and definitions of Q, L, A<com:Sub>1< / com:Sub>', A<com:Sub>2< / com:Sub>', *, and ** are the same as those in formula (I') and formula (II') of any one of claims 8 to 17.

19. The antibody-drug conjugate of claim 18, wherein L<com:Sub>5< / com:Sub> is the direct bond or [Image disponible dans le document PDF, Image available in the PDF document] represents an attachment site to Ab, <com:Math><semantics>•<annotation encoding="application / x-tex">\bullet< / annotation>< / semantics>< / com:Math> indicates that <com:Math><semantics>Z3<annotation encoding="application / x-tex">Z_3< / annotation>< / semantics>< / com:Math> is linked to Q', and Z<com:Sub>3< / com:Sub> is a click probe, a sulfhydryl group, or a precursor thereof capable of binding to Q' after reaction; Z<com:Sub>1< / com:Sub> and Z<com:Sub>2< / com:Sub> are each independently selected from -C(O)NH-, -C(O)O-, -C(O)-, -OC(O)-, - NHC(O)-, -NH-, -O-, -OC(O)NH-, or -NHC(O)O-; q<com:Sub>1< / com:Sub> is 0, 1, 2, 3, 4, 5, 6, 7, or 8; q<com:Sub>2< / com:Sub> is 1, 2, 3, 4, 5, 6, 7, or 8; q<com:Sub>3< / com:Sub> is 1, 2, 3, 4, 5, 6, 7, or 8; q<com:Sub>4< / com:Sub> is 1, 2, 3, 4, 5, 6, 7, or 8; Z<com:Sub>3< / com:Sub> is a click probe or a sulfhydryl group or a precursor thereof that can be linked to Q' after a metal-free click reaction, and preferably, Z<com:Sub>3< / com:Sub> is an azido group; and / or [Image disponible dans le document PDF, Image available in the PDF document] Q' is selected from the following: 1 1 1 0 S S N Н <com:Math><semantics>N=<annotation encoding="application / x-tex">N=< / annotation>< / semantics>< / com:Math> N 1 O Н 0- O, and , wherein • represents an attachment site to <com:Math><semantics>L5<annotation encoding="application / x-tex">L_5< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>∼><annotation encoding="application / x-tex">\stackrel{>}{\sim}< / annotation>< / semantics>< / com:Math> represents an attachment site to <com:Math><semantics>L4<annotation encoding="application / x-tex">L_4< / annotation>< / semantics>< / com:Math>.

20. The antibody-drug conjugate of claim 18, wherein L<com:Sub>5< / com:Sub> is the direct bond or [Image disponible dans le document PDF, Image available in the PDF document] • and preferably, <com:Math><semantics>L5<annotation encoding="application / x-tex">L_5< / annotation>< / semantics>< / com:Math> is the direct bond or \Z\. <com:Math><semantics>Z2<annotation encoding="application / x-tex">Z_2< / annotation>< / semantics>< / com:Math> <com:Math><semantics>Z3•<annotation encoding="application / x-tex">Z_3^{\bullet}< / annotation>< / semantics>< / com:Math>; and / or <com:Math><semantics>Z1<annotation encoding="application / x-tex">Z_1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>Z2<annotation encoding="application / x-tex">Z_2< / annotation>< / semantics>< / com:Math> are each independently -C(O)NH-.

21. The antibody-drug conjugate of claim 18, wherein L<com:Sub>5< / com:Sub>-Q' is selected from the following: [Image disponible dans le document PDF, Image available in the PDF document] and <com:Math><semantics>34<annotation encoding="application / x-tex">\frac{3}{4}< / annotation>< / semantics>< / com:Math> represents an attachment site to L<com:Sub>4< / com:Sub>; preferably, <com:Math><semantics>L5<annotation encoding="application / x-tex">L_5< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>Q′<annotation encoding="application / x-tex">Q'< / annotation>< / semantics>< / com:Math> is selected from [Image disponible dans le document PDF, Image available in the PDF document] and [Image disponible dans le document PDF, Image available in the PDF document] , and more preferably, <com:Math><semantics>Z1<annotation encoding="application / x-tex">Z_1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>Z2<annotation encoding="application / x-tex">Z_2< / annotation>< / semantics>< / com:Math> are each independently -C(O)NH-.

22. The antibody-drug conjugate of claim 18, wherein Ab is selected from a mouse-derived antibody, a chimeric antibody, a humanized antibody, a fully human antibody, or an antigen-binding fragment thereof; and preferably, Ab is selected from anti-HER2 (ErbB2) antibody, anti-EGFR antibody, anti-B7-H3 antibody, anti-c-Met antibody, anti-HER3 (ErbB3) antibody, anti-HER4 (ErbB4) antibody, anti-ROR1 antibody, anti-CLDN6 antibody, anti-CLDN9 antibody, anti-CLDN18.2 antibody, anti-NaPi-2b antibody, anti-TNF-α antibody, anti-ENPP3 antibody, anti-DLL3 antibody, anti-CD20 antibody, anti-CD22 antibody, anti-CD30 antibody, anti-CD33 antibody, anti-CD37 antibody, anti-CD38 antibody, anti-CD44 antibody, anti-CD45 antibody, anti- CD47 antibody, anti-CD48 antibody, anti-CD56 antibody, anti-CD70 antibody, anti-CD73 antibody, anti-CD98 antibody, anti-CD105 antibody, anti-CEA antibody, anti-EphA2 antibody, anti-MUCI antibody, anti-Lewis Y antibody, anti-VEGFR antibody, anti-GPNMB antibody, anti-Integrin antibody, anti-PSMA antibody, anti-Tenascin-C antibody, anti-SLC44A4 antibody, anti-CD79 antibody, anti-TROP-2 antibody, anti-CD79B antibody, anti-Mesothelin antibody, anti-Nectin-4 antibody, anti-TPBG antibody, or an antigen-binding fragment thereof.

23. The antibody-drug conjugate of claim 22, wherein Ab is the anti-HER2 (ErbB2) antibody or the antigen-binding fragment thereof; or Ab is selected from the monoclonal antibody or the antigen-binding fragment thereof, or preferably, selected from Trastuzumab, Cetuximab, Pertuzumab, Nimotuzumab, Enoblituzumab, Emibetuzumab, Inotuzumab, Pinatuzumab Vedotin, Brentuximab Vedotin, Gemtuzumab, Bivatuzumab, Lorvotuzumab, or an antigen-binding fragment thereof.

24. The antibody-drug conjugate of claim 18, wherein formula (I") is one of the following: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] ʼn [Image disponible dans le document PDF, Image available in the PDF document] _ ___ [Image disponible dans le document PDF, Image available in the PDF document] ___ n n n 1 [Image disponible dans le document PDF, Image available in the PDF document] T-LA29 <com:Math><semantics>⊔𝗇<annotation encoding="application / x-tex">\sqcup_{\mathsf{n}}< / annotation>< / semantics>< / com:Math> [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] n [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] • [Image disponible dans le document PDF, Image available in the PDF document] ٦.

25. A pharmaceutical composition, comprising the eribulin derivative of any one of claims 1 to 17 or the antibody-drug conjugate of any one of claims 18 to 24, and one or more pharmaceutically acceptable carriers or excipients.

26. Use of the eribulin derivative of any one of claims 1 to 17 in preparation of an antibody- drug conjugate.

27. Use of the eribulin derivative of any one of claims 1 to 17, the antibody-drug conjugate of any one of claims 18 to 24, or the pharmaceutical composition of claim 25 in preparation of a medicament for treating tumors or cancers.

28. The use of claim 27, wherein the tumor or cancer is selected from a solid tumor or hematological tumor, and is preferably selected from breast cancer, gastric cancer, colon cancer, pancreatic cancer, kidney cancer, ovarian cancer, lung cancer, soft tissue sarcoma, liposarcoma, non- small cell lung cancer, melanoma, head and neck cancer, cervical cancer, and prostate cancer, and is more preferably HER-2-positive breast cancer, triple-negative breast cancer, HER-2-positive triple- negative breast cancer, clear cell renal cell carcinoma, small cell lung cancer, non-small cell lung cancer, and large cell lung cancer.