Camptothecin derivative, antibody-drug conjugate thereof and use thereof

Abstract

Disclosed are a camptothecin derivative, an antibody-drug conjugate thereof and the use thereof. Specifically provided is a camptothecin compound as represented by formula II. The camptothecin derivative, the compound formed by linking the camptothecin derivative and a linker, or the antibody-drug conjugate thereof exhibit relatively high cell killing activity, and can be used for ADC development.

Description

Camptothecin derivatives, their antibody-drug conjugates and their uses

[0001] This application claims priority to Chinese Patent Application No. 2025103735027, filed on March 27, 2025, and Chinese Patent Application No. 2025118799252, filed on December 12, 2025. The full text of the aforementioned Chinese patent applications is incorporated herein by reference. Technical Field

[0002] This invention specifically relates to camptothecin derivatives, their antibody-drug conjugates, and their uses. Background Technology

[0003] DNA topoisomerases are a class of essential enzymes widely distributed in organisms. They are a collective term for enzymes that catalyze the interconversion of DNA topological isomers, mainly divided into topoisomerase I and topoisomerase II. During the normal cell cycle, topoisomerases control DNA structural changes by catalyzing the breakage and rejoining of the phosphodiester backbone of the DNA strand. Topoisomerase I is highly expressed in various tumor cells, such as those of colon cancer, cervical cancer, and ovarian cancer, and its activity is significantly increased in S-phase tumor cells. Therefore, inhibitors of topoisomerase I activity can selectively inhibit DNA replication in proliferating tumor cells.

[0004] Studies have shown that camptothecin can inhibit DNA breakage and rejoining reactions mediated by topoisomerase I by forming a ternary complex with the DNA strand, thereby inhibiting DNA synthesis, leading to tumor cell death, and exhibiting anti-tumor activity. Due to this property, camptothecin derivatives such as irinotecan and topotecan have been developed as anti-tumor drugs for use in tumor chemotherapy.

[0005] In recent years, camptothecin derivatives have achieved great success in the application of antibody-drug conjugates (ADCs), especially Enhertu and Sacutuzumab govitecan, making the development of novel ADCs a hot topic in the field of cancer treatment.

[0006] Antibody-drug conjugates (ADCs) are therapeutic agents composed of antibodies, small molecule drugs, and linkers that conjugate the antibodies and drugs. They combine the tumor-killing activity of small molecule drugs with the high selectivity, stability, and favorable pharmacokinetic characteristics of antibodies, thereby producing a selective tumor-killing therapeutic effect.

[0007] Enhertu and Sacutuzumab govitecan use Dxd and SN38 as small molecule toxins for killing tumors, respectively. In clinical trials, several serious adverse reactions were observed, particularly interstitial lung inflammation with Enhertu and gastrointestinal toxicity with Sacutuzumab govitecan, which are believed to be highly correlated with the small molecule toxins used. Meanwhile, the linker-payload platforms related to Dxd and SN38 have not shown the same excellent efficacy in the development of other ADCs. Therefore, there remains a significant need in ADC development to develop new camptothecin-like compounds to enhance antitumor activity and mitigate adverse side effects. Summary of the Invention

[0008] The purpose of this invention is to provide a camptothecin derivative, its antibody-drug conjugate, and its uses. The camptothecin derivative, the compound formed by linking the camptothecin derivative with a linker, or its antibody-drug conjugate has high cell-killing activity and can be used in the development of ADCs.

[0009] This invention provides a camptothecin-type compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, wherein the camptothecin-type compound is a compound as shown in Formula II:

[0010] Among them, R 5 and R 6 Independent of H, D, halogen, C 1-12 Alkyl or C 1-12 alkoxy; or, R 5 and R 6 Together with the carbon atoms they are attached to, they form 5-6 membered carbon rings or 5-6 membered heterocycles;

[0011] X is -O- or -N(R) 9 )-;

[0012] R 7 For H or by one or more R 7-1 Replacement C 1-12 Alkyl; R 7-1 Independently hydroxyl, amino, or halogen;

[0013] When X is -O-, R 8 For hydrogen, C 1-12 Alkyl or with one or more R 8-1 Replacement C 1-12 Alkyl; R 8-1 Independently hydroxyl, amino, halogen, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, with one or more R 8-1-1 Replacement C3-10 cycloalkyl, with one or more R 8-1-2 Substituted 3-10 membered heterocyclic alkyl groups or -N(R) 8-1- 3 )C(O)-R 8-1-4 ;

[0014] R 8-1-1 and R 8-1-2 Independently hydroxyl, amino, or halogen;

[0015] R 8-1-3 For H, C 1-12 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, with one or more R 8a Replacement C1-C 12 Alkyl, with one or more R 8b Replacement C 3-10 cycloalkyl or with one or more R 8c Substituted 3-10 membered heterocyclic alkyl groups;

[0016] R 8-1-4 C 1-12 Alkyl or with one or more R 8d Replacement C 1-12 alkyl;

[0017] R 8a R 8b R 8c and R 8d Independently hydroxyl, amino, or halogen;

[0018] When X is -N(R) 9 When )-, R 8 and R 9 And the nitrogen and carbon atoms connected to it form 5-6 member nitrogen-containing heterocycles.

[0019] In a preferred embodiment, certain groups in the camptothecin compounds, their pharmaceutically acceptable salts, their solvates, or solvates of their pharmaceutically acceptable salts have the following definitions, and the definitions of groups not mentioned are as described in any embodiment of the present invention (hereinafter referred to as "in a certain embodiment").

[0020] In one particular scheme, R 5 and R 6 Independent of H, D, halogen, C 1-12 Alkyl or C 1-12 alkoxy; or, R 5 and R 6 Together with the carbon atoms they are attached to, they form 5-6 membered carbon rings or 5-6 membered heterocycles;

[0021] X is -O- or -N(R) 9 )-;

[0022] R 7 For one or more R 7-1 Replacement C 1-12 Alkyl; R 7-1 Independently hydroxyl, amino, or halogen;

[0023] When X is -O-, R 8 For hydrogen, C 1-12 Alkyl or with one or more R 8-1 Replacement C 1-12 Alkyl; R 8-1 Independently hydroxyl, amino, halogen, C 4-10 Cycloalkyl, 4-10 membered heterocyclic alkyl, with one or more R 8-1-1 Replacement C 4-10 cycloalkyl, with one or more R 8-1-2 Substituted 4-10 membered heterocyclic alkyl groups or -N(R) 8-1- 3 )C(O)-R 8-1-4 ;

[0024] R 8-1-1 and R 8-1-2 Independently hydroxyl, amino, or halogen;

[0025] R 8-1-3 For H, C 1-12 Alkyl, C 4-10 Cycloalkyl, 4-10 membered heterocyclic alkyl, with one or more R 8a Replacement C1-C 12 Alkyl, with one or more R 8b Replacement C 4-10 cycloalkyl or with one or more R 8c Substituted 4-10 membered heterocyclic alkyl groups;

[0026] R 8-1-4 C 1-12 Alkyl or with one or more R 8d Replacement C 1-12 alkyl;

[0027] R 8a R 8b R 8c and R 8d Independently hydroxyl, amino, or halogen;

[0028] When X is -N(R) 9 When )-, R 8 and R 9 And the nitrogen and carbon atoms connected to it form 5-6 member nitrogen-containing heterocycles.

[0029] In one particular scheme, R 5 and R 6 Independent of H, D, halogen, C 1-12 Alkyl or C 1-12 alkoxy; or, R 5 and R 6 Together with the carbon atoms they are attached to, they form 5-6 membered carbon rings or 5-6 membered heterocycles;

[0030] X is -O- or -N(R) 9 )-;

[0031] R 7 For one or more R 7-1 Replacement C 1-12 Alkyl; R 7-1 Independently hydroxyl, amino, or halogen;

[0032] When X is -O-, R 8 C 1-12 Alkyl or with one or more R 8-1 Replacement C 1-12 Alkyl; R 8-1 Independently hydroxyl, amino, halogen, C 4-10 Cycloalkyl, 4-10 membered heterocyclic alkyl, with one or more R 8-1-1 Replacement C 4-10 cycloalkyl, with one or more R 8-1-2 Substituted 4-10 membered heterocyclic alkyl groups or -N(R) 8-1-3 )C(O)-R 8-1-4 ;

[0033] R 8-1-1 and R 8-1-2 Independently hydroxyl, amino, or halogen;

[0034] R 8-1-3 For H, C 1-12 Alkyl, C 4-10 Cycloalkyl, 4-10 membered heterocyclic alkyl, with one or more R 8a Replacement C1-C 12 Alkyl, with one or more R 8b Replacement C 4-10 cycloalkyl or with one or more R 8c Substituted 4-10 membered heterocyclic alkyl groups;

[0035] R 8-1-4 C 1-12 Alkyl or with one or more R 8d Replacement C 1-12 alkyl;

[0036] R8a R 8b R 8c and R 8d Independently hydroxyl, amino, or halogen;

[0037] When X is -N(R) 9 When )-, R 8 and R 9 And the nitrogen and carbon atoms connected to it form 5-6 member nitrogen-containing heterocycles.

[0038] In one scheme, the R 5 and R 6 In, the C 1-12 Alkyl groups are independently C 1-6 Alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, and methyl, for example.

[0039] In one scheme, the R 5 and R 6 In, the C 1-12 Alkyl groups are independently C 1-6 Alkoxy groups, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy, and methoxy, for example.

[0040] In one scheme, the R 5 R 6 R 7-1 R 8-1 R 8-1-1 R 8-1-2 R 8a R 8b R 8c and R 8d In this context, the halogen is independently fluorine, chlorine, bromine, or iodine, such as fluorine.

[0041] In a certain scheme, when R 5 and R 6 When the carbon atom it is attached to forms a 5-6 membered heterocycle, the 5-6 membered heterocycle is a 5-6 membered saturated or unsaturated heterocycle with heteroatoms of O or N, and the number of heteroatoms can be 1 or 2 independently. Preferably, it is a 5-6 membered saturated or unsaturated heterocycle with heteroatoms of O and the number of heteroatoms of 2.

[0042] In one scheme, the R 7 In the context, the phrase "by one or more R" refers to... 7-1 Replacement C 1-12 The "C" in "alkyl" 1-12 "alkyl" is independently C 1-6Alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, and for example, ethyl, n-propyl, or isobutyl, preferably ethyl.

[0043] In one scheme, the R 8 R 8-1-3 and R 8-1-4 In the middle, the "C" mentioned 1-12 Alkyl group, "with one or more R 8-1 Replacement C 1-12 Alkyl group, "with one or more R 8a Replacement C1-C 12 Alkyl" and "with one or more R 8d Replacement C1-C 12 The "C" in "alkyl" 1-12 "alkyl" is independently C 1-6 Alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, and also, for example, methyl or ethyl.

[0044] In one scheme, the R 8-1 and R 8-1-3 In the text, the "3-10 membered heterocyclic alkyl group" and "with one or more R" are mentioned. 8-1-2 Substituted 3-10 membered heterocyclic alkyl groups and "substituted by one or more R groups" 8c The "3-10-membered heterocyclic alkyl" in "substituted 3-10-membered heterocyclic alkyl" is independently a 4-10-membered heterocyclic alkyl, for example, a 4-10-membered monocyclic or polycyclic (e.g., fused, bridged, or spirocyclic) heterocyclic alkyl with the heteroatom selected from N, O, or S, and the number of heteroatoms is 1, 2, or 3. Preferably, it is a 5-6-membered saturated heterocyclic alkyl with the heteroatom being O or N, and the number of heteroatoms can independently be 1 or 2.

[0045] In a certain scheme, when X is -N(R) 9 )-, R 8 and R 9 When the nitrogen atom and carbon atom connected thereto form a 5-6 member nitrogen-containing heterocycle, the 5-6 member nitrogen-containing heterocycle is a 5-6 member saturated nitrogen-containing heterocycle with N as the heteroatom and 1 heteroatom.

[0046] In one particular scheme, R 8-1 and R 8-1-3 In the middle, the "C" mentioned 3-10 "cycloalkyl", "by one or more R" 8-1-1 Replacement C 3-10 "cycloalkyl", "by one or more R" 8b Replacement C 3-10 The "C" in "cycloalkyl" 3-10 "Cycloalkyl" is independently C4-10 cycloalkyl, such as C 5-6 Cycloalkyl.

[0047] In one particular scheme, R 5 and R 6 Independent of H, halogen, C 1-6 Alkyl or C 1-6 alkoxy; or, R 5 and R 6 Together with the carbon atoms they are attached to, they form 5-6 membered heterocycles.

[0048] In one particular scheme, R 5 It is H or a halogen, preferably H.

[0049] In one particular scheme, R 6 For H, C 1-6 Alkyl or C 1-6 Alkoxy group, preferably H.

[0050] In one particular scheme, when X is -O-, R 8 For hydrogen, C 1-6 Alkyl or with one or more R 8-1 Replacement C 1-6 Alkyl; R 8-1 It is independently a 5-6 membered heterocyclic alkyl group or a 5-6 membered heterocyclic alkyl group substituted with one or more halogens; preferably a 5-6 membered heterocyclic alkyl group substituted with one or more halogens.

[0051] In one particular scheme, when X is -O-, R 8 C 1-6 Alkyl or with one or more R 8-1 Replacement C 1-6 Alkyl; R 8-1 It is independently a 5-6 membered heterocyclic alkyl group or a 5-6 membered heterocyclic alkyl group substituted with one or more halogens; preferably a 5-6 membered heterocyclic alkyl group substituted with one or more halogens.

[0052] In one particular scheme, X is -O-.

[0053] In one particular scheme, when X is -O-, R 8 C 1-6 alkyl.

[0054] In one particular scheme, R 7 For one or more R 7-1 Replacement C 1-6 Alkyl; R 7-1 It is independently hydroxyl, amino or halogen, preferably hydroxyl or amino, more preferably hydroxyl.

[0055] In one embodiment, the compound represented by formula II is a compound represented by formula II-A:

[0056] R 5 It is H or halogen;

[0057] R 6 For H, C 1-6 Alkyl or C 1-6 Alkoxy;

[0058] R 5 and R 6 Together with the carbon atoms they are attached to, they form 5-6 membered heterocycles;

[0059] R 7 For one or more R 7-1 Replacement C 1-6 Alkyl; R 7-1 It can be independently hydroxyl or amino, preferably hydroxyl;

[0060] R 8 For hydrogen, C 1-6 Alkyl or with one or more R 8-1 Replacement C 1-6 Alkyl; R 8-1 It is independently a 5-6 membered heterocyclic alkyl group or a 5-6 membered heterocyclic alkyl group substituted with one or more halogens, preferably a 5-6 membered heterocyclic alkyl group substituted with one or more halogens;

[0061] R 8 C is preferred 1-6 Alkyl or with one or more R 8-1 Replacement C 1-6 Alkyl; R 8-1 It is independently a 5-6 membered heterocyclic alkyl group or a 5-6 membered heterocyclic alkyl group substituted with one or more halogens, preferably a 5-6 membered heterocyclic alkyl group substituted with one or more halogens;

[0062] R 8 C is preferred. 1-6 alkyl.

[0063] In one particular scheme, R 5 It can be H or F.

[0064] In one particular scheme, R 6 It can be H, methyl, or methoxy.

[0065] In one particular scheme, R 5 and R 6 Together with the carbon atoms they are attached to form ( (Represents bonds shared with the parent nucleus structure).

[0066] In one scheme, -XR 7 for

[0067] In one particular scheme, R 8 For hydrogen, ethyl, Preferably ethyl,

[0068] In a certain scheme, when X is -N(R) 9 When )-, R 7 For H, -CH2CH2OH or -CH2CH2NH2, R 8 and R 9 And the nitrogen and carbon atoms it connects to form a 6-membered nitrogen-containing saturated heterocycle.

[0069] In one possible solution, X is -N(R) 9 When )-, R 7 For -CH2CH2OH, R 8 and R 9 And the nitrogen and carbon atoms it is connected to form a 6-membered nitrogen-containing saturated heterocycle.

[0070] In one embodiment, the compound represented by formula II is a compound represented by formula II-B:

[0071] Among them, R 5 and R 6 The definition is independent as described in any embodiment of the present invention;

[0072] Ideally, R 5 It is a halogen; R 6 C 1-6 Alkyl or C 1-6 Alkoxy;

[0073] Or R 5 and R 6 Together with the carbon atoms they are attached to, they form 5-6 membered heterocycles.

[0074] In one embodiment, the compound represented by formula II is a compound represented by formula II-C:

[0075] R 5 It is a halogen;

[0076] R 6 For H or C 1-6 alkyl;

[0077] R 7For H or by one or more R 7-1 Replacement C 1-6 Alkyl; R 7-1 It is independently a hydroxyl or amino group, preferably a hydroxyl group.

[0078] This invention provides a camptothecin-type compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, wherein the camptothecin-type compound is any one of the following compounds:

[0079] The present invention also provides compounds as shown in Formula III as follows:

[0080] Compound II, as previously defined, connects with the linker precursor L via... Linkage; where O originates from the hydroxyl group in compound II, and NH originates from the linker precursor L;

[0081] Alternatively, compound II can interact with linker precursor L via... Linkage; where NH comes from the amino group in compound II, and C(O) comes from the linker precursor L.

[0082] In this invention, the linker precursor refers to a group at one end that has been linked to the payload molecule in the drug conjugate, but at the other end has not yet been linked to an antibody group; after the other end of the linker precursor is linked to the antibody, the linker precursor forms a linker in the drug conjugate that links the antibody and the payload molecule; the linker may or may not be cleavable.

[0083] In one particular scheme, the hydroxyl group in "O originates from the hydroxyl group in compound II" refers to R. 7 Or R 8 Any hydroxyl group in it, preferably R 7 The hydroxyl group in it.

[0084] In one scheme, the amino group in "NH is derived from the amino group in compound II" refers to R. 7 Or R 8 Any amino group in it, preferably R 7 The amino group in it.

[0085] In one particular scheme, L is LD is a commonly used connector in the ADC field, and the linker precursor is linked to the antibody via LD; LD can link the antibody to L 1 (if it exists) or L 2 L 1 For single keys or connecting units; L 2It is a single amino acid residue or a short peptide composed of 2-10 amino acid residues, wherein the amino acid is a natural amino acid or a non-natural amino acid; L 3 It is a spacer.

[0086] In one scheme, LD is Ring A is a 5-6 membered heteroolefin ring or a 5-6 membered heteroaromatic ring, wherein one or more carbon atoms in the 5-6 membered heteroolefin ring are replaced by C(O); the heteroatom types of the 5-6 membered heteroolefin ring and the 5-6 membered heteroaromatic ring are independently selected from one, two, or three of N, O, and S; the number of heteroatoms is independently one, two, or three; R L It is a leaveable group, such as -S(O)2-C 1-6 Alkyl group; p is 0 or 1.

[0087] In one of the schemes, L 1 Independently Each Z is independently C 1-6 Alkylene; each t is an independent integer from 1 to 16; preferably, L 1 Bit "1" is connected to ring A; bit "2" is connected to L. 2 connect.

[0088] In one of the schemes, L 2 Independently, it is a single amino acid residue, dipeptide residue, tripeptide residue, or tetrapeptide residue, wherein the carbonyl group in the single amino acid residue, dipeptide residue, tripeptide residue, or tetrapeptide residue may further be combined with... The NH group in the residue is linked to the NH group; preferably, the carbonyl group in the individual amino acid residue, dipeptide residue, tripeptide residue, and tetrapeptide residue is linked to the L group. 3 Connection; the NH and L in the individual amino acid residues, dipeptide residues, tripeptide residues and tetrapeptide residues 1 connect.

[0089] In one particular scheme, R L In the context, the -S(O)2-C 1-6 C in alkyl 1-6 Alkyl group is C 1-4 Alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, and methyl, for example.

[0090] In one embodiment, in ring A, the number of alkene bonds in the 5-6 membered heteroolefin ring is one or two, for example, one; the heteroatom in the 5-6 membered heteroolefin ring can be N, and the number of heteroatoms can be one or two, for example, one; for another example

[0091] In one embodiment, in ring A, the heteroatom type of the 5-6 membered heteroaromatic ring is N, and the number of heteroatoms can be 1, 2 or 3, for example 2; another example is a pyridine ring, pyrimidine ring, pyrazine ring or pyridazine ring, and yet another example is a pyrimidine ring.

[0092] In one scheme, in Z, the C 1-6 The alkylene group is a straight-chain alkylene group; for example... For example

[0093] In one particular scheme, R L -S(O)2-C 1-4 Alkyl; preferably -S(O)2-methyl; p is 1.

[0094] In one embodiment, ring A is independently a 5-6 membered heteroolefin ring or a 5-6 membered heteroaromatic ring, wherein the heteroatom in the 5-6 membered heteroolefin ring is N, and the number of heteroatoms is 1 or 2; one or more carbon atoms in the 5-6 membered heteroolefin ring are replaced by C(O); the heteroatom in the 5-6 membered heteroaromatic ring is N, and the number of heteroatoms is 1, 2 or 3; preferably, ring A is independently a 5-6 membered heteroaromatic ring, wherein the heteroatom in the 5-6 membered heteroaromatic ring is N, and the number of heteroatoms is 1, 2 or 3.

[0095] In a given scheme, t is independently 1, 2, 3, 4, 5, 6, 7, or 8, for example, 4 or 8.

[0096] In one of the schemes, L 1 Independently Among them, bit "1" is connected to ring A; bit "2" is connected to L. 2 connect.

[0097] In one of the schemes, L 2 In this context, the amino acid in the individual amino acid residue, dipeptide residue, tripeptide residue, or tetrapeptide residue is independently selected from glycine, phenylalanine, alanine, valine, or... Glycine or phenylalanine are preferred.

[0098] In one of the schemes, L 2 It is a tetrapeptide residue, in which the carbonyl group is related to L 3 Linkage; the NH and L residues in the tetrapeptide 1 connect.

[0099] In one approach, when compound II reacts with linker precursor L via... During connection, L 3 for Among them, NH and L 2 connect;

[0100] Compound II and linker precursor L via During connection, L 3 It does not exist.

[0101] In one of the solutions, for

[0102] In one embodiment, compound II of compound III satisfies the following definition:

[0103] R 5 and R 6 Independent of H, halogen, C 1-6 Alkyl or C 1-6 alkoxy; or, R 5 and R 6 Together with the carbon atoms it is attached to, they form a 5-6 membered heterocycle; preferably H;

[0104] X is -O- or -N(R) 9 -; preferably -O-;

[0105] R 7 For one or more R 7-1 Replacement C 1-6 Alkyl; R 7-1 Independently, it is a hydroxyl group;

[0106] When X is -O-, R 8 C 1-6 alkyl;

[0107] When X is -N(R) 9 When )-, R 8 and R 9 And the nitrogen and carbon atoms connected to it form 5-6 member nitrogen-containing heterocycles.

[0108] In one embodiment, compound II is present in compound III.

[0109] In one embodiment, compound III is any of the following compounds:

[0110] The present invention also provides an antibody-drug conjugate, wherein the antibody-drug conjugate is as follows:

[0111] d is a natural number or decimal between 1 and 8;

[0112] As previously described, compound II is connected to linker G in the same way as compound II is connected to linker precursor L.

[0113] It should be noted that T is linked to G via a compound coupling method understood by those skilled in the art; for example, T is linked to ring B via S on it. Those skilled in the art will understand that one end of G is linked to the thiol group contained in T (antibody) after the disulfide bond is opened (e.g., the disulfide bond can be opened by reducing it with the reducing agent TCEP, generating a thiol group -SH). In other words, the -S- between G and T is not an additional external sulfur atom. The linker can be a degradable or non-degradable linker fragment; one end is linked to compound II; the other end is linked to antibody T.

[0114] In one scheme, the connector G is Among them, LD, L 1 L 2 and L 3 The definition is as described in any of the aforementioned schemes.

[0115] In one scheme, -LD- is Preferably, bit "1" is connected to T, and bit "2" is connected to L. 1 connect.

[0116] In one protocol, T stands for anti-HER2 antibody, such as trastuzumab.

[0117] In one scheme, d is a natural number and / or decimal between 7 and 8; for example, 7.37, 7.83, 7.68, 7.71, 7.90, 7.92, 7.82, 7.52, 7.90, 7.73, 7.60, 7.12 or 7.94; and for another example, 7.37, 7.83 or 7.68.

[0118] In one embodiment, the antibody-drug conjugate is any of the following compounds:

[0119] Where T represents trastuzumab, and d is defined as described in any of the preceding items;

[0120] Preferably, the antibody-drug conjugate is any of the following compounds:

[0121] T stands for trastuzumab.

[0122] The present invention also provides a pharmaceutical composition comprising:

[0123] (1) (Therapeuticly effective amounts) of the compound of formula II as described in any one of the present invention, or a pharmaceutically acceptable salt thereof, or a compound of formula III as described in the present invention, or an antibody-drug conjugate; and

[0124] (2) Pharmaceutical excipients.

[0125] The present invention also provides (therapeuticly effective amount) of a compound as shown in Formula II or a pharmaceutically acceptable salt thereof, a compound as shown in Formula III or a pharmaceutically acceptable salt thereof, or an antibody-drug conjugate; or the use of the above-described pharmaceutical compositions in the preparation of a medicament for the prevention and / or treatment of cancer; wherein the cancer is preferably gastric cancer, pancreatic cancer, lung cancer, or breast cancer.

[0126] This invention provides the use of the antibody-drug conjugate as described in any one of the present invention in the preparation of a medicament for the prevention and / or treatment of cancers associated with the trastuzumab target; wherein the cancers associated with the trastuzumab target are preferably gastric cancer, pancreatic cancer, lung cancer, or breast cancer.

[0127] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0128] The reagents and raw materials used in this invention are all commercially available.

[0129] The positive and progressive effects of this invention are that the compounds of this invention have high cell-killing activity and can be used in the development of ADCs. Detailed Implementation

[0130] The present invention will be described in detail below with reference to embodiments, but this does not imply any adverse limitation on the invention. The present invention has been described in detail, and specific embodiments thereof have been disclosed. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the concept and scope of the invention.

[0131] Example 1 C001 Synthesis Route

[0132] Preparation process:

[0133] Step 1: Synthesis of Compound 2

[0134] Compound 1 (5 g, 35.94 mmol) and hexamethylenetetramine (6.05 g, 43.13 mmol) were dissolved in trifluoroacetic acid (25 mL), and the reaction mixture was stirred at 90°C for 16 hours (under nitrogen protection). TLC showed the starting material disappearing and a new spot appearing. The reaction mixture was evaporated to dryness, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether 1:10 to 1:3) to give compound 2 (1.86 g, yield: 30.97%).

[0135] Step 2: Synthesis of Compound 4

[0136] Compound 2 (1.36 g, 8.14 mmol) was dissolved in acetonitrile (25 mL), followed by the addition of 2-bromoethanol (3.18 g, 24.14 mmol) and potassium carbonate (3.41 g, 24.41 mmol). The reaction mixture was stirred at 80°C for 16 hours. LC-MS showed that the reaction was complete. The reaction mixture was washed with dichloromethane (50 mL x 3) and water (50 mL), and the organic phase was dried, filtered, and concentrated to give crude compound 4 (1.72 g, yield: 100.09%).

[0137] LCMS(ESI): m / z, 212.2 [M+H] +

[0138] Step 3: Synthesis of Compound 5

[0139] Compound 4 (1.70 g, 8.05 mmol), iron powder (2.26 g, 40.25 mmol), and ammonium chloride (4.39 g, 80.50 mmol) were dissolved in ethanol (60 mL) and water (30 mL). The reaction mixture was stirred at 80°C for 2 hours. LC-MS showed that the reaction was complete. After filtration, the filtrate was washed with dichloromethane (50 mL x 3) and water (50 mL), and the organic phase was concentrated to give crude compound 5 (1.14 g, yield: 78.15%).

[0140] LCMS(ESI): m / z, 182.1 [M+H] +

[0141] Step 4: Synthesis of Compound 7

[0142] Compound 5 (684 mg, 3.78 mmol) was dissolved in toluene (15 mL), and compound 6 (1.05 g, 3.78 mmol) and pyridine 4-methylbenzenesulfonic acid (968.03 mg, 3.78 mmol) were added. The reaction mixture was stirred at 120°C for 16 hours. LC-MS showed that the reaction was complete. After the reaction mixture was evaporated to dryness, the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol 20:1 to 10:1) to give compound 7 (984 mg, yield: 38.29%).

[0143] LCMS(ESI): m / z, 409.1 [M+H] +

[0144] Step 5: Synthesis of compound C001

[0145] Compound 7 (984 mg, 2.41 mmol) was dissolved in acetic acid (20 mL), and sulfuric acid (5 mL, 18.4 M) was slowly added dropwise at 0°C while stirring for 10 minutes to obtain solution A. Ferrous sulfate heptahydrate (811.90 mg, 2.89 mmol) was dissolved in water (30 mL) to obtain solution B. Solution A was slowly added dropwise to solution B at 0°C, followed by the sequential addition of formaldehyde (736.50 mg, 12.05 mmol) and hydrogen peroxide (1.37 g, 12.05 mmol, 30%). The reaction mixture was stirred at 0°C for 1 hour. LC-MS showed that the reaction was complete. The reaction mixture was poured into water (20 mL) at 0°C and extracted with dichloromethane (50 mL x 3). The organic phase was dried, filtered, and concentrated. The residue was used to prepare compound C001 (55 mg, Yield: 5.23%) by high-performance liquid chromatography.

[0146] The preparation conditions for high-performance liquid chromatography are as follows:

[0147] (Preparative chromatography manufacturer: Shimadzu, model: LC-20AP. Column: YMC-Triart Prep C18 250*50mm*7um. Mobile phase: water (0.225% HCOOH)-acetonitrile, elution ratio of water from 1% to 24%).

[0148] LCMS(ESI): m / z, 437.1 [M+H] +

[0149] 1H NMR (400MHz, DMSO-d6) δ7.70(d,J=4.3Hz,2H),7.29(s,1H),7.14(p,J=4.7Hz,1H),5.44(s,2H),5.28(s,2H),4.21(t,J=4.9Hz,2H), 3.90(t,J=4.9Hz,2H), 3.42(ddd,J=10.6,7.7,4.4Hz,2H), 1.96–1.79(m,J=7.2Hz,2H), 1.33(t,J=7.3Hz,3H), 0.88(t,J=7.3Hz,3H).

[0150] Example 2: C002 Synthesis Route

[0151] Preparation process:

[0152] Step 1: Synthesis of Compound 2

[0153] Compound 1 (7.70 g, 55.35 mmol) and hexamethylenetetramine (9.31 g, 66.42 mmol) were dissolved in trifluoroacetic acid (38 mL), and the reaction mixture was stirred at 90°C for 16 hours (under nitrogen protection). TLC showed that the starting material disappeared and a new spot appeared. The reaction mixture was evaporated to dryness, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether 1:10 to 1:3) to give compound 2 (3.20 g, yield: 34.59%).

[0154] 1 H NMR (400MHz, DMSO-d6) δ11.50(s,1H),10.28(s,1H),7.75–7.59(m,1H),7.37–7.25(m,2H).

[0155] Step 2: Synthesis of Compound 3

[0156] Compound 2 (3.20 g, 19.15 mmol) was dissolved in acetonitrile (60 mL), followed by the addition of 2-bromoethanol (24.92 g, 191.15 mmol) and potassium carbonate (8.02 g, 57.44 mmol). The reaction mixture was stirred at 80°C for 16 hours. LC-MS showed that the reaction was complete. The reaction mixture was diluted with water (200 mL), extracted with dichloromethane (200 mL x 3), dried, filtered, and concentrated to give crude compound 3 (5.00 g), which was used directly in the next step.

[0157] LCMS(ESI): m / z, 212.2 [M+H] +

[0158] Step 3: Synthesis of Compound 4

[0159] Compound 3 (5.00 g, 23.68 mmol) was dissolved in ethanol (100 mL) and water (50 mL), and iron powder (6.64 g, 118.39 mmol) and ammonium chloride (12.73 g, 236.78 mmol) were added. The reaction mixture was stirred at 80°C for 2 hours. LC-MS showed that the reaction was complete. After filtration, the filtrate was diluted with water (100 mL), extracted with dichloromethane (100 mL x 3), and the organic phase was concentrated to give crude compound 4 (2.10 g, yield: 48.95%).

[0160] LCMS(ESI): m / z, 182.1 [M+H] +

[0161] Step 4: Synthesis of Compound 6

[0162] Compound 4 (2.10 g, 5.80 mmol) was dissolved in toluene (30 mL), and compound 5 (1.61 g, 5.80 mmol) and pyridine 4-methylbenzenesulfonic acid (1.49 g, 5.80 mmol) were added. The reaction mixture was stirred at 120 °C for 16 hours. LC-MS showed that the reaction was complete. After the reaction mixture was evaporated to dryness, the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol 20:1 to 10:1) to give compound 6 (1.50 g, yield: 63.38%).

[0163] LCMS(ESI): m / z, 409.1 [M+H] +

[0164] Step 5: Synthesis of Compound 7

[0165] Compound 6 (800 mg, 1.96 mmol) was dissolved in acetic acid (16 mL), and sulfuric acid (3.80 mL, 95%) was slowly added dropwise at 0°C. The reaction mixture was stirred at 0°C for 10 minutes to obtain solution A. Ferrous sulfate heptahydrate (660.09 mg, 2.35 mmol) was dissolved in water (20 mL) to obtain solution B. Solution A was slowly added dropwise to solution B at 0°C, followed by the sequential addition of formaldehyde (598.78 mg, 9.79 mmol) and hydrogen peroxide (1.11 g, 9.79 mmol, 30%). The reaction mixture was stirred at 0°C for 1 hour. LC-MS showed that the reaction was complete. The reaction solution was poured into water (20 mL) at 0°C and extracted with dichloromethane (50 mL x 3). The organic phase was dried, filtered, and concentrated. The residue was purified by silica gel column chromatography (C18) (ISCO, R-330g SepaFlash Silica Flash Column, Eluent of 5-35% CH3CN@80 mL / min) to obtain compound 7 (240.00 mg, Yield: 28.07%).

[0166] LCMS(ESI): m / z, 437.1 [M+H] +

[0167] Step 6: Synthesis of Compound 8

[0168] Compound 7 (184.24 mg, 422.13 μmol) was dissolved in dichloromethane (5 mL), and 4-dimethylpyridine (104.19 mg, 844.26 μmol) was added. p-Toluenesulfonyl chloride (97.55 mg, 506.56 μmol) was added at 0°C. The reaction mixture was stirred at room temperature for 16 hours. LC-MS showed the reaction was complete. After the reaction mixture was evaporated to dryness, the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol 20:1 to 10:1) to give compound 8 (160.00 mg, yield: 64.17%).

[0169] LCMS(ESI): m / z, 591.1 [M+H] +

[0170] Step 7: Synthesis of Compound 9

[0171] Compound 7 (140 mg, 237.03 μmol) was dissolved in N,N dimethylformamide (5 mL), and sodium azide (60 mg, 913.71 μmol) was added. The reaction mixture was stirred at room temperature for 16 hours. LC-MS showed that the reaction was complete. The filtrate was diluted with water (50 mL), extracted with ethyl acetate (50 mL x 3), dried over the organic phase, filtered, and concentrated to give crude compound 9 (140 mg, crude, yield: 127.99%).

[0172] LCMS(ESI): m / z, 462.2 [M+H] +

[0173] Step 8: Synthesis of compound C002

[0174] Compound 9 (160 mg, 346.71 μmol) was dissolved in methanol (5 mL), and palladium on carbon (40 mg, 5%, 18.79 μmol) was added. The reaction solution was purged three times with hydrogen and stirred at room temperature under a hydrogen atmosphere for 30 minutes. LC-MS showed that the reaction was complete. The reaction solution was filtered, evaporated to dryness, and the residue was purified by high-performance liquid chromatography (preparative chromatograph manufacturer: Shimadzu, model R1; column: YMC-Triart Prep C18 150*30mm*10um; mobile phase: water (0.225% FA)-acetonitrile; elution ratio of water from 10% to 40%) to obtain compound C002 (27.57 mg, yield: 18.26%).

[0175] LCMS(ESI): m / z, 436.2 [M+H] +

[0176] 1 H NMR(400MHz,DMSO-d6)δ8.33(s,1H),7.77–7.67(m,2H),7.30(s,1H),7.21–7.13(m,1H),5.44(s,2H),5.29(s,2H),4. 26(s,4H),3.41–3.34(m,2H),3.20(s,2H),1.97–1.78(m,J=7.3Hz,2H),1.33(t,J=7.3Hz,3H),0.88(t,J=7.3Hz,3H).

[0177] Example 3 Synthetic route of C004-R

[0178] Preparation process:

[0179] Step 1: Synthesis of Compound 2

[0180] Compound 1 (25 g, 111.97 mmol) was dissolved in tetrahydrofuran (150 mL), and then 1 M tert-butyllithium (168 mL) was added dropwise to the solution at -70 °C under a nitrogen atmosphere. The reaction mixture was stirred at -20 °C for 2 h, followed by the addition of propionaldehyde (6.50 g, 111.97 mmol) at -70 °C. The reaction mixture was stirred at -20 °C for 5 h under a nitrogen atmosphere. The target product was detected by liquid chromatography-mass spectrometry (LCMS). The solution was quenched with water and extracted with ethyl acetate (100 mL x 3), washed with brine, and the organic phase was dried over anhydrous sodium sulfate. The filtrate was concentrated under vacuum, and the residue was purified by rapid column chromatography (FCC, tetrahydrofuran: petroleum ether = 10-20%) to give compound 2 (10.60 g, 37.68 mmol, 33.65% yield).

[0181] LC-MS (ESI) [M+Na] + =304.3

[0182] 1 H-NMR(400MHz,CHLOROFORM-D)δ8.56(s,1H),7.66(d,J=8.4Hz,1H),7.18(t,J=8.4Hz,1H),6.56(d,J=8.4Hz,1H),5.38-5 .33(m,1H),3.78(s,3H),2.23(d,J=3.6Hz,1H),1.96-1.85(m,1H),1.82-1.71(m,1H),1.51(s,9H),0.93(t,J=7.2Hz,3H)

[0183] Step 2: Synthesis of Compound 3

[0184] Compound 2 (9.6 g, 34.12 mmol) and DMP (17.36 g, 40.95 mmol) were dissolved in dichloromethane (100 mL). The reaction mixture was stirred at 25 °C for 12 hours. The target product was detected by liquid chromatography-mass spectrometry (LC-MS). The solution was quenched with aqueous sodium thiosulfate and extracted with ethyl acetate (50 mL x 3), washed with brine, and dried over anhydrous sodium sulfate. The filtrate was concentrated under vacuum, and the residue was purified by rapid column chromatography (FCC, tetrahydrofuran: petroleum ether = 0-10%) to give compound 3 (8.60 g, 30.79 mmol, 90.23% yield).

[0185] LC-MS(ESI)[M+H-100] + / [M+Na] + =180.3 / 302.8

[0186] 1 H-NMR(400MHz,CHLOROFORM-D)δ9.23(s,1H),7.85(d,J=8.4Hz,1H),7.34(t,J=8.4Hz,1H),6 .61(d,J=8.4Hz,1H),3.86(s,3H),2.94(q,J=7.2Hz,2H),1.50(s,9H),1.16(t,J=7.2Hz,3H)

[0187] Step 3: Synthesis of Compound 4

[0188] Compound 3 (8.6 g, 30.79 mmol) was dissolved in 4 M HCl / 1,4-dioxane solution (90 mL). The reaction mixture was stirred at 25 °C for 12 hours. The target product was detected by liquid chromatography-mass spectrometry (LC-MS). The solution was concentrated under vacuum to give crude compound 4 (5.00 g, 23.18 mmol, 75.30% yield, HCl salt), which could be used directly in the next reaction.

[0189] LC-MS(ESI)[M+H] + =180.2

[0190] Step 4: Synthesis of Compound 5

[0191] Compound 4 (1.02 g, 5.70 mmol), compound 5a (1 g, 3.80 mmol), and p-toluenesulfonic acid monohydrate (433.06 mg, 2.28 mmol) were dissolved in toluene (20 mL). The reaction mixture was heated to 110 °C with stirring and reacted for 12 hours. The target product was detected by liquid chromatography-mass spectrometry (LC-MS). The solution was concentrated under vacuum to obtain a crude product. The crude product was dissolved in methanol (5 mL), and a solid precipitated out. The solid was filtered. The solid was concentrated under vacuum to obtain compound 5 (1.20 g, 2.95 mmol, 77.72% yield).

[0192] LC-MS(ESI)[M+H] + / [2M+H] + =407.3 / 835.6

[0193] Step 5: Synthesis of compound int.1

[0194] Compound 5 (1.2 g, 2.95 mmol) was dissolved in 20 mL of 48% hydrobromic acid aqueous solution. The reaction mixture was heated to 110 °C with stirring and continued to react for 12 hours. The target product was detected by liquid chromatography-mass spectrometry (LC-MS). The solution was concentrated under vacuum, and the residue was purified by preparative high-performance liquid chromatography (Pre-HPLC) using a Durashell C18(L) 10 μm Octopus PLUS column (21.2 × 250 mm, Waters Corporation). Gradient elution was performed over 30 minutes, transitioning from a 35% acetonitrile-water system to a 60% acetonitrile-water system, with the aqueous phase containing 0.1% formic acid, to finally obtain Int.1 (930.00 mg, 2.37 mmol, 80.27% yield).

[0195] LC-MS(ESI)[M+H] + / [2M+H] + =393.3 / 807.5

[0196] 1 H-NMR(400MHz,DMSO-D6)δ7.60-7.59(m,2H),7.28(s,1H),7.05-7.01(m,1H),6.53(s,1H),5.44(s, 2H),5.29(s,2H),3.45-3.37(m,2H),1.92-1.81(m,2H),1.34(t,J=7.2Hz,3H),0.88(t,J=7.2Hz,3H)

[0197] Step 6: Synthesis of compound C004-R

[0198] Compound Int.1 (300 mg, 764.52 μmol) was dissolved in a 1:1 volume mixture of tetrahydrofuran (2 mL) and water (2 mL). Compound 6 (222.01 mg, 3.82 mmol) and NaOH (91.74 mg, 2.29 mmol) were then added to this solution. The reaction mixture was heated to 40 °C with stirring and reacted for 9 hours. The target product was detected by liquid chromatography-mass spectrometry (LC-MS). The solution was concentrated under vacuum, and the residue was purified by preparative high-performance liquid chromatography (Pre-HPLC) using a Durashell C18(L) 10 μm Octopus PLUS column (21.2 × 250 mm, Waters Corporation). A gradient elution from 30% acetonitrile-water to 50% acetonitrile-water was performed over 30 minutes, with the aqueous phase containing 0.1% formic acid, yielding 120 mg of product. The 120 mg product was purified again by preparative high-performance liquid chromatography (Pre-HPLC). This time, a Nanochrom ChromCore C18 column (21.2 × 250 mm, 10 μm, Waters Corporation) was used. Gradient elution from 35% acetonitrile-water to 39% acetonitrile-water was performed over 10 minutes. The aqueous phase contained 0.1% formic acid, and the flow rate was 20 mL / min. The final product was compound C004-R (37.40 mg, 83.02 μmol, 10.86% yield).

[0199] LC-MS(ESI)[M+H] + =451.3

[0200] 1 H-NMR (400MHz, DMSO-D6) δ7.72-7.67(m,2H),7.29(s,1H),7.14(q,J=3.2Hz,1H),6.53(s,1H),5.44(s,2H),5.29(s,2H),4.99(d,J=4.8Hz,1H), 4.18-4.13(m,1H),4.05(d,J=5.2Hz,2H),3.55-3.45(m,1H),3.39(t,J= 7.6Hz,1H),1.94-1.80(m,2H),1.34-1.27(m,6H),0.88(t,J=7.2Hz,3H)

[0201] Example 4: Synthetic route of C004-S

[0202] Preparation process:

[0203] Step 1: Synthesis of compound C004-S

[0204] Compound Int.1 (170 mg, 433.23 μmol) and NaOH (51.98 mg, 1.30 mmol) were dissolved in a mixed solution of tetrahydrofuran (2 mL):H₂O (2 mL), followed by the addition of (2S)-2-methylethylene oxide (125.81 mg, 2.17 mmol). The reaction mixture was heated to 40 °C with stirring and reacted for 12 hours. The target product was detected by liquid chromatography-mass spectrometry (LC-MS). The solution was concentrated under vacuum, and the residue was purified by preparative high-performance liquid chromatography (Pre-HPLC) using a Durashell C18(L) 10 μm Octopus PLUS column (21.2 × 250 mm, Waters Corporation). Gradient elution from 30% acetonitrile-water to 60% acetonitrile-water was performed over 30 minutes, with the aqueous phase containing 0.1% formic acid, to give compound C004-S (59.70 mg, 127.09 μmol, 29.34% yield).

[0205] LC-MS(ESI)[M+H] + =451.4

[0206] 1 H-NMR (400MHz, DMSO-D6) δ7.72-7.68(m,2H),7.29(s,1H),7.14(q,J=3.2Hz,1H),6.55(s,1H),5.44(s,2H),5.29(s,2H),5.00(d,J=3. 6Hz,1H),4.15(d,J=4.0Hz,1H),4.05(d,J=5.2Hz,2H),3.51-3.40(m,2H),1.94-1.80(m,2H),1.34-1.28(m,6H),0.88(t,J=7.2Hz,3H)

[0207] Example 5: Synthesis route of C005

[0208] Preparation process:

[0209] Synthesis of compound C005

[0210] Compound Int.1 (250 mg, 637.10 μmol) and NaOH (76.45 mg, 1.91 mmol) were dissolved in a 1:1 mixture of tetrahydrofuran (2 mL):H₂O (2 mL). Then, 2,2-dimethylethylene oxide (459.38 mg, 6.37 mmol) was added to this solution. The reaction mixture was heated to 45 °C with stirring and reacted for 12 hours. The target product was detected by liquid chromatography-mass spectrometry (LC-MS). The solution was concentrated under vacuum, and the residue was purified by preparative high-performance liquid chromatography (Pre-HPLC) using a Durashell C18(L) 10 μm Octopus PLUS column (21.2 × 250 mm, Waters Corporation). Gradient elution from 30% acetonitrile-water to 60% acetonitrile-water was performed over 30 minutes, with the aqueous phase containing 0.1% formic acid, to finally obtain compound C005 (77.40 mg, 154.80 μmol, 24.30% yield).

[0211] LC-MS(ESI)[M+H] + =465.4

[0212] 1 H-NMR (400MHz, DMSO-D6) δ7.75-7.71(m,2H),7.30(s,1H),7.18(dd,J=6.8,2.4Hz,1H),6.55(s,1H),5.44(s,2H),5.3 2(s,2H),4.78(s,1H),3.98(s,2H),3.57-3.47(m,2H),1.92-1.79(m,2H),1.32(q,J=7.2Hz,9H),0.88(t,J=7.2Hz,3H)

[0213] Example 6 Synthesis route of C003

[0214] Preparation process:

[0215] Compound Int.1 (250 mg, 637.10 μmol) and K₂CO₃ (263.76 mg, 1.91 mmol) were dissolved in acetonitrile (3 mL), followed by the addition of 3-bromopropanol (177.10 mg, 1.27 mmol). The reaction mixture was heated to 80 °C with stirring and reacted for 12 hours. The target product was detected by liquid chromatography-mass spectrometry (LC-MS). The solution was purified by preparative high-performance liquid chromatography (Pre-HPLC) using a Durashell C18(L) 10 μm Octopus PLUS column (21.2 × 250 mm, Waters Corporation), with gradient elution from 30% acetonitrile-water to 60% acetonitrile-water over 30 minutes, wherein the aqueous phase contained 0.1% formic acid, finally yielding compound C003 (76.80 mg, 163.22 μmol, 25.62% yield).

[0216] LC-MS(ESI)[M+H] + / [2M+H] + =451.3 / 923.7

[0217] 1 H-NMR (400MHz, DMSO-D6) δ7.71 (dd, J=13.2, 8.8Hz, 2H), 7.29 (s, 1H), 7.17 ( q,J=4.4Hz,1H),6.55(s,1H),5.44(s,2H),5.30(s,2H),4.70(t,J=4.8Hz,1 H),4.26(t,J=6.4Hz,2H),3.68(q,J=5.6Hz,2H),3.42(t,J=15.6Hz,2H),2. 09-1.99(m,2H),1.94-1.75(m,2H),1.32(t,J=7.2Hz,3H),0.90-0.84(m,3H)

[0218] Example 7 C007 Synthesis Route

[0219] Preparation and Synthesis:

[0220] Step A: Synthesis of Compound 2

[0221] At room temperature, ethylene glycol (33.0 g, 531.9 mmol, 5.0 equivalent), triethyl orthoformate (13.5 g, 91.5 mmol, 0.86 equivalent), and p-toluenesulfonic acid (0.18 g, 1.1 mmol, 0.01 equivalent) were added to a DCE (532.0 mL) solution of compound 1 (30.0 g, 106.4 mmol, 1.0 equivalent), and nitrogen was introduced. The reaction mixture was heated to 80 °C and reacted for 10 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and washed successively with 300 mL of saturated sodium bicarbonate solution, 300 mL of water, and 300 mL of saturated brine. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (EA:PE = 1:99) to give compound 2 (31.0 g, 90% yield).

[0222] 1 H NMR (400MHz, CDCl3) δ7.35 (d, J = 7.7Hz, 2H), 6.35 (s, 1H), 4.33 (td, J = 6.4, 4.2Hz, 2H), 4.08 (td, J = 6.4, 4.1Hz, 2H).

[0223] Step B: Synthesis of Compound 3

[0224] A solution of compound 2 (31.0 g, 95.7 mmol, 1.0 equivalent) in tetrahydrofuran (480 mL) was purged with nitrogen three times and cooled to -78 °C. LDA (2 M) (62.2 mL, 124.4 mmol, 1.3 equivalent) was added dropwise to the reaction solution, and the reaction was carried out at -78 °C for 1 hour. Iodomethane (15.0 g, 105.2 mmol, 1.1 equivalent) was added dropwise to the reaction solution, and the reaction was carried out at -78 °C for 2 hours, then raised to 0 °C and reacted for 1 hour. After the reaction was complete, the reaction solution was quenched with 100 mL of water, extracted with 200 mL of ethyl acetate, washed with 200 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (EA:PE = 2:98) to give compound 3 (29.0 g, 89% yield).

[0225] 1 H NMR (400MHz, CDCl3) δ7.33(d,J=8.6Hz,1H),6.43(s,1H),4.33(td,J=6.5,4.3Hz,2H),4.08(td,J=6.6,4.3Hz,2H),2.32(d,J=2.5Hz,3H).

[0226] Step C: Synthesis of Compound 5

[0227] At room temperature, Pd₂(dba)₃ (3.9 g, 4.3 mmol, 0.05 equivalent), Xantphos (4.9 g, 8.5 mmol, 0.1 equivalent), and Cs₂CO₃ (55.4 g, 170.6 mmol, 2.0 equivalent) were added to a toluene (430 mL) solution of compound 3 (29.0 g, 85.3 mmol, 1.0 equivalent) and compound 4 (18.5 g, 102.4 mmol, 1.2 equivalent). The reaction mixture was stirred at 80 °C for 24 h under nitrogen protection. After the reaction was complete, the reaction mixture was cooled and filtered. The filtrate was evaporated to dryness, dissolved in 500 mL of ethyl acetate, washed successively with 200 mL of water and 200 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (EA:PE = 5:95) to give compound 5 (25.0 g, 67% yield). LCMS (ESI) [M+1] + =440.2

[0228] 1 H NMR (400MHz, CDCl3) δ7.76(d,J=7.4Hz,2H),7.47(d,J=7.1Hz,1H),7.40(t,J=7.5Hz,3H),7.30(d,J=4.7Hz,3H) ,7.25(s,1H),6.47(s,1H),5.92(d,J=10.2Hz,1H),4.10–4.05(m,2H),3.94–3.88(m,2H),2.22(d,J=2.3Hz,3H).

[0229] Step D: Synthesis of Compound 6

[0230] At room temperature, Pd(dppf)Cl2 (0.5 g, 0.7 mmol, 0.1 equivalent) and AcOK (2.0 g, 20.5 mmol, 3.0 equivalent) were added to a 1,4-dioxane (34 mL) solution of compound 5 (3.0 g, 6.8 mmol, 1.0 equivalent) and pinacol diboronate (2.6 g, 10.3 mmol, 1.5 equivalent). The reaction mixture was stirred at 100 °C for 16 hours under nitrogen protection. After the reaction was complete, the reaction mixture was cooled and filtered. The filtrate was evaporated to dryness, dissolved in 50 mL of ethyl acetate, washed successively with 20 mL of water and 20 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (EA:PE = 10:90) to give compound 6 (1.1 g, 33% yield). LCMS (ESI) [M+1] + =488.4

[0231] Step E: Synthesis of Compound 7

[0232] A solution of compound 6 (1.1 g, 2.3 mmol, 1.0 equivalent) in tetrahydrofuran (11 mL) was cooled to 0 °C, and sodium hydroxide (0.18 g, 4.5 mmol, 2.0 equivalent) and hydrogen peroxide (30%) (1.0 g, 9.0 mmol, 4.0 equivalent) were added. The reaction mixture was stirred at 0 °C for 3 hours under nitrogen protection. After the reaction was complete, the pH of the reaction mixture was adjusted to 7 with 1 M hydrochloric acid aqueous solution, extracted with 50 mL of ethyl acetate, washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (EA:PE = 15:85) to give compound 7 (510 mg, yield 60%). LCMS (ESI) [M+1] + =378.3

[0233] Step F: Synthesis of Compound 9

[0234] Compound 8 (0.3 g, 2.0 mmol, 1.5 equivalent) and CMBP (0.5 g, 2.0 mmol, 1.5 equivalent) were added to a toluene (6.8 mL) solution of compound 7 (0.51 g, 1.4 mmol, 1.0 equivalent) at room temperature. The reaction mixture was stirred at 110 °C for 16 hours under nitrogen protection. After the reaction was complete, the reaction mixture was diluted with 50 mL of ethyl acetate, washed successively with 20 mL of water and 20 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (EA:PE = 5:95) to give compound 9 (0.54 g, 78% yield). LCMS (ESI) [M+1] + =512.4

[0235] Step G: Synthesis of Compound 10

[0236] At room temperature, a methanol solution (30 mL, 4 mol / L) of hydrochloric acid was added to a methanol solution (30 mL, 4 mol / L) containing compound 9 (2.5 g, 4.91 mmol, 1.0 equivalent). After stirring at room temperature for 5 hours, the reaction was confirmed by TLC. The reaction solution was then concentrated under reduced pressure, and DCM (70 mL), (Boc)₂O (1.25 g, 5.75 mmol, 1.2 equivalent), and DIPEA (1.5 g, 11.6 mmol, 2.4 equivalent) were added sequentially. The reaction was stirred at room temperature for 16 hours under nitrogen protection. After the reaction was confirmed by TLC, the reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to give compound 10 (1.9 g, 95% yield). LCMS (ESI) [M+1-56] + 348.1

[0237] Step H: Synthesis of Compound 11

[0238] Compound 10 (1.7 g, 4.2 mmol, 1.0 equivalent) was dissolved in tetrahydrofuran (20.0 mL), and then ethyl magnesium bromide (10.5 mL, 10.5 mmol, 2.5 equivalent) was added under nitrogen protection at 0°C. The mixture was stirred at 0°C for 3 hours. After the reaction was complete, the reaction solution was poured into 100.0 mL of saturated ammonium chloride aqueous solution and extracted twice with ethyl acetate. The organic phases were combined, washed successively with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to give compound 11 (1.3 g, 72% yield). LCMS (ESI) [M+1-56-18] + =360.4

[0239] 1 H NMR(400MHz, CDCl3)δ8.50(s,1H),7.65(d,J=12.0Hz,1H),7.40–7.22(m,5H),5.26(d,J=7.1Hz,1H),4.72–4.41(m, 2H),4.09–3.62(m,4H),2.14(d,J=1.3Hz,3H),1.90(m,1H),1.73–1.62(m,1H),1.51(s,9H),0.90(t,J=7.4Hz,3H).

[0240] Step I: Synthesis of Compound 12

[0241] At 0 °C, a solution of compound 11 (1.3 g, 3.0 mmol, 1.0 equivalent) in dichloromethane (13.0 mL) was added fractionally with Desmartin oxidant (3.8 g, 9.0 mmol, 3.0 equivalent), and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction was quenched at 10 °C with 100.0 mL of saturated sodium bicarbonate solution and extracted with dichloromethane. The organic phase was washed with 200.0 mL of brine and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to give compound 12 (1.1 g, 84% yield). LCMS (ESI) [M+1-56] + =376.1

[0242] Step J: Synthesis of Compound 13

[0243] Compound 12 (0.8 g, 2.6 mmol) was dissolved in dichloromethane (10.0 mL), and trifluoroacetic acid (2.0 mL) was added at room temperature and stirred for 2 hours. The reaction mixture was alkalized with saturated sodium bicarbonate solution and then extracted with dichloromethane. The organic phase was concentrated under vacuum, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to give compound 13 (580.0 mg, 95% yield).

[0244] LCMS(ESI)[M+1] + =332.3

[0245] Step K: Synthesis of Compound 15

[0246] Compound 14 (461 mg, 1.8 mmol, 1.0 equivalent) and pyridinium 4-methylbenzenesulfonic acid salt (38.0 mg, 0.2 mmol, 0.1 equivalent) were added to a toluene (10.0 mL) solution of compound 13 (580.0 mg, 1.8 mmol, 1.0 equivalent) at room temperature. The reaction mixture was stirred at 110°C for 4 hours under nitrogen protection. After the reaction was complete, the mixture was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol = 15:1) to give compound 15 (0.9 g, 92% yield). LCMS (ESI) [M+1] + =559.2

[0247] Step L: Synthesis of C007

[0248] At room temperature, a dichloromethane solution of boron trichloride (1.0 M, 1.7 mL, 3.8 equivalents) was slowly added to a dichloromethane solution of compound 15 (250.0 mg, 0.448 mmol, 1.0 equivalent) (6.0 mL). The reaction mixture was allowed to react at room temperature for 0.5 hours. After the reaction was complete, ethanol was added dropwise until the solution became clear. The solution was concentrated under reduced pressure, and the residue was analyzed by preparative HPLC (Column: YMC-Triart C18 250*20.0 mm; 20-95% MeCN in H2O + 0.1% FA) to prepare compound C007 (52.1 mg, yield 24%). LCMS (ESI) [M+1] + =469.4

[0249] 1H NMR (400MHz, DMSO) δ7.74(d,J=10.3Hz,1H),7.29(s,1H),6.52(s,1H),5.44(s,2H),5.31(s,2H),5.10(t,J=5.3Hz,1H),3.93( m,2H),3.87–3.82(m,2H),3.35(m,2H),2.42(d,J=1.8Hz,3H),1.92–1.80(m,2H),1.26(t,J=7.4Hz,3H),0.87(t,J=7.3Hz,3H).

[0250] Example 8 C008 Synthesis Route

[0251] Preparation and synthesis of C008

[0252] Step A: Synthesis of Compound 2

[0253] At room temperature, magnesium dichloride (4.4 g, 46.28 mmol, 7.3 equivalents) and triethylamine (2.4 g, 23.46 mmol, 3.7 equivalents) were slowly added to a solution of compound 1 (900 mg, 6.34 mmol, 1.0 equivalents) in acetonitrile (40.0 mL). Paraformaldehyde (1.4 g, 46.28 mmol, 7.3 equivalents) was added to the reaction solution, and the mixture was heated to 85°C and reacted for 16 hours. After the reaction was complete, the reaction solution was adjusted to acidity with 5% hydrochloric acid aqueous solution and extracted twice with ethyl acetate, 50 mL each time. The organic phases were combined, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (EA:PE = 5:95) to give compound 2 (500 mg, yield 46%).

[0254] 1 H NMR (400MHz, CDCl3) δ11.38(d,J=1.5Hz,1H),9.84(s,1H),7.29(dd,J=8.7,5.7Hz,1H),6.78(dd,J=10.0,8.8Hz,1H),4.00(s,3H).

[0255] Step B: Synthesis of Compound 3

[0256] At room temperature, potassium carbonate powder (1.2 g, 8.82 mmol, 3.0 equivalent) and benzyl-2-bromoethyl ether (759 mg, 3.53 mmol, 1.2 equivalent) were added to a solution of compound 2 (500 mg, 2.94 mmol, 1.0 equivalent) in N,N-dimethylformamide (10.0 mL). The reaction mixture was reacted at 90°C for 3 hours. After the reaction was complete, the mixture was cooled to room temperature and then poured into 30 mL of water. The solution was extracted three times with ethyl acetate. The organic phases were combined, washed twice with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (EA:PE = 5:95) to give compound 3 (600 mg, 67% yield).

[0257] 1 H NMR(400MHz, CDCl3)δ10.39(s,1H),7.56(dd,J=8.8,6.1Hz,1H),7.34–7.28(m,5H),6.92( t,J=9.5Hz,1H),4.56(s,2H),4.45–4.40(m,2H),3.95(d,J=1.1Hz,3H),3.80–3.75(m,2H).

[0258] Step C: Synthesis of Compound 4

[0259] At room temperature, N-bromosuccinimide (420 mg, 2.36 mmol, 1.2 equivalents) and palladium acetate (46 mg, 0.20 mmol, 0.1 equivalents) were added to a solution of compound 3 (600 mg, 1.97 mmol, 1.0 equivalents) in 5.0 mL of 1,2-dichloroethane and 1.0 mL of trifluoroacetic acid. The reaction mixture was stirred at 60°C for 6 hours under nitrogen protection. After the reaction was complete, the reaction mixture was poured into 30 mL of saturated sodium bicarbonate aqueous solution and extracted twice with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (EA:PE = 10:90) to give compound 4 (700 mg, 93% yield).

[0260] 1 H NMR(400MHz, CDCl3)δ10.22(s,1H),7.30–7.21(m,5H),7.13(d,J=10.1Hz,1H ),4.49(s,2H),4.32–4.27(m,2H),3.87(d,J=1.1Hz,3H),3.74–3.69(m,2H).

[0261] Step D: Synthesis of Compound 5

[0262] At room temperature, tert-butyl carbamate (252 mg, 2.20 mmol, 1.2 equivalents), cesium carbonate (1.8 g, 5.49 mmol, 3.0 equivalents), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (175 mg, 0.37 mmol, 0.2 equivalents), and tris(dibenzylacetone)dipalladium (90 mg, 0.18 mmol, 0.1 equivalents) were added to a 10.0 mL toluene solution of compound 4 (700 mg, 1.83 mmol, 1.0 equivalents), and tris(dibenzylacetone)dipalladium (90 mg, 0.18 mmol, 0.1 equivalents). The reaction mixture was stirred at 90°C for 3 hours under nitrogen protection. After the reaction was complete, the toluene was removed by concentration under reduced pressure, followed by extraction with ethyl acetate and water. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (EA:PE = 10:90) to give compound 5 (510 mg, 67% yield).

[0263] 1 H NMR (400MHz, CDCl3) δ10.82(s,1H),10.37(s,1H),7.34(dt,J=14.3,7.0Hz,5H),7.09(d,J= 15.9Hz,1H),4.55(s,2H),4.44–4.39(m,2H),3.86(s,3H),3.77–3.72(m,2H),1.52(s,9H).

[0264] Step E: Synthesis of Compound 6

[0265] Compound 5 (510 mg, 1.22 mmol, 1.0 equivalent) was dissolved in tetrahydrofuran (10.0 mL), and then ethyl magnesium bromide (1 M, 3.7 mL, 3.66 mmol, 3.0 equivalent) was added at 0°C. The mixture was stirred for 3 hours. After the reaction was complete, the reaction solution was poured into 30 mL of saturated ammonium chloride aqueous solution and extracted twice with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (EA:PE = 15:85) to give compound 6 (400 mg, 73% yield).

[0266] 1H NMR (400MHz, CDCl3) δ8.31(s,1H),7.63(d,J=13.4Hz,1H),7.36–7.30(m,5H),5.28–5.24(m,1H),4.53(t,J=9.2Hz,2H),4.28–4.21(m,2H),3.85 (s,3H),3.81–3.77(m,1H),3.74–3.70(m,1H),2.34(d,J=4.0Hz,1H),1. 92–1.81(m,1H),1.73–1.64(m,1H),1.50(s,9H),0.87(d,J=7.4Hz,3H).

[0267] Step F: Synthesis of Compound 7

[0268] Compound 6 (400 mg, 0.89 mmol, 1.0 equivalent) was dissolved in dichloromethane (10.0 mL), and then Dys-Martin oxidant (755 mg, 1.78 mmol, 2.0 equivalent) was added at 0°C. The mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was poured into 30 mL of saturated sodium bicarbonate aqueous solution and extracted twice with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (EA:PE = 15:85) to give compound 7 (230 mg, 58% yield). LCMS (ESI) [M+H] + =448.2

[0269] Step G: Synthesis of Compound 8

[0270] Compound 7 (230 mg, 0.51 mmol, 1.0 equivalent) was dissolved in dichloromethane (5.0 mL), and then trifluoroacetic acid (2.5 mL) was added at 0°C. The mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was poured into 40 mL of saturated sodium bicarbonate aqueous solution and extracted twice with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (EA:PE = 30:70) to give compound 8 (130 mg, 73% yield). LCMS (ESI) [M+H] + =348.1

[0271] Step H: Synthesis of Compound 10

[0272] Compound 8 (100 mg, 0.29 mmol, 1.0 equivalent) was dissolved in toluene (5.0 mL), followed by the addition of pyridine 4-methylbenzenesulfonic acid (8 mg, 0.03 mmol, 0.1 equivalent) and compound 9 (76 mg, 0.29 mmol, 1.0 equivalent) at room temperature. The mixture was then stirred at 110 °C for 16 hours. After the reaction was complete, the solution was concentrated under reduced pressure. The residue was purified by column chromatography (EA:PE = 40:60) to give compound 10 (100 mg, 60% yield). LCMS (ESI) [M+H] + =575.2

[0273] Step I: Synthesis of compound C008

[0274] Compound 10 (100 mg, 0.17 mmol, 1.0 equivalent) was dissolved in dichloromethane (5.0 mL), and then a dichloromethane solution of boron trichloride (1 M, 2.5 mL) was added at 0°C. The mixture was then stirred at room temperature for 1 hour. After the reaction was complete, ethanol was added at 0°C to quench the reaction, and the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: YMC-Actus Triart C18 150*15mm*5um; 10%-95% MeCN in H2O+0.1% FA) to give compound C008 (50.2 mg, 60% yield). LCMS (ESI) [M+H] + =485.2

[0275] 1 H NMR(400MHz,MeOD)δ7.56(d,J=13.4Hz,2H),5.56(d,J=16.3Hz,1H),5.36(d,J=16.2Hz,1H),5.25(s,2H),4.43–4.38(m,2H),4.05 (s,3H),4.00(t,J=4.8Hz,2H),3.45(d,J=7.4Hz,2H),1.95(dt,J=10.7,7.0Hz,2H),1.40(t,J=7.4Hz,3H),1.00(t,J=7.4Hz,3H).

[0276] Example 9 C009 Synthesis Route

[0277] Preparation and synthesis of C009

[0278] Step A: Synthesis of Compound 2

[0279] At room temperature, triethylamine (21.6 mL, 155.4 mmol, 3.7 equivalents) and magnesium dichloride (6.0 g, 63.0 mmol, 1.5 equivalents) were added to a 60 mL solution of acetonitrile containing compound 1 (5.8 g, 42.0 mmol, 1.0 equivalents). Paraformaldehyde (8.5 g, 283.4 mmol, 6.75 equivalents) was added to the reaction solution at 0 °C, and the temperature was raised to 70 °C for 4 hours. After the reaction was complete, the reaction solution was adjusted to acidity with 2N hydrochloric acid aqueous solution at 0 °C, and extracted twice with ethyl acetate, 200.0 mL each time. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 2 (7.9 g, crude product). LCMS(ESI)[M+H] + =167.0

[0280] Step B: Synthesis of Compound 4

[0281] At room temperature, potassium carbonate powder (11.6 g, 84.0 mmol, 2.0 equivalent) and compound 3 (7.3 mL, 46.2 mmol, 1.1 equivalent) were added to a solution of compound 2 (6.98 g, 42.0 mmol, 1.0 equivalent) in N,N-dimethylformamide (125 mL). The reaction mixture was reacted at 60°C for 3 hours. After the reaction was complete, the mixture was cooled to room temperature and then poured into 200.0 mL of water. The mixture was extracted three times with ethyl acetate. The organic phases were combined, washed twice with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 90:10) to give compound 4 (11.3 g, 89% yield). LCMS (ESI) [M+H] + =301.1

[0282] 1 H NMR (400MHz, CDCl3) δ10.30 (s, 1H), 7.48 (d, J = 8.3Hz, 1H), 7.39–7.28 (m, 5H), 6.61 (d,J=8.3Hz,1H),6.01(s,2H),4.59(s,2H),4.57–4.43(m,2H),3.84–3.74(m,2H).

[0283] Step C: Synthesis of Compound 5

[0284] At room temperature, N-bromosuccinimide (326 mg, 1.83 mmol, 1.1 equivalent) and palladium acetate (37 mg, 0.17 mmol, 0.1 equivalent) were added to a mixed solution of compound 4 (500 mg, 1.66 mmol, 1.0 equivalent) in 1,2-dichloroethane (8 mL) and trifluoroacetic acid (2 mL). The reaction mixture was stirred overnight at 60°C under nitrogen protection. N-bromosuccinimide (593 mg, 3.33 mmol, 2.0 equivalent) was added, and the mixture was stirred again overnight at 60°C. After the reaction was complete, the reaction mixture was poured into 100.0 mL of saturated sodium bicarbonate aqueous solution and extracted twice with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 90:10) to give compound 5 (300 mg, 47% yield). LCMS(ESI)[M+1] + =378.9 & 380.9

[0285] 1 H NMR (400MHz, CDCl3) δ10.23(s,1H),7.60(s,1H),7.35–7.27(m,5H),6.08(s,2H),4.56(s,2H),4.53–4.48(m,2H),3.79–3.74(m,2H).

[0286] Step D: Synthesis of Compound 6

[0287] At 0 °C, a nitric acid solution (fuming nitric acid: glacial acetic acid (v / v) = 3:1, 15 mL) was added dropwise to a solution of compound 5 (3.0 g, 7.91 mmol, 1.0 equivalent) in glacial acetic acid (15 mL), and the mixture was stirred at 0 °C for 1 hour. After the reaction was complete, the reaction was quenched with 50 mL of ice water at 0 °C and extracted with dichloromethane. The organic phase was washed with 50.0 mL of saturated sodium bicarbonate solution and 50.0 mL of brine, and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 85:15) to give compound 6 (2.1 g, 79% yield).

[0288] 1 H NMR (400MHz, CDCl3) δ10.10 (s, 1H), 6.24 (s, 2H), 4.82 (dd, J = 5.3, 3.4Hz, 2H), 4.73–4.67 (m, 2H).

[0289] Step E: Synthesis of Compound 7

[0290] At room temperature, wet palladium on carbon (669 mg, 0.63 mmol, 0.1 equivalent, 10%) was added to a 50 mL ethanol solution of compound 6 (2.1 g, 6.29 mmol, 1.0 equivalent). The mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. After the reaction was complete, the reaction solution was filtered and concentrated under reduced pressure to give compound 7 (1.5 g, crude product). LCMS (ESI) [M+1] + =226.0

[0291] 1 H NMR (400MHz, DMSO) δ10.05(s,1H),7.52(s,2H),6.00(s,1H),5.91(s,2H),4.87(t,J=5.6Hz,1H),4.28–4.22(m,2H),3.68–3.64(m,2H).

[0292] Step F: Synthesis of Compound 8

[0293] At room temperature, imidazole (680 mg, 9.99 mmol, 1.5 equivalence) and TBSCl (1.51 g, 9.99 mmol, 1.5 equivalence) were added to a solution of compound 7 (1.5 g, 6.66 mmol, 1.0 equivalence) in dichloromethane (30 mL). The reaction mixture was allowed to react overnight at room temperature. After the reaction was complete, the mixture was quenched with 50 mL of water and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 90:10) to give compound 8 (1.2 g, 53% yield). LCMS (ESI) [M+H] + =340.1

[0294] 1 H NMR (400MHz, CDCl3) δ10.12(s,1H),6.39(s,2H),5.78(s,2H),5.76(s,1H),4.34–4.26(m,2H),3.87–3.83(m,2H),0.82(s,9H),0.00(s,6H).

[0295] Step G: Synthesis of Compound 9

[0296] Compound 8 (1.2 g, 3.53 mmol, 1.0 equivalent) was dissolved in tetrahydrofuran (20 mL) at room temperature, cooled to -78°C, and ethyl magnesium bromide (3.53 mL, 10.6 mmol, 3.0 equivalent) was added under nitrogen protection. The mixture was stirred at -78°C for 3 hours. After the reaction was complete, the reaction solution was quenched with 50 mL of saturated ammonium chloride aqueous solution and extracted twice with ethyl acetate. The organic phases were combined, washed successively with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 80:20) to give compound 9 (1.08 g, 82% yield). LCMS (ESI) [M+1-18] + =352.2

[0297] 1 H NMR(400MHz, CDCl3)δ5.88(s,1H),5.69(s,2H),4.91(t,J=7.3Hz,1H),4.21–4.07(m,2H),3.93 –3.75(m,3H),1.91–1.67(m,2H),0.84(t,J=5.8Hz,3H),0.82–0.80(m,9H),0.01–-0.01(m,6H).

[0298] Step H: Synthesis of Compound 10

[0299] At room temperature, manganese dioxide (1.27 g, 14.61 mmol, 5.0 equivalent) was added fractionally to a solution of compound 9 (1.08 g, 2.92 mmol, 1.0 equivalent) in dichloromethane (24 mL) and tetrahydrofuran (6 mL), and the mixture was stirred overnight at room temperature. After the reaction was complete, the reaction solution was filtered through diatomaceous earth, the filter cake was washed with DCM, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (PE:EA = 80:20) to give compound 10 (340 mg, crude product, yield 31%). LCMS (ESI) [M+1] + =368.2

[0300] Step I: Synthesis of compound C009

[0301] Compound 11 (244 mg, 0.92 mmol, 1.0 equivalent) and pyridinium 4-methylbenzenesulfonic acid salt (23 mg, 0.092 mmol, 0.1 equivalent) were added to a 9 mL toluene solution of compound 10 (340 mg, 0.92 mmol, 1.0 equivalent). The reaction mixture was stirred at 110°C for 3 hours under nitrogen protection. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was used for reverse-phase preparation (Column: YMC-Actus Triart C18 150*20mm*5um; 5%-95% MeCN in H2O+0.1% FA) to give compound C009 (50 mg, yield 11%). LCMS (ESI) [M+1] + =481.3

[0302] 1 H NMR (400MHz, DMSO) δ7.28(s,1H),7.21(s,1H),6.48(s,1H),6.24(s,2H),5.42(s,2H),5.24(s,2H),4.94(t,J=5.2Hz,1H),4.42(t ,J=5.0Hz,2H),3.80(dd,J=10.0,5.1Hz,2H),3.39–3.33(m,2H),1.94–1.74(m,2H),1.29(t,J=7.4Hz,3H),0.87(t,J=7.3Hz,3H).

[0303] Example 10 C010 Synthesis Route

[0304] Preparation and synthesis of CO10

[0305] Step A: Synthesis of Compound 3

[0306] Sodium hydride (3.6 g, 172.5 mmol, 2.0 equivalent) was added to a DMF (100.0 mL) solution of compound 1 (10.0 g, 46.0 mmol, 1.0 equivalent). The reaction mixture was stirred at 0 °C for 30 minutes under nitrogen protection. Then, compound 2 (9.5 g, 46.0 mmol, 1.0 equivalent) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was separated, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 5:1) to give compound 3 (4.0 g, yield 25.0%).

[0307] 1H NMR (400MHz, DMSO) δ11.80(s,1H),7.59(d,J=8.9Hz,1H),7.43–7.35(m,6H),6.65(s,1H),5.17(s,2H),3.51–3.45(m,2H),2.68–2.60(m,2H).

[0308] Step B: Synthesis of Compound 4

[0309] Iron powder (2.2 g, 39.0 mmol, 5.0 equivalent) and ammonium chloride (1.2 g, 23.4 mmol, 3.0 equivalent) were added to a solution of compound 3 (2.7 g, 7.8 mmol, 1.0 equivalent) in EtOH (24.0 mL) and H₂O (6.0 mL). The reaction mixture was stirred at 70 °C for 2 hours. After the reaction was complete, the reaction mixture was filtered through diatomaceous earth and extracted with ethyl acetate and water. The organic layer was separated, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product of compound 4 (2.0 g, 81% yield) was used directly in the next step. LCMS(ESI)[M+1] + =315.1

[0310] Step C: Synthesis of Compound 5

[0311] To a DCM (18 mL) solution of compound 4 (2.0 g, 6.3 mmol, 1.0 equivalent), TFA (9 mL) was added, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then filtered while hot and concentrated under reduced pressure. The solution was purified by prep-HPLC (Column: Triart C18, 250*20.0 mm l.D., 5 μm, 12 nm; 35-95 MeCN in H2O + 0.1% FA) to give compound 5 (1.4 g, 85% yield).

[0312] LCMS(ESI)[M+1] + =258.9

[0313] Step D: Synthesis of Compound 6

[0314] Compound 5 (300.0 mg, 3.5 mmol, 0.1 equivalent) was added to polyphosphoric acid (3 mL), and the reaction mixture was stirred at 90 °C for 1 hour. After the reaction was complete, the reaction mixture was dissolved in water, and the pH was adjusted to 9-10 by adding 60% NaOH aqueous solution. The mixture was extracted three times with chloroform solution. The organic phases were combined and concentrated under reduced pressure, and purified by silica gel column chromatography (DCM:MeOH = 95:5) to give compound 6 (130 mg, yield 46%).

[0315] 1H NMR (400MHz, DMSO) δ11.80(s,1H),7.59(d,J=8.9Hz,1H),7.43–7.35(m,6H),6.65(s,1H),5.17(s,2H),3.51–3.45(m,2H),2.68–2.60(m,2H).

[0316] Step E: Synthesis of Compound 7

[0317] At room temperature, Pd / C (100.0 mg, 10%) was added to a 10.0 mL solution of compound 6 (300.0 mg, 1.25 mmol, 1.0 equivalent) in EtOH. The reaction mixture was purged three times with hydrogen and reacted at room temperature for 16 hours under a hydrogen atmosphere. After the reaction was complete, the mixture was filtered, the filtrate was evaporated to dryness, and the residue was purified by silica gel column chromatography (PE:EA = 2:1) to give compound 7 (160.0 mg, 79% yield).

[0318] 1 H NMR (400MHz, DMSO-d6) δ7.15(s,2H),6.86(t,J=8.0Hz,1H),6.45(s,1H),5.84–5.69(m,2H),3.31(td,J=7.5,7.1,2.1Hz,2H),2.46(t,J=6.9Hz,2H).

[0319] Step F: Synthesis of Compound 8

[0320] To a DCM solution of compound 7 (1.5 g, 9.3 mmol, 1.0 equivalent), pyridine (1.1 g, 13.9 mmol, 1.5 equivalent) and benzyl chloroformate (1.9 g, 11.1 mmol, 1.2 equivalent) were added. The reaction mixture was stirred at 25 °C for 1 h. After the reaction was complete, the reaction mixture was poured into water, separated, and the aqueous phase was extracted again with DCM. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA:DCM = 55:25:20) to give compound 8 (1.6 g, yield 58.3%). LCMS (ESI) [M+1] + =297.0

[0321] 1H NMR (400MHz, DMSO-d6) δ11.78(s,1H),7.53–7.27(m,6H),7.21(t,J=8.2Hz,1H),7.12(d,J=18.0H z,1H),6.38(dd,J=8.4,1.1Hz,1H),5.15(s,2H),3.40–3.35(m,2H),2.58(dd,J=7.9,6.6Hz,2H).

[0322] Step G: Synthesis of Compound 10

[0323] Compound 9 (1.0 g, 6.8 mmol, 2.0 equivalent) was added to a DCE (10.0 mL) solution of compound 8 (1.0 g, 3.4 mmol, 1.0 equivalent), and the reaction mixture was stirred at 70 °C for 2 h. Under LCMS control, 50% of the starting material was no longer converted. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA = 84:16) to give compound 10 (510.0 mg, yield 34.6%). LCMS (ESI) [M+1] + =429.2

[0324] Step H: Synthesis of Compound 11

[0325] Compound 10 (510.0 mg, 1.2 mmol, 1.0 equivalent) was dissolved in a mixed solution of methanol (15.0 mL), dioxane (7.0 mL), water (1.5 mL), and acetic acid (0.2 mL), and palladium on carbon (50.0 mg, 10% wt) was added. The reaction mixture was stirred under a hydrogen atmosphere for 16 hours. After the reaction was complete, the reaction mixture was filtered, the filter cake was washed, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA = 84:16) to give compound 11 (100 mg, yield 28.9%). LCMS (ESI) [M+1] + =297.1

[0326] Step I: Synthesis of Compound 13

[0327] At room temperature, compound 12 (106.2 mg, 0.4 mmol, 1.2 equivalents) and PPTS (8.5 mg, 33.8 μmol, 0.1 equivalents) were added to a 1.0 mL solution of compound 11 (100.0 mg, 0.3 mmol, 1.0 equivalent) in toluene. The reaction mixture was refluxed for 2 hours. After the reaction was complete, the solution was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 91:9) to give compound 13 (100.0 mg, 50% purity, yield 28.3%). LCMS (ESI) [M+1] + =524.2

[0328] Step J: Synthesis of compound C010

[0329] At room temperature, 1M BCl3 (2.0 mL) was added to a 5.0 mL solution of compound 13 (250.0 mg, 50% purity, 23.9 μmol, 1.0 equivalent) in DCM. The reaction mixture was reacted at room temperature for 1 hour. After the reaction was complete, the solution was concentrated under reduced pressure. The residue was purified by preparative HPLC (Column: YMC-Actus Triart C18 150*20mm*5 μm; 5-95% MeCN in H2O+0.1% FA) to obtain compound C010 (6.6 mg, yield 6.4%).

[0330] LCMS(ESI)[M+1] + =434.2

[0331] 1 H NMR (400MHz, DMSO-d6) δ7.59(t,J=8.1Hz,1H),7.32(d,J=8.3Hz,1H),7.28(s,1H),6.76(d,J=7.9Hz,1H),6.49(s,1H),5.43(s,2H),5.22(s,2H), 4.78(t,J=5.4Hz,1H), 3.71(q,J=5.9Hz,2H), 3.57(dt,J=9.9,6.2Hz,4H), 3.26(t,J=6.3Hz,2H), 1.87(hept,J=7.1Hz,2H), 0.88(t,J=7.3Hz,3H).

[0332] Example 11 C011 Synthesis Route

[0333] Preparation and synthesis of CO11

[0334] Step A: Synthesis of Compound 3

[0335] Compound 2 (24.2 g, 172.5 mmol, 1.2 equivalents) was added to a TFA (100.0 mL) solution of compound 1 (20.0 g, 143.8 mmol, 1.0 equivalent). The reaction mixture was stirred at 90 °C for 36 hours under nitrogen protection. The reaction mixture was cooled to room temperature, distilled water was added, and the mixture was stirred for another 2 hours. After the reaction was complete, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was separated, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA:PE = 1:99) to give compound 3 (7.2 g, yield 30.0%).

[0336] 1 H NMR (400MHz, CDCl3) δ12.14(s,1H),10.36(s,1H),7.64(d,J=8.2Hz,1H),7.59(dd,J=7.9,1.1Hz,1H),7.33(d,J=8.4Hz,1H).

[0337] Step B: Synthesis of Compound 5

[0338] Compound 4 (9.7 g, 43.1 mmol, 1.0 equivalent) and potassium carbonate (17.9 g, 129.3 mmol, 3.0 equivalent) were added to a DMF (100.0 mL) solution of compound 3 (7.2 g, 43.1 mmol, 1.0 equivalent). The reaction mixture was stirred at 80 °C for 4 hours. After the reaction was complete, the mixture was poured into water and extracted with ethyl acetate. The organic layer was separated, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA:PE = 20:80) to give compound 5 (10.7 g, yield 82.4%).

[0339] 1 H NMR (400MHz, DMSO) δ10.31(s,1H),7.87–7.72(m,1H),7.59(d,J=8.2Hz,1H),7.53(d,J=8. 0Hz, 1H), 7.39–7.01 (m, 5H), 4.56 (s, 2H), 4.38 (dd, J = 5.3, 3.7Hz, 2H), 3.88–3.69 (m, 2H).

[0340] Step C: Synthesis of Compound 6

[0341] Compound 5 (10.7 g, 35.5 mmol, 1.0 equivalent) was dissolved in a mixture of N-methylpyrrolidone (100.0 mL) and water (20 mL), and iron powder (9.9 g, 177.5 mmol, 5.0 equivalent) and ammonium chloride (7.6 g, 142.0 mmol, 4.0 equivalent) were added. The reaction mixture was stirred at 50 °C for 2 hours under nitrogen protection. The reaction mixture was filtered while hot, and the filtrate was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, and toluene was added to the filtrate. The ethyl acetate was removed by concentration under reduced pressure. The toluene solution of the crude product of compound 6 was used directly in the next step.

[0342] Step D: Synthesis of Compound 8

[0343] To a mixture of compound 6 (crude) and toluene (100.0 mL), PPTS (889.0 mg, 3.5 mmol, 0.1 equivalent) and compound 7 (9.3 g, 35.3 mmol, 1.0 equivalent) were added. The reaction mixture was stirred overnight at 110 °C. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (MeOH:DCM = 2:98) to give compound 8 (5.8 g, yield 32.9%).

[0344] 1 H NMR (400MHz, DMSO) δ8.84(s,1H),7.76(d,J=6.6Hz,2H),7.41–7.33(m,5H),7.32–7.28(m,1H),7.20(dd,J=6.8,1.9Hz,1H),6.52 (s,1H),5.43(s,2H),5.31(s,2H),4.65(s,2H),4.45–4.37(m,2H),3.99–3.92(m,2H),1.94–1.81(m,2H),0.88(t,J=7.3Hz,3H).

[0345] Step E: Synthesis of Compound 9

[0346] Compound 8 (5.8 g, 11.6 mmol, 1.0 equivalent) was dissolved in a mixture of methanol (120 mL) and water (100 mL). Concentrated sulfuric acid (50 mL) was added dropwise at 0 °C, followed by ferrous sulfate heptahydrate (3.2 g, 11.6 mmol, 1.0 equivalent). Then, 30% hydrogen peroxide (10 mL) was added dropwise. The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was poured into water and extracted three times with dichloromethane solution. The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH:DCM = 3:97) to give compound 9 (3.9 g, 63.8% yield).

[0347] 1 H NMR (400MHz, DMSO) δ7.73–7.71(m,1H),7.41–7.20(m,7H),7.15(dd,J=5.6,3.4Hz,1H),6.49(s,1H),5.52(d,J=19.2Hz,3H),5.43(s ,2H),4.63(s,2H),4.33(d,J=4.4Hz,2H),3.99–3.88(m,2H),1.86(td,J=13.9,7.0Hz,2H),1.35–1.24(m,2H),0.88(t,J=7.3Hz,3H).

[0348] Step F: Synthesis of Compound 10

[0349] At 0 °C, SOCl2 (37.0 mg, 0.3 mmol, 1.2 equivalents) was added to a DCM (1.0 mL) solution of compound 9 (136.0 mg, 257.6 μmol, 1.0 equivalent). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (MeOH:DCM = 2:98) to give compound 10 (86 mg, yield 61.1%).

[0350] LCMS(ESI)[M+1] + =547.5

[0351] Step G: Synthesis of Compound 12

[0352] Compound 11 (44.0 mg, 0.5 mmol, 1.0 equivalent) and DIEA (142.0 mg, 1.5 mmol, 3.0 equivalent) were added to a DMSO (4.0 mL) solution of compound 10 (300.0 mg, 0.5 mmol, 1.0 equivalent) at room temperature. The reaction mixture was allowed to react at room temperature for 2 hours. After the reaction was complete, the reaction mixture was poured into 50 mL of water and extracted three times with 20 mL of ethyl acetate each time. The organic phases were combined, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 95:5) to give compound 12 (220.0 mg, yield 63%).

[0353] 1 H NMR (400MHz, DMSO) δ7.68(q,J=8.2Hz,2H),7.36–7.25(m,6H),7.15(d,J=7.5Hz,1H),6.48(s,1H),5.37(d,J=13.5Hz,4H) ,4.59(d,J=7.0Hz,2H),4.54–4.26(m,4H),3.90(s,2H),2.46(s,6H),1.83(dd,J=14.3,6.9Hz,4H),0.84(t,J=7.3Hz,3H).

[0354] Step H: Synthesis of compound C011

[0355] At room temperature, 1M BCl3 (2.0 mL) was added to a 5.0 mL solution of compound 12 (300.0 mg, 0.5 mmol, 1.0 equivalent) in DCM. The reaction mixture was allowed to react at room temperature for 1 hour. After the reaction was complete, the reaction mixture was quenched dropwise with ethanol and concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 95:5) and then by preparative HPLC (Column: Triart C18, 250*20.0 mm l.D., 5 μm, 12 nm; 5-95 MeCN in H2O + 0.1% FA) to give compound C011 (53.9 mg, yield 20%).

[0356] 1 H NMR (400MHz, DMSO) δ8.13(s,1H),7.78–7.69(m,2H),7.31(s,1H),7.19(dd,J=7.0,1.9Hz,1H),6.52(s,1H),5.42(d,J=10.9Hz,4H),5. 05(s,1H),4.53(q,J=13.5Hz,2H),4.24(t,J=4.8Hz,2H),3.90(t,J=4.6Hz,2H),2.64(s,4H),1.98–1.79(m,6H),0.88(t,J=7.3Hz,3H).

[0357] Example 12 C012 Synthesis Route

[0358] Preparation and synthesis of CO12

[0359] Step A: Synthesis of Compound 3

[0360] Compound 2 (24.2 g, 172.5 mmol, 1.2 equivalents) was added to a TFA (100.0 mL) solution of compound 1 (20.0 g, 143.8 mmol, 1.0 equivalent). The reaction mixture was stirred at 90 °C for 36 h under nitrogen protection. The reaction mixture was cooled to room temperature, distilled water was added, and the mixture was stirred for another 2 h. After the reaction was complete, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was separated, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA:PE = 1:99) to give compound 3 (7.2 g, yield 30.0%).

[0361] 1H NMR (400MHz, CDCl3) δ12.14(s,1H),10.36(s,1H),7.64(d,J=8.2Hz,1H),7.59(dd,J=7.9,1.1Hz,1H),7.33(d,J=8.4Hz,1H).

[0362] Step B: Synthesis of Compound 5

[0363] Compound 4 (9.7 g, 43.1 mmol, 1.0 equivalent) and potassium carbonate (17.9 g, 129.3 mmol, 3.0 equivalent) were added to a DMF (100.0 mL) solution of compound 3 (7.2 g, 43.1 mmol, 1.0 equivalent). The reaction mixture was stirred at 80 °C for 4 hours. After the reaction was complete, the mixture was poured into water and extracted with ethyl acetate. The organic layer was separated, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA:PE = 20:80) to give compound 5 (10.7 g, yield 82.4%).

[0364] 1 H NMR (400MHz, DMSO) δ10.31(s,1H),7.87–7.72(m,1H),7.59(d,J=8.2Hz,1H),7.53(d,J=8. 0Hz, 1H), 7.39–7.01 (m, 5H), 4.56 (s, 2H), 4.38 (dd, J = 5.3, 3.7Hz, 2H), 3.88–3.69 (m, 2H).

[0365] Step C: Synthesis of Compound 6

[0366] Compound 5 (10.7 g, 35.5 mmol, 1.0 equivalent) was dissolved in a mixed solution of N-methylpyrrolidone (100.0 mL) and water (20 mL), and iron powder (9.9 g, 177.5 mmol, 5.0 equivalent) and ammonium chloride (7.6 g, 142.0 mmol, 4.0 equivalent) were added. The reaction mixture was stirred at 50 °C for 2 hours under nitrogen protection. The reaction mixture was filtered while hot, and the filtrate was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, toluene was added to the filtrate, and the mixture was concentrated under reduced pressure to remove ethyl acetate. The toluene solution of the crude product of compound 6 was used directly in the next step.

[0367] Step D: Synthesis of Compound 8

[0368] To a 100.0 mL mixture of compound 6 (crude) and toluene (100.0 mL), PPTS (889.0 mg, 3.5 mmol, 0.1 equivalent) and compound 7 (9.3 g, 35.3 mmol, 1.0 equivalent) were added. The reaction mixture was stirred overnight at 110 °C. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (MeOH:DCM = 2:98) to give compound 8 (5.8 g, yield 32.9%).

[0369] 1 H NMR (400MHz, DMSO) δ8.84(s,1H),7.76(d,J=6.6Hz,2H),7.41–7.33(m,5H),7.32–7.28(m,1H),7.20(dd,J=6.8,1.9Hz,1H),6.52 (s,1H),5.43(s,2H),5.31(s,2H),4.65(s,2H),4.45–4.37(m,2H),3.99–3.92(m,2H),1.94–1.81(m,2H),0.88(t,J=7.3Hz,3H).

[0370] Step E: Synthesis of Compound 9

[0371] Compound 8 (5.8 g, 11.6 mmol, 1.0 equivalent) was dissolved in a mixture of methanol (120 mL) and water (100 mL) at 0 °C. Concentrated sulfuric acid (50 mL) was added dropwise, followed by ferrous sulfate heptahydrate (3.2 g, 11.6 mmol, 1.0 equivalent). Then, 30% hydrogen peroxide (10 mL) was added dropwise. The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was poured into water and extracted three times with dichloromethane solution. The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH:DCM = 3:97) to give compound 9 (3.9 g, 63.8% yield).

[0372] 1 H NMR (400MHz, DMSO) δ7.73–7.71(m,1H),7.41–7.20(m,7H),7.15(dd,J=5.6,3.4Hz,1H),6.49(s,1H),5.52(d,J=19.2Hz,3H),5.43(s ,2H),4.63(s,2H),4.33(d,J=4.4Hz,2H),3.99–3.88(m,2H),1.86(td,J=13.9,7.0Hz,2H),1.35–1.24(m,2H),0.88(t,J=7.3Hz,3H).

[0373] Step F: Synthesis of Compound 10

[0374] At 0 °C, SOCl2 (37.0 mg, 0.3 mmol, 1.2 equivalents) was added to a DCM (1.0 mL) solution of compound 9 (136.0 mg, 257.6 μmol, 1.0 equivalent). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (MeOH:DCM = 2:98) to give compound 10 (86 mg, yield 61.1%).

[0375] LCMS(ESI)[M+1] + =547.5

[0376] Step G: Synthesis of Compound 12

[0377] Compound 11 (77.0 mg, 0.9 mmol, 1.0 equivalent) and DIEA (353.0 mg, 2.7 mmol, 3.0 equivalent) were added to a DMSO (5.0 mL) solution of compound 10 (500.0 mg, 0.9 mmol, 1.0 equivalent) at room temperature. The reaction mixture was allowed to react at room temperature for 2 hours. After the reaction was complete, the reaction mixture was purified by preparative HPLC (Column: Triart C18, 250*20.0 mm l.D., 5 μm, 12 nm; 5-95 MeCN in H2O + 0.1% FA) to give compound 12 (300.0 mg, 55% yield).

[0378] 1H NMR (400MHz, DMSO) δ7.79–7.67(m,2H),7.42–7.26(m,6H),7.18(d,J=5.9Hz,1H),6.51(s,1H),5.41(d,J=13.7Hz,4H),4.65(s,2H),4.42 (dd,J=22.4,14.5Hz,4H),3.97(dd,J=5.2,3.3Hz,2H),2.38(s,4H),1.94–1.79(m,2H),1.43(s,4H),1.32(s,2H),0.88(t,J=7.3Hz,3H).

[0379] Step H: Synthesis of compound C012

[0380] At room temperature, 1M BCl3 (2.0 mL) was added to a 5.0 mL solution of compound 12 (300.0 mg, 0.5 mmol, 1.0 equivalent) in DCM. The reaction mixture was allowed to react at room temperature for 1 hour. After the reaction was complete, the reaction mixture was quenched dropwise with ethanol and concentrated under reduced pressure. The residue was purified by column chromatography, followed by preparative HPLC purification (Column: Triart C18, 250*20.0 mm l.D., 5 μm, 12 nm; 5-95 MeCN in H2O + 0.1% FA) to give compound C012 (45.1 mg, yield 18%).

[0381] 1 H NMR (400MHz, DMSO) δ8.14(s,1H),7.77–7.69(m,2H),7.30(s,1H),7.19(dd,J=6.7,2.1Hz,1H),6.51(s,1H),5.41(d,J=14.5Hz,4H),4.41(q, J=14.0Hz,2H),4.24(t,J=4.8Hz,2H),3.90(t,J=4.8Hz,2H),2.49(s,4H),1.93–1.80(m,2H),1.45(d,J=30.9Hz,6H),0.88(t,J=7.3Hz,3H).

[0382] Example 13 C013 Synthesis Route

[0383] Preparation and synthesis of CO13

[0384] Step A: Synthesis of Compound 3

[0385] Compound 2 (24.2 g, 172.5 mmol, 1.2 equivalents) was added to a TFA (100.0 mL) solution of compound 1 (20.0 g, 143.8 mmol, 1.0 equivalent). The reaction mixture was stirred at 90 °C for 36 hours under nitrogen protection. The reaction mixture was cooled to room temperature, distilled water was added, and the mixture was stirred for another 2 hours. After the reaction was complete, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was separated, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA:PE = 1:99) to give compound 3 (7.2 g, yield 30.0%).

[0386] 1H NMR (400MHz, CDCl3) δ12.14(s,1H),10.36(s,1H),7.64(d,J=8.2Hz,1H),7.59(dd,J=7.9,1.1Hz,1H),7.33(d,J=8.4Hz,1H).

[0387] Step B: Synthesis of Compound 5

[0388] Compound 4 (9.7 g, 43.1 mmol, 1.0 equivalent) and potassium carbonate (17.9 g, 129.3 mmol, 3.0 equivalent) were added to a DMF (100.0 mL) solution of compound 3 (7.2 g, 43.1 mmol, 1.0 equivalent). The reaction mixture was stirred at 80 °C for 4 hours. After the reaction was complete, the mixture was poured into water and extracted with ethyl acetate. The organic layer was separated, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA:PE = 20:80) to give compound 5 (10.7 g, yield 82.4%).

[0389] 1 H NMR (400MHz, DMSO) δ10.31(s,1H),7.87–7.72(m,1H),7.59(d,J=8.2Hz,1H),7.53(d,J=8. 0Hz, 1H), 7.39–7.01 (m, 5H), 4.56 (s, 2H), 4.38 (dd, J = 5.3, 3.7Hz, 2H), 3.88–3.69 (m, 2H).

[0390] Step C: Synthesis of Compound 6

[0391] Compound 5 (10.7 g, 35.5 mmol, 1.0 equivalent) was dissolved in a mixture of N-methylpyrrolidone (100.0 mL) and water (20 mL), and iron powder (9.9 g, 177.5 mmol, 5.0 equivalent) and ammonium chloride (7.6 g, 142.0 mmol, 4.0 equivalent) were added. The reaction mixture was stirred at 50 °C for 2 hours under nitrogen protection. The reaction mixture was filtered while hot, and the filtrate was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, and toluene was added to the filtrate. The ethyl acetate was removed by concentration under reduced pressure. The toluene solution of the crude product of compound 6 was used directly in the next step.

[0392] Step D: Synthesis of Compound 8

[0393] To a mixture of compound 6 (crude) and toluene (100.0 mL), PPTS (889.0 mg, 3.5 mmol, 0.1 equivalent) and compound 7 (9.3 g, 35.3 mmol, 1.0 equivalent) were added. The reaction mixture was stirred overnight at 110 °C. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (MeOH:DCM = 2:98) to give compound 8 (5.8 g, yield 32.9%).

[0394] 1 H NMR (400MHz, DMSO) δ8.84(s,1H),7.76(d,J=6.6Hz,2H),7.41–7.33(m,5H),7.32–7.28(m,1H),7.20(dd,J=6.8,1.9Hz,1H),6.52 (s,1H),5.43(s,2H),5.31(s,2H),4.65(s,2H),4.45–4.37(m,2H),3.99–3.92(m,2H),1.94–1.81(m,2H),0.88(t,J=7.3Hz,3H).

[0395] Step E: Synthesis of Compound 9

[0396] Concentrated sulfuric acid (50 mL) was added dropwise to a solution of compound 8 (5.8 g, 11.6 mmol, 1.0 equivalent) in methanol (120 mL) and water (100 mL) at 0 °C, followed by the addition of ferrous sulfate heptahydrate (3.2 g, 11.6 mmol, 1.0 equivalent). Then, 30% hydrogen peroxide (10 mL) was added dropwise. The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was poured into water and extracted three times with dichloromethane solution. The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH:DCM = 3:97) to give compound 9 (3.9 g, yield 63.8%).

[0397] 1 H NMR (400MHz, DMSO) δ7.73–7.71(m,1H),7.41–7.20(m,7H),7.15(dd,J=5.6,3.4Hz,1H),6.49(s,1H),5.52(d,J=19.2Hz,3H),5.43(s ,2H),4.63(s,2H),4.33(d,J=4.4Hz,2H),3.99–3.88(m,2H),1.86(td,J=13.9,7.0Hz,2H),1.35–1.24(m,2H),0.88(t,J=7.3Hz,3H).

[0398] Step F: Synthesis of Compound 10

[0399] At 0 °C, SOCl2 (37.0 mg, 0.3 mmol, 1.2 equivalents) was added to a DCM (1.0 mL) solution of compound 9 (136.0 mg, 257.6 μmol, 1.0 equivalent). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (MeOH:DCM = 2:98) to give compound 10 (86 mg, yield 61.1%).

[0400] LCMS(ESI)[M+1] + =547.5

[0401] Step G: Synthesis of Compound 12

[0402] Compound 11 (80.0 mg, 0.9 mmol, 1.0 equivalent) and DIEA (354.0 mg, 2.7 mmol, 3.0 equivalent) were added to a DMSO (5.0 mL) solution of compound 10 (500.0 mg, 0.9 mmol, 1.0 equivalent) at room temperature. The reaction mixture was allowed to react at room temperature for 2 hours. After the reaction was complete, the reaction mixture was poured into 100 mL of water and extracted three times with 50 mL of ethyl acetate each time. The organic phases were combined, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 95:5) to give compound 12 (500.0 mg, 90% yield). LCMS (ESI) [M+1] + =598.3

[0403] Step H: Synthesis of compound C013

[0404] At room temperature, 1M BCl3 (4.0 mL) was added to a 10.0 mL solution of compound 12 (500.0 mg, 2.7 mmol, 1.0 equivalent) in DCM. The reaction mixture was allowed to react at room temperature for 1 hour. After the reaction was complete, the reaction mixture was quenched dropwise with ethanol and concentrated under reduced pressure. The residue was purified by column chromatography, followed by preparative HPLC purification (Column: Triart C18, 250*20.0 mm l.D., 5 μm, 12 nm; 5-95 MeCN in H2O + 0.1% FA) to give compound C013 (77.7 mg, yield 18%).

[0405] 1H NMR (400MHz, DMSO) δ8.13(s,1H),7.76–7.69(m,2H),7.30(s,1H),7.19(dd,J=6.6,1.9Hz,1H),6.52(s,1H),5.42(d,J=12.9Hz,4H),4. 47(q,J=13.5Hz,2H),4.24(t,J=4.7Hz,2H),3.91(t,J=4.7Hz,2H),3.55(s,4H),2.51(s,4H),1.97–1.77(m,2H),0.88(t,J=7.3Hz,3H).

[0406] Example 14 C014 Synthesis Route

[0407] Preparation and synthesis of C014

[0408] Step A: Synthesis of Compound 2

[0409] At 0°C, thionyl chloride (12 mL, 146.0 mmol, 1.0 equivalent) and DMF (0.5 mL) were added dropwise to a DCM (40 mL) solution of compound 1 (3.6 g, 14.6 mmol, 1.0 equivalent). The reaction mixture was allowed to react at room temperature for 2 hours. After the reaction was complete, the solvent was evaporated to dryness to obtain crude 2-bromo-6-nitrobenzoyl chloride (4.0 g) for later use. At 0°C, DIPEA (20 mL, 73.0 mmol, 5.0 equivalent) was added to a DCM (30 mL) solution of N,O-dimethylhydroxylamine (2.8 g, 29.2 mmol, 2.0 equivalent). The reaction mixture was allowed to react at room temperature for 1 hour. At 0°C, a DCM (20 mL) solution of crude 2-bromo-6-nitrobenzoyl chloride (4.0 g) was added to the reaction mixture and the reaction was allowed to react at room temperature for 12 hours. The starting materials reacted completely. The reaction mixture was poured into 200 mL of water and extracted three times with 200 mL of ethyl acetate each time. The organic phases were combined, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (EA:PE = 1:4) to give compound 2 (2.7 g, yield 64%). LCMS (ESI) [M+H] + =289.2,291.2

[0410] Step B: Synthesis of Compound 3

[0411] Under N2 protection at room temperature, (E)-tert-butyldimethyl((3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)allyl)oxy)silane (3.4 g, 11.3 mmol, 1.2 equivalent), K2CO3 (3.9 g, 28.1 mmol, 3.00 equivalent), and Pd(dppf)Cl2 (686.0 mg, 0.9 mmol, 0.10 equivalent) were added sequentially to a dioxane / H2O (40 mL / 8 mL) solution of compound 2 (2.7 g, 9.4 mmol, 1.0 equivalent), along with Pd(dppf)Cl2 (686.0 mg, 0.9 mmol, 0.10 equivalent). The mixture was purged with nitrogen three times, and the reaction was carried out at 90 °C under N2 protection for 6 hours. After the reactants had completely reacted, the reaction solution was filtered through diatomaceous earth. The filtrate was extracted three times with ethyl acetate (200 mL each time). The organic phases were combined, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (EA:PE = 1:9) to give compound 3 (2.9 g, yield 82%). LCMS (ESI) [M+H] + =381.4

[0412] Step C: Synthesis of Compound 4

[0413] At room temperature, 1.5 g of 10% wet palladium on carbon was added to a THF (50 mL) solution of compound 3 (2.9 g, 7.6 mmol, 1.0 equivalent). The reaction mixture was hydrogenated three times at room temperature for 6 hours. After the reaction was complete, the mixture was filtered through diatomaceous earth, the filter cake was washed with tetrahydrofuran, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (EA:PE = 2:3) to give compound 4 (2.3 g, 88% yield). LCMS (ESI) [M+H] + =353.4

[0414] Step D: Synthesis of Compound 5

[0415] At -78°C, DIBAlH (13 mL, 1.0 M, 13.0 mmol, 2.0 equivalent) was added dropwise to a 20 mL THF solution of compound 4 (2.3 g, 6.5 mmol, 1.0 equivalent). The reaction mixture was stirred at -78°C under nitrogen protection for 2 hours. After the reaction was complete, 10 mL of water, 10 mL of 15% NaOH aqueous solution, and 30 mL of water were added dropwise to the reaction mixture at 0°C. The reaction mixture was filtered, and the filtrate was extracted three times with 200 mL of ethyl acetate each time. The organic phases were combined, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (EA:PE = 1:9) to give compound 5 (1.9 g, 90% yield). LCMS (ESI) [M+H] + =294.4

[0416] Step E: Synthesis of Compound 6

[0417] At -78°C, ethyl magnesium bromide (6.5 mL, 3.0 M, 13.0 mmol, 3.0 equivalent) was added dropwise to a THF (20 mL) solution of compound 5 (1.9 g, 6.5 mmol, 1.0 equivalent). The reaction mixture was stirred at -78°C under nitrogen protection for 2 hours. After the reaction was complete, 10 mL of saturated ammonium chloride aqueous solution was added dropwise to the reaction mixture at 0°C. The reaction mixture was extracted three times with ethyl acetate, 200 mL each time. The organic phases were combined, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (EA:PE = 1:10) to give compound 6 (630 mg, yield 30%). LCMS (ESI) [M-18+1] + =306.4

[0418] Step F: Synthesis of Compound 7

[0419] At room temperature, manganese dioxide (848 mg, 9.7 mmol, 5.0 equivalent) was added to a DCM / THF (16 mL / 4 mL) solution of compound 6 (630 mg, 2.0 mmol, 1.0 equivalent). After reacting at room temperature for 6 hours, the mixture was filtered through diatomaceous earth. The filter cake was washed with DCM, and the filtrate was concentrated under reduced pressure. This reaction was repeated twice. The crude product was purified by column chromatography (EA:PE = 1:3) to give compound 7 (180 mg, 28% yield). LCMS (ESI) [M+H] + =322.4

[0420] Step G: Synthesis of Compound 8

[0421] Compound 9 (147 mg, 0.56 mmol, 1.0 equivalent) and PPTS (15 mg, 0.06 mmol, 0.1 equivalent) were added to a 5 mL solution of compound 7 (180 mg, 0.56 mmol, 1.0 equivalent) in toluene at room temperature. The reaction mixture was stirred at 110 °C for 2 hours under nitrogen protection. After the reaction was complete, the mixture was concentrated under reduced pressure. The crude product was purified by preparative chromatography (EA:PE = 1:1) to give compound 8 (110 mg, 27% yield). LCMS (ESI) [M+H] + =549.6

[0422] Step H: Synthesis of compound C014

[0423] At room temperature, 2 mL of 6.0 M hydrochloric acid in methanol was added dropwise to a MeOH solution (110 mg, 0.2 mmol, 1.0 equivalent). The reaction mixture was stirred at room temperature for 30 minutes. After the reaction was complete, it was concentrated under reduced pressure at low temperature. The crude product was purified by preparative HPLC (Column: Triart C18, 250*20.0 mm*5 μm; 5-95% MeCN in H2O + 0.1% FA) to give compound C014 (40.8 mg, yield 87.1%). LCMS (ESI) [M+H] + =435.2

[0424] 1 H NMR (400MHz, DMSO-d6) δ8.08–7.99(m,1H),7.77–7.70(m,1H),7.55(d,J=6.3Hz,1H),7.31(s,1H),6.52(s,1H),5.44(s,2H),5.35(s,2H),4.7 6–4.55(m,1H),3.52(d,J=4.3Hz,2H),3.28–3.20(m,4H),1.93–1.83(m,2H),1.82–1.74(m,2H),1.32(t,J=7.4Hz,3H),0.88(t,J=7.3Hz,3H).

[0425] Example 15 Synthetic route of C015

[0426] Preparation and synthesis of C015

[0427] Synthesis of Compound 2

[0428] Compound 1 (150.0 g, 177.3 mmol, 1 eq.) was dissolved in 1,2-dichloroethane (500 mL), followed by the addition of ethylene glycol (54.9 g, 886.5 mmol, 48.6 mL, 5 eq.) and p-toluenesulfonic acid (305 mg, 1.77 mmol, 0.01 eq.). The mixture was then stirred at 80 °C for 5 hours. After cooling the reaction solution to 20 °C, it was washed successively with saturated sodium bicarbonate solution (500 mL × 2) and saturated brine (500 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 2 (52.0 g, 90% yield). LCMS-ESI m / z: 327.0 (M+H)+

[0429] 1H NMR (400MHz, CDCl3) δ7.35 (d, J = 7.6Hz, 2H), 6.35 (s, 1H), 4.34-4.28 (m, 2H), 4.12-4.06 (m, 2H).

[0430] Synthesis of Compound 3

[0431] To a toluene (200 mL) solution of compound 2 (20.0 g, 61.3 mmol, 1.0 eq.), diphenylimine (11.0 g, 61.3 mmol, 1.0 eq.), sodium tert-butoxide (11.8 g, 122.6 mmol, 2.0 eq.), Xantphos (3.55 g, 6.13 mmol, 0.1 eq.), and palladium acetate (1.38 g, 6.13 mmol, 0.1 eq.) were added, and the mixture was stirred at 100 °C for 12 hours. The reaction mixture was poured into water (300 mL) and extracted with ethyl acetate (300 mL × 3). The combined organic phases were washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1) to give compound 3 (22 g, yield 84.2%). LCMS-ESI m / z: 426.1(M+H)+.

[0432] Synthesis of Compound 4

[0433] Under nitrogen protection, bis-pinacol boronic acid ester (12.0 g, 47.1 mmol, 2.0 eq.), potassium acetate (4.5 g, 47.1 mmol, 2.0 eq.), and Pd(dppf)Cl2 (3.4 g, 4.70 mmol, 0.2 eq.) were added to an anhydrous 1,4-dioxane (200 mL) solution of compound 3 (10.0 g, 23.5 mmol, 1.0 eq.) in nitrogen atmosphere and the mixture was stirred at 110 °C for 1 h. After cooling to room temperature, water (200 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (250 mL × 2). The organic phases were combined, washed with saturated brine (200 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 8:1) to give compound 4 (9.8 g, yield 88%). LCMS-ESI m / z: 474.3(M+H)+.

[0434] Synthesis of Compound 5

[0435] At 0 °C, sodium hydroxide (592 mg, 14.8 mmol, 2.0 eq.) and 30% hydrogen peroxide (3.35 g, 29.6 mmol, 4.0 eq.) were added sequentially to a tetrahydrofuran (70 mL) solution of compound 4 (3.5 g, 7.40 mmol, 1.0 eq.), and the mixture was stirred for 1 h. The mixture was then heated to room temperature and stirred for another 1 h. The reaction mixture was acidified to pH 6 with 0.1 mol / L dilute hydrochloric acid and extracted with ethyl acetate (150 mL × 2). The combined organic phases were washed sequentially with saturated sodium thiosulfate solution (150 mL × 2) and saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 8:1) to give compound 5 (2.2 g, 6.06 mmol, yield 81%). LCMS-ESI m / z: 364.3(M+H)+.

[0436] Synthesis of Compound 6

[0437] To a solution of compound 5 (2.4 g, 6.61 mmol, 1.0 eq.) in N,N-dimethylformamide (50 mL), (2-bromoethoxy)methylbenzene (1.7 g, 7.93 mmol, 1.2 eq.) and potassium carbonate (1.8 g, 13.2 mmol, 2.0 eq.) were added, followed by stirring at 60 °C for 12 h. After cooling to room temperature, the reaction mixture was filtered, the filtrate was diluted with ethyl acetate (250 mL), washed with saturated brine (150 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude product 6 (3.0 g). This crude product did not require further purification and was used directly in the next reaction. LCMS-ESI m / z: 498.3 (M+H).

[0438] Synthesis of Compound 7

[0439] To a solution of the crude product of compound 6 (3.0 g) in tetrahydrofuran (30 mL), 1 mol / L hydrochloric acid (3 mL) was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with water (100 mL) and extracted with dichloromethane (150 mL × 2). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 reversed-phase column chromatography (0.01% trifluoroacetic acid aqueous solution: acetonitrile = 30:70) to give compound 7 (1.8 g, two-step yield 94%). LCMS-ESI m / z: 290.3(M+H)+.

[0440] Synthesis of Compound 8

[0441] Compound 10 (2.6 g, 9.33 mmol, 1.5 eq.) and PPTS (2.3 g, 9.33 mmol, 1.5 eq.) were added to a toluene (40 mL) solution of compound 7 (1.8 g, 6.22 mmol, 1.0 eq.), and the mixture was stirred at 110 °C for 12 h. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to give compound 8 (1.0 g, 31% yield). LCMS-ESI m / z: 517.2 (M+H)+.

[0442] Synthesis of Compound 9

[0443] At 0 °C, propionaldehyde (337 mg, 5.8 mmol, 10.0 eq.), compound 8 (300 mg, 0.58 mmol, 1.0 eq.), sulfuric acid (1 mL), and 30% hydrogen peroxide (164 mg, 1.45 mmol, 2.5 eq.) were added to a mixed solution of ferrous sulfate heptahydrate (403 mg, 1.45 mmol, 2.5 eq.) and stirred at 0 °C for 0.5 h. The reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (100 mL × 2). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 reversed-phase column chromatography (0.01% trifluoroacetic acid: acetonitrile = 30:70) to give compound 9 (152 mg, yield 48%). LCMS-ESI m / z: 545.3(M+H)+.

[0444] Synthesis of compound C015

[0445] Compound 9 (137 mg, 0.25 mmol, 1.0 eq.) was added to 10 mL of 75% sulfuric acid and stirred at 0 °C for 2 h. The reaction mixture was diluted with 50 mL of water and extracted with dichloromethane (100 mL × 2). The combined organic phases were washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 reversed-phase column chromatography (0.01% trifluoroacetic acid: acetonitrile = 30:70) to give compound C015 (71 mg, yield 64%). LCMS-ESI m / z: 455.3 (M+H)+.

[0446] 1H NMR (400MHz, DMSO-d6): δ7.44(dd,J=2.4Hz,J=10.0Hz,1H),7.29(s,1H),7.14(dd,J=2.4Hz,J=11.2Hz,1H),6.53(s,1H),5.44(s,2H),5.2 9(s,2H),4.25(t,J=4.8Hz,2H),3.90(t,J=4.4Hz,2H),3.44-3.40(m,2H),1.90-1.81(m,2H),1.32(t,J=7.6Hz,3H),0.87(t,J=7.6Hz,3H).

[0447] Example 16 Synthetic route of C016

[0448] Preparation and synthesis of C016

[0449] Synthesis of Compound 2

[0450] Ethylene glycol (54.9 g, 886.5 mmol, 48.6 mL, 5 eq.) and p-toluenesulfonic acid (305 mg, 1.77 mmol, 0.01 eq.) were added to a solution of compound 1 (50.0 g, 177.3 mmol, 1 eq.) in 1,2-dichloroethane (500 mL), and the mixture was stirred at 80 °C for 5 h. After cooling to 20 °C, the mixture was washed successively with saturated sodium bicarbonate solution (500 mL × 2) and saturated brine (500 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 2 (52.0 g, 90% yield) as a yellow solid. LCMS-ESI m / z: 327.0 (M+H)+.

[0451] 1 H NMR (400MHz, CDCl3) δ7.35 (d, J = 7.6Hz, 2H), 6.35 (s, 1H), 4.34-4.28 (m, 2H), 4.12-4.06 (m, 2H).

[0452] Synthesis of Compound 3

[0453] To a toluene (200 mL) solution of compound 2 (20.0 g, 61.3 mmol, 1.0 eq.), diphenylimine (11.0 g, 61.3 mmol, 1.0 eq.), sodium tert-butoxide (11.8 g, 122.6 mmol, 2.0 eq.), Xantphos (3.55 g, 6.13 mmol, 0.1 eq.), and Pd(OAc)₂ (1.38 g, 6.13 mmol, 0.1 eq.) were added, and the mixture was stirred at 100 °C for 12 hours. The reaction mixture was poured into water (300 mL) and extracted with ethyl acetate (300 mL × 3). The combined organic phases were washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1) to give compound 3 (22 g, yield 84.2%). LCMS-ESI m / z: 426.1(M+H)+.

[0454] Synthesis of Compound 4

[0455] Under nitrogen protection, bis-pinacol boronic acid ester (12.0 g, 47.1 mmol, 2.0 eq.), potassium acetate (4.5 g, 47.1 mmol, 2.0 eq.), and Pd(dppf)Cl2 (3.4 g, 4.70 mmol, 0.2 eq.) were added to an anhydrous 1,4-dioxane (200 mL) solution of compound 3 (10.0 g, 23.5 mmol, 1.0 eq.) in nitrogen atmosphere and the mixture was stirred at 110 °C for 1 h. After cooling to room temperature, water (200 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (250 mL × 2). The organic phases were combined, washed with saturated brine (200 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 8:1) to give compound 4 (9.8 g, yield 88%). LCMS-ESI m / z: 474.3(M+H)+.

[0456] Synthesis of Compound 5

[0457] At 0 °C, sodium hydroxide (592 mg, 14.8 mmol, 2.0 eq.) and 30% hydrogen peroxide (3.35 g, 29.6 mmol, 4.0 eq.) were added sequentially to a tetrahydrofuran (70 mL) solution of compound 4 (3.5 g, 7.40 mmol, 1.0 eq.), and the mixture was stirred for 1 h. The mixture was then heated to room temperature and stirred for another 1 h. The reaction mixture was acidified to pH 6 with 0.1 mol / L dilute hydrochloric acid and extracted with ethyl acetate (150 mL × 2). The combined organic phases were washed sequentially with saturated sodium thiosulfate solution (150 mL × 2) and saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 8:1) to give compound 5 (2.2 g, 81% yield). LCMS-ESI m / z: 364.3 (M+H)+.

[0458] Synthesis of Compound 6

[0459] To a solution of compound 5 (2.4 g, 6.61 mmol, 1.0 eq.) in N,N-dimethylformamide (50 mL), (2-bromoethoxy)methylbenzene (1.7 g, 7.93 mmol, 1.2 eq.) and potassium carbonate (1.8 g, 13.2 mmol, 2.0 eq.) were added, followed by stirring at 60 °C for 12 h. After cooling to room temperature, the reaction mixture was filtered, the filtrate was diluted with ethyl acetate (250 mL), washed with saturated brine (150 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude product 6 (3.0 g). This crude product did not require further purification and was used directly in the next reaction. LCMS-ESI m / z: 498.3 (M+H).

[0460] Synthesis of Compound 7

[0461] To a solution of the crude product of compound 6 (3.0 g) in tetrahydrofuran (30 mL), 1 mol / L hydrochloric acid (3 mL) was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with water (100 mL) and extracted with dichloromethane (150 mL × 2). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 reversed-phase column chromatography (0.01% trifluoroacetic acid: acetonitrile = 30:70) to give compound 7 (1.8 g, 94% yield in two steps). LCMS-ESI m / z: 290.3(M+H)+.

[0462] Synthesis of Compound 8

[0463] Compound 12 (2.6 g, 9.33 mmol, 1.5 eq.) and pyridinium p-toluenesulfonate (PPTS, 2.3 g, 9.33 mmol, 1.5 eq.) were added to a toluene (40 mL) solution of compound 7 (1.8 g, 6.22 mmol, 1.0 eq.), and the mixture was stirred at 110 °C for 12 h. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane (DCM):methanol (MeOH) = 20:1) to give compound 8 (1.0 g, 1.94 mmol, yield 31%). LCMS-ESI m / z: 517.2 (M+H)+.

[0464] Synthesis of Compound 9

[0465] A mixture of methanol (10 mL) and water (10 mL) was added to a suspension of compound 8 (650 mg, 1.26 mmol, 1 eq.), followed by the dropwise addition of 96% sulfuric acid (5.3 mL), and then ferrous sulfate heptahydrate (418 mg, 1.5 mmol, 1.2 eq.). At 0 °C, 30% hydrogen peroxide (1 mL, 9.52 mmol, 7.5 eq.) was added dropwise to the resulting mixture, and the reaction was stirred at room temperature for 16 hours. Water (5 mL) was added to the reaction mixture, and the precipitate was filtered off. The precipitate was purified by preparative high-performance liquid chromatography (prep-HPLC) (mobile phase: water-acetonitrile system containing 0.05% trifluoroacetic acid, elution with acetonitrile gradient from 0-65%) to give compound 9 (400 mg, yield 58%). LCMS-ESI m / z: 548.2 (M+H)+.

[0466] Synthesis of Compound 10

[0467] To a solution of compound 9 (400 mg, 0.73 mmol, 1.0 eq.) in dichloromethane (DCM, 10 mL), pyridine (2 mL) and methanesulfonyl chloride (MsCl, 166 mg, 1.46 mmol, 2 eq.) were added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain crude product of compound 10 (500 mg). This crude product did not require further purification and was used directly in the next reaction.

[0468] Synthesis of Compound 11

[0469] To a solution of crude compound 10 (500 mg, 0.73 mmol, 1.0 eq.) in N,N-dimethylformamide (DMF, 10 mL), 4,4-difluoropiperidine (536 mg, 4.45 mmol, 6.1 eq.) was added, followed by stirring at 90 °C for 3 h. The reaction mixture was purified by preparative high-performance liquid chromatography (prep-HPLC) (mobile phase: water-acetonitrile system containing 0.05% trifluoroacetic acid, eluting with acetonitrile gradients from 0-75%) to give compound 11 (160 mg, two-step yield 34%). LCMS-ESI m / z: 650.3 (M+H)+.

[0470] Synthesis of compound C016

[0471] At 0 °C, a solution of boron trichloride (1.0 mol / L n-hexane solution, 2 mL, 8 eq.) was added to a solution of compound 10 (160 mg, 0.25 mmol, 1.0 eq.) in 1,2-dichloroethane (DCE, 10 mL), followed by stirring at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (prep-HPLC) (mobile phase: water-acetonitrile system containing 0.05% trifluoroacetic acid, elution with acetonitrile gradient from 0-50%) to give product C016 (47 mg, 0.084 mmol, yield 34%). LCMS-ESI m / z: 560.3 (M+H)+.

[0472] 1 H NMR (400MHz, CD3OD): δ7.55(s,1H),7.47(d,J=9.6Hz,1H),7.20(d,J=9.6Hz,1H),5.50(d,J=16. 4Hz,1H),5.36(s,2H),5.31(d,J=9.6Hz,1H),5.10-4.90(m,3H),4.42(brs,2H),4.00(t,J=4.4Hz 2H),3.65-3.40(m,3H),2.26(brs,4H),1.91-1.80(m,2H),0.90(t,J=7.2Hz,3H).

[0473] 19 F NMR(400MHz,DMSO-d6)δ106.9,101.1,95.0,73.9ppm

[0474] Example 17 Synthetic route of C017

[0475] Preparation and synthesis of C017

[0476] Synthesis of Compound 2

[0477] At room temperature, ethylene glycol (5.5 g, 88.68 mmol, 5.0 eq.), triethyl orthoformate (2.6 g, 17.74 mmol, 1.0 eq.), and p-toluenesulfonic acid (TsOH, 30.5 mg, 0.17 mmol, 0.01 eq.) were added to a solution of compound 1 (5.0 g, 17.74 mmol, 1.0 eq.) in 1,2-dichloroethane (DCE, 100 mL). The mixture was then stirred at 80 °C for 16 h. After cooling to room temperature, the reaction mixture was washed successively with saturated sodium bicarbonate solution (50 mL × 2) and saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 2 (5.4 g, 93% yield). LCMS-ESI m / z 327.0 (M+H)+.

[0478] 1 H NMR (400MHz, CDCl3) δ7.35 (d, J = 7.6Hz, 2H), 6.34 (s, 1H), 4.28-4.34 (m, 2H), 4.05-4.11 (m, 2H).

[0479] Synthesis of Compound 3

[0480] At -65 °C, a THF solution (10 mL) of compound 2 (5.4 g, 16.57 mmol, 1.0 eq.) was added dropwise to a solution of lithium diisopropylaminodimethylamine (LDA, 2.0 mol / L THF solution, 11 mL, 1.3 eq.) in anhydrous tetrahydrofuran (THF, 50 mL), followed by stirring of the reaction mixture for 1 hour. Iodomethane (1.24 mL, 19.88 mmol, 1.2 eq.) was added dropwise at -65 °C, and the mixture was stirred at this temperature for 2 hours. The mixture was then heated to room temperature and stirred for 12 hours. The reaction was quenched by adding water (20 mL), and extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (eluent: petroleum ether / ethyl acetate = 90 / 10) to give compound 3 (4.5 g, 80% yield). LCMS-ESI m / z 341.0(M+H)+.

[0481] 1 H NMR (400MHz, CDCl3): 7.33 (d, J = 8.4Hz, 1H), 6.43 (s, 1H), 4.28-4.37 (m, 2H), 4.03-4.12 (m, 2H), 2.33 (d, J = 2.4Hz, 3H).

[0482] Synthesis of Compound 4

[0483] Under a nitrogen atmosphere, benzophenone imine (2.5 g, 13.90 mmol, 1.05 eq.), sodium tert-butoxide (t-BuONa, 2.5 g, 26.47 mmol, 2.0 eq.), Xantphos (766 mg, 1.32 mmol, 0.1 eq.), and palladium acetate (Pd(OAc)2, 297 mg, 1.32 mmol, 0.1 eq.) were added to a toluene (100 mL) solution of compound 3 (4.5 g, 13.24 mmol, 1.0 eq.). The reaction mixture was then stirred at 100 °C for 16 h. After cooling to room temperature, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by rapid column chromatography (eluent: petroleum ether / ethyl acetate = 90 / 10) to give compound 4 (3.8 g, 65% yield). LCMS-ESI m / z 440.1 (M+H)+.

[0484] 1 H NMR (400MHz, DMSO-d6) δ7.66(d,J=7.2Hz,2H),7.56(t,J=6.6Hz,1H),7.48(t,J=7.2Hz,2H),7.35(s,3H),7.26(d ,J=5.6Hz,2H),6.31(d,J=10.4Hz,1H),6.23(s,1H),3.97-4.03(m,2H),3.86-3.92(m,2H),2.15(d,J=1.6Hz,3H).

[0485] Synthesis of Compound 5

[0486] Under a nitrogen atmosphere, potassium acetate (2.5 g, 25.89 mmol, 3.0 eq.), bis-pinacol boronic acid ester (2.6 g, 10.36 mmol, 1.2 eq.), and Pd(dppf)Cl2 (316 mg, 0.43 mmol, 0.05 eq.) were added to an anhydrous dimethyl sulfoxide (DMSO, 50 mL) solution of compound 4 (3.8 g, 8.63 mmol, 1.0 eq.). The reaction mixture was then stirred at 110 °C for 1 h under a nitrogen atmosphere. After cooling to room temperature, water (50 mL) was added to the mixture, and the mixture was filtered and extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (eluent: petroleum ether / ethyl acetate = 90 / 10) to give compound 5 (1.8 g, 43% yield). LCMS-ESI m / z 488.4(M+H)+.

[0487] Synthesis of Compound 6

[0488] At 0 °C, sodium hydroxide (295 mg, 7.39 mmol, 2.0 eq.) and 30% hydrogen peroxide (1.7 g, 15.0 mmol, 4.0 eq.) were added sequentially to a tetrahydrofuran (THF, 20 mL) solution of compound 5 (1.8 g, 3.69 mmol, 1.0 eq.), and the mixture was stirred for 1 h. The mixture was then heated to room temperature and stirred for another 1 h. The reaction mixture was acidified to pH 6 with 0.1 mol / L hydrochloric acid and extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed sequentially with saturated sodium thiosulfate solution (20 mL × 2) and saturated brine (30 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (eluent: petroleum ether / ethyl acetate = 90 / 10) to give compound 6 (1.1 g, 79% yield). LCMS-ESI m / z 378.3(M+H)+.

[0489] 1 H NMR (400MHz, DMSO-d6) δ8.80(d,J=0.8Hz,1H),7.65(d,J=6.8Hz,2H),7.54(t,J=7.2Hz,1H),7.47(t,J=7.4Hz,2H),7.34-7.35(m,3H ),7.25(dd,J=3.6Hz,6.4Hz,2H),5.98(s,1H),5.70(d,J=10.4Hz,1H),4.07-4.16(m,2H),3.84-3.93(m,2H),1.91(d,J=1.2Hz,3H).

[0490] Synthesis of Compound 7

[0491] At room temperature, (2-bromoethoxy)methylbenzene (752 mg, 3.50 mmol, 1.2 eq.) and potassium carbonate (1.0 g, 7.29 mmol, 2.5 eq.) were added to a solution of compound 6 (1.1 g, 2.91 mmol, 1.0 eq.) in N,N-dimethylformamide (DMF, 20 mL), followed by stirring at 50 °C for 16 h. After cooling to room temperature, the reaction mixture was filtered, the filtrate was diluted with ethyl acetate (50 mL), washed with saturated brine (15 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (eluent: petroleum ether / ethyl acetate = 90 / 10) to give compound 7 (1.2 g, 80% yield). LCMS-ESI m / z 512.3 (M+H)+.

[0492] Synthesis of Compound 8

[0493] At room temperature, 2 mol / L hydrochloric acid (2 mL) was added to a tetrahydrofuran (THF, 20 mL) solution of compound 7 (1.2 g, 2.35 mmol, 1.0 eq.), and the mixture was stirred for 2 hours. The reaction mixture was diluted with water (20 mL) and extracted with dichloromethane (15 mL × 2). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 reversed-phase column chromatography (mobile phase: water-acetonitrile solution containing 0.01% trifluoroacetic acid, acetonitrile ratio 30%) to give compound 8 (600 mg, yield 84%). LCMS-ESI m / z 304.3(M+H)+.

[0494] 1 H NMR(400MHz,DMSO-d6)δ10.21(s,1H),7.26-7.37(m,5H),6.14(d,J=12.4Hz,1 H),4.55(s,2H),4.17-4.19(m,2H),3.77-3.79(m,2H),1.91(d,J=1.6Hz,3H).

[0495] Synthesis of Compound 9

[0496] At room temperature, compound 12 (781 mg, 2.97 mmol, 1.5 eq.) and PPTS (288 mg, 2.97 mmol, 1.5 eq.) were added to a toluene (10 mL) solution of compound 8 (600 mg, 1.98 mmol, 1.0 eq.), and the mixture was then stirred at 110 °C for 16 h. The reaction mixture was filtered to remove the solvent, and the residue was purified directly by C18 reversed-phase column chromatography (mobile phase: water-acetonitrile solution containing 0.01% trifluoroacetic acid, acetonitrile ratio 30%) to give compound 9 (580 mg, yield 55%). LCMS-ESI m / z 531.3 (M+H)+.

[0497] Synthesis of Compound 10

[0498] At 0 °C, 2-chloroacetaldehyde (40% aqueous solution, 370 mg, 1.88 mmol, 9.9 eq.) and 1 drop of hydrogen peroxide (H2O2) were added to a suspension of compound 9 (100 mg, 0.19 mmol) and ferrous sulfate heptahydrate (FeSO4·7H2O, 131 mg, 0.47 mmol) in 75% sulfuric acid (3 mL), and the mixture was stirred at this temperature for 15 min. The reaction mixture was diluted with ice water (10 mL) and extracted with ethyl acetate (EtOAc, 20 mL × 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (eluting with a gradient of ethyl acetate / petroleum ether = 1:1 to 2:1) to give compound 10 (30 mg, yield 27%). LCMS-ESI m / z 579.3(M+H)+.

[0499] Synthesis of Compound 11

[0500] At 0 °C, 4,4-difluoropiperidine (376 mg, 3.1 mmol) was added to a solution of compound 10 (180 mg, 0.31 mmol) in N,N-dimethylformamide (DMF, 6 mL), followed by stirring of the reaction mixture at room temperature for 1 hour. The reaction solution was purified by reversed-phase high-performance liquid chromatography (C18 column, mobile phase: water-acetonitrile solution containing 10 mmol / L trifluoroacetic acid, acetonitrile gradient elution of 10%-55%) to give compound 11 (120 mg, yield 58%). LCMS-ESI m / z 664.3(M+H)+.

[0501] Synthesis of compound C017

[0502] At 0 °C, boron trichloride (BCl3, 1.44 mL, 1.44 mmol) was added to a solution of compound 11 (120 mg, 0.18 mmol) in 1,2-dichloroethane (DCE, 10 mL), and the reaction mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (prep-HPLC) (mobile phase: water-acetonitrile system containing 0.05% trifluoroacetic acid, elution with acetonitrile gradient from 0-45%) to give product C017 (34 mg, yield 28%). LCMS-ESI m / z 574.4 (M+H)+.

[0503] 1H NMR (400MHz, DMSO-d6): δ9.22-9.06(m,0.5H),7.88(br,1H),7.34(s,1H),6.59(br,1H),5.68-5.07(m,6H),4. 12-3.70(m,4H),3.40-3.30(m,6H),2.45(s,3H),2.27-2.08(m,2H),1.97-1.82(m,2H),0.87(t,J=7.2Hz,3H).

[0504] Example 18 Synthetic route of C018

[0505] Preparation and synthesis of C018

[0506] Synthesis of Compound 2

[0507] Under a nitrogen atmosphere, iodomethane (50.7 g, 357.2 mmol, 2.0 eq.) was added to a mixture of compound 1 (25 g, 178.6 mmol, 1.0 eq.) and cesium carbonate (Cs₂CO₃, 145.5 g, 446.4 mmol, 2.5 eq.) in N,N-dimethylformamide (DMF, 250 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate (EtOAc, 300 mL) and washed with 0.5 mol / L hydrochloric acid (500 mL × 3). The organic phase was then washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 2 (24 g, 87% yield). LCMS-ESI m / z 155.0 (M+H)⁺.

[0508] Synthesis of Compound 3

[0509] To a solution of compound 2 (24 g, 155.8 mmol, 1.0 eq.) in dichloromethane (DCM, 500 mL), m-chloroperoxybenzoic acid (m-CPBA, 40.3 g, 233.8 mmol, 1.5 eq.) was added, and the mixture was stirred at 50 °C for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give crude product 3 (30 g). This crude product did not require further purification and was used directly in the next reaction step.

[0510] Synthesis of Compound 4

[0511] Triethylamine (TEA, 30 mL) was added to a methanol (MeOH, 300 mL) solution of the crude product of compound 3 (30 g), and the mixture was stirred for 10 minutes. The reaction solution was concentrated under reduced pressure to remove methanol. The residue was dissolved in ethyl acetate (EtOAc, 400 mL), washed successively with water (500 mL × 2) and saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1:1) to give compound 4 (20 g, 90% yield in two steps). LCMS-ESI m / z 141.1 (MH)-.

[0512] Synthesis of Compound 5

[0513] At 0 °C, magnesium chloride (MgCl2, 20.4 g, 214.3 mmol, 3.0 eq.) was added fractionally to an acetonitrile (MeCN, 500 mL) solution of compound 4 (10 g, 71.4 mmol, 1.0 eq.), followed by triethylamine (TEA, 14.4 g, 142.9 mmol, 2.0 eq.) and paraformaldehyde (15 g, 499.8 mmol, 7.0 eq.). The reaction mixture was heated to 85 °C and stirred overnight. After cooling to room temperature, the pH was adjusted to 2–3 with 2 mol / L hydrochloric acid, diluted with water (400 mL), and extracted with ethyl acetate (EtOAc, 200 mL × 2). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (prep-HPLC) (mobile phase: water-acetonitrile system containing 0.1% trifluoroacetic acid, elution gradient of acetonitrile from 0-45%) to give compound 5 (5 g, yield 41%). LCMS-ESI m / z 171.0 (M+H)+.

[0514] Synthesis of Compound 6

[0515] To a solution of compound 5 (5 g, 29.4 mmol, 1.0 eq.) in N,N-dimethylformamide (DMF, 50 mL), (2-bromoethoxy)methylbenzene (9.5 g, 44.1 mmol, 1.5 eq.) and potassium carbonate (K₂CO₃, 12.2 g, 88.2 mmol, 3.0 eq.) was added, and the mixture was heated to 55 °C and stirred for 3 hours. The reaction mixture was diluted with water (500 mL) and extracted with ethyl acetate (EtOAc, 200 mL × 2). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10:1) to give compound 6 (6 g, yield 67%). LCMS-ESI m / z 305.2 (M+H).

[0516] Synthesis of Compound 7

[0517] Under a nitrogen atmosphere, N-bromosuccinimide (NBS, 4.2 g, 23.6 mmol, 1.2 eq.) was added to a mixture of compound 6 (6 g, 19.7 mmol, 1.0 eq.), palladium acetate (Pd(OAc)2, 1.3 g, 5.9 mmol, 0.3 eq.), 4-chloro-2-trifluoromethylaniline (1.9 g, 9.9 mmol, 0.5 eq.) in 1,2-dichloroethane / trifluoroacetic acid (DCE / TFA, 150 mL, v / v 5:1), followed by heating to 60 °C and stirring overnight. The reaction mixture was poured into water (300 mL) and extracted with dichloromethane (DCM, 100 mL × 2). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10:1) to give compound 7 (5.8 g, yield 77%). LCMS-ESI m / z 383.2 (M+H)+.

[0518] Synthesis of Compound 8

[0519] Under a nitrogen atmosphere, Pd₂(dba)₃ (1.4 g, 1.5 mmol, 0.1 eq.) and XantPhos (1.7 g, 3 mmol, 0.2 eq.) were added to a mixture of compound 7 (5.8 g, 15.2 mmol, 1.0 eq.), tert-butyloxycarbonylamine (BocNH₂, 1.9 g, 16.7 mmol, 1.1 eq.), and cesium carbonate (Cs₂CO₃, 14.8 g, 45.3 mmol, 3.0 eq.) in toluene (100 mL), followed by heating to 100 °C and stirring overnight. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (EtOAc, 100 mL × 2). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10:1) to give compound 8 (4.2 g, yield 66%). LCMS-ESI m / z 442.3 (M+Na)+.

[0520] Synthesis of Compound 9

[0521] To a mixture of compound 8 (415 mg, 0.91 mmol, 1.0 equivalent) and compound 12 (391 mg, 1.49 mmol, 1.6 equivalent) in toluene (4 mL), pyridinium p-toluenesulfonate (PPTS, 374 mg, 1.49 mmol, 1.6 equivalent) was added, and the mixture was stirred at 110 °C for 16 h. The reaction mixture was concentrated under reduced pressure, diluted with water (30 mL), and extracted with ethyl acetate (EtOAc, 30 mL × 2). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1:2) to give compound 9 (350 mg, 70% yield). LCMS-ESI m / z 547.2 (M+H)+.

[0522] Synthesis of Compound 10

[0523] At 0 °C, 2-chloroacetaldehyde (505 mg, 6.4 mmol, 1.0 equivalent) was added to a mixture of compound 9 (350 mg, 0.64 mmol, 1.0 equivalent) and ferrous sulfate heptahydrate (FeSO4·7H2O, 445 mg, 1.6 mmol, 2.5 equivalent) in 9 mL of 75% sulfuric acid. This was followed by the addition of 3 drops of hydrogen peroxide, and the mixture was stirred at this temperature for 15 minutes. The reaction mixture was diluted with ice water (20 mL) and extracted with ethyl acetate (EtOAc, 30 mL × 2). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1:2) to give compound 10 (180 mg, yield 47%). LCMS-ESI m / z 595.2(M+H)+.

[0524] Synthesis of Compound 11

[0525] At room temperature, 4,4-difluoropiperidine (366 mg, 3.02 mmol, 10 equivalents) was added to a solution of compound 10 (180 mg, 0.30 mmol, 1.0 equivalent) in N,N-dimethylformamide (DMF, 1 mL), and the mixture was stirred for 1 hour. The reaction mixture was diluted with ice water (20 mL) and extracted with ethyl acetate (EtOAc, 30 mL × 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1:2) to give compound 11 (130 mg, 67% yield). LCMS-ESI m / z 680.3(M+H)+.

[0526] Synthesis of compound C018

[0527] Compound 11 (120 mg, 0.18 mmol, 1.0 equivalent) was added to 75% sulfuric acid (3 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ice water (20 mL), and the pH was adjusted to 5-7 with 5 mol / L sodium hydroxide solution. The mixture was then extracted with dichloromethane (DCM, 20 mL × 8). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was first purified by reversed-phase column chromatography (C18 column; elution system: water-acetonitrile solution containing 0.2% ammonium bicarbonate, acetonitrile ratio 40%) to obtain a crude product, which was further purified by preparative high-performance liquid chromatography (prep-HPLC) (C18 column; elution gradient: water-acetonitrile solution containing 0.1% trifluoroacetic acid, acetonitrile ratio 35%-45%) to obtain product C018 (22 mg, yield 21%). LCMS-ESI m / z 590.2(M+H)+.

[0528] 1 H NMR (400MHz, DMSO-d6): δ9.08(s,1H),7.94(s,1H),7.32(s,1H),6.57(s,1H),5.55-5.02(m,6H),4 .46(s,3H),4.07(s,3H),3.84-3.80(m,5H),2.33(s,3H),1.92-1.83(m,3H),0.88(t,J=7.3Hz,3H).

[0529] 19 F NMR(400MHz,DMSO-d6)δ122.3,73.9ppm

[0530] Example 19 Synthetic route of C019

[0531] Preparation and synthesis of C019

[0532] Synthesis of Compound 2

[0533] At 0 °C, boron tribromide (BBr3, 25 mL) was added to a solution of compound 1 (26.0 g, 112.6 mmol, 1.0 equivalent) in 1,2-dichloroethane (DCE, 50 mL), followed by heating to 80 °C and stirring for 48 hours. The reaction solution was concentrated under reduced pressure, and methanol (MeOH, 50 mL) was added to the residue, followed by further concentration under reduced pressure to give compound 2 (16.6 g, 68% yield). LCMS-ESI m / z 217.1 (M+H)+.

[0534] Synthesis of Compound 3

[0535] To a solution of compound 2 (16.6 g, 76.8 mmol, 1.0 equivalent) in N,N-dimethylformamide (DMF, 35 mL), dibromomethane (17.4 g, 99.8 mmol, 1.3 equivalent) and potassium carbonate (13.8 g, 99.8 mmol, 1.3 equivalent) were added, and the mixture was stirred at 60 °C for 18 hours. The reaction solution was purified by reversed-phase column chromatography (C18 column, elution system: water-acetonitrile solution containing 0.05% trifluoroacetic acid, acetonitrile gradient elution from 0-60%) to give compound 3 (11.4 g, yield 65%). LCMS-ESI m / z: 229.1 (M+H)+.

[0536] Synthesis of Compound 4

[0537] To a solution of compound 3 (11.4 g, 50 mmol, 1.0 equivalent) in dichloromethane (DCM, 50 mL), m-chloroperoxybenzoic acid (m-CPBA, 17.2 g, 100 mmol, 2.0 equivalent) was added, and the mixture was stirred at 40 °C for 18 hours. The reaction mixture was poured into a sodium bicarbonate solution (200 mL) and extracted with dichloromethane (300 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 4 (8.9 g, 73% yield). LCMS-ESI m / z: 245.1 (M+H)+.

[0538] Synthesis of Compound 5

[0539] Potassium hydroxide (KOH, 3.1 g, 54.8 mmol, 1.5 equivalents) was added to an ethanol (EtOH, 25 mL) solution of compound 4 (8.9 g, 36.5 mmol, 1.0 equivalents), and the mixture was stirred at 50 °C for 18 hours. The resulting solution was diluted with water (150 mL) and extracted with dichloromethane (DCM, 200 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reversed-phase column chromatography (C18 column, elution system: water-acetonitrile solution containing 0.05% ammonium bicarbonate, acetonitrile gradient elution from 0-40%) to give compound 5 (4.7 g, yield 60%). LCMS-ESI m / z 217.1 (M+H)+.

[0540] Synthesis of Compound 6

[0541] At 0 °C, tin tetrachloride (SnCl4, 11.2 g, 43.2 mmol, 2.0 equivalent) and dichloro(methoxy)methane (7.4 g, 64.8 mmol, 3.0 equivalent) were added dropwise to a solution of compound 5 (4.7 g, 21.8 mmol, 1.0 equivalent) in dichloromethane (DCM, 30 mL), and the mixture was stirred at room temperature for 1 hour. Ice water (30 mL) was added to the resulting solution, and the mixture was extracted with dichloromethane (50 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude product of compound 6 (4.1 g). This crude product did not require further purification and was used directly in the next reaction. LCMS-ESI m / z 245.1(M+H)+.

[0542] Synthesis of Compound 7

[0543] To a solution of the crude product of compound 6 (4.1 g, 16.7 mmol, 1.0 equivalent) in N,N-dimethylformamide (DMF, 25 mL), (2-bromoethoxy)methylbenzene (7.2 g, 33.4 mmol, 2.0 equivalent) and potassium carbonate (K₂CO₃, 4.6 g, 33.4 mmol, 2.0 equivalent) were added, and the mixture was stirred at 60 °C for 16 h. The reaction solution was purified by reversed-phase column chromatography (C18 column, elution system: water-acetonitrile solution containing 0.05% trifluoroacetic acid, acetonitrile gradient elution from 0-75%) to give compound 7 (1.3 g, two-step yield 16%). LCMS-ESI m / z: 379.1 (M+H)⁺.

[0544] Synthesis of Compound 8

[0545] To a toluene (15 mL) solution of compound 7 (1.3 g, 3.4 mmol, 1.0 equivalent), tert-butyloxycarbonylamine (BocNH2, 481 mg, 4.1 mmol, 1.2 equivalent), Pd2(dba)3 (933 mg, 1.0 mmol, 0.3 equivalent), XantPhos (578 mg, 1.0 mmol, 0.3 equivalent), and cesium carbonate (2.2 g, 6.8 mmol, 2.0 equivalent) were added, and the mixture was heated to 100 °C and stirred for 18 hours. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (EtOAc, 50 mL × 2). The combined organic phases were washed successively with water (30 mL × 2) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10:1) to give compound 8 (985 mg, 70% yield). LCMS-ESI m / z: 438.2 (M+Na)+.

[0546] Synthesis of Compound 9

[0547] To a mixture of compound 8 (985 mg, 2.4 mmol, 1.0 equivalent) and compound 10 (947 mg, 3.6 mmol, 1.5 equivalent) in toluene (10 mL), PPTS (1.2 g, 4.7 mmol, 2.0 equivalent) was added, and the mixture was stirred at 110 °C for 16 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1:2) to give compound 9 (900 mg, yield 71%). LCMS-ESI m / :z 543.2(M+H)+.

[0548] Synthesis of Compound 11

[0549] At 0 °C, 75% sulfuric acid (2.5 mL) and ferrous sulfate heptahydrate (FeSO4·7H2O, 1.1 g, 4.0 mmol, 2.5 equivalence) were added to a methanol / water (MeOH / H2O, 6 mL / 6 mL) mixture of compound 9 (900 mg, 1.7 mmol, 1.0 equivalence) at 0 ℃. Hydrogen peroxide (H2O2, 3 mL) was then added dropwise, and the reaction was stirred at room temperature for 16 hours. The resulting solution was purified by reversed-phase column chromatography (C18 column, elution system: water-acetonitrile solution containing 0.05% trifluoroacetic acid, acetonitrile gradient elution from 0-65%) to give compound 11 (340 mg, yield 35%). LCMS-ESI m / z 573.3(M+H)+.

[0550] Synthesis of Compound 12

[0551] At 0 °C, triethylamine (TEA, 119 mg, 1.2 mmol, 2.0 equivalent) and methanesulfonyl chloride (MsCl, 87 mg, 0.78 mmol, 1.3 equivalent) were added to a dichloromethane (DCM, 6 mL) solution of compound 11 (340 mg, 0.6 mmol, 1.0 equivalent), and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to give crude product 12 (350 mg). This crude product did not require further purification and was used directly in the next reaction. LCMS-ESI: m / z 591.2(M+H)+.

[0552] Synthesis of Compound 13

[0553] To a solution of crude compound 12 (350 mg, 0.6 mmol, 1.0 equivalent) in N,N-dimethylformamide (DMF, 5 mL), 4,4-difluoropiperidine (363 mg, 3 mmol, 5.0 equivalent) was added, and the mixture was stirred at 90 °C for 1 h. The reaction solution was purified by reversed-phase column chromatography (C18 column, elution system: water-acetonitrile solution containing 0.05% trifluoroacetic acid, acetonitrile gradient elution from 0-50%) to give compound 13 (110 mg, two-step yield 27%). LCMS-ESI m / z 676.2 (M+H)+.

[0554] Synthesis of compound C019

[0555] To a solution of compound 13 (110 mg, 0.16 mmol, 1.0 equivalent) in 1,2-dichloroethane (DCE, 4 mL), boron trichloride (BCl3, 1 mL) was added, and the mixture was stirred at room temperature for 1 hour. The resulting solution was purged with nitrogen, and the residue was purified by preparative high-performance liquid chromatography (prep-HPLC) (column: C18; elution gradient: water-acetonitrile solution containing 0.1% trifluoroacetic acid, acetonitrile ratio gradient elution 35%-45%), to give product C019 (28 mg, yield 30%). LCMS-ESI m / z: 586.3 (M+H)+.

[0556] 1 H NMR (400MHz, DMSO-d6): δ9.03(s,1H),7.43(s,1H),7.26(s,1H),6.55(s,1H),6.31(S,2H),5.75-5.59(m,1H),5.44(s,2H ),5.34(s,2H),4.57(s,2H),3.82(s,2H),3.70-3.49(m,5H),2.34-2.21(m,4H),1.91-1.83(m,2H),0.87(t,J=8.0Hz,3H).

[0557] 19 F NMR(400MHz,DMSO-d6)δ101.4,95.1,73.5ppm

[0558] Example 20 Synthetic route of C020

[0559] Preparation and synthesis of CO20

[0560] Synthesis of Compound 2

[0561] A mixture of compound 1 (32.0 g, 0.25 mol) and acrylic acid (prop-2-enoic acid, 17.86 g, 0.25 mol) was stirred at 125 °C for 16 hours. After cooling to room temperature, the reaction mixture was poured into a 1 mol / L sodium hydroxide aqueous solution (250 mL) and extracted with ethyl acetate (EA, 200 mL × 3). The aqueous phase was adjusted to pH 3-4 with 1 mol / L hydrochloric acid and then extracted with ethyl acetate (300 mL × 3). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum to give compound 2 (20.0 g, yield: 40.1%). ESI-MS: m / z = 202.1 [M+1]+

[0562] Synthesis of Compound 3

[0563] Compound 2 (20.00 g, 99.42 mmol) was dissolved in Eaton's reagent (200 mL) and reacted with stirring at 100 °C for 1 hour. The reaction mixture was poured into ice water (200 mL) and extracted with dichloromethane (DCM, 300 mL × 3). The combined organic phases were washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum to give the crude product. The crude product was purified by silica gel column chromatography (eluting: petroleum ether / ethyl acetate = 10:1 → 1:1 gradient elution) to give compound 3 (10.0 g, yield: 54.9%). ESI-MS: m / z = 184.1 [M+1]+

[0564] 1 H NMR (400MHz, CDCl3) δ (ppm) 6.17-6.11 (m, 2H), 4.71 (br, 1H), 3.60-3.56 (m, 2H), 2.68 (t, J = 7.2Hz, 2H).

[0565] Synthesis of Compound 4

[0566] At 0 °C, triethylamine (TEA, 16.57 g, 163.77 mmol) and acetyl chloride (8.57 g, 109.18 mmol) were added to a solution of compound 3 (10.00 g, 54.59 mmol) in dichloromethane (DCM, 100 mL), and the mixture was stirred at 25 °C for 2 hours. The reaction solution was concentrated under vacuum to obtain a crude product, which was purified by silica gel column chromatography (eluting with a gradient of petroleum ether / ethyl acetate = 10:1 → 1:1) to give compound 4 (5.5 g, yield: 44.7%). ESI-MS: m / z = 226.1 [M+1]+

[0567] 1 H NMR (400MHz, CDC) l3 )δ(ppm)7.14(d,J=9.6Hz,1H),6.75-6.70(m,1H),4.17(t,J=6.0Hz,2H),2.79(t,J=6.0Hz,2H),2.37(s,3H).

[0568] Synthesis of Compound 5

[0569] At 25 °C, benzylamine (3.14 g, 29.31 mmol) and triethylamine (TEA, 7.40 g, 73.27 mmol) were added to a toluene (55 mL) solution of compound 4 (5.50 g, 24.42 mmol), and the mixture was stirred at 100 °C for 16 hours. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (EA, 50 mL × 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum to give the crude product. The crude product was purified by silica gel column chromatography (eluting: petroleum ether / ethyl acetate = 10:1 → 3:1 gradient elution) to give compound 5 (4.0 g, yield: 52.4%). ESI-MS: m / z = 313.1 [M+1]+

[0570] 1 H NMR (400MHz, CDCl3) δ (ppm) 9.84 (br, 1H), 7.38-7.27 (m, 5H), 6.21-6.15 (m, 2H), 4.43(d,J=5.6Hz,2H),4.15(t,J=6.0Hz,2H),2.73(t,J=6.4Hz,2H),2.30(s,3H).

[0571] Synthesis of Compound 6

[0572] Palladium hydroxide (Pd(OH)₂, 1.40 g) was added to a methanol (MeOH, 30 mL) solution of compound 5 (2.80 g, 12.81 psi) at 30 °C under a hydrogen atmosphere (20 psi), and the reaction was stirred for 16 hours. After filtration, the filter cake was washed with methanol (30 mL), and the filtrate was concentrated to give compound 6 (1.96 g, yield: 98.3%).

[0573] 1 H NMR (400MHz, CDCl3) δ (ppm) 6.71 (br, 2H), 6.26 (d, J = 9.2Hz, 1H), 6.16 (dd, J = 10.4, 2.4Hz, 1H), 4.15 (t, J = 6.0Hz, 2H), 2.71 (t, J = 6.0Hz, 2H), 2.31 (s, 3H).

[0574] Synthesis of Compound 7

[0575] Compound 9 (3.65 g, 13.86 mmol) and p-toluenesulfonic acid monohydrate (TsOH·H2O, 0.48 g, 2.52 mmol) were added to a toluene (30 mL) solution of compound 6 (2.8 g, 12.60 mmol) at 25 °C, and the mixture was stirred at 100 °C for 16 hours. The reaction solution was concentrated under vacuum to obtain a crude product. Ethyl acetate (EA, 10 mL) was added to the crude product and the mixture was scrubbed for 10 minutes. The mixture was then filtered, and the filter cake was dried to constant weight to give compound 7 (4.0 g, crude product). ESI-MS: m / z = 450.2 [M+1]+

[0576] Synthesis of compound C026

[0577] Compound 7 (1.0 g, 2.22 mmol) was dissolved in 10 mL of 4 mol / L hydrochloric acid / dioxane solution and stirred at 80 °C for 1 hour. The reaction solution was concentrated under vacuum to obtain a crude product, which was purified by preparative thin-layer chromatography (Prep-TLC) (developing solvent: dichloromethane / methanol = 10:1) to give compound C026 (350 mg, yield: 38.6%). ESI-MS: m / z = 408.1 [M+1]+

[0578] 1 H NMR(400MHz, DMSO_d6)δ(ppm)7.27(s,1H),7.12(s,1H),6.96(dd,J=10.0,2.4Hz,1H),6.54(dd,J=11.2,2.4Hz,1H),6.5 0(s,1H),5.43(s,2H),5.18(s,2H),3.46(t,J=6.0Hz,2H),3.21-3.16(m,2H),1.90-1.83(m,2H),0.88(t,J=7.2Hz,3H).

[0579] Synthesis of compound C020

[0580] At 25°C, an ethylene oxide solution (4 mL, 3 mol / L) was added to a solution of compound C026 (350 mg, 0.86 mmol) in acetic acid (HOAc, 4 mL), and the mixture was stirred at 80°C for 1 hour. The reaction solution was concentrated to obtain a crude product, which was purified by preparative thin-layer chromatography (Prep-TLC) (developing solvent: dichloromethane / methanol = 10:1) to give compound C020 (51.22 mg, yield: 13.2%). ESI-MS: m / z = 452.3 [M+1]+

[0581] 1H NMR(400MHz, DMSO_d6)δ(ppm)δ7.27(s,1H),6.99(dd,J=10.4,2.0Hz,1H),6.64(dd,J=12.8,2.4Hz,1H),6.50(s,1H),5.43(s,2H),5.21(s,2 H),4.81(t,J=5.6Hz,1H),3.70(dd,J=11.2,5.6Hz,2H),3.63-3.55(m,4H),3.25(t,J=6.4Hz,2H),1.90-1.83(m,2H),0.87(t,J=7.2Hz,3H).

[0582] Example 21 Synthetic route of C022

[0583] Preparation and synthesis of CO22

[0584] Synthesis of Compound 2

[0585] At room temperature, ethylene glycol (5.5 g, 88.68 mmol, 5.0 equivalent), triethyl orthoformate (2.6 g, 17.74 mmol, 1.0 equivalent), and p-toluenesulfonic acid (TsOH, 30.5 mg, 0.17 mmol, 0.01 equivalent) were added to a solution of compound 1 (5.0 g, 17.74 mmol, 1.0 equivalent) in 100 mL of 1,2-dichloroethane (DCE). The mixture was stirred at 80 °C for 16 h. After cooling to room temperature, the reaction solution was washed successively with saturated sodium bicarbonate solution (50 mL × 2) and saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 2 (5.4 g, 93% yield). LCMS-ESI m / z: 327.0 (M+H)+.

[0586] 1 H NMR (400MHz, CDCl3) δ7.35 (d, J = 7.6Hz, 2H), 6.34 (s, 1H), 4.28-4.34 (m, 2H), 4.05-4.11 (m, 2H).

[0587] Synthesis of Compound 3

[0588] At -65°C, a tetrahydrofuran solution (10 mL) of compound 2 (5.4 g, 16.57 mmol, 1.0 equivalent) was added dropwise to an anhydrous tetrahydrofuran (THF, 50 mL) solution of lithium diisopropylamino (LDA, 2.0 mol / L tetrahydrofuran solution, 11 mL, 1.3 equivalents). The mixture was stirred at this temperature for 1 hour. Then, iodomethane (1.24 mL, 19.88 mmol, 1.2 equivalents) was added dropwise at -65°C, and the mixture was stirred at -65°C for 2 hours. The mixture was then heated to room temperature and stirred for 12 hours. The reaction was quenched with water (20 mL) and extracted with ethyl acetate (50 mL × 2). The combined organic phases were washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by rapid column chromatography (eluent: petroleum ether / ethyl acetate = 90:10) to give compound 3 (4.5 g, 80% yield). LCMS-ESI m / z: 341.0 (M+H)+.

[0589] 1 H NMR (400MHz, CDCl3): 7.33 (d, J = 8.4Hz, 1H), 6.43 (s, 1H), 4.28-4.37 (m, 2H), 4.03-4.12 (m, 2H), 2.33 (d, J = 2.4Hz, 3H).

[0590] Synthesis of Compound 4

[0591] Under a nitrogen atmosphere, benzophenone imine (2.5 g, 13.90 mmol, 1.05 equivalent), sodium tert-butoxide (t-BuONa, 2.5 g, 26.47 mmol, 2.0 equivalent), Xantphos (766 mg, 1.32 mmol, 0.1 equivalent), and Pd(OAc)₂ (297 mg, 1.32 mmol, 0.1 equivalent) were added to a toluene (100 mL) solution of compound 3 (4.5 g, 13.24 mmol, 1.0 equivalent), and the mixture was stirred at 100 °C for 12 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by rapid column chromatography (eluent: petroleum ether / ethyl acetate = 90:10) to give compound 4 (3.8 g, 65% yield). LCMS-ESI m / z: 440.1 (M+H)⁺.

[0592] 1H NMR (400MHz, DMSO-d6) δ7.66(d,J=7.2Hz,2H),7.56(t,J=6.6Hz,1H),7.48(t,J=7.2Hz,2H),7.35(s,3H),7.26(d ,J=5.6Hz,2H),6.31(d,J=10.4Hz,1H),6.23(s,1H),3.97-4.03(m,2H),3.86-3.92(m,2H),2.15(d,J=1.6Hz,3H).

[0593] Synthesis of Compound 5

[0594] Under a nitrogen atmosphere, potassium acetate (2.5 g, 25.89 mmol, 3.0 equivalent), pinacol diborate (2.6 g, 10.36 mmol, 1.2 equivalent), and Pd(dppf)Cl2 (316 mg, 0.43 mmol, 0.05 equivalent) were added to an anhydrous dimethyl sulfoxide (DMSO, 50 mL) solution of compound 4 (3.8 g, 8.63 mmol, 1.0 equivalent), and the mixture was stirred at 110 °C for 1 hour. After cooling the reaction solution to room temperature, water (50 mL) was added, and the mixture was filtered and extracted with ethyl acetate (50 mL × 2). The combined organic phases were washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by rapid column chromatography (eluent: petroleum ether / ethyl acetate = 90:10) to give compound 5 (1.8 g, yield 43%). LCMS-ESI m / z: 488.4(M+H)+.

[0595] Synthesis of Compound 6

[0596] At 0 °C, sodium hydroxide (NaOH, 295 mg, 7.39 mmol, 2.0 equivalent) and 30% hydrogen peroxide (H₂O₂, 1.7 g, 2.91 mmol, 4.0 equivalent) were added sequentially to a tetrahydrofuran (THF, 20 mL) solution of compound 5 (1.8 g, 3.69 mmol, 1.0 equivalent) and stirred for 1 hour. The reaction mixture was then heated to room temperature and stirred for another hour. The system was acidified to pH 6 with 0.1 mol / L hydrochloric acid and extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed sequentially with saturated sodium thiosulfate solution (20 mL × 2) and saturated brine (30 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by rapid column chromatography (eluent: petroleum ether / ethyl acetate = 90:10) to give compound 6 (1.1 g, 79% yield). LCMS-ESI m / z: 378.3(M+H)+.

[0597] 1H NMR (400MHz, DMSO-d6) δ8.80(d,J=0.8Hz,1H),7.65(d,J=6.8Hz,2H),7.54(t,J=7.2Hz,1H),7.47(t,J=7.4Hz,2H),7.34-7.35(m,3H ),7.25(dd,J=3.6Hz,6.4Hz,2H),5.98(s,1H),5.70(d,J=10.4Hz,1H),4.07-4.16(m,2H),3.84-3.93(m,2H),1.91(d,J=1.2Hz,3H).

[0598] Synthesis of Compound 7

[0599] At room temperature, (2-bromoethoxy)methylbenzene (752 mg, 3.50 mmol, 1.2 equivalents) and potassium carbonate (K₂CO₃, 1.0 g, 7.29 mmol, 2.5 equivalents) were added to a solution of compound 6 (1.1 g, 2.91 mmol, 1.0 equivalents) in N,N-dimethylformamide (DMF, 20 mL), and the mixture was stirred at 50 °C for 16 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was diluted with ethyl acetate (50 mL), washed with saturated brine (15 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by rapid column chromatography (eluent: petroleum ether / ethyl acetate = 90:10) to give compound 7 (1.2 g, 80% yield). LCMS-ESI m / z: 512.3 (M+H)⁺.

[0600] Synthesis of Compound 8

[0601] At room temperature, 2 mol / L hydrochloric acid (2 mL) was added to a tetrahydrofuran (THF, 20 mL) solution of compound 7 (1.2 g, 2.35 mmol, 1.0 equivalent), and the mixture was stirred for 2 hours. The system was diluted with water (20 mL) and extracted with dichloromethane (15 mL × 2). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by C18 reversed-phase column chromatography (eluent: water-acetonitrile solution containing 0.01% trifluoroacetic acid, acetonitrile ratio 30%) to give compound 8 (600 mg, yield 84%). LCMS-ESI m / z: 304.3(M+H)+.

[0602] 1H NMR(400MHz,DMSO-d6)δ10.21(s,1H),7.26-7.37(m,5H),6.14(d,J=12.4Hz,1 H),4.55(s,2H),4.17-4.19(m,2H),3.77-3.79(m,2H),1.91(d,J=1.6Hz,3H).

[0603] Synthesis of Compound 9

[0604] Compound 10 (781 mg, 2.97 mmol, 1.5 equivalent) and PPTS (288 mg, 2.97 mmol, 1.5 equivalent) were added to a 10 mL toluene solution of compound 8 (600 mg, 1.98 mmol, 1.0 equivalent) at room temperature, and the mixture was stirred at 110 °C for 16 h. The reaction solution was filtered to remove the solvent, and the residue was directly purified by C18 reversed-phase column chromatography (eluent: water-acetonitrile solution containing 0.01% trifluoroacetic acid, acetonitrile ratio 30%) to give compound 9 (580 mg, yield 55%). LCMS-ESI: m / z 531.3 (M+H)+.

[0605] Synthesis of compound CO22

[0606] Under a nitrogen atmosphere and at 0°C, boron trichloride (BCl3, 1.5 mL, 1.5 mmol) was added to a solution of compound 9 (100 mg, 0.19 mmol) in 1,2-dichloroethane (DCE, 10 mL). After the addition was complete, the reaction solution was heated to room temperature and stirred for 2 hours. The reaction solution was concentrated to obtain a residue, which was purified by reversed-phase high-performance liquid chromatography (HPLC) (column: C18 column; elution gradient: water-acetonitrile solution containing 10 mM trifluoroacetic acid, acetonitrile ratio 15% → 90%) to give compound CO22 (22.3 mg, yield 26%). LCMS-ESI m / z: 441.2 (M+H)+.

[0607] 1 H NMR (400MHz, DMSO-d6): δ8.88(s,1H),7.74(d,J=10.8Hz,1H),7.32(s,1H),6.53(s,1H),5.43(s,2H),5.27(s,2H),5.1 4(s,1H),4.09(t,J=4.4Hz,2H),3.86(d,J=4.0Hz,2H),2.41(d,J=1.2Hz,3H),1.91-1.83(m,2H),0.87(t,J=7.2Hz,3H).

[0608] Example 22 Synthetic route of C023

[0609] Preparation and synthesis of CO23

[0610] Synthesis of Compound 2

[0611] Under a nitrogen atmosphere, iodomethane (50.7 g, 357.2 mmol, 2.0 equivalent) was added to a mixture of compound 1 (25 g, 178.6 mmol, 1.0 equivalent) and cesium carbonate (Cs₂CO₃, 145.5 g, 446.4 mmol, 2.5 equivalent) in N,N-dimethylformamide (DMF, 250 mL). The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate (EtOAc, 300 mL), washed with 0.5 mol / L hydrochloric acid (500 mL × 3), and the organic phase was washed with saturated brine (100 mL). After drying over anhydrous sodium sulfate, the mixture was filtered and concentrated under reduced pressure to give compound 2 (24 g, 87% yield). LCMS-ESI m / z: 155.0 (M+H)⁺.

[0612] Synthesis of Compound 3

[0613] To a solution of compound 2 (24 g, 155.8 mmol, 1.0 equivalent) in dichloromethane (DCM, 500 mL), m-chloroperoxybenzoic acid (m-CPBA, 40.3 g, 233.8 mmol, 1.5 equivalent) was added, and the mixture was stirred at 50 °C for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound 3 (30 g). This crude compound did not require further purification and was used directly in the next reaction step.

[0614] Synthesis of Compound 4

[0615] Triethylamine (TEA, 30 mL) was added to a methanol (MeOH, 300 mL) solution of crude compound 3 (30 g), and the mixture was stirred for 10 minutes. The reaction mixture was concentrated under reduced pressure to remove methanol. The residue was dissolved in ethyl acetate (EtOAc, 400 mL), washed successively with water (500 mL × 2) and saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1:1) to give compound 4 (20 g, two-step yield: 90%). LCMS-ESI m / z: 141.1 (MH)-.

[0616] Synthesis of Compound 5

[0617] At 0 °C, magnesium chloride (MgCl2, 20.4 g, 214.3 mmol, 3.0 equivalent) was added in portions to an acetonitrile (MeCN, 500 mL) solution of compound 4 (10 g, 71.4 mmol, 1.0 equivalent), followed by triethylamine (TEA, 14.4 g, 142.9 mmol, 2.0 equivalent) and paraformaldehyde (15 g, 499.8 mmol, 7.0 equivalent). The reaction mixture was heated to 85 °C and stirred overnight. After cooling to room temperature, the pH was adjusted to 2-3 with 2 mol / L hydrochloric acid, water (400 mL) was added, and the mixture was extracted with ethyl acetate (200 mL × 2). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (prep-HPLC) (elution gradient: water-acetonitrile solution containing 0.1% trifluoroacetic acid, acetonitrile ratio 0% → 45%) to give compound 5 (5 g, yield 41%). LCMS-ESI m / z: 171.0 (M+H)+.

[0618] Synthesis of Compound 6

[0619] At 55 °C, (2-bromoethoxy)methylbenzene (9.5 g, 44.1 mmol, 1.5 equivalents) and potassium carbonate (K₂CO₃, 12.2 g, 88.2 mmol, 3.0 equivalents) were added to a solution of compound 5 (5 g, 29.4 mmol, 1.0 equivalents) in N,N-dimethylformamide (DMF, 50 mL), and the mixture was stirred for 3 hours. Water (500 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (EtOAc, 200 mL × 2). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10:1) to give compound 6 (6 g, yield: 67%). LCMS-ESI m / z: 305.2 (M+H)⁺.

[0620] Synthesis of Compound 7

[0621] Under a nitrogen atmosphere, N-bromosuccinimide (NBS, 4.2 g, 23.6 mmol, 1.2 equivalents) was added to a 1,2-dichloroethane / trifluoroacetic acid mixture (DCE / TFA, 150 mL, v / v) containing compound 6 (6 g, 19.7 mmol, 1.0 equivalents), palladium acetate (Pd(OAc)2, 1.3 g, 5.9 mmol, 0.3 equivalents), and 4-chloro-2-(trifluoromethyl)aniline (1.9 g, 9.9 mmol, 0.5 equivalents). The mixture was then heated to 60 °C and stirred overnight. The reaction mixture was poured into water (300 mL) and extracted with dichloromethane (DCM, 100 mL × 2). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10:1) to give compound 7 (5.8 g, yield 77%). LCMS-ESI m / z: 383.2 (M+H)+.

[0622] Synthesis of Compound 8

[0623] Under a nitrogen atmosphere, tris(dibenzylacetone)dipalladium (Pd2(dba)3, 1.4 g, 1.5 mmol, 0.1 equivalent) and xanthanniphosphine (XantPhos, 1.7 g, 3.0 equivalent) were added to a toluene (100 mL) mixture of compound 7 (5.8 g, 15.2 mmol, 1.0 equivalent), tert-butyloxycarbonylamine (BocNH2, 1.9 g, 16.7 mmol, 1.1 equivalent), and cesium carbonate (Cs2CO3, 14.8 g, 45.3 mmol, 3.0 equivalent). The mixture was then heated to 100 °C and stirred overnight. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (EtOAc, 100 mL × 2). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10:1) to give compound 8 (4.2 g, yield 66%). LCMS-ESI m / z: 442.3 (M+Na)+.

[0624] Synthesis of Compound 9

[0625] At 110 °C, PPTS (374 mg, 1.49 mmol, 1.6 equivalent) was added to a mixture of toluene (4 mL) of compound 8 (415 mg, 0.91 mmol, 1.0 equivalent) and compound 10 (391 mg, 1.49 mmol, 1.6 equivalent), and the mixture was stirred for 16 hours. The reaction mixture was concentrated under reduced pressure, and water (30 mL) was added to the residue. The residue was extracted with ethyl acetate (EtOAc, 30 mL × 2). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1:2) to give compound 9 (350 mg, 70% yield). LCMS-ESI m / z: 547.2 (M+H)+.

[0626] Synthesis of compound C023

[0627] Under a hydrogen atmosphere, 10% palladium on carbon (Pd / C, 100 mg, 0.09 mmol, 0.4 equivalent) was added to a tetrahydrofuran (THF, 100 mL) solution of compound 9 (120 mg, 0.22 mmol, 1.0 equivalent), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (prep-HPLC) (column: C18; elution gradient: water-acetonitrile solution containing 0.2% formic acid, acetonitrile ratio 40%→50%) to give compound C023 (20.8 mg, yield 20%). LCMS-ESI m / z: 457.2 (M+H)+.

[0628] 1 H NMR (400MHz, DMSO-d6): δ8.90(s,1H),7.81(d,J=12.1Hz,1H),7.31(s,1H),6.53(s,1H),5.43(s,2H),5.28(s,2H),5.04(t ,J=5.4Hz,1H),4.30(t,J=4.7Hz,2H),4.03(s,3H),3.83(dd,J=9.7,5.1Hz,2H),1.97-1.78(m,2H),0.88(t,J=7.3Hz,3H).

[0629] 19 F NMR(400MHz,DMSO-d6)δ123.2ppm

[0630] Example 23 Synthetic route of C024

[0631] Preparation and synthesis of CO24

[0632] Synthesis of Compound 2

[0633] At 0 °C, m-chloroperoxybenzoic acid (m-CPBA, 616.6 g, 85% by mass, 3.04 mol) was slowly added to a solution of compound 1 (300.0 g, 2.02 mol) in dichloromethane (DCM, 3 L). After the addition was complete, the mixture was heated to 30 °C and stirred for 16 hours. The reaction solution was washed with sodium bicarbonate solution (3 L) and concentrated. A 10% potassium hydroxide aqueous solution (3 L) was added to the residue, and the mixture was stirred at 30 °C for 2 hours. The system was then adjusted to pH 2 and extracted with ethyl acetate (EA, 2 L × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude compound 2 (270.0 g). ESI-MS: m / z = 137.1 [M⁻¹]⁺

[0634] 1 H NMR (400MHz, CDCl3) δ6.73 (t, J = 8.1Hz, 1H), 6.55–6.39 (m, 2H), 5.95 (s, 2H).

[0635] Synthesis of Compound 3

[0636] Under a nitrogen atmosphere, triethylamine (395.6 g, 3.92 mol), magnesium chloride (MgCl2, 372.2 g, 3.92 mol), and paraformaldehyde (176.0 g, 5.87 mol) were added to compound 2 (270.0 g, 1.94 mol) dissolved in 2.7 L of tetrahydrofuran (THF). The mixture was then heated to 70 °C and stirred for 16 h. The reaction mixture was diluted with 6 L of ethyl acetate (EA) and washed successively with 1 mol / L hydrochloric acid (3 L × 2) and saturated sodium bicarbonate solution (3 L × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 3 (230.0 g, 70.8% yield). ESI-MS: m / z = 167.1 [M+1]+

[0637] 1 H NMR (400MHz, CDCl3) δ10.98(br,1H),9.73(s,1H),7.16(d,J=8.2Hz,1H),6.58(d,J=8.2Hz,1H),6.11(s,2H).

[0638] Synthesis of Compound 4

[0639] [(2-bromoethoxy)methyl]benzene (297.8 g, 1.38 mol) and K₂CO₃ (574.1 g, 4.15 mol) were added to a DMF (2.3 L) solution of compound 3 (230.0 g, 1.38 mol). The mixture was heated to 60 °C and stirred for 16 h. The reaction mixture was then poured into water (8 L) and extracted with EA (2 L × 3). The organic phases were combined, washed with saturated brine (2 L × 3), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (eluent: PE / EA = 20 / 1 to 1 / 1) to give compound 4 (263.0 g, yield 63.2%). ESI-MS: m / z = 301.0 [M+1]+

[0640] 1 H NMR(400MHz, CDCl3)δ10.30(br,1H),7.48(d,J=8.3Hz,1H),7.38–7.27(m,5H),6.6 1(d,J=8.3Hz,1H),6.01(s,2H),4.59(s,2H),4.55–4.50(m,2H),3.82–3.76(m,2H).

[0641] Synthesis of Compound 5

[0642] To a mixed solution of compound 4 (263.0 g, 0.88 mol) in 1,2-dichloroethane (DCE, 2.5 L) and trifluoroacetic acid (TFA, 500 mL), N-bromosuccinimide (NBS, 233.6 g, 1.31 mol) and palladium acetate (Pd(OAc)2, 39.4 g, 0.18 mol) were added, and the mixture was heated to 60 °C and stirred for 16 h. After concentration under reduced pressure, the residue was poured into a saturated sodium bicarbonate solution (3 L) and extracted with dichloromethane (DCM, 1 L × 2). The organic phase was dried over anhydrous sodium sulfate (Na2SO4), filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (eluent: PE / EA = 15 / 1 to 1 / 1) to give compound 5 (160.0 g, yield 48.2%). ESI-MS:m / z=379.0,381.1[M+1]+

[0643] 1 H NMR (400MHz, CDCl3) δ10.23(br,1H),7.60(s,1H),7.38–7.19(m,5H),6.08(s,2H),4.56(s,2H),4.53–4.47(m,2H),3.80–3.73(m,2H).

[0644] Synthesis of Compound 6

[0645] To a solution of compound 5 (160 g, 0.42 mol) in acetic acid (HOAc, 800 mL), a nitric acid / acetic acid mixture (3 / 1 v / v, 800 mL) was added at 0 °C. The mixture was stirred at 0 °C for 1 hour. The reaction mixture was poured into ice water (5 L) and extracted with dichloromethane (DCM, 1 L × 3). The combined organic phases were washed with saturated sodium bicarbonate solution (1 L × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: PE / EA = 15 / 1 to 1 / 1) to give compound 6 (60.0 g, yield 42.5%). ESI-MS: m / z = 333.9 / 335.8 [M+1] +

[0646] 1 H NMR (400MHz, CDCl3) δ10.11(br,1H),6.23(s,2H),4.52–4.46(m,2H),3.99–3.91(m,2H).

[0647] Synthesis of Compound 7

[0648] To a solution of compound 6 (30.0 g, 89.8 mmol) in ethanol (EtOH, 500 mL), 10% palladium on carbon (Pd / C, 5 g, 10% by mass) was added, and the mixture was stirred at 25 °C for 16 hours under a hydrogen atmosphere (15 psi). The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to give compound 7 (20.0 g, 98.9% yield). ESI-MS: m / z = 226.1 [M+1]+

[0649] Synthesis of compound C024

[0650] Compound 8 (24.2 g, 92.1 mmol) and p-toluenesulfonic acid (TsOH, 1.75 g, 10.2 mmol) were added to a toluene (240 mL) solution of compound 7 (23.0 g, 0.1 mol). The mixture was heated to 120 °C and stirred for 16 hours. After filtration, the filter cake was washed with dichloromethane (DCM, 500 mL), and the solid product was collected to give crude product CO24 (18 g, yield 38.96%). 200 mg of crude product CO24 was purified by preparative high-performance liquid chromatography (prep-HPLC) and lyophilized to give compound CO24 (24.58 mg, yield 12.3%). ESI-MS: m / z = 453.3 [M+1]+

[0651] 1H NMR(400MHz,DMSO_d6)δ8.75(s,1H),7.28(s,1H),7.25(s,1H),6.25(s,2H),5.41(s,2H),5.23 (s,2H),4.42(t,J=4.8Hz,2H),3.79(t,J=4.8Hz,2H),1.88-1.82(m,2H),0.87(t,J=7.2Hz,3H).

[0652] Example 24 Synthetic route of C025

[0653] Preparation process:

[0654] Compound C025 was synthesized using C020 as a starting material, following the same synthetic method used for intermediates 8 and 9 of compound C002 and the final product C002 in Example 2. ESI-MS: m / z = 451.3 [M+1]+

[0655] Synthesis of Linker-Payload Compounds

[0656] Example 25 Synthetic route of LC001

[0657] Preparation process:

[0658] Synthesis of Compound 2

[0659] Compound 1 (900 mg, 2.29 mmol) was dissolved in 10 equivalents of 3 M ethylene oxide (2a) in a THF (7.5 mL):H₂O (7.5 mL) mixture, followed by the addition of NaOH (91.74 mg, 2.29 mmol). The reaction mixture was stirred at 25 °C for 4 hours. The target product was detected by liquid chromatography-mass spectrometry (LCMS). The solution was concentrated under vacuum, and the residue was purified by preparative high-performance liquid chromatography (Pre-HPLC) using a Durashell C18(L) column, 10 μm Octopus PLUS, 21.2 × 250 mm, Waters Corporation; gradient elution from 30% acetonitrile / water to 50% acetonitrile / water over 30 minutes, with the water containing 0.1% formic acid), to give compound 2.

[0660] LC-MS(ESI)[M+H] + =437.4

[0661] Synthesis of Compound 3

[0662] Compound 2 (313 mg, 717.14 μmol) and compound 3a (396.27 mg, 1.08 mmol) were dissolved in DCM (8 mL), and then TFA (408.85 mg, 3.59 mmol) was added to the solution. The reaction mixture was stirred and heated to 40 °C for 3 hours. The target product was detected by liquid chromatography-mass spectrometry (LC-MS). The solution was concentrated under vacuum, and the residue was purified by preparative high-performance liquid chromatography (Pre-HPLC) (using a Durashell C18(L) column, 10 μm Octopus PLUS column, 21.2 × 250 mm, Waters Corporation; gradient elution from 35% acetonitrile / water to 70% acetonitrile / water, with water containing 0.1% formic acid) over 30 minutes to give compound 3 (202.00 mg, 271.22 μmol, 37.82% yield).

[0663] LC-MS(ESI)[M+H] + =745.7

[0664] Synthesis of Compound 4

[0665] Compound 3 (402 mg, 539.75 μmol) was dissolved in DMF (5 mL), and diethylamine (197.38 mg, 2.70 mmol) was added to the solution at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour. The target product was detected by liquid chromatography-mass spectrometry (LC-MS). The solution was purified by preparative high-performance liquid chromatography (Pre-HPLC) (using a Durashell C18(L) column, 10 μm Octopus PLUS column, 21.2 × 250 mm, Waters Corporation; gradient elution from 20% acetonitrile / water to 50% acetonitrile / water, with water containing 0.1% formic acid) over 30 minutes to give compound 4 (90.00 mg, 172.23 μmol, 31.91% yield).

[0666] LC-MS(ESI)[M+H] + =523.6

[0667] Synthesis of compound LC001

[0668] Compound 4 (80.90 mg, 103.34 μmol), compound 5 (45 mg, 86.12 μmol), and HATU (49.09 mg, 129.17 μmol) were dissolved in DMF (3 mL), followed by the addition of DIPEA (33.39 mg, 258.35 μmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour. The target product was detected by liquid chromatography-mass spectrometry (LC-MS). The solution was purified by preparative high-performance liquid chromatography (Pre-HPLC) using a Durashell C18(L) column, 10 μm Octopus PLUS column, 21.2 × 250 mm, Waters Corporation; gradient elution from 25% acetonitrile / water to 55% acetonitrile / water, with water containing 0.1% formic acid, over 30 minutes, to give compound LC001 (6.10 mg, 4.18 μmol, 4.85% yield).

[0669] LC-MS(ESI)[M+H] + =1288.0

[0670] 1 H-NMR (400MHz, DMSO-D6) δ8.64(t,J=6.8Hz,1H),8.34(t,J=5.6Hz,1H),8.19-8.12(m,2H),8.02(t,J=5.6Hz,1H),7.72-7.71( m,2H),7.30(s,1H),7.24(d,J=4.0Hz,4H),7.18-7.14(m,2H),7.02(s,2H),6.53(s,1H),5.44(s,2H),5.29(s,2H),4.68(d,J=6 .8Hz,2H),4.54-4.47(m,1H),4.30(s,2H),3.89(s,2H),3.78-3.73(m,2H),3.69(d,J=5.6Hz,2H),3.64-3.46(m,38H),3.07(dd ,J=13.6,4.4Hz,1H),2.85-2.76(m,1H),2.38(t,J=6.8Hz,2H),1.93-1.80(m,2H),1.33(t,J=7.2Hz,3H),0.88(t,J=7.2Hz,3H)

[0671] Example 26 Synthetic route of LC002

[0672] Preparation process:

[0673] Synthesis of Compound 2

[0674] Compound 1 (1 g, 5.88 mmol), HATU (2.46 g, 6.46 mmol), and DIPEA (1.90 g, 14.69 mmol) were dissolved in DMF (20 mL). The reaction mixture was stirred at 0 °C for 1 hour, followed by the addition of compound 2a (2.92 g, 5.88 mmol) and stirring at 0 °C for another hour. The target product was detected by liquid chromatography-mass spectrometry (LC-MS). The solution was extracted with ethyl acetate (30 mL × 3), washed with brine, and dried over anhydrous sodium sulfate. The filtrate was concentrated under vacuum, and the residue was purified by rapid column chromatography (FCC, tetrahydrofuran: petroleum ether = 75-100%) to give compound 2 (3.31 g, 5.09 mmol, 86.69% yield).

[0675] LC-MS(ESI)[M+H] + =650.8

[0676] Synthesis of Compound 3

[0677] Compound 2 (1 g, 1.54 mmol) was dissolved in a 1:1 mixture of TFA (6 mL):DCM (6 mL). The reaction mixture was stirred at 0 °C for 1 hour. The target product was detected by liquid chromatography-mass spectrometry (LC-MS). The solution was concentrated under vacuum to obtain the crude product of compound 3, which could be directly used in the next reaction.

[0678] LC-MS(ESI)[M+H] + =594.7

[0679] Synthesis of Compound 4

[0680] Compound 3 (913 mg, 1.54 mmol), HATU (584.38 mg, 1.54 mmol), and DIPEA (596.27 mg, 4.61 mmol) were dissolved in DMF (15 mL). The reaction mixture was stirred at 0 °C for 1 hour, followed by the addition of compound 4a (386.56 mg, 1.38 mmol), and stirring at 0 °C for another 1 hour. The target product was detected by liquid chromatography-mass spectrometry (LC-MS). The solution was purified by preparative high-performance liquid chromatography (Pre-HPLC) using a Durashell C18(L) column, 10 μm Octopus PLUS, 21.2 × 250 mm, Waters Corporation; gradient elution from 30% acetonitrile / water to 60% acetonitrile / water, with water containing 0.1% formic acid, over 30 minutes, to give compound 4 (530.00 mg, 619.91 μmol, 40.31% yield).

[0681] LC-MS(ESI)[M+H]+ =855.6

[0682] 1 H-NMR (400MHz, DMSO-D6) δ8.98(s,2H),8.80(t,J=5.6Hz,1H),8.17(t,J=5.6Hz, 1H),8.11(d,J=8.0Hz,1H),8.00(t,J=5.6Hz,1H),7.29-7.18(m,5H),4.41(td,J =8.4,4.8Hz,1H),3.77-3.66(m,4H),3.63-3.59(m,2H),3.56-3.41(m,34H),3.1 0-3.03(m,1H),2.89(dd,J=13.6,8.8Hz,1H),2.56(s,3H),2.39(t,J=6.4Hz,2H)

[0683] Synthesis of Compound 5

[0684] Compound 4 (530 mg, 619.91 μmol) was dissolved in DCM (8 mL), and then m-chloroperoxybenzoic acid m-CPBA (374.42 mg, 2.17 mmol) was added to the solution. The reaction mixture was stirred at 25 °C for 12 hours. The target product was detected by liquid chromatography-mass spectrometry (LC-MS). The solution was concentrated under vacuum, and the residue was purified by preparative high-performance liquid chromatography (Pre-HPLC) (using a Durashell C18(L) column, 10 μm Octopus PLUS column, 21.2 × 250 mm, Waters Corporation; gradient elution from 25% acetonitrile / water to 60% acetonitrile / water, with water containing 0.1% formic acid, over 30 minutes) to give compound 5 (330.00 mg, 372.06 μmol, 60.02% yield).

[0685] LC-MS(ESI)[M+H] + =887.9

[0686] Synthesis of compound LC002

[0687] Compound 5 (91.66 mg, 103.34 μmol), compound 6 (45 mg, 86.12 μmol), and HATU (49.09 mg, 129.17 μmol) were dissolved in DMF (3 mL), followed by the addition of DIPEA (33.39 mg, 258.35 μmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour. The target product was detected by liquid chromatography-mass spectrometry (LC-MS). The solution was purified by preparative high-performance liquid chromatography (Pre-HPLC) using a Durashell C18(L) column, 10 μm Octopus PLUS column, 21.2 × 250 mm, Waters Corporation; gradient elution from 25% acetonitrile / water to 60% acetonitrile / water, with water containing 0.1% formic acid, over 50 minutes, to give LC002 (21.50 mg, 13.60 μmol, 15.79% yield).

[0688] LC-MS(ESI)[M+H] + =1391.9

[0689] 1 H-NMR (400MHz, DMSO-D6) δ9.37(s,2H),9.13(t,J=4.8Hz,1H),8.65(t,J=6.4Hz,1H),8.35(t,J=5.6Hz,1H),8.20-8.13(m,2H),8.0 4(t,J=5.6Hz,1H),7.72-7.69(m,2H),7.30-7.23(m,5H),7.18-7.14(m,2H),6.53(s,1H),5.44(s,2H),5.29(s,2H),4.69(d,J=6.8 Hz,2H),4.54-4.49(m,1H),4.30(s,2H),3.89(s,2H),3.77-3.73(m,2H),3.70(d,J=5.6Hz,2H),3.57-3.45(m,41H),3.07(dd,J=14 .0,4.4Hz,1H),2.82(dd,J=13.7,9.6Hz,1H),2.39(t,J=6.4Hz,2H),1.92-1.81(m,2H),1.33(t,J=7.2Hz,3H),0.88(t,J=7.2Hz,3H)

[0690] Example 27 Synthetic route of LC004

[0691] Preparation and synthesis of LC004

[0692] Synthesis of Compound 2

[0693] To a DMF (25 mL) solution of compound C001 (1.1 g, 2.52 mmol) and compound 1 (3.53 g, 12.60 mmol), 4-nitrobenzyl p-toluenesulfonic acid (0.54 g, 1.76 mmol) was added, and the reaction mixture was stirred at 60 °C for 8 h. After the reaction was complete, the reaction mixture was filtered and concentrated. The residue was purified by C18 column chromatography to give compound 2 (890 mg, 1.36 mmol, 53.78% yield).

[0694] LCMS: m / z = [M + H] + 657.4.

[0695] Synthesis of Compound 3

[0696] Pd / C 5% (300 mg, 0.14 mmol) was added to a methanol (15 mL) solution of compound 2 (750 mg, 1.14 mmol). The mixture was stirred at room temperature for 2 h under a hydrogen atmosphere. After the reaction was complete, the mixture was filtered and concentrated to give compound 3 (430 mg, 0.82 mmol, 72.05% yield).

[0697] LCMS: m / z = [M + H] + 523.3.

[0698] Synthesis of compound LC004

[0699] Compound 3 (200 mg, 0.38 mol) and compound 4 (180.84 mg, 0.38 mmol) were dissolved in DMF (5 mL), and HATU (152.81 mg, 0.40 mmol) and DIEA (0.20 mL, 1.15 mmol) were added. The reaction mixture was stirred at room temperature for 1 h. After the reaction was complete, the mixture was filtered and concentrated, and then analyzed by Prep-HPLC (C1000 ppm). 18 LC004 (16.3 mg, 4.36% yield) was obtained by purification of 10-95% MeCN in H2O with 0.1% HCOOH.

[0700] LCMS: m / z = [M + H] + 977.2

[0701] 1HNMR: (400MHz, CD3OD) δ7.75–7.73(m,1H),7.66(s,1H),7.71–7.67(m,1H),7.32–7.18(m,1H),7.17–7.11(m,2H),6.76(s,2H),5.62(d,J= 16.4Hz,1H),5.42(d,J=16.4Hz,1H),5.28(d,J=2.0Hz,2H),4.80–4.77(m,4H),4.59–4.53(m,1H),4.35(s,2H),4.05–4.00(m,2H),3.98–3 .90(m,2H),3.88–3.78(m,5H),3.52–3.47(m,2H),3.41(t,J=7.2Hz,2H),3.30–3.25(m,1H),3.22–3.16(m,1H),3.03–2.93(m,1H),2.23(t ,J=7.6Hz,2H),2.05–1.93(m,2H),1.61–1.54(m,2H),1.54–1.46(m,2H),1.41(t,J=7.2Hz,3H),1.35–1.19(m,3H),1.02(t,J=7.2Hz,3H).

[0702] Example 28 Synthetic route of LC005

[0703] Preparation process:

[0704] Synthesis of Compound 2

[0705] At room temperature, compound 1 (224 mg, 0.61 mmol, 1.5 eq.) and PPTS (20 mg, 0.08 mmol, 0.2 eq.) were added to a solution of compound C007 (190 mg, 0.41 mmol, 1.0 eq.) in 1,2-dichloroethane (DCE, 10 mL). The reaction mixture was heated to 50 °C and stirred for 16 hours. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was directly purified by C18 reversed-phase column chromatography (eluent: 30% acetonitrile (MeCN) aqueous solution containing 0.01% trifluoroacetic acid (TFA)) to give compound 2 (260 mg, yield 83%). LCMS-ESI m / z = 777.3(M+H)+.

[0706] Synthesis of Compound 3

[0707] Diethylamine (DEA, 122 mg, 1.67 mmol, 5.0 eq.) was added to a solution of compound 2 (260 mg, 0.33 mmol, 1.0 eq.) in N,N-dimethylformamide (DMF, 5 mL), and the mixture was stirred at room temperature for 2 hours. The reaction solution was then purified directly by C18 reversed-phase column chromatography (eluent: 30% acetonitrile (MeCN) aqueous solution containing 0.01% trifluoroacetic acid (TFA)) to give compound 3 (175 mg, 94% yield). LCMS-ESI m / z = 555.3(M+H)+.

[0708] Synthesis of compound LC005

[0709] At room temperature, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU, 33 mg, 0.09 mmol, 1.2 eq.) and N,N-diisopropylethylamine (DIPEA, 23 mg, 0.18 mmol, 2.5 eq.) were added to a mixed solution of compound 3 (40 mg, 0.07 mmol, 1.0 eq.) and compound 4 (37 mg, 0.08 mmol, 1.1 eq.) in N,N-dimethylformamide (DMF, 1 mL), and the mixture was stirred at room temperature for 2 hours. The reaction solution was directly purified by preparative high-performance liquid chromatography (Prep-HPLC) [column: Ultimate Prep C18 10μm 21.2×250mm; mobile phase: phase A was an aqueous solution containing 0.1% trifluoroacetic acid (TFA), phase B was acetonitrile (MeCN); elution gradient: phase B increased from 35% to 65% within 8 minutes, and was stopped at 19 minutes; flow rate: 30 mL / min], yielding compound LC005 (28 mg, yield 38%). LCMS-ESI m / z = 1010.3(M+H)+.

[0710] 1H NMR (400MHz, DMSO-d6) δ8.63(t,J=6.6Hz,1H),8.34(t,J=5.6Hz,1H),8.14(d,J=8.0Hz,1H),8.09(t,J=5.4Hz,1H),8.03(t,J=5.6Hz,1H),7. 75(d,J=10.0Hz,1H),7.29(s,1H),7.23-7.26(m,4H),7.14-7.19(m,1H ),6.98(s,2H),5.43(s,2H),5.30(s,2H),4.70(d,J=6.4Hz,2H),4.47- 4.52(m,1H),4.02(s,2H),3.83(s,2H),3.71-3.79(m,6H),3.30-3.36(m,5H),3.06(dd,J=4.0Hz,13.8Hz,1H),2.81(dd,J=9.6Hz,13.6Hz,1H ),2.40(s,3H),2.10(t,J=7.6Hz,2H),1.80-1.91(m,2H),1.41-1.50(m,4H),1.25(t,J=7.2Hz,3H),1.13-1.21(m,2H),0.87(t,J=7.4Hz,3H).

[0711] 19 F NMR(400MHz,DMSO-d6)δ110.8ppm

[0712] Example 29 Synthetic route of LC006

[0713] Preparation process:

[0714] Synthesis of Compound 2

[0715] At room temperature, compound 1 (224 mg, 0.61 mmol, 1.5 eq.) and PPTS (20 mg, 0.08 mmol, 0.2 eq.) were added to a solution of compound C007 (190 mg, 0.41 mmol, 1.0 eq.) in 1,2-dichloroethane (DCE, 10 mL). The mixture was heated to 50 °C and stirred for 16 hours. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was directly purified by C18 reversed-phase column chromatography (eluent: 30% acetonitrile (MeCN) aqueous solution containing 0.01% trifluoroacetic acid (TFA)) to give compound 2 (260 mg, yield 83%). LCMS-ESI m / z = 777.3(M+H)+.

[0716] Synthesis of Compound 3

[0717] Diethylamine (122 mg, 1.67 mmol, 5.0 eq.) was added to a DMF (5 mL) solution of compound 2 (260 mg, 0.33 mmol, 1.0 eq.) at room temperature, and the mixture was stirred for 2 h at room temperature. The reaction solution was directly purified by C18 reversed-phase column chromatography (eluent: 30% MeCN aqueous solution containing 0.01% TFA) to give compound 3 (175 mg, yield 94%). LCMS-ESI m / z = 555.3(M+H)+.

[0718] Synthesis of Compound 4

[0719] At room temperature, HATU (29 mg, 0.08 mmol, 1.2 eq.) and DIPEA (20 mg, 0.16 mmol, 2.5 eq.) were added to a DMF mixture of compound 3 (35 mg, 0.07 mmol, 1.1 eq.) and compound 6 (35 mg, 0.07 mmol, 1.1 eq.) (1 mL), and the mixture was stirred at room temperature for 2 h. The reaction solution was then purified directly by C18 reversed-phase column chromatography (eluent: 30% MeCN aqueous solution containing 0.01% TFA) to give compound 4 (55 mg, yield 84%). LCMS-ESI m / z = 1038.3(M+H)+.

[0720] Synthesis of Compound 5

[0721] DEA (19 mg, 0.25 mmol, 5.0 eq.) was added to a 2 mL solution of compound 4 (55 mg, 0.05 mmol, 1.0 eq.) in DMF, and the mixture was stirred at room temperature for 2 h. The reaction solution was then purified directly by C18 reversed-phase column chromatography (eluent: 30% MeCN aqueous solution containing 0.01% TFA) to give compound 5 (35 mg, yield 81%). LCMS-ESI m / z = 816.3(M+H)+.

[0722] Synthesis of compound LC006

[0723] At room temperature, DIPEA (14 mg, 0.11 mmol, 2.5 eq.) was added to a DMF (1 mL) mixture of compound 5 (35 mg, 0.04 mmol, 1.0 eq.) and compound 7 (32 mg, 0.05 mmol, 1.2 eq.), and the mixture was stirred at room temperature for 2 h. The reaction solution was then purified directly by preparative high-performance liquid chromatography (Prep-HPLC) [column: Ultimate Prep C18 10 μm 21.2 × 250 mm; mobile phase: phase A was an aqueous solution containing 0.1% TFA, phase B was MeCN; elution gradient: phase B increased from 35% to 65% within 8 min, and stopped at 19 min; flow rate: 30 mL / min] to give compound LC006 (20 mg, yield 35%). LCMS-ESI m / z = 1319.4 (M+H)+.

[0724] 1 H NMR (400MHz, DMSO-d6) δ8.63(t,J=6.6Hz,1H),8.34(t,J=5.8Hz,1H),8.18(t,J=5.6Hz,1H),8.13(t,J=8.0Hz,1H),8.02(t,J=5.4Hz,1H),7.7 5(d,J=10.0Hz,1H),7.29(s,1H),7.23-7.24(m,4H),7.14-7.19(m,1H) ,7.02(s,2H),5.43(s,2H),5.30(s,2H),4.70(d,J=6.4Hz,2H),4.48-4. 53(m,1H),4.02(s,2H),3.83(s,2H),3.72-3.77(m,4H),3.69(d,J=5.6 Hz,4H),3.51-3.61(m,15H),3.45-3.47(m,16H),3.30-3.34(m,2H),3.0 6(dd,J=4.4Hz,13.8Hz,1H),2.80(dd,J=10.0Hz,13.4Hz,1H),2.36-2.41(m,5H),1.79-1.91(m,2H),1.23-1.26(m,5H),0.87(t,J=7.2Hz,3H).

[0725] 19 F NMR(400MHz,DMSO-d6)δ110.8ppm

[0726] Example 30 Synthetic route of LC007

[0727] Preparation process:

[0728] Synthesis of Compound 2

[0729] At room temperature, PPTS (42 mg, 0.17 mmol, 0.2 eq.) was added to a mixture of compound C008 (400 mg, 0.83 mmol, 1.0 eq.) and compound 1 (365 mg, 0.99 mmol, 1.2 eq.) in dichloromethane (DCM, 20 mL). The reaction mixture was heated to 50 °C and stirred for 16 hours. After concentration under reduced pressure, the residue was purified by rapid silica gel column chromatography (eluent: DCM / MeOH = 20:1) to give compound 2 (350 mg), which was used directly in the next reaction without further purification. LCMS-ESI m / z = 793.3(M+H)+.

[0730] Synthesis of Compound 3

[0731] At room temperature, diethylamine (DEA, 0.5 mL) was added to a solution of compound 2 (350 mg, 0.44 mmol, 1.0 eq.) in N,N-dimethylformamide (DMF, 5 mL), and the mixture was stirred at room temperature for 1 hour. The reaction solution was purified by reversed-phase column chromatography (column: C18; elution gradient: 40% acetonitrile (MeCN) aqueous solution containing 0.1% trifluoroacetic acid (TFA)) to give compound 3 (150 mg, 0.27 mmol, three-step yield 31%). LCMS-ESI m / z = 571.3 (M+H)+.

[0732] Synthesis of compound LC007

[0733] Compound 4 (91 mg, 0.19 mmol, 1.1 eq.), HATU (100 mg, 0.26 mmol, 1.5 eq.), and N,N-diisopropylethylamine (DIEA, 113 mg, 0.88 mmol, 5 eq.) were added to a DMF (3 mL) solution of compound 3 (100 mg, 0.18 mmol, 1.0 eq.) and the mixture was stirred at room temperature for 20 min. The reaction solution was purified by preparative high-performance liquid chromatography (Prep-HPLC) (column: C18 column; elution gradient: MeCN aqueous solution containing 0.1% TFA from 40% to 50%) to give compound LC007 (65.3 mg, yield 35%). LCMS-ESI m / z = 1025.0 (M+H)+.

[0734] 1H NMR (400MHz, DMSO-d6): δ8.60(t,J=6.6Hz,1H),8.33(t,J=5.8Hz,1H),8.13-8.00(m,3H),7.79(d,J=11.7Hz,1H),7. 28(s,1H),7.25-7.13(m,5H),6.99(s,2H),5.43(s,2H),5.29(s,2H),4.66(d,J=7.2Hz,2H),4.52-4.49(m,1H),1.39 -4.38(m,2H),3.99(s,3H),3.85-3.58(m,9H),3.35(t,J=7.0Hz,4H),3.08-3.03(m,1H),2.81-2.77(m,1H),2.10(t, J=7.4Hz,2H),1.93-1.79(m,2H),1.51-1.39(m,4H),1.28(t,J=7.4Hz,3H),1.23-1.12(m,2H),0.87(t,J=7.3Hz,3H).

[0735] 19 F NMR(400MHz,DMSO-d6)δ127.7,74.6ppm

[0736] Example 31 Synthetic route of LC008

[0737] Preparation process:

[0738] Synthesis of Compound 2

[0739] At room temperature, PPTS (42 mg, 0.17 mmol, 0.2 eq.) was added to a mixture of compound C008 (400 mg, 0.83 mmol, 1.0 eq.) and compound 1 (365 mg, 0.99 mmol, 1.2 eq.) in dichloromethane (DCM, 20 mL). The reaction mixture was heated to 50 °C and stirred for 16 hours. After concentration under reduced pressure, the residue was purified by rapid silica gel column chromatography (eluent: DCM / MeOH = 20:1) to give compound 2 (350 mg), which was used directly in the next reaction without further purification. LCMS-ESI m / z = 793.3(M+H)+.

[0740] Synthesis of Compound 3

[0741] Diethylamine (DEA, 0.5 mL) was added to a DMF (5 mL) solution of compound 2 (350 mg, 0.44 mmol, 1.0 eq.) at room temperature, and the mixture was stirred for 1 hour at room temperature. The reaction solution was purified by reversed-phase column chromatography (C18 column; elution conditions: 40% MeCN aqueous solution containing 0.1% TFA) to give compound 3 (150 mg, 31% yield in three steps). LCMS-ESI m / z = 571.3 (M+H)+.

[0742] Synthesis of Compound 4

[0743] At room temperature, compound 6 (290 mg, 0.58 mmol, 1.1 eq.) and N,N-diisopropylethylamine (DIEA, 340 mg, 2.63 mmol, 5 eq.) were added to a DMF (55 mL) mixture of compound 3 (300 mg, 0.53 mmol, 1.0 eq.) and HATU (300 mg, 0.79 mmol, 1.5 eq.), and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was poured into ice water (20 mL), and a precipitate was formed. The precipitate was collected by filtration and dried under reduced pressure to give crude product 4 (500 mg). This product could be used directly in the next reaction without further purification. LCMS-ESI m / z = 1054.4(M+H)+.

[0744] Synthesis of Compound 5

[0745] Diethylamine (DEA, 0.5 mL) was added to a DMF (5 mL) solution of compound 4 (495 mg, 0.47 mmol, 1.0 eq.) at room temperature, and the mixture was stirred for 1 hour at room temperature. The reaction solution was purified by reversed-phase column chromatography (C18 column; elution conditions: 40% MeCN aqueous solution containing 0.1% TFA) to give compound 5 (280 mg, two-step yield 64%). LCMS-ESI m / z = 832.3 (M+H)+.

[0746] Synthesis of compound LC008

[0747] At room temperature, N,N-diisopropylethylamine (DIEA, 78 mg, 0.6 mmol, 5.0 eq.) was added to a DMF mixture of compound 5 (10 mg, 0.12 mmol, 1.0 eq.) and maleimide-ethylene glycol-succinimide ester (Mal-PEG8-NHS ester, 109 mg, 0.18 mmol, 1.5 eq.) in 1 mL, and the mixture was stirred at room temperature for 1 hour. The reaction solution was purified by preparative high-performance liquid chromatography (prep-HPLC) (column: C18 column; elution gradient: MeCN aqueous solution containing 0.1% TFA from 40% to 50%) to give compound LC008 (43 mg, yield 27%). LCMS-ESI m / z = 1357.2 (M+Na)+.

[0748] 1 H NMR (400MHz, DMSO-d6): δ8.61(t,J=6.7Hz,1H),8.34(t,J=5.9Hz,1H),8.21-8.07(m,2H),8.02(t,J=5.7Hz,1H),7.84-7.75(m,1H),7.28(s,1H),7.25 -7.13(m,5H),7.02(s,2H),5.43(s,2H),5.29(s,2H),4.66(d,J=7.6Hz,2H),4.54-4.48(m,1H),4 .40-4.39(m,2H),3.99(s,3H),3.83-3.81(m,2H),3.78-3.77(m,2H),3.69(d,J=5.6Hz,2H),3.64 -3.54(m,6H),3.51-3.46(dd,J=8.0,3.7Hz,33H),3.36-3.34(m,2H),3.07-3.03(m,1H),2.83-2. 77(m,1H),2.38(t,J=6.5Hz,2H),1.90-1.83(m,2H),1.28(t,J=7.4Hz,3H),0.87(t,J=7.3Hz,3H).

[0749] 19 F NMR(400MHz,DMSO-d6)δ124.7,74.6ppm

[0750] Example 32 Synthetic route of LC009

[0751] Preparation process:

[0752] Synthesis of Compound 2

[0753] Compound C009 (1.0 g, 2.08 mmol) and compound 1 (1.97 g, 3.12 mmol) were dissolved in a mixed solvent of dichloromethane (DCM, 100 mL) and tetrahydrofuran (THF, 100 mL), and then added... Molecular sieve (4.0 g) and scandium trifluoromethanesulfonate (Sc(OTf)3, 2.05 g, 4.16 mmol) were reacted at 25 °C with stirring for 16 hours. The precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (eluting: DCM / MeOH = 100 / 1 to 10 / 1, gradient elution) to give compound 2 (860.0 mg, yield 39.3%). ESI-MS: m / z = 1050.3 [M+1]+

[0754] 1 H NMR(400MHz, DMSO_d6)δ8.60(t,J=5.4Hz,1H),8.39–8.29(m,1H),8.15(d,J=7.6Hz,1H),8.09–7.98(m,1H),7.85(d,J=7.4Hz,2H),7.68(d,J=7.6 Hz,2H),7.58(t,J=5.8Hz,1H),7.38-7.36(m,2H),7.30(d,J=7.4Hz,2H) ,7.24–7.18(m,5H),7.15-7.14(m,1H),6.48(s,1H),6.22(s,2H),5.41(s ,2H),5.20(s,2H),4.63(d,J=6.6Hz,2H),4.49(d,J=3.2Hz,3H),4.27(d ,J=6.8Hz,2H),4.20(d,J=6.6Hz,2H),4.10(d,J=4.8Hz,2H),3.79(s,2H) ,3.74(d,J=5.8Hz,2H),3.63-3.61(m,3H),3.09–2.98(m,1H),2.85–2.74 (m,1H),1.86-1.83(m,3H),1.27(t,J=7.2Hz,3H),0.86(t,J=7.1Hz,3H).

[0755] Synthesis of Compound 3

[0756] Compound 2 (860.0 mg, 0.82 mmol) was dissolved in N,N-dimethylformamide (DMF, 10 mL), and piperidine (1 g, 11.76 mmol) was added. The mixture was stirred at 25 °C for 0.5 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. Dichloromethane (DCM, 3 mL) was added to the crude product, and the mixture was ground for 10 min. The solid was collected after filtration to give compound 3 (600.0 mg, yield 88.5%). ESI-MS: m / z = 828.3 [M+1]+

[0757] Synthesis of compound LC009

[0758] Compound 3 (120 mg, 0.145 mmol) was dissolved in N,N-dimethylformamide (DMF, 2 mL), and succinimide 6-(2,5-dioxo-2,5-dihydro-1H-pyrrolo-1-yl)hexanoate (53.6 mg, 0.174 mmol) was added. The mixture was stirred at 25 °C for 16 hours. After filtration, the filtrate was purified by preparative high-performance liquid chromatography (prep-HPLC) and lyophilized to give product LC009 (15.9 mg, yield: 10.74%). ESI-MS: m / z = 1021.3 [M+1]+

[0759] 1 H NMR(400MHz, DMSO_d6)δ8.60(t,J=6.6Hz,1H),8.32(t,J=5.8Hz,1H),8.12(d,J=8.0Hz,1H),8.08(t,J=5.8Hz,1H),8.02(t,J=5.6Hz,1H), 7.29(s,1H),7.25–7.21(m,5H),7.17–7.14(m,1H),6.99–6.97(m,2H),6.24(s,2H),5.42(s,2H),5.23(s,2H),4.64(d,J=6.8Hz,2H),4.54 –4.48(m,3H),3.82–3.79(m,2H),3.78–3.72(m,2H),3.66(d,J=5.8Hz,2H),3.63–3.58(m,1H),3.37–3.30(m,5H),3.07–3.03(m,1H),2.85 –2.76(m,1H),2.09(t,J=7.2,2H),1.88–1.82(m,2H),1.49–1.41(m,4H),1.28(t,J=7.4Hz,3H),1.24–1.14(m,2H),0.87(t,J=7.4Hz,3H).

[0760] Example 33 Synthetic route of LC010

[0761] Synthesis of Compound 2

[0762] Compound C009 (1.0 g, 2.08 mmol) and compound 1 (1.97 g, 3.12 mmol) were dissolved in a mixed solvent of dichloromethane (DCM, 100 mL) and tetrahydrofuran (THF, 100 mL), and then added... Molecular sieve (4.0 g) and scandium trifluoromethanesulfonate (Sc(OTf)3, 2.05 g, 4.16 mmol) were reacted at 25 °C with stirring for 16 hours. The precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (eluting: DCM / MeOH = 100 / 1 to 10 / 1, gradient elution) to give compound 2 (860.0 mg, yield 39.3%). ESI-MS: m / z = 1050.3 [M+1]+

[0763] 1 H NMR(400MHz, DMSO_d6)δ8.60(t,J=5.4Hz,1H),8.39–8.29(m,1H),8.15(d,J=7.6Hz,1H),8.09–7.98(m,1H),7.85(d,J=7.4Hz,2H),7.68(d,J=7.6 Hz,2H),7.58(t,J=5.8Hz,1H),7.38-7.36(m,2H),7.30(d,J=7.4Hz,2H) ,7.24–7.18(m,5H),7.15-7.14(m,1H),6.48(s,1H),6.22(s,2H),5.41(s ,2H),5.20(s,2H),4.63(d,J=6.6Hz,2H),4.49(d,J=3.2Hz,3H),4.27(d ,J=6.8Hz,2H),4.20(d,J=6.6Hz,2H),4.10(d,J=4.8Hz,2H),3.79(s,2H) ,3.74(d,J=5.8Hz,2H),3.63-3.61(m,3H),3.09–2.98(m,1H),2.85–2.74 (m,1H),1.86-1.83(m,3H),1.27(t,J=7.2Hz,3H),0.86(t,J=7.1Hz,3H).

[0764] Synthesis of Compound 3

[0765] Compound 2 (860.0 mg, 0.82 mmol) was dissolved in N,N-dimethylformamide (DMF, 10 mL), and piperidine (1 g, 11.76 mmol) was added. The mixture was stirred at 25 °C for 0.5 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. Dichloromethane (DCM, 3 mL) was added to the crude product, and the mixture was ground for 10 min. The solid was collected after filtration to give compound 3 (600.0 mg, yield 88.5%). ESI-MS: m / z = 828.3 [M+1]+

[0766] Synthesis of compound LC010

[0767] Compound 3 (70 mg, 0.0845 mmol) was dissolved in N,N-dimethylformamide (DMF, 2 mL), and compound 4 (53 mg, 0.0845 mmol) was added. The mixture was stirred at 25 °C for 16 hours. After filtration, the filtrate was purified by preparative high-performance liquid chromatography (prep-HPLC) and lyophilized to give product LCO10 (16.4 mg, yield: 14.5%). ESI-MS: m / z = 1331.4 [M+1]+

[0768] 1 H NMR (400MHz, DMSO_d6) δ8.60(t,J=6.4Hz,1H),8.32(t,J=5.6Hz,1H),8.17(t,J=5.6Hz,1H),8.11(d,J=7.8Hz,1H),8.02(t,J =5.6Hz,1H),7.29(s,1H),7.28–7.20(m,5H),7.17–7.15(m,1H),7.02(s,2H),6.49(s,1H),6.24(s,2H),5.42(s,2H),5.24(s, 2H),4.64(d,J=6.8Hz,2H),4.54–4.46(m,3H),3.82–3.78(m,2H),3.76–3.65(m,5H),3.63–3.53(m,6H),3.53–3.41(m,28H), 3.05–3.02(m,2H),2.86–2.74(m,2H),2.38(t,J=6.4Hz,2H),1.90–1.81(m,2H),1.28(t,J=7.4Hz,3H),0.87(t,J=7.2Hz,3H).

[0769] Example 34 Synthetic route of LC019

[0770] Preparation process:

[0771] Synthesis of Compound 2

[0772] Compound 1 (486 mg, 1.32 mmol, 3.0 eq.) and PPTS (110 mg, 0.44 mmol, 1.0 eq.) were added to a solution of compound C015 (200 mg, 0.44 mmol, 1.0 eq.) in dichloromethane (DCM, 10 mL), and the mixture was stirred at 50 °C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: DCM / MeOH = 20:1) to give compound 2 (250 mg, yield 74%). LCMS-ESI m / z: 763.2 (M+H)+.

[0773] Synthesis of Compound 3

[0774] To a solution of compound 2 (250 mg, 0.33 mmol, 1.0 eq.) in N,N-dimethylformamide (DMF, 10 mL), diethylamine (240 mg, 3.28 mmol, 10.0 eq.) was added, and the mixture was stirred at 25 °C for 30 min. The reaction solution was concentrated under reduced pressure, and the residue was purified by C18 reversed-phase column chromatography (eluent: aqueous solution containing 0.01% TFA / MeCN = 30:70) to give compound 3 (50 mg, yield 28%). LCMS-ESI m / z: 541.3 (M+H)+.

[0775] Synthesis of compound LC019

[0776] Compound 4 (53 mg, 0.11 mmol, 1.2 eq.), HATU (70 mg, 0.19 mmol, 2.0 eq.), and N,N-diisopropylethylamine (DIEA, 48 mg, 0.37 mmol, 4.0 eq.) were added to a solution of compound 3 (50 mg, 0.19 mmol, 2.0 eq.) in N,N-diisopropylethylamine (DIEA, 48 mg, 0.37 mmol, 4.0 eq.), and the mixture was stirred at 25 °C for 30 min. The reaction solution was purified by C18 reversed-phase column chromatography (eluent: aqueous solution containing 0.01% TFA / MeCN = 30:70) to give compound LC019 (33 mg, yield 36%). LCMS-ESI m / z: 995.2 (M+H)+.

[0777] 1H NMR (400MHz, DMSO-d6) δ8.64(t,J=6.4Hz,1H),8.35(t,J=5.6Hz,1H),8.14(d,J=7.9Hz,1H),8.06(dt,J=19.3,5.4 Hz,2H),7.45(dd,J=9.8,2.2Hz,1H),7.29(s,1H),7.23(m,4H),7.15(m,2H),6.99(s,2H),5.44(s,2H),5.28(s,2H) ,4.68(d,J=6.6Hz,2H),4.50(s,1H),4.34(s,2H),3.89(s,2H),3.83–3.71(m,6H),3.35(t,J=7.0Hz,4H),3.06(m,1 H),2.81(m,1H),2.10(t,J=7.4Hz,2H),1.86(m,2H),1.45(m,5H),1.31(m,3H),1.18(m,2H),0.87(t,J=7.2Hz,3H).

[0778] Example 35 Synthetic route of LC020

[0779] Preparation process:

[0780] Synthesis of Compound 2

[0781] Compound 1 (316 mg, 0.86 mmol, 3.0 eq.) and PPTS (72 mg, 0.29 mmol, 1.0 eq.) were added to a solution of compound C016 (160 mg, 0.29 mmol, 1.0 eq.) in dichloromethane (DCM, 10 mL), and the mixture was stirred at 50 °C for 72 hours. The reaction solution was concentrated under vacuum to obtain a crude product, which was purified by reversed-phase column chromatography (column: C18 column, 120 g; elution gradient: MeCN aqueous solution containing 0.1% TFA from 2% to 50%) to give compound 2 (100 mg, yield 40%).

[0782] Synthesis of Compound 3

[0783] To a solution of compound 2 (100 mg, 0.11 mmol, 1.0 eq.) in N,N-dimethylformamide (DMF, 2 mL), diethylamine (85 mg, 1.15 mmol, 10.0 eq.) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was purified by reversed-phase column chromatography (column: C18, 120 g; elution gradient: MeCN aqueous solution containing 0.1% TFA from 2% to 50%) to give compound 3 (60 mg, 80% yield). LCMS-ESI m / z: 646.3 (M+H)+.

[0784] Synthesis of compound LC020

[0785] Compound 4 (44 mg, 0.09 mmol, 1.0 eq.), HATU (71 mg, 0.19 mmol, 2.0 eq.), and N,N-diisopropylethylamine (DIEA, 48 mg, 0.37 mmol, 4.0 eq.) were added to a solution of compound 3 (60 mg, 0.19 mmol, 2.0 eq.) in N,N-dimethylformamide (DMF, 4 mL). The mixture was stirred at room temperature for 15 min. The reaction solution was purified by reversed-phase column chromatography (column: C18, 120 g; elution gradient: MeCN aqueous solution containing 0.1% TFA from 2% to 50%) to give compound LC020 (42 mg, yield 41%). LCMS-ESI m / z: 1100.3(M+H)+.

[0786] 1 H NMR (400MHz, DMSO-d6) δ8.78(s,1H),8.65(m,1H),8.33(t,J=5.8Hz,1H),8.15(d,J=7.7Hz,1H),8.09(t,J=5.6Hz,1H),8.05(d,J =5.3Hz,1H),7.66(d,J=9.0Hz,1H),7.45(d,J=11.0Hz,1H),7.35(s,1H),7.28–7.13(m,5H),6.99(s,2H),6.60(s,1H),5.41(d,J= 36.7Hz,4H),4.68(d,J=6.5Hz,2H),4.48(s,3H),3.92(s,2H),3.78–3.61(m,11H),3.35(t,J=7.1Hz,2H),3.03(d,J=9.9Hz,1H), 2.79(m,1H),2.41–2.21(m,4H),2.09(t,J=7.5Hz,2H),1.93–1.79(m,2H),1.45(m,4H),1.24–1.10(m,2H),0.87(t,J=7.3Hz,3H).

[0787] Example 36 Synthetic route of LC021

[0788] Preparation process:

[0789] Synthesis of Compound 2

[0790] To a solution of compound CO20 (100 mg, 0.22 mmol, 1.0 eq.) in dichloromethane (DCM, 5 mL), PPTS (5 mg, 0.022 mmol, 0.1 eq.) and compound 1 (118 mg, 0.32 mmol, 1.4 eq.) were added, and the mixture was stirred at 50 °C for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by reversed-phase column chromatography (eluent: aqueous solution containing 0.01% TFA / acetonitrile (CH3CN) = 30 / 70) to give compound 2 (50 mg, 30% yield). LCMS-ESI m / z = 760.4 (M+H)+.

[0791] Synthesis of Compound 3

[0792] Compound 2 (50 mg, 0.065 mmol) was dissolved in N,N-dimethylformamide (DMF, 1 mL), and piperidine (28 mg, 0.325 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The solution was then purified by reversed-phase column chromatography (eluent: aqueous solution containing 0.01% TFA / acetonitrile (CH3CN) = 30 / 70) to give compound 3 (30 mg, yield 86%). LCMS-ESI m / z = 538.2 (M+H)+.

[0793] Synthesis of compound LC021

[0794] Compound 3 (30 mg, 0.056 mmol, 1.0 eq.) was dissolved in N,N-dimethylformamide (DMF, 2 mL), and compound 4 (26 mg, 0.056 mmol, 1.0 eq.), HATU (22 mg, 0.056 mmol, 1.0 eq.), and N,N-diisopropylethylamine (DIPEA, 14.5 mg, 0.112 mmol, 2.0 eq.) were added. The mixture was stirred at room temperature for 2 hours. The reaction solution was purified by reversed-phase column chromatography (eluent: aqueous solution containing 0.01% TFA / acetonitrile (CH3CN) = 30 / 70) to give compound LCO21 (24 mg, yield 43%). LCMS-ESI m / z = 992.3(M+H)+.

[0795] 1H NMR (400MHz, DMSO-d6): δ8.53(t,J=5.6Hz,1H),8.28(t,J=6.4Hz,1H),8.12-8.02(m,3H),7.78(s,1H),7.22–7.1 3(m,5H),7.01-6.96(m,3H),6.65(d,J=6.4Hz,3H),5.42(s,2H),5.16(s,2H),4.59(d,J=6.4Hz,2H),4.46-4.42( m,1H),3.80-3.77(m,8H),3.65–3.60(m,4H),3.45–3.40(m,3H),3.35–3.30(m,2H),3.05-3.00(m,1H),2.90-2.8 5(m,1H),2.11(t,J=7.2Hz,2H),1.90-1.80(m,2H),1.45-1.40(m,4H),1.23-1.20(m,2H),0.88(t,J=7.2Hz,3H).

[0796] Example 37 Synthetic route of LC022

[0797] Preparation process:

[0798] Synthesis of Compound 2

[0799] At room temperature, compound 1 (201 mg, 0.56 mmol, 4.0 eq.) and PPTS (24 mg, 0.10 mmol, 0.7 eq.) were added to a solution of compound CO22 (60 mg, 0.14 mmol, 1.0 eq.) in dichloromethane (DCM, 10 mL), and the mixture was stirred at 50 °C for 24 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: DCM / MeOH = 20:1) to give compound 2 (40 mg, yield 39%). LCMS-ESI m / z: 749.5 (M+H)+.

[0800] Synthesis of Compound 3

[0801] At room temperature, diethylamine (39 mg, 0.53 mmol, 10.0 eq.) was added to a solution of compound 2 (40 mg, 0.05 mmol, 1.0 eq.) in N,N-dimethylformamide (DMF, 2 mL), followed by stirring at 25 °C for 30 min. The reaction solution was concentrated under reduced pressure, and the residue was purified by C18 reversed-phase column chromatography (eluent: aqueous solution containing 0.01% TFA / MeCN = 30:70) to give compound 3 (30 mg, yield 87%). LCMS-ESI m / z: 527.4 (M+H)+.

[0802] Synthesis of compound LC022

[0803] At room temperature, compound 4 (27 mg, 0.06 mmol, 1.0 eq.), HATU (26 mg, 0.07 mmol, 1.2 eq.), and N,N-diisopropylethylamine (DIEA, 15 mg, 0.11 mmol, 2.0 eq.) were added to a solution of compound 3 (30 mg, 0.05 mmol, 1.0 eq.) in N,N-dimethylformamide (DMF, 3 mL), and the mixture was stirred at 25 °C for 1 hour. The reaction mixture was purified by C18 reversed-phase column chromatography (eluent: aqueous solution containing 0.01% TFA / MeCN = 30:70) to give compound LCO22 (30 mg, 60% yield). LCMS-ESI m / z: 981.6 (M+H)+.

[0804] Example 38 Synthetic route of LC023

[0805] Preparation process:

[0806] Synthesis of Compound 2

[0807] At room temperature, PPTS (5 mg, 0.022 mmol, 0.1 eq.) and compound 1 (118 mg, 0.32 mmol, 1.4 eq.) were added to a solution of compound C024 (100 mg, 0.22 mmol, 1.0 eq.) in dichloromethane (DCM, 5 mL), and the mixture was stirred at 50 °C for 18 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by reversed-phase column chromatography (eluent: aqueous solution containing 0.01% TFA / acetonitrile (CH3CN) = 30:70) to give compound 2 (50 mg, 30% yield). LCMS-ESI m / z = 761.4 (M+H)+.

[0808] Synthesis of Compound 3

[0809] At room temperature, piperidine (28 mg, 0.325 mmol, 5.0 eq.) was added to a solution of compound 2 (50 mg, 0.065 mmol, 1.0 eq.) in N,N-dimethylformamide (DMF, 1 mL), and the mixture was stirred at room temperature for 2 hours. The reaction solution was purified by reversed-phase column chromatography (eluent: aqueous solution containing 0.01% TFA / acetonitrile (CH3CN) = 30:70) to give compound 3 (30 mg, yield 86%). LCMS-ESI m / z = 539.2 (M+H)+.

[0810] Synthesis of compound LC023

[0811] Compound 3 (30 mg, 0.056 mmol, 1.0 eq.) was dissolved in N,N-dimethylformamide (DMF, 2 mL), and compound 4 (26 mg, 0.056 mmol, 1.0 eq.) and HATU (22 mg, 0.056 mmol, 1.0 eq.) were added. The mixture was stirred at room temperature for 10 min. Then, N,N-diisopropylethylamine (DIPEA, 14.5 mg, 0.112 mmol, 2.0 eq.) was added to the reaction mixture, and the mixture was stirred at room temperature for another 2 h. The reaction mixture was purified by reversed-phase column chromatography (eluent: aqueous solution containing 0.01% TFA / acetonitrile (CH3CN) = 30:70) to give compound LCO23 (24 mg, 43% yield). LCMS-ESI m / z = 993.3(M+H)+.

[0812] 1 H NMR (400MHz, DMSO-d6): δ9.81(s,1H),8.46(d,J=5.6Hz,1H),8.24(d,J=6.9Hz,1H),8.10(dd ,J=16.3,7.9Hz,2H),7.58(d,J=8.5Hz,2H),7.44–7.10(m,9H),5.36(t,1H),4.93–4.74(m,4 H),4.39–4.29(m,2H),4.11(s,2H),3.80-3.77(m,3H),3.55–3.49(m,4H),3.26(d,J=11.6Hz ,2H),3.03–2.88(m,8H),1.44(d,J=6.3Hz,3H),1.31(d,J=7.1Hz,3H),1.23(d,J=7.1Hz,3H)

[0813] Example 39: Preparation of ADC

[0814] Take 0.1 mL of antibody (trastuzumab for injection). Add 50 mg / mL of TCEP (tris(2-carboxyethyl)phosphine) to the reaction tube and dilute to 10 mg / mL with PBS (pH 7.4). Add 66.67 μL of 10 mM TCEP (tris(2-carboxyethyl)phosphine) to the antibody solution, mix well, and let stand at room temperature for 3 hours. Add 50 μL of DMSO solution containing 30 mg / mL Linker-Payload to the above solution system, mix well, and let stand at room temperature for 4 hours. After the reaction is complete, ultrafilter the solution to histidine-hydrochloric acid (pH 6.0) using a 30,000 MWCO protein concentrator. Obtain the antibody conjugates, and then perform DAR value detection by HIC-HPLC. The results are shown in Table 1.

[0815] Table 1. Quality analysis results of ADC samples

[0816] Cell viability test

[0817] Example 1: Cell killing experiment of Payload

[0818] SK-BR-3 (ATCC), CAPAN-1 (ATCC), MDA-MB-468 (ATCC), U-87MG (Nanjing Kebai), NCI-H292 (Nanjing Kebai), LOVO (Nanjing Kebai), MDA-MB-453 (Nanjing Kebai), AGS (Nanjing Kebai) cells, and NCI-N87 (Nanjing Kebai), JIMT-1 (Nanjing Kebai), Calu-3 (ATCC), HCC1954 (Nanjing Kebai), HCC1569 (Nanjing Kebai), BT474 (ATCC), KPL-4 (Nanjing Kebai) cells were selected as cell lines for in vitro detection. 2000 cells were seeded per well in a 96-well cell culture plate. The payload to be tested was first prepared as a stock solution using DMSO, and then... The FBS cell culture medium was prepared into 10 concentration gradients: 10000, 2000, 400, 80, 16, 3.2, 0.64, 0.128, 0.0256, and 0 μg / mL. Equal volumes of these solutions were added to 96-well cell culture plates and incubated at 37°C in a 5% CO2 incubator for 96 hours. After incubation, the cell culture plates were removed from the incubator and allowed to stand at room temperature for 30 minutes. An equal volume of CTG (Promega) was added and mixed thoroughly. After standing for 10 minutes, the luminescence value was measured using an M5 microplate reader, and the IC50 was calculated. 50 The test results are shown in Table 2. The results show that the newly developed payload has superior cell-killing activity.

[0819] Table 2 Results of cell viability test

[0820] Example 2: Cell killing effect of ADC

[0821] SK-BR-3 and MDA-MB-468, as well as NCI-N87, JIMT-1, MDA-MB-453, Calu-3, HCC1569, BT474, KPL-4, and Capan-1 cells were selected as cell lines for in vitro detection. 2000 cells per well were seeded in 96-well cell culture plates. The ADC to be tested was prepared in 10% FBS medium to create 10 concentration gradients (1000, 200, 40, 8, 1.6, 0.32, 0.064, 0.0128, 0.00256, and 0 nM) of the above-mentioned cell culture medium. Equal volumes of these solutions were added to the 96-well cell culture plates and incubated at 37°C in a 5% CO2 incubator for 144 h. After incubation, the cell culture plates were removed from the incubator and allowed to stand at room temperature for 30 min. Add an equal volume of CTG to the culture medium and mix well. After standing for 10 minutes, measure the luminescence value using an M5 microplate reader and calculate the IC50. 50 Results. The cell-killing results of SK-BR-3 cells are shown in Table 3, and the cell-killing results of MDA-MB-468 cells are shown in Table 4. The results show that the newly developed payload-corresponding ADC has superior cell-killing activity.

[0822] Table 3: SK-BR-3 cell killing results

[0823] Table 4: Results of MDA-MB-468 cell killing

[0824] Example 3: ADC endocytosis activity experiment

[0825] ADC endocytic activity was detected using SK-BR-3 and CAPAN-1 cells via FACS. Cells were digested with trypsin and washed once with FACS buffer (PBS containing 1% BSA). After centrifugation, cells were resuspended in FACS buffer and the cell density was adjusted to 4 × 10⁻⁶ cells / year. 6Cells were centrifuged at 20 μg / mL and pre-chilled on ice for 30 minutes. The sample was diluted with FACS buffer to 20 μg / mL and pre-chilled on ice for 30 minutes. An equal volume of cell suspension and diluted sample was added to an EP tube, and the tubes were incubated at 4°C for 2 hours, followed by washing three times with pre-chilled FACS buffer. Cells were resuspended in 250 μL of pre-chilled FACS buffer. 100 μL of cell suspension and 1.1 mL of pre-chilled FACS buffer were added to a 37°C preheated EP tube, and 100 μL of cell suspension and 1.1 mL of pre-chilled FACS buffer were added to a 4°C pre-chilled EP tube. At 0, 1, 2, 4, and 20 hours, 100 μL of the resulting mixture was transferred to pre-chilled 96-well plates. After centrifugation, cells were added to PE-labeled goat anti-human IgG secondary antibody in pre-chilled FACS buffer. After incubation at 4°C for 1 hour, the cells were washed twice with pre-chilled FACS buffer. Cell fluorescence was detected by flow cytometry (Backman CytoFLEX) after resuspending cells in PBS. Endocytosis activity (%) = (1 - MFI 37℃ / MFI 4℃) × 100.

[0826] Experimental results: The relevant ADCs have a good cellular endocytosis effect.

[0827] Example 4: Bystander Kill of ADC

[0828] HER2-positive SK-BR-3 cells and HER2-negative MDA-MB-468 cells were mixed at a ratio of 2:1, 2×10⁻⁶ 5 Add one sample to each well of a 6-well plate, then add an equal volume of sample to bring the final concentration to 1 nM. Incubate at 37°C in a 5% CO2 cell incubator for 4 days. After incubation, digest and collect the cells for counting. Drug-treated cells are then treated with PE-labeled goat anti-human IgG (…). For secondary antibody staining (catalog number AB98596), control cells were first incubated with HER2 antibody for 30 min, washed, and then stained with PE-labeled goat anti-human IgG. After secondary antibody incubation, the cells were washed, and the proportion of PE-positive and PE-negative cells was analyzed by flow cytometry. The absolute number of PE-positive and PE-negative cells in each group was calculated based on the total cell count. PE-positive cells were HER2-positive cells SK-BR-3, and PE-negative cells were HER2-negative cells MDA-MB-468.

[0829] Experimental results: The relevant ADCs have high bystander kill activity.

[0830] Example 5: In vivo efficacy of ADC

[0831] Antitumor effects of HER2-ADC in Balb / c nude mouse models with subcutaneous transplantation of human tumor cells.

[0832] Tumor cells NCI-N87, JIMT-1, MDA-MB-453, Calu-3, HCC1569, BT474, KPL-4, and Capan-1 were subcutaneously in Balb / c nude mice.

[0833] Based on tumor volume and animal weight, mice were randomly divided into 6 groups of 5 mice each, with an average tumor volume of approximately 150-200 mm. 3 The drug is administered via tail vein injection, as a single dose.

[0834] Tumor volume is presented as mean ± SEM. Tumor volume comparisons between groups were performed using Student's t-test / ANOVA. A p-value < 0.05 was considered statistically significant. Graphpad Prism 8.0 software was used for analysis.

[0835] The formula for calculating tumor volume (TV) is: TV = 0.5 × major diameter × minor diameter 2 .

[0836] Tumor inhibition rate (TGI): TGI = [1 - (average tumor volume at each measurement in a certain treatment group - average tumor volume at the start of administration in that treatment group) / (average tumor volume at each measurement in the negative control group - average tumor volume at the start of administration in the negative control group)] × 100%.

[0837] Tumor volume changes in each group were observed until day 42 during this trial, and the corresponding tumor inhibition rates of each treatment group compared with the PBS group (day 42). Compared with the PBS group, all ADC administration groups significantly inhibited tumor growth.

[0838] Example 6: Liver microsomal stability and plasma stability

[0839] Liver microsomal metabolic stability test

[0840] Experimental objective: To detect the metabolic stability of the disclosed compound in liver microsomes of different species.

[0841] The experimental materials are shown in Table 5 below.

[0842] Table 5

[0843] Experimental Methods: Each incubation system contained phosphate-buffered saline (PBS, pH 7.4), liver microsomal protein, the test sample (acetonitrile solution), and NADPH. Incubation was performed in a water bath at 37°C. The reaction was terminated by adding 3 volumes of ice-cold acetonitrile (containing internal standard) after 0, 5, 15, 30, and 60 min. After centrifugation, 150 μL of the supernatant was collected and 150 μL of ultrapure water was added. The remaining content of the original substrate was determined by LC-MS / MS. The parameters of liver microsomal metabolism were calculated using first-order kinetic equations, as shown in Table 6 below.

[0844] Table 6. Liver microsomal stability of the compounds disclosed herein

[0845] Conclusion: The compounds of this disclosure exhibit a faster metabolic rate and shorter metabolic half-life in terms of liver microsomal stability, which can reduce the risk of toxic side effects caused by the corresponding ADC free load. In particular, the compounds of this disclosure are more effective in terms of rat liver microsomal stability and human liver microsomal stability. Therefore, the compounds of this disclosure have better metabolic properties as ADC loads.

[0846] Plasma stability test

[0847] The experimental materials are shown in Table 7 below.

[0848] Table 7

[0849] Experimental Methods: A stock solution (10 mmol concentration) for each test compound was prepared using dimethyl sulfoxide (DMSO). The stock solution for each compound was then diluted to a concentration of 100 μmol with 50% acetonitrile. Plasma incubation experiments were performed in duplicate in 96-well plates at 37°C. A total volume of 495 μL of plasma was preheated at 37°C for 5 minutes. Then, 5 μL of a 100 μmol concentration of the test compound or positive control was added to the incubation well containing plasma and mixed with a pipette to obtain a homogeneous suspension. Immediately afterward, 60 μL of the incubation solution was transferred as the 0-hour sample to the well of the "quench" plate and mixed with a pipette. At 0, 15, 30, 60, and 120 minutes, the incubation solution was mixed with a pipette, and at each time point, a 60 μL sample of the incubation solution was sequentially transferred to the well of a separate "quench" plate and mixed with a pipette. Add 300 μL of acetonitrile containing the internal standard to the "quenching" plate. Centrifuge the 96-well plate at 6000 g for 10 minutes. After centrifugation, aliquot 100 μL of the supernatant into each well of a 96-well plate, each well containing 100 μL of pure water. Analyze the aliquots by liquid chromatography-tandem mass spectrometry (LC / MS / MS). The peak area ratio of the test compound to the internal standard will be plotted as the percentage (residual percentage) of the relevant zero-time point control in each reaction.

[0850] The metabolic rate (k) is the slope of a linear regression of the logarithm of the remaining percentage against the incubation time. The in vitro half-life (T1 / 2) is calculated as -0.693 / k.

[0851] Table 8. Plasma stability of the disclosed compounds

[0852] Conclusion: The compounds of this disclosure exhibit rapid metabolic rate and short metabolic half-life in terms of plasma stability, which can reduce the risk of toxic side effects caused by the corresponding ADC plasma free load. In particular, the compounds of this disclosure show better stability in mouse and human plasma, thus the compounds of this disclosure have better metabolic properties as ADC loads.

Claims

A camptothecin-type compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, wherein the camptothecin-type compound is a compound as shown in Formula II: in, R 5 and R 6 Independent of H, D, halogen, C 1-12 Alkyl or C 1-12 alkoxy; or, R 5 and R 6 Together with the carbon atoms they are attached to, they form 5-6 membered carbon rings or 5-6 membered heterocycles; X is -O- or -N(R) 9 )-; R 7 For H or by one or more R 7-1 Replacement C 1-12 Alkyl; R 7-1 Independently hydroxyl, amino, or halogen; When X is -O-, R 8 For hydrogen, C 1-12 Alkyl or with one or more R 8-1 Replacement C 1-12 Alkyl; R 8-1 Independently hydroxyl, amino, halogen, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, with one or more R 8-1-1 Replacement C 3-10 cycloalkyl, with one or more R 8-1-2 Substituted 3-10 membered heterocyclic alkyl groups or -N(R) 8-1-3 )C(O)-R 8-1-4 ; R 8-1-1 and R 8-1-2 Independently hydroxyl, amino, or halogen; R 8-1-3 For H, C 1-12 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, with one or more R 8a Replacement C1-C 12 Alkyl, with one or more R 8b Replacement C 3-10 cycloalkyl or with one or more R 8c Substituted 3-10 membered heterocyclic alkyl groups; R 8-1-4 C 1-12 Alkyl or with one or more R 8d Replacement C 1-12 alkyl; R 8a R 8b R 8c and R 8d Independently hydroxyl, amino, or halogen; When X is -N(R) 9 When )-, R 8 and R 9 And the nitrogen and carbon atoms connected to it form 5-6 member nitrogen-containing heterocycles. The camptothecin-like compound, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof as described in claim 1, is characterized in that... The camptothecin-like compounds satisfy any of the following schemes: Option 1: R 5 and R 6 Independent of H, D, halogen, C 1-12 Alkyl or C 1-12 alkoxy; or, R 5 and R 6 Together with the carbon atoms they are attached to, they form 5-6 membered carbon rings or 5-6 membered heterocycles; X is -O- or -N(R) 9 )-; R 7 For one or more R 7-1 Replacement C 1-12 Alkyl; R 7-1 Independently hydroxyl, amino, or halogen; When X is -O-, R 8 For hydrogen, C 1-12 Alkyl or with one or more R 8-1 Replacement C 1-12 Alkyl; R 8-1 Independently hydroxyl, amino, halogen, C 4-10 Cycloalkyl, 4-10 membered heterocyclic alkyl, with one or more R 8-1-1 Replacement C 4-10 cycloalkyl, with one or more R 8-1-2 Substituted 4-10 membered heterocyclic alkyl groups or -N(R) 8-1-3 )C(O)-R 8-1-4 ; R 8-1-1 and R 8-1-2 Independently hydroxyl, amino, or halogen; R 8-1-3 For H, C 1-12 Alkyl, C 4-10 Cycloalkyl, 4-10 membered heterocyclic alkyl, with one or more R 8a Replacement C1-C 12 Alkyl, with one or more R 8b Replacement C 4-10 cycloalkyl or with one or more R 8c Substituted 4-10 membered heterocyclic alkyl groups; R 8-1-4 C 1-12 Alkyl or with one or more R 8d Replacement C 1-12 alkyl; R 8a R 8b R 8c and R 8d Independently hydroxyl, amino, or halogen; When X is -N(R) 9 When )-, R 8 and R 9 And the nitrogen and carbon atoms it connects to form 5-6 member nitrogen-containing heterocycles; Option 2: R 5 and R 6 Independent of H, D, halogen, C 1-12 Alkyl or C 1-12 alkoxy; or, R 5 and R 6 Together with the carbon atoms they are attached to, they form 5-6 membered carbon rings or 5-6 membered heterocycles; X is -O- or -N(R) 9 )-; R 7 For one or more R 7-1 Replacement C 1-12 Alkyl; R 7-1 Independently hydroxyl, amino, or halogen; When X is -O-, R 8 C 1-12 Alkyl or with one or more R 8-1 Replacement C 1-12 Alkyl; R 8-1 Independently hydroxyl, amino, halogen, C 4-10 Cycloalkyl, 4-10 membered heterocyclic alkyl, with one or more R 8-1-1 Replacement C 4-10 cycloalkyl, with one or more R 8-1-2 Substituted 4-10 membered heterocyclic alkyl groups or -N(R) 8-1- 3 )C(O)-R 8-1-4 ; R 8-1-1 and R 8-1-2 Independently hydroxyl, amino, or halogen; R 8-1-3 For H, C 1-12 Alkyl, C 4-10 Cycloalkyl, 4-10 membered heterocyclic alkyl, with one or more R 8a Replacement C1-C 12 Alkyl, with one or more R 8b Replacement C 4-10 cycloalkyl or with one or more R 8c Substituted 4-10 membered heterocyclic alkyl groups; R 8-1-4 C 1-12 Alkyl or with one or more R 8d Replacement C 1-12 alkyl; R 8a R 8b R 8c and R 8d Independently hydroxyl, amino, or halogen; When X is -N(R) 9 When )-, R 8 and R 9 And the nitrogen and carbon atoms connected to it form 5-6 member nitrogen-containing heterocycles. The camptothecin-like compound, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof as described in claim 1 or 2, is characterized in that... The camptothecin-like compounds satisfy one or more of the following conditions: (1)R 5 and R 6 In, the C 1-12 Alkyl groups are independently C 1-6 alkyl; (2)R 5 and R 6 In, the C 1-12 Alkyl groups are independently C 1-6 Alkoxy; (3)R 5 R 6 R 7-1 R 8-1 R 8-1-1 R 8-1-2 R 8a R 8b R 8c and R 8d In this context, the halogen is independently fluorine, chlorine, bromine, or iodine; (4) When R 5 and R 6 When the carbon atom it is attached to forms a 5-6 membered heterocycle, the 5-6 membered heterocycle is a 5-6 membered saturated or unsaturated heterocycle with O or N heteroatoms, and the number of heteroatoms can be 1 or 2. (5)R 7 In the context, "by one or more R" 7-1 Replacement C 1-12 The "C" in "alkyl" 1-12 "alkyl" is independently C 1-6 alkyl; (6)R 8 R 8-1-3 and R 8-1-4 In the middle, the "C" 1-12 Alkyl group, "with one or more R 8-1 Replacement C 1-12 Alkyl group, "with one or more R 8a Replacement C1-C 12 Alkyl" and "with one or more R 8d Replacement C1-C 12 The "C" in "alkyl" 1-12 "alkyl" is independently C 1-6 alkyl; (7)R 8-1 and R 8-1-3 In the text, the "3-10 membered heterocyclic alkyl", "with one or more R" 8-1-2 Substituted 3-10 membered heterocyclic alkyl groups and "with one or more R 8c The "3-10-membered heterocyclic alkyl" in "substituted 3-10-membered heterocyclic alkyl" is independently a 4-10-membered heterocyclic alkyl, for example, a 4-10-membered monocyclic or polycyclic heterocyclic alkyl with heteroatoms selected from N, O or S and having 1, 2 or 3 heteroatoms; (8) When X is -N(R) 9 )-, R 8 and R 9 When the nitrogen atom and carbon atom connected thereto form a 5-6 member nitrogen-containing heterocycle, the 5-6 member nitrogen-containing heterocycle is a 5-6 member saturated nitrogen-containing heterocycle with N heteroatom and 1 heteroatom. and (9)R 8-1 and R 8-1-3 In the middle, the "C" 3-10 "cycloalkyl", "with one or more R" 8-1-1 Replacement C 3-10 "cycloalkyl", "with one or more R" 8b Replacement C 3-10 The "C" in "cycloalkyl" 3-10 "Cycloalkyl" is independently C 4-10 Cycloalkyl. The camptothecin-like compounds, their pharmaceutically acceptable salts, their solvates, or solvates of their pharmaceutically acceptable salts as described in claim 3 are characterized in that... The camptothecin-like compounds satisfy one or more of the following conditions: (1) The R 5 and R 6 In the middle, the "C" 1-12 "alkyl" is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, for example, methyl; (2) The R 5 and R 6 In, the C 1-12 The alkoxy group is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy, such as methoxy; (3) The R 5 R 6 R 7-1 R 8-1 R 8-1-1 R 8-1-2 R 8a R 8b R 8c and R 8d In this context, the halogen is independently fluorine; (4) When R 5 and R 6 When the carbon atom it is attached to forms a 5-6 membered heterocycle, the 5-6 membered heterocycle is a 5-membered saturated or unsaturated heterocycle with O as the heteroatom and 2 heteroatoms. (5) The R 7 In the context, "by one or more R" 7-1 Replacement C 1-12 The "C" in "alkyl" 1-12 "alkyl" is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, for example, ethyl; (6) The R 8 R 8-1-3 and R 8-1-4 In the middle, the "C" 1-12 Alkyl group, "with one or more R 8-1 Replacement C 1-12 Alkyl group, "with one or more R 8a Replacement C1-C 12 Alkyl" and "with one or more R 8d Replacement C1-C 12 The "C" in "alkyl" 1-12 "alkyl" is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, such as methyl or ethyl; (7) The R 8-1 and R 8-1-3 In the text, the "3-10 membered heterocyclic alkyl", "with one or more R" 8-1-2 Substituted 3-10 membered heterocyclic alkyl groups and "with one or more R 8c In the phrase "substituted 3-10-membered heterocyclic alkyl", "3-10-membered heterocyclic alkyl" is independently a 5-6-membered saturated heterocyclic alkyl with heteroatoms of O or N, and the number of heteroatoms can be independently one or two, for example... and (8)R 8-1 and R 8-1-3 In the middle, the "C" 3-10 "cycloalkyl", "with one or more R" 8-1-1 Replacement C 3-10 "cycloalkyl", "with one or more R" 8b Replacement C 3-10 The "C" in "cycloalkyl" 3-10 "Cycloalkyl" is independently C 5-6 Cycloalkyl. The camptothecin-like compound, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof as described in claim 1 or 2, is characterized in that... The camptothecin-like compounds satisfy one or more of the following conditions: (1)R 5 and R 6 Independent of H, halogen, C 1-6 Alkyl or C 1-6 alkoxy; or, R 5 and R 6 Together with the carbon atoms they are attached to, they form 5-6 membered heterocycles; (2) X is -O-; preferably, when X is -O-, R 8 For hydrogen, C 1-6 Alkyl or with one or more R 8-1 Replacement C 1-6 Alkyl; R 8-1 It is independently a 5-6 membered heterocyclic alkyl group or a 5-6 membered heterocyclic alkyl group substituted with one or more halogens; preferably a 5-6 membered heterocyclic alkyl group substituted with one or more halogens; More preferably, when X is -O-, R 8 C 1-6 Alkyl or with one or more R 8-1 Replacement C 1-6 Alkyl; R 8-1 It is independently a 5-6 membered heterocyclic alkyl group or a 5-6 membered heterocyclic alkyl group substituted with one or more halogens; preferably a 5-6 membered heterocyclic alkyl group substituted with one or more halogens; and (3)R 7 For one or more R 7-1 Replacement C 1-6 Alkyl; R 7-1 Independently hydroxyl, amino, or halogen; Preferably, R 7 For one or more R 7-1 Replacement C 1-6 Alkyl; R 7-1 It can be hydroxyl or amino on its own. The camptothecin-like compounds, their pharmaceutically acceptable salts, their solvates, or solvates of their pharmaceutically acceptable salts as described in claim 5, are characterized in that... The camptothecin-like compounds satisfy one or more of the following conditions: (1)R 5 It is H or halogen, preferably H; (2)R 6 For H, C 1-6 Alkyl or C 1-6 Alkoxy group, preferably H; (3) When X is -O-, R 8 C 1-6 alkyl; and (4)R 7 For one or more R 7-1 Replacement C 1-6 Alkyl; R 7-1 Independently, it is a hydroxyl group. The camptothecin-like compounds, their pharmaceutically acceptable salts, their solvates, or solvates of their pharmaceutically acceptable salts as described in claim 5, are characterized in that... The camptothecin-like compounds satisfy one or more of the following conditions: (1)R 5 For H or F; (2)R 6 It is H, methyl, or methoxy; (3) When "R 5 and R 6 When R and the carbon atoms it is attached to form a 5-6 membered carbon ring or a 5-6 membered heterocycle, 5 and R 6 Together with the carbon atoms they are attached to form (4) When X is -O-, -XR 7 for (5) When X is -O-, R 8 For hydrogen, ethyl, Preferably ethyl, and (6) when X is -N(R) 9 When )-, R 7 For H, -CH2CH2OH or -CH2CH2NH2, R 8 and R 9 And the nitrogen and carbon atoms it connects to form a 6-membered nitrogen-containing saturated heterocycle; preferably R 7 For -CH2CH2OH, R 8 and R 9 And the nitrogen and carbon atoms it is connected to form a 6-membered nitrogen-containing saturated heterocycle. The camptothecin-like compound, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof as described in claim 1 or 2, is characterized in that... The compound represented by formula II is a compound represented by formula II-B or II-C: Among them, R 5 and R 6 The definition is independent of any one of claims 1-7; Ideally, R 5 It is a halogen; R 6 C 1-6 Alkyl or C 1-6 Alkoxy; Or R 5 and R 6 Together with the carbon atoms they are attached to, they form 5-6 membered heterocycles; R 5 and R 6 The definition is independent of any one of claims 1-7; Ideally, R 5 It is a halogen; R 6 For H or C 1-6 alkyl; R 7 For H or by one or more R 7-1 Replacement C 1-6 Alkyl; R 7-1 It is independently a hydroxyl or amino group, preferably a hydroxyl group. A camptothecin-type compound, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, The camptothecin-like compound is any one of the following compounds: A compound as shown in Formula III: in, Compound II is the compound of formula II as described in claim 1, wherein compound II is connected to linker precursor L via... Linkage; where O originates from the hydroxyl group in compound II, and NH originates from the linker precursor L; Alternatively, compound II can interact with linker precursor L via... Linkage; where NH originates from the amino group in compound II, and C(O) originates from the linker precursor L; Preferably, L is LD is a commonly used connector in the ADC field, and the linker precursor is linked to the antibody via LD; LD can link the antibody to L 1 or L 2 L 1 For single keys or connecting units; L 2 It is a single amino acid residue or a short peptide composed of 2-10 amino acid residues, wherein the amino acid is a natural amino acid or a non-natural amino acid; L 3 It is a spacer. The compound of Formula III as claimed in claim 10, characterized in that, It meets one or more of the following conditions: (1) The hydroxyl group in "O comes from the hydroxyl group in compound II" refers to R. 7 Or R 8 Any hydroxyl group in it, preferably R 7 hydroxyl groups in; (2) The amino group in "NH originates from the amino group in compound II" refers to R. 7 Or R 8 Any amino group in it, preferably R 7 amino groups in the text; (3) LD is Ring A is a 5-6 membered heteroolefin ring or a 5-6 membered heteroaromatic ring, wherein one or more carbon atoms in the 5-6 membered heteroolefin ring are replaced by C(O); the heteroatom types of the 5-6 membered heteroolefin ring and the 5-6 membered heteroaromatic ring are independently selected from one, two, or three of N, O, and S; the number of heteroatoms is independently one, two, or three; R L It is a leaveable group, such as -S(O)2-C 1-6 Alkyl group; p is 0 or 1; (4)L 1 Independently Each Z is independently C 1-6 Alkylene; each t is an independent integer from 1 to 16; preferably, L 1 Bit "1" is connected to ring A; bit "2" is connected to L. 2 connect; and (5)L 2 Independently, it is a single amino acid residue, dipeptide residue, tripeptide residue, or tetrapeptide residue, wherein the carbonyl group in the single amino acid residue, dipeptide residue, tripeptide residue, or tetrapeptide residue may further be combined with... The NH group in the residue is linked to the NH group; preferably, the carbonyl group in the individual amino acid residue, dipeptide residue, tripeptide residue, and tetrapeptide residue is linked to the L group. 3 Connection; the NH and L in the individual amino acid residues, dipeptide residues, tripeptide residues and tetrapeptide residues 1 connect. The compound of Formula III as claimed in claim 11, characterized in that, It meets one or more of the following conditions: (1) In this ring, ring A is independently a 5-6 membered heteroolefin ring or a 5-6 membered heteroaromatic ring, wherein the heteroatom in the 5-6 membered heteroolefin ring is N, and the number of heteroatoms is 1 or 2; one or more carbon atoms in the 5-6 membered heteroolefin ring are replaced by C(O); the heteroatom in the 5-6 membered heteroaromatic ring is N, and the number of heteroatoms is 1, 2, or 3; preferably, for (2)L 1 Independently In this configuration, bit "1" is connected to ring A; bit "2" is connected to L. 2 connect; (3) In Z, the C 1-6 Alkylenes are straight-chain alkylenes, for example (4) t can be 1, 2, 3, 4, 5, 6, 7 or 8 independently, for example 4 or 8; (5)L 2 In this context, the amino acid in the individual amino acid residue, dipeptide residue, tripeptide residue, or tetrapeptide residue is independently selected from glycine, phenylalanine, alanine, valine, or... Glycine or phenylalanine are preferred; (6)L 2 It is a tetrapeptide residue, in which the carbonyl group is related to L 3 Linkage; the NH and L residues in the tetrapeptide 1 connect; and (7) when compound II is connected to linker precursor L via During connection, L 3 for Among them, NH and L 2 connect; When compound II and linker precursor L pass through During connection, L 3 It does not exist. The compound of Formula III as claimed in claim 10, characterized in that, Compound III is any of the following compounds: An antibody-drug conjugate, wherein the antibody-drug conjugate is as follows: d is a natural number or decimal from 1 to 8, such as a natural number or decimal from 7 to 8; for example, 7.37, 7.83, 7.68, 7.71, 7.90, 7.92, 7.82, 7.52, 7.90, 7.73, 7.60, 7.12, or 7.94; further for example, 7.37, 7.83, or 7.68; Compound II as described in claim 10 is connected to linker G in the same manner as compound II is connected to linker precursor L in claim 10. Connector G is Among them, LD, L 1 L 2 and L 3 The definition is as defined in claim 10; T stands for anti-HER2 antibody, such as trastuzumab. The antibody-drug conjugate as described in claim 14, characterized in that, The antibody-drug conjugate is any of the following compounds: Wherein, T is trastuzumab, and d is defined as described in claim 14; Preferably, the antibody-drug conjugate is any of the following compounds: T stands for trastuzumab. A pharmaceutical composition comprising: (1) The compound of Formula II as claimed in claim 1 or 2 or a pharmaceutically acceptable salt thereof, the compound of Formula III as claimed in claim 10 or a pharmaceutically acceptable salt thereof, or the antibody-drug conjugate as claimed in claim 14; (2) Pharmaceutical excipients. The use of a compound of Formula II as claimed in claim 1 or 2, or a pharmaceutically acceptable salt thereof, a compound of Formula III as claimed in claim 10, or an antibody-drug conjugate as claimed in claim 14; or a pharmaceutical composition as claimed in claim 16 in the preparation of a medicament for the prevention and / or treatment of cancer, wherein the cancer is preferably gastric cancer, pancreatic cancer, lung cancer, or breast cancer. The use of the antibody-drug conjugate as described in claim 14 in the preparation of a medicament for the prevention and / or treatment of cancers associated with the trastuzumab target; wherein the cancers associated with the trastuzumab target are preferably gastric cancer, pancreatic cancer, lung cancer, or breast cancer.

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