Lipoprotein (a) inhibitor

Abstract

The present invention relates to the field of chemical pharmaceutics, relates to a lipoprotein (a) inhibitor, and specifically provides a compound having a structure as represented by formula (0), or an isomer, isotopically labeled compound or prodrug thereof, or a pharmaceutically acceptable salt, ester, hydrate or solvate thereof. The present invention exhibits a greater inhibitory activity against Lp(a) assembly and oxidized phospholipid-apolipoprotein(a), and better PK (oral bioavailability, and plasma exposure and hepatic exposure of a drug).

Description

A lipoprotein (a) inhibitor

[0001] Citation of relevant applications

[0002] This application claims priority to Chinese Patent Application No. 202510197245.6 filed on February 21, 2025 and Chinese Patent Application No. 202511183831.1 filed on August 22, 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 provides a lipoprotein(a) inhibitor. 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) is 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 druggable compounds for lowering plasma Lp(a) levels, making some progress in the field of cardiovascular disease, but there are currently no small molecule Lp(a) drugs on the market.

[0006] Therefore, there is an urgent need to develop cardiovascular drugs that meet clinical needs. Summary of the Invention

[0007] In view of the above-mentioned technological status, the present invention provides a lipoprotein (a) inhibitor, its pharmaceutical composition, and its application. It exhibits significantly superior PK (oral bioavailability, plasma drug exposure, and liver exposure), stronger oxidized phospholipid-apolipoprotein (a) (OxPL-apo(a)) inhibitory activity, and higher Lp(a) selectivity and pharmacokinetic properties (oral bioavailability, etc.).

[0008] This invention provides a lipoprotein (a) inhibitor with the structure shown in formula (0), its isomers, isotopically labeled compounds, prodrugs, or pharmaceutically acceptable salts, esters, hydrates, or solvates thereof:

[0009] in,

[0010] R is selected from

[0011] Ring C is selected from C 6-10 Aryl, 5-10 membered heteroaryl, or 3-12 membered heterocyclic; the C 6-10 Aryl, 5-10-membered heteroaryl, and 3-12-membered heterocyclic groups are optionally and independently bounded by 1, 2, or 3 groups selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl or C 1-6 Substituents of haloalkoxy groups;

[0012] n0 is selected from 0, 1 or 2; preferably, n0 is selected from 0 or 1; more preferably, n0 is 0;

[0013] n1 is selected from 1, 2 or 3, and n2 is selected from 1 or 2; preferably, n1 is selected from 2 and n2 is selected from 1, or n1 is selected from 2 and n2 is selected from 2.

[0014] L is selected from: Preferably, L is selected from

[0015] Rb is selected from: H, -COO-Rc, -CONR d R e -NH2, -NHCO-Rc, -CN, -NO2, -CH2COO-Rc, -CH2CONH-Rc, -CH2CH2COOH, -CH2NH2 or -CH2CN; preferably -COOH;

[0016] Rc is selected from H or C. 1-6 alkyl;

[0017] R dR e Each is independently selected from H or C 1-6 Alkyl; preferably, R d R e One of them is H, and the other is C. 1-6 alkyl;

[0018] R ○ Selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy; preferably, R ○ Selected from halogens (e.g., F, Cl), C 1-4 Alkyl (e.g., methyl), C 1-4 Alkyl groups (e.g., methoxy groups); preferably, R ○ Selected from halogens (e.g., F, Cl), C 1-4 Alkyl (e.g., methyl); more preferably, R ○ Halogens (e.g., F);

[0019] Ring A is selected from C 6-10 aryl, 5-10 membered heteroaryl, or 3-10 membered heterocyclic, wherein C 6-10 The aryl, 5-10-membered heteroaryl, and 3-10-membered heterocyclic groups are each independently selected by 1, 2, or 3 (preferably 1) groups from deuterium, halogen, hydroxyl, C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Substitution with cycloalkyl or 3-6 membered heterocyclic groups;

[0020] Ring B is selected from C 8-10 Fused bicyclic cyclic hydrocarbon group, 8-10 membered fused bicyclic heterocyclic group, or 8-10 membered fused bicyclic heteroaryl group; the C 8-10 The fused bicyclic cyclic hydrocarbon group, the 8-10 fused bicyclic heterocyclic group, and the 8-10 fused bicyclic heteroaryl group are each independently selected by 1, 2, or 3 groups chosen from deuterium, halogen, amino, oxo group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 Substitution with cycloalkyl or 3-6 membered heterocyclic groups; optionally, the two substituents attached to the same carbon atom form a C12 group. 3-6 Cycloalkyl or 4-7 membered heterocyclic groups; provided that ring B is selected from C. 8-10 When fused with bicyclic hydrocarbon groups, the C 8-10 In fused bicyclic hydrocarbon groups, at least one amino group is substituted.

[0021] n3 is selected from 0 or 1, preferably n3 is 1;

[0022] The condition is: when n3 is 0, L is selected from...

[0023] In this invention, as one embodiment, the lipoprotein (a) inhibitor described herein, its isomers, isotopically labeled compounds, prodrugs, or pharmaceutically acceptable salts, esters, hydrates, or solvates, wherein the compounds are shown in formula (I):

[0024] Wherein, Rb, B, A, n3, R, L, n1, and n2 are defined as in any embodiment of the present invention.

[0025] In this invention, as one embodiment, ring A is selected from 4- to 10-membered heterocyclic groups, C 6-10 aryl or 5-10 membered heteroaryl, wherein the 4-10 membered heterocyclic group, C 6-10 The aryl group and the 5- to 10-membered heteroaryl group are each independently selected by 1, 2, or 3 ions from halogen, hydroxyl group, C-hydroxyl group, etc. 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Substituents of cycloalkyl groups;

[0026] The heteroatoms in the 4-10 membered heterocyclic group and the 5-10 membered heteroaryl group are selected from N, O or S. The number of heteroatoms in the 4-10 membered heterocyclic group and the 5-10 membered heteroaryl group is one or more. When two or more heteroatoms are included, they may be the same, partially the same or completely different.

[0027] In this invention, as one embodiment, ring A is selected from:

[0028] Preferred Preferred Preferred Preferred

[0029] Among them, the key marked with "#B" is connected to ring B, and the key marked with "#L" is connected to L;

[0030] The structures shown in A-1', A-2', A-3, A-4, A-4', and A-2'-1 are each independently aromatic groups;

[0031] A1, A2, A3, A4, A 12 A 13 A 14 A 15 A 16 A 17 A 18 A19 A 22 A 23 A 26 A 27 A 28 Each is independently selected from CH or N; preferably, A1, A2, A3, and A4 are all CH; preferably, one of A1, A2, A3, and A4 is N (for example, A1 is N, and A2, A3, and A4 are all CH; or, for example, A2 is N, and A1, A3, and A4 are all CH); preferably, two of A1, A2, A3, and A4 are N (for example, A1 and A4 are CH, and A2 and A3 are N); preferably, three of A1, A2, A3, and A4 are N; preferably, A 12 A 13 All are CH; preferably, A 12 A 13 One of them is N; preferably, A 12 A 13 All are N; preferably, A 14 A 15 All are CH; preferably, A 14 A 15 One of them is N; preferably, A 16 A 17 A 18 A 19 All are CH; preferably, A 16 A 17 A 18 A 19 One of them is N; preferably, A 16 A 17 A 18 A 19 Two of them are N (e.g., A). 16 A 19 For N, A 17 A 18 (CH); preferably, A 22 A 23 All are CH; preferably, A 26 A 27 A 28 All are CH;

[0032] A5, A7, A8, A 10 A 11 Each is independently selected from N, O, S, CH or NH; preferably, at least one of A5, A7, and A8 is selected from S, N, O or NH; preferably, A 10 A 11At least one of them is selected from S, N, O or NH; preferably, A5 is selected from CH and N, A7 is selected from NH, O and S, and A8 is selected from CH and N; preferably, A5 is selected from N, A7 is selected from S, and A8 is selected from CH; preferably, A 10 Selected from NH, O and S, A 11 Selected from CH and N, or A 11 Selected from NH, O and S, A 10 Selected from CH and N;

[0033] A6 and A9 are each independently selected from C or N; preferably, both A6 and A9 are C.

[0034] A 20 A 21 Each is independently selected from CH or N, and A 20 A 21 At least one of them is selected from N;

[0035] A 24 A 25 Each is independently selected from CH2, NH, O, or S, and at least one of them is selected from NH, O, or S; preferably, A 24 A 25 All are O;

[0036] A 29 A 30 Each is independently selected from CH2, NH, O, or S; preferably, A 29 For CH2, A 30 It is O;

[0037] m1 and m2 are each independently selected from 0, 1, 2 or 3, preferably 0 or 1; preferably, m1 is selected from 0 or 1, more preferably 0; preferably, m2 is selected from 0.

[0038] t1, t2, t3, and t4 are each independently selected from 1, 2, or 3; preferably, t1, t2, t3, and t4 are each independently selected from 1 or 2; preferably, t3 is selected from 1 and 2; more preferably, t3 is 1;

[0039] R 1a R 2a Each is independently selected from deuterium, halogen, hydroxyl, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl; preferably, R 1a Selected from halogens, C 1-4 Alkyl, C 1-4 Alkoxy; preferably, R 1a Selected from halogens (e.g., F, Cl), C 1-4 Alkyl (e.g., methyl); preferably, R1a It is a halogen (e.g., F); preferably, R 2a Selected from halogens, hydroxyl groups, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl; preferably, R 2a Selected from halogens (e.g., F, Cl), C 1-4 Alkyl (e.g., methyl); preferably, R 2a Halogens (e.g., F);

[0040] It can be a single bond or a double bond, wherein the two adjacent chemical bonds are not both double bonds.

[0041] In this invention, as one embodiment, ring A is selected from:

[0042] Preferred Preferred

[0043] Among them, the key marked with "#B" is connected to ring B, and the key marked with "#L" is connected to L;

[0044] The structures shown in A-1', A-2', A-3, and A-4 are each independently aromatic groups;

[0045] A1, A2, A3, A4, A 12 A 13 A 14 A 15 A 16 A 17 A 18 A 19 A 22 A 23 A 26 A 27 A 28 Each is independently selected from CH or N; preferably, A1, A2, A3, and A4 are all CH; preferably, one of A1, A2, A3, and A4 is N; preferably, two of A1, A2, A3, and A4 are N; preferably, three of A1, A2, A3, and A4 are N; preferably, A 12 A 13 All are CH; preferably, A 12 A 13 One of them is N; preferably, A 12 A 13 All are N; preferably, A 14 A 15 All are CH; preferably, A14 A 15 One of them is N; preferably, A 16 A 17 A 18 A 19 All are CH; preferably, A 16 A 17 A 18 A 19 One of them is N; preferably, A 16 A 17 A 18 A 19 Two of them are N (e.g., A). 16 A 19 For N, A 17 A 18 (CH); preferably, A 22 A 23 All are CH; preferably, A 26 A 27 A 28 All are CH;

[0046] A5, A7, A8, A 10 A 11 Each is independently selected from N, O, S, CH or NH; preferably, at least one of A5, A7, and A8 is selected from S, N, O or NH; preferably, A 10 A 11 At least one of them must be selected from S, N, O, or NH;

[0047] A6 and A9 are each independently selected from C or N; preferably, both A6 and A9 are C.

[0048] A 20 A 21 Each is independently selected from CH or N, and A 20 A 21 At least one of them is selected from N;

[0049] A 24 A 25 Each is independently selected from CH2, NH, O, or S, and at least one of them is selected from NH, O, or S; preferably, A 24 A 25 All are O;

[0050] A 29 A 30 Each is independently selected from CH2, NH, O, or S; preferably, A 29 For CH2, A 30 It is O;

[0051] m1 and m2 are each independently selected from 0, 1, 2 or 3, preferably 0 or 1;

[0052] t1, t2, t3, and t4 are each independently selected from 1, 2, or 3; preferably, t1, t2, t3, and t4 are each independently selected from 1 or 2.

[0053] R 1a R 2a Each is independently selected from deuterium, halogen, hydroxyl, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl; preferably, R 1a Selected from halogens, C 1-4 Alkyl, C 1-4 Alkoxy; preferably, R 1a Selected from halogens (e.g., F, Cl), C 1-4 Alkyl (e.g., methyl); preferably, R 1a It is a halogen (e.g., F); preferably, R 2a Selected from halogens, hydroxyl groups, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl; preferably, R 2a Selected from halogens (e.g., F, Cl), C 1-4 Alkyl (e.g., methyl); preferably, R 2a Halogens (e.g., F);

[0054] It can be a single bond or a double bond, wherein the two adjacent chemical bonds are not both double bonds.

[0055] In this invention, as one embodiment, the R 1a It is selected from F, methyl or methoxy; preferably F or methyl; more preferably F.

[0056] In this invention, as one embodiment, the R 2a It is selected from methyl, ethyl, isopropyl, halogen (e.g., F), hydroxy, cyclopropyl or methoxy; preferably F.

[0057] In this invention, as one embodiment, ring A is selected from:

[0058] Preferably, ring A is The key marked "#B" is connected to ring B, and the key marked "#L" is connected to ring L.

[0059] In this invention, as one embodiment, ring B is selected from C.8-10 Fused bicyclic cyclic hydrocarbon group, 8-10 membered fused bicyclic heterocyclic group, or 8-10 membered fused bicyclic heteroaryl group; the C 8-10 The fused bicyclic cyclic hydrocarbon group, the 8-10 fused bicyclic heterocyclic group, and the 8-10 fused bicyclic heteroaryl group are each independently selected by 1, 2, or 3 groups chosen from halogen, amino, oxo, C 1-6 Alkyl, C 1-6 Substituents of the haloalkyl group; optionally, two substituents attached to the same carbon atom form a C12 group. 3-6 Cycloalkyl or 4-7 membered heterocyclic groups; provided that ring B is selected from C. 8-10 When fused with bicyclic hydrocarbon groups, the C 8-10 In fused bicyclic hydrocarbon groups, at least one amino group is substituted.

[0060] The heteroatoms in the 8-10 fused bicyclic heterocyclic group and the 8-10 fused bicyclic heteroaryl group are selected from N, O or S. The number of heteroatoms in the 8-10 fused bicyclic heterocyclic group and the 8-10 fused bicyclic heteroaryl group is one or more. When two or more heteroatoms are included, they may be the same, partially the same or completely different. Preferably, the 8-10 fused bicyclic heterocyclic group and the 8-10 fused bicyclic heteroaryl group contain at least one nitrogen heteroatom.

[0061] In this invention, as one embodiment, ring B is selected from:

[0062] Preferred Preferred Preferred

[0063] The key identified by "#Rb" is connected to Rb;

[0064] B 1-a B 1-b B 1-c B 1-d B 1-e B 2-a B 2-b B 2-c B 2-d B 2-e ,B3,B4,B5,B6,B7,B8,B9,B 10 B 11 B 12 B 14 Each is independently selected from CH or N; among them, B9 and B 10 B 11 B 12At least one of them is N;

[0065] B 13 B 15 Each is independently selected from S, NH, or O;

[0066] s1, s2, s3, s4, s5, s6, s7, s8, s9, and s10 are each independently selected from 1 or 2;

[0067] u1, u2, u3, u4, u5, u6, u7, u8, u10, and u12 are each independently selected from 0, 1, or 2, preferably 0 or 1, and more preferably 0;

[0068] u9, u11, and u13 are each independently selected from 0 or 1, with 0 being more preferred;

[0069] R1, R3, R5, R8, R 10 R 12 Each is independently selected from deuterium, halogen, oxo group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy group; optionally, two R1 atoms attached to the same carbon atom form C 3-6 Cycloalkyl; preferably methyl or oxo; optionally, two R1 groups attached to the same carbon atom form a cyclopropyl group;

[0070] R2, R4, R6, R7, R9, R 11 R 13 Each is independently selected from deuterium, halogens, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy; preferably methyl, halogen (e.g., F, Cl) or trifluoromethyl; more preferably halogen (e.g., F, Cl) or C 1-4 Alkyl (e.g., methyl).

[0071] In this invention, as one embodiment, ring B is selected from:

[0072] Preferably, ring B is selected from Preferably, ring B is selected from More preferably, ring B is selected from The key identified by "#Rb" is connected to Rb.

[0073] In this invention, as one embodiment, the... Selected from:

[0074] Preferably, Selected from Preferably, Selected from

[0075] In this invention, as one embodiment, the ring C is selected from:

[0076] Preferred Preferred Preferred More

[0077] Among them, the key marked with #L is connected to L;

[0078] C1, C2, C3, C4, C 10 C 11 C 12 C 13 C 14 C 15 C 16 C 17 C 21 C 22 C 23 Each is independently selected from CH or N; preferably, C1, C2, C3, and C4 are all CH; preferably, C 10、 C 11 All are CH; preferably, C 12、 C 13、 C 14、 C 15 One or two of them are N, and the rest are CH2; preferably, C 12 C 15 Both are N, C 13 C 14 All are CH; preferably, C 16 C 17 All are CH; preferably, C 21 C 22 C 23 All are CH;

[0079] C5, C7, and C8 are each independently selected from N, O, S, CH, or NH; preferably, C5 is selected from CH or N; preferably, C5 is N; preferably, C8 is selected from O or S; preferably, C8 is S; preferably, C7 is CH.

[0080] C6 and C9 are each independently selected from C or N; preferably, both C6 and C9 are C.

[0081] C 18 C 19 C 20 C 24 C 25 Each is independently selected from CH2, NH, O, or S, and C 18 C 19 C 20 At least one of them is selected from NH, O or S, C 24 C 25 One and only one of them is selected from NH, O or S; preferably, C 18 C 20 Both are O, C 19 CH2; preferably, C 24 CH2, C 25 It is O;

[0082] q is selected from 1, 2 or 3, preferably 1 or 2, preferably 1;

[0083] It can be a single bond or a double bond, wherein the two adjacent chemical bonds are not both double bonds;

[0084] The structures shown in C-1, C-2, C-3, C-3', and C-2-1 are each independently aromatic groups;

[0085] The C-1, C-2, C-3, C-3', C-4, C-5, C-2-1, and C-4-1 are optionally and independently substituted by one, two, or three (preferably one) substituents selected from halogen, cyano, hydroxyl, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, or C1-4 haloalkoxy.

[0086] Preferably, the C-1 is optionally selected from halogen, cyano, hydroxyl, C... 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl or C 1-4 The alkyl group is substituted by a halogenated alkoxy group; preferably, one or two (preferably one) C-1 groups are selected from halogens (e.g., F, Cl) or C. 1-4 Alkyl (e.g., methyl) substituents; preferably, the C-1 is optionally substituted with one or two (preferably one) halogens (e.g., F);

[0087] Preferably, C-1, C-2, C-3, C-3', C-4, C-5, C-2-1, and C-4-1 are not replaced;

[0088] Preferably, C-2, C-3, C-3', C-4, C-5, C-2-1, and C-4-1 are not replaced.

[0089] In this invention, as one embodiment, the ring C is selected from:

[0090] Preferred

[0091] Among them, the key marked with #L is connected to L;

[0092] C1, C2, C3, C4, C 10 C 11 C 12 C 13 C 14 C 15 C 16 C 17 C 21 C 22 C 23 Each is independently selected from CH or N; preferably, C1, C2, C3, and C4 are all CH; preferably, C 10 C 11 All are CH; preferably, C 12 C 13 C 14 C 15 One or two of them are N, and the rest are CH2; preferably, C 12 C 15 Both are N, C 13 C 14 All are CH; preferably, C 16 C 17 All are CH; preferably, C 21 C 22 C 23 All are CH;

[0093] C5, C7, and C8 are each independently selected from N, O, S, CH, or NH; preferably, C5 is selected from CH or N; preferably, C5 is N; preferably, C8 is selected from O or S; preferably, C8 is S; preferably, C7 is CH.

[0094] C6 and C9 are each independently selected from C or N; preferably, both C6 and C9 are C.

[0095] C 18 C 19 C 20 C 24 C 25 Each is independently selected from CH2, NH, O, or S, and C 18C 19 C 20 At least one of them is selected from NH, O or S, C 24 C 25 One and only one of them is selected from NH, O or S; preferably, C 18 C 20 Both are O, C 19 CH2; preferably, C 24 CH2, C 25 It is O;

[0096] q is selected from 1, 2, or 3, with 1 or 2 being preferred;

[0097] It can be a single bond or a double bond, wherein the two adjacent chemical bonds are not both double bonds;

[0098] The structures shown in C-1, C-2, C-3, and C-2-1 are each independently aromatic groups;

[0099] The C-1, C-2, C-3, C-4, C-5, and C-2-1 are optionally and independently selected from 1, 2, or 3 (preferably 1) groups selected from halogen, cyano, hydroxyl, and C. 1-4 Alkyl, C 1-4 Alkoxy, C=haloalkyl or C= 1-4 Substituents of haloalkoxy groups;

[0100] Preferably, the C-1 is optionally selected from halogen, cyano, hydroxyl, C... 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl or C 1-4 The alkyl group is substituted by a halogenated alkoxy group; preferably, one or two (preferably one) C-1 groups are selected from halogens (e.g., F, Cl) or C. 1-4 Alkyl (e.g., methyl) substituents; preferably, the C-1 is optionally substituted with one or two (preferably one) halogens (e.g., F);

[0101] Preferably, C-1, C-2, C-3, C-4, C-5, and C-2-1 are not replaced.

[0102] In this invention, as one embodiment, the ring C is selected from: Each of the above groups may optionally be independently bound by one or two elements selected from halogens (e.g., F, C). 1-4 Alkyl or C 1-4 The alkoxy group is substituted; wherein the bond marked #L is attached to L;

[0103] Preferably, ring C is selected from: None of the above groups are substituted; wherein the bond marked #L is attached to L;

[0104] Preferably, ring C is selected from: Among them, the key marked with #L is connected to L;

[0105] Preferably, ring C is selected from Among them, the key marked with #L is connected to L;

[0106] More preferably, ring C is The key marked with #L is connected to L.

[0107] In this invention, as one embodiment, 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 The keys marked "*1", "*2", and "*3" are each independently connected to R. (or ); preferably, the key marked "*1" is connected to The key marked with "*2" is connected to R, and the key marked with "*3" is connected to... (or ).

[0108] This invention provides a lipoprotein (a) inhibitor with the structure shown in formula (I), an isomer, an isotopically labeled compound, a prodrug, or a pharmaceutically acceptable salt, ester, hydrate, or solvate thereof:

[0109] in,

[0110] R is selected from or

[0111] Ring C is selected from C 6-10 Aryl or 5-10 heteroaryl groups;

[0112] n1 is selected from 1, 2 or 3, and n2 is selected from 1 or 2; preferably, n1 is selected from 2 and n2 is selected from 1, or n1 is selected from 2 and n2 is selected from 2.

[0113] L is selected from:

[0114] Rb is selected from: H, -COO-Rc, -CONR d R e -NH2, -NHCO-Rc, -CN, -NO2, -CH2COO-Rc, -CH2CONH-Rc, -CH2CH2COOH, -CH2NH2 or -CH2CN; preferably -COOH;

[0115] Rc is selected from H or C. 1-6 alkyl;

[0116] R d R e Each is independently selected from H or C 1-6 alkyl;

[0117] Ring A is selected from C 6-10 aryl, 5-10 membered heteroaryl, or 3-10 membered heterocyclic, wherein C 6-10 The aryl, 5-10-membered heteroaryl, and 3-10-membered heterocyclic groups are each independently selected by 1, 2, or 3 (preferably 1) groups from deuterium, halogen, hydroxyl, C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Substitution with cycloalkyl or 3-6 membered heterocyclic groups;

[0118] Ring B is selected from C 8-10 Fused bicyclic cyclic hydrocarbon group, 8-10 membered fused bicyclic heterocyclic group, or 8-10 membered fused bicyclic heteroaryl group; the C 8-10 The fused bicyclic cyclic hydrocarbon group, the 8-10 fused bicyclic heterocyclic group, and the 8-10 fused bicyclic heteroaryl group are each independently selected by 1, 2, or 3 groups chosen from deuterium, halogen, amino, oxo group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 Substitution with cycloalkyl or 3-6 membered heterocyclic groups, or two substituents attached to the same carbon atom to form a C12 group. 3-6 Cycloalkyl or 4-7 membered heterocyclic groups; provided that ring B is selected from C. 8-10 When fused with bicyclic hydrocarbon groups, the C 8-10 The fused bicyclic cyclic hydrocarbon group is replaced by an amino group;

[0119] n3 is selected from 0 or 1, with the condition that when n3 is 0, L is selected from...

[0120] In this invention, as one embodiment, ring A is selected from 4-7 membered heterocyclic alkyl groups, C... 6-10 Aryl or 5-10-membered heteroaryl, wherein the 4-7-membered heterocyclic alkyl group, C 6-10 The aryl group and the 5- to 10-membered heteroaryl group are each independently selected by 1, 2, or 3 ions from halogen, hydroxyl group, C-hydroxyl group, etc. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Substituents of cycloalkyl groups;

[0121] The heteroatoms in the 4-7 membered heterocyclic alkyl groups and the 5-10 membered heteroaryl groups are selected from N, O or S. The number of heteroatoms in the 4-7 membered heterocyclic alkyl groups and the 5-10 membered heteroaryl groups is one or more. When two or more heteroatoms are included, they may be the same, partially the same or completely different.

[0122] In this invention, as one embodiment, ring A is selected from:

[0123] Among them, the key marked with "#B" is connected to ring B, and the key marked with "#L" is connected to L;

[0124] The structures shown in A-1, A-2, A-3, and A-4 are each independently aromatic groups;

[0125] A1, A2, A3, A4, A 12 A 13 A 14 A 15 A 16 A 17 A 18 A 19 Each is independently selected from CH or N;

[0126] A5, A7, A8, A 10 A 11 Each is independently selected from N, O, S, CH or NH;

[0127] A6 and A9 are each independently selected from C or N;

[0128] A 20 A 21 Each is independently selected from CH or N, and A 20 A 21 At least one of them is selected from N;

[0129] m1 and m2 are each independently selected from 0, 1, 2 or 3, preferably 0 or 1;

[0130] t1 and t2 are each independently selected from 1, 2, or 3;

[0131] R8 and R9 are each independently selected from deuterium, halogen, hydroxyl group, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl;

[0132] It can be a single bond or a double bond, wherein the two adjacent chemical bonds are not both double bonds.

[0133] In this invention, as one embodiment, R8 is selected from hydrogen or methyl;

[0134] R9 is selected from methyl, ethyl, isopropyl, halogen, hydroxy, cyclopropyl, or methoxy.

[0135] In this invention, as one embodiment, ring A is selected from:

[0136] The key marked "#B" is connected to ring B, and the key marked "#L" is connected to ring L.

[0137] In this invention, as one embodiment, ring B is selected from C. 8-10 Fused bicyclic cyclic hydrocarbon group, 8-10 membered fused bicyclic heterocyclic group, or 8-10 membered fused bicyclic heteroaryl group; the C 8-10 The fused bicyclic cyclic hydrocarbon group, the 8-10 fused bicyclic heterocyclic group, and the 8-10 fused bicyclic heteroaryl group are each independently selected by 1, 2, or 3 groups chosen from halogen, amino, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, or two substituents attached to the same carbon atom, form C. 3-6 Cycloalkyl or 4-7 membered heterocyclic groups; provided that ring B is selected from C. 8-10 When fused with bicyclic hydrocarbon groups, the C 8-10 The fused bicyclic cyclic hydrocarbon group is replaced by an amino group;

[0138] The heteroatoms in the 8-10 fused bicyclic heterocyclic group and the 8-10 fused bicyclic heteroaryl group are selected from N, O or S. The number of heteroatoms in the 8-10 fused bicyclic heterocyclic group and the 8-10 fused bicyclic heteroaryl group is one or more. When two or more heteroatoms are included, they may be the same, partially the same or completely different.

[0139] In this invention, as one embodiment, ring B is selected from:

[0140] The key identified by "#Rb" is connected to Rb;

[0141] B 1-a B 1-b B 1-c B 2-a B 2-b B 2-c ,B3,B4,B5,B6,B7,B8,B9,B 10 B 11 B 12 B 14 Each is independently selected from CH or N;

[0142] B 13 B 15 Each is independently selected from S, NH, or O;

[0143] s1, s2, s3, s4, s5, s6, s7, and s8 are each independently selected from 1 or 2;

[0144] u1, u2, u3, u4, u5, u6, u7, u8, u10, and u12 are each independently selected from 0, 1, or 2, preferably 0 or 1;

[0145] u9, u11, and u13 are each independently selected from 0 or 1;

[0146] R1, R3, R5, R8, R 10 R 12 Each is independently selected from deuterium, halogen, oxo group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy groups; or two R1 atoms bonded to the same carbon atom to form a C group. 3-6 Cycloalkyl; preferably methyl or oxo; or two R1 groups attached to the same carbon atom to form a cyclopropyl group;

[0147] R2, R4, R6, R7, R9, R 11 R 13 Each is independently selected from deuterium, halogens, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy; preferably methyl, halogen (e.g., F, Cl) or trifluoromethyl.

[0148] In this invention, as one embodiment, ring B is selected from:

[0149] The key identified by "#Rb" is connected to Rb.

[0150] In this invention, as one embodiment, the... Selected from:

[0151] In this invention, as one embodiment, the ring C is selected from:

[0152] Among them, the key marked with #L is connected to L;

[0153] C1, C2, C3, C4, C 10、 C 11、 C 12、 C 13、 C 14、 C 15 Each is independently selected from CH or N; C5, C7, and C8 are independently selected from N, O, S, CH, or NH;

[0154] C6 and C9 are each independently selected from C or N;

[0155] It can be a single bond or a double bond, wherein the two adjacent chemical bonds are not both double bonds;

[0156] The structures shown in C-1, C-2, and C-3 are each independently aromatic groups.

[0157] In this invention, as one embodiment, the ring C is selected from: The key marked with #L is connected to L.

[0158] In this invention, as one embodiment, L is selected from... Among them, the key marked "*1", the key marked "*2", and the key marked "*3" are each independently connected to R. The key marked "*1" is preferred for connection. The key marked with "*2" is connected to R, and the key marked with "*3" is connected to...

[0159] In this invention, as one embodiment, the compound has the structure shown in formula II or III:

[0160] Among them, R b A, B, C, L, n1, n2, n3 are defined as any of the above terms.

[0161] In this invention, as one embodiment, the compound has the structure shown in Formula IV:

[0162] Among them, the keys marked with "a" and "b" are located in the middle position of ring A, the keys marked with "c" and "d" are located in the middle position of ring C, and the keys marked with "e" and "f" are located in the adjacent position of ring D.

[0163] n1 is selected from 1, 2 or 3, and n2 is selected from 1 or 2; preferably, n1 is selected from 2 and n2 is selected from 1, or n1 is selected from 2 and n2 is selected from 2; preferably, n1 is selected from 2 and n2 is selected from 1; preferably, both n1 and n2 are 2.

[0164] Preferably, in formula (IV), at least one of the two groups (n1, n2) is n1+n2=3;

[0165] Ring D is selected from phenyl, 5-6-membered heteroaryl; preferably, ring D is selected from phenyl, pyridyl, pyrazinyl, thiophenyl, furanyl, pyrroleyl or imidazolyl; preferably, ring D is selected from phenyl, 6-membered azaaryl; preferably, ring D is selected from phenyl, pyridyl or pyrazinyl; more preferably, ring D is selected from phenyl;

[0166] The ring D is optionally selected from one or two elements chosen from deuterium, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 The alkyl group is substituted with a substituent of a haloalkoxy group; preferably, ring D is optionally replaced by one selected from halogens (e.g., F, Cl), C. 1-6 Alkyl (e.g., methyl) or C 1-6 The alkyl group is substituted with a substituent of a haloalkyl group (e.g., trifluoromethyl); preferably, ring D is optionally replaced by a halogen (e.g., F, Cl) or C. 1-4 The alkyl group (e.g., methyl) is substituted; preferably, ring D is not substituted;

[0167] Ring E is selected from 5-6 membered heterocyclic groups, preferably 5-6 membered nitrogen-containing heterocyclic groups; preferably having 1 N atom and 0 or 1 heteroatom selected from O or S; preferably having 1 N atom; preferably 5-6 membered nitrogen-containing heterocyclic groups having 1 N atom and 0 or 1 heteroatom selected from O or S; preferably 5-6 membered nitrogen-containing heterocyclic groups having 1 N atom and 0 heteroatoms selected from O or S; preferably pyrrolidinyl, piperidinyl, 1,3-oxazinyl or piperazine; more preferably pyrrolidinyl or piperidinyl; preferably ring E is selected from pyrrolidinyl, piperidinyl, 1,3-oxazinyl or piperazine; preferably ring E is selected from pyrrolidinyl or piperidinyl; preferably ring E is pyrrolidinyl;

[0168] Preferably, Selected from Preferred Preferred Among them, s1, s2, s5, s6, s7, s8, and B 1-a B 2-a B 1-b B 2-b B 13 B 14 B 15 R2, R9, R 11 R 13 u2, u9, u11, and u13 are as defined above;

[0169] Preferably, s1 and s2 are both 1, or one of s1 and s2 is selected from 1 and the other is selected from 2; more preferably, s1 and s2 are both 1.

[0170] Preferably, s5 and s6 are both 1, or one of s5 and s6 is selected from 1 and the other is selected from 2; more preferably, one of s5 and s6 is selected from 1 and the other is selected from 2 (for example, s5 is selected from 1 and s6 is selected from 2; or for example, s5 is selected from 2 and s6 is selected from 1).

[0171] Preferably, s7 and s8 are both 1, or one of s7 and s8 is selected from 1 and the other is selected from 2; more preferably, one of s7 and s8 is selected from 1 and the other is selected from 2 (for example, s7 is selected from 1 and s8 is selected from 2; or for example, s7 is selected from 2 and s8 is selected from 1).

[0172] Preferably, B 1-a B 2-a Both are CH, or B 1-a B 2-a Both are N, or B 1-a B 2-a One of them is selected from N, and the other is selected from CH; preferably, B 1-a B 2-a All are CH;

[0173] Preferably, B 1-b B 2-b Both are CH, or B 1-b B 2-b One of them is selected from N, and the other is selected from CH; preferably, B 1-b B 2-b All are CH;

[0174] Preferably, B 13 Selected from S;

[0175] Preferably, B 14 Selected from N;

[0176] Preferably, B 15 Selected from S;

[0177] Preferably, R2 is selected from halogens, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Halogenated alkoxy groups; preferably halogens, C 1-4 Alkyl and C 1-4 Halogenated alkyl groups, preferably halogens (e.g., F, Cl) and C. 1-4 Alkyl groups (e.g., methyl groups);

[0178] Preferably, R9 is selected from C 1-4 Alkyl and C 1-4 Halogenated alkyl groups, preferably C 1-4 Alkyl groups (e.g., methyl groups);

[0179] Preferably, R 11 Selected from halogens, C 1-4 Alkyl and C 1-4 Halogenated alkyl groups, preferably halogens (e.g., F, Cl) and C. 1-4 Alkyl groups (e.g., methyl groups);

[0180] Preferably, R 13 Selected from C 1-4 Alkyl and C 1-4 Halogenated alkyl groups, preferably C 1-4 Alkyl groups (e.g., methyl groups);

[0181] Preferably, u2 is selected from 0 and 1, and more preferably 0;

[0182] Preferably, u9 is selected from 0 and 1, and more preferably 0;

[0183] Preferably, u11 is selected from 0 and 1, and more preferably 0;

[0184] Preferably, u13 is selected from 0 and 1, and more preferably 0;

[0185] Preferably, Selected from Among them, s1, s2, and B 1-a B 2-a R2 and u2 are as defined in any embodiment of the present invention; preferably, s1 and s2 are both 1; preferably, B 1-a B 2-a All are CH; preferably, B 1-a B 2-a All are N; preferably, B 1-a B 2-a One of them is CH, and the other is N; preferably, R2 is selected from halogens, C 1-4 Alkyl, C1-4 Haloalkyl, C 1-4 Alkoxy or C 1-4 Haloalkoxy group; preferably, R2 is selected from halogens (e.g., F, Cl) or C. 1-4 Alkyl (e.g., methyl); preferably, u2 is selected from 0 or 1; preferably, u2 is 0; preferably, Selected from Preferably, Selected from Preferred Preferred Preferred Preferred Preferred

[0186] Preferably, ring A is selected from phenyl, 5-6 membered monocyclic heteroaryl, 9-10 membered fused bicyclic heteroaryl or benzo5-6 membered monocyclic heterocyclic group; preferably, ring A is selected from phenyl, 5-6 membered monocyclic heteroaryl or 9-10 membered fused bicyclic heteroaryl; more preferably, ring A is selected from phenyl or 5-6 membered monocyclic heteroaryl.

[0187] The rings A are optionally each independently selected from 1 or 2 (preferably 1) halogens, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl or C 1-4 The alkyl group is substituted with a substituent; preferably, each of the ring A is optionally and independently replaced by one or two (preferably one) substituents selected from halogens (e.g., F, Cl) or C. 1-4 Alkyl groups (e.g., methyl) are substituted; preferably, ring A is optionally substituted independently by one or two (preferably one) halogens (e.g., F); preferably, ring A is unsubstituted.

[0188] Preferably, ring A is selected from Preferred Preferred Where A1-A 19 A 22 A 23 R 1a R 2a m1, m2, and t3 are as defined in any embodiment of the present invention;

[0189] Preferably, ring A is selected from Preferably, ring A is selected from More

[0190] The rings A are optionally each independently selected from 1 or 2 (preferably 1) halogens, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl or C 1-4 The alkyl group is substituted with a substituent; preferably, each of the ring A is optionally and independently replaced by one or two (preferably one) substituents selected from halogens (e.g., F, Cl) or C. 1-4 Alkyl groups (e.g., methyl) are substituted; preferably, ring A is optionally substituted independently by one or two (preferably one) halogens (e.g., F); preferably, ring A is unsubstituted.

[0191] Preferably, ring C is selected from phenyl, 5-6 membered monocyclic heteroaryl, 9-10 membered fused bicyclic heteroaryl or benzo5-6 membered monocyclic heterocyclic group; preferably, ring C is selected from phenyl, 5-6 membered monocyclic heteroaryl or 9-10 membered fused bicyclic heteroaryl; preferably phenyl or 5-6 membered monocyclic heteroaryl.

[0192] Preferably, ring C is selected from Preferred Preferred Among them, C1-C4, C5, C7, C8, C 10 -C 17 , q as described in any embodiment of the present invention;

[0193] Preferably, ring C is selected from Preferred Preferred Preferred Among them, C1-C4, C5, C7, C8, C 10 -C 17 , q as described in any embodiment of the present invention;

[0194] Preferably, ring C is selected from Preferred More

[0195] Preferably, ring C is selected from

[0196] The rings C are optionally each independently selected from 1 or 2 (preferably 1) halogens, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl or C 1-4The alkyl group is substituted with a substituent of the alkyl group; preferably, each of the ring Cs is optionally and independently selected from one or two (preferably one) halogens (e.g., F, Cl) or C. 1-4 Alkyl groups (e.g., methyl) are substituted; preferably, the ring Cs are each optionally and independently substituted with one or two (preferably one) halogens (e.g., F); preferably, the ring Cs are not substituted;

[0197] Rb is selected from H, -COORc, or -CONR. d R e Preferably, Rb is selected from -COORc;

[0198] Rc is selected from H and C. 1-6 Alkyl; R d R e Each is independently selected from H and C. 1-6 alkyl;

[0199] Preferably, Rc is selected from H and C. 1-4 alkyl;

[0200] Preferably, R d R e One of them is selected from H, and the other is selected from C. 1-4 alkyl;

[0201] Preferably, Rb is selected from -COOH.

[0202] In this invention, as one embodiment, the compound has the structure shown in Formula V:

[0203] Among them, the keys marked with "a" and "b" are located in the middle position of ring A, the keys marked with "c" and "d" are located in the middle position of ring C, and the keys marked with "e" and "f" are located in the adjacent position of ring D.

[0204] Rb, D, E, A, C, n1, n2, n3, L are as defined above;

[0205] Preferably, L is selected from The key marked "*1" is connected to b, the key marked "*2" is connected to c, and the key marked "*3" is connected to...

[0206] Preferably, L is selected from The key marked with "*1" is connected to b, the key marked with "*2" is connected to c, and the key marked with "*3" is connected to b.

[0207] Preferably, L is selected from Preferably, L is selected from Preferably, L is selected from Preferably, L is selected from The key marked with "*1" is connected to b, the key marked with "*2" is connected to c, and the key marked with "*3" is connected to b.

[0208] Preferably, L is selected from The key marked with "*1" is connected to b, the key marked with "*2" is connected to c, and the key marked with "*3" is connected to b.

[0209] In this invention, as one embodiment, the compound has the structure shown in Formula VI:

[0210] Among them, the keys marked with "a" and "b" are located in the intermediate position of ring A, and the keys marked with "e" and "f" are located in the adjacent position of ring D;

[0211] Rb, D, E, A, n1, n2, L are as defined above;

[0212] Preferably, L is selected from Preferably, L is selected from The key marked "*3" is connected to

[0213] The lipoprotein(a) inhibitor, its isomers, isotopically labeled compounds, prodrugs, or pharmaceutically acceptable salts, esters, hydrates, or solvates thereof described in this invention are selected from:

[0214] The lipoprotein(a) inhibitor, its isomers, isotopically labeled compounds, prodrugs, or pharmaceutically acceptable salts, esters, hydrates, or solvates thereof described in this invention are selected from:

[0215] The present invention provides a pharmaceutical composition comprising any of the compounds described above, an isomer, an isotopically labeled compound, a prodrug, or a pharmaceutically acceptable salt, ester, hydrate, or solvate thereof as an active ingredient.

[0216] The use of the compounds, isomers, isotopically labeled compounds, prodrugs, or pharmaceutically acceptable salts, esters, hydrates or solvates thereof, or the pharmaceutical compositions thereof, in the preparation of medicaments for the prevention and / or treatment of diseases associated with Lp(a).

[0217] 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.

[0218] 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.

[0219] In this invention, as one embodiment, the disease related to Lp(a) is a disease related to lowering Lp(a) levels.

[0220] In this invention, as one of the embodiments, the diseases related to Lp(a) are cardiovascular diseases, including but not limited to atherosclerosis, stroke, hyperlipidemia, elevated Lp(a) levels, thrombosis, coronary heart disease, aortic stenosis, etc.

[0221] 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.

[0222] The various embodiments of the present invention can be combined in any way.

[0223] In a second aspect, the present invention provides a method for preparing a compound of formula I, the method comprising:

[0224] Synthesis Route 1:

[0225] Among them, Rb PG Selected from Rb or its protected form (when Rb contains functional groups that readily participate in side reactions (such as -COOH), a protecting group needs to be applied to it during the reaction to avoid interference (for example, if Rb is -COOH, then Rb PG Option -COOtBu));

[0226] PG represents a protecting group, such as Boc; preferably, PG is attached to the cyclic nitrogen atom in ring E;

[0227] D, E, A, C, e, f, a, b, c, d, n1, n2, Rb are as defined in any embodiment of the present invention;

[0228] Step 1: Compound 1-1-3 is generated by reductive amination of compound 1-1-1 and compound 1-1-2, or by reductive amination of compound 1-1-15 and compound 1-1-10;

[0229] Step 2: Compound 1-1-6 is generated by reductive amination of compound 1-1-3 and compound 1-1-4, or by substitution of compound 1-1-3 and compound 1-1-5.

[0230] Step 3: Deprotection of compound 1-1-6 yields compound 1-1-7.

[0231] Synthesis Route 2:

[0232] Among them, Rb PG Selected from Rb or its protected form (when Rb contains functional groups that readily participate in side reactions (such as -COOH), a protecting group needs to be applied to it during the reaction to avoid interference (for example, if Rb is -COOH, then Rb PG Option -COOtBu));

[0233] PG represents a protecting group, such as Boc; preferably, PG is attached to the cyclic nitrogen atom in ring E;

[0234] D, E, A, C, e, f, a, b, c, d, n1, n2, Rb are as defined in any embodiment of the present invention;

[0235] Step 1: Compound 1-1-9 is generated by reductive amination of compound 1-1-1 and compound 1-1-8, or by reductive amination of compound 1-1-15 and compound 1-1-4;

[0236] Step 2: Compound 1-1-6 is generated by reductive amination of compound 1-1-9 and compound 1-1-10, or by substitution of compound 1-1-9 and compound 1-1-11.

[0237] Step 3: Deprotection of compound 1-1-6 yields compound 1-1-7.

[0238] Synthesis Route 3:

[0239] Among them, Rb PG Selected from Rb or its protected form (when Rb contains functional groups that readily participate in side reactions (such as -COOH), a protecting group needs to be applied to it during the reaction to avoid interference (for example, if Rb is -COOH, then Rb PG Option -COOtBu));

[0240] PG represents a protecting group, such as Boc; preferably, PG is attached to the cyclic nitrogen atom in ring E;

[0241] D, E, A, C, e, f, a, b, c, d, n1, n2, Rb are as defined in any embodiment of the present invention;

[0242] Step 1: Compound 1-1-12 is generated by reductive amination of compound 1-1-4 and compound 1-1-2, or by reductive amination of compound 1-1-8 and compound 1-1-10.

[0243] Step 2: Compound 1-1-6 is generated by reductive amination of compound 1-1-12 and compound 1-1-13, or by substitution of compound 1-1-12 and compound 1-1-14.

[0244] Step 3: Deprotection of compound 1-1-6 yields compound 1-1-7.

[0245] Synthesis Route 4:

[0246] Among them, Rb PG Selected from Rb or its protected form (when Rb contains functional groups that readily participate in side reactions (such as -COOH), a protecting group needs to be applied to it during the reaction to avoid interference (for example, if Rb is -COOH, then Rb PG Option -COOtBu));

[0247] PG represents a protecting group, such as Boc; preferably, PG is attached to the cyclic nitrogen atom in ring E;

[0248] D, E, A, e, f, a, b, n1, n2, Rb are as defined in any embodiment of the present invention;

[0249] Step 1: Compound 1-1-16 is generated by reductive amination of compound 1-1-1 and compound 1-1-2, or by reductive amination of compound 1-1-15 and compound 1-1-10.

[0250] Step 2: Deprotection of compound 1-1-16 yields compound 1-1-17.

[0251] Synthesis Route 5:

[0252] Among them, Rb PG Selected from Rb or its protected form (when Rb contains functional groups that readily participate in side reactions (such as -COOH), a protecting group needs to be applied to it during the reaction to avoid interference (for example, if Rb is -COOH, then Rb PG Option -COOtBu));

[0253] PG represents a protecting group, such as Boc; preferably, PG is attached to the cyclic nitrogen atom in ring E;

[0254] D, E, A, C, e, f, a, b, c, d, n1, n2, Rb are as defined in any embodiment of the present invention;

[0255] Step 1: Compound 1-1-19 is generated by a substitution reaction between compound 1-1-18 and compound 1-1-2;

[0256] Step 2: Compound 1-1-20 is generated by reductive amination of compound 1-1-19 and compound 1-1-4, or by substitution of compound 1-1-19 and compound 1-1-5.

[0257] Step 3: Deprotection of compound 1-1-20 yields compound 1-1-21.

[0258] Synthesis Route 6:

[0259] Among them, Rb PG Selected from Rb or its protected form (when Rb contains functional groups that readily participate in side reactions (such as -COOH), a protecting group needs to be applied to it during the reaction to avoid interference (for example, if Rb is -COOH, then Rb PG Option -COOtBu));

[0260] PG represents a protecting group, such as Boc; preferably, PG is attached to the cyclic nitrogen atom in ring E;

[0261] D, E, A, C, e, f, a, b, c, d, n1, n2, Rb are as defined in any embodiment of the present invention;

[0262] Step 1: Compound 1-1-24 is generated by esterification of compound 1-1-22 and compound 1-1-23;

[0263] Step 2: Compound 1-1-25 is generated by a substitution reaction between compound 1-1-24 and compound 1-1-2;

[0264] Step 3: Compound 1-1-26 is generated by a substitution reaction between compound 1-1-25 and compound 1-1-14;

[0265] Step 4: Deprotection of compound 1-1-26 yields compound 1-1-27.

[0266] Synthesis Route 7:

[0267] Among them, Rb PG Selected from Rb or its protected form (when Rb contains functional groups that readily participate in side reactions (such as -COOH), a protecting group needs to be applied to it during the reaction to avoid interference (for example, if Rb is -COOH, then Rb PG Option -COOtBu));

[0268] PG represents a protecting group, such as Boc; preferably, PG is attached to the cyclic nitrogen atom in ring E;

[0269] D, E, A, C, e, f, a, b, c, d, n1, n2, n3, Rb are as defined in any embodiment of the present invention;

[0270] Step 1: Compound 1-1-29 is generated by esterification of compound 1-1-28 and compound 1-1-23;

[0271] Step 2: Compound 1-1-29 and compound 1-1-2 undergo a substitution reaction to generate compound 1-1-30;

[0272] Step 3: Compound 1-1-31 is generated by a substitution reaction between compound 1-1-30 and compound 1-1-5;

[0273] Step 4: Deprotection of compound 1-1-31 yields compound 1-1-32.

[0274] Terminology Explanation

[0275] 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.

[0276] 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.

[0277] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, such as a straight-chain or branched group containing 1-6 carbon atoms, including but not limited to 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, 1,1,2-trimethylpropyl, and other aliphatic alkyl groups.

[0278] The terms "alkoxy" and "cycloalkoxy" refer to -O-alkyl and -O-(cycloalkyl), respectively, with alkyl and cycloalkyl defined as described in the context. These include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexyloxy.

[0279] As used herein, the term "cycloalkyl group" refers to a saturated (i.e., "cycloalkyl" and "cycloalkylene") or partially unsaturated (i.e., having one or more double bonds (i.e., "cycloalkenyl" and "cycloalkylene") and / or triple bonds within the ring) monocyclic or polycyclic hydrocarbon ring having, for example, 3-12 (suitably 3-10, 8-10, 3-8, 3-7, 3-6, 4-6 or 5-6) ring carbon atoms, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, etc. In some embodiments, the cycloalkyl group includes aryl-fused cycloalkyl groups, provided that the entire ring system is non-aromatic, for example...

[0280] As used herein, the term "cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclic, including spirocyclic, fused, or bridged systems (e.g., bicyclic [1.1.1]pentyl, bicyclic [2.2.1]heptyl, bicyclic [3.2.1]octyl, or bicyclic [5.2.0]nonyl, decahydronaphthyl, etc.). The cycloalkyl group has 3-15 carbon atoms, suitably 3-12, 3-10, 3-8, 3-7, 3-6, 4-6, or 5-6 carbon atoms. For example, the term "C 3-6 "Cycloalkyl" and "C" 3-6 "Cycloalkylene" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring with 3 to 6 cyclic carbon atoms (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl).

[0281] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group with a conjugated π-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl.

[0282] The term "aromatic heterol" (also known as "heteroaryl") refers to a heteroaromatic system containing heteroatoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl groups are preferably 5 to 12-membered, such as imidazolyl, furanyl, thiophene, thiazolyl, pyrazolyl, oxazolyl, pyrrole, tetrazolyl, pyridyl, pyrimidinyl, thiadiazolyl, pyrazinyl, carbazole, indole, quinoxaline, etc., with thiophene or thiazolyl being the most preferred.

[0283] The term "aromatic group" refers to an organic functional group composed of a monocyclic or fused polycyclic aromatic hydrocarbon ring with a conjugated π-electron system, including aryl and heteroaryl groups.

[0284] As used herein, the term "heterocyclic" refers to a monocyclic or polycyclic (e.g., bicyclic) cyclic structure that is saturated (i.e., "heterocyclic alkyl" and "heterocyclic alkylene") or partially unsaturated (e.g., having one or more double bonds (i.e., "heterocyclic alkenyl" and "heterocyclic alkenyl") within the ring, having 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms and one or more (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur, but excluding the -OO-, -OS-, or -SS- ring portions. The heterocycle may be connected to the remainder of the molecule by any of the carbon atoms or a nitrogen atom (if present). Specifically, a 3-12 membered heterocycle is a ring having 3-12 (e.g., 3-10, 3-8, 3-7, 3-6, 4-11, 4-9, 4-7, 4-6, 5-12, 5-6, 6-10, 6-9, 6-8, 7-11, 8-10, or 8-12) ring atoms, said ring atoms including carbon atoms and heteroatoms. The heterocyclic group includes aryl or heteroaryl fused heterocyclic groups, provided the entire ring system is non-aromatic. Examples that can be listed include, but are not limited to, ethylene oxide, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, dioxolinyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, hexahydropyrimidinyl, triazinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, azetidinyl, dihydropyrrolyl, dihydroimidazolyl, azetidinyl, and azetidinyl.

[0285] The term "halogenated" refers to a group that can be replaced by any one or more F, Cl, Br, or I atoms.

[0286] 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. Detailed Implementation

[0287] The following examples and test cases are used to further illustrate the present invention, but do not limit the scope of the present invention in any way.

[0288] Example: Synthesis of Compounds

[0289] Reference object 1 was prepared according to the method in Example 1 of CN114008021A. The structure of reference object 1 is as follows:

[0290] Preparation Example 1: Synthesis of inter 1

[0291] 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.

[0292] Step 2): Dissolve inter 1b (6.2 g, 25.51 mmol, 1.0 equivalent) in dichloromethane (50 mL), add di-tert-butyl dicarbonate (6.68 g, 30.61 mmol, 1.2 equivalent) and triethylamine (10.61 mL, 76.52 mmol, 3.0 equivalent), 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 = 1.42 min.

[0293] Step 3): Dissolve inter 1c (4.6 g, 13.27 mmol, 1.0 equivalence) in ethanol (36 mL), and add iron powder (7.5 g, 134.31 mmol, 10.0 equivalence). Then add ammonium chloride (7.0 g, 130.87 mmol, 10.0 equivalence) 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.

[0294] Step 4): Add 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (1.4 g, 1.91 mmol, 0.17 equivalents) to a solution of inter 1d (3.5 g, 11.18 mmol, 1.0 equivalent) 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 to 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 = 1.25 min.

[0295] 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.

[0296] Preparation Example 2: Synthesis of inter 2

[0297] 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.

[0298] Preparation Example 3: Synthesis of inter 3

[0299] Under a nitrogen atmosphere, inter 3a (5 g, 21.81 mmol, 1.0 equivalent) was dissolved in tetrahydrofuran (50 mL), and triethylamine (7.56 mL, 54.52 mmol, 2.5 equivalent) was added at 0 °C, followed by pentanoyl chloride (3.16 g, 26.17 mmol, 1.2 equivalent). The reaction mixture was stirred at 0 °C for 30 min. Lithium chloride (1.11 g, 26.17 mmol, 1.2 equivalent) and inter 3b (3.86 g, 21.81 mmol, 1.0 equivalent) 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).

[0300] Preparation Example 4: Synthesis of inter 4

[0301] Step 1): Dissolve inter 3 (1.0 g, 2.57 mmol, 1.0 equivalent) in tetrahydrofuran (20 mL), and add bis(trimethylsilylaminolithium) (1.0 M tetrahydrofuran solution, 2.83 mL, 2.83 mmol, 1.1 equivalent) at 0 °C, stirring for 30 min at the same temperature. Then add a tetrahydrofuran solution (3 mL) of compound inter 4a (0.71 g, 2.83 mmol, 1.1 equivalent). Stir at 0 °C for 16 h to room temperature. Quench the reaction mixture with saturated citric acid aqueous solution (50 mL), extract with tert-butyl methyl ether (50 mL × 3), and wash with water (50 mL) and saturated brine (50 mL). Combine the organic layers, dry with anhydrous sodium sulfate, and filter. Concentrate the filtrate under reduced pressure. Purify the residue by silica gel column chromatography (petroleum ether / tert-butyl methyl ether = 1 / 1) to give inter4b. ESI m / z 501.2 [M+H-tert-butyl] + .LCMS:product:Rt=2.283min; 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).

[0302] 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 for 2 hours, slowly raising to room temperature. 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. 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). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give inter 4c. ESI m / z 342.1 [M+H-tert-butyl] + .LCMS:product:Rt=1.362min.

[0303] Step 3): Dissolve inter 4c (7.3 g, 18.33 mmol, 1.0 equivalent) in tetrahydrofuran (50 mL), and add inter 4d (18.36 g, 91.64 mmol, 5.0 equivalent). 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] + .LCMS:product:Rt=1.695min.

[0304] Step 4): Dissolve inter 4e (4.0 g, 8.80 mmol, 1.0 equivalent) in N,N-dimethylformamide (80 mL), add triethylsilane (4.09 g, 35.21 mmol, 4.0 equivalent), triethylamine (6.10 mL, 44.01 mmol, 5.0 equivalent), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (0.65 g, 0.88 mmol, 0.1 equivalent). Stir the mixture at 90 °C and 15 psi for 16 hours under carbon monoxide protection. Extract the mixture with water (50 mL), 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] +.LCMS:product:Rt=1.390min.

[0305] Preparation Example 5: Synthesis of inter 5

[0306] Step 1): Dissolve inter 4 (1 g, 2.48 mmol, 1.0 equivalent) in methanol (15 mL), then add sodium borohydride (0.11 g, 2.97 mmol, 1.2 equivalent) at 0 °C. Stir the reaction mixture at 0 °C for 10 min. Pour the mixture into water (20 mL), extract with ethyl acetate (3 × 20 mL), combine the organic phases, 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 = 2 / 1) to give inter 5a. ESI m / z 428.2 [M+Na]+.LCMS:product:Rt = 1.302 min.

[0307] 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 obtain inter 5. ESI m / z 358.0 [M-2C(CH3)3+H] + .LCMS:product:Rt=1.482min.

[0308] Preparation Example 6: Synthesis of inter 6

[0309] 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 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] + .LCMS:product:Rt=1.401min.

[0310] Step 2): Under a nitrogen atmosphere, 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 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 solution of sodium bisulfite (2.26 g, 21.74 mmol, 15 equivalence) in water, 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 inter 6c. ESI m / z 367.1 [M + Na] + .LCMS:product:Rt=1.178min.

[0311] 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.

[0312] Step 4): Add Raney nickel (103.65 mg, 0.47 mmol, 1.0 equivalent) to a solution containing tetrahydrofuran (5 mL) and ammonia (0.2 mL). Purge with hydrogen gas and stir the reaction mixture at room temperature for 6 hours. Filter the mixture and concentrate under reduced pressure to obtain Inter 6. ESI m / z 405.2 [M+H] + .LCMS:product:Rt=0.997min.

[0313] Preparation Example 7: Synthesis of inter 7

[0314] 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] + .LCMS:product:Rt=1.966min.

[0315] Step 2): Dissolve inter 7a (350.0 mg, 0.65 mmol) in a mixture of methanol (5 mL) and water (1 mL), and add lithium hydroxide monohydrate (40.6 mg, 0.97 mmol, 1.5 equivalents). 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 inter 7. ESI m / z 442.2 [M + Na] + .LCMS:product:Rt=1.726min.

[0316] Example 1: Synthesis of Compound 1

[0317] Step 1): Dissolve inter 1 (480 mg, 1.29 mmol, 1.0 equivalence) in dioxane (10 mL) and water (2 mL), then add (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). 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 1 g of the compound. ESI m / z 326.1 [MC(CH3)3+H] + .LCMS:product:R t = 1.41 min.

[0318] Step 2): 1 g (400 mg, 1.05 mmol, 1.0 equivalence) of the compound was dissolved in dichloromethane (10 mL), and Inter 6 (467 mg, 1.15 mmol, 1.0 equivalence), acetic acid (20 mg, 0.11 mmol, 0.1 equivalence), and sodium triacetoxyborohydride (667 mg, 3.15 mmol, 3.0 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 (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 1 h. ESI m / z 770.5 [M+H] + .LCMS:product:R t = 1.23 min.

[0319] Step 3): Compound 1h (380 mg, 0.47 mmol, 1.0 equivalence) was dissolved in N,N-dimethylformamide (10 mL), and Inter 5 (244 mg, 0.52 mmol, 1.1 equivalence) and potassium carbonate (196 mg, 1.42 mmol, 3.0 equivalence) were added. The reaction mixture was stirred at room temperature for 16 hours. 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 (40 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 1i. ESI m / z 1157.6 [M+H] + .LCMS:product:R t = 1.58 min.

[0320] Step 4): Compound 1i (180 mg, 0.23 mmol, 1.0 equivalent) was dissolved in tetrahydrofuran (2 mL), methanol (2 mL), and water (2 mL), and lithium hydroxide monohydrate (76 mg, 1.81 mmol, 10.0 equivalent) was added. The reaction mixture was stirred at 50 °C for 16 hours. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (15 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Crude compound 1j was obtained and used in the next step without further purification. ESI m / z 1144.6 [M+H] + .LCMS:product:R t = 1.48 min.

[0321] Step 5): Compound 1j (180 mg, 0.15 mmol, 1.0 equivalence) was dissolved in hydrochloric acid / dioxane (8 mL, 4 M) and stirred at room temperature for 16 hours. The resulting reaction mixture was concentrated and purified by preparative high-performance liquid chromatography (ammonium bicarbonate) to obtain compound 1. ESI m / z 731.3 [M+H] + .LCMS:product:Rt=1.06min. 1 HNMR(400MHz,D2O)δ7.39–6.94(m,14H),4.44(t,J=36.8Hz,4H),3.49(s,6H),3.30–2.9 1(m,6H),2.83–2.45(m,6H),2.32(d,J=6.4Hz,4H),1.98(s,2H),1.59(d,J=8.4Hz,2H).

[0322] Example 2: Synthesis of Compound 2

[0323] Compound 1 (150 mg, 0.11 mmol, 1.0 equivalence) was dissolved in hydrochloric acid / dioxane (5 mL) and stirred at room temperature for 16 hours. The reaction mixture was concentrated and purified by preparative high-performance liquid chromatography (ammonium bicarbonate) to give compound 2. ESI m / z 745.3 [M+H] + .LCMS:product:R t = 1.25min. 1HNMR(400MHz,D2O)δ7.84(s,1H),7.46(d,J=7.6Hz,1H),7.33(ddd,J=33.0,17.0,8.7Hz,7H),7.16(t,J=12 .8Hz,5H),4.69–4.51(m,4H),4.33–4.16(m,6H),3.63–3.48(m,5H),3.38(dd,J=14.5,5.8Hz,2H),3.20(dd, J=18.5,10.3Hz,2H),3.02(t,J=10.9Hz,2H),2.88(dd,J=13.3,4.5Hz,2H),2.79(dd,J=21.7,11.5Hz,2H), 2.69(td,J=9.7,4.9Hz,2H), 2.51(dd,J=17.0,8.2Hz,2H), 2.11(dd,J=11.2,4.8Hz,2H), 1.75–1.64(m,2H).

[0324] Example 3: Synthesis of Compound 3

[0325] Step 1): Compound 3a (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 obtain compound 3b. ESI m / z 259.0 [M+H] + .LCMS:product:R t = 0.38min.

[0326] Step 2): Compound 3b (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 3c. ESI m / z 302.9 [MC(CH3)3+H] + .LCMS:product:R t = 1.39 min.

[0327] Step 3): Compound 3c (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, an ammonium chloride solution (1140 mg, 21.31 mmol, 10 equivalence) in water (5 mL) was added to the mixture, and the mixture was 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 obtain compound 3d. ESI m / z 327.0 [M+H] + .LCMS:product:R t = 1.30 min.

[0328] Step 4): Compound 3d (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 then 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 3e. ESI m / z 307.2 [M+H] + .LCMS:product:R t = 1.27 min.

[0329] Step 5): Compound 3e (400 mg, 1.25 mmol, 1.0 equivalence) was dissolved in acetonitrile (10 mL), and then tert-butyl nitrite (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 then 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 3f. ESI m / z 314.0 [MC(CH3)3+H] + .LCMS:product:R t = 1.39 min.

[0330] Step 6): Compound 3f (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 3 g of compound. ESI m / z 418.2 [M+Na] + .LCMS:product:R t = 1.41 min.

[0331] Step 7): 3 g (100 mg, 0.24 mmol, 1.0 equivalence) of the compound 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 hours. The reaction mixture was quenched with saturated sodium bicarbonate solution (10 mL) and extracted with dichloromethane (2 × 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 3 h. ESI m / z 784.4 [M+H] + .LCMS:product:R t = 1.29 min.

[0332] Step 8): Compound 3h (120 mg, 0.15 mmol, 1.0 equivalence) was dissolved in N,N-dimethylformamide (5 mL), and Inter 5 (79 mg, 0.17 mmol, 1.1 equivalence) and potassium carbonate (64 mg, 0.46 mmol, 3.0 equivalence) were added. The reaction mixture was stirred at 25 °C for 16 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 silica gel column chromatography (petroleum ether / tert-butyl methyl ether = 1 / 1) to give compound 3i. ESI m / z 1172.8 [M+H] + .LCMS:product:R t = 1.64 min.

[0333] Step 9): Compound 3i (100 mg, 0.08 mmol, 1.0 equivalent) was dissolved in tetrahydrofuran (1 mL), methanol (1 mL), and water (1 mL), and lithium hydroxide monohydrate (35 mg, 0.83 mmol, 10.0 equivalent) was added. The reaction mixture was stirred at 50 °C for 24 hours. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Crude compound 3j was obtained and used in the next step without further purification. ESI m / z 1158.8 [M+H]+.LCMS:product:R t = 1.59 min.

[0334] Step 10): Add 1 mL of trifluoroacetic acid to a 3 mL solution of compound 3j (90 mg, 0.07 mmol, 1.0 equivalence) in dichloromethane. Stir the reaction mixture at 25 °C for 16 hours. The resulting reaction mixture was concentrated and purified by preparative high-performance liquid chromatography (ammonium bicarbonate) to obtain compound 3. ESI m / z 745.3 [M+H] + .LCMS:product:Rt=1.10min. 1 HNMR(400MHz,D2O)δ7.37–7.20(m,7H),7.20–7.01(m,7H),4.31(s,2H),3.64(s,6H),3.43(s,2H),3.27(t,J=9.9Hz, 4H),3.15–2.92(m,4H),2.69(dd,J=40.9,8.6Hz,6H),2.44–2.22(m,4H),2.02(s,2H),1.63(dd,J=20.7,11.1Hz,2H).

[0335] Example 4: Synthesis of Compound 4

[0336] Step 1): Triethylamine (6.99 mL, 50.40 mmol, 2.0 equivalent) was added to an ethanol (50 mL) solution containing compound 4a (5 g, 25.09 mmol, 1.0 equivalent), tert-butyl 2-cyanoacetate (3.6 g, 25.50 mmol, 1.0 equivalent), and sulfur powder (0.87 g, 25.53 mmol, 1.0 equivalent). The mixture was stirred at 85 °C for 4 hours. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (80 mL × 3) and washed with brine (100 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether / methyl tert-butyl ether = 1 / 0 to 1 / 1) to give compound 4b. ESI m / z 355.2 [M+H]+ .LCMS:product:R t = 1.476 min.

[0337] Step 2): 0.42 g tert-butyl nitrite (4.07 mmol, 1.5 equivalents) and cuprous bromide (0.46 g, 3.21 mmol, 1.2 equivalents) were dissolved in acetonitrile solution (10 mL) and stirred at 0 °C for 1 hour. Then, compound 4b (1 g, 2.70 mmol, 1.0 equivalents) was added. The mixture was stirred at 15 °C for 18 hours. Water (40 mL) was added to the mixture, followed by extraction with ethyl acetate (50 mL × 2). The organic phases were combined, washed with brine (50 mL × 3), dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the residue. The crude product was purified by rapid column chromatography (petroleum ether / methyl tert-butyl ether = 1 / 0 to 4 / 1) to give compound 4c. ESI m / z 442.0 [M + Na] + .LCMS:product:R t = 1.651 min.

[0338] Step 3): To a mixed solution of compound 4c (270 mg, 0.44 mmol, 1.0 equivalence) in dioxane (5 mL) and water (1 mL), add (3-formaldehydephenyl)boronic acid (100 mg, 0.67 mmol, 1.5 equivalence), potassium phosphate (250 mg, 1.18 mmol, 2.68 equivalence), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (33 mg, 0.05 mmol, 0.1 equivalence), and stir at 90 °C for 16 hours under a nitrogen atmosphere. Then add water (40 mL) to the mixture and extract with ethyl acetate (50 mL × 2). Combine the organic phases, wash with brine (50 mL × 3), dry with anhydrous sodium sulfate, and concentrate under vacuum to obtain the crude product. The crude product is purified by column chromatography (petroleum ether / methyl tert-butyl ether = 1 / 0 to 3 / 1) to obtain compound 4d. ESI m / z 466.2 [M+Na] + .LCMS:product:R t = 1.594 min.

[0339] Step 4): To a solution of compound 4d (160 mg, 0.28 mmol, 1.0 equivalence) and inter 6 (160 mg, 0.36 mmol, 1.27 equivalence) in dichloromethane (5 mL), acetic acid (0.06 mL, 1.00 mmol) and sodium triacetoxyborohydride (190 mg, 0.90 mmol, 3.18 equivalence) were added. The mixture was stirred at 15 °C for 2 hours. A saturated sodium bicarbonate aqueous solution (30 mL) was added to the mixture, followed by extraction with dichloromethane (20 mL × 3). The organic phases were combined, washed with brine (50 mL × 2), 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 = 1 / 0 to 1 / 1) to give compound 4e. ESI m / z 832.4 [M+H] + .LCMS:product:R t = 1.382 min.

[0340] Step 5): Compound 4e (170 mg, 0.19 mmol, 1.0 equivalence) and inter 5 (100 mg, 0.21 mmol, 1.13 equivalence) were dissolved in N,N-dimethylformamide (3 mL), and potassium carbonate (66 mg, 0.48 mmol, 2.52 equivalence) was added. The mixture was stirred at 15 °C for 16 hours. Water (30 mL) was added to the mixture, and then it was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with brine (30 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was purified by rapid column chromatography (petroleum ether / methyl tert-butyl ether = 1 / 0 to 3 / 2) to give compound 4f. ESI m / z 1220.6 [M+H] + .LCMS:product:R t = 1.946 min.

[0341] Step 6): Trifluoroacetic acid (1 mL, 13.07 mmol) was added to a solution of compound 4f (160 mg, 0.11 mmol, 1.0 equivalence) in dichloromethane (2 mL). The mixture was stirred at 15 °C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was purified by preparative high-performance liquid chromatography (ammonium bicarbonate) to give compound 4. ESI m / z 751.2 [M+H] + .LCMS:product:R t = 1.095 min. 1H NMR(400MHz,D2O)δ7.51(d,J=9.5Hz,1H),7.46–7.39(m,2H),7.30(dd,J=17.4,9.9Hz,3H),7 .23(d,J=7.4Hz,2H),7.18(d,J=7.3Hz,2H),7.13(s,2H),4.39(s,2H),4.12(s,6H),3.50(t,J =5.3Hz,2H),3.43(dd,J=11.3,2.7Hz,2H),3.33(dd,J=10.7,8.5Hz,2H),3.17(dd,J=17.2,8. 4Hz,2H),2.95–2.83(m,4H),2.74(s,4H),2.39(s,4H),2.11–1.99(m,2H),1.70–1.59(m,2H).

[0342] Example 5: Synthesis of Compound 5

[0343] Step 1): Under nitrogen protection at 0°C, N-bromosuccinimide (2.15 g, 12.08 mmol, 1.0 equivalent) was added dropwise to a dichloromethane (60 mL) solution containing compound 5a (3 g, 12.08 mmol, 1.0 equivalent). The mixture was heated to room temperature and stirred for 2 hours. The reaction mixture was poured into a 10% potassium carbonate aqueous solution (200 mL) and extracted with dichloromethane (100 mL). The organic phase was washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1), and then slurried with petroleum ether / methyl tert-butyl ether (6:1, 10 mL). The mixture was filtered and separated, and the filter cake was washed with petroleum ether / methyl tert-butyl ether (6:1, 10 mL). The resulting solid was dissolved in tetrahydrofuran (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 5b. ESI m / z 327.0 [M+H] + .LCMS:product:Rt=1.321min.

[0344] Step 2): In an 80 mL sealed tube, compound 5b (2.3 g, 7.03 mmol, 1.0 equivalent) was dissolved in a mixed solution of N,N-dimethylformamide (20 mL) and methanol (20 mL). 4-Dimethylaminopyridine (1.72 g, 14.06 mmol, 2.0 equivalent) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (1.15 g, 1.41 mmol, 0.2 equivalent) were added. Nitrogen gas was introduced, and then octacarbonyl dicobalt (1.20 g, 3.51 mmol, 0.5 equivalent) was quickly added. The mixture was stirred at 100 °C for 18 hours. The reaction mixture was concentrated to remove methanol, diluted with water (60 mL), and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate 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 / 2) to give compound 5c. ESI m / z 251.2 [MC(CH3)3+H] + .LCMS:product:Rt=1.280min. 1 H NMR (400MHz, CDCl3) δ7.01(d,J=8.5Hz,1H),6.69(d,J=8.4Hz,1H),4.48(s,2H),3.92(s,3H),3.56(t,J=5.9Hz,2H),2.98(t,J=5.9Hz,2H),1.51(s,9H).

[0345] Step 3): Under nitrogen protection at 0°C, tert-butyl nitrite (1.07 g, 10.38 mmol, 2.0 equivalence) was added dropwise to a 20 mL solution of acetonitrile containing compound 5c (1.95 g, 5.19 mmol, 1.0 equivalence). The reaction mixture was stirred at 0°C for 1 hour. Subsequently, cuprous bromide (1.12 g, 7.79 mmol, 1.5 equivalence) was added in portions while maintaining 0°C. The reaction mixture was then heated to 60°C and stirred for 5 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (10 mL × 2). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and the filtrate 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 = 4 / 1) to obtain compound 5d. ESI m / z 314.0 [MC(CH3)3+H] + .LCMS:product:Rt=1.408min.

[0346] Step 4): Compound 5d (519 mg, 0.93 mmol, 1.0 equivalent) was dissolved in a mixed solution of 1,4-dioxane (10 mL) and water (2 mL). (3-Formylphenyl)boronic acid (210 mg, 1.40 mmol, 1.5 equivalent), potassium phosphate (496 mg, 2.34 mmol, 2.5 equivalent), and 1,1-bis(diphenylphosphine)diberberine palladium dichloride (68 mg, 0.09 mmol, 0.1 equivalent) were added. The reaction mixture was stirred at 90 °C for 16 hours under nitrogen protection. The mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give compound 5e. ESI m / z 418.2 [M+Na] + .LCMS:product:Rt=1.460min.

[0347] Step 5): To a solution of compound 5e (250 mg, 0.52 mmol, 1.0 equivalence) in dichloromethane (10 mL), add inter 6 (229 mg, 0.57 mmol, 1.1 equivalence) and sodium triacetoxyborohydride (327 mg, 1.55 mmol, 3.0 equivalence). Stir the reaction mixture at room temperature for 2 hours. Quench the reaction mixture with saturated sodium bicarbonate solution (20 mL) and extract with dichloromethane (10 mL × 2). Combine the organic phases, wash with saturated brine (20 mL), dry to anhydrous sodium sulfate, and filter. Concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 1 / 1) to give compound 5f. ESI m / z 784.4 [M+H] + .LCMS:product:Rt=1.268min.

[0348] Step 6): To a solution of N,N-dimethylformamide (5 mL) containing compound 5f (391 mg, 0.45 mmol, 1.0 equivalence), add inter5 (232 mg, 0.50 mmol, 1.1 equivalence) and potassium carbonate (187 mg, 1.35 mmol, 3.0 equivalence). The reaction mixture was stirred at room temperature for 16 hours. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (8 mL × 3). The combined organic phases were washed with saturated brine (40 mL × 3), 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 = 50 / 1) to give 5 g of the compound. ESI m / z 1171.6 [M+H] + .LCMS:product:Rt=1.882min.

[0349] Step 7): Dissolve 5 g (380 mg, 0.23 mmol, 1.0 equivalence) of the compound in methanol (5 mL), and add dropwise 0.8 mL of saturated potassium hydroxide aqueous solution until a precipitate is almost formed. Stir the mixture at 70 °C for 5 days. Concentrate the mixture under reduced pressure to obtain the compound 5 h. ESI m / z 1045.6 [M-2C(CH3)3+H] + .LCMS:product:Rt=1.338min.

[0350] Step 8): Compound 5h (500 mg, 0.19 mmol, 1.0 equivalent) was dissolved in a mixed solution of dichloromethane (6 mL) and trifluoroacetic acid (3 mL), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated and purified by preparative high-performance liquid chromatography (ammonium bicarbonate) to obtain compound 5. ESI m / z 746.3 [M+H]+.LCMS:product:Rt=1.104 min. 1 H NMR(400MHz,D2O)δ7.41–7.32(m,3H),7.30(d,J=4.6Hz,1H),7.24(t,J=7.3Hz, 2H),7.20–7.08(m,8H),4.30(s,2H),3.63(d,J=9.0Hz,6H),3.45(t,J=6.4Hz,2 H),3.27(dd,J=18.4,10.9Hz,4H),3.15–2.96(m,4H),2.89–2.61(m,6H),2.37( ddt,J=24.1,16.1,9.0Hz,4H),2.03(dd,J=16.7,7.1Hz,2H),1.70–1.46(m,2H).

[0351] Example 6: Synthesis of Compound 6

[0352] 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 6a (10 g, 41.10 mmol, 1.0 equivalence) in 100 mL of tetrahydrofuran, followed by pentanoyl 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 6b. ESI m / z 425.2 [M+Na] + .LCMS:product:Rt=1.337min.

[0353] Step 2): At 0°C, a solution of compound 6b (3.0 g, 7.45 mmol, 1.0 equivalence) in tetrahydrofuran (30 mL) under a nitrogen atmosphere was added to lithium bis(trimethylsilylamino)ene (8.20 mL, 8.20 mmol, 1.1 equivalence). 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 6c. ESI m / z 593.2 [M + Na] + .LCMS:product:Rt=1.588min.

[0354] Step 3): Under a nitrogen atmosphere, compound 6c (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 a 7 mL solution of lithium hydroxide hydrate (0.31 g, 7.35 mmol, 2.0 equivalent). The reaction mixture was stirred at 0 °C for 2 hours, then quenched with a 20 mL solution of sodium bisulfite (0.73 g, 55.12 mmol, 15 equivalent) in water, and the pH was adjusted to 9 with an aqueous solution of sodium hydroxide (1 M). The solution was extracted 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 6d. ESI m / z 356.0 [M+H-tert-butyl] + .LCMS:product:Rt=1.351min.

[0355] Step 4): O-tert-butyl-N,N'-diisopropylisourea (5.34 g, 26.68 mmol, 5.0 equivalent) was added to a tetrahydrofuran solution (20 mL) of compound 6d (2.2 g, 5.34 mmol, 1.0 equivalent). 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 6e. ESI m / z 468.0 [M+H] + .LCMS:product:Rt=1.662min;

[0356] Step 5): Triethylsilane (1.0 g, 8.62 mmol, 4.0 equivalent), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (160 mg, 0.22 mmol, 0.1 equivalent), and triethylamine (1.49 mL, 10.78 mmol, 5.0 equivalent) were added to a solution of compound 6f (1.01 g, 2.16 mmol, 1.0 equivalent) in N,N-dimethylformamide (25 mL). 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 6f. ESI m / z 440.2 [M+Na] + .LCMS:product:Rt=1.506min.

[0357] Step 6): To a solution of compound 1i (135 mg, 0.15 mmol, 1.0 equivalence) in dichloromethane (5 mL), compound 6f (215 mg, 0.52 mmol, 3.0 equivalence), acetic acid (96 mg, 0.52 mmol, 3.0 equivalence), and sodium triacetoxyborohydride (109 mg, 0.52 mmol, 3.0 equivalence) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution (20 mL) and extracted with dichloromethane (10 mL × 2). The combined organic phases were 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 / tert-butyl methyl ether = 1 / 1) to give compound 6 g. ESI m / z 1172.8 [M+H] + .LCMS:product:R t = 1.663 min.

[0358] Step 7): 6 g (234 mg, 0.15 mmol, 1.0 equivalent) of the compound was added to a mixed solution of tetrahydrofuran (2 mL), methanol (2 mL), and water (2 mL). Lithium hydroxide hydrate (61 mg, 1.45 mmol, 10.0 equivalent) was added, and the reaction mixture was stirred at 55 °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 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under vacuum to obtain crude compound 6 h, which could be used for the next reaction without further purification. ESI m / z 1157.8 [M+H] + .LCMS:product:R t = 1.598min.

[0359] Step 8): Compound 6 (180 mg, 0.13 mmol, 1.0 equivalence) was added to a mixture of trifluoroacetic acid (3 mL) and dichloromethane (3 mL), and the reaction mixture was stirred at room temperature for 16 hours. The resulting reaction mixture was concentrated and purified by preparative high-performance liquid chromatography (ammonium bicarbonate) to obtain compound 6. ESI m / z 746.7 [M+H] + .LCMS:product:Rt=1.067min. 1 HNMR(400MHz,D2O)δ7.37(s,1H),7.34–7.21(m,4H),7.18(d,J=7.3Hz,2H),7.09(d,J =14.4Hz,7H),4.53(s,2H),4.41(s,2H),3.58(s,6H),3.32–3.17(m,4H),3.07(d,J=7. 8Hz,1H),2.69(dd,J=21.3,10.5Hz,5H),2.59(t,J=11.9Hz,2H),2.37–2.17(m,3H),1. 98(s,1H),1.80(dd,J=40.2,12.6Hz,2H),1.59(s,2H),1.33(dd,J=30.3,13.1Hz,2H).

[0360] Example 7: Synthesis of Compound 7

[0361] Step 1): Compound 7a (300 mg, 1.01 mmol, 1.0 equivalent) was dissolved in dioxane (3 mL) and water (0.6 mL). At 25°C, (3-formaldehydephenyl)boronic acid (200 mg, 1.33 mmol, 1.3 equivalent), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (84 mg, 0.10 mmol, 0.1 equivalent), and potassium phosphate (653 mg, 3.08 mmol, 3.0 equivalent) were added. The reaction mixture was stirred at 100°C for 16 hours under nitrogen protection. 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 = 5 / 1) to obtain compound 7b. ESI m / z 268.0 [MC(CH3)3+H] + .LCMS:product:R t = 1.445 min.

[0362] Step 2): Compound 7b (300 mg, 0.89 mmol, 1.0 equivalence) was dissolved in dichloromethane (5 mL), and Inter 6 (360 mg, 0.89 mmol, 1.0 equivalence), acetic acid (17 mg, 0.09 mmol, 0.1 equivalence), and sodium triacetylborohydride (566 mg, 2.67 mmol, 3.0 equivalence) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine (30 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 = 5 / 1) to give compound 7c. ESI m / z 712.5 [M+H] + .LCMS:product:R t = 1.178 min.

[0363] Step 3): Compound 7c (230 mg, 0.32 mmol, 1.0 equivalence) was dissolved in N,N-dimethylformamide (3 mL), and Inter 5 (151 mg, 0.32 mmol, 1.0 equivalence) and potassium carbonate (88 mg, 0.64 mmol, 2.0 equivalence) were added. The reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (20 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 = 1 / 1) to obtain compound 7d. ESI m / z 1099.8 [M+H] + .LCMS:product:R t = 1.672 min.

[0364] Step 4): Compound 7d (200 mg, 0.18 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 solvent was concentrated under vacuum to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography (ammonium bicarbonate) to obtain compound 7. ESI m / z 687.4 [M+H] + .LCMS:product:Rt=0.648min. 1H NMR (400MHz, D2O) δ7.51 (s, 1H), 7.43 (s, 2H), 7.35 (d, J = 12.2Hz, 3H), 7.22 (s,3H),7.16(d,J=7.8Hz,2H),7.08(d,J=6.1Hz,4H),4.54(s,4H),3.97(s, 6H),3.43–3.28(m,4H),3.15(q,J=10.5,9.8Hz,2H),2.84(t,J=9.8Hz,2H) ,2.72–2.59(m,4H),2.36(d,J=7.0Hz,4H),2.01(s,2H),1.72–1.56(m,2H).

[0365] Example 8: Synthesis of Compound 8

[0366] Step 1): Compound 1j (200 mg, 0.17 mmol, 1.0 equivalence), benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate (133 mg, 0.35 mmol, 2.0 equivalence), and N,N-diisopropylethylamine (113 mg, 0.52 mmol, 5.0 equivalence) were dissolved in dichloromethane (5 mL) at room temperature and the mixture was stirred for 0.5 h at room temperature. Then, methylamine hydrochloride (35.43 mg, 0.87 mmol, 3.0 equivalence) was added, and the mixture was stirred for 2.5 h at room temperature. The reaction solution was concentrated under vacuum and diluted with acetonitrile (3 mL). The solution was purified by reverse-phase C18 column chromatography (acetonitrile / water (0.1% formic acid)) to obtain compound 8a. ESI m / z: 1179.6 [M+23] + .LCMS:product:Rt=1.460min.

[0367] Step 2): Add 2 mL of trifluoroacetic acid to a 2 mL solution of compound 8a (180 mg, 0.09 mmol, 1.0 equivalence) in dichloromethane and stir at room temperature for 16 hours. Concentrate the reaction solution under vacuum and dilute with acetonitrile (3 mL). Purify by preparative high-performance liquid chromatography (formic acid) to obtain compound 8. ESI m / z 372.8 [M / 2+H] + .LCMS:product:Rt=0.844min. 1H NMR(400MHz,D2O)δ8.45(s,1H),7.55(d,J=4.8Hz,2H),7.49(d,J=11.0Hz,2H),7.40 (t,J=8.0Hz,3H),7.32(d,J=6.9Hz,3H),7.29–7.20(m,4H),4.75(s,4H),4.23(s,6H) ,3.55(dd,J=11.9,6.2Hz,2H),3.46–3.38(m,2H),3.30–3.22(m,2H),3.00(t,J=10. 2Hz,2H),2.80(s,4H),2.60(s,3H),2.47(s,4H),2.13(s,2H),1.76(d,J=8.7Hz,2H).

[0368] Example 9: Synthesis of Compound 9

[0369] Step 1): 1 g (0.5 g, 1.31 mmol, 1.0 equivalence) of compound was dissolved in dichloromethane (20 mL), and Inter 6 (0.5 g, 1.31 mmol, 1.0 equivalence), acetic acid (0.06 g, 0.13 mmol, 0.1 equivalence), and sodium triacetylborohydride (0.83 g, 3.93 mmol, 3.0 equivalence) were added. The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was then quenched with an aqueous solution of sodium bicarbonate (20 mL), filtered, and extracted with dichloromethane (2 × 20 mL). The organic phases were combined, 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 / 1) to give compound 9a. ESI m / z 1136.6 [M+H] + .LCMS:product:Rt=1.544min.

[0370] Step 2): Compound 9a (150 mg, 0.12 mmol, 1.0 equivalent) was dissolved in dichloromethane (1.5 mL), and then trifluoroacetic acid (1.5 mL) was added. The reaction mixture was stirred at 25 °C for 16 hours. The solvent was concentrated under vacuum to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography (ammonium bicarbonate) to obtain compound 9. ESI m / z 779.4 [M+H] + .LCMS:product:Rt=0.628min. 1H NMR(400MHz,D2O)δ7.76(s,2H),7.42(t,J=7.7Hz,2H),7.36–7.24(m,7H),7. 21(d,J=9.8Hz,3H),7.10(s,2H),4.64(d,J=9.4Hz,8H),4.13(s,6H),3.50(s, 7H),3.35(t,J=10.1Hz,1H),3.18(q,J=10.4,9.9Hz,1H),2.92(t,J=10.3Hz, 1H), 2.69 (d, J = 5.9Hz, 2H), 2.39 (s, 2H), 2.04 (s, 1H), 1.67 (t, J = 11.2Hz, 1H).

[0371] Example 10: Synthesis of Compound 10

[0372] Step 1): Compound 9a (220 mg, 0.17 mmol, 1.0 eq) was dissolved in methanol (1 mL) and tetrahydrofuran (1.5 mL), and lithium hydroxide hydrate (4 mol aqueous solution, 2.5 mL, 10.00 mmol, 57.0 eq) was added. The reaction mixture was stirred at 50 °C for 2 days. The pH of the reaction mixture was adjusted to 7 with 1 mol hydrochloric acid solution. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 × 20 mL). The organic layers were combined, washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give compound 10a. ESI m / z 1108.4 [M+H] + .LCMS:product:R t = 1.418 min.

[0373] Step 2): Compound 10a (100 mg, 0.08 mmol, 1.0 equivalence) was dissolved in dichloromethane (1.5 mL), followed by the addition of trifluoroacetic acid (1.5 mL). The reaction mixture was stirred at 25 °C for 16 hours. The solvent was concentrated under vacuum to obtain a crude product. The crude product was purified by preparative high-performance liquid chromatography (ammonium bicarbonate) to obtain compound 10. ESI m / z 751.3 [M+H] + .

[0374] LCMS:product:Rt = 1.115 min.

[0375] 1H NMR(400MHz,D2O)δ7.34(s,2H),7.19(d,J=18.8Hz,8H),7.09(d,J=26.6Hz,4H),6.96(s,2H),4.50(s,4H),4.34(s,4H),3.62(s,6H),3 .21(d,J=10.1Hz,1H),3.06(dd,J=21.4,11.3Hz,2H),2.72–2.46(m,3H),2.30–2.15(m,2H),1.96(s,1H),1.54(q,J=11.1,10.2Hz,1H).

[0376] Example 11: Synthesis of Compound 11

[0377] Step 1): Under nitrogen protection at 0°C, phosphorus tribromide (2.91 mL, 30.92 mmol, 2.0 equivalent) was added dropwise to a dichloromethane (20 mL) solution of compound 11d1 (3 g, 15.46 mmol, 1.0 equivalent), 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 11d2. ESI m / z 257.8 [M+H] + .LCMS:product:Rt=1.103min. 1 H NMR (400MHz, MeOD) δ7.59 (s, 1H), 4.59 (d, J = 0.6Hz, 2H).

[0378] Step 2): Under nitrogen protection at 0°C, 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 minutes. Subsequently, a tetrahydrofuran (10 mL) solution containing compound 11d2 (2.50 g, 9.73 mmol, 1.1 equivalence) was added. The reaction mixture was brought to room temperature and stirred for 2 hours. 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 11d3. ESI m / z 508.0 [M+H-tert-butyl] +.LCMS:product:Rt=1.472min.

[0379] Step 3): Under nitrogen protection at 0°C, hydrogen peroxide (30% aqueous solution, 3.92 mL, 50.49 mmol, 10 equivalents) was added dropwise to a tetrahydrofuran (24 mL) solution of compound 11d3 (2.85 g, 5.05 mmol, 1.0 equivalents), followed by an 8 mL solution of water containing lithium hydroxide hydrate (0.42 g, 10.10 mmol, 2.0 equivalents). The reaction mixture was stirred at 0°C for 2 hours, then quenched with a 30 mL solution of water containing sodium bisulfite (7.88 g, 75.73 mmol, 15 equivalents), and the pH was adjusted to 9 with an aqueous solution of sodium hydroxide (1 M). 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 11d4. ESI m / z 427.0 [M + Na] + .LCMS:product:Rt=1.172min.

[0380] Step 4): To a tetrahydrofuran solution (20 mL) of compound 11d4 (1.93 g, 4.76 mmol, 1.0 equivalence), O-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 obtain compound 11d5. ESI m / z 349.0 [M + H-tert-buty × 2] + .LCMS:product:Rt=1.519min.

[0381] Step 5): Compound 11d5 (300 mg, 0.63 mmol, 1.0 equivalent) was dissolved in N,N-dimethylacetamide (2 mL), and zinc cyanide (74 mg, 0.63 mmol, 1.0 equivalent), 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene palladium dichloride (48 mg, 0.06 mmol, 0.1 equivalent), and N,N-diisopropylethylamine (244 mg, 1.89 mmol, 3.0 equivalent) 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 11d6. ESI m / z 430.2 [M+Na] + .LCMS:product:Rt=1.798min.

[0382] Step 6): To tetrahydrofuran (2 mL) containing compound 11d6 (240 mg, 0.56 mmol, 1.0 equivalent), add Raney nickel (122 mg, 0.56 mmol, 1.0 equivalent). 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 11d. ESI m / z 412.2 [M+H] + .LCMS:product:Rt=0.947min.

[0383] Step 7): Acetic acid (0.10 mL, 1.67 mmol) and sodium triacetoxyborohydride (926 mg, 4.37 mmol, 5.0 equivalence) were added to a solution of compound 11d (600 mg, 1.46 mmol, 1.68 equivalence) and compound 1 g (340 mg, 0.87 mmol, 1.0 equivalence) in dichloromethane (10 mL). The mixture was stirred at 15 °C for 2 hours. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution (100 mL) and extracted with dichloromethane (100 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 / tert-butyl methyl ether = 1 / 1) to give compound 11a. ESI m / z 777.4 [M+H] + .LCMS:product:R t = 1.504 min.

[0384] Step 8): Acetic acid (0.06 mL, 1.0 mmol) and sodium triacetoxyborohydride (114 mg, 0.54 mmol, 3.0 mmol) were added to a solution of compound 11a (150 mg, 0.18 mmol, 1.0 equivalence) and inter 4 (130 mg, 0.32 mmol, 1.8 equivalence) in dichloromethane (5 mL). The mixture was stirred at 15 °C for 2 hours. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution (100 mL) and extracted with dichloromethane (100 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 / tert-butyl methyl ether = 3 / 1) to give compound 11b. ESI m / z 1165.4 [M+H] + .LCMS:product:R t = 2.087 min.

[0385] Step 9): Compound 11b (180 mg, 0.15 mmol, 1.0 equivalence) was added to tetrahydrofuran (1 mL), methanol (1 mL), and water (1 mL), followed by lithium hydroxide monohydrate (122 mg, 2.91 mmol, 19.86 equivalence). The reaction mixture was stirred at 50 °C for 16 hours. The reaction mixture was poured into water (20 mL), the pH was adjusted to 5 with dilute hydrochloric acid (1 M), and extracted with ethyl acetate (15 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 11c. ESI m / z 1150.6 [M+H] + .LCMS:product:R t = 1.804 min.

[0386] Step 10): Compound 11c (130 mg, 0.10 mmol, 1.0 equivalence) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated and purified by preparative high-performance liquid chromatography (formic acid) to obtain compound 11. ESI m / z 738.3 [M+H] + .LCMS:product:Rt=0.614min. 1HNMR(400MHz,D2O)δ7.48–7.16(m,11H),4.65(s,4H),4.46(s,2H),4.31(d, J=14.5Hz,4H),3.44(dd,J=11.6,7.5Hz,2H),3.34(td,J=8.3,4.2Hz,2H),3. 17(dd,J=18.4,10.6Hz,2H),2.97–2.78(m,4H),2.73(d,J=6.4Hz,2H),2.60 –2.49(m,1H),2.38(m,3H),2.06(dd,J=10.1,4.9Hz,2H),1.76–1.55(m,2H).

[0387] Example 12: Synthesis of Compound 12

[0388] Step 1): Compound 11a (200 mg, 0.24 mmol, 1.0 equivalent) and compound 6f (158 mg, 0.36 mmol, 1.5 equivalent) were dissolved in dichloromethane (15 mL), and acetic acid (0.12 mL, 2.16 mmol, 9.0 equivalent) and sodium triacetoxyborohydride (152 mg, 0.72 mmol, 3.0 equivalent) were added. The 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 × 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 = 1 / 1) to give compound 12a. ESI m / z 1179.6 [M+H] + .LCMS:product:R t = 2.18 min.

[0389] Step 2): Compound 12a (260 mg, 0.18 mmol, 1.0 equivalent) was dissolved in a solution of tetrahydrofuran (5 mL), methanol (5 mL), and water (5 mL), and lithium hydroxide monohydrate (74 mg, 1.76 mmol, 10.0 equivalent) was added. The mixture was stirred at 50 °C for 16 hours. The reaction mixture was poured into water (10 mL), the pH was adjusted to 6 with 1 M HCl, 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 compound 12b. ESI m / z 1164.6 [M+H] + .LCMS:product:R t = 1.81 min.

[0390] Step 3): Compound 12b (210 mg, 0.14 mmol, 1.0 equivalence) was dissolved in dichloromethane (9 mL), and trifluoroacetic acid (3 mL) was added. The mixture was stirred at 25 °C for 16 hours. After concentration, the reaction mixture was purified by preparative high-performance liquid chromatography (formic acid) to obtain compound 12. ESI m / z 752.2 [M+H] + .LCMS:product:Rt=0.96min; 1 H NMR(400MHz,D2O)δ7.37(dd,J=65.6,18.5Hz,11H),4.64(s,4H),4.45(d,J=56.6Hz,6H),3.51–3.30(m,4 H),3.18(s,1H),2.90(d,J=12.2Hz,6H),2.53(d,J=85.1Hz,4H),2.06(s,2H),1.79(s,3H),1.45(s,2H).

[0391] Example 13: Synthesis of Compound 13

[0392] Step 1): To a solution of 1,4-dioxane (20 mL) containing inter 1 (1.4 g, 5.61 mmol, 2.0 equivalence) and pinacol diboronate (1.4 g, 5.61 mmol, 2.0 equivalence), 1,1-bis(diphenylphosphine)diberberine palladium dichloride (205.4 mg, 0.28 mmol, 0.1 equivalence) and potassium acetate (826.52 mg, 8.42 mmol, 3.0 equivalence) were added. The mixture was purged with nitrogen three times, then heated to 100 °C under reflux and stirred for 3 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 layers were dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid column chromatography (ethyl acetate / petroleum ether = 1 / 1) to give compound 13a. ESI m / z 404.6 [M+H] + .LCMS:product:Rt=1.877min.

[0393] Step 2): Compound 13a (300 mg, 0.74 mmol, 1.0 equivalent) was added to dioxane (5 mL) and water (1 mL), followed by 3-bromo-1-iodobenzene (631.36 mg, 2.23 mmol, 3.0 equivalent), potassium carbonate (205.6 mg, 1.49 mmol, 2.0 equivalent), and 1,1-bis(diphenylphosphine)dimerferropalladium dichloride (54.4 mg, 0.07 mmol, 0.1 equivalent). The reaction mixture was reacted at 70 °C for 3 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to obtain 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 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 (ethyl acetate / petroleum ether = 1 / 1) to obtain compound 13b. ESI m / z 456.0 [M+Na] + .LCMS:product:Rt=1.808min.

[0394] Step 3): To a solution of compound 13b (280.0 mg, 0.65 mmol, 1.0 equivalence) in acetonitrile (10 mL), propyneamine (140.6 mg, 2.55 mmol, 2.0 equivalence), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (61.6 mg, 0.12 mmol, 0.2 equivalence), tetrabutylammonium fluoride in (1 M) tetrahydrofuran (0.65 mL, 0.65 mmol, 1.0 equivalence), and palladium acetate (14.5 mg, 0.06 mmol, 0.1 equivalence) were added. The reaction mixture was stirred at 50 °C for 18 hours under nitrogen protection. 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 organic phases were combined, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane / methanol = 20 / 1) to give compound 13c. ESI m / z 407.2 [M+H] + .LCMS:product:Rt=1.160min.

[0395] Step 4): Compound 13c (0.1 g, 0.25 mmol, 1.0 equivalence) was dissolved in N,N-dimethylformamide (2 mL), and cesium carbonate (240.2 mg, 0.75 mmol, 3.0 equivalence) and inter 5 (345.7 mg, 0.75 mmol, 3.0 equivalence) were added. The reaction mixture was stirred at room temperature for 3 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 reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / methyl tert-butyl ether = 1 / 3) to give compound 13d. ESI m / z 1204.7 [M + Na] + .LCMS:product:Rt=1.605min.

[0396] Step 5): Lithium hydroxide monohydrate (27.70 mg, 0.66 mmol, 6.0 equivalence) and water (1 mL) were added to a solution of compound 13d (130.2 mg, 0.11 mmol, 1.0 equivalence) in methanol (1 mL) and tetrahydrofuran (1 mL). The reaction mixture was stirred at 50 °C for 16 hours. The resulting reaction mixture was neutralized to pH 3 with dilute hydrochloric acid. The mixture was extracted with ethyl acetate (20 mL × 3), and the organic phase was concentrated under reduced pressure to give compound 13e. ESI m / z 1168.6 [M+H] + .LCMS:product:Rt=1.537min.

[0397] Step 6): Add 2 mL of trifluoroacetic acid to a solution of dichloromethane containing compound 13e (120.0 mg, 0.10 mmol, 1.0 equivalence). Stir the reaction mixture at room temperature for 16 hours. The resulting reaction mixture was concentrated and purified by preparative high-performance liquid chromatography (ammonium bicarbonate) to obtain compound 13. ESI m / z 378.3 [M / 2+H] + .LCMS:product:Rt=1.058min. 1H NMR(400MHz,D2O)δ7.47–7.37(m,3H),7.37–7.28(m,2H),7.18(t,J=7.2Hz,2H),7.13–7.00(m,7H),4.53(s,2H),4.35(s,2H),3.64(s,4H),3.34 –3.18(m,6H),3.18–3.04(m,2H),2.68(dd,J=18.4,9.2Hz,4H),2.57(d, J=9.6Hz,2H),2.39–2.22(m,4H),2.06–1.90(m,2H),1.69–1.52(m,2H).

[0398] Example 14: Synthesis of Compound 14

[0399] Step 1): Dissolve inter 1 (300 mg, 0.69 mmol, 1.0 equivalence) in dioxane (10 mL), add benzyl mercaptan (97 μL, 0.83 mmol, 1.2 equivalence), tris(dibenzylacetone)dipalladium (63.55 mg, 0.07 mmol, 0.1 equivalence), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (80.31 mg, 0.14 mmol, 0.2 equivalence), and N,N-diisopropylethylamine (179.3 mg, 1.39 mmol, 2.0 equivalence). Stir the reaction mixture at 100 °C for 18 hours under nitrogen atmosphere. Concentrate the reaction mixture under reduced pressure. Purify the residue by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 10 / 1) to give compound 14a. ESI m / z 498.2 [M+Na] + .LCMS:product:Rt=2.109min.

[0400] Step 2): Compound 14a (230.1 mg, 0.48 mmol, 1.0 equivalence) was dissolved in water (0.25 mL), acetic acid (0.4 mL), and acetonitrile (10 mL), followed by the addition of 1,3-dichloro-4,4-dimethyl-2-oxotetrahydro-1H-imidazol-5-one (190.5 mg, 0.97 mmol, 2.0 equivalence). 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 to 0 °C, and 5% sodium bicarbonate aqueous solution (10 mL) was added. The mixture was stirred for 5 min, and the organic phase was then separated. The organic phase was concentrated under vacuum to give compound 14b. ESI m / z 396.0 [M-56+H] + .LCMS:product:Rt=1.754min.

[0401] Step 3): Compound 14b (200.0 mg, 0.40 mmol, 1.0 equivalence) was dissolved in dichloromethane (5 mL), and Inter 6 (193.4 mg, 0.48 mmol, 1.2 equivalence) and triethylamine (110 μL, 0.8 mmol, 2.0 equivalence) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give compound 14c. ESI m / z 720.2 [M-Boc+H] + .LCMS:product:Rt=1.900min.

[0402] Step 4): Compound 14c (220.1 mg, 0.27 mmol, 1.0 equivalence) was dissolved in N,N-dimethylformamide (2 mL), followed by the addition of inter 5 (251.4 mg, 0.54 mmol, 2.0 equivalence) and cesium carbonate (262.2 mg, 0.80 mmol, 3.0 equivalence). The reaction mixture was stirred at 50 °C 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 reduced pressure to obtain the crude product. The crude product was purified by rapid column chromatography (petroleum ether / methyl tert-butyl ether = 1 / 5) to obtain compound 14d. ESI m / z 1108.6 [M-Boc+H] + .LCMS:product:Rt=1.883min.

[0403] Step 5): Compound 14d (250.1 mg, 0.21 mmol, 1.0 equivalent) was added to a mixed solution of methanol (2 mL) and tetrahydrofuran (2 mL), followed by lithium hydroxide monohydrate (52.1 mg, 1.24 mmol, 6.0 equivalent) and water (2 mL). The reaction mixture was stirred at 50 °C for 16 hours. The resulting reaction mixture was neutralized to pH 3 with hydrochloric acid (10% aqueous solution). The mixture was extracted with ethyl acetate (30 mL × 3), and the organic phase was concentrated under reduced pressure to give compound 14e. ESI m / z 1093.6 [M-Boc+H] + .LCMS:product:Rt=1.784min.

[0404] Step 6): Compound 14e (220.0 mg, 0.18 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 16 hours. The resulting reaction mixture was concentrated and purified by preparative high-performance liquid chromatography (ammonium bicarbonate) to obtain compound 14. ESI m / z 391.2 [M / 2+H] + .LCMS:product:Rt=0.626min.1 HNMR(400MHz,D2O)δ7.78(d,J=7.4Hz,1H),7.69–7.54(m,3H),7.45(s,1H),7.19–7. 07(m,3H),6.97(dd,J=28.1,7.6Hz,4H),6.82(s,2H),4.62(d,J=15.0Hz,4H),4.32( s,4H),3.28(dt,J=11.6,7.4Hz,4H),3.12(dd,J=18.0,10.6Hz,2H),2.77–2.56(m,4 H),2.47(d,J=13.5Hz,2H),2.34–2.23(m,4H),2.08–1.92(m,2H),1.68–1.54(m,2H).

[0405] Example 15: Synthesis of Compound 15

[0406] Step 1): 1 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 15f1. ESI m / z 328.2 [MC(CH3)3+H] + .LCMS:product:Rt=1.21min.

[0407] 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 15f1 (1 g, 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 15f. ESI m / z 392.0 [M-tert-butyl+H] + .LCMS:product:R t =1.498min.

[0408] Step 3): 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 15b. ESI m / z 569.2 [M+Na] + .LCMS:product:Rt=1.420min.

[0409] Step 4): To a solution of compound 15b (500 mg, 0.79 mmol, 1.0 equivalence) and inter 6 (350 mg, 0.87 mmol, 1.1 equivalence) in dichloromethane (8 mL), triethylamine (159 mg, 1.57 mmol, 2.0 equivalence) and 4-dimethylaminopyridine (10 mg, 0.08 mmol, 0.1 equivalence) were added. The reaction mixture was stirred at room temperature for 4 hours. The mixture was poured into water (10 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 = 1 / 2) to give compound 15c. ESI m / z 736.4 [M-Boc+H] + .LCMS:product:R t = 1.675min.

[0410] Step 5): Under nitrogen protection at 0°C, sodium hydroxide (66 mg, 1.64 mmol, 5.0 equivalence) was added to a solution of N,N-dimethylformamide (5 mL) containing compound 15c (300 mg, 0.33 mmol, 1.0 equivalence), and the reaction mixture was stirred at 0°C for 30 minutes. Subsequently, a solution of N,N-dimethylformamide (2 mL) containing compound 15f (320 mg, 0.71 mmol, 2.2 equivalence) was added, and the reaction mixture was heated to room temperature and stirred for 1.5 hours. The mixture was quenched with saturated ammonium chloride aqueous solution (15 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, 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 / 3) to give compound 15d. LCMS:product:Rt = 2.341 min.

[0411] Step 6): Compound 15d (272 mg, 0.23 mmol, 1.0 equivalent) was added to a mixed solution of tetrahydrofuran (2 mL), methanol (2 mL), and water (2 mL), followed by lithium hydroxide hydrate (95 mg, 2.26 mmol, 10.0 equivalent). The reaction mixture was stirred at 50 °C for 16 hours. The mixture was concentrated under reduced pressure to remove methanol and tetrahydrofuran. The residue was dissolved in water (10 mL), acidified to pH 5 with dilute hydrochloric acid (1 M), and extracted with ethyl acetate (6 × 2 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 15e. ESI m / z 988.5 [M-Boc×2+H] + .LCMS:product:R t = 2.174 min.

[0412] Step 7): Compound 15e (260 mg, 0.17 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 3 hours. The resulting reaction mixture was concentrated and purified by preparative high-performance liquid chromatography (formic acid) to obtain compound 15. ESI m / z 775.3 [M+H] + .LCMS:product:Rt=1.035min. 1 H NMR(400MHz,D2O)δ7.69–6.59(m,14H),4.96(s,2H),4.55(s,2H),4.40(s,6H),3.25(s,4H) ),3.07(s,2H),2.73(d,J=77.8Hz,8H),2.27(s,2H),1.99(s,2H),1.52(d,J=54.6Hz,2H).

[0413] Example 16: Synthesis of Compound 16

[0414] Step 1): Dissolve inter 4e (0.58 g, 1.28 mmol, 1.0 equivalence) in acetonitrile (10 mL), add propan-2-yn-1-amine (140.6 mg, 2.55 mmol, 2.0 equivalence), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (243.4 mg, 0.51 mmol, 0.4 equivalence), tetrabutylammonium fluoride in 1 mol / L tetrahydrofuran solution (1.91 mL, 1.91 mmol, 1.5 equivalence), and palladium acetate (57.31 mg, 0.26 mmol, 0.2 equivalence). Stir the reaction mixture at 50 °C for 18 hours under nitrogen protection. Concentrate the resulting reaction mixture under reduced pressure to obtain a crude product. Dilute the crude product with ethyl acetate (50 mL) and water (50 mL), and extract with ethyl acetate (3 × 50 mL). The organic layer was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound 16a. ESI m / z 429.3 [M+H] + .LCMS:product:Rt=0.994min.

[0415] Step 2): Compound 16a (220 mg, 0.46 mmol, 1.0 equivalence) was dissolved in dichloromethane (5 mL), and 1 g of compound (157 mg, 0.37 mmol, 0.8 equivalence), sodium triacetoxyborohydride (326 mg, 1.54 mmol, 3.0 equivalence), and acetic acid (0.00 mL, 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 organic layers were combined, washed with brine (50 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 = 1 / 1) to obtain compound 16b. ESI m / z = 1160.6 [M+H] + .LCMS:product:R t = 1.711 min.

[0416] Step 3): Compound 16b (250 mg, 0.18 mmol, 1.0 equivalence) was dissolved in methanol (1 mL) and tetrahydrofuran (1 mL), and lithium hydroxide (4 mol aqueous solution, 2 mL, 8.00 mmol, 44.4 equivalence) was added. The reaction mixture was stirred at 50 °C for 18 hours. The pH of the reaction mixture was adjusted to 7 with 1 mol 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 brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give compound 16c. ESI m / z = 1131.4 [M+H]+ .LCMS:product:R t = 1.415 min.

[0417] Step 4): Compound 16c (200 mg, 0.12 mmol, 1.0 equivalence) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (2 mL) was added. The reaction mixture was stirred at 25 °C for 18 hours. The solvent was concentrated under vacuum to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography (formic acid) to obtain compound 16. ESI m / z = 775.3 [M+H] + .LCMS:product:Rt=1.035min. 1 H NMR(400MHz,D2O)δ7.41(d,J=17.8Hz,10H),7.27(s,2H),7.24–7.15(m,4H),4. 58(s,4H),4.42(d,J=18.0Hz,8H),3.91(s,2H),3.40(dd,J=11.7,7.1Hz,1H),3 .35–3.27(m,1H),3.17(dd,J=10.9,7.7Hz,1H),2.84–2.77(m,1H),2.69–2.55( m,2H),2.38–2.26(m,2H),2.02(d,J=11.2Hz,1H),1.62(dd,J=13.1,9.0Hz,1H)

[0418] Example 17: Synthesis of Compound 17

[0419] Step 1): Compound 18j (800 mg, 2.27 mmol, 1.0 equivalence) was dissolved in N,N-dimethylformamide (15 mL), methanol (5 mL) and triethylamine (5 mL) were added, followed by 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (265 mg, 0.36 mmol, 0.16 equivalence). The mixture was stirred at 90 °C under a CO atmosphere at 15 psi for 16 hours. The mixture was poured into water (20 mL) and extracted with ethyl acetate (10 mL × 3). The organic layers were combined, washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid column chromatography (dichloromethane / ethyl acetate = 1 / 1) to give compound 17a. ESI m / z 294.2 [M+H] + .LCMS:product:Rt=1.29min.

[0420] Step 2): Compound 17a (430 mg, 1.04 mmol, 1.0 equivalence) was dissolved in acetonitrile (8 mL), and 2-methyl-2-(nitrooxy)propane (322 mg, 3.12 mmol, 3.0 equivalence) and cuprous chloride (I) (309 mg, 3.12 mmol, 3.0 equivalence) were added. The mixture was stirred at 70 °C for 16 hours. The mixture was then poured into water (10 mL) and extracted with ethyl acetate (10 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 / ethyl acetate = 3 / 1) to give compound 17b. ESI m / z 313.1 [M+H] + .LCMS:product:Rt=1.23min.

[0421] Step 3): Compound 17b (0.18 g, 0.58 mmol, 1.0 equivalence) was dissolved in dioxane (10 mL) and water (2 mL), and (3-formylphenyl)boronic acid (0.11 g, 0.71 mmol, 1.2 equivalence), potassium phosphate (0.31 g, 1.48 mmol, 2.5 equivalence), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (0.04 g, 0.06 mmol, 0.1 equivalence) were added. The reaction mixture was heated to 90 °C and stirred for 16 hours under nitrogen protection. The reaction mixture was concentrated under reduced pressure. The residue was purified by rapid column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give compound 17c. ESI m / z 383.2 [M+H] + .LCMS:product:Rt=1.22min.

[0422] Step 4): Compound 17c (200 mg, 0.47 mmol, 1.0 equivalence) was dissolved in dichloromethane (10 mL), and Inter 6 (210 mg, 0.52 mmol, 1.1 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 reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was quenched with saturated sodium bicarbonate solution (10 mL), extracted with dichloromethane (2 × 20 mL), the organic phases 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 17d. ESI m / z 771.4 [M+H] + .LCMS:product:Rt=1.22min.

[0423] Step 5): Compound 17d (300 mg, 0.38 mmol, 1.0 equivalence) was dissolved in N,N-dimethylformamide (10 mL), and inter5 (218 mg, 0.47 mmol, 1.2 equivalence) and potassium carbonate (135 mg, 0.98 mmol, 2.5 equivalence) were added. The reaction mixture was stirred at 25 °C for 16 hours. The mixture was poured into water (20 mL) and extracted with ethyl acetate (10 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 silica gel column chromatography (petroleum ether / tert-butyl methyl ether = 1 / 1) to give compound 17e. ESI m / z 1160.6 [M+H]+. LCMS:product:Rt = 1.53 min.

[0424] Step 6): Compound 17e (260 mg, 0.22 mmol, 1.0 equivalent) was dissolved in tetrahydrofuran (5 mL), methanol (5 mL), and water (5 mL), and lithium hydroxide monohydrate (93 mg, 2.22 mmol, 10.0 equivalent) was added. The reaction mixture was stirred at 50 °C for 16 hours. The reaction mixture was poured into water (20 mL), acidified to pH 5 with 1 M hydrochloric acid, and then extracted with ethyl acetate (10 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 17f. ESI m / z 1167.6 [M + Na] + .LCMS:product:Rt=1.47min.

[0425] Step 7): Compound 17f (260 mg, 0.22 mmol, 1.0 equivalence) was dissolved in dichloromethane (15 mL), and then trifluoroacetic acid (3 mL) was added. The reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was concentrated and purified by preparative high-performance liquid chromatography (formic acid) to obtain compound 17. ESI m / z 732.3 [M+H] + .LCMS:product:Rt=0.95min; 1H NMR(400MHz,D2O)δ7.89(s,1H),7.64(d,J=7.8Hz,1H),7.51(t,J=7.7Hz,1H),7.45(s,1H),7.34(t, J=7.7Hz,3H),7.27(d,J=7.6Hz,2H),7.23–7.09(m,4H),4.76(s,2H),4.64(s,2H),4.29(d,J=17.1H z,6H),3.51(dd,J=11.6,7.6Hz,2H),3.34(dd,J=8.6,3.1Hz,2H),3.19(d,J=7.7Hz,2H),3.03–2.90 (m,2H),2.85–2.67(m,4H),2.57–2.36(m,4H),2.07(d,J=6.7Hz,2H),1.68(dq,J=18.8,9.4Hz,2H).

[0426] Example 18: Synthesis of Compound 18

[0427] Step 1): Compound 18a (40.0 g, 205.0 mmol, 1.0 equivalent) was dissolved in dichloromethane (360 mL), followed by the addition of m-chloroperoxybenzoic acid (117.9 g, 512.4 mmol, 2.5 equivalent) in portions. The reaction was stirred at 25 °C for 12 hours. The reaction mixture was filtered, and the filtrate was quenched with an aqueous solution of sodium sulfite (200 mL) and sodium bicarbonate (500 mL). The aqueous layer was separated and extracted with dichloromethane / methanol = 20:1 (400 mL × 2). The organic phases were combined, washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove most of the solvent. Ethyl acetate (20 mL) was added to the residue, followed by the slow addition of petroleum ether (200 mL). The solid was collected by filtration and dried under vacuum to give compound 18b. ESI m / z 212.0 [M+H] + .

[0428] Step 2): Compound 18b (58.0 g, 274.7 mmol, 1.0 equivalent) was dissolved in toluene (500 mL), and phosphorus trichloride (128 mL, 1.373 mol, 5.0 equivalent) was added. The reaction mixture was stirred at 120 °C for 3 hours. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography, eluting with petroleum ether / dichloromethane (0-64%) to give compound 18c. ESI m / z 229.9 [M+H] + . 1HNMR (400MHz, CDCl3) δ8.17(d,J=8.3Hz,1H),7.51(d,J=8.3Hz,1H),3.99(s,3H),3.94(s,3H).

[0429] Step 3): Compound 18c (13.0 g, 56.62 mmol, 1.0 equivalent) was dissolved in tetrahydrofuran (300 mL) and methanol (6 mL). Under nitrogen protection, lithium borohydride (3.08 g, 141.5 mmol, 2.5 equivalent) was added in portions at 0 °C. The reaction mixture was heated to 25 °C and stirred at this temperature for 3 hours. Then, the reaction mixture was slowly added to a saturated sodium bicarbonate aqueous solution (100 mL) at 0 °C. Ethyl acetate (200 mL) was then added. The mixture was stirred at 0 °C for 20 minutes. The mixture was then filtered and separated. The organic phase was 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 using dichloromethane / methanol (0-8%) as eluent to give compound 18d. ESI m / z 174.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.86(d,J=8.0Hz,1H),7.42(d,J=8.1Hz,1H),5.42–5.13(m,2H),4.62(s,2H),4.51(s,2H).

[0430] Step 4): A solution of thionyl chloride (100 mL) containing compound 18d (8.0 g, 46.08 mmol, 1.0 equivalent) was stirred for 5 hours at 25 °C. The reaction mixture was then concentrated under reduced pressure to obtain a residue. The residue was diluted with ethyl acetate (200 mL). The organic layer was slowly added to ice-cold saturated sodium bicarbonate aqueous solution (150 mL). The mixture was stirred at 25 °C for 10 minutes. The aqueous layer was separated and extracted with ethyl acetate (100 mL × 2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 18e. ESI m / z 209.9, 211.9 [M+H] + .

[0431] Step 5): To a solution of compound 18e (9.6 g, 42.87 mmol, 1.0 equivalent) and N,N-diisopropylethylamine (16.62 g, 128.6 mmol, 3.0 equivalent) in dichloromethane (120 mL), (2,4-dimethoxyphenyl)methylamine (7.89 g, 47.16 mmol, 1.1 equivalent) was added. The reaction mixture was stirred at 25 °C for 12 hours. The reaction mixture was poured into water (100 mL). The aqueous layer was separated and extracted with dichloromethane (100 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 to obtain the residue. The residue was purified by silica gel column chromatography, eluting with petroleum ether / dichloromethane (0-66%) to give compound 18f. ESI m / z 305.0 [M+H] + . 1 H NMR(400MHz, CDCl3)δ7.41(d,J=7.9Hz,1H),7.27–7.24(m,1H),7.11(d,J=7.9Hz,1H),6 .52–6.46(m,2H),4.04–4.00(m,2H),3.98–3.94(m,2H),3.89(s,2H),3.84–3.81(m,6H).

[0432] Step 6): Compound 18f (6.5 g, 18.98 mmol, 1.0 equivalent), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (2.20 g, 3.80 mmol, 0.2 equivalent), tris(dibenzylacetone)dipalladium (1.74 g, 1.90 mmol, 0.1 equivalent), cesium carbonate (15.46 g, 47.45 mmol, 2.5 equivalent), and benzophenone imine (6.20 g, 28.47 mmol, 1.5 equivalent) were dissolved in dioxane (100 mL). The reaction mixture was degassed and purged with nitrogen three times. The reaction mixture was stirred at 100 °C for 12 hours under nitrogen protection. The reaction mixture was diluted with dichloromethane (100 mL) and filtered. The filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (0-46%) and dichloromethane / ethyl acetate (46%) to give 18 g of the compound. ESI m / z 450.6 [M+H] + . 1H NMR (400MHz, CDCl3) δ7.81–7.77(m,2H),7.49–7.45(m,1H),7.42–7.37(m,2H),7.30–7.27(m,2H),7.26–7.24(m,2H),7.20–7 .15(m,3H),6.50–6.46(m,2H),6.29(d,J=8.0Hz,1H),3.97–3.94(m,2H),3.90–3.88(m,2H),3.87(s,2H),3.84–3.82(m,6H).

[0433] Step 7): 18 g (9.1 g, 17.21 mmol) of the compound was dissolved in 100 mL of trifluoroacetic acid and stirred at 85 °C for 12 hours. The reaction mixture was concentrated under reduced pressure to give compound 18h. ESI m / z 136.0 [M+H] + .

[0434] Step 8): Compound 18i (2.0 g, 14.80 mmol, 1.0 equivalence) and triethylamine (12.31 mL, 88.78 mmol, 6.0 equivalence) were dissolved in dichloromethane (50 mL), followed by the addition of di-tert-butyl dicarbonate anhydride (4.84 g, 22.19 mmol, 1.5 equivalence). The reaction mixture was stirred at 25 °C for 12 hours. The reaction was then quenched with water (100 mL). The aqueous phase was separated and extracted with dichloromethane (50 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 to obtain a residue. The residue was purified by silica gel column chromatography, eluting with dichloromethane / (dichloromethane / methanol = 10:1) (0–12%) to give compound 18i. ESI m / z 236.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.35–7.26(m,1H),6.45–6.36(m,1H),4.61–4.35(m,6H),1.51(s,9H).

[0435] Step 9): Compound 18i (1.35 g, 5.74 mmol, 1.0 equivalent) was dissolved in acetonitrile (25 mL), and then N-bromosuccinimide (1.23 g, 6.89 mmol, 1.2 equivalent) was added in portions. The reaction mixture was stirred at 25 °C for 2 hours. The reaction was then quenched with an aqueous sodium bicarbonate solution (25 mL). The aqueous layer was separated and extracted with dichloromethane (25 mL × 3). 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 to obtain the residue. The residue was purified by silica gel column chromatography, eluting with dichloromethane / methanol (0–3%) to give compound 18j. ESI m / z 313.9, 315.9 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.72(d,J=7.9Hz,1H),6.25(d,J=3.1Hz,2H),4.44–4.39(m,2H),4.32–4.27(m,2H),1.44(s,9H).

[0436] Step 10): Compound 18j (750 mg, 2.39 mmol, 1.0 equivalent), (3-formaldehydephenyl)boronic acid (393.72 mg, 2.63 mmol, 1.1 equivalent), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (174.67 mg, 0.24 mmol, 0.1 equivalent), and potassium phosphate (1.52 g, 7.16 mmol, 3.0 equivalent) were mixed in dioxane (10 mL) and water (2 mL). The reaction mixture was bubbled with nitrogen for 2 minutes. Then, it was stirred at 90 °C for 2 hours. The reaction mixture was diluted with water (10 mL) and dichloromethane (20 mL), the aqueous phase was separated, and extracted with dichloromethane (10 mL × 2). The organic phases 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, v / v) (0-12%) to give compound 18K. ESI m / z 340.2 [M+H] + . 1 HNMR (400MHz, CDCl3) δ10.09–10.07(m,1H),7.99–7.90(m,2H),7.77–7.71(m ,1H),7.69–7.63(m,1H),7.32–7.27(m,1H),4.67–4.53(m,6H),1.54(s,9H).

[0437] Step 11): To a 5 mL acetonitrile solution containing compound 18K (363 mg, 0.93 mmol, 1.0 equivalent) and cuprous bromide (266.96 mg, 1.86 mmol, 1.5 equivalent), tert-butyl nitrite (143.93 mg, 1.40 mmol, 2.0 equivalent) was added. The reaction mixture was stirred at 60 °C for 4 hours. Then, cuprous bromide (130.0 mg) and tert-butyl nitrite (70 mg) were added. The reaction mixture was stirred at 60 °C for 12 hours. The reaction mixture was diluted with dichloromethane (10 mL) and a saturated sodium bicarbonate aqueous solution (10 mL). The mixture was filtered. The aqueous phase was separated and 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 petroleum ether / ethyl acetate (0-24%) to give compound 18l. ESI m / z 403.4, 405.4 [M+H] + . 1 HNMR(400MHz, CDCl3)δ10.10(s,1H),7.99–7.94(m,1H),7.94–7.91(m,1H),7.73–7 .69(m,1H),7.69–7.64(m,1H),7.58–7.49(m,1H),4.79–4.69(m,4H),1.54(s,9H).

[0438] Step 12): Compound 18l (180 mg, 0.45 mmol, 1.0 equivalent) was dissolved in methanol (8 mL) with triethylamine (0.2 mL, 1.34 mmol, 3.0 equivalent) and 1,1'-bis(diphenylphosphine)ferrocene palladium(II) dichloride (65.32 mg, 0.09 mmol, 0.2 equivalent), and subjected to three degassing and carbon monoxide purging treatments. The reaction solution was stirred at 80 °C in a carbon monoxide atmosphere (15 psi) for 12 hours. The reaction solution was concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (0-30%) as eluent to obtain compound 18m. ESI m / z 383.2 [M+H] + .

[0439] Step 13): Compound 18m (120 mg, 0.31 mmol, 1.0 equivalence) and inter 6 (153.60 mg, 0.34 mmol, 1.1 equivalence) were dissolved in 1,2-dichloroethane (5 mL), followed by the addition of acetic acid (18.65 mg, 0.31 mmol, 1.0 equivalence). The reaction mixture was stirred at 45 °C for 1 hour. Sodium borohydride acetate (197.52 mg, 0.93 mmol, 3.0 equivalence) was then added. The reaction mixture was stirred at 45 °C for another hour. The reaction was then quenched with a saturated aqueous solution of sodium bicarbonate (5 mL) and dichloromethane (5 mL). The aqueous phase was separated and extracted with dichloromethane (5 mL × 3). The combined organic phases were washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography, eluting with dichloromethane / (dichloromethane / methanol = 10:1) (0-20%) to give compound 18n. ESI m / z 771.6 [M+H] + .

[0440] Step 14): Acetic acid (15.54 mg, 0.26 mmol, 1.0 equivalence) was added to a solution of dichloroethane (5 mL) containing compound 18n (210 mg, 0.26 mmol, 1.0 equivalence) and inter 4 (240.2 mg, 0.60 mmol, 2.3 equivalence). The reaction mixture was stirred at 45 °C for 1 hour. Then sodium borohydride acetate (164.53 mg, 0.78 mmol, 3.0 equivalence) was added. The reaction mixture was stirred at 45 °C for 1 hour. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution (5 mL) and dichloromethane (5 mL). The aqueous phase was separated and extracted with dichloromethane (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) (0-20%) to give compound 18o. ESI m / z 1160.0 [M+H]+.

[0441] Step 15): To a solution containing 220 mg (0.17 mmol, 1.0 equivalence) of compound 18o (3 mL) in tetrahydrofuran (3 mL), methanol (3 mL), and water (3 mL), lithium hydroxide monohydrate (43.51 mg, 1.04 mmol, 6.0 equivalence) was added. The reaction mixture was stirred at 50 °C for 3 hours. The reaction solution was concentrated under reduced pressure to remove most of the solvent. It was then acidified with hydrochloric acid (1 M) to pH 4-5. Extraction was performed 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 / methanol (0-10%) to give compound 18p. ESI m / z 1145.0 [M+H]+ .

[0442] Step 16): Trifluoroacetic acid (3 mL) was added to a solution of dichloromethane (3 mL) containing compound 18p (160 mg, 0.14 mmol, 1.0 equivalent). 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 preparative high-performance liquid chromatography (ammonium bicarbonate) to obtain compound 18. ESI m / z 730.3 [MH] - . 1 H NMR(400MHz,D2O)δ7.60(s,1H),7.39–7.32(m,2H),7.30–7.25(m,2H),7 .24–7.20(m,2H),7.13–7.08(m,6H),4.52(s,2H),4.45(s,2H),3.80–3. 64(m,6H),3.32–3.26(m,4H),3.15–3.07(m,2H),2.80–2.68(m,4H),2.6 5–2.59(m,2H),2.40–2.30(m,4H),2.05–1.97(m,2H),1.67–1.57(m,2H).

[0443] Example 19: Synthesis of Compound 19

[0444] Step 1): Compound 13a (470 mg, 1.17 mmol, 1.0 equivalent) and 6-bromopyridaldehyde (216.78 mg, 1.17 mmol, 1.0 equivalent) were dissolved in 1,4-dioxane (9 mL) and water (3 mL). (1,1'-bis(diphenylphosphino)ferrocene)palladium dichloride (85.28 mg, 0.12 mmol, 0.1 equivalent) and potassium carbonate (483.19 mg, 3.50 mmol, 3.0 equivalent) were added. The mixture was purged with nitrogen three times, heated to 100 °C under reflux and stirred for 16 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography with petroleum ether / tert-butyl methyl ether = 1 / 1 to give compound 19a. ESI m / z 383.2 [M+H] + .LCMS:product:Rt=1.559min.

[0445] Step 2): Compound 19a (360 mg, 0.94 mmol, 1.0 equivalence) and inter 6 (457.01 mg, 1.13 mmol, 1.2 equivalence) were dissolved in dichloromethane (10 mL), and acetic acid (0.11 mL, 1.88 mmol, 2.0 equivalence) was added. The mixture was stirred for 30 minutes, followed by the addition of sodium triacetoxyborohydride (598.55 mg, 2.82 mmol, 3.0 equivalence). The mixture was stirred at room temperature for 3 hours. 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 / tert-butyl methyl ether = 1 / 3 to give compound 19b. ESI m / z 771.4 [M+H] + .LCMS:product:Rt=1.519min.

[0446] Step 3): Compound 19b (260 mg, 0.34 mmol, 1.0 equivalence) and inter4 (136.08 mg, 0.34 mmol, 1.0 equivalence) were dissolved in dichloromethane (2 mL), and acetic acid (0.01 mL, 0.17 mmol, 0.52 equivalence) was added. The mixture was stirred for 30 minutes, and then sodium triacetoxyborohydride (214.42 mg, 1.01 mmol, 3.0 equivalence) was added. The mixture was stirred at room temperature for 3 hours. The reaction mixture was added to a saturated aqueous solution of sodium bicarbonate (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 / tert-butyl methyl ether = 1 / 1 to give compound 19c. ESI m / z 1158.4 [M+H] + .LCMS:product:Rt=1.744min.

[0447] Step 4): Compound 19c (220 mg, 0.19 mmol, 1.0 equivalence) was dissolved in tetrahydrofuran (3 mL), methanol (3 mL), and water (2 mL), and lithium hydroxide monohydrate (47.81 mg, 1.14 mmol, 6.0 equivalence) was added. The mixture was stirred at 50 °C for 16 hours. Then, water (30 mL) was added to the reaction mixture, and the pH was adjusted to 3 with 1 M hydrochloric acid. Extraction was performed with ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to give compound 19d. ESI m / z 1144.4 [M+H] + .LCMS:product:Rt=1.677min.

[0448] Step 5): Compound 19d (160 mg, 0.14 mmol, 1.0 equivalence) was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (4 mL, 52.27 mmol) was added. 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 19. ESI m / z 732.3 [M+H] + .LCMS:product:Rt=0.964min; 1 H NMR(400MHz,D2O)δ7.74(t,J=7.8Hz,1H),7.45(s,1H),7.39(d,J=5.4Hz,2H),7.35(d,J=7.7Hz, 1H),7.26–7.16(m,6H),7.10(d,J=7.1Hz,2H),4.61(d,J=7.9Hz,4H),3.76(d,J=25.0Hz,6H),3. 28(dd,J=11.6,8.0Hz,4H),3.11(dd,J=18.4,10.7Hz,2H),2.80–2.72(m,4H),2.65(dd,J=13.6, 5.6Hz,2H),2.42–2.29(m,4H),2.03(ddd,J=15.9,8.3,5.0Hz,2H),1.62(dq,J=13.0,9.5Hz,2H).

[0449] Example 20: Synthesis of Compound 20

[0450] Step 1): Di-tert-butyl dicarbonate (16.15 g, 74.00 mmol, 1.3 equivalence) was added to dichloromethane (150 mL) containing compound 20a (10.0 g, 56.92 mmol, 1.0 equivalence) and triethylamine (23.7 mL, 170.8 mmol, 3.0 equivalence) at 0 °C. The reaction mixture was heated to 25 °C and stirred at 25 °C for 12 hours. The reaction mixture was quenched with water (200 mL). The aqueous layer was separated and extracted with dichloromethane (100 mL × 3). The organic layers were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the residue. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (0-16%) to give compound 20b. ESI m / z 184.0 [M+H-56] + .LCMS:product:Rt=1.314min. 1H NMR (400MHz, CDCl3) δ7.12(d,J=5.1Hz,1H),6.78(d,J=5.2Hz,1H),4.50(d,J=1.8Hz,2H),3.72(t,J=5.7Hz,2H),2.84(t,J=5.8Hz,2H),1.49(s,9H).

[0451] Step 2): Liquid bromine (24.0 g, 150.4 mmol, 4.0 equivalence) was added to a chloroform (150 mL) solution containing compound 20b (37.60 mmol, 1.0 equivalence) at 0 °C. The reaction mixture was stirred at 60 °C for 16 hours. The reaction mixture was cooled to 0 °C and diluted with dichloromethane (200 mL). Then, saturated aqueous sodium sulfite solution (150 mL) and saturated aqueous sodium bicarbonate solution (150 mL) were slowly added. The aqueous layer was separated and extracted with dichloromethane (100 mL × 3). The organic layers were combined, washed with saturated brine (100 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 / methanol (0–9%) to give compound 20c. ESI m / z 295.8, 297.8 [M+H] + .LCMS:product:Rt=1.077min. 1 H NMR (400MHz, DMSO-d6) δ3.57–3.51(m,2H),2.92(t,J=5.6Hz,2H),2.62–2.57(m,2H).

[0452] Step 3): Add zinc powder (1.25 g, 19.19 mmol, 3.0 equivalent) to a solution of acetic acid (30 mL) containing compound 20c (1.9 g, 6.40 mmol, 1.0 equivalent). Stir the reaction mixture at 25 °C for 5 minutes. Then slowly add concentrated hydrochloric acid (1 mL). Heat the reaction mixture to 85 °C and stir at this temperature for 3 hours. Filter the reaction mixture, and concentrate the filtrate under reduced pressure to give compound 20d. ESI m / z 217.9, 219.9 [M+H] + .LCMS:product:Rt=0.267min.

[0453] Step 4): Di-tert-butyl dicarbonate (1.82 g, 8.34 mmol, 1.0 equivalent) was added to dichloromethane (20 mL) containing compound 20d (1.40 g, 6.42 mmol, 1.0 equivalent) and triethylamine (2.7 mL, 19.26 mmol, 3.0 equivalent). The reaction mixture was stirred at 25 °C for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography, using petroleum ether / ethyl acetate (0-12%) as eluent to give compound 20e. ESI m / z 261.9, 263.9 [M+H-56] + .LCMS:product:Rt=3.258min. 1 H NMR (400MHz, CDCl3) δ7.08 (s, 1H), 4.37 (s, 2H), 3.70 (t, J = 5.7Hz, 2H), 2.82 (t, J = 5.7Hz, 2H), 1.49 (s, 9H).

[0454] Step 5): The mixture containing compound 20e (4.0 g, 12.57 mmol, 1.0 equivalence), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (920 mg, 1.26 mmol, 0.1 equivalence), and triethylamine (5.2 mL, 37.71 mmol, 3.0 equivalence) in methanol (50 mL) was degassed three times and backfilled with carbon monoxide. The reaction mixture was stirred for 12 hours at 70 °C under a carbon monoxide (15 psi) atmosphere. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (0-8%) to give compound 20f. ESI m / z 242.0 [M+H-56] + .LCMS:product:Rt=1.250min. 1 H NMR (400MHz, CDCl3) δ7.96(s,1H),4.73(t,J=1.8Hz,2H),3.86(s,3H),3.72(t,J=5.7Hz,2H),2.87–2.82(m,2H),1.50(s,9H).

[0455] Step 6): Compound 20f (2.5 g, 8.41 mmol, 1.0 equivalent) was dissolved in N,N-dimethylformamide (30 mL), and N-bromosuccinimide (1.95 g, 10.93 mmol, 1.3 equivalent) was added in portions. The reaction mixture was stirred at 40 °C for 3 hours. The reaction mixture was poured into ice water (120 mL). The aqueous phase was extracted with ethyl acetate (30 mL × 2). The organic phases were combined, washed with saturated brine (30 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 using petroleum ether / ethyl acetate (0-8%) as eluent to give compound 20 g. ESI m / z 319.8, 321.8 [M+H] + .LCMS:product:Rt=1.333min. 1 H NMR (400MHz, CDCl3) δ4.62(d,J=1.9Hz,2H),3.88(s,3H),3.69(t,J=5.7Hz,2H),2.73(t,J=5.8Hz,2H),1.48(s,9H).

[0456] Step 7): 20 g (749.0 mg, 1.87 mmol, 1.0 equivalence) of compound, 3-(dihydroxyboryl)benzaldehyde (364.7 mg, 2.43 mmol, 1.3 equivalence), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (136.92 mg, 0.19 mmol, 0.1 equivalence), and potassium phosphate (1.19 g, 5.61 mmol, 3.0 equivalence) were dissolved in dioxane (10 mL) and water (2 mL). The reaction mixture was bubbled with N2 for 1 minute. Then, it was stirred at 85 °C for 2 hours. The reaction mixture was diluted with water (5 mL) and ethyl acetate (5 mL). The aqueous phase was separated and 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 petroleum ether / ethyl acetate (0-8%) to give the compound for 20 h. ESI m / z 346.0 [M+H-56] + .LCMS:product:Rt=1.317min. 1 H NMR(400MHz, CDCl3)δ10.05(s,1H),7.93–7.88(m,2H),7.70–7.65(m,1H),7.60–7.53(m,1H) ,4.76–4.66(m,2H),3.76(t,J=5.7Hz,2H),3.69(s,3H),2.87(t,J=5.7Hz,2H),1.52(s,9H).

[0457] Step 8): A solution of dichloroethane (5 mL) containing compound 20h (150 mg, 0.36 mmol, 1.0 equivalence), inter 6 (146.6 mg, 0.36 mmol, 1.0 equivalence), and acetic acid (2.18 mg, 0.04 mmol, 0.1 equivalence) was stirred at 35 °C for 30 min. Then, sodium triacetoxyborohydride (230.43 mg, 1.09 mmol, 3.0 equivalence) was added. The reaction was continued at 35 °C with stirring for another 30 min. The reaction mixture was quenched with a saturated sodium bicarbonate aqueous solution (5 mL). The aqueous layer was separated and extracted with dichloromethane (5 mL × 3). The combined organic phases were 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 / methanol (0-6%), followed by preparative thin-layer chromatography (dichloromethane / methanol = 20:1, v / v) to give compound 20i. ESI m / z 790.4 [M+H] + .LCMS:product:Rt=1.086min.

[0458] Step 9): Acetic acid (13.7 mg, 0.23 mmol, 1.0 equivalence) was added to a solution of dichloroethane (5 mL) containing compound 20i (180 mg, 0.2 mmol, 1.0 equivalence) and inter 4 (183.88 mg, 0.46 mmol, 2.0 equivalence). The reaction mixture was stirred at 35 °C for 30 min. Then sodium triacetoxyborohydride (144.9 mg, 0.68 mmol, 3.0 equivalence) was added. The reaction mixture was stirred at 35 °C for 1 h. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution (5 mL). The aqueous phase was separated and extracted with dichloromethane (3 mL × 3). The organic phases 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 petroleum ether / methyl tert-butyl ether (0-36%) to give compound 20j. ESI m / z 1177.6 [M+H] + .LCMS:product:Rt=1.728min.

[0459] Step 10): Compound 20kJ (173 mg, 0.13 mmol, 1.0 equivalence) was added to a mixed solution containing tetrahydrofuran (1 mL), methanol (1 mL), and water (1 mL), followed by lithium hydroxide monohydrate (31.82 mg, 0.76 mmol, 6.0 equivalence). The reaction mixture was stirred at 50 °C for 6 hours. The reaction mixture was concentrated to remove most of the solvent. The reaction mixture was diluted with dichloromethane (5 mL) and acidified with 1 M hydrochloric acid to pH 4-5. The aqueous phase was separated and extracted with dichloromethane (3 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 20kJ. ESI m / z 1163.6 [M+H] + .LCMS:product:Rt=1.663min.

[0460] Step 11): Add 2 mL of trifluoroacetic acid to 2 mL of dichloromethane containing compound 20k (150 mg, 0.10 mmol, 1.0 equivalence). Stir the reaction mixture at 35 °C for 4 hours. Concentrate the reaction mixture under reduced pressure to obtain a residue. Purify the residue by preparative high-performance liquid chromatography (ammonium bicarbonate) to obtain compound 20. ESI m / z 751.0 [M+H] + .LCMS:product:Rt=1.126min. 1 H NMR(400MHz,D2O)δ7.58–7.55(m,1H),7.50–7.46(m,1H),7.42–7.38(m,2H),7.37–7.33(m, 2H),7.29–7.21(m,6H),4.49(s,2H),4.42–4.32(m,6H),3.64–3.57(m,4H),3.47–3.41(m,2H ),3.31–3.24(m,2H),3.19(t,J=6.2Hz,2H),3.09(t,J=10.9Hz,2H),2.98–2.93(m,2H),2.9 0–2.83(m,2H),2.81–2.74(m,2H),2.63–2.54(m,2H),2.22–2.14(m,2H),1.83–1.72(m,2H).

[0461] Example 21: Synthesis of Compound 21

[0462] Step 1): Compound 16a (200 mg, 0.46 mmol, 1.0 equivalence) and 1 g of compound (122 mg, 0.32 mmol, 0.7 equivalence) were dissolved in methanol (2 mL), and sodium cyanoborohydride (87 mg, 1.38 mmol, 3.0 equivalence) and acetic acid (3 mg, 0.04 mmol, 0.1 equivalence) were added. The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 × 20 mL). The organic layers were combined, 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 = 1 / 3) to give compound 21a. ESI m / z = 794.4 [M+H] + .LCMS:product:Rt=1.230min.

[0463] Step 2): Compound 21a (130 mg, 0.16 mmol, 1.0 equivalence) was dissolved in N,N-dimethylformamide (2 mL), and inter 5 (75 mg, 0.16 mmol, 1.0 equivalence) and cesium carbonate (104 mg, 0.32 mmol, 2.0 equivalence) were added. The reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 × 20 mL). The organic layers were combined, washed with saturated brine (30 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 = 1 / 1) to obtain compound 21b. ESI m / z = 1182.4 [M+H] + .LCMS:product:Rt=1.631min.

[0464] Step 3): Compound 21b (140 mg, 0.11 mmol, 1.0 equivalence) was dissolved in methanol (1 mL) and tetrahydrofuran (1 mL), and an aqueous solution of lithium hydroxide (2 mL, 4 mol in water, 8.00 mmol, 72.0 equivalence) was added. The reaction mixture was stirred at 50 °C for 16 hours. The pH of the reaction mixture was adjusted to 7 with 1 mol hydrochloric acid solution. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 × 20 mL). The organic layers were combined, washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give compound 21c. ESI m / z = 1167.6 [M+H] + .LCMS:product:Rt=1.683min.

[0465] Step 4): Compound 21c (110 mg, 0.09 mmol, 1.0 equivalence) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred at 25 °C for 16 hours. The solvent was concentrated under vacuum to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography (formic acid) to obtain compound 21. ESI m / z = 755.3 [M+H] + .LCMS:product:Rt=0.705min. 1 H NMR(400MHz,D2O)δ7.46–7.39(m,5H),7.26(dd,J=28.1,12.2Hz,9H),4.59(s,2H),4.45(s,2H),4.21(d,J=13.5Hz,4H),3.74(s,2H),3 .45–3.28(m,4H),3.16(p,J=8.8Hz,2H),2.84(d,J=12.7Hz,2H),2.69(d,J=15.0Hz,4H),2.36(s,4H),2.03(s,2H),1.70–1.57(m,2H).

[0466] Example 22: Synthesis of Compound 22

[0467] Step 1): Compound 22a (14 g, 57.12 mmol, 1.0 equivalent) was dissolved in ethanol (200 mL), and glyoxal (40% aqueous solution, 7.83 mL, 171.37 mmol, 3.0 equivalent) 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 22b. ESI m / z 269.0 [M+H] + .LCMS:product:Rt=1.376min.

[0468] Step 2): Under a nitrogen atmosphere, compound 22b (12 g, 44.93 mmol, 1.0 equivalent) was dissolved in dichloromethane (300 mL), and diisobutylaluminum hydride (1.5 M toluene solution, 74.88 mL, 112.33 mmol, 2.5 equivalent) 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 22c. ESI m / z 239.0 [M+H] + .LCMS:product:Rt=0.971min.

[0469] Step 3): Compound 22c (4.0 g, 16.73 mmol, 1.0 equivalent) was dissolved in N,N-dimethylformamide (40 mL), and phosphorus tribromide (4.72 mL, 50.19 mmol, 3.0 equivalent) 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 22d. ESI m / z 302.8 [M+H] + .LCMS:product:Rt=1.410min.

[0470] 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 22d (3.6 g, 11.92 mmol, 0.77 equivalence) was added, and the mixture was stirred at 0 °C for 5 h 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 22e. ESI m / z 553.0 [M+H-tert-butyl] + .LCMS:product:Rt=1.733min.

[0471] Step 5): Compound 22e (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 for 2 hours, slowly raising the temperature to room temperature. 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 22f. ESI m / z 394.0 [M+H-tert-butyl] + .LCMS:product:Rt=1.418min.

[0472] Step 6): Compound 22f (1.6 g, 3.55 mmol, 1.0 equivalent) and O-tert-butyl-N,N'-diisopropylisourea (7.12 g, 35.53 mmol, 10.0 equivalent) 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 22 g. ESI m / z 452.0 [M+H-tert-butyl]+.LCMS:product:Rt = 1.775 min.

[0473] Step 7): 22 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 to give the compound 22 h. ESI m / z 400.2 [M+H-tert-butyl] + .LCMS:product:Rt=1.685min.

[0474] Step 8): Compound 22i (300 mg, 0.66 mmol, 1.0 equivalence) and inter 6 (319.69 mg, 0.79 mmol, 1.2 equivalence) were dissolved in dichloromethane (10 mL), and acetic acid (0.08 mL, 1.32 mmol, 2.0 equivalence) was added and stirred at room temperature for 30 min. Then, sodium triacetoxyborohydride (418.71 mg, 1.98 mmol, 3.0 equivalence) was added. The mixture was stirred at the same temperature for 3 h. The reaction mixture was added to a saturated aqueous sodium bicarbonate solution (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 rapid column chromatography, eluting with petroleum ether / tert-butyl methyl ether = 1 / 1 to give compound 22i. ESI m / z 844.4 [M+H] + .LCMS:product:Rt=1.566min.

[0475] Step 9): Compound 22i (260 mg, 0.31 mmol, 1.0 equivalence) and compound 15f (206.22 mg, 0.46 mmol, 1.5 equivalence) were dissolved in N,N-dimethylformamide (10 mL), and potassium carbonate (127.70 mg, 0.92 mmol, 3.0 equivalence) was added. The mixture was stirred at room temperature for 16 hours. Then, ethyl acetate (30 mL) and water (30 mL) were added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL × 3) and washed with brine (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 rapid column chromatography with petroleum ether / tert-butyl methyl ether = 1 / 1 to give compound 22j. ESI m / z 1209.6 [M+H] + .LCMS:product:Rt=1.776min.

[0476] Step 10): Compound 22j (230 mg, 0.19 mmol, 1.0 equivalent) was dissolved in a solution of tetrahydrofuran (3 mL), methanol (3 mL), and water (2 mL), and lithium hydroxide monohydrate (47.87 mg, 1.14 mmol, 6.0 equivalent) was added. The mixture was stirred at 50 °C for 16 hours. Then, water (30 mL) was added to the reaction mixture, the pH was adjusted to 3 with 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 22k. ESI m / z 1195.4 [M+H] + .LCMS:product:Rt=1.661min.

[0477] Step 11): Compound 22k (170 mg, 0.14 mmol, 1.0 equivalence) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (4 mL, 52.27 mmol) was added. 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 then purified by preparative high-performance liquid chromatography (formic acid) to give compound 22k. ESI m / z 783.4 [M+H] + .LCMS:product:Rt=1.024min; 1H NMR(400MHz,D2O)δ8.73(d,J=1.8Hz,1H),8.68(d,J=1.9Hz,1H),8.37(s,2H),7.65(s,1H),7.42(s,1H),7. 38(s,1H),7.27(d,J=5.7Hz,4H),7.18(d,J=8.3Hz,2H),7.02(s,1H),4.72(s,6H),4.67(d,J=10.8Hz,4H),3 .47(ddd,J=23.5,11.7,7.1Hz,2H),3.40–3.30(m,2H),3.19(ddd,J=21.9,13.5,9.5Hz,2H),2.99–2.86(m,2 H),2.78(s,2H),2.65(d,J=8.7Hz,2H),2.49–2.33(m,4H),2.05(dd,J=11.7,5.2Hz,2H),1.75–1.61(m,2H).

[0478] Example 23: Synthesis of Compound 23

[0479] Step 1): Compound 23a (10 g, 37.13 mmol, 1 equivalent) was dissolved in a solution of dichloromethane (100 mL), and triethylamine (10.29 mL, 74.25 mmol, 2 equivalents), 4-dimethylaminopyridine (0.45 g, 3.71 mmol, 0.1 equivalents), and di-tert-butyl dicarbonate (12.79 mL, 55.69 mmol, 1.5 equivalents) were added. The mixture was stirred at 25 °C for 16 hours. The reaction mixture was quenched with water (300 mL) and extracted with dichloromethane (200 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was slurried with petroleum ether and ethyl acetate at a ratio of 2:1 (50 mL, 5 mL / g) for 0.5 hours, filtered, and the filter cake was concentrated under vacuum to give compound 23b. ESI m / z 314.2 [M+H-56] + .LCMS:product:Rt=1.715min.

[0480] Step 2): Compound 23b (10 g, 27.07 mmol, 1 equivalent) was added to tetrahydrofuran (50 mL), followed by 10% palladium on carbon (Pd / C, 2.88 g, 27.07 mmol, 1 equivalent). The reaction mixture was stirred at 25 °C in a hydrogen atmosphere for 3 hours. The reaction mixture was filtered and concentrated under reduced pressure to give compound 23c. ESI m / z 224.0 [M+H-56] + .LCMS:product:Rt=1.134min.

[0481] Step 3): Pyridine (5.49 mL, 68.02 mmol, 2 equivalents) was added to a solution of compound 23c (9.5 g, 34.01 mmol, 1 equivalent) in dichloromethane (150 mL). Then, trifluoromethanesulfonic anhydride (12.38 g, 43.87 mmol, 1.29 equivalents) dissolved in dichloromethane (15 mL) was added to the mixture at 0 °C. The mixture was stirred at 25 °C for 4 hours. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution (50 mL) and extracted with dichloromethane (2 × 40 mL). The combined organic phases were 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 = 3 / 1) to give compound 23d. ESI m / z 356.6 [M+H-56] + .LCMS:product:Rt=1.448min.

[0482] Step 4): Compound 23d (10 g, 24.31 mmol, 1 equivalent) was dissolved in N,N-dimethylformamide (60 mL), and bis[5-(diphenylphosphino)cyclopentadienyl]-λ2-iron(II)palladium chloride (1.42 g, 1.94 mmol, 0.08 equivalent), methanol (20 mL), and triethylamine (20 mL) were added. The mixture was stirred at 90 °C under carbon monoxide for 18 hours. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (2 × 40 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under vacuum to obtain a residue. The residue was then purified by column chromatography (petroleum ether / tert-butyl methyl ether = 1 / 0 to 3 / 2) to give compound 23e. ESI m / z 322.2 [M+H] + .LCMS:product:Rt=1.234min.

[0483] Step 5): Compound 23e (6 g, 18.67 mmol, 1 equivalent) was dissolved in a solution of dichloromethane (10 mL), and tribromoborane (13.82 mL, 27.63 mmol, 1.5 equivalent) dissolved in dichloromethane (10 mL) was added at 0 °C. The mixture was stirred at 25 °C for 2 hours. The reaction mixture was quenched with methanol (30 mL) and then concentrated under reduced pressure to give compound 23f. ESI m / z 194.0 [M+1] + .LCMS:product:Rt=0.314min.

[0484] Step 6): Compound 23f (3.5 g, 18.12 mmol, 1 equivalent) was dissolved in dichloromethane (10 mL), and di-tert-butyl dicarbonate (6.36 mL, 27.17 mmol, 1.5 equivalent) and triethylamine (7.53 mL, 54.35 mmol, 3 equivalent) were added. The mixture was stirred at 25 °C for 2 hours. The mixture was poured into water (200 mL) and then extracted with dichloromethane (100 mL × 3). The combined organic phases were washed with brine (100 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 23 g. ESI m / z 238.0 [M+H-56] + .LCMS:product:Rt=1.193min.

[0485] Step 7): 23 g (10 g, 30.88 mmol, 1 equivalent) of compound was dissolved in N,N-dimethylformamide (10 mL), and potassium bicarbonate (3.09 g, 30.88 mmol, 1 equivalent) and methyl iodide (1.15 mL, 18.53 mmol, 0.6 equivalent) were added. The mixture was stirred at 25 °C for 3 hours. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / tert-butyl methyl ether = 7 / 3) to give compound 23 h. ESI m / z 252.0 [M+H-56] + .LCMS:product:Rt=1.387min.

[0486] Step 8): Pyridine (1.18 mL, 14.61 mmol, 2.73 equivalents) was added to a solution of compound 23i (1.8 g, 5.35 mmol, 1 equivalent) in dichloromethane (8 mL). Then, trifluoromethanesulfonic anhydride (1.09 mL, 7.71 mmol, 1.44 equivalents) dissolved in dichloromethane (8 mL) was added to the mixture at 0 °C. The mixture was stirred at 20 °C for 4 hours. The reaction mixture was poured into water (60 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was then purified by rapid column chromatography (petroleum ether / tert-butyl methyl ether = 4 / 1) to give compound 23i. ESI m / z 384.0 [M+H-56] + .LCMS:product:Rt=1.423min.

[0487] Step 9): Add a mixture of dioxane (10 mL) and water (3 mL) of compound 23i (500 mg, 1.14 mmol, 1 equivalent), 3-(dihydroxyboryl)benzene-1-carboxaldehyde (341.24 mg, 2.28 mmol, 2 equivalents), to potassium phosphate (724.60 mg, 3.41 mmol, 3 equivalents) and bis[5-(diphenylphosphino)cyclopentadienyl]-λ2-iron(II)palladium chloride (83.26 mg, 0.11 mmol, 0.1 equivalents) at 25 °C. Stir the mixture at 100 °C for 16 hours. Quench the reaction mixture with ice water. Extract the mixture with ethyl acetate (3 × 20 mL). Wash the combined organic layers with saturated brine (60 mL), dry with anhydrous sodium sulfate, filter, and concentrate under vacuum to obtain the crude product. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give compound 23j. ESI m / z 340.2 [M+H-56] + .LCMS:product:Rt=1.362min.

[0488] Step 10): Compound 23j (273.70 mg, 0.69 mmol, 0.7 equivalence) was added to inter 6 (400 mg, 0.99 mmol, 1 equivalence) in a solution of dichloromethane (15 mL) at 25 °C, followed by the addition of acetic acid (0.06 mL, 0.99 mmol, 1 equivalence). The mixture was stirred at room temperature for 30 minutes. Sodium cyanoborohydride (186.40 mg, 2.97 mmol, 3 equivalence) was added, and stirring continued. The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was quenched with a saturated aqueous solution of sodium bicarbonate (50 mL) and extracted with dichloromethane (50 mL × 2). 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 / methyl tert-butyl ether = 1 / 0 to 1 / 3) to give compound 23k. ESI m / z 784.4 [M+H] + .LCMS:product:Rt=1.248min.

[0489] Step 11): Compound 23k (300 mg, 0.38 mmol, 1 equivalent) was added to N,N-dimethylformamide (10 mL), followed by potassium carbonate (158.65 mg, 1.15 mmol, 3 equivalent) and inter 5 (197.17 mg, 0.42 mmol, 1.1 equivalent) at 25 °C. The mixture was stirred at 25 °C for 16 hours. The mixture was poured into water (30 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (30 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 23k. ESI m / z 1171.6 [M+H] + .LCMS:product:Rt=1.553min.

[0490] Step 12): Compound 23l (200 mg, 0.17 mmol, 1 equivalent) was dissolved in a solution of methanol (3 mL) / tetrahydrofuran (3 mL) / water (3 mL), and lithium hydroxide monohydrate (71.63 mg, 1.71 mmol, 10 equivalent) was added. The reaction was carried out at 25 °C. The mixture was stirred at 50 °C for 16 hours. The mixture was concentrated under reduced pressure to remove methanol and tetrahydrofuran. The residue was poured into water (10 mL), acidified to pH 5 with 1 mol hydrochloric acid, and extracted with ethyl acetate (3 × 6 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 23m. ESI m / z 1157.4 [M+H] + .LCMS:product:Rt=1.478min.

[0491] Step 13): Compound 23m (200 mg, 0.17 mmol, 1 equivalent) was dissolved in trifluoroacetic acid (1 mL) / dichloromethane (5 mL) and stirred at 25 °C for 16 hours. The reaction mixture was concentrated and purified by preparative high-performance liquid chromatography (ammonium bicarbonate) to obtain compound 23. ESI m / z 745.4 [M+H] + .LCMS:product:Rt=0.712min. 1H NMR(400MHz,D2O)δ7.34(d,J=8,1Hz,2H),7.24(d,J=9.3Hz,5H),7.11(dd,J= 18.0,10.2Hz,6H),6.95(s,1H),4.16(s,2H),3.81(s,6H),3.42(t,J=6.1Hz,2 H),3.29(t,J=9.7Hz,4H),3.17-2.98(m,4H),2.68(ddd,J=34.9,17.0,7.1Hz ,6H),2.32(dd,J=14.2,6.8Hz,4H),2.00(d,J=3.7Hz,2H),1.72-1.47(m,2H).

[0492] Example 24: Synthesis of Compound 24

[0493] Step 1): Compound 15f1 (220 mg, 0.56 mmol, 1.0 equivalence) was dissolved in acetonitrile (10 mL), and bis(2,5-dioxopyrrolidone-1-yl) carbonate (245 mg, 0.96 mmol, 1.7 equivalence) and triethylamine (0.16 mL, 1.15 mmol, 2.0 equivalence) were added. The reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give compound 24a. ESI m / z 547.1 [M+Na] + .LCMS:product:Rt=1.33min.

[0494] Step 2): Compound 24a (300 mg, 0.57 mmol, 1.0 equivalence) was dissolved in 1,2-dichloroethane (15 mL), and Inter 6 (278 mg, 0.69 mmol, 1.2 equivalence), triethylamine (0.16 mL, 1.15 mmol, 2.0 equivalence), and 4-dimethylaminopyridine (7 mg, 0.06 mmol, 0.1 equivalence) were added. The reaction was stirred at 25 °C for 16 hours. The mixture was extracted with saturated sodium bicarbonate solution (20 mL) and dichloromethane (20 mL × 3). The organic phases 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 = 3 / 1) to give compound 24b. ESI m / z 714.4 [M-Boc+H] + .LCMS:product:Rt=1.66min.

[0495] Step 3): Compound 24b (200 mg, 0.25 mmol, 1.0 equivalence) was dissolved in N,N-dimethylformamide (8 mL), and sodium hydrogen hydrate (39 mg, 0.98 mmol, purity: 60%, 4.0 equivalence) was added. The mixture was stirred at 25 °C for 0.5 h. Then, inter 5 (138 mg, 0.29 mmol, 1.2 equivalence) was added, 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 column chromatography (petroleum ether / tert-butyl methyl ether = 1 / 1) to give compound 24c. ESI m / z 1101.6 [M-Boc+H] + .LCMS:product:Rt=2.24min.

[0496] Step 4): Compound 24c (180 mg, 0.23 mmol, 1.0 equivalent) was dissolved in a solution of tetrahydrofuran (5 mL), methanol (5 mL), and water (5 mL), and lithium hydroxide monohydrate (45 mg, 1.07 mmol, 10.0 equivalent) 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 6 with 1 M HCl, and extracted with ethyl acetate (3 × 10 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 24d. ESI m / z 1087.6 [M+H] + .LCMS:product:Rt=2.09min.

[0497] Step 5): Compound 24d (160 mg, 0.13 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 (ammonium bicarbonate) to obtain compound 24. ESI m / z 775.4 [M+H] + .LCMS:product:Rt=1.01min; 1H NMR(400MHz,D2O)δ7.40(s,1H),7.33(d,J=6.4Hz,2H),7.24–7.12(m,3H),7. 06(s,2H),6.97(d,J=16.3Hz,4H),6.86(d,J=24.0Hz,2H),5.13(d,J=3.7Hz,2 H),4.60(s,2H),4.46(s,2H),4.38(s,4H),3.29(s,3H),3.14(d,J=9.5Hz,3H) ,2.66(dd,J=39.9,30.7Hz,5H),2.43–2.18(m,5H),1.99(s,2H),1.61(s,2H).

[0498] Example 25: Synthesis of Compound 25

[0499] Step 1): At -78°C, a tetrahydrofuran solution (4.21 mL, 4.21 mmol, 3 equivalents) of diisobutylaluminum hydride was added to an inter 1 (500 mg, 1.40 mmol, 1 equivalent) solution of tetrahydrofuran (10 mmol). The mixture was stirred at 25°C for 4 hours under nitrogen. The reaction mixture was quenched with sodium sulfate decahydrate and methanol, filtered, and concentrated under vacuum to give compound 25a. ESI m / z 274.0 [M+H-56] + .LCMS:product:Rt=1.372min.

[0500] Step 2): To a solution of acetonitrile (5 mL) containing compound 25a (230 mg, 0.70 mmol, 1 equivalent), bis(2,5-dioxopyrrolidone-1-yl) carbonate (215.42 mg, 0.84 mmol, 1.2 equivalent) and triethylamine (0.19 mL, 1.40 mmol, 2 equivalent) were added, and the mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give compound 25b. ESI m / z 491.0 [M+23] + .LCMS:product:Rt=1.446min.

[0501] Step 3): To a solution of compound 25b (300 mg, 0.64 mmol, 1 equivalent) in dichloroethane (10 mL), inter 6 (310.34 mg, 0.77 mmol, 1.2 equivalent), 4-dimethylpyridine (7.81 mg, 0.06 mmol, 0.1 equivalent), and triethylamine (0.18 mL, 1.28 mmol, 2 equivalent) were added, and the mixture was stirred at 25 °C for 4 hours. The mixture was poured into water (10 mL) and extracted with dichloromethane (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 / methyl tert-butyl ether = 1 / 2) to give compound 25c. ESI m / z 658.2 [M-100] + .LCMS:product:Rt=1.650min.

[0502] Step 4): Compound 25c (430 mg, 0.57 mmol, 1 equivalent) was added to a mixed solution of N,N-dimethylformamide (6 mL), methanol (2 mL), and triethylamine (2 mL), followed by [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (62.20 mg, 0.09 mmol, 0.15 equivalent). The mixture was stirred at 90 °C under a carbon monoxide atmosphere for 16 hours. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (2 × 40 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the residue. The residue was then purified by rapid column chromatography (petroleum ether / tert-butyl methyl ether = 1 / 0 to 3 / 2) to give compound 25d. ESI m / z 760.3 [M+23] + .LCMS:product:Rt=1.599min.

[0503] Step 5): Sodium hydride (65.05 mg, 1.63 mmol, 5 equivalents) and inter 5 (335.19 mg, 0.72 mmol, 2.2 equivalents) were added to a solution of compound 25d (240 mg, 0.33 mmol, 1 equivalent) in N,N-dimethylformamide (10 mL), and the mixture was stirred at 25 °C for 2 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 (dichloromethane:methanol = 10:1) to give compound 25e. ESI m / z 1012.6 [M-100] + .LCMS:product:Rt=2.123min.

[0504] Step 6): Add 3 mL of trifluoroacetic acid to a solution of compound 25e (400 mg, 0.36 mmol, 1 equivalent) in dichloromethane (3 mL), and stir the mixture at 25 °C for 18 hours. Concentrate the resulting reaction mixture and purify it by preparative high-performance liquid chromatography (ammonium bicarbonate) to obtain compound 25. ESI m / z 699.3 [M+H] + .LCMS:product:Rt=0.603min. 1 H NMR(400MHz,D2O)δ7.45-6.74(m,10H),5.42-5.21(m,2H),4.70-4.62(m,2H),4.53-4.35(m, 6H), 3.32 (d, J = 17.4Hz, 4H), 3.11 (s, 2H), 2.97-2.62 (m, 6H), 2.47-1.95 (m, 6H), 1.53 (s, 2H).

[0505] Example 26: Synthesis of Compound 26

[0506] Step 1): Compound 26a (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 26b. ESI m / z = 414.2 [M+H] + .LCMS:product:Rt=1.180min.

[0507] Step 2): Compound 26b (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 26c. ESI m / z = 149.7 [M+H] + .LCMS:product:Rt=0.252min.

[0508] Step 3): Compound 26c (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 obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 40 / 1) to obtain compound 26d. ESI m / z = 250.2 [M+H] + .LCMS:product:Rt=0.698min.

[0509] Step 4): Compound 26d (2 g, 6.43 mmol, 1.0 equivalent) was dissolved in acetonitrile (30 mL), and N-bromosuccinimide (1.5 g, 8.43 mmol, 1.2 equivalent) 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 26e. ESI m / z = 328.0 [M+H] + .LCMS:product:Rt=1.065min.

[0510] Step 5): Compound 26e (1.4 g, 4.04 mmol, 1.0 equivalent) 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 equivalent) 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 26f. ESI m / z = 308.2 [M+H] + .LCMS:product:Rt=0.905min.

[0511] Step 6): Compound 26f (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 26 g. ESI m / z = 327.2 [M+H] + .LCMS:product:Rt=1.224min.

[0512] Step 7): 26 g (290 mg, 0.72 mmol, 1.0 equivalent) 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 equivalent), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (63 mg, 0.09 mmol, 0.1 equivalent), and potassium phosphate (541 mg, 2.55 mmol, 3.0 equivalent). 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 26h. ESI m / z = 397.2 [M+H] + .LCMS:product:Rt=1.417min.

[0513] Step 8): Compound 26h (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 26i. ESI m / z = 785.4 [M+H] + .LCMS:product:Rt=1.248min.

[0514] Step 9): Compound 26i (220 mg, 0.28 mmol, 1.0 equivalence) was dissolved in N,N-dimethylformamide (3 mL), and Inter 5 (131 mg, 0.28 mmol, 1.0 equivalence) and potassium carbonate (77 mg, 0.56 mmol, 2.0 equivalence) were added. The reaction mixture was stirred at 25 °C for 16 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 obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 3 / 1) to obtain compound 26j. ESI m / z = 1172.6 [M+H] + .LCMS:product:Rt=1.652min.

[0515] Step 10): Compound 26J (250 mg, 0.21 mmol, 1.0 equivalence) was dissolved in tetrahydrofuran (1.5 mL) and methanol (1.5 mL), and lithium hydroxide (4 M in H2O, 3 mL, 12.00 mmol, 57.0 equivalence) was added. The reaction mixture was stirred at 50 °C for 16 hours. The pH of the reaction mixture was adjusted to 7 with 1 M hydrochloric acid aqueous solution. The reaction mixture was diluted with H2O (50 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give compound 26K. ESI m / z = 1158.6 [M+H] + .LCMS:product:Rt=1.600min.

[0516] Step 11): Compound 26k (190 mg, 0.13 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 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 (ammonium bicarbonate) to obtain compound 26. ESI m / z = 746.3 [M+H] + .LCMS:product:Rt=1.018min. 1H NMR(400MHz,D2O)δ7.66(s,1H),7.42(ddd,J=32.1,18.3,7.6Hz,4H),7.27(t, J=7.7Hz,2H),7.21–7.13(m,6H),4.34(s,2H),3.81(d,J=12.8Hz,6H),3.53(t, J=6.4Hz,2H),3.30(ddd,J=12.3,10.2,5.6Hz,4H),3.13(q,J=11.7,9.8Hz,4H ),2.84–2.64(m,6H),2.44–2.30(m,4H),2.09–1.96(m,2H),1.71–1.57(m,2H).

[0517] Example 27: Synthesis of Compound 27

[0518] Step 1): At 25°C, azobisisobutyronitrile (1.91 g, 11.64 mmol, 0.2 equivalence) was added to a solution of dichloroethane (200 mL) containing compound 27a (10.8 g, 58.19 mmol, 1.0 equivalence) and N-bromosuccinimide (16.57 g, 93.10 mmol, 1.6 equivalence). The reaction mixture was stirred at 80°C for 2 hours. After the reaction was complete, the resulting reaction mixture was filtered and concentrated under reduced pressure to obtain compound 27b. ESI m / z 343.8 [M+H] + .LCMS:product:Rt=1.405min.

[0519] Step 2): At 25°C, N,N-diisopropylethylamine (20.4 mL, 116.5 mmol, 2.0 equivalence) and diethyl phosphite (3.7 mL, 29.12 mmol, 0.5 equivalence) were added to a 300 mL solution of tetrahydrofuran containing compound 27b (20.0 g, 58.24 mmol, 1.0 equivalence). The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give compound 27c. ESI m / z 266.0 [M+H] + .LCMS:product:Rt=1.081min.

[0520] Step 3): At 0°C, trimethylcyanosilane (16.9 g, 170.1 mmol, 5.0 equivalent) was slowly added dropwise to a methanol (150 mL) solution containing compound 27c (9.00 g, 34.03 mmol, 1.0 equivalent) and potassium fluoride (9.88 g, 170.1 mmol, 5.0 equivalent). The reaction mixture was heated to 25°C and stirred at this temperature for 12 hours. After the reaction was complete, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was diluted with ethyl acetate (200 mL) and water (100 mL). After separating the aqueous phase, the aqueous phase was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and then 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 petroleum ether / ethyl acetate (0-50%) to give compound 27d. ESI m / z 210.9 [M+H] + .LCMS:product:Rt=0.825min. 1 H NMR (400MHz, CDCl3) δ7.98 (dd, J=8.3, 0.7Hz, 1H), 7.59 (d, J=8.3Hz, 1H), 4.26 (s, 2H), 4.01 (s, 3H).

[0521] Step 4): Compound 27d (5.00 g, 22.55 mmol, 1.0 equivalent) and cobalt chloride hexahydrate (18.8 g, 78.93 mmol, 3.5 equivalent) were dissolved in methanol (100 mL). Sodium borohydride (3.84 g, 101.5 mmol, 4.5 equivalent) was added in portions at 0 °C. The reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was filtered, and the filter cake was washed with dichloromethane / methanol = 10:1 (200 mL). The filtrate was concentrated under reduced pressure to remove most of the solvent. The residue was diluted with dichloromethane / methanol = 10:1 (100 mL) and washed with saturated brine (60 mL). The aqueous phase was extracted with dichloromethane / methanol = 10:1 (100 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 / methanol (0-15%) to give compound 27e. ESI m / z 182.9 [M+H] + .LCMS:product:Rt=0.633min. 1 H NMR (400MHz, DMSO-d6) δ8.27(s,1H),7.86(d,J=8.1Hz,1H),7.60(d,J=8.1Hz,1H),3.45–3.35(m,2H),3.01–2.91(m,2H).

[0522] Step 5): At 0°C, boranetetrahydrofuran (34.4 mL, 34.41 mmol, 3.0 equivalent) (1 M tetrahydrofuran solution) was added dropwise to a tetrahydrofuran (20 mL) solution containing compound 27e (2.38 g, 11.47 mmol, 1.0 equivalent). The reaction mixture was stirred at 80°C for 1 hour. The reaction mixture was quenched with methanol (20 mL) at 0°C. The mixture was concentrated to obtain a residue. The residue was dissolved in methanol (40 mL) and concentrated hydrochloric acid (10 mL) and stirred at 80°C for 1 hour. Then, it was concentrated under reduced pressure to obtain compound 27f. ESI m / z 169.0 [M+H] + .LCMS:product:Rt=0.208min.

[0523] Step 6): Compound 27f (1.93 g, 11.45 mmol, 1.0 equivalence) and triethylamine (4.8 mL, 34.34 mmol, 3.0 equivalence) were dissolved in dichloromethane (40 mL), followed by the addition of di-tert-butyl carbonate (3.75 g, 17.17 mmol, 1.5 equivalence). The reaction mixture was stirred at 25 °C for 12 hours. The reaction mixture was diluted with dichloromethane (30 mL) and water (50 mL). After separation of the aqueous phase, the aqueous phase was extracted with dichloromethane (30 mL × 3). 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 to obtain the residue. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (0–16%) as eluent to obtain compound 27 g. ESI m / z 269.0 [M+H] + .LCMS:product:Rt=1.192min. 1 H NMR (400MHz, CDCl3) δ7.41(d,J=8.1Hz,1H),7.14(d,J=8.0Hz,1H),4.64(d,J=1.2Hz,2H),3.68(t,J=5.8Hz,2H),2.81(t,J=5.9Hz,2H),1.48(s,9H).

[0524] Step 7): 27 g (780 mg, 2.76 mmol, 1.0 equivalent) of compound, diphenyl ketone imine (900 mg, 4.96 mmol, 1.8 equivalent), 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene (478.6 mg, 0.83 mmol, 0.3 equivalent), tris(dibenzyl indeneacetone)dipalladium (378.74 mg, 0.41 mmol, 0.15 equivalent), and cesium carbonate (2.25 g, 6.89 mmol, 2.5 equivalent) were dissolved in dioxane (15 mL). After vacuum deoxygenation, the mixture was backfilled three times with nitrogen. Under nitrogen protection, the reaction solution was stirred at 110 °C for 12 hours. After the reaction was complete, the reaction solution was diluted with dichloromethane (30 mL) and filtered. The filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography, eluting with a petroleum ether / ethyl acetate (0-20%) gradient to give the compound for 27 h. ESI m / z 414.2 [M+H] + .LCMS:product:Rt=1.308min.

[0525] Step 8): Compound 27i (1.45 g, 2.66 mmol, 1.0 equivalence) was dissolved in methanol (20 mL), and hydroxylamine hydrochloride (0.56 g, 7.99 mmol, 3.0 equivalence) and sodium acetate (0.77 g, 9.33 mmol, 3.5 equivalence) were added. The reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to remove most of the solvent. The residue was diluted with dichloromethane (30 mL) and washed successively with saturated sodium bicarbonate aqueous solution (10 mL) and saturated brine (10 mL). The organic phase was 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 / methanol (0-4%) to give compound 27i. ESI m / z 250.1 [M+H] + .LCMS:product:Rt=0.683min. 1 H NMR (400MHz, CDCl3) δ7.24(d,J=8.3Hz,1H),6.39(d,J=8.3Hz,1H),4.85(s,2H),4.50(s,2H),3.64(t,J=5.7Hz,2H),2.68(t,J=5.9Hz,2H),1.49(s,9H).

[0526] Step 9): N-bromosuccinimide (391 mg, 2.19 mmol, 1.2 equivalence) was added fractionally to an acetonitrile (5 mL) solution containing compound 27i (480 mg, 1.83 mmol, 1.0 equivalence). The reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was quenched with saturated sodium bicarbonate (5 mL) and saturated sodium sulfite (5 mL). The aqueous phase was extracted with dichloromethane (10 mL × 3). The combined organic phases were washed with saturated brine (10 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 using dichloromethane / methanol (0–3%) as eluent to obtain compound 27j. ESI m / z 328.0, 330.0 [M+H] + .LCMS:product:Rt=1.067min. 1 H NMR (400MHz, CDCl3) δ7.51 (s, 1H), 5.31–5.07 (m, 2H), 4.49 (s, 2H), 3.64 (t, J = 5.8Hz, 2H), 2.70 (t, J = 5.9Hz, 2H), 1.49 (s, 9H).

[0527] Step 10): Compound 27j (600 mg, 1.55 mmol, 1.0 equivalent), (3-formylphenyl)boronic acid (302.89 mg, 2.02 mmol, 1.3 equivalent), potassium phosphate (989.50 mg, 4.66 mmol, 3.0 equivalent), and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (113.70 mg, 0.16 mmol, 0.1 equivalent) were mixed in dioxane (10 mL) and water (2 mL), degassed, and backfilled with nitrogen three times. The reaction solution was stirred at 90 °C for 2 hours under nitrogen protection. After the reaction was completed, the reaction solution was diluted with dichloromethane (20 mL) and water (10 mL). The aqueous phase was separated and extracted with dichloromethane (10 mL × 3). The combined organic phases were washed with saturated brine (10 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 a dichloromethane / methanol (0-3%) gradient to give compound 27K. ESI m / z 354.1 [M+H] + .LCMS:product:Rt=0.867min. 1 H NMR (400MHz, CDCl3) δ10.08(s,1H),7.98–7.89(m,2H),7.76–7.49(m,3H),4.72–4.51(m,2H),3.77–3.66(m,2H),2.81–2.67(m,2H),1.51(s,9H).

[0528] Step 11): Compound 27K (500 mg, 1.32 mmol, 1.0 equivalent) and cuprous bromide (283 mg, 1.97 mmol, 1.5 equivalent) were dissolved in acetonitrile (10 mL), and tert-butyl nitrite (271 mg, 2.63 mmol, 2.0 equivalent) was added. The reaction mixture was stirred at 70 °C for 3 hours. Then, cuprous bromide (283 mg, 1.97 mmol, 1.5 equivalent) and tert-butyl nitrite (271 mg, 2.63 mmol, 2.0 equivalent) were added again. The reaction mixture was stirred at 70 °C for another 12 hours. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution (10 mL) and dichloromethane (10 mL). The mixture was filtered, and the aqueous phase was separated and extracted with dichloromethane (10 mL × 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (0-24%) as eluent to give compound 27l. ESI m / z 417.0, 419.0 [M+H] + .LCMS:product:Rt=1.300min.

[0529] Step 12): Compound 27l (140 mg, 0.33 mmol, 1.0 equivalent), triethylamine (101 mg, 1.00 mmol, 3.0 equivalent), and 1,1'-bis(diphenylphosphine)ferrocene palladium(II) dichloride (72.91 mg, 0.10 mmol, 0.3 equivalent) were dissolved in methanol (10 mL). The reaction solution was degassed and purged three times with carbon monoxide. The reaction solution was stirred at 80 °C for 12 hours under a carbon monoxide atmosphere of 15 psi. The reaction solution was concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (0-26%) to give compound 27m. ESI m / z 397.1 [M+H] + .LCMS:product:Rt=1.158min.

[0530] Step 13): Compound 27m (76.0 mg, 0.19 mmol, 1.0 equivalence), inter 6 (93.1 mg, 0.23 mmol, 1.2 equivalence), and acetic acid (11.5 mg, 0.19 mmol, 1.0 equivalence) were dissolved in dichloroethane (5 mL). The reaction mixture was stirred at 45 °C for 10 minutes. Then, sodium borohydride acetate (122 mg, 0.580 mmol, 3.0 equivalence) was added. The reaction mixture was stirred at 45 °C for 1 hour. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution (5 mL). After separating the aqueous phase, the aqueous phase was extracted with dichloromethane (5 mL × 3). The combined organic phases were washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. Compound 27n was obtained by purification of the crude product by preparative thin-layer chromatography (dichloromethane / methanol = 20:1, v / v). ESI m / z 785.4 [M+H] + .LCMS:product:Rt=1.180min.

[0531] Step 14): Compound 27n (120 mg, 0.15 mmol, 1.0 equivalence), inter 4 (135 mg, 0.33 mmol, 2.3 equivalence), and acetic acid (8.72 mg, 0.15 mmol, 1.0 equivalence) were dissolved in dichloroethane (5 mL) and stirred at 45 °C for 10 min. Subsequently, sodium acetate borohydride (92.3 mg, 0.44 mmol, 3.0 eq) was added. The reaction mixture was stirred at 45 °C for 1 h. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution (5 mL). The aqueous phase was separated and extracted with dichloromethane (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 preparative thin-layer chromatography (dichloromethane / methanol = 20:1) to obtain compound 27o. ESI m / z 1172.6 [M+H] + .LCMS:product:Rt=1.524min.

[0532] Step 15): To a mixed solution containing 2 mL of tetrahydrofuran, 2 mL of methanol, and 2 mL of water (155 mg, 0.12 mmol, 1.0 equivalence), lithium hydroxide monohydrate (29.3 mg, 0.70 mmol, 6.0 equivalence) was added. The reaction solution was stirred at 50 °C for 3 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to remove most of the solvent. The aqueous phase was diluted with 10 mL of dichloromethane and 2 mL of water, and acidified with hydrochloric acid (1 M) to pH 5-6. After separating the aqueous phase, it 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 give compound 27p. ESI m / z 1158.6 [M+H] + .LCMS:product:Rt=1.469min.

[0533] Step 16): Compound 27p (150 mg, 0.10 mmol, 1.0 equivalence) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (3 mL) was added. The reaction solution was stirred at 45 °C for 2 hours. The reaction solution was then concentrated under reduced pressure to obtain the residue. The residue was purified by preparative high-performance liquid chromatography (preparative HPLC, mobile phase containing formic acid) to obtain compound 27. ESI m / z 746.3 [M+H] + .LCMS:product:Rt=1.099min. 1 H NMR(400MHz,D2O)δ7.39(s,1H),7.35–7.27(m,2H),7.26–7.16(m,4H),7.10–7.04(m,6H),4.21(s,2H),3.69–3.50(m,6H),3.37–3.19(m,6 H),3.13–3.04(m,2H),2.97–2.88(m,2H),2.73–2.64(m,4H),2.61–2.53(m,2H),2.37–2.24(m,4H),2.03–1.93(m,2H),1.66–1.54(m,2H).

[0534] Example 28: Synthesis of Compound 28

[0535] Step 1): To an ethanol (30 mL) solution containing compound 28a (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 reaction solution was filtered, and the filter cake was washed with ethyl acetate (50 mL). The combined filtrates were 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 under reduced pressure to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 1 / 1) to give compound 28b. ESI m / z 327.2 [M+H] + .LCMS:product:Rt=1.310min.

[0536] Step 2): At 0°C, cuprous bromide (5.33 g, 37.14 mmol, 1.5 equivalence) was added to a 100 mL solution of acetonitrile containing tert-butyl nitrite (5.89 mL, 49.52 mmol, 2.0 equivalence). The mixture was stirred at 0°C for 1 hour. Subsequently, compound 28b (8.35 g, 24.76 mmol, 1.0 equivalence) was added in portions at 0°C. The mixture was stirred at room temperature for 2 hours. The mixture was diluted with water (200 mL) and then extracted with ethyl acetate (80 mL × 3). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, 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 = 5 / 1) to give compound 28c. ESI m / z 291.9 [M-Boc+H] + .LCMS:product:Rt=1.573min.

[0537] Step 3): To a mixed solvent containing 3 mL of dioxane (300 mg, 0.55 mmol, 1.0 equivalence) and 0.6 mL of water, add (3-formylphenyl)boronic acid (123 mg, 0.82 mmol, 1.5 equivalence), potassium phosphate (348 mg, 1.64 mmol, 3.0 equivalence), and 1,1-bis(diphenylphosphine)diberberine palladium dichloride (40 mg, 0.05 mmol, 0.1 equivalence). The mixture was stirred at 90 °C for 16 hours under nitrogen protection. The reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (8 mL x 3). The combined organic phases were washed with saturated brine (20 mL), 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 / 1) to give compound 28d. ESI m / z 316.2 [M-Boc+H] + .LCMS:product:Rt=1.450min.

[0538] Step 4): To a solution of compound 28d (148 mg, 0.30 mmol, 0.5 equivalence) in dichloromethane (5 mL), add compound 11d (250 mg, 0.61 mmol, 1.0 equivalence), sodium triacetoxyborohydride (386 mg, 1.82 mmol, 3.0 equivalence), and acetic acid (0.1 mL). Stir the mixture at room temperature for 2 hours. Then add compound 28d (118 mg, 0.24 mmol, 0.4 equivalence), and stir the reaction mixture at room temperature for 2 hours. Quench the reaction mixture with saturated sodium bicarbonate aqueous solution (10 mL) and extract with dichloromethane (8 mL × 2). Wash the combined organic layers with saturated brine (20 mL), dry to anhydrous sodium sulfate, and filter. Concentrate the filtrate under reduced pressure. Purify the residue by silica gel column chromatography (dichloromethane / ethyl acetate = 1 / 1) to give compound 28e. ESI m / z 811.4 [M+H] + .LCMS:product:Rt=1.290min.

[0539] Step 5): To a solution of N,N-dimethylformamide (5 mL) containing compound 28e (380 mg, 0.47 mmol, 1.0 equivalence), add inter 5 (262 mg, 0.56 mmol, 1.2 equivalence) and potassium carbonate (193 mg, 1.40 mmol, 3.0 equivalence). Stir the mixture at room temperature for 16 hours. Dilute the reaction solution with water (15 mL) and extract with ethyl acetate (8 mL × 3). Wash the combined organic phases with saturated brine (40 mL × 3), dry with 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 = 1 / 1) to give compound 28f. ESI m / z 550.0 [(M-Boc) / 2+H] + .LCMS:product:Rt=2.174min.

[0540] Step 6): Lithium hydroxide (107 mg, 2.54 mmol, 10.0 equivalent) was added to a mixed solution containing compound 28f (418 mg, 0.25 mmol, 1.0 equivalent) of methanol (2 mL), tetrahydrofuran (2 mL), and water (2 mL). The reaction mixture was stirred at 60 °C for 18 hours. The reaction mixture was concentrated under reduced pressure. The residue was added to water (10 mL), acidified to pH 5 with 1 M hydrochloric acid aqueous solution, and extracted with ethyl acetate (2 × 6 mL). The combined organic phases were 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 compound 28 g. ESI m / z 1192.4 [M + Na] + .LCMS:product:Rt=2.044min.

[0541] Step 7): 28 g (256 mg, 0.17 mmol, 1.0 equivalence) of compound 28 was dissolved in a mixed solution of dichloromethane (3 mL) and trifluoroacetic acid (3 mL). The mixture was stirred at room temperature for 5 hours. The reaction solution was concentrated and purified by preparative high-performance liquid chromatography (formic acid) to obtain compound 28. ESI m / z 759.3 [M+H] + .LCMS:product:Rt=1.035min. 1H NMR(400MHz,D2O)δ7.46(d,J=6.4Hz,2H),7.38(t,J=7.8Hz,1H),7.30(dd,J=15.5,7.7Hz ,2H),7.21(d,J=18.7Hz,3H),7.15(s,1H),4.38(s,2H),4.23(s,2H),4.07(d,J=5.9Hz,4 H),3.50(t,J=6.2Hz,2H),3.45–3.26(m,4H),3.15(p,J=9.0Hz,2H),2.99–2.65(m,8H),2 .53(td,J=9.8,4.9Hz,1H),2.39(h,J=8.8Hz,3H),2.08–2.01(m,2H),1.76–1.57(m,2H).

[0542] Example 29: Synthesis of Compound 29

[0543] Step 1): Compound 29a (5.0 g, 52.57 mmol, 1.0 equivalent) was dissolved in ethylene glycol dimethyl ether (250 mL), and ethyl 3-bromo-2-oxopropionate (12.3 g, 63.09 mmol, 1.2 equivalent) was added. The mixture was stirred at 0 °C for 0.5 h until a solid precipitated. The reaction mixture was filtered, and the filter cake was washed with diethyl ether (10 mL × 3). The solid was dissolved in 250 mL of anhydrous ethanol and reacted under reflux for 4 h. The reaction mixture was concentrated under reduced pressure, and 100 mL of dichloromethane was added. The mixture was washed successively with saturated sodium carbonate solution (200 mL) and saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 29b. ESI m / z 192.1 [M+H] + .LCMS:product:Rt=0.678min.

[0544] Step 2): 5% Pd / C (456.4 mg, 4.29 mmol, 1.0 equivalent) was added to a methanol (10 mL) solution of compound 29b (1.5 g, 6.43 mmol, 1.0 equivalent). The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 18 hours. The suspension was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate (20 mL), and the filtrate was concentrated under reduced pressure to give compound 29c. ESI m / z 196.1 [M+H] + .LCMS:product:Rt=0.218min.

[0545] Step 3): Compound 29c (800.0 mg, 4.10 mmol, 1.0 equivalence) was added to tetrahydrofuran (20 mL), followed by triethylamine (0.57 mL, 4.10 mmol, 1.0 equivalence) and di-tert-butyl carbonate (894.3 mg, 4.10 mmol, 1.0 equivalence). The mixture was stirred at room temperature for 3 hours. The mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain compound 29d. ESI m / z 296.2 [M+H] + .LCMS:product:Rt=1.152min. 1 H NMR (400MHz, CDCl3) δ7.58(s,1H),4.75(s,2H),4.39(q,J=7.2Hz,2H),4.07(t,J= 5.6Hz, 2H), 3.90 (t, J = 5.2Hz, 2H), 1.50 (d, J = 6.0Hz, 12H), 1.41 (t, J = 7.2Hz, 3H).

[0546] Step 4): Compound 29d (730.1 mg, 2.47 mmol, 1.0 equivalence) was dissolved in N,N-dimethylformamide (5 mL), and N-bromosuccinimide (571.9 mg, 3.21 mmol, 1.3 equivalence) was added. The 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 (30 mL × 3) and dried over anhydrous sodium sulfate, then concentrated under reduced pressure to give the crude product. The residue was purified by rapid column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 29e. ESI m / z 374.0 [M+H] + .LCMS:product:Rt=1.391min.

[0547] Step 5): Compound 29e (560.2 mg, 1.50 mmol, 1.0 mg, etc.) was dissolved in a 3 / 1 (10 mL) mixture of dioxane / water. 3-(dihydroxyboryl)benzaldehyde (336.5 mg, 2.24 mmol, 1.5 mg, etc.), dichloro[1,1'-bis(diphenylphosphine)ferrocene]palladium (109.4 mg, 0.15 mmol, 0.1 mg, etc.), and potassium phosphate (635.2 mg, 2.99 mmol, 2.0 mg, etc.) were added. The mixture was stirred at 90 °C for 3 hours. The mixture was poured into water (50 mL) and then extracted with ethyl acetate (3 × 40 mL). The combined organic phases were washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by rapid column chromatography (petroleum ether / ethyl acetate = 1 / 3) to obtain compound 29f. ESI m / z 400.2 [M+H] + .LCMS:product:Rt=1.114min.

[0548] Step 6): Sodium triacetoxyborohydride (955.0 mg, 4.51 mmol, 6.0 equivalence) was added to a solution of compound 29f (300.0 mg, 0.75 mmol, 1.0 equivalence) and inter 6 (364.6 mg, 0.90 mmol, 1.2 equivalence) in dichloromethane (6 mL). The reaction mixture was stirred at room temperature for 18 hours. The mixture was poured into water (30 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with saturated brine (30 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 29 g. ESI m / z 788.4 [M+H] + .LCMS:product:Rt=1.139min.

[0549] Step 7): To a solution of 29 g (0.2 g, 0.25 mmol, 1.0 equivalence) of compound N,N-dimethylformamide (2 mL), add Inter 5 (178.3 mg, 0.38 mmol, 1.5 equivalence) and potassium carbonate (70.1 mg, 0.51 mmol, 2.0 equivalence). The reaction mixture was stirred at room temperature for 4 hours. The mixture was poured into water (40 mL) and extracted with ethyl acetate (3 times × 20 mL). The combined organic layers were washed with saturated brine (30 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 / methyl tert-butyl ether = 1 / 5) to give compound 29 h. ESI m / z 1198.6 [M + Na] + .LCMS:product:Rt=1.466min.

[0550] Step 8): Compound 29h (0.2 g, 0.17 mmol, 1.0 equivalence) was dissolved in methanol (1 mL) and tetrahydrofuran (1 mL), and lithium hydroxide monohydrate (35.6 mg, 0.85 mmol, 5.0 equivalence) and water (1 mL) were added. The reaction mixture was stirred at 60 °C for 6 hours. The resulting reaction mixture was neutralized to pH 3 with dilute hydrochloric acid. The mixture was extracted with ethyl acetate (30 mL × 3), and the organic phase was concentrated under reduced pressure to give compound 29i. ESI m / z 1169.6 [M + Na] + .LCMS:product:Rt=1.392min.

[0551] Step 9): Compound 29i (180.2 mg, 0.16 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 16 hours. The resulting reaction mixture was concentrated and purified by a purifying liquid chromatography (ammonium bicarbonate) to obtain compound 29. ESI m / z 368.3 [M / 2+H] + .LCMS:product:Rt=1.039min. 1 H NMR(400MHz,D2O)δ7.49(t,J=7.6Hz,1H),7.42(d,J=7.6Hz,1H),7.39–7.29(m,3H),7. 21(dd,J=12.8,8.4Hz,7H),4.17(s,6H),4.06(s,2H),3.69(s,2H),3.45(dd,J=11.6,6 .8Hz,2H),3.34(ddd,J=11.6,8.5,3.6Hz,2H),3.23–3.11(m,4H),2.96–2.87(m,2H),2 .72(d,J=6.4Hz,4H),2.41(d,J=13.6Hz,4H),2.05(d,J=4.0Hz,2H),1.74–1.58(m,2H).

[0552] Example 30: Synthesis of Compound 30

[0553] Step 1): Compound 3f (250.1 mg, 0.68 mmol, 1.0 equivalent) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborane) (342.94 mg, 1.35 mmol, 2.0 equivalent) were dissolved in 1,4-dioxane (20 mL), followed by the addition of dichloro[1,1'-bis(diphenylphosphine)ferrocene]palladium (49.4 mg, 0.07 mmol, 0.1 equivalent) and potassium acetate (198.80 mg, 2.03 mmol, 3.0 equivalent). The mixture was purged three times with nitrogen, then heated to 100 °C under reflux and stirred for 3 hours. The organic phase was concentrated under vacuum. The crude product was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 0 / 1) to give compound 30c. ESI m / z 418.4 [M+H] + .LCMS:product:Rt=1.404min.

[0554] Step 2): Dissolve inter 6 (230 mg, 0.57 mmol, 1.0 equivalence) in dichloromethane (5 mL), add compound 30a (105.75 mg, 0.57 mmol, 1.0 equivalence) and sodium triacetoxyborohydride (180.74 mg, 0.85 mmol, 1.5 equivalence). Stir the reaction mixture at room temperature for 1 hour. Pour the mixture into water (30 mL) and extract with ethyl acetate (30 mL × 3). Wash the combined organic layers with brine (30 mL × 3), dry with sodium sulfate, and concentrate under reduced pressure to obtain the crude product. Purify the crude product by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 9) to give compound 30b. ESI m / z 574.2 [M+H] + .LCMS:product:Rt=1.369min.

[0555] Step 3): Compound 30c (160 mg, 0.28 mmol, 1.0 equivalence) was dissolved in 1,4-dioxane (3 mL) and water (1 mL). Compound 30b (116.21 mg, 0.28 mmol, 1.0 equivalence), potassium carbonate (76.97 mg, 0.56 mmol, 2.0 equivalence), and dichloro[1,1'-bis(diphenylphosphine)ferrocene]palladium (20.38 mg, 0.03 mmol, 0.1 equivalence) were added. The reaction mixture was stirred at 90 °C under a nitrogen atmosphere for 2 hours. The mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with saturated brine (10 mL × 3), dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 3) to obtain compound 30d. ESI m / z 784.8 [M+H] +.LCMS:product:Rt=1.527min.

[0556] Step 4): Compound 30d (0.14 g, 0.18 mmol, 1.0 equivalence) was dissolved in N,N-dimethylformamide (5 mL), and inter5 (125.3 mg, 0.27 mmol, 1.5 equivalence) and potassium carbonate (49.2 mg, 0.36 mmol, 2.0 equivalence) were added. 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 combined organic phases were washed with saturated brine (40 mL × 3), 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 / methyl tert-butyl ether = 1 / 5) to give compound 30e. ESI m / z 1173.6 [M-Boc+H] + .LCMS:product:Rt=1.511min.

[0557] Step 5): To a solution of compound 30e (0.12 g, 0.10 mmol, 1.0 equivalence) in methanol (2 mL) and tetrahydrofuran (2 mL), lithium hydroxide monohydrate (25.7 mg, 0.6 mmol, 6.0 equivalence) and water (2 mL) were added. The reaction mixture was stirred at 60 °C for 18 hours. The resulting reaction mixture was neutralized to pH 3 with 10% aqueous hydrochloric acid. The mixture was extracted with ethyl acetate (30 mL × 3), and the organic phase was concentrated under reduced pressure to give compound 30f. ESI m / z 451.8 [M-Boc-Boc-56+H] + .LCMS:product:Rt=1.604min.

[0558] Step 6): Add 2 mL of trifluoroacetic acid to a solution of compound 30f (110.0 mg, 0.11 mmol, 1.0 equivalence) in dichloromethane (2 mL). Stir the reaction mixture at room temperature for 16 hours. The resulting reaction mixture was concentrated and purified by preparative high-performance liquid chromatography (ammonium bicarbonate) to give compound 30. ESI m / z 373.8 [M / 2+H] + .LCMS:product:Rt=0.634min. 1HNMR(400MHz,D2O)δ8.30(d,J=5.2Hz,1H),7.26(d,J=3.6Hz,2H),7.24–7.10(m, 5H),7.03(dd,J=17.2,9.8Hz,5H),4.31(s,2H),3.72(s,2H),3.63(s,4H),3.43( t,J=6.4Hz,2H),3.31–3.17(m,4H),3.15–2.98(m,4H),2.74–2.61(m,4H),2.56( dd,J=13.6,5.6Hz,2H),2.39–2.21(m,4H),2.06–1.93(m,2H),1.68–1.51(m,2H).

[0559] Example 31: Synthesis of Compound 31

[0560] Step 1): Compound 30a (2 g, 10.75 mmol, 1.0 equivalence), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxoborane) (4.10 g, 16.13 mmol, 1.5 equivalence) were dissolved in dioxane (30 mL), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (0.79 g, 1.08 mmol, 0.1 equivalence) and potassium acetate (3.17 g, 32.26 mmol, 3.0 equivalence) were added. The mixture was purged with nitrogen three times, then heated to 100 °C under reflux and stirred for 5 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, filtered through diatomaceous earth, and concentrated under reduced pressure to give compound 31a. ESI m / z 234.1 [M+H] + .LCMS:product:Rt=0.942min.

[0561] Step 2): Compound 28c (117-2, 200 mg, 0.51 mmol, 1.0 equivalent) and compound 31a (921.52 mg, 3.63 mmol, 5.0 equivalent) were dissolved in 1,4-dioxane (9 mL) and water (3 mL). Then, [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (33.40 mg, 0.05 mmol, 0.1 equivalent) and potassium carbonate (212.46 mg, 1.54 mmol, 3.0 equivalent) were added. The mixture was purged with nitrogen three times, then heated to 10 °C under reflux and stirred for 3 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography with petroleum ether / tert-butyl methyl ether = 1 / 1 to give compound 31b. ESI m / z 417.2 [M+H] + .LCMS:product:Rt=1.670min.

[0562] Step 3): Compound 31b (330 mg, 0.79 mmol, 1.0 equivalence) and inter 6 (384.65 mg, 0.95 mmol, 1.2 equivalence) were dissolved in dichloromethane (10 mL), and acetic acid (0.01 mL, 0.17 mmol) was added and stirred for 30 minutes. Then, sodium triacetoxyborohydride (503.78 mg, 2.38 mmol, 3.0 equivalence) was added. The mixture was stirred at room temperature for 3 hours. A saturated sodium bicarbonate 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 / tert-butyl methyl ether = 1 / 5 to give compound 31c. ESI m / z 805.4 [M+H] + .LCMS:product:Rt=1.552min.

[0563] Step 4): Compound 31c (500 mg, 0.61 mmol, 1.0 equivalence) and inter 4 (343.01 mg, 1.22 mmol, 1.3 equivalence) were dissolved in dichloromethane (5 mL), and acetic acid (0.01 mL, 0.17 mmol) was added and stirred for 30 minutes. Then, sodium triacetoxyborohydride (157.96 mg, 0.75 mmol, 3.0 equivalence) was added. The mixture was stirred at room temperature for 3 hours. A saturated aqueous solution of sodium bicarbonate (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 using dichloromethane / tert-butyl methyl ether = 1 / 5 to give compound 31d. ESI m / z 468.8. [M-2Boc-tert-butyl / 2+H] + .LCMS:product:Rt=1.851min.

[0564] Step 5): Compound 31d (200 mg, 0.17 mmol, 1.0 equivalent) was dissolved in a mixed solution of tetrahydrofuran (2 mL), methanol (4 mL), and water (2 mL), followed by the addition of lithium hydroxide monohydrate (42.22 mg, 1.01 mmol, 6.0 equivalent). The mixture was stirred at 50 °C for 16 hours. Water (30 mL) was added to the reaction mixture, the pH was adjusted to 3 with 1 M hydrochloric acid, and the mixture was 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 31e. ESI m / z 1164.4 [M+H] + .LCMS:product:Rt=1.741min.

[0565] Step 6): Compound 31e (170 mg, 0.15 mmol, 1.0 equivalence) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (3 mL, 39.20 mmol) was added. 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 (formic acid) to obtain compound 31. ESI m / z 752.2 [M+H] + .LCMS:product:Rt=0.978min. 1 H NMR(400MHz,D2O)δ8.43(d,J=5.3Hz,1H),7.39(d,J=5.2Hz,1H),7.30–7.22(m,4H),7. 16(dd,J=16.4,8.1Hz,5H),4.41(d,J=14.4Hz,6H),4.32(s,2H),3.48(dt,J=11.1,6.2 Hz,4H),3.34(t,J=8.6Hz,2H),3.18(dd,J=18.3,10.4Hz,2H),2.91(dd,J=12.8,7.4Hz ,4H),2.69(d,J=6.1Hz,4H),2.46–2.36(m,4H),2.10–2.01(m,2H),1.73–1.60(m,2H).

[0566] Example 32: Synthesis of Compounds 32 and 33

[0567] Step 1): Diethyl 2-oxomalactone (7.98 g, 45.82 mmol, 1.0 equivalent) was added to an ethanol (100 mL) solution containing compound 32a (5.00 g, 45.82 mmol, 1.0 equivalent). The reaction mixture was stirred at 100 °C for 3 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was dissolved in ethyl acetate (50 mL), and then petroleum ether (50 mL) was added. The mixture was stirred at 25 °C for 30 minutes. The solid was collected by filtration and dried under vacuum to give a mixture of compounds 32b1 and 32b2. ESI m / z 220.0 [M+H] + .LCMS:product:Rt=0.600min and Rt=0.708. 1 H NMR (400MHz, DMSO-d6) δ13.09(s,1H),8.99–8.70(m,1H),8.58–8.48(m,1H),7.80–7.24(m,1H),4.43–4.35(m,2H),1.32(t,J=7.1Hz,3H).

[0568] Step 2): A mixture of compounds 32b1 and 32b2 (5.40 g, 23.65 mmol, 1.0 equivalent) was added to toluene (60 mL), followed by phosphorus oxychloride (21.76 g, 141.9 mmol, 6.0 equivalent). The reaction mixture was stirred at 110 °C for 3 hours. The reaction solution was concentrated under reduced pressure to remove the solvent. The mixture was diluted with ethyl acetate (100 mL) and alkalized with saturated sodium bicarbonate solution until the pH reached 7-8. The aqueous phase was separated and extracted with ethyl acetate (50 mL × 3). 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 to obtain the residue. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (0-18%) to give a mixture of compounds 32c1 and 32c2. ESI m / z 238.0 [M+H] + .LCMS:product:Rt=0.992. 1 H NMR (400MHz, CDCl3) δ9.64–9.49(m,1H),8.96–8.88(m,1H),8.02–7.87(m,1H),4.58(q,J=7.1Hz,2H),1.51–1.46(m,3H).

[0569] Step 3): A mixture of compounds 32c1 and 32c2 (3.20 g, 12.80 mmol, 1.0 equivalent) and (bromomethyl)benzene (2.41 g, 14.07 mmol, 1.1 equivalent) were dissolved in acetonitrile (40 mL). The reaction mixture was heated to 80 °C and reacted for 12 hours. After cooling the reaction mixture to 25 °C, sodium borohydride acetate (16.3 g, 76.80 mmol, 6.0 equivalent) was added. The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was slowly poured into ice-cold saturated sodium bicarbonate (100 mL) and dichloromethane (100 mL). The aqueous layer was separated and extracted with dichloromethane (50 mL × 3). 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 to obtain the residue. The residue was purified by silica gel column chromatography, using petroleum ether / ethyl acetate (0-24%) as eluent to give compound 32d. ESI m / z 332.5 [M+H] + .LCMS:product:Rt=0.867.

[0570] Step 4): Compound 32d (2.30 g, 5.20 mmol, 1.0 equivalent), (3-formaldehydephenyl)boronic acid (0.94 g, 6.24 mmol, 1.2 equivalent), potassium carbonate (2.16 g, 15.60 mmol, 3.0 equivalent), and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (0.380 g, 0.52 mmol, 0.1 equivalent) were dissolved in dioxane (25 mL) and water (5 mL). The reaction solution was degassed and purged with nitrogen three times. The reaction solution was stirred at 90 °C for 2 hours under nitrogen protection. The reaction solution was then diluted with ethyl acetate (20 mL) and water (20 mL). The aqueous phase was separated and extracted with ethyl acetate (20 mL × 3). 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 to obtain the residue. The residue was purified by silica gel column chromatography, and eluted with petroleum ether / ethyl acetate (0-36%) to give compound 32e. ESI m / z 402.5 [M+H] + .LCMS:product:Rt=2.050. 1 H NMR(400MHz, CDCl3)δ10.07(s,1H),8.10(t,J=1.8Hz,1H),7.99–7.95(m,1H),7.83–7.79(m,1H),7.62(t,J=7.7Hz,1H),7 .45–7.31(m,5H),4.29(q,J=7.2Hz,2H),3.96–3.74(m,4H),3.31–3.12(m,2H),3.07–2.86(m,2H),1.17(t,J=7.1Hz,3H).

[0571] Step 5): Compound 32e (1.200 g, 2.90 mmol, 1.0 eq) was dissolved in methanol (20 mL), and 10% palladium on carbon (0.200 g, 0.16 mmol, 0.05 eq) and 10% palladium hydroxide on carbon (0.200 g, 0.14 mmol, 0.05 eq) were added. The reaction solution was degassed and purged with hydrogen three times. The reaction solution was stirred at 25 °C under a hydrogen atmosphere (15 psi) for 12 hours. The reaction solution was filtered. The filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography, eluting with dichloromethane / methanol (0-8%) to obtain compound 32f. ESI m / z 314.0 [M+H] + .LCMS:product:Rt=0.583. 1H NMR(400MHz, CDCl3)δ7.61(d,J=1.9Hz,1H),7.49–7.40(m,3H),4.75(s,2H),4.32 –4.19(m,4H),3.31(t,J=6.0Hz,2H),3.13(t,J=6.0Hz,2H),1.16(t,J=7.1Hz,3H).

[0572] Step 6): Compound 32f (500.0 mg, 1.55 mmol, 1.0 equivalence) and di-tert-butyl dicarbonate (506.7 mg, 2.32 mmol, 1.5 equivalence) were dissolved in dichloromethane (10 mL), and then triethylamine (0.64 mL, 4.64 mmol, 3.0 equivalence) was added. The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (0-50%) as eluent to obtain compound 32 g. ESI m / z 414.2 [M+H] + .LCMS:product:Rt=1.092. 1 H NMR (400MHz, CDCl3) δ7.64(s,1H),7.52–7.44(m,3H),4.82(s,2H),4.78(s,2H),4.28(q,J=7 .1Hz,2H),3.86(t,J=5.8Hz,2H),3.15(t,J=5.8Hz,2H),1.51(s,9H),1.17(t,J=7.1Hz,3H).

[0573] Step 7): Dichloromethane (10 mL) containing 32 g (486 mg, 1.18 mmol, 1.0 equivalence) of the compound was added fractionally to Dysmartin reagent (747.81 mg, 1.76 mmol, 1.5 equivalence). The reaction mixture was stirred at 25 °C for 1 hour. Subsequently, dichloromethane (10 mL) was added to the reaction mixture and the mixture was filtered. The filtrate was quenched with saturated sodium bicarbonate aqueous solution (5 mL) and saturated sodium sulfite aqueous solution (5 mL). The aqueous phase was separated and extracted with dichloromethane (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 using petroleum ether / ethyl acetate (0-25%) as eluent to give compound 32h. ESI m / z 412.1 [M+H] + .LCMS:product:Rt=1.200. 1H NMR (400MHz, CDCl3) δ10.09(s,1H),8.18–8.10(m,1H),8.01–7.98(m,1H),7.88–7.83(m,1H),7.69–7.61(m,1H),4. 83(s,2H),4.30(q,J=7.1Hz,2H),3.87(t,J=5.9Hz,2H),3.17(t,J=5.9Hz,2H),1.51(s,9H),1.17(t,J=7.1Hz,3H).

[0574] Step 8): Compound 32h (280.0 mg, 0.63 mmol, 1.0 equivalent), Inter 6 (256.0 mg, 0.63 mmol, 1.0 equivalent), and acetic acid (38.00 mg, 0.63 mmol, 1.0 equivalent) were dissolved in dichloroethane (5 mL) and stirred at 45 °C for 30 minutes. Then, sodium borohydride acetate (402.4 mg, 1.90 mmol, 3.0 equivalent) was added, and the reaction mixture was stirred at 45 °C for 1 hour. The reaction mixture was quenched with a saturated sodium bicarbonate aqueous solution (5 mL). The aqueous layer was separated and extracted with dichloromethane (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 crude product. The crude product was purified by silica gel column chromatography, eluting with dichloromethane / dichloromethane-methanol (10:1) (0-18%) to give compound 32i. ESI m / z 800.4 [M+H] + .LCMS:product:Rt=1.506.

[0575] Step 9): A solution of dichloroethane (8 mL) containing compound 32i (250.0 mg, 0.31 mmol, 1.0 equivalence), inter 4 (315.3 mg, 0.78 mmol, 2.5 equivalence), and acetic acid (18.80 mg, 0.31 mmol, 1.0 equivalence) was stirred at 45 °C for 30 minutes. Then, sodium borohydride acetate (264.9 mg, 1.25 mmol, 4.0 equivalence) was added. The reaction mixture was stirred at 45 °C for 1 hour. The reaction mixture was quenched with saturated sodium bicarbonate (10 mL). The aqueous phase was separated and extracted with dichloromethane (10 mL × 3). The organic phases were combined, washed with saturated brine (10 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 / methanol (dichloromethane / methanol = 10:1) (0-12%) to give compound 32j. ESI m / z 1187.6 [M+H] + .LCMS:product:Rt=1.883.

[0576] Step 10): Compound 32k (480.0 mg, 0.30 mmol, 1.0 equivalence) was dissolved in methanol (3 mL), water (3 mL), and tetrahydrofuran (3 mL), and lithium hydroxide monohydrate (74.69 mg, 1.78 mmol, 6.0 equivalence) was added. The reaction mixture was stirred at 50 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to remove most of the solvent. It was then acidified to pH 4-5 with hydrochloric acid (1 M). The aqueous phase was extracted with dichloromethane (10 mL × 3). The organic phases 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 / methanol (0-10%) to give compound 32k. ESI m / z 1160.6 [M+H] + .LCMS:product:Rt=1.487.

[0577] Step 11): Compound 32k (274 mg, 0.23 mmol, 1.0 equivalent) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (2 mL) was added. The reaction mixture was stirred at 40 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative high-performance liquid chromatography (using ammonium bicarbonate as the mobile phase) to obtain compounds 32 and 33, respectively.

[0578] Compound 32

[0579] LCMS:product:ESI m / z 747.3[M+H] + Rt = 1.017.

[0580] 1 H NMR(400MHz,D2O)δ7.59–7.53(m,1H),7.49–7.43(m,2H),7.40–7.36(m,1H),7.29–7.23(m,2H),7.19–7.12(m,6H),4.20(s,2H),3.97–3.77( m,6H),3.39–3.26(m,6H),3.17–3.06(m,4H),2.86–2.79(m,2H),2.75– 2.63(m,4H),2.42–2.31(m,4H),2.07–1.98(m,2H),1.70–1.59(m,2H).

[0581] Compound 33

[0582] LCMS:product:ESI m / z 701.4[MH] - Rt = 0.843.

[0583] 1H NMR(400MHz,D2O)δ8.09(s,1H),7.34–7.23(m,2H),7.06–7.01(m,2H),6.99–6.92(m,6H),6.89–6.84(m,2H),3.66(s,2H),3.27–3.21(m,2 H),3.17–2.97(m,12H),2.80–2.71(m,2H),2.67–2.55(m,4H),2.49–2.40(m,2H),2.33–2.20(m,4H),1.99–1.90(m,2H),1.65–1.55(m,2H).

[0584] Example 34: Synthesis of Compound 34

[0585] Step 1): Compound 34a (500 mg, 2.51 mmol, 1.0 equivalent) was dissolved in dioxane (10 mL), followed by the addition of 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,3,2-dioxaborane (956.83 mg, 3.77 mmol, 1.5 equivalent), potassium acetate (493.06 mg, 5.02 mmol, 2.0 equivalent), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (183.80 mg, 0.25 mmol, 0.1 equivalent). The mixture was stirred at 100 °C for 3 hours under nitrogen protection. The mixture was then concentrated directly under reduced pressure. The residue was purified by rapid column chromatography (petroleum ether / ethyl acetate = 8 / 1) to give compound 34b. ESI m / z 247.1 [M+H] + .LCMS:product:Rt=1.39min.

[0586] Step 2): Compound 17b (270 mg, 0.85 mmol, 1.0 equivalence) was dissolved in 1,4-dioxane (10.0 mL) and water (2 mL), followed by the addition of compound 34b (271.42 mg, 1.03 mmol, 1.2 equivalence), potassium phosphate (453.53 mg, 2.14 mmol, 2.5 equivalence), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (62.54 mg, 0.09 mmol, 0.1 equivalence). The reaction was heated to 90 °C for 2 hours. The mixture was concentrated under reduced pressure. The residue was purified by rapid column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give compound 34c. ESI m / z 397.2 [M+H] + .LCMS:product:Rt=1.23min.

[0587] Step 3): Compound 34c (270 mg, 0.65 mmol, 1.0 equivalence) was dissolved in 1,2-dichloroethane (15 mL), and Inter 6 (277.73 mg, 0.69 mmol, 1.05 equivalence) and acetic acid (12.20 mg, 0.07 mmol) were added. The mixture was stirred at 45 °C for 0.5 h. Then, sodium triacetoxyborohydride (415.71 mg, 1.96 mmol) was added, and the mixture was stirred at 45 °C for 1 h. 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 = 0 / 1) to give compound 34d. ESI m / z 785.4 [M+H] + .LCMS:product:Rt=1.20min.

[0588] Step 4): Compound 34d (200 mg, 0.23 mmol, 1.0 equivalence) was dissolved in 1,2-dichloroethane (8 mL), and Inter 5 (233.89 mg, 0.58 mmol, 2.5 equivalence) and acetic acid (4.33 mg, 0.02 mmol, 0.1 equivalence) were added. The mixture was stirred at 45 °C for 0.5 h. Then, sodium triacetoxyborohydride (147.41 mg, 0.70 mmol, 3.0 equivalence) was added and stirred at 45 °C for 1 h. 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 subjected to silica gel column chromatography (petroleum ether / methyl tert-butyl = 0 / 1) to give compound 34e. ESI m / z 1172.6 [M+H] + .LCMS:product:Rt=1.55min.

[0589] Step 5): Compound 34e (280 mg, 0.22 mmol, 1.0 equivalent) was dissolved in tetrahydrofuran (2 mL), methanol (2 mL), and water (2 mL), and lithium hydroxide monohydrate (94.19 mg, 2.24 mmol, 10.0 equivalent) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water (10 mL), acidified to pH 5 with 1 M hydrochloric acid aqueous solution, 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 compound 34f. ESI m / z 1158.6 [M+H] + .LCMS:product:Rt=1.53min.

[0590] Step 6): Compound 34f (260 mg, 0.19 mmol, 1.0 equivalence) was dissolved in dichloromethane (9 mL), and trifluoroacetic acid (3 mL) was added. The mixture was stirred at 25 °C for 16 hours. The reaction mixture was concentrated and purified by preparative high-performance liquid chromatography (formic acid) to give compound 34. ESI m / z 746.3 [M+H] + .LCMS:product:Rt=2.16min. 1 H NMR(400MHz,D2O)δ7.93(s,1H),7.44–7.21(m,11H),4.77(s,2H),4.61(s,2 H),4.32(d,J=10.1Hz,6H),3.50(dd,J=11.5,6.9Hz,2H),3.35(ddd,J=11.9 ,8.5,3.5Hz,2H),3.24–3.13(m,2H),3.01–2.90(m,2H),2.76(q,J=13.5Hz, 4H),2.49–2.36(m,4H),2.12–2.00(m,2H),1.79(s,3H),1.73–1.62(m,2H).

[0591] Example 35: Synthesis of Compound 35

[0592] Step 1): Compound 35a (2.50 g, 12.31 mmol, 1.0 eq), potassium acetate (2.42 g, 24.63 mmol, 2.0 eq), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (0.90 g, 1.23 mmol, 0.1 eq), and bis(pinacolyl)diboron (4.69 g, 18.47 mmol, 1.5 eq) were dissolved in dioxane (35 mL). The mixture was deoxygenated under vacuum and purged with nitrogen three times. Then, under nitrogen protection, the reaction mixture was stirred at 80 °C for 4 hours. After the reaction was completed, the reaction mixture was diluted with ethyl acetate and petroleum ether (1:1) (100 mL) and filtered. The filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography and eluted with pure petroleum ether (100%) to obtain compound 35b. 1 H NMR (400MHz, CDCl3) δ10.41(s,1H),8.08–7.89(m,2H),7.29–7.25(m,1H),1.38(s,12H).

[0593] Step 2): Compound 17b (300 mg, 0.95 mmol, 1.0 equivalent), compound 35b (475 mg, 1.90 mmol, 2.0 equivalent), potassium phosphate (605 mg, 2.85 mmol, 3.0 equivalent), and 1,1'-bis(diphenylphosphine)ferrocene palladium(II) dichloride (69.5 mg, 0.09 mmol, 0.1 equivalent) were mixed in dioxane (5 mL) and water (1 mL), degassed, and backfilled with nitrogen three times. Under nitrogen protection, the reaction mixture was stirred at 80 °C for 2 hours. After the reaction was complete, the reaction solution was diluted with ethyl acetate (10 mL) and water (5 mL). After separating the aqueous phase, the aqueous phase was extracted with ethyl acetate (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 petroleum ether / ethyl acetate (0-24%) to give compound 35c. ESI m / z 401.2 [M+H] + .LCMS:product:Rt=1.192min.

[0594] Step 3): Compound 35c (360 mg, 0.89 mmol, 1.0 equivalence), inter 6 (396.1 mg, 0.98 mmol, 1.1 equivalence), and acetic acid (53.45 mg, 0.89 mmol, 1.0 equivalence) were dissolved in dichloroethane (6 mL) and stirred at 45 °C for 20 minutes. Then, sodium borohydride acetate (565.9 mg, 2.67 mmol, 3.0 equivalence) was added. The reaction mixture was stirred at 45 °C for 1 hour. The reaction mixture was quenched with an aqueous sodium bicarbonate solution (15 mL). After separating the aqueous phase, it was extracted with dichloromethane (10 mL × 3). The combined organic phases were washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate before filtration. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography, eluting with dichloromethane / (dichloromethane / methanol = 10:1) (0-25%) to give compound 35d. ESI m / z 789.4 [M+H] + .LCMS:product:Rt=1.485min.

[0595] Step 4): Compound 35d (250 mg, 0.31 mmol, 1.0 equivalence), inter4 (313.3 mg, 0.78 mmol, 2.5 equivalence), and acetic acid (18.65 mg, 0.31 mmol, 1.0 equivalence) were dissolved in dichloroethane (8 mL) and stirred at 45 °C for 30 min. Sodium borohydride acetate (197.4 mg, 0.93 mmol, 3.0 equivalence) was then added. The reaction mixture was stirred at 45 °C for 1 h. The reaction was quenched by adding an aqueous sodium bicarbonate solution (15 mL). The aqueous phase was separated and extracted with dichloromethane (10 mL × 3). The combined organic layers were washed with saturated brine (10 mL), 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 dichloromethane / (dichloromethane / methanol = 10:1) (0-36%) to give compound 35e. ESI m / z 1176.6 [M+H] + .LCMS:product:Rt=1.876min.

[0596] Step 5): Compound 35e (370 mg, 0.26 mmol, 1.0 equivalence) was dissolved in tetrahydrofuran (4 mL), methanol (4 mL), and water (4 mL), followed by the addition of lithium hydroxide monohydrate (64.93 mg, 1.55 mmol, 6.0 equivalence). The reaction mixture was stirred at 25 °C for 12 hours. The reaction mixture was diluted with water (5 mL) and acidified to pH 5-6 with hydrochloric acid (1 M) at 0 °C. The aqueous phase was extracted with dichloromethane (10 mL × 3). The combined organic layers were washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 35f. ESI m / z 1162.6 [M+H] + .LCMS:product:Rt=1.558min.

[0597] Step 6): A solution of compound 35f (350 mg, 0.24 mmol, 1.0 equivalent) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (2 mL) was added. The reaction solution was stirred at 25 °C for 3 hours. The reaction solution was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative high-performance liquid chromatography (ammonium bicarbonate) to obtain compound 35. ESI m / z 750.3 [M+H]+.LCMS:product:Rt=0.969min. 1H NMR(400MHz,D2O)δ7.92(s,1H),7.41–7.34(m,2H),7.24–7.18(m,3H),7.12–7.08(m,6H),4.60(s,2H),4.45(s,2H),3.81–3.65(m,6H) ,3.30–3.24(m,4H),3.13–3.06(m,2H),2.78–2.69(m,4H),2.65–2.59(m,2H),2.40–2.30(m,4H),2.04–1.97(m,2H),1.65–1.55(m,2H).

[0598] Example 36: Synthesis of Compound 36

[0599] Step 1): Compound 13a (500 mg, 1.24 mmol, 1.0 equivalent) and 5-bromo-3-chloropyrazine (239.82 mg, 1.24 mmol, 1.0 equivalent) were dissolved in 1,4-dioxane (10 mL) and water (3 mL), followed by the addition of 1,1'-bis(diphenylphosphine)ferrocene palladium(II) dichloride (90.72 mg, 0.12 mmol, 0.1 equivalent) and potassium carbonate (514.03 mg, 3.72 mmol, 3.0 equivalent). The mixture was purged three times with nitrogen, then heated to 100 °C under reflux and stirred for 3 hours. The resulting reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography with petroleum ether / ethyl acetate = 1 / 1 to give compound 36a. ESI m / z 390.0 [M+H] + .LCMS:product:Rt=1.471min.

[0600] Step 2): Compound 36a (360 mg, 0.92 mmol, 1.0 equivalence) and zinc cyanide (325.29 mg, 2.77 mmol, 3.0 equivalence) were dissolved in N,N-dimethylacetamide (10 mL), followed by the addition of 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) palladium dichloride (139.62 mg, 0.18 mmol, 0.2 equivalence) and N,N-diisopropylethylamine (0.48 mL, 2.77 mmol, 3.0 equivalence). The mixture was purged three times with nitrogen, then heated to 140 °C under reflux and stirred for 16 hours. The resulting reaction mixture was cooled to room temperature and filtered. Water (20 mL) was added to the filtrate, and the mixture was extracted with ethyl acetate (20 mL × 3) and washed with saturated brine (20 mL × 2). The residue was purified by column chromatography with petroleum ether / tert-butyl methyl ether = 1 / 1 to give compound 36b. ESI m / z 381.2 [M+H] + .LCMS:product:Rt=1.448min.

[0601] Step 3): Compound 36b (130 mg, 0.34 mmol, 1.0 equivalent) was dissolved in methanol (10 mL), and 10% palladium on carbon (130 mg, 0.12 mmol) was added. The mixture was purged three times with hydrogen and stirred at room temperature for 5 hours. The resulting reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give compound 36c. ESI m / z 385.2 [M+H] + .LCMS:product:Rt=1.004min.

[0602] Step 4): Compound 36c (60 mg, 0.16 mmol, 1.0 equivalence) and inter 4 (188.93 mg, 0.47 mmol, 3.0 equivalence) were dissolved in dichloromethane (5 mL), followed by the addition of acetic acid (0.01 mL, 0.17 mmol). After stirring for 30 minutes, sodium triacetoxyborohydride (198.47 mg, 0.94 mmol, 6.0 equivalence) was added. The mixture was stirred at room temperature for 16 hours. A saturated aqueous solution of sodium bicarbonate (20 mL) was added to the reaction mixture, and the mixture was 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 with petroleum ether / tert-butyl methyl ether = 1 / 1 to give compound 36d. ESI m / z 1159.6 [M+H] + .LCMS:product:Rt=1.902min.

[0603] Step 5): Compound 36d (70 mg, 0.06 mmol, 1.0 equivalence) was dissolved in tetrahydrofuran (2 mL), methanol (4 mL), and water (2 mL), followed by the addition of lithium hydroxide monohydrate (15.20 mg, 0.36 mmol, 6.0 equivalence). The mixture was stirred at 50 °C for 16 hours. Water (30 mL) was added to the reaction mixture, the pH was adjusted to 3 with 1 M hydrochloric acid, and the mixture was 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 36e. ESI m / z 1145.6 [M+H] + .LCMS:product:Rt=1.807min.

[0604] Step 6): Compound 36e (60 mg, 0.05 mmol, 1.0 equivalence) was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (3 mL). The mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to give the crude product. Compound 36 was then purified by preparative high-performance liquid chromatography (formic acid). ESI m / z 733.3 [M+H] +.LCMS:product:Rt=0.596min. 1 H NMR(400MHz,D2O)δ8.92(s,1H),7.54(s,1H),7.43(s,1H),7.26–6.99(m,9 H),4.70–4.69(m,2H),4.68(s,2H),4.26–3.81(m,6H),3.31(td,J=11.2,5 .0Hz,4H),3.13(dd,J=18.3,10.5Hz,2H),2.83–2.73(m,2H),2.71–2.49(m ,4H),2.42–2.25(m,4H),2.12–1.87(m,2H),1.62(td,J=18.4,9.1Hz,2H).

[0605] Example 37: Synthesis of Compound 37

[0606] Step 1): Compound 3f (400 mg, 1.08 mmol, 1.0 equivalence) was dissolved in acetonitrile (8 mL), and but-3-yn-1-amine (149.32 mg, 2.16 mmol, 2.0 equivalence), palladium(II) acetate (48.51 mg, 0.22 mmol, 0.2 equivalence), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (206.02 mg, 0.43 mmol, 0.4 equivalence), and tetrabutylammonium fluoride (1.62 mL, 1.5 equivalence, 1 M tetrahydrofuran solution) were added. The reaction mixture was stirred at 50 °C for 16 hours. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (dichloromethane / methanol = 10 / 1) to give compound 37a. ESI m / z 359.2 [M+H] + .LCMS:product:Rt=0.96min.

[0607] Step 2): Compound 37a (140 mg, 0.32 mmol, 1.0 equivalence) was dissolved in N,N-dimethylformamide (5 mL), and Inter 5 (379.65 mg, 0.81 mmol, 2.5 equivalence) and potassium carbonate (156.81 mg, 1.13 mmol, 3.5 equivalence) were added. The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layers were 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 / methyl tert-butyl ether = 3 / 1) to give compound 37b. ESI m / z 1134.6 [M+H] + .LCMS:product:Rt=1.46min.

[0608] Step 3): Compound 37b (300 mg, 0.26 mmol, 1.0 equivalent) was dissolved in a solution of tetrahydrofuran (3 mL), methanol (3 mL), and water (3 mL), and lithium hydroxide monohydrate (111.06 mg, 2.65 mmol, 10.0 equivalent) 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 aqueous solution, 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 compound 37c. ESI m / z 1120.6 [M+H] + .LCMS:product:Rt=1.51min.

[0609] Step 4): Compound 37c (280 mg, 0.23 mmol, 1.0 equivalence) was dissolved in dichloromethane (9 mL), and trifluoroacetic acid (3 mL) was added. The mixture was stirred at 25 °C for 16 hours. The reaction mixture was concentrated and purified by preparative high-performance liquid chromatography (formic acid) to obtain compound 37. ESI m / z 708.4 [M+H] + .LCMS:product:Rt=1.24min. 1 H NMR(400MHz,D2O)δ7.44–7.16(m,10H),4.45(s,2H),4.37(s,4H),3.53–3.42(m,5H),3.34(m,3H),3.19(m,3H ),2.95–2.88(m,2H),2.84–2.74(m,3H),2.65(m,4H),2.39(m,4H),2.04(m,2H),1.67(dd,J=12.9,8.8Hz,2H).

[0610] Example 38: Synthesis of Compound 38

[0611] Step 1): Boron tribromide (8.3 mL, 86.14 mmol, 2.0 equivalent) was added to a solution of compound 38a (10 g, 43.28 mmol, 1.0 equivalent) in 100 mL of dichloromethane at 0 °C, and the mixture was slowly brought back to room temperature with stirring for 2 hours. The reaction mixture was then quenched with methanol (100 mL), and subsequently concentrated under vacuum to obtain compound 38b. ESI m / z 218.9 [M+H] + .LCMS:product:Rt=0.818min.

[0612] Step 2): 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 38b (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 anhydrous 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 obtain compound 38c. ESI m / z 230.8 [M+H] + .LCMS:product:Rt=1.097min.

[0613] Step 3): Sodium borohydride (1 g, 26.43 mmol, 2.0 equivalent) was added to a methanol solution (30 mL) of compound 38c (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 × 3). The organic phases were combined, washed with saturated brine (40 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 38d. ESI m / z 215.0 [M + H - H₂O] + .LCMS:product:Rt=0.944min.

[0614] Step 4): Triphenylphosphine (3.7 g, 14.11 mmol, 1.1 equivalent) and N-bromosuccinimide (2.7 g, 15.17 mmol, 1.2 equivalent) were added to a dichloromethane solution (60 mL) of compound 38d (3.2 g, 12.73 mmol, 1.0 equivalent), and the mixture was stirred at room temperature for 3 hours. A saturated sodium bicarbonate aqueous solution (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 anhydrous 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 obtain compound 38e. 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).

[0615] Step 5): 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 38e (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 organic phases were combined, 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 38f. ESI m / z 623.2 [M + Na] + .LCMS:product:Rt=1.490min.

[0616] Step 6): At 0°C, hydrogen peroxide (30% aqueous solution, 1.90 mL, 24.47 mmol, 10.0 equivalent) was added dropwise to tetrahydrofuran (15 mL) of compound 38f (1.6 g, 2.44 mmol, 1.0 equivalent). Then, a solution of lithium hydroxide (0.21 g, 5.00 mmol, 2.0 equivalent) 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 38 g of the compound. ESI m / z 388.0 [MC(CH3)3+H] + .LCMS:product:Rt=0.937min.

[0617] Step 7): To a 10 mL solution of tetrahydrofuran containing 38 g (950 mg, 2.15 mmol, 1.0 equivalence) of the compound, add 2.4 mL of O-tert-butyl-N,N'-diisopropylisourea (10.67 mmol, 5.0 equivalence). The reaction mixture was stirred at 65 °C for 0.5 h. The reaction mixture was filtered to remove the white solid, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / tert-butyl methyl ether = 4 / 1) to give compound 38 h. ESI m / z 388.0 [M-2C(CH3)3+H] + .LCMS:product:Rt=1.629min.

[0618] Step 8): To N,N-dimethylacetamide (30 mL) containing compound 38h (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 nitrogen 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 anhydrous 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 38i. ESI m / z 333.0[M-2(tert-butyl)+H] +.LCMS:product:Rt=1.473min.

[0619] Step 9): To a tetrahydrofuran solution (15 mL) containing compound 38i (1.34 g, 2.95 mmol), add Raney nickel (1 g, 17.04 mmol) and ammonia water (0.25 mL, 14.27 mmol). 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 38j. ESI m / z 449.2 [M+H] + .LCMS:product:Rt=1.006min.

[0620] Step 10): Compound 38j (300.0 mg, 0.66 mmol, 1.0 equivalent) was added to methanol (10 mL), followed by 1 g of compound (251.12 mg, 0.66 mmol, 1.0 equivalent). The reaction mixture was stirred at 50 °C for 2 hours. Sodium borohydride (49.81 mg, 1.32 mmol, 2.0 equivalent) 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 anhydrous 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 38k. ESI m / z 814.4 [M+H] + .LCMS:product:Rt=1.211min.

[0621] Step 11): Compound 38k (510.1 mg, 0.63 mmol, 1.0 equivalence) was added to a dichloromethane solution (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 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 = 1 / 9) to give compound 38l. ESI m / z 1079.6 [M+H] + .LCMS:product:Rt=1.404min.

[0622] Step 12): Compound 38l (500.0 mg, 0.46 mmol, 1.0 equivalent) was dissolved in a 5 mL solution of dimethylamine in tetrahydrofuran (2 M). 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 obtain compound 38m. ESI m / z 857.6 [M+H] + .LCMS:product:Rt=1.234min.

[0623] Step 13): Dissolve inter 7 (50 mg, 0.12 mmol, 1.0 equivalence) in N,N-dimethylformamide (1 mL), then add 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (50 mg, 0.13 mmol, 1.1 equivalence) and N,N-diisopropylethylamine (60 mg, 0.46 mmol, 3.9 equivalence). Stir the mixture at 25 °C for 0.5 h, then add compound 38m (100 mg, 0.12 mmol, 1.0 equivalence), and continue the reaction for 2 h. Add water (40 mL) to the mixture, then extract with ethyl acetate (30 mL × 3). Wash the combined organic phases with brine (40 mL × 3), dry with anhydrous sodium sulfate, and concentrate under reduced pressure. The residue was subsequently purified by rapid column chromatography (petroleum ether / methyl tert-butyl ether = 1 / 0 to 3 / 7) to give compound 38n. ESI m / z 580.0 [M-Boc+H] + .LCMS:product:Rt=1.631min.

[0624] Step 14): Compound 38n (120 mg, 0.08 mmol) was dissolved in methanol (1 mL), tetrahydrofuran (1 mL), and water (1 mL), and lithium hydroxide monohydrate (36 mg, 0.86 mmol) was added. The reaction mixture was stirred at 50 °C for 18 hours. The reaction mixture was adjusted to pH 6–7 with hydrochloric acid (4 mol / L), and then extracted with ethyl acetate (20 mL × 3). The organic phases were combined and concentrated under reduced pressure to give crude compound 38o. ESI m / z 573.0 [M-Boc+H] + .LCMS:product:Rt=1.409min.

[0625] Step 15): Compound 38 (110 mg, 0.07 mmol, 1.0 equivalence) was dissolved in dichloromethane solution (2 mL), and trifluoroacetic acid (1 mL) was added. 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 obtain compound 38. ESI m / z 832.3 [M+H] +.LCMS:product:Rt=0.796min. 1 H NMR(400MHz,D2O)δ7.44–7.11(m,9H),6.90(s,1H),6.55(s,2H),5.54(s,2H),4.52(s,2H),4.29(s,2H),3.58(d,J =32.3Hz,4H),3.42–2.98(m,8H),2.89–2.51(m,7H),2.45–2.17(m,5H),2.01(s,2H),1.60(dd,J=20.3,9.6Hz,2H).

[0626] Example 39: Synthesis of Compound 39

[0627] Step 1): Dissolve inter 1 (500 mg, 1.4 mmol, 1.0 equivalence) in dioxane (10 mL) and water (2 mL), then add (4-fluoro-3-formylphenyl)boronic acid (306 mg, 1.82 mmol, 1.3 equivalence), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (102 mg, 0.14 mmol, 0.1 equivalence), and potassium phosphate (600 g, 2.83 mmol, 2.0 equivalence). 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 39a. ESI m / z 344.0 [MC(CH3)3+H] + . LCMS:product:Rt=1.354min. 1 H NMR (400MHz, CDCl3) δ10.44(s,1H),7.82(dd,J=6.5,2.4Hz,2H),7.55(s,1H),7.24(dd,J=10.0,8.6Hz,2H),4.77(s,4H),3.72(s,3H),1.56(s,9H). 19 F NMR (377MHz, CDCl3) δ -124.07.

[0628] Step 2): Compound 39a (200 mg, 0.50 mmol, 1.0 equivalence) was dissolved in 1,2-dichloroethane (10 mL), and inter 2 (400 mg, 0.51 mmol, 1.0 equivalence), acetic acid (60 mg, 1.0 mmol, 2 equivalence), and sodium triacetoxyborohydride (320 mg, 1.51 mmol, 3.0 equivalence) were added. The reaction mixture was stirred at 50 °C for 18 hours. The reaction mixture was quenched with saturated sodium bicarbonate solution (20 mL) and extracted with dichloromethane (30 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 39b. ESI m / z 1175.4 [M+H] + .LCMS:product:Rt=1.609min.

[0629] Step 3): Compound 39b (150 mg, 0.12 mmol, 1.0 equivalent) was dissolved in tetrahydrofuran (2 mL), methanol (2 mL), and water (2 mL), and lithium hydroxide monohydrate (73 mg, 1.74 mmol, 15.0 equivalent) was added. The reaction mixture was stirred at 50 °C for 16 hours. The reaction mixture was poured into water (20 mL), the pH was adjusted to 6 with dilute hydrochloric acid (1 M), and the mixture was extracted with ethyl acetate (15 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 39c. ESI m / z 1162.4 [M+H] + .LCMS:product:Rt=1.536min.

[0630] Step 4): Compound 39c (130 mg, 0.1 mmol, 1.0 equivalence) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (0.5 mL) was added. The mixture was stirred at room temperature for 16 hours. The resulting reaction mixture was concentrated and purified by preparative high-performance liquid chromatography (formic acid) to obtain compound 39. ESI m / z 749.3 [M+H] + .LCMS:product:Rt=0.884min. 1 H NMR(400MHz,D2O)δ8.31(s,1H),7.48–7.13(m,13H),4.62(s,4H),4.31(d,J=11.6Hz,6H),3.45(dd,J=11.5,7.0Hz,2H),3.32(ddd,J=11 .9,8.6,3.4Hz,2H),3.23–3.09(m,2H),2.97–2.84(m,2H),2.80–2.61(m,4H),2.47–2.31(m,4H),2.12–1.94(m,2H),1.72–1.56(m,2H).

[0631] Example 40: Synthesis of Compound 40

[0632] Step 1): Dissolve (2-fluoro-5-formylphenyl)boronic acid (282.8 mg, 1.68 mmol, 1.2 equivalences) in dioxane (10 mL) and water (2 mL), add inter 1 (500.0 mg, 1.40 mmol, 1.0 equivalences), potassium phosphate (893.8 mg, 4.21 mmol, 3.0 equivalences), and dichloro[1,1'-bis(diphenylphosphine)ferrocene]palladium (102.7 mg, 0.14 mmol, 0.1 equivalences). Heat the mixture to 90 °C and react for 2 hours. Pour the mixture into water (50 mL) and extract with ethyl acetate (3 × 40 mL). Wash the combined organic phases with saturated brine (30 mL × 3), dry to anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. Purify the crude product by rapid column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 40a. ESI m / z 422.2 [M+Na] + .LCMS:product:Rt=1.478min.

[0633] Step 2): Dissolve inter 2 (150.0 mg, 0.19 mmol, 1.0 equivalence) in dichloroethane (10 mL), add compound 40a (226.9 mg, 0.57 mmol, 3.0 equivalence) and sodium triacetoxyborohydride (120.4 mg, 0.57 mmol, 3.0 equivalence). Heat the mixture to 50 °C and react for 18 hours. Pour the mixture into water (30 mL) and extract with ethyl acetate (30 mL × 3). Wash the combined organic layers with brine (30 mL × 3), dry with sodium sulfate, and concentrate under reduced pressure to obtain the crude product. Purify the crude product by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 2) to obtain compound 40b. ESI m / z 1175.6 [M+H] + .LCMS:product:Rt=1.718min.

[0634] Step 3): Compound 40b (220.0 mg, 0.15 mmol, 1.0 equivalence) was dissolved in methanol (3 mL) and tetrahydrofuran (3 mL), and lithium hydroxide monohydrate (62.8 mg, 1.5 mmol, 10.0 equivalence) and water (3 mL) were added. The reaction mixture was stirred at 50 °C for 16 hours. The resulting reaction mixture was neutralized 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 40c. ESI m / z 1161.6 [M+H] +.LCMS:product:Rt=1.646min.

[0635] Step 4): Compound 40c (190.1 mg, 0.13 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 resulting reaction mixture was concentrated and purified by preparative high-performance liquid chromatography (ammonium bicarbonate) to obtain compound 40. ESI m / z 375.2 [M / 2+H] + .LCMS:product:Rt=0.860min. 1 H NMR(400MHz,D2O)δ7.50(s,1H),7.30–7.02(m,12H),4.58(s,2H),4.46(s,2H),3.67(s,6H),3.39–3.21(m,4H),3 .11(dd,J=18.4,10.4Hz,2H),2.68(dt,J=39.2,11.2Hz,6H),2.44–2.22(m,4H),2.00(s,2H),1.73–1.54(m,2H).

[0636] Example 41: Synthesis of Compound 41

[0637] Step 1): Under nitrogen protection at 0°C, lithium bis(trimethylsilyl)amino (1M in THF, 42.84mL, 42.84mmol, 1.3equivalent) was added to a solution of tetrahydrofuran (120mL) containing inter 3 (12.80g, 32.95mmol, 1.0equivalent). The reaction mixture was stirred at 0°C for 30 minutes. Subsequently, a solution of tetrahydrofuran (50mL) containing 2-bromo-4-(bromomethyl)-1-fluorobenzene (SM1, 9.71g, 36.25mmol, 1.1equivalent) was added. The reaction mixture was heated to room temperature and stirred for 4 hours. The mixture was quenched with saturated ammonium chloride aqueous solution (200mL) and extracted with ethyl acetate (100mL × 3). The organic phases were combined, washed with saturated ammonium chloride aqueous solution (500mL), 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 41d1. ESI m / z 519.0 [M-tert-butyl+H] + .LCMS:product:Rt=1.397min.

[0638] Step 2): A solution of tetrahydrofuran (100 mL) containing compound 41d1 (10.71 g, 16.01 mmol, 1.0 equivalent) was stirred and cooled to 0°C. Hydrogen peroxide (30% aqueous solution, 6.21 mL, 80.03 mmol, 5.0 equivalent) was added dropwise, followed by an aqueous solution of lithium hydroxide (1.07 g, 25.61 mmol, 1.6 equivalent) (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 equivalent) 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 crude compound 41d2. ESI m / z 362.0 [M-tert-butyl+H] + .LCMS:product:Rt=1.157min.

[0639] Step 3): To a solution of compound 41d2 (8.4 g, 15.74 mmol) in tetrahydrofuran (100 mL), add O-tert-butyl-N,N'-diisopropylisourea (12.61 g, 62.96 mmol, 4.0 equivalents). Stir the mixture at 65 °C for 2 hours. Filter the mixture, wash the filter cake with ethyl acetate (100 mL × 3), and combine the filtrates. Concentrate to dryness under reduced pressure. Purify the residue by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 1 / 1) to give compound 41d3. ESI m / z 362.0 [M-tert-butyl-tert-butyl+H] + .LCMS:product:Rt=1.620min.

[0640] Step 4): In a solution of N,N-dimethylacetamide (50 mL) containing compound 41d3 (5.4 g, 10.97 mmol, 1.0 equivalent), zinc cyanide (1.29 g, 10.97 mmol, 1.0 equivalent), N,N-diisopropylethylamine (5.73 mL, 32.92 mmol, 3.0 equivalent), and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) palladium dichloride (830 mg, 1.10 mmol, 0.1 equivalent) 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 x 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. The residue was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 2 / 1) to give compound 41d4. ESI m / z 441.2 [M+Na]+ .LCMS:product:Rt=1.433min.

[0641] Step 5): To a solution of compound 41d4 (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). Stir the reaction mixture at room temperature in a hydrogen atmosphere for 5 hours. Filter the reaction solution through diatomaceous earth, wash the filter cake with tetrahydrofuran (200 mL), and concentrate the filtrate to dryness under reduced pressure to obtain the crude compound 41d. ESI m / z 423.2 [M+H] + .LCMS:product:Rt=0.927min.

[0642] Step 6): Add a solution of lithium hydroxide (236 mg, 5.61 mmol, 4.0 equivalent) in water (1 mL) to a tetrahydrofuran solution (5 mL) containing inter 1 (500 mg, 0.40 mmol, 1.0 equivalent). Stir the reaction mixture at 60 °C for 3 hours. Concentrate the reaction mixture under reduced pressure. Pour the residue into water (10 mL), adjust the pH to 5 with 1 M HCl, and extract with ethyl acetate (2 × 8 mL). Dry the combined organic phases with anhydrous sodium sulfate and filter. Concentrate the filtrate under reduced pressure to give compound 41a. ESI m / z 287.9 ​​[M-tert-butyl+H] + .LCMS:product:Rt=0.823min.

[0643] Step 7): To a solution of tetrahydrofuran (5 mL) containing compound 41a (440 mg, 1.11 mmol, 1.0 equivalence), add O-tert-butyl-N,N'-diisopropylisourea (886 mg, 4.42 mmol, 4.0 equivalence). Filter the mixture through filter paper to remove the solid. Wash the solid with ethyl acetate (8 mL × 2). Concentrate the combined filtrates to dryness under reduced pressure. Purify the residue by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 1 / 1) to give compound 41b. ESI m / z 342.0 [M-tert-butyl+H] + .LCMS:product:Rt=1.523min.

[0644] Step 8): To a mixed solution containing 10 mL of dioxane (406 mg, 0.95 mmol, 1.0 equivalence) and 2 mL of water, add (3-formylphenyl)boronic acid (213 mg, 1.42 mmol, 1.5 equivalence), potassium phosphate (604 mmol, 2.84 mmol, 3.0 equivalence), and 1,1-bis(diphenylphosphine)diberberine palladium dichloride (69 mg, 0.09 mmol, 0.1 equivalence). The reaction mixture was stirred at 90 °C for 18 hours under nitrogen protection. 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 (20 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 / ethyl acetate = 4 / 1) to give compound 41c. ESI m / z 368.2 [M-tert-butyl+H] + .LCMS:product:Rt=1.371min.

[0645] Step 9): To a solution of compound 41c (241 mg, 0.50 mmol, 0.5 equivalence) in dichloromethane (15 mL), add compound 41d (450 mg, 1.00 mmol, 1.0 equivalence), sodium triacetylborohydride (637 mg, 3.00 mmol, 3.0 equivalence), and acetic acid (0.1 mL). Stir the reaction mixture at room temperature for 2 hours. Quench the reaction mixture with saturated sodium bicarbonate solution (30 mL) and extract with dichloromethane (10 mL × 2). Wash the combined organic phases with saturated brine (30 mL), dry the organic phase to anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Purify the residue by silica gel column chromatography (petroleum ether / tetrahydrofuran = 1 / 1) to give compound 41e. ESI m / z 830.4 [M+H] + .LCMS:product:Rt=1.354min.

[0646] Step 10): To an N,N-dimethylformamide (8 mL) solution containing compound 41e (442 mg, 0.48 mmol, 1.0 equivalence), add inter5 (295 mg, 0.63 mmol, 1.3 equivalence) and potassium carbonate (201 mg, 1.45 mmol, 3.0 equivalence). Stir the mixture at room temperature for 16 hours. Dilute the mixture with water (25 mL) and extract with ethyl acetate (10 mL × 3). Wash the combined organic phases with saturated brine (50 mL × 3), dry over anhydrous sodium sulfate, and concentrate the filtrate under vacuum. Purify the residue by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 1 / 1) to give compound 41f. ESI m / z 559.5 [(M-Boc) / 2+H] +.LCMS:product:Rt=1.828min.

[0647] Step 11): Compound 41f (272 mg, 0.19 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 16 hours. The reaction mixture was concentrated and purified by preparative high-performance liquid chromatography (formic acid) to obtain compound 41. ESI m / z 749.3 [M+H] + .LCMS:product:Rt=1.304min. 1 H NMR(400MHz,D2O)δ7.52–7.38(m,3H),7.37–7.13(m,8H),7.05(t,J=9.2Hz,2H),4. 62(s,4H),4.30(s,6H),3.47(dd,J=11.6,7.0Hz,2H),3.40–3.26(m,2H),3.17(dt, J=19.0,9.5Hz,2H),2.93(dd,J=14.8,6.1Hz,2H),2.72(dt,J=28.2,11.5Hz,4H),2 .42(ddd,J=19.3,12.2,8.0Hz,4H),2.04(dd,J=6.7,3.1Hz,2H),1.73–1.57(m,2H).

[0648] Example 42: Synthesis of Compound 42

[0649] Step 1): Dissolve inter 3 (10.6 g, 27.29 mmol, 1.0 equivalent) in tetrahydrofuran (200 mL), add lithium bis(trimethylsilylamino)amine (35.47 mL, 35.47 mmol, 1.3 equivalent) at -78 °C, and stir for 30 minutes 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 equivalent), allow to warm naturally to room temperature, and stir for 5 hours. Quench the reaction mixture with 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 42a. ESI m / z 519.1 [M-56+H] + .LCMS:product:Rt=2.018min.

[0650] Step 2): Compound 42a (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 42b. ESI m / z 360.0 [M-56+H] + .LCMS:product:Rt=1.408min.

[0651] Step 3): Compound 42b (15.0 g, 28.83 mmol, 1.0 equivalence) was dissolved in tetrahydrofuran (200 mL), and O-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), dried over anhydrous sodium sulfate, and filtered. 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 42c. ESI m / z 494.2 [M + Na] + .LCMS:product:Rt=1.476min.

[0652] Step 4): To a solution (50 mL) of N,N-dimethylacetamide containing compound 42c (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-bisdiphenylphosphine-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 42d. ESI m / z 307.0 [M-56-56+H] + .LCMS:product:Rt=1.738min.

[0653] Step 5): Compound 42d (1.4 g, 3.35 mmol, 1.0 equivalent) was dissolved in tetrahydrofuran (20 mL) and ammonia (1 mL), and then Raney nickel (0.73 g, 3.35 mmol, 1.0 equivalent) 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 42e. ESI m / z 423.2 [M+H] + .LCMS:product:Rt=0.991min.

[0654] Step 6): Compound 42e (400 mg, 0.95 mmol, 1.0 equivalent) was dissolved in methanol (10 mL), and 1 g of compound (397.2 mg, 1.04 mmol, 1.1 equivalent) was added. The reaction mixture was stirred at 50 °C for 2 hours, and then sodium borohydride (71.6 mg, 1.89 mmol, 2.0 equivalent) was added. The reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 2). 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 (dichloromethane / methanol = 10 / 1) to give compound 42f. ESI m / z 788.4 [M+H] + .LCMS:product:Rt=1.292min.

[0655] Step 7): Compound 42f (200.1 mg, 0.25 mmol, 1.0 equivalence) was dissolved in N,N-dimethylformamide (10 mL), followed by the addition of inter 5 (237.8 mg, 0.51 mmol, 2.0 equivalence) and cesium carbonate (206.8 mg, 0.63 mmol, 2.5 equivalence). The reaction mixture was stirred at room temperature for 18 hours. The mixture was poured into water (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 (dichloromethane / methanol = 10 / 1) to give compound 42 g. ESI m / z 1176.6 [M+H] + .LCMS:product:Rt=1.563min.

[0656] Step 8): 42 g (280.0 mg, 0.24 mmol, 1.0 equivalent) of the compound was dissolved in methanol (3 mL) and tetrahydrofuran (3 mL), and lithium hydroxide monohydrate (99.9 mg, 2.4 mmol, 10.0 equivalent) and water (3 mL) were added. The reaction mixture was stirred at 50 °C for 18 hours. The resulting reaction mixture was neutralized to pH 3 with 10% hydrochloric acid aqueous solution. Extraction was performed with ethyl acetate (30 mL × 3), and the organic phase was concentrated under reduced pressure to give compound 42 h. ESI m / z 1162.6 [M+H] + .LCMS:product:Rt=1.483min.

[0657] Step 9): Compound 42h (250 mg, 0.22 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 mixture was concentrated and purified by p...

Claims

1. A lipoprotein (a) inhibitor of the structure shown in formula (0), an isomer, an isotopically labeled compound, a prodrug, or a pharmaceutically acceptable salt, ester, hydrate, or solvate thereof: in, R is selected from Ring C is selected from C 6-10 Aryl, 5-10 membered heteroaryl, or 3-12 membered heterocyclic; the C 6-10 Aryl, 5-10-membered heteroaryl, and 3-12-membered heterocyclic groups are optionally and independently bounded by 1, 2, or 3 groups selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl or C 1-6 Substituents of haloalkoxy groups; n0 is selected from 0, 1 or 2; preferably, n0 is selected from 0 or 1; more preferably, n0 is 0; n1 is selected from 1, 2 or 3, and n2 is selected from 1 or 2; preferably, n1 is selected from 2 and n2 is selected from 1, or n1 is selected from 2 and n2 is selected from 2. L is selected from: Preferably, L is selected from Rb is selected from: H, -COO-Rc, -CONR d R e -NH2, -NHCO-Rc, -CN, -NO2, -CH2COO-Rc, -CH2CONH-Rc, -CH2CH2COOH, -CH2NH2 or -CH2CN; preferably -COOH; Rc is selected from H or C. 1-6 alkyl; R d R e Each is independently selected from H or C 1-6 Alkyl; preferably, R d R e One of them is H, and the other is C. 1-6 alkyl; R o Selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy; preferably, R o Selected from halogens (e.g., F, Cl), C 1-4 Alkyl (e.g., methyl), C 1-4 Alkyl groups (e.g., methoxy groups); preferably, R o Selected from halogens (e.g., F, Cl), C 1-4 Alkyl (e.g., methyl); more preferably, R o Halogens (e.g., F); Ring A is selected from C 6-10 aryl, 5-10 membered heteroaryl, or 3-10 membered heterocyclic, wherein C 6-10 The aryl, 5-10-membered heteroaryl, and 3-10-membered heterocyclic groups are each independently selected by 1, 2, or 3 (preferably 1) groups from deuterium, halogen, hydroxyl, C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Substitution with cycloalkyl or 3-6 membered heterocyclic groups; Ring B is selected from C 8-10 Fused bicyclic cyclic hydrocarbon group, 8-10 membered fused bicyclic heterocyclic group, or 8-10 membered fused bicyclic heteroaryl group; the C 8-10 The fused bicyclic cyclic hydrocarbon group, the 8-10 fused bicyclic heterocyclic group, and the 8-10 fused bicyclic heteroaryl group are each independently selected by 1, 2, or 3 groups chosen from deuterium, halogen, amino, oxo group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 Substitution with cycloalkyl or 3-6 membered heterocyclic groups; optionally, the two substituents attached to the same carbon atom form a C12 group. 3-6 Cycloalkyl or 4-7 membered heterocyclic groups; provided that ring B is selected from C. 8-10 When fused with bicyclic hydrocarbon groups, the C 8-10 In fused bicyclic hydrocarbon groups, at least one amino group is substituted. n3 is selected from 0 or 1, preferably n3 is 1; The condition is: when n3 is 0, L is selected from...

2. The lipoprotein(a) inhibitor according to claim 1, wherein the isomer, isotopically labeled compound, prodrug, or pharmaceutically acceptable salt, ester, hydrate, or solvate thereof, is a compound of formula (I): in, Rb, B, A, n3, R, L, n1, n2 are as defined in claim 1.

3. The lipoprotein(a) inhibitor according to claim 1 or 2, characterized in that, The ring A is selected from 4- to 10-membered heterocyclic groups, C 6-10 aryl or 5-10 membered heteroaryl, wherein the 4-10 membered heterocyclic group, C 6-10 The aryl group and the 5- to 10-membered heteroaryl group are each independently selected by 1, 2, or 3 ions from halogen, hydroxyl group, C-hydroxyl group, etc. 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Substituents of cycloalkyl groups; The heteroatoms in the 4-10 membered heterocyclic group and the 5-10 membered heteroaryl group are selected from N, O or S. The number of heteroatoms in the 4-10 membered heterocyclic group and the 5-10 membered heteroaryl group is one or more. When two or more heteroatoms are included, they may be the same, partially the same or completely different.

4. The lipoprotein(a) inhibitor according to claim 3, characterized in that, The ring A is selected from: Preferred Preferred Preferred Preferred Among them, the key marked with "#B" is connected to ring B, and the key marked with "#L" is connected to L; The structures shown in A-1', A-2', A-3, A-4, A-4', and A-2'-1 are each independently aromatic groups; A1, A2, A3, A4, A 12 A 13 A 14 A 15 A 16 A 17 A 18 A 19 A 22 A 23 A 26 A 27 A 28 Each is independently selected from CH or N; preferably, A1, A2, A3, and A4 are all CH; preferably, one of A1, A2, A3, and A4 is N (for example, A1 is N, and A2, A3, and A4 are all CH; or, for example, A2 is N, and A1, A3, and A4 are all CH); preferably, two of A1, A2, A3, and A4 are N (for example, A1 and A4 are CH, and A2 and A3 are N); preferably, three of A1, A2, A3, and A4 are N; preferably, A 12 A 13 All are CH; preferably, A 12 A 13 One of them is N; preferably, A 12 A 13 All are N; preferably, A 14 A 15 All are CH; preferably, A 14 A 15 One of them is N; preferably, A 16 A 17 A 18 A 19 All are CH; preferably, A 16 A 17 A 18 A 19 One of them is N; preferably, A 16 A 17 A 18 A 19 Two of them are N (e.g., A). 16 A 19 For N, A 17 A 18 (CH); preferably, A 22 A 23 All are CH; preferably, A 26 A 27 A 28 All are CH; A5, A7, A8, A 10 A 11 Each is independently selected from N, O, S, CH or NH; preferably, at least one of A5, A7, and A8 is selected from S, N, O or NH; preferably, A 10 A 11 At least one of them is selected from S, N, O or NH; preferably, A5 is selected from CH and N, A7 is selected from NH, O and S, and A8 is selected from CH and N; preferably, A5 is selected from N, A7 is selected from S, and A8 is selected from CH; preferably, A 10 Selected from NH, O and S, A 11 Selected from CH and N, or A 11 Selected from NH, O and S, A 10 Selected from CH and N; A6 and A9 are each independently selected from C or N; preferably, both A6 and A9 are C. A 20 A 21 Each is independently selected from CH or N, and A 20 A 21 At least one of them is selected from N; A 24 A 25 Each is independently selected from CH2, NH, O, or S, with at least one selected from NH, O, or S; preferably, A 24 A 25 All are O; A 29 A 30 Each is independently selected from CH2, NH, O, or S; preferably, A 29 For CH2, A 30 It is O; m1 and m2 are each independently selected from 0, 1, 2 or 3, preferably 0 or 1; preferably, m1 is selected from 0 or 1, more preferably 0; preferably, m2 is selected from 0. t1, t2, t3, and t4 are each independently selected from 1, 2, or 3; preferably, t1, t2, t3, and t4 are each independently selected from 1 or 2; preferably, t3 is selected from 1 and 2; more preferably, t3 is 1; R 1a R 2a Each is independently selected from deuterium, halogen, hydroxyl, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic alkyl; preferably, R 1a Selected from halogens, C 1-4 Alkyl, C 1-4 Alkoxy; preferably, R 1a Selected from halogens (e.g., F, Cl), C 1-4 Alkyl (e.g., methyl); preferably, R 1a It is a halogen (e.g., F); preferably, R 2a Selected from halogens, hydroxyl groups, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl; preferably, R 2a Selected from halogens (e.g., F, Cl), C 1-4 Alkyl (e.g., methyl); preferably, R 2a Halogens (e.g., F); It can be a single bond or a double bond, wherein the two adjacent chemical bonds are not both double bonds.

5. The lipoprotein(a) inhibitor according to claim 4, characterized in that, The R 1a Selected from F, methyl or methoxy; preferably F or methyl; more preferably F; The R 2a It is selected from methyl, ethyl, isopropyl, halogen (e.g., F), hydroxy, cyclopropyl or methoxy; preferably F.

6. The lipoprotein(a) inhibitor according to any one of claims 3-5, characterized in that, The ring A is selected from: Preferably, ring A is The key marked "#B" is connected to ring B, and the key marked "#L" is connected to ring L.

7. The lipoprotein(a) inhibitor according to claim 1 or 2, characterized in that, The ring B is selected from C. 8-10 Fused bicyclic cyclic hydrocarbon group, 8-10 membered fused bicyclic heterocyclic group, or 8-10 membered fused bicyclic heteroaryl group; the C 8-10 The fused bicyclic cyclic hydrocarbon group, the 8-10 fused bicyclic heterocyclic group, and the 8-10 fused bicyclic heteroaryl group are each independently selected by 1, 2, or 3 groups chosen from halogen, amino, oxo, C 1-6 Alkyl, C 1-6 Substituents of the haloalkyl group; optionally, two substituents attached to the same carbon atom form a C12 group. 3-6 Cycloalkyl or 4-7 membered heterocyclic groups; provided that ring B is selected from C. 8-10 When fused with bicyclic hydrocarbon groups, the C 8-10 In fused bicyclic hydrocarbon groups, at least one amino group is substituted. The heteroatoms in the 8-10 fused bicyclic heterocyclic group and the 8-10 fused bicyclic heteroaryl group are selected from N, O or S. The number of heteroatoms in the 8-10 fused bicyclic heterocyclic group and the 8-10 fused bicyclic heteroaryl group is one or more. When two or more heteroatoms are included, they may be the same, partially the same or completely different. Preferably, the 8-10 fused bicyclic heterocyclic group and the 8-10 fused bicyclic heteroaryl group contain at least one nitrogen heteroatom.

8. The lipoprotein(a) inhibitor according to claim 7, characterized in that, The ring B is selected from: Preferred Preferred Preferred The key identified by "#Rb" is connected to Rb; B 1-a B 1-b B 1-c B 1-d B 1-e B 2-a B 2-b B 2-c B 2-d B 2-e ,B3,B4,B5,B6,B7,B8,B9,B 10 B 11 B 12 B 14 Each is independently selected from CH or N; among them, B9 and B 10 B 11 B 12 At least one of them is N; B 13 B 15 Each is independently selected from S, NH, or O; s1, s2, s3, s4, s5, s6, s7, s8, s9, and s10 are each independently selected from 1 or 2; u1, u2, u3, u4, u5, u6, u7, u8, u10, and u12 are each independently selected from 0, 1, or 2, preferably 0 or 1, and more preferably 0; u9, u11, and u13 are each independently selected from 0 or 1, with 0 being more preferred; R1, R3, R5, R8, R 10 R 12 Each is independently selected from deuterium, halogen, oxo group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy group; alternatively, two R1 atoms attached to the same carbon atom form C 3-6 Cycloalkyl; preferably methyl or oxo; optionally, two R1 groups attached to the same carbon atom form a cyclopropyl group; R2, R4, R6, R7, R9, R 11 R 13 Each is independently selected from deuterium, halogens, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy; preferably methyl, halogen (e.g., F, Cl) or trifluoromethyl; more preferably halogen (e.g., F, Cl) or C 1-4 Alkyl (e.g., methyl).

9. The lipoprotein(a) inhibitor according to claim 7 or 8, characterized in that, The ring B is selected from: Preferably, ring B is selected from Preferably, ring B is selected from More preferably, ring B is selected from The key identified by "#Rb" is connected to Rb.

10. The lipoprotein(a) inhibitor according to claim 1 or 2, characterized in that, The Selected from: Preferably, Selected from Preferably, Selected from 11. The lipoprotein(a) inhibitor according to claim 1 or 2, characterized in that, The ring C is selected from: Preferred Preferred Preferred More Among them, the key marked with #L is connected to L; C1, C2, C3, C4, C 10 C 11 C 12 C 13 C 14 C 15 C 16 C 17 C 21 C 22 C 23 Each is independently selected from CH or N; preferably, C1, C2, C3, and C4 are all CH; preferably, C 10、 C 11 All are CH; preferably, C 12、 C 13、 C 14、 C 15 One or two of them are N, and the rest are CH2; preferably, C 12 C 15 Both are N, C 13 C 14 All are CH; preferably, C 16 C 17 All are CH; preferably, C 21 C 22 C 23 All are CH; C5, C7, and C8 are each independently selected from N, O, S, CH, or NH; preferably, C5 is selected from CH or N; preferably, C5 is N; preferably, C8 is selected from O or S; preferably, C8 is S; preferably, C7 is CH. C6 and C9 are each independently selected from C or N; preferably, both C6 and C9 are C. C 18 C 19 C 20 C 24 C 25 Each is independently selected from CH2, NH, O, or S, and C 18 C 19 C 20 At least one of them is selected from NH, O or S, C 24 C 25 One and only one of them is selected from NH, O or S; preferably, C 18 C 20 Both are O, C 19 CH2; preferably, C 24 CH2, C 25 It is O; q is selected from 1, 2 or 3, preferably 1 or 2, preferably 1; It can be a single bond or a double bond, wherein the two adjacent chemical bonds are not both double bonds; The structures shown in C-1, C-2, C-3, C-3', and C-2-1 are each independently aromatic groups; The C-1, C-2, C-3, C-3', C-4, C-5, C-2-1, and C-4-1 are optionally and independently substituted by one, two, or three (preferably one) substituents selected from halogen, cyano, hydroxyl, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, or C1-4 haloalkoxy. Preferably, the C-1 is optionally selected from halogen, cyano, hydroxyl, C... 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl or C 1-4 The alkyl group is substituted by a halogenated alkoxy group; preferably, one or two (preferably one) C-1 groups are selected from halogens (e.g., F, Cl) or C. 1-4 Alkyl (e.g., methyl) substituents; preferably, the C-1 is optionally substituted with one or two (preferably one) halogens (e.g., F); Preferably, C-1, C-2, C-3, C-3', C-4, C-5, C-2-1, and C-4-1 are not substituted; preferably, C-2, C-3, C-3', C-4, C-5, C-2-1, and C-4-1 are not substituted.

12. The lipoprotein(a) inhibitor according to claim 11, characterized in that, The ring C is selected from: Each of the above groups may optionally be independently bound by one or two elements selected from halogens (e.g., F, C). 1-4 Alkyl or C 1-4 The alkoxy group is substituted; wherein the bond marked #L is attached to L; Preferably, ring C is selected from: None of the above groups are substituted; wherein the bond marked #L is attached to L; Preferably, ring C is selected from: Among them, the key marked with #L is connected to L; Preferably, ring C is selected from Among them, the key marked with #L is connected to L; More preferably, ring C is The key marked with #L is connected to L.

13. The lipoprotein(a) inhibitor according to any one of claims 1-12, wherein the isomer, isotopically labeled compound, prodrug, or pharmaceutically acceptable salt, ester, hydrate, or solvate thereof, wherein the 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 The keys marked "*1", "*2", and "*3" are each independently connected to R. (or ); preferably, the key marked "*1" is connected to The key marked "*2" is connected to R, and the key marked "*3" is connected to... (or ).

14. The lipoprotein(a) inhibitor according to any one of claims 1-13, wherein the isomer, isotopically labeled compound, prodrug, or pharmaceutically acceptable salt, ester, hydrate, or solvate thereof, the compound having the structure shown in formula II or III: in, R b A, B, C, L, n1, n2, n3 as defined in any one of claims 1-13.

15. The lipoprotein(a) inhibitor according to any one of claims 1-14, its isomers, isotopically labeled compounds, prodrugs, or pharmaceutically acceptable salts, esters, hydrates, or solvates thereof, wherein the compound has the structure shown in Formula IV: in, The keys identified by "a" and "b" are located in the middle position of ring A, the keys identified by "c" and "d" are located in the middle position of ring C, and the keys identified by "e" and "f" are located in the adjacent position of ring D. n1 is selected from 1, 2 or 3, and n2 is selected from 1 or 2; preferably, n1 is selected from 2 and n2 is selected from 1, or n1 is selected from 2 and n2 is selected from 2; preferably, n1 is selected from 2 and n2 is selected from 1; preferably, both n1 and n2 are 2. Preferably, in formula (IV), at least one of the two groups (n1, n2) is n1+n2=3; Ring D is selected from phenyl, 5-6-membered heteroaryl; preferably, ring D is selected from phenyl, pyridyl, pyrazinyl, thiophenyl, furanyl, pyrroleyl or imidazolyl; preferably, ring D is selected from phenyl, 6-membered azaaryl; preferably, ring D is selected from phenyl, pyridyl or pyrazinyl; more preferably, ring D is selected from phenyl; The ring D is optionally selected from one or two elements chosen from deuterium, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 The alkyl group is substituted with a substituent of a haloalkoxy group; preferably, ring D is optionally replaced by one selected from halogens (e.g., F, Cl), C. 1-6 Alkyl (e.g., methyl) or C 1-6 The alkyl group is substituted with a substituent of a haloalkyl group (e.g., trifluoromethyl); preferably, ring D is optionally replaced by a halogen (e.g., F, Cl) or C. 1-4 The alkyl group (e.g., methyl) is substituted; preferably, ring D is not substituted; Ring E is selected from 5-6 membered heterocyclic groups, preferably 5-6 membered nitrogen-containing heterocyclic groups; preferably 5-6 membered nitrogen-containing heterocyclic groups have 1 N atom and 0 or 1 heteroatom selected from O or S; preferably 5-6 membered nitrogen-containing heterocyclic groups have 1 N atom and 0 heteroatoms selected from O or S; preferably ring E is selected from pyrrolidinyl, piperidinyl, 1,3-oxazinyl or piperazine; preferably ring E is selected from pyrrolidinyl or piperidinyl; preferably ring E is pyrrolidinyl. Preferably, Selected from Preferred Preferred Among them, s1, s2, s5, s6, s7, s8, and B 1-a B 2-a B 1-b B 2-b B 13 B 14 B 15 R2, R9, R 11 R 13 u2, u9, u11, u13 are as defined in claim 8 above; Preferably, s1 and s2 are both 1, or one of s1 and s2 is selected from 1 and the other is selected from 2; more preferably, s1 and s2 are both 1. Preferably, s5 and s6 are both 1, or one of s5 and s6 is selected from 1 and the other is selected from 2; more preferably, one of s5 and s6 is selected from 1 and the other is selected from 2 (for example, s5 is selected from 1 and s6 is selected from 2; or for example, s5 is selected from 2 and s6 is selected from 1). Preferably, s7 and s8 are both 1, or one of s7 and s8 is selected from 1 and the other is selected from 2; more preferably, one of s7 and s8 is selected from 1 and the other is selected from 2 (for example, s7 is selected from 1 and s8 is selected from 2; or for example, s7 is selected from 2 and s8 is selected from 1). Preferably, B 1-a B 2-a Both are CH, or B 1-a B 2-a Both are N, or B 1-a B 2-a One of them is selected from N, and the other is selected from CH; preferably, B 1-a B 2-a All are CH; Preferably, B 1-b B 2-b Both are CH, or B 1-b B 2-b One of them is selected from N, and the other is selected from CH; preferably, B 1-b B 2-b All are CH; Preferably, B 13 Selected from S; Preferably, B 14 Selected from N; Preferably, B 15 Selected from S; Preferably, R2 is selected from halogens, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Halogenated alkoxy groups; preferably halogens, C 1-4 Alkyl and C 1-4 Halogenated alkyl groups, preferably halogens (e.g., F, Cl) and C. 1-4 Alkyl groups (e.g., methyl groups); Preferably, R9 is selected from C 1-4 Alkyl and C 1-4 Halogenated alkyl groups, preferably C 1-4 Alkyl groups (e.g., methyl groups); Preferably, R 11 Selected from halogens, C 1-4 Alkyl and C 1-4 Halogenated alkyl groups, preferably halogens (e.g., F, Cl) and C. 1-4 Alkyl groups (e.g., methyl groups); Preferably, R 13 Selected from C 1-4 Alkyl and C 1-4 Halogenated alkyl groups, preferably C 1-4 Alkyl groups (e.g., methyl groups); Preferably, u2 is selected from 0 and 1, and more preferably 0; Preferably, u9 is selected from 0 and 1, and more preferably 0; Preferably, u11 is selected from 0 and 1, and more preferably 0; Preferably, u13 is selected from 0 and 1, and more preferably 0; More preferably, Selected from Preferred Preferred Preferred Preferred Preferred Preferably, ring A is selected from phenyl, 5-6 membered monocyclic heteroaryl, 9-10 membered fused bicyclic heteroaryl, or benzo5-6 membered monocyclic heterocyclic group; more preferably, ring A is selected from phenyl or 5-6 membered monocyclic heteroaryl; optionally, each of ring A is independently surrounded by one or two (preferably one) groups selected from halogens, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl or C 1-4 The alkyl group is substituted with a substituent; preferably, each of the ring A is optionally and independently replaced by one or two (preferably one) substituents selected from halogens (e.g., F, Cl) or C. 1-4 Alkyl (e.g., methyl) substituents are used; preferably, ring A is optionally substituted independently by one or two (preferably one) halogens (e.g., F); preferably, ring A is not substituted. Preferably, ring A is selected from Preferred Preferred Where A1-A 19 A 22 A 23 R 1a R 2a m1, m2, and t3 are as defined in claim 4; Preferably, ring A is selected from Preferably, ring A is selected from More The rings A are optionally each independently selected from 1 or 2 (preferably 1) halogens, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl or C 1-4 The alkyl group is substituted with a substituent; preferably, each of the ring A is optionally and independently replaced by one or two (preferably one) substituents selected from halogens (e.g., F, Cl) or C. 1-4 Alkyl (e.g., methyl) substituents are used; preferably, ring A is optionally substituted independently by one or two (preferably one) halogens (e.g., F); preferably, ring A is not substituted. Preferably, the ring C is selected from phenyl, 5-6 membered monocyclic heteroaryl, 9-10 membered fused bicyclic heteroaryl or benzo5-6 membered monocyclic heterocyclic group; preferably phenyl or 5-6 membered monocyclic heteroaryl. Preferably, ring C is selected from Preferred Preferred Preferred Among them, C1-C4, C5, C7, C8, C 10 -C 17 q is as described in claim 11; Preferably, ring C is selected from Preferred More Preferably, ring C is selected from The rings C are optionally each independently selected from 1 or 2 (preferably 1) halogens, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl or C 1-4 The alkyl group is substituted with a substituent of the alkyl group; preferably, each of the ring Cs is optionally and independently selected from one or two (preferably one) halogens (e.g., F, Cl) or C. 1-4 Alkyl (e.g., methyl) substituents are used; preferably, the ring Cs are each optionally and independently substituted with one or two (preferably one) halogens (e.g., F); preferably, the ring Cs are not substituted. Rb is selected from H, -COORc, or -CONR. d R e Preferably, Rb is selected from -COORc; Rc is selected from H and C. 1-6 Alkyl group; preferably, Rc is selected from H and C. 1-4 alkyl; R d R e Each is independently selected from H or C 1-6 Alkyl; preferably, R d R e One of them is selected from H, and the other is selected from C. 1-4 alkyl; Preferably, Rb is selected from -COOH.

16. The compound according to any one of claims 1-15, its isomers, isotopically labeled compounds, prodrugs, or pharmaceutically acceptable salts, esters, hydrates, or solvates thereof, wherein the compound has the structure shown in Formula V: in, The keys identified by "a" and "b" are located in the middle position of ring A, the keys identified by "c" and "d" are located in the middle position of ring C, and the keys identified by "e" and "f" are located in the adjacent position of ring D. Rb, D, E, A, C, n1, n2, n3, L are as defined in claims 1-15 above; Preferably, L is selected from The key marked with "*1" is connected to b, the key marked with "*2" is connected to c, and the key marked with "*3" is connected to b. Preferably, L is selected from The key marked with "*1" is connected to b, the key marked with "*2" is connected to c, and the key marked with "*3" is connected to b. Preferably, L is selected from Preferably, L is selected from Preferably, L is selected from Preferably, L is selected from The key marked with "*1" is connected to b, the key marked with "*2" is connected to c, and the key marked with "*3" is connected to b. Preferably, L is selected from The key marked with "*1" is connected to b, the key marked with "*2" is connected to c, and the key marked with "*3" is connected to b.

17. The lipoprotein(a) inhibitor 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 the structure shown in Formula VI: in, The keys identified by "a" and "b" are located between the points in ring A, and the keys identified by "e" and "f" are located adjacent to the points in ring D. Rb, D, E, A, n1, n2, L are as defined in any of the preceding claims; Preferably, L is selected from Preferably, L is selected from The key marked "*3" is connected to 18. The lipoprotein(a) inhibitor, its isomers, isotopically labeled compounds, prodrugs, or pharmaceutically acceptable salts, esters, hydrates, or solvates thereof according to claims 1-17, characterized in that, The compound is selected from:

19. A pharmaceutical composition comprising, as an active ingredient, a compound according to any one of claims 1-18, an isomer thereof, an isotopically labeled compound thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof, ester thereof, hydrate thereof or solvate thereof.

20. The use of the compound of any one of claims 1-18, its isomers, isotopically labeled compounds, prodrugs, or pharmaceutically acceptable salts, esters, hydrates or solvates thereof, or the pharmaceutical composition of claim 19, in the preparation of a medicament for the prevention and / or treatment of diseases and medicines related to Lp(a).

21. The application according to claim 20, characterized in that, The diseases associated with Lp(a) are cardiovascular diseases, including but not limited to atherosclerosis, stroke, hyperlipidemia, elevated Lp(a) levels, thrombosis, coronary heart disease, and aortic stenosis.

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