Five-membered aromatic heterocyclic derivative for inhibiting lipoprotein(a)

Abstract

The present invention relates to the field of medicine, and in particular to a five-membered aromatic heterocyclic derivative for inhibiting lipoprotein(a) (Lp(a)). Specifically provided is a compound represented by formula (I) or an isomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutically acceptable salt, ester, hydrate or solvate thereof. The compound of the present invention has the advantages of a stronger apolipoprotein(a) (Apo(a))-binding capability, a capability of more effectively lowering the level of Lp(a), stronger inhibitory activity against oxidized phospholipid-Apo(a), better pharmacokinetic properties, and high Lp(a) selectivity, and can be used for preparing a drug for treating cardiovascular diseases.

Description

Five-membered aromatic heterocyclic derivatives for inhibiting lipoprotein (a)

[0001] Citation of relevant applications

[0002] This application claims priority to Chinese patent application No. 202510197444.7 filed with the China National Intellectual Property Administration on February 21, 2025, and Chinese patent application No. 202511094464.8 filed with the China National Intellectual Property Administration on August 6, 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 to a five-membered aromatic heterocyclic derivative for inhibiting lipoprotein (a). 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 pharmaceutically viable compounds for lowering plasma Lp(a) levels, achieving some progress in the field of cardiovascular disease. However, there are currently no marketed small-molecule Lp(a) drugs. Therefore, there is an urgent need to develop cardiovascular drugs that meet clinical needs.

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

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

[0008] Therefore, there is an urgent need to develop cardiovascular drugs with higher Lp(a) selectivity, more effective reduction of Lp(a) levels, and to meet clinical needs. Summary of the Invention

[0009] In view of the above-mentioned technological status, the present invention provides a five-membered aromatic heterocyclic derivative for inhibiting lipoprotein (a), a pharmaceutical composition thereof, and its application. It exhibits significantly better 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.).

[0010] This invention provides a compound of formula (I), its isomers, isotopically labeled compounds, prodrugs, or pharmaceutically acceptable salts, esters, hydrates, or solvates, wherein the compound of formula (I) is shown below:

[0011] Rings A, B, and C are each independently selected from: C 3-10 Cycloalkyl, 5-10 membered heterocyclic, 5-10 membered aromatic heterocyclic or C 6-10 The aryl group, wherein the heteroatom of the 5-10 membered heterocyclic group or the 5-10 membered aryl heterocyclic group is selected from one or more of N, O, and S; optionally, the C 3-10 Cycloalkyl, 5-10 membered heterocyclic, 5-10 membered aromatic heterocyclic, C 6-10 Each aryl group is independently substituted by at least one substituent selected from group G.

[0012] The group G is selected from:

[0013] 1)C 1-6 Alkyl, wherein C 1-6 The alkyl group is optionally selected independently from one or more of deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Substitution of alkoxy groups;

[0014] 2)C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, wherein C 3-6 The cycloalkyl group and the 3-6 membered heterocyclic group are optionally each independently selected independently by one or more groups selected from deuterium, halogen, hydroxyl, cyano, amino, or C. 1-6 Substitution of alkoxy groups;

[0015] 3) Deuterium;

[0016] 4)-NH2;

[0017] 5) Cyano group;

[0018] 6) Oxo (=O);

[0019] 7) Halogens;

[0020] 8) Hydroxyl group;

[0021] 9)-C(=O)OC 1-6 alkyl;

[0022] 10)-C(=O)R c , where R c Selected from C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0023] 11)C 1-6 Alkoxy, where C 1-6 The alkoxy group is optionally surrounded by one or more elements independently selected from halogen, hydroxyl, or C. 1-6 Substitution of alkoxy groups;

[0024] L is selected from:

[0025] Preferably, L is selected from

[0026] Preferably, L is selected from

[0027] R1, R2, and R3 are each independently selected from: C 5-10 Cycloalkyl, 5-10 membered heterocyclic group, -CH2-5-10 membered heterocyclic group, or =CH-5-10 membered heterocyclic group, wherein the heteroatom of the 5-10 membered heterocyclic group is selected from one or more heteroatoms selected from N, O, and S; optionally, the C 5-10 The cycloalkyl group and the 5-10 membered heterocyclic group are each independently substituted by at least one substituent selected from group G; wherein, the C 5-10 The cycloalkyl group is substituted with at least one amino group, and the 5-10 membered heterocyclic group contains at least one nitrogen atom; preferably, the C 5-10 Cycloalkyl groups and 5-10 membered heterocyclic groups are saturated;

[0028] R4 is selected from hydrogen, deuterium, halogen, or C. 1-5 Alkyl, or

[0029] R4, R3 and the atoms they are bonded to form C 5-10 Cycloalkyl, 5-10 membered heterocyclic groups, optionally C 5-10The cycloalkyl group or 5-10 membered heterocyclic group is substituted by one or more of the following substituents: deuterium, -NH2, halogen, C 1-6 Alkyl, -OH, C 1-6 alkoxy; wherein, the C 5-10 The cycloalkyl group is substituted with at least one amino group, and the 5-10 membered heterocyclic group contains at least one nitrogen atom; preferably, the C 5-10 Cycloalkyl groups and 5-10 membered heterocyclic groups are saturated;

[0030] And it meets the following conditions:

[0031] 1) Rings A, B, and C are not simultaneously benzene rings; or,

[0032] When rings A, B, and C are all benzene rings, L is selected from... or,

[0033] When rings A, B, and C are all benzene rings, at least one of R1, R2, and R3 is selected from... or,

[0034] When rings A, B, and C are all benzene rings, R4 and R3 form nitrogen-containing spirocyclic rings with the atoms they are attached to; or

[0035] 2) When any two of rings A, B, and C are benzene rings, the remaining one is not a pyridine ring.

[0036] This invention provides a compound of formula (I), its isomers, isotopically labeled compounds, prodrugs, or pharmaceutically acceptable salts, esters, hydrates, or solvates, wherein the compound of formula (I) is shown below:

[0037] Rings A, B, and C are each independently selected from: C 3-10 Cycloalkyl, 5-10 membered heterocyclic, 5-10 membered aromatic heterocyclic, C 6-10 Aryl group, wherein the 5-10 membered heterocyclic group or 5-10 membered aromatic heterocyclic group comprises one or more heteroatoms selected from N, O, and S; optionally, the C 3-10 Cycloalkyl, 5-10 membered heterocyclic, 5-10 membered aromatic heterocyclic, C 6-10 Each aryl group is independently substituted by at least one substituent selected from group G.

[0038] The group G is:

[0039] 1)C 1-6 Alkyl, wherein C 1-6 The alkyl group is optionally selected independently from one or more of deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Substitution of alkoxy groups;

[0040] 2)C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, wherein C 3-6 The cycloalkyl group, a 3-6 membered heterocyclic group, is optionally surrounded by one or more groups independently selected from deuterium, halogen, hydroxyl, cyano, amino, or C. 1-6 Substitution of alkoxy groups;

[0041] 3) Deuterium;

[0042] 4)-NH2;

[0043] 5) Cyano group;

[0044] 6) Oxo (=O);

[0045] 7) Halogens;

[0046] 8) Hydroxyl group;

[0047] 9)-C(=O)OC 1-6 alkyl;

[0048] 10)-C(=O)R c , where R c Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl groups;

[0049] 11)C 1-6 Alkoxy, where C 1-6 The alkoxy group is optionally surrounded by one or more elements independently selected from halogen, hydroxyl, or C. 1-6 Substitution of alkoxy groups;

[0050] L is selected from:

[0051] Preferably, L is selected from

[0052] When the L substituents are asymmetric structures, the substituents they are attached to can be interchanged;

[0053] R1, R2, and R3 are each independently selected from: C 5-10 Cycloalkyl, 5-10 membered heterocyclic, -CH2-5-10 membered heterocyclic, =CH-5-10 membered heterocyclic, wherein the 5-10 membered heterocyclic or 5-10 membered aromatic heterocyclic includes one or more heteroatoms selected from N, O, and S; optionally, the C 5-10 The cycloalkyl group and the 5-10 membered heterocyclic group are each independently substituted by at least one substituent selected from group G; wherein, the C 5-10 The cycloalkyl group is substituted with at least one amino group, and the 5-10 membered heterocyclic group contains at least one nitrogen atom; preferably, the C 5-10 Cycloalkyl groups and 5-10 membered heterocyclic groups are saturated;

[0054] R4 is selected from hydrogen, deuterium, halogen, or C. 1-5 Alkyl, or

[0055] R4, R3 and the atoms they are bonded to form C 5-10 Cycloalkyl or 5-10 membered heterocyclic group, optionally C 5-10 The cycloalkyl group or 5-10 membered heterocyclic group is substituted by one or more of the following substituents: deuterium, -NH2, halogen, C 1-6 Alkyl, -OH, C 1-6 alkoxy; wherein, the C 5-10 The cycloalkyl group is substituted with at least one amino group, and the 5-10 membered heterocyclic group contains at least one nitrogen atom; preferably, the C 5-10 Cycloalkyl groups and 5-10 membered heterocyclic groups are saturated;

[0056] And it meets the following conditions:

[0057] 1) Rings A, B, and C are not simultaneously benzene rings; or

[0058] When rings A, B, and C are all benzene rings, L is selected from... or

[0059] When rings A, B, and C are all benzene rings, at least one of R1, R2, and R3 is selected from... or

[0060] When rings A, B, and C are all benzene rings, R4 and R3 form nitrogen-containing spirocyclic rings with the atoms they are attached to; or

[0061] 2) When any two of rings A, B, and C are benzene rings, the remaining one is not a pyridine ring.

[0062] In this invention, as one of the embodiments, L is selected from: The key marked "#A" is connected to ring A, the key marked "#B" is connected to ring B, and the key marked "#C" is connected to ring C.

[0063] In this invention, as one embodiment, L is further selected from: Among them, the key marked with "#A" is connected to ring A, the key marked with "#B" is connected to ring B, and the key marked with "#C" is connected to ring C;

[0064] Preferably, L is selected from The key marked "#A" is connected to ring A, the key marked "#B" is connected to ring B, and the key marked "#C" is connected to ring C.

[0065] In this invention, as one of the embodiments, L is selected from: The key marked "#A" is connected to ring A, the key marked "#B" is connected to ring B, and the key marked "#C" is connected to ring C.

[0066] In this invention, at least one of ring A, ring B, and ring C is selected from a 5-membered heteroaryl group, and the heteroatom is selected from nitrogen, oxygen, or sulfur; preferably, the 5-membered heteroaryl group has one sulfur heteroatom and 0 or one nitrogen heteroatom.

[0067] In this invention, as one embodiment, group G is selected from:

[0068] 1) -CH3, -CH2CH3, isopropyl, cyclopropyl;

[0069] 2)-NH2;

[0070] 3) F, Cl;

[0071] 4) -OH, -CH2-OH;

[0072] 5)-C(O)OCH3;

[0073] 6) -OCH3, -CH2OCH3.

[0074] In this invention, as one embodiment, rings A, B, and C are each independently selected from C. 9-10 Fused bicyclic cycloalkyl, 9-10 fused bicyclic heterocyclic group, 5-6 fused monocyclic heteroaryl, 9-10 fused bicyclic heteroaryl, phenyl, naphthyl, wherein C 9-10 The fused bicyclic cycloalkyl, 9-10 fused bicyclic heterocyclic, 5-6 fused monocyclic heteroaryl, 9-10 fused bicyclic heteroaryl, phenyl, and naphthyl are optionally and independently substituted by 1, 2, or 3 substituents selected from group G.

[0075] Preferably, ring A, ring B, and ring C are each independently selected from:

[0076] in,

[0077] It represents a single bond or a double bond; two adjacent chemical bonds cannot both be a double bond.

[0078] The key marked with "#" is connected to L;

[0079] The structures shown in Q-1, Q-3, Q-5, and Q-6 are each independently heteroaryl groups;

[0080] The structures shown in Q-2 and Q-4 are each independently aryl or heteroaryl;

[0081] The structures shown in Q-7 and Q-8 are each independently cycloalkyl or heterocyclic groups;

[0082] Q0, Q 10 Q 11 Q 31 Each is independently selected from C or N;

[0083] Q1, Q2, Q3, Q 12 Q 13 Q 14 Q 24 Q 25 Each is independently selected from CH, N, O, S, and NH;

[0084] Q4, Q5, Q6, Q7, Q8, Q9, Q 15 Q 16 Q 17 Q 18 Q 19 Q 20 Q 21 Q 22 Q 23 Q 26 Q 27 Q 28 Q 29 Q 30 Q 32 Q 33 Q 37 Q 38 Q 39 Each is independently selected from CH or N;

[0085] Q 34 Q 35 Q 36 Q 40 Q 41 Each is independently selected from CH2, O, S, and NH;

[0086] R G The substituent is selected from any substituent in group G, wherein i is selected from 0, 1, 2, 3 or 4.

[0087] In this invention, as one of the embodiments, R G Selected from halogens (e.g., F, Cl), hydroxyl groups, C 1-4 Alkyl (e.g., methyl, isopropyl), C 1-4 Alkyl groups (e.g., methoxy groups), hydroxyl groups 1-4 Alkylene (e.g., -CH2OH), C 1-4 Alkoxy C 1-4Alkylene (e.g., -CH2OCH3), C 3-6 Saturated cycloalkyl groups (e.g., cyclopropyl), -C(O)OC 1-4 Alkyl group (e.g., -C(O)OCH3); preferably, R G Selected from halogen or C 1-4 alkyl.

[0088] In this invention, as one embodiment, i is selected from 0, 1, or 2; more preferably, i is selected from 0 or 1.

[0089] In this invention, as one embodiment, the 5-10 aryl heterogroups are selected from pyrrole, furanyl, thiophene, pyrazolyl, imidazole, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, triazolyl, oxadiazolyl, or thiazolyl, preferably thiophene or thiazolyl.

[0090] In this invention, as one embodiment, rings A, B, and C are each independently selected from: The key marked with "#" is connected to L.

[0091] In this invention, as one embodiment, R1, R2, and R3 are each independently selected from: C 5-7 Saturated monocyclic cycloalkyl groups, 5-7 membered saturated monocyclic heterocyclic groups, 7-9 membered saturated fused bicyclic heterocyclic groups, 7-9 membered saturated bridged bicyclic heterocyclic groups, 7-9 membered saturated spirobicyclic heterocyclic groups, -CH2-5-7 membered saturated monocyclic heterocyclic groups, or =CH-5-7 membered saturated monocyclic heterocyclic groups, wherein any cycloalkyl group is at least substituted with an amino group, and any heterocyclic group contains at least one nitrogen atom; optionally, the cycloalkyl group and the heterocyclic group are each independently selected from deuterium, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 Substitution with cycloalkyl groups or 3-6 membered heterocyclic groups;

[0092] Preferably, R1, R2, and R3 are each independently selected from:

[0093] in,

[0094] Indicates a single bond or a double bond;

[0095] Y0 is selected from CH2 or CH;

[0096] Y1, Y 14 Y 20 Y21 Y 24 Each is independently selected from CH or N;

[0097] Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, Y 10 Y 11 Y 12 Y 13 Y 15 Y 16 Y 17 Y 18 Y 19 Y 22 Y 23 Y 25 Y 26 Y 27 Y 28 Y 29 Y 30 Y 31 Y 32 Y 33 Y 34 Each is independently selected from CH2, NH, O, or S;

[0098] R y Selected from C 1-6 Alkyl (preferably CH3), C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, -NH2, halogen (e.g., F, Cl), deuterium; e' is selected from 0, 1, 2, 3 or 4;

[0099] The condition is that the following conditions are met:

[0100] 1) When Y1 is selected from CH, and Y2, Y3, Y4, Y5, and Y6 are selected from CH2, e' is not 0, and at least one R is selected. y Selected from -NH2;

[0101] 2) When Y7, Y8, Y9, Y 10 When the Ry is selected from CH2, e' is not 0, and at least one Ry is selected from -NH2;

[0102] 3) When Y 24 Selected from CH, and Y 25 Y 26 Y 27 Y 28 Y 29 Y 30 When selected from CH2, e' is not 0, and at least one R y Selected from -NH2;

[0103] 4) When Y1, Y2, Y3, Y4, Y5, and Y6 are not all carbon atoms, at least one of them must be selected from nitrogen heteroatoms;

[0104] 5) When Y7, Y8, Y9, Y 10 When they are not both carbon atoms, at least one of them must be selected from nitrogen heteroatoms;

[0105] 6) When Y 24 Y 25 Y 26 Y 27 Y 28 Y 29 Y 30 When they are not both carbon atoms, at least one of them must be selected from nitrogen heteroatoms;

[0106] 7)Y 11 Y 12 Y 13 At least one of them is selected from nitrogen heteroatoms;

[0107] 8)Y 14 Y 15 Y 16 Y 17 Y 18 At least one of them is selected from nitrogen heteroatoms;

[0108] 9)Y 19 Y 20 Y 21 Y 22 Y 23 At least one of them is selected from nitrogen heteroatoms;

[0109] 10)Y 31 Y 32 Y 33 Y 34 At least one of them is selected from nitrogen heteroatoms.

[0110] In this invention, as one embodiment, R1, R2, and R3 are each independently selected from:

[0111] in,

[0112] Ring D is selected from 5-6 member monocyclic heterocyclic groups, C 3-6 Monocyclic cycloalkyl;

[0113] Ring E is selected from 4-6 member monocyclic heterocyclic groups, C 3-6 Monocyclic cycloalkyl;

[0114] Ring F is selected from 4-6 member monocyclic heterocyclic groups, C 3-6 Monocyclic cycloalkyl;

[0115] Ring H is selected from 4-6 member monocyclic heterocyclic groups, C 3-6 Monocyclic cycloalkyl;

[0116] R D R E R F R H Each is independently selected from C 1-6 Alkyl (preferably CH3), C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic groups, -NH2, halogens (e.g., F, Cl) or deuterium;

[0117] e' is selected from 0, 1, 2, 3 or 4;

[0118] The condition is that the following conditions are met:

[0119] 1) When both ring D and ring E are cycloalkyl, e' is not 0, and at least one of ring D or ring E is substituted by an amino group;

[0120] 2) When both ring F and ring H are cycloalkyl, e' is not 0, and at least one of ring F or ring H is substituted by an amino group;

[0121] 3) When ring D and ring E are not both cycloalkyl, at least one of ring D and ring E is a nitrogen-containing heterocyclic group;

[0122] 4) When ring F and ring H are not both cycloalkyl, at least one of ring F and ring H is a nitrogen-containing heterocyclic group;

[0123] Preferably,

[0124] Ring D is selected from 5-6 member saturated monocyclic heterocyclic groups, C 5-6 Saturated monocyclic cycloalkyl; more preferably C 5-6 Saturated monocyclic cycloalkyl groups;

[0125] Ring E is selected from 5-6 member saturated monocyclic heterocyclic groups, C 5-6 Saturated monocyclic cycloalkyl groups; more preferably, 5-6 membered saturated nitrogen-containing monocyclic heterocyclic groups;

[0126] Ring F is selected from 4-6 member saturated monocyclic heterocyclic groups, C 4-6 Saturated monocyclic cycloalkyl; more preferably 4-6 Elemental saturated nitrogen-containing monocyclic heterocyclic group, C 4-6 Saturated monocyclic cycloalkyl groups;

[0127] Ring H is selected from 4-6 member saturated monocyclic heterocyclic groups, C 3-6 Saturated monocyclic cycloalkyl groups; more preferably 4-6 membered saturated nitrogen-containing monocyclic heterocyclic groups, C 3-6 Saturated monocyclic cycloalkyl groups;

[0128] Preferably,

[0129] Ring D is selected from C 5-6 Saturated monocyclic cycloalkyl groups, wherein ring E is selected from 5-6 membered saturated nitrogen-containing monocyclic heterocyclic groups;

[0130] Ring F is selected from 4-6 member saturated nitrogen-containing monocyclic heterocyclic groups and ring H is selected from C. 3-6 Saturated monocyclic cycloalkyl groups, or

[0131] Ring F is selected from C 4-6 The saturated monocyclic cycloalkyl group has a ring H selected from 4-6 member saturated nitrogen-containing monocyclic heterocyclic groups.

[0132] In this invention, as one embodiment, R4, R3 and their connected atoms form the following ring:

[0133] in,

[0134] Ring D is selected from 5-6 member monocyclic heterocyclic groups, C 3-6 Monocyclic cycloalkyl;

[0135] Ring E is selected from 4-6 member monocyclic heterocyclic groups, C 3-6 Monocyclic cycloalkyl;

[0136] Ring F is selected from 4-6 member monocyclic heterocyclic groups, C 3-6 Monocyclic cycloalkyl;

[0137] Ring H is selected from 4-6 member monocyclic heterocyclic groups, C 3-6 Monocyclic cycloalkyl;

[0138] R D R E R F R H Each is independently selected from C 1-6 Alkyl (preferably CH3), C 1-6 Alkoxy, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, -NH2, halogens (e.g., F, Cl), or deuterium,

[0139] e' is selected from 0, 1, 2, 3 or 4;

[0140] The condition is that the following conditions are met:

[0141] 1) When both ring D and ring E are cycloalkyl, e' is not 0, and at least one of ring D or ring E is substituted by an amino group;

[0142] 2) When both ring F and ring H are cycloalkyl, e' is not 0, and at least one of ring F or ring H is substituted by an amino group;

[0143] 3) When ring D and ring E are not both cycloalkyl, at least one of ring D and ring E is a nitrogen-containing heterocyclic group;

[0144] 4) When ring F and ring H are not both cycloalkyl, at least one of ring F and ring H is a nitrogen-containing heterocyclic group;

[0145] Preferably, R4, R3 and the atoms they are connected to form the following rings:

[0146] M1, M2, M3, M4, M5, M6, and M7 are each independently selected from NH, CH2, O, or S;

[0147] M8, M9, M 10 Each is independently selected from NH or CH2;

[0148] R5 is selected from deuterium, -NH2, halogens, and C. 1-3 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocyclic groups,

[0149] c' is selected from 0, 1, 2, 3 or 4;

[0150] The condition is that the following conditions are met:

[0151] 1) When M1, M2, M3, and M4 are all selected from CH2, c' is not 0, and at least one R5 is selected from -NH2;

[0152] 2) When M5, M6, and M7 are all selected from CH2, c' is not 0, and at least one R5 is selected from -NH2;

[0153] 3) When M8 is selected from CH2, c' is not 0, and at least one R5 is selected from -NH2;

[0154] 4) When M9 is selected from CH2, c' is not 0, and at least one R5 is selected from -NH2;

[0155] 5) When M 10 When selected from CH2, c' is not 0, and at least one R5 is selected from -NH2;

[0156] 6) When M1, M2, M3, and M4 are not all selected from CH2, at least one of them must be selected from NH;

[0157] 7) When M5, M6, and M7 are not all selected from CH2, at least one of them must be selected from NH.

[0158] In this invention, as one embodiment, R1, R2, and R3 are each independently selected from:

[0159] In this invention, as one embodiment, R4, R3 and their connected atoms form the following ring:

[0160] In this invention, the above-mentioned compound, its isomers, isotopically labeled compounds, prodrugs, or pharmaceutically acceptable salts, esters, hydrates, or solvates thereof, as a further preferred structure, have the structure shown in Formula II:

[0161] Among them, the keys marked with "a" and "b" are located in the interpositions of ring A, and the keys marked with "c" and "d" are located in the interpositions of ring B;

[0162] R1, R2, R3, R G i, Q0, Q1, Q2, Q3, ring A, and ring B are as defined above;

[0163] Preferably, R1, R2, and R3 are each independently selected from pyrrolidinyl, piperidinyl, or azircycloheptyl; more preferably, R1, R2, and R3 are each independently selected from...

[0164] Preferably, ring A and ring B are each independently selected from 5-membered heteroaryl, 6-membered heteroaryl, or phenyl (more preferably, both ring A and ring B are phenyl, or one of ring A and ring B is phenyl and the other is 5-membered heteroaryl), and ring A and ring B are optionally each independently separated by one or two elements selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Saturated cycloalkyl, hydroxyl, hydroxyl C 1-6 Alkylene, -C(=O)OC 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Substituents of alkylene groups; preferably, the 5-membered heteroaryl group is selected from pyrrole, furanyl, thiophene, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, triazolyl, oxadiazolyl or thiadiazolyl, preferably thiophene or thiazolyl;

[0165] Preferably, The group is selected from pyrrole, furanyl, thiophene, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, triazolyl, oxadiazolyl, or thiadiazolyl, preferably thiophene or thiazolyl; more preferably, Selected from The key marked with "#" is connected to L;

[0166] R G Selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C3-6 Saturated cycloalkyl, hydroxyl, hydroxyl C 1-6 Alkylene, -C(=O)OC 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkylene; preferably, R G Selected from halogens, C 1-6 alkyl;

[0167] i is selected from 0, 1, 2 or 3, preferably 0, 1 or 2;

[0168] Preferably, Selected from

[0169] In this invention, as one embodiment, the compound has the structure shown in formula (III):

[0170] Among them, the keys marked with "a" and "b" are located in the interposition of ring A, the keys marked with "c" and "d" are located in the interposition of ring B, and the keys marked with "e" and "f" are located in the interposition of ring C.

[0171] R1, R2, R3, and R4 are defined as described above, provided that at least one of R1, R2, and R3 is... Alternatively, R3 and R4 form

[0172] As defined above, rings A, B, and C are preferably each independently selected from phenyl, pyridyl, or 5-membered heteroaryl (more preferably, rings A, B, and C are all phenyl, or at least one of rings A, B, and C is a 5-membered heteroaryl), and rings A and B are optionally each independently selected from one or two halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Saturated cycloalkyl, hydroxyl, hydroxyl C 1-6 Alkylene, -C(=O)OC 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Substituents of alkylene groups;

[0173] Preferably, the 5-membered heteroaryl group is selected from pyrrole, furanyl, thiophene, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, triazolyl, oxadiazolyl, or thiadiazolyl, preferably thiophene or thiazolyl; more preferably... The key marked with "#" is connected to L.

[0174] In this invention, as one embodiment, the compound described herein is shown in Formula IV:

[0175] Among them, the bonds marked with "a" and "b" are located in the interposition of ring A;

[0176] R1 is selected from Preferably, R1 is

[0177] Ring A is selected from Preferred Preferred Preferred The keys marked with "#" correspond to the keys marked with "a", Q0, Q1, Q2, Q3, Q4, Q5, Q6, Q7, Q 15 Q 16 Q 17 Q 18 Q 19 Q 20 Q 32 Q 33 Q 34 Q 35 Q 36 R G As defined in any embodiment of the present invention; preferably, Q0 is C; preferably, Q2 is selected from N, CH or S; preferably, Q2 is selected from CH and N; preferably, Q2 is selected from S; preferably, Q1 is selected from S, NH, N or O; preferably, Q1 is selected from S, NH and O; preferably, Q1 is selected from S; preferably, Q3 is CH; preferably, Q4, Q5, Q6, and Q7 are all CH; preferably, one of Q4, Q5, Q6, and Q7 is N, and the rest are CH; preferably, two of Q4, Q5, Q6, and Q7 are N, and the rest are CH; preferably, Q 15 Q 16 All are CH; preferably, Q 17 Q 18 Q 19 Q 20 All are CH; preferably, Q 17 Q 18 Q 19 Q 20 One of them is N, and the rest are CH; preferably, Q 17 Q 18 Q 19 Q 20 Two of them are N, and the rest are CH; preferably, Q 17 Q 20 For N, Q 18 Q 19 CH; preferably, Q 32 Q 33 All are CH; preferably, Q35 CH2; preferably, Q 34 Q 36 For O; preferably, R G Selected from halogens (e.g., F, Cl) or C 1-4 Alkyl (e.g., methyl); preferably, i is selected from 0 or 1;

[0178] Preferably, ring A is selected from The keys marked with "#" correspond to the keys marked with "a", Q1-Q7, Q 15 -Q 20 Q 32 Q 33 Q 34 Q 36 R G i is as defined in any embodiment of the present invention;

[0179] Preferably, ring A is selected from The key marked with "#" corresponds to the key marked with "a";

[0180] Preferably, ring A is selected from The key marked with "#" corresponds to the key marked with "a";

[0181] R3 is selected from

[0182] R4 is hydrogen; or

[0183] R4, R3 and the atoms they are attached to form

[0184] Preferably, R3 is selected from

[0185] R4 is hydrogen; or

[0186] R4, R3 and the atoms they are attached to form

[0187] Preferably, R3 is selected from

[0188] R4 is hydrogen; or

[0189] R4, R3 and the atoms they are attached to form

[0190] Preferably, R3 is selected from

[0191] R4 is hydrogen; or

[0192] R4, R3 and the atoms they are attached to form

[0193] Preferably, R3 is selected from

[0194] R4 is hydrogen; or

[0195] R4, R3 and the atoms they are attached to form

[0196] Preferably, R3 is selected from

[0197] R4 is hydrogen; or

[0198] R4, R3 and the atoms they are attached to form

[0199] The condition is that when ring A is phenyl, R1 is tetrahydropyrrolyl, and R4 is hydrogen, R3 is not...

[0200] In this invention, as one embodiment, the compound described herein is as shown in Formula V:

[0201] Among them, the keys marked with "c" and "d" are located in the interpositions of ring B, and the keys marked with "e" and "f" are located in the interpositions of ring C;

[0202] R g Selected from hydrogen, halogens (e.g., F, Cl) or C 1-4 Alkyl (e.g., methyl); preferably, R g Selected from hydrogen or C 1-4 Alkyl (e.g., methyl); preferably, R g Selected from hydrogen;

[0203] R2 and R3 are each selected independently. Preferably, R2 and R3 are both Or one of R2 and R3 can be selected. The other one is selected from

[0204] Rings B and C are each independently selected The key marked with "#" corresponds to the key marked with "c" or "e";

[0205] Preferably, ring B is selected from The key marked with "#" corresponds to the key marked with "c";

[0206] Preferably, ring C is selected from The key marked with "#" corresponds to the key marked with "e".

[0207] In this invention, as one embodiment, the compound described herein is as shown in formula (VI):

[0208] Among them, the keys marked with "c" and "d" are located in the interpositions of ring B, and the keys marked with "e" and "f" are located in the interpositions of ring C;

[0209] R1, R2, and R3 are each independently selected

[0210] Preferably, R1, R2, and R3 are all

[0211] Preferably, one of R1, R2, and R3 is The rest are

[0212] Rings B and C are each independently selected Preferably, rings B and C are each independently selected from... The key marked with "#" corresponds to the key marked with "c" or "e";

[0213] Preferably, ring B is selected from Preferably, ring B is selected from The key marked with "#" corresponds to the key marked with "c";

[0214] Preferably, ring C is selected from Preferably, ring C is selected from The key marked with "#" corresponds to the key marked with "e";

[0215] L is selected from Preferably, L is selected from The key marked with "#c" is connected to the c position corresponding to ring B, and the key marked with "#e" is connected to the e position corresponding to ring C.

[0216] In this invention, as one embodiment, the compound of this invention is shown in formula (VII):

[0217] Among them, the keys marked with "a" and "b" are located in the interposition of ring A, the keys marked with "c" and "d" are located in the interposition of ring B, and the keys marked with "e" and "f" are located in the interposition of ring C.

[0218] R1, R2, and R3 are each independently selected

[0219] Preferably, R1, R2, and R3 are all

[0220] Preferably, one of R1, R2, and R3 is The rest are

[0221] Rings A, B, and C are each independently selected Preferred Preferred Preferred The keys marked with "#" correspond to the keys marked with "a", "c", or "e", and are Q0, Q1, Q2, Q3, Q4, Q5, Q6, Q7, Q... 15 Q 16 Q 17 Q 18 Q 19 Q 20 Q 32 Q 33 Q 34 Q 35 Q 36 R G As defined in any embodiment of the present invention; preferably, Q0 is C; preferably, Q2 is selected from N, CH or S; preferably, Q2 is selected from CH and N; preferably, Q2 is selected from S; preferably, Q1 is selected from S, NH, N or O; preferably, Q1 is selected from S, NH and O; preferably, Q1 is selected from S; preferably, Q3 is CH; preferably, Q4, Q5, Q6, and Q7 are all CH; preferably, one of Q4, Q5, Q6, and Q7 is N, and the rest are CH; preferably, two of Q4, Q5, Q6, and Q7 are N, and the rest are CH; preferably, Q 15 Q 16 All are CH; preferably, Q 17 Q 18 Q 19 Q 20 All are CH; preferably, Q 17 Q 18 Q 19 Q 20 One of them is N, and the rest are CH; preferably, Q 17 Q 18 Q 19 Q 20 Two of them are N, and the rest are CH; preferably, Q 17 Q 20 For N, Q 18 Q 19 CH; preferably, Q 32 Q 33 All are CH; preferably, Q 35 CH2; preferably, Q 34 Q36 For O; preferably, R G Selected from halogens (e.g., F, Cl) or C 1-4 Alkyl (e.g., methyl); preferably, i is selected from 0 or 1;

[0222] Preferably, rings A, B, and C are each independently selected from... The keys marked with "#" correspond to the keys marked with "a", "c", or "e", Q1-Q7, Q 15 -Q 20 Q 32 Q 33 Q 34 Q 36 R G i is as defined in any embodiment of the present invention;

[0223] Preferably, rings A, B, and C are all Alternatively, one of rings A, B, and C can be selected from... (Preferred) The remaining two are selected from The key marked with "#" corresponds to the key marked with "a", "c" or "e";

[0224] Preferably, rings A, B, and C are each independently selected from... The key marked with "#" corresponds to the key marked with "a", "c" or "e";

[0225] Preferably, rings A, B, and C are each independently selected from... Alternatively, one of rings A, B, and C can be selected from... The remaining two are selected from The key marked with "#" corresponds to the key marked with "a", "c" or "e";

[0226] Preferably, rings A, B, and C are all Alternatively, one of rings A, B, and C can be selected from... The remaining two are selected from The key marked with "#" corresponds to the key marked with "a", "c" or "e";

[0227] L is selected from Preferably, L is selected from The key marked "#A" is connected to ring A, the key marked "#B" is connected to ring B, and the key marked "#C" is connected to ring C.

[0228] As one embodiment, the compound, its isomer, isotopically labeled compound, prodrug, or pharmaceutically acceptable salt, ester, hydrate, or solvate thereof described in this invention is selected from:

[0229] As one implementation scheme, the compounds described in this invention are selected from:

[0230] As one implementation scheme, the compounds described in this invention are selected from:

[0231] As one of the implementation schemes, the compound described in this invention is not and its isomers.

[0232] The various embodiments of the present invention can be combined in any way.

[0233] The present invention provides a pharmaceutical composition comprising the compound, isomer thereof, isotopically labeled compound, prodrug thereof, or pharmaceutically acceptable salt, ester, hydrate or solvate thereof, as well as a pharmaceutically acceptable carrier, diluent or excipient, according to any of the embodiments described above.

[0234] The present invention provides the use of the above-described compounds, their isomers, isotopically labeled compounds, prodrugs, or pharmaceutically acceptable salts, esters, hydrates or solvates thereof, and the above-described pharmaceutical compositions in the preparation of medicaments for the prevention and / or treatment of diseases associated with lowering Lp(a) levels.

[0235] 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.

[0236] 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.

[0237] In this invention, as one embodiment, the Lp(a)-related disease is a disease related to lowering Lp(a) levels.

[0238] The diseases associated with Lp(a) levels are cardiovascular diseases, including but not limited to atherosclerosis, stroke, hyperlipidemia, elevated Lp(a) levels, thrombosis, coronary heart disease, and aortic stenosis.

[0239] 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.

[0240] The compounds of the present invention have advantages such as stronger Apo(a) binding ability, more effective ability to reduce Lp(a) levels, better pharmacokinetic properties, and high Lp(a) selectivity, and can be used to prepare drugs for the treatment of cardiovascular diseases to meet clinical needs.

[0241] Terminology Explanation

[0242] 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.

[0243] The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule. It can be divided into two types: cis-trans isomers and enantiomers, or further into two main categories: enantiomers and diastereomers.

[0244] The term "tautomer" refers to a functional group isomer that is produced by the rapid movement of an atom in a molecule between two positions.

[0245] The term "diastereomer" refers to a stereoisomer of a molecule that has two or more chiral centers and is not a mirror image of the molecule.

[0246] The term "racemate" refers to an equimolar mixture of two enantiomers that lack optical activity.

[0247] The term "cis-trans isomers" refers to stereoisomers formed because the two carbon atoms connected by a double bond cannot rotate freely around the σ bond. They are divided into cis isomers and trans isomers: cis isomers are those where the two identical atoms or groups are on the same side of the double bond; trans isomers are those where the two identical atoms or groups are on opposite sides of the double bond.

[0248] 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.

[0249] The term "alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group, with C1... 1-6 For example, alkyl groups are straight-chain or branched groups containing 1-6 carbon atoms, including but not limited to aliphatic alkyl groups such as methyl, ethyl, propyl, pentyl, hexyl, tert-butyl, sec-butyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, 1-ethyl-2-methylpropyl, and 1,1,2-trimethylpropyl.

[0250] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic carbon chain structure molecule, containing, for example, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, including but not limited to cyclopropane, cyclobutane, cyclopentane, and cyclohexane. The cycloalkyl group includes fused rings, spiro rings, bridged rings, and combinations thereof. Cycloalkyl groups include aryl-fused cycloalkyl groups, provided the entire ring system is non-aromatic, for example...

[0251] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, for example, containing 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 ring atoms, wherein one or more (e.g., 1, 2, 3, 4, 5, or 6) ring atoms are each independently selected from nitrogen, oxygen, sulfur, or phosphorus heteroatoms, and the remaining ring atoms are carbon. The heterocyclic group includes fused rings, spirocyclic rings, bridged rings (e.g., 6-9 membered bridged ring heterocyclic groups), and combinations thereof; the heterocyclic group includes monocyclic heterocyclic groups, and groups with at least one heterocyclic ring in polycyclic (e.g., bicyclic, tricyclic) groups, such as benzo[a]heterocyclic groups, etc.

[0252] The term "spirocyclic" refers to a saturated or partially unsaturated bicyclic or polycyclic (e.g., tricyclic) group, wherein any one of the rings shares a carbon atom with at least one of the other rings.

[0253] The term "bridged ring" refers to a saturated or partially unsaturated bicyclic or polycyclic (e.g., tricyclic) group, wherein any one of the rings shares three or more ring atoms with at least one of the other rings.

[0254] The term "aromatic heteroaryl" (also known as "heteroaryl") refers to a monocyclic or fused polycyclic group (i.e., a ring sharing adjacent ring edges) having a conjugated π-electron system and containing a heteroatom on the ring, wherein the heteroatom is selected from oxygen, sulfur, and nitrogen. Examples include 5-18 membered heteroaryl groups, preferably 5-12 membered or 13-18 membered heteroaryl groups, such as imidazolyl, furanyl, thiophene, thiazolyl, pyrazolyl, oxazolyl, pyrroleyl, tetrazolyl, pyridinyl, pyrimidinyl, thiadiazolyl, pyrazinyl, carbazoleyl, indolyl, etc., preferably imidazolyl, pyrazolyl, pyrimidinyl, or thiazolyl; more preferably pyrazolyl or thiazolyl. "Heteroaromatic ring" (also known as "aromatic heterocyclic ring") refers to the ring system within the heteroaryl group.

[0255] The term "alkoxy" refers to -O-alkyl, where alkyl is defined as described above, including but not limited to methoxy, ethoxy, propoxy, butoxy, etc.

[0256] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group with a conjugated π-electron system, preferably 6-10 members, such as phenyl and naphthyl. "Aromatic ring" refers to the ring system within the aryl group.

[0257] The term "halogenated" refers to a group that can be replaced by any one or more F, Cl, Br, or I atoms.

[0258] 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. The term "pharmaceuticalally acceptable solvate" includes solvents such as water, ethanol, acetic acid, N,N-dimethylformamide, dimethyl sulfoxide, isopropanol, acetonitrile, tetrahydrofuran, acetone, or propylene glycol.

[0259] In this invention, carbon atoms marked with an asterisk (*) in the structural formula of a compound represent chiral centers and signify that the compound is a specific stereoisomer. In reaction formulas involving stereochemistry, two or more identical drawings of compounds containing chiral centers marked with an asterisk (*) essentially represent two or more different stereoisomers of that structure. For example... The structures of 17-P1 and 17-P2 are drawn to be exactly the same, but they are actually different stereoisomers. Detailed Implementation

[0260] The following examples are provided to further illustrate the present invention, but are not intended to limit the scope of the invention in any way.

[0261] Example: Synthesis of Compounds

[0262] Preparation of reference object 1:

[0263] Reference object 1 was prepared according to the method of Example 1 in CN114008021A.

[0264] Preparation Example 1: Synthesis of inter 1

[0265] Under a nitrogen atmosphere at 0°C, triethylamine (14.24 mL, 102.76 mmol, 2.5 equivalence) was added to a stirred solution of tetrahydrofuran (100 mL) containing inter 1a (10 g, 41.10 mmol, 1.0 equivalence), 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 inter 1b (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 inter 1. ESI m / z 425.2 [M+Na] + .LCMS:product:Rt=1.337min.

[0266] Preparation Example 2: Synthesis of inter 2

[0267] 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.

[0268] Preparation Example 3: Synthesis of inter 3

[0269] Under a nitrogen atmosphere, inter 3a (5 g, 21.81 mmol, 1.0 equivalence) was dissolved in tetrahydrofuran (50 mL), and triethylamine (7.56 mL, 54.52 mmol, 2.5 equivalence) was added at 0 °C, followed by pentanoyl chloride (3.16 g, 26.17 mmol, 1.2 equivalence). The reaction mixture was stirred at 0 °C for 30 min. Lithium chloride (1.11 g, 26.17 mmol, 1.2 equivalence) and inter 3b (3.86 g, 21.81 mmol, 1.0 equivalence) were then added. The mixture was stirred at room temperature for 18 h. The mixture was diluted with water (80 mL) and extracted with ethyl acetate (40 mL × 2). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give inter 3. ESI m / z 411.2 [M+Na] + .

[0270] Preparation Example 4: Synthesis of inter 4

[0271] 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 inter 4a (0.71 g, 2.83 mmol, 1.1 equivalent) in tetrahydrofuran solution (3 mL). 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 inter 4b. ESI m / z 501.2 [M+H-tert-butyl] + .LCMS:product:Rt=2.283min; 1H 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).

[0272] 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 warming 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 compound inter 4c. ESI m / z 342.1 [M+H-tert-butyl] + .LCMS:product:Rt=1.362min.

[0273] Step 3): Dissolve inter 4c (7.3 g, 18.33 mmol, 1.0 equivalence) in tetrahydrofuran (50 mL), and add inter 4d (18.36 g, 91.64 mmol, 5.0 equivalence). Stir the reaction mixture at 65 °C for 2 hours. Filter the reaction mixture to remove the white solid, and concentrate the filtrate under reduced pressure. Purify the residue by silica gel column chromatography (petroleum ether / tert-butyl methyl ether = 3 / 1) to obtain inter 4e. ESI m / z 342.0 [M-2C(CH3)3+H] + .LCMS:product:Rt=1.695min.

[0274] Step 4): Dissolve inter 4e (4.0 g, 8.80 mmol, 1.0 equivalence) in N,N-dimethylformamide (80 mL), add triethylsilane (4.09 g, 35.21 mmol, 4.0 equivalence), triethylamine (6.10 mL, 44.01 mmol, 5.0 equivalence), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (0.65 g, 0.88 mmol, 0.1 equivalence). Stir the mixture at 90 °C and 15 psi for 16 hours under carbon monoxide protection. Extract the mixture with water (50 mL) and ethyl acetate (3 × 30 mL), combine the organic layers, wash with saturated brine (30 mL × 3), dry to anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain inter 4. ESI m / z 426.2 [M+Na] + .LCMS:product:Rt=1.390min.

[0275] Preparation Example 5: Synthesis of inter 5

[0276] 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=1.302min.

[0277] Step 2): Inter 5a (610 mg, 1.50 mmol, 1.0 equivalence) was dissolved in dichloromethane (8 mL), and carbon tetrabromide (548.71 mg, 1.65 mmol, 1.1 equivalence) and triphenylphosphine (473.43 mg, 1.81 mmol, 1.2 equivalence) were added. The reaction mixture was stirred at 25 °C for 16 hours. The mixture was poured into water (20 mL), extracted with dichloromethane (3 × 10 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / tert-butyl methyl ether = 1 / 1) to give Inter 5. ESI m / z 358.0 [M-2C(CH3)3+H] + .LCMS:product:Rt=1.482min.

[0278] Preparation Example 6: Synthesis of inter 6

[0279] Step 1): Under a nitrogen atmosphere, inter 3 (1.0 g, 2.57 mmol, 1.0 equivalent) was dissolved in tetrahydrofuran (10 mL) and cooled at 0 °C, followed by the addition of lithium bis(trimethylsilyl)amino (2.83 mL, 2.83 mmol, 1.1 equivalent). The reaction mixture was stirred at 0 °C for 30 min. Subsequently, a tetrahydrofuran (10 mL) solution of compound inter 6a (0.55 g, 2.83 mmol, 1.1 equivalent) was added. The reaction mixture was stirred at room temperature for 2 h. The mixture was quenched with saturated ammonium chloride solution (20 mL) and extracted with ethyl acetate (30 mL × 2). The organic phases were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 9 / 1) to give inter 6b. ESI m / z 526.2 [M+Na] + .LCMS:product:Rt=1.401min.

[0280] 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.

[0281] 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.

[0282] Step 4): To a solution containing inter 6e (190 mg, 0.47 mmol, 1.0 equivalence) in tetrahydrofuran (5 mL) and ammonia (0.2 mL), Raney nickel (103.65 mg, 0.47 mmol, 1.0 equivalence) was added. Hydrogen gas was introduced, and the reaction mixture was stirred at room temperature for 6 hours. The mixture was filtered and concentrated under reduced pressure to give inter 6. ESI m / z 405.2 [M+H] + .LCMS:product:Rt=0.997min.

[0283] Preparation Example 7: Synthesis of inter 7

[0284] 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 cobalt (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). The reaction mixture was stirred at 110 °C for 18 hours under nitrogen. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 1 / 1) to give inter 7a. ESI m / z 456.2 [M+Na]+. LCMS:product:Rt = 1.966 min.

[0285] Step 2): Dissolve inter 7a (350.0 mg, 0.65 mmol) in a mixture of methanol (5 mL) and water (1 mL), then add lithium hydroxide monohydrate (40.6 mg, 0.97 mmol, 1.5 equivalence). Stir the reaction mixture at room temperature for 18 hours. Neutralize the resulting reaction mixture with dilute hydrochloric acid to pH 3. Extract the mixture with ethyl acetate (50 mL × 2), and concentrate the organic phase under reduced pressure to give inter 7. ESI m / z 442.2 [M + Na] + .LCMS:product:Rt=1.726min.

[0286] Example 1: Synthesis of Compound 1

[0287] Step 1): Sodium hydroxide (0.38 g, 9.38 mmol, 3.0 equivalent) was added to a tetrahydrofuran solution (10 mL) of triethyl phosphonoacetate (3.15 g, 14.07 mmol, 3.0 equivalent) in mineral oil (60% dispersion in mineral oil, 2.0 equivalent). The reaction mixture was stirred at 0 °C for 30 min, and then compound 1a (1 g, 4.69 mmol, 1.0 equivalent) was gradually added. The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched with a saturated ammonium chloride solution (20 mL) and then extracted with ethyl acetate (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 / ethyl acetate = 10 / 1) to give compound 1b. ESI m / z 306.2 [M + Na] + .LCMS:product:Rt=1.30min.

[0288] Step 2): Compound 1b (0.96 g, 3.39 mmol, 1.0 equivalent) was dissolved in 10 mL of ethanol solution, and palladium / carbon (0.18 g, 1.70 mmol, 0.5 equivalent) was added. The reaction mixture was stirred at room temperature under hydrogen protection at 15 psi for 16 hours. The mixture was filtered to remove Pd / C, and the filtrate was concentrated under reduced pressure to give crude compound 1c, which was used directly for the next step without further purification. ESI m / z 308.2 [M+Na] + .LCMS:product:Rt=1.34min.

[0289] Step 3): Compound 1c (0.85 g, 2.98 mmol, 1.0 equivalence) was dissolved in tetrahydrofuran (5 mL) and water (1 mL), and lithium hydroxide (0.50 g, 11.91 mmol, 4.0 equivalence) was added. The reaction mixture was stirred at 50 °C for 16 hours. The reaction mixture was poured into water (10 mL), extracted with ethyl acetate (10 mL × 3), and then the aqueous phase was acidified to pH 5 with 1 M hydrochloric acid 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 1d. ESI m / z 280.2 [M + Na] + .LCMS:product:Rt=1.08min.

[0290] Step 4): Compound 1d (0.69 g, 2.68 mmol, 1.0 equivalence) was dissolved in tetrahydrofuran (5 mL), and triethylamine (0.93 mL, 6.70 mmol, 2.5 equivalence) and tervapotranol chloride (0.39 g, 3.22 mmol, 1.2 equivalence) were added at 0 °C, and the mixture was stirred under nitrogen protection for 0.5 h. Then, a tetrahydrofuran solution (5 mL) of lithium chloride (0.14 g, 3.22 mmol, 1.2 equivalence) and (S)-4-benzyloxazolidine-2-one (0.48 g, 2.68 mmol, 1.0 equivalence) was added, and the mixture was stirred at 25 °C for 16 h. The mixture was diluted with water (30 mL), extracted with ethyl acetate (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 = 3 / 1) to give compound 1e. ESI m / z 439.2 [M+Na] + .LCMS:product:Rt=1.34min.

[0291] Step 5): Compound 1e (820 mg, 1.97 mmol, 1.0 equivalence) was dissolved in tetrahydrofuran (10 mL) under nitrogen protection at 0 °C, and lithium bis(trimethylsilyl)amino (2.17 mL, 2.17 mmol, 1.1 equivalence) was added. The reaction mixture was stirred at 0 °C for 0.5 h. Subsequently, a tetrahydrofuran solution (5 mL) of 1-bromo-3-(bromomethyl)benzene (492.04 mg, 1.97 mmol, 1.0 equivalence) was added. The reaction mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was quenched with saturated ammonium chloride aqueous solution (20 mL), and then extracted with ethyl acetate (20 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / tert-butyl methyl ether = 2 / 1) to give compound 1f. ESI m / z 607.2 [M + Na] + .LCMS:product:Rt=1.56min.

[0292] Step 6): Under nitrogen protection, compound 1f (0.73 g, 1.25 mmol, 1.0 equivalence) was dissolved in tetrahydrofuran (15 mL) solution, and hydrogen peroxide (30% aqueous solution, 0.97 mL, 12.47 mmol, 10.0 equivalence) was added dropwise at 0 °C, followed by an aqueous solution of lithium hydroxide monohydrate (0.10 g, 2.49 mmol, 2.0 equivalence) (5 mL). The reaction mixture was stirred at 0 °C for 2 hours. A sodium bisulfite (1.95 g, 18.70 mmol, 15 equivalence) aqueous solution (30 mL) was slowly added dropwise to the reaction mixture, and the mixture was stirred at 0 °C for 30 minutes. The reaction mixture was then neutralized to pH 9 with sodium hydroxide (4.0 M) 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 1 g of compound. ESI m / z 370.0 [MC(CH3)3+H] + .LCMS:product:Rt=1.03min.

[0293] Step 7): Dissolve 1 g (0.53 g, 1.24 mmol, 1.0 equivalence) of the compound in 10 mL of tetrahydrofuran solution, and add O-tert-butyl-N,N'-diisopropylisourea (1.25 g, 6.22 mmol, 5.0 equivalence). Stir the reaction mixture at 65 °C for 2 hours. Filter the reaction mixture to remove the white solid, and concentrate the filtrate under reduced pressure. Purify the residue by silica gel column chromatography (petroleum ether / tert-butyl methyl ether = 2 / 1) to give the compound 1 h. ESI m / z 372.0 [M-2C(CH3)3+H] + .LCMS:product:Rt=1.77min.

[0294] Step 8): Compound 1h (440.00 mg, 0.91 mmol, 1.0 equivalence) was dissolved in N,N-dimethylformamide (10 mL), and triethylsilane (424.19 mg, 3.65 mmol, 4.0 equivalence), triethylamine (0.63 mL, 4.56 mmol, 5.0 equivalence), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (67.65 mg, 0.09 mmol, 0.1 equivalence) were added. The reaction mixture was stirred at 90 °C under carbon monoxide protection for 16 hours. The mixture was extracted with water (20 mL) and ethyl acetate (2 mL × 3). The organic layers were combined, washed with saturated brine (15 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give compound 1i. ESI m / z 454.2 [M + Na] + .LCMS:product:Rt=1.45min.

[0295] Step 9): Compound 1i (230 mg, 0.53 mmol, 1.0 equivalence) was dissolved in dichloromethane (3 mL), and Inter 6 (237.16 mg, 0.59 mmol, 1.1 equivalence), acetic acid (9.89 mg, 0.05 mmol, 0.1 equivalence), and sodium triacetoxyborohydride (338.85 mg, 1.60 mmol, 3.0 equivalence) were added. The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was quenched with saturated sodium bicarbonate solution (20 mL) and extracted with dichloromethane (20 mL × 2). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / tert-butyl methyl ether = 1 / 1) to give compound 1j. ESI m / z 820.8 [M+H] + .LCMS:product:Rt=1.32min.

[0296] Step 10): Compound 1j (130 mg, 0.16 mmol, 1.0 equivalence) was dissolved in N,N-dimethylformamide (5 mL), and Inter 5 (81.68 mg, 0.17 mmol, 1.1 equivalence) and potassium carbonate (65.72 mg, 0.48 mmol, 3.0 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 (20 mL × 3). The organic layers were combined, washed with saturated brine (15 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give compound 1k. ESI m / z 1207.8 [M+H]+. LCMS:product:Rt = 1.59 min.

[0297] Step 11): Compound 1k (140 mg, 0.12 mmol, 1.0 equivalence) was dissolved in hydrochloric acid / dioxane solution (5 mL, 4 M) and stirred at 25 °C for 16 hours. The resulting reaction mixture was concentrated and purified by preparative high-performance liquid chromatography (ammonium bicarbonate) to give compound 1. ESI m / z 370.3 [M / 2+H] + .LCMS:product:Rt=1.08min. 1 H NMR(400MHz,D2O)δ7.32–7.25(m,3H),7.25–7.05(m,9H),3.87(s,6H),3.46–3.21(m,6H),3.20–2.91(m,6H),2.90–2.62 (m,8H),2.43–2.33(m,4H),2.09–1.95(m,3H),1.89(d,J=17.2Hz,2H),1.66(dd,J=13.2,9.2Hz,4H),1.43–1.30(m,1H).

[0298] Example 2: Synthesis of Compound 2

[0299] Step 1): Sodium hydroxide (60% dispersion in mineral oil, 3.61 g, 90.34 mmol, 2.0 equivalence) was added to a tetrahydrofuran solution (100 mL) of triethyl phosphoroacetate (30.38 g, 135.51 mmol, 3.0 equivalence) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. Subsequently, compound 2a (9 g, 45.17 mmol, 1.0 equivalence) was added in portions at 0 °C. The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched with a saturated ammonium chloride solution (200 mL) and then extracted with ethyl acetate (200 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 / 2) to give compound 2b. ESI m / z 214.0 [MC(CH3)3+H] + .LCMS:product:Rt=1.278min.

[0300] Step 2): Compound 2b (7.1 g, 26.36 mmol, 1.0 equivalence) was added to ethanol (70 mL), followed by wet palladium on carbon (3 g, 28.19 mmol, 10%). The reaction mixture was stirred at room temperature for 16 hours under hydrogen protection at 15 psi. The mixture was filtered to remove the palladium on carbon, and the filtrate was concentrated under reduced pressure to give crude compound 2c, which was used in the next reaction without further purification. ESI m / z 294.2 [M+Na] + .LCMS:product:Rt=1.282min.

[0301] Step 3): Lithium hydroxide (10.21 g, 41.96 mmol, 10.0 equivalent) was added to a solution containing 20 mL of tetrahydrofuran, 20 mL of methanol, and 20 mL of water (6.6 g, 24.32 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was acidified to pH 5 with 1 M dilute hydrochloric acid and extracted with ethyl acetate (150 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 2d. ESI m / z 188.0 [MC(CH3)3+H] + .LCMS:product:Rt=1.02min; 1H NMR (400MHz, CDCl3) δ3.65–3.38(m,2H),3.36–3.20(m,1H),2.90(dt,J=19.6,9.7Hz,1H),2.41(t,J=7.6Hz,2H),2 .17(dd,J=14.9,7.4Hz,1H),2.06–1.98(m,1H),1.75(q,J=7.3Hz,2H),1.59–1.49(m,1H),1.45(d,J=16.7Hz,9H).

[0302] Step 4): To a tetrahydrofuran (40 mL) solution containing compound 2d (5.4 g, 22.19 mmol, 1.0 equivalence), triethylamine (7.69 mL, 55.49 mmol, 2.5 equivalence) was added at 0 °C, followed by pentanoyl chloride (3.21 g, 26.63 mmol, 1.2 equivalence). The mixture was stirred under nitrogen for 0.5 h. Then, a tetrahydrofuran (40 mL) solution of lithium chloride (1.13 g, 26.63 mmol, 1.2 equivalence) and (S)-4-benzyloxazolidine-2-one (3.92 g, 22.19 mmol, 1.0 equivalence) was added, and the mixture was stirred at 25 °C for 16 h. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (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 / tert-butyl methyl ether = 1 / 2) to give compound 2e. ESI m / z 425.2 [M+Na] + .LCMS:product:Rt=1.36min.

[0303] Step 5): Compound 2e (3 g, 7.45 mmol, 1.0 equivalence) was dissolved in tetrahydrofuran (20 mL) at 0 °C under a nitrogen atmosphere, and lithium bis(trimethylsilylamino)lithium (8.20 mL, 8.20 mmol, 1.1 equivalence) was added. The reaction mixture was stirred at 0 °C for 0.5 h. Subsequently, a tetrahydrofuran solution (20 mL) of 1-bromo-3-(bromomethyl)benzene (2.24 g, 8.94 mmol, 1.2 equivalence) was added. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with saturated ammonium chloride solution (20 mL) and then extracted with ethyl acetate (30 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 / tert-butyl methyl ether = 2 / 3) to give compound 2f. ESI m / z 471.2 [M+H-Boc] + .LCMS:product:Rt=2.324min.

[0304] Step 6): Under a nitrogen atmosphere, compound 2f (3.16 g, 5.53 mmol, 1.0 equivalence) was added to tetrahydrofuran (30 mL), cooled to 0 °C, and hydrogen peroxide (30% aqueous solution, 4.45 mL, 55.29 mmol, 10.0 equivalence) was slowly added dropwise, followed by an aqueous solution of lithium hydroxide (0.51 g, 12.16 mmol, 2.2 equivalence) (6 mL). The reaction mixture was stirred at 0 °C for 0.5 h. The reaction mixture was quenched with an aqueous solution of sodium bisulfite (8.63 g, 82.94 mmol, 15 equivalence) (64 mL), and stirred at 0 °C for 30 min. The resulting mixture was then concentrated under reduced pressure. The pH of the solution was adjusted to 8–9 with an aqueous solution of sodium hydroxide (1 M), and the remaining aqueous phase was extracted with methyl tert-butyl ether (20 mL × 2). The aqueous phase was acidified to pH 5 with citric acid (1M) solution and extracted with methyl tert-butyl ether (20 mL × 3). The organic phases were combined, washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2 g of the compound. ESI m / z 356.0 [M-CC(CH3)3+H] + .LCMS:product:Rt=1.343min.

[0305] Step 7): Add O-tert-butyl-N,N'-diisopropylisourea (4.86 g, 24.25 mmol, 5.0 equivalent) to 2 g (2 g, 4.85 mmol, 1.0 equivalent) of the compound in 20 mL of tetrahydrofuran solution. Stir the reaction mixture at 65 °C for 18 hours. Remove the white solid by filtration, and concentrate the filtrate under reduced pressure. Purify the residue by silica gel column chromatography (petroleum ether / tert-butyl methyl ether = 4 / 1) to give compound 2h. ESI m / z 358.0 [M-2CC(CH3)3+H] + .LCMS:product:Rt=1.657min. 1 H NMR (400MHz, CDCl3) δ7.36 (d, J = 6.9 Hz, 2H), 7.20–7.08 (m, 2H), 3.50 (ddd, J =37.3,23.0,8.7Hz,2H),3.31–3.17(m,1H),2.93–2.77(m,2H),2.74–2.66(m ,1H),2.58(ddd,J=15.0,10.1,5.1Hz,1H),2.21–2.09(m,1H),2.00(dd,J=14 .0,5.3Hz,1H),1.89–1.74(m,1H),1.49–1.46(m,9H),1.35(d,J=5.0Hz,9H).

[0306] Step 8): Compound 2h (1.50 g, 3.20 mmol, 1.0 equivalence) was dissolved in N,N-dimethylformamide (25 mL), and triethylsilane (1.49 g, 12.81 mmol, 4.0 equivalence), triethylamine (2.22 mL, 16.01 mmol, 5.0 equivalence), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (0.24 g, 0.32 mmol, 0.1 equivalence) were added. The reaction mixture was stirred at 90 °C under a carbon monoxide atmosphere for 16 hours. The mixture was poured into water (60 mL) and extracted with ethyl acetate (40 mL × 3). The organic phases were combined, washed with 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 2i. ESI m / z 440.2 [M+Na] + .LCMS:product:Rt=1.492min.

[0307] Step 9): To a solution of compound 2i (250 mg, 0.60 mmol, 1.0 equivalence) in dichloromethane (3 mL), add Inter 6 (230 mg, 0.59 mmol, 0.98 equivalence), acetic acid (107.86 mg, 1.80 mmol, 3.0 equivalence), and sodium triacetoxyborohydride (380.68 mg, 1.80 mmol, 3.0 equivalence). The reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was quenched with saturated sodium bicarbonate solution (30 mL) and extracted with dichloromethane (30 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 (dichloromethane / methanol = 2 / 25) to give compound 2j. ESI m / z 806.4 [M+H] + .LCMS:product:Rt=1.663min.

[0308] Step 10): Compound 2j (120 mg, 0.15 mmol, 1.0 equivalence) was dissolved in N,N-dimethylformamide (3 mL), and inter5 (76.71 mg, 0.16 mmol, 1.1 equivalence) and potassium carbonate (61.72 mg, 0.45 mmol, 3.0 equivalence) were added. The reaction mixture was stirred at 25 °C for 18 hours. The mixture was poured into water (30 mL) and extracted with ethyl acetate (20 mL × 3). The organic layers were combined, washed with brine (30 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 3) to give compound 2k. ESI m / z 1194.6 [M+H] + .LCMS:product:Rt=1.909min.

[0309] Step 11): Compound 2k (160 mg, 0.13 mmol, 1.0 equivalence) was dissolved in a dioxane solution of hydrogen chloride (3 mL, 4 M) and stirred at 25 °C for 16 hours. The resulting reaction mixture was concentrated and purified by preparative high-performance liquid chromatography (ammonium bicarbonate) to give compound 2. ESI m / z 725.2 [M+H] + .LCMS:product:Rt=1.086min; 1 H NMR(400MHz,D2O)δ7.18(dt,J=51.4,9.9Hz,12H),3.55(s,6H),3.38–2.97(m,9H),2.87–2.53( m,8H),2.52–2.28(m,6H),2.16–1.89(m,4H),1.65(td,J=18.3,9.2Hz,3H),1.52–1.11(m,2H).

[0310] Example 3: Synthesis of Compound 3

[0311] Step 1): Compound 3a (4 g, 22.47 mmol, 1.0 equivalence) was dissolved in carbon tetrachloride (50 mL), and N-bromosuccinimide (4.40 g, 24.71 mmol, 1.1 equivalence) and azobisisobutyronitrile (0.37 g, 2.25 mmol, 0.1 equivalence) were added. The reaction mixture was stirred at 80 °C for 16 hours. The resulting 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 layers were combined, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to give a mixture of compounds 3b and 3bb, which were used in the next step without further purification. ESI m / z 255.8 [M+H] + and 333.7[M+H] + .LCMS:product:Rt=1.387min; Rt=1.559min.

[0312] Step 2): A mixture of compounds 3b and 3bb (15.4 g, 59.94 mmol, 1.0 equivalence) was dissolved in tetrahydrofuran (50 mL), and N,N-diisopropylethylamine (24.08 mL, 137.85 mmol, 2.3 equivalence) and diethyl phosphite (3.84 mL, 29.97 mmol, 0.5 equivalence) were added. The reaction mixture was stirred at room temperature for 2 hours. Water (50 mL) was then added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic 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 (petroleum ether / tert-butyl methyl ether = 1 / 1) to give compound 3c. ESI m / z 255.8 [M+H] + .LCMS:product:Rt=1.389min. 1 HNMR (400MHz, DMSO-d6) δ7.77 (s, 1H), 5.03 (d, J = 0.5Hz, 2H).

[0313] Step 3): Under a nitrogen atmosphere, inter 3 (4.0 g, 10.30 mmol, 1.0 equivalence) was dissolved in tetrahydrofuran (40 mL), and bis(trimethylsilylaminolithium) (1.0 M tetrahydrofuran solution, 11.47 mL, 11.47 mmol, 1.1 equivalence) was added at 0 °C, and the mixture was stirred for 30 min. Then, a tetrahydrofuran solution (10 mL) of compound 3c (3.18 g, 12.38 mmol, 1.2 equivalence) was added, and the mixture was stirred at 0 °C for 16 h to room temperature. The reaction mixture was quenched with saturated ammonium chloride aqueous solution (100 mL) and extracted with tert-butyl methyl ether (100 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 (petroleum ether / tert-butyl methyl ether = 1 / 1) to give compound 3d. ESI m / z 508.1 [M+H-tert-butyl] + .LCMS:product:Rt=2.129min.

[0314] Step 4): Compound 3d (4.2 g, 7.44 mmol, 1.0 equivalence) was dissolved in tetrahydrofuran (40 mL), and hydrogen peroxide (30% aqueous solution, 5.78 mL, 74.40 mmol, 10.0 equivalence) was added at 0 °C. Then, an aqueous solution of lithium hydroxide (0.55 g, 13.11 mmol, 1.76 equivalence) (10 mL) was added, and the mixture was stirred for 2 hours, slowly raising it to room temperature. The resulting reaction mixture was quenched with an aqueous solution of sodium bisulfite (10.00 g, 96.11 mmol, 12.92 equivalence) (30 mL) and stirred at 0 °C for 30 minutes. The reaction mixture was then neutralized to pH 9 with sodium hydroxide solution (2.0 M) and extracted with tert-butyl methyl ether (100 mL × 3). The aqueous layer was separated, the pH was adjusted to 5 with an aqueous solution of citric acid (1.0 M), and extracted with tert-butyl methyl ether (100 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to give compound 3e. ESI m / z 349.0 [M+H-tert-butyl] + .LCMS:product:Rt=1.400min.

[0315] Step 5): Compound 3e (2.3 g, 5.67 mmol, 1.0 equivalent) and compound 3f (4.56 g, 22.76 mmol, 4.0 equivalent) were dissolved in tetrahydrofuran (30 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 × 2). The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / tert-butyl methyl ether = 1 / 1) to give compound 3 g. ESI m / z 405.0 [M+H-tert-butyl] + .LCMS:product:Rt=1.779min.

[0316] Step 6): 3 g of compound (1.6 g, 3.47 mmol, 1.0 equivalence) was dissolved in isopropanol (40 mL), and compound 3h (1.40 g, 10.45 mmol, 3.0 equivalence), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.29 g, 0.35 mmol, 0.1 equivalence), and triethylamine (1.44 mL, 10.40 mmol, 3.0 equivalence) were added. The mixture was purged three times under nitrogen, then heated to 80 °C under reflux and stirred for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether / tert-butyl methyl ether = 1 / 1) to give compound 3i. ESI m / z 353.2 [M+H-tert-butyl] + .LCMS:product:Rt=2.137min.

[0317] Step 7): Compound 3i (450 mg, 1.10 mmol, 1.0 equivalence) was dissolved in 1,4-dioxane (9 mL) and water (3 mL), and 2,6-dimethylpyridine (0.26 mL, 2.20 mmol, 2.0 equivalence) and potassium osmium tetroxide (40.59 mg, 0.11 mmol, 0.1 equivalence) were added. The mixture was stirred at room temperature for 30 min, then sodium periodate (942.36 mg, 4.41 mmol, 4.0 equivalence) was added, and the mixture was stirred at the same temperature for 3 h. The reaction mixture was added to water (50 mL), extracted with tert-butyl methyl ether (50 mL × 3), the organic layers were combined, washed with an aqueous sodium thiosulfate solution (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid column chromatography (petroleum ether / tert-butyl methyl ether = 1 / 1) to give compound 3j. ESI m / z 299.0[M+H-2tert-butyl] + .LCMS:product:Rt=1.651min

[0318] Step 8): Compound 3j (220 mg, 0.54 mmol, 1.0 equivalence) and inter 6 (260.20 mg, 0.64 mmol, 1.19 equivalence) were dissolved in dichloromethane (5 mL), acetic acid (0.05 mL, 0.87 mmol) was added, and the mixture was stirred for 30 min. Then, sodium triacetoxyborohydride (340.83 mg, 1.61 mmol, 2.98 equivalence) was added. The mixture was stirred at the same temperature for 16 h. A saturated aqueous sodium carbonate solution (50 mL) was then added to the reaction mixture, and the mixture was extracted with dichloromethane (50 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid column chromatography (petroleum ether / tert-butyl methyl ether = 1 / 1) to give compound 3k. ESI m / z 799.4 [M+H]+.LCMS:product:Rt = 1.581 min.

[0319] Step 9): Compound 3k (140 mg, 0.18 mmol, 1.0 equivalence) and inter 5 (106.69 mg, 0.23 mmol, 1.3 equivalence) were dissolved in N,N-dimethylformamide (5 mL), and potassium carbonate (72.64 mg, 0.53 mmol, 3.0 equivalence) was added. The mixture was stirred at room temperature for 16 hours. The resulting reaction mixture was added to water (30 mL), extracted with tert-butyl methyl ether (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 (petroleum ether / tert-butyl methyl ether = 1 / 1) to give compound 3l. ESI m / z 1186.6 [M+H] +.LCMS:product:Rt=2.139min;

[0320] Step 10): Compound 3 (140 mg, 0.12 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 reaction mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative high-performance liquid chromatography (formic acid) to obtain compound 3. ESI m / z 718.4 [M+H] + .LCMS:product:Rt=0.332min;. 1 HNMR(400MHz,D2O)δ7.56(s,1H),7.32(t,J=7.6Hz,2H),7.26(d,J=7.7Hz ,2H),7.21–7.14(m,4H),4.43(s,2H),4.26(s,4H),3.58–3.42(m,3H),3.3 9–3.28(m,3H),3.19(ddd,J=18.7,10.8,7.0Hz,3H),3.03–2.89(m,5H),2. 80–2.70(m,4H),2.48–2.34(m,6H),2.12–1.97(m,3H),1.78–1.58(m,3H).

[0321] Example 4: Synthesis of Compound 4

[0322] Step 1): Sodium borohydride (2083.0 mg, 55.06 mmol) and compound 4a (3.8 g, 18.35 mmol) were dissolved in tetrahydrofuran (50 mL). The mixture was cooled to 0 °C. Iodine (4.6 g, 18.35 mmol) was dissolved in tetrahydrofuran (5 mL) and added dropwise to the mixture, producing a large amount of hydrogen gas. Gas generation ceased after the iodine solution was completely added. The reaction was heated to reflux and stirred for 18 hours. The reaction was cooled to room temperature, and methanol was slowly added until the solution became clear. The mixture was concentrated under reduced pressure. Dichloromethane (50 mL) was added to the residue and washed with a 2 mol / L sodium carbonate solution and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 9 / 1) to give compound 4b. ESI m / z 174.9 [M-H2O+H] + .LCMS:product:Rt=0.939min.

[0323] Step 2): Compound 4b (3.5 g, 18.13 mmol) was dissolved in dichloromethane (50 mL), and phosphorus tribromide (3.4 mL, 36.26 mmol, 2.0 equivalence) was added. The reaction mixture was stirred at room temperature for 2 hours. A saturated sodium bicarbonate solution (50 mL) was added dropwise to the mixture, and the mixture was extracted with ethyl acetate (80 mL × 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 50 / 1) to give compound 4c. 1 HNMR (400MHz, CDCl3) δ7.17 (s, 1H), 7.08 (d, J = 1.5Hz, 1H), 4.41 (s, 2H).

[0324] Step 3): Under an ice bath and nitrogen atmosphere, inter 3 (2.2 g, 5.66 mmol, 1.0 equivalence) was dissolved in tetrahydrofuran (20 mL), and bis(trimethylsilyl)aminolithium (6.23 mL, 6.23 mmol, 1.1 equivalence) was added. The reaction mixture was stirred at 0 °C for 30 min. Subsequently, compound 4c (1.45 g, 5.66 mmol) was dissolved in tetrahydrofuran (20 mL) and added dropwise to the above reaction system. The reaction mixture was heated to room temperature and stirred for 2 h. The mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate (60 mL × 2). The organic phases were combined, washed with brine, 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 = 9 / 1) to give compound 4d. ESI m / z 585.2 [M + Na] + .LCMS:product:Rt=1.549min.

[0325] Step 4): Compound 4d (1.42 g, 2.52 mmol, 1.0 equivalence) was dissolved in tetrahydrofuran (20 mL). Hydrogen peroxide (30% aqueous solution, 1.96 mL, 25.20 mmol, 10 equivalence) was added dropwise under a nitrogen atmosphere at 0 °C, followed by the addition of a 5 mL solution of lithium hydroxide monohydrate (0.3 g, 2.04 mmol, 2.0 equivalence). The reaction mixture was stirred at 0 °C for 2 hours, then quenched with sodium bisulfite (3.93 g, 37.8 mmol, 15 equivalence) solution, and the pH was adjusted to 5 with citric acid (1 M). The aqueous phase was extracted with methyl tert-butyl ether (40 mL × 3), and the combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 4e. ESI m / z 426.0 [M + Na] + .LCMS:product:Rt=1.292min.

[0326] Step 5): Compound 4e (1.0 g, 2.47 mmol, 1.0 equivalence) was dissolved in tetrahydrofuran (50 mL), and O-tert-butyl-N,N'-diisopropylisourea (1.98 g, 9.89 mmol, 4.0 equivalence) was added. The mixture was stirred at 65 °C for 2 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 2). The organic layers were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 1 / 1) to give compound 4f. ESI m / z 483.0 [M + Na] + .LCMS:product:Rt=1.610min.

[0327] Step 6): Compound 4f (750.0 mg, 1.63 mmol, 1.0 equivalence) was dissolved in N,N-dimethylformamide (5 mL), and triethylsilane (757.6 mg, 6.52 mmol, 4.0 equivalence), 4-dimethylaminopyridine (398.0 mg, 3.26 mmol, 2.0 equivalence), octacarbonyldicobalt (278.5 mg, 0.81 mmol, 0.5 equivalence), and 1,1-bis(diphenylphosphine)dimerferropalladium dichloride (120.8 mg, 0.16 mmol, 0.1 equivalence) were added. The reaction mixture was stirred at 60 °C for 2 hours under a nitrogen atmosphere. 10 mL of water was added to the reaction mixture, and extraction was performed with ethyl acetate (10 mL × 2). The organic layers were combined, washed with 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 / ethyl acetate = 5 / 1) to give 4 g of the compound. ESI m / z 432.2 [M+Na] + .LCMS:product:Rt=1.429min.

[0328] Step 7): 4 g (280.0 mg, 0.68 mmol, 1.0 equivalence) of the compound was dissolved in dichloromethane (10 mL), and Inter 6 (222.7 mg, 0.54 mmol, 1.0 equivalence) was added. The reaction mixture was stirred at room temperature for 1 hour. Then, sodium triacetoxyborohydride (345.7 mg, 1.63 mmol, 3.0 equivalence) was added. The reaction mixture was stirred at room temperature for 4 hours. The mixture was diluted with water and extracted with ethyl acetate (10 mL × 2). The organic layers were combined, washed with brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound 4 h. ESI m / z 798.4 [M+H] + .LCMS:product:Rt=1.368min.

[0329] Step 8): To a solution (5 mL) of N,N-dimethylformamide containing compound 4h (220.0 mg, 0.28 mmol, 1.0 equivalence), add inter 5 (167.86 mg, 0.36 mmol, 1.3 equivalence) and potassium carbonate (76.1 mg, 0.55 mmol, 2.0 equivalence). The reaction mixture was stirred at room temperature for 18 hours. The mixture was diluted with water and extracted with ethyl acetate (10 mL × 2). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 1 / 1) to give compound 4i. ESI m / z 543.5 [(M-Boc) / 2+H] + .LCMS:product:Rt=1.953min.

[0330] Step 9): Trifluoroacetic acid (3 mL) was added to a dichloromethane solution (5 mL) of compound 4i (280.0 mg, 0.24 mmol, 1.0 equivalence). The mixture was stirred at room temperature for 18 hours. The resulting reaction mixture was concentrated and purified by preparative high-performance liquid chromatography (ammonium bicarbonate) to give compound 4. ESI m / z 717.3 [M+H]+.LCMS:product:Rt=0.673 min. 1 H NMR(400MHz,D2O)δ7.22(t,J=7.6Hz,2H),7.10(t,J=10.4Hz,6H),6.97(s,1H),6.79(s,1H),3.63(d,J=2.4Hz,2H),3.54–3.41(m,4H), 3.33–3.25(m,6H),3.19–3.04(m,3H),2.81–2.70(m,6H),2.68–2.57(m,3H),2.45–2.29(m,6H),2.08–1.94(m,3H),1.69–1.57(m,3H).

[0331] Example 5: Synthesis of Compound 5

[0332] Step 1): Under nitrogen protection at 0°C, phosphorus tribromide (2.91 mL, 30.92 mmol, 2.0 equivalence) was added dropwise to a solution of compound 5a (3 g, 15.46 mmol, 1.0 equivalence) in dichloromethane (20 mL), and the mixture was slowly brought back to room temperature with stirring for 16 hours. The mixture was poured into water (20 mL) and extracted with dichloromethane (20 mL). The organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 2 / 1) to give compound 5b. 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).

[0333] Step 2): Under nitrogen protection at 0°C, lithium bis(trimethylsilyl)aminolithium (9.73 mL, 9.73 mmol, 1.1 equivalence) was added to a tetrahydrofuran (40 mL) solution containing inter 3 (3.44 g, 8.85 mmol, 1.0 equivalence). The reaction mixture was stirred at 0°C for 30 min. Subsequently, a tetrahydrofuran (10 mL) solution of compound 5b (2.50 g, 9.73 mmol, 1.1 equivalence) was added. The reaction mixture was brought to room temperature and stirred for 2 h. The reaction mixture was quenched with saturated ammonium chloride solution (100 mL) and extracted with ethyl acetate (80 mL × 3). The organic layers were combined, washed with brine (250 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 1 / 3) to give compound 5c. ESI m / z 508.0 [M+H-tert-butyl] + .LCMS:product:Rt=1.472min.

[0334] Step 3): Under nitrogen protection at 0°C, hydrogen peroxide (30% aqueous solution, 3.92 mL, 50.49 mmol, 1.0 equivalent) was added dropwise to a tetrahydrofuran (24 mL) solution of compound 5c (2.85 g, 5.05 mmol, 1.0 equivalent), followed by an aqueous solution (8 mL) of lithium hydroxide hydrate (0.42 g, 10.10 mmol, 2.0 equivalent). The reaction mixture was stirred at 0°C for 2 hours, then quenched with an aqueous solution (30 mL) of sodium bisulfite (7.88 g, 75.73 mmol, 15 equivalent), 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 5d. ESI m / z 427.0 [M + Na] + .LCMS:product:Rt=1.172min.

[0335] Step 4): To a tetrahydrofuran solution (20 mL) of compound 5d (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 give compound 5e. ESI m / z 349.0 [M + H-tert-buty × 2] + .LCMS:product:Rt=1.519min.

[0336] Step 5): To a solution of compound 5e (800 mg, 1.73 mmol, 1.0 equivalence) in isopropanol (10 mL), potassium vinyltrifluoroborate (347 mg, 2.60 mmol, 1.5 equivalence), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (142 mg, 0.17 mmol, 0.1 equivalence), and triethylamine (0.72 mL, 5.20 mmol, 3.0 equivalence) were added. The mixture was stirred at 80 °C for 2 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give compound 5f. ESI m / z 409.2 [M+H] + .LCMS:product:Rt=1.482min.

[0337] Step 6): Ozone was passed through a stirred solution of compound 5f (535 mg, 1.31 mmol, 1.0 equivalence) in dichloromethane (20 mL) at -78 °C, and the reaction was maintained at -78 °C for 2 minutes. Nitrogen was then passed through the mixture, and the reaction was maintained at -78 °C for 5 minutes to remove excess ozone. Dimethyl sulfide (1.96 mL, 26.20 mmol, 20 equivalence) was added to the mixture, and the reaction mixture was slowly raised from -78 °C to room temperature and stirred for 10 minutes. The mixture was diluted with water (20 mL) and extracted with dichloromethane (10 mL × 2). The organic layers 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 / ethyl acetate = 1 / 1) to give 5 g of the compound. ESI m / z 255.0 [M+H-tert-buty-Boc] + .LCMS:product:Rt=1.446min.

[0338] Step 7): To a solution of compound 5 g (162 mg, 0.39 mmol, 1.0 equivalence) and inter 6 (175.60 mg, 0.43 mmol, 1.1 equivalence) in dichloromethane (5 mL), sodium triacetoxyborohydride (211.94 mg, 1.18 mmol, 3.0 equivalence) was added, and the mixture was stirred at room temperature for 3 hours. The mixture was diluted with water (10 mL) and extracted with dichloromethane (10 mL × 2). The organic layers were combined, washed with brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 50 / 1) to give compound 5 h. ESI m / z 799.4 [M+H]+.LCMS:product:Rt = 1.589 min.

[0339] Step 8): Potassium carbonate (147.35 mg, 1.07 mmol, 3.0 equivalence) was added to a solution of N,N-dimethylformamide (3 mL) containing compound 5h (284 mg, 0.36 mmol, 1.0 equivalence) and inter 5 (199.78 mg, 0.43 mmol, 1.2 equivalence). The mixture was stirred at room temperature for 16 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (5 mL × 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 2 / 1) to give compound 5i. ESI m / z 1186.6 [M+H] + .LCMS:product:Rt=1.804min.

[0340] Step 9): Compound 5i (199 mg, 0.17 mmol) was added to hydrogen chloride / 1,4-dioxane (5 mL, 20.00 mmol, 4 M), and the mixture was stirred at room temperature for 2 hours. The resulting reaction mixture was concentrated and purified by preparative high-performance liquid chromatography (ammonium bicarbonate) to give compound 5. ESI m / z 719.3 [M+H]+.LCMS:product:Rt=0.964 min. 1 H NMR(400MHz,D2O)δ7.26–7.13(m,6H),7.07(d,J=7.1Hz,2H),7.03(s,1H),3.81–3.68(m,2H),3.53(s,4H),3.30(td,J=11.4,7.0Hz,6H),3.21– 3.02(m,3H),2.91–2.60(m,9H),2.48(td,J=9.6,5.2Hz,1H),2.35(tt,J =16.8,7.2Hz,5H),2.02(t,J=8.9Hz,3H),1.64(dt,J=22.2,9.1Hz,3H).

[0341] Example 6: Synthesis of Compound 6

[0342] Step 1): To a tetrahydrofuran solution (100 mL) of compound 6a (5.9 g, 42.70 mmol, 1.0 equivalent), tert-butyldimethylchlorosilane (6.44 g, 42.70 mmol, 1.0 equivalent) and imidazole (2.91 g, 42.70 mmol, 1.0 equivalent) were added. The reaction mixture was stirred at room temperature for 18 hours. The mixture 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 6b. 1 H NMR (400MHz, CDCl3) δ7.22(dd,J=9.4,5.2Hz,2H),7.27–7.09(m,4H),7.15(dd,J=8.3,6.4Hz,2H),4.64(s,2H),4.64(s,2H),4 .58(d,J=3.5Hz,2H),4.58(d,J=3.5Hz,2H),1.63(s,1H),1.63(s,2H),0.84(s,9H),0.84(s,9H),-0.00(s,6H),-0.00(s,6H).

[0343] Step 2): Tetrabromomethane (5.2 g, 15.85 mmol, 1.0 equivalent) and triphenylphosphine (4.1 g, 15.85 mmol, 1.0 equivalent) were added to a dichloromethane (50 mL) solution containing compound 6b (4.0 g, 15.85 mmol, 1.0 equivalent). The reaction mixture was stirred at room temperature for 18 hours. The mixture was quenched with saturated sodium bicarbonate solution (200 mL) and extracted with dichloromethane (200 mL × 2). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give compound 6c. 1 H NMR (400MHz, CDCl3) δ7.36–7.15(m,4H),4.73(s,2H),4.53–4.45(m,2H),0.94(d,J=2.0Hz,9H),0.09(d,J=2.4Hz,6H).

[0344] Step 3): Sodium hydroxide (60% dispersed in mineral oil) (253.7 mg, 6.34 mmol, 2.0 equivalence) was added to a solution of tetrahydrofuran (10 mL) containing tert-butyl-2-(dimethoxyphosphono)acetate (1.4 g, 6.34 mmol, 2.0 equivalence). The reaction mixture was stirred at room temperature for 0.5 h. Subsequently, a solution of tetrahydrofuran (10 mL) containing compound 6c (1.0 g, 3.17 mmol, 1.0 equivalence) was added. The reaction mixture was stirred at room temperature for 2 h. The mixture was quenched with a saturated ammonium chloride solution (100 mL) and extracted with ethyl acetate (100 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 to give compound 6d. ESI m / z 481.2 [M + Na] + .LCMS:product:Rt=1.604min

[0345] Step 4): Sodium hydroxide (60% dispersed in mineral oil) (174.9 mg, 4.37 mmol, 1.5 equivalence) was added to a tetrahydrofuran solution (50 mL) of compound 6d (1.91 g, 2.92 mmol, 1.0 equivalence). The reaction mixture was stirred at room temperature for 0.5 h. Subsequently, a tetrahydrofuran solution (10 mL) of tert-butyl 3-formylpyrrolidine-1-carboxylic acid ester (638.9 mg, 3.21 mmol, 1.1 equivalence) was added. The reaction mixture was stirred at room temperature for 2 h. The mixture was quenched with a saturated ammonium chloride solution (100 mL) and extracted with ethyl acetate (100 mL × 2). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 10 / 1) to give compound 6e. ESI m / z 554.4 [M + Na] + .LCMS:product:Rt=1.900min.

[0346] Step 5): To compound 6e (1.2 g, 2.26 mmol, 1.0 equivalence), add tetrabutylammonium fluoride (2 mol / L tetrahydrofuran solution) (2.95 mL, 11.28 mmol, 5.0 equivalence). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give compound 6f. ESI m / z 440.2 [M+Na] + .LCMS:product:Rt=1.405min.

[0347] Step 6): Carbon tetrabromide (357.4 mg, 1.08 mmol, 1.0 equivalent) and triphenylphosphine (282.6 mg, 1.08 mmol, 1.0 equivalent) were added to a dichloromethane solution (50 mL) containing compound 6f (450.0 mg, 1.08 mmol, 1.0 equivalent). The reaction mixture was stirred at room temperature for 18 hours. The mixture was quenched with saturated sodium bicarbonate solution (100 mL) and extracted with dichloromethane (100 mL × 2). The combined organic layers were washed with 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 (petroleum ether / methyl tert-butyl ether = 5 / 1) to give compound 6 g. ESI m / z 502.2 [M + Na] + .LCMS:product:Rt=1.615min.

[0348] Step 7): 6 g (100.0 mg, 0.21 mmol, 1.0 equivalence) of compound was dissolved in N,N-dimethylformamide (10 mL), and cesium carbonate (135.63 mg, 0.42 mmol, 2.0 equivalence) and inter 2 (181.3 mg, 0.23 mmol, 1.1 equivalence) were added. The reaction mixture was stirred at 60 °C for 18 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 2). The organic layers were combined, washed with brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 1 / 1) to give compound 6 h. ESI m / z 1192.6 [M+H] + .LCMS:product:Rt=1.914min.

[0349] Step 8): Compound 6 (200.0 mg, 0.17 mmol, 1.0 equivalence) was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (2 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 (formic acid) to give compound 6. ESI m / z 723.4 [M+H] + .LCMS:product:Rt=0.707min. 1 H NMR(400MHz,D2O)δ8.35(s,1H),7.36–7.24(m,6H),7.14(dd,J=16.4,8.0Hz,6H ),5.10(d,J=9.2Hz,1H),4.19(s,6H),3.53–3.44(m,4H),3.41–3.27(m,4H),3. 26–3.09(m,4H),2.99–2.88(m,2H),2.75(dd,J=18.8,6.6Hz,5H),2.47–2.32(m ,4H),2.07(ddd,J=13.4,10.4,6.8Hz,3H),1.65(ddd,J=18.0,9.0,3.8Hz,3H).

[0350] Example 7: Synthesis of Compound 7

[0351] Step 1): Compound 7b (31.84 g, 142.01 mmol, 3.0 equivalence) was dissolved in tetrahydrofuran (100 mL), and sodium hydrogen (3.79 g, 94.67 mmol, 2.0 equivalence) was added. The mixture was stirred at 0 °C for 30 min. Then, a tetrahydrofuran solution (10 g, 47.34 mmol, 1.0 equivalence) of compound 7a (10 g, 47.34 mmol, 1.0 equivalence) was added, and the mixture was stirred at 0 °C to room temperature for 16 h. The reaction mixture was added to water (100 mL) and extracted with tert-butyl methyl ether (100 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 (petroleum ether / tert-butyl methyl ether = 3 / 1) to give compound 7c. ESI m / z 226.0 [M+H-tert-butyl] + .LCMS:product:Rt=1.558min. 1 H NMR(400MHz,DMSO-d6)δ5.64(t,J=2.2Hz,1H),4.06(q,J=7.1Hz,2H),3.89(s ,4H),3.23(d,J=2.3Hz,2H),3.02(s,2H),1.37(s,9H),1.19(t,J=7.1Hz,3H).

[0352] Step 2): Compound 7c (13 g, 46.21 mmol, 1.0 equivalence) was dissolved in ethanol (100 mL), and 10% palladium / carbon (6 g, 56.38 mmol) was added. The mixture was purged with hydrogen three times, and then stirred at room temperature for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give compound 7d. ESI m / z 228.2 [M+H-tert-butyl] + .LCMS:product:Rt=1.579min.

[0353] Step 3): Compound 7d (12.2 g, 43.05 mmol, 1.0 equivalence) was dissolved in tetrahydrofuran (90 mL) and water (30 mL), and lithium hydroxide (5.42 g, 129.16 mmol, 3.0 equivalence) was added. The mixture was stirred at room temperature for 16 hours. The reaction mixture was adjusted to pH 5 with aqueous citric acid (1.0 M) and extracted with tert-butyl methyl ether (100 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 7e. ESI m / z 200.0 [M+H-tert-butyl] + .LCMS:product:Rt=1.289min.

[0354] Step 4): Compound 7e (9.0 g, 35.25 mmol, 1.0 equivalent) was dissolved in tetrahydrofuran (100 mL), and triethylamine (12.26 mL, 88.45 mmol, 2.5 equivalent) was added. The mixture was stirred at room temperature for 10 min. Then, tertivalyl chloride (5.13 g, 42.54 mmol, 1.2 equivalent) was added, and the mixture was stirred at room temperature for 20 min. Lithium chloride (1.82 g, 42.93 mmol, 1.2 equivalent) and compound 7f (6.27 g, 35.38 mmol, 1.0 equivalent) were then added. The mixture was stirred at room temperature for 16 h. The reaction mixture was added to water (100 mL) and extracted with tert-butyl methyl ether (100 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 (dichloromethane / methanol = 5 / 1) to give compound 7 g. ESI m / z 359.2 [M+H-tert-butyl] + .LCMS:product:Rt=1.640min. 1 H NMR (400MHz, DMSO-d6) δ7.32(t,J=7.2Hz,2H),7.25(t,J=7.3Hz,1H),7.18(d,J=6.9Hz,2H),4.62(ddd,J=10.9,7.7,3.0Hz,1H),4.31(t,J=8.5Hz,1H),4 .17(dd,J=8.8,2.8Hz,1H),3.80(d,J=50.6Hz,4H),3.01–2.80(m,4H),2.50 –2.43(m,1H),2.36–2.26(m,2H),1.86(dd,J=12.5,8.2Hz,2H),1.36(s,9H).

[0355] Step 5): Under a nitrogen atmosphere, 7 g (6 g, 14.48 mmol, 1.0 equivalence) of compound was dissolved in tetrahydrofuran (50 mL). Lithium bis(trimethylsilylamino)ene (1 M tetrahydrofuran solution, 15.92 mL, 15.92 mmol, 1.0 equivalence) was added at 0 °C, and the mixture was stirred for 30 min at the same temperature. Then, a tetrahydrofuran solution (50 mL) of compound 7 h (4.35 g, 17.40 mmol, 1.2 equivalence) was added, and the mixture was stirred at 0 °C to room temperature for 16 h. The reaction mixture was quenched with saturated ammonium chloride aqueous solution (100 mL) and extracted with tert-butyl methyl ether (100 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 (petroleum ether / tert-butyl methyl ether = 1 / 1) to give compound 7i. ESI m / z 527.2 [M+H-tert-butyl] + .LCMS:product:Rt=1.867min.1 H NMR (400MHz, DMSO-d6) δ7.45 (s, 1H), 7.43–7.38 (m, 1H), 7.26 (d, J = 6.5Hz, 2H), 7.22–7.18 (m,3H),6.88(dd,J=6.4,3.0Hz,2H),4.64(ddd,J=10.7,7.7,2.9Hz,1H),4.28(t,J=8.5Hz, 1H),4.16–4.06(m,2H),3.83(s,2H),3.69(s,2H),2.88–2.75(m,3H),2.61(dd,J=13.5,7. 5Hz,1H),2.38(dd,J=16.8,8.4Hz,1H),2.18–2.11(m,2H),1.93–1.82(m,2H),1.35(s,9H).

[0356] Step 6): Compound 7i (6.3 g, 10.80 mmol, 1.0 equivalence) was dissolved in tetrahydrofuran (60 mL), and hydrogen peroxide (30% aqueous solution, 8.38 mL, 107.97 mmol, 10.0 equivalence) was added at 0 °C. Then, an aqueous solution of lithium hydroxide (0.92 g, 21.93 mmol, 2.0 equivalence) (20 mL) was added, and the mixture was stirred at 0 °C to room temperature for 2 hours. The resulting reaction mixture was quenched with an aqueous solution of sodium bisulfite (16.87 g, 162.13 mmol) (30 mL) and stirred at 0 °C for 30 minutes. The reaction mixture was then neutralized to pH 9 with sodium hydroxide (2.0 M) and extracted with tert-butyl methyl ether (100 mL × 3). The aqueous layer was separated, neutralized to pH 5 with an aqueous solution of citric acid (1.0 M), and extracted with tert-butyl methyl ether (100 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 7j. ESI m / z 370.0 [M+H-tert-butyl] + .LCMS:product:Rt=1.622min.

[0357] Step 7): Compounds 7j (3.1 g, 7.31 mmol, 1.0 equivalent) and 7k (5.85 g, 29.22 mmol, 4.0 equivalent) were dissolved in tetrahydrofuran (40 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 × 2). The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether / tert-butyl methyl ether = 1 / 1) to give compound 7l. ESI m / z 370.0 [M + H-2 tert-butyl] + .LCMS:product:Rt=1.951min.

[0358] Step 8): Compound 7l (1.2 g, 2.50 mmol, 1.0 equivalence) was dissolved in N,N-dimethylformamide (15 mL), and (1,1'-bis(diphenylphosphino)ferrocene)palladium dichloride (0.22 g, 0.27 mmol, 0.1 equivalence), triethylamine (1.41 mL, 10.18 mmol, 4.0 equivalence), and triethylsilane (1.24 mL, 7.65 mmol, 3.0 equivalence) were added. The mixture was purged three times with carbon monoxide gas, then heated to reflux at 120 °C and stirred for 16 hours. The reaction mixture was added to water (50 mL), 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 (petroleum ether / tert-butyl methyl ether = 1 / 1) to give compound 7m. ESI m / z 318.0[M+H-2tert-butyl] + .LCMS:product:Rt=1.785min. 1 H NMR(400MHz,DMSO-d6)δ9.98(s,1H),7.77–7.73(m,1H),7.71(s,1H),7.53–7 .50(m,2H),3.86(s,2H),3.71(s,2H),2.75(dd,J=13.6,4.7Hz,1H),2.67(dd, J=13.5,10.2Hz,1H),2.50–2.46(m,1H),2.25(dd,J=7.3,3.8Hz,2H),2.17(dd ,J=14.2,9.0Hz,1H),1.95(dt,J=11.2,9.5Hz,2H),1.36(s,9H),1.23(s,9H).

[0359] Step 9): Compound 7m (490 mg, 1.14 mmol, 1.0 equivalence) and inter 6 (553.79 mg, 1.37 mmol, 1.2 equivalence) were dissolved in dichloromethane (10 mL), and sodium triacetoxyborohydride (725.32 mg, 3.42 mmol, 3.0 equivalence) was added. The mixture was stirred at room temperature for 3 hours. Then, saturated sodium bicarbonate aqueous solution (50 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (50 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid column chromatography (petroleum ether / tert-butyl methyl ether = 1 / 1) to give compound 7n. ESI m / z 818.5 [M+H] + .LCMS:product:Rt=1.662min. 1H NMR(400MHz,DMSO-d6)δ7.17(ddd,J=25.5,14.2,7.3Hz,6H),7.05–7.00(m,2H),3.84(s,2H),3.69(s,2H),3.60 (s,4H),3.55–3.46(m,1H),3.37(s,1H),3.15(dd,J=15.8,6.4Hz,1H),2.97(t,J=10.0Hz,1H),2.72(d,J=8.7Hz, 2H),2.62–2.57(m,2H),2.52(s,1H),2.42(dd,J=15.0,8.4Hz,1H),2.18(ddd,J=18.1,13.4,7.3Hz,4H),1.90(d dd,J=25.3,16.3,8.7Hz,3H),1.59(dd,J=20.4,9.9Hz,1H),1.39(s,9H),1.35(s,9H),1.25(s,9H),1.22(s,9H).

[0360] Step 10): Compound 7n (200 mg, 0.24 mmol, 1.0 equivalence) and inter 5 (137.42 mg, 0.29 mmol, 1.2 equivalence) were dissolved in N,N-dimethylformamide (5 mL), and potassium carbonate (101.36 mg, 0.73 mmol, 3.0 equivalence) was added. The mixture was stirred at room temperature for 16 hours. Water (30 mL) was then added to the reaction mixture, and the mixture was extracted with tert-butyl methyl ether (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 (petroleum ether / tert-butyl methyl ether = 1 / 1) to give compound 7o. ESI m / z 1206.8 [M+H] + .LCMS:product:Rt=1.924min.

[0361] Step 11): Compound 7 (200 mg, 0.17 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 give compound 7. ESI m / z 737.4 [M+H] + .LCMS:product:Rt=1.058min. 1H NMR(400MHz,D2O)δ7.35–7.21(m,6H),7.14(d,J=7.5Hz,3H),7.10(s,3H),4.20(s,6H),4.03(s, 2H),3.90(s,2H),3.51(dd,J=11.7,7.2Hz,2H),3.35(ddd,J=11.9,8.6,3.5Hz,2H),3.24–3.13( m,2H),3.02–2.91(m,2H),2.83–2.66(m,5H),2.61(dd,J=13.6,9.6Hz,1H),2.44(tq,J=19.2,9. 7Hz,5H),2.35–2.20(m,3H),2.14–2.02(m,2H),2.00–1.86(m,2H),1.67(dq,J=12.9,9.3Hz,2H).

[0362] Example 8: Synthesis of Compound 8

[0363] Step 1): To a 2 mL solution of acetonitrile containing inter 5a (500.0 mg, 1.23 mmol, 1.0 equivalence), bis(2,5-dioxopyrrolidone-1-yl) carbonate (379.0 mg, 1.48 mmol, 1.2 equivalence) and triethylamine (249.5 mg, 2.47 mmol, 2.0 equivalence) were added. The reaction mixture was stirred at room temperature for 1 hour. The resulting reaction mixture was concentrated under reduced pressure to give compound 8a. ESI m / z 569.2 [M+Na] + .LCMS:product:Rt=1.691min.

[0364] Step 2): Compound 8a (670 mg, 1.23 mmol, 1.0 equivalence) was dissolved in dichloromethane (5 mL), and compound 13b (626.9 mg, 1.47 mmol, 1.2 equivalence), triethylamine (248 mg, 2.45 mmol, 2.0 equivalence), and 4-dimethylaminopyridine (14.9 mg, 0.12 mmol, 0.1 equivalence) were added. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 2 / 3) to give compound 8b. ESI m / z 843.4 [M+H] + .LCMS:product:Rt=1.678min.

[0365] Step 3): Compound 8b (190.0 mg, 0.23 mmol, 1.0 equivalence) was dissolved in N,N-dimethylformamide (5 mL), and sodium hydroxide (60% dispersed in mineral oil) (36.0 mg, 0.90 mmol, 4.0 equivalence) was added. The reaction mixture was stirred at room temperature for 0.5 h. Then inter 5 (137.2 mg, 0.23 mmol, 1.3 equivalence) was added. The reaction mixture was stirred at room temperature for 1.5 h. The mixture was poured into ammonium chloride (60 mL) and extracted with ethyl acetate (40 mL × 3). 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 residue was purified by flash column chromatography (petroleum ether / methyl tert-butyl ether = 2 / 3) to give compound 8c. ESI m / z 1253.8 [M + Na] + .LCMS:product:Rt=2.529min.

[0366] Step 4): Trifluoroacetic acid (2 mL) was added to a solution of dichloromethane containing compound 8c (150.0 mg, 0.12 mmol, 1.0 equivalence). The reaction mixture was stirred at room temperature for 18 hours. The resulting reaction mixture was concentrated and purified by preparative high-performance liquid chromatography (formic acid) to give compound 8. ESI m / z 381.8 [M / 2+H] + .LCMS:product:Rt=0.966min. 1 HNMR(400MHz,D2O)δ7.26–7.11(m,3H),7.09–6.84(m,6H),5.09(s,2H),4.63(s,2H),4.49(s,2H),3.35(d,J =10.8Hz,6H),3.17(s,3H),2.74(dd,J=38.4,28.4Hz,9H),2.39(s,6H),2.04(s,3H),1.68(d,J=8.8Hz,3H).

[0367] Example 9: Synthesis of Compound 9

[0368] Step 1): 13.5 g (60.22 mmol, 3.0 equivalent) of 2-(diethoxyphosphoryl)ethyl acetate was dissolved in tetrahydrofuran (70 mL), and sodium hydroxide (60% dispersion in mineral oil, 1.6 g, 40.00 mmol, 2.0 equivalent) was added at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. Then, compound 9a (4 g, 20.08 mmol, 1.0 equivalent) was added at 0 °C. The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched with saturated ammonium chloride solution (50 mL) and then extracted with ethyl acetate (40 mL × 3). The organic layers were combined, and the mixture was concentrated under reduced pressure with anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give compound 9b. ESI m / z 292.2 [M+Na] + .LCMS:product:Rt=1.23min.

[0369] Step 2): Compound 9b (5.4 g, 20.05 mmol, 1.0 equivalent) was dissolved in ethanol (60 mL), and 10% palladium / carbon (1 g, 9.40 mmol, 0.5 equivalent) was added. The reaction mixture was stirred at room temperature for 16 hours under hydrogen protection at 15 psi. The mixture was filtered to remove palladium / carbon, and the filtrate was concentrated under reduced pressure to give compound 9c, which was used in the next step without further purification. ESI m / z 294.2 [M+Na] + .LCMS:product:Rt=1.22min.

[0370] Step 3): Compound 9c (5.4 g, 19.90 mmol, 1.0 equivalent) was dissolved in methanol (15 mL), tetrahydrofuran (15 mL), and water (15 mL), and lithium hydroxide monohydrate (3.35 g, 79.84 mmol, 4.0 equivalent) was added. The reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was poured into water (30 mL), extracted with ethyl acetate (20 mL × 3), and then the aqueous phase was acidified to pH 5 with 1 M hydrochloric acid and extracted with ethyl acetate (20 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 9d. ESI m / z 266.1 [M + Na] + .LCMS:product:Rt=1.03min.

[0371] Step 4): Compound 9d (4.8 g, 19.73 mmol, 1.0 equivalence) was dissolved in tetrahydrofuran (60 mL), and triethylamine (6.85 mL, 49.41 mmol, 2.5 equivalence) was added at 0 °C, followed by pivaloyl chloride (2.86 g, 23.72 mmol, 1.2 equivalence). The mixture was stirred under nitrogen protection for 0.5 h. Then, lithium chloride (1.01 g, 23.83 mmol, 1.2 equivalence) and (S)-4-benzyloxazolidin-2-one (3.51 g, 19.81 mmol, 1.0 equivalence) dissolved in tetrahydrofuran (10 mL) were added, and the mixture was stirred at 25 °C for 16 h. The reaction mixture was diluted with water (60 mL) and extracted with ethyl acetate (40 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 = 3 / 1) to give compound 9e. ESI m / z 425.2 [M+Na] + .LCMS:product:Rt=1.29min.

[0372] Step 5): Compound 9e (5.7 g, 14.16 mmol, 1.0 equivalence) was dissolved in tetrahydrofuran (70 mL) under nitrogen protection at 0 °C, and lithium bis(trimethylsilyl)amine (30.30 mL, 30.30 mmol, 2.1 equivalence) was added. The reaction mixture was stirred at 0 °C for 0.5 h. Subsequently, a solution of 1-bromo-3-(bromomethyl)benzene (4.2 g, 16.80 mmol, 1.2 equivalence) in tetrahydrofuran (10 mL) was added. The reaction mixture was brought to room temperature and stirred for 2 h. The reaction mixture was quenched with saturated ammonium chloride solution (40 mL) and extracted with ethyl acetate (30 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 = 2 / 1) to give compound 9f. ESI m / z 473.1 [M-Boc+H] + .LCMS:product:Rt=1.59min.

[0373] Step 6): Under nitrogen protection, compound 9f (1.9 g, 2.89 mmol, 1.0 equivalence) was dissolved in tetrahydrofuran (25 mL), and hydrogen peroxide (30% aqueous solution, 2.05 mL, 26.46 mmol, 9.0 equivalence) was slowly added dropwise at 0 °C, followed by lithium hydroxide monohydrate (0.25 g, 5.96 mmol, 2.0 equivalence) dissolved in water (8 mL). The reaction mixture was stirred at 0 °C for 2 hours. A sodium bisulfite solution (3 g, 28.83 mmol, 10 equivalence) dissolved in water (20 mL) was slowly added dropwise to the reaction mixture, and the mixture was stirred at 0 °C for 30 minutes. The mixture was then neutralized to pH 5 with 1.0 M citric acid aqueous solution and extracted with tert-butyl methyl ether (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 9 g. ESI m / z 412.1 [MH] + .LCMS:product:Rt=0.96min.

[0374] Step 7): 9 g (1.9 g, 2.76 mmol, 1.0 equivalence) of the compound was dissolved in tetrahydrofuran (20 mL), and O-tert-butyl-N,N'-diisopropylisourea (2.8 g, 13.98 mmol, 5.0 equivalence) was added. The reaction mixture was stirred at 65 °C for 2 hours. The reaction solution 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 = 2 / 1) to give compound 9 h. 1 H NMR (400MHz, CDCl3) δ7.29–7.20(m,2H),7.04(dt,J=13.2,7.6Hz,2H),4.45(s,1H),3.96(s,1H),2.80–2.65(m,2H),2.32-2.20(m,1H),2 .14(dt,J=12.5,8.8Hz,1H),2.02(d,J=11.6Hz,1H),1.78–1.67(m,2H),1.63(s,1H),1.40–1.36(m,9H),1.27–1.17(m,9H),1.10(s,2H).

[0375] Step 8): Compound 9h (200 mg, 0.40 mmol) was dissolved in N,N-dimethylformamide (5 mL), and triethylsilane (199 mg, 1.71 mmol, 4.3 equivalences), triethylamine (0.30 mL, 2.13 mmol, 5.3 equivalences), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (31 mg, 0.04 mmol, 0.1 equivalences) were added. The mixture was stirred at 90 °C for 16 hours under carbon monoxide atmosphere. The mixture was extracted with water (20 mL) and ethyl acetate (15 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 / ethyl acetate = 2 / 1) to give compound 9i. ESI m / z 440.2 [M + Na] + .LCMS:product:Rt=1.48min.

[0376] Step 9): Compound 9i (116 mg, 0.20 mmol, 1.0 equivalence) was dissolved in dichloromethane (10 mL), and Inter 6 (81 mg, 0.20 mmol, 1.0 equivalence), acetic acid (4 mg, 0.02 mmol, 0.1 equivalence), and sodium triacetoxyborohydride (127 mg, 0.60 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 compound 9j. ESI m / z 806.6 [M+H]+.LCMS:product:Rt = 1.35 min.

[0377] Step 10): Compound 9j (188 mg, 0.21 mmol, 1.0 equivalence) was dissolved in N,N-dimethylformamide (5 mL), and Inter 5 (110 mg, 0.23 mmol, 1.1 equivalence) and potassium carbonate (89 mg, 0.64 mmol, 3.0 equivalence) were added. The reaction mixture was stirred at room temperature for 2 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 9k. ESI m / z 1193.8 [M+H] + .LCMS:product:Rt=1.60min.

[0378] Step 11): Compound 9k (200 mg, 0.17 mmol) was dissolved in hydrochloric acid / dioxane (8 mL, 4 M) and stirred at 25 °C for 16 hours. The reaction solution was concentrated and purified by preparative high-performance liquid chromatography (ammonium bicarbonate) to obtain compound 9. ESI m / z 725.4 [M+H] + .LCMS:product:Rt=1.06min. 1 H NMR(400MHz,D2O)δ7.26(q,J=7.2Hz,3H),7.21–7.07(m,9H),3.61(s,7H),3.31(ddd,J=12.0,9.8,5.6Hz,4H),3.18–3.06(m,2H),2.86–2.63(m ,8H),2.45–2.31(m,4H),2.30–1.99(m,5H),1.83(dd,J=17.6,12.0Hz,2 H),1.75–1.59(m,3H),1.52(dt,J=14.0,8.8Hz,1H),1.38–1.25(m,1H).

[0379] Example 10: Synthesis of Compound 10

[0380] Step 1): Compound 10a (8 g, 45.18 mmol, 1.0 equivalence) was dissolved in methanol (40 mL) and N,N-dimethylacetamide (40 mL), followed by the addition of 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (3.31 g, 4.52 mmol, 0.1 equivalence) and triethylamine (18.79 mL, 135.55 mmol, 3.0 equivalence). The mixture was purged three times with carbon monoxide gas, then heated to 80 °C under reflux and stirred for 16 hours. The reaction mixture was subjected to reduced pressure to remove methanol and filtered. The filtrate was diluted with ethyl acetate (200 mL) and water (200 mL), extracted with ethyl acetate (200 mL × 3), and washed with brine (200 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 (petroleum ether / dichloromethane = 5 / 1) to give compound 10b. ESI m / z 157.0 [M+H] + .LCMS:product:Rt=1.405min.

[0381] Step 2): Compound 10b (4 g, 25.61 mmol, 1.0 equivalence) was dissolved in N,N-dimethylformamide (50 mL), and N-bromosuccinimide (4.56 g, 25.61 mmol, 1.0 equivalence) was added. The mixture was stirred at room temperature for 3 hours. Water (100 mL) was then added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL × 3) and washed 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 purified by rapid column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give compound 10c. LCMS:product:Rt = 1.617 min.

[0382] Step 3): Under a nitrogen atmosphere, compound 10c (4.0 g, 17.01 mmol, 1.0 equivalence) was dissolved in dichloromethane (50 mL), and diisobutylaluminum hydride (1.5 M toluene solution, 28.36 mL, 42.54 mmol, 2.5 equivalence) was slowly added dropwise at -78 °C. The mixture was stirred for 16 hours, slowly rising to room temperature. Then, water (6.0 mL) and 15% sodium hydroxide solution (6.0 mL) were added to the reaction mixture, followed by the addition of water (6.0 mL × 3) and stirring for 30 minutes. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure to give compound 10d. ESI m / z 188.8 [M-H₂O+H] + .LCMS:product:Rt=1.283min.

[0383] Step 4): Compound 10d (4 g, 19.32 mmol, 1.0 equivalence) was dissolved in N,N-dimethylformamide (60 mL), and phosphorus tribromide (5.45 mL, 57.95 mmol, 3.0 equivalence) was added dropwise at 0 °C. The mixture was stirred for 3 hours while slowly rising to room temperature. A saturated aqueous solution of sodium bicarbonate (100 mL) was then 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 purified by rapid column chromatography (petroleum ether / tert-butyl methyl ether = 10 / 1) to give compound 10e. ESI m / z 270.8 [M+H] + .LCMS:product:Rt=1.715min

[0384] Step 5): Under a nitrogen atmosphere, inter 3 (6 g, 15.45 mmol, 1.0 equivalence) was dissolved in tetrahydrofuran (60 mL), and then 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 0 °C for 30 min. Subsequently, a tetrahydrofuran solution (60 mL) of compound 10e (4.2 g, 15.56 mmol, 1.0 equivalence) was added dropwise, and the mixture was slowly raised to room temperature over 4 h with stirring. The reaction mixture was quenched with a saturated aqueous ammonium chloride solution (100 mL) and extracted with tert-butyl methyl ether (100 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 silica gel column chromatography (petroleum ether / tert-butyl methyl ether = 1 / 1) to give compound 10f. ESI m / z 521.0 [M+H-tert-butyl] + .LCMS:product:Rt=1.857min.

[0385] Step 6): Compound 10f (4.9 g, 8.48 mmol, 1.0 equivalence) was dissolved in tetrahydrofuran (60 mL), and hydrogen peroxide (30% aqueous solution, 6.59 mL, 84.84 mmol) was added at 0 °C. Then, an aqueous solution of lithium hydroxide (0.71 g, 16.97 mmol, 10.0 equivalence) (20 mL) was added, and the mixture was stirred for 2 hours while slowly brought to room temperature. The resulting reaction mixture was quenched with an aqueous solution of sodium bisulfite (13.24 g, 127.27 mmol, 15.0 equivalence) (20 mL) and stirred at 0 °C for 30 minutes. The reaction mixture was then neutralized to pH 9 with sodium hydroxide (2.0 M) and extracted with tert-butyl methyl ether (150 mL × 3). The aqueous layer was separated, neutralized to pH 5 with an aqueous solution of citric acid (1.0 M), 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 10 g of the compound. ESI m / z 362.0 [M+H-tert-butyl] + .LCMS:product:Rt=1.622min.

[0386] Step 7): Compound 10 g (2.4 g, 5.74 mmol, 1.0 equivalent) and compound 10 h (4.60 g, 22.95 mmol, 4.0 equivalent) were dissolved in tetrahydrofuran (30 mL). The mixture was heated to 65 °C and refluxed with stirring for 2 hours. The resulting reaction mixture was filtered and washed with ethyl acetate (20 mL × 2). The filtrate was concentrated under reduced pressure. The residue was purified by rapid column chromatography (petroleum ether / tert-butyl methyl ether = 1 / 1) to give compound 10 i. ESI m / z 362.0 [M+H-2tert-butyl]+.LCMS:product:Rt = 1.976 min.

[0387] Step 8): Compound 10i (700 mg, 1.48 mmol, 1.0 equivalence) was dissolved in N,N-dimethylformamide (10 mL), and (1,1'-bis(diphenylphosphino)ferrocene)palladium dichloride (120.78 mg, 0.15 mmol, 0.1 equivalence), 4-dimethylaminopyridine (360.50 mg, 2.95 mmol, 2.0 equivalence), and triethylsilane (0.71 mL, 4.43 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 4 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 (petroleum ether / methyl tert-butyl ether = 3 / 1) to give compound 10j. ESI m / z 324.0 [M+H-Boc] + .LCMS:product:Rt=1.747min.

[0388] Step 9): Compound 10kJ (370 mg, 0.87 mmol, 1.0 equivalence) and Inter 6 (424.06 mg, 1.05 mmol, 1.2 equivalence) were dissolved in dichloromethane (5 mL), and acetic acid (0.05 mL, 0.87 mmol, 1.0 equivalence) was added. The mixture was stirred for 30 min. Then sodium triacetoxyborohydride (555.41 mg, 2.62 mmol, 3.0 equivalence) was added. The mixture was stirred at room temperature for 3 h. The reaction mixture was added to a saturated aqueous sodium carbonate 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 (petroleum ether / methyl tert-butyl ether = 1 / 1) to give compound 10kJ. ESI m / z 812.4 [M+H] + .LCMS:product:Rt=1.596min.

[0389] Step 10): Compound 10k (250 mg, 0.31 mmol, 1.0 equivalence) and inter 5 (144.20 mg, 0.31 mmol, 1.0 equivalence) were dissolved in N,N-dimethylformamide (10 mL), and potassium carbonate (127.63 mg, 0.92 mmol, 3.0 equivalence) was added. The mixture was stirred at room temperature for 16 hours. Water (50 mL) was then added to the reaction mixture, 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 (petroleum ether / methyl tert-butyl ether = 1 / 1) to give compound 10k. ESI m / z 1200.8 [M+H] + .LCMS:product:Rt=1.985min.

[0390] Step 11): Compound 10 (170 mg, 0.14 mmol, 1.0 equivalence) was dissolved in dichloromethane (6 mL), and trifluoroacetic acid (6 mL, 78.41 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 10. ESI m / z 731.2 [M+H] + .LCMS:product:Rt=11.052min. 1 H NMR(400MHz,D2O)δ7.23(t,J=7.8Hz,2H),7.12(dd,J=22.6,6.6Hz,6H),6.96(s,1H),3.61–3.46(m,6H),3.34–3.26(m,6H),3.17–3 .08(m,3H),2.81–2.63(m,8H),2.51(dd,J=14.6,4.6Hz,1H),2.42–2.30(m,6H),2.09–2.00(m,3H),1.90(s,3H),1.71–1.59(m,3H).

[0391] Example 11: Synthesis of Compound 11

[0392] Step 1): Liquid bromine (1.3 mL, 22.86 mmol, 1.0 equivalence) and ferric tribromide (680 mg, 2.30 mmol, 0.1 equivalence) were added to a chloroform (110 mL) solution of compound 11a (4280 mg, 22.86 mmol, 1.0 equivalence). The reaction mixture was stirred at room temperature for 18 hours. The solid was collected by filtration, washed with methyl tert-butyl ether (100 mL × 2), and dried to give compound 11b. ESI m / z 267.9 [M+H] + .LCMS:product:Rt=1.598min.

[0393] Step 2): Compound 11b (4.8 g, 17.14 mmol, 1.0 equivalent) was added to acetic acid (120 mL) and stirred at 15 °C in an ice bath. A mixed solution of sodium nitrite (1.4 g, 20.29 mmol, 1.18 equivalent) in concentrated sulfuric acid (15 mL, 279.90 mmol, 16.33 equivalent) and acetic acid (15 mL) was added. The resulting mixture was stirred for 2.5 h, then a methanol (100 mL) solution of cuprous oxide (7.4 g, 51.41 mmol, 3.0 equivalent) was added, and the mixture was stirred at 60 °C for 1 h, then cooled to room temperature. The reaction mixture was filtered, and the filter cake was washed with ethyl acetate (200 mL). The aqueous phase was alkalized to pH 7 with sodium bicarbonate solution. The suspension was separated by filtration. The filter cake was washed with water (100 mL) and then dried under reduced pressure to give compound 11c. 1 H NMR (400MHz, DMSO-d6) δ8.67(s,1H),8.25(d,J=1.6Hz,1H),8.22(dd,J=13.2,8.4Hz,2H),7.85(ddd,J=8.4,7.0,1.2Hz,1H),7.77–7.70(m,1H).

[0394] Step 3): To a tetrahydrofuran solution (10 M) of the borane dimethyl sulfide tetrahydrofuran complex (1.27 mL, 12.74 mmol, 4.0 equivalence) of compound 11c (4.2 g, 13.38 mmol, 1.0 equivalence) (10 mL), a tetrahydrofuran solution (10 M) of the borane dimethyl sulfide tetrahydrofuran complex was added. The reaction mixture was stirred at room temperature for 4 hours. The mixture was quenched with methanol (20 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 3 / 1) to give compound 11d. ESI m / z 218.9 [M-OH] + .LCMS:product:Rt=1.523min.

[0395] Step 4): Compound 11d (700 mg, 2.80 mmol, 1.0 equivalence) was dissolved in dichloromethane (10 mL), and phosphorus tribromide (1.1 g, 4.06 mmol, 1.45 equivalence) was added. The reaction mixture was stirred at room temperature for 1 hour. The mixture was then quenched with saturated sodium bicarbonate solution (40 mL) and extracted with ethyl acetate (80 mL × 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 50 / 1) to give compound 11e. 1 H NMR(400MHz, DMSO-d6)δ8.15–8.07(m,2H),7.98(dd,J=15.1,4.5Hz,2H),7.76–7.63(m,2H),4.89(s,2H)

[0396] Step 5): Under a nitrogen atmosphere, inter 3 (1.4 g, 3.60 mmol, 1.0 equivalence) was dissolved in tetrahydrofuran (20 mL) and cooled to 0 °C. Then, lithium bis(trimethylsilyl)amino (4.32 mL, 4.32 mmol, 1.2 equivalence) was added. The reaction mixture was stirred at 0 °C for 30 min. Next, a tetrahydrofuran solution (20 mL) of compound 11e (1081.1 mg, 3.60 mmol, 1.0 equivalence) was added. The reaction mixture was slowly heated to room temperature and stirred for 2 h. The mixture was quenched with saturated ammonium chloride solution (40 mL) and extracted with ethyl acetate (60 mL × 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 2 / 3) to give compound 11f. ESI m / z 629.2 [M+Na] + .LCMS:product:Rt=1.896min.

[0397] Step 6): Compound 11f (0.8 g, 1.05 mmol, 1.0 equivalent) was added to tetrahydrofuran (20 mL) under a nitrogen atmosphere at 0 °C, followed by the slow dropwise addition of hydrogen peroxide (30% aqueous solution, 0.65 mL, 8.43 mmol, 8.0 equivalent), and then a solution of lithium hydroxide monohydrate (88.49 mg, 2.11 mmol, 2.0 equivalent) dissolved in water (3 mL). The reaction mixture was stirred at 0 °C for 2 hours, then quenched with sodium bisulfite solution (1.09 g, 10.53 mmol, 10.0 equivalent), and the pH was adjusted to 5 with citric acid (1 M). The aqueous phase was extracted with methyl tert-butyl ether (40 mL × 3), and the combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 11 g. ESI m / z 392.0 [M-56+H] + .LCMS:product:Rt=1.382min.

[0398] Step 7): Add O-tert-butyl-N,N'-diisopropylisourea (804.2 mg, 4.01 mmol, 5.0 equivalent) to a tetrahydrofuran solution (5 mL) of 11 g (450 mg, 0.8 mmol, 1.0 equivalent). Stir the mixture at 65 °C for 2 hours. Dilute the mixture with water (20 mL) and extract with ethyl acetate (20 mL × 2). Combine the organic phases, wash with brine (50 mL), 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 = 1 / 1) to give compound 11 h. ESI m / z 528.2 [M+Na]+. LCMS:product:Rt = 1.991 min.

[0399] Step 8): To a solution of N,N-dimethylacetamide (10 mL) containing compound 11h (310 mg, 0.60 mmol, 1.0 equivalence), zinc cyanide (100 mg, 0.85 mmol, 1.43 equivalence), N,N-diisopropylethylamine (200 mg, 1.55 mmol, 2.6 equivalence), and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) palladium dichloride (100 mg, 0.13 mmol, 0.22 equivalence) were added. The reaction mixture was stirred and heated to 85 °C for 2 hours under a nitrogen atmosphere. The mixture was diluted with water (10 mL) and then extracted with ethyl acetate (10 mL × 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 2) to give compound 11i. ESI m / z 473.2 [M+Na] + .LCMS:product:Rt=1.545min.

[0400] Step 9): To a tetrahydrofuran solution (5 mL) containing compound 11i (200 mg, 0.43 mmol, 1.0 equivalence), add Raney nickel (95 mg, 0.43 mmol, 1.0 equivalence) and ammonia (0.1 mL). The reaction mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The suspension was filtered through diatomaceous earth, washed with ethyl acetate (20 mL), and the filtrate was concentrated under reduced pressure to give compound 11j. ESI m / z 455.2 [M+H] + .LCMS:product:Rt=1.091min.

[0401] Step 10): Inter 4 (135.8 mg, 0.34 mmol, 1.0 equivalence) and sodium triacetoxyborohydride (214 mg, 1.1 mmol, 3.0 equivalence) were added to a solution of compound 11j (170 mg, 0.34 mmol, 1.0 equivalence) in dichloromethane (10 mL). The reaction mixture was stirred at room temperature for 4 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound 11k. ESI m / z 842.4 [M+H] + .LCMS:product:Rt=1.409min

[0402] Step 11): To a solution of N,N-dimethylformamide (5 mL) containing compound 11k (130.0 mg, 0.15 mmol, 1.0 equivalence), add inter 5 (84.3 mg, 0.18 mmol, 1.2 equivalence) and potassium carbonate (60.8 mg, 0.44 mmol, 2.93 equivalence). The reaction mixture was stirred at room temperature for 18 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 2). The combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 1 / 2) to give compound 11l. ESI m / z 565.5 [(M-Boc) / 2+H] + .LCMS:product:Rt=1.961min.

[0403] Step 12): Add 2 mL of trifluoroacetic acid to a solution of compound 11 (130 mg, 0.10 mmol, 1.0 equivalence) in dichloromethane. Stir the mixture at room temperature for 18 hours. The resulting reaction mixture was concentrated and purified by high-performance liquid chromatography (ammonium bicarbonate) to give compound 11. ESI m / z 761.4 [M+H] + .LCMS:product:Rt=0.763min. 1 HNMR(400MHz,D2O)δ7.80(d,J=7.6Hz,1H),7.73(s,1H),7.42(dd,J=13.2,5.3Hz,2H),7.34–7.23(m,5H), 7.13(dd,J=19.2,9.5Hz,4H),7.02(d,J=8.4Hz,1H),4.62(s,2H),4.45–4.20(m,4H),3.52(ddd,J=26.4,11 .8,8.2Hz,3H),3.32(dd,J=16.4,5.9Hz,3H),3.15(dd,J=15.6,8.3Hz,3H),2.96(ddd,J=36.4,24.4,12.54 Hz,5H),2.78(ddd,J=32.0,16.8,9.2Hz,5H),2.67–2.40(m,5H),2.06(d,J=7.2Hz,3H),1.76–1.54(m,3H).

[0404] Example 12: Synthesis of Compound 12

[0405] Step 1): Compound 12a (14 g, 57.12 mmol, 1.0 equivalence) was dissolved in ethanol (200 mL), and compound 12b (40% aqueous solution, 7.83 mL, 171.37 mmol, 3.0 equivalence) was added. The mixture was stirred at 80 °C for 16 hours. The resulting reaction mixture was filtered and washed with ethanol (50 mL) to give compound 12c. ESI m / z 269.0 [M+H] + .LCMS:product:Rt=1.376min

[0406] Step 2): Under a nitrogen atmosphere, compound 12c (12 g, 44.93 mmol, 1.0 equivalence) was dissolved in dichloromethane (300 mL), and diisobutylaluminum hydride (1.5 M toluene solution, 74.88 mL, 112.33 mmol, 2.5 equivalence) was added dropwise at -78 °C. The mixture was stirred for 16 h, with the temperature slowly increased to room temperature during this period. 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 min. The resulting insoluble matter was removed by filtration, the solvent was evaporated from the filtrate under reduced pressure, and then 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 petroleum ether / ethyl acetate = 1 / 1 to give compound 12d. ESI m / z 239.0 [M+H] + .LCMS:product:Rt=0.971min.

[0407] Step 3): Compound 12d (4.0 g, 16.73 mmol, 1.0 equivalence) was dissolved in N,N-dimethylformamide (40 mL), and phosphorus tribromide (4.72 mL, 50.19 mmol, 3.0 equivalence) was added dropwise at 0 °C. The mixture was stirred for 3 hours, with the temperature slowly increased to room temperature during this period. A saturated aqueous solution of sodium bicarbonate (100 mL) was then added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL × 3), followed by washing with brine (100 mL). The combined organic layers were 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 12e. ESI m / z 302.8 [M+H] + .LCMS:product:Rt=1.410min.

[0408] 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 12e (3.6 g, 11.92 mmol, 0.77 equivalence) was added, and the mixture was stirred for 5 h, with the temperature slowly increased 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 (petroleum ether / tert-butyl methyl ether = 1 / 1) to give compound 12f. ESI m / z 553.0 [M+H-tert-butyl] + .LCMS:product:Rt=1.733min.

[0409] Step 5): Compound 12f (4.7 g, 7.71 mmol, 1.0 equivalence) was dissolved in tetrahydrofuran (60 mL), and hydrogen peroxide (30% aqueous solution, 5.99 mL, 77.11 mmol, 10.0 equivalence) was added at 0 °C. Then, an aqueous solution of lithium hydroxide (0.65 g, 15.42 mmol, 2.0 equivalence) (20 mL) was added, and the mixture was stirred for 2 hours, with the temperature slowly increased to room temperature. The resulting reaction mixture was quenched with an aqueous solution of sodium bisulfite (12.03 g, 115.66 mmol, 15.0 equivalence) (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 12 g of the compound. ESI m / z 394.0 [M+H-tert-butyl] + .LCMS:product:Rt=1.418min.

[0410] Step 6): Compound 12 g (1.6 g, 3.55 mmol, 1.0 equivalent) and compound 12 h (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 12 i. ESI m / z 452.0 [M+H-tert-butyl] +.LCMS:product:Rt=1.775min.

[0411] Step 7): Compound 12i (500 mg, 0.99 mmol, 1.0 equivalence) 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), 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 compound 12j. ESI m / z 400.2 [M+H-tert-butyl] + .LCMS:product:Rt=1.698min.

[0412] Step 8): Compound 12J (320 mg, 0.70 mmol, 1.0 equivalence) and Inter 6 (341.00 mg, 0.84 mmol, 1.2 equivalence) were dissolved in dichloromethane (10 mL), and acetic acid (0.08 mL, 1.40 mmol, 2.0 equivalence) was added and stirred for 30 min. Then, sodium triacetoxyborohydride (446.62 mg, 2.11 mmol, 3.0 equivalence) was added. The mixture was stirred at room temperature for 3 h. The reaction mixture was added to a saturated aqueous solution of sodium bicarbonate (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 12K. ESI m / z 844.4 [M+H] + .LCMS:product:Rt=1.574min.

[0413] Step 9): Compound 12k (360 mg, 0.43 mmol, 1.0 equivalence) and inter 5 (239.73 mg, 0.51 mmol, 1.2 equivalence) were dissolved in N,N-dimethylformamide (10 mL), and potassium carbonate (176.82 mg, 1.28 mmol, 3.0 equivalence) was added. The mixture was stirred at room temperature for 16 hours. Then, ethyl acetate (50 mL) and water (50 mL) were added to the reaction mixture, 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 with petroleum ether / tert-butyl methyl ether = 1 / 1 to give compound 12l. ESI m / z 1231.8 [M+H] + .LCMS:product:Rt=1.819min.

[0414] Step 10): Compound 12 (200 mg, 0.16 mmol, 1.0 eq) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (5 mL, 65.34 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 12. ESI m / z 763.2 [M+H] + .LCMS:product:Rt=1.036min. 1 H NMR(400MHz,D2O)δ8.58(d,J=15.6Hz,2H),7.50(d,J=9.6Hz,2H),7.14(t,J=7.5Hz,2H),7. 06(d,J=7.6Hz,2H),6.99(d,J=7.5Hz,2H),6.92(s,2H),4.06(s,2H),3.69(s,4H),3.38–3.2 5(m,6H),3.16–3.06(m,3H),2.91–2.81(m,2H),2.73(dd,J=11.4,7.5Hz,3H),2.63(dd,J=13 .1,8.8Hz,2H),2.51–2.41(m,3H),2.40–2.28(m,5H),2.07–1.97(m,3H),1.71–1.58(m,3H).

[0415] Example 13: Synthesis of Compound 13

[0416] Step 1): Compound 5e (300 mg, 0.63 mmol, 1.0 equivalence) was dissolved in N,N-dimethylacetamide (2 mL), and zinc cyanide (74 mg, 0.63 mmol, 1.0 equivalence), 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene palladium dichloride (48 mg, 0.06 mmol, 0.1 equivalence), and N,N-diisopropylethylamine (244 mg, 1.89 mmol, 3.0 equivalence) were added. The reaction mixture was stirred at 85 °C for 2 hours under nitrogen protection. The mixture was diluted with water (5 mL) and extracted with ethyl acetate (5 mL × 2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 2 / 1) to give compound 13a. ESI m / z 430.2 [M + Na] + .LCMS:product:Rt=1.798min.

[0417] Step 2): To tetrahydrofuran (2 mL) containing compound 13a (240 mg, 0.56 mmol, 1.0 equivalence), Raney nickel (122 mg, 0.56 mmol, 1.0 equivalence) was added. The reaction mixture was stirred for 4 hours at room temperature under hydrogen protection. The mixture was filtered and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to give compound 13b. ESI m / z 412.2 [M+H] + .LCMS:product:Rt=0.947min.

[0418] Step 3): To a solution of compound 13b (104 mg, 0.25 mmol, 1.0 equivalence) in dichloromethane (8 mL), sodium triacetylborohydride (160 mg, 0.75 mmol, 3.0 equivalence) was added. The mixture was stirred at room temperature for 3 hours. The mixture was diluted with water (10 mL) and extracted with dichloromethane (10 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. The residue was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 1 / 9) to give compound 13c. ESI m / z 806.4 [M+H] + .LCMS:product:Rt=1.316min.

[0419] Step 4): To a solution of compound 13c (150 mg, 0.17 mmol, 1.0 equivalence) and inter 4 (209 mg, 0.52 mmol, 3.0 equivalence) in dichloromethane (8 mL), acetic acid (0.1 mL, 1.75 mmol, 10 equivalence) was added, and the mixture was stirred at room temperature for 2 days. Sodium triacetylborohydride (183 mg, 0.86 mmol, 5.0 equivalence) was added, and the mixture was stirred at room temperature for 2 days. The mixture was diluted with water (15 mL) and extracted with dichloromethane (10 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. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 50 / 1) to give compound 13d. ESI m / z 1194.1 [M+H] + .LCMS:product:Rt=2.218min.

[0420] Step 5): Compound 13d (103 mg, 0.09 mmol) was added to a mixed solution of dichloromethane (2 mL) and trifluoroacetic acid (2 mL), and the reaction mixture was stirred at room temperature for 5 hours. The resulting reaction mixture was concentrated and purified by preparative high-performance liquid chromatography (ammonium bicarbonate) to give compound 13. ESI m / z 725.3 [M+H] + .LCMS:product:Rt=0.566min. 1 H NMR(400MHz,D2O)δ7.27–7.21(m,3H),7.09(d,J=11.5Hz,3H),3.90(s,4H),3.66(s,2H),3.40–3.27(m,6H),3.22–3.08(m,3H),2.94– 2.62(m,9H),2.51(td,J=9.7,5.3Hz,2H),2.46–2.30(m,4H),2.05(dtd,J=13.5,7.0,3.4Hz,3H),1.67(ddt,J=14.6,9.2,7.5Hz,3H).

[0421] Example 14: Synthesis of Compound 14

[0422] Step 1): Under a nitrogen atmosphere, inter 1 (1.5 g, 3.73 mmol, 1.0 equivalence) was dissolved in tetrahydrofuran (50 mL), cooled to 0 °C, and then lithium bis(trimethylsilyl)amino (4.85 mL, 4.85 mmol, 1.3 equivalence) was added. The reaction mixture was stirred at 0 °C for 30 min. Subsequently, a tetrahydrofuran solution (50 mL) of compound 5b (1.16 g, 4.48 mmol, 1.2 equivalence) was added. The reaction mixture was allowed to warm naturally to room temperature and stirred for 2 h. The mixture was quenched with saturated ammonium chloride solution (100 mL) and extracted with ethyl acetate (100 mL × 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 3 / 2) to give compound 14a. ESI m / z 522.0 [M-56+H] + .LCMS:product:Rt=1.952min.

[0423] Step 2): Under a nitrogen atmosphere, compound 14a (1500 mg, 1.79 mmol, 1.0 equivalence) was dissolved in tetrahydrofuran (20 mL). Hydrogen peroxide (30% aqueous solution, 1.63 mL, 21.01 mmol, 11.74 equivalence) was added dropwise at 0 °C, followed by the addition of a 10 mL solution of lithium hydroxide monohydrate (220.0 mg, 5.24 mmol, 2.3 equivalence). The reaction mixture was stirred at 0 °C for 2 hours, then quenched with sodium bisulfite solution (2.73 g, 26.27 mmol, 14.68 equivalence), and the pH was adjusted to 5 with citric acid (1 M). The aqueous phase was extracted with methyl tert-butyl ether (100 mL × 3), and the combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 14b. ESI m / z 441.0 [M+Na] + .LCMS:product:Rt=1.552min.

[0424] Step 3): Compound 14b (1500 mg, 2.50 mmol) was dissolved in tetrahydrofuran (10 mL), and O-tert-butyl-N,N'-diisopropylisourea (2.5 g, 12.52 mmol, 5.0 equivalence) was added. The mixture was stirred at 65 °C for 2 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 2). The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 1 / 1) to give compound 14c. ESI m / z 497.1 [M+H] + .LCMS:product:Rt=1.991min.

[0425] Step 4): To a solution of N,N-dimethylacetamide (10 mL) containing compound 14c (460.0 mg, 0.87 mmol, 1.0 equivalence), zinc cyanide (102.2 mg, 0.87 mmol, 1.0 equivalence), N,N-diisopropylethylamine (337.6 mg, 2.61 mmol, 3.0 equivalence), and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) palladium dichloride (65.8 mg, 0.09 mmol, 0.1 equivalence) were added. The reaction mixture was stirred at 85 °C under a nitrogen atmosphere for 2 hours. The mixture was poured into water (60 mL) and then extracted with ethyl acetate (3 × 40 mL). The organic phases were combined, washed with brine (40 mL × 3), dried over 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 = 2 / 1) to give compound 14d. ESI m / z 444.2 [M+Na] + .LCMS:product:Rt=1.881min.

[0426] Step 5): To a solution of compound 14d (300 mg, 0.68 mmol, 1.0 equivalence) in tetrahydrofuran (10 mL), Raney nickel (147.7 mg, 0.68 mmol, 1.0 equivalence) and ammonia (0.1 mL) were added. The reaction mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The suspension was filtered through diatomaceous earth, and the diatomaceous earth was washed with ethyl acetate (20 mL). The filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to give compound 14e. ESI m / z 426.2 [M+H] + .LCMS:product:Rt=0.974min.

[0427] Step 6): Compound 14e (100 mg, 0.23 mmol, 1.0 equivalence) was dissolved in dichloromethane (10 mL), and Inter 4 (94.8 mg, 0.23 mmol, 1.0 equivalence) and sodium triacetoxyborohydride (149.4 mg, 0.7 mmol, 3.0 equivalence) were added. The reaction mixture was stirred at room temperature for 4 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 1 / 3) to give compound 14f. ESI m / z 813.4 [M+H] + .LCMS:product:Rt=1.597min.

[0428] Step 7): To a solution (5 mL) of N,N-dimethylformamide containing compound 14f (90.0 mg, 0.10 mmol, 1.0 equivalence), add inter 5 (47.0 mg, 0.10 mmol, 1.01 equivalence) and potassium carbonate (42.0 mg, 0.30 mmol, 3.05 equivalence). The reaction mixture was stirred at room temperature for 18 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 2). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound 14 g. ESI m / z 623.0 [M / 2 + Na] + .LCMS:product:Rt=2.060min

[0429] Step 8): Add 2 mL of trifluoroacetic acid to a solution of 14 g (100.0 mg, 0.07 mmol, 1.0 equivalence) in dichloromethane (2 mL). Stir the mixture at room temperature for 4 hours. The resulting reaction mixture was concentrated and purified by preparative high-performance liquid chromatography (formic acid) to give compound 14. ESI m / z 733.3 [M+H] + .LCMS:product:Rt=0.978min. 1 HNMR(400MHz,D2O)δ8.36(s,5H),7.36–7.15(m,9H),4.44(s,2H),4.30(s,4H),3.55–3.28(m,6H),3.25–3.11(m,2H),3.0 3–2.81(m,6H),2.81–2.67(m,4H),2.54–2.34(m,5H),2.07(dd,J=10.0,3.2Hz,3H),1.87–1.63(m,4H),1.58–1.43(m,2H)

[0430] Example 15: Synthesis of Compound 15

[0431] Step 1): Under nitrogen protection at 0°C, inter 1 (5 g, 12.42 mmol, 1.0 equivalence) was dissolved in tetrahydrofuran (60 mL), followed by the addition of lithium bis(trimethylsilylamino)amine (13.7 mL, 13.70 mmol, 1.1 equivalence). The reaction mixture was stirred at 0°C for 0.5 h. Subsequently, a tetrahydrofuran solution (10 mL) of 3-(bromomethyl)benzonitrile (2.45 g, 12.50 mmol, 1.01 equivalence) was added. The reaction mixture was brought to room temperature and stirred for 2 h. The reaction mixture was quenched with saturated ammonium chloride solution (80 mL) and extracted with ethyl acetate (50 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 = 2 / 1) to give compound 15a. ESI m / z 462.2 [MC(CH3)3+H] + .LCMS:product:Rt=1.52min.

[0432] Step 2): Compound 15a (4.1 g, 7.92 mmol, 1.0 equivalence) was dissolved in tetrahydrofuran (40 mL) at 0 °C, followed by the dropwise addition of hydrogen peroxide (30% aqueous solution, 4.93 mL, 63.51 mmol, 8.0 equivalence), and then a 12 mL aqueous solution of lithium hydroxide monohydrate (0.67 g, 15.97 mmol, 2.0 equivalence). The reaction mixture was stirred at 0 °C for 2 hours. A 20 mL aqueous solution of sodium bisulfite (9.9 g, 95.15 mmol, 12.0 equivalence) was slowly added dropwise to the reaction mixture, and the mixture was stirred at 0 °C for 30 minutes. Subsequently, the mixture was neutralized to pH 5 with 1.0 M citric acid aqueous solution and extracted with tert-butyl methyl ether (30 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 15b. ESI m / z 303.1 [MC(CH3)3+H] + .LCMS:product:Rt=0.90min.

[0433] Step 3): Compound 15b (4 g, 6.14 mmol, 1.0 equivalence) was dissolved in tetrahydrofuran (50 mL), and O-tert-butyl-N,N'-diisopropylisourea (6.2 g, 30.95 mmol, 5.0 equivalence) was added. The reaction mixture was stirred at 65 °C for 2 hours. 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 = 2 / 1) to give compound 15c. ESI m / z 303.1 [M-2C(CH3)3+H] + .LCMS:product:Rt=1.55min.

[0434] Step 4): Compound 15c (0.7 g, 1.69 mmol, 1.0 equivalent) was dissolved in tetrahydrofuran (30 mL), and Raney nickel (0.21 g, 3.58 mmol, 2.0 equivalent) and ammonium hydroxide (0.02 g, 0.57 mmol, 0.3 equivalent) were added. The reaction mixture was stirred at 25 °C for 4 hours under hydrogen protection. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give compound 15d. ESI m / z 419.4 [M+H] + .LCMS:product:Rt=1.00min.

[0435] Step 5): Compound 15d (150 mg, 0.33 mmol, 1.0 equivalence) was dissolved in dichloromethane (10 mL), and 5 g of compound (152 mg, 0.36 mmol, 1.1 equivalence), acetic acid (6 mg, 0.03 mmol, 0.1 equivalence), and sodium triacetoxyborohydride (210 mg, 0.99 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 compound 15e. ESI m / z 813.4 [M+H] + .LCMS:product:Rt=1.34min.

[0436] Step 6): Compound 15e (230 mg, 0.18 mmol, 1.0 equivalence) was dissolved in N,N-dimethylformamide (8 mL), and Inter 5 (146 mg, 0.31 mmol, 1.7 equivalence) and potassium carbonate (118 mg, 0.85 mmol, 4.7 equivalence) were added. The reaction mixture was stirred at room temperature for 16 hours. The mixture was extracted with water (20 mL) and ethyl acetate (20 mL × 2). 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 15f. ESI m / z 1201.6 [M+H] + .LCMS:product:Rt=1.74min.

[0437] Step 7): Compound 15f (200 mg, 0.15 mmol, 1.0 equivalence) was dissolved in hydrochloric acid / dioxane (10 mL, 4 M) and stirred at 25 °C for 16 hours. The reaction mixture was concentrated and purified by preparative high-performance liquid chromatography (ammonium bicarbonate) to give compound 15. ESI m / z 732.3 [M+H] + .LCMS:product:Rt=1.00min.1 HNMR(400MHz,D2O)δ7.28–7.13(m,6H),7.07(dd,J=14.9,4.8Hz,3H),3.79(q,J=15 .4Hz,2H),3.66–3.49(m,4H),3.33(dd,J=11.5,8.7Hz,6H),3.20–3.07(m,2H),2.9 4–2.62(m,10H),2.55–2.45(m,1H),2.33(ddd,J=23.4,16.4,8.6Hz,4H),1.97(dd, J=28.8,15.9Hz,3H),1.80(d,J=14.8Hz,1H),1.74–1.58(m,3H),1.51–1.27(m,2H).

[0438] Example 16: Synthesis of Compound 16

[0439] Step 1): To a carbon tetrachloride (200 mL) solution containing compound 16a (20 g, 108.16 mmol, 1.0 equivalence), azobisisobutyronitrile (1.78 g, 10.80 mmol, 0.1 equivalence) and N-bromosuccinimide (20.20 g, 113.48 mmol, 1.05 equivalence) were added at room temperature. The reaction mixture was stirred at 80 °C for 5 hours. After filtration, the organic phase was concentrated under reduced pressure to dryness, and the residue was purified by silica gel column chromatography (petroleum ether) to give compound 16b. ESI m / z 281.2 [M+H2O] + .LCMS:product:Rt=1.514min.

[0440] Step 2): Under nitrogen protection at 0°C, lithium bis(trimethylsilylaminolithium) (19.82 mL, 19.82 mmol, 1.1 equivalence) was added to a tetrahydrofuran (100 mL) solution containing inter 3 (7.32 g, 18.02 mmol, 1.0 equivalence). The reaction mixture was stirred at 0°C for 30 min. Subsequently, a tetrahydrofuran (20 mL) solution of compound 16b (7.32 g, 21.62 mmol, 1.2 equivalence) was added. The reaction mixture was brought to room temperature and stirred for 3 h. The mixture was quenched with a saturated ammonium chloride aqueous solution (200 mL) and extracted with ethyl acetate (100 mL × 2). The combined organic phases were washed with saturated brine (400 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 16c. ESI m / z 515.2 [M+H-tert-butyl] + .LCMS:product:Rt=1.556min.

[0441] Step 3): Under nitrogen protection, hydrogen peroxide (30% aqueous solution, 9.35 mL, 120.36 mmol, 10.0 equivalent) was added dropwise to a tetrahydrofuran (90 mL) solution containing compound 16c (8.32 g, 12.04 mmol, 1.0 equivalent), followed by a solution of lithium hydroxide (1.01 g, 24.07 mmol, 2.0 equivalent) in water (30 mL). The reaction mixture was stirred at room temperature for 2 hours, then quenched with a solution of sodium bisulfite (18.79 g, 180.55 mmol, 15.0 equivalent) in water (100 mL), and the pH was adjusted to 5 with citric acid (1 M). The aqueous phase was extracted with methyl tert-butyl ether (50 mL × 3), 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 obtain compound 16d. ESI m / z 358.0 [M+H-tert-buty] + .LCMS:product:Rt=1.314min.

[0442] Step 4): To a solution of compound 16d (4.57 g, 10.67 mmol, 1.0 equivalent) in tetrahydrofuran (50 mL), add O-tert-butyl-N,N'-diisopropylisourea (10.69 g, 53.34 mmol, 5.0 equivalent). The mixture is stirred at 65 °C for 2 hours. The suspension is filtered through filter paper, and the filter cake is washed with ethyl acetate (20 mL × 2). The combined filtrates are concentrated to dryness, and the residue is purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 3 / 1) to give compound 16e. ESI m / z 490.2 [M + Na] + .LCMS:product:Rt=1.636min.

[0443] Step 5): Compound 16e (2.70 g, 5.68 mmol, 1.0 equivalence), triethylsilane (2.64 g, 22.72 mmol, 4.0 equivalence), 1,1-bis(diphenylphosphine)dimerferropalladium dichloride (420 mg, 0.57 mmol, 0.1 equivalence), and triethylamine (3.94 mL, 28.40 mmol, 5.0 equivalence) were added to N,N-dimethylformamide (50 mL). The mixture was stirred at 90 °C for 16 hours under CO protection. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 16i. ESI m / z 440.2 [M + Na] +.LCMS:product:Rt=1.473min.

[0444] Step 6): To a solution of compound 16e (800 mg, 1.67 mmol, 1.0 equivalence) in N,N-dimethylacetamide (10 mL), zinc cyanide (196 mg, 1.67 mmol, 1.0 equivalence), 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene palladium dichloride (126 mg, 0.17 mmol, 0.1 equivalence), and N,N-diisopropylethylamine (649 mg, 5.06 mmol, 3.0 equivalence) were added. The mixture was stirred at 85 °C for 2 hours under nitrogen protection. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (10 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, and the residue was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 3 / 1) to give compound 16f. ESI m / z 437.2 [M+Na] + .LCMS:product:Rt=1.506min.

[0445] Step 7): To a tetrahydrofuran (10 mL) solution of compound 16f (338 mg, 0.82 mmol, 1.0 equivalence), Raney nickel (178 mg, 0.82 mmol, 1.0 equivalence) was added, and the reaction mixture was stirred for 4 hours under hydrogen protection at room temperature. The mixture was filtered and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to give compound 16 g. ESI m / z 419.4 [M+H]+.LCMS:product:Rt=0.982 min.

[0446] Step 8): Add sodium triacetylborohydride (254 mg, 1.20 mmol, 3.0 equivalence) to a solution of 16 g (219 mg, 0.40 mmol, 1.0 equivalence) of compound and 5 g (230 mg, 0.40 mmol, 1.0 equivalence) of compound in 10 mL of dichloromethane. Stir the mixture at room temperature for 3 hours. Dilute the mixture with water (20 mL) and extract with dichloromethane (10 mL × 2). Combine the organic phases, wash with saturated brine (30 mL), 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 = 1 / 9) to give compound 16h. ESI m / z 813.4 [M+H] + .LCMS:product:Rt=1.306min.

[0447] Step 9): To a solution of compound 16h (300 mg, 0.32 mmol, 1.0 equivalence) and compound 16i (178 mg, 0.41 mmol, 1.3 equivalence) in dichloromethane (10 mL), acetic acid (0.1 mL, 1.60 mmol, 5.0 equivalence) was added, and the mixture was stirred at room temperature for 16 hours. Sodium triacetylborohydride (201 mg, 0.95 mmol, 3.0 equivalence) was added, and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with 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 = 0 / 1) to give compound 16j. ESI m / z 1215.6 [M+H] + .LCMS:product:Rt=1.757min.

[0448] Step 10): Compound 16j (225 mg, 0.15 mmol, 1.0 equivalence) was dissolved in a mixed solution of dichloromethane (2 mL) and trifluoroacetic acid (2 mL), and the mixture was stirred at room temperature for 2 hours. The resulting reaction mixture was concentrated and purified by preparative high-performance liquid chromatography (ammonium bicarbonate) to give compound 16. ESI m / z 747.4 [M+H] + .LCMS:product:Rt=1.057min. 1 H NMR(400MHz,D2O)δ7.02(s,1H),6.97(s,2H),6.93(s,2H),6.90(s,2H),3.80–3.66(m,2H ),3.48(s,4H),3.28(dtd,J=14.7,7.2,3.7Hz,6H),3.10(dddd,J=14.5,11.7,10.0,7.2H z,3H),2.91–2.66(m,7H),2.59(dd,J=13.6,5.3Hz,2H),2.47(td,J=9.7,5.2Hz,1H),2.4 2–2.23(m,5H),2.19(s,6H),2.01(dq,J=10.1,3.7Hz,3H),1.63(dq,J=13.0,9.2Hz,3H).

[0449] Example 17: Synthesis of compounds 17-P1 and 17-P2

[0450] Step 1): Compound 17a (10 g, 71.36 mmol, 1.0 equivalence) was dissolved in tetrahydrofuran (150 mL), and sodium hydrogen (4.3 g, 107.50 mmol, purity: 60%, 1.5 equivalence) was added at 0 °C. The mixture was stirred at 0 °C for 30 min. Then, (2-(chloromethoxy)ethyl)trimethylsilane (13.1 g, 78.57 mmol, 1.1 equivalence) was added to the mixture at 0 °C, and the mixture was stirred at 25 °C for 4 h. The reaction mixture was quenched with saturated ammonium chloride solution (150 mL) and extracted with ethyl acetate (40 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 17b. ESI m / z 271.2 [M+H] + .LCMS:product:Rt=1.24min. 1 H NMR (400MHz, CDCl3) δ7.80 (s, 1H), 7.76 (d, J = 1.3Hz, 1H), 5.36 (s, 2H), 4.41 (q, J = 7.1H z,2H),3.60–3.46(m,2H),1.42(t,J=7.1Hz,3H),1.05–0.83(m,2H),0.04–0.02(m,9H).

[0451] Step 2): Compound 17b (11 g, 40.68 mmol, 1.0 equivalence) was dissolved in chloroform (150 mL), and N-bromosuccinimide (8.3 g, 46.63 mmol, 1.15 equivalence) and azobisisobutyronitrile (0.68 g, 4.14 mmol, 0.1 equivalence) were added at 25 °C. The mixture was stirred at 60 °C for 4 hours. The mixture was poured into a saturated sodium bicarbonate aqueous solution (60 mL) and extracted with dichloromethane (50 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 / ethyl acetate = 3 / 1) to give compound 17c. ESI m / z 349.0 [M+H] + .LCMS:product:Rt=1.28min.

[0452] Step 3): Compound 17c (13.26 g, 37.96 mmol, 1.0 equivalent) was dissolved in dichloromethane (200 mL), and diisobutylaluminum hydride (63 mL, 94.50 mmol, 2.5 equivalent, dissolved in toluene at a concentration of 1.5 M) was added at -78 °C. The mixture was stirred at -78 °C for 5 min, then heated to 25 °C and stirred for 16 h. The reaction mixture was quenched with sodium sulfate decahydrate (10 g) and methanol (50 mL), filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with ethyl acetate (30 mL) and water (30 mL), extracted with ethyl acetate (30 mL × 3), dried, filtered, and concentrated again under reduced pressure. Then, it was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 17d. ESI m / z 307.0 [M+H]+.LCMS:product:Rt = 1.12 min.

[0453] Step 4): A solution of compound 17d (1.5 g, 4.88 mmol, 1.0 equivalence) in dichloromethane (30 mL) was mixed with triphenylphosphine (1.42 g, 5.41 mmol, 1.11 equivalence) and N-bromosuccinimide (0.97 g, 5.45 mmol, 1.12 equivalence) at 0 °C. The mixture was stirred at 25 °C for 4 hours. The mixture was then poured into a saturated sodium bicarbonate solution (20 mL) and extracted with dichloromethane (15 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 / ethyl acetate = 3 / 1) to give compound 17e. ESI m / z 370.9 [M+H] + .LCMS:product:Rt=1.35min.

[0454] Step 5): 18 g (0.85 g, 2.92 mmol, 1.0 equivalence) of compound 17e was dissolved in tetrahydrofuran (20 mL), and lithium bis(trimethylsilylamino)ene (4.4 mL, 4.40 mmol, 1.5 equivalence) was added at 0 °C. The mixture was stirred at 0 °C for 30 min. Subsequently, a tetrahydrofuran (5 mL) solution of compound 17e (1.1 g, 2.97 mmol, 1.02 equivalence) was added. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with saturated ammonium chloride solution (30 mL) and extracted with ethyl acetate (20 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / tert-butyl methyl ether = 1 / 1) to give compound 17f. ESI m / z 574.2 [M+H] + .LCMS:product:Rt=1.68min.

[0455] Step 6): Compound 17f (1 g, 1.74 mmol, 1.0 equivalence) was dissolved in 10 mL of N,N-dimethylacetamide solution, and zinc cyanide (0.26 g, 2.21 mmol, 1.27 equivalence), N,N-diisopropylethylamine (1.1 g, 8.51 mmol, 4.89 equivalence), and dichloro[9,9-dimethyl-4,5-bis(diphenylphosphine)oxanthracene]palladium(II) (0.27 g, 0.36 mmol, 0.21 equivalence) were added. The mixture was stirred at 85 °C for 2 hours under nitrogen protection. The mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL × 3). The organic layers were combined, washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give two enantiomers. The first isomer eluted was compound 17g-B. ESI m / z 465.2 [MC(CH3)3+H] + LCMS:product:Rt = 1.65 min. Second eluted isomer compound 17 g-A. ESI m / z 421.3 [M-Boc+H]+. LCMS:product:Rt = 1.63 min.

[0456] Step 7): Compound 17g-A (440 mg, 0.71 mmol, 1.0 equivalence) was dissolved in tetrahydrofuran (15 mL) solution, and Raney nickel (420 mg, 7.16 mmol, 10 equivalence) and ammonium hydroxide (25 mg, 0.71 mmol, 1.0 equivalence) were added. The reaction mixture was stirred at 25 °C for 16 hours under hydrogen protection. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give compound 17h-A. ESI m / z 525.4 [M+H] + .LCMS:product:Rt=1.054min.

[0457] Step 8): Compound 17h-A (200 mg, 0.29 mmol, 1.0 equivalence) was dissolved in dichloromethane (10 mL), and Inter 4 (350 mg, 0.87 mmol, 2.99 equivalence), acetic acid (6 mg, 0.03 mmol, 0.11 equivalence), and sodium triacetoxyborohydride (368 mg, 1.74 mmol, 5.99 equivalence) were added. The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was quenched with saturated sodium bicarbonate solution (20 mL) and extracted with dichloromethane (20 mL × 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 17i-A. ESI m / z 600.6 [1 / 2(M-Boc) + H] + .LCMS:product:Rt=1.916min.

[0458] Step 9): Compound 17i-A (280 mg, 0.22 mmol, 1.0 equivalence) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (3 mL) was added. The reaction mixture was stirred at 25 °C for 16 hours. The reaction solution was concentrated and purified by preparative high-performance liquid chromatography (ammonium bicarbonate) to give compound 17-P1. ESI m / z 351.3 [M / 2+H] + .LCMS:product:Rt=0.73min. 1 HNMR(400MHz,D2O)δ7.22(t,J=7.4Hz,2H),7.10(dd,J=14.5,8.5Hz,6H),6.72(s,1H),3.63–3.51(m,6H),3.42–3.27(m,6H), 3.19–3.07(m,3H),2.94–2.81(m,3H),2.78–2.62(m,6H),2.38(tt,J=17.5,8.8Hz,6H),2.18–2.00(m,3H),1.74–1.51(m,3H).

[0459] Step 10): Compound 17g-B (220 mg, 0.38 mmol, 1.0 equivalence) was dissolved in tetrahydrofuran (8 mL), and Raney nickel (230 mg, 3.92 mmol, 10 equivalence) and ammonium hydroxide (14 mg, 0.40 mmol, 1.0 equivalence) were added. The reaction mixture was stirred at 25 °C for 4 hours under hydrogen protection. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give compound 17g-B. ESI m / z 525.3 [M+H] + .LCMS:product:Rt=1.495min.

[0460] Step 11): Compound 17h-B (220 mg, 0.37 mmol, 1.0 equivalence) was dissolved in dichloromethane (10 mL), and Inter 4 (366 mg, 0.91 mmol, 2.43 equivalence), acetic acid (7 mg, 0.04 mmol, 0.1 equivalence), and sodium triacetoxyborohydride (231 mg, 1.09 mmol, 2.92 equivalence) were added. The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was quenched with saturated sodium bicarbonate solution (20 mL) and extracted with dichloromethane (20 mL × 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 17i-B. ESI m / z 600.6 [1 / 2(M-Boc) + H] + .LCMS:product:Rt=1.631min.

[0461] Step 12): Compound 17i-B (300 mg, 0.22 mmol, 1.0 equivalence) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (3 mL) was added. The reaction mixture was stirred at 25 °C for 16 hours. The reaction solution was concentrated and purified by preparative high-performance liquid chromatography (ammonium bicarbonate) to give compound 17-P2. ESI m / z 351.2 [M / 2+H] + .LCMS:product:Rt=0.71min. 1 HNMR(400MHz,D2O)δ7.23(d,J=7.3Hz,2H),7.12(d,J=5.8Hz,6H),6.73(s,1H),3.62–3.47(m,6H),3.44–3.27(m ,6H),3.15(d,J=9.6Hz,3H),2.92–2.64(m,8H),2.58(s,1H),2.46–2.25(m,6H),2.05(s,3H),1.77–1.56(m,3H).

[0462] Example 18: Synthesis of Compound 18

[0463] Step 1): To a solution of 18 g of compound 1 (3 g, 13.08 mmol, 1.0 equivalence) in tetrahydrofuran (30 mL), O-tert-butyl-N,N'-diisopropylisourea (14.71 mL, 65.42 mmol, 5.0 equivalence) was added, and the mixture was stirred at 65 °C for 2 hours. The mixture was filtered and concentrated under reduced pressure to obtain the residue. The residue was then purified by column chromatography (petroleum ether / methyl tert-butyl ether = 1 / 0 to 5 / 1) to obtain compound 18 g. ESI m / z 308.2 [M+Na] + .LCMS:product:Rt=1.364min.

[0464] Step 2): Compound 18a (15 g, 85.44 mmol, 1.0 equivalent) and sodium acetate (28 g, 341.34 mmol, 4.0 equivalent) were dissolved in a mixed solution of acetic anhydride (10 mL) and acetic acid (80 mL). The reaction mixture was stirred at 120 °C for 16 hours. The reaction was then quenched with sodium bicarbonate (300 mL), followed by extraction with ethyl acetate (200 mL × 3). The organic phases were combined, 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 (petroleum ether / tert-butyl methyl ether = 3 / 7) to give compound 18b. ESI m / z 200.0 [M+H] + .LCMS:product:Rt=0.758min.

[0465] Step 3): Compound 18b (11.5 g, 57.17 mmol, 1.0 equivalent) was dissolved in 200 mL of methanol solution. Potassium carbonate (3.95 g, 28.59 mmol, 0.5 equivalent) was added at 0 °C, and the mixture was stirred at 0 °C for 1 hour. The mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 9 / 1) to obtain compound 18c. ESI m / z 158.0 [M+H] + .LCMS:product:Rt=0.321min.

[0466] Step 4): Compound 18c (4.2 g, 26.73 mmol, 1.0 equivalence) was added to a tetrahydrofuran solution (10 mL), followed by the addition of N,N-diisopropylethylamine (13 mL, 81.47 mmol, 3.0 equivalence) and tert-butyldimethylsilane trifluoromethanesulfonate (7.4 mL, 32.19 mmol, 1.2 equivalence). The mixture was stirred at room temperature for 2 hours. The mixture was poured into water (60 mL) and extracted with ethyl acetate (40 mL × 3). The organic phases were combined, washed with brine (60 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue. The residue was purified by rapid column chromatography (petroleum ether / tert-butyl methyl ether = 7 / 3) to give compound 18d. ESI m / z 272.2 [M+H] + .LCMS:product:Rt=1.382min.

[0467] Step 5): Compound 18d (6.9 g, 25.35 mmol, 1.0 equivalence) was dissolved in dichloromethane (80 mL) at -78 °C, and then diisobutylaluminum hydride (42 mL, 63.00 mmol, 2.5 equivalence) was added dropwise under nitrogen protection. The mixture was stirred at -78 °C for 3 hours until room temperature. The reaction mixture was quenched with sodium sulfate decahydrate (8 g) and methanol (20 mL), then filtered and concentrated under reduced pressure to obtain the crude product. The crude product was dissolved in dichloromethane (80 mL), washed with water (40 mL × 2), dried, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by rapid column chromatography (petroleum ether / tert-butyl methyl ether = 3 / 7) to give compound 18e. ESI m / z 244.2 [M+H] + .LCMS:product:Rt=1.174min.

[0468] Step 6): Triphenylphosphine (1.09 g, 4.16 mmol, 1.0 equivalent) and N-bromosuccinimide (0.74 g, 4.16 mmol, 1.0 equivalent) were added to a dichloromethane (20 mL) solution containing compound 18e (1 g, 4.11 mmol, 1.0 equivalent), and the temperature was maintained at 0 °C. The mixture was stirred at room temperature for 3 hours. The mixture was poured into a sodium bicarbonate solution (30 mL) and then extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with brine (20 mL × 3), dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the residue. The residue was purified by rapid column chromatography (petroleum ether / methyl tert-butyl ether = 1 / 0 to 4 / 1) to give compound 18f. ESI m / z 306.0 [M+H] + .LCMS:product:Rt=1.477min.

[0469] Step 7): Under a nitrogen atmosphere, 18 g (430 mg, 1.51 mmol, 1.0 equivalence) of compound 18 was dissolved in tetrahydrofuran solution (6 mL), and 2.3 mL (2.30 mmol, 1.53 equivalence) of bis(trimethylsilylaminolithium) was added with stirring at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. Subsequently, a tetrahydrofuran solution (6 mL) of compound 18f (540 mg, 1.50 mmol, 1.0 equivalence) was added. The reaction mixture was slowly heated to room temperature and stirred for 3 h. The resulting reaction mixture was quenched with saturated aqueous citric acid solution (30 mL), extracted with ethyl acetate (30 mL × 3), and washed with water (40 mL) and brine (40 mL). The combined organic 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 (petroleum ether / tert-butyl methyl ether = 7 / 3) to give compound 18h. ESI m / z 511.3 [M+H] + .LCMS:product:Rt=1.670min.

[0470] Step 8): To a tetrahydrofuran solution (5 mL) containing compound 18h ​​(520 mg, 1.02 mmol, 1.0 equivalence), add a 2M tetrahydrofuran solution of tetrabutylammonium fluoride (3 mL, 3.00 mmol, 3.0 equivalence) and stir at room temperature for 2 hours. Pour the mixture into water (20 mL) and extract with ethyl acetate (20 mL × 3). Combine the organic phases, wash with brine (20 mL × 3), dry with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the residue. Purify the residue by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 1 / 0 to 3 / 7) to give compound 18i. ESI m / z 419.2 [M + Na] + .LCMS:product:Rt=1.183min.

[0471] Step 9): Triethylamine (0.25 mL, 1.80 mmol, 3.0 equivalence) and methanesulfonyl chloride (100 mg, 0.87 mmol, 1.5 equivalence) were added to N,N-dimethylformamide (2 mL) containing compound 18i (240 mg, 0.57 mmol, 1.0 equivalence). The mixture was stirred at room temperature for 30 minutes, and then lithium chloride (80 mg, 1.89 mmol, 3.3 equivalence) was added and stirred for another 30 minutes. Water (20 mL) was then added to the mixture, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, washed with brine (20 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 18j. ESI m / z 437.2 [M + Na] + .LCMS:product:Rt=1.380min.

[0472] Step 10): Cesium carbonate (350 mg, 1.07 mmol, 2.0 equivalence) was added to a solution (6 mL) of N,N-dimethylformamide containing compound 18k (220 mg, 0.53 mmol, 1.0 equivalence) and inter 2 (420 mg, 0.53 mmol, 1.0 equivalence), and the mixture was stirred at 60 °C for 18 hours. The mixture was then added to water (20 mL) and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with brine (20 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 / methyl tert-butyl ether = 1 / 0 to 3 / 1) to give compound 18k. ESI m / z 1194.6 [M + Na] + .LCMS:product:Rt=1.793min.

[0473] Step 11): Add 1 mL of trifluoroacetic acid to a 2 mL solution of compound 18k (100 mg, 0.08 mmol, 1.0 equivalence) in dichloromethane and stir at room temperature for 18 hours. The resulting reaction mixture was concentrated and purified by preparative high-performance liquid chromatography (formic acid) to obtain compound 18. ESI m / z 702.4 [M+H] + .LCMS:product:Rt=0.582&0.597min. 1H NMR(400MHz,D2O)δ7.59(s,1H),7.33(t,J=7.6Hz,2H),7.28–7.16(m,6H),4.18(s,6H),3.48(dd,J=11.5,6.8Hz,2H),3.37(dd,J=19.2,10.3Hz,4 H),3.19(dd,J=18.2,10.7Hz,3H),2.99–2.88(m,3H),2.73(dd,J=25.8,8 .6Hz, 6H), 2.40 (d, J = 16.2Hz, 6H), 2.32–2.01 (m, 3H), 1.77–1.60 (m, 3H).

[0474] Example 19: Synthesis of Compound 19

[0475] Step 1): Boron tribromide (8.3 mL, 86.14 mmol, 2.0 equivalence) was added to a solution of compound 19a1 (10 g, 43.28 mmol, 1.0 equivalence) in dichloromethane (100 mL) at 0 °C, and the mixture was slowly brought back to room temperature and stirred for 2 hours. The reaction mixture was then quenched with methanol (100 mL) and concentrated under vacuum to give compound 19a. ESI m / z 218.9 [M+H] + .LCMS:product:Rt=0.818min.

[0476] 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 19a (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 give compound 19b. ESI m / z 230.8 [M+H] + .LCMS:product:Rt=1.097min.

[0477] Step 3): Sodium borohydride (1 g, 26.43 mmol, 1.0 equivalent) was added to a methanol solution (30 mL) of compound 19b (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 combined organic phases were washed with saturated brine (40 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 19c. ESI m / z 215.0 [M + H - H₂O] + .LCMS:product:Rt=0.944min.

[0478] Step 4): Triphenylphosphine (3.7 g, 14.11 mmol, 1.1 equivalence) and N-bromosuccinimide (2.7 g, 15.17 mmol, 1.2 equivalence) were added to a dichloromethane solution (60 mL) of compound 19c (3.2 g, 12.73 mmol, 1.0 equivalence), and the mixture was stirred at room temperature for 3 hours. A saturated aqueous solution of sodium bicarbonate (50 mL) was added to the mixture, followed by extraction with dichloromethane (30 mL × 2). The organic phases were combined, washed with saturated brine (50 mL × 2), dried over 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 give compound 19d. LCMS:product:Rt = 1.319 min. 1 H NMR (400MHz, CDCl3) δ7.02 (d, J = 1.5Hz, 1H), 6.82 (d, J = 1.5Hz, 1H), 6.06 (s, 2H), 4.40 (s, 2H).

[0479] Step 5): Under a nitrogen atmosphere, inter 3 (2 g, 5.15 mmol, 1.0 equivalence) was dissolved in tetrahydrofuran (12 mL), 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 19d (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 saturated aqueous citric acid solution (30 mL), extracted with ethyl acetate (30 mL × 3), and washed with water (40 mL) and brine (40 mL). The combined organic phases were dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid column chromatography (petroleum ether / tert-butyl methyl ether = 2 / 3) to give compound 19e. ESI m / z 623.2 [M + Na] + .LCMS:product:Rt=1.490min.

[0480] Step 6): At 0°C, hydrogen peroxide (30% aqueous solution, 1.90 mL, 24.47 mmol, 10.0 equivalence) was added dropwise to tetrahydrofuran (15 mL) containing compound 19e (1.6 g, 2.44 mmol, 1.0 equivalence). Then, a solution of lithium hydroxide (0.21 g, 5.00 mmol, 2.0 equivalence) in water (5 mL) was added. The reaction mixture was stirred at 0°C for 2 hours. The resulting reaction mixture was quenched with an aqueous solution of sodium bisulfite (3.80 g, 36.52 mmol) (40 mL) and stirred at 0°C for 30 minutes. The reaction mixture was then neutralized to pH 10 with sodium hydroxide (1.0 M) and extracted with methyl tert-butyl ether (40 mL × 3). The aqueous layer was separated, neutralized to pH 5 with an aqueous solution of citric acid (1.0 M), and extracted with methyl tert-butyl ether (50 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to give compound 19f. ESI m / z 388.0 [MC(CH3)3+H] + .LCMS:product:Rt=0.937min.

[0481] Step 7): To a tetrahydrofuran solution (10 mL) containing compound 19f (950 mg, 2.15 mmol, 1.0 equivalence), add O-tert-butyl-N,N'-diisopropylisourea (2.4 mL, 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 19 g. ESI m / z 388.0 [M-2C(CH3)3+H] + .LCMS:product:Rt=1.629min.

[0482] Step 8): To a solution of 19 g (400 mg, 0.79 mmol, 1.0 equivalence) of compound in N,N-dimethylformamide (6 mL), triethylsilane (0.39 mL, 2.41 mmol, 3.0 equivalence), 4-dimethylaminopyridine (194 mg, 1.59 mmol, 2.0 equivalence), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (58 mg, 0.08 mmol, 0.1 equivalence) were added. The reaction mixture was stirred at 90 °C for 16 hours under a carbon monoxide atmosphere. The mixture was poured into water (50 mmol) and extracted with ethyl acetate (30 mmol × 3). The organic phases were combined, washed with brine (30 mmol × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid column chromatography (petroleum ether / ethyl acetate = 3 / 2) to give compound 19 h. ESI m / z 470.2 [M+Na] +.LCMS:product:Rt=1.412min.

[0483] Step 9): To a solution of compound 19i (100 mg, 0.22 mmol, 1.0 equivalence) in dichloromethane (3 mL), add Inter 6 (100 mg, 0.25 mmol, 1.1 equivalence), acetic acid (60 mg, 1.00 mmol, 4.47 equivalence), and sodium triacetoxyborohydride (140 mg, 0.66 mmol, 3.0 equivalence). The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution (50 mL) and extracted with dichloromethane (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 (dichloromethane / methanol = 1 / 0 to 24 / 1) to give compound 19i. ESI m / z 836.4 [M+H] + .LCMS:product:Rt=1.367min.

[0484] Step 10): To a solution (2 mL) of N,N-dimethylformamide containing compound 19i (170 mg, 0.20 mmol, 1.0 equivalence), add inter 5 (110 mg, 0.23 mmol, 1.15 equivalence) and cesium carbonate (200 mg, 0.61 mmol, 3.0 equivalence). The reaction mixture was stirred at 25 °C for 18 hours. The mixture was poured into water (30 mL) and extracted with ethyl acetate (20 mL × 3). The organic layers were combined, washed with brine (30 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / tert-butyl methyl ether = 1 / 1) to give compound 19j. ESI m / z 1224.6 [M+H] + .LCMS:product:Rt=1.592min.

[0485] Step 11): Compound 19j (200 mg, 0.16 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 18 hours. The resulting reaction mixture was concentrated and purified by preparative high-performance liquid chromatography (ammonium bicarbonate) to obtain compound 19. ESI m / z 755.4 [M+H] + .LCMS:product:Rt=0.701min. 1H NMR(400MHz,D2O)δ7.25(t,J=7.6Hz,2H),7.14(dd,J=18.4,8.3Hz,6H),6.61(d,J=25.4Hz,2H),5.84(s,2H),3.59(s,4H),3.53(s ,2H),3.39–3.26(m,6H),3.20–3.07(m,3H),2.86–2.58(m,9H),2.44–2.30(m,6H),2.05(dd,J=8.4,4.5Hz,3H),1.72–1.60(m,3H).

[0486] Example 20: Synthesis of Compound 20

[0487] Step 1): Under nitrogen protection at 0°C, lithium bis(trimethylsilylaminolithium) (13.66 mL, 13.66 mmol, 1.1 equivalence) was added to a tetrahydrofuran (50 mL) solution containing inter 1 (5 g, 12.42 mmol, 1.0 equivalence) and molecular sieve 4A (5 g). The reaction mixture was stirred at 0°C for 30 min. Subsequently, a tetrahydrofuran (10 mL) solution of compound 6c (4.44 g, 13.66 mmol, 1.1 equivalence) was added dropwise to the reaction mixture. The reaction mixture was slowly heated to room temperature and stirred for 3 h. The reaction mixture was quenched with saturated citric acid aqueous solution (100 mL) and extracted with methyl tert-butyl ether (50 mL × 3). The combined organic phases were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness. The residue was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 3 / 1) to give compound 20a. ESI m / z 659.4 [M+Na] + .LCMS:product:Rt=1.770min.

[0488] Step 2): Under nitrogen protection at 0°C, hydrogen peroxide (30% aqueous solution, 2.10 mL, 27.07 mmol, 1.0 equivalent) was added dropwise to a tetrahydrofuran (18 mL) solution containing compound 20a (1.82 g, 2.71 mmol, 1.0 equivalent), followed by a 6 mL aqueous solution of lithium chloride (0.23 g, 5.41 mmol, 2.0 equivalent). The reaction mixture was stirred at 0°C for 2 hours, then quenched with a 50 mL aqueous solution of sodium bisulfite (4.22 g, 40.60 mmol, 15 equivalent), and the pH was adjusted to 9 with a 1 M sodium hydroxide aqueous solution. The mixture was washed with methyl tert-butyl ether (30 mL × 3). The aqueous phase was then acidified to pH 5 with a 1 M citric acid 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 20b. ESI m / z 500.2 [M + Na] + .LCMS:product:Rt=1.645min.

[0489] Step 3): To a 20 mL solution of tetrahydrofuran containing compound 20b (1.92 g, 3.21 mmol, 1.0 equivalence), add O-tert-butyl-N,N'-diisopropylisourea (5.37 g, 16.81 mmol, 5.0 equivalence). Stir the reaction mixture at 65 °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 / methyl tert-butyl ether = 1 / 1) to give compound 20c. ESI m / z 556.4 [M+Na] + .LCMS:product:Rt=2.328min.

[0490] Step 4): To a solution of compound 20c (737 mg, 1.35 mmol, 1.0 equivalence) in tetrahydrofuran (10 mL), tetrabutylammonium fluoride (2.70 mL, 2.70 mmol, 2.0 equivalence, 1 M in tetrahydrofuran) was added. The mixture was stirred at room temperature for 2 hours. The resulting reaction mixture was concentrated and purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 1 / 2) to give compound 20d. ESI m / z 442.2 [M+Na] + .LCMS:product:Rt=1.412min.

[0491] Step 5): Under nitrogen protection at 0°C, triethylamine (0.18 mL, 1.32 mmol, 1.5 equivalence) was added to a dichloromethane (10 mL) solution of compound 20d (383 mg, 0.88 mmol, 1.0 equivalence), followed by a dichloromethane (1 mL) solution of methanesulfonyl chloride (0.07 mL, 0.97 mmol, 1.1 equivalence). The mixture was brought to room temperature and stirred for 2 hours. The reaction mixture was quenched with an aqueous sodium bicarbonate solution (10 mL) and extracted with dichloromethane (8 mL × 2). The organic compound was washed with brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 20e. ESI m / z 520.2 [M + Na] + .LCMS:product:Rt=1.476min.

[0492] Step 6): Compound 20e (361 mg, 0.48 mmol, 1.1 equivalence) and potassium thioacetate (60 mg, 0.53 mmol, 1.0 equivalence) were added to dimethyl sulfoxide (6 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (8 mL × 2). The organic phases were combined, washed with brine (20 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 (petroleum ether / methyl tert-butyl ether = 4 / 1) to give compound 20f. ESI m / z 500.2 [M + Na] + .LCMS:product:Rt=1.636min.

[0493] Step 7): Under nitrogen atmosphere at 0°C, compound 20f (220 mg, 0.38 mmol, 1.0 equivalence) was dissolved in a mixed solution of acetonitrile (5 mL), acetic acid (0.5 mL), and water (0.5 mL), followed by dropwise addition of 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (151 mg, 0.77 mmol, 2.0 equivalence). The reaction mixture was stirred at 0°C for 10 minutes. The mixture was then concentrated under reduced pressure. The residue was dissolved in dichloromethane (10 mL), cooled to 0°C, and quenched with a saturated aqueous solution of sodium bicarbonate (6 mL). After stirring the mixture for 5 minutes, the organic phase was separated, washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness to give 20 g of compound. ESI m / z 390.0 [M-2(tert-butyl)+H] + .LCMS:product:Rt=1.551min.

[0494] Step 8): To dichloromethane (5 mL) containing 20 g (200 mg, 0.28 mmol, 1.0 equivalence) of the compound and triethylamine (0.12 mL, 0.85 mmol, 3.0 equivalence), Inter 6 (114 mg, 0.28 mmol, 1.0 equivalence) was added. The mixture was stirred at room temperature for 18 hours. The mixture was diluted with water (10 mL) and extracted with dichloromethane (10 mL × 2). The organic layers were combined, washed with 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 = 2 / 1) to give compound 20h. ESI m / z 892.4 [M + Na] + .LCMS:product:Rt=1.997min.

[0495] Step 9): To N,N-dimethylformamide (2 mL) containing compound 20h (25 mg, 0.03 mmol, 1.0 equivalence) and inter 5 (24 mg, 0.05 mmol, 2.0 equivalence), cesium carbonate (25 mg, 0.08 mmol, 3.0 equivalence) was added, and the reaction mixture was stirred at 60 °C for 3 hours. The mixture was then extracted with water (10 mL) and ethyl acetate (5 mL × 3). The organic layers were combined, washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 2 / 1) to give compound 20i. LCMS:product:Rt = 2.609 min.

[0496] Step 10): Compound 20i (28 mg, 0.02 mmol, 1.0 equivalence) was added to a mixture of dichloromethane (1.5 mL) and trifluoroacetic acid (0.5 mL), and the 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 give compound 20. ESI m / z 789.3 [M+H] + .LCMS:product:Rt=0.642min. 1H NMR(400MHz,D2O)δ7.33–7.20(m,2H),7.18(t,J=7.5Hz,2H),7.07(d,J=8.3Hz,3H),7.0 0(t,J=8.2Hz,3H),6.94(s,2H),4.43(s,2H),4.10(s,4H),3.41–3.29(m,5H),3.24–3.09 (m,3H),2.91–2.75(m,4H),2.70(t,J=9.7Hz,3H),2.59(dd,J=19.1,12.5Hz,3H),2.40– 2.27(m,5H),2.04(s,2H),1.94–1.79(m,2H),1.66(t,J=11.2Hz,3H),1.51–1.34(m,2H).

[0497] Example 21: Synthesis of Compound 21

[0498] Step 1): To a carbon tetrachloride (20 mL) solution of compound 21a (2 g, 12.72 mmol, 1.0 equivalence), N-bromosuccinimide (2.7 g, 15.27 mmol, 1.2 equivalence) and azobisisobutyronitrile (0.41 g, 2.54 mmol, 0.2 equivalence) were added. The reaction mixture was stirred at 80 °C for 18 hours. The resulting 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 to give compound 21-1a, which was used in the next reaction without further purification. ESI m / z 315.8 [M+H] + .LCMS:product:Rt=1.10min.

[0499] Step 2): Compound 21-1a (3.0 g, 9.52 mmol, 1.0 equivalence) was added to a tetrahydrofuran (50 mL) solution, followed by N,N-diisopropylethylamine (2.83 g, 21.91 mmol, 2.3 equivalence) and diethyl phosphite (0.65 g, 4.76 mmol, 0.5 equivalence). The reaction mixture was stirred at room temperature for 2 hours. Water (50 mL) was then added to the resulting reaction mixture, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by rapid column chromatography (dichloromethane / tert-butyl methyl ether = 1 / 1) to give compound 21b. ESI m / z 236.0 [M+H] + .LCMS:product:Rt=0.971min.

[0500] Step 3): Add inter 3 (3.0 g, 7.72 mmol, 1.0 equivalent) to tetrahydrofuran (50 mL), and add bis(trimethylsilylaminolithium) (10.0 mL, 10.0 mmol, 1.3 equivalent) under a nitrogen atmosphere at 0 °C. Stir the reaction mixture at 0 °C for 30 min. Then, add tetrahydrofuran (50 mL) containing compound 21b (2.3 g, 9.27 mmol, 1.2 equivalent). Slowly heat the reaction mixture to room temperature and stir for 2 h. Quench the mixture with saturated ammonium chloride solution (100 mL) and extract with ethyl acetate (200 mL × 2). Combine the organic phases and wash with brine (50 mL), dry to anhydrous sodium sulfate and filter. Concentrate the filtrate under reduced pressure to obtain the residue, which is purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 1 / 1) to give compound 21c. ESI m / z 566.1 [M + Na] + .LCMS:product:Rt=1.340min.

[0501] Step 4): Under nitrogen protection, compound 21c (0.9 g, 1.66 mmol, 1.0 equivalence) was dissolved in tetrahydrofuran (5 mL), and hydrogen peroxide (30% aqueous solution, 1.46 mL, 13.24 mmol, 8.0 equivalence) and an aqueous solution containing lithium hydroxide monohydrate (104.2 mg, 2.48 mmol, 1.5 equivalence) were slowly added dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 4 hours, then quenched with sodium bisulfite solution (1.7 g, 16.56 mmol, 10.0 equivalence), and the pH was adjusted to 5 with citric acid (1 M). The aqueous phase was extracted with methyl tert-butyl ether (100 mL × 3), and the combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 21d. ESI m / z 407.0 [M + Na] + .LCMS:product:Rt=1.060min.

[0502] Step 5): To a tetrahydrofuran solution (10 mL) of compound 21d (0.9 g, 1.68 mmol, 1.0 equivalence), O-tert-butyl-N,N'-diisopropylisourea (0.98 g, 4.92 mmol, 3.0 equivalence) was added, and the mixture was stirred at 65 °C for 2 h. The mixture was diluted with water (20 mL) and then extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 1 / 1) to give compound 21e. ESI m / z 463.2 [M + Na] + .LCMS:product:Rt=1.304min.

[0503] Step 6): Compound 21e (300.0 mg, 0.69 mmol, 1.0 equivalence) was dissolved in methanol (5 mL) and water (1 mL), and lithium hydroxide monohydrate (58.29 mg, 1.39 mmol, 2.0 equivalence) was added. The reaction mixture was stirred at room temperature for 18 hours. The pH of the reaction mixture was then neutralized to 3 with 1 mol / L hydrochloric acid solution. The mixture was extracted with ethyl acetate (50 mL × 2), and the organic phase was concentrated under reduced pressure to give compound 21f. ESI m / z 425.2 [M + Na] + .LCMS:product:Rt=1.305min.

[0504] Step 7): Compound 21f (250.0 mg, 0.59 mmol, 1.0 equivalence) was added to N,N-dimethylformamide (10 mL), followed by N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (334.3 mg, 0.88 mmol, 1.5 equivalence), N,N-diisopropylethylamine (151.5 mg, 1.17 mmol, 2.0 equivalence), and inter 6 (237.1 mg, 0.59 mmol, 1.0 equivalence). 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 reduced pressure to give the crude product. The crude product was purified by rapid column chromatography (petroleum ether / methyl tert-butyl ether = 1 / 1) to give 21 g of the compound. ESI m / z 835.4 [M+Na] + .LCMS:product:Rt=1.758min.

[0505] Step 8): Sodium hydroxide (60% dispersed in mineral oil) (35.4 mg, 0.88 mmol, 4.0 equivalence) was added to a solution (5 mL) of N,N-dimethylformamide containing 21 g (180 mg, 0.22 mmol, 1.0 equivalence). The reaction mixture was stirred at room temperature for 0.5 h. Then, inter 5 (114 mg, 0.24 mmol, 1.1 equivalence) was added. The reaction mixture was stirred at room temperature for 1.5 h. The mixture was poured into a saturated aqueous solution of ammonium chloride (60 mL) and extracted with ethyl acetate (40 mL × 3). The organic phases were combined, washed with brine, 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 / 1) to give compound 21 h. ESI m / z 1222.6 [M+Na] + .LCMS:product:Rt=2.556min.

[0506] Step 9): Compound 21h (150.0 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 room temperature for 18 hours. The resulting reaction mixture was concentrated and purified by high-performance liquid chromatography (ammonium bicarbonate method) to give compound 21. ESI m / z 366.8 [M / 2+H] + .LCMS:product:Rt=0.562min. 1 HNMR(400MHz,D2O)δ7.38(s,1H),7.24(dt,J=10.4,7.6Hz,2H),7.07(dt,J=21 .6,8.0Hz,5H),6.93(s,1H),5.04(dd,J=83.2,16.0Hz,2H),4.63(d,J=16.4Hz ,2H),3.31(ddd,J=13.2,11.6,7.8Hz,5H),3.19–2.93(m,5H),2.89–2.63(m,8 H),2.52–2.27(m,6H),2.12–1.95(m,3H),1.65(ddt,J=27.2,13.2,9.2Hz,3H)

[0507] Example 22: Synthesis of Compound 22

[0508] Step 1): Under a nitrogen atmosphere, inter 1 (6.5 g, 16.15 mmol, 1.0 equivalence) was dissolved in tetrahydrofuran (50 mL) and cooled to 0 °C. Then, lithium bis(trimethylsilyl)amino (19.38 mL, 19.38 mmol, 1.2 equivalence) was added. The reaction mixture was stirred at 0 °C for 30 min. Next, a tetrahydrofuran solution (50 mL) of compound 21b (4.0 g, 16.94 mmol, 1.05 equivalence) was added. The reaction mixture was stirred at room temperature for 2 h. The mixture was quenched with saturated ammonium chloride solution (100 mL) and extracted with ethyl acetate (200 mL × 2). The organic phases were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 1 / 1) to give compound 22c. ESI m / z 580.2 [M+Na] + .LCMS:product:Rt=1.613min.

[0509] Step 2): Under a nitrogen atmosphere, 50 mL of tetrahydrofuran containing 1.5 g (2.69 mmol, 1.0 equivalence) of compound 22c was cooled to 0 °C, and hydrogen peroxide (30% aqueous solution, 2.0 mL, 26.90 mmol, 10.0 equivalence) was slowly added dropwise, followed by a 10 mL solution of lithium hydroxide monohydrate (169.3 mg, 4.03 mmol, 1.5 equivalence) in water. The reaction mixture was stirred at 0 °C for 4 hours, then quenched with sodium bisulfite solution (2.8 g, 16.56 mmol, 10.0 equivalence), and the pH was adjusted to 5 with citric acid (1 M). The aqueous phase was extracted with methyl tert-butyl ether (100 mL × 3), and the combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 22d. ESI m / z 421.1 [M + Na] + .LCMS:product:Rt=1.39min.

[0510] Step 3): Compound 22d (0.5 g, 0.50 mmol, 1.0 equivalence) was dissolved in tetrahydrofuran (10 mL), and O-tert-butyl-N,N'-diisopropylisourea (0.5 g, 2.50 mmol, 5.0 equivalence) was added. The mixture was stirred at 65 °C for 2 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 2). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 1 / 1) to give compound 22e. ESI m / z 477.2 [M + Na] + .LCMS:product:Rt=1.402min.

[0511] Step 4): Compound 22e (300.0 mg, 0.66 mmol) was dissolved in methanol (4 mL) and water (2 mL), and lithium hydroxide monohydrate (55.38 mg, 1.32 mmol, 2.0 equivalence) was added. The reaction mixture was stirred at room temperature for 18 hours. The resulting reaction mixture was neutralized to pH 3 with 1 M hydrochloric acid. The mixture was extracted with ethyl acetate (50 mL × 2), and the organic phase was concentrated under reduced pressure to give compound 22f. ESI m / z 463.2 [M + Na] + .LCMS:product:Rt=1.384min.

[0512] Step 5): To a solution of N,N-dimethylformamide (5 mL) containing compound 22f (350.0 mg, 0.56 mmol, 1.0 equivalence), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (317.1 mg, 0.83 mmol, 1.5 equivalence), N,N-diisopropylethylamine (215.6 mg, 1.67 mmol, 3.0 equivalence), and inter 6 (298.7 mg, 0.67 mmol, 1.2 equivalence) were added. The reaction mixture was stirred at room temperature for 1 hour. 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 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 / 1) to give 22 g of the compound. ESI m / z 849.4 [M+Na] + .LCMS:product:Rt=1.784min.

[0513] Step 6): Sodium hydroxide (60% dispersed in mineral oil) (27.86 mg, 0.70 mmol, 4.0 equivalence) was added to a solution (5 mL) of N,N-dimethylformamide containing 22 g (160 mg, 0.17 mmol, 1.0 equivalence) of compound 22 g (160 mg, 0.17 mmol, 1.0 equivalence). The reaction mixture was stirred at room temperature for 0.5 h. Then, inter 5 (106.0 mg, 0.23 mmol, 1.3 equivalence) was added. The reaction mixture was stirred at room temperature for 1.5 h. The mixture was poured into an aqueous solution of ammonium chloride (60 mL) and extracted with ethyl acetate (40 mL × 3). The combined organic phases were washed with brine (40 mL × 3), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by flash column chromatography (petroleum ether / methyl tert-butyl ether = 1 / 9) to give compound 22 h. ESI m / z 1114.6 [M-Boc+H] + .LCMS:product:Rt=2.621min.

[0514] Step 7): Add 2 mL of trifluoroacetic acid to a solution of compound 22h (202.0 mg, 0.14 mmol, 1.0 equivalence) in dichloromethane. Stir the reaction mixture at room temperature for 18 hours. The resulting reaction mixture was concentrated and purified by high-performance liquid chromatography (ammonium bicarbonate) to give compound 22. ESI m / z 373.8 [M / 2+H] + .LCMS:product:Rt=0.635min. 1H NMR(400MHz,D2O)δ7.36(s,1H),7.30–7.17(m,2H),7.17–6.98(m,5H),6.94(s,1 H),5.03(dd,J=53.2,15.6Hz,2H),4.66–4.52(m,2H),3.45–3.23(m,5H),3.15(d d,J=19.2,9.2Hz,3H),2.96–2.50(m,10H),2.45–2.29(m,5H),2.08–1.97(m,2H) ,1.89(d,J=13.6Hz,1H),1.70(ddd,J=16.0,12.8,8.8Hz,4H),1.47–1.22(m,2H).

[0515] Example 23: Synthesis of Compound 23

[0516] 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 23a. ESI m / z 429.3 [M+H] + .LCMS:product:Rt=0.994min.

[0517] Step 2): Compound 23a (0.1 g, 0.23 mmol, 1.0 equivalence), cesium carbonate (380 mg, 1.17 mmol, 5.0 equivalence), and inter 5 (273.2 mg, 0.58 mmol, 2.5 equivalence) were added to N,N-dimethylformamide (5 mL). The reaction mixture was stirred at room temperature for 18 hours. The mixture was poured into water (60 mL) and extracted with ethyl acetate (3 × 40 mL). The organic compound was washed with brine (40 mL × 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by rapid column chromatography (petroleum ether / methyl tert-butyl ether = 1 / 1) to give compound 23b. ESI m / z 1204.8 [M+H] + .LCMS:product:Rt=2.042min.

[0518] Step 3): Dichloromethane (2 mL) and trifluoroacetic acid (2 mL) were added to compound 23b (180.0 mg, 0.15 mmol, 1.0 equivalence). The reaction mixture was stirred at room temperature for 18 hours. The resulting reaction mixture was concentrated and purified by pre-prepared high-performance liquid chromatography (formic acid) to give compound 23. ESI m / z 368.4 [M / 2+H] + .LCMS:product:Rt=0.672min. 1 H NMR(400MHz,D2O)δ7.47–7.28(m,12H),4.45(s,4H),3.90(s,2H),3.57–3.44(m,3H),3.35(dd,J=21.6,9.2Hz,3H),3.25–3 .11(m,3H),3.02–2.85(m,3H),2.87–2.68(m,6H),2.55–2.32(m,6H),2.06(d,J=6.4Hz,3H),1.68(dt,J=21.6,10.9Hz,3H).

[0519] Example 24: Synthesis of Compound 24

[0520] Step 1): Compound 24a (3 g, 12.43 mmol, 1.0 equivalence) and potassium carbonate (2.6 g, 18.81 mmol, 1.5 equivalence) were dissolved in N,N-dimethylformamide (30 mL), and iodomethane (1 mL, 16.06 mmol, 1.3 equivalence) was added. The mixture was stirred at 15 °C for 18 hours. Water (80 mL) was added, followed by extraction with ethyl acetate (30 mL × 3). The organic phases were combined, washed with brine (40 mL × 4), dried over anhydrous sodium sulfate, and concentrated under vacuum to give compound 24b. ESI m / z 200.0 [M+H-tert-butyl]+.LCMS:product:Rt=1.185 min.

[0521] Step 2): Under a nitrogen atmosphere, compound 24b (3.1 g, 11.89 mmol, 1.0 equivalence) was dissolved in tetrahydrofuran (30 mL), and then lithium diisopropylamino (9.6 mL, 19.20 mmol, 1.6 equivalence) was added at 0 °C and stirred at the same temperature for 1 h. Then, a solution of 1-bromo-3-(bromomethyl)benzene (3 g, 12.00 mmol, 1.01 equivalence) in tetrahydrofuran (30 mL) was added, and the mixture was stirred at 15 °C for 17 h. The mixture was quenched with a saturated aqueous ammonium chloride solution (50 mL) and then extracted with ethyl acetate (50 mL × 2). The combined organic phases were washed with brine (50 mL × 2), dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain a residue. The residue was purified by silica gel chromatography (petroleum ether / tert-butyl methyl ether = 2 / 1) to give compound 24c. ESI m / z 368.0 [M+H-tert-butyl] + .LCMS:product:Rt=1.509min.

[0522] Step 3): Compound 24c (340 mg, 0.71 mmol, 1.0 equivalence) was dissolved in N,N-dimethylformamide (6 mL), and dichloro[1,1'-bis(diphenylphosphine)ferrocene]palladium (52 ​​mg, 0.07 mmol, 0.1 equivalence), 4-dimethylaminopyridine (174 mg, 1.42 mmol, 2.0 equivalence), and triethylsilane (0.4 mL, 2.48 mmol, 3.5 equivalence) were added. The mixture was purged three times with carbon monoxide gas, then heated to reflux and stirred at 90 °C for 16 hours. The mixture was poured into water (40 mL) and extracted with ethyl acetate (30 mL × 3). The organic compound was washed with brine (50 mL × 3), dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the residue. The residue was purified by silica gel column chromatography (petroleum ether / tert-butyl methyl ether = 3 / 2) to give compound 24d. ESI m / z 318.2 [M+H-tert-butyl] +.LCMS:product:Rt=1.445min.

[0523] Step 4): Compound 13b (236 mg, 0.57 mmol, 1.6 equivalence) and compound 24d (150 mg, 0.36 mmol, 1.0 equivalence) were dissolved in 6 mL of dichloromethane, and acetic acid (0.10 mL, 1.67 mmol) and sodium triacetoxyborohydride (228 mg, 1.08 mmol, 3.0 equivalence) were added. The mixture was stirred at 15 °C for 1 hour. Then, saturated sodium bicarbonate aqueous solution (50 mL) was added, and the mixture was extracted with dichloromethane (40 mL × 3 times). The organic phases were combined, washed with brine (50 mL × 2 times), dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the residue. The residue was purified by silica gel chromatography (petroleum ether / tert-butyl methyl ether = 1 / 9) to give compound 24e. ESI m / z 769.4 [M+H] + .LCMS:product:Rt=1.465min.

[0524] Step 5): Compound 24e (190 mg, 0.21 mmol, 1.0 equivalence) and inter 4 (83 mg, 0.21 mmol, 1.0 equivalence) were dissolved in 5 mL of dichloromethane, and acetic acid (0.10 mL) and sodium triacetoxyborohydride (131 mg, 0.62 mmol, 3.0 equivalence) were added. The mixture was stirred at room temperature for 2 hours. Then, saturated sodium bicarbonate aqueous solution (20 mL) was added, and the mixture was extracted with dichloromethane (10 mL × 2 times). The organic phases were combined, washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the residue. The residue was purified by silica gel chromatography (petroleum ether / tert-butyl methyl ether = 1 / 1) to give compound 24f. ESI m / z 1157.6 [M+H] + .LCMS:product:Rt=2.016min.

[0525] Step 6): Compound 24f (230 mg, 0.18 mmol, 1.0 equivalence) was added to a mixed solution of tetrahydrofuran (2 mL), methanol (2 mL), and water (2 mL), followed by lithium hydroxide hydrate (73 mg, 1.73 mmol, 10.0 equivalence). The reaction mixture was stirred at 50 °C for 16 hours. The mixture was concentrated under vacuum to remove methanol and tetrahydrofuran. The residue was diluted with water (6 mL), acidified to pH 5 with aqueous hydrochloric acid (1 M), and extracted with ethyl acetate (4 × 3 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under vacuum to give compound 24 g. ESI m / z 1142.6 [M+H] + .LCMS:product:Rt=1.658min.

[0526] Step 7): 24 g (232 mg, 0.17 mmol, 1.0 equivalence) of compound 24 was added to a mixture of trifluoroacetic acid (2 mL) and dichloromethane (2 mL), and the reaction mixture was stirred at room temperature for 5 hours. The resulting reaction mixture was concentrated and purified by preparative high-performance liquid chromatography (ammonium bicarbonate) to obtain compound 24. ESI m / z 730.3 [M+H]+.LCMS:product:Rt=0.964min. 1 H NMR(400MHz,D2O)δ7.27–7.15(m,6H),7.12–6.99(m,3H),4.06(d,J=150.2Hz,2 H),3.83–3.70(m,2H),3.63–3.41(m,6H),3.33(ddt,J=11.9,8.7,5.9Hz,4H),3 .14(qd,J=10.6,7.1Hz,2H),2.92–2.62(m,8H),2.60–2.45(m,1H),2.45–2.28( m,5H),2.20(t,J=12.3Hz,2H),2.03(dd,J=7.0,3.3Hz,2H),1.75–1.58(m,2H).

[0527] Example 25: Synthesis of Compound 25

[0528] Step 1): To a solution of N,N-dimethylformamide (5 mL) containing compound 21f (200.0 mg, 0.47 mmol, 1.0 equivalence), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (267.4 mg, 0.70 mmol, 1.5 equivalence), N,N-diisopropylethylamine (121.2 mg, 0.94 mmol, 2.0 equivalence), and compound 15d (215.9 mg, 0.52 mmol, 1.1 equivalence) were 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. The residue was purified by rapid column chromatography (petroleum ether / methyl tert-butyl ether = 1 / 1) to give compound 25a. ESI m / z 849.4 [M+Na] + .LCMS:product:Rt=1.790min.

[0529] Step 2): Compound 25a (160 mg, 0.19 mmol, 1.0 equivalence) was dissolved in N,N-dimethylformamide (5 mL), and sodium hydroxide (60% dispersed in mineral oil) (30.95 mg, 0.77 mmol, 4.0 equivalence) was added. The reaction mixture was stirred at room temperature for 0.5 h. Then, inter 5 (117.8 mg, 0.25 mmol, 1.3 equivalence) was added. The reaction mixture was stirred at room temperature for 1.5 h. The mixture was poured into a saturated ammonium chloride solution (60 mL) and extracted with ethyl acetate (40 mL × 3). 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 column chromatography (petroleum ether / methyl tert-butyl ether = 1 / 1) to give compound 25b. ESI m / z 1237.7 [M + Na] + .LCMS:product:Rt=2.595min.

[0530] Step 3): Trifluoroacetic acid (2 mL) was added to a solution of dichloromethane containing compound 25b (190.0 mg, 0.16 mmol, 1.0 equivalence). The reaction mixture was stirred at room temperature for 18 hours. The resulting reaction mixture was concentrated and purified by high-performance liquid chromatography (ammonium bicarbonate) to give compound 25. ESI m / z 373.8 [M / 2+H] + .LCMS:product:Rt=0.916min. 1 HNMR(400MHz,D2O)δ7.38(s,1H),7.30–7.16(m,2H),7.16–6.87(m,6H),5.04(dt, J=26.8,16.0Hz,2H),4.68–4.52(m,2H),3.31(t,J=20.4Hz,5H),3.13(dd,J=29.6 ,20.4Hz,3H),3.01–2.56(m,10H),2.56–2.23(m,5H),2.02(d,J=11.2Hz,3H),1.8 1(d,J=15.6Hz,1H), 1.65(dd,J=25.6,13.2Hz,3H), 1.44(dd,J=25.6,12.0Hz,2H).

[0531] Example 26: Synthesis of compounds 26-P1 and 26-P2

[0532] Step 1): Compound 26a (10 g, 47.38 mmol, 1.0 equivalent) was dissolved in methanol (100 mL), and sodium borohydride (2.7 g, 71.37 mmol, 1.5 equivalent) was added at 0 °C. The reaction mixture was reacted at 0 °C for one hour under nitrogen protection. The reaction mixture was then diluted with water (200 mL) and extracted with ethyl acetate (3 × 200 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give compound 26b. ESI m / z = 195.0 [M-(OH)-+H] + .LCMS:product:Rt=1.075min.

[0533] Step 2): Compound 26b (10 g, 46.93 mmol, 1.0 equivalence) was dissolved in N,N-dimethylformamide (100 mL), and tert-butyldimethylchlorosilane (9.2 g, 61.04 mmol, 1.3 equivalence) and imidazole (8 g, 117.51 ​​mmol, 2.5 equivalence) were added at 25 °C. The reaction mixture was stirred at 25 °C for 4 hours. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (3 × 200 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 1 / 0) to give compound 26c. ESI m / z = 327.0 [M+H] + .LCMS:product:Rt=2.452min.

[0534] Step 3): Compound 26c (14 g, 42.77 mmol, 1.00 equivalence) was dissolved in tetrahydrofuran (120 mL), and then n-butyllithium (18 mL, 45.00 mmol, 1.2 equivalence) was added dropwise at -78 °C. The reaction mixture was stirred at -78 °C for 30 min. N,N-dimethylformamide (3.2 mL, 41.33 mmol, 1.1 equivalence) was added dropwise at -78 °C, and then stirred at -78 °C for 1 h. The reaction mixture was diluted with water (250 mL) and extracted with ethyl acetate (3 × 200 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 10 / 1) to give compound 26d. ESI m / z = 280.2 [M-(OH)-+Na] + .LCMS:product:Rt=2.181min.

[0535] Step 4): Compound 26d (10.4 g, 37.68 mmol, 1.00 equivalent) was dissolved in methanol (30 mL), and then sodium borohydride (0.6 g, 15.86 mmol, 1.50 equivalent) was added at 0 °C. The reaction mixture was stirred at 0 °C for 30 min under nitrogen protection. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 × 100 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 (petroleum ether / methyl tert-butyl ether = 4 / 1) to give compound 26e. ESI m / z = 147.2 [M-OTBS+H] + .LCMS:product:Rt=1.525min.

[0536] Step 5): Compound 26e (4 g, 14.38 mmol, 1.00 equivalent) was dissolved in dichloromethane (20 mL), and N-bromosuccinimide (2.6 g, 14.38 mmol, 1.00 equivalent) and triphenylphosphine (3.7 g, 14.38 mmol, 1.00 equivalent) were added. The reaction mixture was stirred at 0 °C for 1 hour. The reaction mixture was diluted with water (100 mL) and extracted with dichloromethane (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 (petroleum ether / methyl tert-butyl ether = 20 / 1) to give compound 26f. ESI m / z = 210.0 [M-OTBS+H] + .LCMS:product:Rt=2.311min.

[0537] Step 6): Compound 26f (4 g, 11.76 mmol, 1.00 equivalent) was dissolved in tetrahydrofuran (30 mL), and lithium bis(trimethylsilylamino)hydroxide (14 mL, 14.11 mmol, 1.20 equivalent) was added dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour. Inter 3 (4 g, 11.76 mmol, 1.00 equivalent) was dissolved in tetrahydrofuran (30 mL) and added dropwise to the reaction mixture at 0 °C. The reaction mixture was stirred at 0 °C for 2 hours under nitrogen protection. 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 = 2 / 1) to give compound 26 g. ESI m / z = 671.4 [M + Na] + .LCMS:product:Rt=2.470min.

[0538] Step 7): 26 g (4 g, 6.17 mmol, 1.00 equivalent) of the compound was dissolved in tetrahydrofuran (25 mL), and hydrogen peroxide (5 mL, 61.70 mmol, 10.00 equivalent) was added at 0 °C. Lithium hydroxide (0.52 g, 12.34 mmol, 2.00 equivalent) was then dissolved in water (8 mL) and added to the reaction mixture. The reaction was stirred from 0 °C to 25 °C for 1 hour. The resulting reaction mixture was quenched with sodium bisulfite (9.0 g, 86.38 mmol, 14.00 equivalent) in water (8 mL) and stirred at 0 °C for 30 minutes. The reaction mixture was then adjusted to pH 3 with 1 M hydrochloric acid and extracted with ethyl acetate (50 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 26 h. ESI m / z = 512.2 [M + Na] + .LCMS:product:Rt=2.063min.

[0539] Step 8): Compound 26h (4.3 g, 8.79 mmol, 1.00 equivalence) was dissolved in tetrahydrofuran solution (30 mL), and O-tert-butyl-N,N'-diisopropylisourea (13.8 mL, 61.53 mmol, 7.00 equivalence) was added. The reaction mixture was stirred at 65 °C for 2 hours. The reaction mixture was 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 = 5 / 1) to give compound 26i. ESI m / z = 568.4 [M+Na]+. LCMS:product:Rt = 2.586 min.

[0540] Step 9): Compound 26i (1.6 g, 2.93 mmol, 1.00 equivalent) was dissolved in tetrahydrofuran (5 mL), and tetrabutylammonium fluoride (15 mL, 14.65 mmol, 5.00 equivalent) was 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 (petroleum ether / methyl tert-butyl ether = 1 / 1) to give compound 26j. ESI m / z = 454.2 [M + Na] + .LCMS:product:Rt=1.686min.

[0541] Step 10): Compound 26j (770 mg, 1.78 mmol, 1.0 equivalence) was dissolved in dichloromethane (8 mL), and Dys-Martin oxidant (1.5 g, 3.57 mmol, 2.0 equivalence) was added. The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was then diluted with water (100 mL) and extracted with dichloromethane (3 × 50 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 / 1) to give compound 26k. ESI m / z = 452.2 [M + Na] + .LCMS:product:Rt=1.850min.

[0542] Step 11): Compound 26k (340 mg, 1.18 mmol, 1.0 equivalence) and inter 6 (340 mg, 0.76 mmol, 1.2 equivalence) were dissolved in methanol (4 mL), and sodium cyanoborohydride (120 mg, 1.91 mmol, 3.0 equivalence) and acetic acid (4 mg, 0.07 mmol, 0.1 equivalence) were added. The reaction mixture was stirred at 60 °C for 2 days. The reaction mixture was diluted with water (100 mL) and extracted with dichloromethane (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 preparative high-performance liquid chromatography (formic acid) to give compound 26l. ESI m / z = 818.6 [M+H] + .LCMS:product:Rt=1.758min.

[0543] Step 12): Compound 26l (180 mg, 0.31 mmol, 1.0 equivalence) was purified and separated by supercritical fluid chromatography [ethanol (0.1% diethylamine)] to obtain compounds 26l-P1 and 26l-P2.

[0544] SFC:26l-P1:Rt=2.366min.

[0545] SFC:26l-P2:Rt=2.752min.

[0546] Step 13): Compound 26l-P1 (78 mg, 0.10 mmol, 1.0 equivalence) was dissolved in N,N-dimethylformamide (2 mL), and inter5 (53 mg, 0.12 mmol, 1.2 equivalence) and potassium carbonate (27 mg, 0.20 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 phases were combined, 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 = 1 / 1) to give compound 26m-P1. ESI m / z = 1206.8 [M+H] + .LCMS:product:Rt=1.606min.

[0547] Step 14): Compound 26l-P2 (100 mg, 0.12 mmol, 1.0 equivalence) was dissolved in N,N-dimethylformamide (2 mL), and Inter 5 (68 mg, 0.14 mmol, 1.2 equivalence) and potassium carbonate (33 mg, 0.24 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 phases were combined, 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 = 1 / 1) to give compound 26m-P2. ESI m / z = 1206.6 [M+H] + .LCMS:product:Rt=1.593min.

[0548] Step 15): Compound 26m-P1 (120 mg, 0.09 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 16 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography (formic acid) to obtain compound 26-P1. ESI m / z = 737.4 [M+H] + .LCMS:product:Rt=0.678min. 1HNMR(400MHz,D2O)δ7.42(d,J=7.5Hz,1H),7.28(dd,J=14.3,7.5Hz,10H),4.93(d,J=8 .5Hz,1H),4.18(s,4H),3.56(ddd,J=23.2,11.6,7.2Hz,3H),3.37(ddd,J=12.7,8.7,4 .5Hz,3H),3.26–3.17(m,3H),3.16–3.03(m,2H),2.99(q,J=10.1Hz,3H),2.86–2.67(m ,6H),2.59(dd,J=16.6,7.9Hz,2H),2.54–2.37(m,6H),2.08(s,3H),1.76–1.63(m,3H).

[0549] Step 16): Compound 26m-P2 (140 mg, 0.11 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 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 26-P2. ESI m / z = 737.4 [M+H] + .LCMS:product:Rt=0.677min. 1 H NMR(400MHz,D2O)δ7.35(t,J=4.5Hz,1H),7.32–6.76(m,10H),4.95(d,J=8.3Hz,1H),4.17(s ,4H),3.58–3.49(m,3H),3.36(ddd,J=12.1,8.5,3.8Hz,3H),3.21(dq,J=11.8,5.7,5.2Hz,3H ),3.17–3.01(m,2H),2.97(t,J=10.5Hz,3H),2.88–2.69(m,6H),2.58(dt,J=9.8,4.7Hz,2H), 2.46(dq,J=17.5,8.8,8.3Hz,6H), 2.09(d,J=7.5Hz,3H), 1.69(ddd,J=13.5,9.4,5.2Hz,3H).

[0550] Example 27: Synthesis of Compound 27

[0551] Step 1): Compound 22e (3 g, 6.60 mmol, 1.0 equivalence) was dissolved in ethanol (30 mL), and sodium borohydride (0.75 g, 19.80 mmol, 3.0 equivalence) was added at 0 °C. The mixture was stirred at 0 °C for 16 hours until room temperature. The resulting reaction mixture was added to water (50 mL) and extracted with ethyl acetate (50 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with petroleum ether / ethyl acetate = 1 / 1 to give compound 27a. ESI m / z 427.2 [M+H] + .LCMS:product:Rt=1.341min.

[0552] Step 2): Compound 27a (650 mg, 1.58 mmol, 1.0 equivalence) was dissolved in dichloromethane (40 mL), and Dys-Martin oxidant (3.88 g, 9.14 mmol, 1.5 equivalence) was added. The mixture was stirred at room temperature for 2 hours. The resulting reaction mixture was quenched with saturated sodium sulfite aqueous solution, extracted with dichloromethane (50 mL × 2), and washed with saturated sodium bicarbonate aqueous solution. The organic layers were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with petroleum ether / tert-butyl methyl ether = 1 / 1 to give compound 27b. ESI m / z 447.2 [M + Na] + .LCMS:product:Rt=1.696min.

[0553] Step 3): Compound 27b (600 mg, 1.41 mmol, 1.0 equivalence) and compound 13b (697.96 mg, 1.70 mmol, 1.2 equivalence) were dissolved in dichloromethane (10 mL), and acetic acid (0.01 mL, 0.17 mmol) was added. The mixture was stirred for 30 min, followed by the addition of sodium triacetoxyborohydride (898.57 mg, 4.24 mmol, 3.0 equivalence). The mixture was stirred at room temperature for 3 h. The reaction mixture was added to a saturated aqueous solution of sodium bicarbonate (50 mL) and extracted with dichloromethane (50 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with petroleum ether / tert-butyl methyl ether = 1 / 1 to give compound 27c. ESI m / z 820.4 [M+H] + .LCMS:product:Rt=1.596min.

[0554] Step 4): Compound 27c (800 mg, 0.98 mmol) and (9H-fluorene-9-yl)methyl(2-oxoethyl)carbamate (548.82 mg, 1.95 mmol, 2.0 equivalence) were dissolved in dichloromethane (20 mL), and acetic acid (0.02 mL, 0.35 mmol) was added and stirred for 30 min. Then, sodium triacetoxyborohydride (620.22 mg, 2.93 mmol, 3.0 equivalence) was added. The mixture was stirred at room temperature for 3 h. A saturated aqueous solution of sodium bicarbonate (50 mL) was then added to the reaction mixture, and the mixture was extracted with dichloromethane (50 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using dichloromethane / ethyl acetate = 1 / 1 to give compound 27d. ESI m / z 1085.4 [M+H] + .LCMS:product:Rt=2.078min.

[0555] Step 5): Compound 27d (800 mg, 0.74 mmol, 1.0 equivalence) was dissolved in tetrahydrofuran (2.0 M) of dimethylamine (10 mL, 20.00 mmol). The mixture was stirred at room temperature for 3 hours. The resulting reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography in dichloromethane / methanol (1 / 1) to give compound 27e. ESI m / z 863.4 [M+H] + .LCMS:product:Rt=1.542min.

[0556] Step 6): Compound 27e (320 mg, 0.37 mmol, 1.0 equivalence) and inter 7 (171.08 mg, 0.41 mmol, 1.1 equivalence) were dissolved in N,N-dimethylformamide (10 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (183.25 mg, 0.48 mmol, 1.3 equivalence) and N,N-diisopropylethylamine (0.19 mL, 1.11 mmol, 3.0 equivalence) were added. The reaction mixture was stirred at room temperature for 3 hours. Water (30 mL) was added to the reaction mixture and it was extracted with ethyl acetate (30 mL × 3), followed by washing with brine (30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography with petroleum ether / ethyl acetate = 1 / 5 to give compound 27f. ESI m / z 583.0 [M-Boc / 2+H] + .LCMS:product:Rt=2.065min.

[0557] Step 7): Compound 27f (130 mg, 0.10 mmol, 1.0 equivalence) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (3 mL) was added. The mixture was stirred at room temperature for 16 hours. The resulting reaction mixture was concentrated under reduced pressure to give a crude product. Compound 27 was then purified by preparative high-performance liquid chromatography (HPLC). ESI m / z 796.3 [M+H]+.LCMS:product:Rt=0.415 min. 1 H NMR(400MHz,D2O)δ7.51(d,J=4.8Hz,2H),7.38(d,J=3.6Hz,2H),6.96(d,J=14.1Hz,2H),3.97(s,4H),3.55–3.40(m,3H),3.33(dd,J=15.3, 7.8Hz,5H),3.23–3.10(m,2H),2.97–2.69(m,12H),2.53–2.28(m,5H),2.01(dd,J=32.3,8.9Hz,3H),1.83–1.61(m,4H),1.49–1.33(m,2H).

[0558] Example 28: Synthesis of Compound 28

[0559] Step 1): Compound 14f (210 mg, 0.24 mmol, 1.0 equivalence) was dissolved in dichloromethane (10 mL), and (9H-fluorene-9-yl)methyl(2-oxoethyl)carbamate (80 mg, 0.28 mmol, 1.2 equivalence), acetic acid (5 mg, 0.03 mmol, 0.1 equivalence), and sodium triacetoxyborohydride (164 mg, 0.77 mmol, 3.0 equivalence) were added. The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched with saturated sodium bicarbonate solution (20 mL) and extracted with dichloromethane (20 mL × 2). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / tert-butyl methyl ether = 1 / 1) to give compound 28a. ESI m / z 1079.6 [M+H] + .LCMS:product:Rt=1.69min.

[0560] Step 2): Compound 28a (200 mg, 0.15 mmol, 1.0 equivalence) was dissolved in dimethylamine (5 mL, 10.00 mmol, 2 M in tetrahydrofuran) and stirred at 25 °C for 2 hours. The reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give compound 28b. ESI m / z 856.6 [M+H] + .LCMS:product:Rt=1.47min.

[0561] Step 3): To a solution of N,N-dimethylformamide (5 mL) containing inter 7 (146 mg, 0.31 mmol, 1.0 equivalence), N,N-diisopropylethylamine (122 mg, 0.94 mmol, 3.0 equivalence) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethylurea hexafluorophosphate (179 mg, 0.47 mmol, 1.5 equivalence) were added, and the mixture was stirred at room temperature for 0.5 h. Compound 28b (300 mg, 0.31 mmol, 1.0 equivalence) was added, and the mixture was stirred at room temperature for 1.5 h. The mixture was diluted with water (12 mL) and extracted with ethyl acetate (5 mL × 3). The organic phases were combined, washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / methyl tert-butyl ether = 1 / 2) to give compound 28c. ESI m / z 1258.6 [M+H] + .LCMS:product:Rt=1.629min.

[0562] Step 4): Compound 28c (140 mg, 0.11 mmol, 1.0 equivalence) was added to a mixed solvent of dichloromethane (1 mL) and trifluoroacetic acid (0.5 mL). The mixture was stirred at room temperature for 18 hours. After concentration, the reaction mixture was purified by preparative high-performance liquid chromatography (preparative grade HPLC (formic acid)) to obtain compound 28. ESI m / z 395.3 [1 / 2 M + H] + .LCMS:product:Rt=0.607min. 1 H NMR(400MHz,D2O)δ7.44(d,J=11.2Hz,2H),7.35(d,J=5.8Hz,2H),7.22–7.12( m,3H),7.07(s,1H),7.02(s,1H),4.17(s,2H),3.91(s,2H),3.45(dd,J=11.6,6 .5Hz,3H),3.35–3.22(m,5H),3.19–3.04(m,2H),3.00–2.66(m,10H),2.61–2.2 3(m,7H),2.07–1.86(m,3H),1.78–1.50(m,4H),1.34(dd,J=29.6,15.7Hz,2H).

[0563] Example 29: Synthesis of Compound 29

[0564] Step 1): Compound 27e (260 mg, 0.30 mmol, 1.0 equivalence) and inter 4 (145.85 mg, 0.36 mmol, 1.2 equivalence) were dissolved in dichloromethane (5 mL), and acetic acid (0.01 mL, 0.17 mmol) was added and stirred for 30 min. Then, sodium triacetoxyborohydride (191.51 mg, 0.90 mmol, 3.0 equivalence) was added. The mixture was stirred at room temperature for 3 h. The resulting reaction mixture was added to a saturated aqueous solution of sodium bicarbonate (30 mL) and extracted with dichloromethane (30 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by dichloromethane / methanol = 10 / 1 column chromatography to give compound 29a. ESI m / z 1250.6 [M+H]+.LCMS:product:Rt = 1.800 min.

[0565] Step 2): Compound 29a (200 mg, 0.16 mmol, 1.0 equivalence) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (3 mL) was added. The mixture was stirred at room temperature for 16 hours. The resulting reaction mixture was concentrated under reduced pressure to give a crude product. This crude product was then purified by preparative high-performance liquid chromatography (formic acid) to give compound 29. ESI m / z 782.3 [M+H] + .LCMS:product:Rt=0.465min. 1 H NMR(400MHz,D2O)δ7.33(t,J=7.5Hz,1H),7.24(dd,J=13.9,6.5Hz,3H),7.05(d, J=9.5Hz,2H),4.17–4.08(m,2H),4.03–3.93(m,4H),3.54–3.32(m,6H),3.24–3.0 8(m,4H),2.90(ddd,J=27.1,21.6,12.7Hz,8H),2.80–2.69(m,4H),2.54–2.34(m ,5H),2.04(ddd,J=23.7,13.1,8.8Hz,3H),1.82–1.61(m,4H),1.51–1.33(m,2H).

[0566] Test example:

[0567] Test Example 1: Lp(a) Assembly Inhibition Detection

[0568] The cells used in this experiment were wild-type HepG2 cells and a stable cell line overexpressing Apo(a)-HEK293. Serially diluted compounds were added to 96-well plates (Corning, 3599) and combined with the conditioned medium for HepG2 cells and the conditioned medium for Apo(a)-HEK293 cells. All three were co-incubated at 37°C for 2 hours for in vitro assembly. The reaction was then terminated by adding 6-aminocaproic acid (EACA) to a final concentration of 150 mM. Lp(a) was detected using a sandwich ELISA with anti-Lp(a) capture antibody (Abcam, ab27622) and HRP-conjugated anti-ApoB detection antibody. The absorbance was read at 450 nm on an Envision microscope.

[0569] The quality control results of the compounds were evaluated using HepG2 conditioned medium (50-fold dilution) and 0.1% DMSO + 25.45 mM HCl. The percentage inhibition rate of Lp(a) assembly of the test compounds at each concentration was calculated. The data were analyzed using a concentration-inhibition rate nonlinear regression analysis in GraphPad Prism 9 to obtain the IC50 of the compounds. 50 value.

[0570] The compounds of this invention have been tested and found to have high Lp(a) assembly inhibition activity. The test results of some compounds are shown in Table 1.

[0571] Table 1

[0572] Test Example 2: Apo(a) and OxPL binding inhibition

[0573] The cells used in this experiment were HepG2 cells overexpressing Apo(a). The serially diluted compounds were incubated with Apo(a)-HepG2 cells at 37°C and 5% CO2 for 24 hours, and the cell supernatant (containing: DMEM + 10% FBS + 1% PS + 20mM HEPES) was collected. The reaction was then terminated by adding 6-aminocaproic acid (EACA) to 150mM. Apo(a)-OxPL was detected using ELISA with mouse anti-OxPL capture antibody (Creatives biolabs, HPAB-0399-YJ), rabbit anti-Lp(a) antibody (Abcam, ab242565), and HRP-conjugated anti-rabbit IgG antibody (CST, 7074S). The signal was read at 450nm on an Envision microscope.

[0574] The quality control results of the compounds were evaluated using a combination of DMEM (DMEM + 10% FBS + 1% PS + 20mM HEPES) and cell supernatant without the compounds. The percentage inhibition rate of the tested compounds against Apo(a) and OxPL binding at each concentration was calculated. The data were analyzed using a concentration-inhibition rate nonlinear regression analysis in GraphPad Prism9 to obtain the IC50 values ​​of the compounds. 50 value.

[0575] The compounds of this invention have been tested and found to have good Apo(a)-OxPL binding inhibition activity. The test results of some compounds are shown in Table 2 below.

[0576] Table 2

[0577] Test Example 3: Human plasminogen affinity MST assay

[0578] The affinity of the compound of this invention for human plasminogen was determined by micro-thermophoresis (MST) on a Nanotemper Monolith molecular interaction instrument. Human plasminogen (Active) was purchased from Abogen (Shanghai) Trading Co., Ltd. and labeled using an Alexa Fluor 647 fluorescent protein labeling kit (A20173, Invitrogen). The final concentration of the labeled protein in the assay was 5 nanomoles, and the ligand (compound) was titrated at a 1:1 dilution, starting from 500 micromoles. All binding reactants were incubated at room temperature for 5 minutes and then loaded into standard glass capillary tubes (MO-K022, Nanotemper Technologies). Protein detection was performed using the Nano Red detection channel with LED excitation power set to 80% and MST power set to high, allowing for initial fluorescence difference checks for 3 seconds before MST activation, followed by 25 seconds of thermophoresis and 1 second before MST deactivation. Data were analyzed and exported using MO.Affinity Analysis v3.0.5 software.

[0579] Tests showed that the compounds of this invention have a certain affinity for human plasminogen and high selectivity for Lp(a). Some data are shown in Table 3.

[0580] Table 3

[0581] Test Example 4: Pharmacokinetic Detection

[0582] Drug metabolism pharmacokinetic property assessment

[0583] 1. Laboratory animals

[0584] The test animals used in this study were female C57bl6j mice (6-9 weeks old, Beijing Vital River Laboratory Animal Technology Co., Ltd.), which were divided into oral and intravenous administration groups. The oral administration group was fasted overnight before administration, and was given food and free access to water 4 hours after administration of the test product.

[0585] 2. Preparation of drug formulations

[0586] According to the protocol requirements, weigh and prepare the compound to be tested. The solvent is 1% hydroxyethyl cellulose + 0.25% Tween 80 or physiological saline.

[0587] 3. Animal drug administration and sample collection

[0588] Animals were administered the prepared compound via intravenous injection or oral gavage. Whole blood was collected at 0.033, 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 h after intravenous injection and at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 h after oral administration. The blood was centrifuged at 8000 rpm for 7 min at 4 °C, and the supernatant plasma was collected and stored at -80 °C for analysis.

[0589] 4. Plasma sample testing

[0590] Dilute the analyte stock solution with pure water to prepare a series of working solutions, add them to the blank plasma matrix, and prepare a standard curve and quality control samples. Take an appropriate volume of plasma sample and add an appropriate amount of 7.5% TCA solution containing internal standard (200 nM dichloroadenosine) according to the response to precipitate proteins. After centrifuging all samples at 4000 rpm for 10 min, take an appropriate amount of supernatant, add 1% ammonia to adjust the pH to 3-4, mix well, and then perform LC-MS / MS analysis.

[0591] 5. Parameter Calculation

[0592] Based on the tested concentration, a blood drug concentration-time curve was plotted. Using WinNonlin software and a non-compartmental model, the curves were calculated, including: half-life (T1 / 2) and area under the curve (AUC). 0-t) Pharmacokinetic parameters such as clearance rate (CL), steady-state volume of distribution (Vss), and bioavailability (F) are also considered.

[0593] Drug-induced liver-to-blood ratio assessment

[0594] 1. Laboratory animals

[0595] The test animals used in this study were female C57bl6j mice (6-9 weeks old, Beijing Vital River Laboratory Animal Technology Co., Ltd.), which were divided into an oral gavage group and a non-oral group. The oral group was fasted overnight before administration of the test product, and was given food and free access to water 4 hours after administration.

[0596] 2. Preparation of drug formulations

[0597] According to the protocol requirements, weigh and prepare the compound to be tested using 1% hydroxyethyl cellulose + 0.25% Tween 80 as the solvent.

[0598] 3. Animal drug administration and blood sample collection

[0599] Animals were administered the prepared compound orally via gavage. Whole blood and liver were collected at 0.5h, 2h, 4h, 24h and 48h after administration. Whole blood was centrifuged at 8000rpm for 7min at 4℃, and the supernatant plasma was collected. Both liver and plasma were stored at -80℃ for analysis.

[0600] 4. Plasma sample testing

[0601] Dilute the analyte stock solution with pure water to prepare a series of working solutions, add them to the blank plasma matrix, and prepare a standard curve and quality control samples. Take an appropriate volume of plasma sample and add an appropriate amount of 7.5% TCA solution containing internal standard (200 nM dichloroadenosine) according to the response to precipitate proteins. After centrifuging all samples at 4000 rpm for 10 min, take an appropriate amount of supernatant, add 1% ammonia to adjust the pH to 3-4, mix well, and then perform LC-MS / MS analysis.

[0602] 5. Liver sample testing

[0603] Liver samples and blank liver samples were added to PBS at a 1:2 mass-to-volume ratio, homogenized with steel balls, and placed on ice for later use. The stock solutions of the analytes were diluted with pure water to prepare a series of working solutions, which were then added to the blank liver matrix to prepare standard curves and quality control samples. An appropriate volume of liver sample was taken, and protein precipitation was performed by adding an appropriate amount of 7.5% TCA solution containing the internal standard (200 nM dichloroadenosine) according to the response. After centrifuging all samples at 4000 rpm for 10 min, an appropriate amount of the supernatant was taken, and the pH was adjusted to 3–4 with 1% ammonia. After mixing, the samples were analyzed by LC-MS / MS.

[0604] 5. Parameter Calculation

[0605] Based on the tested concentration, a blood drug concentration-time curve was plotted. Using WinNonlin software, calculations were performed using a non-compartmental model, including: half-life (T0). 1 / 2 ), Area under the curve (AUC) 0-t Pharmacokinetic parameters such as bioavailability (F).

[0606] Tests have shown that some compounds of this invention have good pharmacokinetic parameters, and some test results are shown in Table 4.

[0607] Table 4. Plasma p-kJ parameters of the oral compound in mice.

[0608] Test Example 5: Apo(a) and OxPL binding inhibition

[0609] The cells used in this experiment were HEK293 cells overexpressing Apo(a). The serially diluted compounds were incubated with Apo(a)-HEK293 cells at 37°C and 5% CO2 for 24 hours, and the cell supernatant (containing: DMEM + 10% FBS + 1% PS + 20mM HEPES) was collected. The reaction was then terminated by adding 6-aminocaproic acid (EACA) to 150mM. Apo(a)-OxPL was detected using an ELISA assay with rabbit anti-Lp(a) capture antibody (Abcam, ab242565), human anti-OxPL antibody (E06-Fc), and HRP-conjugated anti-IgG antibody (CST, 7074). The signal was read at 450nm on an Envision microscope.

[0610] The quality control results of the compounds were evaluated using a culture medium group (DMEM + 10% FBS + 1% PS + 20mM HEPES) and a group containing cell supernatant without the compounds. The percentage inhibition rate of the tested compounds against the binding of Apo(a) and OxPL at each concentration was calculated. The data were analyzed using a concentration-inhibition rate nonlinear regression analysis in GraphPad Prism 9 to obtain the IC50 values ​​of the compounds. Some test results are shown in Table 5.

[0611] Testing showed that the compounds of this invention exhibit good Apo(a)-OxPL binding inhibitory activity. The Apo(a)-OxPL binding inhibitory activity of the compounds of this invention is significantly superior to that of reference compound 1.

[0612] Table 5 Note: Average value (n = ), where n is the number of tests.

Claims

1. A compound of formula (I), its isomers, isotopically labeled compounds, prodrugs, or pharmaceutically acceptable salts, esters, hydrates, or solvates thereof, wherein the compound of formula (I) is as follows: Rings A, B, and C are each independently selected from: C 3-10 Cycloalkyl, 5-10 membered heterocyclic, 5-10 membered aromatic heterocyclic or C 6-10 The aryl group, wherein the heteroatom of the 5-10 membered heterocyclic group or the 5-10 membered aryl heterogroup is selected from one or more of N, O, and S; optionally, the C 3-10 cycloalkyl, 5-10 membered heterocyclic, 5-10 membered aromatic heterocyclic, C 6-10 Each aryl group is independently substituted by at least one substituent selected from group G. The group G is selected from: 1)C 1-6 Alkyl, wherein C 1-6 The alkyl group is optionally selected independently from one or more of deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Substitution of alkoxy groups; 2)C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, wherein C 3-6 The cycloalkyl group and the 3-6 membered heterocyclic group are optionally each independently selected from one or more deuterium, halogen, hydroxyl, cyano, amino, or C. 1-6 Substitution of alkoxy groups; 3) Deuterium; 4)-NH2; 5) Cyano group; 6) Oxo (=O); 7) Halogens; 8) Hydroxyl group; 9)-C(=O)OC 1-6 alkyl; 10)-C(=O)R c ,in, R c Selected from C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; 11)C 1-6 Alkoxy, where C 1-6 The alkoxy group is optionally surrounded by one or more elements independently selected from halogen, hydroxyl, or C. 1-6 Substitution of alkoxy groups; L is selected from: Preferably, L is selected from Preferably, L is selected from R1, R2, and R3 are each independently selected from: C 5-10 Cycloalkyl, 5-10 membered heterocyclic group, -CH2-5-10 membered heterocyclic group, or =CH-5-10 membered heterocyclic group, wherein the heteroatom of the 5-10 membered heterocyclic group is selected from one or more heteroatoms selected from N, O, and S; optionally, the C 5-10 The cycloalkyl group and the 5-10 membered heterocyclic group are each independently substituted by at least one substituent selected from group G; wherein, the C 5-10 The cycloalkyl group is substituted with at least one amino group, and the 5-10 membered heterocyclic group contains at least one nitrogen atom; preferably, the C 5-10 Cycloalkyl groups and 5-10 membered heterocyclic groups are saturated; R4 is selected from hydrogen, deuterium, halogen, or C. 1-5 Alkyl, or R4, R3 and the atoms they are bonded to form C 5-10 Cycloalkyl, 5-10 membered heterocyclic groups, optionally C 5-10 The cycloalkyl group or 5-10 membered heterocyclic group is substituted by one or more of the following substituents: deuterium, -NH2, halogen, C 1-6 Alkyl, -OH, C 1-6 alkoxy; wherein, the C 5-10 The cycloalkyl group is substituted with at least one amino group, and the 5-10 membered heterocyclic group contains at least one nitrogen atom; preferably, the C 5-10 Cycloalkyl groups and 5-10 membered heterocyclic groups are saturated; And it meets the following conditions: 1) Rings A, B, and C are not simultaneously benzene rings; or, When rings A, B, and C are all benzene rings, L is selected from... or, When rings A, B, and C are all benzene rings, at least one of R1, R2, and R3 is selected from... or, When rings A, B, and C are all benzene rings, R4 and R3 form nitrogen-containing spirocyclic rings with the atoms they are attached to; or 2) When any two of rings A, B, and C are benzene rings, the remaining one is not a pyridine ring.

2. The compound, its isomers, isotopically labeled compounds, prodrugs, or pharmaceutically acceptable salts, esters, hydrates, or solvates according to claim 1, characterized in that, L is selected from: Preferably, L is selected from: Preferably, L is selected from: In this configuration, the key marked "#A" is connected to ring A, the key marked "#B" is connected to ring B, and the key marked "#C" is connected to ring C.

3. The compound, its isomers, isotopically labeled compounds, prodrugs, or pharmaceutically acceptable salts, esters, hydrates, or solvates thereof according to claim 1, characterized in that, At least one of ring A, ring B, and ring C is selected from a 5-membered heteroaryl group, and the heteroatom is selected from nitrogen, oxygen, or sulfur; preferably, the 5-membered heteroaryl group has one sulfur heteroatom and 0 or one nitrogen heteroatom.

4. The compound, its isomers, isotopically labeled compounds, prodrugs, or pharmaceutically acceptable salts, esters, hydrates, or solvates thereof according to claim 1, characterized in that, The group G is selected from: 1) -CH3, -CH2CH3, isopropyl, cyclopropyl; 2)-NH2; 3) F, Cl; 4) -OH, -CH2-OH; 5)-C(O)OCH3; 6) -OCH3, -CH2OCH3.

5. The compound, its isomers, isotopically labeled compounds, prodrugs, or pharmaceutically acceptable salts, esters, hydrates, or solvates thereof according to claim 1, characterized in that, Rings A, B, and C are each independently selected from C. 9-10 Fused bicyclic cycloalkyl groups, 9-10 fused bicyclic heterocyclic groups, 5-6 fused monocyclic heteroaryl groups, 9-10 fused bicyclic heteroaryl groups, phenyl groups, and naphthyl groups, wherein C 9-10 The fused bicyclic cycloalkyl, 9-10 fused bicyclic heterocyclic, 5-6 fused monocyclic heteroaryl, 9-10 fused bicyclic heteroaryl, phenyl, and naphthyl are optionally and independently substituted by 1, 2, or 3 substituents selected from group G. Preferably, ring A, ring B, and ring C are each independently selected from: in, It represents a single bond or a double bond; two adjacent chemical bonds cannot both be a double bond. The key marked with "#" is connected to L; The structures shown in Q-1, Q-3, Q-5, and Q-6 are each independently heteroaryl groups; The structures shown in Q-2 and Q-4 are each independently aryl or heteroaryl; The structures shown in Q-7 and Q-8 are each independently cycloalkyl or heterocyclic groups; Q0, Q 10 Q 11 Q 31 Each is independently selected from C or N; Q1, Q2, Q3, Q 12 Q 13 Q 14 Q 24 Q 25 Each is independently selected from CH, N, O, S, or NH; Q4, Q5, Q6, Q7, Q8, Q9, Q 15 Q 16 Q 17 Q 18 Q 19 Q 20 Q 21 Q 22 Q 23 Q 26 Q 27 Q 28 Q 29 Q 30 Q 32 Q 33 Q 37 Q 38 Q 39 Each is independently selected from CH or N; Q 34 Q 35 Q 36 Q 40 Q 41 Each is independently selected from CH2, O, S, or NH; R G The substituent is selected from any substituent in group G, wherein i is selected from 0, 1, 2, 3 or 4; Preferably, R G Selected from halogens (e.g., F, Cl), hydroxyl groups, C 1-4 Alkyl (e.g., methyl, isopropyl), C 1-4 Alkyl groups (e.g., methoxy groups), hydroxyl groups 1-4 Alkylene (e.g., -CH2OH), C 1-4 Alkoxy C 1-4 Alkylene (e.g., -CH2OCH3), C 3-6 Saturated cycloalkyl groups (e.g., cyclopropyl), -C(O)OC 1-4 Alkyl group (e.g., -C(O)OCH3); preferably, R G Selected from halogen or C 1-4 alkyl; Preferably, i is selected from 0, 1, or 2; more preferably, i is selected from 0 or 1.

6. The compound, its isomers, isotopically labeled compounds, prodrugs, or pharmaceutically acceptable salts, esters, hydrates, or solvates thereof according to claim 1, characterized in that, The 5-10 aryl heterogroups are selected from pyrrole, furanyl, thiophene, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, triazolyl, oxadiazolyl, and thiadiazolyl, preferably thiophene or thiazolyl.

7. The compound, its isomers, isotopically labeled compounds, prodrugs, or pharmaceutically acceptable salts, esters, hydrates, or solvates thereof according to claim 1, characterized in that, Ring A, ring B, and ring C are each independently selected from: The key marked with "#" is connected to L.

8. The compound, its isomers, isotopically labeled compounds, prodrugs, or pharmaceutically acceptable salts, esters, hydrates, or solvates thereof according to claim 1, characterized in that, R1, R2, and R3 are each independently selected from: C 5-7 Saturated monocyclic cycloalkyl groups, 5-7 membered saturated monocyclic heterocyclic groups, 7-9 membered saturated fused bicyclic heterocyclic groups, 7-9 membered saturated bridged bicyclic heterocyclic groups, 7-9 membered saturated spirobicyclic heterocyclic groups, -CH2-5-7 membered saturated monocyclic heterocyclic groups, or =CH-5-7 membered saturated monocyclic heterocyclic groups, wherein, Each of the cycloalkyl groups is substituted with at least one amino group, and each of the heterocyclic groups contains at least one nitrogen atom. Optionally, the cycloalkyl group and the heterocyclic group are each independently selected from deuterium, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 Substitution with cycloalkyl groups or 3-6 membered heterocyclic groups; Preferably, R1, R2, and R3 are each independently selected from: in, Indicates a single bond or a double bond; Y0 is selected from CH2 or CH; Y1, Y 14 Y 20 Y 21 Y 24 Each is independently selected from CH or N; Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, Y 10 , Y 11 , Y 12 , Y 13 , Y 15 , Y 16 , Y 17 , Y 18 , Y 19 , Y 22 , Y 23 , Y 25 , Y 26 , Y 27 , Y 28 , Y 29 , Y 30 , Y 31 , Y 32 , Y 33 , Y<2000105>are each independently selected from CH2, NH, O or S; R y Selected from C 1-6 Alkyl (preferably CH3), C 1-6 Alkoxy, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, -NH2, halogens (e.g., F, Cl), deuterium; e' is selected from 0, 1, 2, 3 or 4; The condition is that the following conditions are met: 1) When Y1 is selected from CH, and Y2, Y3, Y4, Y5, and Y6 are selected from CH2, e' is not 0, and at least one R is selected. y Selected from -NH2; 2) When Y7, Y8, Y9, Y 10 When selected from CH2, e' is not 0, and at least one R y Selected from -NH2; 3) When Y 24 Selected from CH, and Y 25 Y 26 Y 27 Y 28 Y 29 Y 30 When selected from CH2, e' is not 0, and at least one R y Selected from -NH2; 4) When Y1, Y2, Y3, Y4, Y5, and Y6 are not all carbon atoms, at least one of them must be selected from nitrogen heteroatoms; 5) When Y7, Y8, Y9, Y 10 When they are not both carbon atoms, at least one of them must be selected from nitrogen heteroatoms; 6) When Y 24 Y 25 Y 26 Y 27 Y 28 Y 29 Y 30 When they are not both carbon atoms, at least one of them must be selected from nitrogen heteroatoms; 7)Y 11 Y 12 Y 13 At least one of them is selected from nitrogen heteroatoms; 8)Y 14 Y 15 Y 16 Y 17 Y 18 At least one of them is selected from nitrogen heteroatoms; 9)Y 19 Y 20 Y 21 Y 22 Y 23 At least one of them is selected from nitrogen heteroatoms; 10)Y 31 Y 32 Y 33 Y 34 At least one of them is selected from nitrogen heteroatoms.

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

10. The compound, its isomers, isotopically labeled compounds, prodrugs, or pharmaceutically acceptable salts, esters, hydrates, or solvates thereof according to claim 1, characterized in that, R4, R3, and the atoms they are connected to form the following rings: in, Ring D is selected from 5-6 member monocyclic heterocyclic groups, C 3-6 Monocyclic cycloalkyl; Ring E is selected from 4-6 member monocyclic heterocyclic groups, C 3-6 Monocyclic cycloalkyl; Ring F is selected from 4-6 member monocyclic heterocyclic groups, C 3-6 Monocyclic cycloalkyl; Ring H is selected from 4-6 member monocyclic heterocyclic groups, C 3-6 Monocyclic cycloalkyl; R D R E R F R H Each was independently selected from C 1-6 Alkyl (preferably CH3), C 1-6 Alkoxy, C 3-6 Cycloalkyl groups, 3-6 membered heterocyclic groups, -NH2, halogens (e.g., F, Cl), or deuterium, e' is selected from 0, 1, 2, 3 or 4; The condition is that the following conditions are met: 1) When both ring D and ring E are cycloalkyl, e' is not 0, and at least one of ring D or ring E is substituted by an amino group; 2) When both ring F and ring H are cycloalkyl, e' is not 0, and at least one of ring F or ring H is substituted by an amino group; 3) When ring D and ring E are not both cycloalkyl, at least one of ring D and ring E is a nitrogen-containing heterocyclic group; 4) When ring F and ring H are not both cycloalkyl, at least one of ring F and ring H is a nitrogen-containing heterocyclic group; Preferably, R4, R3 and the atoms they are connected to form the following rings: M1, M2, M3, M4, M5, M6, and M7 are each independently selected from NH, CH2, O, and S; M8, M9, M 10 Each is independently selected from NH or CH2; R5 is selected from deuterium, -NH2, halogens, and C. 1-3 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocyclic groups, c' is selected from 0, 1, 2, 3 or 4; The condition is that the following conditions are met: 1) When M1, M2, M3, and M4 are all selected from CH2, c' is not 0, and at least one R5 is selected from -NH2; 2) When M5, M6, and M7 are all selected from CH2, c' is not 0, and at least one R5 is selected from -NH2; 3) When M8 is selected from CH2, c' is not 0, and at least one R5 is selected from -NH2; 4) When M9 is selected from CH2, c' is not 0, and at least one R5 is selected from -NH2; 5) When M 10 When the R5 is selected from CH2, c' is not 0, and at least one R5 is selected from -NH2; 6) When M1, M2, M3, and M4 are not all selected from CH2, at least one of them must be selected from NH; 7) When M5, M6, and M7 are not all selected from CH2, at least one of them must be selected from NH.

11. The compound, its isomers, isotopically labeled compounds, prodrugs, or pharmaceutically acceptable salts, esters, hydrates, or solvates thereof according to claim 1, characterized in that, R1, R2, and R3 are each independently selected from:

12. The compound, its isomers, isotopically labeled compounds, prodrugs, or pharmaceutically acceptable salts, esters, hydrates, or solvates thereof according to claim 1, characterized in that, R4, R3, and the atoms they are connected to form the following rings:

13. The compound, its isomers, isotopically labeled compounds, prodrugs, or pharmaceutically acceptable salts, esters, hydrates, or solvates thereof according to claim 1, wherein the compound has the structure shown in Formula II: in, The keys identified by "a" and "b" are located in the interpositions of ring A, and the keys identified by "c" and "d" are located in the interpositions of ring B; R1, R2, R3, R G i, Q0, Q1, Q2, Q3, ring A, and ring B are as defined in any of the preceding claims; Preferably, R1, R2, and R3 are each independently selected from pyrrolidinyl, piperidinyl, or azircycloheptyl; more preferably, R1, R2, and R3 are each independently selected from... Preferably, ring A and ring B are each independently selected from 5-membered heteroaryl, 6-membered heteroaryl, or phenyl (more preferably, both ring A and ring B are phenyl, or one of ring A and ring B is phenyl and the other is 5-membered heteroaryl), and ring A and ring B are optionally each independently separated by one or two elements selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Saturated cycloalkyl, hydroxyl, hydroxyl C 1-6 Alkylene, -C(=O)OC 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Substituents of alkylene groups; preferably, the 5-membered heteroaryl group is selected from pyrrole, furanyl, thiophene, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, triazolyl, oxadiazolyl or thiadiazolyl, preferably thiophene or thiazolyl; Preferably, The group is selected from pyrrole, furanyl, thiophene, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, triazolyl, oxadiazolyl, or thiadiazolyl, preferably thiophene or thiazolyl; more preferably, Selected from The key marked with "#" is connected to L; R G Selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Saturated cycloalkyl, hydroxyl, hydroxyl C 1-6 Alkylene, -C(=O)OC 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkylene; preferably, R G Selected from halogens, C 1-6 alkyl; i is selected from 0, 1, 2 or 3, preferably 0, 1 or 2; Preferably, Selected from 14. The compound, its isomers, isotopically labeled compounds, prodrugs, or pharmaceutically acceptable salts, esters, hydrates, or solvates thereof according to claim 1, wherein the compound has the structure shown in Formula III: in, The keys identified by "a" and "b" are located in the interpositions of ring A, the keys identified by "c" and "d" are located in the interpositions of ring B, and the keys identified by "e" and "f" are located in the interpositions of ring C. R1, R2, R3, and R4 are as defined in any of the preceding claims, provided that at least one of R1, R2, and R3 is or, R3 and R4 form Rings A, B, and C are as defined in any of the preceding claims. Preferably, rings A, B, and C are each independently selected from phenyl, pyridyl, or 5-membered heteroaryl (more preferably, rings A, B, and C are all phenyl, or at least one of rings A, B, and C is a 5-membered heteroaryl), and rings A and B are optionally each independently selected from one or two halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Saturated cycloalkyl, hydroxyl, hydroxyl C 1-6 Alkylene, -C(=O)OC 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Substituents of alkylene groups; Preferably, the 5-membered heteroaryl group is selected from pyrrole, furanyl, thiophene, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, triazolyl, oxadiazolyl, or thiazolyl; preferably thiophene or thiazolyl. More The key marked with "#" is connected to L.

15. The compound, its isomers, isotopically labeled compounds, prodrugs, or pharmaceutically acceptable salts, esters, hydrates, or solvates thereof according to claim 1, wherein the compound has the structure shown in Formula IV: in, The bonds identified by "a" and "b" are located between ring A; R1 is selected from Preferably, R1 is Ring A is selected from Preferred Preferred Preferred In this context, the keys marked with "#" correspond to the keys marked with "a", such as Q0, Q1, Q2, Q3, Q4, Q5, Q6, Q7, Q... 15 Q 16 Q 17 Q 18 Q 19 Q 20 Q 32 Q 33 Q 34 Q 35 Q 36 R G i. As defined in claim 5; preferably, Q0 is C; preferably, Q2 is selected from N, CH or S; preferably, Q2 is selected from CH and N; preferably, Q2 is selected from S; preferably, Q1 is selected from S, NH, N or O; preferably, Q1 is selected from S, NH and O; preferably, Q1 is selected from S; preferably, Q3 is CH; preferably, Q4, Q5, Q6 and Q7 are all CH; preferably, one of Q4, Q5, Q6 and Q7 is N, and the rest are CH; preferably, two of Q4, Q5, Q6 and Q7 are N, and the rest are CH; preferably, Q 15 Q 16 All are CH; preferably, Q 17 Q 18 Q 19 Q 20 All are CH; preferably, Q 17 Q 18 Q 19 Q 20 One of them is N, and the rest are CH; preferably, Q 17 Q 18 Q 19 Q 20 Two of them are N, and the rest are CH; preferably, Q 17 Q 20 For N, Q 18 Q 19 CH; preferably, Q 32 Q 33 All are CH; preferably, Q 35 CH2; preferably, Q 34 Q 36 For O; preferably, R G Selected from halogens (e.g., F, Cl) or C 1-4 Alkyl (e.g., methyl); preferably, i is selected from 0 or 1; Preferably, ring A is selected from The key marked with "#" corresponds to the key marked with "a"; Preferably, ring A is selected from The key marked with "#" corresponds to the key marked with "a"; R3 is selected from R4 is hydrogen; or R4, R3 and the atoms they are attached to form Preferably, R3 is selected from R4 is hydrogen; or R4, R3 and the atoms they are attached to form Preferably, R3 is selected from R4 is hydrogen; or R4, R3 and the atoms they are attached to form Preferably, R3 is selected from R4 is hydrogen; or R4, R3 and the atoms they are attached to form Preferably, R3 is selected from R4 is hydrogen; or R4, R3 and the atoms they are attached to form Preferably, R3 is selected from R4 is hydrogen; or R4, R3 and the atoms they are attached to form The condition is that when ring A is phenyl, R1 is tetrahydropyrrolyl, and R4 is hydrogen, R3 is not...

16. The compound, its isomers, isotopically labeled compounds, prodrugs, or pharmaceutically acceptable salts, esters, hydrates, or solvates thereof according to claim 1, wherein the compound has the structure shown in Formula V: in, The keys marked with "c" and "d" are located in the interpositions of ring B, and the keys marked with "e" and "f" are located in the interpositions of ring C; R g Selected from hydrogen, halogens (e.g., F, Cl) or C 1-4 Alkyl (e.g., methyl); preferably, R g Selected from hydrogen or C 1-4 Alkyl (e.g., methyl); preferably, R g Selected from hydrogen; R2 and R3 are each selected independently. Preferably, R2 and R3 are both Or one of R2 and R3 can be selected. The other one is selected from Rings B and C are each independently selected The key marked with "#" corresponds to the key marked with "c" or "e"; Preferably, ring B is selected from The key marked with "#" corresponds to the key marked with "c"; Preferably, ring C is selected from The key marked with "#" corresponds to the key marked with "e".

17. The compound, its isomers, isotopically labeled compounds, prodrugs, or pharmaceutically acceptable salts, esters, hydrates, or solvates thereof according to claim 1, wherein the compound has the structure shown in Formula VI: in, The keys marked with "c" and "d" are located in the interpositions of ring B, and the keys marked with "e" and "f" are located in the interpositions of ring C; R1, R2, and R3 are each independently selected Preferably, R1, R2, and R3 are all Preferably, one of R1, R2, and R3 is The rest are Rings B and C are each independently selected The key marked with "#" corresponds to the key marked with "c" or "e"; Preferably, ring B is selected from The key marked with "#" corresponds to the key marked with "c"; Preferably, ring C is selected from The key marked with "#" corresponds to the key marked with "e"; L is selected from Preferably, L is selected from The key marked with "#c" is connected to the c position corresponding to ring B, and the key marked with "#e" is connected to the e position corresponding to ring C.

18. The compound, its isomers, isotopically labeled compounds, prodrugs, or pharmaceutically acceptable salts, esters, hydrates, or solvates thereof according to claim 1, wherein the compound has the structure shown in Formula VII: in, The keys identified by "a" and "b" are located in the interpositions of ring A, the keys identified by "c" and "d" are located in the interpositions of ring B, and the keys identified by "e" and "f" are located in the interpositions of ring C. R1, R2, and R3 are each independently selected Preferably, R1, R2, and R3 are all Preferably, one of R1, R2, and R3 is The rest are Rings A, B, and C are each independently selected Preferred Preferred Preferred Among them, the key marked with "#" corresponds to the key marked with "a", "c" or "e", Q0, Q1, Q2, Q3, Q4, Q5, Q6, Q7, Q 15 Q 16 Q 17 Q 18 Q 19 Q 20 Q 32 Q 33 Q 34 Q 35 Q 36 R G i. As defined in claim 5; preferably, Q0 is C; preferably, Q2 is selected from N, CH or S; preferably, Q2 is selected from CH and N; preferably, Q2 is selected from S; preferably, Q1 is selected from S, NH, N or O; preferably, Q1 is selected from S, NH and O; preferably, Q1 is selected from S; preferably, Q3 is CH; preferably, Q4, Q5, Q6 and Q7 are all CH; preferably, one of Q4, Q5, Q6 and Q7 is N, and the rest are CH; preferably, two of Q4, Q5, Q6 and Q7 are N, and the rest are CH; preferably, Q 15 Q 16 All are CH; preferably, Q 17 Q 18 Q 19 Q 20 All are CH; preferably, Q 17 Q 18 Q 19 Q 20 One of them is N, and the rest are CH; preferably, Q 17 Q 18 Q 19 Q 20 Two of them are N, and the rest are CH; preferably, Q 17 Q 20 For N, Q 18 Q 19 CH; preferably, Q 32 Q 33 All are CH; preferably, Q 35 CH2; preferably, Q 34 Q 36 For O; preferably, R G Selected from halogens (e.g., F, Cl) or C 1-4 Alkyl (e.g., methyl); preferably, i is selected from 0 or 1; Preferably, rings A, B, and C are all Alternatively, one of rings A, B, and C can be selected from... (Preferred) The remaining two are selected from The key marked with "#" corresponds to the key marked with "a", "c" or "e"; Preferably, rings A, B, and C are each independently selected from... The key marked with "#" corresponds to the key marked with "a", "c" or "e"; Preferably, rings A, B, and C are each independently selected from... Alternatively, one of rings A, B, and C can be selected from... The remaining two are selected from The key marked with "#" corresponds to the key marked with "a", "c" or "e"; Preferably, rings A, B, and C are all Alternatively, one of rings A, B, and C can be selected from... The remaining two are selected from The key marked with "#" corresponds to the key marked with "a", "c" or "e"; L is selected from Preferably, L is selected from In this configuration, the key marked "#A" is connected to ring A, the key marked "#B" is connected to ring B, and the key marked "#C" is connected to ring C.

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

20. A pharmaceutical composition comprising the compound of any one of claims 1-19, its isomers, isotopically labeled compounds, prodrugs, or pharmaceutically acceptable salts, esters, hydrates or solvates thereof, or pharmaceutically acceptable carriers, diluents or excipients thereof.

21. The use of the compound, isomer, isotopically labeled compound, prodrug, or pharmaceutically acceptable salt, ester, hydrate or solvate thereof, or the pharmaceutical composition of claim 20, in the preparation of a medicament for the prevention and / or treatment of diseases associated with Lp(a).

22. The application according to claim 21, characterized in that, The diseases associated with Lp(a) are cardiovascular diseases, including atherosclerosis, stroke, hyperlipidemia, elevated Lp(a) levels, thrombosis, coronary heart disease, and aortic stenosis.

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