Indole compound and indole dimer compound, and use thereof as sting agonist

Abstract

The present invention provides a compound, which is a compound of formula (I) or a stereoisomer, a tautomer, a solvate, or a pharmaceutically acceptable salt of the compound of formula (I), and use thereof as a STING agonist and in the prevention or treatment of a cell proliferative disease, especially for the prevention or treatment of a tumor and cancer.

Description

Indole compounds and indole dimers and their use as STING agonists Technical Field

[0001] This invention belongs to the field of biopharmaceutical technology. Specifically, this invention relates to an indole compound and an indole dimer compound and their use as STING agonists. More specifically, this invention relates to a compound, a dimer compound, an STING agonist, a pharmaceutical composition, and their use. Background Technology

[0002] Interferon gene-stimulating factor (STING, also known as transmembrane protein 173 / TMEM173 / MPYS / MITA / ERIS) is a signal transduction molecule encoded by the TMEM173 gene in the human body. STING is a 379-amino acid protein composed of several transmembrane domains. STING protein is expressed in several endothelial and epithelial cell types, as well as hematopoietic lineages such as T cells, dendritic cells (DCs), and macrophages. STING is associated with the endoplasmic reticulum (ER) in cells and plays a major role in controlling the transcription of many host defense genes, including type I interferon (IFN) and pro-inflammatory cytokines.

[0003] Tumor immunotherapy has gradually become an important and highly promising direction in cancer treatment. In immunotherapy, effectively enhancing the immune response in the tumor microenvironment and alleviating immune tolerance are core issues concerning treatment efficacy. As a recently discovered novel pattern recognition receptor, the stimulator of interferon genes (STING) pathway has attracted the research and development interest of many large pharmaceutical companies. Summary of the Invention

[0004] In a first aspect, the present invention provides a compound that is a compound of formula (I) or a stereoisomer, tautomer, solvate, or pharmaceutically acceptable salt of a compound of formula (I):

[0005] Among them, R7 and R8 are independently derived from H, halogen, -CN, and -OR. 14 -NHR 14 or -R 14 Alternatively, R7 and R8 may be connected together with adjacent atoms to form a 4- to 7-membered heterocycle, the 4- to 7-membered heterocycle containing at least one heteroatom of O, N, and S; or one of R7 and R8 may be connected via A to... Connected;

[0006] R7' and R8' are each independently of H, halogen, -CN, -OR. 14-NHR 14 or -R 14 ;

[0007] A is empty or -C 1～10 alkylene-, wherein the -C 1～10 Alkylene groups are optionally surrounded by one or more halogens, -OH, -C(O)OH, -C(O)-, -SH, -NH2, -NHC(O)-C 1～10 Alkyl, -NO2, or -CN substituted;

[0008] R1 and R1' are each independently empty, and -C can be arbitrarily replaced by one or more R9s. 1～10 Alkylene, -C(O)-C optionally substituted with one or more R9 groups 1～10 Alkylene-, or -C(NOH)-C optionally substituted with one or more R9 groups. 2～10 Alkylene, -C(O)-C optionally substituted with one or more R9 groups 1～10 alkene-, -C(O)-C optionally substituted with one or more R9 groups 1～10 Cycloalkylene-, -C(O)-C optionally substituted with one or more R9 groups 2～10 alkenyl-, -C(O)-C optionally substituted with one or more R9s 2～10 Ethyne- or -C(O)-NR 10 R 11 -;

[0009] R2 and R2' are independently -CN, -C(O)-, and -C(O)R, respectively. 12 -C(O)N(R) 12 )2 or 4-7 membered heterocycles, wherein the 4-7 membered heterocycles contain at least one heteroatom selected from O, N and S;

[0010] R3, R3', R4, and R4' are each independently H, halogen, or optionally controlled by one or more R 13 Replacement -C 1～10 Alkyl, optionally with one or more R 13 Replacement -C 1～10 Alkoxy, optionally with one or more R 13 Replacement -C 2～10 alkenyl, optionally with one or more R 13 Replacement -C 2～10 alkynyl group, optionally with one or more R 13 Substituted -C(O)-C 1～10 Alkyl, optionally with one or more R 13 Substituted -C(O)-C 1～10 Alkoxy, optionally with one or more R 13Substituted -C(O)-C 2～10 alkenyl, optionally with one or more R 13 Substituted -C(O)-C 2～10 alkynyl group, optionally with one or more R 13 Replacement -C 0～10 Alkyl-C(O)OH, optionally with one or more R 13 Replacement -C 1～10 Alkoxy-C(O)OH, optionally with one or more R 13 Replacement -C 2～10 alkenyl-C(O)OH or optionally with one or more R 13 Replacement -C 2～10 Alkyne group -C(O)OH;

[0011] R5, R5', R6, and R6' are each independently H, halogen, or -C. 1～10 Alkyl, -C 1～10 Alkoxy, -C 1～10 cycloalkyl, -C 2～10 alkenyl or -C 2～10 alkynyl group;

[0012] Each R9 is independently selected from halogens, -OH, -C(O)OH, -SH, -NH2, -NO2, -CN, phenyl, -C 1～10 Alkyl or -C 1～10 alkoxy, wherein the -C 1～10 Alkyl and -C 1～10 The alkoxy group may be optionally divided by one or more halogens, -OH, -C(O)OH, -C(O)-, -SH, -NH2, -NO2, -CN, -C 1～10 Alkyl or -C 1～10 Alkyl substitution;

[0013] Each R 10 Independently selected from H, -C 1～10 Alkyl, -C 2～10 alkenyl or -C 2～6 alkynyl group, wherein the -C 1～10 Alkyl, -C 2～10 alkenyl or -C 2～10 The alkynyl group is optionally surrounded by one or more halogens, -OH, or -C(O)OR. 15 , -C(O)-, -SH, -NH2, -NO2, -CN, -C 1～10 Alkyl or -C 1～10 Alkyl substitution;

[0014] Each R 11 Independently selected from H, halogens, -OH, -C(O)OH, -SH, -NH2, -NO2, -CN, phenyl, -C1～10 Alkyl, -C 1～10 Alkoxy, -C 2～10 alkenyl or -C 2～10 alkynyl group, wherein the -C 1～10 Alkyl, -C 1～10 Alkoxy, -C 2～10 alkenyl or -C 2～10 The alkynyl group may be optionally surrounded by one or more halogens, -OH, -C(O)OH, -C(O)-, -SH, -NH2, -NO2, -CN, -C 1～10 Alkyl and -C 1～10 Alkyl substitution;

[0015] Each R 12 Independently selected from H, -OR 15 -C 1～10 Alkyl, -C 2～10 alkenyl, -C 2～10 alkynyl group, -C 5～7 aryl or 4- to 7-membered rings, wherein the -OR 15 -C 1～10 Alkyl, -C 2～10 alkenyl, -C 5～7 Aryl or -C 2～10 The alkynyl group may be optionally surrounded by one or more halogens, -OH, -C(O)-, -C(O)OH, -SH, -NH2, -NO2, -CN, phenyl, -C 1～10 Alkyl and -C 1～10 Alkyl substitution;

[0016] Each R 13 Independently selected from halogens, -OH, -C(O)OH, -SH, -NH2, -NO2, -CN, -C 1～10 Alkyl and -C 1～10 alkoxy, wherein the -C 1～10 Alkyl and -C 1～10 The alkoxy group may be optionally divided by one or more halogens, -OH, -C(O)OH, -C(O)-, -SH, -NH2, -NO2, -CN, -C 1～10 Alkyl or -C 1～10 Alkyl substitution;

[0017] Each R 14 Independently selected from H, -Bn, halogens, -C 1～10 Alkyl, -C 2～10 alkenyl or -C 2～10 alkynyl group, wherein the -C 1～10 Alkyl, -C 2～10 alkenyl or -C 2～10The alkenyl group may be optionally surrounded by one or more halogens, -OH, -C(O)OH, -C(O)-, -SH, -NH2, -NO2, -CN, -C 1～10 Alkyl or -C 1～10 Alkyl substitution;

[0018] Each R 15 Independently selected from H or -C 1～10 alkyl;

[0019] X1, X1', X2 and X2' are each independently C or N, and X1 and X2 are not both C at the same time, and X1' and X2' are both C at the same time;

[0020] X3, X3', X4, X4', X5, and X5' are each independently C or N; or one of X1 and X2, X3, and R1 are connected together with adjacent atoms to form a 4- to 7-membered heterocycle, the 4- to 7-membered heterocycle containing N or Se; or one of X1' and X2', X3', and R1' are connected together with adjacent atoms to form a 4- to 7-membered heterocycle, the 4- to 7-membered heterocycle containing N or Se.

[0021] Each Each can be either empty or chemically bonded independently.

[0022] The compounds of formula (I) according to embodiments of the present invention, or their stereoisomers, tautomers, solvates, or pharmaceutically acceptable salts thereof, can effectively activate the STING protein and can act as STING agonists to effectively prevent or treat cell proliferation diseases, such as tumors and cancers. The compounds of the present invention can effectively activate the STING pathway and have important research value for their application in clinical immunotherapy for tumors.

[0023] In this article, "each "Each is independently empty or chemically bonded" means that X1 and X3 are connected by a single or double bond, X2 and X3 are connected by a single or double bond, X1' and X3' are connected by a single or double bond, and X2' and X3' are connected by a single or double bond. For example, the bond between X1 and X3... Empty, X1 and X3 are connected by a single bond; the relationship between X1 and X3 The bonds are chemical bonds, with X1 and X3 linked by a double bond.

[0024] It should be noted that "X1 and X3 are connected by a single or double bond" can be -CN-, -C=N-, -NN-, -N=N-; "X1 and X3 are connected by a single or double bond" can be -CC-, -C=C-, -CN-, -C=N-, -NN-, -N=N-; "X1' and X3' are connected by a single or double bond" can be -CN-, -C=N-, -NN-, -N=N-; "X1' and X3' are connected by a single or double bond" can be -CC-, -C=C-, -CN-, -C=N-, -NN-, -N=N-.

[0025] This invention proposes a compound that is a compound of formula (I) or a stereoisomer, tautomer, solvate, or pharmaceutically acceptable salt of a compound of formula (I):

[0026] Among them, R7 and R8 are independently derived from H, halogen, -CN, and -OR. 14 -NHR 14 or -R 14 Alternatively, R7 and R8 may be connected together with adjacent atoms to form a 4- to 7-membered heterocycle, the 4- to 7-membered heterocycle containing at least one heteroatom of O, N, and S; or one of R7 and R8 may be connected via A to... Connected;

[0027] R7' and R8' are each independently of H, halogen, -CN, -OR. 14 -NHR 14 or -R 14 ;

[0028] A is empty or -C 1～6 alkylene-, wherein the -C 1～6 Alkylene groups are optionally surrounded by one or more halogens, -OH, -C(O)OH, -C(O)-, -SH, -NH2, -NHC(O)-C 1～3 Alkyl, -NO2, or -CN substituted;

[0029] R1 and R1' are each independently empty, and -C can be arbitrarily replaced by one or more R9s. 1～6 Alkylene, -C(O)-C optionally substituted with one or more R9 groups 1～6 Alkylene-, or -C(NOH)-C optionally substituted with one or more R9 groups. 2～5 Alkylene, -C(O)-C optionally substituted with one or more R9 groups 1～6 alkene-, -C(O)-C optionally substituted with one or more R9 groups 1～6 Cycloalkylene-, -C(O)-C optionally substituted with one or more R9 groups2～6 alkenyl-, -C(O)-C optionally substituted with one or more R9s 2～6 Ethyne- or -C(O)-NR 10 R 11 -;

[0030] R2 and R2' are independently -CN, -C(O)-, and -C(O)R, respectively. 12 -C(O)N(R) 12 )2 or 4-7 membered heterocycles, wherein the 4-7 membered heterocycles contain at least one heteroatom selected from O, N and S;

[0031] R3, R3', R4, and R4' are each independently H, halogen, or optionally controlled by one or more R 13 Replacement -C 1～6 Alkyl, optionally with one or more R 13 Replacement -C 1～6 Alkoxy, optionally with one or more R 13 Replacement -C 2～6 alkenyl, optionally with one or more R 13 Replacement -C 2～6 alkynyl group, optionally with one or more R 13 Substituted -C(O)-C 1～6 Alkyl, optionally with one or more R 13 Substituted -C(O)-C 1～6 Alkoxy, optionally with one or more R 13 Substituted -C(O)-C 2～6 alkenyl, optionally with one or more R 13 Substituted -C(O)-C 2～6 alkynyl group, optionally with one or more R 13 Replacement -C 0～6 Alkyl-C(O)OH, optionally with one or more R 13 Replacement -C 1～6 Alkoxy-C(O)OH, optionally with one or more R 13 Replacement -C 2～6 alkenyl-C(O)OH or optionally with one or more R 13 Replacement -C 2～6 Alkyne group -C(O)OH;

[0032] R5, R5', R6, and R6' are each independently H, halogen, or -C. 1～6 Alkyl, -C 1～6 Alkoxy, -C 1～6 cycloalkyl, -C 2～6 alkenyl or -C 2～6 alkynyl group;

[0033] Each R9 is independently selected from halogens, -OH, -C(O)OH, -SH, -NH2, -NO2, -CN, phenyl, -C 1～6 Alkyl or -C 1～6 alkoxy, wherein the -C 1～6 Alkyl and -C 1～6 The alkoxy group may be optionally divided by one or more halogens, -OH, -C(O)OH, -C(O)-, -SH, -NH2, -NO2, -CN, -C 1～3 Alkyl or -C 1～3 Alkyl substitution;

[0034] Each R 10 Independently selected from H, -C 1～6 Alkyl, -C 2～6 alkenyl or -C 2～6 alkynyl group, wherein the -C 1～6 Alkyl, -C 2～6 alkenyl or -C 2～6 The alkynyl group is optionally surrounded by one or more halogens, -OH, or -C(O)OR. 15 , -C(O)-, -SH, -NH2, -NO2, -CN, -C 1～3 Alkyl or -C 1～3 Alkyl substitution;

[0035] Each R 11 Independently selected from H, halogens, -OH, -C(O)OH, -SH, -NH2, -NO2, -CN, phenyl, -C 1～6 Alkyl, -C 1～6 Alkoxy, -C 2～6 alkenyl or -C 2～6 alkynyl group, wherein the -C 1～6 Alkyl, -C 1～6 Alkoxy, -C 2～6 alkenyl or -C 2～6 The alkynyl group may be optionally surrounded by one or more halogens, -OH, -C(O)OH, -C(O)-, -SH, -NH2, -NO2, -CN, -C 1～3 Alkyl and -C 1～3 Alkyl substitution;

[0036] Each R 12 Independently selected from H, -OR 15 -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 alkynyl group, -C 5～7 aryl or 4- to 7-membered rings, wherein the -OR 15 -C 1～6 Alkyl, -C 2～6alkenyl, -C 5～7 Aryl or -C 2～6 The alkynyl group may be optionally surrounded by one or more halogens, -OH, -C(O)-, -C(O)OH, -SH, -NH2, -NO2, -CN, phenyl, -C 1～3 Alkyl and -C 1～3 Alkyl substitution;

[0037] Each R 13 Independently selected from halogens, -OH, -C(O)OH, -SH, -NH2, -NO2, -CN, -C 1～6 Alkyl and -C 1～6 alkoxy, wherein the -C 1～6 Alkyl and -C 1～6 The alkoxy group may be optionally divided by one or more halogens, -OH, -C(O)OH, -C(O)-, -SH, -NH2, -NO2, -CN, -C 1～3 Alkyl or -C 1～3 Alkyl substitution;

[0038] Each R 14 Independently selected from H, -Bn, halogens, -C 1～6 Alkyl, -C 2～6 alkenyl or -C 2～6 alkynyl group, wherein the -C 1～6 Alkyl, -C 2～6 alkenyl or -C 2～6 The alkenyl group may be optionally surrounded by one or more halogens, -OH, -C(O)OH, -C(O)-, -SH, -NH2, -NO2, -CN, -C 1～3 Alkyl or -C 1～3 Alkyl substitution;

[0039] Each R 15 Independently selected from H or -C 1～3 alkyl;

[0040] X1, X1', X2 and X2' are each independently C or N, and X1 and X2 are not both C at the same time, and X1' and X2' are both C at the same time;

[0041] X3, X3', X4, X4', X5, and X5' are each independently C or N; or one of X1 and X2, X3, and R1 are connected together with adjacent atoms to form a 4- to 7-membered heterocycle, the 4- to 7-membered heterocycle containing N or Se; or one of X1' and X2', X3', and R1' are connected together with adjacent atoms to form a 4- to 7-membered heterocycle, the 4- to 7-membered heterocycle containing N or Se.

[0042] Each Each can be either empty or chemically bonded independently.

[0043] According to an embodiment of the invention, R1 and R1' are each independently -C optionally replaced by one or more R9s. 1～6 Alkylene, -C(O)-C optionally substituted with one or more R9 groups 1～6 Alkylene, -C(O)-C optionally substituted with one or more R9 groups 1～6 Cycloalkylene or -C(O)-NR 10 R 11 -

[0044] According to embodiments of the present invention, each R9 is independently selected from halogens, -C 1～3 Alkyl and -C 1～3 alkoxy, wherein the -C 1～3 Alkyl and -C 1～3 The alkoxy group may be optionally divided by one or more halogens, -OH, -C(O)OH, -SH, -NH2, -NO2, -CN, -C 1～3 Alkyl or -C 1～3 Alkyl-substituted.

[0045] In some preferred embodiments of the present invention, each R9 is independently selected from halogens, -C 1～3 Alkyl or -C 1～3 Alkyl group.

[0046] According to an embodiment of the present invention, each R 10 Independently selected from -C 1～4 Alkyl, wherein the -C 1～4 The alkyl group may be optionally surrounded by one or more halogens, -OH, -SH, -NH2, -NO2, -CN, or -C. 1～2 Alkyl substitution.

[0047] According to an embodiment of the present invention, each R 11 Independently selected from H, halogen, -C 1～4 Alkyl, wherein the -C 1～4 The alkyl group may be optionally substituted with one or more halogens, -OH, -SH, -NH2, -NO2, or -CN.

[0048] According to an embodiment of the present invention, R1 and R1' are each independently -C(O)-NR 10 R 11 - At this time, one of X1 and X2, and the N of X3 and R1, together with the adjacent atoms, form a 4- to 7-membered heterocycle.

[0049] According to an embodiment of the present invention, R2 is -C(O)R 12 -C(O)N(R) 12 )2 or 4-7 membered heterocycles, wherein the 4-7 membered heterocycles contain at least one heteroatom selected from O, N and S.

[0050] According to an embodiment of the present invention, each R 12 Independently selected from H, -OR 15 or -C 1～3 Alkyl group, wherein the -OR 15 or -C 1～3 The alkyl group may be optionally substituted with one or more halogens, -OH, -C(O)OH, -C(O)-, -SH, -NH2, -NO2, -CN or phenyl.

[0051] According to an embodiment of the present invention, each R 15 Independently selected from H or -C 1～3 alkyl.

[0052] According to an embodiment of the present invention, each R 13 Independently selected from -C 1～3 Alkyl, wherein the -C 1～3 The alkyl group may be optionally substituted with one or more halogens, -OH, -C(O)OH, -C(O)-, -SH, -NH2, -NO2 or -CN.

[0053] According to embodiments of the present invention, R3 and R4 are each independently H, a halogen, or a -C optionally substituted with one or more -OH groups. 1～3 Alkyl or -C 0～2 Alkyl-C(O)OH.

[0054] According to an embodiment of the present invention, R5 and R6 are each independently H, halogen, or -C. 1～3 alkyl.

[0055] According to an embodiment of the present invention, R7 and R8 are each independently -OR 14 Alternatively, R7 and R8 are connected together with the adjacent atoms to form a 4- to 7-membered heterocycle, which contains at least one heteroatom of O, N and S.

[0056] According to an embodiment of the present invention, each R 14 -C independently selected from H, optionally substituted by one or more halogens 1～3 Alkyl groups or -C groups optionally substituted with one or more halogens 2～3 Alkenyl group.

[0057] According to an embodiment of the present invention, X1 is C and X2 is N or Se, or X1 is N or Se and X2 is C.

[0058] According to an embodiment of the present invention, X3, X4 and X5 are C.

[0059] In one optional embodiment of this application, X3 is C, X1 is C, and X2 is N or Se, or X1 is N or Se, X2 is C, and X3 is C.

[0060] According to an embodiment of the present invention, X1' is C and X2' is N or Se, or X1' is N or Se and X2' is C.

[0061] According to an embodiment of the present invention, X3', X4' and X5' are C.

[0062] In one optional embodiment of this application, X3' is C, X1' is C, and X2' is N or Se, or X1' is N or Se, X2' is C, and X3' is C.

[0063] According to embodiments of the present invention, the compound is a compound of formula (Ia) or a stereoisomer, tautomer, solvate, or pharmaceutically acceptable salt of a compound of formula (Ia):

[0064] According to an embodiment of the present invention, in the compound represented by formula (Ia), R1 is -C(OH)-C 1～5 Alkylene, -C(O)-C 2～5 Alkylene, -C(O)-C 2～4 Cycloalkylene or -C(O)-NR 10 R 11 -;

[0065] R 10 It is H or -CH3;

[0066] R 11 -C 2～4 alkyl;

[0067] R2 is -C(O)OH, -C(O)OCH3, -C(O)OCH2CH3, -C(O)N(H)OCH3, -C(O)N(H)(CH2)2OH or

[0068] R3 is H, -CH3, -CH2CH3, -C(O)CH3, -C 1～5 Alkylene -C(O)OH or -C(O)OH;

[0069] R4, R5 and R6 are each independently H or halogen;

[0070] R7 and R8 are each independently -OH, optionally halogenated as -OCH3 or -OCH2CH=CH2.

[0071] According to an embodiment of the present invention, -R1-R2 has the following structure:

[0072] and -C(O)OH.

[0073] According to embodiments of the present invention, the compound is a stereoisomer, tautomer, solvate, or pharmaceutically acceptable salt of the compound represented by formula (VI):

[0074] Among them, R 1a It is hydrogen or -CH3;

[0075] R 1b and R 1c Each can be independently H or halogen;

[0076] R 1d It can be -OH, -OCH3, or -OCH2CH3;

[0077] R 1f -CH3 or -CH2-CH ＝ CH2;

[0078] R 1g for

[0079] Among them, R 1f for At that time, R 1d It is not -OH.

[0080] In a second aspect, the present invention provides a compound that is a stereoisomer, tautomer, solvate, or pharmaceutically acceptable salt of a compound having the following structure:

[0081] The compounds, stereoisomers, tautomers, solvates, or pharmaceutically acceptable salts thereof according to embodiments of the present invention can effectively activate STING proteins and can act as STING agonists to effectively prevent or treat cell proliferation diseases such as tumors and cancers.

[0082] In a third aspect, the present invention provides a dimer compound that is a dimer compound of formula (II), (III) or (IV), or a stereoisomer, tautomer, solvate, or pharmaceutically acceptable salt of a dimer compound of formula (II), (III) or (IV):

[0083] Where A is empty or -C 1～10 alkylene-, wherein the -C 1～10 Alkylene groups are optionally surrounded by one or more halogens, -OH, -C(O)OH, -C(O)-, -SH, -NH2, -NHC(O)-C 1～10 Alkyl, -NO2, or -CN substituted;

[0084] R1 and R1' are each independently empty and can be arbitrarily replaced by one or more R9s. 1～10 Alkylene-, or -C(NOH)-C optionally substituted with one or more R9 groups. 1～10 Alkylene, optionally substituted with one or more R9-C(NOAc)-C 2～10 Alkylene, -C(O)-C optionally substituted with one or more R9 groups 1～10 alkene-, -C(O)-C optionally substituted with one or more R9 groups 1～10 Cycloalkylene-, -C(O)-C optionally substituted with one or more R9 groups 2～10 alkenyl-, -C(O)-C optionally substituted with one or more R9s 2～10 Ethyne- or -C(O)-NR 10 R 11 -;

[0085] R2 and R2' are independently -CN, -C(O)-, and -C(O)R, respectively. 12 -C(O)N(R) 12 )2 or 4-7 membered heterocycles, wherein the 4-7 membered heterocycles contain at least one heteroatom selected from O, N and S;

[0086] R3, R3', R4, and R4' are each independently H, halogen, or optionally controlled by one or more R 13 Replacement -C 1～10 Alkyl, optionally with one or more R 13 Replacement -C 1～10 Alkoxy, optionally with one or more R 13 Replacement -C 2～10 alkenyl, optionally with one or more R 13 Replacement -C 2～10 alkynyl group, optionally with one or more R 13 Substituted -C(O)-C 1～10 Alkyl, optionally with one or more R 13 Substituted -C(O)-C 1～10 Alkoxy, optionally with one or more R 13 Substituted -C(O)-C 2～10 alkenyl, optionally with one or more R 13Substituted -C(O)-C 2～10 alkynyl group, optionally with one or more R 13 Replacement -C 0～10 Alkyl-C(O)OH, optionally with one or more R 13 Replacement -C 1～10 Alkoxy-C(O)OH, optionally with one or more R 13 Replacement -C 2～10 alkenyl-C(O)OH or optionally with one or more R 13 Replacement -C 2～10 Alkyne group -C(O)OH;

[0087] R5, R5', R6, and R6' are each independently H, halogen, or -C. 1～6 Alkyl, -C 1～6 Alkoxy, -C 1～6 cycloalkyl, -C 2～6 alkenyl or -C 2～6 alkynyl group;

[0088] R7, R7', R8, and R8' are each independently H, halogen, -CN, or -OR. 14 -NHR 14 or -R 14 ;

[0089] Each R9 is independently selected from H, halogen, -OH, -C(O)OH, -SH, -NH2, -NO2, -CN, phenyl, -C 1～10 Alkyl or -C 1～10 alkoxy, wherein the -C 1～10 Alkyl and -C 1～10 The alkoxy group may be optionally divided by one or more halogens, -OH, -C(O)OH, -C(O)-, -SH, -NH2, -NO2, -CN, -C 1～10 Alkyl or -C 1～3 Alkyl substitution;

[0090] Each R 10 Independently selected from H, -C 1～10 Alkyl, -C 2～10 alkenyl or -C 2～10 alkynyl group, wherein the -C 1～10 Alkyl, -C 2～10 alkenyl or -C 2～10 The alkynyl group is optionally surrounded by one or more halogens, -OH, or -C(O)OR. 15 , -C(O)-, -SH, -NH2, -NO2, -CN, -C 1～10 Alkyl or -C 1～10 Alkyl substitution;

[0091] Each R11 Independently selected from H, halogens, -OH, -C(O)OH, -SH, -NH2, -NO2, -CN, phenyl, -C 1～10 Alkyl, -C 1～10 Alkoxy, -C 2～10 alkenyl or -C 2～10 alkynyl group, wherein the -C 1～10 Alkyl, -C 1～10 Alkoxy, -C 2～10 alkenyl or -C 2～10 The alkynyl group may be optionally surrounded by one or more halogens, -OH, -C(O)OH, -C(O)-, -SH, -NH2, -NO2, -CN, -C 1～10 Alkyl and -C 1～10 Alkyl substitution;

[0092] Each R 12 Independently selected from H, -OR 15 -C 1～10 Alkyl, -C 2～10 alkenyl, -C 2～10 alkynyl group, -C 5～7 Aryl or 4- to 7-membered rings, wherein the -C 1～10 Alkyl, -C 2～10 alkenyl, -C 5～7 Aryl or -C 2～10 The alkynyl group may be optionally surrounded by one or more halogens, -OH, -C(O)-, -C(O)OH, -SH, -NH2, -NO2, -CN, phenyl, -C 1～10 Alkyl and -C 1～10 Alkyl substitution;

[0093] Each R 13 Independently selected from halogens, -OH, -C(O)OH, -SH, -NH2, -NO2, -CN, -C 1～10 Alkyl and -C 1～10 alkoxy, wherein the -C 1～10 Alkyl and -C 1～10 The alkoxy group may be optionally divided by one or more halogens, -OH, -C(O)OH, -C(O)-, -SH, -NH2, -NO2, -CN, -C 1～10 Alkyl or -C 1～10 Alkyl substitution;

[0094] Each R 14 Independently selected from H, -Bn, halogens, -C 1～10 Alkyl, -C 2～10 alkenyl or -C 2～10 alkynyl group, wherein the -C 1～10 Alkyl, -C 2～10 alkenyl or -C2～10 The alkenyl group may be optionally surrounded by one or more halogens, -OH, -C(O)OH, -C(O)-, -SH, -NH2, -NO2, -CN, -C 1～10 Alkyl or -C 1～10 Alkyl substitution;

[0095] Each R 15 Independently selected from H or -C 1～10 alkyl;

[0096] X1, X1', X2 and X2' are each independently C, N, S or Se, and X1 and X2 are not both C at the same time, and X1' and X2' are both C at the same time;

[0097] X3, X3', X4, X4', X5, and X5' are each independently C or N; or one of X1' and X2', X3', and R1' are connected together with adjacent atoms to form a 4- to 7-membered heterocycle, which contains N or Se;

[0098] Each Each can be either empty or chemically bonded independently.

[0099] The dimer compound of formula (II), formula (III) or formula (IV) according to embodiments of the present invention, or its stereoisomer, its tautomer, its solvate, or its pharmaceutically acceptable salt, can effectively activate the STING protein and can act as a STING agonist to effectively prevent or treat cell proliferation diseases, such as tumors and cancer.

[0100] In this article, "each "Each is independently empty or chemically bonded" means that X1 and X3 are connected by a single or double bond, X2 and X3 are connected by a single or double bond, X1' and X3' are connected by a single or double bond, and X2' and X3' are connected by a single or double bond.

[0101] This invention proposes a dimer compound, which is a dimer compound of formula (II), (III) or (IV), or a stereoisomer, tautomer, solvate, or pharmaceutically acceptable salt of a dimer compound of formula (II), (III) or (IV):

[0102] Where A is empty or -C 1～6 alkylene-, wherein the -C 1～6 Alkylene groups are optionally surrounded by one or more halogens, -OH, -C(O)OH, -C(O)-, -SH, -NH2, -NHC(O)-C 1～3 Alkyl, -NO2, or -CN substituted;

[0103] R1 and R1' are each independently empty and can be arbitrarily replaced by one or more R9s. 1～6 Alkylene-, or -C(NOH)-C optionally substituted with one or more R9 groups. 1～6 Alkylene, optionally substituted with one or more R9-C(NOAc)-C 2～5 Alkylene, -C(O)-C optionally substituted with one or more R9 groups 1～6 alkene-, -C(O)-C optionally substituted with one or more R9 groups 1～6 Cycloalkylene-, -C(O)-C optionally substituted with one or more R9 groups 2～6 alkenyl-, -C(O)-C optionally substituted with one or more R9s 2～6 Ethyne- or -C(O)-NR 10 R 11 -;

[0104] R2 and R2' are independently -CN, -C(O)-, and -C(O)R, respectively. 12 -C(O)N(R) 12 )2 or 4-7 membered heterocycles, wherein the 4-7 membered heterocycles contain at least one heteroatom selected from O, N and S;

[0105] R3, R3', R4, and R4' are each independently H, halogen, or optionally controlled by one or more R 13 Replacement -C 1～6 Alkyl, optionally with one or more R 13 Replacement -C 1～6 Alkoxy, optionally with one or more R 13 Replacement -C 2～6 alkenyl, optionally with one or more R 13 Replacement -C 2～6 alkynyl group, optionally with one or more R 13 Substituted -C(O)-C 1～6 Alkyl, optionally with one or more R 13 Substituted -C(O)-C 1～6 Alkoxy, optionally with one or more R 13 Substituted -C(O)-C 2～6 alkenyl, optionally with one or more R 13 Substituted -C(O)-C 2～6 alkynyl group, optionally with one or more R 13 Replacement -C 0～6 Alkyl-C(O)OH, optionally with one or more R 13 Replacement -C 1～6 Alkoxy-C(O)OH, optionally with one or more R 13 Replacement -C2～6 alkenyl-C(O)OH or optionally with one or more R 13 Replacement -C 2～6 Alkyne group -C(O)OH;

[0106] R5, R5', R6, and R6' are each independently H, halogen, or -C. 1～6 Alkyl, -C 1～6 Alkoxy, -C 1～6 cycloalkyl, -C 2～6 alkenyl or -C 2～6 alkynyl group;

[0107] R7, R7', R8, and R8' are each independently H, halogen, -CN, or -OR. 14 -NHR 14 or -R 14 ;

[0108] Each R9 is independently selected from H, halogen, -OH, -C(O)OH, -SH, -NH2, -NO2, -CN, phenyl, -C 1～6 Alkyl or -C 1～6 alkoxy, wherein the -C 1～6 Alkyl and -C 1～6 The alkoxy group may be optionally divided by one or more halogens, -OH, -C(O)OH, -C(O)-, -SH, -NH2, -NO2, -CN, -C 1～3 Alkyl or -C 1～3 Alkyl substitution;

[0109] Each R 10 Independently selected from H, -C 1～6 Alkyl, -C 2～6 alkenyl or -C 2～6 alkynyl group, wherein the -C 1～6 Alkyl, -C 2～6 alkenyl or -C 2～6 The alkynyl group is optionally surrounded by one or more halogens, -OH, or -C(O)OR. 15 , -C(O)-, -SH, -NH2, -NO2, -CN, -C 1～3 Alkyl or -C 1～3 Alkyl substitution;

[0110] Each R 11 Independently selected from H, halogens, -OH, -C(O)OH, -SH, -NH2, -NO2, -CN, phenyl, -C 1～6 Alkyl, -C 1～6 Alkoxy, -C 2～6 alkenyl or -C 2～6 alkynyl group, wherein the -C 1～6 Alkyl, -C1～6 Alkoxy, -C 2～6 alkenyl or -C 2～6 The alkynyl group may be optionally surrounded by one or more halogens, -OH, -C(O)OH, -C(O)-, -SH, -NH2, -NO2, -CN, -C 1～3 Alkyl and -C 1～3 Alkyl substitution;

[0111] Each R 12 Independently selected from H, -OR 15 -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 alkynyl group, -C 5～7 Aryl or 4- to 7-membered rings, wherein the -C 1～6 Alkyl, -C 2～6 alkenyl, -C 5～7 Aryl or -C 2～6 The alkynyl group may be optionally surrounded by one or more halogens, -OH, -C(O)-, -C(O)OH, -SH, -NH2, -NO2, -CN, phenyl, -C 1～3 Alkyl and -C 1～3 Alkyl substitution;

[0112] Each R 13 Independently selected from halogens, -OH, -C(O)OH, -SH, -NH2, -NO2, -CN, -C 1～6 Alkyl and -C 1～6 alkoxy, wherein the -C 1～6 Alkyl and -C 1～6 The alkoxy group may be optionally divided by one or more halogens, -OH, -C(O)OH, -C(O)-, -SH, -NH2, -NO2, -CN, -C 1～3 Alkyl or -C 1～3 Alkyl substitution;

[0113] Each R 14 Independently selected from H, -Bn, halogens, -C 1～6 Alkyl, -C 2～6 alkenyl or -C 2～6 alkynyl group, wherein the -C 1～6 Alkyl, -C 2～6 alkenyl or -C 2～6 The alkenyl group may be optionally surrounded by one or more halogens, -OH, -C(O)OH, -C(O)-, -SH, -NH2, -NO2, -CN, -C 1～3 Alkyl or -C 1～3 Alkyl substitution;

[0114] Each R 15 Independently selected from H or -C1～3 alkyl;

[0115] X1, X1', X2 and X2' are each independently C, N, S or Se, and X1 and X2 are not both C at the same time, and X1' and X2' are both C at the same time;

[0116] X3, X3', X4, X4', X5, and X5' are each independently C or N;

[0117] Each Each can be either empty or chemically bonded independently.

[0118] According to an embodiment of the invention, R1 and R1' are each independently -C(O)-C optionally replaced by one or more R9. 1～6 alkylene- or -C(O)-NR 10 R 11 -

[0119] According to an embodiment of the present invention, each R9 is independently selected from halogens and -C. 1～3 Alkyl, wherein the -C 1～3 The alkyl group may be optionally substituted with one or more halogens, -OH, -SH, -NH2, -NO2, or -CN.

[0120] According to an embodiment of the present invention, each R 10 Independently selected from -C 1～3 Alkyl, wherein the -C 1～3 The alkyl group may be optionally substituted with one or more halogens, -OH, -SH, -NH2, -NO2, or -CN.

[0121] According to an embodiment of the present invention, each R 11 Independently selected from H or -C 1～3 Alkyl, wherein the -C 1～3 The alkyl group may be optionally substituted with one or more halogens, -OH, -SH, -NH2, -NO2, or -CN.

[0122] According to an embodiment of the present invention, R2 and R2' are each independently -C(O)R 12 or -C(O)N(R) 12 )2.

[0123] According to an embodiment of the present invention, each R 12 Independently selected from H, -OR 15 or -C 1～3 Alkyl, wherein the -C 1～3 The alkyl group may be optionally substituted with one or more halogens, -OH, -SH, -NH2, -NO2, or -CN.

[0124] According to an embodiment of the present invention, each R15 Independently selected from H or -C 1～3 alkyl.

[0125] According to embodiments of the present invention, R3, R3', R4, R4', R5, R5', R6 and R6' are each independently H, halogen or -C. 1～3 alkyl.

[0126] According to an embodiment of the present invention, R7, R7', R8, and R8' are each independently -C. 1～3 Alkyl group.

[0127] According to an embodiment of the present invention, A is empty or -C 1～4 alkylene, wherein the -C 1～4 Alkylenes are optionally surrounded by one or more halogens, -OH, -SH, -NH2, -NHC(O)-C 1～3 Alkyl, -NO2 or -CN substituted.

[0128] According to an embodiment of the present invention, X1 is C and X2 is N or Se, or X1 is N or Se and X2 is C.

[0129] According to an embodiment of the present invention, X3, X4 and X5 are C.

[0130] In one optional embodiment of this application, X3 is C, X1 is C, and X2 is N or Se, or X1 is N or Se, X2 is C, and X3 is C.

[0131] According to an embodiment of the present invention, X1' is C and X2' is N or Se, or X1' is N or Se and X2' is C.

[0132] According to an embodiment of the present invention, X3', X4' and X5' are C.

[0133] In one optional embodiment of this application, X3' is C, X1' is C, and X2' is N or Se, or X1' is N or Se, X2' is C, and X3' is C.

[0134] According to embodiments of the present invention, the dimer compound is a dimer compound of formula (V), or a stereoisomer, tautomer, solvate, or pharmaceutically acceptable salt of a dimer compound of formula (V).

[0135] According to an embodiment of the present invention, in the compound represented by formula (V), A is

[0136] R 2a and R 2b Each independently And R 2a and R 2b Not both containing N;

[0137] R 2c and R 2d Each can be independently -OH, -NH2, -OCH3, -OCH2CH3, -OCH2(CH3)2, -OCH2CH2(CH3)2 or C 5～7 Aryloxy.

[0138] According to an embodiment of the present invention, R 2c and R 2d Each can be independently -OH, -OCH3, or -OCH2CH3.

[0139] In a fourth aspect, the present invention provides a dimer compound that is a dimer compound with the following structure or a stereoisomer, tautomer, solvate, or pharmaceutically acceptable salt thereof with the following structure:

[0140] The dimer compounds, stereoisomers, tautomers, solvates, or pharmaceutically acceptable salts thereof according to embodiments of the present invention can effectively activate STING proteins and can act as STING agonists to effectively prevent or treat cell proliferation diseases such as tumors and cancers.

[0141] In a fifth aspect of the invention, the invention provides for the use of a compound described in the first or second aspect, or a dimer compound described in the third or fourth aspect, as a STING agonist.

[0142] In a sixth aspect of the invention, the invention provides a STING agonist comprising the compound described in the first or second aspect or the dimer compound described in the third or fourth aspect, and optionally a pharmaceutically acceptable carrier, excipient, or mediator.

[0143] In a seventh aspect of the invention, the invention provides a pharmaceutical composition comprising the compound described in the first or second aspect, the dimer compound described in the third or fourth aspect, or the STING agonist described in the sixth aspect.

[0144] According to embodiments of the present invention, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, excipient, or mediator.

[0145] In an eighth aspect of the invention, the invention provides a compound described in the first or second aspect, a dimer compound described in the third or fourth aspect, a STING agonist described in the sixth aspect, or a pharmaceutical composition described in the seventh aspect, for the prevention or treatment of cell proliferation diseases, or for use as follows:

[0146] Prevention or treatment of cell proliferation diseases, and / or

[0147] Preparation for use in the prevention or treatment of cell proliferation diseases.

[0148] According to an embodiment of the present invention, the cell proliferation disease is a tumor or cancer.

[0149] In a ninth aspect of the invention, the invention provides a method for preventing or treating cell proliferation diseases, comprising: administering to a subject a pharmaceutically acceptable dose of a compound described in the first or second aspect, a dimer compound described in the third or fourth aspect, a STING agonist described in the sixth aspect, or a pharmaceutical composition described in the seventh aspect.

[0150] The effective amount of the compounds, dimer compounds, STING agonists, or pharmaceutical compositions described in this invention may vary depending on the administration method and the severity of the disease to be treated. A preferred effective amount can be determined by those skilled in the art based on various factors (e.g., through clinical trials). These factors include, but are not limited to, the patient's age, weight, general health condition, sex, diet, administration time, drug combination, the severity of the disease to be treated, and the route of administration. For example, depending on the treatment requirements, several separate doses may be administered daily, such as four times a day, three times a day, twice a day, once a day, or every other day, or the number of daily doses may be proportionally reduced; or, the pharmaceutical compositions or gels of this invention may be administered for at least one year or longer, preferably at least one month, more preferably at least one week, and most preferably at least one day, to achieve continuous remission of tumors or cancer.

[0151] The compounds, dimer compounds, STING agonists, or pharmaceutical compositions of the present invention can be incorporated into suitable pharmaceuticals, which can be prepared in various forms, such as liquid, semi-solid, and solid dosage forms, including but not limited to solid dosage forms, semi-solid dosage forms, liquid dosage forms, and gaseous dosage forms. Various routes of administration of the compounds, dimer compounds, STING agonists, pharmaceutical compositions, or pharmaceuticals of the present invention are contemplated, including peritoneal, intravenous, intramuscular, subcutaneous, dermal, oral, topical, nasal, pulmonary, rectal, and topical administration; however, the present invention is not limited to these exemplified routes of administration.

[0152] Additional aspects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. Attached Figure Description

[0153] The above and / or additional aspects and advantages of the present invention will become apparent and readily understood from the description of the embodiments taken in conjunction with the following drawings, in which:

[0154] Figure 1 shows the structural formula of diABZI, the positive control compound of Test Example 1 of the present invention;

[0155] Figure 2 shows the change in body weight of mice in Test Example 2 of this invention after administration of compound 643;

[0156] Figure 3 shows the results of IFN-β cytokine in mouse serum samples in Test Example 2 of this invention;

[0157] Figure 4 shows the average drug concentration-time curve of compound 643 in mouse blood in Test Example 2 of the present invention;

[0158] Figure 5 shows the weight changes of mice after drug administration in Test Example 2 of this invention;

[0159] Figure 6 shows the results of detecting the cytokine IFN-β in serum samples in Test Example 2 of the present invention;

[0160] Figure 7 shows the average drug concentration-time curve of compound D-18 in mouse blood in Test Example 2 of the present invention;

[0161] Figure 8 shows the average drug concentration-time curve of compound D-18 in mouse tumors in Test Example 2 of the present invention. Detailed Implementation

[0162] The embodiments of the present invention are described in detail below. The embodiments described below are exemplary and are only used to explain the present invention, and should not be construed as limiting the present invention.

[0163] It should be noted that the terms "first" and "second" are used for descriptive purposes only and should not be construed as indicating or implying relative importance or implicitly specifying the number of indicated technical features. Therefore, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature. Furthermore, in the description of this invention, unless otherwise stated, "a plurality of" means two or more.

[0164] It should be noted that the structural and chemical formula descriptions of the embodiments or implementations of this invention are intended to cover all alternatives, modifications, and equivalent technical solutions, all of which are within the scope of this invention as defined in the claims. Those skilled in the art will recognize that many similar or equivalent methods and materials can be used to practice this invention. This invention is by no means limited to the methods and materials described herein. In the event that one or more of the linked documents, patents, and similar materials differ from or contradict this application (including but not limited to defined terminology, terminology application, described techniques, etc.), this invention shall prevail.

[0165] It should be further appreciated that certain features of the invention, for clarity, have been described in multiple independent embodiments or implementations, but may also be provided in combination in a single embodiment or implementation. Conversely, various features of the invention, for brevity, have been described in a single embodiment or implementation, but may also be provided individually or in any suitable sub-combination.

[0166] Unless otherwise indicated, the technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains, and unless otherwise indicated, all patent publications cited in the entirety of this disclosure are incorporated herein by reference.

[0167] Unless otherwise stated, the following definitions will apply in this invention. For the purposes of this invention, chemical elements are defined according to the periodic table, CAS version, and the Chemical Handbook, 75th Ed, 1994. Furthermore, general principles of organic chemistry are found in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007; therefore, all contents of this invention are incorporated herein by reference.

[0168] In this document, the terms “comprising” or “including” are open-ended expressions, meaning that they include the contents specified in this invention, but do not exclude other aspects.

[0169] This document also includes isotopically labeled compounds of the present invention that are identical to those compounds described herein except that one or more atoms are replaced by atoms with atomic masses or mass numbers different from those commonly found in nature. Exemplary isotopes that may also be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as... 2 H, 3 H, 13 C 14 C 15 N、 16 O、 17 O、 31 P, 32 P, 36 S, 18 F and 37 Cl.

[0170] Compounds of the present invention comprising other isotopes of the aforementioned isotopes and / or other atoms, as well as pharmaceutically acceptable salts of said compounds, are included within the scope of this invention. Isotope-labeled compounds of the present invention, such as radioactive isotopes, are also included. 3 H and 14 The incorporation of tritium into the compounds of this invention can be used for drug and / or substrate tissue distribution analysis. Due to its ease of preparation and detection, tritium-substituted compounds... 3 H, and carbon-14, i.e. 14 C isotopes are particularly preferred. In addition, heavier isotopes, such as deuterium, are used. 2 H substitution can offer therapeutic advantages stemming from greater metabolic stability, such as increased in vivo half-life or reduced dose requirements. Therefore, it may be preferred in some cases.

[0171] The stereochemical definitions and conventions used in this invention are generally in accordance with S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds,” John Wiley & Sons, Inc., New York, 1994. The compounds of this invention may contain asymmetric or chiral centers, and thus exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of this invention, including but not limited to diastereomers, enantiomers, and atropisomers, and mixtures thereof such as racemic mixtures, are also included within the scope of this invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. When describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to the chiral centers (or multiple chiral centers) in the molecule. The prefixes d and l, or (+) and (-), are symbols used to specify the plane-polarized rotation caused by a compound, where (-) or l indicates that the compound is levorotatory. Compounds prefixed with (+) or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers may also be called enantiomers, and mixtures of such isomers are generally called mixtures of enantiomers. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may occur when there is no stereoselectivity or stereospecificity in a chemical reaction or method.

[0172] Depending on the choice of raw materials and methods, the compounds of this invention can exist as one or a mixture of possible isomers, for example, as pure optical isomers, or as mixtures of isomers, such as as racemic and non-corresponding isomer mixtures, depending on the number of asymmetric carbon atoms. Optically active (R)- or (S)- isomers can be prepared using chiral synthons or chiral formulations, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituent may be cis or trans (cis- or trans-) configuration.

[0173] The compounds of this invention may contain asymmetric or chiral centers, and thus exist in different stereoisomer forms. It is contemplated that all stereoisomer forms of the compounds of this invention, including but not limited to diastereomers, enantiomers, atropisomers, and geometric (or conformational) isomers and mixtures thereof, such as racemic mixtures, are within the scope of this invention.

[0174] Unless otherwise stated, the structures described in this invention also represent all isomers including this structure (e.g., enantiomers, diastereotropic atropisomers, and geometric (or conformational) forms; for example, R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers). Therefore, individual stereochemical isomers of the compounds of this invention, as well as mixtures of enantiomers, diastereomeric mixtures, and mixtures of geometric isomers (or conformational isomers), are all within the scope of this invention.

[0175] Any asymmetric atom (e.g., carbon) in the compounds of this invention can exist in a racemic or enantiomerically enriched form, such as (R)-, (S)-, or (R,S)- configuration. In some embodiments, each asymmetric atom has at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% enantiomeric excess in the (R)- or (S)- configuration. If possible, substituents on atoms having unsaturated double bonds can be present in cis-(Z)- or trans-(E)- form.

[0176] Therefore, as described in this invention, the compounds of this invention can exist in the form of one of the possible isomers, rotational isomers, tautomers, tautomers, or mixtures thereof, for example, in the form of essentially pure geometric (cis or trans) isomers, diastereomers, optical isomers (enantiomers), racemates, or mixtures thereof.

[0177] Any mixture of isomers can be separated into pure or substantially pure geometric or optical isomers, diastereomers, and racemates based on the physicochemical differences of the components, for example by chromatography and / or stepwise crystallization.

[0178] Racemic derivatives of any resulting end product or intermediate can be separated into optical enantiomers using known methods, such as by separating salts of their diastereomers. Racemic products can also be separated by chiral chromatography, such as high-performance liquid chromatography (HPLC) using chiral adsorbents. In particular, enantiomers can be prepared by asymmetric synthesis (e.g., Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2nd Ed. Robert E. Gawley, Jeffrey Aubé, Elsevier, Oxford, UK, 2012); Eliel, ELStereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, SH Tables of Resolving Agents and Optical Resolutions p. 268 (ELEliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972).

[0179] In this document, the terms "tautomer" or "tautomer form" refer to structural isomers with different energies that can interconvert through a low energy barrier. If tautomerization is possible (e.g., in solution), chemical equilibrium can be achieved in the tautomer. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions via the rearrangement of some bonding electrons. Unless otherwise indicated, all tautomer forms of the compounds of this invention are within the scope of this invention.

[0180] In this document, the term "solvent" refers to an association formed by one or more solvent molecules with the compounds of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association formed by solvent molecules that are water.

[0181] In this document, the term "pharmaceutically acceptable" means that a substance or composition must be chemically and / or toxicologically compatible with other components of the formulation and / or the mammals to which it is treated.

[0182] In this document, the term "pharmaceutically acceptable salt" refers to both organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well-known in the field, as described in the literature: SMBerge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19. Pharmaceutically acceptable salts formed from non-toxic acids include, but are not limited to, inorganic acid salts (such as hydrochlorides, hydrobromic acids, phosphates, sulfates, and perchlorates) formed by reaction with amino groups, and organic acid salts (such as acetates, oxalates, maleates, tartrates, citrates, succinates, and malonates), or salts obtained by other methods described in the literature, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, transbutenedioic acid, glucono-heptahydrate, glycerophosphate, gluconate, hemisulfate, heptahydrate, hexanoate, hydroiodate, 2-hydroxy-ethanesulfonate, lacturonate, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pyruvate, pectinate, persulfate, 3-phenylpropionate, picrate, pentanoate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts obtained by means of appropriate bases include alkali metals, alkaline earth metals, ammonium, and nitrogen. + (C 1～4 Salts of alkyl groups (4). This invention also contemplates quaternary ammonium salts formed from any compound containing an N group. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts, and amine cations that resist the formation of equilibrium ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C 1～8 Sulfonates and aromatic sulfonates.

[0183] In this document, the terms “optionally,” “optionally,” or “optionally” generally refer to an event or condition that may, but may not, occur, and the description includes both cases in which the event or condition occurs and cases in which the event or condition does not occur.

[0184] In this document, the terms "optionally substituted," "optionally substituted," and "substituted or unsubstituted" are used interchangeably. Generally, the term "optionally," whether preceding or following the term "substituted," indicates that one or more hydrogen atoms in the given structure are substituted by a specific substituent. Unless otherwise indicated, an optional substituent may be substituted at each substituted position of the group. When more than one position in the given structural formula can be substituted by one or more substituents selected from a specific group, the substituents may be substituted at the same or different positions. The substituents mentioned may be, but are not limited to, F, Cl, Br, CN, OH, NH2, NO2, etc.

[0185] In this document, the term "one or more" (e.g., in the definition of substituents in compounds of the general formula of the present invention) means "one, two, three, four or five, especially one, two, three or four, more especially one, two or three, and even more especially one or two".

[0186] Additionally, it should be noted that, unless otherwise explicitly stated, the descriptive terms “each…independently is”, “…each independently is”, and “…independently is” used in this invention are interchangeable and should be interpreted broadly. They can mean that the specific options expressed by the same symbols in different groups do not affect each other, or that the specific options expressed by the same symbols in the same group do not affect each other.

[0187] In this article, the term "halogen" refers to a fluorine, chlorine, bromine, or iodine atom.

[0188] In this paper, the minimum and maximum carbon atom content in hydrocarbon groups are indicated by prefixes, for example, prefix C. a～b This refers to a carbon atom containing "a" to "b". For example, "C 1～n "C" refers to a saturated / unsaturated carbon chain, either straight or branched, containing 1, 2, 3, 4, 5, ..., or n carbon atoms; further understanding, "C" 1～n "Should be interpreted as any subranges included, such as C" 1～6 In, containing C 1～5 C 1～4 C 1～3 C 1～2 C 2～5 C 2～4 C 2～3 C3～5 C 3～4 C 4～5 .

[0189] In this article, the term "C" 1～6 "Alkyl" refers to a straight-chain or branched saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5, or 6 carbon atoms, such as C64. 1～5 Alkyl, C 1～4 Alkyl, C 1～3 Alkyl, C 2～5 Alkyl, C 2～4 Alkyl, C 2～3 Alkyl groups. These include, but are not limited to, methyl, ethyl, n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3), tert-butyl (t-Bu, -C(CH3)3), and n-pentyl (-CH2CH2CH2C). H2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), n-hexyl ( -CH2CH2CH2CH2CH2CH3), 2-hexyl(-CH(CH3)CH2CH2CH2CH3), 3-hexyl(-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl(-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl(-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl(-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl(-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl(-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl(-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl(-CH(CH3)C(CH3)3), wherein the alkyl groups may be independently unsubstituted or substituted by one or more substituents described in this invention.

[0190] In this article, the term "C" 2～6"Alkenyl" refers to a straight-chain or branched monovalent hydrocarbon group having 2, 3, 4, 5, or 6 carbon atoms, wherein at least one C-C position is in an sp2 double bond unsaturated state. The alkenyl group can be independently unsubstituted or substituted by one or more substituents described in this invention, including groups with "cis," "trans," or "Z" or "E" orientations. Specific examples include, but are not limited to, allyl (-CH=CH2), allyl (-CH2CH=CH2), etc. For example, C... 2～5 alkenyl, C 2～4 alkenyl, C 2～3 alkenyl, C 3～6 alkenyl, C 3～5 alkenyl, C 3～4 Alkenyl group.

[0191] In this article, the term "C" 2～6 "Alynyl" refers to a straight-chain or branched monovalent hydrocarbon group having 2, 3, 4, 5, or 6 carbon atoms, wherein at least one C-C position is sp triple unsaturated. The alkynyl group may be independently unsubstituted or substituted by one or more substituents described in this invention. Specific examples include, but are not limited to, ethyl alkynyl (-C≡CH2), propynyl alkynyl (-CH2C≡CH), 1-propynyl (-C≡C-CH3), etc. For example, C... 2～5 alkynyl group, C 2～4 alkynyl group, C 2～3 alkynyl group, C 3～6 alkynyl group, C 3～5 alkynyl group, C 3～4 Alkyne group.

[0192] In this article, the term "C" 1～6 "Alkoxy" refers to a C-type compound containing the formula "-O-alkyl". 1～6 Alkyl, wherein the term "alkyl" is as defined above. Examples include: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, pentoxy, isopentoxy, and n-hexyloxy, or isomers of the above groups. In particular, the "C1-C6 alkoxy" may contain 1, 2, 3, 4, or 5 carbon atoms ("C1-C6 alkoxy"). 1～5 Alkoxy group), preferably, may contain 1, 2, 3 or 4 carbon atoms ("C"). 1～4 (alkoxy group).

[0193] In this article, the term "C" 1～6 "Cycloalkyl" or "1- to 6-membered cycloalkyl" refers to a saturated monovalent mono- or bicyclic hydrocarbon ring containing 1, 2, 3, 4, 5, or 6 carbon atoms. The C... 3～6 Cycloalkyl groups are monocyclic hydrocarbon rings, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0194] In this article, the term "alkylene" refers to a group formed by removing one hydrogen atom from an "alkyl" group, wherein "C" 1～6 "alkylene" includes methylene, ethylene, propylene, and isopropylene (e.g., ...). ), butylide (such as) ), pentylene (e.g.) ), hexyl (such as) )wait.

[0195] In this article, the term "cycloalkylene" refers to a group formed by removing one more hydrogen atom from a "cycloalkyl" group.

[0196] In this document, the terms "heterocyclic alkyl," "heterocyclic," and "heterocyclic alkane" all refer to a saturated ring or a non-aromatic unsaturated ring containing at least one heteroatom; where heteroatoms refer to nitrogen, oxygen, sulfur, etc. Typically, it represents a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system with multiple ring atoms, containing one, two, or three cyclic heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon.

[0197] The 4-7 membered heterocycles mentioned in this invention refer to 4, 5, 6 or 7 membered saturated or unsaturated heterocycles. The unsaturation refers to the presence of carbon-carbon double bonds, carbon-carbon triple bonds, carbon-oxygen double bonds, carbon-sulfur double bonds, carbon-nitrogen triple bonds, etc. in the group or molecule.

[0198] In this paper, the terms "-OR", "-NRR", etc. refer to R groups being connected to oxygen or nitrogen atoms by a single bond.

[0199] In this article, the oxygen atom in the term "-C(O)R" etc. is connected to a carbon or sulfur atom by a double bond.

[0200] It should be noted that the term "C" is used in this article. 1～10 For example, in "C" 1～10 "alkyl" or "C" 1～10 In the context of the definition of "alkoxy", it refers to an alkyl group having a finite number of carbon atoms, i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. Further understanding, the term "C"... 1～10 "Should be interpreted as any subranges included, such as C" 1～10 C 1～9 C 1～8 C 1～7 C 1～6 C 2～10 C 2～9 C 2～8 C 2～7 C 2～6 C 2～5 C 2～4 C 2～3 C3～10 C 3～9 C 3～8 C 3～7 C 3～6 C 3～5 C 3～4 C 1～2 C 1～3 C 1～4 C 1～5 Especially C 1～2 C 1～3 C 1～4 C 1～5 C 1～6 Especially C 1～4 .

[0201] Similarly, as used herein, the term "C" is used throughout this document. 2～10 For example, in "C" 2～10 "Alkenyl" and "C" 2～10 In the context of the definition of "alkynyl", it should be understood to refer to an alkenyl or alkynyl group having a finite number of carbon atoms, i.e., 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. Further understanding, the term "C" refers to... 2～10 "Should be interpreted as any subranges included, such as C" 2～10 C 2～9 C 2～8 C 2～7 C 2～6 C 2～5 C 2～4 C 2～3 C 3～10 C 3～9 C 3～8 C 3～7 C 3～6 C 3～5 C 3～4 Especially C 2～3 .

[0202] In the description of the functional groups of this invention It is used to describe the position of the substituent group.

[0203] In this document, the term "pharmaceuticalally acceptable excipient" includes any solvent, dispersion medium, coating material, surfactant, antioxidant, preservative (e.g., antibacterial, antifungal), isotonic agent, salt, pharmaceutical stabilizer, binder, excipient, dispersant, lubricant, sweetener, flavoring agent, colorant, or combination thereof, all of which are known to those skilled in the art (as described in Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Except in cases where any conventional carrier is incompatible with the active ingredient, its use in therapeutic or pharmaceutical compositions is covered.

[0204] In this document, the term "administration" refers to the introduction of a predetermined amount of a substance into a patient in a suitable manner. The recombinant cell or pharmaceutical composition of the present invention can be administered via any common route, as long as it can reach the intended tissue. Various routes of administration are contemplated, including peritoneal, intravenous, intramuscular, subcutaneous, etc., but the present invention is not limited to these exemplified routes of administration. Preferably, the compositions of the present invention are administered via intravenous or subcutaneous injection.

[0205] In this document, the term "treatment" refers to the administration of a drug or compound to an individual to achieve a desired pharmacological and / or physiological effect. This effect may be preventative in terms of complete or partial prevention of a disease or its symptoms, and / or therapeutic in terms of partial or complete cure of a disease and / or adverse effects caused by the disease. As used herein, "treatment" encompasses diseases in mammals, particularly humans, including: (a) prevention of disease or the onset of a condition in an individual who is susceptible but has not yet been diagnosed with the disease; (b) inhibition of disease, such as blocking disease progression; or (c) relief of disease, such as reducing symptoms associated with the disease. As used herein, "treatment" encompasses any administration of a drug or compound to an individual to treat, cure, relieve, improve, reduce, or inhibit the individual's disease, including but not limited to administration of a drug containing a compound described herein to an individual in need.

[0206] In this document, the terms "cancer" or "tumor" can refer to any unregulated cell growth. Examples include, but are not limited to, lung cancer (e.g., non-small cell lung cancer), papillary thyroid carcinoma, glioblastoma multiforme, colon cancer, rectal cancer, head and neck cancer, kidney cancer, bladder cancer, breast cancer, ovarian cancer, liver cancer, bile duct cancer, sarcoma, acute myeloid leukemia, large cell neuroendocrine carcinoma, neuroblastoma, prostate cancer, neuroblastoma, pancreatic cancer, melanoma, head and neck squamous cell carcinoma, cervical cancer, skin cancer, glioma, esophageal cancer, oral squamous cell carcinoma, or gastric cancer, etc.

[0207] The present invention will be explained below with reference to embodiments. Those skilled in the art will understand that the following embodiments are for illustrative purposes only and should not be considered as limiting the scope of the invention. Where specific techniques or conditions are not specified in the embodiments, they are performed according to the techniques or conditions described in the literature in the field or according to the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be obtained commercially.

[0208] Example 1: Preparation of Monomer Compounds

[0209] 1. Synthesis of compounds M-1 and M-2

[0210] Step 1: 4-Dimethylaminopyridine (4.5 mg, 0.037 mmol), di-tert-butyl dicarbonate (122.2 mg, 0.56 mmol), and triethylamine (154.3 μL, 1.11 mmol) were added to a solution of 5,6-dimethoxy-1H-indole (65.5 mg, 0.37 mmol) in dichloromethane (10 mL). The reaction mixture was stirred at room temperature for 4 hours, quenched with 10 mL of water, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue purified by silica gel column chromatography to give M-1-int-1 (94.2 mg, 0.34 mmol, 93% yield).

[0211] Step 2: Under nitrogen protection, 2,2,6,6-tetramethylpiperidine (TEMP, 72 mg, 0.51 mmol) was dissolved in 1 mL of anhydrous tetrahydrofuran. At -78°C, 20.4 μL (0.51 mmol, 2.5 M hexane solution) was added dropwise to the reaction flask, and the mixture was stirred at this temperature for 1 hour. A tetrahydrofuran solution of M-1-int-1 (94.2 mg, 0.34 mmol) (2 mL) was added dropwise to the reaction solution. After stirring the reaction solution at -78°C for one hour, a tetrahydrofuran solution of 2,2-dimethylsuccinic anhydride (87.1 mg, 0.68 mmol) (1 mL) was added to the reaction solution, and the mixture was stirred at -78°C for another hour. The mixture was then brought to room temperature and stirred overnight. After the reaction was complete, a small amount of water and hydrochloric acid were added to quench the reaction, and the pH was adjusted to 3. The crude product was concentrated and purified by silica gel column chromatography (20:80 = ethyl acetate: petroleum ether) to obtain a mixture of M-1-int-2 and M-1-int-3 (48.7 mg, 0.12 mmol, 35% yield).

[0212] Step 3: Trifluoroacetic acid (89.1 μL, 1.2 mmol) was added dropwise to a solution of M-1-int-2 and M-1-int-3 (48.7 mg, 0.12 mmol) in dichloromethane (2 mL), and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was extracted with ethyl acetate and water. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (20:80 = ethyl acetate: petroleum ether) to give a mixture of M-1-int-4 and M-1-int-5 (33.6 mg, 0.11 mmol, 96% yield).

[0213] Step 4: Diazomethane (165 μL, 0.33 mmol, 2.0 M n-hexane solution) was added dropwise to a methanol (1 mL) and diethyl ether (1 mL) solution of M-1-int-4 and M-1-int-5 (33.6 mg, 0.11 mmol). The reaction was carried out at room temperature for 2 h. After the reaction was complete, the reaction solution was concentrated, and the residue was extracted with ethyl acetate and water. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and finally purified by silica gel column chromatography to obtain a mixture of M-1-int-6 and M-1-int-7 (31.9 mg, 0.10 mmol, 91% yield).

[0214] Step 5: Cesium carbonate (48.9 mg, 0.15 mmol) and methyl iodide (18.7 μL, 0.3 mmol) were added to a 2 mL solution of acetonitrile in which a mixture of M-1-int-6 and M-1-int-7 (31.9 mg, 0.10 mmol) was added. The mixture was heated to 80 °C and reacted for 12 h. After the reaction was complete, the reaction solution was concentrated, and the residue was extracted with ethyl acetate and water. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by preparative chromatography to obtain M-1 (9.3 mg, 0.028 mmol, 28% yield) and M-2 (17 mg, 0.051 mmol, 51% yield), respectively.

[0215] M-1:Purity:98%; HRMS(ESI)m / z:[M+H] + Calcd for C 18 H 24 NO5 334.1654; Found 334.1658; 1 H NMR (600MHz, DMSO-d6) δ7.25(s,1H),7.09(s,1H),7.03(s,1H),3.85(s,3H),3.81(s,3H),3.76(s,3H),3.49(s,3H),2.87(s,2H),1.41(s,6H).

[0216] M-2:Purity:97%; HRMS(ESI)m / z:[M+H] + Calcd for C 18 H 24 NO5 334.1654; Found 334.1654; 1 H NMR (600MHz, DMSO-d6) δ7.36(s,1H),7.10(s,1H),7.04(s,1H),3.93(s,3H),3.86(s,3H),3.77(s,3H),3.57(s,3H),3.26(s,2H),1.22(s,6H).

[0217] 2. Synthesis of M-3 compound

[0218] 33 mg of M-1 (0.1 mmol) prepared in Part 1 of this example was dissolved in a mixed solvent of 3.0 mL THF, 3.0 mL MeOH, and 1.0 mL H2O. 12 mg of LiOH (0.5 mmol) was added in portions, and the mixture was heated to 50 °C and reacted for 12 h. After the reaction was complete, the reaction solution was cooled to room temperature, poured into water, and the pH was adjusted to 1-2 with 1N HCl aqueous solution. The solution was extracted with ethyl acetate, the organic layers were combined, dried, concentrated, and separated by column chromatography to obtain 16 mg of M-3.

[0219] M-3:Purity:99%; HRMS(ESI)m / z:[MH] - Calcd for C 17 H 20 NO5 318.1341;Found 318.1360; 1 H NMR (600MHz, DMSO-d6) δ7.34(s,1H),7.10(s,1H),7.04(s,1H),3.94(s,3H),3.86(s,3H),3.77(s,3H),3.19(s,2H),1.20(s,6H).

[0220] 3. Synthesis of M-4 compounds

[0221] 33 mg of M-2 (0.1 mmol) prepared in Part 1 of this example was dissolved in a mixed solvent of 3.0 mL THF, 3.0 mL MeOH, and 1.0 mL H2O. 12 mg of LiOH (0.5 mmol) was added in portions, and the mixture was heated to 50 °C and reacted for 12 h. After the reaction was complete, the reaction solution was cooled to room temperature, poured into water, and the pH was adjusted to 1-2 with 1 N HCl aqueous solution. The solution was extracted with ethyl acetate, the organic layers were combined, dried, concentrated, and separated by column chromatography to obtain 13 mg of M-4.

[0222] M-4:Purity:99%; HRMS(ESI)m / z:[MH] - Calcd for C 17 H 20 NO5 318.1341; Found 318.1354; 1 H NMR (600MHz, DMSO-d6) δ7.17(s,1H),7.09(s,1H),7.02(s,1H),3.85(s,3H),3.78(s,3H),3.76(s,3H),2.79(s,2H),1.36(s,6H).

[0223] 4. Synthesis of compounds M-5 and M-6

[0224] At -78°C, t-BuLi (0.94 mg, 0.72 mmol) was added dropwise to a THF (2.0 mL) solution containing M-1-int-1 (100.0 mg, 0.36 mmol) prepared in Part 1 of this example, and then the mixture was stirred at room temperature for 16 hours. The reaction was quenched at 0°C with a saturated ammonium chloride aqueous solution (10.0 mL), diluted with water (5.0 mL), extracted with EtOAc (10.0 mL), dried over anhydrous Na2SO4, filtered, concentrated, and the residue was purified by thin-layer chromatography (PE:EA = 5:1) to give white solids M-5 (25.0 mg, 0.063 mmol, yield 17.7%) and M-6 (10 mg, 0.025 mmol, yield 7.1%).

[0225] M-5: MS m / z (ESI): 336.0 [M+H] + ; 1H NMR (400MHz, DMSO) δ12.23(s,1H),7.47(s,1H),7.42(s,1H),7.21(s,1H),3.84(s,3H),3.81(s,3H),3.26(dd,J =17.2,7.4Hz,1H),2.96(dd,J=17.2,5.6Hz,1H),2.86(dd,J=13.4,7.2Hz,1H),1.54(s,9H),1.33-1.10(m,3H).

[0226] M-6: MS m / z (ESI): 336.1 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ7.62(s,1H),7.20(s,1H),7.01(s,1H),3.98(s,3H),3.93(s,3H),3.67(dd,J=13.4 ,7.2Hz,1H),2.97(dd,J=16.8,7.6Hz,1H),2.50(dd,J=16.8,5.6Hz,1H),1.59(s,9H),1.36-1.22(m,3H).

[0227] 5. Synthesis of M-7 compounds

[0228] At -78°C, n-BuLi (0.56 mL, 0.56 mmol) was added dropwise to a THF (1.0 mL) solution containing 2,2,6,6-tetramethylpiperidine (TEMP, 59.0 mg, 0.41 mmol). After 15 min, M-1-int-1 (50.0 mg, 0.18 mmol) prepared in Part 1 of this example was added, and the reaction was continued at -78°C for 40 min. Then, 3,4-dimethylfuran-2,5-dione (45.0 mg, 0.36 mmol) was added, and the reaction was continued for another 20 min. After the reaction was completed, the reaction was quenched with saturated NH4Cl (10.0 mL), diluted with water (5.0 mL), and extracted with EtOAc (10.0 mL). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated. Thin-layer chromatography (10-100% EtOAc / hexane) was prepared to give a white solid M-7 (12.0 mg, 0.031 mmol, yield 16.6%).

[0229] M-1:MS m / z(ESI):348.1[M-56+H] + ; 1H NMR(400MHz, CDCl3)δ8.62(s,1H),7.57(s,1H),6.91(s,1H),6.29(s,1H),3.93 (s,3H),3.90(s,3H),2.23(d,J=1.2Hz,3H),1.93(d,J=1.2Hz,3H),1.78(s,9H).

[0230] 6. Synthesis of compounds M-8, M-9 and M-10

[0231] Step 1: At -78°C, n-BuLi (1.1 mL, 2.7 mmol) was added dropwise to a THF (5.0 mL) solution containing 2,2,6,6-tetramethylpiperidine (TEMP, 2.16 mmol). After 15 min, M-1-int-1 (500 mg, 1.8 mmol) prepared in Part 1 of this example was added, and the mixture was stirred for 40 min. 3-oxabicyclo[3.1.0]hexane-2,4-dione (303.0 mg, 2.70 mmol) was added at -78°C, and the reaction was continued for 20 min. After the reaction was complete, the reaction was quenched with saturated NH4Cl aqueous solution (10.0 mL), diluted with water (5.0 mL), extracted with EtOAc (10.0 mL), dried over anhydrous NaSO4, filtered, concentrated, and a thin layer was prepared (10-100% ethyl acetate / hexane) to give a white solid M-8-int-1 (100.0 mg, 0.25 mmol, yield 14.2%).

[0232] M-8-int-1:MS m / z(ESI):334.0[M-56+H] + .

[0233] Step 2: At 0°C, add HCl aqueous solution (92.5 mg, 2.57 mmol) to EA (2.0 mL) solution containing M-8-int-1 (100.0 mg, 0.26 mmol), stir at room temperature for 4 h, concentrate, and purify the crude product by column chromatography (DCM:MeOH = 20:1) to obtain brown liquid M-8 (80.0 mg, crude product).

[0234] Step 3: Dissolve M-8 (80.0 mg, 0.28 mmol) in DMF (2.0 mL), then add NaOH (33.0 mg, 0.83 mmol) and CH3I (196.4 mg, 1.38 mmol) sequentially, and stir at 45 °C for 16 h. After the reaction is complete, add HCl aqueous solution (10.0 mL, 1 M) under ice bath, extract with EtOAc (10.0 mL), dry the organic phase with anhydrous Na2SO4, filter, and concentrate. Prepare thin-layer chromatography (10–100% ethyl acetate / hexane) to obtain yellow solid M-9 (1.22 mg, 0.0038 mmol, yield 1.5%).

[0235] M-9: MS m / z (ESI): 318.2 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ7.37(s,1H),7.05(s,1H),6.73(s,1H),4.03(s,3H),3.99(s,3H),3.93(s ,3H),3.74(s,3H),3.14-3.10(m,1H),2.35-2.31(m,1H),1.64-1.51(m,1H),1.30-1.22(m,1H).

[0236] Step 4: At room temperature, M-9 (180.0 mg, crude product) and LiOH (71.0 mg, 1.70 mmol) were added to THF / H2O (2.0 mL) and stirred for 16 h. After the reaction was complete, the reaction was quenched by adding HCl (10.0 mL, 1.0 M) under ice bath conditions, extracted with EtOAc (10.0 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated. Thin-layer chromatography (10-100% DCM / MeOH) was used to purify the product to obtain a white solid M-10 (2.14 mg, 0.0038 mmol, yield 1.24%).

[0237] M-10: MS m / z (ESI): 304.1 [M+H] + ; 1 H NMR(400MHz,MeOD)δ7.48(s,1H),7.16(s,1H),6.94(s,1H),4.00(s,3H),3.94(s,3H),3 .86(s,3H),3.31-3.29(m,3H),3.16-3.12(m,1H),2.18-2.13(m,1H),1.53-1.44(m,2H).

[0238] 7. Synthesis of M-11 compounds

[0239] Step 1: At -78°C, n-BuLi (2.5M / hexane, 1.08mL) was added dropwise to a THF (10.0mL) solution of 2,2,6,6-tetramethylpiperidine (TEMP, 2.16mmol) and stirred at a constant temperature for 1 hour. Then, M-1-int-1 (500mg, 1.80mmol) and 3-oxabicyclo[3.2.0]heptane-2,4-dione (341.07mg, 2.70mmol) prepared in Part 1 of this example were added, and the mixture was stirred at -78°C for 1 hour. The reaction was quenched with ice-cold saturated ammonium chloride aqueous solution (20.0 mL), extracted with EtOAc (20.0 mL × 2), washed with saturated brine (10.0 mL), dried over anhydrous Na2SO4, filtered and concentrated, and the residue was purified by rapid column chromatography (PE:EA = 2:1) to give M-11-int-1 (108.0 mg, 267.70 μmol, yield 14.9%).

[0240] M-11-int-1:MS m / z(ESI):348.1[M-56+H] + .

[0241] Step 2: M-11-int-1 (80 mg, 198.30 μmol), CH3I (42.2 mg, 297.45 μmol), and K2CO3 (32.8 mg, 238.00 μmol) were added sequentially to DMF (2.0 mL), and stirred at room temperature for 16 h. The reaction was quenched with water (20.0 mL), extracted with EtOAc (20.0 mL × 2), washed with saturated brine (15.0 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by thin-layer chromatography (petroleum ether: EtOAc = 5:1) to obtain a colorless oily tert-butyl 5,6-dimethoxy-2-(2-methoxycarbonylcyclobutanecarbonyl)indole-1-carboxylic acid M-11-int-2 (28.0 mg, 67.07 μmol, yield 33.8%).

[0242] M-11-int-2:MS m / z(ESI):362.1[M-56+H] + .

[0243] Step 3: M-11-int-2 (62.0 mg, 148.52 μmol) and TFA (16.93 mg, 148.52 μmol) were dissolved in DCM (3 mL) and stirred at room temperature for 3 hours. The solution was concentrated, diluted with water, extracted with EtOAc (20.0 mL × 2), washed with saturated brine (15.0 mL × 3), dried over anhydrous Na₂SO₄, and filtered and concentrated. The residue was purified by TLC (petroleum ether: EtOAc = 2:1) to give a colorless oily methyl 5-(5,6-dimethoxy-1-methylindole-2-yl)-5-oxo-valerate M-11-int-3 (30.0 mg, 93.94 μmol, yield 24.88%).

[0244] M-11-int-3:MS m / z(ESI):318.2[M+H] + .

[0245] Step 4: Dissolve M-11-int-3 (27 mg, 85.08 μmol) in DMF (2.0 mL), add sodium hydride (2.45 mg, 102.10 μmol) in portions at 0 °C, stir at a constant temperature for 1 hour, add CH3I (24.15 mg, 170.17 μmol), and stir at room temperature for 16 hours. Quench the reaction with ice water, extract with EtOAc (2 x 20 mL), wash with saturated brine (15.0 mL), dry with anhydrous Na2SO4, filter and concentrate. The residue is purified by thin-layer chromatography (PE:EtOAc = 2:1) to obtain colorless oily methyl 2-(5,6-dimethoxy-1-methylindole-2-carbonyl)cyclobutanecarboxylate M-11-int-4 (24.0 mg, 72.43 μmol, yield 85.13%).

[0246] M-11-int-4:MS m / z(ESI):332.2[M+H] + ;

[0247] Step 5: Dissolve M-11-int-4 (20.0 mg, 60.36 μmol) and LiOH (1.7 mg, 72.43 μmol) in THF:H₂O = 5:1 (6.0 mL) and stir at room temperature for 3 hours. Dilute with water, extract with EtOAc (2 x 20.0 mL), wash with brine (15.0 mL), dry with anhydrous Na₂SO₄, and filter to concentrate. The residue is purified by thin-layer chromatography (petroleum ether:EtOAc = 2:1) to give a white solid 2-(5,6-dimethoxy-1-methylindole-2-carbonyl)cyclobutanecarboxylic acid M-11 (6.0 mg, 18.91 μmol, yield 31.33%).

[0248] M-11: MS m / z (ESI): 318.1 [M+H] + ; 1 H NMR (400MHz, MeOD) δ7.34(s,1H),7.12(s,1H),6.94(s,1H),4.31-4.23(m,1H),4.03(s,3H),3.93(s,3H),3.85(s,3H),2.26-2.15(m,4H).

[0249] 8. Synthesis of M-12 compound

[0250] Step 1: Dissolve M-1-int-1 (300 mg, 1.08 mmol) prepared in Part 1 of this example in THF (2.0 mL). Slowly add t-Buli (1.6 M / hexane, 1.35 mL) at -78 °C, and stir at a constant temperature for 40 min. Add hexahydroisobenzofuran-1,3-dione (250.16 mg, 1.62 mmol), and heat to room temperature and stir overnight. Quench the reaction with saturated NH4Cl aqueous solution (10.0 mL), dilute with water (5.0 mL), and extract with EtOAc (10.0 mL). Dry in anhydrous Na2SO4, filter, and concentrate. Silica gel chromatography (10–100% EtOAc / hexane, linear gradient; diatomaceous earth dry loading) yields white solid M-12-int-1 (220 mg, 509.88 μmol, yield 47.13%).

[0251] M-12-int-1:MS m / z(ESI):376.00[M-56+H] + .

[0252] Step 2: Dissolve 170.0 mg (393.99 μmol) of M-12-int-1 in HCl / EA (2.0 mL) and stir at room temperature for 16 hours. Concentrate the solution, and purify the residue by column chromatography (DCM:MeOH = 20:1) to obtain a brown oily substance of M-12-int-2 (120.0 mg (362.14 μmol), yield 91.92%).

[0253] M-12-int-2:MS m / z(ESI):332.05[M+H] + .

[0254] Step 3: M-12-int-2 (80.0 mg, 241.43 μmol), NaOH (29.0 mg, 0.83 mmol), and MeI (171.34 mg, 1.21 mmol) were added to DMF (2.0 mL) and stirred at 45 °C for 16 hours. The reaction was quenched with HCl (10.0 mL, 1 M), extracted with EtOAc (10.0 mL), dried over anhydrous Na2SO4, filtered, concentrated, and subjected to column chromatography (10-100% EtOAc / hexane) to obtain a white solid M-12 (7.4 mg, 21.45 μmol, yield 8.88%).

[0255] M-12: MS m / z (ESI): 346.0 [M+H] + ; 1 H NMR (400MHz, Methanol-d4) δ7.24(s,1H),7.14(s,1H),6.94(s,1H),3.87(d,J=10.2Hz,6H),3.51(s,3H),3.50 -3.42(m,1H),2.88-2.76(m,1H),2.17-2.06(m,2H),1.92-1.81(m,2H),1.58-1.45(m,2H),1.45-1.32(m,2H).

[0256] 9. Synthesis of compounds M-13 and M-14

[0257] Step 1: TEMP (2.16 mmol) was added to tetrahydrofuran (6.0 mL) with stirring at -78 °C, followed by n-butyllithium (2.70 mmol), and the mixture was stirred for 1 hour. M-1-int-1 (500.0 mg, 1.80 mmol) prepared in Part 1 of this example and glutaric anhydride (308.6 mg, 2.70 mmol) were added sequentially to the above mixture, and the reaction was stirred at -78 °C for 1 hour. The resulting mixture was diluted with ice water and extracted with ethyl acetate (2 x 20.0 mL), washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE:EA = 2:1) to give a brown oily liquid M-13-int-1 (230.0 mg, 587.61 μmol, yield 32.67%).

[0258] M-13-int-1:MS m / z(ESI):292.2[M-100+H] + .

[0259] Step 2: M-13-int-1 (230.0 mg, 587.61 μmol), trifluoroacetic acid (335.0 mg, 2.94 mmol), and dichloromethane (6.0 mL) were mixed and stirred at room temperature for 3 hours. The resulting mixture was diluted with water and extracted with ethyl acetate (2 x 20.0 mL), washed with saturated brine (2 x 15.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative thin-layer chromatography (petroleum ether:ethyl acetate = 2:1) to give a colorless oily liquid M-13-int-2 (130.0 mg, 446.28 μmol, 75.95% yield).

[0260] M-13-int-2:MS m / z(ESI):292.1[M+H] + .

[0261] Step 3: M-13-int-2 (110.0 mg, 377.62 μmol), methyl iodide (214.4 mg, 1.51 mmol), and sodium hydroxide (30.2 mg, 755.24 μmol) were added to DMF (4.0 mL), and the resulting mixture was stirred at 45 °C for 16 hours. The resulting mixture was diluted with water and extracted with ethyl acetate (2 x 20.0 mL), washed with saturated brine (2 x 15.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified using a preparative plate (petroleum ether:ethyl acetate = 2:1) to give a colorless oily liquid M-13 (30.0 mg, 93.94 μmol, 24.88% yield).

[0262] M-13: MS m / z (ESI): 320.0 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ7.34(s,1H),7.11(s,1H),7.05(s,1H),3.98(s,3H),3.87(s,3H), 3.78(s,3H),3.60(s,3H),2.95(t,J=7.2Hz,2H),2.40(t,J=7.2Hz,2H),1.94-1.82(m,2H).

[0263] Step 4: A mixture of M-13 (30.0 mg, 93.94 μmol) and lithium hydroxide (2.70 mg, 112.73 μmol) was added to a tetrahydrofuran:water mixture of 5:1 (6 mL) and stirred at room temperature for 2 hours. The resulting mixture was diluted with water, extracted with ethyl acetate (2 x 20 mL), washed with saturated brine (2 x 15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified using a preparative plate (petroleum ether:ethyl acetate = 2:1) to give a white solid M-14 (6.0 mg, 19.65 μmol, 20.92% yield).

[0264] M-14: MS m / z (ESI): 305.95 [M+H] + ; 1 H NMR(400MHz,MeOD)δ7.20(s,1H),7.12(s,1H),6.94(s,1H),3.88(s,3H),3.85(s,3H),3 .66(s,3H),2.96(t,J=7.2Hz,2H),2.44(t,J=7.2Hz,2H),2.03(dd,J=14.8,7.2Hz,2H).

[0265] 10. Synthesis of compound M-15

[0266] Step 1: 5-Methoxy-4-azaindole (600.0 mg, 4.05 mmol), DMAP (494.7 mg, 4.05 mmol), triethylamine (818.03 mg, 8.08 mmol), and di-tert-butyl dicarbonate (1.33 g, 6.07 mmol) were added to a solution of dichloromethane (6.0 mL). The resulting mixture was stirred at room temperature for 16 hours. The mixture was concentrated under vacuum, diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE:EA = 5:1) to give a white solid M-15-int-1 (720.0 mg, 2.90 mmol, 71.61% yield).

[0267] M-15-int-1:MS m / z(ESI):249.0[M+H] + .

[0268] Step 2: At -78°C, tert-butyllithium (1.61 mmol, 1.24 mL) was slowly added to a stirred mixture of M-15-int-1 (200.0 mg, 806.32 μmol) and tetrahydrofuran (6.0 mL). The mixture was stirred at -78°C for 1 hour. Then, 3-methyltetrahydrofuran-2,5-dione (138.0 mg, 1.21 mmol) was added to the solution, and the reaction was stirred at room temperature for 16 hours. The resulting mixture was diluted with ice water and extracted with ethyl acetate (2 x 20.0 mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by thin-layer chromatography (petroleum ether:ethyl acetate = 2:1) to give M-15-int-2 (12.7 mg, 0.035 mmol, yield 4.38%).

[0269] M-15-int-2:MS m / z(ESI):363.1[M+H] + .

[0270] Step 3: Add ethyl acetate (3.0 mL) to a mixture of M-15-int-2 (12.7 mg, 0.035 mmol, 1.00 eq) and HCl / EtOAc (3 M, 1.0 mL), and stir at room temperature for 2 hours. Concentrate the resulting mixture under vacuum, dilute with water, extract with ethyl acetate (2 x 10.0 mL), wash with saturated brine (2 x 10.0 mL), dry with anhydrous sodium sulfate, filter, and concentrate. Purify the residue using a petroleum ether:ethyl acetate = 2:1 plate preparation to give a white solid M-15 (2.7 mg, 0.010 mmol, yield 29.4%).

[0271] M-15: MS m / z (ESI): 263.1 [M+H] + ; 1 H NMR(400MHz,MeOD)δ7.77(d,J=8.8Hz,1H),7.22(s,1H),6.78(d,J=8.8Hz,1H),3.95 (s,3H),3.42(dd,J=18.4,9.6Hz,1H),3.05(d,J=12.8Hz,1H),1.28(d,J=6.8Hz,3H).

[0272] Synthesis of compounds M-11, M-16, M-17, M-18, and M-19

[0273] Step 1: At 0°C, sodium hydride (481.4 mg, 12.04 mmol, 60% dispersed in mineral oil) was added in portions to a DMF (20.0 mL) solution containing ethyl 5,6-dimethoxyindole-2-carboxylate (2.0 g, 8.02 mmol). The resulting mixture was stirred at room temperature for 0.5 h, followed by dropwise addition of iodomethane (3.4 g, 24.07 mmol), and stirring for 3 h. The reaction was quenched with a saturated ammonium chloride aqueous solution (50.0 mL) at 0°C, extracted with ethyl acetate (20.0 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to give a white solid of M-16-int-1 (2.1 g, 7.98 mmol, 99.4% yield).

[0274] M-16-int-1:MS m / z(ESI):264.1[M+H] + .

[0275] Step 2: Under argon protection and at -78°C, lithium bis(trimethylsilyl)amino (1M, 8.36mL, 8.36mmol) was added dropwise to a THF (10mL) solution containing dimethyl methylphosphonate (777.6mg, 6.27mmol), and the mixture was stirred at -78°C for 1 hour. Then, a solution of M-16-int-1 (1.1g, 4.18mmol) in 5mL THF was added dropwise to the mixture. The mixture was heated to room temperature and stirred for 2 hours. The reaction was quenched with a saturated aqueous ammonium chloride solution (100.0mL). Extraction was performed using DCM (50.0mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by gel column chromatography (DCM:MeOH = 20:1) to give a white solid M-16-int-2 (1.2g, 3.52mmol, yield 84.2%).

[0276] M-16-int-2:MS m / z(ESI):342.1[M+H] + .

[0277] Step 3: Under argon protection, sodium hydride (220.0 mg, 5.50 mmol, 60% dispersed in mineral oil) was added dropwise to a THF (10.0 mL) solution containing M-16-int-2 (1.25 g, 3.67 mmol). The resulting mixture was stirred at 0 °C for 30 min. Then, methyl 2-oxopropionate (561.5 mg, 5.50 mmol) was added dropwise over 10 min at 0 °C, followed by stirring at room temperature for 2 h. The reaction was quenched with ice water (100.0 mL) and extracted with ethyl acetate (50.0 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by gel column chromatography (PE:EA = 8:1) to give a bright yellow solid M-16-int-3 (1.1 g, 3.47 mmol, yield 94.5%).

[0278] M-16-int-3:MS m / z(ESI):318.1[M+H] + .

[0279] Step 4: Pd / C (10%, 120.0 mg) was added to a MeOH (10.0 mL) solution containing SG-001-14 (1.18 g, 3.72 mmol). The resulting mixture was then stirred at room temperature under hydrogen for 3 hours. The mixture was filtered, the filtrate was concentrated, and purified by gel column chromatography (PE:EA = 10:1) to give a white solid M-16 (1.05 g, 3.29 mmol, yield 88.4%).

[0280] M-16: MS m / z (ESI): 320.2 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ7.38(s,1H),7.11(s,1H),7.05(s,1H),3.95(s,3H),3.87(s,3H),3.78(s, 3H),3.60(s,3H),3.29-3.35(m,1H),3.06-3.11(m,1H),2.93-2.97(m,1H),1.17(d,J=7.2Hz,3H).

[0281] Step 5: Lithium hydroxide monohydrate (31.6 mg, 0.752 mmol) was added to a solution of MeOH (2.0 mL) and water (1.0 mL) containing M-16 (60.0 mg, 0.188 mmol), and stirred at room temperature for 16 hours. The pH of the mixture was adjusted to 3 with dilute hydrochloric acid (50.0 mL), and purified by Perp-HPLC (column: Waters Xbridge 20*150 mm 10 μm 10 μm, C18, mobile phase A: water, mobile phase B: ACN) to obtain a white solid M-17 (30.0 mg, 0.10 mmol, yield 52.3%).

[0282] M-17: MS m / z (ESI): 306.1 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ7.24(s,1H),7.03(s,1H),6.73(s,1H),4.04(s,3H),3.99( s,3H),3.93(s,3H),3.37-3.41(m,1H),3.07-3.17(m,2H),1.32(d,J=7.2Hz,3H).

[0283] Step 6: M-17 (45.0 mg, 0.147 mmol) was separated by chiral resolution (CO2 / MeOH / DEA 5%–40% 1.5 ml / min OJ, 3 μm, 3.0 × 100 (Daicel)); retention time / min, P1: 4.066 min, P2: 4.381 min), yielding M-18 (15.2 mg, 0.0498 mmol, yield 33.9%, 99.42% ee) and M-19 (16.2 mg, 0.0531 mmol, yield 36.1%, 98.10% ee).

[0284] M-18 / M-19:MS m / z(ESI):306.1[M+H] + ;

[0285] M-18: 1 H NMR(400MHz,DMSO-d6)δ7.36(s,1H),7.11(s,1H),7.05(s,1H),3.96(s,3H),3.86 (s,3H),3.78(s,3H),3.30-3.33(m,1H),2.83-3.01(m,2H),1.14(d,J=7.2Hz,3H).

[0286] M-19: 1H NMR(400MHz,DMSO-d6)δ12.04(br.s,1H),7.37(s,1H),7.11(s,1H),7.05(s,1H),3.96(s,3 H),3.87(s,3H),3.78(s,3H),3.30-3.33(m,1H),2.86-3.11(m,2H),1.16(d,J=7.2Hz,3H).

[0287] 12. Synthesis of M-20 compound

[0288] Methaniel hydrochloride (44.2 mg, 655.04 μmol), HATU (64.7 mg, 170.31 μmol), and N,N-diisopropylethylamine (169.3 mg, 1.31 mmol) were added to a solution of N,N-dimethylformamide (1.0 mL) containing M-17 (40.0 mg, 131.01 μmol) prepared in Part 11 of this example, and then stirred at room temperature for 16 hours. Water (10.0 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10.0 mL x 3). The organic phase was washed with water (10.0 mL x 3) and saturated brine (10.0 mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to give a white solid M-20 (21.0 mg, 65.96 μmol, yield 50.4%).

[0289] M-20: MS m / z (ESI): 319.1 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ7.79(d,J=4.4Hz,1H),7.34(s,1H),7.11(s,1H),7.04(s,1H),3.95(s,3H), 3.87(s,3H),3.78(s,3H),3.24(m,1H),2.92-2.77(m,2H),2.56(d,J=4.6Hz,3H),1.18-0.97(m,3H).

[0290] 13. Synthesis of Compound M-21

[0291] HATU (59.8 mg, 0.16 mmol), N,N-diisopropylethylamine (50.8 mg, 0.39 mmol), and dimethylamine (0.197 mL, 0.39 mmol, 2 M tetrahydrofuran solution) were added to a solution of dichloromethane (2.0 mL) containing M-17 (40.0 mg, 0.13 mmol) prepared in Part 11 of this example. The mixture was then stirred at room temperature for 16 hours. The reaction solution was concentrated and purified by preparative thin-layer chromatography (dichloromethane / methanol = 20 / 1) to give a white solid M-21 (8.3 mg, 25.10 μmol, yield 19.2%).

[0292] M-21: MS m / z (ESI): 333.1 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ7.36(s,1H),7.12(s,1H),7.04(s,1H),7.04(s,1H),3.94(s,3H),3.86(s,3H),3.78 (s,3H),3.42-3.33(m,2H),3.09(s,3H),2.89(dd,J=4.4Hz,16.8Hz,1H),2.81(s,3H),1.06(d,J=6.8Hz,3H).

[0293] 14. Synthesis of compound M-22

[0294] Step 1: M-17 (180.0 mg, 0.59 mmol) prepared in Part 11 of this example was dissolved in DMF (3.0 mL), and O-benzylhydroxylamine (145.2 mg, 1.18 mmol), HATU (333.6 mg, 0.88 mmol), and N,N-diisopropylethylamine (380.9 mg, 2.95 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. The mixture was diluted with water (10.0 mL), extracted with ethyl acetate (20.0 mL × 3), and washed with brine. The solution was dried over anhydrous sodium sulfate and concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to give a white solid compound M-22-int-1 (120.0 mg, 0.29 mmol, yield 62.2%).

[0295] M-22-int-1:MS m / z(ESI):411.3[M+H] + .

[0296] Step 2: M-22-int-1 (150.0 mg, 0.37 mmol) was dissolved in MeOH (3.0 mL) and Pd / C (15.0 mg, 10% wt, 50% water) was added. The reaction mixture was stirred at room temperature for 6 hours under a hydrogen balloon. After the reaction was complete, the mixture was filtered and concentrated under reduced pressure, and purified by reverse column chromatography (0.1% FA in water, acetonitrile) to give a white solid compound M-22 (6.44 mg, 0.020 mmol, yield 5.5%).

[0297] M-22: MS m / z (ESI): 264.3 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ9.71(s,1H),7.03(s,1H),7.01(s,1H),6.90(s,1H),6.23(s,1H),3.88-3.83(m ,1H),3.82(s,3H),3.79(d,J=2.8Hz,1H),3.77(d,J=2.4Hz,1H),3.74(s,3H),3.67(s,3H),1.87(s,3H).

[0298] 15. Synthesis of compound M-23

[0299] Step 1: M-22-int-1 (50.0 mg, 0.12 mmol), copper acetate (22.1 mg, 0.12 mmol), 4-dimethylaminopyridine (44.7 mg, 0.37 mmol), and cyclopropylboronic acid (20.9 mg, 0.24 mmol) prepared in Part 14 of this embodiment were suspended in toluene (1.0 mL) solution. NaHMDS (1 M tetrahydrofuran solution, 0.24 mL, 0.24 mmol) was added to the above solution. The reaction system was replaced with oxygen and stirred at 90 °C for 16 hours. The reaction solution was filtered through diatomaceous earth and washed with dichloromethane. The filtrate was concentrated and purified by high performance liquid chromatography (HPLC) (mobile phase A: 0.1% trifluoroacetic acid aqueous solution, mobile phase B: acetonitrile) to obtain white solid M-23-int-1 (8.0 mg, 17.76 μmol, yield 14.6%).

[0300] M-23-int-1:MS m / z(ESI):451.3[M+H] + ; 1H NMR (400MHz, CDCl3) δ7.44-7.46(m,2H),7.32-7.39(m,4H),7.02(s,1H),6.72(s,1H),4.99-5.04(m,2H),4.01(s ,3H),3.98(s,3H),3.78(s,3H),3.48-3.60(m,2H),2.92-3.03(m,2H),1.18(d,J=6.8Hz,3H),0.88-0.96(m,4H).

[0301] Step 2: Dissolve M-23-int-1 (20.0 mg, 44.39 μmol) in MeOH (2.0 mL) and add Pd / C (4.0 mg, 20% wt.). Replace the reaction system with hydrogen gas and stir at room temperature for 16 hours. Filter the reaction solution through a diatomaceous earth filter and concentrate the filtrate. Purify the residue by preparative high-performance liquid chromatography (HPLC) (mobile phase A: 0.1% trifluoroacetic acid aqueous solution, mobile phase B: acetonitrile) to obtain a white solid M-22 (6.0 mg, 16.65 μmol, yield 37.5%).

[0302] M-23:MS m / z(ESI):361.1[M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ9.57(br.s,1H),7.36(s,1H),7.12(s,1H),7.05(s,1H),3.95(s,3H),3.87(s,3H),3. 78(s,3H),3.37-3.50(m,1H),3.01-3.10(m,1H),2.85-2.90(m,1H),1.07(d,J=7.2Hz,3H),0.63-0.78(m,4H).

[0303] 16. Synthesis of compounds M-24 and M-25

[0304] Step 1: To a solution of N,N-dimethylformamide DMF (2.0 mL) containing M-17 (0.2 g, 655.04 μmol) prepared in Part 11 of this Example, methoxyamine hydrochloride (164.1 mg, 1.97 mmol), HATU (298.9 mg, 786.05 μmol), and N,N-diisopropylethylamine (846.6 mg, 6.55 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (20.0 mL) and extracted with ethyl acetate (10.0 mL x 3). The organic phase was washed three times with water and then with saturated brine. The solution was dried over anhydrous sodium sulfate and concentrated. The solution was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to give a grayish-white solid M-24 (208.0 mg, 622.07 μmol, yield 94.97%).

[0305] M-24: MS m / z (ESI): 335.1 [M+H] + .

[0306] Step 2: Sodium hydride (60%, 28.7 mg, 717.78 μmol) was added to a 4.0 mL solution of M-24 (0.2 g, 598.15 μmol) in N,N-dimethylformamide at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 h, and benzyl bromide (153.5 mg, 897.22 μmol) was added dropwise to the reaction mixture. The reaction mixture was then brought to room temperature and stirred for 3 h. The reaction mixture was quenched with water (10.0 mL) and extracted with ethyl acetate (10.0 mL x 3). The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to give a white solid M-25 (0.084 g, 204.65 μmol, yield 34.21%).

[0307] M-25: MS m / z (ESI): 425.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ7.38(s,1H),7.36-7.30(m,2H),7.27(d,J=6.0Hz,3H),7.12(s,1H),7.05(s,1H),4.89(d,J=16.0Hz, 1H),4.67(d,J=15.6Hz,1H),3.97(s,3H),3.87(s,3H),3.78(s,6H),3.43(m,2H),3.05-2.87(m,1H),1.13(t,J=14.4Hz,3H).

[0308] Synthesis of compounds 17, M-26, M-27 and M-28

[0309] Step 1: HATU (161.9 mg, 0.43 mmol), N,N-diisopropylethylamine (127.0 mg, 0.98 mmol), and ammonium chloride (22.8 mg, 0.43 mmol) were added to a solution of dichloromethane (5.0 mL) containing M-17 (0.0 mg, 0.33 mmol, 1.00 eq) prepared in Part 11 of this Example. The reaction solution was stirred at room temperature for 16 hours. The reaction solution was concentrated and separated by thin-layer preparative chromatography (dichloromethane / methanol = 10 / 1) to obtain a white solid M-26 (60.0 mg, 0.26 mmol, yield 80.2%).

[0310] M-26: MS m / z (ESI): 305.2 [M+H] + ;1H NMR(400MHz,DMSO-d6)δ7.32-7.35(m,2H),7.12(s,1H),7.05(s,1H),6.71(s,1H),3.96(s, 3H),3.87(s,3H),3.78(s,3H),3.23-3.32(m,1H),2.80-2.85(m,2H),1.09(d,J=6.8Hz,3H).

[0311] Step 2: At -10°C, trifluoroacetic anhydride (66.3 mg, 0.32 mmol) was added dropwise to a tetrahydrofuran (5.0 mL) solution containing M-26 (80.0 mg, 0.26 mmol) and pyridine (104.0 mg, 1.32 mmol). The reaction mixture was slowly brought to room temperature and stirred for 3 hours. The reaction mixture was quenched with saturated sodium bicarbonate (10.0 mL), extracted with dichloromethane (10.0 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by thin-layer preparative chromatography (petroleum ether: ethyl acetate = 3:1) to obtain a white solid M-27 (60.0 mg, 0.21 mmol, yield 79.7%).

[0312] Step 3: Tetrabutylammonium fluoride (661.2 mg, 2.10 mmol) and trimethylsilane azide (241.4 mg, 2.10 mmol) were added to a solution of M-27 (30.0 mg, 0.11 mmol) in 3.0 mL of tetrahydrofuran. The reaction was stirred at 100 °C for 20 hours under sealed conditions. The solution was then concentrated and purified by reversed-phase chromatography (C18; 0.1% formic acid aqueous solution / acetonitrile) and preparative thin-layer chromatography (DCM / MeOH = 20 / 1) to give a white solid M-28 (10.0 mg, 24.29 μmol, yield 28.9%).

[0313] LCMS: Retention time: 1.291 min; MS m / z (ESI): 330.0 [M+H] + ;

[0314] 1 H NMR(400MHz,DMSO-d6)δ16.12(br.s,1H),7.41(s,1H),7.12(s,1H),7.05(s,1H),3.94(s,3H),3.87( s,3H),3.78(s,3H),3.68-3.75(m,1H),3.50-3.55(m,1H),3.34-3.38(m,1H),1.36(d,J=6.8Hz,3H).

[0315] Synthesis of compounds M-29 and M-30

[0316] Step 1: Add aluminum chloride (834 mg, 6.26 mmol) to a DCM (10.0 mL) solution containing M-17 (200 mg, 0.63 mmol) prepared in Part 11 of this Example, and stir the resulting mixture at room temperature for 16 hours. Then, carefully treat the mixture with water (50.0 mL), extract the mixture with ethyl acetate (20.0 mL × 3), dry with anhydrous sodium sulfate, filter, concentrate, and purify by preparative plate (EA / PE = 1 / 3) to obtain M-29 (25.0 mg, 81.88 μmol, 13.1% yield) and M-30 (150.0 mg, 491.28 μmol, 78.5% yield).

[0317] M-29 / M-30:LCMS: Retention time: 1.13 min, 1.18 min; MS m / z (ESI): 306.1 [M+H] + ;

[0318] M-29: 1 H NMR(400MHz,DMSO-d6)δ8.72(s,1H),δ7.31(s,1H),7.00(s,1H),6.97(s,1H),3.96(s,3H),3.88(s ,3H),3.59(s,3H),3.29-3.35(m,1H),3.06-3.11(m,1H),2.93-2.97(m,1H),1.16(d,J=7.2Hz,3H).

[0319] M-30: 1H NMR(400MHz,DMSO-d6)δ9.35(s,1H),δ7.35(s,1H),7.09(s,1H),6.83(s,1H),3.86(s,3H),3.80(s ,3H),3.59(s,3H),3.27-3.30(m,1H),3.04-3.08(m,1H),2.92-2.96(m,1H),1.16(d,J=7.2Hz,3H).

[0320] 19. Synthesis of compounds M-31 and M-32

[0321] Step 1: Dissolve M-30 (80.0 mg, 262.02 μmol) and potassium hydroxide (29.4 mg, 524.03 μmol) prepared in Part 18 of this example in water (0.2 mL) and acetonitrile (2.0 mL), then add 1-((bromo(difluoro)methyl)-ethoxyphosphoryl)oxyethane (111.94 mg, 419.23 μmol, 1.60 eq). Stir the resulting mixture at room temperature for 3 hours, add water to the reaction solution and extract with ethyl acetate, dry with anhydrous sodium sulfate, filter and concentrate, and purify by thin-layer preparative chromatography (ethyl acetate / petroleum ether = 1 / 3) to obtain M-31 (50.0 mg, 140.71 μmol, yield 53.7%).

[0322] M-31: MS m / z (ESI): 356.1 [M+H] + .

[0323] Step 2: M-31 (23.0 mg, 64.73 μmol, 1.00 eq) was dissolved in water (0.5 mL) and methanol (2.0 mL), and then lithium hydroxide monohydrate (8.2 mg, 194.18 μmol, 4.00 eq) was added. The resulting mixture was stirred at room temperature for 16 hours. The mixture was adjusted to pH < 3 with dilute hydrochloric acid (1 M) and purified by preparative high-performance liquid chromatography (C18; mobile phase A: water, mobile phase B: acetonitrile) to give a white solid M-32 (11.0 mg, 32.23 μmol, yield 49.8%).

[0324] M-32: MS m / z (ESI): 342.1 [M+H] +.1H NMR (400MHz, DMSO-d6)7.45(d,J=2.8Hz,2H),7.34(s,1H),7.13(t,J=74.8Hz,1H),3.95(s,3H) ,3.85(s,3H),3.33-3.38(m,1H),3.01-3.08(m,1H),2.84-2.93(m,1H),1.17(d,J=7.2Hz,3H). 19 F NMR(377MHz,DMSO-d6)δ-81.29.

[0325] 20. Synthesis of compound M-33

[0326] Lithium hydroxide monohydrate (16.5 mg, 0.393 mmol) was added to a mixture of methanol (2.0 mL) and water (1.0 mL) containing M-30 (30.0 mg, 0.0983 mmol) prepared in Part 18 of this example. The resulting mixture was stirred at room temperature for 16 hours. The pH of the mixture was adjusted to 3 with dilute hydrochloric acid and purified by Perp-HPLC (Column: Waters Xbridge 20*150mm 10µm, C18, Mobile Phase A:water, B:ACN) to obtain a white solid M-33 (20.0 mg, 68.66 µmol, 69.8% yield).

[0327] M-33:MS m / z(ESI):292.1[M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ12.15(br.s,1H),δ9.38(br.s,1H),δ7.33(s,1H),7.09(s,1H),6.83( s,1H),3.87(s,3H),3.80(s,3H),3.25-3.30(m,1H),2.83-2.98(m,2H),1.14(d,J=7.2Hz,3H).

[0328] 21. Synthesis of Compound M-34

[0329] Lithium hydroxide monohydrate (5.5 mg, 0.13 mmol) was added to a mixture of methanol (1.0 mL) and water (0.5 mL) containing M-29 (10.0 mg, 32.75 μmol) prepared in Part 18 of this example. The resulting mixture was stirred at room temperature for 16 hours. The pH of the mixture was adjusted to 3 with dilute hydrochloric acid and purified by Perp-HPLC (Column: Waters Xbridge 20*150mm 10 μm, C18, Mobile Phase A:water, B:ACN) to obtain a white solid M-34 (8.0 mg, 27.46 μmol, 83.8% yield).

[0330] M-34: MS m / z (ESI): 292.1 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ12.13(br.s,1H),δ8.72(s,1H),δ7.29(s,1H),7.00(s,1H),6.96(s, 1H),3.94(s,3H),3.88(s,3H),3.25-3.32(m,1H),2.86-2.98(m,2H),1.14(d,J=7.2Hz,3H).

[0331] 22. Synthesis of M-35 compounds

[0332] Step 1: At -78°C, boron tribromide (dissolved in 1M dichloromethane, 13.8 mL, 13.78 mmol) was added to a solution of M-17 (440.0 mg, 1.38 mmol) prepared in Part 11 of this Example in 10.0 mL of dichloromethane. The mixture was stirred at room temperature for 3 hours. The mixture was carefully quenched with water (20.0 mL), extracted with dichloromethane (20.0 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by Perp-HPLC (Column: Waters Xbridge 20*150 mm 10 μm, C18, Mobile Phase A: water, B: ACN) to give a white solid M-35-int-1 (230.0 mg, 0.79 mmol, yield 57.6%).

[0333] M-35-int-1:MS m / z(ESI):292.1[M+H] + .

[0334] Step 2: Potassium carbonate (56.9 mg, 0.41 mmol) and 1,3-dibromopropane (104.0 mg, 0.52 mmol) were added to a 2.0 mL DMF solution containing M-35-int-1 (30.0 mg, 0.10 mmol). The resulting mixture was stirred at 75 °C for 16 hours. The mixture was diluted with water (20.0 mL), extracted with ethyl acetate (10.0 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by Perp-HPLC (Column: Waters Xbridge 20*150 mm 10 μm, C18, Mobile Phase A: water, B: ACN) to obtain a white solid M-35 (5.75 mg, 0.0173 mmol, yield 10.5%).

[0335] M-35: MS m / z (ESI): 332.1 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ7.29(s,1H),δ7.21(s,1H),6.98(s,1H),4.16-4.24(m,4H),3.97(s,3H), 3.46(s,3H),3.40-3.46(m,1H),3.00-3.12(m,2H),2.21(t,J=4.8Hz,2H),1.27(d,J=6.8Hz,3H).

[0336] 23. Synthesis of Compound M-36

[0337] Potassium carbonate (56.9 mg, 411.95 μmol) and 3-bromopropane-1-ol (42.9 mg, 308.96 μmol) were added to a 2.0 mL DMF solution containing M-35-int-1 (30.0 mg, 102.99 μmol) prepared in step 22 of this embodiment to obtain a mixture. The mixture was stirred at 80 °C for 16 hours. The mixture was diluted with water (20.0 mL), extracted with ethyl acetate (10.0 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by Perp-HPLC (Column: Waters Xbridge 20*150 mm 10 μm, C18, Mobile Phase A: water, B: ACN, 0.1% FA) to obtain a colorless oily liquid M-36 (1.22 mg, 2.99 μmol, yield 2.9%).

[0338] M-36: MS m / z (ESI): 408.3 [M+H] + ; 1H NMR (400MHz, CDCl3) δ7.21(s,1H),7.06(s,1H),6.75(s,1H),4.26-4.29(t,J=5.8Hz,2H),4.21-4.24(t,J=5.6Hz,2H),4.01(s,3H), 3.88-3.92(m,4H),3.71(s,3H),3.39-3.45(m,1H),3.11-3.13(m,1H),2.99-3.04(m,1H),2.09-2.15(m,4H),1.27(d,J=6.8Hz,3H).

[0339] 24. Synthesis of compounds M-37 and M-38

[0340] Step 1: Sodium hydride (14.0 mg, 351.60 μmol, 60% in paraffin oil) was added to a tetrahydrofuran (5.0 mL) solution containing M-16-int-2 (0.1 g, 293.00 μmol) prepared in step 11 of this embodiment at 0 °C. The reaction solution was stirred at 0 °C for 30 minutes. Then, methyl benzoate (72.15 mg, 439.50 μmol) was added dropwise to the reaction solution at 0 °C, and the mixture was brought to room temperature and stirred for 2 hours. The reaction solution was quenched with water (20.0 mL) and extracted with ethyl acetate (10.0 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 8:1) to give a bright yellow solid M-37-int-1 (0.1 g, 263.57 μmol, yield 89.96%).

[0341] Step 2: Add Pd / C (10.0 mg of 10% carbon wetted with approximately 55% water) to a methanol (2.0 mL) solution of M-37-int-1 (80 mg, 210.86 μmol). Stir the reaction solution at room temperature for 3 hours under a hydrogen balloon. Filter the reaction solution through diatomaceous earth, concentrate the filtrate, and purify it by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain a white solid M-37 (40 mg, 104.87 μmol, 49.74% yield).

[0342] M-37: MS m / z (ESI): 382.1 [M+H] + ; 1H NMR (400MHz, Methanol-d4) δ7.38-7.24 (m, 6H), 6.94 (s, 1H), 4.23 (dd, J = 10.2, 4.6H z,1H),3.99(s,3H),3.93(s,3H),3.91-3.80(m,4H),3.67(s,3H),3.39-3.33(m,1H).

[0343] Step 3: Lithium hydroxide (7.53 mg, 314.61 μmol) was added to a mixed solution of methanol (2.0 mL) and water (1.0 mL) containing M-37 (30.0 mg, 78.65 μmol). The reaction solution was stirred at room temperature for 16 hours. The pH of the reaction solution was adjusted to <3 with dilute hydrochloric acid, and then purified by preparative high-performance liquid chromatography (C18, mobile phase A: water, mobile phase B: acetonitrile) to obtain a white solid M-38 (26.30 mg, 71.59 μmol, yield 91.01%).

[0344] M-38: MS m / z (ESI): 368.1 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ7.44(s,1H),7.42-7.31(m,4H),7.31-7.23(m,1H),7.09(s,1H),7.06(s,1H),4 .11(dd,J=10.2,4.6Hz,1H),3.96(s,3H),3.87(s,3H),3.84-3.73(m,4H),3.24(dd,J=17.2,4.8Hz,1H).

[0345] 25. Synthesis of compound M-39

[0346] Step 1: At 0°C, M-16-int-2 (200.0 mg, 0.57 mmol) prepared in step 11 of this embodiment was dissolved in tetrahydrofuran (4.0 mL), followed by the addition of sodium hydride (20.2 mg, 0.88 mmol, 60% in paraffin liquid). The mixture was stirred at 0°C for 30 minutes under argon protection. Then, ethyl 3,3,3-trifluoropyruvate (149.5 mg, 0.88 mmol) was added dropwise at 0°C. The mixture was stirred at room temperature for 1 h under argon protection. Subsequently, it was quenched with saturated ammonium chloride (10.0 mL), diluted with water (5.0 mL), and extracted with ethyl acetate (10.0 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography (ethyl acetate / hexane = 10:1) to give a white solid M-39-int-1 (74.0 mg, 0.19 mmol, yield 32.8%).

[0347] M-39-int-1:MS m / z(ESI):386.0[M+H] + .

[0348] Step 2: M-39-int-1 (60.0 mg, 0.15 mmol) and Pd / C (6.0 mg, 10%) were suspended in methanol (4.0 mL) and stirred for 4 hours at room temperature under a hydrogen atmosphere. The reaction was then detected by LCMS. The reaction mixture was filtered and concentrated under vacuum. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20:1) to give M-39 as a white solid (30.9 mg, 0.079 mmol, yield 51.2%).

[0349] M-39: MS m / z (ESI): 388.1 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ7.52(s,1H),7.10(s,1H),7.07(s,1H),4.20-4.17(m,2H)3.99-3.95( m,4H),3.87(s,3H),3.79(s,3H),3.68-3.61(m,1H),3.50-3.45(m,1H),1.19(t,J=8.0Hz,1H); 19 F NMR(377MHz,DMSO-d6)δ-66.37(s).

[0350] 26. Synthesis of compounds M-40 and M-41

[0351] Step 1: Sodium hydride (46.9 mg, 1.95 mmol, 60% in paraffin oil) was added to a tetrahydrofuran (4.0 mL) solution of M-16-int-2 (0.2 g, 586.00 μmol) at 0 °C. The reaction mixture was stirred at 0 °C for 30 minutes. Then, ethyl 2-oxo-3-methylbutyrate (169.0 mg, 1.17 mmol) was added dropwise to the reaction mixture. The reaction mixture was quenched with water (20.0 mL) and extracted with ethyl acetate (10.0 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 8 / 1) to give a yellow oily substance M-40-int-1 (0.12 g, 333.88 μmol, yield 57.0%).

[0352] M-40-int-1:MS m / z(ESI):360.1[M+H] + ;

[0353] Step 2: Pd / C (10% carbon wetted with approximately 55% water, 20.0 mg) was added to a methanol (2.0 mL) solution of M-40-int-1 (0.1 g, 278.23 μmol). The reaction mixture was stirred at 40 °C for 1 hour under a hydrogen balloon. The reaction mixture was filtered through diatomaceous earth, the filtrate was concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain a white solid M-40 (96.0 mg, 265.61 μmol, yield 95.5%).

[0354] M-40: MS m / z (ESI): 362.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ7.44(s,1H),7.11(s,1H),7.05(s,1H),4.05(m,2H),3.94(s,3H),3.87(s,3H),3.78(s,3H),3.30-3.25(m ,1H),3.05(dd,J=17.0,3.6Hz,1H),2.80-2.70(m,1H),1.96(dd,J=13.2,6.6Hz,1H),1.15(t,J=7.2Hz,3H),0.95(t,J=6.8Hz,6H).

[0355] Step 3: Lithium hydroxide (58.1 mg, 1.38 mmol) was added to a mixture of M-40 (40.0 mg, 115.14 μmol) in tetrahydrofuran (1.0 mL), methanol (0.5 mL), and water (0.5 mL). The reaction mixture was stirred at room temperature for 16 hours. The pH of the reaction mixture was adjusted to <3 with dilute hydrochloric acid, extracted with ethyl acetate (5.0 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to give a white solid M-41 (21.1 mg, 63.41 μmol, yield 55.1%).

[0356] M-41: MS m / z (ESI): 334.1 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ12.06(br.s,1H),7.42(s,1H),7.12(s,1H),7.05(s,1H),3.95(s,3H),3.87(s,3H),3.78(s,3H) ,3.33(d,J=8.4Hz,1H),2.97(d,J=17.2Hz,1H),2.78-2.69(m,1H),1.99(dd,J=12.8,6.6Hz,1H),0.95(d,J=6.8Hz,6H).

[0357] 27. Synthesis of compounds M-42 and M-43

[0358] Step 1: Sodium hydride (42.2 mg, 1.05 mmol, 60% in paraffin oil) was added to a tetrahydrofuran (5.0 mL) solution of M-16-int-2 (300.0 mg, 0.88 mmol, 1.00 eq) at 0 °C, and the reaction mixture was stirred at 0 °C for 30 min. Then, ethyl 2-butanone (172.0 mg, 1.32 mmol) was added dropwise to the reaction mixture at 0 °C, and the mixture was brought to room temperature and stirred for 2 h. The reaction mixture was quenched with water (20.0 mL) and extracted with ethyl acetate (10.0 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 8:1) to give a bright yellow solid M-42-int-1 (265.0 mg, 0.764 mmol, yield 87.3%).

[0359] M-42-int-1:MS m / z(ESI):346.1[M+H] + .

[0360] Step 2: Pd / C (10% carbon wetted with approximately 55% water, 27.0 mg) was added to a methanol (5.0 mL) solution of M-42-int-1 (265.0 mg, 0.77 mmol). The reaction mixture was stirred at room temperature for 1 hour under a hydrogen balloon. The reaction mixture was filtered through diatomaceous earth, the filtrate was concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to give a white solid M-42 (200.0 mg, 0.58 mmol, yield 75.0%).

[0361] M-42: MS m / z (ESI): 348.2 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ7.40(s,1H),7.11(s,1H),7.05(s,1H),4.00-4.10(m,2H)3.95(s,3H),3.87(s,3H),3.78(s,3H), 3.26-3.31(m,1H),3.05-3.10(m,1H),2.78-2.82(m,1H),1.57-1.64(m,2H),1.15(t,J=7.2Hz,3H),0.91(t,J=7.2Hz,3H).

[0362] Step 3: Lithium hydroxide monohydrate (19.3 mg, 0.46 mmol) was added to a mixture of M-42 (40.0 mg, 115.14 μmol) in methanol (2.0 mL) and water (1.0 mL). The reaction mixture was stirred at room temperature for 16 hours. The pH of the reaction mixture was adjusted to <3 with dilute hydrochloric acid and then purified by preparative high-performance liquid chromatography (C18, A: water, B: acetonitrile) to obtain a white solid M-43 (15.0 mg, 46.97 μmol, yield 40.8%).

[0363] M-43:MS m / z(ESI):320.0[M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ12.06(br.s,1H),7.39(s,1H),7.11(s,1H),7.05(s,1H),3.96(s,3H),3.87(s,3H),3. 78(s,3H),3.25-3.32(m,1H),2.97-3.01(m,1H),2.74-2.78(m,1H),1.55-1.64(m,2H),0.92(t,J=7.2Hz,3H).

[0364] 28. Synthesis of compound M-44

[0365] Step 1: Ethyl 5,6-dimethoxyindole-2-carboxylate (2.0 g, 8.02 mmol) was dissolved in a solution of tetrahydrofuran / N,N-dimethylformamide = 4 / 1 (50.0 mL), and sodium hydride (481.42 mg, 12.04 mmol, 60% dispersed in paraffin liquid) was added. The mixture was stirred at 0 °C under argon protection for 0.5 h. 2-(trimethylsilyl)ethoxymethyl chloride (16.0 g, 9.63 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 h. The reaction mixture was then quenched with saturated ammonium chloride (50.0 mL) and extracted with ethyl acetate (50.0 mL × 3). The solution was dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to give a white solid M-44-int-1 (2.3 g, 6.06 mmol, yield 75.7%).

[0366] Step 2: Under nitrogen protection, bis(trimethylsilyl)lithium aziroxide (7.91 mL, 7.91 mmol, 1 M in tetrahydrofuran) was added to a solution of M-44-int-1 (2.0 g, 5.27 mmol) in tetrahydrofuran (40.0 mL) and stirred for 0.5 h. Then, dimethyl methylphosphonate (1.0 g, 8.06 mmol) was added to the reaction mixture and stirred at room temperature for 16 h. Subsequently, the reaction mixture was quenched with saturated ammonium chloride (10.0 mL), diluted with water (30.0 mL), extracted with EtOAc (30.0 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (PE:EA = 1:1) to give a yellow solid M-44-int-2 (2.0 g, 4.37 mmol, yield 83.0%).

[0367] M-44-int-2: 1 H NMR (400MHz, CDCl3) δ7.31(d,J=1.6Hz,1H),7.03(d,J=2.4Hz,1H),6.92(d,J=2.0Hz,1H),5.99(d,J=2.4Hz,2H),3.96(d,J=2.4Hz,3H),3. 91(d,J=2.8Hz,3H),3.83-3.78(m,3H),3.77-3.73(m,3H),3.58-3.56(m,2H),3.54-3.48(m,2H),0.88-0.83(m,2H),-0.07--0.21(m,9H).

[0368] Step 3: M-44-int-2 (1.2 g, 2.62 mmol, 1.00 eq) was dissolved in tetrahydrofuran (20.0 mL) and sodium hydride (105.0 mg, 2.63 mmol, in 60% paraffin liquid) was added. The mixture was stirred at 0 °C under argon protection for 0.5 h. Methyl 2-oxopropionate (401.3 mg, 3.93 mmol) was then added to the reaction mixture, and the mixture was stirred at room temperature for 2 h. The reaction was then quenched with saturated ammonium chloride (10.0 mL), diluted with water (20.0 mL), extracted with ethyl acetate (20.0 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain M-44-int-3 (500.0 mg, 1.15 mmol, yield 43.9%) as a yellow oil.

[0369] M-44-int-3:MS m / z(ESI):456.3[M+Na] + .

[0370] Step 4: M-44-int-3 (1.0 mg, 2.31 mmol) was dissolved in MeOH (8.0 mL) and Pd / C (100.0 mg, 10% wt, 50% water) was added. The mixture was stirred at 25 °C for 2 hours under a hydrogen balloon. After the reaction was complete, the mixture was filtered and concentrated under reduced pressure. The solution was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to give compound M-44-int-4 (600.0 mg, 1.38 mmol, yield 60.0%) as a white solid.

[0371] M-44-int-4:MS m / z(ESI):458.3[M+H] + .

[0372] Step 5: M-44-int-4 (20.0 mg, 0.04 mmol) was dissolved in tetrahydrofuran (3.0 mL) at room temperature, and tetrabutylammonium fluoride (24.01 mg, 0.09 mmol) was added. The reaction mixture was then stirred at 60 °C for 16 hours. After the reaction was complete, the reaction mixture was diluted with water (10.0 mL) and extracted with ethyl acetate (10.0 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by preparative thin-layer chromatography (petroleum ether / ethyl acetate = 3 / 1) to give M-44 as a white solid (1.63 mg, 0.005 mmol, yield 11.6%).

[0373] M-44:MS m / z(ESI):318.0[M-18+H] + ; 1H NMR(400MHz,MeOD)δ7.55(s,1H),7.28(s,1H),7.18(s,1H),6.10(s,2H),4.04(s,3H),3.98( s,3H),3.78(s,3H),3.52(dd,J=16.4,8.0Hz,1H),3.26-3.09(m,2H),1.36(d,J=7.2Hz,3H).

[0374] 29. Synthesis of compounds M-45 and M-46

[0375] Step 1: Dissolve tert-butyl acetate (1.32 g, 11.39 mmol) in THF (20.0 mL), and add LiHDMS (11.4 mL, 11.39 mol, 1 M in THF) at -78 °C under nitrogen protection. Stir the mixture at this temperature for 30 minutes. Then add ethyl 5,6-dimethoxy-1-methyl-1-H-indole-2-carboxylate (1.0 g, 3.80 mmol) dissolved in tetrahydrofuran (10.0 mL). Bring the mixture to room temperature and stir for 2 hours. The mixture was treated with an aqueous solution of ammonium chloride (50.0 mL), extracted with DCM (50.0 mL × 2), and purified by silica gel column chromatography (PE / EA = 3 / 1) to give tert-butyl 3-(5,6-dimethoxy-1-methylindole-2-yl)-3-oxopropionate M-45-int-1 (1.1 g, 3.30 mmol, yield 86.9%) as a white solid.

[0376] M-45-int-1:MS m / z(ESI):278.1[M-56+H] + .

[0377] Step 2: Dissolve M-45-int-1 (1.0 g, 3.00 mmol) in DCM (10.0 mL) and add 2,2,2-trifluoroacetic acid (2.98 g, 26.14 mmol, 2 mL). Stir the mixture at room temperature for 16 hours. Remove the solvent under vacuum to obtain a brown, oily crude product M-45-int-2 (830.0 g, 2.99 mmol, 99.8% yield). This crude product can be used directly in the next step without purification.

[0378] M-45-int-2:MS m / z(ESI):278.1[M+H] + .

[0379] Step 3: M-45-int-2 (830 mg, 2.99 mmol) was dissolved in toluene (10.0 mL) and stirred at 80 °C for 1 hour. The mixture was concentrated under vacuum and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give 1-(5,6-dimethoxy-1-methylindol-2-yl)acetone M-45-int-3 (680.0 mg, 2.92 mmol, yield 97.4%) as a white solid.

[0380] M-45-int-3:MS m / z(ESI):234.1[M+H] + .

[0381] Step 4: Sodium metal (19.7 mg, 857.40 μmol) was added to methanol (2.0 mL) and stirred at room temperature for 10 minutes. Then M-45-int-3 (50.0 mg, 214.35 μmol) was added. The mixture was stirred for another 30 minutes. Then diethyl oxalate (46.99 mg, 321.53 μmol) was added and stirred at 80 °C for 2 hours. The mixture was concentrated and purified by preparative thin-layer chromatography (dichloromethane / methanol = 20 / 1) to give a yellow solid of (Z)-4-(5,6-dimethoxy-1-methylindole-2-yl)-2-hydroxy-4-oxobutyl-2-enoic acid methyl ester M-45-int-4 (50.0 mg, 156.59 μmol, yield 73.1%).

[0382] M-45-int-4:MS m / z(ESI):320.2[M+H] + .

[0383] Step 5: Dissolve M-45-int-4 (120.0 mg, 375.81 μmol) in tetrahydrofuran (5.0 mL) and methanol (2.0 mL), then add diazomethyl(trimethyl)silane (85.9 mg, 751.62 μmol, 2 M in hexane). Stir the mixture at 25 °C for 16 hours. Concentrate the mixture and purify it by preparative thin-layer chromatography (petroleum ether / ethyl acetate = 2 / 1) to give a yellow solid (Z)-4-(5,6-dimethoxy-1-methylindol-2-yl)-2-methoxy-4-oxobutyl-2-enoate methyl ester M-45-int-5 (88.0 mg, 264.00 μmol, yield 70.3%).

[0384] M-45-int-5:MS m / z(ESI):334.0[M+H] + .

[0385] Step 6: Dissolve M-45-int-5 (80.0 mg, 30.00 μmol) in methanol (3.0 mL) and add Pd / C (10%, 8.0 mg). Stir the mixture at 25 °C under H2 for 16 hours. Filter and concentrate the mixture, and purify it by thin-layer preparative chromatography (petroleum ether / ethyl acetate = 2 / 1) to give a white solid M-45 (35.0 mg, 104.37 μmol, yield 43.5%).

[0386] M-45: MS m / z (ESI): 336.3 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ7.39(s,1H),7.10(s,1H),7.06(s,1H),4.32(dd,J=7.6,4.8Hz,1H),3.97 (s,3H),3.87(s,3H),3.78(s,3H),3.33-3.43(m,1H),3.31(s,3H),3.23(dd,J=16.4,4.8Hz,1H).

[0387] Step 7: Dissolve M-45 (20.0 mg, 59.6 μmol) in water (1.0 mL) and methanol (2.0 mL), then add lithium hydroxide monohydrate (10.01 mg, 238.56 μmol). Stir the mixture at 25 °C for 16 hours. Purify by preparative high performance liquid chromatography (C18, A: 0.1% formic acid aqueous solution, B: acetonitrile) to give white solid M-46 (2.38 mg, 7.41 μmol, yield 12.4%).

[0388] M-46: MS m / z (ESI): 322.2 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ7.38(s,1H),7.11(s,1H),7.06(s,1H),4.16-4.45(m,1H ),3.98(s,3H),3.87(s,3H),3.78(s,3H),3.28-3.29(m,4H),3.08-3.20(m,1H).

[0389] 30. Synthesis of compounds M-47 and M-48

[0390] Step 1: Sodium hydride (7.5 g, 188.0 mmol) was added to a solution of N,N-dimethylformamide (200.0 mL) containing 5-methoxy-indole-2-carboxylic acid (9.0 g, 47.0 mol) at 0 °C. The resulting mixture was stirred at 0 °C for 10 minutes. Iodimethane was then added. The mixture was stirred at room temperature for 16 hours, quenched with saturated ammonium chloride (50.0 mL), diluted with water (50.0 mL), extracted with ethyl acetate (100.0 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated, and purified by silica gel column chromatography (10–100%, ethyl acetate / petroleum ether) to give crude product M-47-int-1 (12.8 g, 58.4 mmol), a white solid.

[0391] M-47-int-1:MS m / z(ESI):220.1[M+H] + .

[0392] Step 2: Under argon protection, LiHMDS (116.0 mL, 116.0 mmol, 1 M in THF) was added to a tetrahydrofuran (200.0 mL) solution containing M-47-int-1 (12.8 g, 58.0 mmol) and dimethyl methylphosphonate (10.8 g, 87.0 mmol) at -78 °C. The mixture was then slowly brought to room temperature and stirred for 3 hours. The reaction was quenched with saturated ammonium chloride (50.0 mL), diluted with water (50.0 mL), and extracted with ethyl acetate (100.0 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (10–100%, ethyl acetate / petroleum ether) to give crude M-47-int-2 (15.0 g, 48.0 mmol, yield 82.8%) as a white solid.

[0393] M-47-int-2:MS m / z(ESI):312.1[M+H].

[0394] Step 3: At 0°C, sodium hydride (60% in paraffin oil, 2.5 g, 62.55 mmol, 1.50 eq) was added to a solution of tetrahydrofuran (200.0 mL) containing M-47-int-2 (13.0 g, 41.70 mmol, 1.00 eq), and the mixture was stirred at 0°C for 30 minutes. Then, methyl pyruvate (6.39 g, 62.55 mmol, 1.50 eq) was added dropwise to the reaction mixture, and the mixture was brought to room temperature and stirred for 1 hour. The reaction was then quenched with saturated ammonium chloride (50.0 mL), diluted with water (50.0 mL), extracted with ethyl acetate (100.0 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (10–100% ethyl acetate / petroleum ether) to give a yellow solid M-47-int-3 (16.0 g, 55.68 mmol, crude).

[0395] M-47-int-3:MS m / z(ESI):288.1[M+H] + .

[0396] Step 4: Dissolve M-47-int-3 (15.0 g, 52.0 mmol, 1.00 eq) in methanol (20.0 mL), then add Pd / C (1.0 g, 10%). Stir at 40 °C for three hours under a hydrogen balloon. The reaction was monitored by LCMS and the starting material was detected. Filter the reaction solution, concentrate the filtrate, and purify it by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1) to obtain white solid M-47 (5.0 g, 0.017 mol, yield 33.1%) and white solid M-48 (40.71 mg).

[0397] M-47: MS m / z (ESI): 290.1 ​​[M+H] + ;

[0398] 1 H NMR (400MHz, DMSO-d6) δ7.49(d,J=12.0Hz,1H),7.43(s,1H),7.14(d,J=2.4Hz,1H),7.03(dd,J=2.4Hz,1H),3.95( s,3H),3.79(s,3H),3.60(s,3H),3.31-3.36(m,1H),3.07-3.17(m,1H),2.93-3.00(m,1H),1.18(d,J=12.0Hz,3H).

[0399] M-48: MS m / z (ESI): 304.1 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ7.43(d,J=9.2Hz,1H),7.17(d,J=2.4Hz,1H),7.01(dd,J=9.2,2.4Hz,1H),3.82(d,J=7.6Hz,6H ),3.61(s,3H),3.36-3.25(m,1H),3.10(dd,J=17.6,4.8Hz,1H),3.05-2.96(m,1H),2.58(s,3H),1.21(d,J=7.2Hz,3H).

[0400] 31. Synthesis of compound M-49

[0401] M-47 (100.0 mg, 0.35 mmol) and lithium hydroxide (30.0 mg, 0.69 mmol) prepared in Part 31 of this example were dissolved in a mixed solution of tetrahydrofuran and water (v / v = 2 / 1, 2.0 mL) and stirred at 40 °C for 16 hours. The resulting reaction solution was adjusted to pH < 3 with dilute hydrochloric acid (1 N), diluted with water (10.0 mL), and extracted with ethyl acetate (10.0 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The reaction residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give a white solid M-49 (21.9 mg, 0.079 mmol, yield 22.0%).

[0402] M-49: MS m / z (ESI): 276.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ7.49(d,J=9.2Hz,1H),7.41(s,1H),7.15(d,J=2.4Hz,1H),7.02(dd,J=9.2,2.4Hz,1H),3.96(s, 3H), 3.78 (s, 3H), 3.25–3.43 (m, 7H), 3.03 (dd, J = 16.8, 5.4Hz, 1H), 2.88 (dd, J = 13.6, 7.4Hz, 1H), 1.17 (d, J = 7.2Hz, 3H).

[0403] 32. Synthesis of M-50 compounds

[0404] At -78°C, boron tribromide (6.92 mL, 6.92 mmol, 1 M dichloromethane solution) was added dropwise to a 2.0 mL solution of dichloromethane containing M-47 (200.0 mg, 0.69 mmol) prepared in Part 30 of this example. The temperature was then slowly raised to 0°C and stirred for 2 hours under argon protection. The reaction solution was quenched with methanol and diluted with water (10.0 mL), and extracted with ethyl acetate (10.0 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to give a white solid M-50 (4.98 mg, 0.018 mmol, 2.6% yield).

[0405] M-50: MS m / z (ESI): 298.1 [M+Na] + ; 1 H NMR (400MHz, CDCl3) δ7.24 (s, 1H), 7.19 (s, 1H), δ7.05 (d, J = 2.4Hz, 1H), 6.98 (dd, J = 8.9, 2.4H z,1H),4.01(s,3H),3.71(s,3H),3.48-3.42(m,1H),3.14-3.01(m,2H),1.28(d,J=8.0Hz,1H).

[0406] 33. Synthesis of Compound M-51

[0407] 250 mg of ethyl 5,6-dimethoxyindole-2-carboxylate (1.0 mmol) was added to 5.0 mL of THF, followed by the addition of 224 mg of potassium tert-butoxide (2.0 mmol) and 150 mg of ethyl acrylate (1.5 mmol). The mixture was heated to 70 °C and reacted for 12 h. The reaction solution was cooled to room temperature, and most of the solvent was evaporated. The residue was poured into 5.0 mL of ice water, and the pH was adjusted to 1-2 with 1 N hydrochloric acid aqueous solution. The mixture was extracted with ethyl acetate, and the organic layers were combined, dried, concentrated, and subjected to column chromatography to obtain 90 mg of M-51.

[0408] M-51:purity:96%; 1 H NMR(400MHz,DMSO-d6)δ7.18(s,1H),7.17(s,1H),6.94(s,1H),4.68–4.55(m,2H),.39(dd, J=7.9,4.2Hz,1H),4.18(d,J=7.0Hz,2H),3.88(s,3H),3.80(s,3H),1.23(t,J=7.1Hz,3H).

[0409] 34. Synthesis of compound M-52

[0410] Step 1: Dissolve 250 mg of ethyl 5,6-dimethoxyindole-2-carboxylate (1 mmol) in 5 mL of DMF, and slowly add 44 mg of NaH (1.2 mmol) under ice bath conditions, then heat to room temperature. React at room temperature for 1 h, then slowly add 390 mg of ethyl 4-bromobutyrate (2 mmol) dropwise to the reaction solution, and continue the reaction at room temperature for 12 h. After the reaction is complete, quench with water, extract with ethyl acetate, combine the organic layers, dry, concentrate, and precipitate by column chromatography to obtain 261 mg of M-52-int-1.

[0411] Step 2: Dissolve 182 mg of intermediate M-52-int-1 (0.5 mmol) in 10.0 mL THF, add 112 mg of potassium tert-butoxide in portions, heat to 70 °C, and react for 12 h. Concentrate the reaction solution, pour the residue into water, adjust the pH to 1-2 with 1 N hydrochloric acid aqueous solution, extract with ethyl acetate, combine the organic layers, dry, concentrate, and column chromatography to obtain 70 mg of a pair of enol tautomers M-52 (ketone / alcohol ratio approximately 4:1).

[0412] M-52-ol: 1 H NMR(400MHz,DMSO-d6)δ7.14(s,1H),7.12(s,1H),7.09(s,1H),4.46–4.38(m,1H),4. 22–4.10(m,4H),3.91–3.87(m,1H),3.87(s,3H),3.78(s,3H),1.23(t,J=7.1Hz,3H).

[0413] 35. Synthesis of compound M-53

[0414] Step 1: Dissolve 250 mg of ethyl 5,6-dimethoxyindole-2-carboxylate (1 mmol, 1.0 eq) in 10 mL of LDM. Add 44 mg of NaH (1.2 mmol, 1.2 eq) in portions under ice bath conditions, and slowly heat to room temperature. After reacting at room temperature for 1 h, slowly add 418 mg of ethyl 5-bromopentanoate (2 mmol, 2.0 eq) dropwise to the reaction solution and react at room temperature for 12 h. After the reaction is complete, quench with water, extract with ethyl acetate, combine the organic layers, dry, concentrate, and precipitate by column chromatography to obtain 245 mg of M-53-int-1.

[0415] Step 2: Dissolve 189 mg of intermediate M-53-int-1 (0.5 mmol, 1.0 eq) in 10.0 mL THF, add 112 mg of potassium tert-butoxide (1.0 mmol, 2.0 eq) in portions, heat to 70 °C, and react for 12 h. Concentrate the reaction solution, pour the residue into water, adjust the pH to 1-2 with 1 N hydrochloric acid aqueous solution, extract with ethyl acetate, combine the organic layers, dry, concentrate, and column chromatography to obtain 86 mg of a pair of enol tautomers M-53 (ketone / alcohol ratio approximately 2:1).

[0416] M-53-ol: 1 H NMR(400MHz,DMSO-d6)δ7.27(s,1H),7.16(s,1H),7.15(s,1H),4.33–4.26(m,2H),4. 22–4.18(m,3H),3.92(s,3H),3.82(s,3H),2.26–1.95(m,4H),1.26(t,J=7.1Hz,3H).

[0417] 36. Synthesis of compounds M-54 and M-55

[0418] Step 1: Dissolve 235 mg of 5,6-dimethoxy-1-methyl-1-H-indole-2-carboxylic acid (1 mmol, 1.0 eq), 456 mg of HATU (1.2 mmol, 1.2 eq), and 258 mg of DIPEA (2 mmol, 2.0 eq) in 10 mL of THF and react at room temperature for 1 h. Add 234 mg of methyl 3-(methylamino)propionate (2 mmol, 2.0 eq) to the reaction solution, heat to 60 °C, and react for 12 h. After the reaction is complete, cool the reaction solution to room temperature, pour it into water, extract with ethyl acetate, combine the organic layers, and wash the organic layer with 1 N HCl aqueous solution. Dry the organic layer, concentrate it, and separate it by column chromatography to obtain 234 mg of M-54.

[0419] M-54:purity:99%;HRMS(ESI)m / z:[M+Na] + Calcd for C 17 H 22 N2NaO5 357.1426; Found 357.1423; 1H NMR(600MHz,Chloroform-d)δ7.03(s,1H),6.78(s,1H),6.54(s,1H),3.97(s,3H),3.91(s ,3H),3.87(t,J=7.0Hz,2H),3.81(s,3H),3.69(s,3H),3.20(s,3H),2.70(t,J=7.0Hz,2H).

[0420] Step 2: Dissolve 100 mg M-54 (0.3 mmol) in a mixed solvent of 3.0 mL THF, 3.0 mL MeOH, and 1.0 mL H2O. Add 36 mg LiOH (1.5 mmol) in portions, heat to 50 °C, and react for 12 h. After the reaction is complete, cool the reaction solution to room temperature, pour it into water, adjust the pH to 1-2 with 1 N HCl aqueous solution, extract with ethyl acetate, combine the organic layers, dry, concentrate, and separate by column chromatography to obtain 43 mg M-55.

[0421] M-55:purity:99%;HRMS(ESI)m / z:[M+H] + Calcd for C 16 H 21 N2O5 321.1450; Found 321.1448; 1 H NMR (600MHz, DMSO-d6) δ12.39(br s,1H), δ7.07(s,1H),7.04(s,1H),6.53(s,1H),3.83(s,3H),3.73(s,3H),3.71(br s,2H),3.70(s,3H),3.04(s,3H),2.57(t,J=7.0Hz,2H).

[0422] 37. Synthesis of compounds M-56 and M-57

[0423] Step 1: Dissolve 150 mg of 5,6-dimethoxy-1-methyl-1-H-indole-2-carboxylic acid (0.64 mmol), 239 mg of HATU (0.77 mmol), and 330 mg of DIPEA (2.56 mmol) in 10 mL of THF and react at room temperature for 1 h. Add 214 mg of methyl 3-amino-2,2-dimethylpropionate hydrochloride (2 mmol) to the reaction solution, heat to 60 °C, and react for 12 h. After the reaction is complete, cool the reaction solution to room temperature, pour it into water, extract with ethyl acetate, combine the organic layers, and wash the organic layer with 1N HCl aqueous solution. Dry the organic layer, concentrate it, and separate it by column chromatography to obtain 188 mg of M-56-int-1.

[0424] Step 2: Dissolve 235 mg M-56-int-1 (0.5 mmol) in 10 mL DMF. Add 40 mg NaH (1.0 mmol, 60% dispersed in oil) in portions under ice bath conditions. Slowly heat to room temperature and react for 1 h. Slowly add 234 mg MeI (2 mmol) to the reaction solution and continue the reaction for 12 h. After the reaction is complete, quench the reaction solution with saturated ammonium chloride aqueous solution under ice bath conditions. Dilute with water, extract with ethyl acetate, combine the organic layers, dry, concentrate, and separate by column chromatography to obtain 109 mg M-56.

[0425] M-56:purity:99%;HRMS(ESI)m / z:[M+Na] + Calcd for C 19 H 26 N2NaO5 385.1739; Found 385.1745; 1 H NMR(400MHz,DMSO-d6)δ7.07(s,1H),7.04(s,1H),6.57(s,1H),3.83(s,3H),3.75(s,3H),3.73(br s,2H),3.70(s,3H),3.60(s,3H),3.04(s,3H),1.15(s,6H).

[0426] Step 3: Dissolve 109 mg M-56 (0.3 mmol) in a mixed solvent of 3.0 mL THF, 3.0 mL MeOH, and 1.0 mL H2O. Add 36 mg LiOH (1.5 mmol) in portions, heat to 50 °C, and react for 12 h. After the reaction is complete, cool the reaction solution to room temperature, pour it into water, adjust the pH to 1-2 with 1 N HCl aqueous solution, extract with ethyl acetate, combine the organic layers, dry, concentrate, and separate by column chromatography (DCM / MeOH / HCOOH) to obtain 35 mg M-57.

[0427] M-57:LCMS:Rt:4.43min; purity:97%; HRMS(ESI)m / z:[M+H] + Calcd for C 16 H 21 N2O5 321.1450; Found 321.1448; 1H NMR(600MHz,DMSO-d6)δ12.46(s,1H),7.07(s,1H),7.04(s,1H),6.56(s,1H),3.83(s,3H),3.75(s,3H),3.73(br s,2H),3.71(s,3H),3.07(s,4H),1.13(s,6H).

[0428] Synthesis of compounds 38, M-58, and M-59

[0429] Step 1: Dissolve 470 mg of 5,6-dimethoxy-1-methyl-1-H-indole-2-carboxylic acid (2 mmol), 912 mg of HATU (2.4 mmol), and 330 mg of DIPEA (4 mmol) in 20 mL of THF and react at room temperature for 1 h. Add 612 mg of methyl 3-amino-2-methylpropionate hydrochloride (4 mmol) to the reaction solution, heat to 60 °C, and react for 12 h. After the reaction is complete, cool the reaction solution to room temperature, pour it into water, extract with ethyl acetate, combine the organic layers, and wash the organic layer with 1 N HCl aqueous solution. Dry the organic layer, concentrate it, and separate it by column chromatography to obtain 434 mg of M-58.

[0430] M-58:purity:97%;HRMS(ESI)m / z:[M+Na] + Calcd for C 17 H 22 N2NaO5 357.1426; Found 357.1422; 1 H NMR (600MHz, DMSO-d6) δ8.39(t,J=6.0Hz,1H),7.08(s,1H),7.03(s,1H),6.94(s,1H),3.93(s,3H),3.84(s,3 H),3.76(s,3H),3.61(s,3H),3.46–3.41(m,1H),3.31–3.26(m,1H),2.80–2.72(m,1H),1.10(d,J=7.0Hz,3H).

[0431] Step 2: Dissolve 167 mg M-58 (0.5 mmol) in a mixed solvent of 6.0 mL THF, 6.0 mL MeOH, and 2.0 mL H2O. Add 60 mg LiOH (2.5 mmol) in portions, heat to 50 °C, and react for 12 h. After the reaction is complete, cool the reaction solution to room temperature, pour it into water, adjust the pH to 1-2 with 1N HCl aqueous solution, extract with ethyl acetate, combine the organic layers, dry, concentrate, and separate by column chromatography (DCM / MeOH / HCOOH) to obtain 128 mg M-59.

[0432] M-59:purity:99%;HRMS(ESI)m / z:[M+Na] + Calcd for C 16 H 20 N2NaO5 343.1270; Found 343.1266; 1 H NMR (600MHz, DMSO-d6) δ8.41(t,J=5.8Hz,1H),7.07(s,1H),7.03(s,1H),6.95(s,1H),3.94(s,3H),3.84(s,3H),3. 76(s,3H),3.41(dt,J=12.5,5.9Hz,1H),3.26(dt,J=13.0,6.3Hz,1H),2.62(q,J=7.0Hz,1H),1.07(d,J=7.0Hz,3H).

[0433] 39. Synthesis of compounds M-60 and M-61

[0434] Step 1: Dissolve 235 mg of 5,6-dimethoxy-1-methyl-1-H-indole-2-carboxylic acid (1 mmol), 456 mg of HATU (1.2 mmol), and 258 mg of DIPEA (2.0 mmol) in 10 mL of THF and react at room temperature for 1 h. Add 262 mg of methyl 3-amino-2,2-dimethylpropionate (2 mmol) to the reaction solution, heat to 60 °C, and react for 12 h. After the reaction is complete, cool the reaction solution to room temperature, pour it into water, extract with ethyl acetate, combine the organic layers, and wash the organic layer with 1 N HCl aqueous solution. Dry the organic layer, concentrate it, and separate it by column chromatography to obtain 209 mg of M-60.

[0435] M-60:purity:98%;HRMS(ESI)m / z:[M+Na] + Calcd for C 18 H 24 N2NaO5 371.1583; Found 371.1582;1 H NMR(600MHz,DMSO-d6)δ8.23(t,J=6.5Hz,1H),7.09(s,1H),7.03(s,1H),6.95(s,1H),3 .91(s,3H),3.84(s,3H),3.76(s,3H),3.61(s,3H),3.40(d,J=6.4Hz,2H),1.15(s,6H).

[0436] Step 2: Dissolve 104 mg M-60 (0.3 mmol) in a mixed solvent of 3.0 mL THF, 3.0 mL MeOH, and 1.0 mL H2O. Add 36 mg LiOH (1.5 mmol) in portions, heat to 50 °C, and react for 12 h. After the reaction is complete, cool the reaction solution to room temperature, pour it into water, adjust the pH to 1-2 with 1 N HCl aqueous solution, extract with ethyl acetate, combine the organic layers, dry, concentrate, and separate by column chromatography (DCM / MeOH / HCOOH) to obtain 32 mg M-61.

[0437] M-61:purity:97%;HRMS(ESI)m / z:[M+Na] + Calcd for C 17 H 22 N2NaO5 357.1426; Found 357.1425; 1 H NMR(600MHz,DMSO-d6)δ8.29(t,J=6.3Hz,1H),7.07(s,1H),7.03(s,1H),6.93(s ,1H),3.92(s,3H),3.83(s,3H),3.75(s,3H),3.35(d,J=5.9Hz,2H),1.10(s,6H).

[0438] 40. Synthesis of compounds M-62 and M-63

[0439] Step 1: Dissolve 150 mg of 5,6-dimethoxy-1-methyl-1-H-indole-2-carboxylic acid (0.64 mmol), 239 mg of HATU (0.77 mmol), and 330 mg of DIPEA (2.56 mmol) in 10 mL of THF and react at room temperature for 1 h. Add 197 mg of methyl 3-amino-2-methylpropionate hydrochloride (1.28 mmol) to the reaction solution, heat to 60 °C, and react for 12 h. After the reaction is complete, cool the reaction solution to room temperature, pour it into water, extract with ethyl acetate, combine the organic layers, and wash the organic layer with 1 N HCl aqueous solution. Dry the organic layer, concentrate it, and separate it by column chromatography to obtain 150 mg of M-62-int-1.

[0440] Step 2: Dissolve 167 mg M-62-int-1 (0.5 mmol) in 10 mL DMF. Add 40 mg NaH (1.0 mmol, 60% dispersed in oil) in portions under ice bath conditions. Slowly heat to room temperature and react for 1 h. Slowly add 234 mg MeI (2 mmol) to the reaction solution and continue the reaction for 12 h. After the reaction is complete, quench the reaction solution with saturated ammonium chloride aqueous solution under ice bath conditions. Dilute with water, extract with ethyl acetate, combine the organic layers, dry, concentrate, and separate by column chromatography to obtain 115 mg M-62.

[0441] M-62:purity:99%;HRMS(ESI)m / z:[M+Na] + Calcd for C 18 H 24 N2NaO5 371.1583; Found 371.1594; 1 H NMR(600MHz,DMSO-d6)δ7.08(s,1H),7.05(s,1H),6.54(s,1H),3.84(s,3H),3 .76(s,3H),3.70(s,4H),3.64–3.60(m,2H),3.60(s,3H),3.06(s,3H),2.93(br s,1H),1.06(br s,3H).

[0442] Step 3: Dissolve 105 mg M-62 (0.3 mmol) in a mixed solvent of 3.0 mL THF, 3.0 mL MeOH, and 1.0 mL H2O. Add 36 mg LiOH (1.5 mmol) in portions, heat to 50 °C, and react for 12 h. After the reaction is complete, cool the reaction solution to room temperature, pour it into water, adjust the pH to 1-2 with 1 N HCl aqueous solution, extract with ethyl acetate, combine the organic layers, dry, concentrate, and separate by column chromatography (DCM / MeOH / HCOOH) to obtain 40 mg M-63.

[0443] M-63:HRMS(ESI)m / z:[MH] - Calcd for 17 H 21 N2O5 333.1450; Found 333.1458; 1H NMR(600MHz,DMSO-d6)δ7.07(s,1H),7.04(s,1H),6.52(s,1H),3.83(s,3H),3.75(s,3H),3.69(s,3H),3.65–3.60(m,2H),3.05(s,3H),2.80(br s,1H),1.02(s,3H).

[0444] 41. Synthesis of compounds M-64 and M-65

[0445] Step 1: Dissolve 150 mg of 5,6-dimethoxy-1-methyl-1-H-indole-2-carboxylic acid (0.64 mmol), 239 mg of HATU (0.77 mmol), and 330 mg of DIPEA (2.56 mmol) in 10 mL of THF and react at room temperature for 1 h. Add 179 mg of sarcosine methyl ester hydrochloride (1.28 mmol) to the reaction solution, heat to 60 °C, and react for 12 h. After the reaction is complete, cool the reaction solution to room temperature, pour it into water, extract with ethyl acetate, combine the organic layers, and wash the organic layer with 1 N HCl aqueous solution. Dry the organic layer, concentrate it, and separate it by column chromatography to obtain 182 mg of M-64.

[0446] M-64:purity:99%;HRMS(ESI)m / z:[M+Na] + Calcd for C 16 H 20 N2NaO5 343.1270; Found 343.1274; 1 H NMR(600MHz,DMSO-d6)δ7.08(s,1H),7.04(s,1H),6.64(s,0.65H),6.42(s,0.35H),4.39(s,0.7H),4 .27(s,1.3H),3.84(s,3H),3.76(s,3H),3.72(s,3H),3.70(s,3H),3.17(s,1.95H),3.02(s,1.05H).

[0447] Step 2: Dissolve 96 mg M-64 (0.3 mmol) in a mixed solvent of 3.0 mL THF, 3.0 mL MeOH, and 1.0 mL H2O. Add 36 mg LiOH (1.5 mmol) in portions, heat to 50 °C, and react for 12 h. After the reaction is complete, cool the reaction solution to room temperature, pour it into water, adjust the pH to 1-2 with 1 N HCl aqueous solution, extract with ethyl acetate, combine the organic layers, dry, concentrate, and separate by column chromatography (DCM / MeOH / HCOOH) to obtain 51 mg M-65.

[0448] M-65:purity:95%; HRMS(ESI)m / z:[M+H] + Calcd for C 15 H 19 N2O5 307.1294; Found 307.1298; 1 H NMR(600MHz,DMSO-d6)δ7.08(s,1H),7.05(s,1H),6.62(s,0.5H),6.45(s,0.5H),4.24(s ,1H),4.17(s,1H),3.84(s,3H),3.76(s,3H),3.72(s,3H),3.15(s,1.5H),3.01(s,1.5H).

[0449] 42. Synthesis of compounds M-66 and M-67

[0450] Step 1: Dissolve 235 mg of 5,6-dimethoxy-1-methyl-1-H-indole-2-carboxylic acid (1 mmol, 1.0 eq), 456 mg of HATU (1.2 mmol, 1.2 eq), and 516 mg of DIPEA (4 mmol, 4.0 eq) in 10 mL of THF and react at room temperature for 1 h. Add 278 mg of methyl 3-aminopropionate hydrochloride (2 mmol, 2.0 eq) to the reaction solution, heat to 60 °C, and react for 12 h. After the reaction is complete, cool the reaction solution to room temperature, pour it into water, extract with ethyl acetate, combine the organic layers, and wash the organic layer with 1 N HCl aqueous solution. Dry the organic layer, concentrate it, and separate it by column chromatography to obtain 208 mg of M-66.

[0451] M-66:purity:91%; HRMS(ESI)m / z:[M+Na] + Calcd for C 16 H 20 N2NaO5 343.1270; Found 343.1263; 1 H NMR(600MHz,DMSO-d6)δ8.36(t,J=5.5Hz,1H),7.07(s,1H),7.03(s,1H),6.93(s,1H),3.94(s, 3H),3.83(s,3H),3.76(s,3H),3.61(s,3H),3.47(td,J=7.0,5.5Hz,2H),2.59(t,J=7.0Hz,2H).

[0452] Step 2: Dissolve 96 mg M-66 (0.3 mmol, 1.0 eq) in a mixed solvent of 3.0 mL THF, 3.0 mL MeOH, and 1.0 mL H2O. Add 36 mg LiOH (1.5 mmol, 5.0 eq) in portions, heat to 50 °C, and react for 12 h. After the reaction is complete, cool the reaction solution to room temperature, pour it into water, adjust the pH to 1-2 with 1 N HCl aqueous solution, extract with ethyl acetate, combine the organic layers, dry, concentrate, and separate by column chromatography (DCM / MeOH / HCOOH) to obtain 43 mg M-67.

[0453] M-67:purity:95%; HRMS(ESI)m / z:[M+H] + Calcd for C 15 H 18 N2NaO5 329.1113; Found 329.1108; 1 H NMR(600MHz,DMSO-d6)δ12.19(s,1H),8.33(t,J=5.6Hz,1H),7.07(s,1H),7.03(s,1H),6.94(s ,1H),3.94(s,2H),3.83(s,2H),3.76(s,2H),3.43(td,J=7.1,5.5Hz,2H),2.51(t,J=7.2Hz,2H)

[0454] 43. Synthesis of compounds M-68, M-69 and M-70

[0455] 1-Chloromethyl-4-fluoro-1,4-diazobicyclo[2.2.2]xenane (tetrafluoroborate) (1.66 g, 4.70 mmol) was added to 10 mL of acetonitrile and 10 mL of dichloromethane solution containing M-16 (1.00 g, 3.13 mmol) prepared in Part 11 of this Example, and stirred overnight at 55°C. The reaction solution was extracted with ethyl acetate and water, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and pre-purified by silica gel column chromatography (20:80 ethyl acetate-petroleum ether). Further purification by preparative chromatography yielded M-68 (11 mg, 0.033 mmol, 1% yield), M-69 (8 mg, 0.024 mmol, 0.8% yield), and M-69 (10 mg, 0.03 mmol, 0.9% yield), respectively.

[0456] M-68:HRMS(ESI)m / z:[M+H] + Calcd for C 17 H 20FNO5 337.1326,found:338.1401; 1 H NMR(600MHz,CDCl3)δ6.98(s,1H),6.67(s,1H),3.98(s,3H),3.94(s,6H),3.72(s,3H),3.42(dd,J=17.4,8.3Hz,1H),3.15–3.07(m,1H),3.07–3.00(m,1H),1.29(d,J=7.0Hz,1H);13C NMR(151MHz,CDCl3)δ190.71,176.40,154.35,154.32,150.36,148.70,137.18,137.10,133.70,132.31,132.23,110.37,110.23,107.92,87.82,87.80,62.04,62.02,56.43,51.94,42.75,35.18,32.55,17.24.

[0457] M-69:HRMS(ESI)m / z:[M+H] + Calcd for C 17 H 20 FNO5 337.1326,found:338.1404; 1 H NMR(600MHz,CDCl3)δ7.33(s,1H),6.52(s,1H),4.01(s,3H),3.97(s,3H),3.94(s,3H),3.71(s,3H),3.44(dd,J=16.7,8.0Hz,1H),3.15–3.07(m,1H),3.03(dd,J=16.8,5.4Hz,1H),1.28(d,J=7.0Hz,3H);13C NMR(151MHz,CDCl3)δ188.76,188.73,176.58,151.76,150.71,148.98,146.26,132.21,132.18,118.08,117.96,106.98,106.87,98.07,91.48,56.10,56.06,51.81,44.58,44.53,34.75,32.10,17.23.

[0458] M-70:HRMS(ESI)m / z:[M+H] + Calcd for C 17 H 20 FNO5 337.1326,found:338.1403; 1H NMR (400MHz, CDCl3) δ7.88(s,1H),6.71(s,1H),3.95(d,J=5.9Hz,6H),3.72(s,3H),3.67(s,3H),3.34(dd d,J=17.2,8.0,2.4Hz,1H),3.21–3.11(m,1H),2.92(ddd,J=17.2,5.5,2.3Hz,1H),1.29(d,J=7.1Hz,3H).

[0459] 44. Synthesis of M-71 compound

[0460] Lithium hydroxide (4.3 mg, 178 μmol) was added to a tetrahydrofuran (1 mL) / ethanol (0.5 mL) / water (0.5 mL) solution containing M-69 (6.0 mg, 17.8 μmol) prepared in Part 43 of this example, and the mixture was stirred at 60 °C for 3 hours. The reaction solution was quenched with dilute hydrochloric acid, the pH was adjusted to 3, and then extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography to give M-71 (4.8 mg, 14.8 μmol, 83% yield).

[0461] M-71: 1 H NMR (600MHz, CDCl3) δ7.32(s,1H),6.52(s,1H),4.00(s,3H),3.96(s,3H),3.94(s,3H),3.44(d d,J=16.8,7.9Hz,1H),3.17–3.10(m,1H),3.07(dd,J=16.9,5.2Hz,1H),1.32(d,J=7.0Hz,3H); 13 C NMR (151MHz, CDCl3) δ190.53,181.57,154.41,154.38,150.33,148.68,137.23,137.15,133.53,132. 32,132.24,110.38,110.24,108.04,87.83,87.81,62.04,62.02,56.43,42.42,35.02,32.57,17.05.

[0462] 45. Synthesis of compound M-72

[0463] Lithium hydroxide (4.3 mg, 178 μmol) was added to a tetrahydrofuran (1 mL) / ethanol (0.5 mL) / water (0.5 mL) solution containing M-68 (6.0 mg, 17.8 μmol) prepared in Part 43 of this example, and stirred at 60 °C for 3 hours. The reaction solution was quenched with dilute hydrochloric acid, the pH was adjusted to 3, and then extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography to give 4-(3-fluoro-5,6-dimethoxy-1-methyl-1H-indol-2-yl)-2-methyl-4-oxobutyric acid M-72 (4.6 mg, 14.2 μmol, 80% yield).

[0464] M-72: 1 H NMR(600MHz,DMSO-d6)δ7.07(s,1H),7.06(s,1H),3.89(s,3H),3.88(s,3H),3.8 1(s,3H),3.24(dd,J=16.8,7.6Hz,1H),2.97-2.86(m,2H),1.18(d,J=5.7Hz,3H); 13 C NMR(151MHz,DMSO)δ188.87,177.30,152.11,150.06,148.34,146.79,132.35,118.11,1 17.99,106.56,106.45,98.27,93.32,56.37,56.21,44.59,44.54,34.77,32.60,17.54.

[0465] 46. ​​Synthesis of Compound M-73

[0466] Step 1: Under nitrogen protection at 0°C, sodium hydrogen (1.23 g, 30.69 mmol, 60% dispersed in mineral oil) was added to a tetrahydrofuran (60 mL) solution of ethyl 5,6-dimethoxyindole-2-carboxylate (5.1 g, 20.46 mmol). After stirring the reaction solution at this temperature for 1 hour, benzenesulfonyl chloride (7.22 g, 40.9 mmol) was slowly added dropwise to the above reaction solution, and stirring was continued at 0°C for 1 hour, followed by stirring at room temperature for 12 hours. The reaction was quenched with water, and the reaction solution was adjusted to neutral with dilute hydrochloric acid. The solution was then extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to give M-73-int-1 (4.3 g, 11.04 mmol, 85% yield).

[0467] Step 2: 1-Chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octaneditetrafluoroboric acid was added to a solution of M-73-int-1 (1.00 g, 2.57 mmol) in dichloromethane (10 mL) and acetonitrile (10 mL). The reaction mixture was stirred overnight at 55°C and the solvent was removed by rotary evaporation under reduced pressure. The residue was extracted with ethyl acetate and water, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain a mixture of F-030 and F-050. Finally, preparative chromatography was used to purify the mixture to obtain pure M-73-int-2 (8 mg, 0.020 mmol, 0.76% yield) and M-73-int-3 (7 mg, 0.017 mmol, 0.67% yield), respectively.

[0468] Step 3: Lithium hydroxide (58.9 mg, 2.5 mmol) was added to a tetrahydrofuran (10 mL) / ethanol (5 mL) / water (5 mL) solution of M-73-int-2 (100.0 mg, 0.25 mmol) and stirred at 60 °C for 3 hours. The reaction solution was quenched with dilute hydrochloric acid, the pH was adjusted to 3, and then extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography to give M-73-int-4 (85.5 mg, 0.22 mmol, 90% yield).

[0469] Step 4: Dissolve M-73-int-4 (85.5 mg, 0.22 mmol) in diphenyl ether (5 mL). After stirring the reaction solution at 260 °C for 3 hours, purify it by silica gel column chromatography to obtain M-73-int-5 (27.5 mg, 0.14 mmol, 64% yield).

[0470] Step 5: 4-Dimethylaminopyridine (1.7 mg, 0.014 mmol), di-tert-butyl dicarbonate (45.8 mg, 0.21 mmol), and triethylamine (58.4 μL, 0.42 mmol) were added to a solution of M-73-int-5 (27.5 mg, 0.14 mmol) in 10 mL of dichloromethane. The reaction mixture was stirred at room temperature for 4 hours, quenched with 10 mL of water, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue purified by silica gel column chromatography to give M-73-int-6 (38.4 mg, 0.13 mmol, 93% yield).

[0471] Step 6: Under nitrogen protection, dissolve 2,2,6,6-tetramethylpiperidine (72 mg, 0.51 mmol) in 1 mL of anhydrous tetrahydrofuran and cool to -78°C. Add n-butyllithium (20.4 μL, 0.51 mmol, 2.5 M n-hexane solution) dropwise to the above reaction flask and stir at this temperature for 1 hour. Add 2 mL of a tetrahydrofuran solution of M-73-int-6 (100 mg, 0.34 mmol) dropwise to the above reaction solution. After stirring the reaction solution at -78°C for one hour, add 1 mL of a tetrahydrofuran solution of 2,2-dimethylsuccinic anhydride (87.1 mg, 0.68 mmol) to the above reaction solution and continue stirring at this temperature for 1 hour. Then raise the temperature to room temperature and stir overnight. Quench the reaction with a small amount of water and hydrochloric acid and adjust the pH to 3. The crude product was concentrated and purified by silica gel column chromatography (20:80 = ethyl acetate: petroleum ether) to obtain a mixture of F-034 and F-035 (50.2 mg, 0.12 mmol, 35% yield).

[0472] Step 7: Trifluoroacetic acid (89.1 μL, 1.2 mmol) was added dropwise to a 2 mL solution of M-73-int-7 and M-73-int-8 (50.2 mg, 0.12 mmol) in dichloromethane and stirred at room temperature for 2 hours. The mixture was then extracted with ethyl acetate and water. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (20:80 = ethyl acetate: petroleum ether) to give a mixture of M-73-int-9 and M-73-int-10 (36.9 mg, 0.11 mmol, 92% yield).

[0473] Step 8: Diazomethane (165 μL, 0.33 mmol, 2.0 M n-hexane solution) was added dropwise to a solution of M-73-int-9 and M-73-int-10 (36.9 mg, 0.11 mmol) in methanol (1 mL) and diethyl ether (1 mL). The reaction mixture was stirred at room temperature for 2 hours and then distilled under reduced pressure. The residue was extracted with ethyl acetate and water, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and finally purified by silica gel column chromatography to obtain a mixture of M-73-int-11 and M-73-int-12 (35.3 mg, 0.10 mmol, 91% yield).

[0474] Step 9: Cesium carbonate (48.9 mg, 0.15 mmol) and methyl iodide (18.7 μL, 0.3 mmol) were added to acetonitrile (2 mL) solutions of M-73-int-11 and M-73-int-12 (35.3 mg, 0.10 mmol). The reaction mixture was stirred at 80 °C for 12 hours, and the solvent was removed by rotary evaporation under reduced pressure. The residue was extracted with ethyl acetate and water. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by silica gel column chromatography. Preparative chromatography was used to purify the organic phase to obtain M-73 (10 mg, 0.028 mmol, 28% yield) and M-74 (18 mg, 0.051 mmol, 51% yield), respectively.

[0475] M-73: 1 H NMR (600MHz, CDCl3) δ7.15(s,1H),6.55(s,1H),3.96(s,4H),3.93(s,4H),3.88(s,3H),3.60(s,3H),2.88(s,2H),1.52(s,6H).

[0476] 47. Synthesis of compounds M-75 and M-76

[0477] Step 1: Lithium hydroxide (58.9 mg, 2.5 mmol) was added to a tetrahydrofuran (10 mL) / EtOH (5 mL) / water (5 mL) solution containing M-73-int-3 (100.0 mg, 0.25 mmol) and stirred at 60 °C for 3 hours. The mixture was then quenched with dilute hydrochloric acid, and the pH was adjusted to 3. The mixture was extracted with ethyl acetate and water. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and finally purified by silica gel column chromatography to obtain M-75-int-1 (85.5 mg, 0.22 mmol, 90% yield).

[0478] Step 2: M-75-int-1 (85.5 mg, 0.22 mmol) was dissolved in diphenyl ether (5 mL). The reaction solution was stirred at 260 °C for 3 hours and then purified by silica gel column chromatography to obtain M-75-int-2 (27.5 mg, 0.14 mmol, 64% yield).

[0479] Step 3: 4-Dimethylaminopyridine (1.7 mg, 0.014 mmol), di-tert-butyl dicarbonate (45.8 mg, 0.21 mmol), and triethylamine (58.4 μL, 0.42 mmol) were added to M-75-int-2 (27.5 mg, 0.14 mmol) to obtain a solution of dichloromethane (10 mL). The reaction mixture was stirred at room temperature for 4 hours, evaporated to dryness, and extracted with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and finally purified by silica gel column chromatography to obtain M-75-int-3 (38.4 mg, 0.13 mmol, 93% yield).

[0480] Step 4: Under nitrogen protection, dissolve 2,2,6,6-tetramethylpiperidine (72 mg, 0.51 mmol) in 1 mL of anhydrous tetrahydrofuran and cool to -78°C. Add n-butyllithium (20.4 μL, 0.51 mmol, 2.5 M n-hexane solution) dropwise to the above reaction flask and stir at this temperature for 1 hour. Add 2 mL of a tetrahydrofuran solution of M-75-int-3 (100 mg, 0.34 mmol) dropwise to the above reaction solution. After stirring the reaction solution at -78°C for one hour, add 1 mL of a tetrahydrofuran solution of 2,2-dimethylsuccinic anhydride (87.1 mg, 0.68 mmol) to the above reaction solution and continue stirring at this temperature for 1 hour. Then raise the temperature to room temperature and stir overnight. Quench the reaction with a small amount of water and hydrochloric acid and adjust the pH to 3. The crude product was concentrated and purified by silica gel column chromatography (20:80 = ethyl acetate: petroleum ether) to obtain a mixture of M-75-int-4 and M-75-int-5 (50.2 mg, 0.12 mmol, 35% yield).

[0481] Step 5: Trifluoroacetic acid (89.1 μL, 1.2 mmol) was added dropwise to a solution of M-75-int-4 and M-75-int-5 (50.2 mg, 0.12 mmol) in dichloromethane (2 mL), and the mixture was stirred at room temperature for 2 hours. The mixture was then extracted with ethyl acetate and water. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (20:80 = ethyl acetate: petroleum ether) to obtain M-75-int-6 and M-75-int-7 (36.9 mg, 0.11 mmol, 92% yield).

[0482] Step 6: Diazomethane (165 μL, 0.33 mmol, 2.0 M n-hexane solution) was added dropwise to a solution of M-75-int-6 and M-75-int-7 (36.9 mg, 0.11 mmol) in methanol (1 mL) and diethyl ether (1 mL). The reaction mixture was stirred at room temperature for 2 hours and then distilled under reduced pressure. The residue was extracted with ethyl acetate and water, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and finally purified by silica gel column chromatography to obtain M-75-int-8 and M-75-int-9 (35.3 mg, 0.10 mmol, 91% yield).

[0483] Step 7: Cesium carbonate (48.9 mg, 0.15 mmol) and methyl iodide (18.7 μL, 0.3 mmol) were added to acetonitrile (2 mL) solutions of M-75-int-8 and M-75-int-9 (35.3 mg, 0.10 mmol). The reaction mixture was stirred at 80 °C for 12 hours, and the solvent was removed by rotary evaporation under reduced pressure. The residue was extracted with ethyl acetate and water. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, purified by silica gel column chromatography, and then purified by preparative chromatography to obtain M-75 (10 mg, 0.028 mmol, 28% yield) and M-76 (18 mg, 0.051 mmol, 51% yield), respectively.

[0484] M-75: 1 H NMR (600MHz, CDCl3) δ6.99(d,J=1.8Hz,1H),6.82(d,J=0.8Hz,1H),4.06(s,3H),3.97(s,3H),3.89(s,3H),3.60(s,3H),2.86(s,2H),1.49(s,6H); 13 C NMR (151MHz, CDCl3) δ198.66,171.91,149.16,149.14,144.87,136.46,135.09,123.71,123.46,123. 41,122.53,122.49,115.94,111.39,108.22,97.96,62.09,56.40,51.57,45.98,45.63,34.56,26.79.

[0485] M-76: 1 H NMR (600MHz, CDCl3) δ7.13(d,J=1.7Hz,1H),6.81(d,J=1.1Hz,1H),4.21(d,J=1.0H z,3H),3.98(d,J=0.4Hz,3H),3.90(s,3H),3.70(s,3H),3.25(s,2H),1.32(s,6H);13 C NMR (151MHz, CDCl3) δ190.85,177.86,149.33,149.32,144.86,144.79,143.16,137.27,137.19,137.12,1 35.52,124.77,124.72,122.47,122.43,111.41,98.06,62.04,56.38,52.01,49.61,40.42,34.76,25.73.

[0486] 48. Synthesis of compound M-77

[0487] Lithium hydroxide (4.1 mg, 171 μmol) was added to a tetrahydrofuran (1 mL) / ethanol (0.5 mL) / water (0.5 mL) solution of M-75 (6.0 mg, 17.1 μmol) prepared in Part 50 of this example, and the mixture was stirred at 60 °C for 3 hours. The reaction solution was quenched with dilute hydrochloric acid, the pH was adjusted to 3, and then extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography to give M-77 (4.8 mg, 14.2 μmol, 83% yield).

[0488] M-77: 1 H NMR (600MHz, CDCl3) δ6.99(s,1H),6.81(s,1H),4.01(s,3H),3.97(s,3H),3.89(s,3H),2.88(s,2H),1.50(s,6H); 13 C NMR (151MHz, CDCl3) δ198.56,176.60,149.22,144.84,143.21,136.59,136.51,134.79,123.58, 123.53,122.49,122.45,108.53,97.99,62.08,62.06,56.40,45.87,45.46,34.56,34.51,26.85.

[0489] 49. Synthesis of M-78 compound

[0490] Lithium hydroxide (4.1 mg, 171 μmol) was added to a tetrahydrofuran (1 mL) / ethanol (0.5 mL) / water (0.5 mL) solution of M-76 (6.0 mg, 17.1 μmol) prepared in Part 50 of this example, and the mixture was stirred at 60 °C for 3 hours. The reaction solution was quenched with dilute hydrochloric acid, the pH was adjusted to 3, and then extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography to give M-78 (4.2 mg, 12.5 μmol, 73% yield).

[0491] M-78: 1 H NMR (600MHz, CDCl3) δ7.15 (d, J = 1.5 Hz, 1H), 6.81 (d, J = 0.5 Hz, 1H), 4.22 (s, 3H), 3.98 (s, 3H), 3.90 (s, 3H), 3.28 (s, 2H), 1.36 (s, 6H); 13 C NMR (151MHz, CDCl3) δ190.87,181.33,149.37,144.77,143.13,137.32,135.31,129.93,129.90,124.92, 124.87,122.46,122.42,111.69,98.07,62.07,62.05,56.37,49.21,40.16,34.86,34.80,29.33,25.66.

[0492] 50. Synthesis of compound M-79

[0493] Step 1: Methyl (S)-2,3-dihydroxypropionate (500.0 mg, 4.16 mmol) and imidazole (283.4 mg, 4.16 mmol) were dissolved in DCM (5.0 mL) at 0 °C, and tert-butyldimethylchlorosilane (342.8 mg, 4.16 mmol) was added. The mixture was then stirred at room temperature for 1 hour. After the reaction was complete, the mixture was diluted with water and extracted with ethyl acetate, followed by washing with brine. The solution was then dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to give M-79-int-1 (500.0 mg, 2.13 mmol, yield 51.2%).

[0494] Step 2: M-79-int-1 (400.0 mg, 1.71 mmol) was dissolved in dichloromethane (8.0 mL) at 0 °C, and Dys-Martin oxidant (868.7 mg, 2.05 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC. After the reaction was complete, the mixture was diluted with water and extracted with ethyl acetate, followed by washing with brine. The organic layer was then dried over anhydrous Na2SO4 and concentrated under reduced pressure. The purified compound methyl 3-(tert-butyl(dimethyl)silyl)oxy-2-oxopropionate M-79-int-2 (400.0 mg, 1.72 mmol, 100% yield) was obtained by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1).

[0495] Step 3: M-79-int-2 (300.0 mg, 0.87 mmol) was dissolved in tetrahydrofuran (6.0 mL) at 0 °C, and sodium hydride (70.3 mg, 1.76 mmol, 60% in paraffin oil) was added. The mixture was stirred at 0 °C for 30 min under argon protection. Then, M-79-int-2 (246.3 mg, 1.76 mmol) was added dropwise at 0 °C. The mixture was stirred at room temperature for 1 h under argon protection. The reaction mixture was then quenched with saturated ammonium chloride (20.0 mL), diluted with water (20.0 mL), and extracted with ethyl acetate (50.0 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) gave a yellow solid M-79-int-3 (260.0 mg, 0.56 mmol, yield 66.1%).

[0496] M-79-int-3:MS m / z(ESI):448.4[M+H] + .

[0497] Step 4: M-79-int-3 (200.0 mg, 0.43 mmol) and Pd / C (52.6 mg, 10%) were dissolved in methanol (4.0 mL) and stirred at room temperature for 4 hours under a hydrogen balloon. The reaction was then detected by LCMS. The reaction solution was filtered, and the filtrate was concentrated under vacuum. The crude product was purified by silica gel column chromatography (PE:EA = 20:1) to give M-79-int-4 (140.0 mg, 0.30 mmol, yield 70.0%) as a white solid.

[0498] M-79-int-4:MS m / z(ESI):450.5[M+H] + .

[0499] Step 5: SG-111-7 (140.0 mg, 0.31 mmol) was dissolved in tetrahydrofuran (3.0 mL) at 0 °C, and tetrabutylammonium fluoride (162.8 mg, 0.62 mmol) was added. The mixture was then stirred at room temperature for 16 hours. Saturated ammonium chloride (5.0 mL) was added, diluted with water, and the mixture was extracted with ethyl acetate (5.0 mL × 3). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give M-79 (29.4 mg, 87.52 μmol, yield 28.8%).

[0500] M-79: MS m / z (ESI): 336.3 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ7.36(s,1H),7.13(s,1H),7.05(s,1H),4.93(t,J=5.4Hz,1H),3.95(s,3H),3.8 7(s,3H),3.78(s,3H),3.64(t,J=5.6Hz,2H),3.34-3.39(m,1H),3.06-3.17(m,1H),δ3.00-3.05(m,1H).

[0501] Example 2: Preparation of Dimeric Compounds

[0502] 1. Synthesis of D-1 and D-2 compounds

[0503] Step 1: To a solution of acetonitrile (5.0 mL) containing M-29 (67.00 mg, 219.44 μmol) prepared in Step 18 of Example 1, add 1,3-dibromopropane (88.60 mg, 438.88 μmol) and potassium carbonate (151.64 mg, 1.10 mmol). Stir the mixture at 70 °C for 16 hours. Remove the solvent under vacuum and purify using a preparative plate (PE / EA = 3 / 1) to obtain D-1-int-1 (48.00 mg, 112.60 μmol, yield 51.31%).

[0504] D-1-int-1:MS m / z(ESI):426.1,428.1[M+H] + .

[0505] Step 2: Potassium carbonate (46.68 mg, 337.79 μmol) and M-30 (25.0 mg, 81.88 μmol) prepared in Step 18 of Example 1 were added to a DMF (1.0 mL) solution of D-1-int-1 (48.00 mg, 112.60 μmol). The reaction mixture was stirred at 80 °C for 16 hours. The reaction mixture was concentrated under high vacuum and purified by preparative plate (DCM / MeOH = 20 / 1) to give a white solid D-1 (70.00 mg, 107.57 μmol, 95.54% yield).

[0506] D-1:MS m / z(ESI):651.1[M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ7.38(s,1H),7.36(s,1H),7.18(s,1H),7.13(s,1H),7.1 1(s,1H),7.06(s,1H),4.27(t,J=6.2Hz,2H),4.17(t,J=6.2Hz,2H),3.94(d,J=5 .6Hz,6H),3.86(s,3H),3.79(s,3H),3.59(s,6H),3.31-3.26(m,2H),3.08(dd,J =17.2,5.6Hz,2H),2.99-2.89(m,2H),2.30-2.23(m,2H),1.17(d,J=7.1Hz,6H).

[0507] Step 3: Lithium hydroxide monohydrate (8.25 mg, 196.71 μmol) was added to a solution of D-1 (32.00 mg, 49.18 μmol) in methanol (2.0 mL) and water (1.0 mL). The mixture was stirred at 25 °C for 16 hours. The pH of the mixture was adjusted to 3 with dilute hydrochloric acid (1 N), and D-2 (5.00 mg, 8.03 μmol, 16.33% yield) was purified by PERP-HPLC.

[0508] D-2:MS m / z(ESI): 623.2 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ12.11(br.s,2H),7.37(s,1H),7.34(s,1H),7.18(s,1H), 7.13(s,2H),7.11(s,2H),7.06(s,1H),4.27(t,J=6.2Hz,2H),4.17(t,J=6.2Hz,2 H),3.95(d,J=5.9Hz,6H),3.86(s,3H),3.79(s,3H),3.30-3.24(m,2H),2.98(dd, J=16.8,5.6Hz,2H),2.92-2.82(m,2H),2.30-2.22(m,2H),1.15(d,J=7.2Hz,6H).

[0509] 2. Synthesis of D-3 compounds

[0510] Step 1: Potassium carbonate (34.0 mg, 0.25 mmol) and 1,3-dibromopropane (33.1 mg, 0.16 mmol) were added to a 1.0 mL solution of acetonitrile (25.0 mg, 81.88 μmol) containing M-30 prepared in Step 18 of Example 1. The reaction mixture was stirred at 70 °C for 16 hours. The reaction mixture was filtered and concentrated to give crude D-3-int-1 (35.0 mg, 81.88 μmol, 100% yield).

[0511] D-3-int-1:MS m / z(ESI):426.2,428.2[M+H] + .

[0512] Step 2: Potassium carbonate (34.0 mg, 0.25 mmol) and M-30 (25.0 mg, 81.88 μmol) were added to a DMF (1.0 mL) solution of D-3-int-1 (34.9 mg, 81.88 μmol). The reaction mixture was stirred at 80 °C for 16 hours. The reaction mixture was concentrated under high vacuum and purified by preparative agar (DCM / MeOH = 20 / 1) to give a white solid D-3 (18.0 mg, 27.66 μmol, two-step yield 33.8%).

[0513] D-3:MS m / z(ESI): 651.3 [M+H] + ; 1H NMR (400MHz, CDCl3) δ7.20 (s, 2H), 7.03 (s, 2H), 6.81 (s, 2H), 4.39 (t, J = 6.0Hz, 4H), 3.96 (s, 6H), 3.89 (s,6H),3.70(s,6H),3.37-3.43(m,2H),2.98-3.13(m,4H),2.49-2.52(m,2H),1.27(d,J=7.2Hz,6H).

[0514] 3. Synthesis of D-4 and D-5 compounds

[0515] Step 1: K2CO3 (339.5 mg, 2.46 mmol) was added to a MeCN (5.0 mL) solution containing M-29 (250.0 mg, 818.80 μmol) prepared in Step 18 of Example 1 and 1,3-dibromopropane (826.5 mg, 4.09 mmol), and the mixture was stirred at 70 °C for 16 hours. The mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to give D-4-int-1 (0.3 g, 703.73 μmol, yield 85.9%) as a grayish-white solid.

[0516] D-4-int-1:MS m / z(ESI):426.1[M+H] + .

[0517] Step 2: Add M-29 (71.6 mg, 234.58 μmol) and K₂CO₃ (97.3 mg, 703.73 μmol) to a solution of D-4-int-1 (100.0 mg, 234.58 μmol) in DMF (2.0 mL). Stir the mixture at 70 °C for 16 hours. Filter the mixture and concentrate the filtrate. Purify the residue by preparative TLC (petroleum ether: ethyl acetate = 1:1) to give D-4 as a grayish-white solid (67.0 mg, 0.12 mmol, yield 42.1%).

[0518] D-4: MS m / z (ESI): 673.2 [M+Na] + ; 1H NMR (400MHz, DMSO-d6) δ7.36(s,2H),7.17(s,2H),7.06(s,2H),4.16(t,J=6.2Hz,4H),3.95(s,6H),3.87(s,6H),3.59(s,6H),3.33 –3.27(m,2H),3.10(d,J=5.4Hz,1H),3.06(d,J=5.4Hz,1H),2.99–2.91(m,2H),2.23(dd,J=12.0,6.0Hz,2H),1.17(d,J=7.2Hz,6H).

[0519] Step 3: LiOHH2O (9.7 mg, 230.52 μmol) was added to a mixed solution containing D-4 (30.0 mg, 46.10 μmol) in THF (1.0 mL), MeOH (0.5 mL), H2O (0.5 mL), and DMSO (0.5 mL). The mixture was stirred at room temperature for 16 hours, and the mixture was concentrated to remove the organic layer. The residue was extracted with EtOAc (5.0 mL x 2) and water (10.0 mL). The pH of the aqueous layer was adjusted to 1-2 with HCl (1 N, aq). The filter cake was filtered and dried to give D-5 as a white solid (24.9 mg, 40.09 μmol, yield 86.95%).

[0520] D-5: MS m / z (ESI): 623.3 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ12.05(s,2H),7.35(s,2H),7.18(s,2H),7.06(s,2H),4.16(t,J=6.2Hz,4H),3.96(s,6H),3.87(s,6H),3.27 (d,J=8.2Hz,2H),2.99(dd,J=16.8,5.6Hz,2H),2.87(dd,J=13.2,7.6Hz,2H),2.54(s,4H),2.27-2.17(m,2H),1.16(d,J=7.2Hz,6H).

[0521] 4. Synthesis of D-6 and D-7 compounds

[0522] Step 1: LiHMDS (1M in THF, 0.88mL, 0.88mmol) was added to a THF (10.0mL) solution containing tert-butyl acetate (102.7mg, 0.88mmol). The mixture was stirred at -78°C for 1 hour, followed by dropwise addition of ethyl 5-(benzyloxy)-6-methoxy-1-methyl-1H-indole-2-carboxylate (100.0mg, 0.29mmol, 1.00 equivalent, dissolved in 2.0mL THF). The reaction mixture was stirred at room temperature for 2 hours. The mixture was carefully treated with an aqueous solution of ammonium chloride (50.0mL). The mixture was extracted with ethyl acetate (20.0mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by preparative plate (EA / PE = 1 / 3) to give D-6-int-1 (120.0mg, 0.29mmol, 99.3% yield).

[0523] D-6-int-1:MS m / z(ESI):354.1[M-56+H] + .

[0524] Step 2: Potassium tert-butoxide (164.4 mg, 1.47 mmol) and hexadecyltrimethylammonium bromide (44.5 mg, 0.12 mmol) were added to a solution of tert-butanol (20.0 mL) containing D-6-int-1 (500.0 mg, 1.22 mmol), and the mixture was heated to 80 °C. Then ethyl acrylate (122.3 mg, 1.22 mmol) was added. The reaction mixture was stirred at 80 °C for 0.5 hours. The mixture was treated with an aqueous solution of ammonium chloride (20.0 mL), extracted with ethyl acetate (20.0 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (EA / PE = 1 / 8) to give crude D-6-int-2 (600.0 mg, 1.18 mmol, 96.4% yield, 95% purity).

[0525] D-6-int-2:MS m / z(ESI):454.3[M-56+H] + .

[0526] Step 3: Trifluoroacetic acid (1.50 mL, 19.62 mmol) was added to a DCM (5.0 mL) solution containing D-6-int-2 (500.0 mg, 0.98 mmol), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated to obtain crude D-6-int-3 (445.0 mg, 0.98 mmol) without purification.

[0527] D-6-int-3:MS m / z(ESI):454.2[M+H]+ .

[0528] Step 4: Dissolve D-6-int-3 (445 mg, 0.98 mmol) in toluene (10.0 mL), heat to 80 °C, and stir for 3 hours. Concentrate the reaction mixture under high vacuum and purify by high performance liquid chromatography (Column: Waters Xbridge 20*150 mm 10 μm, C18, Mobile Phase A: water, B: ACN, 0.5% FA) to obtain D-6-int-4 (210.0 mg, 0.51 mmol, two-step yield 52.3%).

[0529] D-6-int-4:MS m / z(ESI):410.3[M+H] + ; 1 H NMR (400MHz, CDCl3) δ7.46-7.48(m,2H), δ7.31-7.39(m,2H), δ7.15(s,1H),7.06(s,1H),6.75(s,1H),5.17(s,2H),4.11-4. 16(m,2H),4.04(s,3H),3.99(s,3H),2.96(t,J=7.4Hz,2H),2.41(t,J=7.2Hz,2H),2.05-2.10(m,2H),1.25(t,J=7.0Hz,3H).

[0530] Step 5: Add Pd / C (10% carbon, approximately 55% water, 16.0 mg, mass ratio 10%) to a 5.0 mL ethanol solution of D-6-int-4 (160.0 mg, 0.39 mmol). Stir the mixture at room temperature under hydrogen for 1 hour. Filter the mixture, and concentrate and purify the filtrate by silica gel column chromatography (PE:EA = 3:1) to give a white solid D-6-int-5 (110 mg, 0.34 mmol, 88.2% yield).

[0531] D-6-int-5:MS m / z(ESI):320.1[M+H]+; 1 H NMR(400MHz,DMSO-d6)δ8.70(s,1H),δ7.25(s,1H),7.00(s,1H),6.96(s,1H),4.03-4.08(m,2H),3.95(s,3H),3.88 (s,3H),3.42-3.44(m,1H),2.92(t,J=7.2Hz,2H),2.37(t,J=7.4Hz,2H),1.85-1.89(m,2H),1.17(t,J=7.2Hz,3H).

[0532] Step 6: Dissolve D-6-int-5 (30.0 mg, 93.94 μmol) in acetonitrile (1.0 mL), and add potassium carbonate (39.0 mg, 281.82 μmol) and 1,3-dibromopropane (38.0 mg, 187.88 μmol). Stir the reaction mixture at 70 °C for 16 hours. Filter and concentrate the reaction mixture to obtain unpurified crude D-6-int-6 (34.5 mg, 78.28 μmol).

[0533] D-6-int-6:MS m / z(ESI):440.1,442.1[M+H] + .

[0534] Step 7: Dissolve D-6-int-6 (34.5 mg, 78.28 μmol) in DMF (1.0 mL), and add potassium carbonate (34.0 mg, 234.85 μmol) and D-6-int-5 (25.0 mg, 7828 μmol). Stir the reaction mixture at 80 °C for 16 hours. Concentrate the reaction mixture under high vacuum and purify it by preparative thin-layer chromatography (dichloromethane / methanol = 20 / 1) to give a white solid D-6 (25.0 mg, 36.83 μmol, yield 47.1%).

[0535] D-6: MS m / z (ESI): 679.2 [M+H] + ,1H NMR (400MHz, CDCl3) δ7.17(s,2H),7.12(s,2H),6.73(s,2H),4.29(t,J=6.2Hz,4H),4.14(q,J=7.2Hz,4H),4.0 4(s,6H),3.95(s,6H),2.97(t,J=7.2Hz,4H),2.43(t,J=7.4Hz,6H),2.04-2.11(m,4H),1.26(t,J=7.2Hz,6H).

[0536] Step 8: D-6 (20.0 mg, 29.47 μmol) was dissolved in a mixture of methanol (2.0 mL) and water (1.0 mL), and lithium hydroxide monohydrate (5.0 mg, 0.13 mmol) was added. The mixture was then stirred at room temperature for 16 hours. The reaction mixture was adjusted to pH < 4 with dilute hydrochloric acid and purified by preparative high-performance liquid chromatography (A: 0.1% TFA aqueous solution, B: acetonitrile) to give white solid D-7 (8.0 mg, 0.0128 mmol, yield 43.6%).

[0537] D-7:MS m / z(ESI):623.3[M+H] +; 1 H NMR (400MHz, CDCl3) δ12.06(br.s,2H),7.31(s,2H),7.17(s,2H),7.06(s,2H),4.15(t,J=6.0Hz,4H),3.9 7(s,6H),3.87(s,6H),2.94(t,J=7.4Hz,4H),2.31(t,J=7.4Hz,4H),2.18-2.25(m,2H),1.81-1.88(m,4H).

[0538] 5. Synthesis of D-8 compounds

[0539] D-6-int-5 (30.0 mg, 93.94 μmol) prepared in step 52 of Example 1 was dissolved in acetonitrile (1.0 mL), and potassium carbonate (39.0 mg, 281.82 μmol) and D-4-int-1 (40.1 mg, 93.94 μmol) were added. The mixture was then stirred at 80 °C for 16 hours. The reaction mixture was filtered and concentrated under high vacuum, and purified by preparative thin-layer chromatography (dichloromethane / methanol = 20 / 1) to give a white solid D-8 (25.0 mg, 37.61 μmol, yield 40.0%).

[0540] D-8: MS m / z (ESI): 665.4 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ7.18(d,J=4.8Hz,2H),7.12(d,J=0.8Hz,2H),6.72(d,J=3 .6Hz,2H),4.29(t,J=6.2Hz,4H),4.14(q,J=7.2Hz,2H),4.02(d,J=7.6Hz,6H),3 .94(d,J=1.4Hz,6H),3.71(s,3H),3.41(dd,J=16.4,7.6Hz,1H),3.07-3.16(m,1 H),2.93-3.06(m,3H),2.39-2.47(m,4H),2.02-2.14(m,2H),1.22-1.30(m,6H).

[0541] 6. Synthesis of D-9 compounds

[0542] Step 1: M-29 (200.0 mg, 0.66 mmol) prepared in Step 18 of Example 1 was dissolved in acetonitrile (5.0 mL) at room temperature, and potassium carbonate (452.7 mg, 3.28 mmol) and 1,4-dibromobutane (707.2 mg, 3.28 mmol) were added. The reaction mixture was then stirred at 80 °C for 16 hours. After the reaction was complete, the mixture was diluted with water (20.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The solution was then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The solution was purified by silica gel column chromatography to give a yellow oil, D-9-int-1 (70.0 mg, 0.16 mmol, yield 5.2%).

[0543] D-9-int-1:MS m / z(ESI):440.3,442.3[M+H] + .

[0544] Step 2: D-9-int-1 (70.0 mg, 0.16 mmol) was dissolved in acetonitrile (5.0 mL) at room temperature, and potassium carbonate (109.85 mg, 0.79 mmol, 5.00 eq) and M-29 (48.54 mg, 0.16 mmol) prepared in step 18 of Example 1 were added. The reaction mixture was then stirred at 80 °C for 16 hours. After the reaction was complete, the reaction mixture was diluted with water (10.0 mL) and then with ethyl acetate (10.0 mL × 3). The solution was then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The solution was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to give D-9 as a white solid (15.0 mg, 0.02 mmol, yield 14.2%).

[0545] D-9: MS m / z (ESI): 665.6 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ7.19(s,2H),7.07(s,2H),6.71(s,2H),4.14–4.17(m,4H),4.02(s,6H),3.94(s,6H),3.71(s,6H),3.41( dd,J=16.4,7.6Hz,2H),3.12(dd,J=13.6,6.4Hz,2H),3.01(dd,J=16.4,6.0Hz,2H),2.10-2.13(m,4H),1.27(d,J=6.8Hz,6H).

[0546] 7. Synthesis of compounds D-10 and D-11

[0547] Step 1: M-29 (1.0 g, 3.28 mmol) and 2-(chloromethyl)ethylene oxide (1.52 g, 16.38 mmol) prepared in Step 18 of Example 1 were dissolved in acetone (15.0 mL), followed by the addition of potassium carbonate (905.3 mg, 6.55 mmol) and tetrabutylammonium bromide (527.91 mg, 1.64 mmol). The mixture was stirred at 60 °C for 16 hours. The mixture was diluted with water (50.0 mL) and extracted with ethyl acetate (50.0 mL × 3). The organic layer was washed with brine, dried over anhydrous Na₂SO₄, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to give a white solid D-10-int-1 (802.0 mg, 2.22 mmol, yield 67.76%).

[0548] D-10-int-1:MS m / z(ESI):362.3[M+H] + .

[0549] Step 2: D-10-int-1 (850.0 mg, 2.35 mmol) was dissolved in a dry solution of N-methylpyrrolidone (15.0 mL), and M-29 (718.14 mg, 2.35 mmol) and potassium carbonate (650.13 mg, 4.70 mmol) prepared in Step 18 of Example 1 were added. The reaction was heated in a microwave oven and stirred at 150 °C for 2 hours. The mixture was filtered and concentrated, and purified by preparative high-performance liquid chromatography (C18, 0.1% formic acid aqueous solution, acetonitrile) to give a white solid D-10 (760.0 mg, 1.14 mmol, yield 48.47%).

[0550] D-10: MS m / z (ESI): 667.6 [M+H] + .

[0551] Step 3: D-10 (760.0 mg, 1.14 mmol) was dissolved in dichloromethane (15.0 mL), and then triethylamine (346.1 mg, 3.42 mmol) and methanesulfonyl chloride (195.87 mg, 1.71 mmol) were added. The mixture was stirred at room temperature for 3 hours. The desired MS was obtained by LC-MS. The mixture was treated with aqueous ammonium chloride solution and extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered and concentrated, and purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to give a grayish-white solid D-11-int-1 (624.0 mg, 837.80 μmol, yield 73.50%).

[0552] D-11-int-1:MS m / z(ESI):745.6[M+H] + .

[0553] Step 4: Dissolve D-11-int-1 (620.0 mg, 832.43 μmol) in a solution of N,N-dimethylformamide (10.0 mL) and add sodium azide (432.9 mg, 6.66 mmol). Stir the mixture at 80 °C for 48 hours. Treat the mixture with water (50.0 mL) and extract with ethyl acetate (20.0 mL × 3), dry with anhydrous sodium sulfate, filter, concentrate, and purify by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to give a grayish-white solid D-11-int-2 (440.0 mg, 636.09 μmol, yield 76.41%).

[0554] D-11-int-2:MS m / z(ESI):692.4[M+H] + .

[0555] Step 5: Dissolve D-11-int-2 (440 mg, 636.09 μmol) in a solution of tetrahydrofuran (10.0 mL) and add Pd / C (45.0 mg, 10% C, moistened with approximately 55% water). Stir the mixture under a hydrogen balloon at room temperature for 6 hours. Filter and concentrate the mixture. Purify the residue by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give a white solid D-11 (350.0 mg, 525.74 μmol, yield 82.65%).

[0556] D-11: MS m / z (ESI): 666.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ7.35(s,2H),7.18(s,2H),7.06(s,2H),4.06(dd,J=9.6,5.6Hz,2H),3.99(t,J=4.8Hz,2H),3.95(s,6H),3.8 7(s,6H),3.59(s,6H),3.48-3.41(m,1H),3.31-3.28(m,2H),3.08(dd,J=17.2,5.2Hz,2H),3.01-2.90(m,2H),1.17(d,J=7.2Hz,6H).

[0557] 8. Synthesis of D-12 compounds

[0558] Step 1: Dissolve D-11 (73.6 mg, 0.11 mmol) prepared in Part 7 of this example in 1.0 mL of tetrahydrofuran. Add Ac2O (33.8 mg, 0.33 mmol) and DIPEA (21.4 mg, 0.17 mmol) to the solution and react at 25 °C for 2 hours. After evaporating the solvent, purify the crude product by rapid column chromatography to obtain the white product D-12-int-1 (61.5 mg, 86.9 μmol), with a yield of 79%.

[0559] Step 2: Dissolve D-12-int-1 (28.4 mg, 40 μmol) in 0.5 mL of DMF. Add 0.4 mL of tert-butanol and 0.2 mL of water to the solution, then add lithium hydroxide (2.9 mg, 0.12 mmol). Stir the reaction mixture at 25 °C for 6 hours. After the reaction is complete, add 0.12 mL of HCl (1.0 N) to neutralize the reaction solution to pH 7.0. Extract three times with 3 mL of water and 5 mL of ethyl acetate. Wash the organic layer with saturated brine and concentrate to obtain D-12 in 87% yield.

[0560] D-12: MS m / z (ESI): 680.6 [M+H] + HRMS m / z: 680.3183 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ8.22(s,1H),8.22(d,J=7.5Hz,1H),7.34(d,J=3.1Hz,2H),7.34(d,J=3. 1Hz,2H),7.24(d,J=2.7Hz,2H),7.24(d,J=2.7Hz,2H),7.07(s,2H),7.07(s,2H),4.13(d,J=5.6 Hz,4H),3.96(s,6H),3.86(s,6H),3.41–3.21(m,22H),3.07–2.93(m,2H),2.88(dd,J=8.1,4.8H z,2H),2.50(dt,J=3.6,1.8Hz,25H),1.90(s,3H),1.24(d,J=8.4Hz,5H),1.16(d,J=7.2Hz,6H).

[0561] 9. Synthesis of D-13 compounds

[0562] The D-11 (11.2 mg, 16.8 μmol) prepared in Part 7 of this example was dissolved in 0.2 mL of tert-butanol and 0.1 mL of water. Lithium hydroxide (1.2 mg, 0.05 mmol) was added. The reaction mixture was stirred at 25 °C for 6 hours. After the reaction was completed, 0.05 mL of HCl (1.0 N) was added to neutralize the reaction solution to pH 7.0. The mixture was extracted three times with 3 mL of water and 5 mL of ethyl acetate. The organic layer was washed with saturated brine and concentrated to give a white solid D-13 (7.8 mg, 12.2 μmol, yield 73%).

[0563] D-13: MS m / z (ESI): 638.56 [M+H] + HRMS m / z: 638.2714 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ12.12(s,2H),8.38(s,3H),7.41(s,2H),7.30(s,2H),7.13(s,2H),4.29(ddd,J=16.3,10.5,5.2Hz,4H),3.97(s,7H),3.89 (s,6H),3.29(d,J=8.4Hz,2H),3.00(dd,J=16.9,5.4Hz,2H),2.93–2.82(m,2H),2.00(dd,J=14.7,7.2Hz,1H),1.23(s,2H),1.17(d,J=7.2Hz,6H).

[0564] 10. Synthesis of D-14 compounds

[0565] Step 1: Dissolve D-11 (148.1 mg, 0.22 mmol) prepared in Part 7 of this example in 1.0 mL of tetrahydrofuran, add Boc2O (72.8 mg, 0.33 mmol), and stir at 25 °C for 2 hours. After evaporation and concentration, rapid column chromatography yields a white solid D-14-int-1 (113 mg, 0.15 mmol), in 66% yield.

[0566] Step 2: Dissolve D-14-int-1 (24.5 mg, 32 μmol) in 0.9 mL of tert-butanol and 0.3 mL of water. Add lithium hydroxide (0.3 mg, 0.1 mmol). Stir the reaction mixture at 25 °C for 6 hours. After the reaction is complete, add 0.05 mL of HCl (1.0 N) to neutralize the reaction solution to pH 7.0. Add 3 mL of water and 5 mL of ethyl acetate for extraction three times. Wash the organic layer with saturated brine and concentrate to obtain the crude product D-14-int-2.

[0567] Step 3: Dissolve the crude product D-14-int-2 obtained in Step 2 in 1.0 mL of DMF, add HATU (18.2 mg, 0.05 mmol), 3-amino-1-propanol (9.6 mg, 0.13 mmol), and DIPEA (16.5 mg, 0.13 mmol), stir at 25 °C for 4 hours, and then evaporate and concentrate the reaction solution to obtain the crude product D-14-int-3.

[0568] Step 4: Add the crude product D-14-int-3 obtained in Step 3 to 0.6 ml of 5% TFA / DCM and stir for 2 hours. After the reaction is complete, concentrate the reaction solution and purify it by rapid column chromatography to obtain a white solid D-14 (13.4 μmol).

[0569] D-14: MS m / z (ESI): 752.61 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ7.84(t,J=5.6Hz,2H),7.35(s,2H),7.25(s,2H),7.09(s,2H ),4.38(s,2H),4.16(ddd,J=27.2,9.9,5.5Hz,4H),3.96(s,6H),3.88(s,6H),3.75–3 .67(m,1H),3.38(dd,J=10.3,6.0Hz,4H),3.25(td,J=9.9,4.9Hz,2H),3.07(q,J=6. 7Hz, 4H), 2.85 (dt, J=10.9, 6.1Hz, 4H), 1.52 (p, J=6.6Hz, 4H), 1.08 (d, J=6.6Hz, 6H).

[0570] 11. Synthesis of compounds D-15, D-16 and D-17

[0571] The D-4 prepared in Part 3 of this embodiment was subjected to chiral resolution to obtain chiral pure compounds D-15, D-16, and D-17. Chiral resolution conditions: System Waters UPCC; Column name DAICEL Column size 100*3mm 3μm; Mobile Phase A Supercritical CO2; Mobile Phase B MeOH (0.1%DEA):ACN=1:1; Wavelength 214nm; Flow 1.5mL / min; Column temp 35℃; Back Pressure (psi) 1800psi.

[0572] 12. Synthesis of compounds D-18, D-19 and D-20

[0573] The D-15 (26 mg, 0.04 mmol) prepared in Part 10 of this embodiment was dissolved in a mixed solvent of tetrahydrofuran / dimethyl sulfoxide / dichloromethane / methanol / water (0.20 mL / 0.40 mL / 0.20 mL / 0.20 mL / 0.20 mL). Lithium hydroxide (3.8 mg, 0.16 mmol) was added under stirring, and the system was stirred at room temperature for 16 hours. After completion, 1.0 M dilute hydrochloric acid was added to adjust the pH to 2-3, and dichloromethane (40 mL × 3) was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and washed with acetone (10 mL × 3). The filtrate was concentrated, and the remaining solvent was removed using a high-vacuum oil pump. The product residue was then purified by slurrying with n-hexane / dichlorohexane to obtain most of the target product. The mother liquor was filtered, concentrated, and further purified by preparative liquid chromatography to obtain a small amount of the target product. The two are combined and then dried in a freeze dryer to obtain a creamy white or light yellow solid, D-18.

[0574] The reaction is performed in the same manner as the synthesis of D-18 described above, using D-17 prepared in Part 10 of this example as the raw material, to obtain a light yellow solid D-19.

[0575] The reaction is performed in the same manner as the synthesis of D-18 described above, using D-16 prepared in Part 10 of this example as the raw material, to obtain a light yellow solid, D-20.

[0576] Chiral analysis conditions: Column IC-3 (IC30CE-PH006); Column size 0.46cm ID MeOH50% EtOH 50%; HPLC Shimadzu LC 20A QA&QC-HPLC-12.

[0577] 13. Synthesis of compounds D-21 and D-22

[0578] Step 1: Dissolve 3.1 g of 5-(benzyloxy)-6-methoxy-1-methyl-1H-indole-2-carboxylic acid (10 mmol), 4.6 g of HATU (12 mmol), and 2.6 g of DIPEA (20 mmol) in 310 mL of THF and react at room temperature for 1 h. Add 2.4 g of methyl 3-(methylamino)propionate (20 mmol) to the reaction solution, heat to 60 °C, and react for 12 h. After the reaction is complete, cool the reaction solution to room temperature, pour it into water, extract with ethyl acetate, combine the organic layers, and wash the organic layer with 1N HCl aqueous solution. Dry the organic layer, concentrate it, and separate it by column chromatography to obtain 2.5 g of D-21-int-1.

[0579] Step 2: Dissolve 2.1 g of D-21-int-1 (5.1 mmol) in 40 mL of methanol, add 0.2 g of 10% Pd / C (10% wt.), heat to 50 °C, and react under a hydrogen balloon for 12 h. After the reaction is complete, filter, concentrate the filtrate, and precipitate by column chromatography to obtain 1.3 g of D-21-int-2.

[0580] Step 3: Dissolve 640 mg D-21-int-2 (2.0 mmol) and 2.0 g 1,3-dibromopropane (10.0 mmol) in 20 mL of acetonitrile, add 828 mg potassium carbonate (6.0 mmol) in portions, heat to 70 °C, and react for 16 h. After the reaction is complete, filter, concentrate the filtrate, and precipitate by column chromatography to obtain 441 mg D-21-int-3.

[0581] Step 4: Dissolve 440 mg D-21-int-3 (1.0 mmol), 640 mg intermediate D-21-int-3 (2.0 mmol), and 414 mg potassium carbonate (3.0 mmol) in 30.0 mL of DMF, heat to 70 °C, and react for 16 h. After the reaction is complete, dilute with water, extract with ethyl acetate, combine the organic layers, dry, concentrate, and obtain 347 mg D-21 by column chromatography.

[0582] D-21:HRMS(ESI)m / z:[M+Na] + Calcd for C 35 H 44 N4NaO 10 703.2955; Found 703.2954; 1H NMR (600MHz, DMSO-d6) δ7.12(s,2H),7.04(s,2H),6.52(s,2H),4.13(t,J=6.2Hz,4H),3.83(s,6H),3. 76–3.71(m,4H),3.69(s,6H),3.59(s,6H),3.04(s,6H),2.66(t,J=7.1Hz,2H),2.18(p,J=6.3Hz,2H).

[0583] Step 5: Dissolve 136 mg D-21 (0.2 mmol) in a mixed solvent of 3.0 mL THF, 3.0 mL MeOH, and 1.0 mL H2O. Add 24 mg LiOH (1.0 mmol) in portions, heat to 50 °C, and react for 12 h. After the reaction is complete, cool the reaction solution to room temperature, concentrate it, pour the residue into water, adjust the pH to 1-2 with 1N HCl aqueous solution, extract with ethyl acetate, combine the organic layers, dry, concentrate, and separate by column chromatography to obtain 56 mg D-22.

[0584] D-22:HRMS(ESI)m / z:[M+H] + Calcd for C 33 H 41 N4O 10 653.2823; Found 653.2823; 1 H NMR(600MHz,DMSO-d6)δ7.11(s,2H),7.04(s,2H),6.49(s,2H),4.14(t,J=6.2Hz,4H),3.8 3(s,6H),3.69(s,6H),3.68(s,4H),3.03(s,6H),2.55–2.50(m,4H),2.17(p,J=6.2Hz,1H).

[0585] 14. Synthesis of compounds D-23 and D-24

[0586] Step 1: Dissolve 3.1 g of 5-(benzyloxy)-6-methoxy-1-methyl-1H-indole-2-carboxylic acid (10 mmol), 4.6 g of HATU (12 mmol), and 5.2 g of DIPEA (40 mmol) in 310 mL of THF and react at room temperature for 1 h. Add 2.48 g of methyl 3-aminopropionate hydrochloride (20 mmol) to the reaction solution, heat to 60 °C, and react for 12 h. After the reaction is complete, cool the reaction solution to room temperature, pour it into water, extract with ethyl acetate, combine the organic layers, and wash the organic layer with 1N HCl aqueous solution. Dry the organic layer, concentrate it, and separate it by column chromatography to obtain 2.8 g of D-23-int-1.

[0587] Step 2: Dissolve 2.0 g of intermediate D-23-int-1 (5.1 mmol) in 40 mL of methanol, add 0.2 g of 10% Pd / C (10% wt.), heat to 50 °C, and react under a hydrogen balloon for 12 h. After the reaction is complete, filter, concentrate the filtrate, and precipitate by column chromatography to obtain 1.3 g of D-23-int-2.

[0588] Step 3: Dissolve 612 mg D-23-int-2 (2.0 mmol) and 2.0 g 1,3-dibromopropane (10.0 mmol) in 20 mL of acetonitrile, add 828 mg potassium carbonate (6.0 mmol) in portions, heat to 70 °C, and react for 16 h. After the reaction is complete, filter, concentrate the filtrate, and obtain 556 mg D-23-int-3 by column chromatography.

[0589] Step 4: Dissolve 426 mg of intermediate D-23-int-3 (1.0 mmol), 612 mg of intermediate D-23-int-2 (2.0 mmol), and 414 mg of potassium carbonate (3.0 mmol) in 30.0 mL of DMF, heat to 70 °C, and react for 16 h. After the reaction is complete, dilute with water, extract with ethyl acetate, combine the organic layers, dry and filter, and obtain 196 mg of D-23 by column chromatography.

[0590] D-23:purity:94%; HRMS(ESI)m / z:[M+H] + Calcd for C 33 H 41 N4O 10 653.2823; Found 653.2823; 1H NMR (600MHz, DMSO-d6) δ8.37(t,J=5.7Hz,2H),7.13(s,2H),7.03(s,2H),6.91(s,2H),4.13(t,J= 6.2Hz, 4H), 3.92 (s, 6H), 3.82 (s, 3H), 3.60 (s, 6H), 2.58 (t, J = 7.0Hz, 4H), 2.18 (p, J = 6.2Hz, 2H).

[0591] Step 5: Dissolve 130 mg D-23 (0.2 mmol) in a mixed solvent of 3.0 mL THF, 3.0 mL MeOH, and 1.0 mL H2O. Add 24 mg LiOH (1.0 mmol) in portions, heat to 50 °C, and react for 12 h. After the reaction is complete, cool the reaction solution to room temperature, pour it into water, adjust the pH to 1-2 with 1 N HCl aqueous solution, extract with ethyl acetate, combine the organic layers, dry, concentrate, and separate by column chromatography to obtain 62 mg D-24.

[0592] D-24:purity:97%; HRMS(ESI)m / z:[M+H] + Calcd for C 31 H 37 N4O 10 625.2510; Found 625.2508; 1 H NMR(600MHz,DMSO-d6)δ12.11(s,2H),8.34(t,J=5.6Hz,2H),7.14(s,2H),7.04(s,2H),6.93(s,2 H), 4.14 (t, J = 6.3Hz, 4H), 3.94 (s, 6H), 3.83 (s, 6H), 3.43 (q, J = 6.9Hz, 4H), 2.50 (p, J = 6.3Hz, 2H).

[0593] 15. Synthesis of compounds D-25 and D-26

[0594] Step 1: Dissolve 440 mg of intermediate D-21-int-3 (1.0 mmol) prepared in step 13 of Example 2, 610 mg of M-29 (2.0 mmol) prepared in step 18 of Example 1, and 414 mg of potassium carbonate (3.0 mmol) in 30.0 mL of DMF. Heat to 70 °C and react for 16 h. After the reaction is complete, cool to room temperature, dilute with water, extract with ethyl acetate, combine the organic layers, dry, concentrate, and obtain 228 mg of D-25 by column chromatography.

[0595] D-25:purity:99%; HRMS(ESI)m / z:[M+H] + Calcd for C 35 H 44 N3O 10 666.3027; Found 666.3027; 1 H NMR(600MHz,DMSO-d6)δ7.36(s,1H),7.17(s,1H),7.13(s,1H),7.05(s,2H),6 .52(s,1H),4.17–4.12(m,4H),3.95(s,3H),3.86(s,3H),3.84(s,3H),3.74(br s,3H),3.70(s,3H),3.60(s,3H),3.59(s,3H),3.34–3.29(m,2H),3.08(dd,J=17.0,5.4Hz,1H), 3.05(s,2H),2.98–2.91(m,1H),2.66(t,J=7.1Hz,2H),2.23–2.17(m,2H),1.17(d,J=7.1Hz,3H).

[0596] Step 2: Dissolve 133 mg D-25 (0.2 mmol) in a mixed solvent of 6.0 mL THF, 6.0 mL MeOH, and 2.0 mL H2O. Add 24 mg LiOH (1.0 mmol) in portions, heat to 50 °C, and react for 12 h. After the reaction is complete, cool the reaction solution to room temperature, concentrate it, pour the residue into water, adjust the pH to 1-2 with 1 N HCl aqueous solution, extract with ethyl acetate, combine the organic layers, dry, concentrate, and separate by column chromatography to obtain 45 mg D-26.

[0597] D-26:purity:96%;HRMS(ESI)m / z:[M+Na] + Calcd for C 33 H 39 N3NaO 10 660.2533; Found 660.2515; 1H NMR(600MHz,DMSO-d6)δ12.23(s,2H),7.36(s,1H),7.18(s,1H),7.14(s,1H),7.06(s,1H),7 .06(s,1H),6.52(s,1H),4.17–4.12(m,4H),3.97(s,3H),3.87(s,3H),3.84(s,3H),3.71(br s,3H),3.71(s,3H),3.34–3.29(m,1H),3.05(br s,2H),2.99(dd,J=16.8,5.5Hz,1H),2.92–2.85(m,1H),2.58(t,J=7.2Hz,2H),2.21(p,J=6.3Hz,2H),1.17(d,J=7.2Hz,3H).

[0598] 16. Synthesis of compounds D-27 and D-28

[0599] The D-26 prepared in step 15 of Example 2 was separated by a chiral column to obtain D-27 (ee value 98%) and D-28 (ee value 98%). Separation conditions: Column: CHIRALCEL OZ-H (OZH0CE-BO005); Column size: 0.46 cm ID × 25 cm L; Mobile phase: MeOH / FAc = 100 / 0.1 (V / V); Flow rate: 1.0 ml / min; Wave length: UV 365 nm; Temperature: 35℃; Shimadzu LC-20AT CP-HPLC-09.

[0600] 17. Synthesis of compound D-29

[0601] The D-5 (17.2 mg, 27.6 μmol) prepared in Part 3 of this example was dissolved in 1.0 mL of DMF. HATU (42 mg, 0.11 mmol), 3-amino-1-propanol (8.3 mg, 0.11 mmol), and DIPEA (17.8 mg, 0.14 mmol) were added to the solution, and the reaction was carried out at 25 °C for 4 hours. After concentration, the crude product was purified by rapid column chromatography to obtain a white solid D-29 (9.4 mg, 12.8 μmol, 47% yield).

[0602] D-29: MS m / z (ESI): 737.67 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ7.83(t,J=5.6Hz,2H),7.32(s,2H),7.18(s,2H),7.05(s ,2H),4.38(t,J=5.3Hz,2H),4.16(t,J=6.2Hz,4H),3.95(s,6H),3.87(s,6H),3. 38(dd,J=11.6,6.2Hz,4H),3.23(d,J=8.2Hz,2H),3.07(q,J=6.4Hz,4H),2.84(d t,J=6.0,5.4Hz,4H),2.22(s,2H),1.52(t,J=6.6Hz,4H),1.07(d,J=6.6Hz,6H).

[0603] 18. Synthesis of D-30 compound

[0604] The D-5 (23.4 mg, 37.6 μmol) prepared in Part 3 of this example was dissolved in 12 mL of DMF. HATU (14.3 mg, 37.6 μmol), 3-amino-1-propanol (2.8 mg, 37.6 μmol), and diisopropylamine (4.8 mg, 37.6 μmol) were added to the solution, and the reaction was carried out at 25 °C for 4 hours. After concentration, the crude product was purified by rapid column chromatography to obtain a white solid D-30 (4.8 mg, 7.1 μmol, 19% yield).

[0605] D-30: MS m / z (ESI): 680.6 [M+H] + ; 1 H NMR (600MHz, DMSO-d6) δ12.11(s,1H),7.83(t,J=5.7Hz,1H),7.35(s,1H),7.32(s,1H),7.18(d,J=1.7 Hz,3H),7.05(d,J=5.6Hz,2H),4.16(s,4H),3.95(d,J=5.2Hz,6H),3.87(d,J=1.5Hz,6H),3.38(d,J=6. 3Hz,2H),3.23(dd,J=15.2,6.9Hz,2H),3.07(td,J=7.0,2.3Hz,2H),2.90–2.79(m,2H),2.23(dd,J=12 .3,6.1Hz,2H),1.99–1.95(m,2H),1.52(p,J=6.6Hz,2H),1.16(d,J=7.2Hz,3H),1.07(d,J=6.7Hz,3H).

[0606] 19. Synthesis of compound D-31

[0607] The D-5 (40 mg, 64.3 μmol), N,N'-dicyclohexylcarbodiimide (39.8 mg, 192.9 μmol), 4-dimethylaminopyridine (1.6 mg, 12.8 μmol), and benzyl alcohol (27.8 mg, 257.2 μmol) prepared in Part 3 of this embodiment were dissolved in dichloromethane (1 mL). After stirring the reaction solution for 12 hours, the pH was adjusted to approximately 3 with dilute hydrochloric acid. The solution was then crudely purified using a silica gel column, and further purified using the pre-prepared solution to obtain D-31 (42 mg, 52.3 μmol, 81% yield).

[0608] D-31: 1 H NMR (400MHz, CDCl3) δ7.34–7.27(m,10H),7.17(s,2H),7.11(s,2H),6.71(s,2H),5.13(q,J=12.4Hz,4H),4.30(t,J=6.2Hz,4H),3.99(s,6H ),3.94(s,6H),3.42(dd,J=16.4,7.8Hz,2H),3.27–3.12(m,2H),3.01(dd,J=16.5,5.9Hz,2H),2.43(p,J=6.2Hz,2H),1.29(d,J=7.1Hz,6H); 13 C NMR (101MHz, CDCl3) δ190.36,175.85,151.36,145.56,136.11,133.51,128.47,128.06,1 28.02,118.73,111.63,105.13,92.12,66.43,66.36,56.13,42.65,35.54,32.40,17.22.

[0609] 20. Synthesis of compound D-32

[0610] The D-5 (40 mg, 64.3 μmol), N,N'-dicyclohexylcarbodiimide (39.8 mg, 192.9 μmol), 4-dimethylaminopyridine (1.6 mg, 12.8 μmol), and isopropanol (15.5 mg, 257.2 μmol) prepared in Part 3 of this embodiment were dissolved in dichloromethane (1 mL). After stirring the reaction solution for 12 hours, the pH was adjusted to approximately 3 with dilute hydrochloric acid. The solution was then crudely purified using a silica gel column chromatography method, and further purified using the pre-prepared solution to obtain D-32 (14 mg, 19.3 μmol, 30% yield).

[0611] D-32: 1H NMR (600MHz, CDCl3) δ7.19(s,2H),7.12(s,2H),6.72(s,2H),5.01(hept,J=6.2Hz,2H),4.30(t,J=6.2Hz,4H),4.02(s,6H),3.94(s,6H),3.38( dd,J=16.4,7.7Hz,2H),3.10–3.02(m,2H),2.97(dd,J=16.4,6.1Hz,2H),2.43(p,J=6.1Hz,2H),1.26(d,J=7.1Hz,6H),1.22(t,J=6.6Hz,12H); 13 C NMR (151MHz, CDCl3) δ190.60,175.54,151.30,145.54,136.07,133.60,118.73,111.56 ,105.15,92.14,67.69,66.43,56.12,42.68,35.70,32.40,29.31,21.76,21.74,17.24.

[0612] 21. Synthesis of compound D-33

[0613] The D-5 (40 mg, 64.3 μmol), N,N'-dicyclohexylcarbodiimide (39.8 mg, 192.9 μmol), 4-dimethylaminopyridine (1.6 mg, 12.8 μmol), and isobutanol (19.0 mg, 257.2 μmol) prepared in Part 3 of this embodiment were dissolved in dichloromethane (1 mL). After stirring the reaction solution for 12 hours, the pH was adjusted to approximately 3 with dilute hydrochloric acid. The solution was then crudely purified using a silica gel column, and further purified using the pre-prepared solution to obtain D-33 (12 mg, 16.1 μmol, 25% yield).

[0614] D-33: 1 H NMR (600MHz, CDCl3) δ7.19(s,2H),7.12(s,2H),6.72(s,2H),4.30(hept,J=6.2Hz,4H),4.02(s,6H),3.94(s,6H),3.88(t,J=6.2Hz,4H),3.41(dd,J=1 6.4,7.7Hz,2H),3.17–3.10(m,2H),2.99(dd,J=16.4,6.1Hz,2H),2.48–2.4 0(m,2H),1.98–1.88(m,2H),1.28(d,J=7.1Hz,6H),0.91(t,J=6.6Hz,12H); 1H NMR (600MHz, CDCl3) δ7.19,7.12,6.72,4.30,4.30,4.30,4.28,4.01,3.94,3.91,3.90,3.90,3.89,3.88,3.87,3.87,3.86,3.43,3.42,3.4 0,3.39,3.15,3.15,3.14,3.13,3.11,3.10,3.01,3.00,2.98,2.97,2 .44,2.43,2.41,1.95,1.94,1.92,1.90,1.29,1.28,0.91,0.91,0.91.

[0615] 22. Synthesis of positive control compound D-34 and positive control compound D-35

[0616] Step 1: To a solution of 2-fluoro-4,5-dimethoxybenzaldehyde (5.0 g, 27.15 mmol) in DMF (100.0 mL), ethyl mercaptoacetate (3.5 g, 32.97 mmol) and K₂CO₃ (13.4 g, 97.10 mmol) were added, and the mixture was stirred at 60 °C for 16 hours. The mixture was extracted with EtOAc (100.0 mL x 3) and H₂O (200.0 mL), the organic phase was dried and concentrated, and purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to give a yellow solid D-34-int-1 (5.6 g, 22.20 mmol, yield 81.8%).

[0617] D-34-int-1:MS m / z(ESI):253.1[M+H]+.

[0618] Step 2: Dissolve D-34-int-1 (5.6 g, 22.20 mmol) in THF (50.0 mL), and add a solution of LiOH (4.7 g, 196.24 mmol) in H2O (25.0 mL) dropwise at 0 °C. Raise the reactants from 0 °C to room temperature and stir for 16 h. Quench the reaction with ice water (100.0 mL), adjust the pH to 1-2 with HCl (1N) at 0 °C, extract the mixture with EtOAc (50.0 mL x 3), dry and concentrate the organic layer. Purify the residue by column chromatography (petroleum ether: ethyl acetate = 1:1) to give D-34-int-2 (3.2 g, 13.43 mmol, yield 69.5%) as a white solid.

[0619] D-34-int-2: 1H NMR (400MHz, DMSO-d6) δ7.94(s,1H),7.58(s,1H),7.48(s,1H),3.85(s,3H),3.82(s,3H).

[0620] Step 3: Cu₂O (7.7 g, 53.72 mmol) was added to a solution of D-34-int-2 (3.2 g, 13.43 mmol) in DMF (60.0 mL), and the reaction mixture was stirred at 140 °C for 16 hours. After cooling to room temperature, the mixture was extracted with EtOAc (100.0 mL x 3) and H₂O (200.0 mL), and the EtOAc layer was dried and concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 30:1) to give D-34-int-3 (2.4 g, 12.36 mmol, yield 92.0%) as a white solid.

[0621] D-34-int-3:MS m / z(ESI):195.2[M+H] + .

[0622] Step 4: At 0°C, 3,3-dimethyltetrahydrofuran-2,5-dione (1.7 g, 13.38 mmol) was added dropwise to a DCM solution (25.0 mL) containing D-34-int-3 (1.3 g, 6.69 mmol) and aluminum trichloride (1.8 g, 13.38 mmol). The reaction mixture was heated from 0°C to room temperature and stirred for 16 h. The reaction was quenched with ice water (50.0 mL) and extracted with DCM (20 mL x 3). The DCM layer was dried and concentrated to give a pale yellow solid D-34-int-4 (1.2 g, 3.72 mmol, yield 55.6%).

[0623] D-34-int-4:MS m / z(ESI):323.1[M+H] + .

[0624] Step 5: Iodomethane (1.1 g, 7.63 mmol) was added dropwise to a solution of D-34-int-4 (0.8 g, 2.54 mmol), potassium carbonate (703.1 mg, 5.09 mmol, 2.00 eq) in DMF (2.0 mL). The reaction mixture was stirred at room temperature for 16 hours. The mixture was diluted in H2O (40.0 mL), extracted with EtOAc (20.0 mL x 3), the EtOAc layer was dried and concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to give a yellow solid D-34-int-5 (560.0 mg, 1.66 mmol, 65.5% yield).

[0625] D-34-int-5:MS m / z(ESI):337.1[M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ8.18(s,1H),7.59(s,1H),7.45(s,1H),3.86(s,3H),3.84(s,3H),3.57(s,3H),3.36(s,2H),1.24(s,6H).

[0626] Step 6: Aluminum trichloride (4.0 g, 29.73 mmol) was added in portions to a solution of D-34-int-5 (1.0 g, 2.97 mmol) in DCM (20.0 mL) at room temperature, and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with H2O (40.0 mL), extracted with DCM (20.0 mL x 3), the DCM layer was dried and concentrated. The residue was purified by SFC to give D-34-int-6 (158.0 mg, 490.11 μmol, yield 16.5%) as a white solid.

[0627] D-34-int-6:MS m / z(ESI):323.1[M+H]+; 1 H NMR (400MHz, DMSO-d6) δ9.40(s,1H),8.14(s,1H),7.54(s,1H),7.31(s,1H),3.87(s,3H),3.57(s,3H),3.34(s,2H),1.24(s,6H).

[0628] Step 7: To a solution of D-34-int-6 (50.0 mg, 155.10 μmol) in MeCN (2.0 mL), add 1,3-dibromopropane (93.9 mg, 465.30 μmol) and K₂CO₃ (42.9 mg, 310.20 μmol) and stir at 60 °C for 16 hours. After cooling to room temperature, concentrate the mixture. Purify the residue by preparative TLC (petroleum ether: ethyl acetate = 3:1) to give D-34-int-7 (67.0 mg, 151.12 μmol, 97.4% yield) as a white solid.

[0629] D-34-int-7:MS m / z(ESI):445.1[M+H]+.

[0630] Step 8: Add D-34-int-6 (41.5 mg, 128.57 μmol) and K2CO3 (35.5 mg, 257.13 μmol) to a solution of D-34-int-7 (57.0 mg, 128.57 μmol) in MeCN (2.0 mL), and stir at 60 °C for 16 hours. After cooling to room temperature, concentrate the mixture. The residue was purified by preparative TLC (petroleum ether: ethyl acetate = 3:1) to give a white solid D-34 (60.0 mg, 87.61 μmol, yield 68.2%).

[0631] D-34: MS m / z (ESI): 685.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ8.14(s,2H),7.61(s,2H),7.51(s,2H),4.23(t,J=6.0H z,4H),3.86(s,6H),3.57(s,6H),3.35(s,4H),2.36-2.21(m,2H),1.24(s,12H).

[0632] Step 9: Dissolve D-34 (55.0 mg, 80.31 μmol) in THF (2.0 mL), MeOH (1.0 mL), and add dropwise a solution of LiOH (9.6 mg, 401.57 μmol) in H₂O (1.0 mL). Stir the mixture at room temperature for 16 h. Concentrate the mixture, dilute the residue in ice water (5.0 mL), adjust the pH to 1-2 with HCl (1N), extract the mixture with EtOAc (5.0 mL x 3), dry and concentrate the EtOAc layer. Purify the residue by preparative HPLC to give D-35 (1.8 mg, 2.80 μmol, yield 3.5%) as a white solid.

[0633] D-35: MS m / z (ESI): 655.0 [MH] - ; 1 H NMR(400MHz,DMSO-d6)δ12.05(s,2H),8.13(s,2H),7.60(s,2H),7.52(s,2H), 4.23(s,4H),3.86(s,6H),3.29(s,4H),2.31(d,J=15.8Hz,2H),1.23(s,12H).

[0634] 23. Synthesis of compounds D-36 and D-37

[0635] Step 1: Dissolve intermediate M-29 (3.05 g, 10 mmol), potassium carbonate (3.45 g, 25 mmol), and benzyl bromide (1.43 mL, 12 mmol) in acetonitrile (20 mL). After stirring the reaction solution for 12 hours, crudely purify it by silica gel column chromatography to obtain D-36-int-1 (3.6 g, 9.11 mmol, yield 91%).

[0636] Step 2: D-36-int-1 (3.6 g, 9.11 mmol) and lithium hydroxide (875 mg, 36.4 mmol) were dissolved in THF / MeOH / H2O (50 mL / 25 mL / 25 mL) and stirred for 12 hours. After concentration, the reaction solution was purified directly by rapid column chromatography (300-400 mesh silica gel, dichloromethane / methanol = 20 / 1) to obtain D-36-int-1 (3.2 g, 8.4 mmol, yield 92%).

[0637] Step 3: D-36-int-1 (200 mg, 525 μmol), 1-hydroxybenzotriazole (85.3 mg, 631 μmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (118.1 mg, 616 μmol) were dissolved in dichloromethane (1.6 mL) and activated for 10 minutes. Then, ammonium chloride (41.7 mg, 780 μmol) and triethylamine (108 μL, 777 μmol) were added to the above reaction solution. After stirring the reaction solution for 12 hours, D-36-int-2 (131 mg, 345 μmol, yield 66%) was crudely purified by silica gel column chromatography.

[0638] Step 4: Add a mixture of D-36-int-2 (131 mg, 345 μmol) and methanol / dichloromethane (5.0 mL / 0.5 mL) to a vial, add one drop of water while stirring, and then add palladium / carbon (13.1 mg, 10% wt in 55% H2O). Insert a hydrogen balloon into the reaction apparatus and stir the system at 23°C for 2.0-2.5 hours. Filter the reaction mixture directly through a sintered glass funnel containing diatomaceous earth, wash with dichloromethane, concentrate the filtrate, and perform direct rapid column chromatography (300-400 mesh silica gel, methanol / dichloromethane = 10 / 90) to obtain D-36-int-3 (78.3 mg, 270 μmol, yield 78%).

[0639] Step 5: Add D-36-int-3 (78.3 mg, 270 μmol), anhydrous N,N'-dimethylformamide (0.5 mL), and anhydrous potassium carbonate (111.8 mg, 810 μmol) to the vial. The reaction system was stirred at 65°C for 1.0 h, and then an anhydrous N,N'-dimethylformamide solution (0.5 mL) of D-1-int-1 (172 mg, 405 μmol) obtained in step 1 was added. The mixture was stirred at 65°C for another 16 h, diluted with 10 mL of ethyl acetate, quenched dropwise with 10 mL of water, and then the pH was adjusted to 4-5 with 1.0 M dilute hydrochloric acid. The mixture was extracted with ethyl acetate (30 mL × 3), and the organic phases were combined. The mixture was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by direct rapid column chromatography (300-400 mesh silica gel, methanol / dichloromethane = 5 / 95) to obtain D-36 (78.3 mg, 123 μmol, 46% yield).

[0640] D-36: 1 H NMR (400MHz, CDCl3) δ7.20 (s, 1H), 7.18 (s, 1H), 7.11 (s, 2H), 6.71 (d, J = 3.5Hz, 2 H),5.86(brs,1H),5.31(brs,1H),4.29(t,J=6.0Hz,4H),4.02(s,6H),3.94(s,6H ),3.71(s,3H),3.49–3.35(m,2H),3.11(dq,J=14.4,7.2Hz,1H),3.02(qd,J=12.5 ,4.9Hz,3H),2.43(p,J=6.2Hz,2H),1.28(d,J=1.4Hz,3H),1.27(d,J=1.9Hz,3H); 13 C NMR (101MHz, CDCl3) δ191.11,190.43,178.35,176.61,151.45,151.35,145.59,145.55,136.21,136.11,133.43,133.38,118.7 5,118.72,112.09,111.62,105.08,92.12,92.05,66.37,56.11,51.91,43.27,42.70,35.75,35.29,32.41,29.28,17.93,17.25.

[0641] Step 6: Dissolve D-36 (20 mg, 31.5 μmol) and lithium hydroxide (3 mg, 125 μmol) in THF / MeOH / H₂O (0.5 mL / 0.25 mL / 0.25 mL) and stir for 12 hours. After concentrating the reaction solution, perform direct rapid column chromatography (300-400 mesh silica gel, dichloromethane / methanol = 20 / 1) to obtain D-37.

[0642] 24. Synthesis of compounds D-38 and D-39

[0643] Step 1: Dissolve D-36-int-1 (100 mg, 253 μmol), pyridine (28.8 μL, 356 μmol), and hydroxylamine hydrochloride (46.2 mg, 655 μmol) obtained in Step 23 in ethanol (1.14 mL). After stirring the reaction solution at 60 °C for 12 hours, crudely purify it by silica gel column chromatography to obtain D-38-int-1 (70 mg, 171 μmol, 67% yield).

[0644] Step 2: D-38-int-1 (70 mg, 171 μmol), N,N'-dicyclohexylcarbodiimide (52.8 mg, 256 μmol), 4-dimethylaminopyridine (2 mg, 16 μmol), and acetic acid (14.6 μL, 255 μmol) were dissolved in dichloromethane (2 mL). After stirring the reaction solution for 12 hours, D-38-int-2 (64 mg, 142 μmol, yield 68%) was crudely purified by silica gel column chromatography.

[0645] Step 3: Add a mixture of D-38-int-2 (64 mg, 142 μmol) and methanol / dichloromethane (5.0 mL / 0.5 mL) to a vial. Add one drop of water while stirring, followed by palladium / carbon (6.4 mg, 10% wt in 55% H2O). Insert a hydrogen balloon into the reaction apparatus and stir the system at 23°C for 2.0–2.5 hours. Filter the reaction mixture directly through a sintered glass funnel containing diatomaceous earth, wash with dichloromethane, concentrate the filtrate, and perform direct rapid column chromatography (300–400 mesh silica gel, petroleum ether / acetone = 4 / 1–3 / 1) to obtain D-38-int-3 (16.9 mg, 46.7 μmol, 33% yield).

[0646] Step 4: Add D-38-int-3 (16.9 mg, 46.7 μmol), anhydrous N,N'-dimethylformamide (0.5 mL), and anhydrous potassium carbonate (19.3 mg, 140 μmol) to the vial. The reaction system was stirred at 65°C for 1.0 h, and then an anhydrous N,N'-dimethylformamide solution (0.5 mL) of D-1-int-1 (30 mg, 70.6 μmol) obtained in step 1 was added. The mixture was stirred at 65°C for another 16 h, diluted with 10 mL of ethyl acetate, quenched dropwise with 10 mL of water, and then the pH was adjusted to 4-5 with 1.0 M dilute hydrochloric acid. The mixture was extracted with ethyl acetate (30 mL × 3), and the organic phases were combined. The mixture was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by direct rapid column chromatography (300-400 mesh silica gel, petroleum ether / acetone = 3 / 1-2 / 1-1 / 1) to obtain D-38 (5.9 mg, 8.3 μmol, yield 18%).

[0647] D-38: 1 H NMR (400MHz, CDCl3) δ7.07 (s, 1H), 6.99 (d, J = 2.0Hz, 2H), 6.67 (s, 1H), 6.64 (s, 1 H),6.59(s,1H),4.17(t,J=6.2Hz,4H),3.89(s,6H),3.82(s,6H),3.58(s,3H),3 .48(s,3H),3.28(dd,J=16.4,7.7Hz,1H),3.09–2.85(m,4H),2.83–2.72(m,1H), 2.29(p,J=6.2Hz,2H),2.14(s,3H),1.27(d,J=7.1Hz,3H),1.22(d,J=7.0Hz,3H).

[0648] Step 5: Dissolve D-38 (5.4 mg, 7.6 μmol) and lithium hydroxide (1.8 mg, 76 μmol) in THF / MeOH / H2O (0.5 mL / 0.25 mL / 0.25 mL) and stir for 12 hours. After concentrating the reaction solution, purify it directly by rapid column chromatography (300-400 mesh silica gel, dichloromethane / methanol = 20 / 1) or by preparative liquid chromatography to obtain D-39 (1.8 mg, 2.8 μmol, yield 37%).

[0649] D-39: 1H NMR(400MHz,CD3CN)δ7.17(s,1H),7.05(s,1H),7.02(s,1H),6.82(d,J=1.5Hz,2H ),6.52(s,1H),4.11(q,J=6.4Hz,4H),3.89(s,3H),3.81(s,3H),3.78(s,3H),3.7 6(s,3H),3.25(dd,J=16.8,8.3Hz,1H),2.96(t,J=4.2Hz,1H),2.89(ddd,J=21.3, 11.8,7.6Hz,4H),2.83–2.72(m,2H),1.14(d,J=7.1Hz,3H),1.03(d,J=6.9Hz,3H).

[0650] Test Example 1: THP-1 Cell Screening Experiment Using Compounds to Activate Interferon Gene Stimulating Protein (STING)

[0651] THP1-Dual cells are a reporter cell line modified from human THP-1 cells. Their IRF_Luc reporter system induces the secretion of luciferase after activation of the interferon regulatory factor (IRF) pathway. By providing the appropriate substrate and reacting with the enzyme, the resulting fluorescence signal can be detected to determine the secretion of luciferase and further reflect the intensity of IRF pathway activation. Therefore, when a compound activates the interferon gene-stimulated protein (STING) in cells, its downstream IRF3 pathway is activated, inducing luciferase secretion. The activity of the compound in activating STING can be analyzed by detecting the fluorescence intensity. Based on this, the activation effect of the compound prepared in Example 1 on STING protein was detected using THP1-Dual cells. The specific experimental method is as follows:

[0652] 1. The monomeric compound prepared in Example 1 or the dimer compound prepared in Example 2 were diluted with DMSO. Then, using a Labcyte echo ultrasonic pipetting system, a certain amount (10–400 nmL) of the compound was added to each well of a 384-well cell culture plate to achieve a maximum final concentration of 100 μM or 50 μM in the culture system (20 μL or 40 μL), followed by a three-fold serial dilution. Ten concentrations were prepared for each compound, with three replicates for each concentration. Positive control compounds were MSA-2 (purchased from MedChemExpress), diABZI (purchased from MCE and Selleckchem, structural formula shown in Figure 1), D-34 (internal synthesis), and D-35 (internal synthesis). The control group (without drug) received the same volume of DMSO (referred to as the DMSO group). The concentration range of highly active compounds was adjusted as needed to calculate EC50. 50 Each group has three parallel groups.

[0653] 2. Collect THP1-Dual cells by centrifugation at 400×g for 5 minutes, resuspend in fresh culture medium, and adjust the concentration to 5×10⁻⁶. 5 cells / mL. Add 20 μL or 40 μL of cells to each well, and set up a blank control group by adding only the same volume of cell-free culture medium (Blank group). After incubation in an incubator for 20 hours, centrifuge and collect the supernatant to detect the Luminescence signal.

[0654] 3. After centrifugation at 400×g for 5 minutes, transfer 5 μL of supernatant from each well to a new 384-well plate, and add 7 μL of the substrate Quanti-Luc. TM Gold (purchased from Invivogen). After incubation at room temperature for 1.5–2 hours, the fluorescence signal of each well was detected using a multi-functional fluorescent microplate reader (Biotek Synergy Neo2).

[0655] 4. Calculate the signal fold increase for each compound at each concentration. Fluorescence signal fold increase = (signal value of compound test group - signal value of blank control group) / (signal value of DMSO group - signal value of blank control group). Use GraphPad Prism 8 software to perform a four-parameter nonlinear fitting (log(agonist) vs. response) on the log value of the concentration and the corresponding fluorescence signal fold increase to generate the half-maximum effective concentration (EC50). 50 For specific abbreviations, please refer to Table 1 (monomer compounds prepared in Example 1) and Table 2 (dimer compounds prepared in Example 2).

[0656] The structure of MSA-2 in this test case is as follows:

[0657] Table 1: EC5 values ​​of each compound 50 result A represents EC 50 <0.1μM, B indicates EC 50 The concentration ranges from 0.1 to 0.85 μM (excluding 0.85 μM), where C indicates EC. 50 The range is 0.85-9.9 μM (excluding 9.9 μM), where D represents EC. 50 ≥9.9μM.

[0658] Table 2: EC5 values ​​of each compound 50 result A+ indicates EC 50 <0.01μM (10nM), A indicates EC 50 The concentration is 0.01-0.1 μM (excluding 0.1 μM, 10-100 nM), and B indicates EC. 50 The range is 0.1-0.85 μM (excluding 0.85 μM).

[0659] Test Example 2: Animal In Vivo Experiments of Compounds

[0660] 1. Animal in vivo antitumor effect test of the compound

[0661] Seven-week-old female C57BL / 6 mice were subcutaneously injected with 1×10⁻⁶ spores on their backs. 6 MC38 cells, until the tumor forms and reaches approximately 50 mm 3 After size determination, the tumors were randomly divided into groups of 8. Compound D-18 (prepared in Part 8 of Example 2) was administered via tail vein and gavage. The tail vein doses were 0.01 mg / kg, 0.04 mg / kg, and 0.07 mg / kg. The vehicle served as the solvent control group (5% DMSO + 5% solubilol (polyethylene glycol-15-hydroxystearate) + 90% saline (physiological saline), 200 μL / kg). The drugs were administered three times on days 1, 4, and 8, and observed for approximately 4 weeks. Tumor size was recorded, and the results are shown in Figure 2. 0.5 hours after the last administration, blood was collected via the submandibular vein. Each blood sample collected via the submandibular vein was transferred to a test tube containing heparin sodium anticoagulant and then centrifuged at 5000 rpm for 10 minutes at 4°C to separate the plasma. The resulting plasma samples were transferred to centrifuge tubes and stored at -80°C for drug concentration determination, and the results are shown in Figure 3. Four hours after the last administration, blood was drawn via the submandibular vein to detect the cytokine IFN-β in serum samples, and the results are shown in Figure 4. The results showed that the compound had a dose-dependent effect and significantly inhibited tumor growth.

[0662] 2. Cytotoxicity or animal toxicity tests of the compound.

[0663] Eight 7-week-old female Balb / c mice were administered compound D-18 (prepared in Part 8 of Example 2) via tail vein at doses of 0.1 mg / kg, 0.05 mg / kg, and 0.02 mg / kg, three times on days 1, 4, and 8. The mice were observed for two weeks, and changes in body weight and overall condition were monitored. Blood samples were collected via the submandibular vein at 2, 4, 8, and 24 hours after the first administration. Each blood sample collected via the submandibular vein was transferred to a tube containing heparin sodium anticoagulant and centrifuged at 5000 rpm for 10 minutes at 4°C to separate the plasma. The resulting plasma samples were transferred to centrifuge tubes and stored at -80°C. The changes in body weight after administration are shown in Figure 5. The results showed no significant decrease in body weight after administration, indicating that compound D-18 had no significant toxicity at the administered doses. The results of detecting the cytokine IFN-β in serum samples are shown in Figure 6. The results show that compound D-18 can activate the immune response and promote the release of IFN-β, with the high dose of 0.1 mg / kg showing the most significant effect.

[0664] 3. Pharmacokinetic data of the compound

[0665] Eight 7-week-old male CD1 mice were administered compound D-18 at single intravenous injections of 0.07 mg / kg and 0.15 mg / kg via tail vein. Blood samples were collected from the submandibular vein at 5 minutes, 0.25, 0.5, 1, 2, 4, 8, and 24 hours post-administration. Each blood sample collected via the submandibular vein was transferred to a tube containing heparin sodium anticoagulant and then centrifuged at 5000 rpm for 10 minutes at 4°C to separate the plasma. The resulting plasma samples were transferred to centrifuge tubes and stored at -80°C for LC-MS / MS analysis. The mean drug concentration-time curve of compound D-18 in mouse blood is shown in Figure 7.

[0666] 4. Accumulation of compounds in tumors

[0667] Seven-week-old female C57BL / 6 mice were subcutaneously injected with 1×10⁻⁶ spores on their backs. 6 MC38 cells, until the tumor forms and reaches approximately 500 mm 3 After size determination, mice were randomly divided into groups of three. Compound D-18 (0.1 mg / kg) was administered via a single intravenous injection via the tail vein. Mice were sacrificed at 0.5, 4, 7, and 24 hours post-administration, and tumors were removed. Tumor tissue was lysed using lysis buffer and centrifuged at 10,000 rpm for 10 minutes at 4°C, and the supernatant was collected. The supernatant samples were transferred to centrifuge tubes for LC-MS / MS analysis. The mean drug concentration-time curve of compound D-18 in mouse tumors is shown in Figure 8.

[0668] Test Example 3: Detection of the binding ability of the compound to the STING protein

[0669] The binding activity of compounds to human wild-type (WT) STING protein (Revity, catalog number 64BDSTGPEG), human STING AQ mutant protein (Revity, catalog number 64BDSTGQPEG), human STING H232 mutant protein (Revity, catalog number 64BDSTGHPEG), and mouse STING protein (catalog number 64BDSTGMPEG) was detected using a commercially available STING binding kit from Cisbio. This kit operates on the principle of fluorescence resonance energy transfer (FRET). The kit contains three main components: STING protein tagged with six histones (6His), a terbium-labeled specific anti-6His antibody as the energy donor, and a d2-labeled STING ligand as the energy acceptor. When the donor and acceptor are close together, energy is transferred from the donor to the acceptor, causing the latter to fluoresce, and a high signal value is detected by the microplate reader. When the compound is added, the d2-labeled STING ligand is replaced, preventing energy transfer, resulting in weak fluorescence and a low detection signal value.

[0670] Follow the specific experimental procedures outlined in the product instructions:

[0671] 1. Dilute the 5× dilution buffer and 5× detection buffer to 1× using ultrapure water, respectively.

[0672] 2. Add 2.5 μL of 1× dilution buffer to each well of a white 384 shallow well plate.

[0673] 3. On 384PP or 384LDV plates, serially dilute the monomeric compound prepared in Example 1 or the dimer prepared in Example 2 with DMSO at 2 to 5 times, to 6-12 different concentration points. According to the required final concentration, use a Labcyte echo pipetting system to add a certain amount (2.5–250 nmL) of the compound to each well of a white 384 shallow-well plate, ensuring that the DMSO content in a 10 μL reaction system does not exceed 2.5%. The positive control compound was diABZI (purchased from MCE and Selleckchem, its specific structural formula is shown in Figure 1).

[0674] 4. Dilute 50× 6His STING protein to 1× using 1× detection buffer, and add 2.5 μL of 6His STING protein to each well.

[0675] 5. Dilute 50×6His antibody to 1× using 1× detection buffer, and dilute d2-labeled STING ligand to 1× using 1× detection buffer. Mix the two at a 1:1 ratio and add 5 μL of the mixture to each well.

[0676] 6. After sealing with plastic film, incubate at room temperature for 3 hours or overnight. Detect the fluorescence signals at 665nm and 620nm using a multi-functional microplate reader. Calculate the ratio = (665nm signal value / 620nm signal value) × 10. 4 The X-axis represents the logarithmic value of the concentration, and the Y-axis represents the ratio. GraphPad Prism 8 fits the IC. 50 The test results are shown in Table 3.

[0677] Table 3: Competitive binding IC50 of various compounds to different STING proteins 50 result A+ indicates IC 50 <0.01μM (10nM), A indicates IC 50 The range is 0.01-0.1 μM (excluding 0.1 μM, 10-100 nM), and B indicates IC. 50 The range is 0.1-0.85μM (excluding 0.85μM), where C represents IC. 50 The range is 0.85-9.9μM (excluding 9.9μM), where D indicates IC. 50 ≥9.9μM, N / A indicates not tested.

[0678] Test Example 4: Detection of the killing ability of compounds on tumor cells using a co-culture system of tumor target cells and PBMCs

[0679] STING agonists possess potent anti-tumor activity by activating the immune system. In in vitro experiments, STING agonists activated PBMCs to kill tumor cells through co-culturing with human peripheral blood mononuclear cells (PBMCs). The specific experimental procedures are as follows:

[0680] 1. Resuscitate frozen healthy human PBMC cells (purchased from Shanghai Aoneng Biotechnology Co., Ltd.) one day in advance and culture them overnight in RPMI-1640 complete medium, 5% CO2, 37℃ cell culture incubator.

[0681] 2. The monomeric compound prepared in Example 1 or the dimer compound prepared in Example 2 was serially diluted 5-fold with DMSO on 384PP or 384LDV plates. Using a Labcyte echo ultrasonic pipetting system, 40 nL of the compound was added to each well of a white 384 shallow-well plate, resulting in nine different concentration points (final concentration of 40 μL system ranging from 1000 nM to 0.00256 nM). 40 nL of DMSO was added to the experimental control group. The positive control compound was diABZI (purchased from MCE and Selleckchem, structural formula shown in Figure 1).

[0682] 3. In addition to the compounds, 20 μL of 2000 tumor cells were seeded into each well of a 384-well plate in the experimental group, and 20 μL of five times the amount of PBMC (10,000 cells / well) was added. The cells were incubated in a cell culture incubator for 48 hours. A "DMSO control" was also set up: containing 40 nL of DMSO, 20 μL of PBMC, and 20 μL of tumor cells (such as bladder cancer cells T24, bladder cancer cells RT-4, bladder cancer cells UM-UC-3, bladder cancer cells 5637, breast cancer cells SK-BR-3, breast cancer cells MDA-MB-231, breast cancer cells HCC1954, colon cancer cells HT-29, sarcoma cells HT-1080, ovarian cancer cells SK-OV-3, gastric cancer cells SNU-5, lung cancer cells HCC827, rectal cancer, thyroid cancer cells SW579, brain tumor cells SF126, neuroblastoma cells SH-SY5Y, glioma cells U251, and head and neck cancer cells Detroit). 562, oral squamous cell carcinoma cells HSC-2, renal cell carcinoma cells 769-P, liver cancer cells HuH-7, cholangiocarcinoma cells HCCC-9810, leukemia cells K562, lymphoma cells Raji, myeloma cells MM1.S, prostate cancer cells PC-3, pancreatic cancer cells AsPC-1, melanoma cells A-375, cervical cancer cells HeLa, endometrial cancer cells AN3-CA, skin cancer cells A2058, esophageal cancer cells TE-1, rhabdomyosarcoma cells A-673); A “PBMC group” was set up: containing 40 nL of compound, 20 μL of PBMC, and 20 μL of cell culture medium, without tumor cells; A “PBMC group DMSO control” was set up: containing 40 nL of DMSO, 20 μL of PBMC, and 20 μL of cell culture medium, without tumor cells.

[0683] 4. Add 20 μL of CTG (purchased from Promega) to each well, and detect the fluorescence signal using a multi-functional microplate reader. The tumor cell survival rate (%) corresponding to the same concentration of compound is calculated as follows: (Experimental group signal value - PBMC group signal value) / (Experimental group DMSO control signal value - PBMC group DMSO control signal value) × 100%. The X-axis represents the logarithmic value of the concentration, and the Y-axis represents the tumor cell survival rate. GraphPad Prism 8 is used to fit the IC50 values. 50 The killing ability of the compounds against tumor cells was evaluated. Some results are shown in Table 4.

[0684] Table 4: IC50 of each compound activating PBMCs to kill tumor cells 50 result A+ indicates IC 50 <0.01μM (10nM), A indicates IC 50The range is 0.01-0.1 μM (excluding 0.1 μM, 10-100 nM), and B indicates IC. 50 The range is 0.1-0.85μM (excluding 0.85μM), where C represents IC. 50 The range is 0.85-9.9μM (excluding 9.9μM), where D indicates IC. 50 ≥9.9μM, N / A indicates not tested.

[0685] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0686] Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those skilled in the art can make changes, modifications, substitutions and variations to the above embodiments within the scope of the present invention.

Claims

A compound, which is a compound of formula (I) or a stereoisomer, tautomer, solvate, or pharmaceutically acceptable salt of a compound of formula (I): in, R7 and R8 are independently derived from H, halogen, -CN, and -OR. 14 -NHR 14 or -R 14 Alternatively, R7 and R8 may be connected together with adjacent atoms to form a 4- to 7-membered heterocycle, the 4- to 7-membered heterocycle containing at least one heteroatom of O, N, and S; or one of R7 and R8 may be connected via A to... Connected; R7' and R8' are each independently of H, halogen, -CN, -OR. 14 -NHR 14 or -R 14 ; A is empty or -C 1～10 alkylene-, wherein the -C 1～10 Alkylene groups are optionally surrounded by one or more halogens, -OH, -C(O)OH, -C(O)-, -SH, -NH2, -NHC(O)-C 1～10 Alkyl, -NO2, or -CN substituted; R1 and R1' are each independently empty, and -C can be arbitrarily replaced by one or more R9s. 1～10 Alkylene, -C(O)-C optionally substituted with one or more R9 groups 1～10 Alkylene-, or -C(NOH)-C optionally substituted with one or more R9 groups. 2～10 Alkylene, -C(O)-C optionally substituted with one or more R9 groups 1～10 alkene-, -C(O)-C optionally substituted with one or more R9 groups 1～10 Cycloalkylene-, -C(O)-C optionally substituted with one or more R9 groups 2～10 alkenyl-, -C(O)-C optionally substituted with one or more R9s 2～10 Ethyne- or -C(O)-NR 10 R 11 -; R2 and R2' are independently -CN, -C(O)-, and -C(O)R, respectively. 12 -C(O)N(R) 12 )2 or 4-7 membered heterocycles, wherein the 4-7 membered heterocycles contain at least one heteroatom selected from O, N and S; R3, R3', R4, and R4' are each independently H, halogen, or optionally controlled by one or more R 13 Replacement -C 1～10 Alkyl, optionally with one or more R 13 Replacement -C 1～10 Alkoxy, optionally with one or more R 13 Replacement -C 2～10 alkenyl, optionally with one or more R 13 Replacement -C 2～10 alkynyl group, optionally with one or more R 13 Substituted -C(O)-C 1～10 Alkyl, optionally with one or more R 13 Substituted -C(O)-C 1～10 Alkoxy, optionally with one or more R 13 Substituted -C(O)-C 2～10 alkenyl, optionally with one or more R 13 Substituted -C(O)-C 2～10 alkynyl group, optionally with one or more R 13 Replacement -C 0～10 Alkyl-C(O)OH, optionally with one or more R 13 Replacement -C 1～10 Alkoxy-C(O)OH, optionally with one or more R 13 Replacement -C 2～10 alkenyl-C(O)OH or optionally with one or more R 13 Replacement -C 2～10 Alkyne group -C(O)OH; R5, R5', R6, and R6' are each independently H, halogen, or -C. 1～10 Alkyl, -C 1～6 Alkoxy, -C 1～10 cycloalkyl, -C 2～10 alkenyl or -C 2～10 alkynyl group; Each R9 is independently selected from halogens, -OH, -C(O)OH, -SH, -NH2, -NO2, -CN, phenyl, -C 1～10 Alkyl or -C 1～10 alkoxy, wherein the -C 1～10 Alkyl and -C 1～10 The alkoxy group may be optionally divided by one or more halogens, -OH, -C(O)OH, -C(O)-, -SH, -NH2, -NO2, -CN, -C 1～10 Alkyl or -C 1～10 Alkyl substitution; Each R 10 Independently selected from H, -C 1～10 Alkyl, -C 2～10 alkenyl or -C 2～10 alkynyl group, wherein the -C 1～10 Alkyl, -C 2～10 alkenyl or -C 2～10 The alkynyl group is optionally surrounded by one or more halogens, -OH, or -C(O)OR. 15 , -C(O)-, -SH, -NH2, -NO2, -CN, -C 1～10 Alkyl or -C 1～10 Alkyl substitution; Each R 11 Independently selected from H, halogens, -OH, -C(O)OH, -SH, -NH2, -NO2, -CN, phenyl, -C 1～10 Alkyl, -C 1～10 Alkoxy, -C 2～10 alkenyl or -C 2～10 alkynyl group, wherein the -C 1～10 Alkyl, -C 1～10 Alkoxy, -C 2～10 alkenyl or -C 2～10 The alkynyl group may be optionally surrounded by one or more halogens, -OH, -C(O)OH, -C(O)-, -SH, -NH2, -NO2, -CN, -C 1～10 Alkyl and -C 1～10 Alkyl substitution; Each R 12 Independently selected from H, -OR 15 -C 1～10 Alkyl, -C 2～10 alkenyl, -C 2～10 alkynyl group, -C 5～7 aryl or 4- to 7-membered rings, wherein the -OR 15 -C 1～10 Alkyl, -C 2～10 alkenyl, -C 5～7 Aryl or -C 2～10 The alkynyl group may be optionally surrounded by one or more halogens, -OH, -C(O)-, -C(O)OH, -SH, -NH2, -NO2, -CN, phenyl, -C 1～10 Alkyl and -C 1～10 Alkyl substitution; Each R 13 Independently selected from halogens, -OH, -C(O)OH, -SH, -NH2, -NO2, -CN, -C 1～10 Alkyl and -C 1～10 alkoxy, wherein the -C 1～10 Alkyl and -C 1～10 The alkoxy group may be optionally divided by one or more halogens, -OH, -C(O)OH, -C(O)-, -SH, -NH2, -NO2, -CN, -C 1～10 Alkyl or -C 1～10 Alkyl substitution; Each R 14 Independently selected from H, -Bn, halogens, -C 1～10 Alkyl, -C 2～10 alkenyl or -C 2～10 alkynyl group, wherein the -C 1～10 Alkyl, -C 2～10 alkenyl or -C 2～10 The alkenyl group may be optionally surrounded by one or more halogens, -OH, -C(O)OH, -C(O)-, -SH, -NH2, -NO2, -CN, -C 1～10 Alkyl or -C 1～10 Alkyl substitution; Each R 15 Independently selected from H or -C 1～10 alkyl; X1, X1', X2 and X2' are each independently C or N, and X1 and X2 are not both C at the same time, and X1' and X2' are both C at the same time; X3, X3', X4, X4', X5, and X5' are each independently C or N; or one of X1 and X2, X3, and R1 are connected together with adjacent atoms to form a 4- to 7-membered heterocycle, the 4- to 7-membered heterocycle containing N or Se; or one of X1' and X2', X3', and R1' are connected together with adjacent atoms to form a 4- to 7-membered heterocycle, the 4- to 7-membered heterocycle containing N or Se. Each Each can be either empty or chemically bonded independently. [Amended according to Rule 26, 31.12.2024] A compound, which is a compound of formula (I) or a stereoisomer, tautomer, solvate, or pharmaceutically acceptable salt of a compound of formula (I): in, R7 and R8 are independently derived from H, halogen, -CN, and -OR. 14 -NHR 14 or -R 14 Alternatively, R7 and R8 may be connected together with adjacent atoms to form a 4- to 7-membered heterocycle, the 4- to 7-membered heterocycle containing at least one heteroatom of O, N, and S; or one of R7 and R8 may be connected via A to... Connected; R7' and R8' are each independently of H, halogen, -CN, -OR. 14 -NHR 14 or -R 14 ; A is empty or -C 1～6 alkylene-, wherein the -C 1～6 Alkylene groups are optionally surrounded by one or more halogens, -OH, -C(O)OH, -C(O)-, -SH, -NH2, -NHC(O)-C 1～3 Alkyl, -NO2, or -CN substituted; R1 and R1' are each independently empty, and -C can be arbitrarily replaced by one or more R9s. 1～6 Alkylene, -C(O)-C optionally substituted with one or more R9 groups 1～6 Alkylene-, or -C(NOH)-C optionally substituted with one or more R9 groups. 2～5 Alkylene, -C(O)-C optionally substituted with one or more R9 groups 1～6 alkene-, -C(O)-C optionally substituted with one or more R9 groups 1～6 Cycloalkylene-, -C(O)-C optionally substituted with one or more R9 groups 2～6 alkenyl-, -C(O)-C optionally substituted with one or more R9s 2～6 Ethyne- or -C(O)-NR 10 R 11 -; R2 and R2' are independently -CN, -C(O)-, and -C(O)R, respectively. 12 -C(O)N(R) 12 )2 or 4-7 membered heterocycles, wherein the 4-7 membered heterocycles contain at least one heteroatom selected from O, N and S; R3, R3', R4, and R4' are each independently H, halogen, or optionally controlled by one or more R 13 Replacement -C 1～6 Alkyl, optionally with one or more R 13 Replacement -C 1～6 Alkoxy, optionally with one or more R 13 Replacement -C 2～6 alkenyl, optionally with one or more R 13 Replacement -C 2～6 alkynyl group, optionally with one or more R 13 Substituted -C(O)-C 1～6 Alkyl, optionally with one or more R 13 Substituted -C(O)-C 1～6 Alkoxy, optionally with one or more R 13 Substituted -C(O)-C 2～6 alkenyl, optionally with one or more R 13 Substituted -C(O)-C 2～6 alkynyl group, optionally with one or more R 13 Replacement -C 0～6 Alkyl-C(O)OH, optionally with one or more R 13 Replacement -C 1～6 Alkoxy-C(O)OH, optionally with one or more R 13 Replacement -C 2～6 alkenyl-C(O)OH or optionally with one or more R 13 Replacement -C 2～6 Alkyne group -C(O)OH; R5, R5', R6, and R6' are each independently H, halogen, or -C. 1～6 Alkyl, -C 1～6 Alkoxy, -C 1～6 cycloalkyl, -C 2～6 alkenyl or -C 2～6 alkynyl group; Each R9 is independently selected from halogens, -OH, -C(O)OH, -SH, -NH2, -NO2, -CN, phenyl, -C 1～6 Alkyl or -C 1～6 alkoxy, wherein the -C 1～6 Alkyl and -C 1～6 The alkoxy group may be optionally divided by one or more halogens, -OH, -C(O)OH, -C(O)-, -SH, -NH2, -NO2, -CN, -C 1～3 Alkyl or -C 1～3 Alkyl substitution; Each R 10 Independently selected from H, -C 1～6 Alkyl, -C 2～6 alkenyl or -C 2～6 alkynyl group, wherein the -C 1～6 Alkyl, -C 2～6 alkenyl or -C 2～6 The alkynyl group is optionally surrounded by one or more halogens, -OH, or -C(O)OR. 15 , -C(O)-, -SH, -NH2, -NO2, -CN, -C 1～3 Alkyl or -C 1～3 Alkyl substitution; Each R 11 Independently selected from H, halogens, -OH, -C(O)OH, -SH, -NH2, -NO2, -CN, phenyl, -C 1～6 Alkyl, -C 1～6 Alkoxy, -C 2～6 alkenyl or -C 2～6 alkynyl group, wherein the -C 1～6 Alkyl, -C 1～6 Alkoxy, -C 2～6 alkenyl or -C 2～6 The alkynyl group may be optionally surrounded by one or more halogens, -OH, -C(O)OH, -C(O)-, -SH, -NH2, -NO2, -CN, -C 1～3 Alkyl and -C 1～3 Alkyl substitution; Each R 12 Independently selected from H, -OR 15 -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 alkynyl group, -C 5～7 aryl or 4- to 7-membered rings, wherein the -OR 15 -C 1～6 Alkyl, -C 2～6 alkenyl, -C 5～7 Aryl or -C 2～6 The alkynyl group may be optionally surrounded by one or more halogens, -OH, -C(O)-, -C(O)OH, -SH, -NH2, -NO2, -CN, phenyl, -C 1～3 Alkyl and -C 1～3 Alkyl substitution; Each R 13 Independently selected from halogens, -OH, -C(O)OH, -SH, -NH2, -NO2, -CN, -C 1～6 Alkyl and -C 1～6 alkoxy, wherein the -C 1～6 Alkyl and -C 1～6 The alkoxy group may be optionally divided by one or more halogens, -OH, -C(O)OH, -C(O)-, -SH, -NH2, -NO2, -CN, -C 1～3 Alkyl or -C 1～3 Alkyl substitution; Each R 14 Independently selected from H, -Bn, halogens, -C 1～6 Alkyl, -C 2～6 alkenyl or -C 2～6 alkynyl group, wherein the -C 1～6 Alkyl, -C 2～6 alkenyl or -C 2～6 The alkenyl group may be optionally surrounded by one or more halogens, -OH, -C(O)OH, -C(O)-, -SH, -NH2, -NO2, -CN, -C 1～3 Alkyl or -C 1～3 Alkyl substitution; Each R 15 Independently selected from H or -C 1～3 alkyl; X1, X1', X2 and X2' are each independently C or N, and X1 and X2 are not both C at the same time, and X1' and X2' are both C at the same time; X3, X3', X4, X4', X5, and X5' are each independently C or N; or one of X1 and X2, X3, and R1 are connected together with adjacent atoms to form a 4- to 7-membered heterocycle, the 4- to 7-membered heterocycle containing N or Se; or one of X1' and X2', X3', and R1' are connected together with adjacent atoms to form a 4- to 7-membered heterocycle, the 4- to 7-membered heterocycle containing N or Se. Each Each can be either empty or chemically bonded independently. [Amended according to Rule 26, 31.12.2024] The compound according to claim 1 or 2 is characterized in that, The compound has at least one of the following characteristics: i) R1 and R1' are each independently -C arbitrarily replaced by one or more R9s. 1～6 Alkylene, -C(O)-C optionally substituted with one or more R9 groups 1～6 Alkylene, -C(O)-C optionally substituted with one or more R9 groups 1～6 Cycloalkylene or -C(O)-NR 10 R 11 -; or, R1 and R1' are each independently -C(O)-NR 10 R 11 - When one of X1 and X2, and the N atoms of X3 and R1 are connected together with the adjacent atoms to form a 4- to 7-membered heterocycle; ii) R2 is -C(O)R 12 -C(O)N(R) 12 )2 or 4-7 membered heterocyclic rings, of which, The 4- to 7-membered heterocycles contain at least one heteroatom selected from O, N, and S; iii) R3 and R4 are each independently H, halogen, or -C optionally substituted with one or more -OH groups. 1～3 Alkyl or -C 0～2 Alkyl-C(O)OH; iv) R5 and R6 are each independently H, halogen, or -C 1～3 alkyl; v) R7 and R8 are each independently -OR 14 Alternatively, R7 and R8 may be connected together with the adjacent atoms to form a 4- to 7-membered heterocycle, wherein the 4- to 7-membered heterocycle contains at least one heteroatom of O, N and S. vi) Each R9 is independently selected from halogens, -C 1～3 Alkyl and -C 1～3 alkoxy, wherein the -C 1～3 Alkyl and -C 1～3 The alkoxy group may be optionally divided by one or more halogens, -OH, -C(O)OH, -SH, -NH2, -NO2, -CN, -C 1～3 Alkyl or -C 1～3 Alkyl substitution; vii) Each R 10 Independently selected from -C 1～4 Alkyl, wherein the -C 1～4 The alkyl group may be optionally surrounded by one or more halogens, -OH, -SH, -NH2, -NO2, -CN, or -C. 1～2 Alkyl substitution; viii) Each R 11 Independently selected from H, halogen, -C 1～4 Alkyl, wherein the -C 1～4 The alkyl group may be optionally substituted with one or more halogens, -OH, -SH, -NH2, -NO2, or -CN; ix) each R 12 Independently selected from H, -OR 15 or -C 1～3 Alkyl group, wherein the -OR 15 or -C 1～3 The alkyl group may be optionally substituted with one or more halogens, -OH, -C(O)OH, -C(O)-, -SH, -NH2, -NO2, -CN or phenyl; x) Each R 14 -C independently selected from H, optionally substituted by one or more halogens 1～3 Alkyl groups or -C groups optionally substituted with one or more halogens 2～3 alkenyl; xi) each R 15 Independently selected from H or -C 1～3 alkyl; xii) X1 is C, X2 is N or Se, or X1 is N or Se, X2 is C; xiii) X3, X4 and X5 are C. The compound according to claim 1 or 2, characterized in that, Each R9 is independently selected from halogens, -C 1～3 Alkyl or -C 1～3 Alkyl group. The compound according to claim 1 or 2, characterized in that, The compound is a compound of formula (Ia) or a stereoisomer, tautomer, solvate, or pharmaceutically acceptable salt of a compound of formula (Ia). The compound according to claim 5, characterized in that, The compound has at least one of the following characteristics: i) R1 is -C(OH)-C 1～5 Alkylene, -C(O)-C 2～5 Alkylene, -C(O)-C 2～4 Cycloalkylene, -C(O)-NR 10 R 11 -or-C(NOH)-C 2～5 Alkylene; ii)R 10 It is H or -CH3; iii)R 11 -C 2～4 alkyl; iv) R2 is -C(O)OH, -C(O)OCH3, -C(O)OCH2CH3, -C(O)N(H)OCH3, -C(O)N(H)(CH2)2OH or v) R3 is H, -CH3, -CH2CH3, -C(O)CH3, -C 1～5 Alkylene -C(O)OH or -C(O)OH; vi) R4, R5 and R6 are each independently H or halogen; vii) R7 and R8 are each independently -OH, optionally substituted with halogens as -OCH3 or -OCH2CH=CH2. The compound according to claim 1 or 2, characterized in that, -R1-R2 has the following structure: and -C(O)OH. The compound according to claim 1 or 2, characterized in that, The compound is a stereoisomer, tautomer, solvate, or pharmaceutically acceptable salt of the compound represented by formula (VI): Among them, R 1a It is hydrogen or -CH3; R 1b and R 1c Each can be independently H or halogen; R 1d It can be -OH, -OCH3, or -OCH2CH3; R 1f -CH3 or -CH2-CH ＝ CH2; R 1g for Among them, R 1f for At that time, R 1d It is not -OH. A compound that is a stereoisomer, tautomer, solvate, or pharmaceutically acceptable salt of a compound with the following structure: A dimer compound, which is a dimer compound of formula (II), formula (III) or formula (IV), or a stereoisomer, tautomer, solvate, or pharmaceutically acceptable salt of a dimer compound of formula (II), formula (III) or formula (IV): in, A is empty or -C 1～10 alkylene-, wherein the -C 1～10 Alkylene groups are optionally surrounded by one or more halogens, -OH, -C(O)OH, -C(O)-, -SH, -NH2, -NHC(O)-C 1～10 Alkyl, -NO2, or -CN substituted; R1 and R1' are each independently empty and can be arbitrarily replaced by one or more R9s. 1～10 Alkylene-, or -C(NOH)-C optionally substituted with one or more R9 groups. 2～10 Alkylene, -C(O)-C optionally substituted with one or more R9 groups 1～10 alkene-, -C(O)-C optionally substituted with one or more R9 groups 1～10 Cycloalkylene-, -C(O)-C optionally substituted with one or more R9 groups 2～10 alkenyl-, -C(O)-C optionally substituted with one or more R9s 2～10 Ethyne- or -C(O)-NR 10 R 11 -; R2 and R2' are independently -CN, -C(O)-, and -C(O)R, respectively. 12 -C(O)N(R) 12 )2 or 4-7 membered heterocycles, wherein the 4-7 membered heterocycles contain at least one heteroatom selected from O, N and S; R3, R3', R4, and R4' are each independently H, halogen, or optionally controlled by one or more R 13 Replacement -C 1～10 Alkyl, optionally with one or more R 13 Replacement -C 1～10 Alkoxy, optionally with one or more R 13 Replacement -C 2～10 alkenyl, optionally with one or more R 13 Replacement -C 2～10 alkynyl group, optionally with one or more R 13 Substituted -C(O)-C 1～10 Alkyl, optionally with one or more R 13 Substituted -C(O)-C 1～10 Alkoxy, optionally with one or more R 13 Substituted -C(O)-C 2～10 alkenyl, optionally with one or more R 13 Substituted -C(O)-C 2～10 alkynyl group, optionally with one or more R 13 Replacement -C 0～10 Alkyl-C(O)OH, optionally with one or more R 13 Replacement -C 1～10 Alkoxy-C(O)OH, optionally with one or more R 13 Replacement -C 2～10 alkenyl-C(O)OH or optionally with one or more R 13 Replacement -C 2～10 Alkyne group -C(O)OH; R5, R5', R6, and R6' are each independently H, halogen, or -C. 1～10 Alkyl, -C 1～10 Alkoxy, -C 1～10 cycloalkyl, -C 2～10 alkenyl or -C 2～10 alkynyl group; R7, R7', R8, and R8' are each independently H, halogen, -CN, or -OR. 14 -NHR 14 or -R 14 ; Each R9 is independently selected from H, halogen, -OH, -C(O)OH, -SH, -NH2, -NO2, -CN, phenyl, -C 1～10 Alkyl or -C 1～10 alkoxy, wherein the -C 1～10 Alkyl and -C 1～10 The alkoxy group may be optionally divided by one or more halogens, -OH, -C(O)OH, -C(O)-, -SH, -NH2, -NO2, -CN, -C 1～10 Alkyl or -C 1～10 Alkyl substitution; Each R 10 Independently selected from H, -C 1～10 Alkyl, -C 2～10 alkenyl or -C 2～10 alkynyl group, wherein the -C 1～10 Alkyl, -C 2～10 alkenyl or -C 2～10 The alkynyl group is optionally surrounded by one or more halogens, -OH, or -C(O)OR. 15 , -C(O)-, -SH, -NH2, -NO2, -CN, -C 1～10 Alkyl or -C 1～10 Alkyl substitution; Each R 11 Independently selected from H, halogens, -OH, -C(O)OH, -SH, -NH2, -NO2, -CN, phenyl, -C 1～10 Alkyl, -C 1～10 Alkoxy, -C 2～10 alkenyl or -C 2～10 alkynyl group, wherein the -C 1～10 Alkyl, -C 1～10 Alkoxy, -C 2～10 alkenyl or -C 2～10 The alkynyl group may be optionally surrounded by one or more halogens, -OH, -C(O)OH, -C(O)-, -SH, -NH2, -NO2, -CN, -C 1～10 Alkyl and -C 1～10 Alkyl substitution; Each R 12 Independently selected from H, -OR 15 -C 1～10 Alkyl, -C 2～10 alkenyl, -C 2～10 alkynyl group, -C 5～7 Aryl or 4- to 7-membered rings, wherein the -C 1～10 Alkyl, -C 2～10 alkenyl, -C 5～7 Aryl or -C 2～10 The alkynyl group may be optionally surrounded by one or more halogens, -OH, -C(O)-, -C(O)OH, -SH, -NH2, -NO2, -CN, phenyl, -C 1～10 Alkyl and -C 1～10 Alkyl substitution; Each R 13 Independently selected from halogens, -OH, -C(O)OH, -SH, -NH2, -NO2, -CN, -C 1～10 Alkyl and -C 1～10 alkoxy, wherein the -C 1～10 Alkyl and -C 1～10 The alkoxy group may be optionally divided by one or more halogens, -OH, -C(O)OH, -C(O)-, -SH, -NH2, -NO2, -CN, -C 1～10 Alkyl or -C 1～10 Alkyl substitution; Each R 14 Independently selected from H, -Bn, halogens, -C 1～10 Alkyl, -C 2～10 alkenyl or -C 2～10 alkynyl group, wherein the -C 1～10 Alkyl, -C 2～10 alkenyl or -C 2～10 The alkenyl group may be optionally surrounded by one or more halogens, -OH, -C(O)OH, -C(O)-, -SH, -NH2, -NO2, -CN, -C 1～10 Alkyl or -C 1～10 Alkyl substitution; Each R 15 Independently selected from H or -C 1～10 alkyl; X1, X1', X2 and X2' are each independently C, N, S or Se, and X1 and X2 are not both C at the same time, and X1' and X2' are both C at the same time; X3, X3', X4, X4', X5, and X5' are each independently C or N; or one of X1' and X2', X3', and R1' are connected together with adjacent atoms to form a 4- to 7-membered heterocycle, which contains N or Se; Each Each can be either empty or chemically bonded independently. A dimer compound, which is a dimer compound of formula (II), formula (III) or formula (IV), or a stereoisomer, tautomer, solvate, or pharmaceutically acceptable salt of a dimer compound of formula (II), formula (III) or formula (IV): in, A is empty or -C 1～6 alkylene-, wherein the -C 1～6 Alkylene groups are optionally surrounded by one or more halogens, -OH, -C(O)OH, -C(O)-, -SH, -NH2, -NHC(O)-C 1～3 Alkyl, -NO2, or -CN substituted; R1 and R1' are each independently empty and can be arbitrarily replaced by one or more R9s. 1～6 Alkylene-, or -C(NOH)-C optionally substituted with one or more R9 groups. 1～6 Alkylene, optionally substituted with one or more R9-C(NOAc)-C 2～5 Alkylene, -C(O)-C optionally substituted with one or more R9 groups 1～6 alkene-, -C(O)-C optionally substituted with one or more R9 groups 1～6 Cycloalkylene-, -C(O)-C optionally substituted with one or more R9 groups 2～6 alkenyl-, -C(O)-C optionally substituted with one or more R9s 2～6 Ethyne- or -C(O)-NR 10 R 11 -; R2 and R2' are independently -CN, -C(O)-, and -C(O)R, respectively. 12 -C(O)N(R) 12 )2 or 4-7 membered heterocycles, wherein the 4-7 membered heterocycles contain at least one heteroatom selected from O, N and S; R3, R3', R4, and R4' are each independently H, halogen, or optionally controlled by one or more R 13 Replacement -C 1～6 Alkyl, optionally with one or more R 13 Replacement -C 1～6 Alkoxy, optionally with one or more R 13 Replacement -C 2～6 alkenyl, optionally with one or more R 13 Replacement -C 2～6 alkynyl group, optionally with one or more R 13 Substituted -C(O)-C 1～6 Alkyl, optionally with one or more R 13 Substituted -C(O)-C 1～6 Alkoxy, optionally with one or more R 13 Substituted -C(O)-C 2～6 alkenyl, optionally with one or more R 13 Substituted -C(O)-C 2～6 alkynyl group, optionally with one or more R 13 Replacement -C 0～6 Alkyl-C(O)OH, optionally with one or more R 13 Replacement -C 1～6 Alkoxy-C(O)OH, optionally with one or more R 13 Replacement -C 2～6 alkenyl-C(O)OH or optionally with one or more R 13 Replacement -C 2～6 Alkyne group -C(O)OH; R5, R5', R6, and R6' are each independently H, halogen, or -C. 1～6 Alkyl, -C 1～6 Alkoxy, -C 1～6 cycloalkyl, -C 2～6 alkenyl or -C 2～6 alkynyl group; R7, R7', R8, and R8' are each independently H, halogen, -CN, or -OR. 14 -NHR 14 or -R 14 ; Each R9 is independently selected from H, halogen, -OH, -C(O)OH, -SH, -NH2, -NO2, -CN, phenyl, -C 1～6 Alkyl or -C 1～6 alkoxy, wherein the -C 1～6 Alkyl and -C 1～6 The alkoxy group may be optionally divided by one or more halogens, -OH, -C(O)OH, -C(O)-, -SH, -NH2, -NO2, -CN, -C 1～3 Alkyl or -C 1～3 Alkyl substitution; Each R 10 Independently selected from H, -C 1～6 Alkyl, -C 2～6 alkenyl or -C 2～6 alkynyl group, wherein the -C 1～6 Alkyl, -C 2～6 alkenyl or -C 2～6 The alkynyl group is optionally surrounded by one or more halogens, -OH, or -C(O)OR. 15 , -C(O)-, -SH, -NH2, -NO2, -CN, -C 1～3 Alkyl or -C 1～3 Alkyl substitution; Each R 11 Independently selected from H, halogens, -OH, -C(O)OH, -SH, -NH2, -NO2, -CN, phenyl, -C 1～6 Alkyl, -C 1～6 Alkoxy, -C 2～6 alkenyl or -C 2～6 alkynyl group, wherein the -C 1～6 Alkyl, -C 1～6 Alkoxy, -C 2～6 alkenyl or -C 2～6 The alkynyl group may be optionally surrounded by one or more halogens, -OH, -C(O)OH, -C(O)-, -SH, -NH2, -NO2, -CN, -C 1～3 Alkyl and -C 1～3 Alkyl substitution; Each R 12 Independently selected from H, -OR 15 -C 1～6 Alkyl, -C 2～6 alkenyl, -C 2～6 alkynyl group, -C 5～7 Aryl or 4- to 7-membered rings, wherein the -C 1～6 Alkyl, -C 2～6 alkenyl, -C 5～7 Aryl or -C 2～6 The alkynyl group may be optionally surrounded by one or more halogens, -OH, -C(O)-, -C(O)OH, -SH, -NH2, -NO2, -CN, phenyl, -C 1～3 Alkyl and -C 1～3 Alkyl substitution; Each R 13 Independently selected from halogens, -OH, -C(O)OH, -SH, -NH2, -NO2, -CN, -C 1～6 Alkyl and -C 1～6 alkoxy, wherein the -C 1～6 Alkyl and -C 1～6 The alkoxy group may be optionally divided by one or more halogens, -OH, -C(O)OH, -C(O)-, -SH, -NH2, -NO2, -CN, -C 1～3 Alkyl or -C 1～3 Alkyl substitution; Each R 14 Independently selected from H, -Bn, halogens, -C 1～6 Alkyl, -C 2～6 alkenyl or -C 2～6 alkynyl group, wherein the -C 1～6 Alkyl, -C 2～6 alkenyl or -C 2～6 The alkenyl group may be optionally surrounded by one or more halogens, -OH, -C(O)OH, -C(O)-, -SH, -NH2, -NO2, -CN, -C 1～3 Alkyl or -C 1～3 Alkyl substitution; Each R 15 Independently selected from H or -C 1～3 alkyl; X1, X1', X2 and X2' are each independently C, N, S or Se, and X1 and X2 are not both C at the same time, and X1' and X2' are both C at the same time; X3, X3', X4, X4', X5, and X5' are each independently C or N; Each Each can be either empty or chemically bonded independently. The dimer compound according to claim 10 or 11 is characterized in that, The dimer compound has at least one of the following characteristics: i) R1 and R1' are each independently -C(O)-C arbitrarily replaced by one or more R9s. 1～6 Alkylene-, optionally substituted with one or more R9-C(NOH)-C 1～6 Alkylene or -C(O)-NR 10 R 11 -; ii) R2 and R2' are each independently -C(O)R 12 or -C(O)N(R) 12 )2; iii) R3, R3', R4, R4', R5, R5', R6, and R6' are each independently H, halogen, or -C. 1～3 alkyl; iv) R7, R7', R8, and R8' are each independently -C 1～3 Alkyl groups; v) Each R9 is independently selected from halogens and -C 1～3 Alkyl, wherein the -C 1～3 The alkyl group may be optionally substituted with one or more halogens, -OH, -SH, -NH2, -NO2, or -CN; vi) Each R 10 Independently selected from -C 1～3 Alkyl, wherein the -C 1～3 The alkyl group may be optionally substituted with one or more halogens, -OH, -SH, -NH2, -NO2, or -CN; vii) Each R 11 Independently selected from H or -C 1～3 Alkyl, wherein the -C 1～3 The alkyl group may be optionally substituted with one or more halogens, -OH, -SH, -NH2, -NO2, or -CN; viii) Each R 12 Independently selected from H, -OR 15 or -C 1～3 Alkyl, wherein the -C 1～3 The alkyl group may be optionally substituted with one or more halogens, -OH, -SH, -NH2, -NO2, or -CN; ix) each R 15 Independently selected from H or -C 1～3 alkyl; x)A is empty or -C 1～4 alkylene, wherein the -C 1～4 Alkylenes are optionally surrounded by one or more halogens, -OH, -SH, -NH2, -NHC(O)-C 1～3 Alkyl, -NO2 or -CN substituted. The dimer compound according to claim 10 or 11 is characterized in that, The dimer compound is a dimer compound of formula (V), or a stereoisomer, tautomer, solvate, or pharmaceutically acceptable salt of a dimer compound of formula (V). Where A is R 2a and R 2b Each independently And R 2a and R 2b Not both containing N; R 2c and R 2d Each can be independently -OH, -NH2, -OCH3, -OCH2CH3, -OCH2(CH3)2, -OCH2CH2(CH3)2 or C 5～7 Aryloxy. A dimer compound, which is a stereoisomer, tautomer, solvate, or pharmaceutically acceptable salt of a dimer compound with the following structure: Use of the compound according to any one of claims 1 to 9 or the dimer compound according to any one of claims 10 to 14 as a STING agonist. A STING agonist, characterized in that, It includes the compound according to any one of claims 1 to 9 or the dimer compound according to any one of claims 10 to 14, and optionally a pharmaceutically acceptable carrier, excipient, or mediator. A pharmaceutical composition, characterized in that, Includes the compound according to any one of claims 1 to 9, or the dimer compound according to any one of claims 10 to 14, or the STING agonist according to claim 16, and optionally a pharmaceutically acceptable carrier, excipient, or mediator. The compound according to any one of claims 1 to 9, the dimer compound according to any one of claims 10 to 14, the STING agonist according to claim 16, or the pharmaceutical composition according to claim 17, is used for the prevention or treatment of cell proliferation diseases, or has the following uses: Prevention or treatment of cell proliferation diseases, and / or Preparation for use in the prevention or treatment of cell proliferation diseases; Optionally, the cell proliferation disease is a tumor or cancer. A method for preventing or treating cell proliferation diseases, characterized in that, include: The subject is given a pharmaceutically acceptable dose of the compound of any one of claims 1 to 9, the dimer compound of any one of claims 10 to 14, the STING agonist of claim 16, or the pharmaceutical composition of claim 17. Optionally, the cell proliferation disease is a tumor or cancer.

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