Lipoprotein(a) inhibitor and use thereof

Abstract

The present invention relates to the field of medicine, and pertains to a lipoprotein(a) inhibitor and a use thereof. Specifically provided are a compound represented by formula (I'), an isomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutically acceptable salt, ester, hydrate, or solvate thereof. The compound of the present invention exhibits a stronger binding affinity for Apo(a), a greater ability to reduce Lp(a) levels more effectively, stronger inhibitory activity against oxidized phospholipids on apolipoprotein(a), favorable pharmacokinetic properties, and high Lp(a) selectivity, among other advantages, and can be used in the preparation of a drug for treating cardiovascular diseases.

Description

A lipoprotein (a) inhibitor and its application

[0001] Citation of relevant applications

[0002] This application claims priority to Chinese patent application No. 202510298193.1 filed with the China National Intellectual Property Administration on March 13, 2025, and Chinese patent application No. 202511371069.X filed with the China National Intellectual Property Administration on September 24, 2025, the contents of which are incorporated herein by reference in their entirety and for all purposes. Technical Field

[0003] This invention relates to the field of chemical pharmaceuticals, and specifically to a lipoprotein(a) inhibitor and its application. Background Technology

[0004] LPA is the name of the gene encoding apolipoprotein(a), primarily expressed in the liver. Apolipoprotein(a) binds to apo(B)-100 via disulfide bonds, combining with a lipid core to form lipoprotein(a) (Lp(a)) particles. Lp(a) particles are specialized large lipoprotein molecules rich in cholesterol, coated with cholesterol and phospholipids, and embedded with hydrophilic apolipoprotein components apolipoprotein(a) and apo(B)-100. Lp(a) can enter and deposit on the blood vessel wall, promoting atherosclerosis. Lp(a) is structurally homologous to plasminogen (PLG) and can compete with plasminogen for fibrin binding sites, thereby inhibiting fibrinogen hydrolysis and promoting thrombus formation. Studies have shown that oxidized phospholipids are mainly carried and transported by Lp(a), binding to apolipoprotein(a) and LDL particles, exhibiting pro-inflammatory and pro-atherosclerotic effects. Furthermore, apolipoprotein(a) containing oxidized phospholipids also induces increased release of inflammatory factors. Therefore, Lp(a) and its bound OxPL are closely associated with atherosclerosis and thrombosis. Studies have shown that blood Lp(a) levels are an independent risk factor for cardiovascular disease, stroke, and atherosclerotic stenosis. Human Lp(a) levels are genetically determined and do not change significantly with changes in diet, exercise, or other lifestyle factors.

[0005] Several companies have disclosed a series of pharmaceutically viable compounds for lowering plasma Lp(a) levels, achieving some progress in the field of cardiovascular disease. However, there are currently no marketed small-molecule Lp(a) drugs. Therefore, there is an urgent need to develop cardiovascular drugs that meet clinical needs.

[0006] WO2020247429A1 discloses a tetrahydropyrrole compound, of which compound 1 has low oral bioavailability, for example, the oral bioavailability of mice is only 12.7% when administered orally at 10 mg / kg.

[0007] CN118271234A discloses a piperidine derivative, its composition and application, wherein compound 16 (Example 16) has the potential to further enhance its Lp(a) assembly inhibition activity.

[0008] Therefore, there is an urgent need to develop cardiovascular drugs with stronger Apo(a) binding ability, higher Lp(a) selectivity, more effective reduction of Lp(a) levels, stronger oxidized phospholipid-apolipoprotein(a) inhibitory activity, and that meet clinical needs. Summary of the Invention

[0009] In view of the above-mentioned technical status, the present invention provides a compound of formula (I'), its isomers, isotopically labeled compounds, prodrugs, or pharmaceutically acceptable salts, esters, hydrates or solvates thereof, wherein the compound of formula (I') is shown below:

[0010] Ring A, ring B, ring C, and ring D are each independently selected from: 5-10-membered heterocyclic groups, 5-10-membered aromatic heterocyclic groups, or phenyl groups. The heteroatoms in the 5-10-membered heterocyclic groups or 5-10-membered aromatic heterocyclic groups are selected from N, O, or S, or combinations of two or three of them. When the 5-10-membered heterocyclic group or 5-10-membered aromatic heterocyclic group includes two heteroatoms, the heteroatoms are the same or different. When the 5-10-membered heterocyclic group or 5-10-membered aromatic heterocyclic group includes three heteroatoms, the heteroatoms are the same, partially the same, or completely different. Optionally, the 5-10-membered heterocyclic group, 5-10-membered aromatic heterocyclic group, and phenyl group are each independently substituted by at least one substituent selected from group G.

[0011] The group G is selected from:

[0012] 1)C 1-6 Alkyl, wherein C 1-6 The alkyl group is optionally composed of one or more radicals independently selected from deuterium, halogen, hydroxyl, cyano, amino, or C. 1-6 Substitution of alkoxy groups;

[0013] 2) Deuterium;

[0014] 3)-NH2;

[0015] 4) Cyano group;

[0016] 5) Oxo (=O);

[0017] 6) Halogens;

[0018] 7) Hydroxyl group;

[0019] 8)C 1-6 Alkoxy, where C 1-6The alkoxy group is optionally surrounded by one or more groups independently selected from deuterium, halogen, hydroxyl, cyano, amino, or C. 1-6 Substitution of alkoxy groups;

[0020] 9)C 3-10 cycloalkyl, wherein C 3-10 The cycloalkyl group is optionally composed of one or more radicals independently selected from deuterium, halogen, hydroxyl, cyano, amino, or C. 1-6 Substitution of alkoxy groups;

[0021] 10) A 3-12 membered heterocyclic group, wherein the 3-12 membered heterocyclic group is optionally composed of one or more independently selected from deuterium, halogen, hydroxyl, cyano, amino, or C. 1-6 Substitution of alkoxy groups;

[0022] L is selected from:

[0023] Preferably, L is selected from

[0024] Preferably, L is selected from

[0025] Preferably, L is selected from

[0026] Preferably, L is selected from

[0027] Preferably, L is selected from

[0028] Preferably, L is

[0029] X is selected from -S(=O)2-, -CH2-, or -H, preferably -CH2-; when X is -H, Y, R7, R8, and Rx' do not exist;

[0030] Y is selected from C or N, preferably Y is C; when Y is selected from N, one of R7 and R8 does not exist;

[0031] R X ', Rz, and Rz' are each independently selected Tetrazole, -COOH, -CH2COOH, -CH2OH, -CH2CH2OH, -COOCH3, -COOCH2CH3, -COOCH2CH2CH3, -CONH2, -NH2, -NHCOCH3,

[0032] Preferred ions are -COOH, -OH, -CONH2, and -CH2COOH; more preferably -OH, tetrazolium, -COOH, -CH2COOH, -CH2OH, and -CONH2; or R X 'for -CO-Rx;

[0033] R1, R3, R5, and R7 are each independently selected from C. 4-10 Cycloalkyl or 4-10 membered heterocyclic groups, preferably C 5-10 Cycloalkyl or 5-10 membered heterocyclic groups, wherein the heteroatoms of the 5-10 membered heterocyclic group are selected from N, O, or S, or combinations of two or three of them, wherein when the 5-10 membered heterocyclic group comprises two heteroatoms, the heteroatoms may be the same or different, and when the 5-10 membered heterocyclic group comprises three heteroatoms, the heteroatoms may be the same, partially the same, or completely different; optionally, the C 5-10 The cycloalkyl group and the 5-10 membered heterocyclic group are each independently substituted by at least one substituent selected from group G; wherein, the C 5-10 The cycloalkyl group is substituted with at least one amino group, and the 5-10 membered heterocyclic group contains at least one nitrogen atom;

[0034] R2, R4, R6, R8, and R9 are each independently selected from hydrogen, deuterium, halogens, or C. 1-6 Alkyl; or

[0035] C forms between R1, R2 and their connected atoms; between R3, R4 and their connected atoms; between R5, R6 and their connected atoms; or between R7, R8 and their connected atoms. 5-10 Cycloalkyl, 5-10 membered heterocyclic groups, optionally C 5-10 The cycloalkyl group or 5-10 membered heterocyclic group is substituted by one or more of the following substituents: deuterium, -NH2, halogen, C 1-6 Alkyl, -OH, C 1-6 alkoxy; wherein, the C 5-10 The cycloalkyl group is substituted with at least one amino group, and the 5-10 membered heterocyclic group contains at least one nitrogen atom;

[0036] Alternatively, C forms between R4, R9 and the atoms they are connected to. 8-10 cycloalkyl, 8-10 membered heterocyclic groups, optionally C 8-10 The cycloalkyl or 8-10 membered heterocyclic group is substituted with one or more substituents selected from group G; wherein, the C 8-10 The cycloalkyl group is substituted with at least one amino group, and the 8-10 membered heterocyclic group contains at least one nitrogen atom; when R4, R9 and the atoms attached to them form a C 8-10 R3 is absent when the group consists of cycloalkyl or 8-10 membered heterocyclic groups;

[0037] The condition is that the stated formula (I') is not a compound, its isomer, isotopically labeled compound, prodrug, or a pharmaceutically acceptable salt, ester, hydrate, or solvate thereof:

[0038] As one embodiment, the present invention provides a compound of formula (I), its isomers, isotopically labeled compounds, prodrugs, or pharmaceutically acceptable salts, esters, hydrates, or solvates thereof, wherein the compound of formula (I) is shown below:

[0039] Rings A, B, C, and D are each independently selected from: 5-10 membered heterocyclic groups (e.g., 5, 6, 7, 8, 9, 10 members, which can be 5-6 membered heterocyclic groups), 5-10 membered aromatic heterocyclic groups (e.g., 5, 6, 7, 8, 9, 10 members, which can be 5-6 membered aromatic heterocyclic groups), or phenyl groups. The heteroatoms in the 5-10 membered heterocyclic groups and 5-10 membered aromatic heterocyclic groups are selected from N, O, or S, or combinations of two or three of these. When the 5-10 membered heterocyclic group or 5-10 membered aromatic heterocyclic group comprises two heteroatoms, the heteroatoms may be the same or different. When the 5-10 membered heterocyclic group or 5-10 membered aromatic heterocyclic group comprises three heteroatoms, the heteroatoms may be the same, partially the same, or completely different. Optionally, each of the 5-10 membered heterocyclic group, 5-10 membered aromatic heterocyclic group, and phenyl group is independently substituted by at least one substituent selected from group G.

[0040] The group G is selected from:

[0041] 1)C 1-6 Alkyl, wherein C 1-6 The alkyl group is optionally composed of one or more radicals independently selected from deuterium, halogen, hydroxyl, cyano, amino, or C. 1-6 Substitution of alkoxy groups;

[0042] 2) Deuterium;

[0043] 3)-NH2;

[0044] 4) Cyano group;

[0045] 5) Oxo (=O);

[0046] 6) Halogens;

[0047] 7) Hydroxyl group;

[0048] 8)C 1-6 Alkoxy, where C 1-6 The alkoxy group is optionally surrounded by one or more groups independently selected from deuterium, halogen, hydroxyl, cyano, amino, or C. 1-6 Substitution of alkoxy groups;

[0049] 9)C 3-10cycloalkyl, wherein C 3-10 The cycloalkyl group is optionally composed of one or more radicals independently selected from deuterium, halogen, hydroxyl, cyano, amino, or C. 1-6 Substitution of alkoxy groups;

[0050] 10) A 3-12 membered heterocyclic group, wherein the 3-12 membered heterocyclic group is optionally composed of one or more independently selected from deuterium, halogen, hydroxyl, cyano, amino, or C. 1-6 Substitution of alkoxy groups;

[0051] L is selected from:

[0052] Preferably, L is selected from

[0053] Preferably, L is selected from

[0054] Preferably, L is selected from

[0055] Preferably, L is selected from

[0056] Preferably, L is selected from

[0057] Preferably, L is selected from

[0058] X is selected from -S(=O)2-, -CH2-, or -H, preferably -CH2-; when X is selected from -H, Y, R7, R8, and -CO-Rx do not exist;

[0059] Y is selected from C or N, preferably Y is C; when Y is selected from N, one of R7 and R8 does not exist;

[0060] R X Selected from Or -OH, preferably, R X It is -OH;

[0061] R1, R3, R5, and R7 are each independently selected from C. 5-10 Cycloalkyl, 5-10 membered heterocyclic groups, wherein the heteroatoms of the 5-10 membered heterocyclic group are selected from N, O, or S, or combinations of two or three of them, wherein when the 5-10 membered heterocyclic group comprises two heteroatoms, the heteroatoms may be the same or different, and when the 5-10 membered heterocyclic group comprises three heteroatoms, the heteroatoms may be the same, partially the same, or completely different; optionally, the C 5-10The cycloalkyl group and the 5-10 membered heterocyclic group are each independently substituted by at least one substituent selected from group G; wherein, the C 5-10 The cycloalkyl group is substituted with at least one amino group, and the 5-10 membered heterocyclic group contains at least one nitrogen atom;

[0062] R2, R4, R6, R8, and R9 are each independently selected from hydrogen, deuterium, halogens, or C. 1-6 Alkyl; or

[0063] C forms between R1, R2 and their connected atoms; between R3, R4 and their connected atoms; between R5, R6 and their connected atoms; or between R7, R8 and their connected atoms. 5-10 Cycloalkyl, 5-10 membered heterocyclic groups, optionally C 5-10 The cycloalkyl group or 5-10 membered heterocyclic group is substituted by one or more of the following substituents: deuterium, -NH2, halogen, C 1-6 Alkyl, -OH, C 1-6 alkoxy; wherein, the C 5-10 The cycloalkyl group is substituted with at least one amino group, and the 5-10 membered heterocyclic group contains at least one nitrogen atom; or

[0064] C forms between R4, R9 and the atoms they are connected to. 8-10 cycloalkyl, 8-10 membered heterocyclic groups, optionally C 8-10 The cycloalkyl or 8-10 membered heterocyclic group is substituted with one or more substituents selected from group G; wherein, the C 8-10 The cycloalkyl group is substituted with at least one amino group, and the 8-10 membered heterocyclic group contains at least one nitrogen atom; when R4, R9 and the atoms attached to them form a C 8-10 R3 is absent when the group consists of cycloalkyl or 8-10 membered heterocyclic groups;

[0065] The condition is that formula (I) is not a compound, its isomer, isotopically labeled compound, prodrug, or a pharmaceutically acceptable salt, ester, hydrate, or solvate thereof:

[0066] In this invention, as one embodiment, the compound represented by formula (I), its isomers, isotopically labeled compounds, prodrugs, or pharmaceutically acceptable salts, esters, hydrates, or solvates thereof, wherein the compound represented by formula (I) is as follows:

[0067] Rings A, B, C, and D are each independently selected from: 5-6 membered heterocyclic groups, 5-6 membered aromatic heterogroups, or benzene rings, wherein the heteroatoms include N, O, S, or combinations of two or three thereof, and optionally each of the 5-6 membered heterocyclic group, 5-6 membered aromatic heterogroup, and benzene ring is independently substituted by at least one substituent selected from group G.

[0068] The group G is:

[0069] 1)C 1-6 Alkyl, wherein C 1-6 The alkyl group is optionally composed of one or more radicals independently selected from deuterium, halogen, hydroxyl, cyano, amino, or C. 1-6 Substitution of alkoxy groups;

[0070] 2) Deuterium;

[0071] 3)-NH2;

[0072] 4) Cyano group;

[0073] 5) Oxo (=O);

[0074] 6) Halogens;

[0075] 7) Hydroxyl group;

[0076] 8)C 1-6 Alkoxy, where C 1-6 The alkoxy group is optionally surrounded by one or more groups independently selected from deuterium, halogen, hydroxyl, cyano, amino, or C. 1-6 Substitution of alkoxy groups;

[0077] 9)C 3-10 cycloalkyl, wherein C 3-10 The cycloalkyl group is optionally composed of one or more radicals independently selected from deuterium, halogen, hydroxyl, cyano, amino, or C. 1-6 Substitution of alkoxy groups;

[0078] 10) A 3-12 membered heterocyclic group, wherein the 3-12 membered heterocyclic group is optionally composed of one or more independently selected from deuterium, halogen, hydroxyl, cyano, amino, or C. 1-6 Substitution of alkoxy groups;

[0079] L is selected from:

[0080] Preferably, L is selected from

[0081] X is -S(=O)2- or -CH2- or -H; when X is selected from -H, Y, R7, R8, and -CO-Rx do not exist;

[0082] Y is C or N; when Y is selected from N, one of R7 and R8 does not exist;

[0083] R X for or -OH;

[0084] R1, R3, R5, and R7 are each independently selected from: C 5-10 Cycloalkyl, 5-10 membered heterocyclic group, wherein the heteroatom comprises N, O, S or a combination of two or three of them; optionally, the C 5-10 The cycloalkyl group and the 5-10 membered heterocyclic group are each independently substituted by at least one substituent selected from group G, wherein the C 5-10 The cycloalkyl group is substituted with at least one amino group, and the 5-10 membered heterocyclic group contains at least one nitrogen atom;

[0085] R2, R4, R6, R8, and R9 are each independently selected from: hydrogen, deuterium, halogen, or carbon. 1-6 Alkyl; or

[0086] C forms between R1, R2 and their connected atoms; between R3, R4 and their connected atoms; between R5, R6 and their connected atoms; or between R7, R8 and their connected atoms. 5-10 Cycloalkyl, 5-10 membered heterocyclic groups, optionally C 5-10 The cycloalkyl group or 5-10 membered heterocyclic group is substituted by one or more of the following substituents: deuterium, -NH2, halogen, C 1-6 Alkyl, -OH, C 1-6 alkoxy; wherein, the C 5-10 The cycloalkyl group is substituted with at least one amino group, and the 5-10 membered heterocyclic group contains at least one nitrogen atom; or

[0087] C forms between R4, R9 and the atoms they are connected to. 8-10 cycloalkyl, 8-10 membered heterocyclic groups, optionally C 8-10 The cycloalkyl or 8-10 membered heterocyclic group is substituted with one or more substituents selected from group G; wherein, the C 8-10 The cycloalkyl group is substituted with at least one amino group, and the 8-10 membered heterocyclic group contains at least one nitrogen atom; when R4, R9 and the atoms attached to them form a C 8-10 R3 is absent when the group consists of cycloalkyl or 8-10 membered heterocyclic groups;

[0088] The condition is that formula (I) is not a compound, its isomer, isotopically labeled compound, prodrug, or a pharmaceutically acceptable salt, ester, hydrate, or solvate thereof:

[0089] In this invention, as one embodiment, the compound, its isomers, isotopically labeled compounds, prodrugs, or pharmaceutically acceptable salts, esters, hydrates, or solvates thereof, wherein the following conditions are met:

[0090] 1) At least one of rings A, B, C, and D is selected from 5-membered heteroaryl groups; or

[0091] 2) R4 and R9, together with the atoms they are bonded to, form C. 8-10 Fused bicyclic cycloalkyl or 8-10 fused bicyclic heterocyclic groups, and R3 is absent, optionally C 8-10 The fused bicyclic cycloalkyl group or the 8-10 membered fused bicyclic heterocyclic group is replaced by one or more substituents selected from group G, wherein the C 8-10 The fused bicyclic cycloalkyl group is at least substituted with an amino group, and the 8-10 fused bicyclic heterocyclic group contains at least one nitrogen atom; preferably, R4, R9 together with the atoms attached to them form an 8-10 fused bicyclic heterocyclic group, and R3 is absent; optionally, the 8-10 fused bicyclic heterocyclic group is substituted with one or more substituents selected from group G, wherein the 8-10 fused bicyclic heterocyclic group contains at least one nitrogen atom; more preferably, the 8-10 fused bicyclic heterocyclic group is selected from benzopyrrolidinyl, benzopiperidinyl, 5-6 fused heteroarylpyrrolidinyl, or 5-6 fused heteroarylpiperidinyl.

[0092] The compounds, isomers, isotopically labeled compounds, prodrugs, or pharmaceutically acceptable salts, esters, hydrates, or solvates thereof described in this invention have the following formula (II).

[0093] Wherein, n1, n2, n3, and n4 are each independently selected from 1, 2, or 3; preferably, n1 and n2 are both selected from 2, or one of n1 and n2 is selected from 1 and the other is selected from 2; preferably, n3 and n4 are both selected from 2, or one of n3 and n4 is selected from 1 and the other is selected from 2;

[0094] L, R1, R2, R4, R3, R9, ring A, ring B, ring C, and ring D are as defined in any embodiment of the present invention.

[0095] In this invention, as one embodiment, group G is selected from:

[0096] 1) Halogen;

[0097] 2)-NH2;

[0098] 3)-OH;

[0099] 4)C 1-6 Alkyl, wherein C 1-6The alkyl group may optionally be replaced by one or more halogens;

[0100] 5)C 1-6 Alkoxy, where C 1-6 The alkoxy group may optionally be substituted by one or more halogens;

[0101] 6)C 3-6 Saturated cycloalkyl groups.

[0102] In this invention, as one embodiment, group G is selected from:

[0103] 1) Halogens (e.g., F, Cl, preferably F);

[0104] 2)C 1-4 Alkyl (e.g., methyl).

[0105] In this invention, as one embodiment, group G is selected from:

[0106] 1)-CH3;

[0107] 2)-NH2;

[0108] 3) F or Cl;

[0109] 4)-OH;

[0110] 5)-OCH3

[0111] 6) Cyclopropyl.

[0112] In this invention, as one embodiment, group G is selected from one or more of the following groups:

[0113] 1)-CH3;

[0114] 2)-NH2;

[0115] 3) F or Cl; or

[0116] 4) -OH or -CH2-OH.

[0117] In this invention, as one embodiment, ring A, ring B, ring C, and ring D are each independently selected from 5-6-membered heteroaryl, phenyl, 9-10-membered heteroaryl, and 9-10-membered heterocyclic groups; the 5-6-membered heteroaryl, phenyl, 9-10-membered heteroaryl, and 9-10-membered heterocyclic groups are optionally each independently substituted by at least one substituent selected from group G; preferably, ring A, ring B, ring C, and ring D are each independently selected from phenyl, 5-6-membered monocyclic heteroaryl, 9-10-membered bicyclic heteroaryl, and benzo5-6-membered monocyclic heterocyclic groups; the phenyl, 5-6-membered monocyclic heteroaryl, 9-10-membered bicyclic heteroaryl, and benzo5-6-membered monocyclic heterocyclic groups are optionally each independently substituted by 1, 2, or 3 (preferably 1) substituents selected from group G;

[0118] Preferably, rings A, B, C, and D are each independently selected from... (Preferred) ),

[0119] in, Representing single or double bonds, and adjacent to each other. Not both are double bonds;

[0120] The key marked with "#" is connected to L;

[0121] The group in the structure shown in Q-1 is a 5-membered heteroaryl group, wherein Q1, Q2, and Q3 are each independently selected from CH, NH, N, S, and O, and at least one of Q1, Q2, and Q3 is selected from NH, N, S, and O; preferably, Q1 is selected from NH, O, and S, and Q2 and Q3 are each independently selected from CH and N; preferably, Q2 is N, Q1 is S, and Q3 is CH.

[0122] Q4, Q5, Q6, Q7, Q8, Q9, Q 10 Q 11 Q 12 Q 13 Q 14 Q 15 Q 16 Q 17 Q 18 Q 19 Q 20 Q 21 Each is independently selected from CH or N; preferably, Q4, Q5, Q6, and Q7 are all CH; preferably, one or two of Q4, Q5, Q6, and Q7 are N; preferably, Q8 and Q9 are both CH; preferably, Q 10 Q 11 Q 12 Q 13 One or both of them are N; preferably, Q 10 Q 13 Both are N, Q 11 Q 12 All are CH; preferably, Q 14 Q 15 All are CH; preferably, Q 16 Q 17 Q 18 All are CH; preferably, Q 19 Q 20 Q 21 All are CH;

[0123] t is selected from 1, 2, or 3; preferably t is selected from 1 or 2; preferably t is 1;

[0124] Each R G The substituent is independently selected from any substituent in group G, where j is selected from 0, 1, 2, 3, or 4;

[0125] Preferably, each R G Independently selected from deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl or 4-7 membered heterocyclic groups; preferably, each R G Independently selected from halogens (e.g., F, Cl, Br, I, preferably F, Cl), hydroxyl groups, C 1-4 Alkyl (e.g., methyl, ethyl, propyl, butyl, preferably methyl) or C 1-4 Alkyl groups (e.g., methoxy, ethoxy, propoxy, butoxy, preferably methoxy); preferably, each R G Independently selected from halogens (e.g., F, Cl, Br, I, preferably F and Cl), C 1-4 Alkyl (e.g., methyl, ethyl, propyl, butyl, preferably methyl) or C 1-4 Alkyl groups (e.g., methoxy, ethoxy, propoxy, butoxy, preferably methoxy); preferably, each R G Independently selected from halogens (e.g., F, Cl, Br, I, preferably F, Cl) or C 1-4 Alkyl groups (e.g., methyl, ethyl, propyl, butyl, preferably methyl); preferably, each R G It is a halogen (e.g., F, Cl, Br, I, preferably F);

[0126] Preferably, j is selected from 0 or 1; preferably, j is 0;

[0127] Preferably, rings A, B, C, and D are each independently selected from... (Preferred) ), Preferably, at least two of rings A, B, C, and D are selected from...

[0128] In this invention, as one of the embodiments, Preferred The key marked with "#" is connected to L.

[0129] In this invention, as one embodiment, ring A, ring B, ring C, and ring D are each independently selected from 5-6-membered heteroaryl or phenyl groups; each of the 5-6-membered heteroaryl or phenyl groups is independently substituted by at least one substituent selected from group G.

[0130] Preferably, rings A, B, C, and D are each independently selected from...

[0131] in, Representing single or double bonds, and adjacent to each other. Not both are double bonds;

[0132] The key marked with "#" is connected to L;

[0133] Q1, Q2, and Q3 are each independently selected from CH, NH, N, S, and O;

[0134] Q4, Q5, Q6, and Q7 are each independently selected from CH or N;

[0135] Each R G The substituent is selected from any substituent in group G, and j is selected from 0, 1, 2, 3 or 4;

[0136] Preferably, R G Selected from deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 4-7 membered heterocyclic groups; more preferably, R G Selected from halogens, hydroxyl groups, or C 1-6 alkyl;

[0137] Preferably, j is selected from 0 or 1.

[0138] In this invention, as one embodiment, the 5-6 aryl aromatic heterogroup is selected from pyrroleyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, triazolyl, oxadiazolyl, thiazolyl, pyridinyl or pyrimidinyl, preferably thiophenyl or thiazolyl.

[0139] In this invention, as one embodiment, rings A, B, C, and D are each independently selected from:

[0140] Preferably, rings A, B, C, and D are each independently selected from... The key marked with "#" is connected to L.

[0141] In this invention, as one embodiment, rings A, B, C, and D are each independently selected from:

[0142] The key marked with "#" is connected to L.

[0143] In this invention, as one embodiment, R9 is selected from hydrogen, deuterium, halogen, or C. 1-4 Alkyl group; preferably, R9 is selected from hydrogen, halogen or C 1-4 Alkyl group; preferably, R9 is hydrogen.

[0144] In this invention, as one embodiment, R1, R3, R5, and R7 are each independently selected from:

[0145] in,

[0146] Y1, Y 20 Y 21 Each is independently selected from CH or N;

[0147] Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, Y 10 Y 11 Y 12 Y 13 Y 19 Y 22 Y 23 Each atom is independently selected from CH2, NH, O, or S; no two adjacent atoms are heteroatoms at the same time;

[0148] Each R y Each was independently selected from C 1-6 Alkyl groups (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, preferably CH3), C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -NH2, halogen (e.g., F, Cl, Br, I, preferably F, Cl), or deuterium; e is selected from 0, 1, 2, 3 or 4;

[0149] Preferably, each R y Each was independently selected from C 1-6 Alkyl groups (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, preferably CH3), C 1-6 Alkoxy, C 3-6 Saturated cycloalkyl groups, 3-6 membered saturated heterocyclic groups, -NH2, halogens (e.g., F, Cl, Br, I, preferably F and Cl);

[0150] Preferably, e is selected from 0 or 1; more preferably, e is 0;

[0151] The condition is that the following conditions are met:

[0152] 1) When Y1 is selected from CH and Y2, Y3, Y4, Y5, and Y6 are selected from CH2, e is not 0, and at least one R is selected. y Selected from -NH2;

[0153] 2) When Y7, Y8, Y9, Y 10 When selected from CH2, e is not 0, and at least one R is selected. y Selected from -NH2;

[0154] 3) When Y1, Y2, Y3, Y4, Y5, and Y6 are not all carbon atoms, at least one of them must be selected from nitrogen heteroatoms;

[0155] 4) When Y7, Y8, Y9, Y 10 When they are not both carbon atoms, at least one of them must be selected from nitrogen heteroatoms;

[0156] 5)Y 11 Y 12 Y 13 At least one of them is selected from nitrogen heteroatoms;

[0157] 6)Y 19 Y 20 Y 21 Y 22 Y 23 At least one of them is selected from nitrogen heteroatoms; and / or

[0158] R2, R4, R6, and R8 are each independently selected from hydrogen, deuterium, halogens, or C. 1-4 Alkyl groups; and / or

[0159] R9 is selected from hydrogen, halogen, or C. 1-4 alkyl;

[0160] Preferably, R1, R3, R5, and R7 are each independently selected from... Wherein Y1 is selected from CH or N; Y3, Y4, and Y6 are each independently selected from CH2, NH, or O, and no two adjacent ring atoms are simultaneously selected from NH or O, and at least one of Y3, Y4, and Y6 is NH (preferably Y3 or Y4 is NH, more preferably Y4 is NH); each R y Independently selected from halogen or C 1-4 Alkyl; e is selected from 0 or 1, preferably e is 0; and / or

[0161] R2, R4, R6, and R8 are all hydrogen; and / or

[0162] R9 is selected from hydrogen, halogen, or C. 1-4 Alkyl group; preferably, R9 is hydrogen.

[0163] In this invention, as one embodiment, R1, R3, R5, and R7 are each independently selected from:

[0164] in,

[0165] Y1, Y 20 Y 21Each is independently selected from CH or N;

[0166] Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, Y 10 Y 11 Y 12 Y 13 Y 19 Y 22 Y 23 Each atom is independently selected from CH2, NH, O, or S; no two adjacent atoms are heteroatoms at the same time;

[0167] Each R y Each was independently selected from C 1-6 Alkyl (preferably CH3), C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -NH2, halogen (e.g., F, Cl) or deuterium; e is selected from 0, 1, 2, 3 or 4;

[0168] Preferably, each R y Each was independently selected from C 1-6 Alkyl (preferably CH3), C 1-6 Alkoxy groups, C3-6 saturated cycloalkyl groups, 3-6 membered saturated heterocyclic groups, -NH2, halogens (e.g., F, Cl);

[0169] Preferably, e is selected from 0 or 1; more preferably, e is selected from 0;

[0170] The condition is that the following conditions are met:

[0171] 1) When Y1 is selected from CH and Y2, Y3, Y4, Y5, and Y6 are selected from CH2, e is not 0, and at least one R is selected. y Selected from -NH2;

[0172] 2) When Y7, Y8, Y9, Y 10 When selected from CH2, e is not 0, and at least one R is selected. y Selected from -NH2;

[0173] 3) When Y1, Y2, Y3, Y4, Y5, and Y6 are not all carbon atoms, at least one of them must be selected from nitrogen heteroatoms;

[0174] 4) When Y7, Y8, Y9, Y 10 When they are not both carbon atoms, at least one of them must be selected from nitrogen heteroatoms;

[0175] 5)Y 11 Y 12 Y 13 At least one of them is selected from nitrogen heteroatoms;

[0176] 6)Y19 Y 20 Y 21 Y 22 Y 23 At least one of them is selected from nitrogen heteroatoms.

[0177] In this invention, as one embodiment, R1, R3, R5, and R7 are each independently selected from:

[0178] in,

[0179] Cyclop P is selected from 5-6 member monocyclic heterocyclic groups, C 3-6 Monocyclic cycloalkyl;

[0180] Ring E is selected from 4-6 member monocyclic heterocyclic groups, C 3-6 Monocyclic cycloalkyl;

[0181] Ring F is selected from 4-6 member monocyclic heterocyclic groups, C 3-6 Monocyclic cycloalkyl;

[0182] Ring H is selected from 4-6 member monocyclic heterocyclic groups, C 3-6 Monocyclic cycloalkyl;

[0183] Each R P R E R F R H Each was independently selected from C 1-6 Alkyl groups (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, preferably CH3), C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -NH2, halogen (e.g., F, Cl, Br, I, preferably F, Cl), deuterium, e selected from 0, 1, 2, 3, 4;

[0184] Preferably, each R P R E R F R H Each was independently selected from C 1-6 Alkyl groups (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, preferably CH3), C 1-6 Alkoxy, C 3-6 Saturated cycloalkyl groups, 3-6 membered saturated heterocyclic groups, -NH2, halogens (e.g., F, Cl, Br, I, preferably F and Cl);

[0185] Preferably, e is selected from 0 or 1, more preferably, e is selected from 0;

[0186] The condition is that the following conditions are met:

[0187] 1) When both ring P and ring E are cycloalkyl, e is not 0, and at least one of ring P or ring E is substituted by an amino group;

[0188] 2) When both ring F and ring H are cycloalkyl, e is not 0, and at least one of ring F or ring H is substituted by an amino group;

[0189] 3) When ring P and ring E are not both cycloalkyl, at least one of ring P and ring E is a nitrogen-containing heterocyclic group;

[0190] 4) When ring F and ring H are not both cycloalkyl, at least one of ring F and ring H is a nitrogen-containing heterocyclic group;

[0191] Preferably,

[0192] Cyclone P is selected from 5-6 member saturated monocyclic heterocyclic groups, C 5-6 Saturated monocyclic cycloalkyl; more preferably C 5-6 Saturated monocyclic cycloalkyl groups;

[0193] Ring E is selected from 5-6 member saturated monocyclic heterocyclic groups, C 5-6 Saturated monocyclic cycloalkyl groups; more preferably, 5-6 membered saturated nitrogen-containing monocyclic heterocyclic groups;

[0194] Ring F is selected from 4-6 member saturated monocyclic heterocyclic groups, C 4-6 Saturated monocyclic cycloalkyl groups; more preferably 4-6 membered saturated nitrogen-containing monocyclic heterocyclic groups, C 4-6 Saturated monocyclic cycloalkyl groups;

[0195] Ring H is selected from 4-6 member saturated monocyclic heterocyclic groups, C 3-6 Saturated monocyclic cycloalkyl groups; more preferably 4-6 membered saturated nitrogen-containing monocyclic heterocyclic groups, C 3-6 Saturated monocyclic cycloalkyl groups;

[0196] Preferably,

[0197] Ring P is selected from C 5-6 Saturated monocyclic cycloalkyl groups, wherein ring E is selected from 5-6 membered saturated nitrogen-containing monocyclic heterocyclic groups;

[0198] Ring F is selected from 4-6 member saturated nitrogen-containing monocyclic heterocyclic groups and ring H is selected from C. 3-6 Saturated monocyclic cycloalkyl, or ring F selected from C 4-6 Saturated monocyclic cycloalkyl groups with ring H selected from 4-6 membered saturated nitrogen-containing monocyclic heterocyclic groups; and / or

[0199] R2, R4, R6, and R8 are each independently selected from hydrogen, deuterium, halogens, or C. 1-4 Alkyl groups; and / or

[0200] R9 is selected from hydrogen, halogen, or C. 1-4 Alkyl group, preferably, R9 is hydrogen.

[0201] In this invention, as one embodiment, R1, R2 and their connected atoms, R3, R4 and their connected atoms, R5, R6 and their connected atoms, or R7, R8 and their connected atoms together form the following rings:

[0202] in,

[0203] Cyclop P is selected from 5-6 member monocyclic heterocyclic groups, C 3-6 Monocyclic cycloalkyl;

[0204] Ring E is selected from 4-6 member monocyclic heterocyclic groups, C 3-6 Monocyclic cycloalkyl;

[0205] Ring F is selected from 4-6 member monocyclic heterocyclic groups, C 3-6 Monocyclic cycloalkyl;

[0206] Ring H is selected from 4-6 member monocyclic heterocyclic groups, C 3-6 Monocyclic cycloalkyl;

[0207] Each R P R E R F R H Each was independently selected from C 1-6 Alkyl (preferably CH3), C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups, -NH2, halogens (e.g., F, Cl), deuterium; e is selected from 0, 1, 2, 3, 4;

[0208] Preferably, each R P R E R F R H Each was independently selected from C 1-6 Alkyl (preferably CH3), C 1-6 Alkoxy groups, C3-6 saturated cycloalkyl groups, 3-6 membered saturated heterocyclic groups, -NH2, halogens (e.g., F, Cl);

[0209] Preferably, e is selected from 0 or 1, more preferably, e is selected from 0;

[0210] The condition is that the following conditions are met:

[0211] 1) When both ring P and ring E are cycloalkyl, e is not 0, and at least one of ring P or ring E is substituted by an amino group;

[0212] 2) When both ring F and ring H are cycloalkyl, e is not 0, and at least one of ring F or ring H is substituted by an amino group;

[0213] 3) When ring P and ring E are not both cycloalkyl, at least one of ring P and ring E is a nitrogen-containing heterocyclic group;

[0214] 4) When ring F and ring H are not both cycloalkyl, at least one of ring F and ring H is a nitrogen-containing heterocyclic group;

[0215] Preferably,

[0216] Ring P is selected from C 5-6 Saturated monocyclic cycloalkyl groups, wherein ring E is selected from 5-6 membered saturated nitrogen-containing monocyclic heterocyclic groups;

[0217] Ring F is selected from 4-6 member saturated nitrogen-containing monocyclic heterocyclic groups and ring H is selected from C. 3-6 Saturated monocyclic cycloalkyl, or ring F selected from C 4-6 Saturated monocyclic cycloalkyl groups with ring H selected from 4-6 membered saturated nitrogen-containing monocyclic heterocyclic groups; and / or

[0218] R9 is selected from hydrogen, halogen, or C. 1-4 Alkyl group, preferably, R9 is hydrogen.

[0219] In this invention, as one embodiment, R1, R3, R5, and R7 are each independently selected from: and / or

[0220] R2, R4, R6, and R8 are each independently selected from hydrogen, halogen, or C. 1-4 Alkyl groups; and / or

[0221] R9 is selected from hydrogen, halogen, or C. 1-4 Alkyl group; preferably, R9 is hydrogen.

[0222] In this invention, as one embodiment, R1, R3, R5, and R7 are each independently selected from: Preferably, at least two of R1, R3, R5, and R7 are and / or

[0223] R2, R4, R6, and R8 are all hydrogen; and / or

[0224] R9 is selected from hydrogen, halogen, or C. 1-4 Alkyl group; preferably, R9 is hydrogen.

[0225] In this invention, as one embodiment, the following rings are formed between R1, R2 and their connected atoms, between R3, R4 and their connected atoms, between R5, R6 and their connected atoms, or between R7, R8 and their connected atoms: and / or

[0226] R9 is selected from hydrogen, halogen, or C. 1-4 Alkyl group; preferably, R9 is hydrogen.

[0227] In this invention, as one embodiment, R4, R9 and their connected atoms form the following rings:

[0228] (For example )or

[0229] The key marked with "#" is connected to ring B;

[0230] B1, B2, B3, B6, B7, B8, B9, B 12 B 13 B 14 B 15 B 16 B 17 B 18 B 19 B 20 B 21 B 22 B 23 B 24 B 26 B 27 B 28 Each atom is independently selected from CH2, NH, S, or O, and adjacent atoms are not simultaneously selected from heteroatoms;

[0231] B4, B5, B 10 B 11 Each is independently selected from CH or N; preferably, B4 and B5 are both CH; preferably, B4 is CH and B5 is N, or B4 is N and B5 is CH; preferably, B4 and B5 are both N; preferably, B 10 B 11 All are CH; preferably, B 10 For CH, B 11 For N, or B 10 For N, B 11 CH; preferably, B 10 B 11 All are N;

[0232] Each R G Each substituent is independently selected from any substituent in group G, and i is selected from 0, 1, or 2;

[0233] The following conditions must be met:

[0234] 1) At least one of B1, B2, and B3 is selected from NH;

[0235] 2) At least one of B6, B7, B8, and B9 is selected from NH;

[0236] 3)B12 B 13 B 14 B 15 At least one of them is selected from NH;

[0237] 4)B 17 B 18 B 19 At least one of them is selected from NH;

[0238] 5)B 21 B 22 B 23 B 24 At least one of them is selected from NH;

[0239] 6)B 26 B 27 B 28 At least one of them is selected from NH;

[0240] Preferably, one of B1, B2, and B3 is selected from NH, and the others are selected from CH2; one of B6, B7, B8, and B9 is selected from NH, and the others are selected from CH2; B 12 B 13 B 14 B 15 One of them is selected from NH, and the rest are selected from CH2; B 17 B 18 B 19 One of them is selected from NH, and the rest are selected from CH2; B 21 B 22 B 23 B 24 One of them is selected from NH, and the rest are selected from CH2; B 26 B 27 B 28 One of them is selected from NH, and the rest are selected from CH2;

[0241] Preferably, B 16 B 20 Each is independently selected from NH, S, or O; preferably, B 16 B 20 S;

[0242] Preferably, each R G Independently selected from halogens, hydroxyl groups, and C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 4-7 membered heterocyclic groups; preferably, each R G Independently selected from halogens, hydroxyl groups, and C 1-4 Alkyl, C1-4 Alkoxy, C 3-6 Saturated cycloalkyl; preferably, each R G Independently selected from halogens (e.g., F, Cl, Br, I, preferably F, Cl) or C 1-4 Alkyl groups (e.g., methyl, ethyl, propyl, butyl, preferably methyl); preferably, each R G It is a halogen (e.g., F, Cl, Br, I, preferably F);

[0243] Preferably, i is selected from 0 or 1; more preferably, i is selected from 0;

[0244] Preferably, R4, R9 and the atoms they are connected to form the following rings: Preferred Preferred More The key marked with "#" is connected to ring B.

[0245] In this invention, as one embodiment, the compound, its isomers, isotopically labeled compounds, prodrugs, or pharmaceutically acceptable salts, esters, hydrates, or solvates thereof, are characterized in that R4, R9, and the atoms they are attached to form the following rings:

[0246] The key marked with "#" is connected to ring B;

[0247] B1, B2, B3, B6, B7, B8, B9, B 12 B 13 B 14 B 15 B 16 B 17 B 18 B 19 B 20 B 21 B 22 B 23 B 26 B 27 B 28 Each atom is independently selected from CH2, NH, S, and O, and adjacent atoms are not simultaneously selected from heteroatoms; B4, B5, B 10 B 11 Each is independently selected from CH or N;

[0248] Each R G Each substituent is independently selected from any substituent in group G, and i is selected from 0, 1, or 2;

[0249] The following conditions must be met:

[0250] 1) At least one of B1, B2, and B3 is selected from NH;

[0251] 2) At least one of B6, B7, B8, and B9 is selected from NH;

[0252] 3)B 12 B 13 B 14 B 15 At least one of them is selected from NH;

[0253] 4)B 17 B 18 B 19 At least one of them is selected from NH;

[0254] 5)B 21 B 22 B 23 At least one of them is selected from NH;

[0255] 6)B 26 B 27 B 28 At least one of them is selected from NH;

[0256] Preferably, one of B1, B2, and B3 is selected from NH, and the others are selected from CH2; one of B6, B7, B8, and B9 is selected from NH, and the others are selected from CH2; B 12 B 13 B 14 B 15 One of them is selected from NH, and the rest are selected from CH2; B 17 B 18 B 19 One of them is selected from NH, and the rest are selected from CH2; B 21 B 22 B 23 One of them is selected from NH, and the rest are selected from CH2; B 26 B 27 B 28 One of them is selected from NH, and the rest are selected from CH2;

[0257] Preferably, R G Selected from halogens, hydroxyl groups, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 4-7 membered heterocyclic groups; more preferably, R G Selected from halogens, hydroxyl groups, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl;

[0258] Preferably, i is selected from 0 or 1; more preferably, i is selected from 0.

[0259] In this invention, as one embodiment, the compound, its isomers, isotopically labeled compounds, prodrugs, or pharmaceutically acceptable salts, esters, hydrates, or solvates thereof, wherein R4, R9 and the atoms attached to them form the following rings:

[0260] Preferred Preferred More The key marked with "#" is connected to ring B.

[0261] In this invention, as one embodiment, L is selected from:

[0262] Preferably, L is selected from

[0263] Preferably, L is selected from

[0264] Preferably, L is selected from

[0265] Preferably, L is selected from

[0266] Preferably, L is selected from

[0267] Preferably, L is selected from

[0268] Preferably, L is selected from

[0269] More preferably, L is selected from The key marked "#A" is connected to ring A, the key marked "#B" is connected to ring B, the key marked "#C" is connected to ring C, and the key marked "#D" is connected to ring D.

[0270] In this invention, as one embodiment, the compound, its isomers, isotopically labeled compounds, prodrugs, or pharmaceutically acceptable salts, esters, hydrates, or solvates thereof, wherein,

[0271] L is selected from:

[0272] Preferably, L is selected from The key marked "#A" is connected to ring A, the key marked "#B" is connected to ring B, the key marked "#C" is connected to ring C, and the key marked "#D" is connected to ring D.

[0273] In this invention, as one embodiment, the compound, its isomers, isotopically labeled compounds, prodrugs, or pharmaceutically acceptable salts, esters, hydrates, or solvates thereof are further shown as any of the following structures (II-1) to (II-14):

[0274] Wherein, n5 and n6 are each independently selected from 1, 2 or 3. Preferably, both n5 and n6 are selected from 2, or one of n5 and n6 is selected from 1 and the other is selected from 2.

[0275] m1, m2, m3, and m4 are each independently selected from 0, 1, or 2. Preferably, m1, m2, m3, and m4 are each independently selected from 0 or 1. More preferably, one of m1 and m2 is selected from 0 and the other is selected from 1, and one of m3 and m4 is selected from 0 and the other is selected from 1.

[0276] n1, n2, n3, and n4 are as defined in any embodiment of the present invention;

[0277] R3, R4, R9, A, B, C, and D are as defined in any embodiment of the present invention;

[0278] Preferably, three of rings A, B, C, and D are selected from... The remaining one is selected from Among them, Q1, Q2, Q3, and R G As defined in any embodiment of the present invention, the key marked with "#" is connected to the corresponding L;

[0279] Preferably, two of rings A, B, C, and D are selected from... The remaining two are selected from Among them, Q1, Q2, Q3, and R G As defined in any embodiment of the present invention, the key marked with "#" is connected to the corresponding L;

[0280] Preferably, rings A, B, C, and D are all selected from...

[0281] Preferably, two of rings A, B, C, and D are selected from... The remaining two are selected from Among them, Q1-Q3, Q8-Q 13 R G As defined in any embodiment of the present invention, the key marked with "#" is connected to the corresponding L;

[0282] Preferably, two of rings A, B, C, and D are selected from... The remaining two are selected from and / or Among them, Q1-Q3, Q 14 -Q 15 R G As defined in any embodiment of the present invention, the keys marked with "#" are connected to the corresponding L;

[0283] Preferably, rings A, B, C, and D are all selected from...

[0284] Preferably, R4, R9 and the atoms they are connected to form Among them, B1, B2, B3, and R G As defined in any embodiment of the present invention, the key identified by "#" is connected to ring B.

[0285] In this invention, as one embodiment, the compound of this invention is shown in formula (Ⅲ'):

[0286] in, Representing single or double bonds, and adjacent to each other. Not both are double bonds;

[0287] R1, R2, R3, R4, and R9 are as defined in any embodiment of the present invention;

[0288] Q1, Q2, and Q3 are as defined in any embodiment of the present invention.

[0289] In this invention, as one embodiment, the compound, its isomers, isotopically labeled compounds, prodrugs, or pharmaceutically acceptable salts, esters, hydrates, or solvates thereof, further comprises compounds represented by formula (Ⅲ).

[0290] in,

[0291] Representing single or double bonds, and adjacent to each other. Not both are double bonds;

[0292] R1, R2, R3, R4, and R9 are as defined in any embodiment of the present invention;

[0293] Q1, Q2, and Q3 are as defined in any embodiment of the present invention.

[0294] In this invention, as one embodiment, the compound described herein has any structure of formula (IV-1) to (IV-8):

[0295] Among them, n1, n2, n3, n4, n5, n6, A, B, C, D, R G i, B4, B5, B 10 B 11 B 16 As defined in any embodiment of the present invention;

[0296] Preferably, one of n1 and n2 is selected from 1, and the other is selected from 2;

[0297] Preferably, one of n3 and n4 is selected from 1, and the other is selected from 2;

[0298] Preferably, one of n5 and n6 is selected from 1, and the other is selected from 2;

[0299] Preferably, n1 and n2 are both selected from 1;

[0300] Preferably, n3 and n4 are both selected from 1; or

[0301] Preferably, n5 and n6 are both selected from 1;

[0302] Preferably, ring B is

[0303] Preferred ring B is

[0304] More preferably, ring B is

[0305] Preferably, ring A is (Preferred) ),

[0306] Preferred ring A is selected from

[0307] Preferred ring A is selected from

[0308] Preferred ring A is selected from

[0309] Preferred ring A is selected from

[0310] Preferred ring A is selected from

[0311] Preferred ring A is selected from

[0312] More preferably, ring A is

[0313] Preferably, ring C and ring D are selected from...

[0314] The preferred rings C and D are each selected independently.

[0315] The preferred rings C and D are each selected independently.

[0316] More preferably, C and ring D are selected from

[0317] Preferably, each R G Independently selected from halogens (e.g., F, Cl) or C 1-4 Alkyl (e.g., methyl); more preferably, each R G Halogens (e.g., F);

[0318] Preferably, i is selected from 0 or 1; more preferably, i is 0;

[0319] Preferably, B4, B5, B 10 B 11 All are CH;

[0320] The key marked with "#" is connected to the corresponding L;

[0321] Q1-Q 15 R G j and t are as defined in any embodiment of the present invention.

[0322] In this invention, as one embodiment, B4 and B5 are both CH, or B4 is CH and B5 is N, or B4 is N and B5 is CH; preferably, B4 and B5 are both CH.

[0323] In this invention, as one of the embodiments, B 10 B 11 Both are CH, or B 10 For CH, B 11 For N, or B 10 For N, B 11CH; preferably, B 10 B 11 Both are CH, or B 10 For CH, B 11 N; preferably, B 10 B 11 All are CH.

[0324] In this invention, as one embodiment, the compound described herein has any one of the structures shown as (IV-3-1), (IV-4-1), (IV-5-1), (IV-7-1), or (IV-8-1):

[0325] Among them, n1, n2, n3, n4, n5, n6, A, Q4, Q5, Q6, Q7, B4, B5, B 10 B 11 B 16 R G i, j are as defined in any embodiment of the present invention.

[0326] In this invention, as one embodiment, the compound described herein has any structure as shown in formula (V-1) to (V-3):

[0327] Wherein, n7 and n8 are each independently selected from 1, 2 or 3; preferably, n7 and n8 are each independently selected from 1 or 2; preferably, n7 and n8 are both 2; preferably, one of n7 and n8 is 1 and the other is 2;

[0328] n1, n2, n3, n4, n5, n6, A, B, C, D are as defined in any embodiment of the present invention;

[0329] Preferably, in at least two of the groups n1 and n2, n3 and n4, n5 and n6, and n7 and n8, the variable is 1 and the variable is 2, and in at least one group, both variables are 2.

[0330] Preferably, one of n5 and n6 is 1 and the other is 2; one of n7 and n8 is 1 and the other is 2; one of n3 and n4 is 1 and the other is 2; and both n1 and n2 are 2.

[0331] Preferably, one of n5 and n6 is 1 and the other is 2; one of n7 and n8 is 1 and the other is 2; one of n1 and n2 is 1 and the other is 2; and both n3 and n4 are 2.

[0332] Preferably, one of n5 and n6 is 1 and the other is 2; one of n7 and n8 is 1 and the other is 2; n1 and n2 are both 2; n3 and n4 are both 2.

[0333] Preferably, one of n5 and n6 is 1 and the other is 2; both n7 and n8 are 2; one of n3 and n4 is 1 and the other is 2; one of n1 and n2 is 1 and the other is 2.

[0334] Preferably, n5 and n6 are both 2; one of n7 and n8 is 1 and the other is 2; one of n3 and n4 is 1 and the other is 2; one of n1 and n2 is 1 and the other is 2.

[0335] Preferably, rings A, B, C, and D are each independently selected from... (Preferred) ),

[0336] Preferably, rings A, B, C, and D are each independently selected from... (Preferred) ), And at least two of rings A, B, C, and D are selected from

[0337] Preferably, rings A and B are each independently selected from... One of rings C and D is selected from (Preferred) The other is selected from (Preferred) ), Preferably, rings A and B are each independently selected from... One of rings C and D is selected from The other one is selected from

[0338] Preferably, rings A and B are each independently selected from... One of rings C and D is selected from (Preferred) The other is selected from Preferably, rings A and B are each independently selected from... One of rings C and D is selected from The other one is selected from Preferably, rings A and B are each independently selected from... One of rings C and D is selected from The other one is selected from

[0339] Preferably, rings C and D are each independently selected from... One of rings A and B is selected from (Preferred) The other is selected from (Preferred) ), Preferably, rings C and D are each independently selected from... One of rings A and B is selected from The other one is selected from

[0340] Preferably, rings C and D are each independently selected from... One of rings A and B is selected from (Preferred) The other is selected from Preferably, rings C and D are each independently selected from... One of rings A and B is selected from The other one is selected from

[0341] The key marked with "#" is connected to the corresponding L;

[0342] Q1-Q 15 R G j and t are as defined in any embodiment of the present invention.

[0343] In this invention, as one embodiment, the compound described herein has any structure of formula (VI-1) to (VI-3):

[0344] Wherein, n1, n2, n3, n4, C, Q1, Q2, and Q3 are as defined in any embodiment of the present invention;

[0345] Preferably, n1 and n2 are both 2, and one of n3 and n4 is 1 and the other is 2; or one of n1 and n2 is 1 and the other is 2, and both n3 and n4 are 2.

[0346] Preferably, in the general formulas (VI-1) to (VI-3), Q2 is N, Q1 is S, and Q3 is CH;

[0347] Preferably, ring C is selected from (Preferred) ), The keys marked with "#" are connected to L; Q1-Q 15 R Gj and t are as defined in any embodiment of the present invention; preferably, ring C is selected from

[0348] In this invention, as one embodiment, the compound described herein has any structure of formula (VII-1) to (VII-7):

[0349] Among them, n1, n2, n3, n4, n5, n6, n7, n8, Q1, Q2, Q3, Q4, Q5, Q6, Q7, R G j is as defined in any embodiment of the present invention;

[0350] Preferably, in at least two of the groups n1 and n2, n3 and n4, n5 and n6, and n7 and n8, the variable is 1 and the variable is 2, and in at least one group, both variables are 2.

[0351] Preferably, one of n5 and n6 is 1 and the other is 2; one of n7 and n8 is 1 and the other is 2; one of n3 and n4 is 1 and the other is 2; and both n1 and n2 are 2.

[0352] Preferably, one of n5 and n6 is 1 and the other is 2; one of n7 and n8 is 1 and the other is 2; one of n1 and n2 is 1 and the other is 2; and both n3 and n4 are 2.

[0353] Preferably, one of n5 and n6 is 1 and the other is 2; one of n7 and n8 is 1 and the other is 2; n1 and n2 are both 2; n3 and n4 are both 2.

[0354] Preferably, one of n5 and n6 is 1 and the other is 2; both n7 and n8 are 2; one of n3 and n4 is 1 and the other is 2; one of n1 and n2 is 1 and the other is 2.

[0355] Preferably, n5 and n6 are both 2; one of n7 and n8 is 1 and the other is 2; one of n3 and n4 is 1 and the other is 2; one of n1 and n2 is 1 and the other is 2.

[0356] Preferably, ring C is selected from (Preferred) ), Preferably, ring C is selected from More preferably, ring C is selected from

[0357] Preferably, ring A is selected from (Preferred) ), Preferably, ring A is selected from

[0358] Preferably, Q1 is selected from NH, O and S, and Q2 and Q3 are each independently selected from CH and N; preferably, Q2 is N, Q1 is S, and Q3 is CH.

[0359] Preferably, Q4, Q5, Q6, and Q7 are all CH;

[0360] Preferably, both Q8 and Q9 are CH;

[0361] Preferably, Q 10 Q 11 Q 12 Q 13 One or both of them are N; preferably, Q 10 Q 13 Both are N, Q 11 Q 12 All are CH;

[0362] Preferably, Q 14 Q 15 All are CH;

[0363] Preferably, t is selected from 1 or 2; preferably, t is 1.

[0364] Preferably, each R G Independently selected from halogens (e.g., F, Cl, Br, I, preferably F, Cl) or C 1-4 Alkyl groups (e.g., methyl, ethyl, propyl, butyl, preferably methyl); preferably, each R G It is a halogen (e.g., F, Cl, Br, I, preferably F or Cl, more preferably F);

[0365] Preferably, j is selected from 0 or 1; preferably, j is 0;

[0366] The key marked with "#" is connected to the corresponding L.

[0367] In this invention, as one embodiment, the compound, its isomers, isotope-labeled compounds, prodrugs, or pharmaceutically acceptable salts, esters, hydrates, or solvates thereof are selected from:

[0368] In this invention, as one embodiment, the compound, its isomers, isotope-labeled compounds, prodrugs, or pharmaceutically acceptable salts, esters, hydrates, or solvates thereof are selected from:

[0369] In this invention, as one embodiment, the compound, its isomers, isotope-labeled compounds, prodrugs, or pharmaceutically acceptable salts, esters, hydrates, or solvates thereof are selected from:

[0370] In this invention, as one embodiment, the compound, its isomers, isotope-labeled compounds, prodrugs, or pharmaceutically acceptable salts, esters, hydrates, or solvates thereof are selected from:

[0371] The present invention provides a pharmaceutical composition comprising any of the compounds described above, their isomers, isotopically labeled compounds, prodrugs, or pharmaceutically acceptable salts, esters, hydrates or solvates thereof, and pharmaceutically acceptable carriers, diluents or excipients.

[0372] The present invention provides the use of the above-described compounds, their isomers, isotopically labeled compounds, prodrugs, or pharmaceutically acceptable salts, esters, hydrates or solvates thereof, and the above-described pharmaceutical compositions in the preparation of medicaments for the prevention and / or treatment of diseases associated with lowering Lp(a) levels.

[0373] The present invention provides a method for preventing and / or treating diseases associated with lowering Lp(a) levels, the method comprising administering to an individual in need a preventive or therapeutically effective amount of the compound of the present invention, its isomers, isotopically labeled compounds, prodrugs, or pharmaceutically acceptable salts, esters, hydrates or solvates thereof, or pharmaceutical compositions of the present invention.

[0374] The compounds, isomers thereof, isotopically labeled compounds, prodrugs, or pharmaceutically acceptable salts, esters, hydrates or solvates thereof, or pharmaceutical compositions thereof, are used for the prevention and / or treatment of diseases associated with lowering Lp(a) levels.

[0375] In this invention, as one embodiment, the disease associated with reducing Lp(a) levels is a cardiovascular disease, including but not limited to atherosclerosis, stroke, hyperlipidemia, elevated Lp(a) levels, thrombosis, coronary heart disease, aortic stenosis, etc.

[0376] The elevated Lp(a) level refers to a plasma Lp(a) level greater than or equal to approximately 30 mg / dL or 75 nmol / L.

[0377] Compared to the previously disclosed reference compound 1, the compounds of the present invention, such as compounds 4, 10, 13, and 19, have significantly better PK (plasma and liver exposure), as well as better Lp(a) assembly inhibition activity and Lp(a) selectivity.

[0378] Compared with existing technologies, the present invention has superior Lp(a) assembly inhibition activity, Lp(a) selectivity, pharmacokinetic properties (oral bioavailability, drug plasma exposure and liver exposure, etc.) and OxPL-Apo(a) inhibitory activity.

[0379] Any embodiment or implementation of any aspect of the present invention may be combined with other embodiments or implementations, as long as they do not contradict each other. Furthermore, any technical feature in any embodiment or implementation of any aspect of the present invention may be applied to the same technical feature in other embodiments or implementations, as long as they do not contradict each other.

[0380] Terminology Explanation

[0381] The term "isomer" refers to compounds with the same chemical composition but different structures and properties, including but not limited to enantiomers, diastereomers, racemates, stereoisomers, tautomers, and geometric isomers.

[0382] The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule. It can be divided into two types: cis-trans isomers and enantiomers, or further into two main categories: enantiomers and diastereomers.

[0383] The term "tautomer" refers to a functional group isomer that is produced by the rapid movement of an atom in a molecule between two positions.

[0384] The term "diastereomer" refers to a stereoisomer of a molecule that has two or more chiral centers and is not a mirror image of the molecule.

[0385] The term "racemate" refers to an equimolar mixture of two enantiomers that lack optical activity.

[0386] The term "cis-trans isomers" refers to stereoisomers formed because the two carbon atoms connected by a double bond cannot rotate freely around the σ bond. They are divided into cis isomers and trans isomers: cis isomers are those where the two identical atoms or groups are on the same side of the double bond; trans isomers are those where the two identical atoms or groups are on opposite sides of the double bond.

[0387] The term "isotope-labeled compound" refers to a compound in which one or more atoms in its molecule are replaced by its isotope or other easily identifiable nuclide.

[0388] The term "alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group, with C0 as the base group. 1-6 For example, alkyl groups are straight-chain or branched groups with 1-6 carbon atoms, including but not limited to aliphatic alkyl groups such as methyl, ethyl, propyl, pentyl, hexyl, tert-butyl, sec-butyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, 1-ethyl-2-methylpropyl, and 1,1,2-trimethylpropyl.

[0389] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic carbon chain group, for example, having 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, including but not limited to cyclopropane, cyclobutane, cyclopentane, and cyclohexane. The cycloalkyl group includes fused rings, spiro rings, bridged rings, and combinations thereof. Cycloalkyl groups include aryl-fused cycloalkyl groups, provided the entire ring system is non-aromatic, for example...

[0390] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group, for example, having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 ring atoms, wherein one or more (e.g., 1, 2, 3, 4, 5, or 6) ring atoms are each independently selected from nitrogen, oxygen, sulfur, or phosphorus (preferably nitrogen, oxygen, or sulfur), and the remaining ring atoms are carbon. The heterocyclic group includes fused rings, spirocyclic rings, bridged rings (e.g., 6-9 membered bridged ring heterocyclic groups), and combinations thereof; the heterocyclic group includes monocyclic heterocyclic groups and groups with at least one heterocyclic ring in polycyclic (e.g., bicyclic, tricyclic) groups. Heterocyclic groups include aryl-fused heterocyclic groups, heteroaryl-fused heterocyclic groups, or heteroaryl-fused cycloalkyl groups, provided that the entire ring system is non-aromatic, for example...

[0391] The term "spirocyclic" refers to a saturated or partially unsaturated bicyclic or polycyclic (e.g., tricyclic) group, wherein any one of the rings shares a carbon atom with at least one of the other rings.

[0392] The term "bridged ring" refers to a saturated or partially unsaturated bicyclic or polycyclic (e.g., tricyclic) group, wherein any one of the rings shares three or more ring atoms with at least one of the other rings.

[0393] The term "aromatic heteroaryl" (also known as "heteroaryl") refers to a monocyclic or fused polycyclic group (i.e., a ring sharing adjacent ring edges) having a conjugated π-electron system and containing a heteroatom on the ring, wherein the heteroatom is selected from oxygen, sulfur, and nitrogen. Examples include 5-14 membered heteroaryl groups, preferably 5-10 membered heteroaryl groups, such as imidazolyl, furanyl, thiophene, thiazolyl, pyrazolyl, oxazolyl, pyrroleyl, tetrazolyl, pyridinyl, pyrimidinyl, thiadiazole, pyrazinyl, carbazole, indolyl, etc., preferably imidazolyl, pyrazolyl, pyrimidinyl, or thiazolyl; more preferably pyrazolyl or thiazolyl. "Heteroaromatic ring" (also known as "aromatic heterocyclic ring") refers to the ring system within the heteroaryl group.

[0394] The term "alkoxy" refers to -O-alkyl, where alkyl is defined as described above, including but not limited to methoxy, ethoxy, propoxy, butoxy, etc.

[0395] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group with a conjugated π-electron system, preferably 6-10 members, such as phenyl and naphthyl. "Aromatic ring" refers to the ring system within the aryl group.

[0396] The term "halogenated" refers to a group that can be replaced by any one or more F, Cl, Br, or I atoms.

[0397] The term "prodrug" refers to a compound obtained by those skilled in the art through chemical structural modification, which is inactive or has low activity in vitro, but releases the active pharmaceutical ingredient of the present invention through enzymatic or non-enzymatic conversion in vivo to exert its pharmacological effect. This includes, but is not limited to, all prodrugs of the present invention that, when administered to humans or animals, can (directly or indirectly) provide the compound of the present invention or its active metabolites or residues.

[0398] The “pharmaceuticalally acceptable solvate” includes, but is not limited to, solvents such as water, ethanol, acetic acid, N,N-dimethylformamide, dimethyl sulfoxide, isopropanol, acetonitrile, tetrahydrofuran, acetone, or propylene glycol. Detailed Implementation

[0399] The following examples are provided to further illustrate the present invention, but are not intended to limit the scope of the invention in any way.

[0400] Preparation Example 1: Synthesis of inter 1

[0401] Step 1): Dissolve inter 1a (7.7 g, 25.82 mmol, 1.0 equivalence) in concentrated sulfuric acid (40 mL), add potassium nitrate (2.61 g, 25.82 mmol, 1.0 equivalence) at 0 °C, and stir at room temperature for 16 hours. Pour the mixture into ice water (80 mL), extract with ethyl acetate (50 mL × 2), alkalize the aqueous phase to pH 10 with 2 M sodium hydroxide, and extract with ethyl acetate (100 mL × 3). Combine the organic layers, dry to anhydrous sodium sulfate, and concentrate under reduced pressure to obtain inter 1b. ESI m / z 243.2 [M+H] + .LCMS:product:Rt=0.30min.

[0402] Step 2): Dissolve inter 1b (6.2 g, 25.51 mmol, 1.0 equivalence) in dichloromethane (50 mL), add di-tert-butyl dicarbonate (6.68 g, 30.61 mmol, 1.2 equivalence) and triethylamine (10.61 mL, 76.52 mmol, 3.0 equivalence), and stir at room temperature for 2 hours. Pour the mixture into water (20 mL), extract with dichloromethane (20 mL × 3), combine the organic layers, dry to anhydrous sodium sulfate, filter and concentrate under reduced pressure. Purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give inter 1c. ESI m / z 288.9 [MC(CH3)3+H] + .LCMS:product:Rt=1.42min.

[0403] Step 3): Dissolve inter 1c (4.6 g, 13.27 mmol, 1.0 equivalent) in ethanol (36 mL), and add iron powder (7.5 g, 134.31 mmol, 10.0 equivalent). Then add a solution of ammonium chloride (7.0 g, 130.87 mmol, 10.0 equivalent) in water (12 mL), and stir the mixture at room temperature for 3 hours. Filter the reaction mixture, add water (30 mL) to the filtrate, and extract with ethyl acetate (30 mL × 3). Combine the organic layers, dry with anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain crude inter 1d, which is used directly in the next step without purification. ESI m / z 315.0 [M+H] + .LCMS:product:Rt=1.32min.

[0404] Step 4): Add 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (1.4 g, 1.91 mmol, 0.17 equivalence) to a solution of inter 1d (3.5 g, 11.18 mmol, 1.0 equivalence) in N,N-dimethylformamide (60 mL), methanol (20 mL), and triethylamine (20 mL). Stir the mixture at 90 °C and 15 psi for 20 hours under carbon monoxide protection. Extract the mixture with water (50 mL) and ethyl acetate (30 mL × 3). Combine the organic layers, wash with brine (30 mL × 3), dry over anhydrous sodium sulfate, and filter. Concentrate the filtrate under reduced pressure. Purify the residue by rapid column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give inter 1e. ESI m / z 293.2 [M+H] + .LCMS:product:Rt=1.25min.

[0405] Step 5): Dissolve inter 1e (550 mg, 1.79 mmol, 1.0 equivalence) in acetonitrile (10 mL), and add 2-methyl-2-(nitroso)propane (371 mg, 3.60 mmol, 2.0 equivalence) at 0 °C. After stirring the mixture at 0 °C for 1 hour, slowly add cuprous bromide (I) (386 mg, 2.69 mmol, 1.5 equivalence), then heat the reaction to 60 °C and maintain for 6 hours. Pour the mixture into water (10 mL) and extract with ethyl acetate (20 mL × 3). Combine the organic layers, wash with saturated brine (20 mL × 3), dry with anhydrous sodium sulfate, and concentrate under reduced pressure. Purify the residue by rapid column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give inter 1. ESI m / z 302.0 [MC(CH3)3+H] + .LCMS:product:Rt=1.32min.

[0406] Preparation Example 2: Synthesis of inter 2

[0407] Compound inter 6 (350 mg, 0.87 mmol, 1.0 equivalence) was dissolved in dichloromethane (10 mL), followed by inter 4 (384 mg, 0.95 mmol, 1.1 equivalence) and sodium triacetoxyborohydride (550 mg, 2.60 mmol, 3.0 equivalence). The reaction mixture was stirred at room temperature for 4 hours. The mixture was diluted with water and then extracted with ethyl acetate (10 mL × 2). The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give inter 2. ESI m / z 792.6 [M+H] + .LCMS:product:Rt=1.270min.

[0408] Preparation Example 3: Synthesis of inter 3

[0409] Under a nitrogen atmosphere, inter 3a (5 g, 21.81 mmol, 1.0 equivalence) was dissolved in tetrahydrofuran (50 mL), and triethylamine (7.56 mL, 54.52 mmol, 2.5 equivalence) was added at 0 °C, followed by pentanoyl chloride (3.16 g, 26.17 mmol, 1.2 equivalence). The reaction mixture was stirred at 0 °C for 30 min. Lithium chloride (1.11 g, 26.17 mmol, 1.2 equivalence) and inter 3b (3.86 g, 21.81 mmol, 1.0 equivalence) were then added. The mixture was stirred at room temperature for 18 h. The mixture was diluted with water (80 mL) and extracted with ethyl acetate (40 mL × 2). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give inter 3. ESI m / z 411.2 [M+Na] + .LCMS:product:Rt=1.319min. 1 H NMR (400MHz, CDCl3) δ7.42–7.29(m,3H),7.23(d,J=7.1Hz,2H),4.71(s,1H),4.23(t,J=9.6Hz,2H),3.77–3.63(m,1H),3.59–3.41(m,1H),3.39 –3.27(m,2H),3.15–2.94(m,3H),2.81(dt,J=17.6,8.8Hz,1H),2.69(dt,J=15.0,7.5Hz,1H),2.13(s,1H),1.65(s,1H),1.49(d,J=4.4Hz,9H).

[0410] Preparation Example 4: Synthesis of inter 4

[0411] Step 1): Inter 3 (1.0 g, 2.57 mmol, 1.0 equivalent) was dissolved in tetrahydrofuran (20 mL), and bis(trimethylsilylaminolithium) (1.0 M tetrahydrofuran solution, 2.83 mL, 2.83 mmol, 1.1 equivalent) was added at 0 °C, and the mixture was stirred at the same temperature for 30 min. Then, a tetrahydrofuran solution (3 mL) of compound Inter 4a (0.71 g, 2.83 mmol, 1.1 equivalent) was added. The mixture was stirred at 0 °C for 16 h to room temperature. The reaction mixture was quenched with saturated citric acid aqueous solution (50 mL), extracted with tert-butyl methyl ether (50 mL × 3), and washed with water (50 mL) and saturated brine (50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / tert-butyl methyl ether = 1 / 1) to give Inter 4b. ESI m / z 501.2 [M+H-tert-butyl] + .

[0412] LCMS:product:Rt = 2.283 min;

[0413] 1 H NMR (400MHz, DMSO-d6) δ7.51–7.40(m,2H),7.28(d,J=5.5Hz,2H),7.19(dd,J=4.9, 1.6Hz,3H),6.82(s,2H),4.65(s,1H),4.27(s,2H),4.07(d,J=6.3Hz,1H),3.46(s,2 H),3.10(d,J=19.0Hz,1H),3.01–2.88(m,3H),2.76(d,J=12.0Hz,1H),2.57–2.51( m,1H),2.40(s,1H),1.96–1.86(m,1H),1.61(dd,J=25.9,16.1Hz,1H),1.39(s,9H).

[0414] Step 2): Dissolve Inter 4b (500 mg, 0.90 mmol, 1.0 equivalence) in tetrahydrofuran (9 mL) solution, and add hydrogen peroxide (30% aqueous solution, 0.70 mL, 8.97 mmol, 10.0 equivalence) at 0 °C. Then add an aqueous solution of lithium hydroxide (75.27 mg, 1.79 mmol, 2.0 equivalence) (3 mL). Stir at 0 °C to room temperature for 2 hours. Quench the resulting reaction mixture with an aqueous solution of sodium bisulfite (1399.80 mg, 13.45 mmol) (10 mL) and stir at 0 °C for 30 minutes. Then neutralize the reaction mixture to pH 9 with sodium hydroxide (1.0 M) and extract with tert-butyl methyl ether (30 mL × 3). Separate the aqueous layer, neutralize to pH 5 with an aqueous solution of citric acid (1.0 M), and extract with tert-butyl methyl ether (30 mL × 3). Combine the organic layers, dry with anhydrous sodium sulfate, and filter. The filtrate was concentrated under reduced pressure to give inter 4c. ESI m / z 342.1 [M+H-tert-butyl] + .

[0415] LCMS:product:Rt = 1.362min.

[0416] Step 3): Dissolve inter 4c (7.3 g, 18.33 mmol, 1.0 equivalence) in tetrahydrofuran (50 mL), and add inter 4d (18.36 g, 91.64 mmol, 5.0 equivalence). Stir the reaction mixture at 65 °C for 2 hours. Filter the reaction mixture to remove the white solid, and concentrate the filtrate under reduced pressure. Purify the residue by silica gel column chromatography (petroleum ether / tert-butyl methyl ether = 3 / 1) to obtain inter 4e. ESI m / z 342.0 [M-2C(CH3)3+H] + .

[0417] LCMS:product:Rt = 1.695 min.

[0418] Step 4): Dissolve inter 4e (4.0 g, 8.80 mmol, 1.0 equivalence) in N,N-dimethylformamide (80 mL), add triethylsilane (4.09 g, 35.21 mmol, 4.0 equivalence), triethylamine (6.10 mL, 44.01 mmol, 5.0 equivalence), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (0.65 g, 0.88 mmol, 0.1 equivalence). Stir the mixture at 90 °C and 15 psi for 16 hours under carbon monoxide protection. Extract the mixture with water (50 mL) and ethyl acetate (3 × 30 mL), combine the organic layers, wash with saturated brine (30 mL × 3), dry to anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain inter 4. ESI m / z 426.2 [M+Na] + .

[0419] LCMS:product:Rt = 1.390 min.

[0420] Preparation Example 5: Synthesis of inter 5

[0421] Step 1): Inter 4 (1 g, 2.48 mmol, 1.0 equivalent) was dissolved in methanol (15 mL), and then sodium borohydride (0.11 g, 2.97 mmol, 1.2 equivalent) was added at 0 °C. The reaction mixture was stirred at 0 °C for 10 min. The mixture was poured into water (20 mL), extracted with ethyl acetate (3 × 20 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give Inter 5a. ESI m / z 428.2 [M + Na] + .

[0422] LCMS:product:Rt = 1.302 min.

[0423] Step 2): Dissolve inter 5a (610 mg, 1.50 mmol, 1.0 equivalence) in dichloromethane (8 mL), add carbon tetrabromide (548.71 mg, 1.65 mmol, 1.1 equivalence) and triphenylphosphine (473.43 mg, 1.81 mmol, 1.2 equivalence). Stir the reaction mixture at 25 °C for 16 hours. Pour the mixture into water (20 mL), extract with dichloromethane (3 × 10 mL), combine the organic phases, dry to anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Purify the residue by column chromatography (petroleum ether / tert-butyl methyl ether = 1 / 1) to give inter 5. ESI m / z 358.0 [M-2C(CH3)3+H] + .

[0424] LCMS:product:Rt = 1.482 min.

[0425] Preparation Example 6: Synthesis of inter 6

[0426] Step 1): Under a nitrogen atmosphere, inter 3 (1.0 g, 2.57 mmol, 1.0 equivalent) was dissolved in tetrahydrofuran (10 mL) and cooled at 0 °C, followed by the addition of lithium bis(trimethylsilyl)amino (2.83 mL, 2.83 mmol, 1.1 equivalent). The reaction mixture was stirred at 0 °C for 30 min. Subsequently, a tetrahydrofuran (10 mL) solution of compound inter 6a (0.55 g, 2.83 mmol, 1.1 equivalent) was added. The reaction mixture was stirred at room temperature for 2 h. The mixture was quenched with saturated ammonium chloride solution (20 mL) and extracted with ethyl acetate (30 mL × 2). The organic phases were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 9 / 1) to give inter 6b. ESI m / z 526.2 [M+Na] + .

[0427] LCMS:product:Rt = 1.401 min.

[0428] Step 2): Under a nitrogen atmosphere, compound inter 6b (0.73 g, 1.45 mmol, 1.0 equivalence) was dissolved in tetrahydrofuran (10 mL) and stirred at 0 °C. Hydrogen peroxide (30% aqueous solution, 1.13 mL, 14.50 mmol, 10 equivalence) was then added dropwise, followed by a 2 mL aqueous solution of lithium hydroxide monohydrate (0.17 g, 2.90 mmol, 2.0 equivalence). The reaction mixture was stirred at 0 °C for 2 hours, then quenched with a 10 mL aqueous solution of sodium bisulfite (2.26 g, 21.74 mmol, 15 equivalence), and the pH was adjusted to 5 with citric acid (1 M). The aqueous phase was extracted with methyl tert-butyl ether (20 mL × 3), the combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound inter 6c. ESI m / z 367.1 [M+Na] + .

[0429] LCMS:product:Rt = 1.178 min.

[0430] Step 3): Add Inter 6D (1.45 mg, 7.26 mmol, 5 equivalences) to a tetrahydrofuran solution (5 mL) of Inter 6C (0.5 g, 1.45 mmol), and stir the mixture at 60 °C for 1 hour. Dilute the mixture with water (20 mL) and extract with ethyl acetate (20 mL × 2). Combine the organic layers, wash with brine, dry to anhydrous sodium sulfate, and filter. Concentrate the filtrate under reduced pressure. Purify the residue by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 4 / 1) to give Inter 6E. ESI m / z 423.2 [M + Na] + .LCMS:product:Rt=1.394min.

[0431] Step 4): Raney nickel (103.65 mg, 0.47 mmol, 1.0 equivalence) was added to a solution containing tetrahydrofuran (5 mL) and ammonia (0.2 mL). The reaction mixture was stirred at room temperature for 6 hours, and hydrogen was introduced. The mixture was filtered and concentrated under reduced pressure to give inter 6. ESI m / z 405.2 [M+H]+.

[0432] LCMS:product:Rt = 0.997min.

[0433] Preparation Example 7: Synthesis of inter 7

[0434] Step 1): Dissolve inter 4e (0.5 g, 1.10 mmol, 1.0 equivalence) in a solution of dioxane (10 mL) and methanol (10 mL), and add octacarbonyl dicobalt (188.0 mg, 0.55 mmol, 0.5 equivalence), dichloro[1,1'-bis(diphenylphosphine)ferrocene]palladium (90.0 mg, 0.11 mmol, 0.1 equivalence), and 4-dimethylaminopyridine (268.0 mg, 2.19 mmol, 2.0 equivalence). Stir the reaction mixture at 110 °C for 18 hours under nitrogen. Concentrate the reaction mixture under reduced pressure. Purify the residue by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 1 / 1) to give inter 7a. ESI m / z 456.2 [M+Na] + .

[0435] LCMS:product:Rt = 1.966 min.

[0436] Step 2): Dissolve inter 7a (350.0 mg, 0.65 mmol) in a mixture of methanol (5 mL) and water (1 mL), then add lithium hydroxide monohydrate (40.6 mg, 0.97 mmol, 1.5 equivalence). Stir the reaction mixture at room temperature for 18 hours. Neutralize the resulting reaction mixture with dilute hydrochloric acid to pH 3. Extract the mixture with ethyl acetate (50 mL × 2), and concentrate the organic phase under reduced pressure to give inter7. ESI m / z 442.2 [M + Na] + .

[0437] LCMS:product:Rt = 1.726 min.

[0438] Example 1: Synthesis of Compound 1

[0439] Step 1): Under a nitrogen atmosphere at 0°C, triethylamine (14.24 mL, 102.76 mmol, 2.5 equivalence) was added to a stirred solution of compound 1a (10 g, 41.10 mmol, 1.0 equivalence) in 100 mL of tetrahydrofuran, followed by tervapotranol chloride (6.06 mL, 49.32 mmol, 1.2 equivalence). The reaction mixture was stirred at 0°C for 30 min. Lithium chloride (2.10 g, 49.32 mmol, 1.2 equivalence) and (S)-4-benzyloxyoxazolidine-2-one (7.28 g, 41.10 mmol, 1.0 equivalence) were then added. The mixture was heated to room temperature and stirred for 16 h. The mixture was diluted with water (200 mL) and extracted with ethyl acetate (100 mL × 2). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 2) to give compound 1c. ESI m / z 425.2 [M+Na] + .LCMS:product:Rt=1.337min.

[0440] Step 2): A solution of compound 1c (3.0 g, 7.45 mmol, 1.0 equivalence) in tetrahydrofuran (30 mL) was stirred at 0 °C under a nitrogen atmosphere, and lithium bis(trimethylsilylamino)ene (8.20 mL, 8.20 mmol, 1.1 equivalence) was added. The reaction mixture was stirred at 0 °C for 30 min. Subsequently, a solution of 1-bromo-3-(bromomethyl)benzene (2.05 g, 8.20 mmol, 1.1 equivalence) in tetrahydrofuran (10 mL) was added. The reaction mixture was stirred at room temperature for 2 h. The mixture was quenched with saturated ammonium chloride solution (50 mL) and extracted with ethyl acetate (40 mL × 2). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 3 / 1) to give compound 1e. ESI m / z 593.2 [M + Na] + .LCMS:product:Rt=1.588min.

[0441] Step 3): Under a nitrogen atmosphere, compound 1e (2.1 g, 3.67 mmol, 1.0 equivalent) was dissolved in tetrahydrofuran (21 mL) and stirred at 0 °C. Hydrogen peroxide (30% aqueous solution, 2.85 mL, 36.74 mmol, 10 equivalent) was slowly added dropwise, followed by lithium hydroxide hydrate (0.31 g, 7.35 mmol, 2.0 equivalent) in water (7 mL). The reaction mixture was stirred at 0 °C for 2 hours, then quenched with sodium bisulfite (0.73 g, 55.12 mmol, 15 equivalent) in water (20 mL), and the pH was adjusted to 9 with sodium hydroxide aqueous solution (1 M). Extraction was performed with methyl tert-butyl ether (30 mL × 3). The remaining aqueous phase was then acidified to pH 5 with citric acid (1 M) solution. The aqueous phase was extracted with methyl tert-butyl ether (30 mL × 3), the organic phases were combined, washed with brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 1f. ESI m / z 356.0 [M+H-tert-butyl] + .LCMS:product:Rt=1.351min.

[0442] Step 4): To a tetrahydrofuran solution (20 mL) of compound 1f (2.2 g, 5.34 mmol, 1.0 equivalence), 2-tert-butyl-N,N'-diisopropylisourea (1 g, 5.34 g, 26.68 mmol, 5.0 equivalence) was added, and the mixture was stirred at 65 °C for 1 hour. The mixture was diluted with water (30 mL) and then extracted with ethyl acetate (20 mL × 2). The organic layers were combined, washed with brine (80 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 5 / 1) to give compound 1h. ESI m / z 468.0 [M+H] + .LCMS:product:Rt=1.662min.

[0443] Step 5): To a solution of compound 1h (1.01 g, 2.16 mmol, 1.0 equivalence) in N,N-dimethylformamide (25 mL), triethylsilane (1.0 g, 8.62 mmol, 4.0 equivalence), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (160 mg, 0.22 mmol, 0.1 equivalence), and triethylamine (1.49 mL, 10.78 mmol, 5.0 equivalence) were added. The mixture was stirred under a carbon monoxide atmosphere and heated to 90 °C for 16 hours. The mixture was then diluted with water (50 mL) and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with brine (150 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 1i. ESI m / z 440.2 [M+Na] + .LCMS:product:Rt=1.506min.

[0444] Step 6): Sodium triacetoxyborohydride (456.82 mg, 2.16 mmol, 3.0 equivalence) was added to a solution of compound 1i (300 mg, 0.72 mmol, 1.0 equivalence) and inter 6 (319.73 mg, 0.79 mmol, 1.1 equivalence) in dichloromethane (5 mL). The mixture was stirred at room temperature for 3 hours. The mixture was diluted with water (10 mL) and extracted with dichloromethane (8 mL × 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 100 / 1) to give compound 1j. ESI m / z 706.4 [M-Boc] + .LCMS:product:Rt=1.383min.

[0445] Step 7): To a dichloromethane solution (3 mL) containing compound 1j (100 mg, 0.11 mmol, 1.00 equivalence), add (9H-fluorene-9-yl)methyl(2-oxoethyl)carbamate (40 mg, 0.14 mmol, 1.32 equivalence), acetic acid (60 mg, 1.00 mmol, 9.24 equivalence), and sodium triacetoxyborohydride (69 mg, 0.33 mmol, 3.01 equivalence). The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was quenched with a saturated aqueous sodium bicarbonate solution (50 mL) and extracted with dichloromethane (50 mL × 2). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 1 / 0 to 1 / 1) to give compound 1k. ESI m / z 1071.6 [M+H] + .LCMS:product:Rt=1.545min.

[0446] Step 8): To a tetrahydrofuran solution containing compound 1k (85 mg, 0.08 mmol, 1.0 equivalent), dimethylamine (1 mL, 2 mmol, 1M tetrahydrofuran solution) was added to 0.2 mL of the solution, and the mixture was reacted at 25°C for 2 hours. The mixture was concentrated under vacuum to obtain a residue. The residue was then purified by column chromatography (dichloromethane / methanol = 1 / 0 to 9 / 1) to obtain compound 1l. ESI m / z 849.6 [M+H] + .LCMS:product:Rt=1.356min.

[0447] Step 9): To a solution (2 mL) of N,N-dimethylformamide containing compound 1l (60 mg, 0.07 mmol, 1.0 equivalence), add inter 5 (78 mg, 0.17 mmol, 2.42 equivalence) and cesium carbonate (100 mg, 0.31 mmol, 4.46 equivalence). The reaction mixture was stirred at 25 °C for 18 hours. The mixture was poured into water (30 mL) and extracted with ethyl acetate (20 mL × 3). The organic layers were combined, washed with brine (30 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / tert-butyl methyl ether = 1 / 1) to give compound 1m. ESI m / z 762.6 [1 / 2(M-Boc) + H] + .LCMS:product:Rt = 1.666 min.

[0448] Step 10): Add 1 mL of trifluoroacetic acid to a solution of compound 1 M (95 mg, 0.05 mmol, 1.0 equivalence) in dichloromethane (1 mL) and stir at room temperature for 18 hours. The resulting reaction mixture was concentrated and purified by preparative high-performance liquid chromatography (ammonium bicarbonate) to obtain compound 1. ESI m / z 1000.5 [M+H]+ .

[0449] LCMS:product:Rt = 0.719min.

[0450] 1 H NMR(400MHz,D2O)δ7.24(t,J=7.6Hz,4H),7.14(d,J=7.6Hz,4H),7.05(s,4H),6.99 (d,J=6.6Hz,4H),3.57(s,8H),3.38–3.27(m,8H),3.20–3.08(m,3H),2.87–2.59(m, 17H),2.37(tt,J=16.6,8.4Hz,6H),2.28(s,1H),2.02(dd,J=21.8,18.0Hz,4H),1. 80(d,J=13.2Hz,1H), 1.67(dd,J=20.4,10.9Hz,4H), 1.40(dd,J=24.8,12.8Hz,2H).

[0451] Example 2: Synthesis of Compound 2

[0452] Step 1): Under a nitrogen atmosphere, compound 1c (1.5 g, 3.73 mmol, 1.0 equivalence) was dissolved in tetrahydrofuran (50 mL), cooled to 0 °C, and then lithium bis(trimethylsilyl)amino (4.85 mL, 4.85 mmol, 1.3 equivalence) was added. The reaction mixture was stirred at 0 °C for 30 min. Subsequently, a tetrahydrofuran solution (50 mL) of compound 4a-2 (1.16 g, 4.48 mmol, 1.2 equivalence) was added. The reaction mixture was allowed to warm naturally to room temperature and stirred for 2 h. The mixture was quenched with saturated ammonium chloride solution (100 mL) and extracted with ethyl acetate (100 mL × 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 3 / 2) to give compound 2b. ESI m / z 522.0 [M-56+H] + .LCMS:product:Rt=1.952min.

[0453] Step 2): Under a nitrogen atmosphere, compound 2b (1500 mg, 1.79 mmol, 1.0 equivalence) was dissolved in tetrahydrofuran (20 mL). Hydrogen peroxide (30% aqueous solution, 1.63 mL, 21.01 mmol, 11.74 equivalence) was added dropwise at 0 °C, followed by the addition of a solution of lithium hydroxide monohydrate (220.0 mg, 5.24 mmol, 2.3 equivalence) in water (10 mL). The reaction mixture was stirred at 0 °C for 2 hours, then quenched with sodium bisulfite solution (2.73 g, 26.27 mmol, 14.68 equivalence), and the pH was adjusted to 5 with citric acid (1 M). The aqueous phase was extracted with methyl tert-butyl ether (100 mL × 3), and the combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 2c. ESI m / z 441.0 [M + Na] + .LCMS:product:Rt=1.552min.

[0454] Step 3): Compound 2c (1500 mg, 2.50 mmol) was dissolved in tetrahydrofuran (10 mL), and 2-tert-butyl-N,N'-diisopropylisourea (2.5 g, 12.52 mmol, 5.0 equivalence) was added. The mixture was stirred at 65 °C for 2 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 2). The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 1 / 1) to give compound 2d. ESI m / z 497.1 [M+H] + .LCMS:product:Rt=1.991min.

[0455] Step 4): To a solution of N,N-dimethylacetamide (10 mL) containing compound 2d (460.0 mg, 0.87 mmol, 1.0 equivalence), zinc cyanide (102.2 mg, 0.87 mmol, 1.0 equivalence), N,N-diisopropylethylamine (337.6 mg, 2.61 mmol, 3.0 equivalence), and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) palladium dichloride (65.8 mg, 0.09 mmol, 0.1 equivalence) were added. The reaction mixture was stirred at 85 °C under a nitrogen atmosphere for 2 hours. The mixture was poured into water (60 mL) and then extracted with ethyl acetate (3 × 40 mL). The organic phases were combined, washed with brine (40 mL × 3), dried over sodium sulfate, and concentrated under vacuum to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give compound 2e. ESI m / z 444.2 [M+Na] + .LCMS:product:Rt=1.881min.

[0456] Step 5): To a solution of tetrahydrofuran (10 mL) containing compound 2e (300 mg, 0.68 mmol, 1.0 equivalence), Raney nickel (147.7 mg, 0.68 mmol, 1.0 equivalence) and ammonia (0.1 mL) were added. The reaction mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The suspension was filtered through diatomaceous earth, and the diatomaceous earth was washed with ethyl acetate (20 mL). The filtrate was concentrated to dryness under reduced pressure to give the crude product. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to give compound 2f. ESI m / z 426.2 [M+H] + .LCMS:product:Rt=0.974min.

[0457] Step 6): Compound 2f (100 mg, 0.23 mmol, 1.0 equivalence) was dissolved in dichloromethane (10 mL), and Inter 4 (94.8 mg, 0.23 mmol, 1.0 equivalence) and sodium triacetoxyborohydride (149.4 mg, 0.7 mmol, 3.0 equivalence) were added. The reaction mixture was stirred at room temperature for 4 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 1 / 3) to give 2 g of compound. ESI m / z 813.4 [M+H] + .LCMS:product:Rt=1.597min.

[0458] Step 7): 2 g (210 mg, 0.24 mmol, 1.0 equivalence) of the compound was dissolved in dichloromethane (10 mL), and (9H-fluorene-9-yl)methyl(2-oxoethyl)carbamate (80 mg, 0.28 mmol, 1.2 equivalence), acetic acid (5 mg, 0.03 mmol, 0.1 equivalence), and sodium triacetoxyborohydride (164 mg, 0.77 mmol, 3.0 equivalence) were added. The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched with saturated sodium bicarbonate solution (20 mL) and extracted with dichloromethane (20 mL × 2). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / tert-butyl methyl ether = 1 / 1) to give the compound 2 h. ESI m / z 1079.6 [M+H] + .LCMS:product:Rt=1.69min.

[0459] Step 8): Compound 2h (200 mg, 0.15 mmol, 1.0 equivalent) was dissolved in dimethylamine (5 mL, 10.00 mmol, 2 M dissolved in tetrahydrofuran) and stirred at 25 °C for 2 hours. The reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give compound 2i. ESI m / z 856.6 [M+H]+. LCMS:product:Rt = 1.47 min.

[0460] Step 9): Compound 2i (85 mg, 0.08 mmol, 1.0 equivalence) was dissolved in dichloromethane (2 mL), and Inter 4 (160 mg, 0.40 mmol, 5.2 equivalence), acetic acid (19 mg, 0.10 mmol, 1.3 equivalence), and sodium triacetoxyborohydride (105 mg, 0.50 mmol, 6.5 equivalence) were added. The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was quenched with saturated sodium bicarbonate solution (20 mL) and extracted with dichloromethane (20 mL x 2). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / tert-butyl methyl ether = 1 / 1) to give compound 2j. ESI m / z 1244.8 [M+H] + .LCMS:product:Rt=1.67min.

[0461] Step 10): Compound 2j (80 mg, 0.05 mmol, 1.0 equivalence) was dissolved in dichloromethane (3 mL), and Inter 4 (40 mg, 0.10 mmol, 2.0 equivalence) and acetic acid (20 mg, 0.11 mmol, 2.2 equivalence) were added. The reaction mixture was stirred at 60 °C for 2 hours. Then, sodium triacetoxyborohydride (60 mg, 0.28 mmol, 6.0 equivalence) was added to the mixture. The reaction mixture was stirred at 60 °C for 4 hours. The reaction mixture was quenched with saturated sodium bicarbonate solution (20 mL) and extracted with dichloromethane (20 mL × 2). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / tert-butyl methyl ether = 1 / 1) to give compound 2k. ESI m / z 766.2 [M / 2+H] + .LCMS:product:Rt=1.66min.

[0462] Step 11): Compound 2k (65 mg, 0.04 mmol, 1.0 equivalence) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred at 25 °C for 16 hours. After concentration, the reaction mixture was purified by preparative high-performance liquid chromatography (ammonium bicarbonate) to give compound 2. ESI m / z 1007.5 [M+H] + .

[0463] LCMS:product:Rt = 1.06 min.

[0464] 1 HNMR(400MHz,D2O)δ7.21(d,J=7.6Hz,3H),7.17–6.97(m,10H),3.80–3.69(m,2H),3.55(d,J=23.9Hz,6H),3.39–3.25(m,8H),3.19–3.07(m,3 H),2.89–2.71(m,10H),2.68–2.54(m,7H),2.35(d,J=16.4Hz,7H),2.04(s,4H),1.81(d,J=14.5Hz,1H),1.67(d,J=12.0Hz,4H),1.42(s,2H).

[0465] Example 3: Synthesis of Compound 3

[0466] Step 1): To a solution of N,N-dimethylformamide (5 mL) containing inter 7 (146 mg, 0.31 mmol, 1.0 equivalence), N,N-diisopropylethylamine (122 mg, 0.94 mmol, 3.0 equivalence) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethylurea hexafluorophosphate (179 mg, 0.47 mmol, 1.5 equivalence) were added, and the mixture was stirred at room temperature for 0.5 h. Compound 2i (300 mg, 0.31 mmol, 1.0 equivalence) was added, and the mixture was stirred at room temperature for 1.5 h. The mixture was diluted with water (12 mL) and extracted with ethyl acetate (5 mL × 3). The organic phases were combined, washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 1 / 2) to give compound 3a. ESI m / z 1258.6 [M+H] + .LCMS:product:Rt=1.629min.

[0467] Step 2): Under nitrogen protection at 0°C, sodium hydroxide (19 mg, 0.49 mmol, 5.0 equivalence) was added to a solution of N,N-dimethylformamide (5 mL) containing compound 3a (150 mg, 0.10 mmol, 1.0 equivalence), and the reaction mixture was stirred at 0°C for 30 min. Subsequently, a solution of N,N-dimethylformamide (2 mL) containing inter 5 (91 mg, 0.19 mmol, 2.0 equivalence) was added to the reaction mixture, and the mixture was slowly heated to room temperature and stirred for 1.5 h. The mixture was quenched with ice water (15 mL) and extracted with ethyl acetate (8 mL × 3). The combined organic phases were washed with brine (25 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 2 / 1) to give compound 3b. ESI m / z 773.2 [M+H] + .LCMS:product:Rt=2.180min.

[0468] Step 3): Compound 3b (141 mg, 0.08 mmol, 1.0 equivalence) was dissolved in a mixed solution of dichloromethane (2 mL) and trifluoroacetic acid (2 mL), and the mixture was stirred at room temperature for 18 hours. The resulting reaction mixture was concentrated and purified by preparative high-performance liquid chromatography (ammonium bicarbonate) to give compound 3. ESI m / z 1021.4 [M+H] + .

[0469] LCMS:product:Rt = 0.607 min.

[0470] 1 H NMR(400MHz,D2O)δ7.42–6.97(m,12H),6.89–6.73(m,1H),4.61–4.36(m,3H),4.16(s,1H),3.89–3.59(m,2H),3.53–3.26(m,9H),3.28–3.0 1(m,5H),2.97–2.60(m,14H),2.38(d,J=25.1Hz,7H),2.02(d,J=19.6Hz,4H),1.71(dd,J=34.8,21.9Hz,5H),1.41(dd,J=26.4,13.4Hz,2H).

[0471] Example 4: Synthesis of Compound 4

[0472] Step 1): Under nitrogen protection at 0°C, phosphorus tribromide (2.91 mL, 30.92 mmol, 2.0 equivalent) was added dropwise to a solution of compound 4a-1 (3 g, 15.46 mmol, 1.0 equivalent) in dichloromethane (20 mL), and the mixture was slowly brought back to room temperature with stirring for 16 hours. The mixture was poured into water (20 mL) and extracted with dichloromethane (20 mL). The organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 2 / 1) to give compound 4a-2. ESI m / z 257.8 [M+H] + .LCMS:product:Rt=1.103min.

[0473] Step 2): Under nitrogen protection at 0°C, lithium bis(trimethylsilyl)aminolithium (9.73 mL, 9.73 mmol, 1.1 equivalence) was added to a tetrahydrofuran (40 mL) solution containing inter 3 (3.44 g, 8.85 mmol, 1.0 equivalence). The reaction mixture was stirred at 0°C for 30 min. Subsequently, a tetrahydrofuran (10 mL) solution of compound 4a-2 (2.50 g, 9.73 mmol, 1.1 equivalence) was added. The reaction mixture was brought to room temperature and stirred for 2 h. The reaction mixture was quenched with saturated ammonium chloride solution (100 mL) and extracted with ethyl acetate (80 mL × 3). The organic layers were combined, washed with brine (250 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 1 / 3) to give compound 4a-3. ESI m / z 508.0 [M+H-tert-butyl] + .LCMS:product:Rt=1.472min.

[0474] Step 3): Under nitrogen protection at 0°C, hydrogen peroxide (3.92 mL, 50.49 mmol, 1.0 equivalent) was added dropwise to a tetrahydrofuran (24 mL) solution of compound 4a-3 (2.85 g, 5.05 mmol, 1.0 equivalent), followed by an 8 mL solution of lithium hydroxide hydrate (0.42 g, 10.10 mmol, 2.0 equivalent) in water. The reaction mixture was stirred at 0°C for 2 hours, then quenched with a 30 mL solution of sodium bisulfite (7.88 g, 75.73 mmol, 15 equivalent) in water, and the pH was adjusted to 9 with a 1 M sodium hydroxide aqueous solution. The mixture was washed with methyl tert-butyl ether (30 mL × 3). The aqueous phase was acidified to pH 5 with citric acid (1M) solution and then extracted with methyl tert-butyl ether (30 mL × 3). The organic phases were combined, washed with brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 4a-4. ESI m / z 427.0 [M + Na] + .LCMS:product:Rt=1.172min.

[0475] Step 4): To a tetrahydrofuran solution (20 mL) of compound 4a-4 (1.93 g, 4.76 mmol, 1.0 equivalence), 2-tert-butyl-N,N'-diisopropylisourea (4.77 g, 23.81 mmol, 5.0 equivalence) was added, and the mixture was stirred at 65 °C for 2 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 3). The organic layers were combined, washed with brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 1 / 1) to give compound 4a-5. ESI m / z 349.0 [M + H-tert-buty × 2] + .LCMS:product:Rt=1.519min.

[0476] Step 5): Compound 4a-5 (300 mg, 0.63 mmol, 1.0 equivalence) was dissolved in N,N-dimethylacetamide (2 mL), and zinc cyanide (74 mg, 0.63 mmol, 1.0 equivalence), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) palladium dichloride (48 mg, 0.06 mmol, 0.1 equivalence), and N,N-diisopropylethylamine (244 mg, 1.89 mmol, 3.0 equivalence) were added. The reaction mixture was stirred at 85 °C for 2 hours under nitrogen protection. The mixture was diluted with water (5 mL) and extracted with ethyl acetate (5 mL × 2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 2 / 1) to give compound 4a-6. ESI m / z 430.2 [M+Na] + .LCMS:product:Rt=1.798min.

[0477] Step 6): To tetrahydrofuran (2 mL) containing compound 4a-6 (240 mg, 0.56 mmol, 1.0 equivalence), Raney nickel (122 mg, 0.56 mmol, 1.0 equivalence) was added. The reaction mixture was stirred for 4 hours at room temperature under hydrogen protection. The mixture was filtered and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to give compound 4a. ESI m / z 412.2 [M+H] + .LCMS:product:Rt=0.947min.

[0478] Step 7): To a solution of compound 4a (500 mg, 1.21 mmol, 1.0 equivalence) in dichloromethane (10 mL), compound 1i (254 mg, 0.61 mmol, 0.5 equivalence), acetic acid (0.1 mL), and sodium triacetoxyborohydride (772 mg, 3.64 mmol, 3.0 equivalence) were added. The reaction mixture was stirred at room temperature for 1 hour. After adding 1i (203 mg, 0.49 mmol, 0.4 equivalence), the mixture was stirred for another 1 hour. The mixture was diluted with saturated sodium bicarbonate aqueous solution (50 mL) and extracted with dichloromethane (15 mL × 2). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 1 / 1) to give compound 4b. ESI m / z 813.6 [M+H] + .LCMS:product:Rt=1.458min.

[0479] Step 8): To a solution of compound 4b (630 mg, 0.73 mmol, 1.0 equivalence) in dichloromethane (10 mL), add (9H-fluorene-9-yl)methyl(2-oxoethyl)carbamate (247 mg, 0.88 mmol, 1.2 equivalence), acetic acid (14 mg, 0.07 mmol, 0.1 equivalence), and sodium triacetoxyborohydride (465 mg, 2.19 mmol, 3.0 equivalence). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution (50 mL) and extracted with dichloromethane (15 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / tert-butyl methyl ether = 1 / 2) to give compound 4c. ESI m / z 1078.6 [M+H] + .LCMS:product:Rt=2.006min.

[0480] Step 9): Compound 4c (733 mg, 0.52 mmol, 1.0 equivalence) was added to a tetrahydrofuran solution of dimethylamine (8 mL, 16.00 mmol / L), and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (dichloromethane / methanol = 10 / 1) to give compound 4d. ESI m / z 856.4 [M+H] + .

[0481] LCMS:product:Rt = 1.374 min.

[0482] Step 10): To a solution of N,N-dimethylformamide (8 mL) containing inter 7 (270 mg, 0.58 mmol, 1.0 equivalence), N,N-diisopropylethylamine (224 mg, 1.73 mmol, 3.0 equivalence) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethylurea hexafluorophosphate (330 mg, 0.87 mmol, 1.5 equivalence) were added, and the mixture was stirred at room temperature for 0.5 h. Compound 4d (526 mg, 0.58 mmol, 1.0 equivalence) was added, and the mixture was stirred at room temperature for 1.5 h. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (40 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 1 / 2) to give compound 4e. ESI m / z 579.4 [(M-Boc) / 2+H] + LCMS:product:Rt = 1.924 min.

[0483] Step 11): Under nitrogen protection at 0°C, sodium hydroxide (85 mg, 2.12 mmol, 5.0 equivalence) was added to a solution of N,N-dimethylformamide (5 mL) containing compound 4e (558 mg, 0.42 mmol, 1.0 equivalence), and the reaction mixture was stirred at 0°C for 30 min. Subsequently, a solution of N,N-dimethylformamide (2 mL) containing inter 5 (398 mg, 0.85 mmol, 2.0 equivalence) was added to the reaction mixture, and the mixture was slowly heated to room temperature and stirred for 1.5 h. The mixture was quenched with ice water (25 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with brine (50 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 1 / 2) to give compound 4f. ESI m / zm / z=773.2[(M-Boc) / 2+H] + .LCMS:product:Rt=2.113min.

[0484] Step 12): Compound 4f (427 mg, 0.19 mmol, 1.0 equivalence) was dissolved in a mixed solution of dichloromethane (3 mL) and trifluoroacetic acid (3 mL), and the mixture was stirred at room temperature for 6 hours. The resulting reaction mixture was concentrated and purified by preparative high-performance liquid chromatography (formic acid) to give compound 4. ESI m / z 1020.5 [M+H] + .

[0485] LCMS:product:Rt = 0.954 min.

[0486] 1 H NMR(400MHz,D2O)δ7.50–6.91(m,12H),6.88–6.70(m,1H),4.61–4.45(m,2H),4.43–4.29(m,1H),4.20(s,1H),3.78(d,J=64.3Hz,3 H),3.52–3.08(m,13H),3.01–2.54(m,15H),2.52–2.30(m,6H),2.19–1.93(m,4H),1.74(d,J=34.4Hz,5H),1.43(q,J=13.5Hz,2H).

[0487] Example 5: Synthesis of Compound 5

[0488] Step 1): Compound 1e (0.6 g, 1.28 mmol, 1.0 equivalence) was added to a mixed solution of dioxane (10 mL) and methanol (5 mL). Then, octacarbonyl-cobalt (262.8 mg, 0.77 mmol, 0.6 equivalence), 4-dimethylaminopyridine (312.97 mg, 2.56 mmol, 2.0 equivalence), and 1,1-bis(diphenylphosphine)dimerferropalladium dichloride (93.72 mg, 0.13 mmol, 0.1 equivalence) were added. The reaction mixture was stirred at 85 °C for 18 h under nitrogen protection. The reaction mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 1 / 1) to give compound 5a. ESI m / z 348.2 [M-Boc+H] + .LCMS:product:Rt=1.623min.

[0489] Step 2): Compound 5a (410 mg, 0.95 mmol, 1.0 equivalence) was dissolved in a stirred solution of methanol (4 mL) and water (2 mL), followed by the addition of lithium hydroxide monohydrate (230.63 mg, 5.50 mmol, 6.0 equivalence). The reaction mixture was stirred at room temperature for 18 hours. The resulting reaction mixture was neutralized to pH 6 with dilute hydrochloric acid. The mixture was extracted with ethyl acetate (50 mL × 2), and the organic phase was concentrated under reduced pressure to give compound 5b. ESI m / z 456.2 [M + Na] + .LCMS:product:Rt=1.419min.

[0490] Step 3): Compound 4a (560 mg, 1.36 mmol, 1.0 equivalence) was dissolved in dichloromethane (10 mL), and (9H-fluorene-9-yl)methyl(2-oxoethyl)carbamate (344.50 mg, 1.22 mmol, 0.9 equivalence) and sodium triacetoxyborohydride (576.76 mg, 2.72 mmol, 2.0 equivalence) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with saturated sodium bicarbonate solution (20 mL) and extracted with dichloromethane (twice, 20 mL each time). The organic layers were bound, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0 / 1) to give compound 5c. ESI m / z 677.4 [M+H] + .LCMS:product:Rt=1.219min.

[0491] Step 4): Compound 5c (0.42 g, 0.59 mmol, 1.0 equivalence) was dissolved in N,N-dimethylformamide (10 mL), and compound 5b (322.82 mg, 0.74 mmol, 1.2 equivalence), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (471.88 mg, 1.24 mmol, 2.0 equivalence), and N,N-diisopropylethylamine (240.60 mg, 1.86 mmol, 3.0 equivalence) were added. The reaction mixture was stirred at room temperature for 2 hours. The mixture was poured into water (60 mL) and then extracted with ethyl acetate (3 times, 40 mL each time). The organic phases were combined, washed with brine (3 times, 40 mL each time), dried over sodium sulfate, and then concentrated under reduced pressure to give the crude product. The residue was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 1 / 8) to give compound 5d. ESI m / z 1092.6 [M+H] + .LCMS:product:Rt=2.170min.

[0492] Step 5): Compound 5d (290 mg, 0.27 mmol, 1.0 equivalence) was added to tetrahydrofuran (2 M) (5 mL) of dimethylamine and stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (dichloromethane / methanol = 10 / 1) to give compound 5e. ESI m / z 870.6 [M+H] + .

[0493] LCMS:product:Rt = 1.451 min.

[0494] Step 6): To a solution of compound 5e (140 mg, 0.16 mmol, 1.0 equivalence) in dichloromethane (2 mL), inter 4 (194.77 mg, 0.48 mmol, 3.0 equivalence) and sodium triacetoxyborohydride (170.6 mg, 0.80 mmol, 5.0 equivalence) were added, and the reaction mixture was stirred at 40 °C for 18 hours. The reaction mixture was quenched with saturated sodium bicarbonate solution (20 mL) and extracted with dichloromethane (2 × 20 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 9) to give compound 5f. ESI m / z 773.2 [(M-Boc) / 2+H] + .LCMS:product:Rt=2.084min.

[0495] Step 7): Compound 5f (150 mg, 0.07 mmol, 1.0 equivalence) was added to a mixed solution of dichloromethane (2 mL) and trifluoroacetic acid (2 mL). The mixture was stirred at room temperature for 18 hours. The resulting reaction mixture was concentrated and purified by preparative high-performance liquid chromatography (ammonium bicarbonate) to give compound 5. ESI m / z 1020.5 [M+H] + .

[0496] LCMS:product:Rt = 0.617 min.

[0497] 1 H NMR (400MHz, D2O) δ7.37–6.79(m,13H),4.70–4.68(m,2H),4.48(d,J=64.4Hz,2H),3.89(d,J=8.0Hz,1H),3.58(dd,J=23.6,14.0Hz,3H),3. 34(dd,J=16.8,9.6Hz,9H),3.16(dd,J=17.2,8.4Hz,3H),2.95–2.50(m,15H),2.46–2.28(m,6H),2.00(d,J=31.2Hz,4H),1.84–1.27(m,7H).

[0498] Example 6: Synthesis of Compound 6

[0499] Step 1): Inter 1 (480 mg, 1.29 mmol, 1.0 equivalence) was dissolved in dioxane (10 mL) and water (2 mL), and (3-formaldehydephenyl)boronic acid (290 mg, 1.93 mmol, 1.5 equivalence), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (94 mg, 0.13 mmol, 0.1 equivalence), and potassium phosphate (685 mg, 3.23 mmol, 2.5 equivalence) were added. The mixture was stirred at 90 °C for 16 hours under nitrogen protection. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 6a1. ESI m / z 326.1 [MC(CH3)3+H] + .LCMS:product:Rt=1.41min.

[0500] Step 2): To a solution of inter 6 (300 mg, 0.79 mmol, 1.0 equivalence) in dichloromethane (30 mL), compound 6a1 (350 mg, 0.87 mmol, 1.1 equivalence), acetic acid (15 mg, 0.08 mmol, 0.1 equivalence), and sodium triacetoxyborohydride (500 mg, 2.36 mmol, 3.0 equivalence) were added. The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with saturated sodium bicarbonate aqueous solution (50 mL) and extracted with dichloromethane (20 mL × 2). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 1 / 1) to give compound 6a. ESI m / z 770.4 [M+H] + .LCMS:product:Rt=1.498min.

[0501] Step 3): To a solution of compound 6a (400 mg, 0.42 mmol, 1.0 equivalence) in dichloromethane (10 mL), add (9H-fluorene-9-yl)methyl(2-oxoethyl)carbamate (154 mg, 0.55 mmol, 1.3 equivalence), acetic acid (8 mg, 0.04 mmol, 0.1 equivalence), and sodium triacetoxyborohydride (268 mg, 1.27 mmol, 3.0 equivalence). The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution (50 mL) and extracted with dichloromethane (10 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / tert-butyl methyl ether = 1 / 2) to give compound 6b. ESI m / z 1035.6 [M+H] + .LCMS:product:Rt=1.585min.

[0502] Step 4): Compound 6b (585 mg, 0.45 mmol, 1.0 equivalence) was added to a solution of dimethylamine (8 mL, 16.00 mmol, 2 M in tetrahydrofuran). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (dichloromethane / methanol = 50 / 1) to give compound 6c. ESI m / z 813.4 [M+H] + .LCMS:product:Rt=1.557min.

[0503] Step 5): To a solution of inter 7 (165 mg, 0.35 mmol, 1.0 equivalence) in N,N-dimethylformamide (6 mL), add N,N-diisopropylethylamine (137 mg, 1.06 mmol, 3.0 equivalence) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethylurea hexafluorophosphate (201 mg, 0.53 mmol, 1.5 equivalence). Stir the reaction mixture at room temperature for 0.5 h. Add compound 6c (338 mg, 0.35 mmol, 1.0 equivalence), and stir the mixture at room temperature for 1.5 h. Dilute the mixture with water (20 mL) and extract with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 1 / 2) to give compound 6d. ESI m / z 1215.8 [M+H]+. LCMS:product:Rt = 1.644 min.

[0504] Step 6): Under nitrogen protection at 0°C, sodium hydroxide (40 mg, 1.01 mmol, 5.0 equivalence) was added to a solution of N,N-dimethylformamide (7 mL) containing compound 6d (315 mg, 0.20 mmol, 1.0 equivalence), and the reaction mixture was stirred at 0°C for 30 min. Subsequently, a solution of N,N-dimethylformamide (2 mL) containing inter 5 (190 mg, 0.40 mmol, 2.0 equivalence) was added to the reaction mixture, and the mixture was slowly heated to room temperature and stirred for 1.5 h. The mixture was quenched with saturated ammonium chloride solution (20 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with brine (50 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 1 / 2) to give compound 6e. ESI m / z 751.6[(M-Boc) / 2+H] + .LCMS:product:Rt=1.927min.

[0505] Step 7): Compound 6e (300 mg, 0.15 mmol, 1.0 equivalence) was added to a mixed solution of tetrahydrofuran (2 mL), methanol (2 mL), and water (2 mL), followed by lithium hydroxide hydrate (63 mg, 1.50 mmol, 10.0 equivalence). The reaction mixture was stirred at 50 °C for 16 hours. The mixture was concentrated under vacuum to remove methanol and tetrahydrofuran. The residue was diluted with water (10 mL), acidified to pH 5 with aqueous hydrochloric acid (1 M), and extracted with ethyl acetate (10 × 3 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under vacuum to give compound 6f. ESI m / z 744.6 [(M-Boc) / 2+H]+ .LCMS:product:Rt=1.587min.

[0506] Step 8): Compound 6f (252 mg, 0.13 mmol, 1.0 equivalence) was added to a mixture of trifluoroacetic acid (2 mL) and dichloromethane (2 mL), and the reaction mixture was stirred at room temperature for 5 hours. The resulting reaction mixture was concentrated and purified by preparative high-performance liquid chromatography (ammonium bicarbonate) to obtain compound 6. ESI m / z 1020.5 [M+H] + .

[0507] LCMS:product:Rt = 1.028 min.

[0508] 1 H NMR(400MHz,D2O)δ7.53–6.85(m,17H),6.75–6.67(m,1H),4.58(d,J=9.8Hz,2H),4.48(d,J=20.5Hz,2H),4.33(s,1H),4.19 (s,1H),3.56(d,J=58.7Hz,3H),3.38–3.01(m,12H),2.88–2.49(m,10H),2.33(d,J=24.9Hz,7H),2.00(s,3H),1.61(s,3H).

[0509] Example 7: Synthesis of Compound 7

[0510] Step 1): Compound 7a (200 mg, 0.47 mmol) was added to a methanol (15 mL) solution, followed by the addition of ethylenediamine dihydrochloride (626.70 mg, 4.71 mmol) and sodium cyanoborohydride (88.82 mg, 1.41 mmol) in portions, while maintaining the temperature at 25 °C. The reaction mixture was stirred at 25 °C for 2 hours. After the reaction was complete, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 × 10 mL). The organic layer was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative high-performance liquid chromatography (ammonium bicarbonate) to give compound 7b. LCMS: m / z 469.2 [M+H] + .

[0511] Step 2): Compound 7b (25 mg, 0.05 mmol) and inter 4 (130 mg, 0.32 mmol) were dissolved in methanol (10 mL), and sodium cyanoborohydride (16.76 mg, 0.27 mmol) was added at 25 °C. The reaction mixture was stirred at 80 °C for 12 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and filtered. The filtrate was purified to a colorless solution by pre-prepared high-performance liquid chromatography (trifluoroacetic acid conditions). Sodium bicarbonate aqueous solution (20 mL) was added to the solution. The resulting solution was extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine, dried over magnesium persulfate, filtered, and concentrated to give compound 7c. LCMS: m / z 1632.0 [M+H] + .

[0512] Step 3): Hydrochloric acid (10 mL, 4 mol / L in dioxane) was gradually added to compound 7c (70 mg, 0.04 mmol) while maintaining the temperature at 25 °C. The reaction mixture was stirred at 25 °C for 3 hours. After the reaction was complete, the reaction mixture was concentrated under vacuum to obtain compound 7.

[0513] LCMS: m / z 1062.5 [M+H] + .

[0514] 1 H NMR (400MHz, METHANOL-d4) δ = 8.35 (s, 1H), 8.05 (d, J = 7.8Hz, 1H), 7.86 (d, J = 7.3Hz, 1H), 7.68t, J = 7.6Hz, 1H), 7.62 (br s, 2H), 7.55 (br s,1H),7.43-7.30(m,9H),4.49-4.33(m,6H),4.26(br s,2H),3.72(br s,2H),3.63 -3.57(m,4H),3.47-3.40(m,3H),3.29(br s,2H),3.19(t,J=10.3Hz,3H),3.02-2.87(m,9H),2.76(d,J=6.8Hz,2H),2.62(d,J=7.5Hz,3H),2.27-2.17(m,4H),1.81(d,J=9.8Hz,7H),1.54(br s,1H),1.29(s,3H),1.09-0.98(m,2H),0.96-0.73(m,1H).

[0515] Example 8: Synthesis of Compound 8

[0516] Step 1): Under a nitrogen atmosphere, inter 3 (1.0 g, 2.57 mmol, 1.0 equivalent) was dissolved in tetrahydrofuran (10 mL) and stirred. Lithium bis(trimethylsilyl)amino (2.83 mL, 2.83 mmol, 1.1 equivalent) was added at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. Subsequently, a solution of 1-(bromomethyl)-3-nitrobenzene (0.61 g, 2.83 mmol, 1.1 equivalent) in tetrahydrofuran (10 mL) was added. The reaction mixture was heated to room temperature and stirred for 2 h. The mixture was quenched with a saturated aqueous ammonium chloride solution (20 mL) and extracted with ethyl acetate (30 mL × 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 9 / 1) to give compound 8a. ESI m / z 468.2 [M+H-tert-butyl] + .LCMS:product:Rt=1.448min.

[0517] Step 2): Under a nitrogen atmosphere, compound 8a (800 mg, 1.53 mmol, 1.0 equivalence) was dissolved in tetrahydrofuran (10 mL), stirred, and cooled to 0 °C. Hydrogen peroxide (30% aqueous solution, 1.23 mL, 15.28 mmol, 10 equivalence) was then added dropwise, followed by an aqueous solution of lithium hydroxide (141 mg, 3.36 mmol, 2.2 equivalence, 2 mL). The reaction mixture was stirred at 0 °C for 2 hours, then quenched with sodium bisulfite solution (1.3 M, 17.63 mL, 22.92 mmol, 15 equivalence), and the pH was adjusted to 9 with sodium hydroxide solution (2 M). The solution was extracted with methyl tert-butyl ether (20 mL × 2). The remaining aqueous phase was then acidified to pH 5 with citric acid solution (1 M). The aqueous phase was extracted with methyl tert-butyl ether (20 mL × 3), the combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 8b. ESI m / z 309.2 [M+H-tert-butyl] + .LCMS:product:Rt=1.284min.

[0518] Step 3): To a toluene (5 mL) solution of compound 8b (440 mg, 1.21 mmol, 1.0 equivalence), O-tert-butyl-N,N-diisopropylisourea (1209.46 mg, 6.04 mmol, 5 equivalence) was added, and the mixture was stirred at 80 °C for 18 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 4 / 1) to give compound 8c. ESI m / z 443.2 [M + Na] + .LCMS:product:Rt=1.505min.

[0519] Step 4): Compound 8c (400 mg, 0.95 mmol) was dissolved in ethyl acetate (6 mL), and 10% palladium on carbon (200 mg, 1.88 mmol) was added. The mixture was stirred at room temperature under hydrogen atmosphere for 2 hours. The mixture was filtered and concentrated under reduced pressure to give compound 8d. ESI m / z 291.2 [M-Boc] + .LCMS:product:Rt=1.165min.

[0520] Step 5): Compound 8d (330 mg, 0.85 mmol) was dissolved in 2-methyltetrahydrofuran (4 mL), and N,N'-carbonyldiimidazole (82.21 mg, 0.51 mmol, 0.6 equivalence) was added. The mixture was stirred at 70 °C for 18 hours. The mixture was diluted with 20 mL of water and extracted with ethyl acetate (20 mL × 2). The combined organic layers were washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 1 / 4) to give compound 8e. ESI m / z 707.4 [M-Boc] + .LCMS:product:Rt=1.958min.

[0521] Step 6): Compound 8e (430 mg, 0.53 mmol) was dissolved in N,N-dimethylformamide (5 mL), sodium hydroxide (42.62 mg, 1.07 mmol, 2 equivalences) was added, and the mixture was stirred for 0.5 h. Then, inter 5 (299.50 mg, 0.64 mmol, 1.2 equivalences) was added, and the mixture was stirred at room temperature for 1 h. The mixture was quenched with saturated ammonium chloride aqueous solution (40 mL) and extracted with ethyl acetate (30 mL × 2). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 2 / 3) to give crude compound 8f, which was used directly in the next reaction.

[0522] Step 7): Compound 8f (540 mg, 0.45 mmol, 1.0 equivalence) was dissolved in hydrochloric acid / dioxane (5 mL). The solution was stirred at 25 °C for 16 hours. The resulting reaction mixture was concentrated and purified by preparative high-performance liquid chromatography (ammonium bicarbonate) to give compound 8. ESI m / z 957.4 [M+H] + .

[0523] LCMS:product:Rt = 0.594 min;

[0524] 1 H NMR(400MHz,D2O)δ7.20(t,J=7.5Hz,2H),7.07(dd,J=17.4,9.7Hz,6H),6.87(t, J=7.8Hz,2H),6.74(d,J=7.7Hz,2H),6.56(d,J=8.1Hz,2H),6.48(s,2H),4.70–4. 68(s,4H),3.29(ddd,J=11.3,5.4,2.8Hz,4H),3.13(dtd,J=17.4,12.2,7.4Hz,8H ),2.76–2.55(m,10H),2.38–2.19(m,10H),2.06–1.94(m,4H),1.70–1.57(m,4H).

[0525] Example 9: Synthesis of Compound 9

[0526] Step 1): Compound 2d (2.5 g, 5.26 mmol, 1.0 equivalence) was dissolved in methanol (40 mL), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (0.38 g, 0.53 mmol, 0.1 equivalence) and triethylamine (2.19 mL, 15.77 mmol, 3.0 equivalence) were added. The mixture was purged three times with carbon monoxide, and then heated under reflux at 70 °C with stirring for 16 hours. The reaction mixture was concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography with petroleum ether / tert-butyl methyl ether = 1 / 1 to give compound 9a. ESI m / z 477.2 [M+Na] + .LCMS:product:Rt=1.667min.

[0527] Step 2): Compound 9a (3 g, 6.60 mmol, 1.0 equivalence) was dissolved in ethanol (30 mL), and sodium borohydride (0.75 g, 19.80 mmol, 3.0 equivalence) was added at 0 °C. The mixture was stirred at 0 °C for 16 hours until room temperature. The resulting reaction mixture was added to water (50 mL) and extracted with ethyl acetate (50 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with petroleum ether / ethyl acetate = 1 / 1 to give compound 9b. ESI m / z 427.2 [M+H] + .LCMS:product:Rt=1.341min.

[0528] Step 3): Compound 9b (650 mg, 1.58 mmol, 1.0 equivalence) was dissolved in dichloromethane (40 mL), and Dys-Martin oxidant (3.88 g, 9.14 mmol, 1.5 equivalence) was added. The mixture was stirred at room temperature for 2 hours. The resulting reaction mixture was quenched with saturated sodium sulfite aqueous solution, extracted with dichloromethane (50 mL × 2), and washed with saturated sodium bicarbonate aqueous solution. The organic layers were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with petroleum ether / tert-butyl methyl ether = 1 / 1 to give compound 9c. ESI m / z 447.2 [M + Na] + .LCMS:product:Rt=1.696min.

[0529] Step 4): Compound 9c (600 mg, 1.41 mmol, 1.0 equivalence) and compound 4a (697.96 mg, 1.70 mmol, 1.2 equivalence) were dissolved in dichloromethane (10 mL), and acetic acid (0.01 mL, 0.17 mmol) was added. The mixture was stirred for 30 min, followed by the addition of sodium triacetoxyborohydride (898.57 mg, 4.24 mmol, 3.0 equivalence). The mixture was stirred at room temperature for 3 h. The reaction mixture was added to a saturated aqueous solution of sodium bicarbonate (50 mL) and extracted with dichloromethane (50 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with petroleum ether / tert-butyl methyl ether = 1 / 1 to give compound 9d. ESI m / z 820.4 [M+H] + .LCMS:product:Rt=1.596min.

[0530] Step 5): Compound 9d (800 mg, 0.98 mmol) and (9H-fluorene-9-yl)methyl(2-oxoethyl)carbamate (548.82 mg, 1.95 mmol, 2.0 equivalence) were dissolved in dichloromethane (20 mL), and acetic acid (0.02 mL, 0.35 mmol) was added and stirred for 30 min. Then, sodium triacetoxyborohydride (620.22 mg, 2.93 mmol, 3.0 equivalence) was added. The mixture was stirred at room temperature for 3 h. A saturated aqueous solution of sodium bicarbonate (50 mL) was then added to the reaction mixture, and the mixture was extracted with dichloromethane (50 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using dichloromethane / ethyl acetate = 1 / 1 to give compound 9e. ESI m / z 1085.4 [M+H] + .LCMS:product:Rt=2.078min.

[0531] Step 6): Compound 9e (800 mg, 0.74 mmol, 1.0 equivalence) was dissolved in tetrahydrofuran (2.0 M) of dimethylamine (10 mL, 20.00 mmol). The mixture was stirred at room temperature for 3 hours. The resulting reaction mixture was concentrated under reduced pressure to give a crude product. The residue was purified by column chromatography in dichloromethane / methanol (1 / 1) to give compound 9f. ESI m / z 863.4 [M+H] + .LCMS:product:Rt=1.542min.

[0532] Step 7): Compound 9f (260 mg, 0.30 mmol, 1.0 equivalence) and inter 4 (145.85 mg, 0.36 mmol, 1.2 equivalence) were dissolved in dichloromethane (5 mL), and acetic acid (0.01 mL, 0.17 mmol) was added. The mixture was stirred for 30 min, followed by the addition of sodium triacetoxyborohydride (191.51 mg, 0.90 mmol, 3.0 equivalence). The mixture was stirred at room temperature for 3 h. The resulting reaction mixture was added to a saturated aqueous solution of sodium bicarbonate (30 mL) and extracted with dichloromethane (30 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by dichloromethane / methanol = 10 / 1 column chromatography to give 9 g of compound. ESI m / z 1250.6 [M+H] + .LCMS:product:Rt=1.800min.

[0533] Step 8): 9 g (200 mg, 0.16 mmol, 1.0 equivalence) of compound 9 g and inter 7 (87.21 mg, 0.21 mmol, 1.3 equivalence) were dissolved in N,N-dimethylformamide (4 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (79.05 mg, 0.21 mmol, 1.3 equivalence) and N,N-diisopropylethylamine (0.08 mL, 0.48 mmol, 3.0 equivalence) were added. The mixture was stirred at room temperature for 16 hours. The reaction mixture was added to water (20 mL), extracted with ethyl acetate (20 mL × 3), and washed with brine (20 mL × 2). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with petroleum ether / ethyl acetate = 1 / 1 to give compound 9 h. ESI m / z 776.6 [M-100 / 2+H] + .LCMS:product:Rt=2.533min.

[0534] Step 9): Compound 9 (210 mg, 0.13 mmol, 1.0 equivalence) was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (3 mL, 39.20 mmol). The mixture was stirred at room temperature for 16 hours. The resulting reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative high-performance liquid chromatography (formic acid) to give compound 9. ESI m / z 514.3 [M / 2+H] + .

[0535] LCMS:product:Rt = 0.652 min.

[0536] 1H NMR(400MHz,D2O)δ7.35–6.79(m,10H),4.60–4.36(m,2H),3.97–3.84(m,2H),3.59(dd,J=38.3,21.4Hz,3H),3.44–3.0 7(m,12H),2.97–2.30(m,22H),2.01(dd,J=33.0,7.8Hz,4H),1.72(ddd,J=25.5,17.9,11.6Hz,5H),1.53–1.29(m,2H).

[0537] Example 10: Synthesis of Compound 10

[0538] Step 1): Compound 10c1 (2 g, 12.72 mmol, 1.0 equivalence) was dissolved in carbon tetrachloride (20 mL), followed by the addition of N-bromosuccinimide (2.7 g, 15.27 mmol, 1.2 equivalence) and azobisisobutyronitrile (0.41 g, 2.54 mmol, 0.2 equivalence). The reaction mixture was stirred at 80 °C for 18 hours. The reaction mixture was concentrated under reduced pressure to give a crude product. The crude product was diluted with ethyl acetate (50 mL) and water (50 mL), and extracted with ethyl acetate (50 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure to give compound 10c2. ESI m / z 315.8 [M+H] + .LCMS:product:Rt=1.291min.

[0539] Step 2): Compound 10c2 (3.0 g, 9.52 mmol, 1.0 equivalence) was dissolved in tetrahydrofuran (50 mL), and N,N-diisopropylethylamine (2.83 g, 21.91 mmol, 2.3 equivalence) and diethyl phosphate (0.65 g, 4.76 mmol, 0.5 equivalence) were added. The reaction mixture was stirred at room temperature for 2 hours. Water (50 mL) was then added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid column chromatography (dichloromethane / tert-butyl methyl ether = 1 / 1) to give compound 10c3. ESI m / z 236.0 [M+H] + .LCMS:product:Rt=1.094min.

[0540] Step 3): Under a nitrogen atmosphere, compound 1c (6.5 g, 16.15 mmol, 1.0 equivalence) was dissolved in tetrahydrofuran (50 mL) and reacted at 0 °C. Lithium bis(trimethylsilyl)amino (19.38 mL, 19.38 mmol, 1.2 equivalence) was then added. The reaction mixture was stirred at 0 °C for 30 min. Then, a tetrahydrofuran solution (50 mL) of compound 10c3 (4.0 g, 16.94 mmol, 1.05 equivalence) was added. The reaction mixture was stirred at room temperature for 2 h. The mixture was quenched with saturated ammonium chloride solution (100 mL) and extracted with ethyl acetate (200 mL × 2). The organic phases were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 1 / 1) to give compound 10c4. ESI m / z 580.2 [M+Na] + .LCMS:product:Rt=1.613min.

[0541] Step 4): Under a nitrogen atmosphere, a stirred solution of compound 10c4 (1.5 g, 2.69 mmol, 1.0 equivalence) was dissolved in tetrahydrofuran (50 mL) at 0 °C. Hydrogen peroxide (30% aqueous solution, 2.0 mL, 26.90 mmol, 10.0 equivalence) was slowly added dropwise, followed by a solution of lithium hydroxide monohydrate (169.3 mg, 4.03 mmol, 1.5 equivalence) in water (10 mL). The reaction mixture was stirred at 0 °C for 4 hours, then quenched with sodium bisulfite solution (2.8 g, 16.56 mmol, 10.0 equivalence), and the pH was adjusted to 5 with citric acid (1 M). The aqueous phase was extracted with methyl tert-butyl ether (100 mL × 3), and the combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 10c5. ESI m / z 421.1 [M+Na] + .LCMS:product:Rt=1.39min.

[0542] Step 5): Compound 10c5 (0.5 g, 0.50 mmol, 1.0 equivalence) was dissolved in tetrahydrofuran (10 mL), and O-tert-butyl-N,N-diisopropylisourea (0.5 g, 2.50 mmol, 5.0 equivalence) was added. The mixture was stirred at 65 °C for 2 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 2). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 1 / 1) to give compound 10c6. ESI m / z 477.2 [M + Na] +.LCMS:product:Rt=1.402min.

[0543] Step 6): Compound 10c6 (300.0 mg, 0.66 mmol) was dissolved in methanol (4 mL) and water (2 mL), and lithium hydroxide monohydrate (55.38 mg, 1.32 mmol, 2.0 equivalence) was added. The reaction mixture was stirred at room temperature for 18 hours. The resulting reaction mixture was neutralized to pH 3 with 1 M hydrochloric acid. The mixture was extracted with ethyl acetate (50 mL × 2), and the organic phase was concentrated under reduced pressure to give compound 10c. ESI m / z 463.2 [M+Na]+.LCMS:product:Rt = 1.384 min.

[0544] Step 7): Dissolve (9H-fluorene-9-yl)methyl(2-aminoethyl)carbamate hydrochloride (200 mg, 0.63 mmol, 1.0 equivalence), acetic acid (37.67 mg, 0.63 mmol, 1.0 equivalence), and inter4 (886.02 mg, 2.20 mmol, 3.5 equivalence) in dichloroethane (8 mL) and stir at 50 °C for 1 hour. Then add sodium borohydride acetate (398.9 mg, 1.88 mmol, 3.0 equivalence) in portions. Continue stirring the reaction mixture at 50 °C for 2 hours. Then quench the reaction with saturated sodium bicarbonate aqueous solution (10 mL). Separate the aqueous layer and extract with dichloromethane (10 mL × 3). Combine the organic layers, wash with brine (10 mL), dry with anhydrous sodium sulfate, and filter. Concentrate the filtrate under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography, eluting with a dichloromethane / (dichloromethane / methanol = 10:1) (0-38%) mixed solvent to give compound 10a. ESI m / z 1057.6 [M+H] + .LCMS:product:Rt=1.793min.

[0545] Step 8): Compound 10a (760 mg, 0.60 mmol, 1.0 equivalence) was dissolved in a 2 M (10 mL) solution of dimethylamine in tetrahydrofuran. The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography, eluting with dichloromethane / methanol (0-10%) to give compound 10b. ESI m / z 835.6 [M+H] + .LCMS:product:Rt=1.616min.

[0546] Step 9): To a dichloromethane solution (5 mL) containing compound 10b (208 mg, 0.25 mmol, 1.0 equivalence), compound 10c (162.94 mg, 0.37 mmol, 1.5 equivalence), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (112.51 mg, 0.30 mmol, 1.2 equivalence), N,N-diisopropylethylamine (0.13 mL, 0.74 mmol, 3.0 equivalence) was added. The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was then quenched with water (5 mL). The aqueous phase was extracted with dichloromethane (5 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography, eluting with dichloromethane / (dichloromethane / methanol = 10:1) (0-25%) to give compound 10d. ESI m / z 1257.6 [M+H] + .LCMS:product:Rt=1.519min.

[0547] Step 10): Compound 10d (369 mg, 0.22 mmol, 1.0 equivalence) was dissolved in N,N-dimethylformamide (7 mL), and sodium hydride (26.76 mg, 0.67 mmol, 3.0 equivalence) (60%) was added. The reaction mixture was stirred at 25 °C for 30 min. Then inter 5 (104.45 mg, 0.22 mmol, 1.0 equivalence) was added. The reaction mixture was stirred at 25 °C for 3 h. The reaction mixture was quenched with water (15 mL). The aqueous layer was extracted with ethyl acetate (5 mL × 3). The combined organic phases were washed with brine (5 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography, eluting with dichloromethane / (dichloromethane / methanol = 10:1) (0-16%) to give compound 10e. ESI m / z 1645.0 [M+H] + .LCMS:product:Rt=1.657min.

[0548] Step 11): Trifluoroacetic acid (3 mL) was added to dichloromethane containing compound 10e (230 mg, 0.12 mmol, 1.0 equivalence). The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was then concentrated under reduced pressure to obtain a residue. The residue was purified by preparative high-performance liquid chromatography (preparative grade HPLC) (ammonium bicarbonate) to give compound 10. ESI m / z 1018.5 [MH] - .LCMS:product:Rt=1.017min. 1H NMR(400MHz,D2O)δ7.34–7.30(m,1H),7.18–7.12(m,3H),7.09–6.98(m,6H), 6.92–6.83(m,3H),4.92–4.78(m,1H),4.31–4.26(m,1H),4.17–3.84(m,1H), 3.54–3.21(m,12H),3.15–2.86(m,5H),2.79–2.66(m,8H),2.62–2.48(m,6H) ,2.43–2.23(m,8H),2.05–1.96(m,3H),1.70–1.55(m,5H),1.48–1.18(m,2H).

[0549] Example 11: Synthesis of Compound 11

[0550] Step 1): Compound 6a1 (400.1 mg, 1.05 mmol, 0.84 equivalence) was dissolved in dichloromethane (6 mL), and (9H-fluorene-9-yl)methyl(2-aminoethyl)carbamate (400.2 mg, 1.25 mmol, 1.0 equivalence) and sodium triacetoxyborohydride (531.85 mg, 2.51 mmol, 2.0 equivalence) were added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (3 × 40 mL). The organic phases were combined, washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0 / 1) to give compound 11a. ESI m / z 648.3 [M+H] + .LCMS:product:Rt=1.120min.

[0551] Step 2): Compound 11a (400.1 mg, 0.62 mmol, 1.0 equivalence) was dissolved in a 2 M tetrahydrofuran solution (5 mL). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 5 / 1) to give compound 11b. ESI m / z 426.2 [M+H] + .LCMS:product:Rt=0.913min.

[0552] Step 3): To a solution (10 mL) of N,N-dimethylformamide containing compound 11b (100.0 mg, 0.24 mmol, 1.0 equivalence), add inter 5 (440.3 mg, 0.94 mmol, 4.0 equivalence) and cesium carbonate (382.8 mg, 1.18 mmol, 5.0 equivalence). Stir the mixture at 50 °C for 3 hours. Dilute the reaction mixture with water (150 mL) and extract with ethyl acetate (3 × 30 mL). Wash the combined organic phases with brine (20 mL × 3), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to give the crude product. Purify the crude product by silica gel column chromatography (petroleum ether: methyl tert-butyl ether = 0:1) to give compound 11c. ESI m / z 1588.0 [M+H] + .LCMS:product:Rt=1.616min.

[0553] Step 4): Compound 11c (220.1 mg, 0.14 mmol, 1.0 equivalence) was dissolved in methanol (1 mL) and tetrahydrofuran (1 mL), and lithium hydroxide monohydrate (23.2 mg, 0.55 mmol, 4.0 equivalence) and water (1 mL) were added. The reaction mixture was stirred at 50 °C for 18 hours. The resulting reaction mixture was adjusted to pH 3 with 10% hydrochloric acid aqueous solution. The mixture was extracted with ethyl acetate (30 mL × 3), and the organic phase was concentrated under reduced pressure to give compound 11d. ESI m / z 737.6 [M-Boc / 2+H]+.LCMS:product:Rt=1.595min.

[0554] Step 5): Trifluoroacetic acid (3 mL) was added to a solution of dichloromethane (3 mL) containing compound 11d (190.1 mg, 0.12 mmol, 1.0 equivalence). The reaction mixture was stirred at room temperature for 18 hours. The resulting reaction mixture was concentrated and purified by preparative high-performance liquid chromatography (ammonium bicarbonate) to give compound 11. ESI m / z 1006.5 [M+H] + .

[0555] LCMS:product:Rt = 0.732 min.

[0556] 1H NMR(400MHz,D2O)δ7.42–7.34(m,3H),7.26–6.97(m,15H),4.59(s,2H),4.43(s,2H),3.65(d,J=10.4Hz,8H),3.37–3.2 6(m,6H),3.14(dd,J=19.2,9.5Hz,3H),2.85–2.58(m,13H),2.34(d,J=4.4Hz,6H),2.01(s,3H),1.63(d,J=5.2Hz,3H).

[0557] Example 12: Synthesis of Compound 12

[0558] Step 1): Compound 12d1 (1 g, 4.71 mmol) was dissolved in sulfuric acid (6 mL), and potassium nitrate (0.49 g, 4.85 mmol, 1.0 equivalent) was added at 0 °C. The mixture was stirred at 25 °C for 16 hours. The mixture was poured into water at 0 °C (80 mL), producing a large amount of pale yellow solid. The mixture was then filtered to obtain the solid. The solid was washed with water (20 mL) and concentrated under reduced pressure to give compound 12d2. ESI m / z 259.0 [M+H] + .LCMS:product:Rt=0.38min.

[0559] Step 2): Compound 12d2 (0.76 g, 2.96 mmol, 1.0 equivalence) was dissolved in dichloromethane (10 mL), and (2-methylpropyl-2-yl)cyclopentane peroxycarbonate anhydride (0.78 g, 3.57 mmol, 1.2 equivalence) and triethylamine (1.25 mL, 8.99 mmol, 3.0 equivalence) were added. The mixture was stirred at 25 °C for 16 hours. The mixture was poured into water (20 mL), extracted with dichloromethane (20 mL × 3), and the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give compound 12d3. ESI m / z 302.9 [MC(CH3)3+H] + .

[0560] LCMS:product:Rt = 1.39 min.

[0561] Step 3): Compound 12d3 (770 mg, 2.13 mmol, 1.0 equivalence) was dissolved in ethanol (15 mL), and then iron powder (1190 mg, 21.31 mmol, 10 equivalence) was added. Subsequently, ammonium chloride (1140 mg, 21.31 mmol, 10 equivalence) was dissolved in water (5 mL) and added to the mixture, which was then stirred at 25 °C for 2 hours. The reaction mixture was filtered, and the filtrate was extracted with water (10 mL), ethyl acetate (10 mL × 3), and the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 12d4. ESI m / z 327.0 [M+H] + .LCMS:product:Rt=1.30min.

[0562] Step 4): Compound 12d4 (560 mg, 1.68 mmol, 1.0 equivalence) was dissolved in N,N-dimethylformamide (15 mL), and triethylamine (5 mL), methanol (5 mL), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (245 mg, 0.33 mmol, 0.2 equivalence) were added. The mixture was stirred at 90 °C for 16 hours under carbon monoxide protection at 15 psi. The mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL × 3). The organic layers were combined, washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (petroleum ether / tert-butyl methyl ether = 1 / 1) to give compound 12d5. ESI m / z 307.2 [M+H] + .LCMS:product:Rt=1.27min.

[0563] Step 5): Compound 12d5 (400 mg, 1.25 mmol, 1.0 equivalence) was dissolved in acetonitrile (10 mL), and then 2-methyl-2-(nitroso)propane (270 mg, 2.62 mmol, 2.0 equivalence) was added at 0 °C. After stirring the mixture at 0 °C for 1 hour, cuprous bromide (I) (270 mg, 1.88 mmol, 1.5 equivalence) was slowly added, and the reaction was heated to 60 °C and maintained for 5 hours. The mixture was poured into water (10 mL) and extracted with ethyl acetate (20 mL × 3). The organic layers were combined, washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give compound 12d6. ESI m / z 314.0 [MC(CH3)3+H] + .LCMS:product:Rt=1.39min.

[0564] Step 6): Compound 12d6 (240 mg, 0.26 mmol) was dissolved in dioxane (2 mL) and water (0.4 mL), and (3-formaldehydephenyl)boronic acid (97 mg, 0.65 mmol, 2.5 equivalences), tripotassium phosphate (412 mg, 1.94 mmol, 7.5 equivalences), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (40 mg, 0.05 mmol, 0.2 equivalences) were added. The mixture was stirred at 90 °C for 6 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 12d. ESI m / z 418.2 [M+Na] + .LCMS:product:Rt=1.41min.

[0565] Step 7): Inter 6 (3.00 g, 7.42 mmol, 1.0 equivalence) and (9H-fluorene-9-yl)methyl(2-oxoethyl)carbamate (2.41 g, 8.57 mmol, 1.16 equivalence) were dissolved in methanol (20 mL) and stirred for 1 hour. Sodium borohydride (0.57 g, 15.07 mmol, 2.0 equivalence) was then added to the mixture, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water (60 mL) and extracted with ethyl acetate (40 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0 / 1) to give compound 12a. ESI m / z 670.4 [M+H] + .LCMS:product:Rt=1.15min.

[0566] Step 8): Compound 12a (1.5 g, 1.79 mmol, 1.0 equivalence) and inter 7 (0.85 g, 2.03 mmol, 1.1 equivalence) were dissolved in N,N-dimethylformamide (20 mL), and N,N-diisopropylethylamine (0.47 g, 3.64 mmol, 2.0 equivalence) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (1.0 g, 2.63 mmol, 1.5 equivalence) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water (60 mL) and extracted with ethyl acetate (40 mL × 3). The organic layers were combined, washed with saturated brine (40 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 12b. ESI m / z 971.6 [M-Boc+H] + .LCMS:product:Rt=1.82min.

[0567] Step 9): Compound 12b (2.1 g, 1.69 mmol, 1.0 equivalence) was dissolved in a dimethylamine solution of tetrahydrofuran (20 mL, 2 M) and stirred at 25 °C for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give compound 12c. ESI m / z 849.4 [M+H] + .LCMS:product:Rt=1.48min.

[0568] Step 10): Compound 12c (400 mg, 0.47 mmol, 1.0 equivalence) was dissolved in dichloromethane (10 mL), and compound 12d (224 mg, 0.57 mmol, 1.2 equivalence), acetic acid (9 mg, 0.05 mmol, 0.1 equivalence), and sodium triacetoxyborohydride (300 mg, 1.42 mmol, 3.0 equivalence) were added. The mixture was stirred at 40 °C for 5 hours. The reaction mixture was quenched with saturated sodium bicarbonate solution (10 mL) and extracted with dichloromethane (10 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 0 / 1) to give compound 12e. ESI m / z 1229.8 [M+H] + .LCMS:product:Rt=1.45min.

[0569] Step 11): Compound 12e (400 mg, 0.23 mmol, 1.0 equivalence) was dissolved in N,N-dimethylformamide (15 mL), and sodium hydroxide (60% dispersion in mineral oil, 37 mg, 0.92 mmol, 4.0 equivalence) was added. The mixture was stirred at 25 °C for 0.5 h. Then, inter 5 (130 mg, 0.28 mmol, 1.2 equivalence) was added to the mixture, and the mixture was stirred at 25 °C for 1 h. The mixture was poured into water (20 mL) and extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / methyl tert-butyl ether = 1 / 1) to give compound 12f. ESI m / z 758.8 [(M-Boc) / 2+H] + .LCMS:product:Rt=1.60min.

[0570] Step 12): Compound 12f (300 mg, 0.19 mmol, 1.0 equivalence) was dissolved in tetrahydrofuran (3 mL), methanol (3 mL), and water (3 mL). Lithium hydroxide monohydrate (79 mg, 1.88 mmol, 10.0 equivalence) was added, and the reaction was stirred at 60 °C for 16 hours. The reaction mixture was poured into water (10 mL), acidified to pH 5 with 1 M hydrochloric acid, and extracted with ethyl acetate (10 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 12 g of crude compound, which was used in the next step without further purification. ESI m / z 751.7 [(M-Boc) / 2+H] + .LCMS:product:Rt=1.56min.

[0571] Step 13): 12 g (240 mg, 0.15 mmol, 1.0 equivalence) of compound 12 g was dissolved in dichloromethane (9 mL), and trifluoroacetic acid (3 mL) was added. The mixture was stirred at 25 °C for 16 hours. The resulting reaction mixture was concentrated and purified by preparative high-performance liquid chromatography (formic acid) to give compound 12. ESI m / z 1034.6 [M+H] + .LCMS:product:Rt=1.03min. 1 H NMR(400MHz,D2O)δ7.55–6.55(m,18H),4.38(d,J=23.0Hz,8H),3.97–2.96(m,15H),2. 93–2.49(m,11H),2.30(d,J=74.7Hz,6H),2.03(s,3H),1.64(dd,J=20.0,10.4Hz,3H).

[0572] Example 13: Synthesis of Compound 13

[0573] Step 1): To ethanol (30 mL) containing compound 13a (5 g, 25.09 mmol, 1.0 equivalent), ethyl 2-cyanoacetate (2.69 mL, 25.09 mmol, 1.0 equivalent), triethylamine (6.96 mL, 50.19 mmol, 2.0 equivalent), and sulfur (9.76 g, 27.60 mmol, 1.1 equivalent) were added. The mixture was stirred at 80 °C for 3 hours. The mixture was filtered, and the filter cake was washed with ethyl acetate (50 mL). The filtrate was diluted with water (100 mL) and extracted with ethyl acetate (2 × 50 mL). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain the crude product. The residue was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 1 / 1) to give compound 13b. ESI m / z 327.2 [M+H] + .LCMS:product:Rt=1.304min.

[0574] Step 2): Under nitrogen protection at 0°C, cuprous bromide (2.99 g, 20.82 mmol, 1.5 equivalence) was added to an acetonitrile (50 mL) solution containing tert-butyl nitrite (3.30 mL, 27.76 mmol, 2.0 equivalence). The mixture was stirred at 0°C for 1 hour. Subsequently, compound 13b (5 g, 13.88 mmol, 1.0 equivalence) was added in portions at 0°C. The mixture was brought back to room temperature and stirred for 2 hours. The reaction solution was diluted with water (200 mL) and extracted with ethyl acetate (80 mL × 3). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain the crude product. The residue was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 5 / 1) to give compound 13c. ESI m / z 289.9 [M-Boc+H] + .LCMS:product:Rt=1.587min.

[0575] Step 3): To a mixed solution containing compound 13c (580 mg, 0.86 mmol, 1.0 eq) of 1,4-dioxane (5 mL) and water (1 mL), add (3-formylphenyl)boronic acid (257 mg, 1.71 mmol, 2.0 eq), potassium phosphate (546 mg, 2.57 mmol, 3.0 eq), and 1,1-bis(diphenylphosphine)diberberine palladium dichloride (63 mg, 0.09 mmol, 0.1 eq). The mixture was stirred at 90 °C for 3 hours under nitrogen protection. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (8 mL × 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give the crude product. The residue was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 1 / 1) to give compound 13d. ESI m / z 316.1 [M-Boc+H] + .LCMS:product:Rt=1.549min.

[0576] Step 4): To a solution of 13d (345 mg, 0.75 mmol, 1.0 equivalence) in dichloromethane (10 mL), add Inter6 (156 mg, 0.38 mmol, 0.5 equivalence), sodium triacetylborohydride (490 mg, 2.30 mmol, 3.0 equivalence), and acetic acid (0.1 mL). The mixture was stirred at room temperature for 2 hours. Then, Inter6 (156 mg, 0.38 mmol, 0.5 equivalence) was added, and the mixture was stirred at room temperature for another 2 hours. The mixture was quenched with saturated sodium bicarbonate solution (30 mL) and extracted with dichloromethane (10 mL × 2). The combined organic phases were washed with saturated brine (30 mL), filtered, and concentrated to dryness under reduced pressure to give the crude product. The residue was purified by silica gel column chromatography (petroleum ether / tetrahydrofuran = 3 / 1) to give compound 13e. ESI m / z 804.4 [M+H] + .LCMS:product:Rt=1.260min.

[0577] Step 5): To a solution of compound 13e (300 mg, 0.31 mmol, 1.0 equivalence) in dichloromethane (5 mL), add (9H-fluorene-9-yl)methyl(2-oxoethyl)carbamate (104 mg, 0.37 mmol, 1.2 equivalence), acetic acid (6 mg, 0.03 mmol, 0.1 equivalence), and sodium triacetylborohydride (197 mg, 0.93 mmol, 3.0 equivalence). The mixture was stirred at 25 °C for 18 hours. The mixture was quenched with saturated sodium bicarbonate solution (20 mL) and extracted with dichloromethane (2 × 10 mL). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness to give the crude product. The residue was purified by silica gel column chromatography (petroleum ether / tetrahydrofuran = 3 / 1) to give compound 13f. ESI m / z 1069.4 [M+H] + .LCMS:product:Rt=1.800min.

[0578] Step 6): Compound 13f (316 mg, 0.25 mmol, 1.0 equivalence) was dissolved in dimethylamine (5 mL, 10.00 mmol, 2 M tetrahydrofuran solution). The reaction mixture was stirred at 25 °C for 3 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 50 / 1) to give compound 13 g. ESI m / z 847.4 [M+H] + .LCMS:product:Rt=1.396min.

[0579] Step 7): To a solution of N,N-dimethylformamide (5 mL) containing inter 7 (150 mg, 0.36 mmol, 1.0 equivalence), N,N-diisopropylethylamine (139 mg, 1.07 mmol, 3.0 equivalence) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate (204 mg, 0.54 mmol, 1.5 equivalence) were added, and the reaction was stirred at room temperature for 0.5 h. 13 g of the compound (303 mg, 0.34 mmol, 0.95 equivalence) was added to the mixture, and the reaction was stirred at room temperature for 18 h. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (40 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give the crude product. The residue was purified by silica gel column chromatography (petroleum ether / tetrahydrofuran = 3 / 1) to give compound 13 h. ESI m / z 1250.6 [M+H] + .LCMS:product:Rt=1.831min.

[0580] Step 8): Under nitrogen protection at 0°C, sodium hydroxide (21 mg, 0.53 mmol, 3.0 equivalence) was added to a solution of N,N-dimethylformamide (5 mL) containing compound 13h (290 mg, 0.18 mmol, 1.0 equivalence). The reaction mixture was stirred at 0°C for 30 min. Subsequently, a solution of N,N-dimethylformamide (5 mL) containing inter 5 (91 mg, 0.19 mmol, 1.1 eq) was added. The reaction mixture was brought to room temperature and stirred for 1.5 h. The mixture was quenched with saturated ammonium chloride aqueous solution (20 mL) and extracted with ethyl acetate (8 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give crude product. The residue was purified by silica gel column chromatography (petroleum ether / tetrahydrofuran = 4 / 1) to give compound 13i. ESI m / z 768.6[(M-Boc) / 2+H] + .LCMS:product:Rt=1.956min.

[0581] Step 9): Compound 13i (300 mg, 0.12 mmol, 1.0 equivalence) was dissolved in a mixed solution of methanol (2 mL), tetrahydrofuran (2 mL), and water (2 mL). Lithium hydroxide (49 mg, 1.16 mmol, 10.0 equivalence) was added, and the mixture was stirred at 60 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (20 mL), adjusted to pH 5 with 1 M hydrochloric acid aqueous solution, and extracted with ethyl acetate (2 × 8 mL). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the crude product. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to give compound 13j. ESI m / z 754.6 [(M-Boc) / 2+H] + .LCMS:product:Rt=1.916min.

[0582] Step 10): Compound 13j (191 mg, 0.12 mmol, 1.0 equivalence) was dissolved in a mixed solution of dichloromethane (2 mL) and trifluoroacetic acid (2 mL), and the reaction was stirred at room temperature for 3 hours. The mixture was concentrated and purified by preparative high-performance liquid chromatography (formic acid) to obtain compound 13. ESI m / z 1040.4 [M+H] + .

[0583] LCMS:product:Rt = 0.710min.

[0584] 1H NMR(400MHz,D2O)δ7.66–7.28(m,4H),7.28–7.15(m,6H),7.15–6.62(m,6H),4.54–3.85(m,5H),3.65(s,1H),3.56–3. 22(m,11H),3.15(q,J=9.3Hz,3H),2.96(d,J=45.4Hz,5H),2.85–2.56(m,9H),2.52–1.93(m,10H),1.75–1.57(m,2H).

[0585] Example 14: Synthesis of Compound 14

[0586] Step 1): Compound 14a (14 g, 57.12 mmol, 1.0 equivalence) was dissolved in ethanol (200 mL), and glyoxal (40% aqueous solution, 7.83 mL, 171.37 mmol, 3.0 equivalence) was added. The mixture was stirred at 80 °C for 16 hours. The resulting reaction mixture was filtered and washed with ethanol (50 mL) to give compound 14b. ESI m / z 269.0 [M+H] + .LCMS:product:Rt=1.376min.

[0587] Step 2): Under a nitrogen atmosphere, compound 14b (12 g, 44.93 mmol, 1.0 equivalence) was dissolved in dichloromethane (300 mL), and diisobutylaluminum hydride (1.5 M toluene solution, 74.88 mL, 112.33 mmol, 2.5 equivalence) was added dropwise at -78 °C. The mixture was stirred at -78 °C for 16 hours to room temperature. Then, water (16.0 mL) and 15% sodium hydroxide aqueous solution (16.0 mL) were added to the reaction mixture, followed by the addition of water (16.0 mL × 3) and stirring for 30 minutes. The resulting insoluble matter was removed by filtration, the solvent was evaporated from the filtrate under reduced pressure, and the crude product was diluted with ethyl acetate (200 mL) and water (100 mL), and extracted with ethyl acetate (200 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid column chromatography with a petroleum ether / ethyl acetate ratio of 1 / 1 to give compound 14c. ESI m / z 239.0 [M+H] + .LCMS:product:Rt=0.971min.

[0588] Step 3): Compound 14c (4.0 g, 16.73 mmol, 1.0 equivalence) was dissolved in N,N-dimethylformamide (40 mL), and phosphorus tribromide (4.72 mL, 50.19 mmol, 3.0 equivalence) was added dropwise at 0 °C. The mixture was stirred at 0 °C for 3 hours to room temperature. Then, saturated sodium bicarbonate aqueous solution (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL × 3), followed by washing with brine (100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was added to petroleum ether / tert-butyl methyl ether = 10 / 1 (50 mL), stirred at room temperature for 30 minutes, then filtered and washed with petroleum ether (50 mL) to give compound 14d. ESI m / z 302.8 [M+H] + .LCMS:product:Rt=1.410min.

[0589] Step 4): Under a nitrogen atmosphere, inter 3 (6 g, 15.45 mmol, 1.0 equivalence) was dissolved in tetrahydrofuran (60 mL), and bis(trimethylsilylaminolithium) (1.0 M tetrahydrofuran solution, 18.53 mL, 18.53 mmol, 1.2 equivalence) was added at 0 °C, and the mixture was stirred at the same temperature for 30 min. Then, a tetrahydrofuran solution (10 mL) of compound 14d (3.6 g, 11.92 mmol, 0.77 equivalence) was added, and the mixture was stirred at 0 °C for 5 h and slowly heated to room temperature. The reaction mixture was quenched with saturated ammonium chloride aqueous solution (200 mL) and extracted with tert-butyl methyl ether (200 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with petroleum ether / tert-butyl methyl ether = 1 / 1 to give compound 14e. ESI m / z 553.0 [M+H-tert-butyl] + .LCMS:product:Rt=1.733min.

[0590] Step 5): Compound 14e (4.7 g, 7.71 mmol, 1.0 equivalent) was dissolved in tetrahydrofuran (60 mL), and hydrogen peroxide (30% aqueous solution, 5.99 mL, 77.11 mmol, 10.0 equivalent) was added at 0 °C. Then, an aqueous solution of lithium hydroxide (0.65 g, 15.42 mmol, 2.0 equivalent) (20 mL) was added, and the mixture was stirred at 0 °C to room temperature for 2 hours. The resulting reaction mixture was quenched with an aqueous solution of sodium bisulfite (12.03 g, 115.66 mmol, 15.0 equivalent) (20 mL) and stirred at 0 °C for 30 minutes. The reaction mixture was then neutralized to pH 9 with an aqueous solution of sodium hydroxide (2.0 M) and extracted with tert-butyl methyl ether (150 mL × 3). The aqueous layer was separated, neutralized to pH 1 with hydrochloric acid, and extracted with tert-butyl methyl ether (150 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 14f. ESI m / z 394.0 [M+H-tert-butyl] + .LCMS:product:Rt=1.418min.

[0591] Step 6): Compound 14f (1.6 g, 3.55 mmol, 1.0 equivalence) and 2-tert-butyl-N,N'-diisopropylisourea (7.12 g, 35.53 mmol, 10.0 equivalence) were dissolved in tetrahydrofuran (20 mL). The mixture was heated to 65 °C and refluxed with stirring for 2 hours. The reaction mixture was filtered and washed with ethyl acetate (20 mL × 3). The filtrate was concentrated under reduced pressure. The residue was purified by rapid column chromatography with petroleum ether / tert-butyl methyl ether = 1 / 1 to give compound 14 g. ESI m / z 452.0 [M+H-tert-butyl] + .LCMS:product:Rt=1.775min.

[0592] Step 7): 14 g (500 mg, 0.99 mmol, 1.0 equivalence) of the compound was dissolved in N,N-dimethylformamide (10 mL), and (1,1'-bis(diphenylphosphino)ferrocene)palladium dichloride (72.24 mg, 0.10 mmol, 0.1 equivalence), 4-dimethylaminopyridine (241.23 mg, 1.97 mmol, 2.0 equivalence), and triethylsilane (0.48 mL, 2.96 mmol, 3.0 equivalence) were added. The mixture was purged three times with carbon monoxide gas, then heated to 90 °C under reflux and stirred for 5 hours. The reaction mixture was cooled to room temperature, water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3), and washed with brine (50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid column chromatography using petroleum ether / tert-butyl methyl ether = 1 / 1 as eluent, yielding the compound after 14 hours. ESI m / z 400.2 [M+H-tert-butyl] + .LCMS:product:Rt=1.698min.

[0593] Step 8): Compound 2f (156.9 mg, 0.37 mmol, 1.2 equivalences) was dissolved in dichloroethane (5 mL), and compound 14h (140.0 mg, 0.31 mmol, 1.0 equivalences) and sodium triacetoxyborohydride (130.2 mg, 0.61 mmol, 2.0 equivalences) were added. The reaction mixture was stirred at room temperature for 2 hours. The mixture was poured into water (60 mL) and extracted with ethyl acetate (3 × 40 mL). The organic phases were combined, washed with saturated brine (40 mL × 3), dried over anhydrous sodium sulfate, and concentrated under vacuum to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0 / 1) to give compound 14i. ESI m / z 865.4 [M+H] + .LCMS:product:Rt=1.294min.

[0594] Step 9): Compound 14i (240.0 mg, 0.28 mmol, 1.0 equivalence) was dissolved in dichloroethane (5 mL), and (9H-fluorene-9-yl)methyl(2-oxoethyl)carbamate (117.1 mg, 0.42 mmol, 1.5 equivalence) and sodium triacetoxyborohydride (117.6 mg, 0.55 mmol, 2.0 equivalence) were added. The reaction mixture was stirred at room temperature for 2 hours. The mixture was poured into water (60 mL) and extracted with ethyl acetate (3 × 40 mL). The organic phases were combined, washed with brine (40 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0 / 1) to give compound 14j. ESI m / z 1131.6 [M+H] + .LCMS:product:Rt=1.567min.

[0595] Step 10): Compound 14j (800.1 mg, 0.71 mmol, 1.0 equivalence) was dissolved in a 2 M solution of dimethylamine in tetrahydrofuran (2 mL). The reaction mixture was stirred at room temperature for 18 hours. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 4 / 1) to give compound 14k. ESI m / z 908.6 [M+H] + .LCMS:product:Rt=1.220min.

[0596] Step 11): Compound 14k (300.1 mg, 0.33 mmol) was dissolved in tetrahydrofuran (10 mL), and Inter 7 (138.5 mg, 0.33 mmol, 1.0 equivalence), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (125.6 mg, 0.33 mmol, 1.0 equivalence), and N,N-diisopropylethylamine (42.69 mg, 0.33 mmol, 1.0 equivalence) were added. The reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography (dichloromethane / methanol = 4 / 1) to give compound 14l. ESI m / z 1310.8 [M+H] + .LCMS:product:Rt=1.532min.

[0597] Step 12): Compound 14l (400 mg, 0.29 mmol, 1.0 equivalence) was dissolved in N,N-dimethylformamide (5 mL), and sodium hydride (69.6 mg, 1.74 mmol, 6.0 equivalence) was added. The reaction mixture was stirred for 0.5 h. Then, inter 5 (271.8 mg, 0.58 mmol, 2.0 equivalence) was added. The reaction mixture was stirred at room temperature for 4 h. The mixture was quenched with aqueous ammonium chloride solution and extracted with ethyl acetate (30 mL × 5). The organic phase was concentrated under vacuum to give the crude product. The crude product was purified by rapid column chromatography (dichloromethane / methanol = 20 / 1) to give compound 14m. ESI m / z 799.2 [(M-Boc) / 2+H] + .LCMS:product:Rt=1.704min.

[0598] Step 13): Compound 14m (300.1 mg, 0.17 mmol, 1.0 equivalence) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (3 mL) was added. The reaction mixture was stirred at room temperature for 4 hours. The resulting reaction mixture was concentrated and purified by preparative high-performance liquid chromatography (ammonium bicarbonate) to give compound 14. ESI m / z 536.9 [M / 2+H] + .

[0599] LCMS:product:Rt = 0.628 min.

[0600] 1 H NMR(400MHz,D2O)δ8.81–8.49(m,2H),7.78–7.59(m,2H),7.26–6.53(m,9H),4.51–4.26(m,2H),4.15–3.69(m,4H),3.5 1–3.03(m,14H),2.99–2.69(m,10H),2.63–2.13(m,12H),1.97(t,J=18.4Hz,4H),1.82–1.65(m,3H),1.60–1.33(m,3H)

[0601] Example 15: Synthesis of Compound 15

[0602] Step 1): Dissolve inter 7 (3.00 g, 7.15 mmol, 1.0 equivalence) in N,N-dimethylformamide (40 mL), add 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (3.54 g, 9.31 mmol, 1.3 equivalence) and N,N-diisopropylethylamine (2.80 g, 21.66 mmol, 3.0 equivalence). Stir the mixture at 15 °C for 0.5 h, then add 2,2-dimethoxyethylamine (0.90 g, 8.56 mmol, 1.2 equivalence), and continue the reaction for 2 h. Add water (50 mL) to the mixture, then extract with ethyl acetate (30 mL × 3). Wash the combined organic layers with saturated brine (50 mL × 2), dry with anhydrous sodium sulfate, and concentrate under reduced pressure to give the crude product. The residue was purified by rapid column chromatography (petroleum ether / methyl tert-butyl ether = 1 / 0 to 3 / 7) to give compound 15l1. ESI m / z 407.2 [M-Boc+H] + .LCMS:product:Rt=1.612min.

[0603] Step 2): Compound 15l1 (3.36 g, 5.68 mmol, 1.0 equivalence) was dissolved in N,N-dimethylformamide (30 mL), and sodium hydrogen (0.70 g, 17.50 mmol, 3.08 equivalence) was added at 0 °C. The mixture was stirred at 15 °C for 1 hour. Then, a solution of inter 5 (3.20 g, 6.83 mmol, 1.2 equivalence) in N,N-dimethylformamide (30 mL) was added at 0 °C, and the reaction was stirred at 15 °C for 1 hour. The mixture was poured into an aqueous solution of ammonium chloride (100 mL) and then extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with a saturated brine solution (50 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The residue was then purified by rapid column chromatography (n-hexane / methyl tert-butyl ether = 1 / 0 to 1 / 1) to give compound 15l2. ESI m / z 794.4 [M+H] + .LCMS:product:Rt=2.024min.

[0604] Step 3): Compound 15l2 (1.00 g, 1.05 mmol, 1.0 equivalent) was dissolved in acetone (20 mL), and pyridinium-4-methylbenzenesulfonate (3 g, 11.94 mmol, 11.38 equivalent) was added. The mixture was stirred at 50 °C for 36 hours. The reaction mixture was filtered and concentrated to give crude compound 15l. ESI m / z 748.4 [M-Boc+H] + .LCMS:product:Rt=1.939min.

[0605] Step 4): Boron tribromide (8.3 mL, 86.14 mmol, 2.0 equivalence) was added to a solution of compound 15a (10 g, 43.28 mmol, 1.0 equivalence) in dichloromethane (100 mL) at 0 °C, and the mixture was slowly brought back to room temperature and stirred for 2 hours. The reaction mixture was then quenched with methanol (100 mL) and concentrated under vacuum to give compound 15b. ESI m / z 218.9 [M+H] + .LCMS:product:Rt=0.818min.

[0606] Step 5): Potassium fluoride (9.5 g, 163.51 mmol, 5.0 equivalence) and dibromomethane (4.6 mL, 65.62 mmol, 2.0 equivalence) were added to an N,N-dimethylformamide solution (80 mL) of compound 15b (7.3 g, 32.49 mmol, 1.0 equivalence). The mixture was stirred at 100 °C for 18 hours. After filtration, water (300 mL) was added, followed by extraction with ethyl acetate (150 mL × 3). The combined organic phases were washed with brine (200 mL × 3), dried over sodium sulfate, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 1 / 0 to 49 / 1) to give compound 15c. ESI m / z 230.8 [M+H] + .LCMS:product:Rt=1.097min.

[0607] Step 6): Sodium borohydride (1 g, 26.43 mmol, 2.0 equivalent) was added to a methanol solution (30 mL) of compound 15c (3 g, 13.10 mmol, 1.0 equivalent) at 0 °C, and the mixture was stirred at room temperature for 1 hour. The reaction was quenched with ammonium chloride (60 mL), and then extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (40 mL x 3), dried over sodium sulfate, and concentrated under reduced pressure to give compound 15d. ESI m / z 215.0 [M+H-H2O] + .LCMS:product:Rt=0.944min.

[0608] Step 7): Triphenylphosphine (3.7 g, 14.11 mmol, 1.1 equivalence) and N-bromosuccinimide (2.7 g, 15.17 mmol, 1.2 equivalence) were added to a dichloromethane solution (60 mL) of compound 15d (3.2 g, 12.73 mmol, 1.0 equivalence), and the mixture was stirred at room temperature for 3 hours. A saturated aqueous solution of sodium bicarbonate (50 mL) was added to the mixture, followed by extraction with dichloromethane (30 mL × 2). The organic phases were combined, washed with saturated brine (50 mL × 2), dried over sodium sulfate, and concentrated under reduced pressure to obtain the residue. The residue was purified by rapid column chromatography (petroleum ether / tert-butyl methyl ether = 1 / 0 to 4 / 1) to give compound 15e. LCMS:product:Rt = 1.319 min. 1 H NMR (400MHz, CDCl3) δ7.02 (d, J = 1.5 Hz, 1H), 6.82 (d, J = 1.5 Hz, 1H), 6.06 (s, 2H), 4.40 (s, 2H).

[0609] Step 8): Under a nitrogen atmosphere, inter 3 (2 g, 5.15 mmol, 1.0 equivalence) was dissolved in a tetrahydrofuran (12 mL) solution, and bis(trimethylsilylaminolithium) (5.8 mL, 5.80 mmol, 1.13 equivalence) was added at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. Subsequently, a tetrahydrofuran solution (12 mL) of compound 15e (1 g, 3.21 mmol, 0.62 equivalence) was added. The reaction mixture was stirred at room temperature for 3 h. The resulting reaction mixture was quenched with a saturated aqueous citric acid solution (30 mL), extracted with ethyl acetate (30 mL × 3), and washed with water (40 mL) and brine (40 mL). The combined organic phases were dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid column chromatography (petroleum ether / tert-butyl methyl ether = 2 / 3) to give compound 15f. ESI m / z 623.2 [M + Na] + .LCMS:product:Rt=1.490min.

[0610] Step 9): At 0°C, hydrogen peroxide (30% aqueous solution, 1.90 mL, 24.47 mmol, 10.0 equivalence) was added dropwise to tetrahydrofuran (15 mL) of compound 15f (1.6 g, 2.44 mmol, 1.0 equivalence). Then, a solution of lithium hydroxide (0.21 g, 5.00 mmol, 2.0 equivalence) in water (5 mL) was added. The reaction mixture was stirred at 0°C for 2 hours. The resulting reaction mixture was quenched with an aqueous solution of sodium bisulfite (3.80 g, 36.52 mmol) (40 mL) and stirred at 0°C for 30 minutes. The reaction mixture was then neutralized to pH 10 with sodium hydroxide (1.0 M) and extracted with methyl tert-butyl ether (40 mL × 3). The aqueous layer was separated, neutralized to pH 5 with an aqueous solution of citric acid (1.0 M), and extracted with methyl tert-butyl ether (50 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to give 15 g of the compound. ESI m / z 388.0 [MC(CH3)3+H] + .LCMS:product:Rt=0.937min.

[0611] Step 10): Add 2-tert-butyl-N,N'-diisopropylisourea (2.4 mL, 10.67 mmol, 5.0 equivalence) to a tetrahydrofuran solution containing 15 g (950 mg, 2.15 mmol, 1.0 equivalence). Stir the reaction mixture at 65 °C for 0.5 h. Filter the reaction mixture to remove the white solid, and concentrate the filtrate under reduced pressure. Purify the residue by silica gel column chromatography (petroleum ether / tert-butyl methyl ether = 4 / 1) to give compound 15 h. ESI m / z 388.0 [M-2C(CH3)3+H] + .LCMS:product:Rt=1.629min.

[0612] Step 11): To N,N-dimethylacetamide (30 mL) containing compound 15h (1.8 g, 3.50 mmol, 1.0 equivalence), dichloro[9,9-dimethyl-4,5-bis(diphenylphosphine)anthracene]palladium(II) (0.26 g, 0.34 mmol, 0.1 equivalence), zinc cyanide (0.62 g, 5.28 mmol, 1.5 equivalence), and N,N-diisopropylethylamine (1.4 g, 10.83 mmol, 3 equivalence) were added. The reaction mixture was stirred at 85 °C for 18 hours under a N2 atmosphere. The mixture was poured into water (80 mL) and then extracted with ethyl acetate (60 mL × 3). The combined organic layers were washed with brine (40 mL × 3), dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 1 / 1) to give compound 15i. ESI m / z 333.0[M-2(tert-butyl)+H] +.LCMS:product:Rt=1.473min.

[0613] Step 12): To a tetrahydrofuran solution (15 mL) containing compound 15i (1.34 g, 2.95 mmol), Raney nickel (1 g, 17.04 mmol) and ammonia (0.25 mL, 14.27 mmol) were added. The reaction mixture was stirred at 15 °C for 4 hours under a hydrogen atmosphere. The mixture was filtered to remove Raney nickel, and the filtrate was concentrated under reduced pressure to give compound 15j. ESI m / z 449.2 [M+H]+.LCMS:product:Rt=1.006 min.

[0614] Step 13): Compound 15j (200.1 mg, 0.44 mmol, 1.0 equivalence) and compound 9c (204.9 mg, 0.48 mmol, 1.1 equivalence) were dissolved in methanol (5 mL) and stirred at 50 °C for 2 hours. Then, sodium borohydride (33.2 mg, 0.88 mmol, 2.0 equivalence) was added and stirred at room temperature for 1 hour. The mixture was poured into water (60 mL) and extracted with ethyl acetate (3 × 40 mL). The organic phases were combined, washed with brine (40 mL × 3), dried over sodium sulfate, and concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / tetrahydrofuran = 1 / 8) to give compound 15k. ESI m / z 857.4 [M+H]+.LCMS:product:Rt = 1.574 min.

[0615] Step 14): Compound 15k (300.1 mg, 0.35 mmol, 1.0 equivalence) and compound 15l (296.8 mg, 0.35 mmol, 1.0 equivalence) were dissolved in dichloromethane (5 mL), followed by the addition of sodium triacetoxyborohydride (148.4 mg, 0.70 mmol, 2.0 equivalence). The reaction mixture was stirred at room temperature for 3 hours. The mixture was poured into water (60 mL) and extracted with ethyl acetate (3 × 40 mL). The organic phases were combined, washed with brine (40 mL × 3), dried over sodium sulfate, and concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / tetrahydrofuran = 1 / 8) to give compound 15m. ESI m / z 795.2 [(M-Boc) / 2+H] + .LCMS:product:Rt=1.762min.

[0616] Step 15): Compound 15m (400.1 mg, 0.24 mmol 1.0 equivalence) was dissolved in dichloromethane (2 mL), followed by the addition of trifluoroacetic acid (2 mL). The mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated and purified by preparative high-performance liquid chromatography (formic acid) to give compound 15. ESI m / z 532.8 [(M-Boc) / 2+H] + .

[0617] LCMS:product:Rt = 0.968 min.

[0618] 1 H NMR(400MHz,D2O)δ7.46–6.91(m,8H),6.85–6.76(m,2H),6.61(d,J=38.4Hz,1H),5.90–5.72(m,2H),4.55–4.38(m,3H),4.16(s,1H),3.88–3.6 5(m,2H),3.58–3.09(m,14H),2.98–2.60(m,14H),2.53–2.33(m,7H),2. 01(d,J=32.4Hz,4H),1.87–1.59(m,5H),1.45(dd,J=28.4,16.8Hz,2H).

[0619] Example 16: Synthesis of Compound 16

[0620] Step 1): Inter 1 (2 g, 5.61 mmol, 1.0 equivalence) was dissolved in dioxane (20 mL) and water (4 mL), and 3-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)phenol (1.49 g, 6.77 mmol, 1.2 equivalence), potassium phosphate (3 g, 14.13 mmol, 2.5 equivalence), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (0.4 g, 0.55 mmol, 0.1 equivalence) were added. The reaction mixture was heated to 90 °C and reacted for 2 hours. The reaction mixture was then poured into water (30 mL) and extracted with ethyl acetate (40 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by rapid column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give compound 16a. ESI m / z 314.1 [MC(CH3)3+H] + .LCMS:product:Rt=1.27min.

[0621] Step 2): Compound 16a (500 mg, 1.35 mmol, 1.0 equivalence) was dissolved in acetonitrile (10 mL), and benzyl (2-bromoethyl) carbamate (420 mg, 1.63 mmol, 1.2 equivalence) and cesium carbonate (1100 mg, 3.38 mmol, 2.5 equivalence) were added. The mixture was stirred at 80 °C for 4 hours. The mixture was poured into water (30 mL) and extracted with ethyl acetate (20 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (petroleum ether / methyl tert-butyl ether = 1 / 1) to give compound 16b. ESI m / z 447.2 [M-Boc+H] + .LCMS:product:Rt=1.47min.

[0622] Step 3): Compound 16b (1.1 g, 2.01 mmol, 1.0 equivalence) was dissolved in tetrahydrofuran (20 mL), and then palladium / carbon 10% (200 mg, 0.23 mmol, 10.0 equivalence) was added. The mixture was stirred at 25 °C for 4 hours under hydrogen protection. The palladium / carbon was removed by diatomaceous earth filtration, and the filtrate was concentrated under reduced pressure to obtain compound 16c. ESI m / z 413.2 [M+H] + .LCMS:product:Rt=0.92min.

[0623] Step 4): Compound 16c (0.90 g, 1.92 mmol, 1.0 equivalence) was dissolved in dichloromethane (20 mL), and Inter 4 (0.88 g, 2.18 mmol, 1.1 equivalence), acetic acid (0.05 g, 0.27 mmol, 0.1 equivalence), and sodium triacetoxyborohydride (1.4 g, 6.61 mmol, 3.4 equivalence) were added. The mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched with saturated sodium bicarbonate solution (30 mL), followed by extraction with dichloromethane (20 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 0 / 1) to give compound 16d. ESI m / z 800.4 [M+H] + .LCMS:product:Rt=1.44min.

[0624] Step 5): Compound 16d (400 mg, 0.48 mmol, 1.0 equivalence) was dissolved in dichloromethane (10 mL), and (9H-fluorene-9-yl)methyl(2-oxoethyl)carbamate (211 mg, 0.75 mmol, 1.5 equivalence), acetic acid (10 mg, 0.05 mmol, 0.1 equivalence), and sodium triacetoxyborohydride (320 mg, 1.51 mmol, 3.0 equivalence) were added. The mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched with saturated sodium bicarbonate solution (30 mL) and extracted with dichloromethane (20 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / tert-butyl methyl ether = 0 / 1) to give compound 16e. ESI m / z 1065.6 [M+H] + .LCMS:product:Rt=1.39min.

[0625] Step 6): Compound 16e (420 mg, 0.37 mmol, 1.0 equivalent) was dissolved in dimethylamine (8 mL, 2 M tetrahydrofuran solution) and stirred at 25 °C for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (dichloromethane / methanol = 10 / 1) to give compound 16f. ESI m / z 843.4 [M+H]+. LCMS:product:Rt = 1.27 min.

[0626] Step 7): Compound 16f (160 mg, 0.17 mmol) and inter 7 (88 mg, 0.21 mmol, 1.3 equivalences) were dissolved in N,N-dimethylformamide (6 mL), and N,N-diisopropylethylamine (49 mg, 0.38 mmol, 2.3 equivalences) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (110 mg, 0.29 mmol, 1.7 equivalences) were added. The reaction mixture was stirred at room temperature for 2 hours. The mixture was poured into water (60 mL) and extracted with ethyl acetate (40 mL × 3). The combined organic phases were washed with saturated brine (40 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / tetrahydrofuran = 1 / 1) to give compound 16 g. ESI m / z 1245.8 [M+H] + .LCMS:product:Rt=1.44min.

[0627] Step 8): 16 g (200 mg, 0.14 mmol, 1.0 equivalence) of compound 16 g was dissolved in N,N-dimethylformamide (10 mL), and sodium hydroxide (60% mineral oil dispersion, 26 mg, 0.65 mmol, 4.5 equivalence) was added. The mixture was stirred at 25 °C for 0.5 h. Then, inter 5 (113 mg, 0.24 mmol, 1.6 equivalence) was added to the mixture, and the reaction was stirred at 25 °C for 1 h. The mixture was poured into water (20 mL) and extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / methyl tert-butyl ether = 1 / 1) to give compound 16 h. ESI m / z 766.6 [(M-Boc) / 2+H] + .LCMS:product:Rt=1.57min.

[0628] Step 9): Compound 16i (130 mg, 0.06 mmol, 1.0 equivalence) was dissolved in tetrahydrofuran (2 mL), methanol (2 mL), and water (2 mL), and lithium hydroxide monohydrate (27 mg, 0.64 mmol, 10.0 equivalence) was added. The reaction mixture was stirred at 50 °C for 16 hours. The reaction mixture was poured into water (10 mL), acidified to pH 5 with 1 M hydrochloric acid, and extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude compound 16i, which could be used directly in the next step without further purification. ESI m / z 759.6 [(M-Boc) / 2+H] + .LCMS:product:Rt=1.54min.

[0629] Step 10): Compound 16i (120 mg, 0.05 mmol, 1.0 equivalence) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added. The mixture was stirred at 25 °C for 16 hours. The resulting reaction mixture was concentrated and purified by preparative high-performance liquid chromatography (formic acid) to give compound 16. ESI m / z 525.3 [M / 2+H] + .LCMS:product:Rt=1.05min. 1 H NMR(400MHz,D2O)δ7.44–6.79(m,18H),4.63(s,2H),4.51(s,2H),4.44(s,2H),4.23(s,2H),3.90( s,2H),3.79–3.00(m,14H),2.99–2.50(m,10H),2.31(d,J=40.0Hz,6H),2.02(s,3H),1.64(s,3H).

[0630] Example 17: Synthesis of Compound 17

[0631] Step 1): Dissolve inter 1 (1.6 g, 4.01 mmol, 1.0 equivalence) in dioxane (20 mL), and add 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxoborane) (1.3 g, 5.12 mmol, 1.2 equivalence), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (0.3 g, 0.41 mmol, 0.1 equivalence), and potassium acetate (1.2 g, 12.23 mmol, 3.0 equivalence). Stir the reaction mixture at 100 °C for 16 hours. Concentrate the reaction mixture under reduced pressure to obtain a crude product. Purify the crude product by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 17a. ESI m / z = 404.2 [M+H] + .LCMS:product:Rt=1.459min.

[0632] Step 2): Compound 17a (1.6 g, 1.96 mmol, 1.0 equivalence) was dissolved in dioxane (20 mL) and water (2 mL), and 1-bromo-3-iodobenzene (0.7 g, 2.47 mmol, 1.2 equivalence), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (0.15 g, 0.20 mmol, 0.1 equivalence), and potassium carbonate (0.8 g, 5.79 mmol, 3.0 equivalence) were added. The reaction mixture was stirred at 70 °C for 16 hours. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 3 / 1) to give compound 17b. ESI m / z = 376.0 [MC(CH3)3+H] + .LCMS:product:Rt=1.549min.

[0633] Step 3): Compound 17b (1.2 g, 1.87 mmol, 1.0 equivalence) was dissolved in acetonitrile (20 mL), and propan-2-yn-1-amine (0.2 g, 3.63 mmol, 2.0 equivalence), palladium acetate (0.09 g, 0.40 mmol, 0.2 equivalence), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (0.35 g, 0.73 mmol, 0.4 equivalence), and tetrabutylammonium fluoride (2.8 mL, 2.80 mmol, 1.5 equivalence) were added. The reaction mixture was stirred at 50 °C for 16 h. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the crude product. Compound 17c was obtained by silica gel column chromatography (dichloromethane / methanol = 20 / 1). ESI m / z = 407.2 [M+H] + .LCMS:product:Rt=1.005min.

[0634] Step 4): Compound 17c (310 mg, 0.76 mmol, 1.0 equivalence) and inter 4 (276 mg, 0.68 mmol, 0.9 equivalence) were dissolved in methanol (5 mL), and acetic acid (5 mg, 0.07 mmol, 0.1 equivalence) was added. The reaction mixture was stirred at room temperature for 16 hours, then sodium cyanoborohydride (144 mg, 2.28 mmol, 3.0 equivalence) was added, and stirring continued at room temperature for 2 hours. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound 17d. ESI m / z = 794.4 [M+H]+. LCMS:product:Rt = 1.315 min.

[0635] Step 5): Compound 17d (270 mg, 0.34 mmol, 1.0 equivalence) and compound 15f (432 mg, 0.51 mmol, 1.5 equivalence) were dissolved in dichloromethane (5 mL), and acetic acid (2 mg, 0.03 mmol, 0.1 equivalence) and sodium triacetylborohydride (216 mg, 1.02 mmol, 3.0 equivalence) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (100 mL) and extracted with dichloromethane (3 × 50 mL). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 20 / 1) to give compound 17e. ESI m / z = 763.6 [(M-Boc) / 2] + .LCMS:product:Rt=1.670min.

[0636] Step 6): Compound 17e (330 mg, 0.19 mmol, 1.0 equivalence) was dissolved in tetrahydrofuran (1.5 mL) and methanol (1.5 mL), and lithium hydroxide (80 mg, 1.90 mmol, 10.0 equivalence) was added. The reaction mixture was stirred at 50 °C for 16 hours. The reaction mixture was adjusted to pH 7 with 1 M hydrochloric acid solution. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give compound 17f. ESI m / z = 756.6 [(M-Boc+) / 2] + .LCMS:product:Rt=1.634min.

[0637] Step 7): Compound 17f (310 mg, 0.19 mmol, 1.0 equivalence) was dissolved in dichloromethane (1.5 mL), and trifluoroacetic acid (1.5 mL) was added. The reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was concentrated under vacuum to obtain a crude product. The crude product was purified by preparative high-performance liquid chromatography (formic acid) to obtain compound 17. ESI m / z = 1044.5 [M+H] + .LCMS:product:Rt=1.031min. 1HNMR(400MHz,D2O)δ7.49–7.03(m,17H),6.90(s,1H),4.64(d,J=11.2Hz,6H),4.51(s,1H),4.41(d,J=46.3Hz,2H),4.09( s,1H),3.69(d,J=74.6Hz,2H),3.43–3.04(m,11H),2.87–2.53(m,9H),2.45–2.28(m,6H),2.02(s,3H),1.72–1.55(m,3H).

[0638] Example 18: Synthesis of Compound 18

[0639] Step 1): 11 g (1050 mg, 2.75 mmol, 1.0 equivalent) of the compound was dissolved in methanol (10 mL), and sodium borohydride (115 mg, 3.04 mmol, 1.1 equivalent) was added at 0 °C. The reaction was stirred at 25 °C for 1 hour. The mixture was poured into water (30 mL) and extracted with ethyl acetate (3 × 30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 18b1. ESI m / z 328.2 [MC(CH3)3+H] + .LCMS:product:Rt=1.21min.

[0640] Step 2): At 0°C, triphenylphosphine (509 mg, 1.94 mmol, 1.2 equivalence) was slowly added to a solution of dichloromethane (10 mL) containing compound 18b1 (706 mg, 1.62 mmol, 1.0 equivalence) and carbon tetrabromide (644 mg, 1.94 mmol, 1.2 equivalence) with stirring. The reaction mixture was stirred at room temperature for 2 hours. The mixture was poured into water (20 mL) and extracted with dichloromethane (10 mL × 2). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 3 / 1) to give compound 18b. ESI m / z 392.0 [M-tert-butyl+H] + .LCMS:product:Rt=1.498min;

[0641] Step 3): Compound 12c (300.0 mg, 0.35 mmol, 1.0 equivalence) was dissolved in dichloroethane (10 mL), and compound 14h (160.9 mg, 0.35 mmol, 1.0 equivalence) and sodium triacetoxyborohydride (149.7 mg, 0.71 mmol, 2.0 equivalence) were added. The reaction mixture was stirred at 45 °C for 2 hours. The mixture was poured into water (60 mL) and extracted with ethyl acetate (3 × 40 mL). The combined organic phases were washed with brine (40 mL × 3), dried over anhydrous sodium sulfate, and concentrated under vacuum to give the crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound 18a. ESI m / z 1289.8 [M+H] + .LCMS:product:Rt=1.473min.

[0642] Step 4): Compound 18a (290 mg, 0.23 mmol, 1.0 equivalence) was dissolved in N,N-dimethylformamide (2 mL) solution, and sodium hydride (21.6 mg, 0.90 mmol, 4.0 equivalence) was added. The mixture was stirred for 0.5 h. Then, compound 18b (100.44 mg, 0.23 mmol, 1.0 equivalence) was added. The reaction mixture was stirred at room temperature for 2.5 h. The reaction mixture was quenched with aqueous ammonium chloride solution and extracted with ethyl acetate (30 mL × 5 times). The organic phase was concentrated under vacuum to obtain the crude product. The crude product was purified by rapid column chromatography (dichloromethane / methanol = 20 / 1) to obtain compound 18c. ESI m / z 777.7 [(M-Boc) / 2+H] + .LCMS:product:Rt=1.558min.

[0643] Step 5): Compound 18c (200.0 mg, 0.04 mmol, 1.0 equivalence) was dissolved in methanol (2 mL) and tetrahydrofuran (2 mL), and lithium hydroxide monohydrate (9.13 mg, 0.22 mmol, 6.0 equivalence) and water (2 mL) were added. The reaction mixture was stirred at 50 °C for 18 hours. The pH of the reaction solution was adjusted to 4 with 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate (10 mL × 2). The organic phase was concentrated under reduced pressure to give compound 18d. ESI m / z 770.6 [(M-Boc) / 2+H] + .LCMS:product:Rt=1.534min.

[0644] Step 6): Compound 18d (180 mg, 0.03 mmol, 1.0 equivalence) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (2 mL) was added. The reaction mixture was stirred at room temperature for 4 hours. The resulting reaction mixture was concentrated and purified by preparative high-performance liquid chromatography (ammonium bicarbonate) to give compound 18. ESI m / z 536.3 [M / 2+H] + .LCMS:product:Rt=0.683min.

[0645] 1 H NMR(400MHz,D2O)δ8.57(dd,J=35.2,18.0Hz,2H),7.71–7.51(m,2H),7.38(d ,J=11.6Hz,1H),7.32–7.16(m,5H),7.03(dd,J=33.6,16.4Hz,5H),6.86(d,J =46.0Hz,3H),4.62–4.24(m,8H),3.79(s,2H),3.40–3.08(m,10H),2.97–2.6 1(m,8H),2.35(dd,J=66.8,26.0Hz,8H),1.99(s,3H),1.64(d,J=41.6Hz,3H)

[0646] Example 19: Synthesis of Compound 19

[0647] Step 1): Compound 15j (300.0 mg, 0.66 mmol, 1.0 equivalence) was added to methanol (10 mL), followed by compound 6a1 (251.12 mg, 0.66 mmol, 1.0 equivalence). The reaction mixture was stirred at 50 °C for 2 hours. Sodium borohydride (49.81 mg, 1.32 mmol, 2.0 equivalence) was then added. The reaction mixture was stirred at room temperature for 1 hour. The mixture was poured into water (60 mL) and extracted with ethyl acetate (3 × 40 mL). The organic phases were combined, washed with brine (40 mL × 3), dried over sodium sulfate, and concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 8) to give compound 19a. ESI m / z 814.4 [M+H] + .LCMS:product:Rt=1.211min.

[0648] Step 2): Compound 19a (510.1 mg, 0.63 mmol, 1.0 equivalence) was added to a solution of dichloromethane (10 mL), followed by (9H-fluorene-9-yl)methyl(2-oxoethyl)carbamate (264.3 mg, 0.94 mmol, 1.5 equivalence) and sodium triacetoxyborohydride (265.5 mg, 1.25 mmol, 2.0 equivalence). The reaction mixture was stirred at room temperature for 2 hours. The mixture was poured into water (60 mL) and extracted with ethyl acetate (3 × 40 mL). The organic phases were combined, washed with brine (40 mL × 3), dried over sodium sulfate, and concentrated under vacuum to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 9) to give compound 19b. ESI m / z 1079.6 [M+H] + .LCMS:product:Rt=1.404min.

[0649] Step 3): Compound 19b (500.0 mg, 0.46 mmol, 1.0 equivalent) was dissolved in a 2 M (5 mL) solution of dimethylamine in tetrahydrofuran. The mixture was stirred at room temperature for 18 hours. The reaction solution was concentrated under vacuum to obtain a crude product, which was purified by silica gel column chromatography (dichloromethane / methanol = 4 / 1) to give compound 19c. ESI m / z 857.6 [M+H] + .LCMS:product:Rt=1.234min.

[0650] Step 4): Compound 19c (210.1 mg, 0.25 mmol, 1.0 equivalence) was dissolved in tetrahydrofuran (6 mL), and Inter 7 (123.3 mg, 0.29 mmol, 1.2 equivalence), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (186.3 mg, 0.49 mmol, 2.0 equivalence), and N,N-diisopropylethylamine (63.3 mg, 0.49 mmol, 2.0 equivalence) were added. The reaction mixture was stirred at room temperature for 3 hours. The mixture was concentrated under vacuum to obtain a crude product. The crude product was purified by rapid column chromatography (petroleum ether / methyl tert-butyl ether = 1 / 9) to obtain compound 19d. ESI m / z 1259.6 [M+H] + .LCMS:product:Rt=1.437min.

[0651] Step 5): Compound 19d (270.2 mg, 0.21 mmol, 1.0 equivalence) was dissolved in N,N-dimethylformamide (2 mL), and sodium hydride (51.5 mg, 1.29 mmol, 6.0 equivalence) was added. The reaction mixture was stirred at room temperature for 0.5 h. Then inter 5 (201.0 mg, 0.43 mmol, 2.0 equivalence) was added. The reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was extracted with aqueous ammonium chloride solution and extracted with ethyl acetate (30 mL × 5 times). The organic phase was concentrated under vacuum to give the crude product. The crude product was purified by column chromatography (petroleum ether / tetrahydrofuran = 1 / 1) to give compound 19e. ESI m / z 773.6 [(M-Boc) / 2+H] + .LCMS:product:Rt=1.582min.

[0652] Step 6): A solution of compound 19e (210.1 mg, 0.13 mmol, 1.0 equivalence) in tetrahydrofuran (1 mL) and methanol (1 mL) was added to a solution of lithium hydroxide monohydrate (32.1 mg, 0.77 mmol, 6.0 equivalence) in water (1 mL). The mixture was stirred at 55 °C for 18 hours. The pH of the reaction mixture was adjusted to 3 with dilute hydrochloric acid. The mixture was extracted with ethyl acetate (3 × 10 mL), and the organic phase was concentrated under vacuum to give compound 19f. ESI m / z 766.6 [(M-Boc) / 2+H] + .LCMS:product:Rt=1.562min.

[0653] Step 7): Compound 19f (200.2 mg, 0.12 mmol, 1.0 equivalence) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (2 mL) was added. The mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated and purified by preparative high-performance liquid chromatography (ammonium bicarbonate) to give compound 19. ESI m / z 1064.4 [M+H] + .LCMS:product:Rt=0.696min. 1H NMR (400MHz, D2O) δ7.45–7.33(m,4H),7.26–6.88(m,9H),6.73–6.51(m,3H),5.72(d,J=17.2Hz,2H),4.61–4.27(m,6H),3.83(s,2H),3.52(d,J= 59.9Hz,2H),3.30(t,J=18.0Hz,8H),3.17–3.05(m,3H),2.84–2.56(m,8 H),2.57–2.40(m,3H),2.31(d,J=7.2Hz,6H),2.01(s,3H),1.62(s,3H).

[0654] Example 20: Synthesis of Compound 20

[0655] Step 1): Compound 1i (420 mg, 1.01 mmol, 1.0 equivalence) and compound 2f (513.71 mg, 1.21 mmol, 1.2 equivalence) were dissolved in dichloromethane (10 mL), followed by the addition of acetic acid (0.01 mL, 0.17 mmol) and stirring for 30 min. Then, sodium triacetoxyborohydride (639.56 mg, 3.02 mmol, 3.0 equivalence) was added. The mixture was stirred at room temperature for 3 h. The reaction mixture was added to a saturated sodium bicarbonate solution (30 mL) and extracted with dichloromethane (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with petroleum ether / ethyl acetate to give compound 20a. ESI m / z 827.4 [M+H] + .LCMS:product:Rt=1.543min.

[0656] Step 2): Compound 20a (530 mg, 0.64 mmol, 1.0 equivalence) and (9H-fluorene-9-yl)methyl(2-oxoethyl)carbamate (360.51 mg, 1.28 mmol, 2.0 equivalence) were dissolved in dichloromethane (10 mL), and acetic acid (0.01 mL, 0.17 mmol) was added and stirred for 30 min. Then, sodium triacetoxyborohydride (407.41 mg, 1.92 mmol, 3.0 equivalence) was added. The mixture was stirred at room temperature for 3 h. The reaction mixture was added to a saturated aqueous solution of sodium bicarbonate (30 mL) and extracted with dichloromethane (30 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with petroleum ether / ethyl acetate = 1 / 1 to give compound 20b. ESI m / z 1092.4 [M+H] + .LCMS:product:Rt=1.927min.

[0657] Step 3): Compound 20b (440 mg, 0.40 mmol, 1.0 equivalence) was dissolved in tetrahydrofuran (2.0 M) of dimethylamine (10 mL). The mixture was stirred at room temperature for 3 hours. The resulting reaction mixture was concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography using dichloromethane / methanol = 10 / 1 to give compound 20c. ESI m / z 870.4 [M+H] + .LCMS:product:Rt=1.571min.

[0658] Step 4): Compound 20c (170 mg, 0.20 mmol, 1.0 equivalence) and inter 4 (86.71 mg, 0.21 mmol, 1.1 equivalence) were dissolved in dichloromethane (5 mL), and acetic acid (0.01 mL, 0.17 mmol) was added and stirred for 30 min. Then, sodium triacetoxyborohydride (124.21 mg, 0.59 mmol, 3.0 equivalence) was added. The mixture was stirred at room temperature for 3 h. Then, saturated sodium bicarbonate aqueous solution (30 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (30 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with dichloromethane / methanol = 10 / 1 to give compound 20d. ESI m / z 579.4 [M-100 / 2+H] + .LCMS:product:Rt=1.804min.

[0659] Step 5): Compound 20d (210 mg, 0.17 mmol, 1.0 equivalence) and inter 7 (91.06 mg, 0.22 mmol, 1.3 equivalence) were dissolved in DMF (5 mL), followed by the addition of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (82.53 mg, 0.22 mmol, 1.3 equivalence) and N,N-diisopropylethylamine (0.1 mL, 0.57 mmol, 3.4 equivalence). The mixture was stirred at room temperature for 3 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 3) and washed with saturated brine (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with petroleum ether / ethyl acetate = 1 / 1 to give compound 20e. ESI m / z 780.2 [M-100 / 2+H] + .LCMS:product:Rt=2.099min.

[0660] Step 6): Compound 20e (120 mg, 0.07 mmol, 1.0 equivalence) was dissolved in dichloromethane solution (3 mL) and trifluoroacetic acid (3 mL, 39.20 mmol). The mixture was stirred at room temperature for 16 hours. The resulting reaction mixture was concentrated under reduced pressure to give a crude product. The crude product was purified by preparative high-performance liquid chromatography (ammonium bicarbonate) to give compound 20. ESI m / z 517.9 [M / 2+H] + .LCMS:product:Rt=0.946min. 1 H NMR(400MHz,D2O)δ7.36–6.75(m,13H),4.58–4.31(m,2H),3.70(ddd,J=49.9,34.1,15.1Hz,4H),3.41–3 .05(m,12H),2.95–2.51(m,15H),2.31(dd,J=46.4,12.8Hz,7H),2.12–1.54(m,10H),1.51–1.21(m,4H).

[0661] Example 21: Synthesis of Compound 21

[0662] Step 1): Compound 12c (300 mg, 0.35 mmol, 1.0 equivalence), compound 10c (233.48 mg, 0.53 mmol, 1.5 equivalence), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (161.21 mg, 0.42 mmol, 1.2 equivalence) were added to dichloromethane (8 mL), followed by N,N-diisopropylethylamine (136.99 mg, 1.06 mmol, 3.0 equivalence). The reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was then diluted with water (5 mL) and dichloromethane (5 mL). The aqueous phase was separated and extracted with dichloromethane (5 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography, eluting with dichloromethane / (dichloromethane / methanol = 10:1) (0-19%), to give compound 21a. ESI m / z 1171.4 [M+H] + .LCMS:product:Rt=2.215min.

[0663] Step 2): Sodium hydroxide (38.84 mg, 0.97 mmol, 3.0 equivalence) was added to N,N-dimethylformamide (8 mL) containing compound 21a (490 mg, 0.32 mmol, 1.0 equivalence) in 60% mineral oil. The reaction mixture was stirred at 25°C for 30 min. Then, inter 5 (227.43 mg, 0.49 mmol, 1.5 equivalence) was added. The reaction mixture was stirred at 25°C for 3 h. The reaction mixture was quenched with water (10 mL). The aqueous phase was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography, eluting with dichloromethane / (dichloromethane / methanol = 10:1) (0-14%) to give compound 21b.

[0664] Step 3) To a dichloromethane solution (500 mg, 0.27 mmol, 1.0 equivalence) containing compound 21b (4 mL), trifluoroacetic acid (4 mL) was added. The reaction mixture was stirred at 25 °C for 3 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative high-performance liquid chromatography (ammonium bicarbonate) to obtain compound 21. ESI m / z 1034.4 [M+H] + .LCMS:product:Rt=1.985min. 1 HNMR(400MHz,DMSO)δ7.41–7.34(m,1H),7.30–7.18(m,4H),7.17–7.02(m,6H),6.95–6.83(m,2H),4.58–3.98(m,4H),3.80–3.6 0(m,2H),3.53–3.01(m,13H),2.94–2.55(m,13H),2.45–2.26(m,8H),2.09–1.95(m,3H),1.76–1.55(m,5H),1.42–1.16(m,2H).

[0665] Example 22: Synthesis of Compound 22

[0666] Step 1): To a solution of compound 4a (1.56 g, 3.79 mmol, 1 equivalent) in dichloromethane (20 mL), inter 4 (1.15 g, 2.84 mmol, 0.75 equivalent) was added, followed by acetic acid (0.02 mL, 0.38 mmol, 0.1 equivalent) at 25 °C. The mixture was stirred at room temperature for 30 min. Sodium triacetoxyborohydride (1.61 g, 7.58 mmol, 2 equivalent) was added, and the reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (3 × 20 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 0 / 1) to give compound 22a. ESI m / z 799.5 [M+H] + .LCMS:product:Rt=1.247min.

[0667] Step 2): Compound 22a (2.10 g, 2.63 mmol, 1 equivalent) and (9H-fluorene-9-yl)methyl(2-oxoethyl)carbamate (0.74 g, 2.63 mmol, 1 equivalent) were dissolved in dichloromethane (10 mL), and acetic acid (0.02 mL, 0.26 mmol, 0.1 equivalent) was added. The mixture was stirred at 25 °C for 30 min. Sodium triacetoxyborohydride (1.11 g, 5.26 mmol, 2 equivalent) was added. The reaction mixture was stirred at 25 °C for 2 h. The mixture was diluted with water (50 mL) and extracted with dichloromethane (3 × 20 mL). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the crude product. The crude product was purified by silica gel chromatography (petroleum ether / methyl tert-butyl ether = 0 / 1) to give compound 22b. ESI m / z 1064.6 [M+H] + .LCMS:product:Rt=1.594min.

[0668] Step 3): Compound 22b (2.00 g, 1.88 mmol, 1 equivalent) was dissolved in dimethylamine (9.40 mL, 18.79 mmol, 10 equivalents). The mixture was stirred at room temperature for 18 hours. The reaction mixture was filtered and concentrated under vacuum to obtain a crude product. The crude product was purified by silica gel chromatography (dichloromethane:methanol = 10:1) to give compound 22c. ESI m / z 842.6 [M+H] + .LCMS:product:Rt=1.285min.

[0669] Step 4): Compound 22c (650 mg, 0.77 mmol, 1 equivalent) and inter 4 (311.45 mg, 0.77 mmol, 1 equivalent) were added to dichloromethane (10 mL), and acetic acid (0.00 mL, 0.08 mmol, 0.1 equivalent) was added. The mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (327.16 mg, 1.54 mmol, 2 equivalent) was added. The reaction mixture was stirred at 25 °C for 2 hours. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (2 × 40 mL). The combined organic compounds were dried over sodium sulfate and concentrated under vacuum to obtain a residue. The residue was then purified by rapid column chromatography (petroleum ether:ethyl acetate = 0:1) to give compound 22d. ESI m / z 1230.8 [M+H] + .LCMS:product:Rt=1.505min.

[0670] Step 5): Compound 22d (300 mg, 0.24 mmol, 1 equivalent) and compound 5b (126.93 mg, 0.29 mmol, 1.2 equivalent) were dissolved in N,N-dimethylformamide (10 mL), followed by the addition of 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (120.59 mg, 0.32 mmol, 1.3 equivalent) and N,N-diisopropylethylamine (94.60 mg, 0.73 mmol, 3 equivalent). The reaction mixture was stirred at 25 °C for 3 hours. The mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL × 2). The organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 0:1) to give compound 22e. ESI m / z 773.2 [M-100 / 2+1] + .LCMS:product:Rt=1.772min.

[0671] Step 6): Trifluoroacetic acid (1 mL) was added to a solution of compound 22e (120 mg, 0.07 mmol, 1 equivalent) dissolved in dichloromethane (3 mL), and the reaction was stirred at 25 °C for 12 hours. The reaction mixture was concentrated and purified by preparative high-performance liquid chromatography (preparative grade HPLC, formic acid) to give compound 22. ESI m / z 1021.4 [M+H] + .LCMS:product:Rt=0.616min. 1H NMR(400MHz,D2O)δ7.38–6.75(m 13H),4.60–4.33(m,2H),4.12(s,1H),3.84(s,1H),3.64(dd,J=22,6,13.7Hz,2H),3.49-2,97(m,13H),2,95-2.58(m, 14H), 2.44 (dt, J=107.5, 38.3Hz, 8H), 2.01 (d, J=27.1Hz, 4H), 1.73 (d, J=46.9Hz, 5H), 1.40 (dd, J=36.2, 24.0Hz, 2H).

[0672] Example 23: Synthesis of Compound 23

[0673] Step 1): Compound 22c (600 mg, 0.71 mmol, 1.0 equivalence) and compound 1i (297.49 mg, 0.71 mmol, 1.0 equivalence) were dissolved in dichloromethane (10 mL), and acetic acid (0.04 mL, 0.71 mmol) was added. The mixture was stirred for 30 minutes, followed by the addition of sodium triacetoxyborohydride (453.00 mg, 2.14 mmol, 3.0 equivalence). The mixture was stirred at room temperature for 3 hours. The resulting reaction mixture was added to a saturated aqueous solution of sodium bicarbonate (20 mL) and extracted with dichloromethane (20 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using dichloromethane / methanol = 10 / 1 to give compound 23a. ESI m / z 572.6 [M-Boc / 2+H] + .LCMS:product:Rt=1.790min.

[0674] Step 2): Compound 23a (300 mg, 0.24 mmol, 1.0 equivalence) and inter 7 (131.55 mg, 0.31 mmol, 1.3 equivalence) were dissolved in N,N-dimethylformamide (5 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (119.24 mg, 0.31 mmol, 1.3 equivalence) and N,N-diisopropylethylamine (0.13 mL, 0.72 mmol, 3.0 equivalence) were added. The mixture was stirred at room temperature for 16 hours. The reaction mixture was added to water (30 mL), extracted with ethyl acetate (30 mL × 3), and washed with saturated brine (30 mL × 2). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with petroleum ether / ethyl acetate = 1 / 1 to give compound 23b. ESI m / z 773.2 [M-100 / 2+H] +.LCMS:product:Rt=2.107min.

[0675] Step 3): Compound 23b (290 mg, 0.18 mmol, 1.0 equivalence) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (5 mL). The mixture was stirred at room temperature for 16 hours. The resulting reaction mixture was concentrated under reduced pressure to give a crude product. This crude product was then purified by preparative high-performance liquid chromatography (ammonium bicarbonate) to give compound 23. ESI m / z 510.9 [M / 2+H] + .LCMS:product:Rt=0.933min. 1 HNMR(400MHz,D2O)δ7.31–6.91(m,12H),6.77(d,J=7.3Hz,1H),4.56–4.25(m ,2H),3.80(dd,J=31.5,15.0Hz,1H),3.52(dd,J=31.4,18.2Hz,3H),3.38–3.2 2(m,9H),3.20–3.03(m,4H),2.95–2.49(m,15H),2.29(dd,J=38.0,29.8Hz,7H ),2.12–1.89(m,4H),1.70(ddd,J=25.4,20.7,9.1Hz,5H),1.47–1.25(m,2H).

[0676] Example 24: Synthesis of Compound 24

[0677] Step 1): Compound 1h (950 mg, 2.03 mmol, 1.0 equivalence) was dissolved in a solution of N,N-dimethylacetamide (15 mL), and dichloro[9,9-dimethyl-4,5-bis(diphenylphosphino)oxanthracene]palladium(II) (154 mg, 0.20 mmol, 0.1 equivalence), zinc cyanide (360 mg, 3.07 mmol, 1.5 equivalence), and N,N-diisopropylethylamine (800 mg, 3.05 mmol, 3 equivalence) were added. The reaction mixture was stirred at 85 °C for 18 h under nitrogen protection. The reaction mixture was poured into water (50 mL) and then extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The residue was purified by rapid column chromatography (petroleum ether / methyl tert-butyl ether = 1 / 4) to give compound 24a. ESI m / z 437.2 [M+Na] + . LCMS:product:Rt=1.473min.

[0678] Step 2): Add Raney nickel (200 mg, 3.41 mmol) and ammonium hydroxide (0.2 mL, 29.01 mmol) to a tetrahydrofuran (5 mL) solution of compound 24a (250 mg, 0.59 mmol). Stir the reaction mixture at 25 °C in a hydrogen atmosphere for 3 hours. Filter the mixture to remove Raney nickel, and concentrate the filtrate under reduced pressure to give compound 24b. ESI m / z 449.2 [M+H] + .LCMS:product:Rt=1.006min.

[0679] Step 3): Compound 24b (200 mg, 0.48 mmol, 1.0 equivalence) was dissolved in dichloromethane (10 mL), and compound 14h (230 mg, 0.50 mmol, 1.06 equivalence), acetic acid (0.2 mL, 3.50 mmol, 7.32 equivalence), and sodium triacetoxyborohydride (310 mg, 1.46 mmol, 3.0 equivalence) were added. The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was quenched with saturated sodium bicarbonate solution (40 mL) and extracted with dichloromethane (20 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 1 / 0 to 1 / 4) to give compound 24c. ESI m / z 858.4 [M+H] + .LCMS:product:Rt=1.578min.

[0680] Step 4): Compound 15l (2000 mg, 2.12 mmol, 9.11 equivalences) and compound 24c (200 mg, 0.23 mmol, 1.0 equivalences) were dissolved in a solution of dichloromethane (10 mL), and acetic acid (2 mL, 5.00 mmol, 21.44 equivalences) and sodium triacetoxyborohydride (300 mg, 1.42 mmol, 6 equivalences) were added. The mixture was stirred at 25 °C for 18 hours. The reaction was then quenched with sodium bicarbonate solution (100 mL), followed by extraction with ethyl acetate (60 mL × 3). The combined organic phases were washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The residue was then purified by rapid column chromatography (petroleum ether / methyl tert-butyl ether = 1 / 0 to 3 / 7) to give compound 24d. ESI m / z 795.8 [1 / 2(M-Boc)+H] + .LCMS:product:Rt=1.934min.

[0681] Step 5): Add 1 mL of trifluoroacetic acid to a solution of compound 24d (260 mg, 0.14 mmol, 1.0 equivalence) and stir at room temperature for 18 hours. Concentrate the reaction mixture and purify by preparative high-performance liquid chromatography (formic acid) to obtain compound 24. ESI m / z 1065.5 [M+H] + .LCMS:product:Rt=0.667min. 1 H NMR(400MHz,D2O)δ8.77(s,1H),8.66(d,J=1.9Hz,1H),7.96(s,1H),7.62(s,1H ),7.51–6.56(m,11H),6.45(d,J=7.4Hz,1H),4.25(s,2H),3.88(s,3H),3.60–3. 31(m,9H),3.29–3.12(m,5H),2.94(dt,J=23.0,12.9Hz,9H),2.79–2.46(m,8H), 2.35(d,J=19.1Hz,5H),2.04(s,4H),1.83–1.60(m,5H),1.43(d,J=12.0Hz,2H).

[0682] Example 25: Synthesis of Compound 25

[0683] Step 1): Inter 4e (0.5 g, 1.10 mmol, 1.0 equivalence) was dissolved in dioxane (4 mL), and benzyl mercaptan (150 μL, 1.32 mmol, 1.2 equivalence), palladium bis(diphenylvinyl) trimer (100.76 mg, 0.11 mmol, 0.1 equivalence), Xantphos (127.3 mg, 0.22 mmol, 0.2 equivalence), and diisopropylamine (284.4 mg, 2.20 mmol, 2.0 equivalence) were added. The reaction mixture was stirred at 110 °C for 18 hours under nitrogen. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / methyl tert-butyl ether = 10 / 1) to give compound 25a. ESI m / z 520.2 [M+Na] + .LCMS:product:Rt=2.213min.

[0684] Step 2): Compound 25a (450.0 mg, 0.81 mmol, 1.0 equivalence) was dissolved in a solution of water (0.2 mL), acetic acid (0.3 mL), and acetonitrile (8 mL). 1,3-Dichloro-4,4-dimethyl-2-oxotetrahydro-1H-imidazol-5-one (320.6 mg, 1.63 mmol, 2.0 equivalence) was added. The reaction mixture was stirred at 0 °C for 20 min. The resulting reaction mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane (5 mL), cooled at 0 °C, and a 5% sodium bicarbonate solution (10 mL) was added. The mixture was stirred for 5 min, and the organic phase was separated. The organic phase was concentrated under vacuum to give compound 25b. ESI m / z 492.2 [M+Na] + .LCMS:product:Rt=1.451min.

[0685] Step 3): Compound 2i (300 mg, 0.35 mmol, 1.0 equivalence) was added to a solution of dichloromethane (10 mL), followed by compound 25b (249.14 mg, 0.53 mmol, 1.5 equivalence) and triethylamine (0.01 mL, 0.11 mmol). The reaction mixture was stirred at room temperature for 1 hour. The mixture was poured into water (60 mL) and extracted with ethyl acetate (3 × 40 mL). The organic phases were combined, washed with brine (40 mL × 3), dried over sodium sulfate, and concentrated under vacuum to give the crude product. The crude product was purified by rapid column chromatography (petroleum ether / methyl tert-butyl ether = 1 / 1) to give compound 25c. ESI m / z 1293.8 [M+H] + .LCMS:product:Rt=1.692min.

[0686] Step 4): Compound 25c (340.1 mg, 0.26 mmol, 1.0 equivalence) was dissolved in N,N-dimethylformamide (10 mL), and Inter 5 (184.7 mg, 0.39 mmol, 1.5 equivalence) and cesium carbonate (256.9 mg, 0.79 mmol, 3.0 equivalence) were added. The reaction mixture was stirred at 50 °C for 2 hours. The mixture was poured into water (60 mL) and extracted with ethyl acetate (3 × 40 mL). The organic phases were combined, washed with brine (40 mL × 3), dried over sodium sulfate, and concentrated under vacuum to obtain the crude product. The crude product was purified by rapid column chromatography (petroleum ether / methyl tert-butyl ether = 1 / 3) to give compound 25d. ESI m / z 791.2 [(M-Boc) / 2+H] + .LCMS:product:Rt=1.912min.

[0687] Step 5): Compound 25d (330 mg, 0.20 mmol, 1.0 equivalence) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (2 mL) was added. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated and purified by preparative high-performance liquid chromatography (ammonium bicarbonate) to obtain compound 25. ESI m / z 528.8 [M / 2+H] + .LCMS:product:Rt=0.644min. 1 HNMR(400MHz,D2O)δ7.47(ddd,J=20.8,17.2,9.6Hz,4H),7.20(t,J=7.6Hz,1H),7. 16–6.99(m,6H),6.92–6.81(m,2H),4.17(s,2H),3.70(dd,J=27.6,15.2Hz,2H),3. 51(s,2H),3.43–3.23(m,8H),3.21–3.05(m,5H),2.90–2.61(m,12H),2.56–2.48(m ,1H),2.44–2.26(m,9H),2.10–1.90(m,4H),1.83–1.58(m,5H),1.51–1.34(m,2H).

[0688] Example 26: Synthesis of Compound 26

[0689] Step 1): To a solution of inter 5a (370 mg, 0.87 mmol, 1.0 equivalence) in acetonitrile (5 mL), bis(2,5-dioxopyrrolidone-1-yl) carbonate (268 mg, 1.05 mmol, 1.2 equivalence) and triethylamine (177 mg, 1.75 mmol, 2.0 equivalence) were added. The reaction mixture was stirred at room temperature for 1 hour. The reaction solution was then concentrated under reduced pressure to give compound 26a. ESI m / z 569.2 [M+Na] + .LCMS:product:Rt=1.420min.

[0690] Step 2): Compound 2i (260.2 mg, 0.30 mmol, 1.0 equivalence) was dissolved in dichloromethane (5 mL), and compound 26a (166.0 mg, 0.30 mmol, 1.0 equivalence), triethylamine (0.08 mL, 0.61 mmol, 2.0 equivalence), and 4-dimethylaminopyridine (3.7 mg, 0.03 mmol, 0.1 equivalence) were added. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 2 / 3) to obtain compound 26b. ESI m / z 1288.8 [M+H]+ .LCMS:product:Rt=1.650min.

[0691] Step 3): Compound 26b (370 mg, 0.29 mmol, 1.0 equivalence) was dissolved in N,N-dimethylformamide (2 mL), and sodium hydride (60%) (34.5 mg, 0.86 mmol, 3.0 equivalence) was added. The reaction mixture was stirred at room temperature for 0.5 h. Then, inter 5 (269.2 mg, 0.86 mmol, 2.0 equivalence) was added. The reaction mixture was stirred at room temperature for 1.5 h. The mixture was quenched in a saturated ammonium chloride solution (60 mL), and then extracted with ethyl acetate (40 mL × 3). The organic phases were combined, washed with brine (40 mL × 3), dried over sodium sulfate, and concentrated under vacuum to obtain the crude product. The crude product was purified by rapid column chromatography (petroleum ether / methyl tert-butyl ether = 1 / 9) to give compound 26c. ESI m / z 788.2 [(M-Boc) / 2+H] + .LCMS:product:Rt=1.843min.

[0692] Step 4): Compound 26c (230 mg, 0.14 mmol, 1.0 equivalence) was dissolved in dichloromethane (2 mL), and then trifluoroacetic acid (2 mL) was added. The reaction mixture was stirred at room temperature for 18 hours. The resulting reaction mixture was concentrated and purified by preparative high-performance liquid chromatography (ammonium bicarbonate) to give compound 26. ESI m / z 525.8 [M / 2+H] + .LCMS:product:Rt=0.666min. 1 HNMR(400MHz,D2O)δ7.26–6.78(m,13H),4.92(d,J=27.2Hz,2H),4.26(q,J=16.0Hz,2H),3.88–3.42 (m,4H),3.42–3.05(m,13H),2.88–2.24(m,22H),2.07–1.57(m,9H),1.40(dd,J=31.6,12.8Hz,2H).

[0693] Example 27: Synthesis of Compound 27

[0694] Step 1): Compound 27a (10 g, 37.31 mmol, 1.0 equivalent) was dissolved in 1,4-dioxane (100 mL), and diphenylmethylimine (7.4 g, 41.04 mmol, 1.1 equivalent), tris(dibenzylacetone)dipalladium (3.4 g, 3.73 mmol, 0.1 equivalent), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (4.3 g, 7.46 mmol, 0.2 equivalent), and cesium carbonate (24.3 g, 74.62 mmol, 2 equivalent) were added. The reaction mixture was stirred at 100 °C for 16 hours. The reaction mixture was then diluted with water (300 mL) and extracted with ethyl acetate (3 × 150 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 3 / 1) to give compound 27b. ESI m / z = 414.2 [M+H] + .LCMS:product:Rt=1.180min.

[0695] Step 2): Compound 27b (13 g, 21.89 mmol, 1.0 equivalent) was dissolved in trifluoroacetic acid (100 mL) and stirred at 70 °C for 16 hours. The solvent was concentrated under reduced pressure to give compound 27c. ESI m / z = 149.7 [M+H] + .LCMS:product:Rt=0.252min.

[0696] Step 3): Compound 27c (12 g, 16.09 mmol, 1.0 equivalence) was dissolved in dichloromethane (100 mL), and di-tert-butyl dicarbonate anhydride (10 mL, 43.53 mmol, 2.7 equivalence) and triethylamine (13 mL, 93.78 mmol, 5.8 equivalence) were added. The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was diluted with water (300 mL) and extracted with dichloromethane (3 × 200 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 40 / 1) to give compound 27d. ESI m / z = 250.2 [M+H] + .LCMS:product:Rt=0.698min.

[0697] Step 4): Compound 27d (2 g, 6.43 mmol, 1.0 equivalence) was dissolved in acetonitrile (30 mL), and N-bromosuccinimide (1.5 g, 8.43 mmol, 1.2 equivalence) was added. The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was then diluted with water (100 mL) and extracted with ethyl acetate (3 × 50 mL). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 27e. ESI m / z = 328.0 [M+H] + .LCMS:product:Rt=1.065min.

[0698] Step 5): Compound 27e (1.4 g, 4.04 mmol, 1.0 equivalence) was dissolved in N,N-dimethylformamide (15 mL), methanol (3 mL), and triethylamine (3 mL), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (473 mg, 0.65 mmol, 0.16 equivalence) was added. The reaction mixture was stirred at 90 °C for 16 hours under carbon monoxide protection. The solvent was removed under vacuum. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give compound 27f. ESI m / z = 308.2 [M+H] + .LCMS:product:Rt=0.905min.

[0699] Step 6): Compound 27f (1.1 g, 3.58 mmol, 1.0 equivalent) was dissolved in acetonitrile (10 mL), and tert-butyl nitrite (1.5 g, 14.55 mmol, 2.0 equivalent) was added at 0 °C. After stirring the mixture at 0 °C for 1 hour, cuprous chloride (1.1 g, 11.11 mmol, 1.5 equivalent) was slowly added to the reaction mixture, and the reaction was then heated to 60 °C and stirred for 16 hours. The solvent was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 3 / 1) to give compound 27 g. ESI m / z = 327.2 [M+H] + .LCMS:product:Rt=1.224min.

[0700] Step 7): 27 g (290 mg, 0.72 mmol, 1.0 equivalence) of compound was dissolved in 1,4-dioxane (5 mL) and water (0.5 mL), followed by the addition of (3-formaldehydephenyl)boronic acid (166 mg, 1.11 mmol, 1.3 equivalence), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (63 mg, 0.09 mmol, 0.1 equivalence), and potassium phosphate (541 mg, 2.55 mmol, 3.0 equivalence). The reaction mixture was stirred at 90 °C under N2 protection for 16 hours. The solvent was concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 1 / 1) to obtain compound 27 h. ESI m / z = 397.2 [M+H] + .LCMS:product:Rt=1.417min.

[0701] Step 8): Compound 27i (180 mg, 0.45 mmol, 1.0 equivalence) was dissolved in dichloromethane (3 mL), and Inter 6 (220 mg, 0.54 mmol, 1.0 equivalence), sodium triacetylborohydride (290 mg, 1.37 mmol, 3.0 equivalence), and acetic acid (3 mg, 0.05 mmol, 0.1 equivalence) were added. The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give compound 27i. ESI m / z = 785.4 [M+H] + .LCMS:product:Rt=1.248min.

[0702] Step 9): Compound 27i (200.1 mg, 0.25 mmol, 1.0 equivalence) was dissolved in dichloromethane (3 mL), and compound 15l (324.1 mg, 0.38 mmol, 1.5 equivalence) and sodium triacetoxyborohydride (161.9 mg, 0.76 mmol, 3.0 equivalence) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water (60 mL) and extracted with ethyl acetate (3 × 40 mL). The combined organic phases were washed with saturated brine (40 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 1 / 3) to give compound 27j. ESI m / z 759.2 [(M-Boc) / 2+H] + .LCMS:product:Rt=1.588min.

[0703] Step 10): Compound 27j (400.0 mg, 0.25 mmol, 1.0 equivalence) was dissolved in methanol (3 mL) and tetrahydrofuran (3 mL), and lithium hydroxide monohydrate (62.3 mg, 1.48 mmol, 6.0 equivalence) and water (3 mL) were added. The reaction mixture was stirred at 55 °C for 18 hours. The reaction mixture was adjusted to pH 4 with hydrochloric acid (1 M). Extraction was performed with ethyl acetate (10 mL × 2), and the organic phase was concentrated under vacuum to give compound 27k. ESI m / z 752.2 [(M-Boc) / 2+H] + .LCMS:product:Rt=1.560min.

[0704] Step 11): Compound 27k (380.1 mg, 0.24 mmol, 1.0 equivalence) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (3 mL) was added. The mixture was stirred at room temperature for 18 hours. The resulting reaction mixture was concentrated under reduced pressure, and the crude product was purified by preparative high-performance liquid chromatography (ammonium bicarbonate) to give compound 27k. ESI m / z 1035.5 [(M+H)] + .LCMS:product:Rt=0.651min. 1 H NMR(400MHz,D2O)δ7.73–6.66(m,17H),4.56–4.26(m,4H),3.97(s,2H),3.74–3.46(m,4H),3.45–3.22(m,8 H),3.20–3.05(m,5H),3.00–2.45(m,11H),2.43–2.21(m,6H),2.02(s,3H),1.64(dd,J=20.0,11.2Hz,3H).

[0705] Example 28: Synthesis of Compound 28

[0706] Step 1): Compound 2f (300.0 mg, 0.70 mmol, 1.0 equivalence) and (9H-fluorene-9-yl)methyl(2-oxoethyl)carbamate (237.9 mg, 0.85 mmol, 1.2 equivalence) were dissolved in methanol (20 mL), and the reaction mixture was stirred at room temperature for 2 hours. Sodium borohydride (53.3 mg, 1.41 mmol, 2.0 equivalence) was then added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with 1 M hydrochloric acid (10 mL) and extracted with dichloromethane (2 × 20 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give compound 28a. ESI m / z 691.4 [M+H] +.LCMS:product:Rt=1.136min.

[0707] Step 2): Compound 28a (280.1 mg, 0.41 mmol, 1.0 equivalence) was dissolved in dimethylformamide (5 mL), followed by the addition of inter7 (255.0 mg, 0.61 mmol, 1.5 equivalence), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate (308.2 mg, 0.81 mmol, 2.0 equivalence), and N,N-diisopropylethylamine (104.7 mg, 0.82 mmol, 2.0 equivalence). The reaction mixture was stirred at room temperature for 18 hours. The mixture was poured into water (50 mL) and extracted with ethyl acetate (3 × 40 mL). The combined organic layers were washed with saturated brine (40 mL × 3), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / tetrahydrofuran = 1 / 1) to give compound 28b. ESI m / z 1092.6 [M+H] + .LCMS:product:Rt=1.750min.

[0708] Step 3): Compound 28b (200.2 mg, 0.18 mmol, 1.0 equivalence) was dissolved in a solution of dimethylamine in tetrahydrofuran (2 M) (5 mL) and stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (dichloromethane / methanol = 10 / 1) to give compound 28c. ESI m / z 870.5 [M+H] + .LCMS:product:Rt=1.248min.

[0709] Step 4): Compound 28c (180.0 mg, 0.21 mmol, 1.0 equivalence) was dissolved in dichloroethane (5 mL), and Inter 4 (250.4 mg, 0.62 mmol, 3.0 equivalence) and sodium triacetoxyborohydride (175.37 mg, 0.83 mmol, 4.0 equivalence) were added. The reaction mixture was stirred at 50 °C for 4 hours. The reaction mixture was quenched with saturated sodium bicarbonate solution (20 mL) and extracted with dichloromethane (2 × 20 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether / tetrahydrofuran = 1 / 1) to give compound 28d. ESI m / z 579.6 [(M-Boc) / 2+H] + .LCMS:product:Rt=1.899min.

[0710] Step 5): Compound 28d (200.0 mg, 0.16 mmol, 1.0 equivalence) was dissolved in N,N-dimethylformamide (2 mL), and sodium hydride (60%) (22.9 mg, 0.95 mmol, 6.0 equivalence) was added. The reaction mixture was stirred at room temperature for 0.5 h. Then inter 5 (149.0 mg, 0.32 mmol, 2.0 equivalence) was added. The reaction mixture was stirred at room temperature for 3.5 h. The mixture was poured into saturated ammonium chloride (60 mL) and extracted with ethyl acetate (40 mL × 3). The combined organic phases were washed with brine (40 mL × 3), dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the crude product. The crude product was purified by rapid column chromatography (petroleum ether / methyl tert-butyl ether = 0 / 1) to give compound 28e. ESI m / z 773.2 [(M-Boc) / 2+H] + .LCMS:product:Rt=1.758min.

[0711] Step 6): Compound 28e (150.1 mg, 0.06 mmol, 1.0 equivalence) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (2 mL) was added. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated and purified by preparative high-performance liquid chromatography (formic acid) to give compound 28. ESI m / z 510.9 [M / 2+H] + .LCMS:product:Rt=0.948min. 1 H NMR(400MHz,D2O)δ7.43–7.05(m,11H),6.85(dd,J=68.4,39.2Hz,2H),4.41(dd,J=56.0,51.2Hz,6H),4.00–3.6 6(m,2H),3.54–3.09(m,13H),2.99–2.71(m,13H),2.59–2.34(m,7H),2.23–1.58(m,9H),1.45(d,J=12.4Hz,2H).

[0712] Example 29: Synthesis of Compound 29

[0713] Step 1): Under nitrogen protection at 0°C, lithium bis(trimethylsilyl)amino (1 M in tetrahydrofuran, 42.84 mL, 42.84 mmol, 1.3 equivalence) was added to a solution of tetrahydrofuran (120 mL) containing inter 3 (12.80 g, 32.95 mmol, 1.0 equivalence). The reaction mixture was stirred at 0°C for 30 min. Subsequently, a solution of tetrahydrofuran (50 mL) containing 2-bromo-4-(bromomethyl)-1-fluorobenzene (9.71 g, 36.25 mmol, 1.1 equivalence) was added. The reaction mixture was stirred at room temperature for 4 h. The mixture was quenched with saturated ammonium chloride aqueous solution (200 mL) and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated ammonium chloride aqueous solution (500 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 1 / 1) to give compound 29a. ESI m / z 519.0 [M-tert-butyl+H] + .LCMS:product:Rt=1.397min.

[0714] Step 2): A solution of tetrahydrofuran (100 mL) containing compound 29a (10.71 g, 16.01 mmol, 1.0 equivalence) was stirred and cooled to 0°C. Hydrogen peroxide (30% aqueous solution, 6.21 mL, 80.03 mmol, 5.0 equivalence) was added dropwise, followed by an aqueous solution of lithium hydroxide (1.07 g, 25.61 mmol, 1.6 equivalence) (20 mL). The reaction mixture was stirred at 0°C for 2 hours. The reaction solution was then slowly poured into an aqueous solution of sodium bisulfite (16.65 g, 160.05 mmol, 10.0 equivalence) cooled to 0°C (200 mL) for quenching. The quenching was stirred for one hour, and the pH was adjusted to 5 with an aqueous solution of hydrochloric acid (1 M). The mixture was extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 29b. ESI m / z 362.0 [M-tert-butyl+H] + .LCMS:product:Rt=1.157min.

[0715] Step 3): To a solution of compound 29b (8.4 g, 15.74 mmol) in tetrahydrofuran (100 mL), 2-tert-butyl-N,N'-diisopropylisourea (12.61 g, 62.96 mmol, 4.0 equivalent) was added, and the mixture was stirred at 65 °C for 2 hours. The mixture was filtered, and the filter cake was washed with ethyl acetate (100 mL × 3). The combined filtrates were concentrated to dryness under reduced pressure to give the crude product. The residue was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 1 / 1) to give compound 29c. ESI m / z 362.0 [M-tert-butyl-tert-butyl+H] + .LCMS:product:Rt=1.620min.

[0716] Step 4): In a solution of N,N-dimethylacetamide (50 mL) containing compound 29c (5.4 g, 10.97 mmol, 1.0 equivalence), zinc cyanide (1.29 g, 10.97 mmol, 1.0 equivalence), N,N-diisopropylethylamine (5.73 mL, 32.92 mmol, 3.0 equivalence), and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) palladium dichloride (830 mg, 1.10 mmol, 0.1 equivalence) were added. The reaction mixture was stirred at 85 °C for 4 hours under nitrogen protection. The mixture was poured into water (150 mL) and extracted with ethyl acetate (3 × 80 mL). The combined organic phases were washed with saturated brine (500 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to obtain the crude product. The residue was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 2 / 1) to give 29d. ESI m / z 441.2 [M+Na] + .LCMS:product:Rt=1.433min.

[0717] Step 5): To a solution of compound 29d (4.60 g, 10.33 mmol, 1.0 equivalent) in tetrahydrofuran (100 mL), add Raney nickel (6.06 g, 103.32 mmol, 10.0 equivalent) and ammonia (0.5 mL). The reaction mixture was stirred at room temperature in a hydrogen atmosphere for 5 hours. The reaction solution was filtered through diatomaceous earth, the filter cake was washed with tetrahydrofuran (200 mL), and the filtrate was concentrated to dryness under reduced pressure to give crude compound 29e. ESI m / z 423.2 [M+H] + .LCMS:product:Rt=0.927min.

[0718] Step 6): To a solution of compound 29e (450 mg, 1.00 mmol, 1.0 equivalence) in dichloromethane (5 mL), compound 9c (224 mg, 0.50 mmol, 0.5 equivalence), sodium triacetylborohydride (637 mg, 3.00 mmol, 3.0 equivalence), and acetic acid (0.1 mL) were added. The reaction mixture was stirred at room temperature for 1 hour. Subsequently, 9c (134 mg, 0.30 mmol, 0.3 equivalence) was added, and stirring was continued at room temperature for 1 hour. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution (30 mL) and extracted with dichloromethane (2 × 10 mL). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 1 / 1) to give compound 29f. ESI m / z 831.4 [M+H] + .LCMS:product:Rt=1.268min.

[0719] Step 7): To a solution of compound 29f (770 mg, 0.77 mmol, 1.0 equivalence) in dichloromethane (10 mL), add (9H-fluorene-9-yl)methyl(2-oxoethyl)carbamate (260 mg, 0.92 mmol, 1.2 equivalence), acetic acid (14 mg, 0.08 mmol, 0.1 equivalence), and sodium triacetylborohydride (489 mg, 2.31 mmol, 3.0 equivalence). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with saturated sodium bicarbonate solution (30 mL) and extracted with dichloromethane (2 × 10 mL). The combined organic phases were dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 3 / 1) to give compound 29 g. ESI m / z 1096.6 [M+H] + .LCMS:product:Rt=1.705min.

[0720] Step 8): 29 g (760 mg, 0.51 mmol, 1.0 equivalence) of compound was added to a solution of dimethylamine (8 mL, 16.00 mmol, 2 M tetrahydrofuran solution). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give compound 29h. ESI m / z 874.6 [M+H] + .LCMS:product:Rt=1.291min.

[0721] Step 9): In a solution of dichloromethane (20 mL) containing compound 29h (372 mg, 0.36 mmol, 1.0 equivalence), inter 4 (72 mg, 0.50 mmol, 0.5 equivalence), acetic acid (7 mg, 0.04 mmol, 0.1 equivalence), and sodium triacetylborohydride (227 mg, 1.07 mmol, 3.0 equivalence) were added. The reaction mixture was stirred at room temperature for 1 hour. Subsequently, inter 4 (58 mg, 0.14 mmol, 0.4 equivalence) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution (30 mL), extracted with dichloromethane (2 × 10 mL), and the combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 0 / 1) to give compound 29i. ESI m / z 581.6[(M-Boc) / 2+H] + .LCMS:product:Rt=1.696min.

[0722] Step 10): To a solution (5 mL) of N,N-dimethylformamide containing inter 7 (160 mg, 0.38 mmol, 1.5 equivalence), add N,N-diisopropylethylamine (0.20 mL, 1.14 mmol, 4.5 equivalence) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate (218 mg, 0.57 mmol, 2.25 equivalence). The reaction mixture was stirred at room temperature for 30 minutes. Subsequently, compound 29i (321 mg, 0.25 mmol, 1.0 equivalence) was added, and the reaction mixture was stirred at room temperature for 2 hours. The mixture was poured into water (20 mL) and extracted with ethyl acetate (8 mL × 3). The combined organic phases were washed with saturated brine (50 mL × 3), filtered through anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 0 / 1) to give compound 29j. ESI m / z 782.2 [(M-Boc) / 2+H] + .LCMS:product:Rt=2.029min.

[0723] Step 11): Compound 29j (374 mg, 0.17 mmol, 1.0 equivalence) was dissolved in a mixed solution of dichloromethane (2 mL) and trifluoroacetic acid (1 mL). The mixture was stirred at room temperature for 16 hours. After concentration, the reaction mixture was purified by preparative high-performance liquid chromatography (formic acid) to give compound 29. ESI m / z 1039.4 [M+H] + .LCMS:product:Rt=0.6037min. 1H NMR(400MHz,D2O)δ7.35–6.76(m,12H),4.55–3.85(m,6H),3.63(dd,J=17.1,9.7Hz,2H),3.49–3.23(m,10H),3.2 0–3.05(m,3H),2.95–2.60(m,14H),2.46–2.30(m,7H),2.03(s,4H),1.78(s,1H),1.71–1.57(m,3H),1.44(s,2H).

[0724] Example 30: Synthesis of Compound 30

[0725] Step 1): Dissolve inter 3 (10.6 g, 27.29 mmol, 1.0 equivalence) in tetrahydrofuran (200 mL), add lithium bis(trimethylsilylamino)amine (35.47 mL, 35.47 mmol, 1.3 equivalence) at -78 °C, and stir for 30 min at the same temperature. Then add a tetrahydrofuran (200 mL) solution of 4-bromo-2-(bromomethyl)-1-fluorobenzene (8.04 g, 30.02 mmol, 1.1 equivalence), allow to warm naturally to room temperature, and stir for 5 h. Quench the reaction mixture in a saturated ammonium chloride solution (400 mL) and extract with ethyl acetate (600 mL × 2). Combine the organic phases, wash with brine (500 mL), dry over anhydrous sodium sulfate, and filter. Concentrate the filtrate under reduced pressure to give compound 30a. ESI m / z 519.1 [M-56+H] + .LCMS:product:Rt=2.018min.

[0726] Step 2): Compound 30a (18.0 g, 25.02 mmol, 1.0 equivalent) was dissolved in tetrahydrofuran (1.0 L) and water (250 mL), followed by the addition of hydrogen peroxide (5.83 mL, 75.07 mmol, 3.0 equivalent) and lithium hydroxide monohydrate (1.57 g, 37.53 mmol, 1.5 equivalent). The reaction mixture was stirred at 0 °C for 4 hours. The reaction mixture was quenched with an aqueous sodium bisulfite solution and the pH was adjusted to 5 with citric acid (1 M). The aqueous phase was extracted with methyl tert-butyl ether (400 mL × 3), and the combined organic phases were washed with brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 30b. ESI m / z 360.0 [M-56+H] + .LCMS:product:Rt=1.408min.

[0727] Step 3): Compound 30b (15.0 g, 28.83 mmol, 1.0 equivalence) was dissolved in tetrahydrofuran (200 mL), and 2-tert-butyl-N,N'-diisopropylisourea (25.95 mL, 115.30 mmol, 4.0 equivalence) was added. The reaction mixture was stirred at 60 °C for 3 hours. The mixture was then diluted with water (200 mL) and extracted with ethyl acetate (200 mL × 2). The combined organic phases were washed with saturated brine (100 mL) and filtered after drying with anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / methyl tert-butyl ether = 1 / 5) to give compound 30c. ESI m / z 494.2 [M + Na] + .LCMS:product:Rt=1.476min.

[0728] Step 4): To a solution (50 mL) of N,N-dimethylacetamide containing compound 30c (5.1 g, 10.80 mmol, 1.0 equivalence), N,N-diisopropylethylamine (4.7 mL, 26.99 mmol, 2.0 equivalence), zinc cyanide (1267.6 mg, 10.8 mmol, 1.0 equivalence), and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) palladium dichloride (816.1 mg, 1.08 mmol, 0.1 equivalence) were added. The mixture was stirred at 85 °C for 18 hours under nitrogen. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL × 2). The combined organic phases were washed with brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 1 / 1) to give compound 30d. ESI m / z 307.0 [M-56-56+H] + .LCMS:product:Rt=1.738min.

[0729] Step 5): Compound 30d (1.4 g, 3.35 mmol, 1.0 equivalence) was dissolved in tetrahydrofuran (20 mL) and ammonia (1 mL), and then Raney nickel (0.73 g, 3.35 mmol, 1.0 equivalence) was added. The reaction mixture was stirred at room temperature under hydrogen atmosphere for 2 hours. The suspension was filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate (200 mL). The filtrate was concentrated under reduced pressure to give compound 30e. ESI m / z 423.2 [M+H] + .LCMS:product:Rt=0.991min.

[0730] Step 6): Compound 9c (397.9 mg, 0.94 mmol, 1.2 equivalences) was dissolved in methanol (10 mL), followed by the addition of compound 30e (330.1 mg, 0.78 mmol, 1.0 equivalences). The reaction mixture was stirred at 50 °C for 2 hours, followed by the addition of sodium borohydride (59.1 mg, 1.56 mmol, 2.0 equivalences), and stirring was continued at room temperature for 1 hour. The reaction mixture was quenched with hydrochloric acid (1 M) (10 mL), extracted with dichloromethane (2 × 20 mL), and the combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 8) to give compound 30f. ESI m / z 831.4 [M+H] + .LCMS:product:Rt=1.374min.

[0731] Step 7): Compound 30f (590.0 mg, 0.71 mmol, 1.0 equivalence) was dissolved in dichloromethane (10 mL), and (9H-fluorene-9-yl)methyl(2-oxoethyl)carbamate (299.5 mg, 1.06 mmol, 1.5 equivalence) and sodium triacetoxyborohydride (300.9 mg, 1.42 mmol, 2.0 equivalence) were added sequentially. The reaction mixture was stirred at room temperature for 4 hours, then poured into water (60 mL) and extracted with dichloromethane (3 × 10 mL). The combined organic phases were washed with saturated brine (3 × 40 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography (dichloromethane / methanol = 11:1) to give 30 g of compound. ESI m / z 1096.6 [M+H] + .LCMS:product:Rt=1.657min.

[0732] Step 8): Add 10 mL of a 2 M solution of dimethylaminetetrahydrofuran to 30 g (770 mg, 0.70 mmol, 1.0 equivalence) of the compound. Stir the reaction mixture at room temperature for 4 hours, then concentrate under reduced pressure. Purify the residue by silica gel column chromatography (dichloromethane / methanol = 8 / 1) to give compound 30 h. ESI m / z 874.4 [M+H] + .LCMS:product:Rt=1.378min.

[0733] Step 9): Inter 4 (240.0 mg, 0.59 mmol, 1.0 equivalence) and sodium triacetoxyborohydride (252.1 mg, 1.19 mmol, 2.0 equivalence) were added to a 2 mL solution of compound 30h (520 mg, 0.59 mmol, 1.0 equivalence) in dichloromethane. The reaction mixture was stirred at room temperature for 4 hours, then poured into water (60 mL) and extracted with dichloromethane (3 × 10 mL). The combined organic phases were washed with saturated brine (40 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 8 / 1) to give compound 30i. ESI m / z 1262.8 [M+H] + .LCMS:product:Rt=1.511min.

[0734] Step 10): Compound 30i (300.0 mg, 0.24 mmol, 1.0 equivalence) was dissolved in N,N-dimethylformamide (10 mL), and Inter 7 (149.6 mg, 0.36 mmol, 1.5 equivalence), N,N-diisopropylethylamine (92.2 mg, 0.71 mmol, 3.0 equivalence), and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (180.8 mg, 0.48 mmol, 2.0 equivalence) were added. The reaction mixture was stirred at room temperature for 4 hours, poured into water (60 mL), and extracted with dichloromethane (3 × 10 mL). The combined organic phases were washed with brine (3 × 40 mL), dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography (petroleum ether / tetrahydrofuran = 1 / 1) to obtain compound 30j. ESI m / z 782.2[(M-Boc) / 2+H]+.LCMS:product:Rt=1.858min.

[0735] Step 11): Compound 30 (200.0 mg, 0.12 mmol, 1.0 equivalence) was dissolved in a mixed solution of dichloromethane (3 mL) and trifluoroacetic acid (3 mL), and the mixture was stirred at room temperature for 18 hours. The reaction solution was concentrated and purified by preparative high-performance liquid chromatography (formic acid) to obtain compound 30. ESI m / z 519.9 [M / 2+H] + .LCMS:product:Rt=0.765min. 1H NMR(400MHz,D2O)δ8.30(s,2H),7.38–6.69(m,12H),4.64–3.80(m,6H),3.68(d,J=17.2Hz,2H),3.37(tt,J=12.4,10.0Hz,8H),3.23– 3.07(m,4H),3.03–2.54(m,14H),2.42(dd,J=23.6,16.8Hz,7H),2.01(dd,J=32.8,15.6Hz,4H),1.87–1.56(m,5H),1.55–1.28(m,2H).

[0736] Example 31: Synthesis of Compound 31

[0737] Step 1): Compound 29e (800 mg, 1.89 mmol, 1.0 equivalence), acetic acid (200 mg, 3.33 mmol, 1.76 equivalence), and inter4 (450 mg, 1.12 mmol, 0.59 equivalence) were dissolved in dichloromethane (15 mL), and sodium triacetoxyborohydride (398.9 mg, 1.88 mmol, 3.0 equivalence) was added. The reaction mixture was stirred at 20 °C for 18 hours. After the reaction was complete, the reaction was quenched with an aqueous sodium bicarbonate solution (50 mL). The aqueous phase was separated and extracted with dichloromethane (3 × 30 mL). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography, eluting with a dichloromethane / (petroleum ether / methyl tert-butyl ether = 1 / 0 to 1 / 1) gradient to give compound 31a. ESI m / z 1057.6 [M+H] + .LCMS:product:Rt=1.793min.

[0738] Step 2): A solution of compound 31a (800 mg, 0.77 mmol, 1.00 equivalence), acetic acid (100 mg, 1.67 mmol, 2.17 equivalence), and (9H-fluorene-9-yl)methyl(2-oxoethyl)carbamate (290 mg, 1.03 mmol, 1.34 equivalence) in dichloromethane (15 mL) was added to sodium triacetoxyborohydride (490 mg, 2.31 mmol, 3.0 equivalence). The reaction mixture was stirred at 20 °C for 18 hours. After the reaction was complete, it was quenched with an aqueous sodium bicarbonate solution (150 mL). The aqueous phase was separated and extracted with dichloromethane (100 mL × 2). The combined organic phases were washed with brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product, which was then purified by silica gel column chromatography (eluent: dichloromethane / petroleum ether: methyl tert-butyl ether = 1:0 to 1:1) to give compound 31b. ESI m / z 810.4 [M+H] + .LCMS:product:Rt=1.496min.

[0739] Step 3): Compound 31b (730 mg, 0.51 mmol, 1.0 equivalence) was dissolved in a tetrahydrofuran solution of dimethylamine (2 mol / L, 7 mL), and the mixture was stirred at 25 °C for 3 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (elution gradient: dichloromethane / methanol 0-10%) to give compound 31c. ESI m / z 853.4 [M+H] + .LCMS:product:Rt=1.656min.

[0740] Step 4): Phosphorus oxychloride (50 mg, 0.33 mmol, 1.0 equivalence) was slowly added dropwise at 0 °C to a mixed solution of compound 31c (280 mg, 0.66 mmol, 2.0 equivalence) and pyridine (4 mL). The reaction mixture was stirred at 25 °C for 1 hour. The reaction was then quenched with an aqueous sodium bicarbonate solution (50 mL), and the aqueous phase was extracted with dichloromethane (50 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography, eluting with a dichloromethane / (dichloromethane:methanol = 10:1) gradient (0-30%) to give compound 31d. ESI m / z 588.4 [1 / 2(M-Boc) + H] + .LCMS:product:Rt=1.826min.

[0741] Step 5): Sodium hydride (30 mg, 0.75 mmol, 3.5 equivalence) (60% mineral oil dispersion) was added to a solution of compound 31d (380 mg, 0.21 mmol, 1.0 equivalence) in N,N-dimethylformamide (4 mL) at 0 °C. The reaction mixture was stirred at 20 °C for 30 min. Then, inter 5 (140 mg, 0.30 mmol, 1.4 equivalence) was added, and the reaction mixture was stirred at 25 °C for 2.5 h. The reaction mixture was quenched with an aqueous solution of ammonium chloride (30 mL), and the aqueous phase was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 1 / 0 to 2 / 3 gradient elution) to give compound 31e. ESI m / z 782.2[1 / 2(M-Boc)+H] + .LCMS:product:Rt=2.001min.

[0742] Step 6): Compound 31e (200 mg, 0.12 mmol, 1.0 equivalence) was added to a dioxane hydrochloride solution (3 mL, 4 M). The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was then concentrated under reduced pressure to obtain a residue. The residue was purified by preparative high-performance liquid chromatography (ammonium bicarbonate) to give compound 31. ESI m / z 1040.4 [MH] - .LCMS:product:Rt=0.741min. 1 H NMR(400MHz,D2O)δ7.43–6.67(m,12H),4.89(d,J=26.3Hz,1H),4.38–3.87(m,3H),3.32(ddd,J=73.1,4 0.9, 24.3Hz, 15H), 2.93–2.12 (m, 23H), 1.99 (s, 3H), 1.79–1.39 (m, 6H), 1.25 (dd, J=26.6, 13.4Hz, 1H).

[0743] 19 F NMR(377MHz,D2O)δ-120.90,-121.07,-121.28.

[0744] Example 32: Synthesis of Compound 32

[0745] Step 1): Compound 30c (1.80 g, 3.81 mmol, 1.0 equivalence) was dissolved in methanol (40 mL), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (0.28 g, 0.38 mmol, 0.1 equivalence) and triethylamine (1.58 mL, 11.43 mmol, 3.0 equivalence) were added. The mixture was purged three times with carbon monoxide (CO), heated to 70 °C under reflux and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure to give a crude product. The residue was purified by column chromatography using petroleum ether / ethyl acetate = 5 / 1 to give compound 32b1. ESI m / z 352.2 [M+100+H] + .LCMS:product:Rt=1.773min.

[0746] Step 2): Compound 32b1 (1.4 g, 3.10 mmol, 1.0 equivalence) was dissolved in methanol (12 mL) and water (4 mL), and lithium hydroxide monohydrate (0.39 g, 9.30 mmol, 3.0 equivalence) was added. The mixture was stirred at room temperature for 16 hours. The resulting reaction mixture was added to water (30 mL), the pH was adjusted to 3 with 1 M hydrochloric acid, and then extracted with ethyl acetate (30 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 32b. ESI m / z 282.0 [M-100-56+H] + .LCMS:product:Rt=1.599min.

[0747] Step 3): Compound 19c (150 mg, 0.18 mmol, 1.0 equivalence) and inter 4 (141.25 mg, 0.35 mmol, 2.0 equivalence) were dissolved in methanol (5 mL), acetic acid (0.01 mL) was added, and the mixture was stirred for 1 hour. Sodium borohydride (9.93 mg, 0.26 mmol, 1.5 equivalence) was added. The mixture was stirred at room temperature for 2 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (20 mL × 3) and washed with saturated sodium bicarbonate aqueous solution (20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with dichloromethane / methanol = 10 / 1 to give compound 32a. ESI m / z 573.0 573.0 [M-100 / 2+H]+.LCMS:product:Rt=1.762min.

[0748] Step 4): Compound 32a (110 mg, 0.09 mmol, 1.0 equivalence) and compound 32b (50.27 mg, 0.11 mmol, 1.3 equivalence) were dissolved in N,N-dimethylformamide (4 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (43.69 mg, 0.11 mmol, 1.3 equivalence) and N,N-diisopropylethylamine (0.05 mL, 0.27 mmol, 3.0 equivalence) were added. The mixture was stirred at room temperature for 16 hours. The reaction mixture was added to water (20 mL), extracted with ethyl acetate (20 mL × 3), and washed with saturated brine (20 mL × 2). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with petroleum ether / ethyl acetate = 1 / 1 to give compound 32c. ESI m / z 782.6 [M-100 / 2+H] + .LCMS:product:Rt=1.901min.

[0749] Step 5): Compound 32c (75 mg, 0.05 mmol, 1.0 equivalence) was dissolved in concentrated hydrochloric acid (2 mL). The mixture was heated and stirred at 60 °C for 16 hours. The reaction mixture was concentrated under reduced pressure to give the crude product. Compound 32 was purified by preparative high-performance liquid chromatography (ammonium bicarbonate). ESI m / z 541.3 [M / 2+H] + .LCMS:product:Rt=1.057min. 1 H NMR(400MHz,D2O)δ7.39(s,1H),7.31(dd,J=16.1,7.1Hz,3H),7.21–6.88(m,8H), 6.84–6.44(m,3H),5.66(d,J=4.2Hz,2H),4.61–4.49(m,3H),4.39(d,J=19.0Hz,2 H),4.24(dd,J=31.0,16.8Hz,1H),3.51(dd,J=55.9,26.0Hz,4H),3.36–3.00(m,1 1H),2.86–2.42(m,10H),2.41–2.17(m,7H),2.08–1.91(m,3H),1.70–1.50(m,3H).

[0750] Example 33: Synthesis of Compound 33

[0751] Step 1): Compound 30d (0.42 g, 1.00 mmol, 1.0 equivalent) was dissolved in water (2 mL), acetic acid (2 mL), and pyridine (4 mL). Raney nickel (0.16 g, 0.72 mmol) and sodium phosphate (0.15 g, 1.79 mmol, 1.5 equivalent) were then added to water (2 mL). The mixture was stirred at 45 °C for 3 hours. The reaction mixture was diluted with 1 M hydrochloric acid (50 mL × 3). The mixture was extracted with ethyl acetate (3 × 40 mL). The combined organic phases were washed with an aqueous sodium bicarbonate solution (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give compound 33a. LCMS:product:Rt = 1.446 min.

[0752] Step 2): To a solution of compound 2i (200.0 mg, 0.23 mmol, 1.0 equivalence) in dichloromethane (6 mL), compound 33a (98.5 mg, 0.23 mmol, 1.0 equivalence) and sodium triacetoxyborohydride (99.0 mg, 0.47 mmol, 2.0 equivalence) were added sequentially. The reaction mixture was stirred at room temperature for 4 hours. The mixture was poured into water (60 mL) and extracted with dichloromethane (3 × 10 mL). The combined organic phases were washed with brine (40 mL × 3), dried over sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / tetrahydrofuran = 1 / 2) to give compound 33b. ESI m / z 1262.8 [M+H] + .LCMS:product:Rt=1.506min.

[0753] Step 3): To a solution of compound 33b (200 mg, 0.16 mmol, 1.0 equivalence) in N,N-dimethylformamide (2 mL), add Inter 7 (99.75 mg, 0.24 mmol, 1.5 equivalence), N,N-diisopropylethylamine (40.9 mg, 0.32 mmol, 2.0 equivalence), and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (120.5 mg, 0.32 mmol, 2.0 equivalence). The reaction mixture was stirred at room temperature for 4 hours, poured into water (60 mL), and extracted with dichloromethane (3 × 10 mL). The combined organic phases were washed with brine (3 × 40 mL), dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The residue was purified by rapid column chromatography (petroleum ether / tetrahydrofuran = 1 / 1) to give compound 33c. ESI m / z 782.2[(M-Boc) / 2+H] + .LCMS:product:Rt=1.829min.

[0754] Step 4): Compound 33c (160.1 mg, 0.10 mmol, 1.0 equivalence) was dissolved in a mixed solution of dichloromethane (2 mL) and trifluoroacetic acid (2 mL). The mixture was stirred at room temperature for 18 hours. The resulting reaction solution was concentrated and purified by preparative high-performance liquid chromatography (formic acid) to obtain compound 33. ESI m / z 519.8 [M / 2+H] + .LCMS:product:Rt=0.624min. 1 H NMR(400MHz,D2O)δ7.41–6.68(m,12H),4.43–4.01(m,4H),3.71(dd,J=25.6,16.8Hz,2H),3.63–3.24(m,10H),3.23–3 .08(m,3H),3.10–2.56(m,15H),2.42(d,J=28.8Hz,7H),2.00(t,J=19.2Hz,4H),1.86–1.55(m,5H),1.51–1.24(m,2H).

[0755] Example 34: Synthesis of Compound 34

[0756] Step 1): 9 g (250 mg, 0.20 mmol, 1.0 equivalence) of compound 32b (113.69 mg, 0.26 mmol, 1.3 equivalence) were dissolved in N,N-dimethylformamide (5 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (98.81 mg, 0.26 mmol, 1.3 equivalence) and N,N-diisopropylethylamine (0.10 mL, 0.60 mmol, 3.0 equivalence) were added. The mixture was stirred at room temperature for 16 hours. Water (30 mL) was then added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL × 3) and washed with saturated brine (30 mL × 2). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with petroleum ether / ethyl acetate = 1 / 1 to give compound 34a. ESI m / z 785.6 [M-100 / 2+H] + .LCMS:product:Rt=2.595min.

[0757] Step 2): Compound 34a (230 mg, 0.14 mmol) was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (3 mL). The reaction mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure to give a crude product. Compound 34 was purified by preparative liquid chromatography (formic acid). ESI m / z 523.3 [M / 2+H] +.LCMS:product:Rt=0.709min. 1 H NMR(400MHz,D2O)δ7.24–6.96(m,8H),6.82(s,1H),4.46(dd,J=36.6,19.1 Hz,2H),3.98–3.84(m,2H),3.70–3.59(m,2H),3.54–3.27(m,10H),3.22–3. 09(m,3H),2.96–2.66(m,14H),2.58–2.34(m,8H),2.05(dd,J=13.0,7.0Hz ,4H),1.70(ddt,J=18.2,13.3,11.8Hz,5H),1.45(dd,J=25.2,12.3Hz,2H).

[0758] Example 35: Synthesis of Compound 35

[0759] Step 1): Inter 4e (6.00 g, 13.20 mmol, 1.0 equivalent) and 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxoborane (3.30 g, 19.64 mmol, 1.5 equivalent) were dissolved in a solution of dioxane (60 mL) and water (12 mL). 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (0.96 g, 1.31 mmol, 0.1 equivalent) and potassium phosphate (8.40 g, 39.57 mmol, 3 equivalent) were added. The reaction mixture was stirred at 80 °C for 18 hours under nitrogen. After filtration, water (300 mL) was added, and the mixture was extracted with ethyl acetate (200 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. The residue was purified by silica gel column chromatography (petroleum ether / tetrahydrofuran = 9 / 1) to give compound 35a. ESI m / z 438.2 [M+Na] + .LCMS:product:Rt=1.619min.

[0760] Step 2): Compound 35a (2.00 g, 4.68 mmol, 1.0 equivalence) was dissolved in a solution of acetonitrile (30 mL) and water (30 mL), and sodium periodate (5.00 g, 23.38 mmol, 5 equivalence) and ruthenium trichloride hydrate (0.20 g) were added. The reaction mixture was stirred at 25 °C for 18 hours. After filtration, ethyl acetate (50 mL) and water (100 mL) were added, and the mixture was extracted with ethyl acetate (50 mL × 3), washed with water (50 mL × 3), dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (dichloromethane / methanol = 97 / 3) to give compound 35b. ESI m / z 456.2 [M + Na]+ .LCMS:product:Rt=1.314min. 1 H NMR (400MHz, DMSO-d6) δ12.30 (s, 1H), 7.22 (t, J = 7.8Hz, 1H), 7.09 (dd, J = 11.4, 7.7Hz,3H),3.51(s,2H),3.37(t,J=8.5Hz,2H),3.16(dd,J=14.9,6.0Hz,1H),3. 00(t,J=10.0Hz,1H),2.72(d,J=9.3Hz,2H),2.49(s,1H),2.31(d,J=20.7Hz,1H) ,1.85(d,J=5.4Hz,1H),1.60(dd,J=19.8,8.7Hz,1H),1.42(s,9H),1.24(s,9H).

[0761] Step 3): Compound 35b (148.36 mg, 0.34 mmol, 1.4 equivalence) and phosphorus oxychloride (74.95 mg, 0.49 mmol, 2.0 equivalence) were added to a pyridine (6 mL) solution of compound 2j (320 mg, 0.24 mmol, 1.0 equivalence). The mixture was stirred at 25 °C for 16 h. The reaction solution was quenched with saturated sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with 1 M hydrochloric acid (20 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0 / 1) to give compound 35c. ESI m / z 780.2 [M-Boc+H] + .LCMS:product:Rt=1.93min.

[0762] Step 4): Add 2 mL of trifluoroacetic acid to a solution of compound 35c (250 mg, 0.15 mmol, 1.0 equivalence) in dichloromethane (6 mL). Stir the mixture at room temperature for 16 hours. After the reaction is complete, concentrate the mixture and purify it by preparative high-performance liquid chromatography (ammonium bicarbonate system) to obtain compound 35. ESI m / z 1034.5 [M+H] + .LCMS:product:Rt=0.97min. 1HNMR(400MHz,D2O)δ7.29–6.69(m,13H),4.54(s,1H),4.27(s,1H),3.86–3.72(m,2H),3.61(d,J=23.8Hz,4H),3. 42–3.04(m,13H),2.89–2.50(m,15H),2.35(d,J=21.7Hz,7H),2.06–1.55(m,9H),1.38(dd,J=27.6,16.8Hz,2H).

[0763] Example 36: Synthesis of Compound 36

[0764] Step 1): Compound 35b (400 mg, 0.78 mmol, 4.85 equivalence) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (200 mg, 0.53 mmol, 3.29 equivalence) were dissolved in N,N-dimethylformamide (4 mL), and N,N-diisopropylethylamine (100 mg, 0.77 mmol, 4.84 equivalence) was added. The mixture was stirred at 25 °C for 0.5 h. Then, a solution of 9 g (200 mg, 0.16 mmol, 1.0 equivalence) of compound in N,N-dimethylformamide (4 mL) was added. The reaction mixture was further reacted at 25 °C for 18 h. Water (50 mL) was added to the reaction mixture. The aqueous phase was extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with saturated brine (40 mL × 3), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography, eluting with petroleum ether / tetrahydrofuran (0-40%) to give compound 36a. ESI m / z 784.0 [1 / 2(M-Boc)+H] + .LCMS:product:Rt=2.591min.

[0765] Step 2): Compound 36a (220 mg, 0.12 mmol, 1.0 equivalence) was dissolved in dioxane hydrochloride solution (2 mL, 4 M) and stirred at room temperature for 18 hours. The resulting reaction mixture was concentrated and purified by preparative high-performance liquid chromatography (formic acid) to give compound 36. LCMS:product:Rt = 0.815 min; 1H NMR(400MHz,D2O)δ7.27–6.68(m,10H),4.60(s,1H),4.41(q,J=15.9Hz,1H),4.01–3.74(m,4H),3.67(d,J=12.3Hz,2H),3.32(d,J=9.3Hz,10 H),3.13(d,J=5.2Hz,3H),2.96–2.47(m,16H),2.45–2.18(m,6H),2.14–1.87(m,4H),1.71(d,J=44.1Hz,5H),1.39(dd,J=27.0,13.3Hz,2H).

[0766] Example 37: Synthesis of Compound 37

[0767] Step 1): Compound 12d (100 mg, 0.24 mmol, 1.0 equivalence) was dissolved in dichloromethane (5 mL), and Inter 6 (112 mg, 0.28 mmol, 1.1 equivalence), acetic acid (5 mg, 0.03 mmol, 0.1 equivalence), and sodium triacetoxyborohydride (160 mg, 0.75 mmol, 3.0 equivalence) were added. The reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was quenched with saturated sodium bicarbonate solution (10 mL) and extracted with dichloromethane (2 x 10 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / tert-butyl methyl ether = 1 / 1) to give compound 37a. ESI m / z 784.4 [M+H] + .LCMS:product:Rt=1.29min.

[0768] Step 2): Compound 37a (13.9 g, 16.84 mmol, 1.00 equivalence), acetic acid (0.31 g, 1.68 mmol, 0.1 equivalence), and (9H-fluorene-9-yl)methyl(2-oxoethyl)carbamate (5.69 g, 20.21 mmol, 1.2 equivalence) were dissolved in dichloromethane (150 mL), and sodium triethoxyborohydride (10.71 g, 50.53 mmol, 3.0 equivalence) was added. The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was quenched with an aqueous sodium bicarbonate solution (200 mL). Extraction was performed with dichloromethane (200 mL × 2). The combined organic layers were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography, eluting with petroleum ether / methyl tert-butyl ether at a ratio of 1 / 0 to 1 / 1, to give compound 37b. ESI m / z 1050.4 [M+H] + .LCMS:product:Rt=1.556min.

[0769] Step 3): Compound 37b (14.8 g, 14.10 mmol, 1.0 equivalence) was dissolved in a solution of dimethylamine in tetrahydrofuran (150 mL, 2 M) and stirred at 25 °C for 3 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography, eluting with dichloromethane / methanol (0-10%) to give compound 37c. ESI m / z 827.4 [M+H] + .LCMS:product:Rt=1.320min.

[0770] Step 4): Compound 37c (8.3 g, 10.04 mmol, 1.00 equivalence) and inter 4 (4.45 g, 11.04 mmol, 1.1 equivalence) were dissolved in methanol (120 mL). The reaction mixture was stirred at 25 °C for 1 hour. Sodium borohydride (0.57 g, 15.05 mmol, 1.5 equivalence) was then added to the reaction mixture, and the mixture was stirred at 25 °C for another 1 hour. The reaction mixture was quenched in ice water (100 mL). Extraction was then performed with ethyl acetate (100 mL × 2). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate = 1 / 0 to 1 / 1, to give compound 37d. ESI m / z 1215.8 [M+H] + .LCMS:product:Rt=1.483min.

[0771] Step 5): Compound 35b (350 mg, 0.68 mmol, 4.12 equivalences) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (250 mg, 0.66 mmol, 3.99 equivalences) were dissolved in N,N-dimethylformamide (5 mL), and N,N-diisopropylethylamine (100 mg, 0.77 mmol, 4.70 equivalences) were added. The mixture was stirred at 25 °C for 0.5 h. Then, a solution of compound 37d (200 mg, 0.16 mmol, 1.0 equivalences) in N,N-dimethylformamide (5 mL) was added. The reaction mixture was further reacted at 25 °C for 18 h. Water (50 mL) was added to the reaction mixture. The aqueous phase was extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with saturated brine (40 mL × 3), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography, eluting with petroleum ether / tetrahydrofuran (0-40%) to give compound 37e. ESI m / z 765.6 [1 / 2(M-Boc)+H] + .LCMS:product:Rt=1.630min.

[0772] Step 6): Compound 37e (200 mg, 0.10 mmol, 1.0 equivalence) was dissolved in concentrated hydrochloric acid (3 mL) and stirred at 60 °C for 18 hours. The reaction mixture was concentrated and purified by preparative high-performance liquid chromatography (ammonium bicarbonate) to give compound 37. ESI m / z 1048.5 [M+H] + .

[0773] LCMS:product:Rt=0.722min;

[0774] 1 H NMR(400MHz,D2O)δ7.38–6.97(m,14H),6.87–6.62(m,4H),4.49–3.97(m,4H),3.49(t,J=13.0Hz,5H),3.42–3.15(m,10H),3.15–2.97(m,4 H),2.93–2.70(m,3H),2.61(td,J=22.0,12.3Hz,6H),2.45(d,J=13.2Hz,4H),2.36–2.16(m,6H),1.97(d,J=3.3Hz,3H),1.74–1.44(m,3H).

[0775] Example 38: Synthesis of Compound 38

[0776] Step 1): Compound 32b (120 mg, 0.27 mmol, 1.67 equivalence) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (110 mg, 0.29 mmol, 1.76 equivalence) were dissolved in N,N-dimethylformamide (3 mL), and N,N-diisopropylethylamine (100 mg, 0.77 mmol, 4.70 equivalence) was added. The mixture was stirred at 25 °C for 0.5 h. Then, a solution of compound 37d (200 mg, 0.16 mmol, 1.0 equivalence) in N,N-dimethylformamide (5 mL) was added. The reaction mixture was further reacted at 25 °C for 18 h. Water (50 mL) was added to the reaction mixture. The aqueous phase was extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with saturated brine (40 mL × 3), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography, eluting with petroleum ether / tetrahydrofuran (0-40%) to give compound 38a. ESI m / z 767.6 [1 / 2(M-Boc)+H] + .LCMS:product:Rt=1.964min.

[0777] Step 2): Compound 38a (190 mg, 0.11 mmol, 1.0 equivalence) was dissolved in concentrated hydrochloric acid (3 mL). The mixture was heated and stirred at 60 °C for 12 hours. The reaction mixture was concentrated under reduced pressure to give the crude product. Compound 38 was purified by preparative high-performance liquid chromatography (formic acid). ESI m / z 1052.4 [M / 2+H] + .LCMS:product:Rt=0.849min. 1 H NMR(400MHz,D2O)δ7.48(t,J=22.2Hz,2H),7.39–7.16(m,7H),7.14–6.94(m,6H),6.80(s,1H),6.56(s,1H),4.48–4.07(m,8H),3.69( s,2H),3.55–3.34(m,6H),3.33–3.06(m,7H),2.98–2.58(m,11H),2.36(d,J=25.4Hz,6H),2.03(s,3H),1.62(dd,J=19.1,9.2Hz,3H).

[0778] 19 F NMR (377MHz, D2O) δ -113.63.

[0779] Experimental Example 1: Detection of Lp(a) Assembly Inhibition

[0780] The cells used in this experiment were wild-type HepG2 cells and a stable cell line overexpressing Apo(a)-HEK293. Serially diluted compounds were added to 96-well plates (Corning, 3599) and combined with the conditioned medium for HepG2 cells and the conditioned medium for Apo(a)-HEK293 cells. All three were co-incubated at 37°C for 2 hours for in vitro assembly. The reaction was then terminated by adding 6-aminocaproic acid (EACA) to a final concentration of 150 mM. Lp(a) was detected using a sandwich ELISA with anti-Lp(a) capture antibody (Abcam, ab27622) and HRP-conjugated anti-ApoB detection antibody. The absorbance was read at 450 nm on an Envision microscope.

[0781] The quality control results of the compounds were evaluated using HepG2 conditional medium (50-fold dilution) and 0.1% DMSO + 25.45 mM HCl. The percentage inhibition rate of Lp(a) assembly of the test compounds at each concentration was calculated. The data were analyzed using a concentration-inhibition rate nonlinear regression analysis in GraphPad Prism 9 to obtain the IC50 of the compounds. 50 Values, and test results for some compounds are shown in Table 1.

[0782] Tests have shown that at least some of the compounds of this invention exhibit high Lp(a) assembly inhibition activity.

[0783] Reference object 1 was prepared according to the method of Example 1 in CN114008021A, and reference object 2 was prepared according to the method of Example 4 in WO2023078333A.

[0784] Table 1

[0785] Experimental Example 2A: Apo(a) and OxPL binding inhibition

[0786] The cells used in this experiment were HepG2 cells overexpressing Apo(a). The serially diluted compounds were incubated with Apo(a)-HepG2 cells at 37°C and 5% CO2 for 24 hours, and the cell supernatant (containing: DMEM + 10% FBS + 1% PS + 20mM HEPES) was collected. The reaction was then terminated by adding 6-aminocaproic acid (EACA) to a final concentration of 150mM. Apo(a)-OxPL was detected using ELISA with mouse anti-OxPL capture antibody (Creatives biolabs, HPAB-0399-YJ), rabbit anti-Lp(a) antibody (Abcam, ab242565), and HRP-conjugated anti-rabbit IgG antibody (CST, 7074S). The signal was read at 450 nm on an Envision microscope.

[0787] The quality control results of the compounds were evaluated using a culture medium group (DMEM + 10% FBS + 1% PS + 20mM HEPES) and a group containing cell supernatant without the compounds. The percentage inhibition rate of the tested compounds against the binding of Apo(a) and OxPL at each concentration was calculated. The data were analyzed using a concentration-inhibition rate nonlinear regression analysis in GraphPad Prism 9 to obtain the IC50 values ​​of the compounds. The test results for some compounds are shown in Table 2A.

[0788] Tests have shown that at least some of the compounds of this invention exhibit good OxPL-Apo(a) binding inhibition activity.

[0789] Table 2A

[0790] Experimental Example 2B: Apo(a) and OxPL binding inhibition

[0791] The cells used in this experiment were HepG2 cells overexpressing Apo(a). The serially diluted compounds were incubated with Apo(a)-HepG2 cells at 37°C and 5% CO2 for 24 hours, and the cell supernatant (containing: DMEM + 10% FBS + 1% PS + 20mM HEPES) was collected. The reaction was then terminated by adding 6-aminocaproic acid (EACA) to 150mM. Apo(a)-OxPL was detected using an ELISA assay with rabbit anti-Lp(a) capture antibody (Abcam, ab242565), human anti-OxPL antibody (E06-Fc), and HRP-conjugated anti-IgG antibody (CST, 7074). The signal was read at 450nm on an Envision microscope.

[0792] The quality control results of the compounds were evaluated using a combination of culture medium (DMEM + 10% FBS + 1% PS + 20mM HEPES) and cell supernatant without the compounds. The percentage inhibition rate of the tested compounds against the binding of Apo(a) and OxPL at each concentration was calculated. The data were analyzed using a concentration-inhibition rate nonlinear regression analysis in GraphPad Prism 9 to obtain the IC50 values ​​of the compounds. Results for some compounds are shown in Table 2B.

[0793] Tests have shown that at least some of the compounds of this invention exhibit good Apo(a)-OxPL binding inhibition activity.

[0794] Table 2B Note: Average value (n = ), where n is the number of tests.

[0795] Experimental Example 3: Pharmacokinetics and Liver-to-Blood Ratio Detection

[0796] Drug metabolism pharmacokinetic property assessment

[0797] 1. Laboratory animals

[0798] The test animals used in this study were female C57bl6j mice (6-9 weeks old, Beijing Vital River Laboratory Animal Technology Co., Ltd.), which were divided into oral and intravenous administration groups. The oral administration group was fasted overnight before administration, and was given food and free access to water 4 hours after administration of the test product.

[0799] 2. Preparation of drug formulations

[0800] According to the protocol requirements, weigh and prepare the compound to be tested using 1% hydroxyethyl cellulose + 0.25% Tween 80 or physiological saline as the solvent.

[0801] 3. Animal drug administration and sample collection

[0802] Animals were given the prepared compound via intravenous injection or oral gavage. Whole blood was collected at 0.033, 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 h after intravenous injection and at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 h after oral administration. The blood was centrifuged at 8000 rpm for 7 min at 4 °C, and the supernatant plasma was collected and stored at -80 °C for analysis.

[0803] 4. Plasma sample testing

[0804] Dilute the analyte stock solution with pure water to prepare a series of working solutions, add them to the blank plasma matrix, and prepare a standard curve and quality control samples. Take an appropriate volume of plasma sample and add an appropriate amount of 7.5% TCA solution containing internal standard (200 nM dichloroadenosine) according to the response to precipitate proteins. After centrifuging all samples at 4000 rpm for 10 min, take an appropriate amount of supernatant, add 1% ammonia to adjust the pH to 3-4, mix well, and then perform LC-MS / MS analysis.

[0805] 5. Parameter Calculation

[0806] Based on the tested concentration, a blood drug concentration-time curve was plotted. Using WinNonlin software and a non-compartmental model, the curves were calculated, including: half-life (T1 / 2) and area under the curve (AUC). 0-t Pharmacokinetic parameters such as clearance rate (CL), steady-state volume of distribution (Vss), and bioavailability (F) are also included.

[0807] Drug-induced liver-to-blood ratio assessment

[0808] 1. Laboratory animals

[0809] The test animals used in this study were female C57bl6j mice (6-9 weeks old, Beijing Vital River Laboratory Animal Technology Co., Ltd.), which were divided into an oral gavage group and a non-oral group. The oral group was fasted overnight before administration of the test product, and was given food and free access to water 4 hours after administration.

[0810] 2. Preparation of drug formulations

[0811] According to the protocol requirements, weigh and prepare the compound to be tested using 1% hydroxyethyl cellulose + 0.25% Tween 80 as the solvent.

[0812] 3. Animal drug administration and blood sample collection

[0813] Animals were administered the prepared compound orally via gavage. Whole blood and liver were collected at 0.5h, 2h, 4h, 24h and 48h after administration. Whole blood was centrifuged at 8000rpm for 7min at 4℃, and the supernatant plasma was collected. Both liver and plasma were stored at -80℃ for analysis.

[0814] 4. Plasma sample testing

[0815] Dilute the analyte stock solution with pure water to prepare a series of working solutions, add them to the blank plasma matrix, and prepare a standard curve and quality control samples. Take an appropriate volume of plasma sample and add an appropriate amount of 7.5% TCA solution containing internal standard (200 nM dichloroadenosine) according to the response to precipitate proteins. After centrifuging all samples at 4000 rpm for 10 min, take an appropriate amount of supernatant, add 1% ammonia to adjust the pH to 3-4, mix well, and then perform LC-MS / MS analysis.

[0816] 5. Liver sample testing

[0817] Liver samples and blank liver samples were added to PBS at a 1:2 mass-to-volume ratio, homogenized with steel balls, and placed on ice for later use. The stock solution of the analyte was diluted with pure water to prepare a series of working solutions, which were then added to the blank liver matrix to prepare a standard curve and quality control samples. An appropriate volume of liver sample was taken, and protein precipitation was performed by adding an appropriate amount of 7.5% TCA solution containing an internal standard (200 nM dichloroadenosine) according to the response. All samples were centrifuged at 4000 rpm for 10 min, and an appropriate amount of the supernatant was taken. The pH was adjusted to 3–4 with 1% ammonia, mixed well, and then analyzed by LC-MS / MS.

[0818] 5. Parameter Calculation

[0819] Based on the tested concentration, a blood drug concentration-time curve was plotted. Using WinNonlin software and a non-compartmental model, the curves were calculated, including: half-life (T1 / 2) and area under the curve (AUC). 0-t Pharmacokinetic parameters such as bioavailability (F).

[0820] Tests have shown that at least some of the compounds of this invention have good pharmacokinetic parameters, and the test results of some compounds are shown in Table 4.

[0821] Table 4. Oral pharmacokinetic parameters of some compounds of this invention in mice.

[0822] Test Example 5: Apo(a) and OxPL binding inhibition

[0823] The cells used in this experiment were HEK293 cells overexpressing Apo(a). The serially diluted compounds were incubated with Apo(a)-HEK293 cells at 37°C and 5% CO2 for 24 hours, and the cell supernatant (containing: DMEM + 10% FBS + 1% PS + 20mM HEPES) was collected. The reaction was then terminated by adding 6-aminocaproic acid (EACA) to a final concentration of 150mM. Apo(a)-OxPL was detected using an ELISA assay with rabbit anti-Lp(a) capture antibody (Abcam, ab242565), human anti-OxPL antibody (E06-Fc), and HRP-conjugated anti-IgG antibody (CST, 707). The absorbance was read at 450 nm on an Envision microscope.

[0824] The quality control results of the compounds were evaluated using a culture medium group (DMEM + 10% FBS + 1% PS + 20mM HEPES) and a group containing cell supernatant without the compounds. The percentage inhibition rate of the tested compounds against the binding of Apo(a) and OxPL at each concentration was calculated. The data were analyzed using a concentration-inhibition rate nonlinear regression analysis in GraphPad Prism 9 to obtain the IC50 values ​​of the compounds. Some test results are shown in Table 5.

[0825] Tests showed that the compounds of this invention have good Apo(a)-OxPL binding inhibition activity, and the Apo(a)-OxPL binding inhibition activity of most compounds is significantly better than that of reference compounds 1 and 2.

[0826] Table 5 Note: Average value (n = ), where n is the number of tests.

Claims

1. A compound of formula (I'), its isomers, isotopically labeled compounds, prodrugs, or pharmaceutically acceptable salts, esters, hydrates, or solvates thereof, wherein the compound of formula (I') is shown below: Rings A, B, C, and D are each independently selected from: 5-10 membered heterocyclic groups, 5-10 membered aromatic heterocyclic groups, or phenyl groups. The heteroatoms in the 5-10 membered heterocyclic group or 5-10 membered aromatic heterocyclic group are selected from N, O, or S, or combinations of two or three of these. When the 5-10 membered heterocyclic group or 5-10 membered aromatic heterocyclic group comprises two heteroatoms, the heteroatoms may be the same or different. When the 5-10 membered heterocyclic group or 5-10 membered aromatic heterocyclic group comprises three heteroatoms, the heteroatoms may be the same, partially the same, or completely different. Optionally, each of the 5-10 membered heterocyclic group, 5-10 membered aromatic heterocyclic group, and phenyl group is independently substituted by at least one substituent selected from group G. The group G is selected from: 1)C 1-6 Alkyl, wherein C 1-6 The alkyl group is optionally composed of one or more radicals independently selected from deuterium, halogen, hydroxyl, cyano, amino, or C. 1-6 Substitution of alkoxy groups; 2) Deuterium; 3)-NH2; 4) Cyano group; 5) Oxo (=O); 6) Halogens; 7) Hydroxyl group; 8)C 1-6 Alkoxy, where C 1-6 The alkoxy group is optionally surrounded by one or more groups independently selected from deuterium, halogen, hydroxyl, cyano, amino, or C. 1-6 Substitution of alkoxy groups; 9)C 3-10 cycloalkyl, wherein C 3-10 The cycloalkyl group is optionally composed of one or more radicals independently selected from deuterium, halogen, hydroxyl, cyano, amino, or C. 1-6 Substitution of alkoxy groups; 10) A 3-12 membered heterocyclic group, wherein the 3-12 membered heterocyclic group is optionally composed of one or more independently selected from deuterium, halogen, hydroxyl, cyano, amino, or C. 1-6 Substitution of alkoxy groups; L is selected from: Preferably, L is selected from Preferably, L is selected from Preferably, L is selected from Preferably, L is selected from Preferably, L is selected from Preferably, L is X is selected from -S(=O)2-, -CH2-, or -H, preferably -CH2-; when X is -H, Y, R7, R8, and Rx' do not exist; Y is selected from C or N, preferably Y is C; when Y is selected from N, one of R7 and R8 does not exist; R X ', Rz, and Rz' are each independently selected Tetrazole, -COOH, -CH2COOH, -CH2OH, -CH2CH2OH, -COOCH3, -COOCH2CH3, -COOCH2CH2CH3, -CONH2, -NH2, -NHCOCH3, Preferred ions are -COOH, -OH, -CONH2, and -CH2COOH; more preferably -OH, tetrazolium, -COOH, -CH2COOH, -CH2OH, and -CONH2; or R X 'for -CO-R x R1, R3, R5, and R7 are each independently selected from C. 4-10 Cycloalkyl or 4-10 membered heterocyclic groups, preferably C 5-10 Cycloalkyl or 5-10 membered heterocyclic groups, wherein the heteroatoms of the 5-10 membered heterocyclic group are selected from N, O, or S, or combinations of two or three of them, wherein when the 5-10 membered heterocyclic group comprises two heteroatoms, the heteroatoms may be the same or different, and when the 5-10 membered heterocyclic group comprises three heteroatoms, the heteroatoms may be the same, partially the same, or completely different; optionally, the C 5-10 The cycloalkyl group and the 5-10 membered heterocyclic group are each independently substituted by at least one substituent selected from group G; wherein, The C 5-10 The cycloalkyl group is substituted with at least one amino group, and the 5-10 membered heterocyclic group contains at least one nitrogen atom; R2, R4, R6, R8, and R9 are each independently selected from hydrogen, deuterium, halogens, or C. 1-6 Alkyl; or C forms between R1, R2 and their connected atoms; between R3, R4 and their connected atoms; between R5, R6 and their connected atoms; or between R7, R8 and their connected atoms. 5-10 Cycloalkyl, 5-10 membered heterocyclic groups, optionally C 5-10 The cycloalkyl group or 5-10 membered heterocyclic group is substituted by one or more of the following substituents: deuterium, -NH2, halogen, C 1-6 Alkyl, -OH, C 1-6 alkoxy; wherein, the C 5-10 The cycloalkyl group is substituted with at least one amino group, and the 5-10 membered heterocyclic group contains at least one nitrogen atom; Alternatively, C forms between R4, R9 and the atoms they are connected to. 8-10 cycloalkyl, 8-10 membered heterocyclic groups, optionally C 8-10 The cycloalkyl or 8-10 membered heterocyclic group is substituted with one or more substituents selected from group G; wherein, the C 8-10 The cycloalkyl group is substituted with at least one amino group, and the 8-10 membered heterocyclic group contains at least one nitrogen atom; when R4, R9 and the atoms attached to them form a C 8-10 R3 is absent when the group consists of cycloalkyl or 8-10 membered heterocyclic groups; The condition is that the stated formula (I') is not a compound, its isomer, isotopically labeled compound, prodrug, or a pharmaceutically acceptable salt, ester, hydrate, or solvate thereof:

2. The compound, its isomers, isotopically labeled compounds, prodrugs, or pharmaceutically acceptable salts, esters, hydrates, or solvates thereof according to claim 1, having a compound of the following formula (I): Rings A, B, C, and D are each independently selected from: 5-10 membered heterocyclic groups (e.g., 5, 6, 7, 8, 9, 10 members, which can be 5-6 membered heterocyclic groups), 5-10 membered aromatic heterocycles, or phenyl groups (e.g., 5, 6, 7, 8, 9, 10 members, which can be 5-6 membered aromatic heterocycles). The heteroatoms in the 5-10 membered heterocyclic group or 5-10 membered aromatic heterocycle are selected from N, O, or S, or combinations of two or three of these. When the 5-10 membered heterocyclic group or 5-10 membered aromatic heterocycle comprises two heteroatoms, the heteroatoms may be the same or different. When the 5-10 membered heterocyclic group or 5-10 membered aromatic heterocycle comprises three heteroatoms, the heteroatoms may be the same, partially the same, or completely different. Optionally, each of the 5-10 membered heterocyclic group, 5-10 membered aromatic heterocycle, and phenyl group is independently substituted by at least one substituent selected from group G. The group G is selected from: 1)C 1-6 Alkyl, wherein C 1-6 The alkyl group is optionally composed of one or more radicals independently selected from deuterium, halogen, hydroxyl, cyano, amino, or C. 1-6 Substitution of alkoxy groups; 2) Deuterium; 3)-NH2; 4) Cyano group; 5) Oxo (=O); 6) Halogens; 7) Hydroxyl group; 8)C 1-6 Alkoxy, where C 1-6 The alkoxy group is optionally surrounded by one or more groups independently selected from deuterium, halogen, hydroxyl, cyano, amino, or C. 1-6 Substitution of alkoxy groups; 9)C 3-10 cycloalkyl, wherein C 3-10 The cycloalkyl group is optionally composed of one or more radicals independently selected from deuterium, halogen, hydroxyl, cyano, amino, or C. 1-6 Substitution of alkoxy groups; 10) A 3-12 membered heterocyclic group, wherein the 3-12 membered heterocyclic group is optionally composed of one or more independently selected from deuterium, halogen, hydroxyl, cyano, amino, or C. 1-6 Substitution of alkoxy groups; L is selected from: Preferably, L is selected from Preferably, L is selected from Preferably, L is selected from Preferably, L is selected from Preferably, L is selected from Preferably, L is X is selected from -S(=O)2-, CH2, or -H, preferably CH2; when X is selected from -H, Y, R7, R8, and -CO-Rx do not exist. Y is selected from C or N, preferably Y is C; when Y is selected from N, one of R7 and R8 does not exist; R X Selected from Or -OH, preferably, R X It is -OH; R1, R3, R5, and R7 are each independently selected from C. 5-10 Cycloalkyl, 5-10 membered heterocyclic group, wherein the heteroatom of the 5-10 membered heterocyclic group is selected from one or a combination of two or three of N, O, and S; optionally, the C 5-10 The cycloalkyl group and the 5-10 membered heterocyclic group are each independently substituted by at least one substituent selected from group G; wherein, The C 5-10 The cycloalkyl group is substituted with at least one amino group, and the 5-10 membered heterocyclic group contains at least one nitrogen atom; R2, R4, R6, R8, and R9 are each independently selected from hydrogen, deuterium, halogens, or C. 1-6 Alkyl; or C forms between R1, R2 and their connected atoms; between R3, R4 and their connected atoms; between R5, R6 and their connected atoms; or between R7, R8 and their connected atoms. 5-10 Cycloalkyl, 5-10 membered heterocyclic groups, optionally C 5-10 The cycloalkyl group or 5-10 membered heterocyclic group is substituted by one or more of the following substituents: deuterium, -NH2, halogen, C 1-6 Alkyl, -OH, C 1-6 alkoxy; wherein, the C 5-10 The cycloalkyl group is substituted with at least one amino group, and the 5-10 membered heterocyclic group contains at least one nitrogen atom; Alternatively, C forms between R4, R9 and the atoms they are connected to. 8-10 cycloalkyl, 8-10 membered heterocyclic groups, optionally C 8-10 The cycloalkyl or 8-10 membered heterocyclic group is substituted with one or more substituents selected from group G; wherein, the C 8-10 The cycloalkyl group is substituted with at least one amino group, and the 8-10 membered heterocyclic group contains at least one nitrogen atom; when R4, R9 and the atoms attached to them form a C 8-10 R3 is absent when the group consists of cycloalkyl or 8-10 membered heterocyclic groups; The condition is that formula (I) is not a compound, its isomer, isotopically labeled compound, prodrug, or a pharmaceutically acceptable salt, ester, hydrate, or solvate thereof:

3. The compound, its isomer, isotopically labeled compound, prodrug, or pharmaceutically acceptable salt, ester, hydrate, or solvate thereof according to claim 1 or 2, wherein the following condition is satisfied: 1) At least one of rings A, B, C, and D is selected from 5-membered heteroaryl groups; or 2) R4 and R9, together with the atoms they are bonded to, form C. 8-10 Fused bicyclic cycloalkyl or 8-10 fused bicyclic heterocyclic groups, and R3 is absent, optionally C 8-10 The fused bicyclic cycloalkyl group or the 8-10 membered fused bicyclic heterocyclic group is replaced by one or more substituents selected from group G, wherein the C 8-10 The fused bicyclic cycloalkyl group is at least substituted with an amino group, and the 8-10 fused bicyclic heterocyclic group contains at least one nitrogen atom; preferably, R4, R9 together with the atoms attached to them form an 8-10 fused bicyclic heterocyclic group, and R3 is absent; optionally, the 8-10 fused bicyclic heterocyclic group is substituted with one or more substituents selected from group G, wherein the 8-10 fused bicyclic heterocyclic group contains at least one nitrogen atom; more preferably, the 8-10 fused bicyclic heterocyclic group is selected from benzopyrrolidinyl, benzopiperidinyl, 5-6 fused heteroarylpyrrolidinyl, or 5-6 fused heteroarylpiperidinyl.

4. The compound, its isomers, isotopically labeled compounds, prodrugs, or pharmaceutically acceptable salts, esters, hydrates, or solvates thereof according to any one of claims 1 to 3, having a compound of formula (II) below. in, n1, n2, n3, and n4 are each independently selected from 1, 2, or 3; preferably, n1 and n2 are both selected from 2, or one of n1 and n2 is selected from 1 and the other is selected from 2; preferably, n3 and n4 are both selected from 2, or one of n3 and n4 is selected from 1 and the other is selected from 2. L, R1, R2, R3, R4, R9, ring A, ring B, ring C, and ring D are as defined in any one of claims 1-3.

5. The compound, its isomer, isotopically labeled compound, prodrug, or pharmaceutically acceptable salt, ester, hydrate, or solvate according to any one of claims 1-4, characterized in that, The group G is selected from: 1)-CH3; 2)-NH2; 3) F or Cl; 4)-OH; 5)-OCH3; 6) Cyclopropyl.

6. The compound, its isomer, isotopically labeled compound, prodrug, or pharmaceutically acceptable salt, ester, hydrate, or solvate according to any one of claims 1 to 5, characterized in that, The rings A, B, C, and D are each independently selected from 5-6-membered heteroaryl, phenyl, 9-10-membered heteroaryl, and 9-10-membered heterocyclic groups; the 5-6-membered heteroaryl, phenyl, 9-10-membered heteroaryl, and 9-10-membered heterocyclic groups are optionally and independently substituted by at least one substituent selected from group G; preferably, the rings A, B, C, and D are each independently selected from phenyl, 5-6-membered monocyclic heteroaryl, 9-10-membered bicyclic heteroaryl, and benzo5-6-membered monocyclic heterocyclic groups; the phenyl, 5-6-membered monocyclic heteroaryl, 9-10-membered bicyclic heteroaryl, and benzo5-6-membered monocyclic heterocyclic groups are optionally and independently substituted by 1, 2, or 3 (preferably 1) substituents selected from group G; Preferably, rings A, B, C, and D are each independently selected from... Q-1 (Preferred) )、 in, Representing single or double bonds, and adjacent to each other. Not both are double bonds; The key marked with "#" is connected to L; The group in the structure shown in Q-1 is a 5-membered heteroaryl group, wherein Q1, Q2, and Q3 are each independently selected from CH, NH, N, S, and O, and at least one of Q1, Q2, and Q3 is selected from NH, N, S, and O; preferably, Q1 is selected from NH, O, and S, and Q2 and Q3 are each independently selected from CH and N; preferably, Q2 is N, Q1 is S, and Q3 is CH. Q4, Q5, Q6, Q7, Q8, Q9, Q 10 Q 11 Q 12 Q 13 Q 14 Q 15 Q 16 Q 17 Q 18 Q 19 Q 20 Q 21 Each is independently selected from CH or N; preferably, Q4, Q5, Q6, and Q7 are all CH; preferably, one or two of Q4, Q5, Q6, and Q7 are N; preferably, Q8 and Q9 are both CH; preferably, Q 10 Q 11 Q 12 Q 13 One or both of them are N; preferably, Q 10 Q 13 Both are N, Q 11 Q 12 All are CH; preferably, Q 14 Q 15 All are CH; preferably, Q 16 Q 17 Q 18 All are CH; preferably, Q 19 Q 20 Q 21 All are CH; t is selected from 1, 2, or 3; preferably t is selected from 1 or 2; preferably t is 1; Each R G The substituent is independently selected from any substituent in group G, where j is selected from 0, 1, 2, 3, or 4; Preferably, each R G Independently selected from deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl or 4-7 membered heterocyclic groups; preferably, each R G Independently selected from halogens (e.g., F, Cl, Br, I, preferably F, Cl), hydroxyl groups, C 1-4 Alkyl (e.g., methyl, ethyl, propyl, butyl, preferably methyl) or C 1-4 Alkyl groups (e.g., methoxy, ethoxy, propoxy, butoxy, preferably methoxy); preferably, each R G Independently selected from halogens (e.g., F, Cl, Br, I, preferably F and Cl), C 1-4 Alkyl (e.g., methyl, ethyl, propyl, butyl, preferably methyl) or C 1-4 Alkyl groups (e.g., methoxy, ethoxy, propoxy, butoxy, preferably methoxy); preferably, each R G Independently selected from halogens (e.g., F, Cl, Br, I, preferably F, Cl) or C 1-4 Alkyl groups (e.g., methyl, ethyl, propyl, butyl, preferably methyl); preferably, each R G It is a halogen (e.g., F, Cl, Br, I, preferably F or Cl, more preferably F); Preferably, j is selected from 0 or 1; preferably, j is 0; Preferably, rings A, B, C, and D are each independently selected from... Q-1 (Preferred) )、 Preferably, at least two of rings A, B, C, and D are selected from...

7. The compound, its isomer, isotopically labeled compound, prodrug, or pharmaceutically acceptable salt, ester, hydrate, or solvate according to any one of claims 1 to 6, characterized in that, The 5-6 aryl heterogroups are selected from pyrrole, furanyl, thiophene, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, triazolyl, oxadiazolyl, thiazolyl, pyridinyl, or pyrimidinyl, with thiophene and thiazolyl being preferred.

8. The compound, its isomer, isotopically labeled compound, prodrug, or pharmaceutically acceptable salt, ester, hydrate, or solvate according to any one of claims 1 to 7, characterized in that, Rings A, B, C, and D are each independently selected from: Preferably, rings A, B, C, and D are each independently selected from... The key marked with "#" is connected to L.

9. The compound, its isomer, isotopically labeled compound, prodrug, or pharmaceutically acceptable salt, ester, hydrate, or solvate according to any one of claims 1 to 8, characterized in that, R1, R3, R5, and R7 are each independently selected from: in, Y1, Y 20 Y 21 Each is independently selected from CH or N; Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, Y 10 Y 11 Y 12 Y 13 Y 19 Y 22 Y 23 Each atom is independently selected from CH2, NH, O, or S; no two adjacent atoms are heteroatoms at the same time; Each R y Each was independently selected from C 1-6 Alkyl groups (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, preferably CH3), C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -NH2, halogen (e.g., F, Cl, Br, I, preferably F, Cl), or deuterium; e is selected from 0, 1, 2, 3 or 4; Preferably, each R y Each was independently selected from C 1-6 Alkyl groups (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, preferably CH3), C 1-6 Alkoxy, C 3-6 Saturated cycloalkyl groups, 3-6 membered saturated heterocyclic groups, -NH2, halogens (e.g., F, Cl, Br, I, preferably F and Cl); Preferably, e is selected from 0 or 1; more preferably, e is 0; The condition is that the following conditions are met: 1) When Y1 is selected from CH and Y2, Y3, Y4, Y5, and Y6 are selected from CH2, e is not 0, and at least one R is selected. y Selected from -NH2; 2) When Y7, Y8, Y9, Y 10 When selected from CH2, e is not 0, and at least one R is selected. y Selected from -NH2; 3) When Y1, Y2, Y3, Y4, Y5, and Y6 are not all carbon atoms, at least one of them must be selected from nitrogen heteroatoms; 4) When Y7, Y8, Y9, Y 10 When they are not both carbon atoms, at least one of them must be selected from nitrogen heteroatoms; 5)Y 11 Y 12 Y 13 At least one of them is selected from nitrogen heteroatoms; 6)Y 19 Y 20 Y 21 Y 22 Y 23 At least one of them is selected from nitrogen heteroatoms; and / or R2, R4, R6, and R8 are each independently selected from hydrogen, deuterium, halogens, or C. 1-4 Alkyl groups; and / or R9 is selected from hydrogen, halogen, or C. 1-4 alkyl; Preferably, R1, R3, R5, and R7 are each independently selected from... Wherein Y1 is selected from CH or N; Y3, Y4, and Y6 are each independently selected from CH2, NH, or O, and no two adjacent ring atoms are simultaneously selected from NH or O, and at least one of Y3, Y4, and Y6 is NH (preferably Y3 or Y4 is NH, more preferably Y4 is NH); each R y Independently selected from halogen or C 1-4 Alkyl; e is selected from 0 or 1, preferably e is 0; and / or R2, R4, R6, and R8 are all hydrogen; and / or R9 is selected from hydrogen, halogen, or C. 1-4 Alkyl group; preferably, R9 is hydrogen.

10. The compound, its isomer, isotopically labeled compound, prodrug, or pharmaceutically acceptable salt, ester, hydrate, or solvate according to claim 1 or 2, characterized in that, R1, R3, R5, and R7 are each independently selected from: in, Cyclop P is selected from 5-6 member monocyclic heterocyclic groups, C 3-6 Monocyclic cycloalkyl; Ring E is selected from 4-6 member monocyclic heterocyclic groups, C 3-6 Monocyclic cycloalkyl; Ring F is selected from 4-6 member monocyclic heterocyclic groups, C 3-6 Monocyclic cycloalkyl; Ring H is selected from 4-6 member monocyclic heterocyclic groups, C 3-6 Monocyclic cycloalkyl; Each R P R E R F R H Each was independently selected from C 1-6 Alkyl groups (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, preferably CH3), C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups, -NH2, halogens (e.g., F, Cl, Br, I, preferably F, Cl), deuterium; e is selected from 0, 1, 2, 3, 4; Preferably, R P R E R F R H Each was independently selected from C 1-6 Alkyl (preferably CH3), C 1-6 Alkoxy, C 3-6 Saturated cycloalkyl groups, 3-6 membered saturated heterocyclic groups, -NH2, halogens (e.g., F, Cl); Preferably, e is selected from 0 or 1, more preferably, e is 0; The condition is that the following conditions are met: 1) When both ring P and ring E are cycloalkyl, e is not 0, and at least one of ring P or ring E is substituted by an amino group; 2) When both ring F and ring H are cycloalkyl, e is not 0, and at least one of ring F or ring H is substituted by an amino group; 3) When ring P and ring E are not both cycloalkyl, at least one of ring P and ring E is a nitrogen-containing heterocyclic group; 4) When ring F and ring H are not both cycloalkyl, at least one of ring F and ring H is a nitrogen-containing heterocyclic group; Preferably, Cyclone P is selected from 5-6 member saturated monocyclic heterocyclic groups, C 5-6 Saturated monocyclic cycloalkyl; more preferably C 5-6 Saturated monocyclic cycloalkyl groups; Ring E is selected from 5-6 member saturated monocyclic heterocyclic groups, C 5-6 Saturated monocyclic cycloalkyl groups; more preferably, 5-6 membered saturated nitrogen-containing monocyclic heterocyclic groups; Ring F is selected from 4-6 member saturated monocyclic heterocyclic groups, C 4-6 Saturated monocyclic cycloalkyl groups; more preferably 4-6 membered saturated nitrogen-containing monocyclic heterocyclic groups, C 4-6 Saturated monocyclic cycloalkyl groups; Ring H is selected from 4-6 member saturated monocyclic heterocyclic groups, C 3-6 Saturated monocyclic cycloalkyl groups; more preferably 4-6 membered saturated nitrogen-containing monocyclic heterocyclic groups, C 3-6 Saturated monocyclic cycloalkyl groups; Preferably, Ring P is selected from C 5-6 Saturated monocyclic cycloalkyl groups, wherein ring E is selected from 5-6 membered saturated nitrogen-containing monocyclic heterocyclic groups; Ring F is selected from 4-6 member saturated nitrogen-containing monocyclic heterocyclic groups and ring H is selected from C. 3-6 Saturated monocyclic cycloalkyl, or ring F selected from C 4-6 Saturated monocyclic cycloalkyl groups with ring H selected from 4-6 membered saturated nitrogen-containing monocyclic heterocyclic groups; and / or R2, R4, R6, and R8 are each independently selected from hydrogen, deuterium, halogens, or C. 1-4 Alkyl groups; and / or R9 is selected from hydrogen, halogen, or C. 1-4 Alkyl group, preferably, R9 is hydrogen.

11. The compound, its isomers, isotopically labeled compounds, prodrugs, or pharmaceutically acceptable salts, esters, hydrates, or solvates thereof according to claim 1 or 2, characterized in that, R1, R2 and their connected atoms, R3, R4 and their connected atoms, R5, R6 and their connected atoms, or R7, R8 and their connected atoms together form the following rings: in, Cyclop P is selected from 5-6 member monocyclic heterocyclic groups, C 3-6 Monocyclic cycloalkyl; Ring E is selected from 4-6 member monocyclic heterocyclic groups, C 3-6 Monocyclic cycloalkyl; Ring F is selected from 4-6 member monocyclic heterocyclic groups, C 3-6 Monocyclic cycloalkyl; Ring H is selected from 4-6 member monocyclic heterocyclic groups, C 3-6 Monocyclic cycloalkyl; Each R P R E R F R H Each was independently selected from C 1-6 Alkyl (preferably CH3), C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups, -NH2, halogens (e.g., F, Cl), deuterium; e is selected from 0, 1, 2, 3, 4; Preferably, each R P R E R F R H Each was independently selected from C 1-6 Alkyl (preferably CH3), C 1-6 Alkoxy groups, C3-6 saturated cycloalkyl groups, 3-6 membered saturated heterocyclic groups, -NH2, halogens (e.g., F, Cl); Preferably, e is selected from 0 or 1, more preferably, e is 0; The condition is that the following conditions are met: 1) When both ring P and ring E are cycloalkyl, e is not 0, and at least one of ring P or ring E is substituted by an amino group; 2) When both ring F and ring H are cycloalkyl, e is not 0, and at least one of ring F or ring H is substituted by an amino group; 3) When ring P and ring E are not both cycloalkyl, at least one of ring P and ring E is a nitrogen-containing heterocyclic group; 4) When ring F and ring H are not both cycloalkyl, at least one of ring F and ring H is a nitrogen-containing heterocyclic group; Preferably, Ring P is selected from C 5-6 Saturated monocyclic cycloalkyl groups, wherein ring E is selected from 5-6 membered saturated nitrogen-containing monocyclic heterocyclic groups; Ring F is selected from 4-6 member saturated nitrogen-containing monocyclic heterocyclic groups and ring H is selected from C. 3-6 Saturated monocyclic cycloalkyl, or ring F selected from C 4-6 Saturated monocyclic cycloalkyl groups with ring H selected from 4-6 membered saturated nitrogen-containing monocyclic heterocyclic groups; and / or R9 is selected from hydrogen, halogen, or C. 1-4 Alkyl group, preferably, R9 is hydrogen.

12. The compound, its isomer, isotopically labeled compound, prodrug, or pharmaceutically acceptable salt, ester, hydrate, or solvate thereof according to claim 1, 2, 9, or 10, characterized in that, R1, R3, R5, and R7 are each independently selected from: and / or R2, R4, R6, and R8 are each independently selected from hydrogen, halogen, or C. 1-4 Alkyl groups; and / or R9 is selected from hydrogen, halogen, or C. 1-4 Alkyl group, preferably, R9 is hydrogen; Preferably, R1, R3, R5, and R7 are each independently selected from: Preferably, at least two of R1, R3, R5, and R7 are and / or R2, R4, R6, and R8 are all hydrogen; and / or R9 is selected from hydrogen, halogen, or C. 1-4 Alkyl group; preferably, R9 is hydrogen.

13. The compound, its isomer, isotopically labeled compound, prodrug, or pharmaceutically acceptable salt, ester, hydrate, or solvate thereof according to claim 1, 2, or 11, characterized in that, The following rings are formed between R1, R2 and their connected atoms, between R3, R4 and their connected atoms, between R5, R6 and their connected atoms, or between R7, R8 and their connected atoms: and / or R9 is selected from hydrogen, halogen, or C. 1-4 Alkyl group; preferably, R9 is hydrogen.

14. The compound, its isomers, isotopically labeled compounds, prodrugs, or pharmaceutically acceptable salts, esters, hydrates, or solvates according to claim 1 or 2, characterized in that, The following rings are formed between R4, R9 and the atoms they are connected to: (For example )or The key marked with "#" is connected to ring B; B1, B2, B3, B6, B7, B8, B9, B 12 B 13 B 14 B 15 B 16 B 17 B 18 B 19 B 20 B 21 B 22 B 23 B 24 B 26 B 27 B 28 Each atom is independently selected from CH2, NH, S, or O, and adjacent atoms are not simultaneously selected from heteroatoms; B4, B5, B 10 B 11 Each is independently selected from CH or N; preferably, B4 and B5 are both CH; preferably, B4 is CH and B5 is N, or B4 is N and B5 is CH; preferably, B4 and B5 are both N; preferably, B 10 B 11 All are CH; preferably, B 10 For CH, B 11 For N, or B 10 For N, B 11 CH; preferably, B 10 B 11 All are N; Each R G Each substituent is independently selected from any substituent in group G, and i is selected from 0, 1, or 2; The following conditions must be met: 1) At least one of B1, B2, and B3 is selected from NH; 2) At least one of B6, B7, B8, and B9 is selected from NH; 3)B 12 B 13 B 14 B 15 At least one of them is selected from NH; 4)B 17 B 18 B 19 At least one of them is selected from NH; 5)B 21 B 22 B 23 B 24 At least one of them is selected from NH; 6)B 26 B 27 B 28 At least one of them is selected from NH; Preferably, one of B1, B2, and B3 is selected from NH, and the others are selected from CH2; one of B6, B7, B8, and B9 is selected from NH, and the others are selected from CH2; B 12 B 13 B 14 B 15 One of them is selected from NH, and the rest are selected from CH2; B 17 B 18 B 19 One of them is selected from NH, and the rest are selected from CH2; B 21 B 22 B 23 B 24 One of them is selected from NH, and the rest are selected from CH2; B 26 B 27 B 28 One of them is selected from NH, and the rest are selected from CH2; Preferably, B 16 B 20 Each is independently selected from NH, S, or O; preferably, B 16 B 20 S; Preferably, each R G Independently selected from halogens, hydroxyl groups, and C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 4-7 membered heterocyclic groups; preferably, each R G Independently selected from halogens, hydroxyl groups, and C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Saturated cycloalkyl; preferably, each R G Independently selected from halogens (e.g., F, Cl, Br, I, preferably F, Cl) or C 1-4 Alkyl groups (e.g., methyl, ethyl, propyl, butyl, preferably methyl); preferably, each R G It is a halogen (e.g., F, Cl, Br, I, preferably F); Preferably, i is selected from 0 or 1; more preferably, i is selected from 0; Preferably, R4, R9 and the atoms they are connected to form the following rings: Preferred Preferred More The key marked with "#" is connected to ring B.

15. The compound, its isomers, isotopically labeled compounds, prodrugs, or pharmaceutically acceptable salts, esters, hydrates, or solvates thereof according to claim 1, 2, or 14, wherein R4, R9, and the atoms to which they are attached form the following rings: Preferred Preferred More The key marked with "#" is connected to ring B.

16. The compound, its isomer, isotopically labeled compound, prodrug, or pharmaceutically acceptable salt, ester, hydrate, or solvate thereof according to claim 1 or 2, wherein, L is selected from: Preferably, L is selected from Preferably, L is selected from Preferably, L is selected from Preferably, L is selected from Preferably, L is selected from Preferably, L is selected from Preferably, L is selected from More preferably, L is selected from The key marked "#A" is connected to ring A, the key marked "#B" is connected to ring B, the key marked "#C" is connected to ring C, and the key marked "#D" is connected to ring D.

17. The compound according to any one of claims 1-16, its isomers, isotopically labeled compounds, prodrugs, or pharmaceutically acceptable salts, esters, hydrates, or solvates thereof, wherein the compound has any structure of formula (II-1) to (II-14): in, n5 and n6 are each independently selected from 1, 2 or 3. Preferably, both n5 and n6 are selected from 2, or one of n5 and n6 is selected from 1 and the other is selected from 2. m1, m2, m3, and m4 are each independently selected from 0, 1, or 2. Preferably, m1, m2, m3, and m4 are each independently selected from 0 or 1. More preferably, one of m1 and m2 is selected from 0 and the other is selected from 1, and one of m3 and m4 is selected from 0 and the other is selected from 1. n1, n2, n3, n4 are as defined in claim 4; R3, R4, R9, A, B, C, and D are as defined in any one of claims 1-16; Preferably, three of rings A, B, C, and D are selected from... The remaining one is selected from Among them, Q1, Q2, Q3, and R G As defined in claim 6, the key identified by "#" is connected to the corresponding L; Preferably, two of rings A, B, C, and D are selected from... The remaining two are selected from Among them, Q1, Q2, Q3, and R G As defined in claim 6, the key identified by "#" is connected to the corresponding L; Preferably, two of rings A, B, C, and D are selected from... The remaining two are selected from and / or Among them, Q1-Q3, Q8-Q 13 R G As defined in claim 6, the key identified by "#" is connected to the corresponding L; Preferably, two of rings A, B, C, and D are selected from... The remaining two are selected from and Among them, Q1-Q3, Q 14 -Q 15 R G As defined in claim 6, the keys identified by "#" are connected to the corresponding L; Preferably, rings A, B, C, and D are all selected from... Preferably, R4, R9 and the atoms they are connected to form Among them, B1, B2, B3, and R G i is as defined in claim 14, wherein the key identified by "#" is connected to ring B.

18. The compound, its isomer, isotopically labeled compound, prodrug, or pharmaceutically acceptable salt, ester, hydrate, or solvate thereof according to any one of claims 1-17, having a compound represented by formula (Ⅲ'), in, Representing single or double bonds, and adjacent to each other. Not both are double bonds; R1, R2, R3, R4, and R9 are as defined in any one of claims 1-3 and 9-13; Q1, Q2, and Q3 are as defined in claim 6.

19. The compound, its isomer, isotopically labeled compound, prodrug, or pharmaceutically acceptable salt, ester, hydrate, or solvate thereof according to claim 1 or 2, wherein the compound has the structure shown in any one of formulas (IV-1) to (IV-8): in, n1, n2, n3, n4, n5, n6, A, B, C, D, R G i, B4, B5, B 10 B 11 B 16 As defined in any one of claims 1-18; Preferably, one of n1 and n2 is selected from 1, and the other is selected from 2; Preferably, one of n3 and n4 is selected from 1, and the other is selected from 2; Preferably, one of n5 and n6 is selected from 1, and the other is selected from 2; Preferably, n1 and n2 are both selected from 1; Preferably, n3 and n4 are both selected from 1; or Preferably, n5 and n6 are both selected from 1; Preferably, ring B is Preferred ring B is More preferably, ring B is Preferably, ring A is selected from (Preferred) )、 Preferred ring A is selected from Preferred ring A is selected from Preferred ring A is selected from Preferred ring A is selected from Preferred ring A is selected from Preferred ring A is selected from More preferably, ring A is Preferably, ring C and ring D are selected from... The preferred rings C and D are each selected independently. The preferred rings C and D are each selected independently. More preferably, C and ring D are selected from Preferably, each R G Independently selected from halogens (e.g., F, Cl) or C 1-4 Alkyl (e.g., methyl); more preferably, each R G Halogens (e.g., F); Preferably, i is selected from 0 or 1; more preferably, i is 0; Preferably, B4 and B5 are both CH, or B4 is CH and B5 is N, or B4 is N and B5 is CH; preferably, B4 and B5 are both CH. Preferably, B 10 B 11 Both are CH, or B 10 For CH, B 11 For N, or B 10 For N, B 11 CH; preferably, B 10 B 11 Both are CH, or B 10 For CH, B 11 N; preferably, B 10 B 11 All are CH; The key marked with "#" is connected to the corresponding L; Q1-Q 15 R G j and t are as defined in claim 6.

20. The compound, its isomers, isotopically labeled compounds, prodrugs, or pharmaceutically acceptable salts, esters, hydrates, or solvates thereof according to claim 19, wherein the compound is as shown in any one of the structures (IV-3-1), (IV-4-1), (IV-5-1), (IV-7-1), or (IV-8-1): in, n1, n2, n3, n4, n5, n6, A, Q4, Q5, Q6, Q7, B4, B5, B 10 B 11 B 16 R G i, j are as defined in any one of claims 1-19.

21. The compound, its isomers, isotopically labeled compounds, prodrugs, or pharmaceutically acceptable salts, esters, hydrates, or solvates thereof according to claim 1 or 2, wherein the compound has the structure shown in any of formulas (V-1) to (V-3): in, n7 and n8 are each independently selected from 1, 2 or 3; preferably, n7 and n8 are each independently selected from 1 or 2; preferably, both n7 and n8 are 2; preferably, one of n7 and n8 is 1 and the other is 2; n1, n2, n3, n4, n5, n6, A, B, C, D as defined in any one of claims 1-18; Preferably, in at least two of the groups n1 and n2, n3 and n4, n5 and n6, and n7 and n8, the variable is 1 and the variable is 2, and in at least one group, both variables are 2. Preferably, one of n5 and n6 is 1 and the other is 2; one of n7 and n8 is 1 and the other is 2; one of n3 and n4 is 1 and the other is 2; and both n1 and n2 are 2. Preferably, one of n5 and n6 is 1 and the other is 2; one of n7 and n8 is 1 and the other is 2; one of n1 and n2 is 1 and the other is 2; and both n3 and n4 are 2. Preferably, one of n5 and n6 is 1 and the other is 2; one of n7 and n8 is 1 and the other is 2; n1 and n2 are both 2; n3 and n4 are both 2. Preferably, one of n5 and n6 is 1 and the other is 2; both n7 and n8 are 2; one of n3 and n4 is 1 and the other is 2; one of n1 and n2 is 1 and the other is 2. Preferably, n5 and n6 are both 2; one of n7 and n8 is 1 and the other is 2; one of n3 and n4 is 1 and the other is 2; one of n1 and n2 is 1 and the other is 2. Preferably, rings A, B, C, and D are each independently selected from... (Preferred) )、 Preferably, rings A, B, C, and D are each independently selected from... (Preferred) )、 And at least two of rings A, B, C, and D are selected from Preferably, rings A and B are each independently selected from... One of rings C and D is selected from (Preferred) The other is selected from (Preferred) )、 Preferably, rings A and B are each independently selected from... One of rings C and D is selected from The other one is selected from Preferably, rings A and B are each independently selected from... One of rings C and D is selected from (Preferred) The other is selected from Preferably, rings A and B are each independently selected from... One of rings C and D is selected from The other one is selected from Preferably, rings A and B are each independently selected from... One of rings C and D is selected from The other one is selected from Preferably, rings C and D are each independently selected from... One of rings A and B is selected from (Preferred) The other is selected from (Preferred) )、 Preferably, rings C and D are each independently selected from... One of rings A and B is selected from The other one is selected from Preferably, rings C and D are each independently selected from... One of rings A and B is selected from (Preferred) The other is selected from Preferably, rings C and D are each independently selected from... One of rings A and B is selected from The other one is selected from The key marked with "#" is connected to the corresponding L; Q1-Q 15 R G j and t are as defined in claim 6.

22. The compound, its isomer, isotopically labeled compound, prodrug, or pharmaceutically acceptable salt, ester, hydrate, or solvate thereof according to claim 1 or 2, wherein the compound has the structure shown in any one of formulas (VI-1) to (VI-3): in, n1, n2, n3, n4, C, Q1, Q2, Q3 are as defined in any of the preceding claims; Preferably, n1 and n2 are both 2, and one of n3 and n4 is 1 and the other is 2; or one of n1 and n2 is 1 and the other is 2, and both n3 and n4 are 2. Preferably, in the general formulas (VI-1) to (VI-3), Q2 is N, Q1 is S, and Q3 is CH; Preferably, ring C is selected from (Preferred) )、 The keys marked with "#" are connected to L; Q1-Q 15 R G j, t are as defined in claim 6; preferably, ring C is selected from...

23. The compound, its isomers, isotopically labeled compounds, prodrugs, or pharmaceutically acceptable salts, esters, hydrates, or solvates thereof according to claim 21, wherein the compound has the structure shown in any of formulas (VII-1) to (VII-7): in, n1, n2, n3, n4, n5, n6, n7, n8, Q1, Q2, Q3, Q4, Q5, Q6, Q7, R G j is defined as in any one of claims 1-22; Preferably, in at least two of the groups n1 and n2, n3 and n4, n5 and n6, and n7 and n8, the variable is 1 and the variable is 2, and in at least one group, both variables are 2. Preferably, one of n5 and n6 is 1 and the other is 2; one of n7 and n8 is 1 and the other is 2; one of n3 and n4 is 1 and the other is 2; and both n1 and n2 are 2. Preferably, one of n5 and n6 is 1 and the other is 2; one of n7 and n8 is 1 and the other is 2; one of n1 and n2 is 1 and the other is 2; and both n3 and n4 are 2. Preferably, one of n5 and n6 is 1 and the other is 2; one of n7 and n8 is 1 and the other is 2; n1 and n2 are both 2; n3 and n4 are both 2. Preferably, one of n5 and n6 is 1 and the other is 2; both n7 and n8 are 2; one of n3 and n4 is 1 and the other is 2; one of n1 and n2 is 1 and the other is 2. Preferably, n5 and n6 are both 2; one of n7 and n8 is 1 and the other is 2; one of n3 and n4 is 1 and the other is 2; one of n1 and n2 is 1 and the other is 2. Preferably, ring C is selected from (Preferred) )、 Preferably, ring C is selected from More preferably, ring C is selected from Preferably, ring A is selected from (Preferred) )、 Preferably, ring A is selected from Preferably, Q1 is selected from NH, O and S, and Q2 and Q3 are each independently selected from CH and N; preferably, Q2 is N, Q1 is S, and Q3 is CH. Preferably, Q4, Q5, Q6, and Q7 are all CH; Preferably, both Q8 and Q9 are CH; Preferably, Q 10 Q 11 Q 12 Q 13 One or both of them are N; preferably, Q 10 Q 13 Both are N, Q 11 Q 12 All are CH; Preferably, Q 14 Q 15 All are CH; Preferably, t is selected from 1 or 2; preferably, t is 1. Preferably, each R G Independently selected from halogens (e.g., F, Cl, Br, I, preferably F, Cl) or C 1-4 Alkyl groups (e.g., methyl, ethyl, propyl, butyl, preferably methyl); preferably, each R G It is a halogen (e.g., F, Cl, Br, I, preferably F or Cl, more preferably F); Preferably, j is selected from 0 or 1; preferably, j is 0; The key marked with "#" is connected to the corresponding L.

24. The compound, its isomers, isotopically labeled compounds, prodrugs, or pharmaceutically acceptable salts, esters, hydrates, or solvates thereof according to claims 1-23, characterized in that, The compound is selected from: Preferably, the compound is selected from: Preferably, the compound is selected from:

25. The compound, its isomers, isotopically labeled compounds, prodrugs, or pharmaceutically acceptable salts, esters, hydrates, or solvates according to claims 1-23, characterized in that, The compound is selected from:

26. A pharmaceutical composition comprising the compound, isomer, isotopically labeled compound, prodrug, or pharmaceutically acceptable salt, ester, hydrate, or solvate thereof, as well as a pharmaceutically acceptable carrier, diluent, or excipient, according to any one of claims 1-25.

27. The use of the compound, isomer, isotopically labeled compound, prodrug, or pharmaceutically acceptable salt, ester, hydrate, or solvate thereof, or the pharmaceutical composition of claim 26, in the preparation of a medicament for the prevention and / or treatment of diseases associated with Lp(a).

28. The application according to claim 27, characterized in that, The diseases associated with Lp(a) are cardiovascular diseases, including atherosclerosis, stroke, hyperlipidemia, elevated Lp(a) levels, thrombosis, coronary heart disease, and aortic stenosis.

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