Toxin molecules suitable for antibody-drug conjugates

Abstract

The invention provides a toxin molecule suitable for an antibody-drug conjugate, and particularly provides a compound as shown in the following formula (A-I), or pharmaceutically acceptable salts, enantiomers, diastereoisomers, racemes, solvates, hydrates, polymorphs, prodrugs or isotope variants of the compound, and mixtures of the compound and the pharmaceutically acceptable salts, the enantiomers, the diastereoisomers, the racemes, the solvates, the hydrates, the polymorphs, the prodrugs or the isotope variants. The compound provided by the invention can be used for preparing drugs for treating diseases related to tumor cell proliferation. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of medicinal chemistry. Specifically, the present invention provides a toxin molecule with tumor cell proliferation inhibitory activity. Background Art

[0002] Antibody-drug conjugates (ADCs) link monoclonal antibodies or antibody fragments to bioactive cytotoxins through stable chemical linker compounds, making full use of the specificity of antibodies for binding to antigens on normal and tumor cells and the high efficiency of cytotoxic substances, while avoiding the defects of low efficacy of the former and excessive side effects of the latter. This means that, compared with traditional chemotherapy drugs in the past, antibody-drug conjugates can bind to tumor cells more precisely and reduce the impact on normal cells.

[0003] Currently, a variety of ADC drugs have been used in clinical practice or clinical research. For example, Kadcyla is an ADC drug formed by trastuzumab targeting Her2 and DM1. At the same time, there are also patent reports on antibodies targeting B7H3 and ADC drugs.

[0004] There are several types of small cytotoxic molecules for antibody-drug conjugates; one of them is camptothecin derivatives, which have antitumor effects by inhibiting topoisomerase I. The application of the camptothecin derivative irinotecan in antibody-conjugated drugs (ADCs) has been reported in the literature, but there is still a need to further develop ADC drugs with better efficacy in this field.

[0005] DNA topoisomerase (Topoisomerase, Topo) is a class of essential enzymes widely present in living organisms and is involved in all key nuclear processes such as DNA replication, transcription, recombination, and repair. According to the different forms of transient DNA strand breaks caused by topoisomerase, topoisomerase can be divided into two major categories: topoisomerase I and topoisomerase II. Topoisomerase I and topoisomerase II jointly catalyze the unwinding of supercoiled DNA during DNA replication, but topoisomerase II involves double-strand breaks, while topoisomerase I only causes single-strand breaks. Camptothecin and its analogs reversibly bind to the DNA topoisomerase I-DNA complex to form a camptothecin and its analogs-DNA topoisomerase I-DNA ternary complex, which terminates progressive unwinding, ultimately leading to the replication fork hitting the ternary complex and causing irreparable DNA breaks, resulting in cell death. Summary of the Invention

[0006] The object of the present invention is to provide a toxin molecule suitable for antibody-conjugated drugs.

[0007] The first aspect of the present invention provides a compound represented by the following formula (I), or a pharmaceutically acceptable salt or hydrate thereof:

[0008]

[0009] Where n is 0 or 1;

[0010] X is selected from the following group: N or CR 0 ;

[0011] R 0 Selected from the group consisting of a hydrogen atom, a deuterium atom, a halogen, a C1-C8 alkyl group, a C1-C8 alkoxy group, OH, NH2, N3 or NO2;

[0012] R 1 Selected from the group consisting of a hydrogen atom, a deuterium atom, a halogen, a C1-C8 alkyl group, a C1-C8 alkoxy group, a C1-C8 haloalkyl group, a C1-C8 haloalkoxy group, N3, NO2, NH2, NH-OH, -NR'R", -COOR', -CONR'R", -NHR"'NR'R", wherein R', R" and R'" are each independently selected from the group consisting of hydrogen, an alkyl group, an aryl group, an arylalkyl group, an acyl group, an alkoxycarbonyl group, and an aryloxycarbonyl group;

[0013] R 2 , R 3 , R 4 , R 5 and R 6 Each is independently selected from the following groups: hydrogen atom, deuterium atom, halogen, hydroxyl, cyano, NH2, NO2, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted C1-C8 alkylthio, substituted or unsubstituted C1-C8 deuterated alkyl, -(CH2) m tri(C1-C4alkyl)silyl, -(CH2) m (C3-C8 cycloalkyl), -(CH2) m (3-12 membered heterocyclic group), -(CH2) m N(R 7 )2、-(CH2) m S(CH2) p R 7 、-(CH2) m S(O)(CH2) p R 7 、-(CH2) m S(O)2(CH2) p R 7 、-(CH2) m NH(CH2) p R 7 、-(CH2)m NHC(O)(CH2) p R 7 、-(CH2) m OC(O)(CH2) p R 7 、-(CH2) m C(O)(CH2) p R 7 、-CH=N(O t Bu); wherein m and p are each independently 0, 1, 2, 3 or 4;

[0014] Or, R 2 and R 3 together with the carbon atom to which they are attached form a substituted or unsubstituted C5-C8 carbocyclic ring or a substituted or unsubstituted 5- to 12-membered heterocyclic group;

[0015] Or, R 2 and R 3 together with the carbon atom to which they are attached form a structure selected from the group consisting of: an unsubstituted or one or more R a -substituted saturated or unsaturated 5- to 6-membered carbocyclic ring, an unsubstituted or one or more R a -substituted saturated or unsaturated 5- to 6-membered heterocyclic ring;

[0016] Or, R 3 and R 4 , or R 4 and R 5 together with the carbon atom to which they are attached form a structure selected from the group consisting of: an unsubstituted or one or more R a -substituted saturated or unsaturated 5- to 12-membered carbocyclic ring, an unsubstituted or one or more R a -substituted saturated or unsaturated 5- to 12-membered heterocyclic ring; said R a is a substituted or unsubstituted substituent selected from the group consisting of: a hydrogen atom, a deuterium atom, a halogen, a nitrile group, a nitro group, a hydroxyl group, an amino group, C1-C6 alkyl-NH-, (C1-C6 alkyl)2N-, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, allyl, benzyl, C6-C 12 aryl, C1-C6 alkoxy-C1-C6 alkyl, C1-C6 alkoxy-carbonyl, phenoxycarbonyl, C2-C6 alkynyl-carbonyl, C2-C6 alkenyl-carbonyl, C3-C6 cycloalkyl-carbonyl, C1-C6 alkyl-sulfonyl, phenyl, 5- to 7-membered heteroaryl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclic group, -(CH2) m N(R 7 )2, -(CH2) m S(CH2) p R7 、 -(CH2) m S(O)(CH2) p R 7 、 -(CH2) m S(O)2(CH2) p R 7 、 -(CH2) m NH(CH2) p R 7 、 -(CH2) m NHC(O)(CH2) p R 7 、 -(CH2) m OC(O)(CH2) p R 7 、 -(CH2) m C(O)(CH2) p R 7 ; wherein, m and p are each independently 0, 1, 2, 3 or 4, preferably 0, 1 or 2;

[0017] Each R 7 is independently selected from the group consisting of: a hydrogen atom, a deuterium atom, a halogen, a substituted or unsubstituted C1-C8 alkyl group, a C1-C8 haloalkyl group, a C1-C8 deuterated alkyl group, a substituted or unsubstituted C1-C8 alkoxy group, a hydroxyl group, an amino group, a cyano group, a nitro group, a mercapto group, a substituted or unsubstituted C1-C8 alkylene-OH, a substituted or unsubstituted C1-C8 alkylene-NH2, SO2Me, -OC(O)(substituted or unsubstituted C1-C4 alkyl), -C(O)(substituted or unsubstituted C1-C4 alkyl), a substituted or unsubstituted phenyl group, a substituted or unsubstituted 5-7 membered heteroaryl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted 3-12 membered heterocyclic group;

[0018] Unless otherwise specified, each of the above groups may be substituted by a substituent selected from the group consisting of: a deuterium atom, a halogen, a nitrile group, a nitro group, a hydroxyl group, an amino group, C1-C6 alkyl-NH-, (C1-C6 alkyl)2N-, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halo C1-C6 alkyl, halo C2-C6 alkenyl, halo C2-C6 alkynyl, halo C1-C6 alkoxy, allyl, benzyl, C6-C 12 aryl, C1-C6 alkoxy-C1-C6 alkyl, C1-C6 alkoxy-carbonyl, phenoxycarbonyl, C2-C6 alkynyl-carbonyl, C2-C6 alkenyl-carbonyl, C3-C6 cycloalkyl-carbonyl, C1-C6 alkyl-sulfonyl, phenyl, 5-7 membered heteroaryl, C3-C8 cycloalkyl, 3-12 membered heterocyclic; and the compound is not a structure selected from the group consisting of:

[0019]

[0020]

[0021]

[0022]

[0023] In another preferred embodiment, the compound of formula I has the structure shown in formula II or formula III as follows:

[0024]

[0025] In another preferred embodiment, the compound of formula I has the structure shown in formula IV or formula V as follows:

[0026]

[0027] In another preferred embodiment, the compound of formula I has the structure shown in formula VI or formula VII as follows:

[0028]

[0029] In another preferred embodiment, it is characterized in that the R 4 is selected from the group consisting of: a hydrogen atom, a deuterium atom, a halogen, a hydroxyl group, a cyano group, NH2, NO2, a substituted or unsubstituted C1-C8 alkyl group, a substituted or unsubstituted C1-C8 alkoxy group, a substituted or unsubstituted C1-C8 alkylthio group, a substituted or unsubstituted C1-C8 deuterated alkyl group, -(CH2) m (C3-C8 cycloalkyl), -(CH2) m (3-12 membered heterocyclic group), -(CH2) m N(R 7 )2, -(CH2) m S(O)(CH2) p R 7 ; wherein m and p are each independently 0, 1 or 2, and the definition of R m is as described above; p R 7 is selected from the group consisting of: a hydrogen atom, a deuterium atom, a halogen, NH2, OH, a substituted or unsubstituted C1-C8 alkyl group, a substituted or unsubstituted C1-C8 alkoxy group; m NH(CH2) p R 7 ; 7 as defined above;

[0030] R 5 is selected from the group consisting of: a hydrogen atom, a deuterium atom, a halogen, NH2, OH, a substituted or unsubstituted C1-C8 alkyl group, a substituted or unsubstituted C1-C8 alkoxy group;

[0031] Alternatively, R 4 and R 5 together with the carbon atom to which it is attached form a structure selected from the group consisting of: an unsubstituted or one or more R a -substituted saturated or unsaturated 5- to 6-membered carbocyclic ring, an unsubstituted or one or more R a -substituted saturated or unsaturated 5- to 6-membered heterocyclic ring; wherein R a is as defined above.

[0032] In another preferred embodiment, R 4 is selected from the group consisting of: a hydrogen atom, a deuterium atom, a halogen, a hydroxyl group, an amino group, a C1-C3 alkyl group, a C1-C3 alkoxy group, a deuterated C1-C3 alkyl group, a deuterated C1-C3 alkoxy group, a halogen-substituted C1-C3 alkyl group, a halogen-substituted C1-C3 alkoxy group, a C2-C4 alkynyl group, a C3-C6 cycloalkyl group;

[0033] In another preferred embodiment, R 5 is selected from the group consisting of: a hydrogen atom, a deuterium atom, a halogen, a hydroxyl group, an amino group, a C1-C3 alkyl group, a C1-C3 alkoxy group, a deuterated C1-C3 alkyl group, a deuterated C1-C3 alkoxy group, a halogen-substituted C1-C3 alkyl group, a halogen-substituted C1-C3 alkoxy group;

[0034] In another preferred embodiment, R 4 is selected from the group consisting of: methyl, ethyl, methoxy, deuterated methoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, ethynyl, cyclopropyl;

[0035] In another preferred embodiment, R 5 is selected from the group consisting of: methyl, ethyl, methoxy, deuterated methoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy;

[0036] In another preferred embodiment, R 4 and R 5 together form a substituted or unsubstituted -OCH2O- or a substituted or unsubstituted -O(CH2)2O-.

[0037] In another preferred embodiment, R 4 and R 5 together form -OCH2O-, -OCF2O- or -O(CH2)2O-.

[0038] In another preferred embodiment, the compound of formula I has the structure shown in formula VIII as follows:

[0039]

[0040] Among them, ring A is an unsubstituted or one or more R- a substituted saturated or unsaturated 5- or 6-membered carbocyclic ring, an unsubstituted or one or more R- a substituted saturated or unsaturated 5- or 6-membered heterocyclic ring; among them, R- a is defined as described above, and R- 1 , R- 2 , R- 3 , R- 6 , and X are defined as described above.

[0041] In another preferred example, the compound of formula I has the structure shown in formula IX as follows:

[0042]

[0043] In another preferred example, the compound of formula I has the structures shown in formulas X-XV as follows:

[0044]

[0045] Among them, ring A may be unsubstituted or arbitrarily substituted; among them, the definition of the substituent is as described in the text.

[0046] In another preferred example, R- 2 and R- 3 each independently selected from the group consisting of: a hydrogen atom, a deuterium atom, a halogen, NH2, a substituted or unsubstituted C1-C8 alkyl group, a substituted or unsubstituted C1-C8 deuterated alkyl group, -(CH2) m (C3-C6 cycloalkyl), -(CH2) m (3- to 6-membered heterocyclic group), -(CH2) m N(R- 7 )2, -(CH2) m OC(O)R- 7 ; where m is 0, 1, 2, 3 or 4, and R- 7 is defined as described above;

[0047] Or, R- 2 and R- 3 together with the carbon atom to which they are attached form a structure selected from the group consisting of: an unsubstituted or one or more R- a substituted saturated or unsaturated 5- or 6-membered carbocyclic ring, an unsubstituted or one or more R- a substituted saturated or unsaturated 5- or 6-membered heterocyclic ring; among them, R- a is defined as described above.

[0048] In another preferred example, the compound of formula I has the structure shown in formula XVI as follows:

[0049]

[0050] R 2 and R 3 together with the carbon atom to which it is attached form a structure selected from the group consisting of: an unsubstituted or one or more R a substituted saturated or unsaturated 5- or 6-membered carbocyclic ring, an unsubstituted or one or more R a substituted saturated or unsaturated 5- or 6-membered heterocyclic ring; wherein, R a is as defined above, and n is 0 or 1.

[0051] In another preferred embodiment, the compound of formula I has the structure shown in formula XVII below:

[0052]

[0053] In another preferred embodiment, the compound of formula I has the structures shown in formulae XVIII - XXII below:

[0054]

[0055] Ring B may be unsubstituted or arbitrarily substituted; wherein, the substituents are as defined in the text.

[0056] In another preferred embodiment, ring B is substituted with a substituent shown by the following formula:

[0057] -(L) x -R 11

[0058] wherein, x is 1, 2, 3, 4, 5 or 6;

[0059] each L is independently selected from the group consisting of: CH2, O, S, NH, NHC(O), C(O), C(NH), S(O), S(O)2, C6-C 10 aryl, 5- to 10-membered heteroaryl, 3- to 8-membered saturated or unsaturated carbocyclic ring, 4- to 10-membered saturated or unsaturated heterocyclic ring;

[0060] R 11 is selected from the group consisting of: OH, SH, NH2.

[0061] In another preferred embodiment, ring B may be unsubstituted or substituted with -(L) x -R 11 arbitrarily;

[0062] wherein, x is any integer from 0 to 10;

[0063] each L is independently selected from the group consisting of: CR W R x 、O、S、NH、NRy 、 NHC(O), C(O), C(NH), S(O), S(O)2, C6-C 10 aryl, 5- to 10-membered heteroaryl, 3- to 8-membered saturated or unsaturated carbocycle, 3- to 10-membered saturated or unsaturated heterocycle;

[0064] R 11 is selected from the group consisting of: a hydrogen atom, OH, SH, NH2, NHR z .

[0065] Said R W , R x , R y and R z each independently is selected from the group consisting of: a hydrogen atom, a deuterium atom, a halogen, a hydroxyl group, NH2, a substituted or unsubstituted C 1-4 alkyl, C 1-4 haloalkyl, C4-C 10 cycloalkylalkyl, a substituted or unsubstituted C3-C6 cycloalkyl.

[0066] In another preferred embodiment, said R a is selected from the group consisting of: a hydrogen atom, a deuterium atom, a halogen, a nitrile group, a nitro group, a hydroxyl group, an amino group, C1-C6 alkyl-NH-, (C1-C6 alkyl)2N-, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halo C1-C6 alkyl, halo C2-C6 alkenyl, halo C2-C6 alkynyl, halo C1-C6 alkoxy, allyl, benzyl, C6-C 12 aryl, C1-C6 alkoxy-C1-C6 alkyl, C1-C6 alkoxy-carbonyl, -(CH2) m N(R 7 )2, -(CH2) m NH(CH2) p R 7 , -(CH2) m NHC(O)(CH2) p R 7 ; wherein m and p are each independently 0, 1, 2, 3 or 4, preferably 0, 1 or 2.

[0067] In another preferred embodiment, R 1 and R 6 are each independently a hydrogen atom.

[0068] In another preferred embodiment, X is independently selected from N, CH.

[0069] In another preferred embodiment, X is independently selected from CH.

[0070] In another preferred embodiment, said R 4 and R5 Each independently selected from the group consisting of: a hydrogen atom, a deuterium atom, a halogen, a hydroxyl group, NH2, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted C1-C4 alkoxy group, a cyclopropyl group;

[0071] Alternatively, R 4 and R 5 together with the carbon atom to which they are attached form an unsubstituted or one or more R a substituted 5- or 6-membered oxaheterocycle; wherein, R a is as defined above.

[0072] In another preferred example, R 2 is selected from the group consisting of: a hydrogen atom, a deuterium atom, a halogen, NH2, a substituted or unsubstituted C1-C8 alkyl group, a substituted or unsubstituted C1-C8 deuterated alkyl group, -(CH2) m (C3-C6 cycloalkyl), -(CH2) m (3- to 6-membered heterocyclic group), -(CH2) m N(R 7 )2, -(CH2) m OC(O)R 7 ; wherein, m is 0, 1, 2, 3 or 4;

[0073] R 3 each is independently selected from the group consisting of: a hydrogen atom, a deuterium atom, a halogen, a substituted or unsubstituted C1-C8 alkyl group, a substituted or unsubstituted C1-C8 deuterated alkyl group, -(CH2) m (C3-C6 cycloalkyl), -(CH2) m (3- to 6-membered heterocyclic group), -(CH2) m N(R 7 )2, -(CH2) m OC(O)R 7 ; wherein, m is 0, 1, 2, 3 or 4;

[0074] Alternatively, R 2 and R 3 together with the carbon atom to which they are attached form a structure selected from the group consisting of: an unsubstituted or one or more R a substituted saturated or unsaturated 5- or 6-membered carbocyclic ring, an unsubstituted or one or more R a substituted saturated or unsaturated 5- or 6-membered heterocyclic ring;

[0075] R 4 is selected from the group consisting of: a hydrogen atom, a deuterium atom, a halogen, a hydroxyl group, a cyano group, NH2, NO2, a substituted or unsubstituted C1-C8 alkyl group, a substituted or unsubstituted C1-C8 alkoxy group;

[0076] R 5Selected from the group consisting of: a hydrogen atom, a deuterium atom, a halogen, a substituted or unsubstituted C1-C8 alkyl group;

[0077] Alternatively, R 4 and R 5 are linked together to jointly form an unsubstituted or one or more R a substituted structure selected from the group consisting of: -OCH2O- or -O(CH2)2O-;

[0078] R 7 is selected from the group consisting of: a hydrogen atom, a deuterium atom, a halogen, a substituted or unsubstituted C1-C8 alkyl group, a hydroxyl group, an amino group, a cyano group, a nitro group, a mercapto group;

[0079] wherein, R a is as defined above.

[0080] In a second aspect of the present invention, there is provided a compound represented by the following formula (A-I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotope variant thereof, and mixtures thereof:

[0081]

[0082] The Ar ring is a 5-6 membered aromatic ring or an aromatic heterocycle, and the Ar ring may be unsubstituted or optionally substituted by R 3 、R 4 、R 5 、R 6 each independently;

[0083] Y is selected from the group consisting of: a chemical bond, a C1-C6 alkylene group, a C1-C6 deuterated alkylene group, -O-, -NH-, -NRb-, -CHR b -;

[0084] X is selected from the group consisting of: N or CR 0 ;

[0085] R 0 is selected from the group consisting of: a hydrogen atom, a deuterium atom, a halogen, a C1-C8 alkyl group, a C1-C8 deuterated alkyl group, a C1-C8 fluoroalkyl group, a C1-C8 alkoxy group, a C1-C8 deuterated alkoxy group, a hydroxyl group, -NH2, -N3, NO2 or a cyano group;

[0086] R 1Selected from the group consisting of a hydrogen atom, a deuterium atom, a halogen, a cyano group, a C1-C8 alkyl group, a C1-C8 deuterated alkyl group, a C1-C8 alkoxy group, a C1-C8 haloalkyl group, a C1-C8 deuterated alkoxy group, a C1-C8 haloalkoxy group, N3, NO2, NH2, NH-OH, -NR'R", -COOR', -CONR'R", -NHR"'NR'R", wherein R', R" and R'" are each independently selected from the group consisting of hydrogen, an alkyl group, an aryl group, an arylalkyl group, an acyl group, an alkoxycarbonyl group, and an aryloxycarbonyl group;

[0087] R 2 , R 3 , R 4 , R 5 and R 6 Each independently selected from the group consisting of a hydrogen atom, a deuterium atom, a halogen, a hydroxyl group, a mercapto group, a cyano group, -NH2, -NO2, -NHR b , -N(Rb)(AA), -O(AA), substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkylene-O(AA), substituted or unsubstituted C1-C8 alkylene-NH(AA), substituted or unsubstituted C1-C8 alkylene-N(R b )(AA), substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted C1-C8 alkylthio, substituted or unsubstituted C1-C8 deuterated alkyl, substituted or unsubstituted C1-C8 deuterated alkoxy, substituted or unsubstituted C1-C8 fluoroalkyl, substituted or unsubstituted C1-C8 fluoroalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, -(CH2) m tri(C1-C4alkyl)silyl, -(CH2) m (C3-C 12 Cycloalkyl), -(CH2) m (C3-C 12 Cycloalkyl)(CH2) p R 7 、-(CH2) m (3-12 membered heterocycloalkyl), -(CH2) m (3-12 membered heterocycloalkyl)(CH2) p R 7 、-(CH2) m (3-12 membered heterocycloalkyl)NHR 7 、-(CH2) m (3-12 membered heterocycloalkyl)N(R 7 )2、-(CH2) m (C3-C 12 Cycloalkyl)OH, -(CH2) m (C3-C 12(cycloalkyl)OR 7 、-(CH2) m (C3-C 12 (cycloalkyl)NH2、-(CH2) m (C3-C 12 (cycloalkyl)NH(C1-C8 alkyl)、-(CH2) m (C3-C 12 (cycloalkyl)NHR 7 、-(CH2) m (3- to 12-membered heterocyclic group)、-(CH2) m (3- to 12-membered heterocyclic group)(CH2) p R 7 、-(CH2) m (3- to 12-membered heterocyclic group)NHR7、-(CH2) m (3- to 12-membered heterocyclic group)N(R7)2、-(C1-C8 alkylene)N(R 7 )2、-(C1-C8 alkylene)N(R 7 )(AA)、-(CH2) m N(R 7 )2、-(CH2) m N(R 7 )(AA)、-(CH2) m OR 7 、-(CH2) m O(AA)、-(CH2) m SR 7 、-(CH2) m S(O)R 7 、-(CH2) m S(O)2R 7 、-(CH2) m S(AA)、-(CH2) m Ph-N(R 7 )2、-(CH2) m Ph-N(R 7 )(AA)、-(CH2) m S(CH2) p R 7 、-(CH2) m S(O)(CH2) p R 7 、-(CH2) m S(O)2(CH2) p R 7 、-(CH2) m NHS(O)2(CH2) p R 7 、-(CH2)m S(O)2NH(CH2) p R 7 、-(CH2) m NHS(O)2NH(CH2) p R 7 、-(CH2) m S(O)2NR 7 (CH2) p R 7 、-(CH2) m NH(CH2) p R 7 、-(CH2) m NHC(O)(CH2) p R 7 、-(CH2) m OC(O)(CH2) p R 7 、-(CH2) m C(O)(CH2) p R 7 、-(CH2) m C(O)NH(CH2) p R 7 、-(CH2) m NR 7 C(O)(CH2) p R 7 、-(CH2) m C(O)NR 7 (CH2) p R 7 、-(CH2) m NHC(O)NH(CH2) p R 7 、-(CH2) m OC(O)NH(CH2) p R 7 、-(CH2) m NHC(O)O(CH2) p R 7 、-(CH2) m NR 7 C(O)NR 7 (CH2) p R 7 、-(CH2) m OC(O)NR 7 (CH2) p R 7 、-(CH2) m NR 7 C(O)O(CH2) pR 7 、 -(CH2) m C(O)O(CH2) p R 7 、 -CH=N(OR 7 )、 -CH=NR 7 、 -CH=N-NHR 7 、 -CH=N-N(R 7 )2、 -NH-NHR 7 、 -NH-N(R 7 )2; wherein, m and p are each independently 0, 1, 2, 3 or 4;

[0088] Or, R 2 、 R 3 、 R 4 、 R 5 and R 6 are each independently selected from -(L) x -R 11 ,

[0089] wherein, x is any integer from 0 to 10;

[0090] Each L is independently selected from the following group: CR w R x 、 O、 S、 NH、 NR y 、 NHC(O)、 C(O)NH、 C(O)、 C(O)O、 OC(O)、 C(NH)、 C(NH)O、 OC(NH)、 C(N-CN)、 S(O)、 S(O)2、 S(O)2NH、 S(O)2NR z 、 NH S(O)2、 NR z S(O)2、 Si(R z )2、 PH、 PR z 、 P(O)、 P(O)NH、 P(O)NR z 、 NHP(O)、 NR z P(O)、 P(O)O、 OP(O)、 -CH=CH-、 -c≡c-、 C=N、 C=N-NH、 C=N-NR z 、 C=N-O、 NH-NH、 NR z -NR z 、 NR z -O、 substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 3-10 membered saturated or unsaturated carbocycle, substituted or unsubstituted 3-10 membered saturated or unsaturated heterocycle;

[0091] R 11Selected from the group: hydrogen atom, OH, SH, NH2, OR z , SR z , NHR z , N(R z )2;

[0092] Said R w , R x , R y and R z are each independently selected from the group: hydrogen atom, deuterium atom, halogen, hydroxyl group, NH2, substituted or unsubstituted C 1-4 alkyl, C 1-4 deuterated alkyl, C 1-4 haloalkyl, substituted or unsubstituted C3-C 10 cycloalkylalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted C3-C 10 heterocyclic alkyl, substituted or unsubstituted C3-C 10 heterocyclic group, C1-C6 alkyl-sulfonyl.

[0093] Alternatively, R 2 and R 3 together with the carbon atom to which they are attached form a structure selected from the group: substituted or unsubstituted C5-C 12 carbocyclic ring, substituted or unsubstituted 5-12 membered heterocyclic group, unsubstituted or substituted by one or more R a substituted saturated or unsaturated 5-12 membered carbocyclic ring, unsubstituted or substituted by one or more R a substituted saturated or unsaturated 5-12 membered heterocyclic ring;

[0094] Alternatively, R 3 and R 4 together with the carbon atom to which they are attached form a structure selected from the group: substituted or unsubstituted C5-C 12 carbocyclic ring, substituted or unsubstituted 5-12 membered heterocyclic group, unsubstituted or substituted by one or more R a substituted saturated or unsaturated 5-12 membered carbocyclic ring, unsubstituted or substituted by one or more R a substituted saturated or unsaturated 5-12 membered heterocyclic ring;

[0095] Alternatively, R 4 and R 5 together with the carbon atom to which they are attached form a structure selected from the group: unsubstituted or substituted by one or more R a substituted saturated or unsaturated 5-12 membered carbocyclic ring, unsubstituted or substituted by one or more R a substituted saturated or unsaturated 5-12 membered heterocyclic ring;

[0096] R8 and R 9 Each is independently selected from the following group: a hydrogen atom, a deuterium atom, a halogen, a hydroxyl group, a cyano group, NH2, NO2, a substituted or unsubstituted C1-C8 alkyl group, a substituted or unsubstituted C1-C8 deuterated alkyl group, a substituted or unsubstituted C1-C8 alkoxy group, a 3-6 membered cycloalkyl group, a 3-6 membered heterocycloalkyl group;

[0097] Or, R 8 and R 9 The carbon atoms connected thereto together form a structure selected from the group consisting of: unsubstituted or substituted with one or more R a substituted saturated or unsaturated 3-6 membered carbon ring, unsubstituted or replaced by one or more R a a substituted saturated or unsaturated 3-6 membered heterocycle;

[0098] R a Each independently selected from the group consisting of a hydrogen atom, a deuterium atom, a halogen, a hydroxyl group, a mercapto group, a cyano group, -NH2, -NO2, -NHR b 、-N(R b )(AA), -O(AA), substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkylene-O(AA), substituted or unsubstituted C1-C8 alkylene-NH(AA), substituted or unsubstituted C1-C8 alkylene-N(R b )(AA), substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted C1-C8 alkylthio, substituted or unsubstituted C1-C8 deuterated alkyl, substituted or unsubstituted C1-C8 deuterated alkoxy, substituted or unsubstituted C1-C8 fluoroalkyl, substituted or unsubstituted C1-C8 fluoroalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, -(CH2) m tri(C1-C4alkyl)silyl, -(CH2) m (C3-C 12 Cycloalkyl), -(CH2) m (C3-C 12 Cycloalkyl)(CH2) p R 7 、-(CH2) m (3-12 membered heterocycloalkyl), -(CH2) m (3-12 membered heterocycloalkyl)(CH2) p R 7 、-(CH2) m (3-12 membered heterocycloalkyl)NHR 7 、-(CH2) m (3-12 membered heterocycloalkyl)N(R 7 )2、-(CH2) m(C3-C 12 cycloalkyl)OH, -(CH2) m (C3-C 12 cycloalkyl)OR 7 , -(CH2) m (C3-C 12 cycloalkyl)NH2, -(CH2) m (C3-C 12 cycloalkyl)NH(C1-C8 alkyl), -(CH2) m (C3-C 12 cycloalkyl)NHR 7 , -(CH2) m (3- to 12-membered heterocyclic group), -(CH2) m (3- to 12-membered heterocyclic group)(CH2) p R 7 , -(CH2) m (3- to 12-membered heterocyclic group)NHR7, -(CH2) m (3- to 12-membered heterocyclic group)N(R7)2, -(C1-C8 alkylene)N(R 7 ), -(C1-C8 alkylene)N(R 7 )(AA), -(CH2) m N(R 7 ), -(CH2) m N(R7)(AA), -(CH2) m OR 7 , -(CH2) m O(AA), -(CH2) m SR 7 , -(CH2) m S(O)R 7 , -(CH2) m S(O)2R 7 , -(CH2) m S(AA), -(CH2) m Ph-N(R 7 ), -(CH2) m Ph-N(R 7 )(AA), -(CH2) m S(CH2) p R 7 , -(CH2) m S(O)(CH2) p R 7 , -(CH2) m S(O)2(CH2) p R 7 , -(CH2) mNHS(O)2(CH2) p R 7 、-(CH2) m S(O)2NH(CH2) p R 7 、-(CH2) m NHS(O)2NH(CH2) p R 7 、-(CH2) m S(O)2NR 7 (CH2) p R 7 、-(CH2) m NH(CH2) p R 7 、-(CH2) m NHC(O)(CH2) p R 7 、-(CH2) m OC(O)(CH2) p R 7 、-(CH2) m C(O)(CH2) p R 7 、-(CH2) m C(O)NH(CH2) p R 7 、-(CH2) m NR 7 C(O)(CH2) p R 7 、-(CH2) m C(O)NR 7 (CH2) p R 7 、-(CH2) m NHC(O)NH(CH2) p R 7 、-(CH2) m OC(O)NH(CH2) p R 7 、-(CH2) m NHC(O)O(CH2) p R 7 、-(CH2) m NR 7 C(O)NR 7 (CH2) p R 7 、-(CH2) m OC(O)NR 7 (CH2) p R 7 、-(CH2)m NR 7 C(O)O(CH2) p R 7 、-(CH2) m C(O)O(CH2) p R 7 、-CH=N(OR 7 ), -CH=NR 7 、-CH=N-NHR 7 、-CH=NN(R 7 )2, -NH-NHR 7 、-NH-N(R 7 )2; wherein m and p are each independently 0, 1, 2, 3 or 4;

[0099] Or, R a Each independently selected from -(L) x -R 11 ,

[0100] Wherein, x is any integer from 0 to 10;

[0101] Each L is independently selected from the group consisting of: CR w R x , O, S, NH, NR y , NHC(O), C(O)NH, C(O), C(O)O, OC(O), C(NH), C(NH)O, OC(NH), C(N-CN), S(O), S(O)2, S(O)2NH, S(O)2NR z 、NH S(O)2、NR z S(O)2、Si(R z )2. PH, PR z 、P(O)、P(O)NH、P(O)NR z 、NHP(O)、NR z P(O), P(O)O, OP(O), -CH=CH-, -c≡c-, C=N, C=N-NH, C=N-NR z 、C=NO、NH-NH、NR z -NR z NR z -O, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 3-10 membered saturated or unsaturated carbocyclic ring, substituted or unsubstituted 3-10 membered saturated or unsaturated heterocyclic ring;

[0102] R 11 Selected from the following group: hydrogen atom, OH, SH, NH2, ORz , SR z , NHR z , N(R z )2;

[0103] The R w , R x , R y and R z each independently selected from the group consisting of: a hydrogen atom, a deuterium atom, a halogen, a hydroxyl group, NH2, a substituted or unsubstituted C 1-4 alkyl, C 1-4 deuterated alkyl, C 1-4 haloalkyl, a substituted or unsubstituted C 3- C 10 cycloalkylalkyl, a substituted or unsubstituted C 3- C 10 cycloalkyl, a substituted or unsubstituted C 3- C 10 heterocyclic alkyl, a substituted or unsubstituted C 3- C 10 heterocyclic group, C1-C6 alkyl-sulfonyl.

[0104] R b is selected from a hydrogen atom, a halogen, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 3-6 membered heterocyclic alkyl;

[0105] AA is selected from an amino acid or a group formed by removing the hydroxyl group in the carboxylic acid structure from a polypeptide structure formed by 2-5 amino acids, and the amino acid can be a natural amino acid or a non-natural amino acid;

[0106] Each R 7Each independently selected from the following group: hydrogen atom, deuterium atom, halogen, -COOH, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted 2-8 membered heteroalkyl, C1-C8 haloalkyl, substituted or unsubstituted C1-C8 deuterated alkyl, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted C1-C8 fluoroalkyl, hydroxy, amino, cyano, nitro, mercapto, N3, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted C1-C8 alkylene-OH, substituted or unsubstituted C1-C8 alkylene-NH2, substituted or unsubstituted C1-C8 alkylene-O-substituted or unsubstituted C1-C8 alkylene-OH, substituted or unsubstituted C1-C8 alkylene-O-substituted or unsubstituted C1-C8 alkylene-NH2, substituted or unsubstituted C1-C8 alkylene-NH-substituted or unsubstituted C1-C8 alkylene-OH, substituted or unsubstituted C1-C8 alkylene-O-substituted or unsubstituted C1-C8 alkylene-NH(C1-C4 alkyl), substituted or unsubstituted C1-C8 alkylene-N(C1-C4 alkyl)-substituted or unsubstituted C1-C8 alkylene-OH, substituted or unsubstituted C1-C8 alkylene-NH(C1-C4 alkyl), substituted or unsubstituted 2-8 membered heteroalkylene-OH, substituted or unsubstituted 2-8 membered heteroalkylene-NH2, substituted or unsubstituted 2-8 membered heteroalkylene-NH(C1-C4 alkyl), SO2(C1-C8 alkyl), SO2O(C1-C8 alkyl), SO2NH(C1-C8 alkyl), -NHC(O)(substituted or unsubstituted C1-C4 alkyl), -N(substituted or unsubstituted C1-C4 alkyl)C(O)(substituted or unsubstituted C1-C4 alkyl), -OC(O)(substituted or unsubstituted C1-C4 alkyl), -OC(O)(substituted or unsubstituted C1-C4 alkylene)OH, -OC(O)(substituted or unsubstituted C1-C4 alkylene)NH2, -OC(O)(substituted or unsubstituted C1-C4 alkylene)NH(substituted or unsubstituted C1-C4 alkyl), -C(O)(substituted or unsubstituted C1-C4 alkyl), -C(O)(substituted or unsubstituted C1-C8 alkylene)OH, -C(O)(substituted or unsubstituted C1-C8 alkylene)NH2, -C(O)(substituted or unsubstituted C1-C8 alkylene)NH(C1-C8 alkyl), substituted or unsubstituted phenyl, substituted or unsubstituted C1-C8 alkylene-substituted or unsubstituted phenyl, substituted or unsubstituted C1-C8 heteroalkylene-substituted or unsubstituted phenyl, substituted or unsubstituted 5-7 membered heteroaryl, substituted or unsubstituted C1-C8 alkylene-substituted or unsubstituted 5-7 membered heteroaryl, substituted or unsubstituted C1-C8 heteroalkylene-substituted or unsubstituted 5-7 membered heteroaryl, substituted or unsubstituted C3-C8 cycloalkylSubstituted or unsubstituted C1-C8 alkylene-substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C1-C8 heteroalkylene-substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic group, substituted or unsubstituted C1-C8 alkylene-substituted or unsubstituted 3-12 membered heterocyclic group, substituted or unsubstituted C1-C8 alkylene-substituted or unsubstituted 3-12 membered heterocyclic group, -CH=N(O(C1-C8 alkyl)), -CH=N(C1-C8 alkyl);

[0107] R 10 Selected from the group consisting of: hydrogen atom, deuterium atom, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxy, C1-C8 deuterated alkyl, C3-C8 cycloalkyl, C4-C 10 Cycloalkylalkyl, C1-C8 alkyl C3-C8 cycloalkyl;

[0108] Unless otherwise specified, each of the above groups may be substituted by substituents selected from the group consisting of: hydrogen atom, deuterium atom, halogen, nitrile group, nitro group, hydroxyl group, amino group, C1-C6 alkyl-NH-, (C1-C6 alkyl)2N-, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halo C1-C6 alkyl, halo C2-C6 alkenyl, halo C2-C6 alkynyl, halo C1-C6 alkoxy, allyl, benzyl, C6-C 12 Aryl, C1-C6 alkoxy-C1-C6 alkyl, C1-C6 alkoxy-carbonyl, phenoxycarbonyl, C2-C6 alkynyl-carbonyl, C2-C6 alkenyl-carbonyl, C3-C6 cycloalkyl-carbonyl, C1-C6 alkyl-sulfonyl, phenyl, 5-7 membered heteroaryl, C3-C8 cycloalkyl, 3-12 membered heterocyclic group; the heterocyclic or heterocyclic group may be a saturated or partially unsaturated structure, but does not have aromaticity; the carbocyclic or heterocyclic ring is a monocyclic, spirocyclic, fused ring or bridged ring; the aromatic ring or heteroaromatic ring may be a monocyclic or fused ring.

[0109] In another preferred embodiment, it is characterized in that in the structure of the compound of formula (A-I), the Structural fragment shown is selected from the group consisting of:

[0110] The Ar ring may be unsubstituted or arbitrarily substituted by R 3 、R 4 、R 5 、R 6 Independently of each other; R 2 、R 3 、R 4 、R 5 、R 6 Are defined as described in the text;

[0111] In another preferred embodiment, it is characterized in that in the structure of the compound of formula (A-I) the structural fragment shown is selected from the group R 2 、R 3 、R 4 、R 5 、R 6 are defined as described in the text;

[0112] In another preferred embodiment, it is characterized in that R 2 and R 3 together with the carbon atom to which they are attached form a structure selected from the group consisting of: a substituted or unsubstituted C5-C 12 carbocyclic ring, a substituted or unsubstituted 5- to 12-membered heterocyclic group, an unsubstituted or saturated or unsaturated 5- to 12-membered carbocyclic ring substituted with one or more R a 、an unsubstituted or saturated or unsaturated 5- to 12-membered heterocyclic ring substituted with one or more R a ; wherein R a is defined as described in the text.

[0113] In another preferred embodiment, it is characterized in that in the structure of the compound of formula (A-I) in the structural fragment shown, R 2 and R 3 on the Ar ring form a ring (B) structure selected from the group consisting of:

[0114]

[0115]

[0116]

[0117] wherein, ring (B) may be unsubstituted or substituted with one to more R a 、R a is defined as described in the text;

[0118] In another preferred embodiment, it is characterized in that R 4 and R 5 together with the carbon atom to which they are attached form a structure selected from the group consisting of: a substituted or unsubstituted C5-C 12 carbocyclic ring, a substituted or unsubstituted 5- to 12-membered heterocyclic group, an unsubstituted or saturated or unsaturated 5- to 12-membered carbocyclic ring substituted with one or more R a 、an unsubstituted or saturated or unsaturated 5- to 12-membered heterocyclic ring substituted with one or more R aSubstituted saturated or unsaturated 5- to 12-membered heterocycles; wherein R a is as defined herein.

[0119] In another preferred embodiment, it is characterized in that in the structure of the compound of formula (A-I) for the structural fragment shown, R on the Ar ring 4 and R 5 form a ring (A) structure selected from the group:

[0120]

[0121]

[0122] wherein, ring (A) may be unsubstituted or substituted by one or more R a substituents, and R a is as defined herein;

[0123] In another preferred embodiment, it is characterized in that R 3 and R 4 together with the carbon atom to which they are attached form a structure selected from the group consisting of: substituted or unsubstituted C5-C 12 carbocyclic ring, substituted or unsubstituted 5- to 12-membered heterocyclic group, unsubstituted or substituted by one or more R a substituted saturated or unsaturated 5- to 12-membered carbocyclic ring, unsubstituted or substituted by one or more R a substituted saturated or unsaturated 5- to 12-membered heterocycles; wherein R a is as defined herein.

[0124] In another preferred embodiment, it is characterized in that in the structure of the compound of formula (A-I) for the structural fragment shown, R on the Ar ring 3 and R 4 form a ring (C) structure selected from the group:

[0125]

[0126]

[0127] wherein, ring (C) may be unsubstituted or substituted by one or more R a substituents, and R a is as defined herein;

[0128] In another preferred embodiment, it is characterized in that the structural fragment shown in the structure of the compound of formula (A-I) is selected from the group

[0129] In another preferred example, it is characterized in that the R 2 , R 3 , R 4 , R 5 , R 6 , R a are each independently selected from the group consisting of: -OH, NH2, -SH, -F, -Cl, -Br, -I, -OMe, -OCD3, -OCF3, OCFH2, OCF2H, OCF3, CN, SMe, S(O)Me, S(O)2Me,

[0130]

[0131]

[0132]

[0133]

[0134]

[0135]

[0136]

[0137]

[0138]

[0139]

[0140]

[0141]

[0142]

[0143]

[0144]

[0145]

[0146]

[0147] In another preferred example, it is characterized in that the X is CH.

[0148] In another preferred example, it is characterized in that Y is a chemical bond, methylene, deuterated methylene, -O-, -NH-.

[0149] In another preferred example, it is characterized in that the R 8 is a hydrogen atom or a deuterium atom.

[0150] In another preferred example, it is characterized in that the R 9 is a hydrogen atom or a deuterium atom.

[0151] In another preferred example, it is characterized in that the R 5 is a hydrogen atom, a deuterium atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a methyl group, a deuterated methyl group, a methoxy group, a deuterated methoxy group, a monofluoromethyl group, a difluoromethyl group, or a trifluoromethyl group.

[0152] In another preferred example, it is characterized in that the R 6 is a hydrogen atom, a deuterium atom, a fluorine atom, or a chlorine atom.

[0153] In another preferred example, it is characterized in that the amino acids in the AA composition are each independently selected from the group consisting of glycine, alanine, valine, leucine, isoleucine, methionine, proline, tryptophan, serine, tyrosine, cysteine, phenylalanine, asparagine, glutamine, threonine, aspartic acid, glutamic acid, lysine, arginine, and histidine;

[0154] In another preferred example, it is characterized in that the AA group is selected from the group consisting of:

[0155]

[0156] In another preferred example, it is characterized in that the compound of formula (A-I) has the structure shown in formula (A-II-1):

[0157]

[0158] Wherein,

[0159] M is selected from the group consisting of: N or CR 5 ;

[0160] R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 8 、R 9 、X, Y are defined as described in the text;

[0161] In another preferred example, it is characterized in that the compound of formula (A-I) has the structure shown in formula (A-II-2) as follows:

[0162]

[0163] Wherein,

[0164] R 2 、R 3 、R 4 、R 5 、R 8 、R 9 are defined as described in the text;

[0165] In another preferred example, it is characterized in that the compound of formula (A-I) has the structure shown in formula (A-II-3) as follows:

[0166]

[0167] Wherein,

[0168] R 2 、R 3 、R 4 、R 5 、R 8 、R 9 are defined as described in the text;

[0169] In another preferred example, it is characterized in that the compound of formula (A-I) has the structure shown in formula (A-II-4) as follows:

[0170]

[0171] Wherein,

[0172] R 2 、R 3 、R 4 、R 5 are defined as described in the text;

[0173] In another preferred example, it is characterized in that the compound of formula (A-I) has the structure shown in formula (A-II-5) as follows:

[0174]

[0175] Wherein,

[0176] R 2 、R 3 、R 4 、R 6 、R 8 、R 9 、M are defined as described in the text;

[0177] In another preferred example, it is characterized in that the R 3 is a hydrogen atom, a deuterium atom, a fluorine atom, a chlorine atom, a nitro group, a cyano group, NH2.

[0178] In another preferred example, it is characterized in that the R 4 is a fluorine atom, a chlorine atom, a bromine atom, a methyl group, a deuterated methyl group, a methoxy group, a cyclopropyl group, an ethynyl group, a difluoromethyl group, a difluoromethoxy group, a trifluoromethyl group, a trifluoromethoxy group, a pentafluorothio group, a nitro group, a cyano group, a hydroxyl group, NH2.

[0179] In another preferred example, it is characterized in that the R 6 is a hydrogen atom, a fluorine atom.

[0180] In another preferred example, it is characterized in that the R 8 is a hydrogen atom, a deuterium atom.

[0181] In another preferred example, it is characterized in that the R 9 is a hydrogen atom, a deuterium atom.

[0182] In another preferred example, it is characterized in that the M is N, C-H, C-F, C-Cl.

[0183] In another preferred example, it is characterized in that the compound of formula (A-I) has the structure shown in formula (A-II-6):

[0184]

[0185] wherein,

[0186] R 2 、R 3 、R 5 、R 6 、R 8 、R 9 are defined as described in the text;

[0187] In another preferred example, it is characterized in that the R 3 is a hydrogen atom, a deuterium atom, a fluorine atom, a chlorine atom, a nitro group, a cyano group, NH2.

[0188] In another preferred example, it is characterized in that the R 5 is a fluorine atom, a chlorine atom, a bromine atom, a methyl group, a deuterated methyl group, a methoxy group, a cyclopropyl group, a difluoromethyl group, a trifluoromethyl group, a trifluoromethoxy group, a pentafluorothio group, a cyano group.

[0189] In another preferred example, it is characterized in that the R 6 is a hydrogen atom, a fluorine atom.

[0190] In another preferred example, it is characterized in that the R 8 is a hydrogen atom or a deuterium atom.

[0191] In another preferred example, it is characterized in that the R 9 is a hydrogen atom or a deuterium atom.

[0192] In another preferred example, it is characterized in that the compound of formula (A-I) has the structure shown in the following formula (A-II-7):

[0193]

[0194] Wherein,

[0195] R 3 、R 4 、R 5 、R 6 、R 8 、R 9 、R 11 、L are defined as described in the text;

[0196] x is any integer from 0 to 10;

[0197] In another preferred example, it is characterized in that the R 3 is a hydrogen atom, a deuterium atom, a fluorine atom, a chlorine atom, a nitro group, a cyano group, NH2.

[0198] In another preferred example, it is characterized in that the R 4 is a fluorine atom, a chlorine atom, a methyl group, a methoxy group, a trifluoromethyl group, a trifluoromethoxy group, a cyclopropyl group, an ethynyl group, OH, NH2.

[0199] In another preferred example, it is characterized in that the R 5 is a fluorine atom, a chlorine atom, a bromine atom, a methyl group, a deuterated methyl group, a methoxy group, a cyclopropyl group, a difluoromethyl group, a trifluoromethyl group, a trifluoromethoxy group, a pentafluorothio group, a cyano group.

[0200] In another preferred example, it is characterized in that the R 6 is a hydrogen atom, a deuterium atom, a fluorine atom.

[0201] In another preferred example, it is characterized in that the R 8 is a hydrogen atom, a deuterium atom.

[0202] In another preferred example, it is characterized in that the R 9 is a hydrogen atom, a deuterium atom.

[0203] In another preferred example, it is characterized in that the compound of formula (A-I) has the structure shown in the following formula (A-II-8):

[0204]

[0205] Among them,

[0206] R 5 、R 6 、R 8 、R 9 、R 10 、Y are defined as described in the text;

[0207] x is any integer from 2 to 10;

[0208] Each L 1 is independently selected from the following group: CR w R x 、O、S、NH、NR y 、NHC(O)、C(O)NH、C(O)、C(O)O、O C(O)、C(NH)、C(NH)O、OC(NH)、C(N-CN)、S(O)、S(O)2、S(O)2NH、S(O)2NR z 、NH S(O)2、NR z S(O)2、Si(R z )2、PH、PR z 、P(O)、P(O)NH、P(O)NR z 、NHP(O)、NR z P(O)、P(O)O、O P(O)、C=N、C=N-NH、C=N-NR z 、C=N-O、NH-NH、NR z -NR z 、NR z -O, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 5-10-membered heteroaryl, substituted or unsubstituted 3-10-membered saturated or unsaturated carbocycle, substituted or unsubstituted 3-10-membered saturated or unsaturated heterocycle;

[0209] R 11 is selected from the following group: hydrogen atom, OH, SH, NH2, OR z 、SR z 、NHR z 、N(R z )2;

[0210] The said R w 、R x 、R y and R z are independently selected from the following group: hydrogen atom, deuterium atom, halogen, hydroxyl group, NH2, substituted or unsubstituted C 1-4 alkyl, C 1-4Deuterated alkyl, C 1-4 Halogenated alkyl, substituted or unsubstituted C3-C 10 Cycloalkylalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Heterocyclic alkyl, substituted or unsubstituted C3-C 10 Heterocyclic group, C1-C6 alkyl-sulfonyl.

[0211] In another preferred example, it is characterized in that the compound of formula (A-I) has the structure shown in formula (A-II-9):

[0212]

[0213] Wherein,

[0214] R 5 、R 6 、R 8 、R 9 Are defined as described in the text;

[0215] x is any integer from 2 to 10;

[0216] Each L 1 Is independently selected from the group consisting of: CR w R x 、O、S、NH、NR y 、NHC(O)、C(O)NH、C(O)、C(O)O、O C(O)、C(NH)、C(NH)O、OC(NH)、C(N-CN)、S(O)、S(O)2、S(O)2NH、S(O)2NR z 、NH S(O)2、NR z S(O)2、Si(R z )2、PH、PR z 、P(O)、P(O)NH、P(O)NR z 、NHP(O)、NR z P(O)、P(O)O、O P(O)、C=N、C=N-NH、C=N-NR z 、C=N-O、NH-NH、NR z -NR z 、NR z -O、substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 3-10 membered saturated or unsaturated carbocycle, substituted or unsubstituted 3-10 membered saturated or unsaturated heterocycle;

[0217] R 11Selected from the following group: hydrogen atom, OH, SH, NH2, OR z , SR z , NHR z , N(R z )2;

[0218] Said R w , R x , R y and R z each independently selected from the following group: hydrogen atom, deuterium atom, halogen, hydroxyl group, NH2, substituted or unsubstituted C 1-4 alkyl, C 1-4 deuterated alkyl, C 1-4 haloalkyl, substituted or unsubstituted C3-C 10 cycloalkylalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted C3-C 10 heterocyclic alkyl, substituted or unsubstituted C3-C 10 heterocyclic group, C1-C6 alkyl-sulfonyl.

[0219] In another preferred embodiment, it is characterized in that the compound of formula (A-I) has the structure shown in formula (A-II-10):

[0220]

[0221] Wherein,

[0222] R 5 , R 6 , R 8 , R 9 , R 10 , Y are defined as described in the text;

[0223] In another preferred embodiment, it is characterized in that said R 5 is a hydrogen atom, deuterium atom, fluorine atom, chlorine atom.

[0224] In another preferred embodiment, it is characterized in that said R 6 is a hydrogen atom, deuterium atom, fluorine atom.

[0225] In another preferred embodiment, it is characterized in that said R 8 is a hydrogen atom, deuterium atom.

[0226] In another preferred embodiment, it is characterized in that said R 9 is a hydrogen atom, deuterium atom.

[0227] In another preferred embodiment, it is characterized in that said R 10is a hydrogen atom, deuterium atom, methyl group, deuterated methyl group, ethyl group, deuterated ethyl group, trifluoromethyl group, trifluoroethyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cyclopropylmethyl group;

[0228] In another preferred example, it is characterized in that the Y is a chemical bond, -CHOMe-, -CHF-;

[0229] In another preferred example, it is characterized in that the compound of formula (A-I) has the structure shown in the following formula (A-II-11):

[0230]

[0231] Wherein,

[0232] R 5 、R 6 、R 8 、R 9 、R 10 are defined as described in the text;

[0233] In another preferred example, it is characterized in that the R 5 is a hydrogen atom, deuterium atom, fluorine atom, chlorine atom.

[0234] In another preferred example, it is characterized in that the R 6 is a hydrogen atom.

[0235] In another preferred example, it is characterized in that the R 8 is a hydrogen atom, deuterium atom.

[0236] In another preferred example, it is characterized in that the R 9 is a hydrogen atom, deuterium atom.

[0237] In another preferred example, it is characterized in that the R 10 is a hydrogen atom, deuterium atom, methyl group, deuterated methyl group, ethyl group, deuterated ethyl group, trifluoromethyl group, trifluoroethyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cyclopropylmethyl group;

[0238] In another preferred example, it is characterized in that the compound of formula (A-I) has the structure shown in the following formula (A-II-12):

[0239]

[0240] Wherein,

[0241] R 2 、R 3 、R 6 、R 8 、R 9 are defined as described in the text;

[0242] In another preferred example, it is characterized in that the compound of formula (A-I) has the structure shown in formula (A-II-13) as follows:

[0243]

[0244] Wherein,

[0245] R 3 、R 6 、R 8 、R 9 、R 11 、L are defined as described in the text; x is any integer from 0 to 10;

[0246] In another preferred example, it is characterized in that the said R 3 is a hydrogen atom, a deuterium atom, a fluorine atom, a chlorine atom, a nitro group, a cyano group, NH2.

[0247] In another preferred example, it is characterized in that the said R 6 is a hydrogen atom, a deuterium atom, a fluorine atom.

[0248] In another preferred example, it is characterized in that the said R 8 is a hydrogen atom, a deuterium atom.

[0249] In another preferred example, it is characterized in that the said R 9 is a hydrogen atom, a deuterium atom.

[0250] In another preferred example, it is characterized in that the compound of formula (A-I) has the structure shown in formula (A-II-14) as follows:

[0251]

[0252] Wherein, R 2 、R 3 、R 6 、R 8 、R 9 are defined as described in the text;

[0253] In another preferred example, it is characterized in that the compound of formula (A-I) has the structure shown in formula (A-II-15) as follows:

[0254]

[0255] Wherein, R 3 、R 6 、R 8 、R 9 、R 11 、L are defined as described in the text; x is any integer from 0 to 10;

[0256] In another preferred example, it is characterized in that the R 3 is a hydrogen atom, a deuterium atom, a fluorine atom, a chlorine atom, a nitro group, a cyano group, NH2.

[0257] In another preferred example, it is characterized in that the R 6 is a hydrogen atom, a deuterium atom, a fluorine atom.

[0258] In another preferred example, it is characterized in that the R 8 is a hydrogen atom, a deuterium atom.

[0259] In another preferred example, it is characterized in that the R 9 is a hydrogen atom, a deuterium atom.

[0260] In another preferred example, it is characterized in that the compound of formula (A-I) has the structure shown in formula (A-II-16):

[0261]

[0262] wherein,

[0263] R 2 , R 3 , R 6 , R 8 , R 9 are defined as described in the text;

[0264] In another preferred example, it is characterized in that the compound of formula (A-I) has the structure shown in formula (A-II-17):

[0265]

[0266] wherein, R 3 , R 6 , R 8 , R 9 , R 11 , L are defined as described in the text; x is any integer from 0 to 10;

[0267] In another preferred example, it is characterized in that the R 3 is a hydrogen atom, a deuterium atom, a fluorine atom, a chlorine atom, a nitro group, a cyano group, NH2.

[0268] In another preferred example, it is characterized in that the R 6 is a hydrogen atom, a deuterium atom, a fluorine atom.

[0269] In another preferred example, it is characterized in that the R 8 is a hydrogen atom, a deuterium atom.

[0270] In another preferred embodiment, it is characterized in that the R 9 is a hydrogen atom or a deuterium atom.

[0271] In another preferred embodiment, it is characterized in that the compound of formula (A-I) has the structure shown in the following formula (A-II-18):

[0272]

[0273] wherein, R 2 , R 3 , R 6 , R 8 , R 9 are defined as described in the text;

[0274] In another preferred embodiment, it is characterized in that the compound of formula (A-I) has the structure shown in the following formula (A-II-19):

[0275]

[0276] wherein, R 3 , R 6 , R 8 , R 9 , R 11 , L are defined as described in the text; x is any integer from 0 to 10;

[0277] In another preferred embodiment, it is characterized in that the R 3 is a hydrogen atom, a deuterium atom, a fluorine atom, a chlorine atom, a nitro group, a cyano group, NH2.

[0278] In another preferred embodiment, it is characterized in that the R 6 is a hydrogen atom, a deuterium atom, a fluorine atom.

[0279] In another preferred embodiment, it is characterized in that the R 8 is a hydrogen atom, a deuterium atom.

[0280] In another preferred embodiment, it is characterized in that the R 9 is a hydrogen atom, a deuterium atom.

[0281] In another preferred embodiment, the compound of formula (A-I) has the structure shown in the following formula VIII:

[0282]

[0283] wherein, n is 0 or 1;

[0284] Ring A is unsubstituted or substituted with one or more R aA substituted saturated or unsaturated 5- or 6-membered carbocyclic ring, an unsubstituted or Ra-substituted saturated or unsaturated 5- or 6-membered heterocyclic ring; wherein, R a is as defined herein, R 1 , R 2 , R 3 , R 6 , and X are as defined herein.

[0285] In another preferred embodiment, the compound of formula (A-I) has the structure shown in formula IX as follows:

[0286]

[0287] Wherein, ring A is an unsubstituted or R a -substituted saturated or unsaturated 5- or 6-membered carbocyclic ring, an unsubstituted or R a -substituted saturated or unsaturated 5- or 6-membered heterocyclic ring; wherein, R a is as defined in claim 1, and R 2 , R 3 are as defined in claim 1.

[0288] In another preferred embodiment, the compound of formula (A-I) has the structures shown in formulas X-XV as follows:

[0289]

[0290] Wherein, R 2 , R 3 are as defined herein;

[0291] Ring A may be unsubstituted or substituted by one or more R a ; wherein, R a is as defined herein.

[0292] In another preferred embodiment, the compound of formula (A-I) has the structure shown in formula XVI as follows:

[0293]

[0294] Wherein, n is 0 or 1;

[0295] R 1 , R 4 , R 5 , R 6 , and X are as defined herein;

[0296] Ring B is selected from the group consisting of: an unsubstituted or R a -substituted saturated or unsaturated 5- to 12-membered carbocyclic ring, an unsubstituted or Ra Substituted saturated or unsaturated 5- to 12-membered heterocycles; wherein, R a is as defined herein.

[0297] In another preferred embodiment, the compound of formula (A-I) has the structure shown in formula XVII as follows:

[0298]

[0299] wherein, R 4 and R 5 are as defined herein;

[0300] Ring B is selected from the group consisting of: unsubstituted or substituted by one or more R a substituted saturated or unsaturated 5- to 12-membered carbocycles, unsubstituted or substituted by one or more R a substituted saturated or unsaturated 5- to 12-membered heterocycles; wherein, R a is as defined herein.

[0301] In another preferred embodiment, the compound of formula (A-I) has the structures shown in formulas XVIII - XXII as follows:

[0302]

[0303] wherein,

[0304] R 4 and R 5 are as defined herein;

[0305] Ring B may be unsubstituted or substituted by one or more R a ; wherein, R a is as defined herein.

[0306] In another preferred embodiment, it is characterized in that the compound of formula (A-I) is selected from the group consisting of:

[0307]

[0308]

[0309]

[0310]

[0311]

[0312]

[0313]

[0314]

[0315]

[0316]

[0317]

[0318]

[0319]

[0320]

[0321]

[0322]

[0323]

[0324]

[0325]

[0326]

[0327]

[0328] In another preferred example, it is characterized in that the compound of formula (A-I) is selected from the following group:

[0329]

[0330]

[0331]

[0332]

[0333]

[0334]

[0335]

[0336]

[0337]

[0338]

[0339]

[0340]

[0341] In another preferred example, it is characterized in that the compound of formula (A-I) is selected from the following group:

[0342]

[0343]

[0344]

[0345]

[0346]

[0347]

[0348]

[0349]

[0350]

[0351]

[0352]

[0353]

[0354] [[ID=B]]

[0355]

[0356]

[0357]

[0358]

[0359]

[0360]

[0361]

[0362]

[0363]

[0364]

[0365] In another preferred embodiment, it is characterized in that the compound of formula (A-I) is selected from the following group:

[0366]

[0367]

[0368]

[0369] In another preferred embodiment, it is characterized in that the compound of formula (A-I) is selected from the following group:

[0370]

[0371]

[0372]

[0373]

[0374]

[0375]

[0376]

[0377]

[0378]

[0379]

[0380]

[0381]

[0382]

[0383]

[0384]

[0385] In another preferred embodiment, it is characterized in that the compound of formula (A-I) is selected from the following group:

[0386]

[0387]

[0388]

[0389]

[0390]

[0391]

[0392]

[0393]

[0394]

[0395] In another preferred example, it is characterized in that the compound of formula (A-I) is selected from the following group:

[0396]

[0397]

[0398] In another preferred example, it is characterized in that the compound of formula (A-I) is selected from the following group:

[0399]

[0400]

[0401] In another preferred example, it is characterized in that the compound of formula (A-I) is selected from the following group:

[0402]

[0403]

[0404]

[0405]

[0406] In another preferred example, it is characterized in that the compound of formula (A-I) is selected from the following group:

[0407]

[0408]

[0409]

[0410] In another preferred example, it is characterized in that the compound of formula (A-I) is selected from the following group:

[0411]

[0412]

[0413]

[0414]

[0415]

[0416]

[0417]

[0418]

[0419] In another preferred example, it is characterized in that the compound of formula (A-I) is selected from the following group:

[0420]

[0421] In another preferred example, it is characterized in that the compound of formula (A-I) is selected from the following group:

[0422]

[0423] In another preferred example, it is characterized in that the compound of formula (A-I) is selected from the following group:

[0424]

[0425] In another preferred example, it is characterized in that the compound of formula (A-I) is selected from the following group:

[0426]

[0427]

[0428] In another preferred example, it is characterized in that the compound of formula (A-I) is selected from the following group:

[0429]

[0430]

[0431] In another preferred example, it is characterized in that the compound of formula (A-I) is selected from the following group:

[0432]

[0433]

[0434]

[0435]

[0436]

[0437]

[0438] In another preferred example, it is characterized in that the compound of formula (A-I) is selected from the following group:

[0439]

[0440]

[0441]

[0442]

[0443]

[0444]

[0445]

[0446]

[0447]

[0448]

[0449]

[0450]

[0451]

[0452]

[0453]

[0454]

[0455]

[0456]

[0457]

[0458]

[0459]

[0460]

[0461]

[0462]

[0463]

[0464] In another preferred example, it is characterized in that the compound of formula (A-I) is selected from the following group:

[0465]

[0466]

[0467]

[0468]

[0469]

[0470]

[0471]

[0472]

[0473]

[0474]

[0475]

[0476]

[0477]

[0478]

[0479]

[0480]

[0481]

[0482] In another preferred example, it is characterized in that the compound of formula (A-I) is selected from the following group:

[0483]

[0484]

[0485]

[0486]

[0487]

[0488]

[0489]

[0490]

[0491]

[0492]

[0493]

[0494]

[0495]

[0496]

[0497]

[0498]

[0499]

[0500]

[0501]

[0502]

[0503]

[0504]

[0505]

[0506]

[0507]

[0508]

[0509]

[0510]

[0511] In a third aspect of the present invention, there is provided a pharmaceutical composition comprising the compound of formula I described in the first aspect of the present invention and the compound of formula A-I described in the second aspect, or a pharmaceutically acceptable salt or hydrate thereof, and one or more pharmaceutically acceptable excipients, diluents or carriers.

[0512] In a fourth aspect of the present invention, there is provided the use of the compound of formula I described in the first aspect of the present invention and the compound of formula A-I described in the second aspect for preparing a pharmaceutical composition for treating diseases related to tumor cell proliferation.

[0513] In another preferred embodiment, the diseases are selected from the group consisting of: breast cancer, ovarian cancer, cervical cancer, lung cancer, uterine cancer, prostate cancer, kidney cancer, urethral cancer, bladder cancer, liver cancer, gastric cancer, endometrial cancer, salivary gland cancer, esophageal cancer, melanoma, glioma, neuroblastoma, sarcoma, pharyngeal cancer, colon cancer, rectal cancer, colorectal cancer, leukemia, bone cancer, skin cancer, thyroid cancer, pancreatic cancer, lymphoma.

[0514] In a fifth aspect of the present invention, there is provided the use of the compound of formula I described in the first aspect of the present invention and the compound of formula A-I described in the second aspect, characterized in that it is used as a toxin molecule for preparing a conjugate drug, and the conjugate drug includes: antibody-drug conjugate, polypeptide-drug conjugate, small molecule conjugate drug, polymer conjugate drug, lipid conjugate drug and protein conjugate drug.

[0515] In a sixth aspect of the present invention, there is provided an intermediate compound represented by the following formula:

[0516]

[0517] Wherein, the definitions of each group are as described above.

[0518] In another preferred embodiment, the compound has the structure represented by formula A-II-b or A-III-b as follows:

[0519]

[0520] In a seventh aspect of the present invention, there is provided a method for preparing the compound of formula A-I described in the second aspect of the present invention, and the method comprises the steps of:

[0521]

[0522] Reacting the compound of formula A-I-a with the compound of formula A-I-b in an inert solvent to obtain the compound of formula A-I.

[0523] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described hereinafter (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be elaborated one by one here. Detailed Description of the Invention

[0524] Through long-term and in-depth research, the present inventors unexpectedly discovered a compound represented by Formula I. The said compound has unexpected activity in inhibiting the proliferation of tumor cells and can be used to treat diseases related to the proliferation of tumor cells. Based on the above discovery, the inventors completed the present invention.

[0525] Definitions

[0526] As used herein, the term "n-membered" (where n is an integer) generally describes the number of ring-forming atoms in a moiety, where the number of ring-forming atoms is n. For example, piperidinyl is an example of a 6-membered heteroalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridinyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydronaphthalene is an example of a 10-membered cycloalkyl ring.

[0527] Throughout the definitions, the term "C n-m " or "C n -C m " indicates a range including the endpoints, where n and m are integers and indicate the number of carbon atoms. Examples include C 1-4 、C 1-6 、C1-C6、C3-C6、C3-C 12 、C5-C 12 and the like.

[0528] As used herein, the term "C n-m alkyl" or "C n -C m alkyl", used alone or in combination with other terms, refers to a saturated hydrocarbon group having n to m carbon atoms that can be straight-chain or branched-chain. In some embodiments, the alkyl contains 1 to 12 carbon atoms, 1 to 10 carbon atoms, 1 to 8 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. Examples of alkyl moieties include (but are not limited to) chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; higher-carbon homologues such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, and the like.

[0529] As used herein, the term "alkenyl" includes straight-chain or branched-chain alkenyl. For example, C2-C6 alkenyl refers to a straight-chain or branched-chain alkenyl having 2-6 carbon atoms, such as vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, or similar groups.

[0530] As used herein, the term "alkynyl" includes straight-chain or branched alkynyl groups. For example, C2-C6 alkynyl refers to straight-chain or branched alkynyl groups having 2-6 carbon atoms, such as ethynyl, propynyl, butynyl, or similar groups.

[0531] As used herein, "cycloalkyl" refers to non-aromatic cycloalkanes that include cycloalkyl and / or alkenyl and / or alkynyl moieties. Cycloalkyl can include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) groups and spiro rings. Cycloalkyl can have 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 ring-forming carbons (C3-C 12 ). The ring-forming carbon atoms of cycloalkyl can be optionally substituted. Cycloalkyl also includes cycloalkylidene. For example, the following structures etc. can all be referred to as cyclohexyl. Exemplary cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcamyl, etc. The definition of cycloalkyl also includes moieties where one or more aromatic rings are fused to the cycloalkyl ring (i.e., having bonds shared with the cycloalkyl ring), such as benzo or thienyl derivatives of cyclopentane, cyclohexane, etc. Cycloalkyls containing fused aromatic rings can be attached via any ring-forming atom (including the ring-forming atoms of the fused aromatic rings).

[0532] As used herein, the term "C1-C 12 cycloalkyl" refers to cycloalkyl having 1-12 carbon atoms. It can be monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or similar groups. It can also be in bicyclic form, such as in bridged or spiro form. Herein, the 1 and 12 in "C1-C 12 cycloalkyl" are only used as examples and are not limiting, and can be arbitrarily replaced with any number from 1-12. The same applies to similar descriptions in other term definitions.

[0533] As used herein, the term "C1-C 12 alkylamino" refers to an amino group substituted by C1-C 12 alkyl, which can be mono-substituted or di-substituted, where the alkyl has n to m carbons; for example, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, tert-butylamino, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, di-tert-butylamino, etc.

[0534] As used herein, the term "C1-C 12"Alkoxy" refers to a group of the formula -O-alkyl, where the alkyl group has 1 to 12 carbons. Exemplary alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), tert-butoxy, and the like. In certain cases, the alkyl group has 1 to 10, 1 to 8, 1 to 6, 1 to 4, or 1 to 3 carbon atoms. For example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, and the like.

[0535] As used herein, the term "C1-C 12 "Alkoxycarbonyl" refers to a group of the formula -C(O)O-alkyl, where the alkyl group can have 1 to 12 carbon atoms. In certain cases, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0536] As used herein, the term "C1-C 12 "Alkylcarbonyl" refers to a group of the formula -C(O)-alkyl, where the alkyl group has 1 to 12 carbon atoms. In certain cases, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0537] As used herein, "heterocycloalkyl" refers to a non-aromatic monocyclic or polycyclic heterocycle having one or more ring heteroatoms selected from O, N, or S. Heterocycloalkyl includes, but is not limited to, monocyclic 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered heterocycloalkyl. Heterocycloalkyl can also include bridged and spiro rings. Exemplary heterocycloalkyl groups include pyrrolidin-2-one, 1,3-isoxazolidin-2-one, pyranyl, tetrahydropyran, oxetanyl, azetidinyl, morpholino, thiomorpholino, piperazinyl, tetrahydrofuryl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, azepanyl, benzazepine, and the like. The ring carbon atoms and heteroatoms of heterocycloalkyl can be optionally substituted with oxo or thio groups (e.g., C(O), S(O), C(S), or S(O)2, etc.). Heterocycloalkyl can be linked through a ring carbon atom or a ring heteroatom. In certain cases, heterocycloalkyl contains 0 to 3 double bonds. In certain cases, heterocycloalkyl contains 0 to 2 double bonds. The definition of heterocycloalkyl also includes a portion where one or more aromatic rings are fused to the heterocycloalkyl ring (i.e., having a shared bond with the heterocycloalkyl ring), such as benzo or thienyl derivatives of piperidine, morpholine, etc. Heterocycloalkyl containing a fused aromatic ring can be linked via any ring atom (including the ring atoms of the fused aromatic ring). In certain cases, heterocycloalkyl has 4 - 10, 4 - 7, or 4 - 6 ring atoms and 1 or 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur and has one or more oxidized ring members.

[0538] As used herein, the term "C6-C 10"Aryl" means an aryl group having 6 to 10 carbon atoms, for example, phenyl or naphthyl and similar groups. An aryl group includes residues formed by the loss of one or more hydrogen atoms. For example, the following structures etc. can all be referred to as phenyl.

[0539] The term "heteroaryl" means a monocyclic or polycyclic aromatic heterocycle having at least one heteroatom ring member selected from sulfur, oxygen, and nitrogen. In some embodiments, the heteroaryl ring has but is not limited to 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, any ring-forming N in the heteroaryl moiety can be an N-oxide. In some embodiments, the heteroaryl has 5 to 14 ring atoms (including carbon atoms) and 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl has but is not limited to 5 to 10 ring atoms (including carbon atoms) and 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In certain cases, the heteroaryl has 5 to 6 ring atoms and 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In certain cases, the heteroaryl is a five- or six-membered heteroaryl ring. In certain cases, the heteroaryl is an eight-, nine-, or ten-membered fused bicyclic heteroaryl ring. Exemplary heteroaryls include but are not limited to pyridinyl / pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, furyl, thienyl, quinolinyl, isoquinolinyl, naphthyridinyl (including 1,2-, 1,3-, 1,4-, 1,5-, 1,6-, 1,7-, 1,8-, 2,3-, and 2,6-naphthyridin), indolyl, indazolyl, benzothienyl, benzofuryl, benzisoxazolyl, imidazo[1,2-b]thiazolyl, purinyl, and the like.

[0540] As used herein, the term "substituted" means that a hydrogen atom is removed and replaced with a substituent. It should be understood that substitution at a given atom is limited by valence. Unless otherwise specified as "substituted or unsubstituted", the groups described in the present invention can be substituted with substituents selected from the following group: halogen, cyano, nitro, hydroxy, amino, C1-C6 alkylamino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halo C1-C6 alkyl, halo C2-C6 alkenyl, halo C2-C6 alkynyl, halo C1-C6 alkoxy, allyl, benzyl, C6-C 12 aryl, C1-C6 alkoxy-C1-C6 alkyl, C1-C6 alkoxy-carbonyl, phenoxycarbonyl, C2-C6 alkynyl-carbonyl, C2-C6 alkenyl-carbonyl, C3-C6 cycloalkyl-carbonyl, C1-C6 alkyl-sulfonyl, etc.

[0541] As used herein, "halogen" or "halo atom" refers to F, Cl, Br, and I. More preferably, the halogen or halo atom is selected from F, Cl, and Br. "Halogenated" means substituted with an atom selected from F, Cl, Br, and I.

[0542] As used herein, the term "cyano" or "nitrile" refers to a group of the formula -C≡N, which may also be written as -CN.

[0543] As used herein, the term "amino" refers to a group of the formula -NH2.

[0544] As used herein, the term "hydroxy" refers to a group of the formula -OH.

[0545] As used herein, the term "mercapto" refers to a group of the formula -SH.

[0546] As used herein, the term "nitro" refers to a group of the formula -NO2.

[0547] Unless otherwise specified, the structural formulas described in the present invention are intended to include all isomeric forms (such as enantiomers, diastereomers, and geometric isomers (or conformational isomers)): for example, the R and S configurations containing an asymmetric center, the (Z) and (E) isomers of a double bond, etc. Therefore, individual stereoisomers of the compounds of the present invention or mixtures of their enantiomers, diastereomers, or geometric isomers (or conformational isomers) are within the scope of the present invention.

[0548] In the present application, the compounds of the present application include the tautomers, mesomers, racemates, enantiomers, and / or diastereomers of the compounds. In the present application, the term "diastereomer" generally refers to stereoisomers having two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers can have different physical properties, such as melting point, boiling point, spectroscopic properties, and reactivity. In the present application, the terms "tautomer" or "tautomeric form" are used interchangeably and generally refer to structural isomers of different energies that can be interconverted through a low energy barrier. For example, prototautomers (also known as prototropic tautomers) include interconversions through proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions through the reorganization of some bonding electrons. In the present application, the term "mesomer" generally refers to a molecule containing asymmetric atoms but having a symmetry element that makes the total optical rotation of the molecule zero. The term "racemate" or "racemic mixture" refers to a composition composed of equimolar amounts of two enantiomeric substances.

[0549] As used herein, the term "tautomer" means that structural isomers with different energies can interconvert over a low energy barrier. For example, proton tautomers (i.e., prototropy) include interconversion through proton migration, such as 1H-indazole and 2H-indazole. Valence tautomers include interconversion through reorganization of some bonding electrons.

[0550] In this application, certain atoms of the compounds of this application may occur in more than one isotope form. For example, hydrogen may exist in the form of protium ( 1 H), deuterium ( 2 H), and tritium ( 3 H), and carbon may exist naturally in three different isotopes ( 12 C, 13 C, and 14 C). Examples of isotopes that can be incorporated into the compounds of this application also include, but are not limited to, 15 N, 18 O, 17 O, 18 F, 32 P, 33 P, 129 I, 131 I, 123 I, 124 I, 125 I, or similar isotopes. Therefore, relative to the natural abundances of these isotopes, the compounds of this application can be enriched in one or more of these isotopes. As is known to those skilled in the art, such isotope-enriched compounds can be used for a variety of purposes. For example, substitution with a heavy isotope such as deuterium ( 2 H) may provide certain therapeutic advantages, which can be due to higher metabolic stability. For example, the natural abundance of deuterium ( 2 H) is approximately 0.015%. Therefore, in nature, there is approximately one deuterium atom for every 6500 hydrogen atoms. Therefore, the deuterium abundance of the deuterium-containing compounds of this application is greater than 0.015% at one or more positions (as appropriate). Unless otherwise specified, the structures described in this application can also include compounds that differ only in the presence or absence of one or more isotope-enriched atoms. For example, compounds that are otherwise identical to the structures of this application except that a hydrogen atom is replaced by deuterium or tritium, or a carbon atom is replaced by carbon-13 or carbon-14, are within the scope of this application.

[0551] In the present application, the term "pharmaceutical composition" generally refers to a mixture containing one or more compounds described in the present application or their physiologically / pharmaceutically acceptable salts or prodrugs, as well as other chemical components, and other components such as physiologically / pharmaceutically acceptable carriers and excipients. The pharmaceutical composition can facilitate the administration to an organism, facilitate the absorption of the active ingredient and thus exert biological activity. The preparation of conventional pharmaceutical compositions can be found in the commonly used techniques in the art.

[0552] In the present application, the term "pharmaceutically acceptable salt" or "medicinal salt" generally refers to the salts of the compounds or ligand-drug conjugates of the present application, or the salts of the compounds described in the present application. Such salts can have safety and / or effectiveness when used in mammals and can have the due biological activity. The antibody-antibody drug conjugate compounds of the present application can form salts with acids. Non-limiting examples of pharmaceutically acceptable salts include: hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, citrate, acetate, succinate, ascorbate, oxalate, nitrate, pectinate, hydrogen phosphate, dihydrogen phosphate, salicylate, hydrogen citrate, tartrate, maleate, fumarate, formate, benzoate, mesylate, esylate, benzenesulfonate, or p-toluenesulfonate.

[0553] As used herein, the term "hydrate" refers to a complex formed by the coordination of the compounds of the present invention with water.

[0554] As used herein, "pharmaceutically acceptable solvate" or "solvate" refers to the combination of one or more solvent molecules with the compounds or conjugates of the present invention. Examples of solvents that form pharmaceutically acceptable solvates include (but are not limited to): water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.

[0555] The compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by the combination of specific embodiments and other chemical synthesis methods, and the equivalent replacement methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present application.

[0556] Pharmaceutical Compositions and Administration Methods

[0557] Since the compounds of the present invention have excellent inhibitory activity against tumor cell proliferation, the compounds of the present invention and their various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compounds of the present invention as the main active ingredient can be used for the prevention and / or treatment (stabilization, alleviation or cure) of diseases related to tumor cell proliferation.

[0558] The pharmaceutical composition of the present invention comprises a compound of the present invention within a safe and effective amount range and a pharmaceutically acceptable excipient or carrier. The "safe and effective amount" herein refers to: an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Generally, the pharmaceutical composition contains 1 - 2000 mg of the compound of the present invention per dose, and more preferably, contains 1 - 200 mg of the compound of the present invention per dose. Preferably, the "per dose" is a capsule or a tablet.

[0559] "Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gelling substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" herein means that the components in the composition can be blended with the compound of the present invention and with each other without significantly reducing the efficacy of the compound. Some examples of pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyhydric alcohols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween ), wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0560] There is no particular limitation on the administration mode of the compound or pharmaceutical composition of the present invention. Representative administration modes include (but are not limited to): oral administration, parenteral (intravenous, intramuscular or subcutaneous).

[0561] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or calcium phosphate, or is mixed with the following components: (a) fillers or bulking agents, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxypropylmethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizing agents, for example, paraffin wax; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glycerol monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain buffering agents.

[0562] Solid dosage forms, such as tablets, dragees, capsules, pills, and granules, can be prepared with coatings and shell materials, such as enteric coatings and other materials well known in the art. They can contain opacifying agents, and the release of the active compound or compounds in such compositions can be delayed and released in a portion of the digestive tract. Examples of embedding components that can be used are polymeric substances and wax-like substances. If necessary, the active compound can also be in the form of microcapsules with one or more of the above excipients.

[0563] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, the liquid dosage forms can contain inert diluents conventionally used in the art, such as water or other solvents, solubilizing agents, and emulsifying agents, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances, etc.

[0564] In addition to these inert diluents, the composition can also contain adjuvants, such as wetting agents, emulsifying agents, and suspending agents, sweetening agents, flavoring agents, and fragrances.

[0565] In addition to the active compound, the suspension can contain suspending agents, for example, ethoxylated isooctadecanol, polyoxyethylene sorbitol, and sorbitan esters, microcrystalline cellulose, aluminum monostearate, and agar, or mixtures of these substances, etc.

[0566] Compositions for parenteral injection can contain physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstituting into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0567] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable therapeutic agents.

[0568] When administered in combination, the pharmaceutical composition further includes one or more (2, 3, 4, or more) other pharmaceutically acceptable therapeutic agents. One or more (2, 3, 4, or more) of the other pharmaceutically acceptable therapeutic agents can be used simultaneously, separately, or sequentially with the compound of the present invention for the prevention and / or treatment of diseases related to tumor cell proliferation.

[0569] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal in need of treatment (such as a human), and the dosage during administration is an effective dosage considered pharmaceutically. For a person weighing 60 kg, the daily dosage is usually 0.1 - 2000 mg, preferably 0.1 - 100 mg, 100 mg - 1000 mg, or 1000 - 2000 mg, or the weekly dosage is usually 0.1 - 2000 mg, preferably 0.1 - 100 mg, 100 mg - 1000 mg, or 1000 - 2000 mg, or the monthly dosage is usually 0.1 - 2000 mg, preferably 0.1 - 100 mg, 100 mg - 1000 mg, or 1000 - 2000 mg. Of course, the specific dosage should also consider factors such as the administration route and the patient's health condition, which are all within the scope of the skills of a skilled physician.

[0570] The present invention will be further illustrated below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental methods without specific conditions noted in the following embodiments are usually carried out under conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are calculated by weight.

[0571] Synthesis Example:

[0572] Example 1

[0573]

[0574] The first step

[0575] 1a (1.95 g, 7.40 mmol) and imidazole (2.52 g, 37.00 mmol) were successively placed in a three-necked flask (100 mL). After purging with nitrogen, anhydrous N,N-dimethylformamide (30 mL) was added to the three-necked flask. The temperature of the mixed system was cooled to 0 °C, and triethylchlorosilane (4.45 g, 29.60 mmol) and 4-dimethylaminopyridine (0.90 g, 7.40 mmol) were successively added. After the addition was complete, the mixed system was kept stirring at 0 °C for 2 hours. The reaction solution was diluted with ethyl acetate (200 mL), and the organic phase was washed with saturated brine (25 mL × 4), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0 - 100%) to obtain 1b-1 (0.90 g) and 1b-2 (1.50 g), with a total yield of 73%.

[0576] 1b-1:

[0577] MS-ESI calculated value [M+H] + 378, the measured value was 378.

[0578] 1b-2:

[0579] MS-ESI calculated value [M+H] + 492, the measured value is 378 (loss of one molecule of TES).

[0580] The second step

[0581] 1b-2 (1.10 g, 2.20 mmol) and Lawesson's reagent (1.80 g, 4.40 mmol) were successively placed in a three-necked flask (100 mL). After purging with nitrogen, anhydrous toluene (30 mL) was added to the three-necked flask. The mixed system was heated to 90 °C and stirred for 5 - 6 hours. The reaction solution was diluted with ethyl acetate (200 mL), and the organic phase was washed with saturated brine (25 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0 - 100%) to obtain 1c (620 mg), yield: 51%.

[0582] MS-ESI calculated value [M+H] + 394, the measured value is 394.

[0583] The third step

[0584] Compound 1c (540 mg, 1.37 mmol) was dissolved in tetrahydrofuran (20 mL). Triethylamine trihydrofluoride (552 mg, 3.43 mmol) was added under an ice bath. After the addition was complete, the mixture was slowly warmed to room temperature and stirred overnight. The reaction solution was diluted with ethyl acetate (100 mL), and the organic phase was washed with saturated brine (25 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0 - 100%) to obtain 1 (210 mg), yield: 55%.

[0585] MS-ESI calculated value [M+H] + 280, the measured value is 280.

[0586] 1 1H NMR (500 MHz, CDCl3) δ 7.56 (s, 1H), 6.12 (d, J = 17.5 Hz, 1H), 5.25 (d, J = 17.5 Hz, 1H), 4.71 - 4.52 (m, 2H), 3.09 - 3.03 (m, 2H), 1.80 (q, J = 7.0 Hz, 2H), 0.96 (t, J = 7.0 Hz, 3H).

[0587] Example 2

[0588]

[0589] The first step

[0590] Under a nitrogen atmosphere, 1.0 M boron trichloride n-heptane solution (94 mL, 94.00 mmol) was added to a dried three-necked flask (500 mL), anhydrous 1,2-dichloroethane (150 mL) was added, and the mixed solution was cooled to 0 °C. 2a (9.00 g, 72.00 mmol) was added in portions. After stirring at 0 °C for ten minutes, chloroacetonitrile (7.05 g, 94.00 mmol) and aluminum trichloride (13.43 g, 101.00 mmol) were added. After the addition was complete, the mixed system was slowly heated to 80 °C and refluxed for 40 hours. The reaction system was cooled to 0 °C, and ice water (50 mL) and hydrochloric acid aqueous solution (1 N, 100 mL) were slowly added in sequence. After continuing to stir at 0 °C for half an hour, liquid separation was carried out. The aqueous phase was extracted with a dichloromethane / methanol mixed solvent (V 二氯甲烷 :V 甲醇 = 4:1, 200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0 - 100%) to obtain crude product 2b (5.5 g), which was directly used for the next step.

[0591] MS-ESI calculated value [M+H] + 202, the measured value was 202.

[0592] The second step

[0593] Under a nitrogen atmosphere, the crude product 2b (700 mg) from the previous step was dissolved in anhydrous dichloromethane (5 mL), benzylamine (3 mL) was added, and the mixed system was stirred at room temperature for 5 hours. The reaction solution was directly concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0 - 100%) to obtain compound 2c (390 mg), yield: 41%.

[0594] MS-ESI calculated value [M+H] + 273, the measured value was 273.

[0595] The third step

[0596] Compound 2c (390 mg, 1.43 mmol) and 10% wet palladium on carbon (90 mg) were successively added to a single-necked flask (100 mL), anhydrous tetrahydrofuran (10 mL) was added, and after replacing the hydrogen with a hydrogen balloon, the mixed system was stirred at room temperature under a hydrogen atmosphere for 20 hours. The reaction system was filtered to remove insoluble substances, and the filtrate was concentrated under reduced pressure to obtain crude product 2d (290 mg).

[0597] MS-ESI calculated value [M+H] + 183, the measured value was 183.

[0598] The fourth step

[0599] Dissolve the crude product 2d (290 mg) from the previous step in a mixed solvent of tetrahydrofuran / water (V 四氢呋喃 :V 水 = 1:1, 10 mL), add 9-fluorenylmethyl chloroformate (410 mg, 1.59 mmol) and potassium carbonate (439 mg, 3.18 mmol), and stir the mixed system at 0 °C for half an hour. Dilute the reaction system with ethyl acetate (100 mL), wash the organic phase with saturated brine (25 mL), dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure to obtain a residue, and purify the residue by silica gel column chromatography (ethyl acetate: petroleum ether = 0 - 100%) to obtain compound 2e (390 mg). The overall yield in two steps is 67%.

[0600] MS-ESI calculated value [M+H] + 405, the measured value is 405.

[0601] The fifth step

[0602] Add 2e (240 mg, 0.59 mmol), 1 (165 mg, 0.59 mmol) and p-toluenesulfonic acid (60 mg, 0.35 mmol) to a Schlenk reaction tube (100 mL) in sequence, add anhydrous toluene (6 mL), and heat the mixed system to 110 °C and stir for 2 hours. Concentrate the reaction solution under reduced pressure to obtain a crude product, and purify the crude product by silica gel column chromatography (ethyl acetate: petroleum ether = 0 - 100%) to obtain compound 2f (120 mg). The yield is 31%.

[0603] MS-ESI calculated value [M+H] + 648, the measured value is 648.

[0604] The sixth step

[0605] Dissolve 2f (120 mg, 0.19 mmol) in anhydrous tetrahydrofuran (2.5 mL), add diethylamine (135 mg, 1.85 mmol), and stir the mixed system at room temperature for 5 hours. Concentrate the reaction system under reduced pressure to obtain a crude product, and purify the crude product by silica gel column chromatography (methanol: dichloromethane = 0 - 100%) to obtain compound 2 (30 mg). The yield is 38%.

[0606] MS-ESI calculated value [M+H] + 426, the measured value is 426.

[0607] 11H NMR (400 MHz, DMSO-d6) δ 8.30 (d, J = 8.4 Hz, 1H), 7.91 (d, J = 10.8 Hz, 1H), 7.80 (s, 1H), 6.69 (s, 1H), 5.93 (d, J = 16.4 Hz, 1H), 5.71 (s, 2H), 5.51 (d, J = 16.8 Hz, 1H), 4.41 (s, 2H), 2.51 (s, 3H), 1.96 1.85 (m, 2H), 0.86 (t, J = 7.2 Hz, 3H).

[0608] Example 3

[0609]

[0610] The first step

[0611] 2 (18 mg, 0.04 mmol) and glycolic acid (6 mg, 0.08 mmol) were successively added to a single-necked flask (25 mL). N,N-Dimethylformamide (1.5 mL) was added. The reaction system was cooled to 0 °C. N,N-Diisopropylethylamine (16 mg, 0.12 mmol) and 2-(7-azabenzotriazol)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (15 mg, 0.04 mmol) were successively added to the reaction system. The reaction system was stirred at 0 °C for half an hour. The reaction solution was diluted with ethyl acetate (100 mL). The organic phase was washed with saturated brine (25 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative thin-layer chromatography (methanol: dichloromethane) to obtain compound 3 (4.4 mg), yield: 21%.

[0612] MS-ESI calculated value [M + H] + 484, the measured value was 484.

[0613] 1 1H NMR (400 MHz, DMSO-d6) δ 8.80 (t, J = 6.0 Hz, 1H), 8.50 (d, J = 8.0 Hz, 1H), 7.94 (d, J = 10.8 Hz, 1H), 7.80 (s, 1H), 6.68 (s, 1H), 5.93 (d, J = 16.8 Hz, 1H), 5.78 (s, 2H), 5.52 (d, J = 16.4 Hz, 1H), 4.89 (d, J = 6.0 Hz, 2H), 3.86 (s, 2H), 2.51 (s, 3H), 1.95 1.83 (m, 2H), 0.86 (t, J = 7.2 Hz, 3H).

[0614] Example 4

[0615]

[0616] The first step

[0617] Under a nitrogen atmosphere, a 1.0 M solution of boron trichloride in n-heptane (12.8 mL, 12.80 mmol) was added to a dried three-necked flask (100 mL). Anhydrous 1,2-dichloroethane (50 mL) was added, and the mixed solution was cooled to 0 °C. 2a (2.00 g, 16.00 mmol) was added in portions. After stirring at 0 °C for ten minutes, 5-bromovaleronitrile (3.63 g, 22.40 mmol) and aluminum trichloride (3.38 g, 22.40 mmol) were added. After the addition was complete, the mixed system was slowly heated to 80 °C and refluxed for 30 hours. The reaction system was cooled to 0 °C, and ice water (50 mL) and aqueous hydrochloric acid solution (1 N, 60 mL) were slowly added in sequence. After continuing to stir at 0 °C for half an hour, liquid separation was carried out. The aqueous phase was extracted with a dichloromethane / methanol mixed solvent (V 二氯甲烷 :V 甲醇 = 4:1, 200 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0 - 100%) to obtain the crude product 4a (3.1 g), which was directly used for the next step.

[0618] MS-ESI calculated value [M+H] + 288, 290, the measured values were 288, 290.

[0619] The second step

[0620] To a Schlenk reaction tube (100 mL), 4a (495 mg), 1 (320 mg, 1.15 mmol), and p-toluenesulfonic acid (198 mg, 1.15 mmol) were added in sequence. Anhydrous toluene (6 mL) was added, and the mixed system was heated to 110 °C and stirred for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0 - 100%) to obtain the crude product 4b (200 mg).

[0621] MS-ESI calculated value [M+H] + 531, 533, the measured values were 531, 533.

[0622] The third step

[0623] Dissolve 4b (90 mg) in hexamethylphosphoramide (0.9 mL) and water (0.1 mL), heat the mixed system to 101 °C and stir for 4 hours. Dilute the reaction system with ethyl acetate (100 mL), wash the organic phase with saturated brine (25 mL x 3), dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure to obtain a residue, and purify the residue by preparative high-performance liquid chromatography to obtain compound 4 (12 mg), yield: 15%.

[0624] MS-ESI calculated value [M+H] + 469, the measured value is 469.

[0625] 1 H NMR (400 MHz, DMSO-d6) δ 8.26 (d, J = 8.0 Hz, 1H), 7.90 (d, J = 10.8 Hz, 1H), 7.79 (s, 1H), 5.92 (d, J = 16.4 Hz, 1H), 5.78 (s, 2H), 5.50 (s, 2H), 5.49 (d, J = 16.4 Hz, 1H), 3.29 - 3.20 (m, 2H), 2.51 (s, 3H), 1.94 - 1.82 (m, 2H), 1.82 - 1.70 (m, 2H), 1.67 - 1.56 (m, 2H), 0.86 (t, J = 7.2 Hz, 3H).

[0626] Example 5

[0627]

[0628] The first step

[0629] Dissolve 5a (2.50 g, 17.00 mmol) in anhydrous dichloromethane (25 mL), cool to 0 °C, add triethylamine (2.60 g, 20.00 mmol) and acetyl chloride (1.40 g, 18.00 mmol) in sequence, and stir the mixed system at 0 °C for 1 hour. Dilute the reaction system with dichloromethane (100 mL), wash the organic phase with saturated brine (25 mL x 3), dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure to obtain a residue, and purify the residue by trituration with methyl tert-butyl ether (50 mL) to obtain compound 5b (2.80 g), yield: 87%.

[0630] MS-ESI calculated value [M+H] + 190, the measured value is 190.

[0631] The second step

[0632] At -20 °C, 5b (2.00 g, 10.60 mmol) was slowly added portionwise to concentrated sulfuric acid (35 mL). After stirring to dissolve, potassium nitrate (1.07 g, 10.58 mmol) was added portionwise. The mixed system was stirred at -20 °C for 1 hour. The reaction system was slowly added dropwise to ice water (100 mL). The aqueous phase was extracted with dichloromethane (500 mL). The organic phase was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by trituration with methyl tert-butyl ether (25 mL) to obtain the first batch of compound 5c (1.00 g). The mother liquor was concentrated and then further triturated with methyl tert-butyl ether (15 mL) to obtain the second batch of compound 5c (1.20 g). The total yield was 89%.

[0633] MS-ESI calculated value [M+H] + 235, the measured value was 235.

[0634] The third step

[0635] 5c (2.10 g, 8.97 mmol) was dissolved in acetone (60 mL). An aqueous solution of magnesium sulfate (1.51 g, 12.56 mmol, 1.5 M) was added. The temperature of the mixed system was lowered to 0 °C, and potassium permanganate (5.95 g, 37.68 mmol) was added portionwise. After the addition was complete, the mixture was stirred at 0 °C for an additional 1.5 hours. The reaction system was filtered to remove insoluble solids. The filter cake was washed with dichloromethane (200 mL). The organic phase was washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0 - 100%) to obtain compound 5d (400 mg). The yield was 18%.

[0636] MS-ESI calculated value [M+H] + 249, the measured value was 249.

[0637] 1 1H NMR (400 MHz, DMSO-d6) δ 12.28 (s, 1H), 8.64 (d, J = 9.2 Hz, 1H), 8.19 (d, J = 9.6 Hz, 1H), 3.12 (t, J = 6.0 Hz, 2H), 2.75 (t, J = 6.4 Hz, 2H), 2.21 (s, 3H), 2.06 - 1.95 (m, 2H).

[0638] The fourth step

[0639] 5d (400 mg, 1.61 mmol) was dissolved in hydrochloric acid aqueous solution (6 N, 6 mL), and the temperature was raised to 80 °C and stirred for reaction for 2.5 h. The reaction solution was diluted with water (25 mL), and sodium bicarbonate was slowly added to adjust the pH to about 9. The aqueous phase was extracted with dichloromethane (100 mL × 2), and the organic phases were combined. The combined organic phase was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure to obtain the crude product 5e (350 mg).

[0640] MS-ESI calculated value [M + H] + 207, the measured value was 207.

[0641] The fifth step

[0642] The crude product 5e (350 mg) from the previous step was dissolved in anhydrous dichloromethane (25 mL). Under ice bath, pyridine (254 mg, 3.22 mmol) and trifluoroacetic anhydride (676 mg, 3.22 mmol) were added successively. The mixed system was stirred at 0 °C for reaction for 0.5 h. The reaction system was diluted with dichloromethane (50 mL). The organic phase was washed with saturated brine (25 mL × 2), dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure to obtain a residue, and the residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0 - 100%) to obtain the compound 5f (410 mg). The yield of two steps was 84%.

[0643] MS-ESI calculated value [M + H] + 303, the measured value was 303.

[0644] 1 H NMR (400 MHz, CDCl3) δ 13.64 (s, 1H), 8.76 (d, J = 9.2 Hz, 1H), 8.14 (d, J = 9.6 Hz, 1H), 3.27 (t, J = 6.0 Hz, 2H), 2.82 (t, J = 6.4 Hz, 2H), 2.21 - 2.11 (m, 2H).

[0645] The sixth step

[0646] 5f (410 mg, 1.36 mmol) was dissolved in a mixed solvent of methanol (50 mL), water (4 mL) and formic acid (4 mL). Under ice bath, zinc powder (1.74 g, 27.20 mmol) was added in batches. The mixed system was stirred at 0 °C for reaction for 0.5 h. The reaction system was filtered to remove insoluble substances. The filter cake was washed successively with ethyl acetate (200 mL) and water (50 mL). The filtrate was slowly added with sodium bicarbonate to adjust the pH to 8 - 9, and liquid separation was carried out. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product 5g (330 mg).

[0647] MS-ESI calculated value [M + H]+ 273, the measured value is 273.

[0648] The seventh step

[0649] Dissolve 5 g (330 mg) of the crude product from the previous step in anhydrous dichloromethane (25 mL). Under an ice bath, successively add triethylamine (260 mg, 2.57 mmol) and acetyl chloride (200 mg, 2.57 mmol). Stir the mixed system at 0 °C for 1 hour. Dilute the reaction system with dichloromethane (50 mL). Wash the organic phase with saturated brine (25 mL × 2), dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure to obtain a residue. Purify the residue by silica gel column chromatography (methanol:dichloromethane = 0 - 100%) to obtain compound 5h (310 mg). The yield in two steps: 72%.

[0650] MS-ESI calculated value [M+H] + 315, the measured value is 315.

[0651] The eighth step

[0652] Dissolve 5h (310 mg, 0.99 mmol) in a mixed solvent of methanol (22 mL) and water (1.5 mL). Add potassium carbonate (550 mg, 3.99 mmol). Heat the mixed system to 50 °C and stir for 1 hour. Dilute the reaction system with dichloromethane (100 mL) and water (25 mL), separate the layers. Wash the aqueous phase with a dichloromethane / methanol mixed solvent (V 二氯甲烷 :V 甲醇 = 4:1, 50 mL), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure to obtain a residue. Purify the residue by silica gel column chromatography (methanol:dichloromethane = 0 - 100%) to obtain compound 5i (205 mg). The yield: 95%.

[0653] MS-ESI calculated value [M+H] + 219, the measured value is 219.

[0654] The ninth step

[0655] Add 5i (200 mg, 0.92 mmol), 1 (257 mg, 0.92 mmol) and p-toluenesulfonic acid (158 mg, 0.92 mmol) successively to a Schlenk reaction tube (100 mL). Add anhydrous toluene (10 mL). Heat the mixed system to 110 °C and stir for 6 hours. Concentrate the reaction system under reduced pressure to obtain a crude product. Purify the crude product by silica gel column chromatography (methanol:dichloromethane = 0 - 100%) to obtain crude product 5j (170 mg), which is directly used for the next step.

[0656] MS-ESI calculated value [M+H]+ 462, the measured value is 462.

[0657] The tenth step

[0658] Dissolve the crude product 5j (170 mg) from the previous step in hydrochloric acid aqueous solution (6N, 2 mL), heat the mixture to 80 °C and stir for 4 hours. Dilute the reaction system with a dichloromethane / methanol mixed solvent (V 二氯甲烷 :V 甲醇 = 10:1, 100 mL) and water (20 mL), slowly add sodium bicarbonate to adjust the pH to about 9, separate the layers, extract the aqueous phase with a dichloromethane / methanol mixed solvent (V 二氯甲烷 :V 甲醇 = 10:1, 100 mL), combine the organic phases, dry over anhydrous sodium sulfate and filter, concentrate the filtrate under reduced pressure to obtain the crude product, and purify the crude product by silica gel column chromatography (methanol:dichloromethane = 0 - 100%) to obtain compound 5 (100 mg), with a two-step yield of 26%.

[0659] MS-ESI calculated value [M+H] + 420, the measured value is 420.

[0660] 1 H NMR (400 MHz, DMSO-d6) δ 7.76 (d, J = 8.8 Hz, 1H), 7.67 (s, 1H), 7.32 (d, J = 9.2 Hz, 1H), 6.62 (s, 1H), 5.91 (d, J = 16.4 Hz, 1H), 5.72 (s, 2H), 5.49 (d, J = 16.8 Hz, 1H), 5.42 (s, 2H), 3.09 (t, J = 5.6 Hz, 2H), 2.76 (t, J = 6.0 Hz, 2H), 2.07 - 1.98 (m, 2H), 1.88 (q, J = 7.2 Hz, 2H), 0.86 (t, J = 7.2 Hz, 3H).

[0661] Example 6

[0662]

[0663]

[0664] The first step

[0665] Dissolve 6a (20.00 g, 159.80 mmol) in a dichloromethane / methanol mixed solvent (V 二氯甲烷 :V 甲醇 = 1:1, 350 mL), cool to 0 °C, dissolve liquid bromine (63.84 g, 399.50 mmol) in a dichloromethane / methanol mixed solvent (V 二氯甲烷 :V甲醇 = 1:1, 50 mL), and then it was added dropwise to the above solution. After the addition was completed, the mixed system was stirred at 25 °C for 4 hours. The reaction solution was concentrated under reduced pressure to obtain a residue. An aqueous sodium thiosulfate solution (1 M, 350 mL) and ethyl acetate (350 mL) were added to the residue for dilution. After the mixed system was stirred for 10 min, an aqueous sodium carbonate solution (1 M, 50 mL) was added, and liquid separation was carried out. The organic phase was washed successively with an aqueous sodium thiosulfate solution (1 M, 230 mL × 1) and saturated brine (230 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0 - 100%) to obtain compound 6b (40 g), yield: 89%.

[0666] 1 1H NMR (400 MHz, CDCl3) δ 7.16 (d, J = 8.4 Hz, 1H), 4.40 (br s, 2H), 2.27 (d, J = 2.4 Hz, 3H).

[0667] The second step

[0668] p-Toluenesulfonic acid (1.83 g, 10.63 mmol) was dissolved in anhydrous acetonitrile (15 mL), stirred until dissolved, and then cooled to 0 °C. Compound 6b (1.00 g, 3.53 mmol) was added. An aqueous solution (2 mL) of potassium iodide (1.47 g, 8.86 mmol) and sodium nitrite (480 mg, 7.10 mmol) was added dropwise to the above reaction solution. The mixed system was stirred at 0 °C for 10 min and then returned to room temperature and stirred for another 1 hour. The reaction system was added to water (8 mL), and the pH of the aqueous phase was adjusted to about 9 with a saturated aqueous sodium bicarbonate solution. Then an aqueous sodium thiosulfate solution (2.5 mL, 2 M) was added. The aqueous phase was extracted with ethyl acetate (30 mL × 3). The above organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0 - 100%) to obtain compound 6c (500 mg), yield: 36%.

[0669] The third step

[0670] Under a nitrogen atmosphere, 6c (9.00 g, 22.85 mmol) was dissolved in anhydrous toluene (54 mL), and the temperature was lowered to -30 °C. Isopropylmagnesium chloride tetrahydrofuran solution (2.82 g, 27.42 mmol, 2 M) was added dropwise. After the addition, the mixture was stirred at -30 °C for an additional 1.5 hours. N,N-Dimethylformamide (5.51 g, 75.42 mmol) was added dropwise. After the addition was complete, the reaction mixture was warmed to 20 °C and stirred for 2 hours. The reaction solution was diluted with saturated aqueous ammonium chloride solution (150 mL), and the aqueous phase was extracted with ethyl acetate (150 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0 - 100%) to obtain compound 6d (4.2 g), yield: 62%.

[0671] 1 H NMR (400 MHz, CDCl3) δ 10.20 (s, 1H), 7.38 (d, J = 8.8 Hz, 1H), 2.35 (d, J = 2.4 Hz, 3H).

[0672] The fourth step

[0673] 6d (4.20 g, 14.19 mmol) was dissolved in anhydrous 1,2-dichloroethane (35 mL), and ethylene glycol (4.43 g, 71.45 mmol), triethyl orthoformate (2.31 g, 5.61 mmol), and p-toluenesulfonic acid (244.40 mg, 1.42 mmol) were added. The reaction mixture was heated to 80 °C and stirred for 12 hours. The reaction solution was washed successively with saturated aqueous sodium carbonate solution (80 mL) and saturated aqueous ammonium chloride solution (80 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0 - 100%) to obtain compound 6e (3.9 g), yield: 81%.

[0674] 1 H NMR (400 MHz, CDCl3) δ 7.33 (d, J = 8.8 Hz, 1H), 6.43 (s, 1H), 4.36 - 4.30 (m, 2H), 4.11 - 4.04 (m, 2H), 2.32 (d, J = 1.2 Hz, 3H).

[0675] The fifth step

[0676] Under nitrogen protection, 6e (1.5 g, 4.41 mmol), diphenylketimine (880 mg, 4.85 mmol), palladium acetate (99 mg, 0.44 mmol), (255 mg, 0.44 mmol), and sodium tert-butoxide (850 mg, 8.82 mmol) were dissolved in anhydrous toluene (15 mL). The mixed system was heated to 100 °C and stirred for 12 hours. The reaction solution was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0 - 100%) to obtain compound 6f (300 mg), yield: 15%.

[0677] 1 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 7.2 Hz, 2H), 7.52 - 7.44 (m, 1H), 7.44 - 7.36 (m, 2H), 7.34 - 7.27 (m, 3H), 7.26 - 7.21 (m, 2H), 6.47 (s, 1H), 5.91 (d, J = 10.4 Hz, 2H), 4.10 - 4.04 (m, 2H), 3.96 - 3.90 (m, 2H), 2.21 (d, J = 2.0 Hz, 3H).

[0678] The sixth step

[0679] Under nitrogen protection, (but-3-en-1-yloxy)(tert-butyl)dimethylsilane (30 mg, 0.16 mmol) was dissolved in anhydrous toluene (1 mL). The temperature was lowered to 0 °C, and 9-borabicyclo[3.3.1]nonane (24 mg, 0.19 mmol) was added. The mixed system was heated to 80 °C and stirred for 20 min, then cooled to 0 °C. An aqueous solution of sodium hydroxide (13 mg, 0.32 mmol) in water (1 mL) was added dropwise. The mixed system was kept at 0 °C and stirred for 10 min. 6f (57 mg, 0.13 mmol), tetrabutylammonium iodide (3 mg, 0.008 mmol), and dichlorobis(diphenylphosphino)ferrocene palladium(II) (3 mg, 0.003 mmol) were added. After addition, the mixed system was heated to 80 °C and stirred for 12 hours. The reaction solution was concentrated under reduced pressure to obtain a residue, which was purified by preparative thin-layer chromatography to obtain compound 6g (40 mg), yield: 56%.

[0680] The seventh step

[0681] 6g (120 mg, 0.22 mmol) was dissolved in anhydrous ethanol (4 mL), and compound 1 (62 mg, 0.22 mmol) and concentrated hydrochloric acid (52.56 mg, 1.44 mmol, 12 N) were added. The mixed system was heated to 80 °C and stirred for 2 hours. The reaction solution was concentrated to obtain a residue, which was purified by preparative thin-layer chromatography to obtain 6 (7 mg), yield: 7%.

[0682] MS-ESI calculated value [M+H] + 469, the measured value is 469.

[0683] 1 H NMR (500 MHz, DMSO-d6) δ 8.98 (s, 1H), 7.80 (d, J = 10.5 Hz, 1H), 7.79 (s, 1H), 5.92 (d, J = 16.5 Hz, 1H), 5.50 (d, J = 16.5 Hz, lH), 5.497 (s, 2H), 3.19 - 3.12 (m, 2H), 2.43 (d, J = 2.0 Hz, 3H), 1.92 - 1.84 (m, 2H), 1.68 - 1.55 (m, 4H), 0.86 (t, J = 7.0 Hz, 3H).

[0684] Example 7

[0685]

[0686]

[0687] The first step

[0688] Dissolve 7a (11.0 g, 67.0 mmol) in trifluoroacetic acid (165 mL), add sodium nitrite (13.78 g, 199.72 mmol) in batches, and stir the mixed system at 25 °C for 12 h. Dilute the reaction system with water (100 mL), extract with dichloromethane (100 mL × 3), combine the organic phases, wash the organic phases with saturated aqueous sodium bicarbonate solution (100 mL × 3), dry over anhydrous sodium sulfate and filter, concentrate the filtrate under reduced pressure to obtain a residue, and purify the residue by silica gel column chromatography (ethyl acetate: petroleum ether = 0 - 100%) to obtain compound 7b (7.20 g), yield: 51%.

[0689] MS-ESI calculated value [M+H] + 210, the measured value is 210.

[0690] The second step

[0691] Dissolve 7b (7.20 g, 34.42 mmol) in a mixed solvent of tetrahydrofuran / water (V 四氢呋喃 :V 水= 3:1, 35 mL), and then wet palladium-carbon (700 mg, 6.58 mmol, 10% w / w) was added. The mixed system was stirred at room temperature under a hydrogen atmosphere for 12 hours. The reaction system was filtered to remove insoluble substances, the filter cake was washed with dichloromethane, the filtrate was concentrated under reduced pressure to obtain a residue, the residue was dried over anhydrous sodium sulfate and then filtered, the filtrate was concentrated under reduced pressure to obtain a residue, and the residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0 - 100%) to obtain compound 7c (5.60 g), yield: 91%.

[0692] MS-ESI calculated value [M+H] + 180, the measured value was 180.

[0693] 1 H NMR (400 MHz, DMSO-d6) δ 7.16 (s, 1H), 6.30 (s, 1H), 5.92 (s, 2H), 2.38 (s, 3H).

[0694] The third step

[0695] 7c (5.50 g, 30.70 mmol) was dissolved in dichloromethane (110 mL). The temperature of the mixed system was lowered to 0 °C, and N,N-diisopropylethylamine (5.95 g, 46.04 mmol) and acetyl chloride (3.61 g, 46.04 mmol) were added dropwise. After the addition was complete, the mixture was stirred at room temperature for 1 hour. The reaction solution was quenched with methanol (5 mL), the reaction solution was concentrated under reduced pressure to obtain a residue, and the residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0 - 100%) to obtain compound 7d (6.60 g), yield: 96%.

[0696] MS-ESI calculated value [M+H] + 222, the measured value was 222.

[0697] 1 H NMR (400 MHz, CDCl3) δ 12.06 (br s, 1H), 8.35 (s, 1H), 7.24 (s, 1H), 6.01 (s, 2H), 2.55 (s, 3H), 2.19 (s, 3H).

[0698] The fourth step

[0699] 7d (6.60 g, 29.84 mmol) was dissolved in glacial acetic acid (105 mL). The temperature of the mixed system was cooled to 0 °C, and liquid bromine (4.77 g, 29.84 mmol) and acetic acid solution of hydrobromic acid (12 M, 4.83 g, 59.68 mmol) were added dropwise successively. After the addition was complete, the reaction was continued to stir at room temperature for 1 hour. The reaction solution was poured into ice water (100 mL), and a solid was precipitated. The solid was filtered, and the filter cake was dissolved in dichloromethane (100 mL). The organic phase was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure to obtain a residue, and the residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0 - 100%) to obtain compound 7e (7.00 g), yield: 78%.

[0700] MS-ESI calculated value [M+H] + 300, 302, the measured values were 300, 302.

[0701] The fifth step

[0702] 7e (5.90 g, 19.67 mmol) was dissolved in absolute ethanol (60 mL), and concentrated hydrochloric acid (12 M, 5.0 mL, 60.00 mmol) was added. After the addition was complete, the temperature of the mixed system was raised to 80 °C and stirred for 4 hours. The reaction solution was concentrated under reduced pressure to obtain a residue, and the residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0 - 100%) to obtain the crude product 7f (4.56 g).

[0703] MS-ESI calculated value [M+H] + 214, 216, the measured values were 214, 216.

[0704] The sixth step

[0705] 7f (4.0 g, 18.70 mmol) was dissolved in anhydrous dichloromethane (40 mL), and benzylamine (10 mL) was added. After the addition was complete, the reaction was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure to obtain a residue, and the residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0 - 100%) to obtain compound 7g (2.5 g), two-step yield: 47%.

[0706] MS-ESI calculated value [M+H] + 285, the measured value was 285.

[0707] The seventh step

[0708] 7g (2.0 g, 7.04 mmol) was dissolved in anhydrous tetrahydrofuran (25 mL), and wet palladium on carbon (200 mg, 10% w / w) was added. The reaction was stirred at 50 °C under a hydrogen atmosphere for 20 hours. The reaction solution was filtered to remove insoluble substances, and the filtrate was concentrated under reduced pressure to obtain the crude product 7h (1.3 g).

[0709] MS-ESI calculated value [M+H] + 195, the measured value is 195.

[0710] The eighth step

[0711] Dissolve the crude product 7h (1.3 g) from the previous step in a mixed solvent of tetrahydrofuran / water (V 四氢呋喃 :V 水 = 2:1, 24 mL), add potassium carbonate (1.85 g, 13.40 mmol) and 9-fluorenylmethyl chloroformate (1.38 g, 5.36 mmol), and stir the reaction system at 0 °C for 1 hour. Dilute the reaction system with water (20 mL) and ethyl acetate (100 mL), separate the layers, wash the organic phase with saturated sodium chloride aqueous solution (250 mL x 2), dry over anhydrous sodium sulfate and filter, concentrate the filtrate under reduced pressure to obtain a residue, and purify the residue by silica gel column chromatography (ethyl acetate: petroleum ether = 0-100%) to obtain compound 7i (820 mg), with a two-step yield of 28%.

[0712] MS-ESI calculated value [M+H] + 417, the measured value is 417.

[0713] The ninth step

[0714] Add 7i (200 mg, 0.48 mmol), 1 (107 mg, 0.38 mmol) and p-toluenesulfonic acid (34 mg, 0.20 mmol) to a Schlenk reaction tube (100 mL) in sequence, add anhydrous toluene (10 mL), and heat the mixed system to 110 °C and stir for 6 hours. Concentrate the reaction system under reduced pressure to obtain a crude product, and purify the crude product by silica gel column chromatography (methanol: dichloromethane = 0-100%) to obtain a crude product 7j (200 mg), which is directly used in the next step.

[0715] MS-ESI calculated value [M+H] + 660, the measured value is 660.

[0716] The tenth step

[0717] Dissolve 7j (200 mg, 0.30 mmol) in anhydrous tetrahydrofuran (5 mL), add piperidine (255 mg, 3.00 mmol), and stir the mixed system at room temperature for 3.5 hours. Concentrate the reaction system under reduced pressure to obtain a crude product, and purify the crude product by silica gel column chromatography (methanol: dichloromethane = 0-100%) to obtain compound 7 (80 mg), with a yield of 61%.

[0718] MS-ESI calculated value [M+H] + 438, the measured value is 438.

[0719] 1 1H NMR (500 MHz, DMSO-d6) δ 7.72 (s, 1H), 7.66 (s, 1H), 7.51 (s, 1H), 6.29 (d, J = 2.0 Hz, 2H), 5.91 (d, J = 16.5 Hz, 1H), 5.48 (d, J = 16.5 Hz, 1H), 4.28 (s, 2H), 1.92 - 1.84 (m, 2H), 0.86 (t, J = 7.0 Hz, 3H).

[0720] Example 8

[0721]

[0722]

[0723] The first step

[0724] 7 (30 mg, 0.07 mmol) and glycolic acid (10.6 mg, 0.14 mmol) were successively added to a single-necked flask (25 mL), anhydrous dichloromethane (1.0 mL) was added, the reaction system was cooled to 0 °C, N,N-diisopropylethylamine (18 mg, 0.14 mmol) and 2-(7-azabenzotriazol)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (24 mg, 0.06 mmol) were successively added to the reaction system, and the reaction system was stirred at 0 °C for half an hour. The reaction solution was concentrated under reduced pressure to obtain a residue, and the residue was purified by silica gel column chromatography (methanol:dichloromethane = 0 - 100%) to obtain compound 8 (12 mg), yield: 35%.

[0725] MS-ESI calculated value [M + H] + 496, the measured value was 496.

[0726] Example 9

[0727]

[0728] The first step

[0729] To a single-necked flask (25 mL), 7 (65 mg, 0.15 mmol) and N-Boc-glycine (52 mg, 0.30 mmol) were added successively. Anhydrous dichloromethane (2 mL) was added, and the reaction system was cooled to 0 °C. N,N-Diisopropylethylamine (39 mg, 0.38 mmol) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (54 mg, 0.14 mmol) were added successively to the reaction system. The reaction system was stirred at 0 °C for half an hour. The reaction solution was concentrated under reduced pressure to obtain a residue, and the residue was purified by silica gel column chromatography (methanol:dichloromethane = 0 - 100%) to obtain compound 9a (80 mg), yield: 90%.

[0730] MS-ESI calculated value [M+H] + 595, the measured value was 595.

[0731] The second step

[0732] 9a (60 mg, 0.10 mmol) was dissolved in anhydrous dichloromethane (4 mL), and trifluoroacetic acid (0.4 mL) was added under an ice bath. The reaction system was restored to room temperature and stirred for 2.5 hours. The reaction solution was concentrated under reduced pressure to obtain a residue, and the residue was purified by silica gel column chromatography (methanol:dichloromethane = 0 - 100%) to obtain compound 9 (15 mg), yield: 30%.

[0733] MS-ESI calculated value [M+H] + 495, the measured value was 495.

[0734] 1 1H NMR (500 MHz, DMSO-d6) δ 7.74 (s, 2H), 7.58 (s, 1H), 6.32 (d, J = 2.0 Hz, 2H), 5.92 (d, J = 16.5 Hz, 1H), 5.73 (s, 2H), 5.50 (d, J = 16.5 Hz, 1H), 4.85 (s, 2H), 3.56 (s, 2H), 1.92 - 1.84 (m, 2H), 0.85 (t, J = 7.0 Hz, 3H).

[0735] Example 10

[0736]

[0737] The first step

[0738] Dissolve 7b (500 mg, 2.39 mmol) in ethanol (2 mL), then add paraformaldehyde (1.08 g, 35.64 mmol) and isopropylamine (3.43 g, 35.89 mmol). The mixed system is stirred at 100 °C for 72 hours. The mixed system is concentrated under reduced pressure to obtain a residue. The residue is diluted with water (10 mL), and the pH of the aqueous phase is adjusted to 7 with saturated sodium bicarbonate aqueous solution. The aqueous phase is extracted with dichloromethane (30 mL × 3). The organic phases are combined, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain a residue. The residue is purified by silica gel column chromatography (methanol:dichloromethane = 0 - 100%) to obtain compound 10a (80 mg), yield: 12%.

[0739] MS-ESI calculated value [M+H] + 281, the measured value is 281.

[0740] 1 H NMR (400 MHz, CDCl3) δ 7.73 (s, 1H), 7.29 (s, 1H), 6.30 (s, 2H), 3.40 - 3.20 (m, 5H), 1.24 (d, J = 6.8 Hz, 6H).

[0741] The second step

[0742] Dissolve 10a (80 mg, 0.29 mmol) in a mixed solvent of tetrahydrofuran / water (V 四氢呋喃 :V 水 = 3:1, 2 mL), and successively add 9-fluorenylmethyloxycarbonyl chloride (74 mg, 0.29 mmol) and sodium bicarbonate (24 mg, 0.29 mmol). The mixed system is stirred at 25 °C for 12 hours. The mixed system is concentrated under reduced pressure to obtain a residue. The residue is diluted with water (10 mL), and the aqueous phase is extracted with dichloromethane (20 mL × 3). The organic phases are combined, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain a residue. The residue is purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0 - 100%) to obtain compound 10b (70 mg), yield: 78%.

[0743] MS-ESI calculated value [M+H] + 503, the measured value is 503.

[0744] The third step

[0745] 10b (540 mg, 1.07 mmol) was dissolved in ethanol (10 mL), and then wet palladium on carbon (10% w / w, 54 mg) was added. The reaction system was heated to 40 °C and stirred for 4 hours. The mixture was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0 - 100%) to obtain compound 10c (360 mg), yield: 71%.

[0746] MS-ESI calculated value [M+H] + 473, the measured value was 473.

[0747] The fourth step

[0748] 10c (150 mg, 0.32 mmol)) was dissolved in anhydrous toluene (4 mL), and then 1 (89 mg, 0.32 mmol), p-toluenesulfonic acid (28 mg, 0.16 mmol) were added. After the addition was complete, the mixture was heated to 120 °C and stirred for 4 hours. The reaction solution was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (methanol: dichloromethane = 0 - 100%) to obtain compound 10d (70 mg), yield: 31%.

[0749] MS-ESI calculated value [M+H] + 716, the measured value was 716.

[0750] The fifth step

[0751] 10d (80 mg, 0.11 mmol) was dissolved in tetrahydrofuran (2 mL), and then piperidine (19 mg, 0.22 mmol) was added. The mixture was heated to 40 °C and stirred for 12 hours. The mixture was concentrated under reduced pressure to obtain a residue, which was purified by preparative thin layer chromatography to obtain compound 10 (30 mg), yield: 55%.

[0752] MS-ESI calculated value [M+H] + 494, the measured value was 494.

[0753] 1 H NMR (400 MHz, DMSO-d6) δ 7.71 (s, 1H), 7.63 (s, 1H), 7.49 (s, 1H), 6.28 (s, 2H), 5.91 (d, J = 16.4 Hz, 1H), 5.47 (d, J = 16.8 Hz, 1H), 5.45 - 5.40 (m, 1H), 3.36 - 3.28 (m, 2H), 3.19 - 3.10 (m, 1H), 3.09 - 3.00 (m, 2H), 1.93 - 1.82 (m, 2H), 1.14 (d, J = 6.4 Hz, 6H), 0.85 (t, J = 7.2 Hz, 3H).

[0754] Example 11

[0755]

[0756] The first step

[0757] Dissolve 11a (2.5 g, 215.14 mmol) in ethanol (30 mL), then add paraformaldehyde (6.82 g, 227.11 mmol) and isopropylamine (21.70 g, 227.06 mmol). The mixed system is stirred at 100 °C for 72 hours. The mixed system is concentrated under reduced pressure to obtain a residue. The residue is diluted with water (30 mL), and the pH of the aqueous phase is adjusted to ~7 with saturated aqueous sodium bicarbonate solution. The aqueous phase is extracted with dichloromethane (100 mL × 3). The organic phases are combined, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain a residue. The residue is purified by silica gel column chromatography (methanol:dichloromethane = 0-100%) to obtain compound 11b (2.20 g), yield: 61%.

[0758] MS-ESI calculated value [M+H] + 237, the measured value is 237.

[0759] The second step

[0760] Dissolve 11b (2.20 g, 9.65 mmol) in a mixed solvent of tetrahydrofuran / water (V 四氢呋喃 :V 水 = 3:1, 13 mL), add 9-fluorenylmethyl chloroformate (3.75 g, 14.50 mmol) and sodium bicarbonate (1.26 g, 14.50 mmol). The mixed system is stirred at 25 °C for 12 hours. The mixed system is concentrated under reduced pressure to obtain a residue. The residue is diluted with water (30 mL), and the aqueous phase is extracted with dichloromethane (20 mL × 3). The organic phases are combined, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain a residue. The residue is purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0-100%) to obtain compound 11c (345 mg), yield: 8%.

[0761] MS-ESI calculated value [M+H] + 459, the measured value is 459.

[0762] The third step

[0763] Dissolve llc (345 mg, 0.72 mmol) in ethanol (10 mL), then add wet palladium on carbon (10% w / w, 35 mg). Heat the mixture to 40 °C and stir for 4 hours. Concentrate the mixture under reduced pressure to obtain a residue. Purify the residue by silica gel column chromatography (ethyl acetate: petroleum ether = 0 - 100%) to obtain compound 11d (220 mg), yield: 71%.

[0764] MS-ESI calculated value [M+H] + 429, the measured value is 429.

[0765] The fourth step

[0766] Dissolve 11d (100 mg, 0.23 mmol) in anhydrous toluene (4 mL), then add 1 (66 mg, 0.24 mmol) and p-toluenesulfonic acid (20 mg, 0.12 mmol). After the addition is complete, heat the mixture to 120 °C and stir for 4 hours. Concentrate the reaction solution under reduced pressure to obtain a residue. Purify the residue by silica gel column chromatography (methanol: dichloromethane = 0 - 100%) to obtain compound 11e (100 mg), yield: 64%.

[0767] MS-ESI calculated value [M+H] + 672, the measured value is 672.

[0768] The fifth step

[0769] Dissolve 11e (80 mg, 0.12 mmol) in tetrahydrofuran (2 mL), then add piperidine (21 mg, 0.25 mmol). Heat the mixture to 40 °C and stir for 12 hours. Concentrate the mixture under reduced pressure to obtain a residue. Purify the residue by thin layer chromatography to obtain compound 11 (6 mg), yield: 11%.

[0770] MS-ESI calculated value [M+H] + 450, the measured value is 450.

[0771] Example 12

[0772]

[0773] The first step

[0774] 12a (5.00 g, 22.00 mmol) was dissolved in dichloromethane (450 mL), and then 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (12.55 g, 33.00 mmol), N,N-diisopropylethylamine (5.69 g, 44.00 mmol), and N-methyl-N-methoxyamine hydrochloride (1.41 g, 33.00 mmol) were added. The mixed system was stirred at 25 °C for 12 h. The reaction system was diluted with dichloromethane (200 mL), and then aqueous hydrochloric acid solution (1 N, 50 mL) was added. After liquid separation, the organic phase was washed successively with saturated aqueous sodium bicarbonate solution (50 mL × 1) and saturated brine (50 mL × 1). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0 - 100%) to obtain compound 12b (5.30 g), yield: 89%.

[0775] The second step

[0776] 4-Bromo-1,2-methylenedioxybenzene (9.37 g, 46.61 mmol) was dissolved in tetrahydrofuran (100 mL). After cooling to -65 °C, n-butyllithium (1.6 M n-hexane solution, 29 mL) was added dropwise. The mixed system was stirred at -65 °C for 0.5 h. 12b (5.04 g, 18.64 mmol) was dissolved in anhydrous tetrahydrofuran (40 mL) and added dropwise to the above reaction system. After the addition was complete, the mixed system was stirred at -65 °C for 3 h. The mixed system was quenched with saturated aqueous ammonium chloride solution (500 mL), and then extracted with ethyl acetate (500 mL × 3). The organic phase was washed with saturated brine (500 mL × 1). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0 - 100%) to obtain compound 12c (4.00 g), yield: 45%.

[0777] 1 H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 8.0 Hz, 1H), 7.44 (s, 1H), 6.82 (d, J = 8.4 Hz, 1H), 6.03 (s, 2H), 2.50 (s, 6H), 1.46 (s, 9H).

[0778] The third step

[0779] Dissolve 12c (3.00 g, 9.05 mmol) in dichloromethane (100 mL), cool the temperature to 0 °C, then add trifluoroacetic acid (27.61 g, 242.15 mmol), and warm the mixed system to 25 °C and stir for 3 hours. Concentrate the mixed system under reduced pressure, dissolve the residue in dichloromethane (40 mL), cool the temperature to 0 °C, and dropwise add N,N-diisopropylethylamine (7.42 g, 57.41 mmol) and trifluoroacetic anhydride (3.85 g, 18.33 mmol). After the addition is complete, warm the mixed system to 25 °C and stir for 4 hours. Quench the mixed system with water (200 mL), extract with ethyl acetate (200 mL x 3), and wash the organic phase with saturated brine (200 mL x 1). Dry the organic phase over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure to obtain a residue, and purify the residue by silica gel column chromatography (ethyl acetate: petroleum ether = 0 - 100%) to obtain compound 12d (2.50 g), yield: 84%.

[0780] The fourth step

[0781] Dissolve 12d (2.50 g, 7.64 mmol) in acetic anhydride (5.8 mL), cool the temperature to 0 °C, add copper nitrate (860 mg, 4.59 mmol) in batches. After the addition is complete, keep the mixed system at 0 °C and stir for 3 hours. Quench the mixed system with water (30 mL), and extract with ethyl acetate (30 mL x 3). Dry the organic phase over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure to obtain a residue, and purify the residue by silica gel column chromatography (ethyl acetate: petroleum ether = 0 - 100%) to obtain compound 12e (900 mg), yield: 75%.

[0782] MS-ESI calculated value [M+H] + 373, the measured value is 373.

[0783] 1 H NMR (400 MHz, CDCl3) δ 7.60 (s, 1H), 6.66 (br s, 1H), 6.64 (s, 1H), 6.21 (s, 2H), 2.43 (s, 6H).

[0784] The fifth step

[0785] Dissolve 12e (400 mg, 1.07 mmol) in ethanol (10 mL), then add wet palladium on carbon (10% w / w, 40 mg), and warm the mixed system to 40 °C and stir for 4 hours. Concentrate the mixed system under reduced pressure to obtain a residue, and purify the residue by silica gel column chromatography (ethyl acetate: petroleum ether = 0 - 100%) to obtain compound 12f (220 mg), yield: 60%.

[0786] MS-ESI calculated value [M+H]+ 343, the measured value is 343.

[0787] The sixth step

[0788] Dissolve 12f (100 mg, 0.29 mmol) in anhydrous toluene (4 mL), then add 1 (82 mg, 0.32 mmol) and p-toluenesulfonic acid (26 mg, 0.15 mmol). After the addition is complete, heat the mixed system to 120 °C and stir for 4 hours. Concentrate the reaction solution under reduced pressure to obtain a residue, and purify the residue by silica gel column chromatography (methanol:dichloromethane = 0-100%) to obtain compound 12g (80 mg), yield: 47%.

[0789] The seventh step

[0790] Dissolve 12g (80 mg, 0.14 mmol) in methanol (4 mL), then add hydrochloric acid (1.6 mL, 4 M). Heat the mixed system to 65 °C and stir for 4 hours. Concentrate the mixed system under reduced pressure to obtain a residue, and purify the residue by silica gel column chromatography (methanol:dichloromethane = 0-100%) to obtain compound 12 (14 mg), yield: 21%.

[0791] MS-ESI calculated value [M+H] + 490, the measured value is 490.

[0792] 1 H NMR (400 MHz, DMSO-d6) δ 7.74 (s, 1H), 7.64 (s, 1H), 7.58 (s, 1H), 6.32 (s, 2H), 5.92 (d, J = 16.4 Hz, 1H), 5.61 (s, 2H), 5.50 (d, J = 16.4 Hz, 1H), 2.81 (s, 6H), 1.93-1.84 (m, 2H), 0.84 (t, J = 7.2 Hz, 3H).

[0793] Example 13

[0794]

[0795] The first step

[0796] Add 13a (15 g, 73.90 mmol) portionwise to a mixed solvent of concentrated sulfuric acid (45 mL) and concentrated nitric acid (12 mL) under an ice bath. After the addition is complete, gradually warm the reaction system to room temperature and stir for 5 hours. Pour the reaction solution into ice water (1 L), precipitate a yellow solid, and filter and dry to obtain compound 13b (22 g).

[0797] The second step

[0798] 13b (750 mg, 3.02 mmol), tert-butyl carbamate (424 mg, 3.62 mmol), Pd2(dba)3 (138 mg, 0.15 mmol), XPhos (288 mg, 0.60 mmol) and cesium carbonate (1.96 g, 6.04 mmol) were successively added into a Schlenk reaction tube. After purging with nitrogen three times, anhydrous toluene (8 mL) was added. The tube was sealed and stirred in an oil bath at 90 °C overnight. The reaction mixture was diluted with ethyl acetate (100 mL). The organic phase was washed successively with water (25 mL×1) and brine (25 mL×2), dried, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0 - 100%) to obtain compound 13c (550 mg), yield: 64%.

[0799] 1 H NMR (400 MHz, DMSO-d6) δ 10.44 (s, 1H), 8.75 (d, J = 6.0 Hz, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.05 (s, 1H), 1.55 (s, 9H).

[0800] The third step

[0801] 13c (500 mg, 1.76 mmol) and ammonium chloride (156 mg, 2.94 mmol) were dissolved in a mixed solvent of ethanol (8 mL) and water (2 mL). Iron powder (394 mg, 7.04 mmol) was added portionwise. The reaction system was heated to 60 °C and stirred for 2 hours. The reaction mixture was diluted with ethyl acetate (100 mL). The organic phase was washed successively with water (25 mL×1) and brine (25 mL×1), dried, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0 - 100%) to obtain compound 13d (310 mg), yield: 69%.

[0802] MS-ESI calculated value [M+H] + 255, the measured value was 255.

[0803] The fourth step

[0804] 13d (250 mg, 0.98 mmol), 1 (167 mg, 0.60 mmol) and p-toluenesulfonic acid (26 mg, 0.15 mmol) were successively added into a Schlenk reaction tube (100 mL). Anhydrous toluene (3 mL) was added. The mixed system was heated to 110 °C and stirred for 2 hours. The reaction system was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (methanol: dichloromethane = 0 - 100%) to obtain crude product 13e (180 mg), which was directly used for the next step.

[0805] MS-ESI calculated value [M+H] + 498, the measured value is 498.

[0806] The fifth step

[0807] Dissolve 13e (45 mg, 0.09 mmol) in anhydrous dichloromethane (1 mL), add trifluoroacetic acid (0.3 mL) under ice bath, and restore the reaction system to room temperature and stir for 5 hours. The reaction solution was concentrated under reduced pressure to obtain a residue, and the residue was purified by silica gel column chromatography (methanol:dichloromethane = 0-100%) to obtain compound 9 (20 mg), yield: 30%.

[0808] MS-ESI calculated value [M+H] + 398, the measured value is 398.

[0809] 1 H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 7.80 (d, J = 12.4 Hz, 1H), 7.70 (s, 1H), 7.16 (d, J = 9.6 Hz, 1H), 5.90 (d, J = 16.4 Hz, 1H), 5.46 (d, J = 16.4 Hz, 1H), 5.43 (s, 2H), 1.93 - 1.80 (m, 2H), 0.85 (t, J = 7.2 Hz, 3H).

[0810] Example 14

[0811]

[0812] The first step

[0813] Add 7 (20 mg, 0.05 mmol) and 2-cyclopropyl-2-hydroxyacetic acid (12 mg, 0.10 mmol) to a single-necked flask (25 mL) in sequence, add anhydrous dichloromethane (1.0 mL), cool the reaction system to 0 °C, and add triethylamine (10 mg, 0.10 mmol) and 2-(7-azabenzotriazol)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (23 mg, 0.06 mmol) to the reaction system in sequence. Stir the reaction system at 0 °C for half an hour. The reaction solution was concentrated under reduced pressure to obtain a residue, and the residue was purified by silica gel column chromatography (methanol:dichloromethane = 0-100%) to obtain compound 14 (12 mg), yield: 49%.

[0814] MS-ESI calculated value [M+H] + 536, the measured value is 536.

[0815] 11H NMR (400 MHz, DMSO-d6) δ 8.66 (t, J = 5.6 Hz, 1H), 7.87 (s, 1H), 7.74 (s, 1H), 7.54 (s, 1H), 6.30 (s, 2H), 5.92 (d, J = 16.4 Hz, 1H), 5.74 (s, 2H), 5.49 (d, J = 16.4 Hz, 1H), 4.75 (d, J = 5.2 Hz, 2H), 3.56 - 3.51 (m, 1H), 1.94 - 1.83 (m, 2H), 1.07 - 0.97 (m, 1H), 0.85 (t, J = 7.2 Hz, 3H), 0.39 - 0.29 (m, 2H), 0.28 - 0.18 (m, 2H).

[0816] Example 15

[0817]

[0818]

[0819] The first step

[0820] To a single-necked flask (25 mL), 7 (20 mg, 0.05 mmol) and lactic acid (9 mg, 0.10 mmol) were successively added. Anhydrous dichloromethane (1.0 mL) was added, and the reaction system was cooled to 0 °C. N,N-Diisopropylethylamine (20 mg, 0.15 mmol) and 2-(7-azabenzotriazol)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (20 mg, 0.05 mmol) were successively added to the reaction system. The reaction system was stirred at 0 °C for half an hour. The reaction solution was concentrated under reduced pressure to obtain a residue, and the residue was purified by silica gel column chromatography (methanol:dichloromethane = 0 - 100%) to obtain compound 15 (10 mg), yield: 43%.

[0821] MS-ESI calculated value [M + H] + 510, the measured value was 510.

[0822] 1 1H NMR (400 MHz, DMSO-d6) δ 8.74 (t, J = 5.2 Hz, 1H), 7.89 (s, 1H), 7.76 (s, 1H), 7.57 (s, 1H), 6.32 (s, 2H), 5.94 (d, J = 16.8 Hz, 1H), 5.74 (s, 2H), 5.51 (d, J = 16.4 Hz, 1H), 4.77 (d, J = 5.6 Hz, 2H), 4.05 - 3.96 (m, 1H), 1.94 - 1.82 (m, 2H), 0.88 (t, J = 7.2 Hz, 3H).

[0823] Example 16

[0824]

[0825] The first step

[0826] 7 (20 mg, 0.05 mmol) and 3-hydroxycyclobutanecarboxylic acid (12 mg, 0.10 mmol) were successively added to a single-necked flask (25 mL). Anhydrous dichloromethane (1.0 mL) was added, and the reaction system was cooled to 0 °C. N,N-Diisopropylethylamine (17 mg, 0.13 mmol) and 2-(7-azabenzotriazol)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (23 mg, 0.06 mmol) were successively added to the reaction system. The reaction system was stirred at 0 °C for half an hour. The reaction solution was concentrated under reduced pressure to obtain a residue, and the residue was purified by silica gel column chromatography (methanol:dichloromethane = 0 - 100%) to obtain compound 16 (15 mg), yield: 61%.

[0827] MS-ESI calculated value [M+H] + 536, the measured value was 536.

[0828] 1 H NMR (400 MHz, DMSO-d6) δ 7.72 (s, 1H), 7.69 (s, 1H), 7.52 (s, 1H), 6.29 (s, 2H), 5.91 (d, J = 16.4 Hz, 1H), 5.58 (s, 2H), 5.48 (d, J = 16.8 Hz, 1H), 4.77 - 4.69 (m, 2H), 3.97 - 3.82 (m, 1H), 2.45 - 2.35 (m, 1H), 2.30 - 2.22 (m, 2H), 2.00 - 1.82 (m, 4H), 0.85 (t, J = 7.2 Hz, 3H).

[0829] Example 17

[0830]

[0831] The first step

[0832] To a single-necked flask (25 mL), 7 (20 mg, 0.05 mmol) and 4-hydroxycyclohexanecarboxylic acid (14 mg, 0.10 mmol) were added successively. Anhydrous dichloromethane (1.0 mL) was added, and the reaction system was cooled to 0 °C. N,N-Diisopropylethylamine (17 mg, 0.13 mmol) and 2-(7-azabenzotriazol)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (23 mg, 0.06 mmol) were added successively to the reaction system. The reaction system was stirred at 0 °C for half an hour. The reaction solution was concentrated under reduced pressure to obtain a residue, and the residue was purified by silica gel column chromatography (methanol:dichloromethane = 0 - 100%) to obtain compound 17 (9 mg), yield: 35%.

[0833] MS-ESI calculated value [M+H] + 564, the measured value was 564.

[0834] 1 H NMR (400 MHz, DMSO-d6) δ 8.60 (s, 1H), 7.73 (s, 1H), 7.71 (s, 1H), 7.54 (s, 1H), 6.30 (s, 2H), 5.92 (d, J = 16.8 Hz, 1H), 5.67 - 5.57 (m, 2H), 5.48 (d, J = 16.4 Hz, 1H), 4.79 - 4.70 (m, 2H), 3.3 (m, 1H), 2.12 - 2.00 (m, 1H), 1.92 - 1.84 (m, 2H), 1.84 - 1.77 (m, 2H), 1.77 - 1.67 (m, 2H), 1.42 - 1.32 (m, 2H), 1.15 - 1.02 (m, 2H), 0.85 (t, J = 7.2 Hz, 3H).

[0835] Example 18

[0836]

[0837] The first step

[0838] 7 (20 mg, 0.05 mmol) and (R)-3-hydroxybutyric acid (10 mg, 0.10 mmol) were successively added to a single-necked flask (25 mL). Anhydrous dichloromethane (1.0 mL) was added, and the reaction system was cooled to 0 °C. N,N-Diisopropylethylamine (20 mg, 0.15 mmol) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (23 mg, 0.06 mmol) were successively added to the reaction system. The reaction system was stirred at 0 °C for half an hour. The reaction solution was concentrated under reduced pressure to obtain a residue, and the residue was purified by silica gel column chromatography (methanol:dichloromethane = 0-100%) to obtain compound 18 (17 mg), yield: 71%.

[0839] MS-ESI calculated value [M+H] + 524, the measured value was 524.

[0840] 1 H NMR (400 MHz, DMSO-d6) δ 7.730 (s, 1H), 7.726 (s, 1H), 7.53 (s, 1H), 6.29 (d, J = 2.0 Hz, 2H), 5.92 (d, J = 16.4 Hz, 1H), 5.64 (s, 2H), 5.49 (d, J = 16.4 Hz, 1H), 4.81-4.65 (m, 2H), 4.00-3.89 (m, 1H), 2.29-2.20 (m, 1H), 2.17-2.09 (m, 1H), 1.94-1.82 (m, 2H), 0.99 (d, J = 6.4 Hz, 3H), 0.85 (t, J = 7.2 Hz, 3H).

[0841] Example 19

[0842]

[0843] The first step

[0844] 7 (20 mg, 0.05 mmol) and (S)-3-hydroxybutyric acid (10 mg, 0.10 mmol) were successively added to a single-necked flask (25 mL). Anhydrous dichloromethane (1.0 mL) was added, and the reaction system was cooled to 0 °C. N,N-Diisopropylethylamine (20 mg, 0.15 mmol) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (23 mg, 0.06 mmol) were successively added to the reaction system. The reaction system was stirred at 0 °C for half an hour. The reaction solution was concentrated under reduced pressure to obtain a residue, and the residue was purified by silica gel column chromatography (methanol:dichloromethane = 0-100%) to obtain compound 19 (15 mg), yield: 63%.

[0845] MS-ESI calculated value [M+H] + 524, the measured value is 524.

[0846] 1 H NMR (400 MHz, DMSO-d6) δ 8.66 (t, J = 5.6 Hz, 1H), 7.73 (s, 2H), 7.54 (s, 1H), 6.30 (s, 2H), 5.92 (d, J = 16.4 Hz, 1H), 5.68 - 5.62 (m, 2H), 5.49 (d, J = 16.4 Hz, 1H), 4.77 - 4.71 (m, 2H), 4.00 - 3.89 (m, 1H), 2.28 - 2.21 (m, 1H), 2.17 - 2.10 (m, 1H), 1.93 - 1.84 (m, 2H), 1.00 (d, J = 6.4 Hz, 3H), 0.85 (t, J = 7.2 Hz, 3H).

[0847] Example 20

[0848]

[0849] The first step

[0850] 2 (20 mg, 0.05 mmol) and 3-hydroxycyclobutanecarboxylic acid (12 mg, 0.10 mmol) were successively added to a single-necked flask (25 mL). Anhydrous dichloromethane (1.0 mL) was added. The reaction system was cooled to 0 °C. N,N-diisopropylethylamine (20 mg, 0.15 mmol) and 2-(7-azabenzotriazol)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (23 mg, 0.06 mmol) were successively added to the reaction system. The reaction system was stirred at 0 °C for half an hour. The reaction solution was concentrated under reduced pressure to obtain a residue, and the residue was purified by silica gel column chromatography (methanol:dichloromethane = 0 - 100%) to obtain compound 20 (15 mg), yield: 61%.

[0851] MS-ESI calculated value [M+H] + 524, the measured value is 524.

[0852] 11H NMR (400 MHz, DMSO-d6) δ 8.30 (d, J = 8.0 Hz, 1H), 7.89 (d, J = 10.8 Hz, 1H), 7.79 (s, 1H), 5.91 (d, J = 16.4 Hz, 1H), 5.61 (s, 2H), 5.49 (d, J = 16.8 Hz, 1H), 4.89 - 4.81 (m, 2H), 3.98 - 3.85 (m, 1H), 2.46 - 2.38 (m, 1H), 2.45 - 2.35 (m, 2H), 1.98 - 1.82 (m, 4H), 0.85 (t, J = 7.2 Hz, 3H).

[0853] Example 21

[0854]

[0855] The first step

[0856] 2 (20 mg, 0.05 mmol) and 4-hydroxycyclohexanecarboxylic acid (14 mg, 0.10 mmol) were successively added to a single-necked flask (25 mL). Anhydrous dichloromethane (1.0 mL) was added. The reaction system was cooled to 0 °C. N,N-diisopropylethylamine (20 mg, 0.15 mmol) and 2-(7-azabenzotriazol)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (23 mg, 0.06 mmol) were successively added to the reaction system. The reaction system was stirred at 0 °C for half an hour. The reaction solution was concentrated under reduced pressure to obtain a residue, and the residue was purified by silica gel column chromatography (methanol:dichloromethane = 0 - 100%) to obtain compound 20 (22 mg), yield: 89%.

[0857] MS-ESI calculated value [M + H] + 552, the measured value was 552.

[0858] 1 1H NMR (400 MHz, DMSO-d6) δ 8.30 (d, J = 8.0 Hz, 1H), 7.91 (d, J = 10.4 Hz, 1H), 7.79 (s, 1H), 5.92 (d, J = 16.8 Hz, 1H), 5.66 - 5.60 (m, 2H), 5.49 (d, J = 16.4 Hz, 1H), 3.36 - 3.25 (m, 1H), 2.14 - 2.04 (m, 1H), 1.92 - 1.85 (m, 2H), 1.85 - 1.68 (m, 4H), 1.55 - 1.35 (m, 2H), 1.16 - 1.02 (m, 2H), 0.86 (t, J = 7.2 Hz, 3H).

[0859] Example 22

[0860]

[0861]

[0862] The first step

[0863] 2 (25 mg, 0.06 mmol) and lactic acid (11 mg, 0.10 mmol) were successively added to a single-necked flask (25 mL). Anhydrous dichloromethane (1.0 mL) was added. The reaction system was cooled to 0 °C. Triethylamine (23 mg, 0.18 mmol) and 2-(7-azabenzotriazol)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (27 mg, 0.07 mmol) were successively added to the reaction system. The reaction system was stirred at 0 °C for half an hour. The reaction solution was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 0 - 100%) to obtain compound 22 (28 mg), yield: 96%.

[0864] MS-ESI calculated value [M+H] + 498, the measured value was 498.

[0865] 1 H NMR (400 MHz, DMSO-d6) δ 8.74 (t, J = 6.0 Hz, 1H), 8.42 (d, J = 8.0 Hz, 1H), 7.92 (d, J = 10.8 Hz, 1H), 7.79 (s, 1H), 5.92 (d, J = 16.4 Hz, 1H), 5.78 - 5.68 (m, 2H), 5.50 (d, J = 16.4 Hz, 1H), 5.00 - 4.76 (m, 2H), 4.06 - 3.95 (m, 1H), 1.94 - 1.82 (m, 2H), 0.86 (t, J = 7.2 Hz, 3H).

[0866] Example 23

[0867]

[0868] The first step

[0869] 2 (25 mg, 0.06 mmol) and 2-cyclopropyl-2-hydroxyacetic acid (14 mg, 0.12 mmol) were successively added to a single-necked flask (25 mL). Anhydrous dichloromethane (1.0 mL) was added. The reaction system was cooled to 0 °C. N,N-diisopropylethylamine (23 mg, 0.18 mmol) and 2-(7-azabenzotriazol)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (34 mg, 0.09 mmol) were successively added to the reaction system. The reaction system was stirred at 0 °C for half an hour. The reaction solution was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 0-100%) to obtain compound 23 (28 mg), yield: 91%.

[0870] MS-ESI calculated value [M+H] + 524, the measured value was 524.

[0871] 1 H NMR (400 MHz, DMSO-d6) δ 8.69 (t, J = 5.6 Hz, 1H), 8.43 (d, J = 7.6 Hz, 1H), 7.92 (d, J = 10.8 Hz, 1H), 7.80 (s, 1H), 5.92 (d, J = 16.4 Hz, 1H), 5.78 - 5.70 (m, 2H), 5.50 (d, J = 16.4 Hz, 1H), 5.00 - 4.79 (m, 2H), 3.57 - 3.52 (m, 1H), 1.94 - 1.82 (m, 2H), 1.09 - 0.97 (m, 1H), 0.86 (t, J = 6.8 Hz, 3H), 0.38 - 0.28 (m, 2H), 0.28 - 0.18 (m, 2H).

[0872] Example 24

[0873]

[0874] The first step

[0875] 2 (20 mg, 0.05 mmol) and (S)-3-hydroxybutyric acid (10 mg, 0.10 mmol) were successively added to a single-necked flask (25 mL). Anhydrous dichloromethane (1.0 mL) was added. The reaction system was cooled to 0 °C. N,N-diisopropylethylamine (19 mg, 0.15 mmol) and 2-(7-azabenzotriazol)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (23 mg, 0.06 mmol) were successively added to the reaction system. The reaction system was stirred at 0 °C for half an hour. The reaction solution was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 0-100%) to obtain compound 24 (18 mg), yield: 75%.

[0876] MS-ESI calculated value [M+H] + 512, the measured value was 512.

[0877] 1 H NMR (400 MHz, DMSO-d6) δ 8.32 (d, J = 8.4 Hz, 1H), 7.91 (d, J = 10.4 Hz, 1H), 7.79 (s, 1H), 5.92 (d, J = 16.8 Hz, 1H), 5.66 (s, 2H), 5.50 (d, J = 16.4 Hz, 1H), 4.91 - 4.76 (m, 2H), 4.00 - 3.90 (m, 1H), 2.31 - 2.22 (m, 1H), 2.20 - 2.10 (m, 1H), 1.93 - 1.84 (m.2H), 0.99 (d, J = 6.4 Hz, 3H), 0.85 (d, J = 7.2 Hz, 3H).

[0878] Example 25

[0879]

[0880] The first step

[0881] To a single-necked flask (25 mL), 2 (25 mg, 0.06 mmol) and (R)-3-hydroxybutyric acid (13 mg, 0.12 mmol) were added successively. Anhydrous dichloromethane (1.0 mL) was added, and the reaction system was cooled to 0 °C. N,N-diisopropylethylamine (23 mg, 0.18 mmol) and 2-(7-azabenzotriazol)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (27 mg, 0.07 mmol) were added successively to the reaction system. The reaction system was stirred at 0 °C for half an hour. The reaction solution was concentrated under reduced pressure to obtain a residue, and the residue was purified by silica gel column chromatography (methanol:dichloromethane = 0 - 100%) to obtain compound 25 (18 mg), yield: 60%.

[0882] MS-ESI calculated value [M+H] + 512, the measured value was 512.

[0883] 11H NMR (400 MHz, DMSO-d6) δ 8.30 (d, J = 8.4 Hz, 1H), 7.89 (d, J = 10.8 Hz, 1H), 7.78 (s, 1H), 5.91 (d, J = 16.4 Hz, 1H), 5.72 - 5.56 (m, 2H), 5.49 (d, J = 16.8 Hz, 1H), 4.92 - 4.76 (m, 2H), 4.00 - 3.90 (m, 1H), 2.30 - 2.22 (m, 1H), 2.20 - 2.10 (m, 1H), 1.94 - 1.82 (m, 2H), 0.99 (d, J = 6.4 Hz, 3H), 0.85 (d, J = 7.2 Hz, 3H).

[0884] Example 26

[0885]

[0886] The first step

[0887] 26a (30 mg, 0.06 mmol) and (S)-3-hydroxybutyric acid (10 mg, 0.12 mmol) were successively added to a single-necked flask (25 mL). Anhydrous dichloromethane (1.0 mL) was added, and the reaction system was cooled to 0 °C. N,N-Diisopropylethylamine (20 mg, 0.15 mmol) and 2-(7-azabenzotriazol)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (27 mg, 0.07 mmol) were successively added to the reaction system. The reaction system was stirred at 0 °C for half an hour. The reaction solution was concentrated under reduced pressure to obtain a residue, and the residue was purified by silica gel column chromatography (methanol:dichloromethane = 0 - 100%) to obtain compound 26 (22 mg), yield: 67%.

[0888] MS-ESI calculated value [M + H] + 538, the measured value was 538.

[0889] 1 1H NMR (400 MHz, DMSO-d6) δ 8.52 (d, J = 8.8 Hz, 1H), 7.793 (d, J = 10.8 Hz, 1H), 7.789 (s, 1H), 5.90 (d, J = 16.4 Hz, 1H), 5.63 - 5.54 (m, 1H), 5.52 - 5.54 (m, 2H), 5.41 - 5.32 (m, 1H), 4.15 - 4.04 (m, 1H), 3.28 - 3.03 (m, 2H), 2.39 (s, 3H), 2.38 - 2.25 (m, 2H), 2.22 - 2.07 (m, 2H), 1.93 - 1.84 (m, 2H), 1.12 (d, J = 6.4 Hz, 3H), 0.85 (t, J = 7.2 Hz, 3H).

[0890] Example 27

[0891]

[0892] The first step

[0893] 26a (45 mg, 0.09 mmol) and (R)-3-hydroxybutyric acid (19 mg, 0.18 mmol) were successively added into a single-necked flask (25 mL). Anhydrous dichloromethane (1.0 mL) was added. The reaction system was cooled to 0 °C. N,N-diisopropylethylamine (30 mg, 0.23 mmol) and 2-(7-azabenzotriazol)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (42 mg, 0.11 mmol) were successively added into the reaction system. The reaction system was stirred at 0 °C for half an hour. The reaction solution was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (methanol:dichloromethane = 0-100%) to obtain compound 27 (45 mg), yield: 91%.

[0894] MS-ESI calculated value [M+H] + 538, the measured value was 538.

[0895] 1 H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J = 8.4 Hz, 1H), 7.80-7.72 (m, 2H), 5.90 (d, J = 16.4 Hz, 1H), 5.62-5.53 (m, 1H), 5.52-5.43 (m, 2H), 5.35 (d, J = 20.0 Hz, 1H), 4.12-4.00 (m, 1H), 3.27-3.05 (m, 2H), 2.44-2.39 (m, 1H), 2.38 (s, 3H), 2.28-2.21 (m, 1H), 2.20-2.08 (m, 2H), 1.93-1.83 (m, 2H), 1.10 (d, J = 6.0 Hz, 3H), 0.85 (t, J = 7.2 Hz, 3H).

[0896] Example 28

[0897]

[0898] The first step

[0899] To a single-necked flask (25 mL), 26a (25 mg, 0.05 mmol) and 3-hydroxycyclobutanecarboxylic acid (12 mg, 0.10 mmol) were added successively. Anhydrous dichloromethane (1.0 mL) was added. The reaction system was cooled to 0 °C. To the reaction system, N,N-diisopropylethylamine (17 mg, 0.13 mmol) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (23 mg, 0.06 mmol) were added successively. The reaction system was stirred at 0 °C for half an hour. The reaction solution was concentrated under reduced pressure to obtain a residue, and the residue was purified by silica gel column chromatography (methanol:dichloromethane = 0-100%) to obtain compound 28 (26 mg), yield: 92%.

[0900] MS-ESI calculated value [M+H] + 550, the measured value was 550.

[0901] 1 H NMR (400 MHz, DMSO-d6) δ 7.81-7.75 (m, 2H), 5.90 (d, J = 16.4 Hz, 1H), 5.60-5.53 (m, 1H), 5.48 (d, J = 16.8 Hz, 1H), 5.41 (d, J = 20.0 Hz, 1H), 5.30 (d, J = 20.0 Hz, 1H), 4.00-3.89 (m, 1H), 3.30-3.05 (m, 2H), 2.38 (s, 3H), 2.25-2.00 (m, 4H), 1.94-1.83 (m, 2H), 0.85 (t, J = 7.2 Hz, 3H).

[0902] Example 29

[0903]

[0904]

[0905] The first step

[0906] To a single-necked flask (25 mL), 26a (30 mg, 0.06 mmol) and cis-3-hydroxycyclobutanecarboxylic acid (14 mg, 0.12 mmol) were added successively. Anhydrous dichloromethane (1.0 mL) was added. The reaction system was cooled to 0 °C. To the reaction system, N,N-diisopropylethylamine (20 mg, 0.15 mmol) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (27 mg, 0.07 mmol) were added successively. The reaction system was stirred at 0 °C for half an hour. The reaction solution was concentrated under reduced pressure to obtain a residue, and the residue was purified by silica gel column chromatography (methanol:dichloromethane = 0-100%) to obtain compound 29 (33 mg), yield: 99%.

[0907] MS-ESI calculated value [M+H] + 550, the measured value is 550.

[0908] 1 H NMR (400 MHz, DMSO-d6) δ 8.49 (d, J = 8.8 Hz, 1H), 7.78 (s, 1H), 7.77 (d, J = 10.4 Hz, 1H), 5.90 (d, J = 16.4 Hz, 1H), 5.61 - 5.52 (m, 1H), 5.48 (d, J = 16.8 Hz, 1H), 5.40 (d, J = 20.0 Hz, 1H), 5.28 (d, J = 20.0 Hz, 1H), 4.01 - 3.89 (m, 1H), 3.30 - 3.05 (m, 2H), 2.38 (s, 3H), 2.25 - 2.00 (m, 4H), 1.94 - 1.82 (m, 2H), 0.85 (t, J = 7.2 Hz, 3H).

[0909] Example 30

[0910]

[0911] The first step

[0912] 26a (30 mg, 0.06 mmol) and trans-3-hydroxycyclobutanecarboxylic acid (14 mg, 0.12 mmol) were successively added to a single-necked flask (25 mL), anhydrous dichloromethane (1.0 mL) was added, the reaction system was cooled to 0 °C, N,N-diisopropylethylamine (20 mg, 0.15 mmol) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (27 mg, 0.07 mmol) were successively added to the reaction system, and the reaction system was stirred at 0 °C for half an hour. The reaction solution was concentrated under reduced pressure to obtain a residue, and the residue was purified by silica gel column chromatography (methanol:dichloromethane = 0 - 100%) to obtain compound 30 (22 mg), yield: 65%.

[0913] MS-ESI calculated value [M+H] + 550, the measured value is 550.

[0914] 11H NMR (400 MHz, DMSO-d6) δ 8.46 (d, J = 8.8 Hz, 1H), 7.79 (d, J = 10.4 Hz, 1H), 7.78 (s, 1H), 5.90 (d, J = 16.4 Hz, 1H), 5.62 - 5.53 (m, 1H), 5.47 (d, J = 16.4 Hz, 1H), 5.44 - 5.27 (m, 2H), 4.42 - 4.32 (m, 1H), 3.28 - 3.06 (m, 2H), 3.00 - 2.90 (m, 1H), 2.38 (s, 3H), 2.25 - 1.98 (m, 4H), 1.94 - 1.82 (m, 2H), 0.85 (t, J = 7.2 Hz, 3H).

[0915] Example 31

[0916]

[0917] The first step

[0918] 26a (30 mg, 0.06 mmol) and 3-hydroxycyclobutanecarboxylic acid (17 mg, 0.12 mmol) were successively added to a single-necked flask (25 mL). Anhydrous dichloromethane (1.0 mL) was added, and the reaction system was cooled to 0 °C. N,N-Diisopropylethylamine (20 mg, 0.15 mmol) and 2-(7-azabenzotriazol)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (27 mg, 0.07 mmol) were successively added to the reaction system. The reaction system was stirred at 0 °C for half an hour. The reaction solution was concentrated under reduced pressure to obtain a residue, and the residue was purified by silica gel column chromatography (methanol:dichloromethane = 0 - 100%) to obtain compound 31 (32 mg), yield: 90%.

[0919] MS-ESI calculated value [M + H] + 578, the measured value was 578.

[0920] 1 1H NMR (400 MHz, DMSO-d6) δ 7.78 (s, 1H), 7.75 (d, J = 11.2 Hz, 1H), 5.89 (d, J = 16.8 Hz, 1H), 5.60 - 5.51 (m, 1H), 5.50 - 5.37 (m, 2H), 5.34 - 5.20 (m, 1H), 3.40 - 3.32 (m, 1H), 3.28 - 3.05 (m, 2H), 2.37 (s, 3H), 2.21 - 2.11 (m, 2H), 2.10 - 2.00 (m, 1H), 1.94 - 1.62 (m, 6H), 1.60 - 1.35 (m, 2H), 1.19 - 1.04 (m, 2H), 0.85 (t, J = 7.2 Hz, 3H).

[0921] Example 32

[0922]

[0923] The first step

[0924] 26a (30 mg, 0.06 mmol) and trans-4-hydroxycyclohexanecarboxylic acid (17 mg, 0.12 mmol) were successively added to a single-necked flask (25 mL). Anhydrous dichloromethane (1.0 mL) was added. The reaction system was cooled to 0 °C. N,N-Diisopropylethylamine (20 mg, 0.15 mmol) and 2-(7-azabenzotriazol)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (27 mg, 0.07 mmol) were successively added to the reaction system. The reaction system was stirred at 0 °C for half an hour. The reaction solution was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 0 - 100%) to obtain compound 32 (25 mg), yield: 70%.

[0925] MS-ESI calculated value [M+H] + 578, the measured value was 578.

[0926] 1 H NMR (400 MHz, DMSO-d6) δ 8.46 (d, J = 8.4 Hz, 1H), 7.80 - 7.73 (m, 2H), 5.90 (d, J = 16.8 Hz, 1H), 5.59 - 5.51 (m, 1H), 5.47 (d, J = 16.4 Hz, 1H), 5.43 (d, J = 19.6 Hz, 1H), 5.27 (d, J = 19.6 Hz, 1H), 3.27 - 3.05 (m, 2H), 2.38 (s, 3H), 2.22 - 2.11 (m, 2H), 2.10 - 2.00 (m, 2H), 1.94 - 1.77 (m, 6H), 1.58 - 1.42 (m, 2H), 1.18 - 1.05 (m, 2H), 0.85 (t, J = 7.2 Hz, 3H).

[0927] Example 33

[0928]

[0929] The first step

[0930] To a single-necked flask (25 mL), 26a (30 mg, 0.06 mmol) and cis-4-hydroxycyclohexanecarboxylic acid (17 mg, 0.12 mmol) were added successively. Anhydrous dichloromethane (1.0 mL) was added, and the reaction system was cooled to 0 °C. To the reaction system, N,N-diisopropylethylamine (20 mg, 0.15 mmol) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (27 mg, 0.07 mmol) were added successively. The reaction system was stirred at 0 °C for half an hour. The reaction solution was concentrated under reduced pressure to obtain a residue, and the residue was purified by silica gel column chromatography (methanol:dichloromethane = 0 - 100%) to obtain compound 33 (25 mg), yield: 79%.

[0931] MS-ESI calculated value [M+H] + 578, the measured value was 578.

[0932] 1 H NMR (400 MHz, DMSO-d6) δ 8.41 (d, J = 8.8 Hz, 1H), 7.78 (s, 1H), 7.77 (d, J = 10.8 Hz, 1H), 5.90 (d, J = 16.4 Hz, 1H), 5.61 - 5.52 (m, 1H), 5.47 (d, J = 16.4 Hz, 1H), 5.44 (d, J = 20.0 Hz, 1H), 5.32 (d, J = 20.0 Hz, 1H), 3.28 - 3.05 (m, 2H), 2.38 (s, 3H), 2.30 - 2.03 (m, 4H), 1.95 - 1.80 (m, 4H), 1.73 - 1.63 (m, 2H), 1.56 - 1.34 (m, 4H), 0.85 (t, J = 7.2 Hz, 3H).

[0933] Example 34

[0934]

[0935]

[0936] The first step

[0937] To a single-necked flask (25 mL), 34a (45 mg, 0.10 mmol) and 2,2-dimethyl-3-hydroxypropanoic acid (24 mg, 0.20 mmol) were added successively. Anhydrous N,N-dimethylformamide (1.5 mL) was added, and N,N-diisopropylethylamine (39 mg, 0.30 mmol) and 2-(7-azabenzotriazol)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (42 mg, 0.11 mmol) were added successively to the reaction system. The reaction system was stirred at room temperature for 1 hour. The reaction solution was diluted with a dichloromethane / methanol (V / V = 3 / 1, 100 mL) mixed solvent. The organic phase was washed successively with saturated aqueous ammonium chloride solution (25 mL × 2) and saturated brine (25 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 0 - 100%) to obtain compound 34 (10 mg), yield: 18%.

[0938] MS-ESI calculated value [M+H] + 552, the measured value was 552.

[0939] Example 35

[0940]

[0941] The first step

[0942] To a single-necked flask (25 mL), 34a (45 mg, 0.10 mmol) and 1-hydroxycyclobutanecarboxylic acid (23 mg, 0.20 mmol) were added successively. Anhydrous N,N-dimethylformamide (1.0 mL) was added, and N,N-diisopropylethylamine (39 mg, 0.30 mmol) and 2-(7-azabenzotriazol)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (42 mg, 0.11 mmol) were added successively to the reaction system. The reaction system was stirred at room temperature for 1 hour. The reaction solution was diluted with a dichloromethane / methanol (V / V = 4 / 1, 100 mL) mixed solvent. The organic phase was washed successively with saturated aqueous ammonium chloride solution (20 mL × 2) and saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 0 - 100%) to obtain compound 35 (48 mg), yield: 87%.

[0943] MS-ESI calculated value [M+H] + 550, the measured value was 550.

[0944] 11H NMR (400 MHz, DMSO-d6) δ 8.31 (d, J = 9.2 Hz, 1H), 7.77 (s, 1H), 7.73 (d, J = 10.8 Hz, 1H), 5.89 (d, J = 16.4 Hz, 1H), 5.63 - 5.53 (m, 1H), 5.46 (d, J = 16.8 Hz, 1H), 5.40 (d, J = 19.6 Hz, 1H), 5.17 (d, J = 19.6 Hz, 1H), 3.29 - 3.17 (m, 1H), 3.14 - 3.01 (m, 1H), 2.36 (s, 3H), 2.25 - 2.05 (m, 5H), 1.95 - 1.77 (m, 4H), 0.84 (t, J = 7.2 Hz, 3H).

[0945] Example 36

[0946]

[0947] The first step

[0948] 34a (45 mg, 0.10 mmol) and 3-hydroxyoxetane-3-carboxylic acid (24 mg, 0.20 mmol) were successively added to a single-necked flask (25 mL). Anhydrous N,N-dimethylformamide (1.0 mL) was added. N,N-diisopropylethylamine (39 mg, 0.30 mmol) and 2-(7-azabenzotriazol)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (42 mg, 0.11 mmol) were successively added to the reaction system. The reaction system was stirred at room temperature for 1 hour. The reaction solution was diluted with a mixed solvent of dichloromethane / methanol (V / V = 4 / 1, 100 mL). The organic phase was washed successively with saturated aqueous ammonium chloride solution (20 mL × 2) and saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 0 - 100%) to obtain compound 36 (43 mg), yield: 78%.

[0949] MS-ESI calculated value [M + H] + 552, the measured value was 552.

[0950] 11H NMR (400 MHz, DMSO-d6) δ 7.77 (s, 1H), 7.71 (d, J = 10.8 Hz, 1H), 5.89 (d, J = 16.4 Hz, 1H), 5.70 - 5.60 (m, 1H), 5.47 (d, J = 16.4 Hz, 1H), 5.32 (d, J = 19.6 Hz, 1H), 5.11 (d, J = 6.4 Hz, 1H), 5.09 - 5.01 (m, 1H), 4.90 (d, J = 6.4 Hz, 1H), 4.64 (d, J = 6.4 Hz, 1H), 4.54 (d, J = 6.4 Hz, 1H), 3.31 - 3.05 (m, 2H), 2.36 (s, 3H), 2.27 - 2.12 (m, 2H), 1.94 - 1.80 (m, 2H), 0.84 (t, J = 6.8 Hz, 3H).

[0951] Example 37

[0952]

[0953] The first step

[0954] 5 (35 mg, 0.08 mmol) and glycolic acid (30 mg, 0.40 mmol) were successively added to a single-necked flask (25 mL), anhydrous N,N-dimethylformamide (1.0 mL) was added, N,N-diisopropylethylamine (32 mg, 0.25 mmol) and 2-(7-azabenzotriazol)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (125 mg, 0.33 mmol) were successively added to the reaction system, and the reaction system was stirred at 40 °C for 6 - 8 hours. The reaction solution was diluted with a dichloromethane / methanol (V / V = 3 / 1, 50 mL) mixed solvent, and the organic phase was successively washed with saturated ammonium chloride aqueous solution (25 mL × 1), water (25 mL × 1) and saturated brine (25 mL × 1), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 0 - 100%) to obtain compound 37 (15 mg), yield: 38%.

[0955] MS-ESI calculated value [M + H] + 478, the measured value was 478.

[0956] 11H NMR (400 MHz, DMSO-d6) δ 8.05 - 7.99 (m, 2H), 7.80 (s, 1H), 5.92 (d, J = 16.8 Hz, 1H), 5.54 - 5.46 (m, 2H), 4.09 (s, 2H), 3.26 - 3.17 (m, 2H), 3.03 - 2.95 (m, 2H), 2.11 - 1.99 (m, 2H), 1.94 - 1.84 (m, 2H), 0.86 (t, J = 7.2 Hz, 3H).

[0957] Example 38

[0958]

[0959] The first step

[0960] 5 (55 mg, 0.08 mmol) and (S)-3-hydroxybutyric acid (42 mg, 0.40 mmol) were successively added to a single-necked flask (25 mL). Anhydrous N,N-dimethylformamide (2.5 mL) was added. N,N-diisopropylethylamine (66 mg, 0.51 mmol) and 2-(7-azabenzotriazol)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (226 mg, 0.59 mmol) were successively added to the reaction system. The reaction system was stirred at 45 °C for 6 - 8 hours. The reaction solution was diluted with a mixed solvent of dichloromethane / methanol (V / V = 4 / 1, 100 mL). The organic phase was successively washed with saturated aqueous ammonium chloride solution (25 mL × 1), water (25 mL × 1), and saturated brine (25 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (methanol: dichloromethane = 0 - 100%) to obtain compound 38 (22 mg), yield: 33%.

[0961] MS-ESI calculated value [M + H] + 506, the measured value was 506.

[0962] 1 1H NMR (400 MHz, DMSO-d6) δ 8.00 - 7.91 (m, 2H), 7.79 (s, 1H), 5.92 (d, J = 16.4 Hz, 1H), 5.55 - 5.45 (m, 3H), 4.18 - 4.08 (m, 1H), 3.24 - 3.17 (m, 2H), 3.04 - 2.94 (m, 2H), 2.21 - 2.14 (m, 1H), 2.09 - 1.99 (m, 2H), 1.93 - 1.83 (m, 2H), 1.51 - 1.42 (m, 1H), 0.90 - 0.80 (m, 6H).

[0963] Example 39

[0964]

[0965]

[0966] The first step

[0967] 5 (58 mg, 0.14 mmol) and 2,2-dimethyl-3-hydroxypropionic acid (182 mg, 1.54 mmol) were successively added to a single-necked flask (25 mL). Anhydrous N,N-dimethylformamide (2.0 mL) was added. N,N-diisopropylethylamine (154 mg, 1.19 mmol) and 2-(7-azabenzotriazol)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (585 mg, 1.54 mmol) were successively added to the reaction system. The reaction system was stirred at 50 °C for 6 - 8 hours. The reaction solution was diluted with a mixed solvent of dichloromethane / methanol (V / V = 4 / 1, 100 mL). The organic phase was washed successively with saturated aqueous ammonium chloride solution (25 mL × 2) and saturated brine (25 mL × 2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain a residue, and the residue was purified by silica gel column chromatography (methanol:dichloromethane = 0 - 100%) to obtain compound 39 (14 mg), yield: 20%.

[0968] MS-ESI calculated value [M+H] + 520, the measured value was 520.

[0969] 1 1H NMR (400 MHz, DMSO-d6) δ 8.00 - 7.97 (m, 2H), 7.79 (s, 1H), 5.92 (d, J = 16.8 Hz, 1H), 5.54 - 5.46 (m, 3H), 3.24 - 3.17 (m, 2H), 3.02 - 2.93 (m, 2H), 2.10 - 2.00 (m, 2H), 1.93 - 1.82 (m, 2H), 1.20 (s, 6H), 0.86 (t, J = 7.2 Hz, 3H).

[0970] Example 40

[0971]

[0972] The first step

[0973] To a single-necked flask (25 mL), 5 (35 mg, 0.08 mmol) and cis-3-hydroxycyclobutanecarboxylic acid (20 mg, 0.17 mmol) were added successively. Anhydrous N,N-dimethylformamide (2.0 mL) was added. To the reaction system, N,N-diisopropylethylamine (33 mg, 0.25 mmol) and 2-(7-azabenzotriazol)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (83 mg, 0.22 mmol) were added successively. The reaction system was stirred at 45 °C for 6 - 8 hours. The reaction solution was diluted with a mixed solvent of dichloromethane / methanol (V / V = 5 / 1, 50 mL). The organic phase was washed successively with saturated ammonium chloride aqueous solution (20 mL × 1) and saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 0 - 100%) to obtain compound 40 (26 mg), yield: 60%.

[0974] MS-ESI calculated value [M+H] + 518, the measured value was 518.

[0975] 1 H NMR (400 MHz, DMSO-d6) δ 7.98 (d, J = 8.8 Hz, 1H), 7.86 (d, J = 9.2 Hz, 1H), 7.79 (s, 1H), 5.92 (d, J = 16.8 Hz, 1H), 5.55 - 5.46 (m, 3H), 4.07 - 3.96 (m, 1H), 3.24 - 3.16 (m, 2H), 3.00 - 2.90 (m, 2H), 2.83 - 2.71 (m, 1H), 2.45 - 2.36 (m, 2H), 2.15 - 1.98 (m, 4H), 1.95 - 1.83 (m, 2H), 0.86 (t, J = 7.6 Hz, 3H).

[0976] Example 41

[0977]

[0978] The first step

[0979] 5 (70 mg, 0.17 mmol) and cis-4-hydroxycyclohexanecarboxylic acid (135 mg, 0.94 mmol) were successively added to a single-necked flask (25 mL). Anhydrous N,N-dimethylformamide (2.0 mL) was added. N,N-diisopropylethylamine (143 mg, 1.11 mmol) and 2-(7-azabenzotriazol)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (452 mg, 1.19 mmol) were successively added to the reaction system. The reaction system was stirred at 45 - 60 °C for 6 - 8 hours. The reaction solution was diluted with a mixed solvent of dichloromethane / methanol (V / V = 4 / 1, 100 mL). The organic phase was washed successively with saturated ammonium chloride aqueous solution (25 mL × 2), water (25 mL × 2), and saturated brine (25 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 0 - 100%) to obtain compound 41 (14 mg), yield: 15%.

[0980] MS-ESI calculated value [M+H] + 546, the measured value was 546.

[0981] 1 H NMR (400 MHz, DMSO-d6) δ 7.98 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.79 (s, 1H), 5.92 (d, J = 16.8 Hz, 1H), 5.55 - 5.45 (m, 3H), 3.87 - 3.77 (m, 1H), 3.26 - 3.16 (m, 2H), 3.01 - 2.90 (m, 2H), 2.10 - 1.99 (m, 2H), 1.97 - 1.82 (m, 4H), 1.77 - 1.66 (m, 2H), 1.65 - 1.45 (m, 4H), 0.86 (t, J = 7.2 Hz, 3H).

[0982] Example 42

[0983]

[0984] The first step

[0985] To a single-necked flask (25 mL), 5 (35 mg, 0.08 mmol) and 1-hydroxycyclopropanecarboxylic acid (25 mg, 0.25 mmol) were added successively. Anhydrous N,N-dimethylformamide (1.0 mL) was added, and N,N-diisopropylethylamine (49 mg, 0.38 mmol) and 2-(7-azabenzotriazol)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (110 mg, 0.29 mmol) were added successively to the reaction system. The reaction system was stirred at 50 °C for 2 hours. The reaction solution was diluted with a mixed solvent of dichloromethane / methanol (V / V = 3 / 1, 100 mL). The organic phase was washed successively with saturated aqueous ammonium chloride solution (25 mL × 2) and saturated brine (25 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 0 - 100%) to obtain compound 42 (19 mg), yield: 45%.

[0986] MS-ESI calculated value [M+H] + 504, the measured value was 504.

[0987] 1 H NMR (400 MHz, DMSO-d6) δ 8.06 - 7.98 (m, 2H), 7.79 (s, 1H), 5.92 (d, J = 16.8 Hz, 1H), 5.54 - 5.46 (m, 3H), 3.25 - 3.17 (m, 2H), 3.06 - 2.97 (m, 2H), 2.12 - 2.01 (m, 2H), 1.95 - 1.84 (m, 2H), 1.20 - 1.15 (m, 2H), 1.06 - 1.00 (m, 2H), 0.86 (t, J = 7.2 Hz, 3H).

[0988] Example 43

[0989]

[0990] The first step

[0991] 5 (47 mg, 0.11 mmol) and 1-hydroxy-cyclobutanecarboxylic acid (83 mg, 0.72 mmol) were successively added to a single-necked flask (25 mL). Anhydrous N,N-dimethylformamide (2.0 mL) was added, and N,N-diisopropylethylamine (71 mg, 0.55 mmol) and 2-(7-azabenzotriazol)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (293 mg, 0.77 mmol) were successively added to the reaction system. The reaction system was stirred at 50 °C for 6 - 8 hours. The reaction solution was diluted with a mixed solvent of dichloromethane / methanol (V / V = 3 / 1, 100 mL). The organic phase was washed successively with saturated aqueous ammonium chloride solution (25 mL × 2) and saturated brine (25 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 0 - 100%) to obtain compound 43 (22 mg), yield: 38%.

[0992] MS-ESI calculated value [M+H] + 518, the measured value was 518.

[0993] 1 H NMR (400 MHz, DMSO-d6) δ 8.05 (d, J = 9.2 Hz, 1H), 8.00 (d, J = 9.2 Hz, 1H), 7.80 (s, 1H), 5.92 (d, J = 16.8 Hz, 1H), 5.54 - 5.46 (m, 3H), 3.24 - 3.17 (m, 2H), 3.00 - 2.92 (m, 2H), 2.24 - 2.13 (m, 4H), 2.10 - 2.00 (m, 2H), 1.94 - 1.76 (m, 4H), 0.86 (t, J = 7.2 Hz, 3H).

[0994] Example 44

[0995]

[0996] The first step

[0997] 5 (50 mg, 0.12 mmol) and 3-hydroxyoxetane-3-carboxylic acid (99 mg, 0.84 mmol) were successively added to a single-necked flask (25 mL). Anhydrous N,N-dimethylformamide (2.0 mL) was added. N,N-diisopropylethylamine (132 mg, 1.02 mmol) and 2-(7-azabenzotriazol)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (456 mg, 1.20 mmol) were successively added to the reaction system. The reaction system was stirred at 50 °C for 6 - 8 hours. The reaction solution was diluted with a dichloromethane / methanol (V / V = 3 / 1, 100 mL) mixed solvent. The organic phase was washed successively with saturated aqueous ammonium chloride solution (20 mL x 2) and saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (methanol: dichloromethane = 0 - 100%) to obtain compound 44 (27 mg), yield: 44%.

[0998] MS-ESI calculated value [M+H] + 520, the measured value was 520.

[0999] 1 H NMR (400 MHz, DMSO-d6) δ 8.02 (d, J = 8.8 Hz, 1H), 7.97 (d, J = 8.8 Hz, 1H), 7.80 (s, 1H), 5.93 (d, J = 16.4 Hz, 1H), 5.54 - 5.46 (m, 3H), 4.89 (d, J = 6.4 Hz, 2H), 4.58 (d, J = 6.4 Hz, 2H), 3.24 - 3.17 (m, 2H), 3.00 - 2.92 (m, 2H), 2.09 - 1.98 (m, 2H), 1.93 - 1.86 (m, 2H), 0.86 (t, J = 7.2 Hz, 3H).

[1000] Example 45

[1001]

[1002] The first step

[1003] 45a (5.00 g, 40.98 mmol) and anhydrous dichloromethane (100 mL) were added to a round-bottom flask and placed in an ice bath. To the above solution, hydroxylamine hydrochloride (4.40 g, 45.08 mmol), N,N-diisopropylethylamine (10.60 g, 81.96 mmol), and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (23.40 g, 61.47 mmol) were added successively. The reaction system was stirred at 0 °C for 2 hours. The reaction solution was diluted with dichloromethane (100 mL). The organic phase was washed successively with water (50 mL × 2) and saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0 - 100%) to obtain compound 45b (5.40 g), yield: 80%.

[1004] 1 H NMR (400 MHz, CDCl3) δ 3.67 (s, 3H), 3.60 (t, J = 6.4 Hz, 2H), 3.15 (s, 3H), 2.59 (t, J = 7.2 Hz, 2H), 2.12 - 2.03 (m, 2H).

[1005] The second step

[1006] Under a nitrogen atmosphere, 45c (1.10 g, 5.50 mmol) and anhydrous tetrahydrofuran (7 mL) were added to a dry three-necked flask and placed in a -78 °C cold bath. To the above solution, butyllithium reagent (1.6 M, 9.7 mL, 6.05 mmol) was added dropwise. After the addition was complete, the reaction system was kept stirring in the -78 °C cold bath for another 0.5 hour. Subsequently, a solution of 45b (0.82 g, 5.00 mmol) in tetrahydrofuran (3 mL) was added. The reaction system was kept stirring in the -78 °C cold bath for 2 hours. The reaction solution was quenched with saturated ammonium chloride aqueous solution and diluted with ethyl acetate (100 mL). The organic phase was washed successively with water (25 mL × 1) and saturated brine (25 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0 - 100%) to obtain compound 45d (1.10 g), yield: 97%.

[1007] 11H NMR (400 MHz, CDCl3) δ 7.58 (dd, J = 8.4, 1.6 Hz, 1H), 7.43 (d, J = 2.0 Hz, 1H), 6.84 (d, J = 8.0 Hz, 1H), 6.81 (s, 1H), 6.03 (s, 2H), 3.65 (t, J = 6.4 Hz, 2H), 3.09 (t, J = 7.2 Hz, 2H), 2.24 - 2.15 (m, 2H).

[1008] The third step

[1009] Under an ice - salt bath, a solution of 45d (500 mg, 2.20 mmol) in acetic acid (2 mL) was added to nitric acid (2 mL). After complete addition, the reaction system was kept under the ice - salt bath and stirred for 4 hours. The reaction solution was diluted with water (50 mL), and the aqueous phase was extracted with ethyl acetate (100 mL). The organic phase was washed successively with saturated aqueous sodium bicarbonate solution (50 mL × 1), water (50 mL × 1), and saturated brine (50 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0 - 100%) to obtain compound 45e (260 mg), yield: 43%.

[1010] 1 1H NMR (400 MHz, CDCl3) δ 7.55 (s, 1H), 6.71 (s, 1H), 6.17 (s, 2H), 3.66 (t, J = 6.4 Hz, 2H), 2.87 (t, J = 7.2 Hz, 2H), 2.29 - 2.18 (m, 2H).

[1011] The fourth step

[1012] Under an ice - salt bath, 45e (150 mg, 0.55 mmol) was dissolved in tetrahydrofuran (2 mL), and platinum dioxide (7.5 mg, 5% w / w) was added. The reaction system was stirred at room temperature overnight under a hydrogen atmosphere. The reaction solution was directly filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product 45f (150 mg), which was directly used for the next step.

[1013] MS - ESI calculated value [M + H] + 242, 244, the measured values were 242, 244.

[1014] The fifth step

[1015] The crude product 45f (145 mg) from the previous step was dissolved in a mixed solvent of acetonitrile / water (1 / 1 mL), potassium hydroxide (40 mg, 0.72 mmol) was added, and the reaction system was heated to 45 °C and stirred for 3 hours. The reaction solution was diluted with water (20 mL) and ethyl acetate (50 mL), separated by liquid-liquid extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 0 - 100%) to obtain compound 45g (53 mg), and the overall yield of the two steps was 48%.

[1016] MS-ESI calculated value [M+H] + 224, the measured value was 224.

[1017] 1 H NMR (400 MHz, CDCl3) δ 7.14 (s, 1H), 6.43 (br s, 2H), 6.14 (s, 1H), 5.90 (s, 2H), 3.73 (t, J = 6.0 Hz, 2H), 2.97 (t, J = 7.2 Hz, 2H), 2.02 - 1.93 (m, 2H).

[1018] The sixth step

[1019] To a Schlenk reaction tube were successively added 45g (60 mg, 0.27 mmol), 1 (89 mg, 0.32 mmol) and p-toluenesulfonic acid (35 mg, 0.20 mmol), anhydrous toluene (4 mL) was added, and the mixed system was heated to 110 °C and stirred for 3 hours. The reaction system was concentrated under reduced pressure to obtain a crude product, and the crude product was purified by silica gel column chromatography (methanol:dichloromethane = 0 - 100%) to obtain compound 45 (27 mg), and the yield was 21%.

[1020] MS-ESI calculated value [M+H] + 467, the measured value was 467.

[1021] 1 H NMR (400 MHz, DMSO-d6) δ 7.72 (s, 1H), 7.62 (s, 1H), 7.51 (s, 1H), 6.29 (s, 2H), 5.92 (d, J = 16.8 Hz, 1H), 5.48 (d, J = 16.4 Hz, 1H), 5.44 (s, 2H), 3.21 - 3.11 (m, 2H), 2.21 - 2.13 (m, 1H), 1.95 - 1.75 (m, 4H), 1.55 - 1.40 (m, 1H), 0.89 - 0.80 (m, 3H).

[1022] Example 46

[1023]

[1024]

[1025] The first step

[1026] Add 2a (10.00 g, 79.9 mmol), water, chloral (14.90 g, 89.9 mmol), sodium sulfate (76.00 g, 535.0 mmol), hydroxylamine hydrochloride (29.00 g, 416.5 mmol) and concentrated hydrochloric acid (8.50 mL) into a 500 mL three-necked flask. Add water (250 mL) to the system. Heat the reaction system to 70 °C and stir for 1 hour. Stop the reaction and cool to room temperature. Add water (200 mL) to the reaction system. Filter the reaction mixture. Wash the filter cake with water (250 mL × 2). Dry the filter cake under reduced pressure to obtain compound 46a (15.4 g), yield: 98%.

[1027] MS-ESI calculated value [M+H] + 197, the measured value is 197.

[1028] The second step

[1029] Add 46a (8.00 g, 40.8 mmol) and concentrated sulfuric acid (80 mL) into a reaction flask. Add zinc powder (4.70 g, 72.0 mmol) to the mixed system. Heat the reaction system to 85 °C and stir for 2 hours. Stop the reaction and cool to room temperature. Pour the reaction solution into ice water (200 mL). Filter. Wash the filter cake with water (50 mL × 4). Dry the filter cake under reduced pressure to obtain compound 46b (7.0 g), yield: 96%.

[1030] MS-ESI calculated value [M+H] + 180, the measured value is 180.

[1031] The third step

[1032] Dissolve compound 46b (7.20 g, 39.9 mmol) in an aqueous sodium hydroxide solution (64 mL, 2.5 mol / L). Slowly add hydrogen peroxide (15.6 mL) to the reaction system, controlling the internal temperature ≤ 45 °C during this period. React at room temperature for 2 hours. Stop the reaction. Adjust the pH of the mixed system to between 4 and 5 with an aqueous hydrochloric acid solution (6 mol / L). Filter. Wash the filter cake with water (50 mL × 3). Dry the filter cake under reduced pressure to obtain compound 46c (5.7 g), yield: 85%.

[1033] MS-ESI calculated value [M+H] + 170, the measured value is 170.

[1034] The fourth step

[1035] Lithium aluminum hydride (3.80 g, 101.5 mmol) was added to anhydrous tetrahydrofuran (50 mL). The mixed system was purged with nitrogen three times and protected by nitrogen. The mixed system was cooled to -10 to 0 °C (by ice-salt bath). Compound 46c (5.7 g, 38.8 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL). The tetrahydrofuran solution of 46c was slowly added dropwise to the above-mentioned mixed solution of lithium aluminum hydride in tetrahydrofuran. After the addition, the reaction system was restored to room temperature and stirred for 2 hours. The reaction system was cooled to -10 to 0 °C, and water (3.8 mL), 15% aqueous sodium hydroxide solution (3.8 mL) and water (3.8 mL) were added dropwise. The mixed system was stirred overnight at room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 46d (5.5 g), yield: 100%.

[1036] MS-ESI calculated value [M-CH2OH] + 138, the measured value was 138.

[1037] The fifth step

[1038] Compound 46d (5.50 g, 38.8 mmol), dichloromethane (200 mL) and activated manganese dioxide (22.00 g) were added to a 500 mL three-necked flask. The reaction system was stirred overnight at room temperature. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 46e (5.3 g), yield: 100%.

[1039] MS-ESI calculated value [M+H] + 154, the measured value was 154.

[1040] The sixth step

[1041] Compound 46e (698.0 mg, 4.6 mmol), compound 1 (1.0 g, 3.8 mmol), p-toluenesulfonic acid (130.7 mg, 0.8 mmol) and anhydrous toluene (20 mL) were added to a 50 mL three-necked flask. The mixed system was heated to 110 °C and stirred for 2 hours. The filtrate was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (methanol:dichloromethane = 0-100%) to obtain compound 46 (800.0 mg), yield: 53%.

[1042] MS-ESI calculated value [M+H] + 397, the measured value was 397.

[1043] 11H NMR (400 MHz, DMSO-d6) δ 8.57 (s, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.78 (d, J = 11.2 Hz, 1H), 7.73 (s, 1H), 5.88 (d, J = 16.4 Hz, 1H), 5.73 (s, 1H), 5.47 (d, J = 16.4 Hz, 1H), 5.32 (s, 2H), 2.42 (s, 3H), 1.88 (q, J = 7.2 Hz, 2H), 0.86 (t, J = 7.2 Hz, 3H).

[1044] Example 47

[1045]

[1046] The first step

[1047] Add 47a (2.50 g, 14.4 mmol), methyl 3-mercaptopropionate (2.17 g, 18.1 mmol) and dry N,N-dimethylformamide (30 mL) to a 50 mL three-necked flask. After the system is clear, add potassium carbonate (3.98 g, 28.8 mmol), and stir for 5 hours under nitrogen protection at room temperature. Add methyl tert-butyl ether (200 mL) and water (200 mL) to the reaction solution in sequence, separate the layers, wash the organic phase with saturated sodium chloride aqueous solution (200 mL × 2), dry the organic phase over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product 47b, which is directly used in the next step.

[1048] MS-ESI calculated value [M+H] + 274, the measured value is 274.

[1049] The second step

[1050] Dissolve the crude product 47b (3.93 g, 14.4 mmol, calculated according to 100% content), ammonium chloride (3.85 g, 72.0 mmol), and ammonium acetate (4.50 g, 72.0 mmol) in a methanol / water mixed solvent (V 甲醇 :V 水 = 5:3, 80 mL), add zinc powder (4.70 g, 72.0 mmol) to the mixed system, and stir the mixed system at room temperature for 4 hours. Adjust the pH of the reaction solution to 12 with saturated sodium carbonate aqueous solution, add dichloromethane (200 mL) and water (200 mL) to the reaction solution, separate the layers, wash the organic phase with saturated sodium chloride aqueous solution (100 mL × 2), dry the organic phase over anhydrous sodium sulfate and then filter, and concentrate the filtrate under reduced pressure to obtain compound 47c (2.20 g), yield: 64%.

[1051] MS-ESI calculated value [M+H] +244, the measured value is 244.

[1052] The third step

[1053] Dissolve compound 47c (1.42 g, 5.8 mmol) in dioxane (10 mL), add concentrated hydrochloric acid (12 M, 10 mL), and heat the reaction system to 65 °C for 3 hours. Stop the reaction, adjust the pH of the mixed system to 5 - 6 with saturated aqueous sodium carbonate solution, add dichloromethane (100 mL) and water (200 mL), separate the layers, wash the organic phase with saturated aqueous sodium chloride solution (100 mL), dry the organic phase over anhydrous sodium sulfate and filter, concentrate the filtrate under reduced pressure to obtain a residue, and purify the residue by silica gel column chromatography (ethyl acetate: petroleum ether = 0 - 100%) to obtain compound 47d (745.5 mg), yield: 56%.

[1054] MS-ESI calculated value [M+H] + 230, the measured value is 230.

[1055] The fourth step

[1056] Dissolve compound 47d (9.40 g, 20.10 mmol) in Eaton's reagent (10 mL), heat the mixed system to 60 °C and stir for 1.5 hours. Cool the reaction solution to room temperature, pour the reaction solution into ice water (100 mL), adjust the pH of the mixed system to 12 with saturated aqueous sodium carbonate solution, extract the mixed system with dichloromethane (100 mL x 2), combine the organic phases, wash the organic phases with saturated aqueous sodium chloride solution (100 mL x 2), dry the organic phases over anhydrous sodium sulfate and filter, concentrate the filtrate under reduced pressure to obtain compound 47e (606.0 mg), yield: 88%.

[1057] MS-ESI calculated value [M+H] + 212, the measured value is 212.

[1058] The fifth step

[1059] In a 50 mL three-necked flask, compound 47e (606.0 mg, 2.9 mmol), 4-dimethylaminopyridine (35.1 mg, 0.3 mmol) and dichloromethane (15 mL) were added. Under an ice-water bath, acetyl chloride (447.5 mg, 5.7 mmol) and triethylamine (580.8 mg, 5.7 mmol) were added successively. After the reaction system naturally returned to room temperature, stirring was continued for 1 hour. The reaction solution was quenched with water (20 mL), and liquid separation was carried out. The aqueous phase was extracted with dichloromethane (100 mL × 2). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0 - 100%) to obtain compound 47f (310.0 mg), yield: 43%.

[1060] MS-ESI calculated value [M+H] + 254, the measured value was 254.

[1061] The sixth step

[1062] Potassium tert-butoxide (141.0 mg, 1.0 mmol) and anhydrous tetrahydrofuran (5 mL) were added to a 50 mL three-necked flask. At -20 °C, compound 47f (236.0 mg, 0.93 mmol) and n-butyl nitrite (120.0 mg, 1.16 mmol) were added successively. After the system was warmed to 5 °C, stirring was continued for 2 hours. Methyl tert-butyl ether (15 mL) was added to the reaction system, and filtration was carried out to collect the solid. The solid was dissolved in acetic acid (5 mL), zinc powder (200.0 mg, 3.1 mmol) was added, and after stirring at room temperature for 5 minutes, acetic anhydride (1 mL) was added, and stirring was continued for 2 hours. A mixed solvent of methanol / dichloromethane (V 甲醇 :V 二氯甲烷 = 3:97, 100 mL) and water (100 mL) were added, and liquid separation was carried out. The organic phase was washed with saturated aqueous sodium bicarbonate (100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (ethyl acetate: dichloromethane = 0 - 100%) to obtain compound 47g (171.0 mg), yield: 59%.

[1063] MS-ESI calculated value [M+H] + 311, the measured value was 311.

[1064] 11H NMR (400 MHz, CDCl3) δ 11.83 (s, 1H), 8.34 (d, J = 12.4 Hz, 1H), 6.80 (s, 1H), 5.04 - 4.76 (m, 1H), 3.60 (dd, J = 12.8, 4.8 Hz, 1H), 3.04 (t, J = 13.2 Hz, 1H), 2.23 (s, 3H), 2.17 (s, 3H), 2.11 (s, 3H).

[1065] Referring to the synthetic routes of Example 2, Example 6, etc., 47 g of the compound was synthesized into compound 47 (a pair of diastereoisomers) through four steps of reactions including de - acetylation protection, Fmoc protection, cyclization condensation, and de - Fmoc protection. Compound 47 - 1 and compound 47 - 2 could be obtained by preparative HPLC separation of 47.

[1066] MS - ESI calculated value [M + H] + 470, the measured value was 470.

[1067] The following compounds were obtained by condensing compound 47 - 1 with the corresponding carboxylic acid or its active ester as the substrate with reference to the synthetic methods of Example 34, etc.

[1068]

[1069]

[1070]

[1071]

[1072]

[1073]

[1074]

[1075]

[1076] Example 82

[1077]

[1078] The first step

[1079] Under nitrogen protection, water (80 mL) and HCl (aq)(80 mL, 6N) was added to a reaction flask (500 mL), and then 82a (8.00 g, 30.00 mmol) (prepared according to WO2022166762A1) was added. The temperature of the mixed system was raised to 100 ± 5 °C and stirred for 4 hours. The reaction system was cooled to 30 °C, and ammonia water (25% - 28%) was slowly added dropwise to the reaction system to adjust the pH to 4 - 5. After the addition was complete, the mixed system was stirred for another 30 minutes, filtered, and the filter cake was washed with water (250 mL x 1). The filter cake was slurried with ethanol (80 mL) at room temperature for 1 hour, filtered, and the filter cake was washed with ethanol (10 mL x 1). The filter cake was collected and dried to obtain 82b (7.00 g), yield: 89%.

[1080] MS-ESI calculated value [M+H] + = 225, 227, the measured values were 225, 227.

[1081] The second step

[1082] Tetrahydrofuran (35 mL), water (35 mL) and 82b (7.00 g, 26.82 mmol) were added to a reaction flask (250 mL). After the temperature of the mixed system was cooled to 0 - 10 °C, potassium carbonate (6.30 g, 45.59 mmol) was added, and then a solution of 9-fluorenylmethyl chloroformate (7.08 g, 27.35 mmol) in tetrahydrofuran (35 mL) was slowly added dropwise (the temperature of the reaction solution was controlled at 0 - 10 °C during the addition). The mixed system was stirred at 0 - 10 °C for 1 hour. The reaction solution was extracted with 2-methyltetrahydrofuran (100 mL x 2), and the organic phase was successively washed with water (100 mL x 1) and saturated brine (100 mL x 1). The organic phase was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure to obtain a residue. Methyl tert-butyl ether (70 mL) was added to the residue, and the mixture was stirred at room temperature for 4 hours, filtered, and the filter cake was washed with methyl tert-butyl ether (10 mL x 1). The filter cake was collected and dried to obtain 82c (10.20 g), yield: 85%.

[1083] MS-ESI calculated value [M+H] + = 447, 449, the measured values were 447, 449.

[1084] The third step

[1085] Under nitrogen protection, toluene (50 mL), acetic acid (50 mL), 1 (5.00 g, 17.92 mmol), 82c (9.60 g, 21.50 mmol) and pyridinium p-toluenesulfonate (2.25 g, 8.96 mmol) were successively added to a reaction flask (250 mL). The mixed system was heated to 110 °C and stirred for 24 hours. The reaction solution was cooled to room temperature, 2-methyltetrahydrofuran (100 mL) and water (100 mL) were added, and liquid separation was carried out. The organic phase was successively washed with water (25 mL × 3) and saturated sodium chloride aqueous solution (25 mL × 1), dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure until no liquid droplets dripped out. The residue was purified by silica gel column chromatography (methanol:dichloromethane = 0 - 100%) to obtain 82d (7.55 g), yield: 61%.

[1086] MS-ESI calculated value [M+H] + = 690, 692, the measured values were 690, 692.

[1087] The fourth step

[1088] Under a nitrogen atmosphere, tetrahydrofuran (100 mL) and 82d (7.50 g, 10.87 mmol) were successively added to a reaction flask. The temperature of the mixed system was lowered to 0 - 5 °C, and piperidine (2.78 g, 32.61 mmol) was slowly added dropwise to the reaction flask. After the addition was complete, the reaction system was maintained at 0 - 5 °C and stirred for 24 hours. An aqueous hydrochloric acid solution (6N) was slowly added dropwise to the reaction flask (the temperature was controlled at 0 - 10 °C during the addition) to adjust the pH to 4 - 5. The mixed system was stirred for another 10 - 15 minutes and concentrated under reduced pressure to obtain a residue. The residue was slurried with water (150 mL) for 2 hours, filtered, and the filter cake was washed with acetonitrile (10 mL × 2). The filter cake was collected, dried, and then separated and purified by preparative HPLC to obtain 82-1 (1.42 g) and 82-2 (1.35 g), yield: 54%.

[1089] MS-ESI calculated value [M+H] + = 468, 470, the measured values were 468, 470.

[1090] The following compounds were obtained by referring to the synthesis method of Example 82.

[1091]

[1092]

[1093]

[1094]

[1095]

[1096] The following compounds are obtained by condensation of compound 82-1 with the corresponding carboxylic acid or its active ester with reference to the synthesis method of Reference Example 34 etc.

[1097]

[1098]

[1099]

[1100]

[1101]

[1102]

[1103] The following compounds are obtained by condensation of compound 85-1 with the corresponding carboxylic acid or its active ester with reference to the synthesis method of Reference Example 34 etc.

[1104]

[1105]

[1106]

[1107]

[1108]

[1109]

[1110]

[1111] The following compounds are obtained by condensation of compound 87-1 with the corresponding carboxylic acid or its active ester with reference to the synthesis method of Reference Example 34 etc.

[1112]

[1113]

[1114]

[1115]

[1116]

[1117]

[1118]

[1119] Biological activity test

[1120] Example of effect implementation 1: KPL-4 tumor cell proliferation inhibition experiment

[1121] Take KPL-4 tumor cells in the logarithmic growth phase, resuspend the cells with fresh RPMI1640 culture medium, count and adjust the cell suspension to 2×10 4 cells / mL. Inoculate the cell suspension into a 96-well cell culture plate, 100 μL / well, and culture overnight in a carbon dioxide incubator (37 °C, 5% CO2). Take out one of the 96-well plates inoculated with cells the next day. After equilibrating to room temperature, add 100 μL of CellTiter-Glo reagent (Promega, USA) that has been pre-equilibrated to room temperature and prepared and mixed evenly to each well of the test plate. After incubating in the dark for 30 minutes, read the luminescence value (recorded as the G0 value) in an enzyme-linked immunosorbent assay reader; take another parallel plate and add different concentrations of the compound to be tested or DMSO (final concentration 0.5%) to the corresponding wells of the test plate. After culturing in a carbon dioxide incubator for 72 h, equilibrate the test plate to room temperature and detect the cell activity using the CellTiter-Glo reagent, recorded as the G3 value.

[1122] Using DXd as the positive control compound, the structure is as follows:

[1123]

[1124] Calculate the cell proliferation rate according to the following formula: Cell proliferation rate (%) = (average G3 value of the compound to be tested wells - average G0 value) / (average G3 value of DMSO control wells - average G0 value) * 100. Use Graphpad Prism software to fit the inhibition curve and calculate the GI 50 value (see the following table).

[1125] Table 1: Results of cell proliferation inhibition experiment

[1126] Example <![CDATA[GI 50 (nM)]]> Example 2 2.82 Example 3 6.27 Example 4 2.23 Example 5 1.84 DXd 45.4a

[1127] Note: a represents the average value of two measurements.

[1128] Table 2: Results of cell proliferation inhibition experiment

[1129]

[1130]

[1131] Table 3: Results of cell proliferation inhibition experiment

[1132] Example <![CDATA[GI 50 (nM)]]> Example 34 7.25 Example 35 3.52 Example 36 7.44

[1133] The results show that multiple compounds of the present invention exhibit high inhibitory proliferation activities in the above-mentioned tumor cell proliferation inhibition experiments, and the activities are significantly better than those of DXd. Due to the excellent tumor cell proliferation inhibitory activities of the compounds of the present invention, they can be used as tumor therapeutic drugs or as toxin molecules for preparing antibody-drug conjugates for treating tumors.

[1134] Effect Example 2: H460 Tumor Cell Proliferation Inhibition Experiment

[1135] H460 cells derived from human large cell lung tumors were cultured in RPMI-1640 medium containing 10% fetal bovine serum. Cell sensitivity was determined by cell growth inhibition assay after 1 or 72 hours of drug exposure. Cells in logarithmic growth were collected and seeded into 6-well plates in duplicate. Twenty-four hours after seeding, the cells were exposed to the drug and counted using a Coulter counter 72 hours after exposure to the drug to determine the IC 50 . IC 50 is defined as the concentration at which cell growth is inhibited by 50% compared to the growth of untreated controls.

[1136] The results show that multiple compounds of the present invention exhibit high inhibitory proliferation activities in the above-mentioned tumor cell proliferation inhibition experiments. Due to the excellent tumor cell proliferation inhibitory activities of the compounds of the present invention, they can be used as tumor therapeutic drugs or as toxin molecules for preparing antibody-drug conjugates for treating tumors.

[1137] Effect Example 3: Topoisomerase-I-Dependent DNA Cleavage Assay

[1138] DNA cleavage was determined using 751-bp BamHI-EcORI DNA SV40 purified gel. DNA fragments were labeled only at the 3'. The DNA cleavage reaction (20,000 cpm / sample) was carried out in 20 ml of 10 mM Tris-HCL (pH 7.6), 150 mM KCl, 5 mM MgCl2, 15 μg / mL BSA, 0.1 mM dithiothreitol and human recombinant enzyme (full-length top1) at 37 °C for 30 min. The reaction was blocked at 42 °C for 45 min using 0.5% SDS and 0.3 mg / mL proteinase K. DNA damage persistence was examined after incubating with 0.6 M NaCl and 10 μM of the drug for 30 minutes at different times. After precipitation, the DNA was resuspended in denaturing buffer (80% formamide, 10 mM NaOH, 0.01 M EDTA and 1 mg / mL dye), and then loaded onto a denaturing gel (7% polyacrylamide in TBE buffer). The fragmentation level of all DNA was determined using a PhosphoImager 425 type (Molecular Dynamics).

[1139] Effect Implementation 4: In vitro tumor growth inhibitory activity of antibody-drug conjugates

[1140] Human ovarian cancer cell lines OVCAR-3 and PA-1 were seeded in 96-well plates at a density of 2000 cells / 100 μL / well in culture medium and then incubated overnight. The next day, each conjugate was added to the cells at a final concentration ranging from 0.01 nM to 100 nM. After 5 days of incubation, the culture medium was removed from the cells and CCK-8 (Cell Counting Kit-8) viability assay was performed according to the manufacturer's instructions. Cell viability was calculated as a percentage of control wells containing only tumor cells.

[1141] Effect Implementation 5: Transporter substrate study

[1142] Purpose of the experiment

[1143] To investigate whether the compounds of this application are substrates of efflux transporters P-gp and BCRP in the Caco-2 cell model, providing a preclinical basis for analyzing drug-drug interactions in pharmacokinetics.

[1144] Experimental method

[1145] 1. Preparation of monolayer cells

[1146] 1) Cell culture medium was added to each well of the Transwell. Then, before cell seeding, the HTS Transwell plate was incubated at 37 °C in 5% CO2 for 1 hour.

[1147] 2) Caco-2 cells were diluted with culture medium and the cell suspension was dispensed into the filter wells of a 96-well HTS Transwell plate. The cells were cultured at 37 °C, 5% CO2, and 95% relative humidity for more than ten days. The cell culture medium was changed regularly.

[1148] 3) The transepithelial electrical resistance of the monolayer cells was measured using a Millicell Epithelial Volt-Ohm detection system. The resistance of each well was recorded. After measuring all wells, the Transwell plate was returned to the incubator.

[1149] The TEER of each well was calculated by the formula. The TEER value of each well should be greater than 230 ohm*cm 2 .

[1150] 2. Preparation for transporter experiment

[1151] 1) The Caco-2 plate was taken out of the incubator. The monolayer was washed twice with pre-warmed HBSS. Then the plate was incubated at 37 °C for 30 minutes.

[1152] 2) Prepare a stock solution of the compound in DMSO and dilute it with HBSS to obtain a working solution. Digoxin is used as a reference substrate for P-gp, and rosuvastatin is used as a reference substrate for BCRP. Propranolol is used as a high permeability marker.

[1153] 3) To determine the drug transport rate in the apical-to-basolateral direction, add the working solution (without inhibitor) to the Transwell insert (apical compartment). Add the receiving plate (basolateral compartment) wells with the transport buffer. To determine the drug transport rate in the basolateral-to-apical direction, add the working solution (without inhibitor) to the receiving plate wells (basolateral compartment). Fill the Transwell insert (apical compartment) with the transport buffer. To determine the drug transport rate in the presence of a P-gp inhibitor, add PSC833 to both the apical and basolateral compartments.

[1154] 4) Transfer the sample from the working solution to the quenching solution to prepare the sample at time 0. Incubate the Transwell plate at 37 °C, 5% CO2 for 2 hours.

[1155] 5) At the end of the transport period, transfer the samples from the apical and basolateral wells to a new 96-well plate. Add cold acetonitrile or methanol containing the appropriate internal standard (IS) to each well of the plate. Vortex for 10 minutes. Centrifuge the samples. Before performing LC-MS / MS analysis, mix an aliquot of the supernatant with an appropriate amount of ultrapure water (depending on the LC-MS / MS signal response and peak shape).

[1156] 6) To determine the amount of Lucifer Yellow leakage after a 2-hour transport period, prepare a stock solution of Lucifer Yellow in DMSO and dilute it with HBSS. Add the Lucifer Yellow solution to the apical chamber. Add the basolateral chamber with HBSS. Incubate the plate at 37 °C for 30 minutes, then directly remove a certain amount from the apical and basolateral wells and transfer it to a new 96-well plate. Measure the Lucifer Yellow fluorescence (to monitor monolayer integrity) at 485 nm excitation and 530 nm emission in a fluorescence plate reader.

[1157] 3. Data analysis

[1158] Calculations are performed using Microsoft Excel. The percentage of the compound remaining at each time point is estimated by determining the peak area ratio from the extracted ion chromatogram.

[1159] For drug transport analysis in the Caco-2 cell model, the apparent permeability coefficient (Papp) can be calculated using the following formula, in cm / s:

[1160] Papp = (C receiving side * V receiving side) / (C initial * T permeation time * S membrane area)

[1161] Among them, the concentration C is in nM, the volume V is in μL, the time T is in s, and the area S is in cm 2 .

[1162] Calculation method of recovery rate:

[1163] Recovery rate = (C received side * V received side + Ct administered side * V administered side + C cell lysate * V cell lysate) / (C initial * V administered side)

[1164] Calculation method of efflux ratio (ER):

[1165] Efflux ratio (ER) = Papp(B to A) / Papp(A to B)

[1166] The experimental results show that Dxd is a substrate of the transporter BCRP, but not a substrate of the transporter P-gp; multiple compounds of the present application are neither substrates of the transporter P-gp nor substrates of the transporter BCRP. Therefore, the risk of clinical drug-drug interaction of the compounds of the present application is relatively low.

[1167] Effect implementation 6: Stability test in human, cynomolgus monkey and SD rat plasma

[1168] 1. Experimental purpose

[1169] The purpose of this study is to evaluate the stability of the compound in human, cynomolgus monkey and SD rat plasma.

[1170] 2. Experimental procedure

[1171] The plasma (EDTA-K2) used in this test was aseptically filtered through a 0.22 μm filter.

[1172] The positive control was prepared as a 10 mM stock solution using DMSO and then diluted to 100 μM using DMSO. 5 μL of the positive control at a concentration of 100 μM was added to 495 μL of plasma. The final concentration of the positive control was 1 μM, divided into 3 replicates, and incubated in a 37 °C water bath. At each time point (0, 5, 15, 30, 60, 120 minutes), 15 μL of the sample was taken and then quickly added to 300 μL of acetonitrile solution containing internal standard.

[1173] 1 μL of the test compound at a concentration of 10 mg / mL was added to 99 μL of plasma. The final concentration of the test compound was 100 μg / mL, divided into 3 replicates, and incubated in a 37 °C carbon dioxide incubator. At each time point (0, 5, 15, 30, 60, 120 minutes), 15 μL of the sample was taken and then quickly added to 300 μL of acetonitrile solution containing internal standard.

[1174] After the experiment, place the 96-well plate on a shaker and vortex for 5 minutes (900 rpm), then centrifuge at 6000×g for 10 minutes (4°C). Dilute the supernatant 1:1 with ultrapure water and analyze the sample using LC-MS / MS.

[1175] Compare the concentrations of the positive control at 5, 15, 30, 60, and 120 minutes with the concentration at 0 minute to determine the percentage of the remaining amount of the compound to be measured at each time point. Use Excel software to calculate the half-life and fit the equation for T 1 / 2 Calculation.

[1176] 3. Data processing

[1177] Use Analyst 1.7.1 software to process the data.

[1178] Terminal elimination rate constant (K) = slope

[1179] T 1 / 2 = LN(2) / slope

[1180] The experimental results show that the compounds of the present application have relatively excellent stability.

[1181] All documents mentioned in the present invention are cited in this application as references, as if each document was individually cited as a reference. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of this application.

Claims

1. A compound represented by the following formula (A-I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotope variant thereof, and mixtures thereof: The Ar ring is a 5- or 6-membered aromatic ring or aromatic heterocyclic ring, and the Ar ring may be unsubstituted or optionally substituted by R 3 , R 4 , R 5 , R 6 each independently; Y is selected from the group consisting of: a chemical bond, a C1-C6 alkylene group, a C1-C6 deuterated alkylene group, -O-, -NH-, -NR b -, -CHR b -; X is selected from the group consisting of: N or CR 0 ; R 0 selected from the group consisting of: a hydrogen atom, a deuterium atom, a halogen, a C1-C8 alkyl group, a C1-C8 deuterated alkyl group, a C1-C8 fluoroalkyl group, a C1-C8 alkoxy group, a C1-C8 deuterated alkoxy group, a hydroxyl group, -NH2, -N3, NO2 or a cyano group; R 1 selected from the group consisting of a hydrogen atom, a deuterium atom, a halogen, a cyano group, a C1-C8 alkyl group, a C1-C8 deuterated alkyl group, a C1-C8 alkoxy group, a C1-C8 haloalkyl group, a C1-C8 deuterated alkoxy group, a C1-C8 haloalkoxy group, N3, NO2, NH2, NH-OH, -NR'R”, -COOR', -CONR'R”, -NHR”'NR'R”; wherein R', R” and R”' are each independently selected from hydrogen, an alkyl group, an aryl group, an arylalkyl group, an acyl group, an alkoxycarbonyl group, an aryloxycarbonyl group; R 2 、R 3 、R 4 、R 5 and R 6 are each independently selected from the group consisting of: a hydrogen atom, a deuterium atom, a halogen, a hydroxyl group, a mercapto group, a cyano group, -NH2, -NO2, -NHR b , -N(R b )(AA), -O(AA), a substituted or unsubstituted C1-C8 alkyl group, a substituted or unsubstituted C1-C8 alkylene-O(AA), a substituted or unsubstituted C1-C8 alkylene-NH(AA), a substituted or unsubstituted C1-C8 alkylene-N(R b )(AA), a substituted or unsubstituted C1-C8 alkoxy group, a substituted or unsubstituted C1-C8 alkylthio group, a substituted or unsubstituted C1-C8 deuterated alkyl group, a substituted or unsubstituted C1-C8 deuterated alkoxy group, a substituted or unsubstituted C1-C8 fluoroalkyl group, a substituted or unsubstituted C1-C8 fluoroalkoxy group, a substituted or unsubstituted C2-C8 alkenyl group, a substituted or unsubstituted C2-C8 alkynyl group, -(CH2) m tris(C1-C4 alkyl) silyl, -(CH2) m (C3-C 12 cycloalkyl), -(CH2) m (C3-C 12 cycloalkyl)(CH2) p R 7 , -(CH2) m (3- to 12-membered heterocycloalkyl), -(CH2) m (3- to 12-membered heterocycloalkyl)(CH2) p R 7 , -(CH2) m (3- to 12-membered heterocycloalkyl)NHR 7 , -(CH2) m (3- to 12-membered heterocycloalkyl)N(R 7 )2, -(CH2) m (C3-C 12 cycloalkyl)OH, -(CH2) m (C3-C 12 cycloalkyl)OR 7 , -(CH2) m (C3-C 12 cycloalkyl)NH2, -(CH2) m (C3-C 12 cycloalkyl)NH(C1-C8 alkyl), -(CH2) m (C3-C 12 cycloalkyl)NHR 7 , -(CH2) m (3- to 12-membered heterocyclic group), -(CH2) m (3- to 12-membered heterocyclic group)(CH2) p R 7 、-(CH2) m (3- to 12-membered heterocyclic group)NHR7、-(CH2) m (3- to 12-membered heterocyclic group)N(R7)2、-(C1-C8 alkylene)N(R 7 )2、-(C1-C8 alkylene)N(R 7 )(AA)、-(CH2) m N(R 7 )2、-(CH2) m N(R 7 )(AA)、-(CH2) m OR 7 、-(CH2) m O(AA)、-(CH2) m SR 7 、-(CH2) m S(O)R 7 、-(CH2) m S(O)2R 7 、-(CH2) m S(AA)、-(CH2) m Ph-N(R 7 )2、-(CH2) m Ph-N(R 7 )(AA)、-(CH2) m S(CH2) p R 7 、-(CH2) m S(O)(CH2) p R 7 、-(CH2) m S(O)2(CH2) p R 7 、-(CH2) m NHS(O)2(CH2) p R 7 、-(CH2) m S(O)2NH(CH2) p R 7 、-(CH2) m NHS(O)2NH(CH2) p R 7 、-(CH2) m S(O)2NR 7 (CH2) p R 7 、-(CH2) m NH(CH2) p R 7 、-(CH2) m NHC(O)(CH2) p R 7 、-(CH2) m OC(O)(CH2) p R 7 、-(CH2) m C(O)(CH2) p R 7 、-(CH2) m C(O)NH(CH2) p R 7 、-(CH2) m NR 7 C(O)(CH2) p R 7 、-(CH2) m C(O)NR 7 (CH2) p R 7 、-(CH2) m NHC(O)NH(CH2) p R 7 、-(CH2) m OC(O)NH(CH2) p R 7 、-(CH2) m NHC(O)O(CH2) p R 7 、-(CH2) m NR 7 C(O)NR 7 (CH2) p R 7 、-(CH2) m OC(O)NR 7 (CH2) p R 7 、-(CH2) m NR 7 C(O)O(CH2) p R 7 、-(CH2) m C(O)O(CH2) p R 7 、-CH=N(OR 7 )、-CH=NR 7 、-CH=N-NHR 7 、-CH=N-N(R 7 )2、-NH-NHR 7 、-NH-N(R 7 ) 2; wherein, m and p are each independently 0, 1, 2, 3 or 4; Alternatively, R 2 、R 3 、R 4 、R 5 and R 6 are each independently selected from -(L) x -R 11 , wherein x is any integer from 0 to 10; Each L is independently selected from the group consisting of: CR w R x , O, S, NH, NR y , NHC(O), C(O)NH, C(O), C(O)O, OC(O), C(NH), C(NH)O, OC(NH), C(N-CN), S(O), S(O)2, S(O)2NH, S(O)2NR z , NH S(O)2, NR z S(O)2, Si(R z )2, PH, PR z , P(O), P(O)NH, P(O)NR z , NHP(O), NR z P(O), P(O)O, OP(O), -CH=CH-, ,, C=N, C=N-NH, C=N-NR z , C=N-O, NH-NH, NR z -NR z , NR z -O, a substituted or unsubstituted C 6- C 10 aryl, a substituted or unsubstituted 5-10 membered heteroaryl, a substituted or unsubstituted 3-10 membered saturated or unsaturated carbocycle, a substituted or unsubstituted 3-10 membered saturated or unsaturated heterocycle; R 11 selected from the group consisting of: a hydrogen atom, OH, SH, NH2, OR z , SR z , NHR z 、 N(R z )2; The R w , R x , R y and R z are each independently selected from the group consisting of: a hydrogen atom, a deuterium atom, a halogen, a hydroxyl group, NH2, a substituted or unsubstituted C 1-4 alkyl, a C 1-4 deuterated alkyl, a C 1-4 haloalkyl, a substituted or unsubstituted C 3- C 10 cycloalkylalkyl, a substituted or unsubstituted C 3- C 10 cycloalkyl, a substituted or unsubstituted C 3- C 10 heterocyclic alkyl, a substituted or unsubstituted C 3- C 10 heterocyclic group, a C1-C6 alkyl-sulfonyl. Alternatively, R 2 and R 3 together with the carbon atom to which it is attached form a structure selected from the group consisting of: a substituted or unsubstituted C5-C 12 carbocyclic ring, a substituted or unsubstituted 5- to 12-membered heterocyclic group, an unsubstituted or R-substituted saturated or unsaturated 5- to 12-membered carbocyclic ring, an unsubstituted or R-substituted saturated or unsaturated 5- to 12-membered heterocyclic ring; a a ​​ Alternatively, R 3 and R 4 together with the carbon atom to which it is attached form a structure selected from the group consisting of: a substituted or unsubstituted C5-C 12 carbocyclic ring, a substituted or unsubstituted 5- to 12-membered heterocyclic group, an unsubstituted or R a substituted saturated or unsaturated 5- to 12-membered carbocyclic ring, an unsubstituted or R a substituted saturated or unsaturated 5- to 12-membered heterocyclic ring; Alternatively, R 4 and R 5 together with the carbon atom to which it is attached form a structure selected from the group consisting of: an unsubstituted or one or more R a substituted saturated or unsaturated 5- to 12-membered carbocyclic ring, an unsubstituted or one or more R a substituted saturated or unsaturated 5- to 12-membered heterocyclic ring; R 8 and R 9 each independently selected from the group consisting of: a hydrogen atom, a deuterium atom, a halogen, a hydroxyl group, a cyano group, NH2, NO2, a substituted or unsubstituted C1-C8 alkyl group, a substituted or unsubstituted C1-C8 deuterated alkyl group, a substituted or unsubstituted C1-C8 alkoxy group, a 3-6 membered cycloalkyl group, and a 3-6 membered heteroalkyl group; Alternatively, R 8 and R 9 together with the carbon atom to which it is attached form a structure selected from the group consisting of: an unsubstituted or R-substituted saturated or unsaturated 3- to 6-membered carbocyclic ring, an unsubstituted or R-substituted saturated or unsaturated 3- to 6-membered heterocyclic ring; a an unsubstituted or R-substituted saturated or unsaturated 3- to 6-membered carbocyclic ring, an unsubstituted or R-substituted saturated or unsaturated 3- to 6-membered heterocyclic ring; a ​ R a Each independently selected from the following group: hydrogen atom, deuterium atom, halogen, hydroxyl group, mercapto group, cyano group, -NH2, -NO2, -NHR b , -N(R b )(AA), -O(AA), substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkylene -O(AA), substituted or unsubstituted C1-C8 alkylene -NH(AA), substituted or unsubstituted C1-C8 alkylene -N(R b )(AA), substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted C1-C8 alkylthio, substituted or unsubstituted C1-C8 deuterated alkyl, substituted or unsubstituted C1-C8 deuterated alkoxy, substituted or unsubstituted C1-C8 fluoroalkyl, substituted or unsubstituted C1-C8 fluoroalkoxy, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, -(CH2) m tris(C1-C4 alkyl) silyl, -(CH2) m (C3-C 12 cycloalkyl), -(CH2) m (C3-C 12 cycloalkyl)(CH2) p R 7 , -(CH2) m (3-12 membered heterocycloalkyl), -(CH2) m (3-12 membered heterocycloalkyl)(CH2) p R 7 , -(CH2) m (3-12 membered heterocycloalkyl)NHR 7 , -(CH2) m (3-12 membered heterocycloalkyl)N(R 7 )2, -(CH2) m (C3-C 12 cycloalkyl)OH, -(CH2) m (C3-C 12 cycloalkyl)OR 7 , -(CH2) m (C3-C 12 cycloalkyl)NH2, -(CH2) m (C3-C 12 cycloalkyl)NH(C1-C8 alkyl), -(CH2) m (C3-C 12 cycloalkyl)NHR 7 , -(CH2) m (3-12 membered heterocyclic group), -(CH2) m (3-12 membered heterocyclic group)(CH2) p R 7 、 -(CH2) m (3 - 12 membered heterocyclic group)NHR7, -(CH2) m (3 - 12 membered heterocyclic group)N(R7)2, -(C1 - C8 alkylene)N(R 7 )2, -(C1 - C8 alkylene)N(R 7 )(AA), -(CH2) m N(R 7 )2, -(CH2) m N(R 7 )(AA), -(CH2) m OR 7 、 -(CH2) m O(AA), -(CH2) m SR 7 、 -(CH2) m S(O)R 7 、 -(CH2) m S(O)2R 7 、 -(CH2) m S(AA), -(CH2) m Ph - N(R 7 )2, -(CH2) m Ph - N(R 7 )(AA), -(CH2) m S(CH2) p R 7 、 -(CH2) m S(O)(CH2) p R 7 、 -(CH2) m S(O)2(CH2) p R 7 、 -(CH2) m NHS(O)2(CH2) p R 7 、 -(CH2) m S(O)2NH(CH2) p R 7 、 -(CH2) m NHS(O)2NH(CH2) p R 7 、 -(CH2) m S(O)2NR 7 (CH2) p R 7 、 -(CH2) m NH(CH2) p R 7 、 -(CH2) m NHC(O)(CH2) p R 7 、-(CH2) m OC(O)(CH2) p R 7 、-(CH2) m C(O)(CH2) p R 7 、-(CH2) m C(O)NH(CH2) p R 7 、-(CH2) m NR 7 C(O)(CH2) p R 7 、-(CH2) m C(O)NR 7 (CH2) p R 7 、-(CH2) m NHC(O)NH(CH2) p R 7 、-(CH2) m OC(O)NH(CH2) p R 7 、-(CH2) m NHC(O)O(CH2) p R 7 、-(CH2) m NR 7 C(O)NR 7 (CH2) p R 7 、-(CH2) m OC(O)NR 7 (CH2) p R 7 、-(CH2) m NR 7 C(O)O(CH2) p R 7 、-(CH2) m C(O)O(CH2) p R 7 、-CH=N(OR 7 )、-CH=NR 7 、-CH=N-NHR 7 、-CH=N-N(R 7 )2、-NH-NHR 7 、-NH-N(R 7 )2; wherein, m and p are each independently 0, 1, 2, 3, or 4; Alternatively, R a each independently selected from -(L) x -R 11 , wherein x is any integer from 0 to 10; Each L is independently selected from the group consisting of: CR w R x 、O, S, NH, NR y 、NHC(O), C(O)NH, C(O), C(O)O, OC(O), C(NH), C(NH)O, OC(NH), C(N-CN), S(O), S(O)2, S(O)2NH, S(O)2NR z 、NH S(O)2, NR z S(O)2, Si(R z )2, PH, PR z 、P(O), P(O)NH, P(O)NR z 、NHP(O), NR z P(O), P(O)O, OP(O), -CH=CH-, ,, C=N, C=N-NH, C=N-NR z 、C=N-O, NH-NH, NR z -NR z 、NR z -O, a substituted or unsubstituted C 6- C 10 aryl, a substituted or unsubstituted 5- to 10-membered heteroaryl, a substituted or unsubstituted 3- to 10-membered saturated or unsaturated carbocycle, a substituted or unsubstituted 3- to 10-membered saturated or unsaturated heterocycle; R 11 selected from the group consisting of: a hydrogen atom, OH, SH, NH2, OR z , SR z , NHR z 、 N(R z )2; Said R w 、R x 、R y and R z are each independently selected from the following group: a hydrogen atom, a deuterium atom, a halogen, a hydroxyl group, NH2, a substituted or unsubstituted C 1-4 alkyl, a C 1-4 deuterated alkyl, a C 1-4 haloalkyl, a substituted or unsubstituted C 3- C 10 cycloalkylalkyl, a substituted or unsubstituted C 3- C 10 cycloalkyl, a substituted or unsubstituted C 3- C 10 heterocyclic alkyl, a substituted or unsubstituted C 3- C 10 heterocyclic group, a C1-C6 alkyl-sulfonyl. R b selected from a hydrogen atom, a halogen, a C1-C6 alkyl group, a C1-C6 deuterated alkyl group, a C1-C6 alkoxy group, a C3-C6 cycloalkyl group, and a 3- to 6-membered heterocycloalkyl group; AA is selected from an amino acid or a group formed by removing the hydroxyl group in the carboxylic acid structure from a polypeptide structure formed by 2 - 5 amino acids, and the amino acid can be a natural amino acid or a non-natural amino acid; Each R 7 Each independently selected from the following group: a hydrogen atom, a deuterium atom, a halogen, -COOH, a substituted or unsubstituted C1-C8 alkyl group, a substituted or unsubstituted 2-8 membered heteroalkyl group, a C1-C8 haloalkyl group, a substituted or unsubstituted C1-C8 deuterated alkyl group, a substituted or unsubstituted C1-C8 alkoxy group, a substituted or unsubstituted C1-C8 fluoroalkyl group, a hydroxy group, an amino group, a cyano group, a nitro group, a mercapto group, N3, a substituted or unsubstituted C2-C8 alkenyl group, a substituted or unsubstituted C2-C8 alkynyl group, a substituted or unsubstituted C1-C8 alkylene-OH, a substituted or unsubstituted C1-C8 alkylene-NH2, a substituted or unsubstituted C1-C8 alkylene-O-substituted or unsubstituted C1-C8 alkylene-OH, a substituted or unsubstituted C1-C8 alkylene-O-substituted or unsubstituted C1-C8 alkylene-NH2, a substituted or unsubstituted C1-C8 alkylene-NH-substituted or unsubstituted C1-C8 alkylene-OH, a substituted or unsubstituted C1-C8 alkylene-O-substituted or unsubstituted C1-C8 alkylene-NH(C1-C4 alkyl), a substituted or unsubstituted C1-C8 alkylene-N(C1-C4 alkyl)-substituted or unsubstituted C1-C8 alkylene-OH, a substituted or unsubstituted C1-C8 alkylene-NH(C1-C4 alkyl), a substituted or unsubstituted 2-8 membered heteroalkylene-OH, a substituted or unsubstituted 2-8 membered heteroalkylene-NH2, a substituted or unsubstituted 2-8 membered heteroalkylene-NH(C1-C4 alkyl), SO2(C1-C8 alkyl), SO2O(C1-C8 alkyl), SO2NH(C1-C8 alkyl), -NHC(O)(substituted or unsubstituted C1-C4 alkyl), -N(substituted or unsubstituted C1-C4 alkyl)C(O)(substituted or unsubstituted C1-C4 alkyl), -OC(O)(substituted or unsubstituted C1-C4 alkyl), -OC(O)(substituted or unsubstituted C1-C4 alkylene)OH, -OC(O)(substituted or unsubstituted C1-C4 alkylene)NH2, -OC(O)(substituted or unsubstituted C1-C4 alkylene)NH(substituted or unsubstituted C1-C4 alkyl), -C(O)(substituted or unsubstituted C1-C4 alkyl), -C(O)(substituted or unsubstituted C1-C8 alkylene)OH, -C(O)(substituted or unsubstituted C1-C8 alkylene)NH2, -C(O)(substituted or unsubstituted C1-C8 alkylene)NH(C1-C8 alkyl), a substituted or unsubstituted phenyl group, a substituted or unsubstituted C1-C8 alkylene-substituted or unsubstituted phenyl group, a substituted or unsubstituted C1-C8 heteroalkylene-substituted or unsubstituted phenyl group, a substituted or unsubstituted 5-7 membered heteroaryl group, a substituted or unsubstituted C1-C8 alkylene-substituted or unsubstituted 5-7 membered heteroaryl group, a substituted or unsubstituted C1-C8 heteroalkylene-substituted or unsubstituted 5-7 membered heteroaryl group, a substituted or unsubstituted C3-C8 cycloalkyl groupSubstituted or unsubstituted C1-C8 alkylene-substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C1-C8 heteroalkylene-substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclic group, substituted or unsubstituted C1-C8 alkylene-substituted or unsubstituted 3-12 membered heterocyclic group, substituted or unsubstituted C1-C8 alkylene-substituted or unsubstituted 3-12 membered heterocyclic group, -CH=N(O(C1-C8 alkyl)), -CH=N(C1-C8 alkyl); R 10 selected from the group consisting of: a hydrogen atom, a deuterium atom, a C1-C8 alkyl group, a C1-C8 haloalkyl group, a C1-C8 alkoxy group, a C1-C8 deuterated alkyl group, a C3-C8 cycloalkyl group, a C4-C 10 cycloalkylalkyl group, a C1-C8 alkyl C3-C8 cycloalkyl group; Unless otherwise specified, each of the above groups may be substituted by a substituent selected from the following group: hydrogen atom, deuterium atom, halogen, nitrile group, nitro group, hydroxyl group, amino group, C1-C6 alkyl-NH-, (C1-C6 alkyl)2N-, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, halogenated C1-C6 alkoxy, allyl, benzyl, C6-C 12 aryl, C1-C6 alkoxy-C1-C6 alkyl, C1-C6 alkoxy-carbonyl, phenoxycarbonyl, C2-C6 alkynyl-carbonyl, C2-C6 alkenyl-carbonyl, C3-C6 cycloalkyl-carbonyl, C1-C6 alkyl-sulfonyl, phenyl, 5-7 membered heteroaryl, C3-C8 cycloalkyl, 3-12 membered heterocyclic group; the heterocyclic or heterocyclic group may be a saturated or partially unsaturated structure but does not have aromaticity; the carbocyclic or heterocyclic ring is a monocyclic, spirocyclic, fused ring or bridged ring; the aromatic ring or heteroaromatic ring may be a monocyclic or fused ring.

2. The compound according to claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, characterized in that, In the structure of the compound of formula (A-I), the structural fragment shown is selected from the following group: The Ar ring may be unsubstituted or optionally substituted by R 3 , R 4 , R 5 , R 6 , each independently; R 2 , R 3 , R 4 , R 5 , R 6 are defined as described in the text.

3. The compound according to claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereoisomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, characterized in that, In the structure of the compound of formula (A-I) The structural fragment shown is selected from the group R 2 、R 3 、R 4 、R 5 、R 6 are defined as described in claim 1.

4. The compound according to claim 3, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, characterized in that, R 2 and R 3 together with the carbon atom to which it is attached form a structure selected from the group consisting of: a substituted or unsubstituted C5-C 12 carbocyclic ring, a substituted or unsubstituted 5- to 12-membered heterocyclic group, an unsubstituted or one or more R a substituted saturated or unsaturated 5- to 12-membered carbocyclic ring, an unsubstituted or one or more R a substituted saturated or unsaturated 5- to 12-membered heterocyclic ring; wherein R a is as defined herein.

5. The compound according to claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereoisomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, characterized in that, The structural fragment shown, R 2 and the R on the Ar ring 3 forming the ring (B) structure are selected from the group: Among them, ring (B) may be unsubstituted or substituted by one or more R a wherein R a is defined as described in the text.

6. The compound according to claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereoisomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, characterized in that, R 4 and R 5 together with the carbon atom to which it is attached form a structure selected from the group consisting of: a substituted or unsubstituted C5-C 12 carbocyclic ring, a substituted or unsubstituted 5- to 12-membered heterocyclic group, an unsubstituted or one or more R a substituted saturated or unsaturated 5- to 12-membered carbocyclic ring, an unsubstituted or one or more R a substituted saturated or unsaturated 5- to 12-membered heterocyclic ring; wherein R a is as defined herein.

7. The compound according to claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, characterized in that, In the structure of the compound of formula (A-I) R on the Ar ring in the structural fragment shown 4 and R 5 forming the ring (A) structure are selected from the group: Among them, ring (A) may be unsubstituted or substituted by one or more R a substituents, and R a is defined as described in claim 1.

8. The compound according to claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereoisomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, characterized in that, R 3 and R 4 together with the carbon atom to which it is attached form a structure selected from the group consisting of: a substituted or unsubstituted C5-C 12 carbocyclic ring, a substituted or unsubstituted 5- to 12-membered heterocyclic group, an unsubstituted or one or more R a substituted saturated or unsaturated 5- to 12-membered carbocyclic ring, an unsubstituted or one or more R a substituted saturated or unsaturated 5- to 12-membered heterocyclic ring; wherein R a is as defined in claim 1.

9. The compound according to claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereoisomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, characterized in that, In the structure of the compound of formula (A-I) R on the Ar ring in the structural fragment shown 3 and R 4 forming the ring (C) structure is selected from the group: Among them, the ring (C) may be unsubstituted or substituted by one or more R a groups, where R a is defined as described in the text.

10. The compound according to claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, characterized in that, In the structure of the compound of formula (I) The structural fragments shown are selected from the following group:

11. The compound according to claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, characterized in that, The said R 2 、R 3 、R 4 、R 5 、R 6 、R a are each independently selected from the group consisting of: -OH, -NH2, -SH, -F, -Cl, -Br, -I, -OMe, -OCD3, -OCF3, OCFH2, OCF2H, OCF3, CN, SMe, S(O)Me, S(O)2Me, 12. The compound according to claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, characterized in that The amino acids in the composition of AA are each independently selected from the following group: glycine, alanine, valine, leucine, isoleucine, methionine, proline, tryptophan, serine, tyrosine, cysteine, phenylalanine, asparagine, glutamine, threonine, aspartic acid, glutamic acid, lysine, arginine and histidine.

13. The compound according to claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, characterized in that, The AA group described above is selected from the following group:

14. The compound according to claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof, and mixtures thereof, characterized in that, The compound of formula (A-I) has the structure shown in the following formula (A-II-1): Wherein, M is selected from the group consisting of: N or CR 5 ; R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 8 、R 9 、X, Y are defined as described in claim 1; or the compound of formula (A-I) has the structure shown in the following formula (A-II-2): Among them, R 2 , R 3 , R 4 , R 5 , R 8 , R 9 are defined as described in claim 1; or the compound of formula (A-I) has the structure shown in the following formula (A-II-3): Among them, R 2 、R 3 、R 4 、R 5 、R 8 、R 9 are defined as described in claim 1; or the compound of formula (A-I) has the structure shown in the following formula (A-II-4): wherein, R 2 , R 3 , R 4 , R 5 are defined as described in claim 1; or the compound of formula (A-I) has the structure shown in the following formula (A-II-5): wherein, R 2 、R 3 、R 4 、R 6 、R 8 、R 9 、M are defined as described in claim 1; or the compound of formula (A-I) has the structure shown in the following formula (A-II-6): wherein, R 2 、R 3 、R 5 、R 6 、R 8 、R 9 are defined as described in claim 1; or the compound of formula (A-I) has the structure shown in the following formula (A-II-7): wherein, R 3 、R 4 、R 5 、R 6 、R 8 、R 9 、R 11 、L are defined as described in claim 1; x is any integer from 0 to 10; or the compound of formula (A-I) has the structure shown in the following formula (A-II-8): wherein, R 5 , R 6 , R 8 , R 9 , R 10 , Y are defined as described in claim 1; x is any integer from 2 to 10; Each L 1 is independently selected from the group consisting of: CR w R x , O, S, NH, NR y , NHC(O), C(O)NH, C(O), C(O)O, OC(O), C(NH), C(NH)O, OC(NH), C(N-CN), S(O), S(O)2, S(O)2NH, S(O)2NR z , NH S(O)2, NR z S(O)2, Si(R z )2, PH, PR z , P(O), P(O)NH, P(O)NR z , NHP(O), NR z P(O), P(O)O, OP(O), C=N, C=N-NH, C=N-NR z , C=N-O, NH-NH, NR z -NR z , NR z -O, a substituted or unsubstituted C 6- C 10 aryl, a substituted or unsubstituted 5-10 membered heteroaryl, a substituted or unsubstituted 3-10 membered saturated or unsaturated carbocycle, a substituted or unsubstituted 3-10 membered saturated or unsaturated heterocycle; R 11 Selected from the group consisting of: a hydrogen atom, OH, SH, NH2, OR z , SR z , NHR z 、 N(R z )2; The R w , R x , R y and R z are each independently selected from the group consisting of: a hydrogen atom, a deuterium atom, a halogen, a hydroxyl group, NH2, a substituted or unsubstituted C 1-4 alkyl, a C 1-4 deuterated alkyl, a C 1-4 haloalkyl, a substituted or unsubstituted C 3- C 10 cycloalkylalkyl, a substituted or unsubstituted C 3- C 10 cycloalkyl, a substituted or unsubstituted C 3- C 10 heterocyclic alkyl, a substituted or unsubstituted C 3- C 10 heterocyclic group, a C1-C6 alkyl-sulfonyl. or the compound of formula (A-I) has the structure shown in the following formula (A-II-9): wherein, R 5 , R 6 , R 8 , R 9 are defined as described in claim 1; x is any integer from 2 to 10; Each L 1 is independently selected from the group consisting of: CR w R x , O, S, NH, NR y , NHC(O), C(O)NH, C(O), C(O)O, OC(O), C(NH), C(NH)O, OC(NH), C(N-CN), S(O), S(O)2, S(O)2NH, S(O)2NR z , NH S(O)2, NR z S(O)2, Si(R z )2, PH, PR z , P(O), P(O)NH, P(O)NR z , NHP(O), NR z P(O), P(O)O, OP(O), C=N, C=N-NH, C=N-NR z , C=N-O, NH-NH, NR z -NR z , NR z -O, a substituted or unsubstituted C 6- C 10 aryl, a substituted or unsubstituted 5- to 10-membered heteroaryl, a substituted or unsubstituted 3- to 10-membered saturated or unsaturated carbocycle, a substituted or unsubstituted 3- to 10-membered saturated or unsaturated heterocycle; R 11 selected from the group consisting of: a hydrogen atom, OH, SH, NH2, OR z , SR z , NHR z 、 N(R z )2; Said R w 、R x 、R y and R z are each independently selected from the group consisting of: a hydrogen atom, a deuterium atom, a halogen, a hydroxyl group, NH2, a substituted or unsubstituted C 1-4 alkyl, a C 1-4 deuterated alkyl, a C 1-4 haloalkyl, a substituted or unsubstituted C 3- C 10 cycloalkylalkyl, a substituted or unsubstituted C 3- C 10 cycloalkyl, a substituted or unsubstituted C 3- C 10 heterocyclic alkyl, a substituted or unsubstituted C 3- C 10 heterocyclic group, a C1-C6 alkyl-sulfonyl group. or the compound of formula (A-I) has the structure shown in the following formula (A-II-10): wherein, R 5 , R 6 , R 8 , R 9 , R 10 , Y are defined as described in claim 1; or the compound of formula (A-I) has the structure shown in the following formula (A-II-11): Among them, R 5 , R 6 , R 8 , R 9 , R 10 are defined as described in claim 1; or the compound of formula (A-I) has the structure shown in the following formula (A-II-12): wherein, R 2 、R 3 、R 6 、R 8 、R 9 are defined as described in claim 1; or the compound of formula (A-I) has the structure shown in the following formula (A-II-13): wherein, R 3 , R 6 , R 8 , R 9 , R 11 , L are defined as described in claim 1; x is any integer from 0 to 10; or the compound of formula (A-I) has the structure shown in formula (A-II-14) as follows: Among them, R 2 , R 3 , R 6 , R 8 , R 9 are defined as described in claim 1; or the compound of formula (A-I) has the structure shown in the following formula (A-II-15): wherein, R 3 , R 6 ), R 8 ), R 9 ), R 11 ), L are defined as described in claim 1; x is any integer from 0 to 10; or the compound of formula (A-I) has the structure shown in formula (A-II-16): wherein, R 2 , R 3 , R 6 , R 8 , R 9 are defined as described in claim 1; or the compound of formula (A-I) has the structure shown in the following formula (A-II-17): wherein, R 3 , R 6 , R 8 , R 9 , R 11 , L are defined as described in claim 1; x is any integer from 0 to 10; or the compound of formula (A-I) has the structure shown in the following formula (A-II-18): wherein, R 2 , R 3 , R 6 , R 8 , R 9 are defined as described in claim 1; or the compound of formula (A-I) has the structure shown in the following formula (A-II-19): wherein, R 3 , R 6 , R 8 , R 9 , R 11 , L are defined as described in claim 1; x is any integer from 0 to 10; or the compound of formula (A-I) has the structure shown in the following formula VIII: wherein n is 0 or 1; Ring A is unsubstituted or substituted by one or more R a substituted saturated or unsaturated 5- or 6-membered carbocyclic ring, unsubstituted or substituted by one or more R a substituted saturated or unsaturated 5- or 6-membered heterocyclic ring; wherein, R a is as defined in claim 1, R 1 , R 2 , R 3 , R 6 , and X are as defined in claim 1. or the compound of formula (A-I) has the structure shown in the following formula IX: Among them, ring A is an unsubstituted or substituted by one or more R a substituted saturated or unsaturated 5- or 6-membered carbocyclic ring, an unsubstituted or substituted by one or more R a substituted saturated or unsaturated 5- or 6-membered heterocyclic ring; wherein, R a is defined as described in claim 1, and R 2 , R 3 is defined as described in claim 1. or the compound of formula (A-I) has the structure shown in the following formulae X - XV: Among them, R 2 , R 3 are defined as described in claim 1; Ring A may be unsubstituted or substituted by one or more R a ; wherein, R a is defined as described in claim 1. or the compound of formula (A-I) has the structure shown in the following formula XVI: wherein n is 0 or 1; R 1 、R 4 、R 5 、R 6 The definitions of R, 1 , R, 4 , R, 5 , R, 6 , and X are as described in claim 1; Ring B is selected from the group consisting of structures: unsubstituted or substituted by one or more R a substituted saturated or unsaturated 5- to 12-membered carbocycles, unsubstituted or substituted by one or more R a substituted saturated or unsaturated 5- to 12-membered heterocycles; wherein R a is as defined in claim 1. or the compound of formula (A-I) has the structure shown in the following formula XVII: Wherein, R 4 and R 5 are defined as described in claim 1; Ring B is selected from the group consisting of structures: unsubstituted or substituted by one or more R a substituted saturated or unsaturated 5- to 12-membered carbocyclic rings, unsubstituted or substituted by one or more R a substituted saturated or unsaturated 5- to 12-membered heterocyclic rings; wherein R a is as defined in claim 1. or the compound of formula (A-I) has a structure shown in the following formulas XVIII-XXII: Wherein, R 4 and R 5 are defined as described in claim 1; Ring B may be unsubstituted or substituted by one or more R a ; wherein, the definition of R a is as described in claim 1.

15. A pharmaceutical composition, which comprises a compound of formula I according to any one of claims 1-11, or a pharmaceutically acceptable salt or hydrate thereof, and one or more pharmaceutically acceptable excipients, diluents or carriers.

16. Use of the compound of formula I according to any one of claims 1-14, characterized in that, For preparing a pharmaceutical composition for treating a disease associated with tumor cell proliferation.

17. Use of the compound of formula I according to any one of claims 1-14, characterized in that, Used as a toxin in an antibody-drug conjugate to prepare an antibody-drug conjugate.

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