Glutarimide compounds and their uses

Abstract

The present invention discloses glutarimide compounds and their uses. Specifically, the present invention discloses a compound represented by formula (VII-0) and its pharma- ceutically acceptable salts. JPEG2024533381000234.jpg63154

Description

[Technical Field]

[0001] This invention relates to a class of glutarimide compounds and their uses. Specifically, it relates to a compound represented by formula (VII) and its pharmaceutically acceptable salts. [Background technology]

[0002] This invention claims the following priority: CN202111050400X, the filing date is September 08, 2021. CN2021113429975, the filing date is November 12, 2021. CN2021113508407, the filing date is November 15, 2021. CN2021113956259, the filing date is November 23, 2021. CN2021115450152, the filing date is December 16, 2021. CN2021116025367, the filing date is December 24, 2021. The application number is CN2022110348171, and the filing date is August 26, 2022.

[0003] Interleukin-1 receptor-associated kinase 4 (IRAK4) is a member of the IRAK family of intracellular serine / threonine kinases and plays a crucial role in protein phosphorylation and cellular signaling. IRAK4 is an important protein in inflammatory and immune response processes mediated by the activation of Toll-like receptors (TLRs) and interleukin-1 receptors (IL-1Rs). As a key protein downstream of the TLR and IL-1R signaling pathways, IRAK4 receives upstream signals and activates the downstream NF-κB and JNK signaling pathways. Therefore, IRAK4 is thought to play a vital role in inflammatory responses and immunomodulation, and is attracting widespread research and development interest as an important therapeutic target.

[0004] After folding, the IRAK4 protein forms a "pocket-like" structure that can bind to ATP and achieve its phosphorylation function. Most current IRAK4 small molecule inhibitors competitively bind to this "pocket" region, thereby inhibiting its phosphorylation function for drug development. However, IRAK4's function is not limited to protein phosphorylation; it also functions by forming a complex with myeloid differentiation factor (MyD88). Since IRAK4's phosphorylation function is required for the activation of the JNK signaling pathway but not for the activation of the NF-κB signaling pathway, it has been shown that IRAK4 has not only kinase function but also scaffold protein function for playing a role in signaling pathways. Therefore, conventional small molecule kinase inhibitors targeting IRAK4 cannot completely block all of IRAK4's biological functions.

[0005] A new research method involves degrading IRAK4 and more thoroughly blocking all of its biological functions. Proteolysis Targeting Chimeras (PROTACs) are a technique that uses the ubiquitin-proteasome system to target specific proteins and induce their intracellular degradation. The ubiquitin-proteasome system is the major pathway for intracellular protein degradation, and its normal physiological function is mainly involved in the removal of intracellular degeneration, mutation, or harmful proteins. More than 80% of intracellular protein degradation depends on the ubiquitin-proteasome system. PROTACs use the cell's own protein disruption mechanisms to remove specific target proteins within the cell. To date, PROTAC technology has become increasingly mature and can be used to target a variety of proteins, including scaffold proteins, transcription factors, enzymes, and regulatory proteins. Therefore, the development of PROTAC molecules that target IRAK4 will more thoroughly block all functions of IRAK4 by degrading and eliminating it, and completely and fundamentally inhibit the IRAK4 signaling pathway, thereby better exerting anti-inflammatory and immunomodulatory effects. [Overview of the project]

[0006] The present invention further provides a compound represented by formula (VII-0) or a pharmaceutically acceptable salt thereof. [ka] however, L1 is [ka] Selected from -(CH2)3- and -O(CH2)3-, L2 is selected from -CR5R6- and O. R1, R2, R3, R4, R5, and R6 are each independently selected from H and halogen. Alternatively, R1 and R2, R3 and R4, R5 and R6 optionally form a cyclopropyl with the carbon atoms to which they are attached, R7 is

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[0007] The present invention further provides a compound represented by formula (VII) or a pharmaceutically acceptable salt thereof. [ka] however, L1 is [ka] Selected from -(CH2)3- and -O(CH2)3-, L2 is selected from -CR5R6- and O. R1, R2, R3, R4, R5, and R6 are each independently selected from H and halogen. Alternatively, R1 and R2, R3 and R4, and R5 and R6 may optionally form cyclopropyl groups with the carbon atoms linked to them. R7 is [ka] Selected from, T1 is selected from CH and N. T2 is selected from CH and N. T3 is selected from CH and N. Ring A is, [ka] Selected from, X1 is selected from CH and N. X2 is selected from NH, O, S, and Se.

[0008] In some embodiments of the present invention, R1, R2, R3, R4, R5, and R6 are each independently selected from H and F, and the other variables are as defined in the present invention.

[0009] In some embodiments of the present invention, L1 is, [ka] Selected from the above, the other variables are as defined in this invention.

[0010] In some embodiments of the present invention, L2 is selected from -CH2- and O, and the other variables are as defined in the present invention.

[0011] In some embodiments of the present invention, the above [ka] Selected from the above, the other variables are as defined in this invention.

[0012] In some embodiments of the present invention, the above structural unit [ka] Selected from the above, the other variables are as defined in this invention.

[0013] In some embodiments of the present invention, the above-mentioned R7 is [ka] Selected from the above, the other variables are as defined in this invention.

[0014] In some embodiments of the present invention, the above-mentioned ring A is [ka] Selected from the above, the other variables are as defined in this invention.

[0015] In some embodiments of the present invention, the above-mentioned ring A is [ka] Selected from the above, the other variables are as defined in this invention.

[0016] The present invention further provides compounds represented by formulas (VII-1), (VII-2), (VII-3), (VII-4), (VII-5), and (VII-6), or pharmaceutically acceptable salts thereof. [ka] [ka] However, X1, X2, R3, R4, T1, and L1 are as defined in the present invention.

[0017] The present invention further provides compounds represented by formulas (VII-1R), (VII-1S), (VII-2R), (VII-2S), (VII-3R), (VII-3S), (VII-4R), and (VII-4S), or pharmaceutically acceptable salts thereof. [ka] [ka] However, X1, X2, R3, R4, T1, and L1 are as defined in the present invention.

[0018] The present invention further provides compounds represented by formulas (VII-1RT), (VII-1ST), (VII-2RT), (VII-2ST), (VII-3RT), (VII-3ST), (VII-5T), and (VII-6T), or pharmaceutically acceptable salts thereof. [ka] [ka] However, X1, X2, R3, R4, T1, and L1 are as defined in the present invention.

[0019] The present invention further provides compounds represented by the following formula or pharmaceutically acceptable salts thereof. [ka] [ka] [ka] [ka] [ka] However, X1, X2, R3, R4, T1, and L1 are as defined in the present invention.

[0020] The present invention further provides a compound represented by formula (IV) or a pharmaceutically acceptable salt thereof. [ka] however, L1 is [ka] Selected from, L2 is selected from -CR5R6-, R1, R2, R3, R4, R5, and R6 are each independently selected from H and halogen. Alternatively, R1 and R2, R3 and R4, and R5 and R6 may optionally form cyclopropyl groups with the carbon atoms linked to them. T1 is selected from CH and N. Ring A is, [ka] Selected from, X1 is selected from CH and N. X2 is selected from NH, O, S, and Se.

[0021] In some embodiments of the present invention, R1, R2, R3, R4, R5, and R6 in formula (IV) are each independently selected from H and F, and the other variables are as defined in the present invention. In some embodiments of the present invention, L1 in formula (IV) is [ka] Selected from the above, the other variables are as defined in this invention.

[0022] In some embodiments of the present invention, L2 in formula (IV) is selected from -CH2-, and the other variables are as defined in the present invention. In some embodiments of the present invention, the structural unit of formula (IV) [ka] Selected from the above, the other variables are as defined in this invention.

[0023] In some embodiments of the present invention, the ring A of formula (IV) is [ka] Selected from the above, the other variables are as defined in this invention. In some embodiments of the present invention, the ring A of formula (IV) is [ka] Selected from the above, the other variables are as defined in this invention.

[0024] The present invention further provides compounds represented by (IV-1) or pharmaceutically acceptable salts thereof. [ka] however, X1 is selected from CH and N. X2 is selected from NH, O, S, and Se.

[0025] The present invention further provides compounds represented by formulas (III-2) and (IV-2) or pharmaceutically acceptable salts thereof. [ka] However, X1 is selected from CH and N. L1, L2, and T1 are as defined in the present invention.

[0026] The present invention further provides compounds represented by formula (I-2) or (IV-2a) or pharmaceutically acceptable salts thereof. [ka] However, T2 is selected from CH and N. L1, L2, and T1 are as defined in the present invention.

[0027] The present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof. [ka] however, L1 is [ka] Selected from, L2 is selected from -CR5R6-, R1, R2, R3, R4, R5, and R6 are each independently selected from H and halogen. Alternatively, R1 and R2, R3 and R4, and R5 and R6 may optionally form cyclopropyl groups with the carbon atoms linked to them. T1 is selected from CH and N. Ring A is, [ka] Selected from, X1 is selected from CH and N. X2 is selected from CH2, NH, O, S, and Se.

[0028] In some embodiments of the present invention, R1, R2, R3, R4, R5, and R6 in formula (I) are each independently selected from H and F, and the other variables are as defined in the present invention. In some embodiments of the present invention, L1 in formula (I) is [ka] Selected from the above, the other variables are as defined in this invention.

[0029] In some embodiments of the present invention, L2 in formula (I) is selected from -CH2-, and the other variables are as defined in the present invention. In some embodiments of the present invention, the structural unit of formula (I) [ka] Selected from the above, the other variables are as defined in this invention.

[0030] In some embodiments of the present invention, the ring A of formula (I) is [ka] Selected from the above, the other variables are as defined in this invention.

[0031] In some embodiments of the present invention, the ring A of formula (I) is [ka] Selected from the above, the other variables are as defined in this invention.

[0032] The present invention further provides compounds represented by formulas (I-1) and (I-2) or pharmaceutically acceptable salts thereof. [ka] However, X1 is selected from CH and N. L1, L2, and T1 are as defined in the present invention.

[0033] The present invention provides a compound represented by formula (II) or a pharmaceutically acceptable salt thereof. [ka] however, L1 is [ka] Selected from, L2 is selected from -CR5R6-, R1, R2, R3, R4, R5, and R6 are each independently selected from H and halogen. Alternatively, R1 and R2, R3 and R4, and R5 and R6 may optionally form cyclopropyl groups with the carbon atoms linked to them. T1 is selected from CH and N. ELM is [ka] Selected from.

[0034] In some embodiments of the present invention, R1, R2, R3, R4, R5, and R6 in formula (II) are each independently selected from H and F, and the other variables are as defined in the present invention. In some embodiments of the present invention, L1 in formula (II) is [ka] Selected from the above, the other variables are as defined in this invention.

[0035] In some embodiments of the present invention, L2 in formula (II) is selected from -CH2-, and the other variables are as defined in the present invention. In some embodiments of the present invention, the structural unit of formula (II) [ka] Selected from the above, the other variables are as defined in this invention.

[0036] The present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof. [ka] however, L1 is [ka] Selected from, L2 is selected from -CR5R6-, R1, R2, R3, R4, R5, and R6 are each independently selected from H or halogen. Alternatively, R1 and R2, R3 and R4, and R5 and R6 may optionally form cyclopropyl groups with the carbon atoms linked to them. T1 is selected from CH and N. Ring A is, [ka] Selected from, X1 is selected from CH or N. X2 is selected from CH2, NH, O, S, or Se.

[0037] In some embodiments of the present invention, R1, R2, R3, R4, R5, and R6 in formula (I) are each independently selected from H and F, and the other variables are as defined in the present invention. In some embodiments of the present invention, L1 in formula (I) is [ka] Selected from the above, the other variables are as defined in this invention.

[0038] In some embodiments of the present invention, L2 in formula (I) is selected from -CH2-, and the other variables are as defined in the present invention. In some embodiments of the present invention, the structural unit of formula (I) [ka] Selected from the above, the other variables are as defined in this invention.

[0039] In some embodiments of the present invention, the ring A of formula (I) is [ka] Selected from the above, the other variables are as defined in this invention. In some embodiments of the present invention, the ring A of formula (I) is [ka] Selected from the above, the other variables are as defined in this invention.

[0040] The present invention further provides a compound represented by formula (III-1), (III-2) or (III-3) or a pharmaceutically acceptable salt thereof.

Chemical formula

[0041] The present invention further provides a compound represented by formula (I-1), (I-2) or (III-3a) or a pharmaceutically acceptable salt thereof.

Chemical formula

[0042] Some further embodiments of the present invention are formed by any combination of the above variables. The present invention further provides the following compound or a pharmaceutically acceptable salt thereof.

Chemical formula

Chemical formula

Chemical formula

[0043] In some embodiments of the present invention, the above compound is selected from the following formulas.

Chemical formula

Chemical formula

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[0044] In some embodiments of the present invention, the above compounds are selected from the following formulas.

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[0045] In some embodiments of the present invention, the above compounds are selected from the following formulas.

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[0046] The present invention further provides the use of the compound of the present invention or a pharmaceutically acceptable salt thereof in the preparation of a pharmacopoeia for the treatment of diseases associated with interleukin-1 receptor-related kinase 4 proteolytic chimeric molecules.

[0047] The present invention further provides a method for treating diseases associated with interleukin-1 receptor-related kinase 4 proteolytic chimeric molecules, comprising administering a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof to a mammal (preferably human) in need of treatment.

[0048] In some embodiments of the present invention, the disease associated with the above-mentioned interleukin-1 receptor-related kinase 4 proteolytic chimeric molecule is selected from inflammatory diseases or immune diseases. The present invention further provides the following synthesis routes. [ka] [ka]

[0049] Technical effects The compounds of the present invention exhibit superior targeted protein degradation effects in K562 IRAK4-HiBiT cells. Oral plasma systemic exposure to the compounds of the present invention is higher. The pharmacokinetic properties of the compounds of the present invention are superior in rodents (mice) and non-rodents (beagle dogs and cynomolgus monkeys). The compounds of the present invention have dose-dependent therapeutic effects on hind paw volume, hind paw arthritis index score, and hind paw load-bearing difference in rats with sodium urate-induced acute gouty arthritis. The compounds of the present invention have ameliorative effects on pathological score, ear thickness increase, and spleen weight in a mouse psoriasis model induced by imiquimod, and also have inhibitory effects on inflammatory factors in the lesioned skin, indicating that the compounds of the present invention have therapeutic effects in this psoriasis model animal, and that the therapeutic effect of high doses (300 mpk) is superior to that of medium and low doses (100 mpk, 30 mpk).

[0050] Definition and explanation Unless otherwise specified, the following terms and phrases used herein are intended to have the meanings set forth below. Unless otherwise defined, certain terms and phrases should not be considered uncertain or ambiguous, but should be understood according to their ordinary meanings. Where trade names appear herein, they are intended to refer to the corresponding product or its active ingredient.

[0051] As used herein, the term “pharmaceutically acceptable” means that, with respect to those compounds, materials, compositions and / or dosage forms, they are within the bounds of sound medical judgment, suitable for use in contact with human and animal tissues, with minimal toxicity, irritation, allergic reactions or other problems or complications, and commensurate with a reasonable benefit / risk ratio. The term "pharmaceutically acceptable salt" refers to a salt of the compound of the present invention prepared from a compound having a specific substituent discovered in the present invention and a relatively non-toxic acid or base. If the compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting such a compound with a sufficient amount of base in a pure solution or a suitable inert solvent. Some specific compounds of the present invention contain both basic and acidic functional groups and can therefore be converted into either a base addition salt or an acid addition salt.

[0052] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing an acidic group or a base by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or free base form of these compounds with a stoichiometric amount of a suitable base or acid in water, an organic solvent, or a mixture of both.

[0053] The term "ubiquitin ligase" refers to a family of proteins that facilitate the transfer of ubiquitin to specific substrate proteins, targeting those proteins for degradation. For example, the E3 ubiquitin ligase protein IAP, alone or in combination with E2 ubiquitin-conjugating enzymes, causes ubiquitin to bind to lysine on target proteins, which then target specific protein substrates for degradation by the proteasome. Thus, E3 ubiquitin ligases, alone or in combination with E2 ubiquitin-conjugating enzymes, are involved in the transfer of ubiquitin to target proteins. Generally, ubiquitin ligases are involved in polyubiquitination, where a second ubiquitin binds to the first, a third ubiquitin binds to the second, and so on. Polyubiquitination labels proteins for degradation by the proteasome. However, there are also some ubiquitination events that are limited to monoubiquitination, where only a single ubiquitin is added to a substrate molecule via a ubiquitin ligase. Monoubiquitinated proteins do not target the proteasome for degradation, but their intracellular location and function can be altered, for example, through binding to other proteins that have domains capable of binding to ubiquitin. Further complicating matters is the fact that different lysines on ubiquitin can be targeted by E3 to form chains. The most common lysine is Lys48 on the ubiquitin chain, which is used to prepare polyubiquitins that are recognized by the proteasome.

[0054] The term "chimeric molecule" refers to a bifunctional molecule containing two small molecule ligands: one that has high affinity for the target protein of interest, and the other that is used to ubiquitinize the protein and recruit E3 ligases that target the protein for proteolysis via the 26S proteasome.

[0055] The therapeutic dose of the compound of the present invention can be determined, for example, based on the specific therapeutic use, the method of administering the compound, the patient's health and condition, and the judgment of the prescribing physician. The proportion or concentration of the compound of the present invention in a pharmaceutical composition may be variable and depend on various factors, including dose, chemical properties (e.g., hydrophobicity), and route of administration.

[0056] The term "treatment" means administering a compound or formulation described in the present invention to improve or eliminate a disease or one or more symptoms associated with said disease, and (i) To inhibit a disease or disease state, that is, to prevent its progression. (ii) Alleviating a disease or disease state, including, that is, resolving the disease or disease state.

[0057] The term “therapeutic dose” means a dose of the compound of the present invention that (i) treats a particular disease, condition, or disorder; (ii) reduces, improves, or eliminates one or more symptoms of a particular disease, condition, or disorder; or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder as described herein. The amount of the compound of the present invention constituting a “therapeutic dose” varies depending on the compound, the disease condition and its severity, the method of administration, and the age of the mammal being treated, but can be routinely determined by those skilled in the art based on their knowledge and the content of this disclosure.

[0058] Unless otherwise required by this invention, the word “comprise” and its English variations, such as “comprises” and “comprising,” throughout this specification and the subsequent claims should be interpreted in an open and comprehensive sense, i.e., “comprises but not limited to.”

[0059] Throughout this specification, the terms “one embodiment,” “an embodiment,” “in another embodiment,” or “in several embodiments” mean that at least one embodiment includes the relevant specific reference elements, structures, or features described in that embodiment. Therefore, the phrases “one embodiment,” “in one embodiment,” “in another embodiment,” or “in several embodiments” appearing in various places throughout this specification do not all refer to the same embodiment. Furthermore, specific elements, structures, or features can be combined in any suitable manner in one or more embodiments.

[0060] Unless otherwise specified, the term "isomer" is intended to include geometric isomers, cis-trans isomers, stereoisomers, enantiomers, optical isomers, diastereomers, and tautomers.

[0061] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. All such compounds envisioned by the present invention include cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures thereof, as well as other mixtures, such as enantiomer or diastereomer-rich mixtures, all of which fall within the scope of the present invention. Other chiral carbon atoms may be present in substituents such as alkyl groups. All of these isomers and mixtures thereof are within the scope of the present invention.

[0062] Unless otherwise specified, the terms "enantiomer" or "optical isomer" refer to stereoisomers that are mirror images of each other. Unless otherwise specified, the terms "cis-trans isomer" or "geometric isomer" refer to the inability of the double bond or the single bond of the ring-forming carbon atoms to rotate freely.

[0063] Unless otherwise specified, the term "diastereomer" refers to stereoisomers in which a molecule has two or more chiral centers and the molecules are non-mirror images of each other.

[0064] Unless otherwise specified, "(+)" indicates dextrorotatory properties, "(-)" indicates levorotatory properties, and "(±)" indicates a racemic mixture.

[0065] [ka]

[0066] Unless otherwise specified, the terms “rich in one isomer,” “rich in isomers,” “rich in one enantiomer,” or “enantiomer-rich” mean that the content of one isomer or enantiomer is less than 100%, and that the content of this isomer or enantiomer is 60% or more, or 70% or more, or 80% or more, or 90% or more, or 95% or more, or 96% or more, or 97% or more, or 98% or more, or 99% or more, or 99.5% or more, or 99.6% or more, or 99.7% or more, or 99.8% or more, or 99.9% or more.

[0067] Unless otherwise specified, the terms "isomer excess" or "enantiomer excess" refer to the difference between the relative percentages of two isomers or two enantiomers. For example, if one isomer or enantiomer is present at 90% and the other isomer or enantiomer is present at 10%, the isomer or enantiomer excess (ee value) is 80%.

[0068] The optically active (R)- and (S)-isomers, as well as the D and L isomers, can be produced by chiral synthesis, chiral reagents, or other conventional techniques. To obtain one enantiomer of a compound of the present invention, it can be produced by asymmetric synthesis or derivatization with a chiral auxiliary agent, where the resulting diastereomer mixture is separated and the auxiliary groups are cleaved to provide the pure enantiomer of the desired type. Alternatively, if the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), a salt of the diastereomer is formed with a suitable optically active acid or base, and then the diastereomer is divided by conventional methods known in the art and recovered to obtain the pure enantiomer. Furthermore, the separation of enantiomers and diastereomers is usually performed using chromatography with a chiral stationary phase, optionally combined with chemical derivatization (e.g., producing a carbamate from an amine).

[0069] The compounds of the present invention may contain unnatural proportions of atomic isotopes in one or more atoms constituting the compound. For example, the compound may contain tritium ( 3 H), Iodine-125( 125 I), C-14( 14 The compounds can be labeled with radioactive isotopes such as C). Alternatively, for example, deuterium can be substituted with hydrogen to form deuterated drugs. The bond formed between deuterium and carbon is stronger than the bond formed between ordinary hydrogen and carbon, and compared to non-deuterated drugs, deuterated drugs have advantages such as reduced toxic side effects, increased drug stability, enhanced efficacy, and extended biological half-life. The conversion of the isotopic composition of the compounds of the present invention is included within the scope of the present invention, whether or not it is radioactive.

[0070] If the listed linking units do not indicate their linking direction, the linking direction is arbitrary, for example, [ka] The linking group L in this case is -MW-, and in this case -MW- links ring A and ring B in the same direction as the reading order from left to right. [ka] It is possible to construct this, and also connect ring A and ring B in the reverse direction of the reading order from left to right. [ka] It is also possible to construct such a combination. The combination of the linking group, substituent and / or its variants is permissible only if such a combination results in a stable compound.

[0071] Unless otherwise stated, if a group has one or more bondable sites, any one or more sites of that group can bond to another group via a chemical bond. If the bonding site of the chemical bond is delocalized and hydrogen atoms are present at the bondable sites, when a chemical bond is formed, the number of hydrogen atoms at those sites decreases to the corresponding valence of the group in proportion to the number of chemical bonds formed. The chemical bond formed when such sites bond to other groups is: [ka]

[0072] For example, the linear solid bond in -OCH3 indicates that it is bonded to another group via an oxygen atom within that group. [ka] The dashed line in the diagram indicates that the nitrogen atom within that group is bonded to another group via both ends. [ka] The wavy line indicates that the phenyl group is bonded to another group via the carbon atoms at positions 1 and 2. [ka] This indicates that any bondable site on the naphthalene ring can be bonded to another group via one chemical bond, and at least, [ka] This includes six methods of joining.

[0073] "Optional" or "at the discretion of the user" means that the event or situation described thereafter may occur, but is not necessarily required to occur, and that the description includes both cases in which the event or situation occurs and cases in which it does not occur.

[0074] The term "substituted" means that one or more hydrogen atoms in a particular atom are substituted by a substituent, and the substituent may include deuterium and hydrogen variants, as long as the valence of the particular atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are substituted. Oxygen substitution does not occur in aromatic groups. The term "optionally substituted" means that the compound may or may not be substituted, and unless otherwise stated, the type and number of substituents are chemically feasible and arbitrary.

[0075] If any of the variables (e.g., R) appear once or more in the composition or structure of a compound, their definitions are independent in each case. Therefore, for example, if a group is substituted with 0 to 2 Rs, the group may be optionally substituted with up to 2 Rs, and in each case, Rs are independently chosen. Furthermore, combinations of substituents and / or their variants are only permitted if such combinations result in a stable compound.

[0076] Unless otherwise specified, the term "halo" or "halogen" means a fluorine, chlorine, bromine, or iodine atom, either by itself or as part of another substituent. Unless otherwise explained, "C1-4 The term "alkyl" is used to refer to a straight-chain or branched saturated hydrocarbon group consisting of 1 to 4 carbon atoms. 1-4 Alkyl contains C 1-2 , C 1-3 and C 2-3 Alkyl compounds may be monovalent (e.g., methyl), divalent (e.g., methylene), and polyvalent (e.g., methine). 1-4 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and butyl (including n-butyl, isobutyl, s-butyl, and t-butyl).

[0077] Unless otherwise explained, "C 1-3 The term "alkyl" is used to refer to a straight-chain or branched saturated hydrocarbon group consisting of 1 to 3 carbon atoms. 1-3 Alkyl contains C 1-2 and C 2-3 Alkyl compounds may be present, and these may be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine).

[0078] Unless otherwise explained, "C 1-3 The term "alkoxy" refers to an alkyl group containing 1 to 3 carbon atoms bonded to the rest of the molecule via one oxygen atom. 1-3 Alkoxy contains C 1-2 , C 2-3 This includes C3 and C2 alkoxys. 1-3 Examples of alkoxys include, but are not limited to, methoxy, ethoxy, and propoxy (including n-propoxy or isopropoxy).

[0079] Unless otherwise specified, the term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are substituted with halogens, and specifically includes monohaloalkyl, dihaloalkyl, and polyhaloalkyl groups. For example, "C 1-3The term "haloalkyl" refers to monohaloalkyl and polyhaloalkyl groups containing 1 to 3 carbon atoms. 1-3 Haloalkyls include C 1-2 , C 2-3 This includes C3, C2, and C1 haloalkyls. 1-3 Examples of haloalkyls include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl.

[0080] Unless otherwise specified, the term "haloalkyl" refers to an alkoxy group in which one or more hydrogen atoms are substituted with halogens, and specifically includes monohaloalkoxy, dihaloalkoxy, and polyhaloalkoxy groups. For example, "C 1-3 "Haloalkoxy" includes monohaloalkoxy and polyhaloalkoxy containing 1 to 3 carbon atoms. 1-3 Haloalkoxy contains C 1-2 , C 2-3 This includes C3, C2, and C1 haloalkoxys. 1-3 Examples of haloalkoxys include, but are not limited to, trifluoromethoxy, trichloromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, pentachloroethoxy, and 3-bromopropoxy.

[0081] Unless otherwise specified, “ring” means substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl, or heteroaryl. The ring includes not only monorings but also bicyclic and polycyclic systems such as spirorings, fused rings, and bridging rings. The number of atoms in a ring is generally defined as the number of members in the ring; for example, a “5- to 7-membered ring” means that 5 to 7 atoms are arranged around it. Unless otherwise specified, a ring optionally contains 1 to 3 heteroatoms. Therefore, “5- to 7-membered rings” include, for example, phenyl, pyridyl, and piperidinyl, while the term “5- to 7-membered heterocycloalkyl” includes pyridyl and piperidinyl, but not phenyl. The term “ring” also includes ring systems containing at least one ring that independently satisfies the above definitions.

[0082] Unless otherwise explained, "C 5-8 "Cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of 5 to 8 carbon atoms, and includes monocyclic and bicyclic systems, where bicyclic systems include spiro rings, fused rings, and bridging rings. 5-8 Cycloalkyls include C 5-6 , C 5-7 , C 6-7 This includes C5, C6, C7, C8 cycloalkyls, which may be monovalent, divalent, or polyvalent. 5-7 Examples of cycloalkyl compounds include cyclopentyl, cyclohexyl, and cycloheptyl. [ka] This includes, but is not limited to, these examples.

[0083] Unless otherwise specified, the term "5-8 membered heterocycloalkyl" means, by itself or in combination with other terms, a saturated cyclic group consisting of 5-8 ring atoms, where 1, 2, 3, or 4 ring atoms are independently selected heteroatoms from O, S, N, Si, or Se, and the remainder are carbon atoms, where the carbon atoms can be oxidized (i.e., C(O)), the nitrogen atom can be optionally quaternized, and the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)). P (where p is 1 or 2). It includes monocyclic and bicyclic systems, where bicyclic systems include spirocyclic, fused, and bridging rings. Furthermore, in the case of the “5- to 8-membered heterocycloalkyl,” the heteroatom can occupy a position bonded to the heterocycloalkyl and the rest of the molecule. Examples of 5-8 member heterocycloalkyls include pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranil (including tetrahydrofuran-2-yl, etc.), tetrahydropyranil, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanil, dithianil, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiadinyl, hexahydropyridazinyl, [ka] This includes, but is not limited to, these examples.

[0084] The structure of the compounds of the present invention can be confirmed by conventional methods well known to those skilled in the art, and if the present invention relates to the absolute configuration of a compound, the absolute configuration can be confirmed by conventional technical means of those skilled in the art. For example, in single-crystal X-ray diffraction (SXRD), the absolute configuration can be confirmed by collecting diffraction intensity data from a cultured single crystal using a Bruker D8 venture diffractometer, using CuKα radiation as the light source, and scanning in φ / ω scanning mode, and then analyzing the crystal structure using a direct method (Shelxs97) after collecting the relevant data.

[0085] The compounds of the present invention can be produced by various synthesis methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent alternative methods well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present invention.

[0086] Compounds are named according to the usual naming conventions in the art, or using ChemDraw® software, and commercially available compounds are named according to the supplier's catalog. The solvent used in this invention can be obtained from a commercially available product. In this invention, the following abbreviations are used: Ph represents phenyl; Me represents methyl; Et represents ethyl; M represents moles per liter; Boc represents the amino protecting group tert-butoxycarbonyl; and room temperature represents 20-25°C. [Modes for carrying out the invention]

[0087] The present invention will be described in detail below with reference to examples, but these examples will not limit the present invention in any way. Although the present invention has been described in detail in this specification, specific embodiments are also disclosed, and it will be clear to those skilled in the art that various changes and improvements can be made to specific embodiments of the present invention without departing from the spirit and scope of the invention.

[0088] Reference example 1 [ka] Synthesis route: [ka]

[0089] Step 1: Synthesis of intermediate BB-1-2 Under nitrogen gas protection at room temperature, compound BB-1-1 (40 g, 416.29 mmol) was dissolved in N,N-dimethylformamide (400 mL). Then, benzyl bromide (74.76 g, 437.10 mmol, 51.92 mL) and cesium carbonate (339.09 g, 1.04 mol) were added sequentially, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, water (1500 mL) was added to the reaction solution, and it was extracted with ethyl acetate (5 × 1000 mL). The organic phases were combined, washed with 10% saline solution (1000 mL × 3), dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. The resulting residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0~20 / 1, volume ratio) to obtain intermediate BB-1-2. MS-ESI m / z: 187.2 [M+H] + .

[0090] Step 2: Synthesis of intermediate BB-1-3 Under nitrogen gas protection at room temperature, intermediate BB-1-2 (58 g, 311.48 mmol) was dissolved in dichloromethane (500 mL), then cooled to 0°C, and diethylaminosulfur trifluoride (150.62 g, 934.43 mmol) was added. The reaction mixture was slowly heated to room temperature and stirred for 16 hours. After the reaction was complete, the mixture was cooled to 0°C, methanol (200 mL) was slowly added dropwise to the reaction solution, then water (1000 mL) was added, and the mixture was extracted with ethyl acetate (1000 mL x 3). The organic phases were combined and washed with saturated sodium bicarbonate solution (1000 mL) and saturated brine (1000 mL), respectively, dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. The resulting residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 20 / 1, volume ratio) to obtain the crude product. To the obtained crude product, 20 mL of petroleum ether was added, the mixture was stirred at room temperature for 2 hours, filtered, the cake was rinsed with 10 mL of petroleum ether, the cake was collected, and the mixture was vacuum-dried to obtain intermediate BB-1-3. MS-ESI m / z: 209.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ: 7.40-7.32 (m, 4H), 7.24-7.22 (m, 2H), 6.73 (t, J = 55.2 Hz, 1H), 6.51 (t, J=1.0 Hz, 1H), 5.33 (s, 2H).

[0091] Step 3: Synthesis of intermediate BB-1-4 At room temperature, intermediate BB-1-3 (26.5 g, 127.28 mmol) was dissolved in methanol (300 mL), and then palladium hydroxide / carbon (5 g, purity: 20%) and hydrochloric acid (2 M, 25 mL) were added sequentially. The reaction mixture was heated to 60 °C and stirred under a hydrogen gas (50 psi) atmosphere for 30 hours. After the reaction was complete, the mixture was cooled to room temperature, filtered to remove insoluble matter, rinsed with methanol (800 mL), and the filtrate was reduced in pressure to remove the solvent and obtain intermediate BB-1-4. 1H NMR (400 MHz, DMSO_d6) δ: 11.41 (br s, 1H), 7.84 (d, J=2.0 Hz, 1H), 7.00 (t, J = 54.8 Hz, 1H), 6.51 (J=1.2 Hz, 1H).

[0092] Step 4: Synthesis of intermediate BB-1-5 At 0°C, intermediate BB-1-4 (30g, 254.06 mmol) was dissolved in concentrated sulfuric acid (300 mL, purity: 98%), and concentrated nitric acid (68.950g, 711.24 mmol, 49.25 mL, purity: 65-68%) was added dropwise. The reaction mixture was stirred at 0°C for 10 minutes, then heated to 115°C and stirred for 16 hours. After the reaction was complete, the mixture was cooled to room temperature, and the reaction solution was slowly poured into ice water (1000 mL) and extracted with ethyl acetate (500 mL x 3). The organic phases were combined and washed with saturated sodium bicarbonate solution (500 mL) and saturated brine (500 mL), respectively, dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure to obtain intermediate BB-1-5. MS-ESI m / z: 164.1 [M+H] + . 1 H NMR (400 MHz, DMSO_d6) δ: 14.39 (s, 1H), 9.00 (s, 1H), 7.31 (t, J = 53.0 Hz, 1H).

[0093] Step 5: Synthesis of intermediate BB-1-6 Under nitrogen gas protection at room temperature, methyl cis-4-hydroxycyclohexanecarboxylate (35 g, 221.25 mmol) was dissolved in dichloromethane (350 mL), then triethylamine (22.39 g, 221.25 mmol, 30.79 mL) was added, the mixture was cooled to 0°C, and methanesulfonyl chloride (31.99 g, 279.26 mmol, 21.61 mL) was slowly added dropwise. After the addition was complete, the reaction mixture was stirred at 0°C for 0.5 hours. After the reaction was complete, water (300 mL) was slowly added, and the mixture was extracted with dichloromethane (300 mL). The organic phase was washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure to obtain the crude product, which was used directly in the next step.

[0094] At room temperature, the crude product and intermediate BB-1-5 (13.5 g, 82.78 mmol) obtained above were dissolved in N,N-dimethylformamide (300 mL), then potassium carbonate (24 g, 173.65 mmol) was added, and the reaction mixture was heated to 80°C and stirred for 16 hours. After the reaction was complete, the mixture was cooled to room temperature, water (100 mL) was added, and the mixture was extracted with ethyl acetate (40 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. The resulting residue was separated by column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 3, volume ratio) to obtain intermediate BB-1-6. 1 H NMR (400 MHz, CDCl3) δ: 8.22 (s, 1H), 7.12 (t, J=53.6 Hz, 1H), 4.25-4.16 (m, 1H), 3.72 (s, 3H), 2.46-2.36 (m, 1H), 2.36-2.28 (m, 2H), 2.28-2.20 (m, 2H), 1.89-1.77 (m, 2H), 1.72-1.60 (m, 2H).

[0095] Step 6: Synthesis of intermediate BB-1-7 At room temperature, wet palladium carbon (1.5 g, purity: 10%) was added to tetrahydrofuran (200 mL), then intermediate BB-1-6 (7.5 g, 24.73 mmol) was added. The reaction mixture was stirred at room temperature and under a hydrogen gas (15 psi) atmosphere for 15 hours. After the reaction was complete, the mixture was filtered to remove insoluble matter, the cake was rinsed with dichloromethane (50 mL x 2), and the filtrate was reduced in pressure to remove the solvent. The resulting residue was separated by column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 2, volume ratio) to obtain intermediate BB-1-7. MS-ESI m / z: 274.1 [M+H] + .

[0096] Step 7: Synthesis of Intermediate BB-1 Under nitrogen gas protection at room temperature, intermediate BB-1-7 (4 g, 14.64 mmol) was dissolved in a mixed solvent of tetrahydrofuran (40 mL) and methanol (5 mL). Then, lithium borohydride tetrahydrofuran solution (2 M, 14.64 mL) was slowly added dropwise. After the addition was complete, the reaction mixture was heated to 60°C and stirred for 1 hour. After the reaction was complete, the mixture was cooled to room temperature, water (20 mL) was slowly added, and the mixture was extracted with ethyl acetate (100 mL x 5). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure to obtain intermediate BB-1. 1 H NMR (400 MHz, CDCl3) δ: 7.03 (s, 1H), 6.69 (t, J =54.8 Hz, 1H), 3.95 (tt, J=4.0 Hz, 12.0 Hz, 1H), 3.51 (d, J=6.4 Hz, 2H), 2.21-2.13 (m, 2H), 2.01-1.93 (m, 2H), 1.77-1.64 (m, 2H), 1.63-1.51 (m, 2H), 1.21-1.09 (m, 2H).

[0097] Reference example 2 [ka] Synthesis route: [ka]

[0098] Step 1: Synthesis of intermediate BB-2-2 At room temperature, intermediate BB-2-1 (5.5 g, 24.38 mmol) and (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (4.96 g, 36.56 mmol) were dissolved in acetonitrile (60 mL). Then, N,N-diisopropylethylamine (9.45 g, 73.13 mmol, 12.74 mL) was added, and the reaction mixture was heated to 60 °C and stirred for 3 hours. After the reaction was complete, the mixture was cooled to room temperature, and the solvent was removed by direct vacuum concentration. The resulting residue was separated by column chromatography (eluent: dichloromethane first, then ethyl acetate) to obtain intermediate BB-2-2. MS-ESI m / z: 289.2 [M+H] + .

[0099] Step 2: Synthesis of intermediate BB-2-3 At room temperature, intermediate BB-2-2 (7 g, 24.28 mmol) and lithium hydroxide monohydrate (5.09 g, 121.40 mmol) were dissolved in a mixed solvent of methanol (70 mL) and water (14 mL). The reaction mixture was heated to 60°C and stirred for 16 hours. After the reaction was complete, the mixture was cooled to room temperature, and the solvent was removed by direct vacuum concentration. Water (150 mL) was added to the resulting residue, and the pH was adjusted to 5-6 with 1 M dilute hydrochloric acid. The mixture was then extracted with ethyl acetate (150 mL x 6). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure to obtain intermediate BB-2-3. 1 H NMR (400 MHz, DMSO_d6) δ: 11.62 (s, 1H), 8.70 (d, J=7.6 Hz, 1H), 8.16 (s, 1H), 6.85-6.30(m, 1H), 5.09 (d, J=75.2 Hz, 1H), 4.73 (s, 1H), 3.76 (d, J=42.4 Hz, 2H), 3.60-3.40 (m, 2H), 1.99-1.90 (m, 2H).

[0100] Step 3: Synthesis of intermediate BB-2-4 At room temperature, intermediate BB-2-3 (3.5 g, 11.80 mmol) was dissolved in acetonitrile (40 mL). Then, N-methylimidazole (3.39 g, 41.29 mmol) and chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (3.97 g, 14.16 mmol) were added sequentially, and the reaction mixture was stirred at room temperature for 1 hour. Next, intermediate BB-1 (3.47 g, 14.16 mmol) was added, and the reaction mixture was continued with stirring for 16 hours. After the reaction was complete, the reaction solution was filtered, the cake was rinsed with acetonitrile (3 mL), the cake was collected, and the mixture was vacuum-dried to obtain intermediate BB-2-4. MS-ESI m / z: 488.3 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ: 9.61 (s, 1H), 8.43 (d, J=5.2 Hz, 2H), 8.32 (d, J=7.6 Hz, 1H), 6.78 (t, J=54.4 Hz, 1H), 6.13 (d, J=8.0 Hz, 1H), 5.46 (s, 1H), 4.80 (s, 1H), 4.07 (td, J=4.0 Hz, 12.0 Hz, 1H), 4.02-3.95 (m, 2H), 3.61-3.47 (m, 4H), 2.28-2.20 (m, 2H), 2.13-2.08 (m, 1H), 2.05-1.96 (m, 3H), 1.88-1.75 (m, 2H), 1.67-1.55 (m, 2H), 1.25-1.13 (m, 2H).

[0101] Step 4: Synthesis of intermediate BB-2 Under room temperature and nitrogen gas protection, intermediate BB-2-4 (160 mg, 328.20 μmol) was dissolved in dichloromethane (5 mL), then Dess-Martin oxidizing agent (167.05 mg, 393.85 μmol) was added, and the reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the reaction solution was filtered, the cake was rinsed with dichloromethane (2 mL), and the filtrate was dried with a stream of nitrogen gas to obtain intermediate BB-2, which was used directly in the next step. MS-ESI m / z: 486.3 [M+H] + .

[0102] Reference example 3 [ka] Synthesis route: [ka]

[0103] Step 1: Synthesis of intermediate BB-3-2 Under room temperature and nitrogen gas protection, compound BB-3-1 (200 g, 930.04 mmol) was dissolved in chloroform (1000 mL) and ethyl acetate (1000 mL). Then, copper bromide (415.45 g, 1.86 mol) was added, and the reaction mixture was heated to 90°C and stirred for 16 hours. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the cake was rinsed with dichloromethane (1.5 L) to obtain a solution of intermediate BB-3-2, which was used directly in the next step.

[0104] Step 2: Synthesis of intermediate BB-3-3 The solution of intermediate BB-3-2 obtained above (3.5 L) was cooled to 0°C, and then triethylamine (141.17 g, 1.40 mol, 194.18 mL) was slowly added dropwise. After the addition was complete, the reaction mixture was slowly heated to room temperature and stirred for 2 hours. After the reaction was complete, water (2 L) was added, the liquid was separated, and the aqueous phase was extracted with dichloromethane (500 mL). The organic phases were combined, washed with saturated brine (1 L x 2), dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure to obtain intermediate BB-3-3.

[0105] Step 3: Synthesis of intermediate BB-3-4 Under room temperature and nitrogen gas protection, intermediate BB-3-3 (198.1 g, 929.93 mmol) was dissolved in toluene (1.5 L), then ethyl triphenylphosphoranylidene (388.76 g, 1.12 mol) was added, and the reaction mixture was heated to 130°C and stirred for 36 hours. After the reaction was complete, the mixture was cooled to room temperature, concentrated under reduced pressure to remove the solvent, and methyl tert-butyl ether (700 mL x 3) was added to the resulting residue. The mixture was stirred at room temperature for 20 minutes, filtered, and the cake was rinsed with methyl tert-butyl ether (100 mL), and the filtrate was collected. The solvent was removed from the filtrate under reduced pressure, and the resulting residue was separated by column chromatography (eluent: petroleum ether / ethyl ethyl ether = 1 / 0 to 70 / 1, volume ratio) to obtain intermediate BB-3-4. 1 H NMR (400 MHz, CDCl3) δ: 7.72 (d, J = 2.0 Hz, 1H), 7.64 (s, 1H), 7.41 (dd, J=2.0 Hz, 8.8 Hz, 1H), 7.36 (d, J=8.8 Hz, 1H), 4.21 (q, J=7.0 Hz, 2H), 3.66 (d, J=0.8 Hz, 2H), 1.30 (t, J=7.2 Hz, 3H).

[0106] Step 4: Synthesis of intermediate BB-3 At room temperature, intermediate BB-3-4 (5 g, 17.66 mmol) was dissolved in N,N-dimethylformamide (50 mL), then acrylamide (1.51 g, 21.19 mmol) and potassium tert-butoxide (2.97 g, 26.49 mmol) were added sequentially, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was poured into 1 M dilute hydrochloric acid (200 mL) and extracted with ethyl acetate (100 mL x 2). The organic phases were combined, washed with 10% saline solution (150 mL x 2), dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. Ethyl acetate (30 mL) was added to the resulting residue, stirred for 10 minutes, filtered, the cake was collected, and vacuum-dried to obtain intermediate BB-3. MS-ESI m / z: 308.0 [M+H] + , 310.1 [M+H+2] + .

[0107] Reference example 4 [ka]

[0108] Synthesis route: [ka]

[0109] Step 1: Synthesis of intermediate BB-4-1 At room temperature and under nitrogen gas protection, intermediate BB-3-4 (5 g, 17.66 mmol), tert-butyl carbamate (2.48 g, 21.19 mmol), potassium phosphate (11.25 g, 52.98 mmol), tris(dibenzylideneacetone)dipalladium (323.44 mg, 353.21 μmol), and 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (299.98 mg, 706.42 μmol) were sequentially added to a mixed solvent of toluene (100 mL) and water (20 mL). The reaction mixture was heated to 110 °C and stirred for 16 hours. After the reaction was complete, the mixture was cooled to room temperature, water (100 mL) was added, and the mixture was filtered. The cake was rinsed with ethyl acetate (100 mL), the filtrates were combined, and the liquid was separated by standing to collect the organic phase. The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was removed by reducing the pressure of the filtrate. The resulting residue was separated by column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 5, volume ratio) to obtain intermediate BB-4-1. 1 H NMR (400 MHz, CDCl3) δ: 7.71 (br s, 1H), 7.62 (s, 1H), 7.37 (d, J=8.8 Hz, 1H), 7.15 (dd, J=2.0 Hz, 8.8 Hz, 1H), 6.58 (s, 1H), 4.20 (q, J=7.2 Hz, 2H), 3.67 (q, J=1.2 Hz, 2H), 1.53 (s, 9H), 1.29 (t, J=7.2 Hz, 3H).

[0110] Step 2: Synthesis of intermediate BB-4-2 At room temperature, intermediate BB-4-1 (5.6 g, 17.54 mmol) and acrylamide (1.50 g, 21.05 mmol) were dissolved in N,N-dimethylformamide (100 mL). Potassium tert-butoxide (1.8 g, 16.04 mmol) was then added, and the reaction mixture was stirred at room temperature for 2 hours. Potassium tert-butoxide (0.6 g, 5.35 mmol) was then added, and the reaction mixture was continued at room temperature for 0.5 hours with stirring. After the reaction was complete, the reaction solution was poured into 1 M dilute hydrochloric acid (300 mL), stirred for 10 minutes, filtered, and the cake was rinsed with water (100 mL) and collected. The obtained cake was separated by column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 1, volume ratio) to obtain intermediate BB-4-2. 1 H NMR (400 MHz, CDCl3) δ: 8.32 (br s, 1H), 7.72 (br s, 1H), 7.53 (s, 1H), 7.39 (d, J=8.8 Hz, 1H), 7.12 (dd, J=2.0 Hz, 8.8 Hz, 1H), 6.71 (br s, 1H), 3.97 (t, J=7.6 Hz, 1H), 2.82-2.63 (m, 2H), 2.39-2.29 (m, 2H), 1.53 (s, 9H).

[0111] Step 3: Synthesis of the hydrochloride salt of intermediate BB-4 At room temperature, intermediate BB-4-2 (2.3 g, 6.68 mmol) was dissolved in ethyl acetate (20 mL), then ethyl acetate hydrochloride solution (4 M, 40 mL) was added, and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was filtered, the cake was rinsed with ethyl acetate (20 mL), the cake was collected, and the mixture was vacuum-dried to obtain the hydrochloride salt of intermediate BB-4. 1H NMR (400 MHz, D2O) δ: 7.85 (s, 1H), 7.67 (d, J=8.8 Hz, 1H), 7.56 (d, J=1.6 Hz, 1H), 7.34 (dd, J=2.0 Hz, 8.8 Hz, 1H), 4.24 (dd, J=5.2 Hz, 12.4 Hz, 1H), 2.91-2.74 (m, 2H), 2.50-2.37 (m, 1H), 2.35-2.25 (m, 1H).

[0112] Reference example 5 [ka] Synthesis route: [ka]

[0113] Step 1: Synthesis of intermediate BB-5-2 Under room temperature and nitrogen gas protection, compound BB-5-1 (200 g, 930.04 mmol) was dissolved in chloroform (1 L) and ethyl acetate (1 L). Then copper bromide (415.45 g, 1.86 mol) was added, and the reaction mixture was heated to 90°C and stirred for 12 hours. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the cake was rinsed with dichloromethane (300 mL x 2). The filtrate was collected to obtain a solution of intermediate BB-5-2, which was used directly in the next step.

[0114] Step 2: Synthesis of intermediate BB-5-3 The solution of intermediate BB-5-2 (273 g, 928.76 mmol) obtained above was cooled to 0°C, and then triethylamine (140.97 g, 1.39 mol, 193.91 mL) was slowly added dropwise. After the addition was complete, the reaction mixture was slowly heated to room temperature and stirred for 1 hour. After the reaction was complete, water (600 mL) was added, the mixture was extracted, the liquid was separated, the organic phase was washed with saturated brine (1 L), dried over anhydrous sodium sulfate, filtered, and half of the solvent was removed from the filtrate under reduced pressure. Toluene (500 mL) was added, and the mixture was further concentrated under reduced pressure to remove the remaining low-boiling point solvent, obtaining a toluene solution of intermediate BB-5-3.

[0115] Step 3: Synthesis of intermediate BB-5-4 At room temperature and under nitrogen gas protection, toluene (2 L) was added to half of the toluene solution of intermediate BB-5-3, then ethyl triphenylphosphoranylidene (161.90 g, 464.73 mmol) was added, and the reaction mixture was heated to 130°C and stirred for 20 hours. After the reaction was complete, it was cooled to room temperature, and the two batches were combined and processed. The solvent was removed by reducing the pressure, and methyl tert-butyl ether (800 mL) was added to the resulting residue. The mixture was stirred at room temperature for 30 minutes, filtered, and the cake was rinsed with methyl tert-butyl ether (100 mL x 2). The solvent was removed from the filtrate under reduced pressure, and the resulting residue was separated by column chromatography (eluent: petroleum ether / ethyl ethyl ether = 100 / 1 to 10 / 1, volume ratio) to obtain intermediate BB-5-4. 1 H NMR (400 MHz, CDCl3) δ: 7.94 (s, 1H), 7.88 (s, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.44 (d, J = 8.4 Hz, 1H), 4.11 (q, J = 7.2 Hz, 2H), 3.79 (s, 2H), 1.19 (t, J = 7.2 Hz, 3H).

[0116] Step 4: Synthesis of intermediate BB-5 At room temperature, intermediate BB-5-4 (5.00 g, 17.66 mmol) was dissolved in N,N-dimethylformamide (50 mL), and then acrylamide (1.51 g, 21.19 mmol) and potassium tert-butoxide (2.97 g, 26.49 mmol) were added sequentially. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was poured into 1 M dilute hydrochloric acid (100 mL) and extracted with ethyl acetate (30 mL x 2). The organic phases were combined, washed with 10% saline solution (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. The resulting residue was separated by column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 1, volume ratio) to obtain intermediate BB-5. MS-ESI m / z: 308.0 [M+H] + , 310.0 [M+H+2] + . 1 H NMR (400 MHz, DMSO_d6) δ: 10.91 (s, 1H), 7.94 (s, 1H), 7.89 (d, J=1.6 Hz, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.42 (dd, J=1.6 Hz, 8.0 Hz, 1H), 4.15 (dd, J=4.8 Hz, 12.0 Hz, 1H), 2.80-2.68 (m, 1H), 2.58 (dt, J=4.0 Hz, 17.2 Hz, 1H), 2.38-2.25 (m, 1H), 2.15-2.05 (m, 1H).

[0117] Reference example 6 [ka] Synthesis route: [ka]

[0118] Step 1: Synthesis of intermediate BB-6-1 Under nitrogen gas protection at room temperature, the intermediate BB-5-4 (10 g, 35.32 mmol), tert-butyl carbamate (4.97 g, 42.39 mmol), potassium phosphate (22.49 g, 105.96 mmol), tris(dibenzylideneacetone)dipalladium (646.88 mg, 706.42 μmol), and 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (599.95 mg, 1.41 mmol) were dissolved in toluene (100 mL) and water (20 mL). The reaction mixture was heated to 110 °C and stirred for 12 hours. After the reaction was complete, the mixture was cooled to room temperature, water (100 mL) was added, and the mixture was extracted with ethyl acetate (70 mL x 3). The organic phases were combined, washed with saturated brine (70 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was reduced to remove the solvent. 70 mL of n-heptane was added to the residue, stirred at room temperature for 10 minutes, filtered, and the cake was collected. 50 mL of n-heptane was added again to the cake, stirred at room temperature for 10 minutes, filtered, the cake was rinsed with 3 x 10 mL of n-heptane, the cake was collected, and vacuum-dried to obtain intermediate BB-6-1. MS-ESI m / z: 264.2 [M-55] + . 1 H NMR (400 MHz, CDCl3) δ: 7.77 (s, 1H), 7.56 (s, 1H), 7.44 (d, J=8.4 Hz, 1H), 7.06 (dd, J=1.6 Hz, 8.4 Hz, 1H), 6.58 (s, 1H), 4.19 (q, J=7.0 Hz, 2H), 3.66 (s, 2H), 1.54 (s, 9H), 1.27 (t, J=7.2 Hz, 3H).

[0119] Step 2: Synthesis of intermediate BB-6-2 At room temperature, intermediate BB-6-1 (9.8 g, 30.69 mmol) and acrylamide (2.62 g, 36.83 mmol) were dissolved in N,N-dimethylformamide (100 mL), then potassium tert-butoxide (6.20 g, 55.24 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was poured into 0.5 M hydrochloric acid (120 mL), then water (300 mL) was added, and the mixture was extracted with ethyl acetate (150 mL x 3). The organic phases were combined, washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. Methyl tert-butyl ether (70 mL) was added to the resulting residue, stirred at room temperature for 0.5 hours, filtered, the cake was rinsed with methyl tert-butyl ether (10 mL x 3), the cake was collected, and vacuum-dried to obtain intermediate BB-6-2. 1 H NMR (400 MHz, DMSO_d6) δ: 10.88 (s, 1H), 9.47 (s, 1H), 7.78 (s, 2H), 7.43 (d, J= 8.8 Hz, 1H), 7.23 (dd, J= 1.4 Hz, 8.6 Hz, 1H), 4.07 (dd, J= 4.8 Hz, 12.0 Hz, 1H), 2.78-2.65 (m, 1H), 2.62-2.53 (m, 1H), 2.35-2.23 (m, 1H), 2.15-2.06 (m, 1H), 1.49 (s, 9H).

[0120] Step 3: Synthesis of the hydrochloride salt of intermediate BB-6 At room temperature, intermediate BB-6-2 (6.6 g, 19.17 mmol) was dissolved in dichloromethane (20 mL), then ethyl acetate hydrochloride solution (4 M, 150 mL) was added, and the reaction mixture was stirred at room temperature for 4 hours. After the reaction was complete, the solvent was removed by reducing the pressure to obtain the hydrochloride salt of intermediate BB-6. 1H NMR (400 MHz, DMSO_d6) δ: 10.92 (s, 1H), 10.06 (s, 2H), 7.98 (s, 1H), 7.66 (d, J= 8.4 Hz, 1H), 7.57 (d, J= 1.6 Hz, 1H), 7.21 (dd, J= 1.8 Hz, 8.2 Hz, 1H), 4.16 (dd, J= 4.8 Hz, 12.0 Hz, 1H), 2.81-2.69 (m, 1H), 2.63-2.54 (m, 1H), 2.39-2.26 (m, 1H), 2.16-2.07 (m, 1H).

[0121] Reference example 7 [ka] Synthesis route: [ka]

[0122] Step 1: Synthesis of intermediate BB-7-2 Under room temperature and nitrogen gas protection, intermediate BB-7-1 (11.39 g, 52.97 mmol) was dissolved in chloroform (100 mL) and ethyl acetate (100 mL). Then copper bromide (23.66 g, 105.93 mmol) was added, and the reaction mixture was heated to 110°C and stirred for 16 hours. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the solvent was removed from the filtrate under reduced pressure. Water (20 mL) was then added to the residue, and it was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. The resulting residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 100 / 1, volume ratio) to obtain intermediate BB-7-2. 1H NMR (400 MHz, CDCl3) δ: 12.39 (s, 1H), 7.81 (dd, J= 1.2 Hz, 8.0 Hz, 1H), 7.76 (dd, J= 1.2 Hz, 8.0 Hz, 1H), 6.88 (t, J=8.0 Hz, 1H), 4.47 (s, 2H).

[0123] Step 2: Synthesis of intermediate BB-7-3 At 0°C, intermediate BB-7-2 (6.86 g, 18.44 mmol) was dissolved in dichloromethane (80 mL), and then triethylamine (1.87 g, 18.44 mmol) was slowly added dropwise. The reaction mixture was slowly heated to room temperature and stirred for 1 hour. After the reaction was complete, the solvent was removed by direct concentration under reduced pressure to obtain the crude product of intermediate BB-7-3, which was used directly in the next step.

[0124] Step 3: Synthesis of intermediate BB-7-4 Under nitrogen gas protection at room temperature, the crude product of intermediate BB-7-3 (3.93 g, 18.45 mmol) was dissolved in toluene (80 mL), then ethyl triphenylphosphoranylidene (9.64 g, 27.67 mmol) was added, and the reaction mixture was heated to 130 °C and stirred for 36 hours. After the reaction was complete, the mixture was cooled to room temperature, concentrated under reduced pressure to remove the solvent, and then water (100 mL) was added to the residue and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. The resulting residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 100 / 1, volume ratio) to obtain intermediate BB-7-4. 1H NMR (400 MHz, CDCl3) δ: 7.72 (s, 1H), 7.52 (dd, J=0.8 Hz, 7.6 Hz, 1H), 7.48 (dd, J=0.8 Hz, 7.6 Hz, 1H), 7.15 (t, J=7.6 Hz, 1H), 4.20 (q, J=7.2 Hz, 2H), 3.70 (d, J=0.8 Hz, 2H), 1.28 (t, J=7.2 Hz, 3H).

[0125] Step 4: Synthesis of Intermediate BB-7 Under nitrogen gas protection at 0°C, intermediate BB-7-4 (4.77 g, 16.85 mmol) was dissolved in N,N-dimethylformamide (30 mL), and then acrylamide (1.20 g, 16.85 mmol) and potassium tert-butoxide (1.89 g, 16.85 mmol) were added sequentially. The reaction mixture was stirred at 0°C for 1 hour. After the reaction was complete, the mixture was poured into saturated ammonium chloride solution (50 mL), producing a large amount of white solid. The mixture was filtered, and the solid was collected. The solid was slurryed with methanol (20 mL x 2) at room temperature, filtered, and the cake was collected. The cake was then vacuum-dried to obtain intermediate BB-7. 1 H NMR (400 MHz, DMSO_d6) δ: 10.92 (s, 1H), 8.04 (s, 1H), 7.62 (dd, J=0.8 Hz, 7.6 Hz, 1H), 7.56 (d, J=7.6 Hz, 1H), 7.21 (t, J=7.6 Hz, 1H), 4.17 (dd, J=4.8 Hz, 12.0 Hz, 1H), 2.79-2.70 (m, 1H), 2.63-2.55 (m, 1H), 2.40-2.27 (m, 1H), 2.16-2.08 (m, 1H).

[0126] Reference example 8 [ka] Synthesis route: [ka]

[0127] Step 1: Synthesis of intermediate BB-8-1 Under room temperature and nitrogen gas protection, intermediate BB-7-4 (2 g, 7.06 mmol) was dissolved in toluene (50 mL) and water (5 mL). Then, tris(dibenzylideneacetone)dipalladium (647 mg, 706.42 μmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (450 mg, 1.06 mmol), potassium phosphate (6 g, 28.26 mmol), and tert-butyl carbamate (1.66 g, 14.13 mmol) were added sequentially. The reaction mixture was heated to 100 °C and stirred for 16 hours. After the reaction was complete, the mixture was cooled to room temperature, the reaction solution was poured into water (20 mL), and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated saline solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. The resulting residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 0 to 10 / 1, volume ratio) to obtain intermediate BB-8-1. 1 H NMR (400 MHz, CDCl3) δ: 7.93 (br s, 1H), 7.62 (s, 1H), 7.24-7.20 (m, 2H), 6.97 (s, 1H), 4.20 (q, J=6.8 Hz, 2H), 3.69 (d, J=0.8 Hz, 2H), 1.56 (s, 9H), 1.28 (t, J=7.2 Hz, 3H).

[0128] Step 2: Synthesis of intermediate BB-8 hydrochloride At room temperature, compound BB-8-1 (1.32 g, 4.13 mmol) was dissolved in ethyl acetate (3 mL), then ethyl acetate hydrochloride solution (4 M, 15 mL) was added, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the solvent was removed by direct concentration under reduced pressure to obtain the hydrochloride salt of the intermediate BB-8.

[0129] Reference example 9 [ka] Synthesis route: [ka]

[0130] Step 1: Synthesis of intermediate BB-9-2 At 0°C, concentrated sulfuric acid (103.08 g, 1.03 mol, 56.02 mL, purity: 98%) was slowly added dropwise to a mixture of compound BB-9-1 (25 g, 112.07 mmol) and ethyl 4-chloroacetoethyl acetate (18.45 g, 112.07 mmol), while controlling the internal temperature to 0-5°C. After the addition was complete, the reaction mixture was raised to room temperature and stirred for 12 hours. Four batches were processed together. After the reaction was complete, the reaction solution was slowly poured into ice water (3 L) while stirring, stirred at room temperature for 10 minutes, filtered, the cake was collected, and vacuum-dried to obtain intermediate BB-9-2. MS-ESI m / z: 323.0 [M+H] + , 325.0 [M+H+2] + .

[0131] Step 2: Synthesis of intermediate BB-9-3 At room temperature, sodium hydroxide (17.65 g, 441.36 mmol) was dissolved in water (700 mL), and then intermediate BB-9-2 (54.40 g, 110.34 mmol, purity: 65.63%) was added. The reaction mixture was heated to 80°C and stirred for 12 hours. Three batches were processed together. After the reaction was complete, the mixture was cooled to room temperature, filtered, the cake was washed with water (500 mL), the cake was collected, and vacuum-dried to obtain intermediate BB-9-3. 1 H NMR (400 MHz, DMSO_d6) δ: 8.50 (d, J = 9.2 Hz, 1H), 8.26 (d, J=2.4 Hz, 1H), 7.84 (s, 1H), 7.76 (d, J=1.6 Hz, 2H), 7.63 (dd, J=2.0 Hz, 8.8 Hz, 1H), 3.50 (s, 2H).

[0132] Step 3: Synthesis of intermediate BB-9-4 At room temperature, intermediate BB-9-3 (33.16 g, 101.37 mmol) was dissolved in ethanol (300 mL), and concentrated sulfuric acid (27.19 g, 271.68 mmol, 14.78 mL, purity: 98%) was slowly added dropwise. The reaction mixture was heated to 80°C and stirred for 12 hours. Two batches were combined and processed. After the reaction was complete, the mixture was cooled to room temperature and concentrated under reduced pressure to remove the solvent. Water (600 mL) was added to the resulting residue and extracted with ethyl acetate (200 mL x 2). The organic phases were combined and washed sequentially with aqueous sodium hydroxide solution (2 M, 300 mL) and saturated brine (500 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure to obtain intermediate BB-9-4. 1 H NMR (400 MHz, CDCl3) δ : 8.13-8.06 (m, 2H), 7.78 (s, 1H), 7.69-7.60 (m, 3H), 4.23 (q, J=7.2 Hz, 2H), 4.03 (s, 2H), 1.27 (t, J=7.2 Hz, 3H).

[0133] Step 4: Synthesis of intermediate BB-9-5 Under room temperature and nitrogen gas protection, the intermediate BB-9-4 (1 g, 3.00 mmol), tris(dibenzylideneacetone)dipalladium (275 mg, 300.14 μmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (191.18 mg, 450.21 mmol), potassium phosphate (2.55 g, 12.01 mmol), and tert-butyl carbamate (527.41 mg, 4.50 mmol) were dissolved in a mixed solvent of toluene (50 mL) and water (5 mL). The reaction mixture was heated to 100 °C and stirred for 12 hours. After the reaction was complete, the mixture was cooled to room temperature, the reaction solution was poured into water (20 mL), and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated saline solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by reducing the pressure of the filtrate. The resulting residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 0 to 10 / 1, volume ratio) to obtain intermediate BB-9-5. MS-ESI m / z: 392.2 [M+Na]+ . 1 1H NMR (400 MHz, CDCl3) δ: 8.14 (d, J = 9.2 Hz, 1H), 8.12 (br s, 1H), 7.74 (s, 1H), 7.67 (d, J = 9.2 Hz, 1H), 7.62 (d, J = 8.8 Hz, 1H), 7.45 (dd, J = 2.2 Hz, 9.0 Hz, 1H), 6.64 (br s, 1H), 4.22 (q, J = 7.0 Hz, 2H), 4.04 (s, 2H), 1.57 (s, 9H), 1.27 (t, J = 7.2 Hz, 3H).

[0134] Step 5: Synthesis of Intermediate BB-9-6 Under 0 °C and nitrogen gas protection, Intermediate BB-9-5 (1.13 g, 2.74 mmol, purity: 89.57%) and acrylamide (234 mg, 3.29 mmol) were dissolved in N,N-dimethylformamide (10 mL). Then potassium tert-butoxide (368.93 mg, 3.29 mmol) was added, and the reaction mixture was stirred at 0 °C for 1 hour for reaction. After the reaction was completed, the reaction solution was slowly poured into a saturated ammonium chloride aqueous solution (30 mL) and extracted with ethyl acetate (15 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. Methanol (10 mL) was added to the obtained residue, stirred at room temperature for 0.5 hour, filtered, and the cake was collected and dried under vacuum to obtain Intermediate BB-9-6. MS-ESI m / z: 417.0 [M+Na-100] + . 1H NMR (400 MHz, CDCl3) δ: 8.13 (br s, 1H), 8.08 (br s, 1H), 7.90 (d, J=8.8 Hz, 1H), 7.71 (d, J=9.2 Hz, 1H), 7.67-7.62 (m, 2H), 7.48 (dd, J=2.4 Hz, 8.8 Hz, 1H), 6.67 (br s, 1H), 4.47 (dd, J= 5.4 Hz, 8.6 Hz, 1H), 2.85-2.71 (m, 2H), 2.55-2.40 (m, 2H), 1.57 (s, 9H).

[0135] Step 6: Synthesis of the hydrochloride salt of intermediate BB-9 At room temperature, intermediate BB-9-6 (421 mg, 1.07 mmol) was dissolved in hydrochloric acid / dioxane solution (4 M, 20 mL), and the reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete, the reaction solution was cooled and poured into saturated ammonium chloride solution (100 mL), extracted with ethyl acetate (10 mL x 3), combined the organic phases, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried. The resulting residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1, volume ratio) to obtain the hydrochloride salt of intermediate BB-9. MS-ESI m / z: 294.9 [M+H] + . 1 H NMR (400 MHz, DMSO_d6) δ: 10.95 (br s, 1H), 8.23 ​​(d, J=9.2 Hz, 1H), 8.04 (s, 1H), 7.88-7.81 (m, 3H), 7.48-7.42 (m, 1H), 4.66 (dd, J=4.4 Hz, 12.4 Hz, 1H), 2.92-2.81 (m, 1H), 2.69-2.60 (m, 1H), 2.46-2.38 (m, 1H), 2.31-2.23 (m, 1H).

[0136] Reference example 10 [ka] Synthesis Route:

Chem.

[0140] Step 2: Synthesis of intermediate BB-11-3 Under nitrogen gas protection at room temperature, intermediate BB-11-2 (87 g, 363.85 mmol) was dissolved in toluene (1 L), cooled to 0°C, and 2,3-dichloro-5,6-dicyanobenzoquinone (90.86 g, 400.24 mmol) was slowly added in batches. The reaction mixture was slowly heated to room temperature and stirred for 15 hours. After the reaction was complete, saturated sodium sulfite aqueous solution (2 L) was added dropwise and stirred for 10 minutes. Then 1 N sodium hydroxide aqueous solution (1 L) was added, and the mixture was extracted with ethyl acetate (500 mL x 3). The organic phases were combined, washed with saturated brine (1 L), dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. Petroleum ether (500 ml) was added to the resulting residue and stirred for 10 minutes. The mixture was filtered, the cake was rinsed with petroleum ether (50 mL x 2), the filtrate was collected, and the solvent was removed by concentrating the filtrate under reduced pressure. The resulting residue was separated by column chromatography (eluent: petroleum ether) to obtain intermediate BB-11-3. 1H NMR (400 MHz, CDCl3) δ: 8.12 (d, J=9.2 Hz, 1H), 7.68 (d, J=8.4 Hz, 1H), 7.60 (d, J=7.6 Hz, 1H), 7.26-7.20 (m, 2H), 7.11 (d, J=2.4 Hz, 1H), 3.92 (s, 3H).

[0141] Step 3: Synthesis of intermediate BB-11-4 Under nitrogen gas protection at room temperature, intermediate BB-11-3 (21.4 g, 90.26 mmol) was dissolved in dichloromethane (250 mL), cooled to 0°C, and boron tribromide (27.13 g, 108.31 mmol, 10.44 mL) was slowly added dropwise. After the addition was complete, the reaction mixture was heated to room temperature and stirred for 3 hours. After the reaction was complete, the reaction solution was poured into ice water (500 mL) and extracted with dichloromethane (200 mL). The organic phase was washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure to obtain intermediate BB-11-4. 1 H NMR (400 MHz, CDCl3) δ:8.15 (d, J=98.8 Hz, 1H), 7.65-7.59 (m, 2H), 7.25 (t, J=7.8 Hz, 1H), 7.19 (dd, J=2.4 Hz, 9.2 Hz, 1H), 7.14 (d, J=2.4 Hz, 1H), 5.03 (s, 1H).

[0142] Step 4: Synthesis of intermediate BB-11-5 At room temperature, intermediate BB-11-4 (20 g, 89.66 mmol) was dissolved in methanesulfonic acid (200 mL), and ethyl 4-chloroacetoethyl acetate (22.14 g, 134.49 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 15 hours. After the reaction was complete, the reaction solution was poured into ice water (1 L), stirred at room temperature for 10 minutes, filtered, the cake was rinsed with water (200 mL x 3), the cake was collected, and the mixture was vacuum-dried to obtain intermediate BB-11-5. 1H NMR (400 MHz, DMSO_d6) δ: 8.58 (d, J=9.2 Hz, 1H), 8.49 (d, J=9.2 Hz, 1H), 8.02 (d, J=7.2 Hz, 1H), 7.74 (d, J=9.2 Hz, 1H), 7.65 (dd, J=7.6 Hz, 8.4 Hz, 1H), 6.93 (s, 1H), 5.41 (s, 2H).

[0143] Step 5: Synthesis of intermediate BB-11-6 At room temperature, intermediate BB-11-5 (29 g, 89.63 mmol) was added to an aqueous solution of sodium hydroxide (2 M, 300 mL), and the reaction mixture was heated to 80°C and stirred for 3 hours. After the reaction was complete, the mixture was cooled to room temperature, water (200 mL) was added, the pH was adjusted to 4 with 6 M hydrochloric acid, and the mixture was extracted with ethyl acetate (300 mL x 3). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. Methyl tert-butyl ether (50 mL) was added to the resulting residue, stirred at room temperature for 10 minutes, filtered, the cake was rinsed with methyl tert-butyl ether (10 mL x 2), the cake was collected, and vacuum-dried to obtain intermediate BB-11-6. MS-ESI m / z: 305.0 [M+H] + , 306.9 [M+H+2] + . 1 H NMR (400 MHz, DMSO_d6) δ : 12.68 (br s, 1H), 8.24 (d, J=8.4 Hz, 1H), 8.12 (t, J=4.6 Hz, 2H), 7.96 (d, J=9.2 Hz, 1H), 7.90 (d, J=7.6 Hz, 1H), 7.54 (t, J=7.8 Hz, 1H), 4.09 (s, 2H).

[0144] Step 6: Synthesis of intermediate BB-11-7 At room temperature, intermediate BB-11-6 (18 g, 58.99 mmol) was dissolved in ethanol (180 mL), concentrated sulfuric acid (5.31 g, 53.09 mmol, 2.89 mL, purity: 98%) was added, and the reaction mixture was heated to 80°C and stirred for 15 hours. After the reaction was complete, the mixture was cooled to room temperature, concentrated under reduced pressure to remove the solvent, and ethyl acetate (300 mL) and saturated sodium bicarbonate aqueous solution (500 mL) were added to the residue. Extraction was performed, and the liquid was separated. The organic phase was washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. Petroleum ether (50 mL) was added to the residue, stirred at room temperature for 10 minutes, filtered, the cake was rinsed with petroleum ether (20 mL x 2), the cake was collected, and vacuum dried to obtain intermediate BB-11-7. 1 H NMR (400 MHz, CDCl3) δ: 8.22 (t, J=8.4 Hz, 2H), 7.84-7.78 (m, 2H), 7.75 (d, J=9.2 Hz, 1H), 7.41 (dd, J=7.6 Hz, 8.4 Hz, 1H), 4.23 (q, J=7.0 Hz, 2H), 4.06 (d, J=0.8 Hz, 2H), 1.26 (t, J=7.2 Hz, 3H).

[0145] Step 7: Synthesis of intermediate BB-11-8 Under room temperature and nitrogen gas protection, the intermediate BB-11-7 (5 g, 15.01 mmol), tris(dibenzylideneacetone)dipalladium (961.96 mg, 1.05 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (892.16 mg, 2.10 mmol), potassium phosphate (12.74 g, 60.03 mmol), and tert-butyl carbamate (2.64 g, 22.51 mmol) were dissolved in a mixed solvent of toluene (50 mL) and water (10 mL). The reaction mixture was heated to 100 °C and stirred for 15 hours. After the reaction was complete, the mixture was cooled to room temperature, filtered, the cake was rinsed with ethyl acetate (30 mL x 3), the filtrate was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. 50 mL of methyl tert-butyl ether was added to the residue, stirred at room temperature for 10 minutes, filtered, the cake was rinsed with 10 mL x 2 of methyl tert-butyl ether, the cake was collected, and vacuum-dried to obtain intermediate BB-11-8.

[0146] Step 8: Synthesis of intermediate BB-11-9 Under nitrogen gas protection at room temperature, the intermediate BB-11-8 (4.2 g, 11.37 mmol) and acrylamide (888.93 mg, 12.51 mmol) were dissolved in N,N-dimethylformamide (40 mL), cooled to 0°C, and potassium tert-butoxide (2.55 g, 22.74 mmol) dissolved in N,N-dimethylformamide (10 mL) was added dropwise. The reaction mixture was heated to room temperature and stirred for 2 hours. After the reaction was complete, the reaction solution was poured into 0.2 M hydrochloric acid (200 mL) and extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. Dichloromethane (20 mL) was added to the resulting residue, stirred at room temperature for 10 minutes, filtered, the cake was rinsed with dichloromethane (10 mL), the cake was collected, and vacuum-dried to obtain intermediate BB-11-9. 1H NMR (400 MHz, DMSO_d6) δ: 10.94 (s, 1H), 9.28 (s, 1H), 8.05-7.92 (m, 3H), 7.79 (d, J=9.6 Hz, 1H), 7.58-7.47 (m, 2H), 4.68 (dd, J=4.4 Hz, 12.0 Hz, 1H), 2.95-2.81 (m, 1H), 2.70-2.56 (m, 1H), 2.47-2.34 (m, 1H), 2.33-2.22 (m, 1H), 1.49 (s, 9H).

[0147] Step 9: Synthesis of the hydrochloride salt of intermediate BB-11 At room temperature, intermediate BB-11-9 (1.3 g, 3.30 mmol) was dissolved in ethyl acetate (5 mL), then ethyl acetate hydrochloride solution (4 M, 50 mL) was added, and the reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the solvent was removed by concentrating under reduced pressure to obtain the hydrochloride salt of intermediate BB-11.

[0148] Reference example 12 [ka] Synthesis route: [ka]

[0149] Synthesis of intermediate BB-12 Under nitrogen gas protection at room temperature, acrylamide (234.67 mg, 3.30 mmol) and intermediate BB-11-7 (1 g, 3.00 mmol) were dissolved in N,N-dimethylformamide (15 mL). Potassium tert-butoxide (370.47 mg, 3.30 mmol) was then added, and the reaction mixture was stirred at room temperature for 0.5 hours. After the reaction was complete, the reaction solution was poured into 0.1 M hydrochloric acid (10 mL) and extracted with dichloromethane (5 mL x 2). The organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. Dichloromethane (5 mL) was added to the resulting residue, stirred at room temperature for 1 hour, filtered, and the cake was rinsed with dichloromethane (1 mL). The cake was collected and vacuum-dried to obtain intermediate BB-12. MS-ESI m / z: 358.1 [M+H] + , 360.1 [M+H+2] + .

[0150] Reference example 13 [ka] Synthesis route: [ka]

[0151] Step 1: Synthesis of intermediate BB-13-2 Under nitrogen gas protection at room temperature, compound BB-13-1 (150 g, 632.67 mmol) was dissolved in dichloromethane (3 L), then acetyl chloride (49.66 g, 632.67 mmol, 45.15 mL) was added, the reaction mixture was cooled to 5-15°C, aluminum trichloride (177.16 g, 1.33 mol) was added in batches, the reaction mixture was raised to room temperature and stirred for 4 hours. Aluminum trichloride (29.53 g, 221.43 mmol) was added, and the reaction was continued at room temperature with stirring for 12 hours. After the reaction was complete, the reaction solution was slowly poured into ice water (3 L), extracted, the liquid was separated, and the aqueous phase was extracted again with dichloromethane (2 L x 2). The organic phases were combined, washed with saturated brine (6 L x 2), dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure to obtain intermediate BB-13-2. MS-ESI m / z: 265.1 [M+H] + , 267.1 [M+H+2] + .

[0152] Step 2: Synthesis of intermediate BB-13-3 Under nitrogen gas protection at room temperature, intermediate BB-13-2 (200 g, 754.43 mmol) and dimethyl carbonate (271.83 g, 3.02 mol, 254.04 mL) were dissolved in tetrahydrofuran (2 L), cooled to 0°C, and potassium tert-butoxide (507.93 g, 4.53 mol) was slowly added. The reaction mixture was heated to 70°C and stirred for 12 hours. After the reaction was complete, the mixture was cooled to room temperature, concentrated under reduced pressure to remove the solvent, and ice water (4 L) was added to the residue. The pH was adjusted to 2-3 with 6 M hydrochloric acid to precipitate a large amount of solid. The mixture was filtered, and the cake was sequentially rinsed with water (1 L) and methyl tert-butyl ether (1 L). The cake was collected and vacuum-dried to obtain intermediate BB-13-3. MS-ESI m / z: 291.0 [M+H] + , 293.0 [M+H+2] + . 1H NMR (400 MHz, DMSO_d6) δ: 9.18 (d, J=9.2 Hz, 1H), 8.30 (d, J=1.2 Hz, 1H), 8.16 (d, J=8.8Hz, 1H), 7.79 (d, J=7.6 Hz, 1H), 7.56 (d, J=8.8 Hz, 1H), 5.83 (s, 1H).

[0153] Step 3: Synthesis of intermediate BB-13-4 At room temperature, intermediate BB-13-3 (200 g, 687.06 mmol), sodium acetate (309.99 g, 3.78 mol), and hydroxylamine hydrochloride (262.59 g, 3.78 mol) were dissolved in ethanol (2 L). The reaction mixture was heated to 80°C and stirred for 12 hours. After the reaction was complete, the mixture was cooled to room temperature, poured into water (2 L), concentrated under reduced pressure to remove the solvent, adjusted the pH to 2-3 with 2 M hydrochloric acid, and extracted with ethyl acetate / tetrahydrofuran = 1 / 1 (2 L x 3, volume ratio). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. Methyl tert-butyl ether (600 mL) was added to the residue, stirred at room temperature for 1 hour, filtered, the cake was collected, and vacuum-dried to obtain intermediate BB-13-4. MS-ESI m / z: 306.0 [M+H] + , 308.0 [M+H+2] + .

[0154] Step 4: Synthesis of intermediate BB-13-5 At room temperature, concentrated sulfuric acid (33.38 g, 333.49 mmol, 18.14 mL, purity: 98%) was dissolved in ethanol (1.3 L). Intermediate BB-13-4 (135 g, 373.32 mmol, purity: 84.65%) was added, and the reaction mixture was heated to 75°C and stirred for 16 hours. After the reaction was complete, the mixture was cooled to room temperature and concentrated under reduced pressure to remove the solvent. Ethanol (600 mL) was added to the residue, and the mixture was stirred at room temperature for 5 minutes. The mixture was filtered, the cake was rinsed with ethanol (100 mL x 2), the cake was collected, and the mixture was vacuum-dried to obtain intermediate BB-13-5. MS-ESI m / z: 334.1 [M+H] + , 336.0 [M+H+2]+ . 1 H NMR (400 MHz, DMSO_d6) δ: 8.47 (d, J=1.6 Hz, 1H), 8.19 (d, J=9.2 Hz, 1H), 8.08 (d, J=8.8 Hz, 1H), 8.00 (d, J=9.2 Hz, 1H), 7.89 (dd, J=2.0 Hz, 8.8 Hz, 1H), 4.51 (s, 2H), 4.14 (q, J=7.2 Hz, 2H), 1.16 (t, J=7.2 Hz, 3H).

[0155] Step 5: Synthesis of intermediate BB-13-6 At room temperature and under nitrogen gas protection, intermediate BB-13-5 (15 g, 44.89 mmol), tris(dibenzylideneacetone)dipalladium (1.44 g, 1.57 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (1.33 g, 3.14 mmol), potassium phosphate (38.11 g, 179.55 mmol), and tert-butyl carbamate (7.89 g, 67.33 mmol) were sequentially added to a mixed solvent of toluene (150 mL) and water (30 mL). The reaction mixture was heated to 100 °C and stirred for 12 hours. After the reaction was complete, the mixture was cooled to room temperature, water (100 mL) and ethyl acetate (150 mL) were added, and the mixture was extracted. The liquid was separated, and the aqueous phase was extracted again with ethyl acetate (200 mL x 3). The organic phases were combined, washed with saturated saline solution (200 mL x 3), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by reducing the pressure of the filtrate. The resulting residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 20 / 1 to 1 / 1, volume ratio) to obtain intermediate BB-13-6. MS-ESI m / z: 371.2 [M+H] + . 1H NMR (400 MHz, CDCl3) δ: 8.20 (br s, 1H), 8.03 (d, J=8.8 Hz, 1H), 7.90 (d, J=9.2 Hz, 1H), 7.67 (d, J=9.2 Hz, 1H), 7.53 (dd, J=2.0 Hz, 8.8 Hz, 1H), 6.75 (s, 1H), 4.31 (s, 2H), 4.21 (q, J=7.2 Hz, 2H), 1.57 (s, 9H), 1.20 (t, J=7.2 Hz, 3H).

[0156] Step 6: Synthesis of intermediate BB-13-7 Under nitrogen gas protection at room temperature, intermediate BB-13-6 (7.3 g, 19.71 mmol) and acrylamide (1.54 g, 21.68 mmol) were dissolved in tetrahydrofuran (70 mL), cooled to 0°C, potassium tert-butoxide (2.43 g, 21.68 mmol) was added, and the reaction mixture was heated to room temperature and stirred for 1 hour. After the reaction was complete, the reaction solution was poured into 0.1 M hydrochloric acid (30 mL) and extracted with ethyl acetate (80 mL x 3). The organic phases were combined, washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. Dichloromethane (5 mL) was added to the resulting residue, stirred at room temperature for 5 minutes, filtered, the cake was rinsed with dichloromethane (3 mL), the cake was collected, and vacuum-dried to obtain intermediate BB-13-7. MS-ESI m / z: 396.2 [M+H] + . 1H NMR (400 MHz, DMSO_d6) δ: 11.12 (s, 1H), 9.66 (s, 1H), 8.36 (s, 1H), 8.13 (d, J=8.8 Hz, 1H), 8.07 (d, J=8.8 Hz, 1H), 7.85 (d, J=9.2 Hz, 1H), 7.68 (dd, J=2.0 Hz, 8.8 Hz, 1H), 5.00 (dd, J=4.8 Hz, 11.6 Hz, 1H), 2.89-2.76 (m, 1H), 2.68-2.60 (m, 1H), 2.59-2.53 (m, 1H), 2.42-2.30 (m, 1H), 1.52 (s, 9H).

[0157] Step 7: Synthesis of the hydrochloride salt of intermediate BB-13 At room temperature, intermediate BB-13-7 (1 g, 2.53 mmol) was dissolved in ethyl acetate (5 mL), then ethyl acetate hydrochloride solution (4 M, 20 mL) was added, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was filtered, the cake was rinsed with ethyl acetate (3 mL x 3), the cake was collected, and the mixture was vacuum-dried to obtain the hydrochloride salt of intermediate BB-13. MS-ESI m / z: 295.9 [M+H] + .

[0158] Reference example 14 [ka] Synthesis route: [ka]

[0159] Synthesis of intermediate BB-14 Under nitrogen gas protection at room temperature, intermediate BB-13-5 (3 g, 8.98 mmol) and acrylamide (701.92 mg, 9.88 mmol) were dissolved in tetrahydrofuran (70 mL), cooled to 0°C, and potassium tert-butoxide (1.21 g, 10.77 mmol) was added in batches. The reaction mixture was heated to room temperature and stirred for 1 hour. After the reaction was complete, the reaction solution was poured into 1 M hydrochloric acid (20 mL) and extracted with ethyl acetate (40 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. Methyl tert-butyl ether (20 mL) was added to the resulting residue, stirred at room temperature for 10 minutes, filtered, the cake was rinsed with methyl tert-butyl ether (5 mL x 2), the cake was collected, and vacuum-dried to obtain intermediate BB-14. MS-ESI m / z: 359.0 [M+H] + , 361.0 [M+H+2] + . 1 H NMR (400 MHz, DMSO_d6) δ: 11.14 (s, 1H), 8.47 (d, J=2.0 Hz, 1H), 8.24-8.17 (m, 2H), 8.01 (d, J=9.2 Hz, 1H), 7.85 (dd, J=2.0 Hz, 8.8 Hz, 1H), 5.06 (dd, J=4.8 Hz, 11.6 Hz, 1H), 2.89-2.78 (m, 1H), 2.70-2.56 (m, 2H), 2.44-2.34 (m, 1H).

[0160] Reference example 15 [ka] Synthesis route: [ka]

[0161] Step 1: Synthesis of intermediate BB-15-2 Under nitrogen gas protection at room temperature, triphenyl phosphite (193.69 g, 624.25 mmol) was dissolved in dichloromethane (1 L), cooled to -70°C, and liquid bromine (108.83 g, 681.00 mmol, 35.11 mL) was added dropwise. After the addition was complete, triethylamine (74.65 g, 737.75 mmol, 102.69 mL) and compound BB-15-1 (100 g, 567.50 mmol) dissolved in dichloromethane (500 mL) were added dropwise in sequence. After the addition was complete, the reaction mixture was slowly heated to room temperature and stirred for 15 hours. After the reaction was complete, the mixture was poured into saturated sodium sulfite aqueous solution (700 mL), stirred for 10 minutes, and extracted with dichloromethane (800 mL). The organic phase was washed with saturated saline solution (800 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. The resulting residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 20 / 1 to 7 / 1, volume ratio) to obtain intermediate BB-15-2. 1 H NMR (400 MHz, DMSO_d6) δ: 7.33 (d, J=8.0 Hz, 1H), 6.84-6.75 (m, 2H), 6.33 (t, J=4.8 Hz, 1H), 3.75 (s, 3H), 2.76 (t, J=8.0 Hz, 2H), 2.32-2.25 (m, 2H).

[0162] Step 2: Synthesis of intermediate BB-15-3 Under nitrogen gas protection at room temperature, intermediate BB-15-2 (39.5 g, 165.20 mmol) was dissolved in toluene (500 mL), cooled to 0°C, and 2,3-dichloro-5,6-dicyanobenzoquinone (41.25 g, 181.72 mmol) was added in batches. The reaction mixture was slowly heated to room temperature and stirred for 12 hours. After the reaction was complete, the mixture was cooled to 0-10°C, saturated sodium sulfite aqueous solution (1 L) and 1 M sodium hydroxide aqueous solution (1 L) were added dropwise, the mixture was filtered, the cake was rinsed with ethyl acetate (300 mL x 3), the cake was discarded, and the filtrate was extracted with ethyl acetate (500 mL x 3). The organic phases were combined, washed with saturated brine (500 mL x 2), dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. The resulting residue was separated by column chromatography (eluent: petroleum ether) to obtain intermediate BB-15-3. MS-ESI m / z: 237.1 [M+H] + , 239.1 [M+H+2] + . 1 H NMR (400 MHz, CDCl3) δ: 8.05 (d, J=9.2 Hz, 1H), 7.60 (d, J=8.0 Hz, 1H), 7.53 (d, J=7.2 Hz, 1H), 7.22-7.13 (m, 2H), 7.04 (s, 1H), 3.85 (s, 3H).

[0163] Step 3: Synthesis of intermediate BB-15-4 At room temperature and under nitrogen gas protection, acetic anhydride (21.53 g, 210.89 mmol, 19.75 mL) was added to dichloromethane (400 mL), cooled to -60°C, and boron trifluoride ethyl ether solution (63.68 g, 210.89 mmol, 55.38 mL, purity: 47%) was added dropwise. The mixture was stirred at -60°C for 10 minutes, and the intermediate BB-15-3 solution (25 g, 105.44 mmol) dissolved in dichloromethane (250 mL) was added dropwise. The reaction mixture was slowly raised to room temperature and stirred for 12 hours. After the reaction was complete, ice water (200 mL) was added, and the mixture was extracted with dichloromethane (100 mL x 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. The resulting residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 100 / 1 to 20 / 1) to obtain intermediate BB-15-4. MS-ESI m / z: 279.0 [M+H] + , 281.0 [M+H+2] + . 1 H NMR (400 MHz, CDCl3) δ: 8.34 (d, J=9.2 Hz, 1H), 7.72 (d, J=8.4 Hz, 1H), 7.67 (dd, J=0.8 Hz, 7.2 Hz, 1H), 7.38 (d, J=9.2 Hz, 1H), 7.31 (dd, J=7.6 Hz, 8.8 Hz, 1H), 4.01 (s, 3H), 2.65 (s, 3H).

[0164] Step 4: Synthesis of intermediate BB-15-5 Under room temperature and nitrogen gas protection, intermediate BB-15-4 (18.8 g, 67.35 mmol) was dissolved in dichloromethane (200 mL), cooled to 0°C, and boron tribromide (20.25 g, 80.82 mmol, 7.79 mL) was added dropwise. The mixture was stirred at 0°C for 1 hour to allow the reaction to proceed. After the reaction was complete, the reaction solution was poured into ice water (300 mL) and extracted with dichloromethane (100 mL x 3). The organic phases were combined, washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure to obtain intermediate BB-15-5. 1H NMR (400 MHz, CDCl3) δ: 13.05 (s, 1H), 8.41 (d, J=9.2 Hz, 1H), 8.04 (d, J=8.8 Hz, 1H), 7.70 (dd, J=0.8 Hz, 7.6 Hz, 1H), 7.40 (dd, J=7.6 Hz, 8.4 Hz, 1H), 7.25 (d, J=9.6 Hz, 1H), 2.85 (s, 3H).

[0165] Step 5: Synthesis of intermediate BB-15-6 Under room temperature and nitrogen gas protection, intermediate BB-15-5 (13 g, 49.04 mmol) and dimethyl carbonate (17.67 g, 196.15 mmol, 16.51 mL) were dissolved in tetrahydrofuran (130 mL), cooled to 0-10°C, and potassium tert-butoxide (33.02 g, 294.23 mmol) was added in batches. The reaction mixture was heated to 70°C and stirred for 12 hours. After the reaction was complete, the mixture was cooled to room temperature, concentrated under reduced pressure to remove the solvent, and the residue was added to ice water (200 mL) and extracted with methyl tert-butyl ether (70 mL x 2). The aqueous phase was adjusted to pH=2 with 6 M hydrochloric acid, a large amount of solid was precipitated, filtered, the cake was washed with water (30 mL x 2), the cake was collected, and vacuum-dried to obtain intermediate BB-15-6. MS-ESI m / z: 291.0 [M+H] + , 293.0 [M+H+2] + . 1 H NMR (400 MHz, DMSO_d6) δ: 13.28 (br s, 1H), 9.38 (t, J=7.2 Hz, 1H), 8.43 (dd, J=6.8 Hz, 9.2 Hz, 1H), 7.96 (t, J=7.2 Hz, 1H), 7.71-7.65 (m, 1H), 7.63-7.56 (m, 1H), 5.92-5.87 (m, 1H).

[0166] Step 6: Synthesis of intermediate BB-15-7 At room temperature, intermediate BB-15-6 (22 g, 75.58 mmol), sodium acetate (43.40 g, 529.03 mmol), and hydroxylamine hydrochloride (36.76 g, 529.03 mmol) were dissolved in ethanol (400 mL). The reaction mixture was heated to 80°C and stirred for 12 hours. After the reaction was complete, the mixture was cooled to room temperature and concentrated under reduced pressure to remove the solvent. Water (100 mL) and methyl tert-butyl ether (50 mL) were added to the residue, and the mixture was stirred at room temperature for 0.5 hours. The mixture was filtered, the cake was rinsed with methyl tert-butyl ether (20 mL x 3), the cake was collected, and the mixture was vacuum-dried to obtain intermediate BB-15-7. MS-ESI m / z: 306.0 [M+H] + , 308.0 [M+H+2] + . 1 H NMR (400 MHz, DMSO_d6) δ: 8.40 (d, J=9.2 Hz, 1H), 8.27 (d, J=8.4 Hz, 1H), 8.05 (d, J=9.2 Hz, 1H), 7.96 (d, J=7.6 Hz, 1H), 7.62 (t, J=8.0 Hz, 1H), 4.25 (s, 2H).

[0167] Step 7: Synthesis of intermediate BB-15-8 At room temperature, intermediate BB-15-7 (15g, 49.00 mmol) was dissolved in ethanol (300 mL), concentrated sulfuric acid (1.29g, 12.87 mmol, 0.7 mL, purity: 98%) was added, and the reaction mixture was heated to 80°C and stirred for 12 hours. After cooling to room temperature, concentrated sulfuric acid (4 mL, purity: 98%) was added, and the reaction mixture was heated to 80°C and stirred for 3 hours. After the reaction was complete, the mixture was cooled to room temperature and concentrated under reduced pressure to remove the solvent. A saturated sodium bicarbonate solution (100 mL) at 0-10°C was added to the residue, and it was extracted with ethyl acetate (70 mL x 3). The organic phases were combined, washed with saturated brine (70 mL x 2), dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure to obtain intermediate BB-15-8. MS-ESI m / z: 334.0 [M+H] + , 336.0 [M+H+2] + . 1H NMR (400 MHz, CDCl3) δ: 8.50 (d, J=9.6 Hz, 1H), 8.10 (d, J=8.4 Hz, 1H), 7.88 (dd, J=0.8 Hz, 7.6 Hz, 1H), 7.81 (d, J=9.2 Hz, 1H), 7.52 (t, J=8.0 Hz, 1H), 4.34 (s, 2H), 4.22 (q, J=7.2 Hz, 2H), 1.21 (t, J=7.2 Hz, 3H).

[0168] Step 8: Synthesis of intermediate BB-15-9 At room temperature and under nitrogen gas protection, intermediate BB-15-8 (9.5 g, 28.43 mmol), tris(dibenzylideneacetone)dipalladium (1.30 g, 1.42 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (1.21 g, 2.84 mmol), potassium phosphate (24.14 g, 113.72 mmol), and tert-butyl carbamate (3.66 g, 31.27 mmol) were sequentially added to a mixed solvent of toluene (90 mL) and water (30 mL). The reaction mixture was heated to 100 °C and stirred for 12 hours. After the reaction was complete, the mixture was cooled to room temperature, water (200 mL) was added, and the mixture was extracted with ethyl acetate (150 mL x 3). The organic phases were combined, washed with saturated brine (200 mL x 2), dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. The resulting residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 6 / 1~2 / 1, volume ratio) to obtain intermediate BB-15-9. MS-ESI m / z: 371.2 [M+H] + . 1 H NMR (400 MHz, DMSO_d6) δ: 8.48 (s, 1H), 8.28 (d, J=9.2 Hz, 1H), 7.95-7.87 (m, 2H), 7.75-7.60 (m, 2H), 4.50 (s, 2H), 4.14 (q, J=7.2 Hz, 2H), 1.50 (s, 9H), 1.16 (t, J=7.2 Hz, 3H).

[0169] Step 9: Synthesis of intermediate BB-15-10 Under nitrogen gas protection at room temperature, intermediate BB-15-9 (2.5 g, 6.75 mmol) was dissolved in tetrahydrofuran (35 mL), then acrylamide (575.69 mg, 8.10 mmol) and potassium tert-butoxide (1.14 g, 10.12 mmol) were added, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was poured into 1 M hydrochloric acid (30 mL) and extracted with ethyl acetate (45 mL x 3). The organic phases were combined, washed with saturated brine (40 mL x 2), dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. The resulting residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1 to 1 / 1, volume ratio) to obtain intermediate BB-15-10. MS-ESI m / z: 396.2 [M+H] + . 1 H NMR (400 MHz, DMSO_d6) δ: 11.14 (s, 1H), 9.46 (s, 1H), 8.29 (d, J=9.6 Hz, 1H), 8.04 (br d, J=7.6 Hz, 1H), 7.93 (d, J=9.2 Hz, 1H), 7.75-7.59 (m, 2H), 5.07 (dd, J=4.8 Hz, 11.2 Hz, 1H), 2.97-2.79 (m, 1H), 2.71-2.56 (m, 2H), 2.43-2.31 (m, 1H), 1.50 (s, 9H).

[0170] Step 10: Synthesis of the hydrochloride salt of intermediate BB-15 At room temperature, intermediate BB-15-10 (1.5 g, 3.79 mmol) was added to ethyl acetate hydrochloride solution (4 M, 15 mL), and the reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete, the mixture was filtered, the cake was rinsed with ethyl acetate (30 mL), the cake was collected, and the mixture was vacuum-dried to obtain the hydrochloride salt of intermediate BB-15. MS-ESI m / z: 296.1 [M+H] + . 1H NMR (400 MHz, DMSO_d6) δ: 11.14 (s, 1H), 8.34 (d, J = 9.6 Hz, 1H), 8.04-7.94 (m, 2H), 7.65 (t, J=8.0 Hz, 1H), 7.46 (d, J=7.6 Hz, 1H), 5.06 (dd, J=4.8 Hz, 11.6 Hz, 1H), 2.95-2.78 (m, 1H), 2.69-2.56 (m, 2H), 2.42-2.31 (m, 1H).

[0171] Example 1 [ka] Synthesis route: [ka]

[0172] Step 1: Synthesis of compound WX001-2 At room temperature, compound WX001-1 (6 g, 32.21 mmol) was dissolved in tetrahydrofuran (60 mL), then ethyl bromo (6.46 g, 38.66 mmol, 4.28 mL) and triethylamine (3.91 g, 38.66 mmol, 5.38 mL) were added sequentially, and the reaction mixture was stirred at room temperature for 4 hours. After the reaction was complete, water (200 mL) was added to the reaction solution and extracted with ethyl acetate (150 mL x 2). The organic phases were combined, washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. Petroleum ether (50 mL) was added to the resulting residue, stirred at room temperature for 5 minutes, filtered, the cake was rinsed with petroleum ether (30 mL), the cake was collected, and the mixture was vacuum-dried to obtain compound WX001-2.

[0173] Step 2: Synthesis of the hydrochloride salt of compound WX001-3 At room temperature, compound WX001-2 (5.5 g, 20.20 mmol) was dissolved in methanol (100 mL), then water (20 mL) and lithium hydroxide monohydrate (1.69 g, 40.39 mmol) were added sequentially. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the solvent was removed by directly reducing the pressure, and the pH was adjusted to 5-6 with 1 M dilute hydrochloric acid. The solvent was then removed by reducing the pressure. The resulting residue was separated using a reversed-phase column (chromatographic column: 800 g Agela C18, mobile phase: water (0.04% hydrochloric acid)-methanol, methanol B%: 10-40%, 15 min) to obtain the hydrochloride salt of compound WX001-3. MS-ESI m / z: 245.2 [M+H] + .

[0174] Step 3: Synthesis of compound WX001-4 At room temperature, the hydrochloride salt of compound WX001-3 (612.43 mg, 1.85 mmol, purity: 84.92%) and triethylamine (720.96 mg, 7.12 mmol) were dissolved in N,N-dimethylformamide (5 mL). Then, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (880.46 mg, 2.32 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. Then, the hydrochloride salt of compound BB-4 (0.5 g, 1.78 mmol) was added, and the reaction mixture was continued at room temperature with stirring for 4 hours. After the reaction was complete, methyl tert-butyl ether (20 mL) was added, the mixture was stirred for 5 minutes, filtered, and the cake was rinsed with methyl tert-butyl ether (5 mL). The filtrates were combined, water (50 mL) and dichloromethane (100 mL) were added, and the liquid was separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was reduced in pressure to remove the solvent. The filtrate was then vacuum-dried to obtain the crude product of compound WX001-4, which was used directly in the next step without further purification. MS-ESI m / z: 471.3 [M+H] + .

[0175] Step 4: Synthesis of the hydrochloride salt of compound WX001-5 At room temperature, the crude product of compound WX001-4 (0.8 g, 1.70 mmol) was dissolved in dichloromethane (5 mL), then ethyl acetate hydrochloride solution (4 M, 20 mL) was added, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was filtered, the cake was rinsed with ethyl acetate (20 mL), the cake was collected, and the mixture was vacuum-dried to obtain the hydrochloride salt of compound WX001-5. 1 H NMR (400 MHz, D2O) δ: 7.78 (s, 1H), 7.64 (d, J=2.0 Hz, 1H), 7.57 (d, J=8.8 Hz, 1H), 7.30 (dd, J=2.0 Hz, 8.8 Hz, 1H), 4.21 (dd, J=5.2 Hz, 12.4 Hz, 1H), 4.06 (s, 2H), 3.62-3.50 (m, 8H), 2.90-2.75 (m, 2H), 2.51-2.38 (m, 1H), 2.33-2.24 (m, 1H).

[0176] Step 5: Synthesis of the hydrochloride salt of compound WX001 Under nitrogen gas protection at room temperature, intermediate BB-2 (75 mg, 154.48 μmol) was dissolved in N,N-dimethylformamide (2 mL). Then, hydrochloride of compound WX001-5 (62.85 mg, 154.48 μmol), potassium acetate (45.48 mg, 463.45 μmol), and acetic acid (0.1 mL) were added sequentially. The reaction mixture was stirred at room temperature for 2 hours. Then, sodium triacetoxyborohydride (130.97 mg, 617.94 μmol) was added, and the reaction was continued at room temperature with stirring for 16 hours. After the reaction was complete, water (5 mL) and ethyl acetate (10 mL) were added to the reaction solution, the liquids were separated, and the aqueous phase was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. The resulting residue was separated by preparative HPLC (chromatography column: Phenomenex luna C18 80×40mm×3μm, mobile phase: water (0.04% hydrochloric acid)-acetonitrile, acetonitrile %: 20%~38%, 7 min) to obtain the hydrochloride salt of the target compound WX001. MS-ESI m / z: 840.5 [M+H] + . 1H NMR (400 MHz, DMSO_d6) δ: 10.94 (s, 1H), 10.71 (br s, 1H), 9.51 (d, J=6.4 Hz, 1H), 8.79 (d, J=7.6 Hz, 1H), 8.50-8.37 (m, 1H), 8.26 (d, J=5.2 Hz, 1H), 7.93 (s, 1H), 7.91 (s, 1H), 7.58 (d, J=8.8 Hz, 1H), 7.47 (d, J=8.8 Hz, 1H), 7.28-6.95 (m, 1H), 6.90-6.42 (m, 1H), 5.18 (d, J=79.2 Hz, 1H), 4.77 (d, J=20.0 Hz, 1H), 4.34-4.09 (m, 6H), 3.40-3.20 (m, 4H), 3.06 (s, 2H), 2.85-2.73 (m, 2H), 2.70-2.57 (m, 4H), 2.35-2.19 (m, 2H), 2.17-1.65 (m, 12H), 1.27-1.13 (m, 2H).

[0177] Example 2

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[0178] ステップ1: Synthesis of compound WX002-1 At room temperature, the hydrochloride salt of compound WX001-3 (0.5 g, 1.78 mmol) and triethylamine (632.58 mg, 6.25 mmol) were dissolved in N,N-dimethylformamide (10 mL). Then, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (812.61 mg, 2.14 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. Then, the hydrochloride salt of intermediate BB-6 (522.08 mg, 1.33 mmol) was added, and the reaction mixture was continued at room temperature with stirring for 16 hours. After the reaction was complete, the reaction solution was filtered, the cake was rinsed with N,N-dimethylformamide (5 mL), then with methyl tert-butyl ether (20 mL), the cake was collected, and the mixture was vacuum-dried to obtain compound WX002-1. MS-ESI m / z: 471.3 [M+H] + . 1 H NMR (400 MHz, DMSO_d6) δ: 10.88 (s, 1H), 9.93 (s, 1H), 8.06 (d, J=1.2 Hz, 1H), 7.83 (s, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.38 (dd, J=1.2 Hz, 8.4 Hz, 1H), 4.10 (dd, J=4.8 Hz, 12.0 Hz, 1H), 3.43-3.36 (m, 4H), 3.35-3.33 (m, 4H), 3.19 (s, 2H), 2.79-2.64 (m, 1H), 2.62-2.54 (m, 1H), 2.37-2.24 (m, 1H), 2.16-2.06 (m, 1H), 1.40 (s, 9H).

[0179] Step 2: Synthesis of the hydrochloride salt of compound WX002-2 At room temperature, compound WX002-1 (0.8 g, 1.70 mmol) was dissolved in ethyl acetate (10 mL), then ethyl acetate hydrochloride solution (4 M, 40 mL) was added, and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was filtered, the cake was rinsed with ethyl acetate (5 mL), the cake was collected, and the mixture was vacuum-dried to obtain the hydrochloride salt of compound WX002-2. MS-ESI m / z: 371.3 [M+H]+ . 1 H NMR (400 MHz, D2O) δ: 7.75 (d, J=1.6 Hz, 1H), 7.66 (s, 1H), 7.43 (d, J=8.4 Hz, 1H), 7.19 (dd, J=1.2 Hz, 8.4 Hz, 1H), 4.31 (s, 2H), 4.10-4.03 (m, 1H), 3.80-3.72 (m, 4H), 3.71-3.63 (m, 4H), 2.78-2.61 (m, 2H), 2.33-2.20 (m, 1H), 2.18-2.09 (m, 1H).

[0180] Step 3: Synthesis of the hydrochloride salt of compound WX002 Under nitrogen gas protection at room temperature, intermediate BB-2 (75 mg, 154.48 μmol) was dissolved in N,N-dimethylformamide (2 mL). Then, hydrochloride of compound WX002-2 (62.85 mg, 154.48 μmol), potassium acetate (45.48 mg, 463.45 μmol), and acetic acid (0.1 mL) were added sequentially. The reaction mixture was stirred at room temperature for 2 hours. Then, sodium triacetoxyborohydride (172.88 mg, 815.68 μmol) was added, and the reaction mixture was continued at room temperature for 16 hours with stirring. After the reaction was complete, water (5 mL) and ethyl acetate (10 mL) were added to the reaction solution, the liquid was separated, and ethyl acetate (20 mL x 3) was added to the aqueous phase for extraction. The organic phases were combined, washed with saturated saline solution (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. The resulting residue was separated by preparative HPLC (chromatography column: Phenomenex luna C18 80 × 40 mm × 3 μm, mobile phase: water (0.04% hydrochloric acid)-acetonitrile, acetonitrile %: 15%~35%, 7 min) to obtain the hydrochloride salt of the target compound WX002. MS-ESI m / z: 840.3 [M+H] + . 1H NMR (400 MHz, DMSO_d6) δ: 10.96 (s, 1H), 10.90 (s, 1H), 9.51 (d, J=6.0 Hz, 1H), 8.79 (d, J=7.6 Hz, 1H), 8.50-8.37 (m, 1H), 8.26 (d, , 5.18 (d, J = 78.4 Hz, 1H), 4.77 (d, J=19.6 Hz, 1H), 4.28-4.09 (m, 6H), 3.48-3.32 (m, 4H), 3.28-3.00 (m, 3H), 2.82-2.65 (m, 3H), 2.63-2.57 (m, 2H), 2.38-2.25 (m, 2H), 2.20-1.65 (m, 12H), 1.28-1.11 (m, 2H).

[0181] Example 3

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[0182] ステップ1: Synthesis of compound WX003-2 Under nitrogen gas protection at room temperature, compound WX003-1 (9 g, 44.72 mmol) was dissolved in tetrahydrofuran (90 mL), cooled to 0°C, and sodium hydride (2.15 g, 53.66 mmol, purity: 60%) was slowly added. The reaction mixture was stirred at 0°C for 30 minutes. Then propargyl bromide (5.32 g, 44.72 mmol) was added, and the reaction mixture was slowly heated to room temperature and stirred for 16 hours. After the reaction was complete, the reaction solution was slowly poured into ice water (100 mL) and extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. The resulting residue was separated by column chromatography (eluent: ethyl acetate / petroleum ether = 0 / 1 to 1 / 1, volume ratio) to obtain compound WX003-2. 1 H NMR (400 MHz, CDCl3) δ: 4.20 (d, J=2.4 Hz, 2H), 3.81-3.67 (m, 3H), 3.15-3.06 (m, 2H), 2.42 (t, J=2.4 Hz, 1H), 1.90-1.81 (m, 2H), 1.59-1.49 (m, 2H), 1.46 (s, 9H).

[0183] Step 2: Synthesis of compound WX003-3 Under room temperature and nitrogen gas protection, intermediate BB-7 (1 g, 3.25 mmol) was dissolved in N,N-dimethylformamide (20 mL). Then, compound WX003-2 (1.16 g, 4.87 mmol), cesium carbonate (3.17 g, 9.74 mmol), cuprous iodide (124 mg, 694 μmol), and bis(triphenylphosphine)palladium(II) dichloride (456 mg, 649 μmol) were added sequentially. The reaction mixture was heated to 80 °C and stirred for 5 hours. After the reaction was complete, the mixture was cooled to room temperature, poured into 1 M hydrochloric acid (80 mL), and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated saline solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. The resulting residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1 to 1 / 1, volume ratio) to obtain compound WX003-3. 1 H NMR (400 MHz, CDCl3) δ: 7.98 (s, 1H), 7.64 (s, 1H), 7.49 (dd, J=1.2 Hz, 7.6 Hz, 1H), 7.44 (dd, J=0.8 Hz, 7.6 Hz, 1H), 7.24 (t, J=7.6 Hz, 1H), 4.53 (s, 2H), 4.00 (t, J=7.6 Hz, 1H), 3.88-3.77 (m, 3H), 3.19-3.10 (m, 2H), 2.88-2.69 (m, 2H), 2.43-2.34 (m, 2H), 1.97-1.88 (m, 2H), 1.67-1.59 (m, 2H), 1.47 (s, 9H).

[0184] Step 3: Synthesis of the hydrochloride salt of compound WX003-4 At room temperature, compound WX003-3 (990 mg, 2.12 mmol) was dissolved in ethyl acetate (5 mL), then ethyl acetate hydrochloride solution (4 M, 33 mL) was added, and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to a volume of 1-2 mL, filtered, the cake was washed with ethyl acetate (12 mL x 2), the cake was collected, and the mixture was vacuum-dried to obtain the hydrochloride salt of compound WX003-4. 1H NMR (400 MHz, DMSO_d6) δ: 10.92 (s, 1H), 8.89-8.80 (m, 2H), 8.00 (s, 1H), 7.65 (dd, J=0.8 Hz, 7.6 Hz, 1H), 7.43 (d, J=7.6 Hz, 1H), 7.26 (t, J=7.6 Hz, 1H), 4.55 (s, 2H), 4.17 (dd, J=4.8 Hz, 12.4 Hz, 1H), 3.90-3.83 (m, 1H), 3.22-3.11 (m, 2H), 3.05-2.94 (m, 2H), 2.81-2.70 (m, 1H), 2.63-2.54 (m, 1H), 2.39-2.27 (m, 1H), 2.17-2.00 (m, 1H), 2.07-2.02 (m, 2H), 1.84-1.73 (m, 2H).

[0185] Step 4: Synthesis of the hydrochloride salt of compound WX003 At room temperature, intermediate BB-2 (149 mg, 307 μmol), compound WX003-4 hydrochloride (123.6 mg, 307 μmol), and potassium acetate (60 mg, 614 μmol) were sequentially added to a mixed solvent of tetrahydrofuran (5 mL) and N,N-dimethylformamide (1 mL). The reaction mixture was stirred at room temperature for 0.5 hours. Then, sodium triacetoxyborohydride (130 mg, 614 μmol) was added, and the reaction mixture was continued at room temperature for 16 hours with stirring. After the reaction was complete, water (1 mL) was added, and the solvent was removed by reducing the pressure and concentrating the mixture. The resulting residue was separated by preparative HPLC (chromatography column: Boston Green ODS 150 × 30 mm × 5 μm, mobile phase: water (0.04% hydrochloric acid)-acetonitrile, acetonitrile %: 22%~42%, 10 min) to obtain the hydrochloride of the target compound WX003. MS-ESI m / z: 836.3 [M+H] + . 1H NMR (400 MHz, DMSO_d6) δ: 10.93 (s, 1H), 9.61-9.45 (m, 2H), 8.80 (d, J=7.6 Hz, 1H), 8.41 (d, J=2.8 Hz, 1H), 8.27 (dd, J=1.6 Hz, 5.6 Hz, 1H), 8.01 (d, J=2.4 Hz, 1H), 7.67 (d, J=7.6 Hz, 1H), 7.44 (d, J=7.2 Hz, 1H), 7.32-6.96 (m, 2H), 6.92-6.43 (m, 1H), 5.18 (d, J=78.4 Hz, 1H), 4.77 (d, J=20.0 Hz, 1H), 4.58 (d, J=2.8 Hz, 2H), 4.29-4.15 (m, 2H), 3.86-3.71 (m, 3H), 3.67-3.59 (m, 2H), 3.42-3.37 (m, 1H), 3.14-2.92 (m, 4H), 2.81-2.71 (m, 1H), 2.69-2.60 (m, 1H), 2.43-2.28 (m, 2H), 2.26-2.18 (m, 1H), 2.17-1.75 (m, 13H), 1.26-1.15 (m, 2H).

[0186] Example 4

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[0187] ステップ1: Synthesis of compound WX004-1 Under nitrogen gas protection at room temperature, intermediate BB-5 (0.85 g, 2.76 mmol), compound WX003-2 (990.24 mg, 4.14 mmol), cuprous iodide (105.08 mg, 551.72 μmol), bis(triphenylphosphine)palladium(II) dichloride (387.25 mg, 551.72 μmol), and cesium carbonate (3.60 g, 11.03 mmol) were dissolved in N,N-dimethylformamide (15 mL). The reaction mixture was heated to 80°C and stirred for 3 hours. After the reaction was complete, the mixture was cooled to room temperature, the reaction solution was poured into water (50 mL), and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. The resulting residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1, volume ratio) to obtain compound WX004-1. MS-ESI m / z: 367.2 [M+H-100] + . 1 H NMR (400 MHz, CDCl3) δ: 7.63 (s, 1H), 7.61 (s, 1H), 7.44 (d, J=8.0 Hz, 1H), 7.35 (dd, J=1.2 Hz, 8.0 Hz, 1H), 4.45 (s, 2H), 3.99 (dd, J=6.8 Hz, 8.8 Hz, 1H), 3.87-3.70 (m, 3H), 3.18-3.09 (m, 2H), 2.87-2.68 (m, 2H), 2.43-2.32 (m, 2H), 1.98-1.86 (m, 2H), 1.67-1.54 (m, 2H), 1.47 (s, 9H).

[0188] Step 2: Synthesis of trifluoroacetate of compound WX004-2 At room temperature, compound WX004-1 (0.47 g, 1.01 mmol) was dissolved in dichloromethane (5 mL), and then trifluoroacetic acid (1.54 g, 13.51 mmol) was slowly added dropwise. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the solvent was removed by direct concentration under reduced pressure. The resulting residue was separated by preparative HPLC (chromatography column: Phenomenex luna C18 100 × 40 mm × 5 μm, mobile phase: water (0.05% trifluoroacetic acid)-acetonitrile, acetonitrile %: 1%~45%, 8 min) to obtain the trifluoroacetate salt of compound WX004-2. 1 H NMR (400 MHz, DMSO_d6) δ: 10.91 (s, 1H), 8.76-8.44 (m, 2H), 8.00 (s, 1H), 7.71 (s, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.32 (dd, J=1.2 Hz, 8.4 Hz, 1H), 4.47 (s, 2H), 4.16 (dd, J=4.8 Hz, 12.0 Hz, 1H), 3.89-3.79 (m, 1H), 3.25-3.14 (m, 2H), 3.09-2.96 (m, 2H), 2.81-2.70 (m, 1H), 2.58 (dt, J=3.6 Hz, 17.2 Hz, 1H), 2.39-2.25 (m, 1H), 2.16-2.07 (m, 1H), 2.06-1.97 (m, 2H), 1.79-1.68 (m, 2H).

[0189] Step 3: Synthesis of the hydrochloride salt of compound WX004 At room temperature, intermediate BB-2 (70 mg, 144.19 μmol) and the trifluoroacetate salt of compound WX004-2 (76.20 mg, 158.60 μmol) were dissolved in a mixed solvent of N,N-dimethylformamide (2 mL) and glacial acetic acid (0.1 mL). Potassium acetate (42.45 mg, 432.56 μmol) was then added, and the reaction mixture was stirred at room temperature for 2 hours. After that, sodium triacetoxyborohydride (91.68 mg, 432.56 μmol) was added, and the reaction mixture was continued at room temperature for 16 hours with stirring. After the reaction was complete, the reaction solution was filtered, and the filtrate was directly separated by preparative HPLC (chromatography column: Phenomenex Luna C18 80 × 40 mm × 3 μm, mobile phase: water (0.04% hydrochloric acid) - acetonitrile, acetonitrile %: 28%~48%, 7 min) to obtain the hydrochloride salt of the target compound WX004. MS-ESI m / z: 836.3 [M+H] + . 1 H NMR (400 MHz, DMSO_d6) δ: 10.92 (s, 1H), 9.73 (br s, 1H),9.51 (d, J=6.4 Hz, 1H), 8.81-8.77 (m, 1H), 8.40 (d, J=4.0 Hz, 1H), 8.26 (d, J=5.6 Hz, 1H), 8.02 (s, 1H), 7.72 (s, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.33 (d, J=8.4 Hz, 1H), 7.27-6.95 (m 1H), 6.91-6.43 (m, 1H), 5.18 (d, J=78.4 Hz, 1H), 4.76 (d, J=19.6 Hz, 1H), 4.49 (s, 2H), 4.33-4.12 (m, 2H), 3.84-3.71 (m, 3H), 3.66-3.50 (m, 2H), 3.39-3.35 (m, 1H), 3.08-2.94 (m, 4H), 2.80-2.69 (m, 1H), 2.68-2.53 (m, 2H), 2.39-2.26 (m, 2H), 2.22-1.76 (m, 13H), 1.26-1.12 (m, 2H).

[0190] Example 5 [ka] Synthesis route: [ka]

[0191] Step 1: Synthesis of compound WX005-1 Under room temperature and nitrogen gas protection, intermediate BB-3 (1 g, 2.23 mmol), compound WX003-2 (799.42 mg, 3.34 mmol), cuprous iodide (84.83 mg, 445.40 μmol), bis(triphenylphosphine)palladium(II) dichloride (312.63 mg, 445.40 μmol), and cesium carbonate (2.90 g, 8.91 mmol) were added to N,N-dimethylformamide (20 mL). The reaction mixture was heated to 80°C and stirred for 5 hours. After the reaction was complete, the mixture was cooled to room temperature, the reaction solution was poured into water (100 mL), and extracted with ethyl acetate (50 mL x 2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The resulting residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1, volume ratio) to obtain compound WX005-1. MS-ESI m / z: 367.2 [M+H-100] + .

[0192] Step 2: Synthesis of trifluoroacetate of compound WX005-2 At room temperature, compound WX005-1 (360.00 mg, 771.66 μmol) was dissolved in dichloromethane (5 mL), and then trifluoroacetic acid (1.54 g, 13.51 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the solvent was removed by concentrating under reduced pressure. The resulting residue was separated by preparative HPLC (chromatography column: Phenomenex Luna C18 100 × 40 mm × 5 μm, mobile phase: water (0.05% trifluoroacetic acid)-acetonitrile, acetonitrile %: 1%~45%, 8 min) to obtain the trifluoroacetate salt of compound WX005-2. 1 H NMR (400 MHz, DMSO_d6) δ: 10.90 (s, 1H), 8.59-8.20 (m, 2H), 7.98 (s, 1H), 7.73 (d, J=1.2 Hz, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.39 (dd, J=1.6 Hz, 8.4 Hz, 1H), 4.46 (s, 2H), 4.15 (dd, J=4.8 Hz, 12.0 Hz, 1H), 3.88-3.78 (m, 1H), 3.24-3.14 (m, 2H), 3.08-2.96 (m, 2H), 2.80-2.64 (m, 2H), 2.43-2.27 (m, 1H), 2.16-2.06 (m, 1H), 2.05-1.93 (m, 2H), 1.78-1.64 (m, 2H).

[0193] Step 3: Synthesis of the hydrochloride salt of compound WX005 At room temperature, intermediate BB-2 (70 mg, 144.19 μmol) and the trifluoroacetate salt of compound WX005-2 (76.20 mg, 158.60 μmol) were dissolved in a mixed solvent of N,N-dimethylformamide (2 mL) and glacial acetic acid (0.1 mL). Potassium acetate (42.45 mg, 432.56 μmol) was then added, and the reaction mixture was stirred at room temperature for 2 hours. After that, sodium triacetoxyborohydride (91.68 mg, 432.56 μmol) was added, and the reaction mixture was continued at room temperature for 16 hours with stirring. After the reaction was complete, the solvent was removed by direct concentration under reduced pressure. The resulting residue was separated by preparative HPLC (chromatography column: Phenomenex Luna 80 × 30 mm × 3 μm, mobile phase: water (0.04% hydrochloric acid) - acetonitrile, acetonitrile %: 20%~35%, 8 min) to obtain the hydrochloride salt of the target compound WX005. MS-ESI m / z: 836.3 [M+H] + . 1 H NMR (400 MHz, DMSO_d6) δ: 10.90 (s, 1H), 9.68 (s, 1H), 9.50 (d, J=6.4 Hz, 1H), 8.78 (d, J=7.6 Hz, 1H), 8.39 (d, J=4.0 Hz, 1H), 8.25 (d, J=5.6 Hz, 1H), 7.98 (s, 1H), 7.76-7.72 (m, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.39 (dd, J=1.6 Hz, 8.8 Hz, 1H), 7.27-6.95 (m, 1H), 6.90-6.43 (m, 1H), 5.17 (d, J=79.6 Hz, 1H), 4.76 (d, J=20.0 Hz, 1H), 4.47 (s, 2H), 4.33-4.12 (m, 2H), 3.98-3.71 (m, 3H), 3.67-3.57 (m, 2H), 3.40-3.33 (m, 1H), 3.16-2.92 (m, 4H), 2.79-2.66 (m, 1H), 2.62-2.55 (m, 1H), 2.38-2.31 (m, 1H), 2.22-1.65 (m, 15H), 1.26-1.10 (m, 2H).

[0194] Example 6 [ka] Synthesis route: [ka]

[0195] Step 1: Synthesis of compound WX006-1 At room temperature, the hydrochloride salt of compound WX001-3 (1.3 g, 5.31 mmol) was dissolved in N,N-dimethylformamide (15 mL). Then, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.62 g, 4.25 mmol), N,N-diisopropylethylamine (1.37 g, 10.63 mmol), and the hydrochloride salt of intermediate BB-8 (906 mg, 3.54 mmol) were added sequentially, and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was poured into water (150 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated saline solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. The resulting residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1 to 7 / 3, volume ratio) to obtain compound WX006-1. 1 H NMR (400 MHz, CDCl3) δ: 9.71 (s, 1H), 8.20 (s, 1H), 7.66 (s, 1H), 7.35-7.29 (m, 1H), 7.26-7.23 (m, 1H), 4.20 (q, J=7.2 Hz, 2H), 3.71 (d, J=1.2 Hz, 2H), 3.59 (m, 4H), 3.26 (m, 2H), 2.65 (m, 4H), 1.49 (s, 9H), 1.28 (t, J=7.2 Hz, 3H).

[0196] Step 2: Synthesis of compound WX006-2 Under 0°C and nitrogen gas protection, compound WX006-1 (1.53 g, 3.43 mmol) was dissolved in N,N-dimethylformamide (20 mL), and then potassium tert-butoxide (462 mg, 4.12 mmol) and acrylamide (293 mg, 4.12 mmol) were added sequentially. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was slowly poured into saturated ammonium chloride aqueous solution (30 mL) and extracted with ethyl acetate (15 mL x 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. The resulting residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1 to 1 / 1, volume ratio) to obtain compound WX006-2. 1 H NMR (400 MHz, CDCl3) δ: 9.74 (s, 1H), 8.27-8.19 (m, 1H), 8.04 (s, 1H), 7.61 (s, 1H), 7.26-7.14 (m, 2H), 4.02 (t, J=7.6 Hz, 1H), 3.58 (s, 4H), 3.26 (s, 2H), 2.86-2.73 (m, 2H), 2.64 (s, 4H), 2.45-2.35 (m, 2H), 1.49 (s, 9H).

[0197] Step 3: Synthesis of the hydrochloride salt of compound WX006-3 At room temperature, compound WX006-2 (150 mg, 2.12 mmol) was dissolved in ethyl acetate (3 mL), then ethyl acetate hydrochloride solution (4 M, 15 mL) was added, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the solvent was removed by direct concentration under reduced pressure to obtain the hydrochloride salt of compound WX006-3, which was used directly in the next step without further purification.

[0198] Step 4: Synthesis of the hydrochloride salt of compound WX006 At room temperature, intermediate BB-2 (149 mg, 307 μmol) was dissolved in a mixed solvent of tetrahydrofuran (5 mL) and N,N-dimethylformamide (1 mL). Then, the hydrochloride salt of compound WX006-3 (125 mg, 307 μmol) and potassium acetate (60 mg, 614 μmol) were added sequentially. The reaction mixture was stirred at room temperature for 0.5 hours. Next, sodium triacetoxyborohydride (130 mg, 614 μmol) was added, and the reaction mixture was continued at room temperature with stirring for 16 hours. After the reaction was complete, water (1 mL) was added to quench the mixture, it was dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. The resulting residue was separated by preparative HPLC (chromatography column: Boston Green ODS 150 × 30 mm × 5 μm, mobile phase: water (0.04% hydrochloric acid)-acetonitrile, acetonitrile %: 15%~35%, 10 min) to obtain the hydrochloride salt of the target compound WX006. MS-ESI m / z: 840.4 [M+H] + . 1 H NMR (400 MHz, DMSO_d6) δ: 10.93 (s, 1H), 10.42 (s, 1H), 9.52 (d, J=7.2 Hz, 1H), 8.78 (d, J=8.0 Hz, 1H), 8.41 (d, J=4.4 Hz, 1H), 8.26 (d, J=5.6 Hz, 1H), 7.97 (s, 1H), 7.73 (d, J=7.6 Hz, 1H), 7.41 (d, J=7.6 Hz, 1H), 7.32-6.96 (m, 3H), 6.90-6.44 (m, 1H), 5.17 (d, J=81.2 Hz, 1H), 4.77 (d, J=20.4 Hz, 1H), 4.29-4.13 (m, 2H), 4.03-3.91 (m, 1H), 3.85-3.79 (m, 2H), 3.77-3.58 (m, 5H), 3.08-2.99 (m, 1H), 2.82-2.71 (m, 2H), 2.70-2.66 (m, 1H), 2.64-2.57 (m, 2H), 2.41-2.27 (m, 2H), 2.17-1.74 (m, 12H),1.30-1.13 (m, 3H).

[0199] Example 7 [ka] Synthesis route: [ka]

[0200] Step 1: Synthesis of compound WX007-1 Under room temperature and nitrogen gas protection, intermediate BB-10 (300 mg, 838 μmol) was dissolved in N,N-dimethylformamide (10 mL). Then, compound WX003-2 (301 mg, 1.26 mmol), cesium carbonate (819 mg, 2.51 mmol), cuprous iodide (32 mg, 168 µl), and bis(triphenylphosphine)palladium(II) dichloride (118 mg, 168 µl) were added sequentially. The reaction mixture was heated to 80 °C and stirred for 3 hours. After the reaction was complete, the mixture was cooled to room temperature, poured into saturated ammonium chloride solution (100 mL), and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated saline solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by reducing the pressure of the filtrate. The resulting residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1 to 1 / 1, volume ratio) to obtain compound WX007-1. MS-ESI m / z: 539.3 [M+Na] + . 1 H NMR (400 MHz, CDCl3) δ: 8.11 (d, J=1.2 Hz, 1H), 8.07 (br s, 1H), 7.93 (d, J=8.8 Hz, 1H), 7.76-7.67 (m, 3H), 7.61 (dd, J=1.6 Hz, 8.8 Hz, 1H), 4.53- 4.46 (m, 3H), 3.88-3.77 (m, 3H), 3.20-3.10 (m, 2H), 2.89-2.77 (m, 2H), 2.60-2.42 (m, 2H), 1.98-1.88 (m, 2H), 1.68-1.60 (m, 2H), 1.47 (s, 9H).

[0201] Step 2: Synthesis of the hydrochloride salt of compound WX007-2 At room temperature, compound WX007-1 (180 mg, 348 μmol) was dissolved in ethyl acetate (10 mL), then ethyl acetate hydrochloride solution (4 M, 10 mL) was added, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the solvent was removed by reducing the pressure, and ethyl acetate (10 mL) was added to the resulting residue. The mixture was concentrated again until 4-5 mL remained, filtered, the cake was rinsed with ethyl acetate (5 mL x 2), the cake was collected, and the mixture was vacuum-dried to obtain the hydrochloride salt of compound WX007-2. MS-ESI m / z: 417.0 [M+H] + .

[0202] Step 3: Synthesis of the hydrochloride salt of compound WX007 Under nitrogen gas protection at room temperature, intermediate BB-2 (149 mg, 307 μmol) was dissolved in tetrahydrofuran (5 mL) and N,N-dimethylformamide (1 mL). Then, hydrochloride of compound WX007-2 (139 mg, 307 μmol) and potassium acetate (90 mg, 921 μmol) were added, and the reaction mixture was stirred at room temperature for 0.5 hours. Next, sodium triacetoxyborohydride (130 mg, 614 μmol) was added, and the reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete, water (1 mL) was added, the mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The resulting residue was separated by preparative HPLC (chromatography column: Boston Green ODS 150 × 30 mm × 5 μm, mobile phase: water (0.04% hydrochloric acid)-acetonitrile, acetonitrile %: 27%~42%, 10 min) to obtain the hydrochloride of the target compound WX007. MS-ESI m / z: 886.4 [M+H] + . 1H NMR (400 MHz, DMSO_d6) δ: 10.95 (s, 1H), 9.51 (d, J=4.4 Hz, 1H), 9.45 (br s, 1H), 8.79 (d, J=7.2 Hz, 1H), 8.40 (d, J=1.6 Hz, 1H), 8.30 - 8.16 (m, 3H), 8.06 (s, 1H), 7.93- 7.85 (m, 2H), 7.58 (d, J=8.0 Hz, 1H), 7.31 - 6.46 (m, 2H), 5.18 (d, J=79.2 Hz, 1H), 4.83 - 4.64 (m, 2H), 4.53 (s, 2H), 4.23 (br s, 1H), 4.00-3.72 (m, 3H), 3.67 - 3.52 (m, 2H), 3.13 - 2.80 (m, 6H), 2.70 - 2.59 (m, 1H), 2.30 - 2.20 (m, 2H), 2.11 - 1.72 (m, 14H), 1.26-1.15 (m, 2H).

[0203] Example 8

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[0204] ステップ1: Synthesis of compound WX008-1 Under room temperature and nitrogen gas protection, the hydrochloride salt of compound WX001-3 (387.74 mg, 1.59 mmol) was dissolved in N,N-dimethylformamide (10 mL). Then, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (482.81 mg, 1.27 mmol), N,N-diisopropylethylamine (410.27 mg, 3.17 mmol), and the hydrochloride salt of intermediate BB-9 (350 mg, 1.06 mmol) were added sequentially, and the reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete, the mixture was poured into water (50 mL) and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated saline solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The resulting residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1 to 1 / 1, volume ratio) to obtain compound WX008-1. MS-ESI m / z: 521.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ: 9.25 (s, 1H), 8.28 (s, 1H), 8.10 (br s, 1H), 7.95 (d, J=8.8 Hz, 1H), 7.77-7.71 (m, 2H), 7.69-7.65 (m, 2H), 4.52-4.45 (m, 1H), 3.60-3.51 (m, 4H), 3.24 (s, 2H), 2.84-2.76 (m, 2H), 2.68-2.60 (m, 4H), 2.56-2.46 (m, 2H), 1.49 (s, 9H).

[0205] Step 2: Synthesis of the hydrochloride salt of compound WX008-2 At room temperature, compound WX008-1 (160 mg, 288 μmol) was dissolved in a 1,4-dioxane hydrochloride solution (4 M, 12 mL), and the reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete, the solvent was removed by reducing the pressure, ethyl acetate (20 mL) was added to the residue, and the solvent was removed again by reducing the pressure to obtain the hydrochloride salt of compound WX008-2. MS-ESI m / z: 421.1 [M+H] + .

[0206] Step 3: Synthesis of the hydrochloride salt of compound WX008 Under nitrogen gas protection at room temperature, intermediate BB-2 (140 mg, 288.37 μmol) was dissolved in tetrahydrofuran (5 mL) and N,N-dimethylformamide (1 mL). Then, hydrochloride of compound WX008-2 (124.03 mg, 271.44 μmol), potassium acetate (84.90 mg, 865.11 μmol), and acetic acid (8.66 mg, 144.19 μmol) were added, and the reaction mixture was stirred at room temperature for 0.5 hours. Next, sodium triacetoxyborohydride (183 mg, 865 μmol) was added, and the reaction mixture was stirred at room temperature for 4 hours. After the reaction was complete, water (20 mL) was added, and the mixture was extracted with ethyl acetate (15 mL x 3) to precipitate the solid. The aqueous and organic phases were discarded, and the solid was dissolved with N,N-dimethylformamide (5 mL). The resulting solution was separated by preparative HPLC (chromatography column: Boston Green ODS 150 × 30 mm × 5 μm, mobile phase: water (0.04% hydrochloric acid)-acetonitrile, acetonitrile %: 28%~48%, 10 min) to obtain the hydrochloride salt of the target compound WX008. MS-ESI m / z: 890.5 [M+H] + . 1H NMR (400 MHz, DMSO_d6) δ: 10.95 (s, 1H), 10.68 (br s, 1H), 9.51 (d, J=6.8 Hz, 1H), 8.78 (d, J=7.6 Hz, 1H), 8.40 (s, 2H), 8.25 (d, J=5.6 Hz, 1H), 8.17 (d, J=8.8 Hz, 1H), 8.00 (s, 1H), 7.80-7.73 (m, 3H), 7.34-6.95 (m, 1H), 6.90-6.42 (m, 1H), 5.17 (d, J=81.2 Hz, 1H), 4.76 (d, J=20.8 Hz, 1H), 4.66 (dd, J=4.0 Hz, 11.6 Hz, 1H), 4.29-4.19 (m, 1H), 4.02-3.88 (m, 3H), 3.84-3.72 (m, 4H), 3.65-3.59 (m, 4H), 3.10-3.00 (m, 1H), 2.93-2.82 (m, 1H), 2.68-2.59 (m, 1H), 2.43-2.21 (m, 4H), 2.12-1.72 (m, 11H), 1.25-1.16 (m, 3H).

[0207] Example 9

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[0208] ステップ1: Synthesis of compound WX009-1 Under room temperature and nitrogen gas protection, compound WX003-2 (400.87 mg, 1.68 μmol), intermediate BB-12 (0.3 g, 837.55 μmol), cuprous iodide (31.90 mg, 167.51 μmol), bis(triphenylphosphine)palladium(II) dichloride (117.58 mg, 167.51 μmol), and N,N-diisopropylethylamine (216.50 mg, 1.68 mmol) were added to dimethyl sulfoxide (4 mL). The reaction mixture was heated to 85°C and stirred for 2.5 hours. After the reaction was complete, the mixture was cooled to room temperature, water (2 mL) was added, and the mixture was extracted with ethyl acetate (5 mL x 2). The organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was reduced in pressure to remove the solvent. The resulting residue was separated by thin-layer chromatography (eluent: petroleum ether / ethyl acetate / dichloromethane = 1 / 1 / 1, volume ratio) to obtain compound WX009-1. MS-ESI m / z: 417.1 [M+H-100] + . 1 H NMR (400 MHz, CDCl3) δ: 8.35 (d, J=8.8 Hz, 1H), 8.06 (s, 1H), 7.99 (d, J=8.4 Hz, 1H), 7.76 (d, J=9.2 Hz, 1H), 7.73-7.68 (m, 2H), 7.54 (dd, J=7.2 Hz, 8.8 Hz, 1H), 4.60 (s, 2H), 4.51 (dd, J=5.2 Hz, 8.8 Hz, 1H), 3.92-3.79 (m, 4H), 3.20-3.12 (m, 2H), 2.87-2.77 (m, 1H), 2.56-2.46 (m, 1H), 2.01-1.92 (m, 2H), 1.91-1.83 (m, 1H), 1.71-1.62 (m, 2H),1.47 (s, 9H).

[0209] Step 2: Synthesis of trifluoroacetate of compound WX009-2 At room temperature, compound WX009-1 (0.1 g, 193.58 μmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (617.19 mg, 5.41 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the solvent was removed by reducing the pressure to obtain the trifluoroacetate salt of compound WX009-2. MS-ESI m / z: 417.1 [M+H] + .

[0210] Step 3: Synthesis of the hydrochloride salt of compound WX009 At room temperature and under nitrogen gas protection, intermediate BB-2 (90 mg, 185.38 μmol), trifluoroacetate of compound WX009-2 (98.34 mg, 185.38 μmol), and potassium acetate (54.58 mg, 556.14 μmol) were added to a mixed solvent of glacial acetic acid (0.1 mL) and N,N-dimethylformamide (2 mL). The reaction mixture was stirred at room temperature for 2 hours, and then sodium triacetoxyborohydride (117.87 mg, 556.14 μmol) was added. The reaction mixture was stirred at room temperature for 15 hours. After the reaction was complete, saturated ammonium chloride (10 mL) was added and extracted with ethyl acetate (5 mL x 2). A large amount of insoluble material precipitated. The organic phase and insoluble material were concentrated under reduced pressure to remove the solvent. The resulting residue was separated and purified by preparative HPLC (chromatography column: Phenomenex Luna 80 × 30 mm × 3 μm, mobile phase: water (0.04% hydrochloric acid) - acetonitrile, acetonitrile %: 25%~45%, 8 min) to obtain the hydrochloride salt of the target compound WX009. MS-ESI m / z: 886.4 [M+H] + . 1H NMR (400 MHz, CD3OD): 8.54-8.48 (m, 1H), 8.38-8.27 (m, 3H), 8.21 (d, J=8.8 Hz, 1H), 7.89 (s, 1H), 7.82-7.77 (m, 1H), 7.69 (d, J=7.2 Hz, 1H), 7.60-7.54 (m, 1H), 7.04-6.71 (m, 2H), 6.46-6.41 (m, 1H), 5.43 (s, 1H), 4.83-4.76 (m, 4H), 4.69-4.62 (m, 3H), 4.26-4.14 (m, 2H), 3.97-3.90 (m, 2H), 3.75-3.63 (m, 2H), 3.54-3.45 (m, 2H), 3.20-3.06 (m, 2H), 2.96-2.4 (m, 1H), 2.81-2.71 (m, 1H), 2.52-2.39 (m, 2H), 2.35-2.15 (m, 4H), 2.13-1.87 (m, 9H), 1.40-1.25 (m, 2H)

[0211] Example 10

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[0212] ステップ1: Synthesis of compound WX010-1 Under nitrogen gas protection at room temperature, the hydrochloride salt of compound WX001-3 (186.73 mg, 665.12 μmol) was dissolved in N,N-dimethylformamide (5 mL), and N,N-diisopropylethylamine (390.73 mg, 3.02 mmol) and O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (344.86 mg, 906.99 μmol) were added. The reaction mixture was stirred at room temperature for 0.5 hours. Then, the hydrochloride salt of intermediate BB-11 (0.2 g, 604.66 μmol) was added, and the reaction mixture was stirred at room temperature for 1.5 hours. After the reaction was complete, water (30 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with 10% saline solution (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was reduced under reduced pressure to remove the solvent. The residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 2 to 0 / 1) to obtain compound WX010-1. MS-ESI m / z: 521.3 [M+H] + .

[0213] Step 2: Synthesis of the hydrochloride salt of compound WX010-2 At room temperature, compound WX010-1 (290 mg, 557.08 μmol) was dissolved in dichloromethane (2 mL), and ethyl acetate hydrochloride solution (4 M, 5 mL) was added. The reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete, the mixture was filtered, the cake was rinsed with ethyl acetate (10 mL), the cake was collected, and the mixture was vacuum-dried to obtain the hydrochloride salt of compound WX010-2. MS-ESI m / z: 421.2 [M+H] + . 1H NMR (400 MHz, DMSO_d6) δ: 10.96 (s, 1H), 10.77 (s, 1H), 9.85 (s, 2H), 8.16-8.03 (m, 3H), 7.86 (d, J=9.6 Hz, 1H), 7.67-7.57 (m, 2H), 4.71 (dd, J=3.6 Hz, 12.0 Hz, 1H), 4.38 (s, 2H), 3.70-3.55 (m, 4H), 3.52-3.35 (m, 4H), 2.97-2.82 (m, 1H), 2.68-2.59 (m, 1H), 2.48-2.37 (m, 1H), 2.35-2.22 (m, 1H).

[0214] Step 3: Synthesis of the hydrochloride salt of compound WX010 Under nitrogen gas protection at room temperature, intermediate BB-2 (190 mg, 391.36 μmol) and the hydrochloride salt of compound WX010-2 (187.76 mg, 410.93 μmol) were dissolved in N,N-dimethylformamide (1 mL). Potassium acetate (115.22 mg, 1.17 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. Next, sodium triacetoxyborohydride (331.78 mg, 1.57 mmol) was added, and the reaction mixture was stirred at room temperature for 40 minutes. After the reaction was complete, 1 M hydrochloric acid (4 mL) was added, and the solvent was removed by reducing the pressure and concentrating. The resulting residue was separated and purified by preparative HPLC (chromatography column: Phenomenex Luna 80 × 30 mm × 3 μm, mobile phase: water (0.04% hydrochloric acid) - acetonitrile, acetonitrile %: 10%~30%, 8 min) to obtain the hydrochloride salt of the target compound WX010. MS-ESI m / z: 890.2 [M+H] + . 1H NMR (400 MHz, DMSO_d6) δ: 10.96 (s, 1H), 10.59 (s, 1H), 9.51 (d, J=6.4 Hz, 1H), 8.79 (d, J=8.0 Hz, 1H), 8.41 (d, J=4.0 Hz, 1H), 8.26 (d, J=5.6 Hz, 1H), 8.15-8.08 (m, 1H), 8.08-8.00 (m, 2H), 7.87 (d, J=9.2 Hz, 1H), 7.68-7.57 (m, 2H), 7.26-6.96 (m, 1H), 6.90-6.40 (m, 1H), 5.18 (d, J=80.0 Hz, 1H), 4.82-4.65 (m, 2H), 4.34-4.16 (m, 2H), 3.81 (s, 2H), 3.75-3.59 (m, 8H), 3.13-3.01 (m, 2H), 2.95-2.85 (m, 1H), 2.70-2.59 (m, 2H), 2.44-2.38 (m, 1H), 2.36-2.20 (m, 2H), 2.13-1.69 (m, 10H), 1.28-1.12 (m, 2H).

[0215] Example 11

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[0216] ステップ1: Synthesis of compound WX011-1 Under nitrogen gas protection at room temperature, intermediate BB-15-8 (0.5 g, 1.50 mmol) and compound WX003-2 (716.14 mg, 2.99 mmol) were dissolved in dimethyl sulfoxide (5 mL). Bis(triphenylphosphine)palladium(II) dichloride (210.05 mg, 299.25 μmol), cuprous iodide (56.99 mg, 299.25 μmol), and N,N-diisopropylethylamine (386.76 mg, 2.99 mmol) were added sequentially, and the reaction mixture was heated to 85°C and stirred for 2 hours. After the reaction was complete, the mixture was cooled to room temperature, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with 10% saline solution (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. The residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 6 / 1) to obtain compound WX011-1. 1 H NMR (400 MHz, CDCl3) δ: 8.53 (d, J=9.2 Hz, 1H), 8.11 (d, J=8.0 Hz, 1H), 7.78 (d, J=9.2 Hz, 1H), 7.75 (d, J=7.6 Hz, 1H), 7.63 (t, J=8.0 Hz, 1H), 4.59 (s, 2H), 4.34 (s, 2H), 4.22 (q, J=7.0 Hz, 2H), 3.89-3.76 (m, 3H), 3.22-3.12 (m, 2H), 2.00-1.91 (m, 2H), 1.72-1.62 (m, 2H), 1.47 (s, 9H), 1.21 (t, J=7.2 Hz, 3H)

[0217] Step 2: Synthesis of compound WX011-2 Under nitrogen gas protection at room temperature, compound WX011-1 (0.3 g, 609.06 μmol) was dissolved in tetrahydrofuran (5 mL), cooled to 0°C, and then acrylamide (47.62 mg, 669.97 μmol) and potassium tert-butoxide (82.01 mg, 730.87 μmol) were added. The reaction mixture was heated to room temperature and stirred for 1.5 hours. After the reaction was complete, 1 M hydrochloric acid was added to adjust the pH to 3-4, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. The resulting residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1-1 / 1, volume ratio) to obtain compound WX011-2. MS-ESI m / z: 418.2 [M+H-100] + . 1 H NMR (400 MHz, CDCl3) δ: 8.58 (d, J=9.2 Hz, 1H), 8.13 (s, 1H), 8.03 (d, J=8.4 Hz, 1H), 7.81 (d, J=9.6 Hz, 1H), 7.77 (dd, J=0.8 Hz, 7.2 Hz, 1H), 7.65 (t, J=8.0 Hz, 1H), 4.74 (dd, J=4.8 Hz, 8.4 Hz, 1H), 4.60 (s, 2H), 3.90-3.76 (m, 3H), 3.23-3.11 (m, 2H), 3.01-2.87 (m, 1H), 2.85-2.67 (m, 2H), 2.65-2.52 (m, 1H), 2.01-1.89 (m, 2H), 1.70-1.62 (m, 2H), 1.47 (s, 9H).

[0218] Step 3: Synthesis of trifluoroacetate of compound WX011-3 At room temperature, compound WX011-2 (0.1 g, 193.21 μmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (61.72 mg, 541.29 μmol, 40.08 μL) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the solvent was removed by concentrating under reduced pressure to obtain the trifluoroacetate salt of compound WX011-3.

[0219] Step 4: Synthesis of the hydrochloride salt of compound WX011 At room temperature and under nitrogen gas protection, intermediate BB-2 (90 mg, 185.38 μmol), trifluoroacetate of compound WX011-3 (98.53 mg, 185.38 μmol), and potassium acetate (54.58 mg, 556.14 μmol) were sequentially added to a mixed solvent of glacial acetic acid (0.1 mL) and N,N-dimethylformamide (1 mL). The reaction mixture was stirred at room temperature for 2 hours. Then, sodium triacetoxyborohydride (117.87 mg, 556.14 μmol) was added, and the reaction mixture was stirred at room temperature for 15 hours. After the reaction was complete, saturated ammonium chloride (10 mL) was added, and the mixture was extracted with ethyl acetate (5 mL x 2). A large amount of insoluble material precipitated, and the organic phase and insoluble material were concentrated under reduced pressure to remove the solvent. The resulting residue was separated and purified by preparative HPLC (chromatography column: Phenomenex Luna 80×30mm×3μm, mobile phase: water (0.04% hydrochloric acid)-acetonitrile, acetonitrile %: 25%~45%, 8 min) to obtain the hydrochloride salt of the target compound WX011. MS-ESI m / z: 887.4 [M+H] + . 1H NMR (400 MHz, MeOD_d4) δ: 8.59 (d, J=9.2 Hz, 1H), 8.51 (t, J=7.6 Hz, 1H), 8.37 (d, J=9.2 Hz, 1H), 8.33-8.26 (m, 2H), 7.91 (d, J=9.2 Hz, 1H), 7.79 (d, J=7.6 Hz, 1H), 7.75-7.68 (m, 1H), 7.06-6.72 (m, 1H), 6.44 (d, J=7.6 Hz, 1H), 5.44 (s, 1H), 5.01 (d, J=4.8 Hz, 10.4 Hz, 1H), 4.96-4.92 (m, 1H), 4.84-4.78 (m, 2H), 4.70 (s, 2H), 4.28-4.15 (m, 2H), 3.98-3.92 (m, 2H), 3.76-3.65 (m, 2H), 3.57-3.46 (m, 2H), 3.24-3.06 (m, 3H), 2.95-2.66 (m, 3H), 2.59-2.50 (m, 1H), 2.47-1.87 (m, 13H), 1.42-1.28 (m, 2H).

[0220] Example 12

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[0221] ステップ1: Synthesis of compound WX012-1 Under nitrogen gas protection at room temperature, the hydrochloride salt of compound WX001-3 (93.09 mg, 331.57 μmol) was dissolved in N,N-dimethylformamide (2 mL). Then, N,N-diisopropylethylamine (194.78 mg, 1.51 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (171.92 mg, 452.14 μmol) were added sequentially, and the reaction mixture was stirred at room temperature for 0.5 hours. Next, the hydrochloride salt of intermediate BB-13 (0.1 g, 301.43 μmol) was added, and the reaction mixture was continued at room temperature with stirring for 2 hours. After the reaction was complete, water (20 mL) was added to the reaction solution, and it was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with 10% saline solution (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure to obtain compound WX012-1. MS-ESI m / z: 522.3 [M+H] + .

[0222] Step 2: Synthesis of the hydrochloride salt of compound WX012-2 At room temperature, compound WX012-1 (150 mg, 287.60 μmol) was dissolved in ethyl acetate (1 mL), then ethyl acetate hydrochloride solution (4 M, 2 mL) was added, and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was filtered, the cake was rinsed with ethyl acetate (10 mL), the cake was collected, and the mixture was vacuum-dried to obtain the hydrochloride salt of compound WX012-2. MS-ESI m / z: 422.2 [M+H] + . 1H NMR (400 MHz, DMSO_d6) δ: 11.25 (s, 1H), 11.14 (s, 1H), 9.85 (s, 2H), 8.52 (d, J=2.0 Hz, 1H), 8.25 (d, J=8.8 Hz, 1H), 8.14 (d, J=9.2 Hz, 1H), 7.96-7.88 (m, 2H), 5.05 (dd, J=4.4 Hz, 11.2 Hz, 1H), 4.29 (s, 2H), 3.60 (s, 4H), 3.45 (s, 4H), 2.90-2.78 (m, 1H), 2.70-2.65 (m, 1H), 2.64-2.56 (m, 1H), 2.45-2.33 (m, 1H).

[0223] Step 3: Synthesis of the hydrochloride salt of compound WX012 At room temperature, intermediate BB-2 (95 mg, 195.68 μmol) and the hydrochloride salt of compound WX012-2 (98.56 mg, 215.25 μmol) were dissolved in N,N-dimethylformamide (2 mL). Then, potassium acetate (57.61 mg, 587.04 μmol) and acetic acid (5.88 mg, 97.84 μmol) were added sequentially, and the reaction mixture was stirred at room temperature for 2 hours. After that, sodium triacetoxyborohydride (165.89 mg, 782.72 μmol) was added, and the reaction mixture was continued at room temperature for 10 hours with stirring. After the reaction was complete, saturated ammonium chloride solution (20 mL) was added to the reaction solution to precipitate the solid, which was then filtered and the cake was collected. The resulting cake was separated by preparative HPLC (chromatography column: Phenomenex Luna 80×40mm×3μm, mobile phase: water (0.04% hydrochloric acid)-acetonitrile, acetonitrile %: 18%~38%, 7 min) to obtain the hydrochloride salt of the target compound WX012. MS-ESI m / z: 891.5 [M+H] + . 1H NMR (400 MHz, DMSO_d6) δ: 11.14 (s, 1H), 11.06 (s, 1H), 9.51 (d, J=6.0 Hz, 1H), 8.78 (d, J=7.2 Hz, 1H), 8.51 (d, J=1.6 Hz, 1H), 8.40 (d, J=3.6 Hz, 1H), 8.26 (d, J=5.6 Hz, 2H), 8.14 (d, J=9.2 Hz, 1H), 7.96-7.87 (m, 2H), 7.27-6.96 (m, 1H), 6.90-6.43 (m, 1H), 5.34-4.98 (m, 2H), 4.76 (d, J=20.0 Hz, 1H), 4.36-4.08 (m, 4H), 3.83-3.71 (m, 5H), 3.15-3.00 (m, 2H), 2.91-2.77 (m, 2H), 2.71-2.58 (m, 4H), 2.43-2.31 (m, 2H), 2.14-1.72 (m, 10H), 1.30-1.10 (m, 2H).

[0224] Example 13

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[0225] ステップ1: Synthesis of compound WX013-1 Under nitrogen gas protection at room temperature, compound WX003-2 (399.77 mg, 1.67 mmol), intermediate BB-14 (0.3 g, 835.25 μmol), cuprous iodide (31.81 mg, 167.05 μmol), bis(triphenylphosphine)palladium(II) dichloride (117.25 mg, 167.05 μmol), and N,N-diisopropylethylamine (215.90 mg, 1.67 mmol) were added to dimethyl sulfoxide (4 mL). The reaction mixture was heated to 85°C and stirred for 2.5 hours. After the reaction was complete, the mixture was cooled to room temperature, water (2 mL) was added, and the mixture was extracted with ethyl acetate (5 mL x 2). The organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. The resulting residue was purified by thin-layer chromatography (eluent: petroleum ether / ethyl acetate / dichloromethane = 1 / 1 / 1, volume ratio) to obtain compound WX013-1. MS-ESI m / z: 418.2 [M+H-100] + . 1 H NMR (400 MHz, CDCl3) δ: 8.13 (br s, 2H), 7.97 (t, J=9.2 Hz, 2H), 7.73 (dd, J=8.8 Hz, 15.2 Hz, 2H), 4.72 (dd, J=4.8 Hz, 8.4 Hz, 1H), 4.49 (s, 2H), 3.91-3.68 (m, 3H), 3.19-3.11 (m, 2H), 3.00-2.89 (m, 1H), 2.85-2.68 (m, 2H), 2.64-2.54 (m, 1H), 1.99-1.88 (m, 2H), 1.68-1.61 (m, 2H), 1.47 (s, 9H).

[0226] Step 2: Synthesis of trifluoroacetate of compound WX013-2 At room temperature, compound WX013-1 (0.1 g, 193.21 μmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (616.00 mg, 5.40 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the solvent was removed by reducing the pressure to obtain the trifluoroacetate salt of compound WX013-2. MS-ESI m / z: 418.2 [M+H] + .

[0227] Step 3: Synthesis of the hydrochloride salt of compound WX013 At room temperature and under nitrogen gas protection, intermediate BB-2 (90 mg, 185.38 μmol), trifluoroacetate of compound WX013-2 (98.53 mg, 185.38 μmol), and potassium acetate (54.58 mg, 556.14 μmol) were added to a mixed solvent of N,N-dimethylformamide (1 mL) and glacial acetic acid (0.1 mL) and the reaction mixture was stirred at room temperature for 2 hours. Next, sodium triacetoxyborohydride (117.87 mg, 556.14 μmol) was added and the reaction mixture was stirred at room temperature for 15 hours. After the reaction was complete, 1 M hydrochloric acid (1 mL) was added, and the resulting solution was separated by preparative HPLC (chromatography column: Phenomenex Luna 80 × 30 mm × 3 μm, mobile phase: water (0.04% hydrochloric acid) - acetonitrile, acetonitrile %: 20%~40%, 8 min) to obtain the hydrochloride salt of the target compound WX013. MS-ESI m / z: 887.4 [M+H] + . 1H NMR (400 MHz, CD3OD) δ: 9.74 (s, 1H), 8.55-8.49 (m, 1H), 8.39-8.34 (m, 1H), 8.32-8.28 (m, 1H), 8.24-8.18 (m, 2H), 8.09 (d, J=8.8 Hz, 1H), 7.84 (d, J=9.2 Hz, 1H), 7.75-7.70 (m, 1H), 7.04-6.72 (m, 1H), 6.44 (d, J=7.6 Hz, 1H), 5.44 (s, 1H), 4.96 (dd, J= 4.8 Hz, 10.4 Hz, 1H), 4.82-4.78 (m, 2H), 4.58-4.55 (m, 2H), 4.28-4.17 (m, 1H), 4.14-4.09 (m, 1H), 3.99-3.84 (m, 2H), 3.75-3.65 (m, 2H), 3.54-3.46 (m, 2H), 3.36-3.33 (m, 1H), 3.20-3.11 (m, 1H), 3.09 (d, J=6.0 Hz, 2H), 2.94-2.63 (m, 3H), 256-2.47 (m, 1H), 2.43-2.34 (m, 1H), 2.31-2.19 (m, 3H), 2.14-1.82 (m, 9H), 1.41–1.26 (m, 2H).

[0228] Example 14

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[0229] ステップ1: Synthesis of compound WX014-1 Under room temperature and nitrogen gas protection, the hydrochloride salt of compound WX001-3 (465.44 mg, 1.66 mmol) was dissolved in N,N-dimethylformamide (10 mL). Then, N,N-diisopropylethylamine (973.92 mg, 7.54 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (859.59 mg, 2.26 mmol) were added sequentially, and the reaction mixture was stirred at room temperature for 0.5 hours. Next, the hydrochloride salt of intermediate BB-15 (0.5 g, 1.51 mmol) was added, and the reaction mixture was continued with stirring at room temperature for 11.5 hours. After the reaction was complete, water (80 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with 10% saline solution (60 mL x 3), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by reducing the pressure of the filtrate. The resulting residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 2 to 0 / 1, volume ratio) to obtain compound WX014-1. MS-ESI m / z: 522.2 [M+H] + .

[0230] Step 2: Synthesis of the hydrochloride salt of compound WX014-2 At room temperature, compound WX014-1 (520 mg, 997.00 μmol) was dissolved in dichloromethane (5 mL), and ethyl acetate hydrochloride solution (4 M, 10 mL) was added. The reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete, the mixture was filtered, the cake was rinsed with ethyl acetate (15 mL), the cake was collected, and the mixture was vacuum-dried to obtain the hydrochloride salt of compound WX014-2. MS-ESI m / z: 422.2 [M+H] + .

[0231] Step 3: Synthesis of the hydrochloride salt of compound WX014 Under nitrogen gas protection at room temperature, intermediate BB-2 (190 mg, 391.36 μmol) and the hydrochloride salt of compound WX014-2 (179.21 mg, 391.36 μmol) were dissolved in N,N-dimethylformamide (5 mL). Potassium acetate (115.22 mg, 1.17 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. Next, sodium triacetoxyborohydride (331.78 mg, 1.57 mmol) was added, and the reaction mixture was stirred at room temperature for 40 minutes. After the reaction was complete, 1 M hydrochloric acid solution (4 mL) was added, and the solvent was removed by reducing the pressure and concentrating. The resulting residue was separated by preparative HPLC (chromatography column: Phenomenex Luna 80 × 30 mm × 3 μm, mobile phase: water (0.04% hydrochloric acid) - acetonitrile, acetonitrile %: 10%~30%, 8 min) to obtain the hydrochloride salt of the target compound WX014. MS-ESI m / z: 891.3 [M+H] + . 1 H NMR (400 MHz, DMSO_d6) δ: 11.15 (s, 1H), 10.71 (s, 1H), 9.51 (d, J=6.4 Hz, 1H), 8.78 (d, J=7.6 Hz, 1H), 8.41 (d, J=3.6 Hz, 1H), 8.36 (d, J=9.2 Hz, 1H), 8.26 (d, J=5.6 Hz, 1H), 8.17 (d, J=5.6 Hz, 1H), 8.00 (d, J=9.2 Hz, 1H), 7.81-7.71 (m, 2H), 7.27-6.96 (m, 1H), 6.90-6.39 (m, 1H), 5.30-5.06 (m, 2H), 4.77 (d, J=19.6 Hz, 1H), 4.39-4.03 (m, 3H), 3.86-3.78 (m, 2H), 3.76-3.57 (m, 8H), 3.14-2.98 (m, 2H), 2.92-2.80 (m, 1H), 2.71-2.53 (m, 3H), 2.46-2.34 (m, 2H), 2.13-2.00 (m, 5H), 1.99-1.73 (m, 5H), 1.29-1.13 (m, 2H).

[0232] Example 15 [ka] Synthesis route: [ka]

[0233] [ka]

[0234] Step 1: Synthesis of compound WX015-2 Under nitrogen gas protection at room temperature, 9.7 g of the hydrochloride salt of compound WX001-3 was dissolved in 50 mL of N,N-dimethylformamide. Then, 8.55 g, 66.15 mmol of N,N-diisopropylethylamine and 16.35 g, 43.00 mmol of O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate were added sequentially. The reaction mixture was stirred at room temperature for 0.5 hours. Next, compound WX015-1 (5 g, 33.08 mmol) was added, and the reaction was continued at room temperature with stirring for 2 hours. After the reaction was complete, 200 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. The resulting residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1, volume ratio) to obtain compound WX015-2. MS-ESI m / z: 378.3 [M+H] + .

[0235] Step 2: Synthesis of compound WX015-3 Under room temperature and nitrogen gas protection, compound WX015-2 (4 g, 10.60 mmol) and dimethyl carbonate (3.82 g, 42.39 mmol, 3.57 mL) were dissolved in tetrahydrofuran (50 mL). Potassium tert-butoxide (7.14 g, 63.59 mmol) was added, and the reaction mixture was heated to 90°C and stirred for 4 hours. After the reaction was complete, the solvent was removed by reducing the pressure, and the mixture was dissolved in ice water (50 mL). Extraction was performed with methyl tert-butyl ether (50 mL x 2), and the aqueous phase was collected. The pH was adjusted to 7 with 6 M hydrochloric acid, and the aqueous phase was concentrated under reduced pressure to obtain compound WX015-3. MS-ESI m / z: 404.2 [M+H] + . 1 H NMR (400 MHz, D2O) δ: 7.78 (d, J=7.6 Hz, 1H), 7.60 (d, J=7.6 Hz, 1H), 7.19 (t, J=7.8 Hz, 1H), 5.17 (s, 1H), 3.58-3.45 (m, 4H), 3.27 (s, 2H), 2.62-2.50 (m, 4H), 1.42 (s, 9H).

[0236] Step 3: Synthesis of compound WX015-4 At room temperature, compound WX015-3 (4.2 g, 10.41 mmol) was dissolved in ethanol (80 mL), sodium acetate (3.42 g, 41.64 mmol) and hydroxylamine hydrochloride (2.53 g, 36.44 mmol) were added, and the reaction mixture was heated to 80°C and stirred for 5 hours. After the reaction was complete, the reaction solution was cooled to room temperature, filtered, the cake was rinsed with dichloromethane (50 mL x 2), the filtrate was concentrated to remove most of the solvent, water (100 mL) was added, and the mixture was extracted with dichloromethane (50 mL x 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound WX015-4. MS-ESI m / z: 419.1 [M+H] + .

[0237] Step 4: Synthesis of compound WX015-5 At 30°C, compound WX015-4 (2.5 g, 5.97 mmol) was dissolved in dichloromethane (40 mL). 4-dimethylaminopyridine (1.09 g, 8.96 mmol) and di-tert-butyl carbonate (2 g, 9.16 mmol, 2.11 mL) were added. The reaction mixture was stirred at 30°C for 1.5 hours. Anhydrous ethanol (2.75 g, 59.75 mmol) was then added, and the reaction was continued for 1 hour. After the reaction was complete, the mixture was poured into water (50 mL), the liquid was separated, the aqueous phase was extracted again with dichloromethane (30 mL), and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The obtained crude product was separated and purified by column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 5) to obtain compound WX015-5. MS-ESI m / z: 447.3 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ: 9.79 (s, 1H), 8.46 (d, J=7.6 Hz, 1H), 7.41 (d, J=7.6 Hz, 1H), 7.32 (t, J=8.0 Hz, 1H), 4.22 (q, J=7.0 Hz, 2H), 4.04 (s, 2H), 3.63-3.54 (m, 4H), 3.26 (s, 2H), 2.69-2.58 (m, 4H), 1.48 (s, 9H), 1.26 (t, J=7.2 Hz, 3H).

[0238] Step 5: Synthesis of compound WX015-6 Under room temperature and nitrogen gas protection, compound WX015-5 (0.92 g, 2.06 mmol) and acrylamide (175.75 mg, 2.47 mmol) were dissolved in tetrahydrofuran (20 mL), cooled to 0°C, and a solution of potassium tert-butoxide in tetrahydrofuran (1 M, 3.09 mL) was added dropwise. The reaction mixture was stirred at 0°C for 1.5 hours. After the reaction was complete, 0.05 M hydrochloric acid (70 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (40 mL x 2) to combine the organic phases. The mixture was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The obtained crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1 to 1 / 1) to obtain compound WX015-6. MS-ESI m / z: 472.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ: 9.83 (s, 1H), 8.49 (d, J=6.4 Hz, 1H), 8.10 (s, 1H), 7.42 (d, J=7.6 Hz, 1H), 7.35 (t, J=7.8 Hz, 1H), 4.34 (dd, J=5.0 Hz, 9.0 Hz, 1H), 3.66-3.52 (m, 4H), 3.27 (s, 2H), 3.06-2.95 (m, 1H), 2.83-2.73 (m, 1H), 2.71-2.56 (m, 5H), 2.53-2.43 (m, 1H), 1.49 (s, 9H).

[0239] Step 6: Synthesis of the hydrochloride salt of compound WX015-7 At room temperature, compound WX015-6 (530 mg, 1.12 mmol) was dissolved in ethyl acetate (1 mL), and hydrochloric acid / ethyl acetate solution (4 M, 30 mL) was added. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the solvent was removed by concentrating under reduced pressure to obtain the hydrochloride salt of compound WX015-7. MS-ESI m / z: 372.1 [M+H] + .

[0240] Step 7: Synthesis of the hydrochloride salt of compound WX015 Under nitrogen gas protection at room temperature, intermediate BB-2 (654.51 mg, 1.35 mmol) and the hydrochloride salt of compound WX015-7 (599 mg) were dissolved in 1,2-dichloroethane (18 mL) and tetrahydrofuran (9 mL). Potassium acetate (291.08 mg, 2.97 mmol) and acetic acid (0.5 mL) were added, and the reaction mixture was stirred at room temperature for 1 hour. Next, sodium triacetoxyborohydride (857.19 mg, 4.04 mmol) was added, and the reaction mixture was stirred at room temperature for 1.5 hours. After the reaction was complete, 10 mL of 1 M hydrochloric acid solution was added, and the solvent was removed by concentrating under reduced pressure. The resulting residue was separated by preparative HPLC (chromatography column: Phenomenex Luna 80×40mm×3μm, mobile phase: water (0.04% hydrochloric acid)-acetonitrile, acetonitrile %: 22%~37%, 7 min) to obtain the hydrochloride salt of the target compound WX015. MS-ESI m / z: 841.3 [M+H] + . 1H NMR (400 MHz, DMSO_d6) δ: 11.50 (s, 1H), 11.12 (s, 2H), 9.50 (d, J=6.0 Hz, 1H), 8.78 (d, J=7.6 Hz, 1H), 8.40 (d, J=3.6 Hz, 1H), 8.26 (d, J=5.6 Hz, 1H), 8.02 (d, J=7.6 Hz, 1H), 7.68 (d, J=7.6 Hz, 1H), 7.40 (t, J=7.8 Hz, 1H), 7.27-6.95 (m, 1H), 6.90-6.41 (m, 1H), 5.27 (s, 1H), 5.08 (s, 1H), 4.76 (d, J=18.8 Hz, 1H), 4.65 (dd, J=4.8 Hz, 12.0 Hz, 1H), 4.50-4.15 (m, 3H), 3.90-3.69 (m, 8H), 3.67-3.55 (m, 2H), 3.54-3.37 (m, 2H), 3.19-3.03 (m, 2H), 2.85-2.72 (m, 1H), 2.69-2.53 (m, 2H), 2.28-2.16 (m, 1H), 2.14-2.03 (m, 4H), 2.02-1.87 (m, 2H), 1.85-1.69 (m, 2H), 1.30-1.10 (m, 2H).

[0241] ステップ8: Synthesis of compound WX015-8 Under nitrogen gas protection at room temperature, intermediate BB-2-4 (80 g, 164.10 mmol) was dissolved in dichloromethane (1.6 L), triphenylphosphine (51.65 g, 196.92 mmol) and imidazole (16.76 g, 246.15 mmol) were added, the reaction mixture was cooled to 0°C, elemental iodine (54.15 g, 213.33 mmol) was added, and the reaction mixture was stirred at room temperature for 14 hours. After the reaction was complete, the reaction solution was poured into saturated sodium sulfite aqueous solution (600 mL), stirred at room temperature until the solution became colorless, filtered, the cake was rinsed with dichloromethane (500 mL x 3), the mother liquor was separated, and the organic phase was collected. The organic phase was washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. Methanol (500 mL) was added to the residue, stirred at room temperature for 1 hour, filtered, the cake was rinsed with methanol (500 mL), the cake was collected, and vacuum-dried to obtain compound WX015-8. MS-ESI m / z: 598.0 [M+H] + .

[0242] Step 9: Synthesis of Compound WX015 Under room temperature and nitrogen gas protection, compound WX015-6 (3 g, 6.36 mmol) was dissolved in dichloromethane (30 mL), and trifluoroacetic acid (9.24 g, 81.04 mmol, 6 mL) was added. The reaction mixture was stirred at room temperature for 4 hours. After the reaction was complete, the solvent was removed by reducing the pressure to obtain the trifluoroacetate of compound WX015-7. MS-ESI m / z: 372.0 [M+H] + .

[0243] Under nitrogen gas protection at room temperature, the trifluoroacetate salt of compound WX015-7 (253.65 g, 310.81 mmol) was dissolved in acetonitrile (3.4 L). N,N-diisopropylethylamine (281.19 g, 2.18 mol) and compound WX015-8 (168.8 g, 282.56 mmol) were added, and the reaction mixture was heated to 80°C and stirred for 23 hours. After the reaction was complete, the reaction solution was poured into acetone (4.3 L) and stirred at room temperature for 12 hours. The mixture was filtered, the cake was rinsed with acetone (400 mL x 4), and the cake was collected. The cake was dissolved in dichloromethane (1.5 L), concentrated under reduced pressure to remove the solvent, and the dissolution and concentration procedure was repeated twice to obtain compound WX015. MS-ESI m / z: 841.3 [M+H] + . 1 H NMR (400 MHz, DMSO_d6) δ: 11.12 (s, 1H), 10.02 (s, 1H), 9.50 (d, J=6.0 Hz, 1H), 8.77 (d, J=7.6 Hz, 1H), 8.39 (d, J=4.4 Hz, 1H), 8.26 (d, J=5.6 Hz, 1H), 8.10 (d, J=7.6 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.36 (t, J=8.0 Hz, 1H), 7.27-6.94 (m, 1H), 6.88-6.41 (m, 1H), 5.17 (d, J=84.4 Hz, 1H), 4.76 (d, J=15.6 Hz, 1H), 4.63 (dd, J=4.8 Hz, 12.0 Hz, 1H), 4.24-4.11 (m, 1H), 3.86-3.71 (m, 2H), 3.66-3.40 (m, 2H), 3.36-3.20 (m, 6H), 2.84-2.72 (m, 1H), 2.69-2.53 (m, 5H), 2.48-2.41 (m, 2H), 2.27-2.10 (m, 3H), 2.09-1.85 (m, 6H), 1.82-1.68 (m, 2H), 1.13-0.97 (m, 2H).

[0244] Example 16 [ka] Synthesis route: [ka]

[0245] Step 1: Synthesis of compound WX016-2 At room temperature and under nitrogen gas protection, titanocene dichloride (1.30 g, 5.02 mmol) and zinc powder (13.31 g, 203.55 mmol) were added to a dry reaction flask, dissolved in tetrahydrofuran (100 mL), and a solution of bromodifluoroethyl acetate (20.37 g, 100.38 mmol, 12.90 mL) in tetrahydrofuran (20 mL) was added dropwise (1 / 10 of the solution was added dropwise first to start the reaction (when the temperature rose significantly), and then the remaining solution was added dropwise). After the dropwise addition was complete, the mixture was stirred for 0.5 hours, filtered, and the filtrate was added to a solution of compound WX016-1 (10 g, 50.19 mmol) in tetrahydrofuran (50 mL), and the mixture was stirred for 12 hours to allow the reaction to proceed. After the reaction was complete, 1M hydrochloric acid was added dropwise to adjust the pH to 3. The mixture was diluted with ethyl acetate (100 mL) and water (100 mL), the liquid was separated, the organic phase was collected, the aqueous phase was extracted with ethyl acetate (50 mL x 3), the organic phases were combined, washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 0 / 1~1 / 1, volume ratio) to obtain compound WX016-2. MS-ESI m / z: 268.0 [M+H-56] + .

[0246] Step 2: Synthesis of compound WX016-3 Under room temperature and nitrogen gas protection, compound WX016-2 (1 g, 3.09 mmol), sulfoxide chloride (2.21 g, 18.56 mmol), and pyridine (1.47 g, 18.56 mmol) were added to dioxane (15 mL). The reaction mixture was stirred for 1.5 hours, then 4-dimethylaminopyridine (37.78 mg, 309.28 μmol) was added, and the reaction was continued with stirring for 12 hours. After the reaction was complete, water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phase was washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The resulting residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 20 / 1 to 9 / 1, volume ratio) to obtain compound WX016-3. MS-ESI m / z: 206.2 [M+H-100] + . 1 H NMR (400 MHz, CDCl3) δ: 6.18 (s, 1H), 4.34 (q, J=7.0 Hz, 2H), 4.02 (d, J=2.0 Hz, 2H), 3.54 (t, J=5.6 Hz, 2H), 2.25 (s, 2H), 1.48 (s, 9H), 1.36 (t, J=7.2 Hz, 3H).

[0247] Step 3: Synthesis of compound WX016-4 At room temperature and under nitrogen gas protection, wet palladium hydroxide (0.5 g, 712.07 μmol, purity: 20%) was added to a hydrogenation flask, followed by methanol (20 mL) and compound WX016-3 (1.5 g, 4.91 mmol). The mixture was purged three times with hydrogen gas, and the reaction mixture was stirred at 40 psi for 12 hours. After the reaction was complete, the mixture was filtered, the cake was rinsed with methanol (50 mL x 4), the filtrate was collected, and the filtrate was concentrated under reduced pressure to remove the residual solvent. The resulting residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 20 / 1 to 10 / 1, volume ratio) to obtain compound WX016-4. MS-ESI m / z: 252.2 [M+H-56] + . 1H NMR (400 MHz, CDCl3) δ: 4.35 (q, J=7.0 Hz, 2H), 4.30-4.15 (m, 2H), 2.68 (t, J=12.8 Hz, 2H), 2.32-2.14 (m, 1H), 1.73 (d, J=12.8 Hz, 2H), 1.49 (d, J=4.8 Hz, 1H), 1.47 (s, 9H), 1.42 (d, J=4.4 Hz, 1H), 1.37 (t, J=7.0 Hz, 3H).

[0248] Step 4: Synthesis of compound WX016-5 Under room temperature and nitrogen gas protection, compound WX016-4 (0.26 g, 845.99 μmol) was dissolved in a mixed solvent of ethanol (5 mL) and water (2 mL). Lithium hydroxide monohydrate (71.00 mg, 1.69 mmol) was added, and the reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was adjusted to pH 2-3 with 1 M hydrochloric acid, causing a solid precipitate. The mixture was filtered, the cake was collected, and vacuum-dried to obtain compound WX016-5. MS-ESI m / z: 224.0 [M+H-56] + . 1 H NMR (400 MHz, DMSO_d6) δ: 4.05-3.94 (m, 2H), 2.80-2.63 (m, 3H), 2.37-2.21 (m, 1H), 1.71-1.61 (m, 2H), 1.39 (s, 9H), 1.27-1.12 (m, 2H).

[0249] Step 5: Synthesis of compound WX016-6 Under room temperature and nitrogen gas protection, compound WX016-5 (0.12 g, 429.68 μmol) was dissolved in N,N-dimethylformamide (5 mL), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (272.29 mg, 716.13 μmol) and N,N-diisopropylethylamine (277.66 mg, 2.15 mmol, 374.20 μL) were added. The reaction mixture was stirred for 0.5 hours, and then the hydrochloride salt of compound BB-8 (91.56 mg) was added, and the reaction was continued with stirring for 12 hours. After the reaction was complete, water (20 mL) was added to the reaction solution and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove residual solvent. The resulting residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1 to 2 / 1, volume ratio) to obtain compound WX016-6. MS-ESI m / z: 425.2 [M+H-56] + . 1 H NMR (400 MHz, CDCl3) δ: 8.45 (s, 1H), 8.16 (d, J=7.6 Hz, 1H), 7.68 (s, 1H), 7.41 (dd, J=1.0, 7.8 Hz, 1H), 4.25-4.17 (m, 3H), 3.71 (d, J=0.8 Hz, 2H), 2.72 (t, J=12.2 Hz, 2H), 2.57-2.42 (m, 1H), 1.84 (d, J=12.8 Hz, 2H), 1.59-1.49 (m, 3H), 1.47 (s, 9H), 1.28 (t, J=7.0 Hz, 3H).

[0250] Step 6: Synthesis of compound WX016-7 Under nitrogen gas protection at room temperature, compound WX016-6 (110 mg, 228.93 μmol) was dissolved in tetrahydrofuran (3 mL), acrylamide (19.53 mg, 274.71 μmol) was added, and the reaction mixture was cooled to 0°C in an ice bath. A solution of potassium tert-butoxide in tetrahydrofuran (1 M, 503.64 μL) was added dropwise, and after the addition was complete, the mixture was returned to room temperature and stirred for 1 hour. After the reaction was complete, the reaction solution was poured into 0.1 M hydrochloric acid (10 mL) and extracted with ethyl acetate (20 mL x 2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. Ethyl acetate (2 mL) was added to the residue, stirred at room temperature for 5 minutes, filtered, the cake was rinsed with ethyl acetate (2 mL x 2), the cake was collected, and the mixture was vacuum-dried to obtain compound WX016-7. MS-ESI m / z: 406.2 [M+H-100] + .

[0251] Step 7: Synthesis of the hydrochloride salt of compound WX016-8 Under room temperature and nitrogen gas protection, compound WX016-7 (70 mg, 138.47 μmol) was dissolved in ethyl acetate (1 mL), and a solution of hydrochloric acid in ethyl acetate (3 mL, 4 M) was added. The reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete, the mixture was filtered, the cake was rinsed with ethyl acetate (3 mL x 3), the cake was collected, and the mixture was vacuum-dried to obtain the hydrochloride salt of compound WX016-8. MS-ESI m / z: 406.2 [M+H] + . 1H NMR (400 MHz, DMSO_d6) δ: 10.92 (s, 1H), 10.80 (s, 1H), 7.94 (s, 1H), 7.53 (dd, J=1.4, 7.0 Hz, 1H), 7.34-7.22 (m, 2H), 4.17 (dd, J=5.0, 12.2 Hz, 1H), 3.38 (d, J=12.8 Hz, 2H), 2.97 (t, J=12.0 Hz, 2H), 2.82-2.70 (m, 1H), 2.69-2.55 (m, 3H), 2.41-2.27 (m, 1H), 2.18-2.07 (m, 1H), 2.03-1.92 (m, 2H), 1.80-1.61 (m, 2H).

[0252] Step 8: Synthesis of the hydrochloride salt of compound WX016 At room temperature and under nitrogen gas protection, 50 mg of the hydrochloride salt of compound WX016-8 was dissolved in 3 mL of 1,2-dichloroethane. Intermediate BB-2 (54.94 mg, 113.16 μmol), potassium acetate (33.32 mg, 339.48 μmol), and glacial acetic acid (3.40 mg, 56.58 μmol, 3.24 μL) were added, and the reaction mixture was stirred at room temperature for 2 hours. Then sodium triacetoxyborohydride (95.93 mg, 452.64 μmol) was added, and the reaction was continued with stirring for 12 hours. After the reaction was complete, 2 mL of 1 M hydrochloric acid was added to the reaction solution and stirred for 5 minutes, and the solvent was removed by concentrating under reduced pressure. The residue was separated by preparative HPLC (chromatography column: Phenomenex Luna 80×30mm×3μm, mobile phase: water (0.04% hydrochloric acid)-acetonitrile, acetonitrile %: 15%~40%, 8 min) to obtain the hydrochloride salt of the target compound WX016. MS-ESI m / z: 875.3 [M+H] + . 1H NMR (400 MHz, DMSO_d6) δ:10.92 (s, 1H), 10.84 (s, 1H), 9.50 (d, J=6.4 Hz, 2H), 8.79 (d, J=8.0 Hz, 1H), 8.41 (d, J=3.6 Hz, 1H), 8.26 (d, 7.95 (s, 1H), 7.53 (d, J=7.6 Hz, 1H), 7.38-6.94 (m, 3H), 6.91-6.36 (m, 1H), 5.36-5.04 (m, 1H), 4.77 (d, J=20.8 Hz, 1H), 4.25-4.12 (m, 2H), 3.85-3.77 (m, 1H), 3.76-3.42 (m, 4H), 3.12-2.90 (m, 4H), 2.82-2.56 (m, 5H), 2.39-2.27 (m, 1H), 2.18-1.89 (m, 11H), 1.88-1.73 (m, 2H), 1.31-1.11 (m, 2H).

[0253] Example 17

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[0254] ステップ1: Synthesis of compound WX017-1 Under nitrogen gas protection at room temperature, compound WX016-5 (0.7 g, 2.51 mmol) was dissolved in N,N-dimethylformamide (10 mL), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.19 g, 3.13 mmol) and N,N-diisopropylethylamine (809.85 mg, 6.27 mmol, 1.09 mL) were added. The reaction mixture was stirred at room temperature for 0.5 hours, then compound WX015-1 (315.73 mg, 2.09 mmol) was added, and the reaction was continued with stirring for 12 hours. After the reaction was complete, water (60 mL) was added to the reaction solution, and it was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The resulting residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1 to 5 / 1, volume ratio) to obtain compound WX017-1. MS-ESI m / z: 313.1 [M+H-100] + . 1 H NMR (400 MHz, CDCl3) δ: 12.94 (s, 1H), 8.74 (s, 1H), 8.59 (dd, J=0.8, 8.0 Hz, 1H), 7.57 (dd, J=1.4, 8.2 Hz, 1H), 6.98 (t, J=8.0 Hz, 1H), 4.29-4.17 (m, 2H), 2.68 (s, 3H), 2.53-2.40 (m, 1H), 1.81 (d, J=12.4 Hz, 2H), 1.59-1.55 (m, 2H), 1.53-1.48 (m, 2H), 1.46 (s, 9H).

[0255] Step 2: Synthesis of compound WX017-2 Under nitrogen gas protection at room temperature, compound WX017-1 (0.67 g, 1.62 mmol) was dissolved in tetrahydrofuran (20 mL), dimethyl carbonate (585.34 mg, 6.50 mmol) was added, and the reaction mixture was cooled to 0°C in an ice bath. Potassium tert-butoxide (1.09 g, 9.75 mmol) was slowly added, and the mixture was then heated to 80°C and stirred for 12 hours. After the reaction was complete, the mixture was cooled to room temperature, concentrated under reduced pressure to remove the solvent, and compound WX017-2 was obtained. MS-ESI m / z: 339.2 [M+H-100] + .

[0256] Step 3: Synthesis of compound WX017-3 Under nitrogen gas protection at room temperature, compound WX017-2 (0.72 g, 1.64 mmol) was dissolved in ethanol (10 mL), hydroxylamine hydrochloride (399.43 mg, 5.75 mmol) was added, and the reaction mixture was heated to 80°C and stirred for 12 hours. After the reaction was complete, the mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure to remove most of the ethanol, water (10 mL) was added, and the pH was adjusted to 6 with aqueous sodium bicarbonate solution. Extraction was performed with dichloromethane / ethanol = 10 / 1 (30 mL x 5), the organic phase was washed with saturated saline solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound WX017-3. MS-ESI m / z: 354.1 [M+H-100] + .

[0257] Step 4: Synthesis of compound WX017-4 At room temperature and under nitrogen gas protection, compound WX017-3 (0.78 g, 1.63 mmol) was dissolved in ethanol (10 mL), concentrated sulfuric acid (326.66 mg, 3.26 mmol) was added, and the reaction mixture was heated to 90°C and stirred for 12 hours. After the reaction was complete, the mixture was cooled to room temperature, water (30 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the residual solvent. The residue was dissolved in tetrahydrofuran (5 mL) and water (5 mL), sodium carbonate (344.86 mg, 3.25 mmol) and di-tert-butyl carbonate (355.06 mg, 1.63 mmol) were added, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, water (30 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated saline solution (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove residual solvent. The resulting residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1 to 2 / 1, volume ratio) to obtain compound WX017-4. MS-ESI m / z: 382.1 [M+H-100] + . 1 H NMR (400 MHz, CDCl3) δ: 8.47 (s, 1H), 8.42 (d, J=8.0 Hz, 1H), 7.53 (d, J=8.0 Hz, 1H), 7.37 (t, J=7.8 Hz, 1H), 4.27-4.19 (m, 3H), 4.06 (s, 2H), 2.79-2.66 (m, 2H), 2.56-2.46 (m, 1H), 1.83 (d, J=12.4 Hz, 2H), 1.59-1.50 (m, 3H), 1.47 (s, 9H), 1.27 (t, J=7.2 Hz, 3H).

[0258] Step 6: Synthesis of compound WX017-5 Under room temperature and nitrogen gas protection, compound WX017-4 (450 mg, 934.60 μmol) and acrylamide (79.72 mg, 1.12 mmol) were dissolved in tetrahydrofuran (5 mL). The reaction mixture was cooled to 0°C in an ice bath, and a solution of potassium tert-butoxide in tetrahydrofuran (1 M, 1.87 mL) was added dropwise. The reaction mixture was stirred at 0°C for 1 hour. After the reaction was complete, the reaction solution was poured into 0.3 M hydrochloric acid (10 mL), extracted with ethyl acetate (20 mL x 3), washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The resulting residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1 to 1 / 1, volume ratio) to obtain compound WX017-5. MS-ESI m / z: 407.1 [M+H-100] + . 1 H NMR (400 MHz, DMSO_d6) δ:11.12 (s, 1H), 10.99 (s, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.61 (d, J=7.6 Hz, 1H), 7.41 (t, J=7.6 Hz, 1H), 4.64 (dd, J=4.8, 12.0 Hz, 1H), 4.11-4.06 (m, 1H), 2.86-2.71 (m, 3H), 2.68-2.53 (m, 3H), 2.27-2.15 (m, 1H), 1.81 (d, J=12.4 Hz, 2H), 1.40 (s, 9H), 1.38-1.32 (m, 2H).

[0259] Step 7: Synthesis of the hydrochloride salt of compound WX017-6 Under nitrogen gas protection at room temperature, compound WX017-5 (290 mg, 572.56 μmol) was dissolved in ethyl acetate (1 mL), and a solution of hydrochloric acid in ethyl acetate (3 mL, 4 M) was added. The reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete, the mixture was filtered, the cake was rinsed with ethyl acetate (3 mL x 3), the cake was collected, and the mixture was vacuum-dried to obtain the hydrochloride salt of compound WX017-6. MS-ESI m / z: 407.1 [M+H] + . 1H NMR (400 MHz, DMSO_d6) δ: 11.13 (s, 1H), 11.09 (s, 1H), 8.74 (s, 2H), 7.80 (d, J=8.0 Hz, 1H), 7.62 (d, J=7.2 Hz, 1H), 7.42 (t, J=7.8 Hz, 1H), 4.65 (dd, J=4.8, 12.0 Hz, 1H), 3.38 (d, J=11.6 Hz, 2H), 2.97 (t, J=12.6 Hz, 2H), 2.85-2.71 (m, 2H), 2.70-2.53 (m, 3H), 2.26-2.16 (m, 1H), 1.96 (d, J=14.0 Hz, 2H), 1.83-1.64 (m, 2H).

[0260] Step 8: Synthesis of the hydrochloride salt of compound WX017 Under nitrogen gas protection at room temperature, 0.1 g of the hydrochloride salt of compound WX017-6 was dissolved in 3 mL of 1,2-dichloroethane and 2 mL of tetrahydrofuran. Intermediate BB-2 (101.29 mg, 208.64 μmol), potassium acetate (61.43 mg, 625.91 μmol), and glacial acetic acid (6.26 mg, 104.32 μmol, 5.97 μL) were added, and the reaction mixture was stirred at room temperature for 2 hours. Then sodium triacetoxyborohydride (176.87 mg, 834.54 μmol) was added, and stirring was continued for 1 hour. After the reaction was complete, 2 mL of 1 M hydrochloric acid was added and the mixture was stirred for 5 minutes. The solvent was removed by concentrating under reduced pressure. The residue was separated by preparative HPLC (chromatography column: Phenomenex C18 75×30mm×3μm, mobile phase: water (0.04% hydrochloric acid)-acetonitrile, acetonitrile %: 12%~42%, 8 min) to obtain the hydrochloride salt of the target compound WX017. MS-ESI m / z: 876.4 [M+H] + . 1H NMR (400 MHz, DMSO_d6) δ:11.13 (s, 2H), 9.51 (d, J=6.8 Hz, 1H), 9.32 (s, 1H), 8.79 (d, J=7.6 Hz, 1H), 8.43-8.20 (m, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.64 (d, J=7.6 Hz, 1H), 7.43 (t, J=7.8 Hz, 1H), 7.31-6.94 (m, 1H), 6.91-6.41 (m, 1H), 5.30-5.03 (m, 1H), 4.77 (d, J=21.6 Hz, 1H), 4.65 (dd, J=5.0, 12.2 Hz, 1H), 4.32-4.16 (m, 2H), 3.85-3.57 (m, 6H), 3.14-2.94 (m, 4H), 2.84-2.74 (m, 2H), 2.69-2.58 (m, 3H), 2.27-2.17 (m, 1H), 2.14-1.89 (m, 10H), 1.87-1.74 (m, 2H), 1.32-1.08 (m, 2H).

[0261] Example 18

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[0262] ステップ1: Synthesis of compound WX018-1 Under nitrogen gas protection at room temperature, intermediate BB-2-1 (1.10 g, 4.88 mmol) was dissolved in acetonitrile (10 mL), and 8-oxa-3-azabicyclo[3.2.1]octane (0.95 g, 6.35 mmol, hydrochloride) and N,N-diisopropylethylamine (1.89 g, 14.65 mmol, 2.55 mL) were added. The reaction mixture was heated to 60°C and stirred for 2 hours. After the reaction was complete, the solvent was removed by reducing the pressure, and water (20 mL) was added to the resulting residue. The mixture was stirred at room temperature for 1 hour to precipitate the solid, filtered, and the cake was washed with water (20 mL x 4). The cake was collected and vacuum-dried to obtain compound WX018-1. MS-ESI m / z: 303.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ: 8.35-8.25 (m, 2H), 6.36 (d, J=8.0 Hz, 1H), 4.53 (s, 2H), 4.35 (q, J=7.4 Hz, 2H), 4.23-3.71 (m, 1H), 3.35 (d, J=12.4 Hz, 2H), 2.00 (t, J=4.6 Hz, 2H), 1.83 (d, J=7.6 Hz, 2H), 1.70 (s, 1H), 1.39 (t, J=7.2 Hz, 3H).

[0263] Step 2: Synthesis of compound WX018-2 Under nitrogen gas protection at room temperature, compound WX018-1 (1.4 g, 4.63 mmol) was dissolved in methanol (15 mL) and water (3 mL). Lithium hydroxide monohydrate (388.61 mg, 9.26 mmol) was added, and the reaction mixture was heated to 60°C and stirred for 12 hours. After the reaction was complete, the mixture was cooled to room temperature, concentrated under reduced pressure to remove methanol, and 1 M hydrochloric acid was added to adjust the pH to 3-4. A large amount of white solid precipitated, which was filtered. The cake was rinsed with water (10 mL x 2), collected, and vacuum-dried to obtain compound WX018-2. MS-ESI m / z: 275.2 [M+H] + . 1H NMR (400 MHz, DMSO_d6) δ:11.70 (s, 1H), 8.73 (d, J=8.0 Hz, 1H), 8.19 (s, 1H), 6.76 (d, J=8.0 Hz, 1H), 4.47 (d, J=2.0 Hz, 2H), 4.30-3.90 (m, 2H), 3.15 (d, J=12.4 Hz, 2H), 1.89-1.80 (m, 2H), 1.73-1.65 (m, 2H).

[0264] Step 3: Synthesis of compound WX018-3 Under room temperature and nitrogen gas protection, compound WX018-2 (0.2 g, 729.20 μmol) was dissolved in acetonitrile (4 mL). Chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (245.52 mg, 875.04 μmol) and N-methylimidazole (209.54 mg, 2.55 mmol, 203.44 μL) were added, and the mixture was stirred for 0.5 hours. Compound BB-1 (178.85 mg, 729.20 μmol) was added, and the reaction mixture was stirred for 2 hours. After the reaction was complete, the mixture was filtered, the cake was rinsed with acetonitrile (3 mL x 3), the cake was collected, and the mixture was vacuum-dried to obtain compound WX018-3. MS-ESI m / z: 502.2 [M+H] + . 1 H NMR (400 MHz, DMSO_d6) δ:9.41 (s, 1H), 8.81 (d, J=7.6 Hz, 1H), 8.38 (s, 1H), 8.28 (s, 1H), 7.27-6.95 (m, 1H), 6.82 (d, J=8.0 Hz, 1H), 4.45 (s, 3H), 4.25-4.10 (m, 2H), 3.25 (d, J=6.0 Hz, 2H), 3.23-3.10 (m, 2H), 2.10-1.99 (m, 2H), 1.93-1.81 (m, 4H), 1.80-1.65 (m, 4H), 1.52-1.35 (m, 1H), 1.16-1.10 (m, 2H).

[0265] Step 4: Synthesis of compound WX018-4 Under nitrogen gas protection at room temperature, compound WX018-3 (320 mg, 638.05 μmol) was dissolved in dichloromethane (6 mL), triphenylphosphine (200.82 mg, 765.66 μmol) and imidazole (65.16 mg, 957.08 μmol) were added, and the reaction mixture was cooled to 0°C in an ice bath. Elemental iodine (210.52 mg, 829.47 μmol) was added, and the mixture was then returned to room temperature and stirred for 12 hours. After the reaction was complete, the reaction solution was poured into saturated sodium sulfite aqueous solution (30 mL) and extracted with dichloromethane (50 mL x 3). The organic phases were combined, washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The resulting residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1 to 0 / 1, volume ratio) to obtain compound WX018-4. MS-ESI m / z: 612.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ: 9.52 (s, 1H), 8.43 (d, J=9.6 Hz, 2H), 8.34 (d, J=8.0 Hz, 1H), 6.77 (t, J=54.2 Hz, 1H), 6.37 (d, J=8.0 Hz, 1H), 4.56 (d, J=2.4 Hz, 2H), 4.11-4.00 (m, 1H), 3.45-3.32 (m, 2H), 3.17 (d, J=6.0 Hz, 2H), 2.27-2.18 (m, 2H), 2.14-2.01 (m, 4H), 1.92-1.79 (m, 4H), 1.67-1.50 (m, 2H), 1.31-1.16 (m, 3H).

[0266] Step 5: Synthesis of the formate of compound WX018 Under nitrogen gas protection at room temperature, 268.38 mg of the trifluoroacetate salt of compound WX015-7 was dissolved in 4 mL of acetonitrile. N,N-diisopropylethylamine (340.32 mg, 2.63 mmol, 458.66 μL) was added, and the mixture was stirred for 5 minutes. Compound WX018-4 (0.23 g, 376.17 μmol) was added, and the reaction mixture was heated to 90°C and stirred for 12 hours. After the reaction was complete, the mixture was cooled to room temperature, concentrated under reduced pressure to remove acetonitrile, water (20 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The resulting residue was separated by preparative HPLC (chromatography column: Phenomenex Luna 80×30mm×3μm, mobile phase: water (0.2% formic acid)-acetonitrile, acetonitrile %: 15%~40%, 8 min) to obtain the formate of the target compound WX018. MS-ESI m / z: 855.5 [M+H] + . 1 1H NMR (400 MHz, DMSO_d6) δ: 11.12 (s, 1H), 10.02 (s, 1H), 9.41 (s, 1H), 8.81 (d, J=8.0 Hz, 1H), 8.38 (s, 1H), 8.28 (s, 1H), 8.15 (s, 1H), 8.10 (d, J=7.6 Hz, 1H), 7.59 (dd, J=0.8, 8.0 Hz, 1H), 7.36 (t, J=8.0 Hz, 1H), 7.10 (t, J=53.8 Hz, 1H), 6.82 (d, J=8.0 Hz, 1H), 4.62 (dd, J=4.8, 11.6 Hz, 1H), 4.45 (s, 2H), 4.27-4.10 (m, 2H), 3.45-3.28 (m, 3H), 3.22-3.14 (m, 1H), 2.86-2.72 (m, 2H), 2.69-2.52 (m, 7H), 2.48-2.41 (m, 2H), 2.27-2.13 (m, 3H), 2.11-1.99 (m, 2H), 1.97-1.83 (m, 4H), 1.82-1.68 (m, 4H), 1.66-1.53 ​​(m, 1H), 1.16-0.93 (m, 2H).

[0267] Example 19

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[0268] ステップ1: Synthesis of compound WX019-1 Under nitrogen gas protection at room temperature, intermediate BB-2-1 (1.06 g, 4.71 mmol) was dissolved in acetonitrile (10 mL), and 8-oxa-3-azabicyclo[3.2.1]octane (1 g, 4.71 mmol) and N,N-diisopropylethylamine (1.83 g, 14.13 mmol, 2.46 mL) were added. The reaction mixture was heated to 60 °C and stirred for 3 hours. After the reaction was complete, the mixture was cooled to room temperature and concentrated under reduced pressure to remove the solvent. Water (20 mL) was added to the resulting residue and stirred at room temperature for 1 hour to precipitate the solid. The mixture was filtered, the cake was washed with water (20 mL x 4), the cake was collected, and the mixture was vacuum-dried to obtain compound WX019-1. MS-ESI m / z: 402.3 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ: 8.35-8.25 (m, 2H), 6.39 (d, J=8.0 Hz, 1H), 4.55-4.30 (m, 5H), 3.46-3.19 (m, 2H), 2.07-1.93 (m, 2H), 1.83-1.70 (m, 2H), 1.69-1.62 (m, 1H), 1.50 (s, 9H), 1.40 (t, J=7.2 Hz, 3H).

[0269] Step 2: Synthesis of compound WX019-2 Under room temperature and nitrogen gas protection, compound WX019-1 (1.35 g, 3.36 mmol) was dissolved in methanol (10 mL) and water (2 mL). Lithium hydroxide monohydrate (282.23 mg, 6.73 mmol) was added, and the reaction mixture was heated to 60°C and stirred for 2 hours. After the reaction was complete, the mixture was cooled to room temperature, concentrated under reduced pressure to remove methanol, and 1 M hydrochloric acid was added to adjust the pH to 3-4. A large amount of white solid precipitated, which was filtered. The cake was rinsed with water (10 mL x 2), collected, and vacuum-dried to obtain compound WX019-2. MS-ESI m / z: 374.2 [M+H] + . 1H NMR (400 MHz, DMSO_d6) δ:11.72 (s, 1H), 8.74 (d, J=7.6 Hz, 1H), 8.19 (s, 1H), 6.79 (d, J=8.0 Hz, 1H), 4.35-4.18 (m, 3H), 3.41-3.25 (m, 3H), 1.93-1.79 (m, 2H), 1.68-1.57 (m, 2H), 1.43 (s, 9H).

[0270] Step 3: Synthesis of compound WX019-3 Under room temperature and nitrogen gas protection, compound WX019-2 (0.4 g, 1.07 mmol) was dissolved in acetonitrile (4 mL). Chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (360.67 mg, 1.29 mmol) and N-methylimidazole (307.83 mg, 3.75 mmol, 298.86 μL) were added, and the mixture was stirred for 0.5 hours. Compound BB-1 (262.74 mg, 1.07 mmol) was added, and the reaction was continued with stirring for 1 hour. After the reaction was complete, the mixture was filtered, the cake was rinsed with acetonitrile (3 mL x 3), the cake was collected, and the mixture was vacuum-dried to obtain compound WX019-3. MS-ESI m / z: 601.4 [M+H] + . 1 H NMR (400 MHz, DMSO_d6) δ: 9.41 (s, 1H), 8.83 (d, J=8.0 Hz, 1H), 8.39 (s, 1H), 8.29 (s, 1H), 7.14 (t, J=53.8 Hz, 1H), 6.84 (d, J=8.0 Hz, 1H), 4.64-4.33 (m, 2H), 4.30-4.13 (m, 3H), 3.76 (s, 1H), 3.53-2.96 (m, 5H), 2.10-2.00 (m, 2H), 1.95-1.81 (m, 4H), 1.80-1.62 (m, 4H), 1.44 (s, 9H), 1.18-1.02 (m, 2H).

[0271] Step 4: Synthesis of compound WX019-4 Under nitrogen gas protection at room temperature, compound WX019-3 (590 mg, 982.26 μmol) was dissolved in dichloromethane (10 mL), triphenylphosphine (309.16 mg, 1.18 mmol) and imidazole (100.31 mg, 1.47 mmol) were added, the reaction mixture was cooled to 0°C, elemental iodine (324.10 mg, 1.28 mmol) was added, and the reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete, the reaction solution was poured into saturated sodium sulfite aqueous solution (30 mL) and extracted with dichloromethane (50 mL x 3). The organic phases were combined, washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The resulting residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1 to 0 / 1, volume ratio) to obtain compound WX019-4. MS-ESI m / z: 711.3 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ: 9.52 (s, 1H), 8.44 (s, 1H), 8.41 (s, 1H), 8.35 (d, J=8.0 Hz, 1H), 6.78 (t, J=54.2 Hz, 1H), 6.40 (d, J=7.6 Hz, 1H), 4.53-4.36 (m, 2H), 4.11-4.01 (m, 1H), 3.45-3.23 (m, 2H), 3.17 (d, J=6.0 Hz, 2H), 2.27-2.18 (m, 2H), 2.14-2.06 (m, 2H), 2.05-1.99 (m, 2H), 1.92-1.79 (m, 2H), 1.78-1.71 (m, 2H), 1.63-1.54 (m, 2H), 1.51 (s, 9H), 1.31-1.16 (m, 3H).

[0272] Step 5: Synthesis of compound WX019-5 Under nitrogen gas protection at room temperature, 291.18 mg of the trifluoroacetate salt of compound WX015-7 was dissolved in 3 mL of acetonitrile, and N,N-diisopropylethylamine (369.24 mg, 2.86 mmol) was added. The reaction mixture was stirred for 5 minutes, and compound WX019-4 (290 mg, 408.13 μmol) was added. The reaction mixture was heated to 90°C and stirred for 12 hours. After the reaction was complete, the mixture was cooled to room temperature, concentrated under reduced pressure to remove acetonitrile, water (20 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The resulting residue was separated by column chromatography (eluent: dichloromethane / methanol = 5 / 1 to 1 / 1, volume ratio) to obtain compound WX019-5. MS-ESI m / z: 954.4 [M+H] + .

[0273] Step 6: Synthesis of the hydrochloride salt of compound WX019 Under nitrogen gas protection at room temperature, compound WX019-5 (0.3 g, 314.45 μmol) was dissolved in ethyl acetate (2 mL), and an ethyl acetate solution of hydrochloric acid (8 mL, 4 M) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was filtered, the cake was rinsed with ethyl acetate (3 mL x 3), and the cake was collected. The cake was separated by preparative HPLC (chromatography column: Phenomenex Luna 80 × 30 mm × 3 μm, mobile phase: water (0.04% hydrochloric acid) - acetonitrile, acetonitrile %: 1%~30%, 8 min) to obtain the hydrochloride salt of the target compound WX019. MS-ESI m / z: 854.4 [M+H] + . 1H NMR (400 MHz, DMSO_d6) δ:11.12 (s, 1H), 10.69 (s, 1H), 9.83 (d, J=10.0 Hz, 1H), 9.64 (s, 1H), 9.37 (s, 1H), 8.92 (d, J=8.0 Hz, 1H), 8.40 (s, 1H), 8.33 (s, 1H), 8.01 (d, J=7.2 Hz, 1H), 7.66 (d, J=8.0 Hz, 1H), 7.39 (t, J=7.8 Hz, 1H), 7.14 (t, J=53.6 Hz, 1H), 6.91 (d, J=8.0 Hz, 1H), 4.64 (dd, J=4.8, 12.0 Hz, 1H), 4.31-4.20 (m, 2H), 4.14 (s, 2H), 4.03-3.86 (m, 2H), 3.76-3.66 (m, 3H), 3.49-3.19 (m, 8H), 3.13-2.97 (m, 2H), 2.85-2.72 (m, 1H), 2.69-2.63 (m, 1H), 2.62-2.53 (m, 1H), 2.27-2.16 (m, 1H), 2.13-1.73 (m, 11H), 1.32-1.09 (m, 2H).

[0274] Example 20

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[0275] ステップ1: Synthesis of compound WX020-2 Under nitrogen gas protection at room temperature, compound WX020-1 (32.88 g, 176.53 mmol) and N,N-diisopropylethylamine (43.46 g, 336.25 mmol) were dissolved in acetonitrile (250 mL). Propargylbromide (25 g, 168.12 mmol, purity: 80%) was added dropwise, and the reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete, saturated ammonium chloride (500 mL) was added to the reaction solution, and it was extracted with ethyl acetate (200 mL x 3). The organic phases were combined and sequentially washed with saturated ammonium chloride (200 mL x 2) and saturated saline solution (200 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent and obtain compound WX020-2. MS-ESI m / z: 225.0 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ: 3.47 (t, J=5.0 Hz, 4H), 3.32 (d, J=2.4 Hz, 2H), 2.51 (t, J=5.0 Hz, 4H), 2.26 (t, J=2.4 Hz, 1H), 1.47 (s, 9H).

[0276] Step 2: Synthesis of compound WX020-5 Under nitrogen gas protection at room temperature, compound WX020-4 (50 g, 232.51 mmol) and dimethyl carbonate (83.78 g, 930.04 mmol) were dissolved in tetrahydrofuran (1.5 L). Potassium tert-butoxide (156.54 g, 1.40 mol) was added, and the reaction mixture was heated to 70°C and stirred for 12 hours. After the reaction was complete, the mixture was cooled to room temperature, concentrated under reduced pressure to remove the solvent, and ice water (1000 mL) was added. The pH was adjusted to 2-3 with 6 M hydrochloric acid, and a white solid precipitated. The mixture was filtered, the cake was rinsed with water (100 mL x 2), the cake was collected, and the mixture was vacuum-dried to obtain compound WX020-5. MS-ESI m / z: 240.9 [M+H] + , 243.7 [M+H+2] + . 1H NMR (400 MHz, DMSO_d6) δ: 12.80 (s, 1H), 7.92 (dd, J=1.4, 7.8 Hz, 1H), 7.81 (dd, J=1.4, 7.8 Hz, 1H), 7.27 (t, J=8.0 Hz, 1H), 5.65 (s, 1H).

[0277] Step 3: Synthesis of compound WX020-6 Under room temperature and nitrogen gas protection, compound WX020-5 (15 g, 62.23 mmol), compound WX020-2 (27.92 g, 124.46 mmol), cuprous iodide (1.19 g, 6.22 mmol), bis(triphenylphosphine)palladium(II) dichloride (4.37 g, 6.22 mmol), and triethylamine (25.19 g, 248.92 mmol) were dissolved in N,N-dimethylformamide (300 mL). The reaction mixture was heated to 80°C and stirred for 3 hours. After the reaction was complete, the mixture was cooled to 0-10°C, poured into ice water (1.2 L), and the pH was adjusted to 5-6 with 1 M hydrochloric acid. The mixture was extracted with ethyl acetate (300 mL x 3), the aqueous phase was collected, and the aqueous phase was concentrated under reduced pressure to obtain compound WX020-6. MS-ESI m / z: 385.1 [M+H] + .

[0278] Step 4: Synthesis of compound WX020-7 Under room temperature and argon gas protection, palladium / carbon hydroxide (7g, 24.92 mmol, purity: 20%) and palladium / carbon (7g, 13.01 mmol, purity: 10%) were suspended in methanol (700 mL). Compound WX020-6 (35g, 91.05 mmol) was added, and the mixture was purged three times with hydrogen gas, controlling the hydrogen gas pressure to 30 psi. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the mixture was filtered, the cake was rinsed with methanol (200 mL x 5), and the filtrate was concentrated under reduced pressure to remove the solvent. Dichloromethane (50 mL) and water (300 mL) were added to the crude product to precipitate the solid, filtered, the cake was rinsed with water (30 mL x 3), the cake was collected, and the mixture was vacuum-dried to obtain compound WX020-7. MS-ESI m / z: 389.1 [M+H] + .1 H NMR (400 MHz, DMSO_d6) δ: 10.21 (s, 1H), 7.71 (d, J=8.0 Hz, 1H), 7.56 (d, J=7.2 Hz, 1H), 7.29 (t, J=7.6 Hz, 1H), 5.71 (s, 1H), 4.10-3.65 (m, 2H), 3.50-3.20 (m, 6H), 3.16-3.10 (m, 2H), 2.82 (t, J=7.6 Hz, 2H), 2.13-1.99 (m, 2H), 1.40 (s, 9H).

[0279] Step 5: Synthesis of compound WX020-8 At room temperature and under argon gas protection, compound WX020-7 (4.40 g, 11.33 mmol) was dissolved in ethanol (50 mL), hydroxylamine hydrochloride (2.75 g, 39.64 mmol) and sodium acetate (3.25 g, 39.64 mmol) were added, and the reaction mixture was heated to 80°C and stirred for 12 hours. After the reaction was complete, the mixture was cooled to room temperature, water (350 mL) was added, and the mixture was extracted with methyl tert-butyl ether (100 mL x 4) to collect the aqueous phase. The organic phase was washed with 5% aqueous sodium bicarbonate solution (50 mL x 3), the organic phase was discarded, and the aqueous phase was collected. The two aqueous phases were combined, the pH was adjusted to 6-7 with 1M hydrochloric acid, and the mixture was extracted with a mixed solvent of dichloromethane and methanol (volume ratio: 10:1, 100 mL x 4). The organic phase was washed with saturated saline solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound WX020-8. MS-ESI m / z: 404.2 [M+H] + . 1 H NMR (400 MHz, DMSO_d6) δ: 7.66 (d, J=7.6 Hz, 1H), 7.47 (d, J=6.8 Hz, 1H), 7.31 (t, J=7.6 Hz, 1H), 4.07 (s, 2H), 3.49-3.39 (m, 4H), 2.91 (t, J=7.6 Hz, 2H), 2.42-2.26 (m, 6H), 1.95-1.79 (m, 2H), 1.39 (s, 9H).

[0280] Step 6: Synthesis of compound WX020-9 At room temperature, compound WX020-8 (1.3 g, 3.22 mmol) was dissolved in anhydrous ethanol (20 mL), concentrated sulfuric acid (632.03 mg, 6.44 mmol) was added, and the reaction mixture was heated to 80 °C and stirred for 12 hours. After the reaction was complete, the mixture was cooled to room temperature and concentrated under reduced pressure to remove the solvent. The residue was dissolved in tetrahydrofuran (17 mL) and water (8 mL), sodium bicarbonate (1.08 g, 12.89 mmol) was added in batches, followed by di-tert-butyl dicarbonate (773.60 mg, 3.54 mmol), and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, water (70 mL) was added and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. The resulting residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1 to 0 / 1, volume ratio) to obtain compound WX020-9. MS-ESI m / z: 432.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ: 7.54 (d, J=7.6 Hz, 1H), 7.35 (d, J=6.8 Hz, 1H), 7.24 (d, J=7.6 Hz, 1H), 4.22 (q, J=7.2 Hz, 2H), 4.04 (s, 2H), 3.51-3.35 (m, 4H), 2.99 (t, J=7.6 Hz, 2H), 2.52-2.30 (m, 6H), 2.03-1.91 (m, 2H), 1.46 (s, 9H), 1.27 (t, J=7.0 Hz, 3H).

[0281] Step 7: Synthesis of compound WX020-10 At room temperature and under argon gas protection, acrylamide (59.30 mg, 834.25 μmol) and compound WX020-9 (0.3 g, 695.21 μmol) were dissolved in anhydrous tetrahydrofuran (6 mL), cooled to 0-5°C in an ice bath, and a solution of potassium tert-butoxide in tetrahydrofuran (1 M, 1.04 mL) was added dropwise. After the addition was complete, the mixture was kept warm and stirred for 1 hour to allow the reaction to proceed. After the reaction was complete, the reaction solution was poured into 0.1 M hydrochloric acid (10.43 mL) and extracted with ethyl acetate (3 mL x 3). The organic phases were combined, washed with saturated brine (3 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The resulting residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate / tetrahydrofuran = 1 / 1 / 0~0 / 1 / 0~0 / 1 / 1, volume ratio) to obtain compound WX020-10. MS-ESI m / z: 457.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ: 8.00 (s, 1H), 7.54 (d, J=8.0 Hz, 1H), 7.38 (d, J=7.2 Hz, 1H), 7.30-7.25 (m, 1H), 4.34 (dd, J=5.2, 8.8 Hz, 1H), 3.52-3.35 (m, 4H), 3.10-2.95 (m, 3H), 2.83-2.71 (m, 1H), 2.69-2.56 (m, 1H), 2.53-2.30 (m, 7H), 2.04-1.90 (m, 2H), 1.47 (s, 9H).

[0282] Step 8: Synthesis of trifluoroacetate of compound WX020-11 At room temperature, compound WX020-10 (107 mg, 234.37 μmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (924.00 mg, 8.10 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was concentrated under reduced pressure to remove the solvent and obtain the trifluoroacetate salt of compound WX020-11. MS-ESI m / z: 357.1 [M+H] + .

[0283] Step 9: Synthesis of the hydrochloride salt of compound WX020 At room temperature, 143.24 mg of the trifluoroacetate salt of compound WX020-11 was dissolved in 2 mL of acetonitrile. N,N-diisopropylethylamine (199.04 mg, 1.54 mmol) was added, and the mixture was stirred for 5 minutes. Compound WX015-8 (115 mg, 192.50 μmol) was then added, and the reaction mixture was heated to 80°C and stirred for 16 hours. After the reaction was complete, the mixture was cooled to room temperature and concentrated under reduced pressure to remove the solvent. The resulting residue was separated by preparative HPLC (chromatography column: Phenomenex Luna 80 × 30 mm × 3 μm, mobile phase: water (0.04% hydrochloric acid)-acetonitrile, acetonitrile %: 1%~35%, 8 min) to obtain the hydrochloride salt of the target compound WX020. MS-ESI m / z: 826.6 [M+H] + . 1 H NMR (400 MHz, DMSO_d6) δ: 12.24-11.82 (m, 1H), 11.76-11.36 (m, 1H), 11.10 (s, 1H), 9.50 (d, J=6.4 Hz, 1H), 8.78 (d, J=7.6 Hz, 1H), 8.39 (d, J=4.0 Hz, 1H), 8.25 (d, J=5.6 Hz, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.55 (d, J=7.2 Hz, 1H), 7.35 (t, J=7.6 Hz, 1H), 7.27-6.94 (m, 1H), 6.91-6.40 (m, 1H), 5.17 (d, J=78.8 Hz, 1H), 4.76 (d, J=17.6 Hz, 1H), 4.62 (dd, J=4.8, 12.0 Hz, 1H), 4.43-4.05 (m, 6H), 3.91-3.40 (m, 8H), 3.32-3.15 (m, 2H), 3.11-2.94 (m, 3H), 2.86-2.72 (m, 1H), 2.68-2.58 (m, 1H), 2.57-2.44 (m, 1H), 2.27-2.15 (m, 3H), 2.13-1.87 (m, 6H), 1.68-1.85 (m, 2H), 1.85-1.67 (m, 2H).

[0284] Example 21 [ka] Synthesis route: [ka]

[0285] Step 1: Synthesis of compound WX021-1 Under room temperature and nitrogen gas protection, compound WX003-1 (10 g, 49.69 mmol) was dissolved in dichloromethane (100 mL), triethylamine (10.06 g, 99.37 mmol, 13.83 mL) was added, the mixture was cooled to 0°C in an ice bath, methanesulfonyl chloride (7.25 g, 63.29 mmol) was added dropwise, and the mixture was stirred for 2 hours. After the reaction was complete, water (100 mL) was added and the mixture was extracted with dichloromethane (100 mL x 2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound WX021-1.

[0286] Step 2: Synthesis of compound WX021-2 Under room temperature and nitrogen gas protection, compound BB-1-5 (6.2 g, 38.02 mmol) and potassium carbonate (10.51 g, 76.04 mmol) were dissolved in N,N-dimethylformamide (120 mL). Compound WX021-1 (14.87 g, 53.22 mmol) was added, and the reaction mixture was heated to 80°C and stirred for 15 hours. After the reaction was complete, the mixture was cooled to room temperature, water (700 mL) was added, and the mixture was extracted with ethyl acetate (300 mL x 2). The organic phases were combined, washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated by column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 5~1 / 3, volume ratio) to obtain compound WX021-2. MS-ESI m / z: 247.1 [M+H-100] + . 1H NMR (400 MHz, CDCl3) δ: 8.23 ​​(s, 1H), 7.12 (t, J=53.4 Hz, 1H), 4.42-4.22 (m, 3H), 2.99-2.80 (m, 2H), 2.26-2.14 (m, 2H), 2.00-1.86 (m, 2H), 1.49 (s, 9H).

[0287] Step 3: Synthesis of compound WX021-3 Under room temperature and argon gas protection, compound WX021-2 (3.58 g, 10.34 mmol) was dissolved in tetrahydrofuran (90 mL), palladium-carbon (1 g, purity: 10%) was added, and the mixture was purged three times with hydrogen gas. The pressure was maintained at 15 psi, and the mixture was stirred for 15 hours. After the reaction was complete, the mixture was filtered, the cake was rinsed with methanol (50 mL x 4), and the filtrate was concentrated under reduced pressure to obtain compound WX021-3. MS-ESI m / z: 261.0 [M+H-56] + .

[0288] Step 4: Synthesis of compound WX021-4 Under nitrogen gas protection at room temperature, intermediate BB-2-3 (0.97 g, 3.73 mmol) was dissolved in acetonitrile (20 mL), chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (1.25 g, 4.47 mmol) and N-methylimidazole (1.07 g, 13.05 mmol) were added, and the mixture was stirred for 10 minutes. Compound WX021-3 (1.30 g, 4.10 mmol) was added, and the reaction mixture was stirred at room temperature for 15 hours. After the reaction was complete, the solvent was removed by reducing the pressure, saturated saline solution (50 mL) was added, and the mixture was extracted with dichloromethane (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1 to 0 / 1, volume ratio) to obtain compound WX021-4. MS-ESI m / z: 559.3 [M+H] + . 1H NMR (400 MHz, CDCl3) δ: 9.61 (s, 1H), 8.43 (d, J=10.0 Hz, 2H), 8.31 (d, J=7.6 Hz, 1H), 6.77 (t, J=54.4 Hz, 1H), 6.12 (d, J=8.0 Hz, 1H), 5.45 (s, 1H), 4.80 (s, 1H), 4.33-4.17 (m, 3H), 4.03-3.94 (m, 2H), 3.62-3.46 (m, 2H), 2.98-2.83 (m, 2H), 2.17-2.07 (m, 3H), 2.03-1.90 (m, 3H), 1.49 (s, 9H).

[0289] Step 5: Synthesis of the hydrochloride salt of compound WX021-5 Under room temperature and nitrogen gas protection, compound WX021-4 (0.51 g, 913.03 μmol) was dissolved in ethyl acetate (2 mL), and a 4 M solution of ethyl acetate hydrochloric acid (20.40 mL) was added. The reaction mixture was stirred at room temperature for 15 hours. After the reaction was complete, the mixture was concentrated under reduced pressure to obtain the hydrochloride salt of compound WX021-5. MS-ESI m / z: 459.1 [M+H] + .

[0290] Step 6: Synthesis of compound WX021-7 Under room temperature and nitrogen gas protection, compound WX021-6 (200 g, 1.32 mol) was dissolved in ethanol (1.5 L), and di-tert-butyl dicarbonate (346.51 g, 1.59 mol) was added in batches. The reaction mixture was heated to 60°C and stirred for 16 hours. After the reaction was complete, the reaction solution was cooled to room temperature and concentrated under reduced pressure to remove the solvent. Isopropanol (500 mL) was added to the residue, cooled to 0°C, stirred for 1 hour, filtered, the cake was rinsed with isopropanol (200 mL), and the filtrate was collected. The filtrate was concentrated under reduced pressure to obtain compound WX021-7. MS-ESI m / z: 196.1 [M+H-56] + . 1H NMR (400 MHz, DMSO_d6) δ: 12.60 (s, 1H), 8.12 (s, 1H), 7.90 (d, J=7.6 Hz, 1H), 7.66 (d, J=8.0 Hz, 1H), 6.94 (d, J=8.0 Hz, 1H), 2.66 (s, 3H), 1.46 (s, 9H).

[0291] Step 7: Synthesis of compound WX021-8 Under nitrogen gas protection at room temperature, compound WX021-7 (200 g, 795.93 mmol), sodium acetate (97.94 g, 1.19 mol), and hydroxylamine hydrochloride (60.84 g, 875.53 mmol) were dissolved in methanol (1.2 L), and the reaction mixture was stirred at room temperature for 16 hours. Next, the temperature was raised to 50°C and the reaction was continued for 1 hour, after which hydroxylamine hydrochloride (11.06 g, 159.19 mmol) was added, and the reaction was continued with stirring for 1 hour. After the reaction was complete, the reaction solution was cooled to room temperature, water (1.5 L) and methyl tert-butyl ether (1.5 L) were added, and the mixture was stirred for 5 minutes. The solution was separated, and the aqueous phase was extracted with methyl tert-butyl ether (500 mL x 2). The organic phases were combined, washed with 10% saline solution (500 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent and obtain compound WX021-8. MS-ESI m / z: 211.1 [M+H-56] + . 1 H NMR (400 MHz, DMSO_d6) δ: 12.27 (s, 1H), 11.67 (s, 1H), 7.82 (s, 1H), 7.69 (d, J=7.2 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H), 6.86 (t, J=8.0 Hz, 1H), 2.27 (s, 3H), 1.46 (s, 9H).

[0292] Step 8: Synthesis of compound WX021-9 Under nitrogen gas protection at room temperature, compound WX021-8 (100 g, 375.53 mmol) and triethylamine (49.40 g, 488.19 mmol) were dissolved in tetrahydrofuran (1 L). N,N'-carbonyldiimidazole (66.98 g, 413.08 mmol) was slowly added, and the reaction mixture was heated to 70°C and stirred for 1 hour. After the reaction was complete, the reaction solution was cooled to room temperature, water (1 L) was added, and the mixture was extracted with a mixed solvent of methyl tert-butyl ether and petroleum ether (volume ratio: 1 / 1, 500 mL x 2). The organic phase was washed with 10% saline solution (500 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent and obtain compound WX021-9. MS-ESI m / z: 249.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ: 8.16 (s, 1H), 7.30 (s, 1H), 7.00 (s, 1H), 2.59 (s, 3H), 1.57 (s, 9H).

[0293] Step 9: Synthesis of Compound WX021-10 Under room temperature and nitrogen gas protection, a tetrahydrofuran solution of lithium diisopropylamide (2M, 741.11 mL) was cooled to -68°C. Dimethyl carbonate (36.72 g, 407.61 mmol, 34.31 mL) and a tetrahydrofuran solution of compound WX021-9 (92 g, 370.55 mmol) were added dropwise, one drop at a time, over approximately 30 minutes until the addition was complete. The temperature was then controlled to -50°C to -68°C, and the mixture was stirred for 30 minutes to allow the reaction to proceed. After the reaction was complete, the reaction solution was slowly poured into saturated ammonium chloride (1.5 L), extracted with ethyl acetate (500 mL x 3), washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent and obtain compound WX021-10. MS-ESI m / z: 307.1 [M+H] + .

[0294] Step 10: Synthesis of compound WX021-11 Under nitrogen gas protection at room temperature, compound WX021-10 (10 g, 32.65 mmol) and acrylamide (2.78 g, 39.18 mmol) were dissolved in tetrahydrofuran (100 mL), cooled to 0-5°C in an ice bath, and added dropwise to a tetrahydrofuran solution of potassium tert-butoxide (1 M, 48.97 mL). After the addition was complete, the mixture was kept warm and stirred for 2 hours. After the reaction was complete, the reaction solution was poured into 1 M hydrochloric acid (150 mL) and extracted with ethyl acetate (150 mL x 2). The organic phases were combined, washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. Methyl tert-butyl ether (150 mL) was added to the crude product, the mixture was stirred at room temperature for 30 minutes, filtered, the cake was rinsed with methyl tert-butyl ether (50 mL), the cake was collected, and the mixture was vacuum-dried to obtain compound WX021-11. 1 H NMR (400 MHz, DMSO_d6) δ: 11.10 (s, 1H), 9.55 (s, 1H), 7.69 (d, J=7.6 Hz, 1H), 7.54 (d, J=7.6 Hz, 1H), 7.30 (t, J=8.0 Hz, 1H), 4.60 (dd, J=5.0, 11.8 Hz, 1H), 2.84-2.72 (m, 1H), 2.66-2.57 (m, 1H), 2.57-2.43 (m, 1H), 2.25-2.15 (m, 1H), 1.49 (s, 9H).

[0295] Step 11: Synthesis of the hydrochloride salt of compound WX021-12 At room temperature, compound WX021-11 (9.4 g, 27.22 mmol) was dissolved in ethyl acetate (50 mL), and a 4 M solution of hydrochloric acid in ethyl acetate (150 mL) was added. The reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete, the mixture was filtered, the cake was rinsed with ethyl acetate (20 mL), and the cake was collected to obtain the hydrochloride salt of compound WX021-12. 1H NMR (400 MHz, DMSO_d6) δ: 11.09 (s, 1H), 8.32 (s, 2H), 7.31 (d, J=7.6 Hz, 1H), 7.26-7.16 (m, 2H), 4.59 (dd, J=4.8, 12.0 Hz, 1H), 2.83-2.71 (m, 1H), 2.65-2.56 (m, 1H), 2.55-2.42 (m, 1H), 2.25-2.15 (m, 1H).

[0296] Step 12: Synthesis of compound WX021-13 Under room temperature and nitrogen gas protection, 300 mg of the hydrochloride salt of compound WX021-12 was dissolved in 6 mL of anhydrous dichloromethane. The mixture was cooled to 0-5°C in an ice bath, and triethylamine (323.30 mg, 3.19 mmol) and chloroacetyl chloride (144.34 mg, 1.28 mmol) were added dropwise in sequence. The mixture was kept warm and stirred for 2 hours, then slowly allowed to return to room temperature and stirred for another 2 hours to allow the reaction to proceed. After the reaction was complete, 20 mL of water was added, and the mixture was extracted with 3 x 7 mL of dichloromethane. The organic phases were combined, washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. The resulting residue and 4-(dimethoxymethyl)piperidine (185.60 mg, 1.17 mmol) were dissolved in acetonitrile (6 mL), sodium iodide (139.78 mg, 932.50 μmol) and N,N-diisopropylethylamine (301.30 mg, 2.33 mmol) were added, and the reaction mixture was heated to 80°C and stirred for 2 hours. After the reaction was complete, the mixture was cooled to room temperature, water (30 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated by column chromatography (eluent: ethyl acetate / dichloromethane / methanol = 1 / 0 / 0~0 / 20 / 1, volume ratio) to obtain compound WX021-13. MS-ESI m / z: 445.1 [M+H] + .

[0297] Step 13: Synthesis of compound WX021-14 Under nitrogen gas protection at room temperature, compound WX021-13 (247 mg, 555.71 μmol) was dissolved in tetrahydrofuran (4 mL), sulfuric acid (2 M, 1 mL) was added, and the reaction mixture was heated to 70°C and stirred for 12 hours. After the reaction was complete, the mixture was cooled to room temperature, water (20 mL) was added, and the mixture was extracted with ethyl acetate (7 mL x 2). The organic phase was discarded. The aqueous phase was adjusted to pH 7-8 with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate (15 mL x 5). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound WX021-14. MS-ESI m / z: 399.1 [M+H] + .

[0298] Step 14: Synthesis of the hydrochloride salt of compound WX021 Under nitrogen gas protection at room temperature, 80 mg of the hydrochloride salt of compound WX021-5 and 64.40 mg (161.64 μmol) of compound WX021-14 were dissolved in a mixed solvent of 1,2-dichloroethane (3 mL) and tetrahydrofuran (1 mL). Potassium acetate (47.59 mg, 484.92 μmol) and glacial acetic acid (0.1 mL) were added, and the reaction mixture was stirred at room temperature for 2 hours. Sodium triacetoxyborohydride (102.77 mg, 484.92 μmol) was added, and the reaction was continued with stirring for 15 hours. After the reaction was complete, 1 mL of 1 M hydrochloric acid was added to the reaction solution, and the solution was concentrated under reduced pressure to remove the organic solvent. The resulting residue was separated by preparative HPLC (chromatography column: Phenomenex Luna 80 × 30 mm × 3 μm, mobile phase: water (0.04% hydrochloric acid) - acetonitrile, acetonitrile %: 1%~30%, 8 min) to obtain the hydrochloride salt of the target compound WX021. MS-ESI m / z: 841.6 [M+H] + . 1H NMR (400 MHz, DMSO_d6) δ: 11.13 (s, 2H), 10.44 (s, 1H), 10.12 (s, 1H), 9.54 (d, J=6.4 Hz, 1H), 8.80 (d, J=7.6 Hz, 1H), 8.46 (d, J=3.2 Hz, 1H), 8.27 (d, J=5.6 Hz, 1H), 8.01 (d, J=7.6 Hz, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.41 (t, J=8.0 Hz, 1H), 7.32-7.00 (m, 1H), 6.91-6.41 (m, 1H), 5.31-5.02 (m, 1H), 4.77 (d, J=20.8 Hz, 1H), 4.65 (dd, J=5.0, 12.2 Hz, 1H), 4.60-4.52 (m, 1H), 4.41-4.23 (m, 2H), 3.83-3.80 (m, 1H), 3.76-3.62 (m, 4H), 3.48-3.36 (m, 2H), 3.29-2.98 (m, 6H), 2.85-2.73 (m, 1H), 2.68-2.52 (m, 2H), 2.48-2.32 (m, 3H), 2.31-1.77 (m, 7H), 1.70-1.54 (m, 2H).

[0299] Example 22

change

change

[0300] ステップ1: Synthesis of compound WX022-1 Under nitrogen gas protection, compound WX020-5 (15 g, 62.23 mmol) was dissolved in N,N-dimethylformamide (250 mL), cuprous iodide (1.19 g, 6.22 mmol), bis(triphenylphosphine)palladium(II) dichloride (4.37 g, 6.22 mmol), and N,N-diisopropylethylamine (32.17 g, 248.92 mmol) were added, and the reaction mixture was heated to 85 °C. A solution of compound WX003-2 (59.57 g, 248.92 mmol) in N,N-dimethylformamide (50 mL) was added dropwise over 2 hours, and after the addition was complete, the reaction was continued for 1 hour with stirring. After the reaction was complete, the mixture was cooled to room temperature, poured into water (1000 mL), extracted with ethyl acetate (300 mL x 3), and the organic phase was discarded. The aqueous phase was collected, adjusted to pH 5-6 with 1M hydrochloric acid, and extracted with ethyl acetate (300 mL x 2). The organic phase was combined, washed with saturated saline solution (500 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound WX022-1. MS-ESI m / z: 300.0 [M+H-100] + .

[0301] Step 2: Synthesis of compound WX022-2 At room temperature and under argon gas protection, palladium / carbon (5g, purity: 10%) and palladium hydroxide / carbon (5g, purity: 20%) were added to methanol (400mL), compound WX022-1 (30g, 75.11 mmol) was added, and the mixture was purged three times with a hydrogen gas balloon. The reaction mixture was stirred at room temperature for 24 hours. This reaction system was filtered, and palladium / carbon (5g, purity: 10%) and palladium hydroxide / carbon (5g, purity: 20%) were added to the filtrate. The hydrogen gas pressure was set to 30 psi, and the reaction was continued at room temperature for 24 hours with stirring. After the reaction was complete, the mixture was filtered, the cake was rinsed with methanol (50mL x 3), and the filtrate was concentrated under reduced pressure. The residue was purified using a reversed-phase column (chromatographic column: DAC-150 luna, flow rate: 650 mL / min, mobile phase: pure water). The fraction was adjusted to pH 7-8 with saturated sodium bicarbonate aqueous solution, concentrated under reduced pressure to remove most of the organic solvent, extracted with dichloromethane (100 mL), and the organic phase was discarded. The aqueous phase was adjusted to pH 5-6 with 1 M hydrochloric acid, extracted with dichloromethane (100 mL x 2), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound WX022-2. MS-ESI m / z: 304.1 [M+H-100] + . 1 H NMR (400 MHz, CDCl3) δ: 11.06 (s, 1H), 7.78 (dd, J=1.4, 7.8 Hz, 1H), 7.44 (dd, J=1.2, 7.6 Hz, 1H), 7.22 (t, J=7.6 Hz, 1H), 5.88 (s, 1H), 3.72-3.62 (m, 2H), 3.47 (t, J=6.2 Hz, 2H), 3.44-3.36 (m, 1H), 3.18-3.03 (m, 2H), 2.94 (t, J=7.4 Hz, 2H), 2.03-1.91 (m, 2H), 1.82-1.71 (m, 2H), 1.54-1.41 (m, 11H).

[0302] Step 3: Synthesis of compound WX022-3 Under room temperature and nitrogen gas protection, compound WX022-2 (1.90 g, 4.71 mmol) was dissolved in ethanol (20 mL), hydroxylamine hydrochloride (1.15 g, 16.48 mmol) and sodium acetate (1.35 g, 16.48 mmol) were added, and the reaction mixture was heated to 85°C and stirred for 15 hours. Hydroxylamine hydrochloride (0.383 g, 5.5 mmol) and sodium acetate (0.45 g, 5.5 mmol) were added, and the reaction was continued with stirring for another 15 hours. After the reaction was complete, the mixture was concentrated under reduced pressure to remove most of the organic solvent, the pH was adjusted to 7-8 with aqueous sodium bicarbonate, and the organic phase was extracted with methyl tert-butyl ether (50 mL x 2) and discarded. The aqueous phase was adjusted to pH 5-6 with 1N hydrochloric acid, extracted with dichloromethane (50 mL x 2), the organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound WX022-3. MS-ESI m / z: 319.1 [M+H-100] + .

[0303] Step 4: Synthesis of compound WX022-4 At room temperature and under nitrogen gas protection, compound WX022-3 (0.87 g, 2.08 mmol) was dissolved in ethanol (10 mL), concentrated sulfuric acid (407.80 mg, 4.16 mmol, purity: 98%) was added dropwise, and the reaction mixture was heated to 85°C and stirred for 15 hours. After the reaction was complete, the mixture was concentrated under reduced pressure to obtain the crude product. At room temperature, the crude product was dissolved in a mixed solvent of tetrahydrofuran (10 mL) and water (5 mL), sodium bicarbonate (523.89 mg, 6.24 mmol) and di-tert-butyl dicarbonate (453.96 mg, 2.08 mmol) were added, and the mixture was stirred for 3 hours. After the reaction was complete, the mixture was extracted with ethyl acetate (10 mL x 2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 4 / 1, volume ratio) to obtain compound WX022-4. MS-ESI m / z: 347.1 [M+H-100] + . 1H NMR (400 MHz, CDCl3) δ: 7.54 (dd, J=0.8, 8.0 Hz, 1H), 7.36 (d, J=6.8 Hz, 1H), 7.24 (d, J=7.6 Hz, 1H), 4.22 (q, J=7.2 Hz, 2H), 4.04 (s, 2H), 3.81-3.71 (m, 2H), 3.50 (t, J=6.2 Hz, 2H), 3.46-3.37 (m, 1H), 3.15-2.98 (m, 4H), 2.13-1.99 (m, 2H), 1.87-1.74 (m, 2H), 1.57-1.39 (m, 11H), 1.27 (t, J = 7.2 Hz, 3H).

[0304] Step 5: Synthesis of compound WX022-5 Under nitrogen gas protection at room temperature, compound WX022-4 (310 mg, 694.23 μmol) was dissolved in anhydrous tetrahydrofuran (6 mL), cooled to 0°C in an ice bath, and lithium diisopropylamide tetrahydrofuran solution (2 M, 520.68 μL) was added dropwise. The mixture was kept warm and stirred for 15 minutes. Acrylamide (59.21 mg, 833.08 μmol) tetrahydrofuran solution (2 mL) was added dropwise, and the reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete, the reaction solution was poured into 1 M hydrochloric acid (10 mL) and extracted with ethyl acetate (5 mL x 3). The organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated by thin-layer chromatography (eluent: petroleum ether / ethyl acetate = 1 / 2, volume ratio) to obtain compound WX022-5. 1H NMR (400 MHz, CDCl3) δ: 8.19 (s, 1H), 7.53 (d, J=8.0 Hz, 1H), 7.38 (d, J=7.2 Hz, 1H), 7.31-7.23 (m, 1H), 4.34 (dd, J=5.4, 8.6 Hz, 1H), 3.85-3.65 (m, 2H), 3.50 (t, J=6.2 Hz, 2H), 3.46-3.38 (m, 1H), 3.15-2.97 (m, 5H), 2.83-2.72 (m, 1H), 2.68-2.56 (m, 1H), 2.52-2.40 (m, 1H), 2.13-2.00 (m, 2H), 1.87-1.74 (m, 2H), 1.57-1.41 (m, 11H).

[0305] Step 6: Synthesis of trifluoroacetate of compound WX022-6 Under nitrogen gas protection at room temperature, compound WX022-5 (92 mg, 195.10 μmol) was dissolved in anhydrous dichloromethane (2 mL), and trifluoroacetic acid (616.00 mg, 5.40 mmol, 0.4 mL) was added. The reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete, the mixture was concentrated under reduced pressure to obtain the trifluoroacetate salt of compound WX022-6. MS-ESI m / z: 372.0 [M+H] + .

[0306] Step 7: Synthesis of the hydrochloride salt of compound WX022 Under nitrogen gas protection at room temperature, 139.2 mg of the trifluoroacetate salt of compound WX022-6 was dissolved in 2 mL of acetonitrile. N,N-diisopropylethylamine (201.72 mg, 1.56 mmol) was added, and the mixture was stirred for 10 minutes. Compound WX015-8 (139.86 mg, 234.11 μmol) was added, and the reaction mixture was heated to 80°C and stirred for 12 hours. After the reaction was complete, the mixture was concentrated under reduced pressure to remove the acetonitrile. The resulting residue was separated by preparative HPLC (chromatography column: Phenomenex Luna 80 × 30 mm × 3 μm, mobile phase: water (0.04% hydrochloric acid)-acetonitrile, acetonitrile %: 25%~55%, 8 min) to obtain the hydrochloride salt of the target compound WX022. MS-ESI m / z: 841.5 [M+H] + . 1 H NMR (400 MHz, DMSO_d6) δ: 11.10 (s, 1H), 9.51 (br d, J=6.4 Hz, 2H), 8.78 (d, J=7.6 Hz, 1H), 8.40 (d, J=4.0 Hz, 1H), 8.25 (d, J=5.6 Hz, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.49 (t, J=7.2 Hz, 1H), 7.36-7.28 (m, 1H), 7.27-6.95 (m, 1H), 6.91-6.42 (m, 1H), 5.34-5.03 (m, 1H), 4.83-4.71 (m, 1H), 4.60 (dd, J=4.8, 12.0 Hz, 1H), 4.32-4.15 (m, 1H), 3.94-3.57 (m, 3H), 3.55-3.25 (m, 5H), 3.07-2.85 (m, 6H), 2.84-2.71 (m, 1H), 2.70-2.55 (m, 2H), 2.25-2.14 (m, 1H), 2.13-1.65 (m, 16H), 1.27-1.07 (m, 2H).

[0307] Example 23 [ka] Synthesis route: [ka]

[0308] Step 1: Synthesis of compound WX023-1 Under nitrogen gas protection at room temperature, compound WX020-4 (10 g, 46.50 mmol) was dissolved in N,N-dimethylformamide (100 mL), potassium carbonate (12.85 g, 93.00 mmol) was added, and the mixture was cooled to 0°C in an ice bath. Iodomethane (19.80 g, 139.50 mmol) was slowly added, and after the addition was complete, the mixture was slowly allowed to return to room temperature and stirred for 3 hours to allow the reaction to proceed. After the reaction was complete, the reaction solution was cooled to 0°C, aqueous ammonia (10 mL) was slowly added, and the mixture was stirred for 15 minutes. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound WX023-1. MS-ESI m / z: 229.1 [M+H] + , 231.1 [M+H+2] + . 1 H NMR (400 MHz, DMSO_d6) δ: 7.83 (dd, J=1.6, 8.0 Hz, 1H), 7.61 (dd, J=1.6, 7.6 Hz, 1H), 7.18 (t, J=7.8 Hz, 1H), 3.80 (s, 3H), 2.58 (s, 3H).

[0309] Step 2: Synthesis of compound WX023-2 Under nitrogen gas protection at room temperature, compound WX023-1 (10 g, 43.65 mmol) and allylboronic acid pinacol ester (14.67 g, 87.31 mmol) were dissolved in 1,4-dioxane (100 mL) and water (10 mL). Potassium carbonate (12.07 g, 87.31 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (3.57 g, 4.37 mmol) were added, and the reaction mixture was heated to 100 °C and stirred for 12 hours. After the reaction was complete, the mixture was cooled to room temperature, water (100 mL) was added to the reaction solution, and it was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 0 / 1, volume ratio) to obtain compound WX023-2. MS-ESI m / z: 191.2 [M+H] + . 1 H NMR (400 MHz, DMSO_d6) δ: 7.44 (dd, J=1.6, 7.6 Hz, 1H), 7.38 (dd, J=1.6, 7.6 Hz, 1H), 7.16 (t, J=7.6 Hz, 1H), 6.04-5.88 (m, 1H), 5.11-5.09 (m, 1H), 5.08-5.05 (m, 1H), 3.69 (s, 3H), 3.42 (d, J=6.4 Hz, 2H), 2.56 (s, 3H).

[0310] Step 3: Synthesis of compound WX023-3 Under nitrogen gas protection at room temperature, compound WX023-2 (7.4 g, 38.90 mmol) was dissolved in a mixed solution of ethyl acetate (150 mL), acetonitrile (150 mL), and water (225 mL). The mixture was cooled to 0°C, and sodium periodate (54.08 g, 252.84 mmol) and ruthenium trichloride (161.38 mg, 777.97 μmol) were added in batches. The mixture was slowly returned to room temperature and stirred for 12 hours to allow the reaction to proceed. After the reaction was complete, the mixture was cooled to 0°C, and saturated sodium sulfite aqueous solution (100 mL) was slowly added to the reaction solution. The mixture was stirred at room temperature for 20 minutes, the pH of the solution was adjusted to 5-6 with 2 M hydrochloric acid, and the solution was extracted with ethyl acetate (500 mL x 3). The organic phases were combined, washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound WX023-3. MS-ESI m / z: 207.1 [MH] - . 1 H NMR (400 MHz, CDCl3) δ: 10.04 (s, 1H), 7.55 (dd, J=1.6, 7.6 Hz, 1H), 7.43 (dd, J=1.2, 7.6 Hz, 1H), 7.16 (t, J=7.6 Hz, 1H), 3.94 (s, 2H), 3.78 (s, 3H), 2.64 (s, 3H).

[0311] Step 4: Synthesis of compound WX023-4 Under nitrogen gas protection at room temperature, compound WX023-3 (4.8 g, 23.05 mmol) was dissolved in N,N-dimethylformamide (50 mL), N,N-diisopropylethylamine (8.94 g, 69.16 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (9.64 g, 25.36 mmol) were added, and the mixture was stirred for 15 minutes. Then, 1-tert-butoxycarbonyl-4-aminopiperidine (4.62 g, 23.05 mmol) was added, and the reaction mixture was stirred at room temperature for 8 hours. After the reaction was complete, the reaction solution was poured into water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with 15% saline solution (100 mL), then with saturated saline solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0~0 / 1, volume ratio) to obtain compound WX023-4. MS-ESI m / z: 389.3 [MH] - . 1 H NMR (400 MHz, CDCl3) δ: 7.52 (dd, J=1.6, 7.6 Hz, 1H), 7.42 (dd, J=1.6, 7.6 Hz, 1H), 7.15 (t, J=7.6 Hz, 1H), 5.78 (d, J=7.6 Hz, 1H), 4.05-3.88 (m, 3H), 3.77 (s, 3H), 3.58 (s, 2H), 2.62 (s, 3H), 1.86-1.82 (m, 2H), 1.50-1.38 (m, 11H), 1.30-1.24 (m, 2H).

[0312] Step 5: Synthesis of compound WX023-5 Under nitrogen gas protection at room temperature, compound WX023-4 (2.1 g, 5.38 mmol) was dissolved in dichloromethane (42 mL), cooled to 0-5°C, and boron tribromide (1.62 g, 6.45 mmol) was added dropwise. The reaction mixture was stirred at 0-5°C for 2 hours. After the reaction was complete, saturated sodium carbonate aqueous solution was added dropwise to adjust the pH to 7-8, and di-tert-butyl dicarbonate (1.41 g, 6.47 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the pH was adjusted to 7 with 1 M hydrochloric acid, and water (70 mL) and dichloromethane (20 mL) were added for extraction. The aqueous phase was extracted with dichloromethane (50 mL x 2). The organic phases were combined, washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound WX023-5. MS-ESI m / z: 321.2 [M+H-56] + .

[0313] Step 6: Synthesis of compound WX023-6 Under room temperature and nitrogen gas protection, compound WX023-5 (2 g, 5.31 mmol) was dissolved in tetrahydrofuran (40 mL). Dimethyl carbonate (1.91 g, 21.25 mmol) and potassium tert-butoxide (3.58 g, 31.88 mmol) were added, and the reaction mixture was heated to 75°C and stirred for 2 hours. After the reaction was complete, the mixture was concentrated under reduced pressure to obtain compound WX023-6. MS-ESI m / z: 303.3 [M+H-100] + .

[0314] Step 7: Synthesis of compound WX023-7 Under room temperature and nitrogen gas protection, compound WX023-6 (2 g, 4.97 mmol) was dissolved in ethanol (60 mL), the pH was adjusted to 6-7 with glacial acetic acid (1.79 g, 29.82 mmol), hydroxylamine hydrochloride (2.59 g, 37.27 mmol) was added, and the reaction mixture was heated to 80°C and stirred for 8 hours. After the reaction was complete, the reaction solution was cooled to room temperature, filtered, the cake was rinsed with ethanol (10 mL x 2), water (15 mL) was added to the filtrate, and the filtrate was concentrated under reduced pressure to remove most of the solvent. Then it was extracted with dichloromethane (30 mL x 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound WX023-7. MS-ESI m / z: 318.2 [M+H-100] + .

[0315] Step 8: Synthesis of compound WX023-8 Under nitrogen gas protection at room temperature, compound WX023-7 (1.2 g, 2.87 mmol) was dissolved in ethanol (10 mL), concentrated sulfuric acid (563.87 mg, 5.75 mmol, 306.45 μL) was added, and the reaction mixture was heated to 70°C and stirred for 6 hours. After the reaction was complete, the solvent was removed by reducing the pressure, tetrahydrofuran (5 mL) was added, and the pH was adjusted to 7 with saturated sodium carbonate aqueous solution. Then di-tert-butyl dicarbonate (750.68 mg, 3.44 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the pH was adjusted to 7 with 1 M hydrochloric acid and extracted with dichloromethane (20 mL x 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 0 / 1, volume ratio) to obtain compound WX023-8. MS-ESI m / z: 346.2 [M+H-100] + . 1H NMR (400 MHz, CDCl3) δ: 7.65 (d, J=8.0 Hz, 1H), 7.52 (d, J=6.8 Hz, 1H), 7.33 (t, J=7.6 Hz, 1H), 5.64 (d, J=7.6 Hz, 1H), 4.23 (q, J=7.12 Hz, 2H), 4.05 (s, 2H), 4.01-3.90 (m, 2H), 3.84 (s, 2H), 2.90-2.82 (m, 2H), 1.92-1.80 (m, 3H), 1.45 (s, 9H), 1.30-1.26 (m, 4H).

[0316] Step 9: Synthesis of trifluoroacetate of compound WX023-9 Under nitrogen gas protection at room temperature, compound WX023-8 (390 mg, 875.41 μmol) was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (2.46 g, 21.61 mmol, 1.6 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was concentrated under reduced pressure to obtain the trifluoroacetate salt of compound WX023-9. MS-ESI m / z: 346.2 [M+H] + .

[0317] Step 10: Synthesis of compound WX023-10 Under nitrogen gas protection at room temperature, 450 mg of the trifluoroacetate salt of compound WX023-9 was dissolved in 5 mL of acetonitrile, and N,N-diisopropylethylamine (619.39 mg, 4.79 mmol) was added. The mixture was stirred for 10 minutes to allow it to react. Compound WX015-8 (520.56 mg, 871.37 μmol) was added, and the reaction mixture was heated to 80°C and continued for 8 hours. After the reaction was complete, the reaction solution was cooled to room temperature, poured into 10 mL of saturated ammonium chloride aqueous solution, and extracted with a mixed solvent of dichloromethane and ethanol (volume ratio: 10:1, 10 mL x 3). The organic phases were combined, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated using a silica gel plate (eluent: dichloromethane / methanol = 8 / 1, volume ratio) to obtain compound WX023-10. MS-ESI m / z: 815.2 [M+H] + . 1 H NMR (400 MHz, DMSO_d6) δ : 9.50 (d, J=5.6 Hz, 1H), 8.78 (d, J=8.0 Hz, 1H), 8.39 (d, J=4.4 Hz, 1H), 8.26 (d, J=5.6 Hz, 1H), 8.19 (d, J=6.8 Hz, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.51 (d, J=7.4 Hz, 1H), 7.34 (t, J=7.6 Hz, 1H), 7.27-6.95 (m, 1H), 6.88- 6.40 (m, 1H), 5.17 (d, J=82.8 Hz, 1H), 4.77 (d, J=16.8 Hz, 1H), 4.19 (s, 2H), 3.81 (s, 2H), 3.75 (s, 2H), 3.68-3.50 (m, 3H), 3.44 (d, J=9.6 Hz, 1H), 2.90-2.75 (m, 2H), 2.25-2.08 (m, 2H), 2.07-1.85 (m, 8H), 1.83-1.67 (m, 4H), 1.65-1.37 (m, 3H), 1.27-1.16 (m, 4H), 1.12-0.97 (m, 2H).

[0318] Step 11: Synthesis of the formate of compound WX023 Under room temperature and nitrogen gas protection, compound WX023-10 (200 mg, 245.44 μmol) was dissolved in tetrahydrofuran (5 mL), cooled to 0°C, and acrylamide (19.19 mg, 269.98 μmol) and a tetrahydrofuran solution of potassium tert-butoxide (1 M, 368.15 μL) were added sequentially. The mixture was then allowed to return to room temperature and stirred for 4 hours to allow the reaction to proceed. After the reaction was complete, the reaction solution was poured into an aqueous solution of formic acid (0.1%, 5 mL), stirred for 2 minutes, and concentrated under reduced pressure to obtain the crude product. The crude product was first separated by preparative HPLC (chromatography column: Phenomenex C18 75×30mm×3μm, mobile phase: water (0.2% formic acid)-acetonitrile, acetonitrile %: 1%~35%, 8 min), and then separated again by preparative HPLC (chromatography column: Phenomenex Luna 80×30mm×3μm, mobile phase: water (0.2% formic acid)-acetonitrile, acetonitrile %: 10%~30%, 8 min) to obtain the formate of the target compound WX023. MS-ESI m / z: 840.3 [M+H] + . 1H NMR (400 MHz, DMSO_d6) δ: 11.09 (s, 1H), 9.50 (d, J=6.4 Hz, 1H), 8.78 (d, J=7.6 Hz, 1H), 8.38 (d, J=4.4 Hz, 1H), 8.26 (d, J=6.0 Hz, 1H), 8.21-8.12 (m, 2H), 7.74-7.65 (m, 1H), 7.55-7.46 (m, 1H), 7.37-7.29 (m, 1H), 7.26-6.94 (m, 1H), 6.90-6.40 (m, 1H), 5.18 (d, J=82.8 Hz, 1H), 4.77 (d, J=18.4 Hz, 1H), 4.60 (dd, J=5.2, 12.0 Hz, 1H), 4.23-4.11 (m, 1H), 3.85-3.78 (m, 2H), 3.77-3.71 (m, 2H), 3.66-3.58 (m, 1H), 3.57-3.50 (m, 1H), 3.48-3.42 (m, 1H), 2.82-2.73 (m, 3H), 2.66-2.58 (m, 1H), 2.57-2.51 (m, 1H), 2.24-2.15 (m, 1H), 2.11 (d, J=6.8 Hz, 2H), 2.07-2.00 (m, 3H), 1.99-1.93 (m, 3H), 1.92-1.83 (m, 2H), 1.79-1.69 (m, 4H), 1.62-1.50 (m, 1H), 1.48-1.38 (m, 2H), 1.10-0.97 (m, 2H).

[0319] Example 24

change

change

[0320] ステップ1: Synthesis of compound WX024-1 Under room temperature and nitrogen gas protection, 300 mg of the hydrochloride salt of compound WX021-12 was dissolved in 6 mL of dichloromethane, cooled to 0-5°C, and triethylamine (323.30 mg, 3.19 mmol) and chloroacetyl chloride (144.34 mg, 1.28 mmol) were added dropwise in sequence. The mixture was kept warm and stirred for 2 hours to allow the reaction to proceed. Then, it was slowly allowed to return to room temperature and stirred for 2 hours to allow the reaction to proceed. After the reaction was complete, water (20 mL) was added to the reaction solution and extracted with dichloromethane (7 mL x 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound WX024-1, which was used directly in the next step.

[0321] Step 2: Synthesis of compound WX024-3 Under nitrogen gas protection at room temperature, 4-hydroxypyridine (9 g, 94.64 mmol), compound WX024-2 (21.99 g, 189.28 mmol), and triphenylphosphine (24.82 g, 94.64 mmol) were dissolved in anhydrous tetrahydrofuran (200 mL), cooled to 0-5°C, and diisopropyl azodicarboxylate (19.14 g, 94.64 mmol, 18.40 mL) was added dropwise. After the addition was complete, the reaction mixture was slowly allowed to return to room temperature and stirred for 12 hours. After the reaction was complete, water (500 mL) was added to the reaction solution and extracted with ethyl acetate (200 mL x 3). The organic phases were combined, washed with saturated brine (200 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The resulting residue was separated by column chromatography (eluent: dichloromethane / methanol = 50 / 1 to 30 / 1, volume ratio) to obtain compound WX024-3. MS-ESI m / z: 194.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ: 8.41 (d, J=6.0 Hz, 2H), 6.86-6.74 (m, 2H), 4.52-4.45 (m, 1H), 3.91-3.79 (m, 1H), 2.09-1.99 (m, 2H), 1.91-1.64 (m, 6H).

[0322] Step 3: Synthesis of compound WX024-4 At room temperature and under argon gas protection, platinum dioxide (660 mg, 2.91 mmol) was suspended in glacial acetic acid (33 mL). Compound WX024-3 (3.3 g, 17.08 mmol) and acetic anhydride (5.45 g, 53.38 mmol) were added, and the mixture was purged three times with hydrogen gas. The hydrogen gas pressure was maintained at 50 psi, and the reaction mixture was heated to 50°C and stirred for 96 hours. After the reaction was complete, the mixture was filtered, the cake was rinsed with methanol (200 mL x 7), the mother liquor was collected, and the solvent was removed by reducing pressure and concentrating. The resulting residue was separated by column chromatography (eluent: dichloromethane / methanol = 100 / 1 to 30 / 1, volume ratio) to obtain compound WX024-4. MS-ESI m / z: 242.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ: 3.95-3.83 (m, 1H), 3.80-3.70 (m, 1H), 3.69-3.58 (m, 2H), 3.56-3.46 (m, 1H), 3.42-3.31 (m, 1H), 3.30-3.18 (m, 1H), 2.09 (s, 3H), 1.85-1.74 (m, 4H), 1.73-1.62 (m, 4H), 1.61-1.48 (m, 4H).

[0323] Step 4: Synthesis of compound WX024-5 Under room temperature and nitrogen gas protection, compound WX024-4 (1.25 g, 5.18 mmol) and triethylamine (1.05 g, 10.36 mmol, 1.44 mL) were dissolved in dichloromethane (12.5 mL), cooled to 0-5°C, and methanesulfonyl chloride (1.04 g, 9.08 mmol) was added dropwise. After the addition was complete, the mixture was kept warm and stirred for 2 hours to allow the reaction to proceed. After the reaction was complete, water (70 mL) was added to the reaction solution and extracted with dichloromethane (20 mL x 3). The organic phases were combined, washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound WX024-5, which was used directly in the next step.

[0324] Step 5: Synthesis of compound WX024-6 Under nitrogen gas protection at room temperature, compound BB-1-5 (0.7 g, 4.29 mmol) was dissolved in N,N-dimethylformamide (14 mL). Potassium carbonate (1.19 g, 8.58 mmol) and compound WX024-5 (1.65 g, 5.15 mmol) were added sequentially. The reaction mixture was heated to 80°C and stirred for 12 hours. After the reaction was complete, the reaction solution was cooled to room temperature, water (50 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The resulting residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1 to 0 / 1, volume ratio) to obtain compound WX024-6. MS-ESI m / z: 387.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ: 8.22 (s, 1H), 7.10 (t, J=53.6 Hz, 1H), 4.26-4.16 (m, 1H), 3.99-3.89 (m, 1H), 3.72-3.63 (m, 2H), 3.54-3.42 (m, 1H), 3.34-3.21 (m, 2H), 2.31-2.22 (m, 2H), 2.19-2.11 (m, 2H), 2.09 (s, 3H), 1.89-1.74 (m, 4H), 1.68-1.46 (m, 4H).

[0325] Step 6: Synthesis of compound WX024-7 Under nitrogen gas protection at room temperature, palladium / carbon (0.1 g, purity: 10%) was suspended in tetrahydrofuran (10 mL), compound WX024-6 (478 mg, 1.24 mmol) was added, and the mixture was purged three times with a hydrogen gas balloon. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was filtered, the cake was rinsed with methanol (50 mL x 5), the filtrate was collected, and the solvent was removed by reducing pressure and concentrating. The resulting residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate / ethanol = 1 / 1 / 0~0 / 1 / 0~0 / 10 / 1, volume ratio) to obtain compound WX024-7. MS-ESI m / z: 357.1 [M+H] + .

[0326] Step 7: Synthesis of compound WX024-8 Under room temperature and nitrogen gas protection, intermediate BB-2-3 (143.70 mg, 552.17 μmol) was dissolved in acetonitrile (3 mL), chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (154.93 mg, 552.17 μmol) and N-methylimidazole (132.23 mg, 1.61 mmol) were added, and the mixture was stirred for 10 minutes. Compound WX024-7 (164 mg, 460.14 μmol) was added, and the reaction was continued with stirring for 16 hours. After the reaction was complete, the reaction solution was poured into ice water (30 mL) and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated using a silica gel plate (eluent: dichloromethane / methanol = 10 / 1, volume ratio) to obtain compound WX024-8. MS-ESI m / z: 599.4 [M+H] + .

[0327] Step 8: Synthesis of compound WX024-9 Under room temperature and nitrogen gas protection, compound WX024-8 (181.5 mg, 303.19 μmol) was dissolved in ethanol (7 mL), sodium hydroxide solution (1 M, 7 mL) was added, and the reaction mixture was heated to 80°C and stirred for 16 hours. After the reaction was complete, the mixture was cooled to room temperature, the pH was adjusted to 7 with 1 M hydrochloric acid, and the solvent was removed by concentrating under reduced pressure to obtain compound WX024-9. MS-ESI m / z: 557.3 [M+H] + .

[0328] Step 9: Synthesis of Compound WX024 Under room temperature and nitrogen gas protection, compound WX024-9 (168.76 mg, 303.19 μmol), compound WX024-1 (126.81 mg, 394.15 μmol), and sodium iodide (59.08 mg, 394.15 μmol) were dissolved in acetonitrile (3 mL). N,N-diisopropylethylamine (156.74 mg, 1.21 mmol, 211.24 μL) was added, and the reaction mixture was heated to 80°C and stirred for 2 hours. After the reaction was complete, the solvent was removed by concentrating under reduced pressure. The obtained residue was first separated by preparative HPLC (chromatography column: Phenomenex luna C18 80×40mm×3μm, mobile phase: water (0.04% hydrochloric acid)-acetonitrile, acetonitrile %: 25%~50%, 7 min), and then separated again by preparative HPLC (chromatography column: Phenomenex C18 75×30mm×3μm, mobile phase: water (10mM ammonium bicarbonate)-acetonitrile, acetonitrile %: 35%~55%, 8 min) to obtain compound WX024. MS-ESI m / z: 842.5 [M+H] + . 1H NMR (400 MHz, DMSO_d6) δ: 11.12 (s, 1H), 11.08 (d, J=6.4 Hz, 1H), 10.02 (s, 1H), 9.50 (d, J=6.4 Hz, 1H), 8.78 (d, J=7.6 Hz, 1H), 8.39 (d, J=3.2 Hz, 1H), 8.25 (d, J=5.6 Hz, 1H), 8.02 (dd, J=2.8, 7.2 Hz, 1H), 7.69 (d, J=7.6 Hz, 1H), 7.41 (t, J=7.8 Hz, 1H), 7.27-6.95 (m, 1H), 6.90-6.40 (m, 1H), 5.17 (d, J=78.4 Hz, 1H), 4.70 (d, J=21.2 Hz, 1H), 4.64 (dd, J=5.0, J=12.2 Hz, 1H), 4.41-4.18 (m, 3H), 3.92-3.78 (m, 2H), 3.76-3.49 (m, 6H), 3.36-3.11 (m, 2H), 2.88-2.72 (m, 1H), 2.68-2.53 (m, 2H), 2.29-2.17 (m, 1H), 2.14-1.67 (m, 12H), 1.49-1.27 (m, 2H).

[0329] Examples 25 and 26 [ka] Synthesis route: [ka]

[0330] Synthesis of hydrochloride salts of compounds WX025 and WX026 The hydrochloride salt (500 mg) of compound WX006 was separated by supercritical fluid chromatography (separation conditions: chromatography column: REGIS(S,S)WHELK-O1 (250 mm × 25 mm, 10 μm), mobile phase: A: CO2, B: EtOH / ACN, B%: 70%~70%, 25 min; analytical method: chromatography column: (S,S)-WHELK-O1, 50 × 4.6 mm ID, 3.5 μm, mobile phase: A: CO2, B: EtOH:ACN = 1:1 (0.1% IPAm, v / v), 4 min). A sample with a retention time of 2.631 min was collected and then separated by preparative HPLC (chromatography column: Phenomenex Luna 80 × 40 mm × 3 μm, mobile phase: water (0.04% hydrochloric acid)-acetonitrile, acetonitrile %: 5%~35%, 7 min) to obtain the hydrochloride salt of compound WX025 (ee%: 99.10%). A sample with a retention time of 5.384 min was collected and then separated by preparative HPLC (chromatography column: Phenomenex Luna 80 × 40 mm × 3 μm, mobile phase: water (0.04% hydrochloric acid)-acetonitrile, acetonitrile %: 5%~35%, 7 min) to obtain the hydrochloride salt of compound WX026 (ee%: 98.94%).

[0331] Hydrochloride salt of compound WX025: 1H NMR (400 MHz, DMSO_d6) δ: 11.18 (s, 1H), 10.92 (s, 1H), 10.58 (s, 1H), 9.50 (d, J=6.4 Hz, 1H), 8.78 (d, J=7.6 Hz, 1H), 8.40 (d, J=3.6 Hz, 1H), 8.26 (d, J=5.6 Hz, 1H), 7.98 (s, 1H), 7.73 (d, J=7.6 Hz, 1H), 7.41 (d, J=7.6 Hz, 1H), 7.27-6.96 (m, 2H), 6.90-6.41 (m, 1H), 5.18 (d, J=79.2 Hz, 1H), 4.76 (d, J=18.8 Hz, 1H), 4.33-4.21 (m, 1H), 4.17 (dd, J=4.8 Hz, 12.0 Hz, 1H), 3.85-3.55 (m, 13H), 3.13-2.95 (m, 2H), 2.82-2.72 (m, 1H), 2.64-2.54 (m, 1H), 2.41-2.26 (m, 1H), 2.18-1.65 (m, 11H), 1.32-1.08 (m, 2H). Compound WX026 acid chloride: 1H NMR (400 MHz, DMSO_d6) δ: 10.92 (s, 1H), 10.44 (s, 1H), 9.51 (d, J=6.0 Hz, 1H), 8.78 (d, J=7.6 Hz, 1H), 8.40 (d, J=4.0 Hz, 1H), 8.25 (d, J=5.6 Hz, 1H), 7.97 (s, 1H), 7.73 (d, J=7.6 Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 7.24 (d, J=7.6 Hz, 1H), 7.22-6.95 (m, 1H), 6.90-6.43 (m, 1H), 5.17 (d, J=79.2 Hz, 1H), 4.77 (d, J=19.6 Hz, 1H), 4.32-4.20 (m, 1H), 4.17 (dd, J=4.8 Hz, 12.0 Hz, 1H), 3.85-3.54 (m, 13H), 3.14-2.95 (m, 2H), 2.82-2.69 (m, 1H), 2.64-2.55 (m, 1H), 2.41-2.27 (m, 1H), 2.19-1.65 (m, 11H), 1.28-1.11 (m, 2H).

[0332] Examples 27 and 28 [ka] Synthesis route: [ka]

[0333] Synthesis of hydrochloride salts of compounds WX027 and WX028 The hydrochloride salt (500 mg) of compound WX015 was separated by supercritical fluid chromatography (separation conditions: chromatography column: REGIS (S,S) WHELK-O1 (250 mm × 25 mm, 10 μm), mobile phase: A: CO2, B: EtOH / ACN (0.1% IPAm, v / v), B%: 65%~65%, 6 min; analytical method: chromatography column: (S,S)-WHELK-O1, 50 × 4.6 mm ID, 3.5 μm, mobile phase: A: CO2, B: EtOH:ACN = 1:1 (0.1% IPAm, v / v), 4 min). A sample with a retention time of 1.678 min was collected and then separated by preparative HPLC (chromatography column: Phenomenex Luna C18 80×40 mm×3 μm, mobile phase: water (0.04% hydrochloric acid)-acetonitrile, acetonitrile %: 23%~43%, 7 min) to obtain the hydrochloride salt of compound WX027 (ee%: 96.68%). A sample with a retention time of 2.265 min was collected and then separated by preparative HPLC (chromatography column: Phenomenex Luna 80×30 mm×3 μm, mobile phase: water (0.04% hydrochloric acid)-acetonitrile, acetonitrile %: 1%~30%, 8 min) to obtain the hydrochloride salt of compound WX028 (ee%: 95.18%).

[0334] Hydrochloride salt of compound WX027: 1H NMR (400 MHz, DMSO_d6) δ: 11.12 (s, 1H), 10.49 (s, 1H), 9.51 (d, J=6.0 Hz, 1H), 8.79 (d, J=8.0 Hz, 1H), 8.41 (d, J=4.4 Hz, 1H), 8.26 (d, J=5.6 Hz, 1H), 8.01 (d, J=7.6 Hz, 1H), 7.65 (d, J=8.0 Hz, 1H), 7.38 (t, J=8.0 Hz, 1H), 7.27-6.95 (m, 1H), 6.90-6.44 (m, 1H), 5.18 (d, J=78.0 Hz, 1H), 4.76 (d, J=20.4 Hz, 1H), 4.64 (dd, J=4.8 Hz, 12.0 Hz, 1H), 4.29-4.18 (m, 1H), 3.85-3.58 (m, 14H), 3.47-3.42 (m, 1H), 3.10-2.96 (m, 2H), 2.84-2.73 (m, 1H), 2.68-2.53 (m, 2H), 2.26-2.16 (m, 1H), 2.12-1.73 (m, 8H), 1.28-1.11 (m, 2H). Compound WX028 acid chloride: 1H NMR (400 MHz, DMSO_d6) δ: 11.12 (s, 1H), 10.47 (s, 1H), 9.51 (d, J=6.0 Hz, 1H), 8.79 (d, J=7.6 Hz, 1H), 8.40 (d, J=4.0 Hz, 1H), 8.26 (d, J=5.6 Hz, 1H), 8.01 (d, J=7.6 Hz, 1H), 7.65 (d, J=8.0 Hz, 1H), 7.38 (t, J=8.0 Hz, 1H), 7.28-6.95 (m, 1H), 6.90-6.43 (m, 1H), 5.18 (d, J=79.2 Hz, 1H), 4.76 (d, J=20.8 Hz, 1H), 4.64 (dd, J=4.8 Hz, 12.0 Hz, 1H), 4.29-4.18 (m, 1H), 3.87-3.41 (m, 14H), 3.10-2.94 (m, 2H), 2.84-2.73 (m, 1H), 2.67-2.53 (m, 2H), 2.25-2.17 (m, 1H), 2.13-1.69 (m, 9H), 1.28-1.11 (m, 2H).

[0335] Biological Tests Experimental Example 1: Evaluation of target protein degradation effects in K562 IRAK4-HiBiT cells Experimental Objective: This experiment aims to detect the degradation effect of the test compound on the target protein IRAK4 in K562 IRAK4-HiBiT cells.

[0336] Experimental materials: 1. Cells and culture medium Cells: K562 IRAK4-HiBiT cells Culture medium: RPMI 1640 + 10% FBS + 2 mM GlutaMax + 1 mM sodium pyruvate + penicillin / streptomycin Positive control: 1000 nM, Negative control: 0.1% DMSO

[0337] 2. Reagents and Consumables [Table 1-1]

[0338] 3.Equipment [Table 1-2]

[0339] Experimental scheme: Day 1 1. Preparation of the compound (1) The powder of the test compound was dissolved in DMSO to a storage concentration of 10 mM, and 9 μL of the 10 mM test compound was manually transferred to columns 1 and 13 of the LDV plate using a pipette. (2) Using a multidrop Combi, 6 μL of DMSO was added to columns 2-12 and 14-24. (3) Using Bravo, the test compounds from columns 1-11 and 13-23 were diluted threefold (3 μL + 6 μL). (4) Following the plate layout, 25 nL of compound solution (columns 1-24 of the LDV plate) was transferred to the experimental plate using Echo. (5) Using Echo, 25 nL of 1 mM positive control solution was transferred to an experimental plate as a 100% decomposition control (i.e., LC, HPE), and 25 nL of DMSO was transferred to an experimental plate as a 0% control (i.e., HC, ZPE).

[0340] 2. Cell Plating (1) Discard the cell culture medium, wash once with DPBS, digest the cells with trypsin, count the cells, and 2 × 10 -5 A cell suspension was prepared at a concentration of cells / mL. (2) Using MultiDropCombi, 25 μL / well of cell suspension was added to the experimental plate containing the test compound at a medium speed. (3) The experimental plate containing the cells was returned to the incubator and cultured at 37°C and 5% CO2 for 16-18 hours.

[0341] Day 2 (1) Using MultiDrop Combi, 25 μL / well of the detection reagent (NanoGlo lysis solution + substrate + LgBit protein) was added to the experimental plate at high speed and shaken for 10 minutes. (2) The mixture was centrifuged at 2000 rpm for 1 minute to remove bubbles. (3) The plates were read using the Envision and US Luminescence detection methods.

[0342] 3. Data Analysis The inhibition rate (IR) of the test compound was calculated using the following formula: IR (%) = (RLU solvent control - RLU compound) / (RLU solvent control - RLU positive control) × 100%, where the solvent control was a blank control. The inhibition rates of the compound at various concentrations were calculated in Excel, and then the inhibition curves were plotted using XLFit software to determine the minimum inhibition rate, maximum inhibition rate, and DC. 50 Related parameters such as these were calculated. The test results are shown in Table 1.

[0343] Table 1. Target protein degradation effect of the present invention compound in K562 IRAK4-HiBiT cells. [Table 1-3]

[0344] Conclusion: The compounds of the present invention exhibit excellent degrading effects on the target protein IRAK4 in K562 IRAK4-HiBiT cells.

[0345] Experimental Example 2: Evaluation of pharmacokinetics of compounds in mice Experimental objective: In this study, CD-1 or C57BL / 6N male mice were selected as test animals, and plasma drug concentrations of the test compound administered intravenously or intragastricly to the mice were quantitatively measured at different time points using LC / MS / MS to evaluate the pharmacokinetic characteristics of the test drug in mice.

[0346] Experimental materials: CD-1 mouse (male, 20-35g, 7-10 weeks old, Beijing Vital River) or C57BL / 6N mouse (male, 20-30g, 7-10 weeks old, Beijing Vital)

[0347] Experimental procedure A: The clarified or suspended solution of the test compound was injected into CD-1 mice (overnight fasted) via the tail vein (solvent: 10% DMSO / 10% Solutol / 80% H2O) and administered intragastricly to CD-1 mice (overnight fasted). For intravenous injections, blood was collected from the saphenous vein at 0 hours (before administration) and at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration. The blood was placed in an EDTA-K2 anticoagulation tube, the mixture was thoroughly vortex-mixed, and the mixture was centrifuged at 3200 g for 10 minutes at 4°C to obtain plasma. For oral intragastric administration, blood was collected from the saphenous vein at 0.25, 0.5, 1, 2, 4, 8, and 24 hours post-administration. This blood was placed in an anticoagulant tube (Jiangsu Kangjian MEDICAL Apparatus Co., Ltd.) containing EDTA-K2, thoroughly vortex-mixed, and centrifuged at 3200 g for 10 minutes at 4°C to obtain plasma. Plasma drug concentrations were measured using LC-MS / MS, and relevant pharmacokinetic parameters were calculated using the non-compartment model linear log-trapezoidal method with Phoenix WinNonlin® Version 6.3 (Pharsight, Mountain View, CA) pharmacokinetic software.

[0348] Experimental procedure B: The clarified or suspended solution of the test compound was injected into C57BL / 6N mice (fasted overnight) via the tail vein (solvent: 5% DMSO / 10% solutol / 85% H2O), or administered intragastricly to C57BL / 6N mice (fasted overnight). For intravenous injections, 50 μL of blood was collected from the cheek puncture at 0 hours (before administration) and at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration. The blood was placed in an anticoagulant tube containing sodium heparin, the mixture was thoroughly vortex-mixed, and the mixture was centrifuged at 6000 g for 3 minutes at 2-8°C. For oral intragastric administration, blood was collected via buccal puncture at 0 hours (before administration) and at 0.083, 0.25, 1, 2, 4, 6, 8, and 24 hours post-administration. The blood was placed in an anticoagulant tube containing heparin sodium, thoroughly vortex-mixed, and centrifuged at 6000 g for 3 minutes at 2–8°C. Plasma drug concentrations were measured using LC-MS / MS, and relevant pharmacokinetic parameters were calculated using the non-compartment model linear log-trapezoidal method with Phoenix WinNonlin 8.2.0 pharmacokinetic software.

[0349] The test results are shown in Table 2. Table 2 Pharmacokinetic parameters of the compound of the present invention in mice [Table 2] Conclusion: Oral plasma systemic exposure (AUC) of the compound of the present invention 0-inf ) is higher. In rodents such as mice, its pharmacokinetic properties are superior.

[0350] Experimental Example 3: Pharmacokinetic evaluation of compounds in beagle dogs Experimental objective: In this study, male beagle dogs were selected as test animals, and plasma drug concentrations of the test compound administered intravenously or intragastricly to the beagle dogs were quantitatively measured at different time points using LC / MS / MS to evaluate the pharmacokinetic characteristics of the test drug in beagle dogs.

[0351] Experimental materials: Beagle (male, 9-11kg, Jiangsu Yadong Experimental Animal Research Institute Co., Ltd.)

[0352] Experimental procedure: The clarified or suspended solution of the test compound was injected into Beagle dogs (by feeding) via the tail vein (solvent: 5% DMSO / 10% Solutol / 85% H2O), or administered intragastricly to Beagle dogs (by feeding). For intravenous injection, 1 mL of blood was collected from the forelimb vein at 0 hours (before administration) and at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration. The blood was placed in an EDTA-2K anticoagulant tube, the mixture was thoroughly vortex-mixed, and the mixture was centrifuged at 6000 g for 3 minutes at 2-8°C. For oral intragastric administration, 1 mL of blood was collected from the forelimb vein at 0 hours (before administration) and at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration. The blood was placed in an EDTA-2K anticoagulant tube, the mixture was thoroughly vortex-mixed, and the mixture was centrifuged at 6000 g for 3 minutes at 2-8°C. Plasma drug concentrations were measured using LC-MS / MS, and the relevant pharmacokinetic parameters were calculated using the non-compartment model linear log-trapezoidal method with Phoenix WinNonlin 8.2.0 pharmacokinetic software.

[0353] The test results are shown in Table 3. Table 3 Pharmacokinetic parameters of the compound of the present invention in Beagle dogs [Table 3] Conclusion: Oral plasma systemic exposure (AUC) of the compound of the present invention 0-inf ) is higher. In non-rodent beagle dogs, its pharmacokinetic properties are superior.

[0354] Experimental Example 4: Pharmacokinetic Evaluation of Compounds in Cynomolgus Monkeys Experimental objective: In this study, male cynomolgus monkeys were selected as test animals, and plasma drug concentrations of the test compound administered intravenously or intragastricly to the monkeys were quantitatively measured at different time points using LC / MS / MS to evaluate the pharmacokinetic characteristics of the test drug in cynomolgus monkeys.

[0355] Experimental materials: Crab-eating macaque (male, 2-5kg, Hainan JINGANG BIOTECH Co., Ltd.)

[0356] Experimental procedure: A clarified solution of the test compound was slowly injected into cynomolgus monkeys via peripheral vein (feeding) (solvent: 5% DMSO / 10% Solutol / 85% H2O), or administered intragastricly to cynomolgus monkeys (feeding). For intravenous injections, 0.5 mL of blood was collected from a peripheral vein at 0 hours (before administration) and at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration. The blood was placed in an EDTA-2K anticoagulant tube, centrifuged at 3200 g for 10 minutes at 2-8°C, and the supernatant was separated. For oral intragastric administration, 0.5 mL of blood was collected from a peripheral vein at 0 hours (before administration) and at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours post-administration. The blood was placed in an EDTA-2K anticoagulant tube, centrifuged at 3200 g for 10 minutes at 2-8°C, and the supernatant was separated. Plasma drug concentrations were measured using LC-MS / MS, and relevant pharmacokinetic parameters were calculated using the non-compartment model linear log-trapezoidal method with Phoenix WinNonlin 6.3 pharmacokinetic software.

[0357] The test results are shown in Table 4. Table 4. Pharmacokinetic parameters of the present invention compound in cynomolgus monkeys. [Table 4]

[0358] Conclusion: Oral plasma systemic exposure (AUC) of the compound of the present invention 0-inf ) is higher. In non-rodent monkeys, its pharmacokinetic properties are superior.

[0359] Experimental Example 5: Study on the preventive and therapeutic effects of compounds on sodium urate-induced acute gouty arthritis in rats. Experimental objective: This study evaluates the prophylactic and therapeutic effects of compounds on sodium urate-induced acute gouty arthritis in rats.

[0360] Experimental materials: Animal: 5-week-old male SD rat, Source: Zhejiang Vital River Laboratory Animal Technology Co., Ltd.

[0361] Experimental reagents: Sodium urate: Sigma, Catalog number: BCCB4889 DMSO: GENERAL-REAGENT, Catalog Number: P1908824 Sterile water for injection: Guangdong Aixida Pharmaceutical Co., Ltd., Catalog number: 200913203. Solutol: BASF SE, Catalog Number: 35907288Q0 Solvent: 10% DMSO + 10% Solutol + 80% H2O.

[0362] Experimental equipment: Toe swelling tester: YLS-7B, Jinan Yiyan Technology Development Co., Ltd. Bipedal balance pain tester: Incapacitance Testers, Linton

[0363] Experimental procedure: Experimental grouping: After a 3-day acclimatization period, basic hind leg volume, arthritis index score, and bilateral hind leg pain threshold were measured for all animals. Fifty animals were selected and divided equally into five groups of 10 animals each, based on body weight, hind leg volume, arthritis index, and bilateral hind leg pain threshold.

[0364] Table 5: Grouping of Experiments [Table 5]

[0365] The day of administration commencement was recorded as D-1, and the drug was administered orally and intragastricly twice daily for 6 consecutive days (D-1 to D4). On D0, one day after administration, and one hour after the first dose, all rats except the blank control group were anesthetized with isoflurane, and 50 μL (50 mg / mL) of sodium urate solution was injected into the joint cavity using the posterior lateral aspect of the right ankle joint as the puncture site to model the joint. Joint swelling peaked at 8–12 hours (and continued for approximately 72 hours). Foot volume was measured before inflammation occurred, and at 2, 5, 8, 11, 24, 48, 72, and 96 hours after inflammation occurred, and the Arthritis Index (AI) score was performed. Pain thresholds were measured using a bipedal balance pain tester before inflammation occurred, and at 2, 24, 48, 72, and 96 hours after inflammation occurred. Photographs of the major swelling in each group of animals were taken and saved at the peak of joint swelling (8–12 hours).

[0366] Clinical observation: The clinical symptoms of experimental animals were observed once a day, and any abnormalities were recorded. Foot volume measurement: Before measurement, the rat's ankle joint was marked with a marker pen, clean water was added to the instrument, and the instrument's values ​​were reset to prepare for measurement. The rat's hind limb was placed in the water so that the marked line on the ankle joint was at the surface of the liquid, and the foot pedal was pressed to read the rat's foot volume. After the measurement was completed, the foot pedal was pressed again to reset and prepare for the next rat's measurement. Arthritis Index (AI): Foot volume was measured, and the modeled foot swelling was scored. Scoring criteria for the Arthritis Index:

[0367] Table 6 Clinical scoring criteria for arthritis [Table 6]

[0368] Data statistics: Experimental data were expressed as Mean ± SD. The data were statistically analyzed using IBM SPSS Statistics 21, and a data point p<0.05 between the two groups was considered statistically significant.

[0369] The test results for foot volume, arthritis index, and hindfoot load-bearing difference are shown in Tables 7, 8, and 9. [Table 7] *Comparison models with p<0.05, **p<0.01, and ***p<0.001

[0370] [Table 8] *Comparison models with p<0.05, **p<0.01, and ***p<0.001

[0371] [Table 9] *Comparison models with p<0.05, **p<0.01, and ***p<0.001

[0372] Experimental conclusion: The compounds of the present invention have dose-dependent therapeutic effects on hind paw volume, hind paw arthritis index score, and hind paw weight-bearing difference in rats with sodium urate-induced acute gouty arthritis.

[0373] Experimental Example 6: Evaluation of the efficacy of a compound against an imiquimod-induced mouse psoriasis model. Experimental objective: We will evaluate the efficacy of the compound in an imiquimod-induced BALB / c mouse psoriasis model. Experimental materials: Animal: BALB / c mouse, male, 18-20g, Source: Zhejiang Vital River Laboratory Animal Technology Co., Ltd.

[0374] Experimental reagents: Imiquimod: 3M Health Care Limited, Drug Registration Number: H20160079 DMSO: Anergy Chemical, Catalog Number: E081359 Solutol: Sigma-Aldrich, Catalog Number: 42966 MC: Sigma-Aldrich, Catalog Number: M0202, Tween 20: Sigma-Aldrich, Catalog Number: 9005-64-5 Solvent: 10% DMSO + 10% Solutol + 80% H2O.

[0375] Experimental equipment: Electronic balance: Sartorius, Catalog number: QUINTIX124-1CN Electronic scale: Shanghai Yueping Science Instrument Co., Ltd., Catalog number: YP10001 Ultrasonic cleaner: Kunshang, Catalog number: KQ3200E Electronic oscillator: Scientific Industries, catalog number: SI-0256. Anesthesia machine: Yuyan Instruments, catalog number: ABS-4.

[0376] Experimental procedure: Experimental grouping and administration: After adaptation, 50 male BALB / c mice were randomly divided into 5 groups (n=6 or 9) according to body weight: normal (control, G1) group, solvent (model, G2) group, low-dose test compound (30 mg / kg, BID, G3) group, medium-dose test compound (100 mg / kg, BID, G4) group, and high-dose test compound (300 mg / kg, BID, G5) group. Model induction: Before applying imiquimod, the hair on the back of the experimental animals was shaved (surface area = 2 × 3 cm). Except for the normal group, imiquimod cream was applied topically at a dose of 62 mg / mouse daily to the shaved back (47 mg) and left ear (15 mg) for 8 consecutive days (from day 0 to day 7). The treatment groups (G2-G5) received intragastric administration of the solvent or test compound twice daily from day -1 to day 6, and only once on day 7. The dosage volume for all groups was 10 mL / kg. (Note: The first application of imiquimod was specified as D0. Since it was administered one day earlier, the first dose was on day -1.)

[0377] Table 10 Grouping of Experiments [Table 10]

[0378] Data collection and analysis: Clinical score: Clinical disease scores for erythema, scaling, and thickness were measured daily according to a grading system, and a cumulative score was calculated.

[0379] Table 11 Scoring system: Erythema, scaling, thickness [Table 11]

[0380] Ear thickness: The thickness of the left ear was measured a total of four times on days 0, 3, 5, and 7, and the increase in ear thickness on day 7 compared to day 0 was calculated. Spleen weight: The spleen weight was measured after the animals were slaughtered on the 7th day. Inflammatory factors: After slaughtering the animals on day 7, skin samples were taken from the lesion sites, and the relative content of interleukin-17, interleukin-6, and tumor necrosis factor α was detected using fluorescence quantitative PCR.

[0381] Experimental results: Experimental data were expressed as Mean ± SEM. The data were statistically analyzed using one-way analysis of variance in Graphpad Prism software, and a data point p<0.05 between the two groups was considered statistically significant. The results of the mouse pathology scores, ear thickness increase, spleen weight, and inflammatory factor tests are shown in Tables 12 and 13.

[0382] Table 12 Effects of test compounds on pathological scores, ear thickness increase, and spleen weight in mouse psoriasis models induced by imiquimod (n=6 or 9) [Table 12] *Comparison models with p<0.05, **p<0.01, and ***p<0.001

[0383] Table 13 Effect of test compounds on the relative content of skin inflammatory factors in imiquimod-induced mouse psoriasis models (n=3 or 9) [Table 13] *Comparison models with p<0.05, **p<0.01, and ***p<0.001

[0384] Experimental conclusion: The compounds of the present invention have ameliorative effects on pathological scores, ear thickness, and spleen weight in imiquimod-induced mouse psoriasis models, and also have inhibitory effects on inflammatory factors in the lesioned skin. The compounds of the present invention have therapeutic effects in this psoriasis model animal, and the therapeutic effect of high doses (300 mpk) is shown to be superior to that of medium and low doses (100 mpk, 30 mpk).

Claims

1. A compound represented by formula (VII) or a pharmaceutically acceptable salt thereof. 【Chemistry 1】 (however, L １ teeth, 【Chemistry 2】 - (CH ２ ) ３ - and -O(CH ２ ) ３ - Selected from, 【Transformation 3】 teeth, 【Chemistry 4】 And, - (CH ２ ) ３ -teeth, 【Transformation 5】 And, -O(CH ２ ) ３ - is, 【Transformation 6】 And, L ２ is, -CR ５ R ６ - and O are selected, R ５ and R ６ Each is independently selected from H, R ７ teeth, 【Transformation 7】 Selected from, T １ It is selected from CH and N, T ２ It is selected from CH and N, T ３ It is selected from CH and N, Ring A is, 【Transformation 8】 Selected from, 【Chemistry 9】 【Chemistry 10】 。）

2. Structural unit 【Chemistry 11】 A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the above.

3. Structural unit 【Chemistry 12】 A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the above.

4. Ring A is, 【Chemistry 13】 A compound according to claim 3 or a pharmaceutically acceptable salt thereof, selected from the above.

5. The compound is selected from structures represented by formulas (VII-1), (VII-2), (VII-3), and (VII-4), and is the compound according to claim 1 or a pharmaceutically acceptable salt thereof. 【Chemistry 14】 (however, 【Chemistry 15】 【Chemistry 16】 ）

6. The compound is selected from structures represented by formulas (VII-1R), (VII-1S), (VII-2R), (VII-2S), (VII-3R), (VII-3S), (VII-4R), and (VII-4S), and is the compound according to claim 1 or a pharmaceutically acceptable salt thereof. 【Chemistry 17】 [Chemistry 18] (however, 【Chemistry 19】 【Chemistry 20】 。）

7. The compound is selected from structures represented by formulas (VII-1RT), (VII-1ST), (VII-2RT), (VII-2ST), (VII-3RT), (VII-3ST), and (VII-5T), and is the compound according to claim 1 or a pharmaceutically acceptable salt thereof. 【Chemistry 21】 【Chemistry 22】 (however, 【Chemistry 23】 【Chemistry 24】 。）

8. The compound is selected from structures represented by the following formula, and is the compound according to claim 1 or a pharmaceutically acceptable salt thereof. 【Chemistry 25】 【Chemistry 26】 【Chemistry 27】 【Chemistry 28】 (however, 【Chemistry 29】 【Transformation 30】 。）

9. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is one of the following compounds or a pharmaceutically acceptable salt thereof. 【Chemistry 31】 【Chemistry 32】

10. The compound is selected from the following formulas, the compound according to claim 9, or a pharmaceutically acceptable salt thereof. 【Transformation 33】 【Transformation 34】

11. The compound is selected from the following formulas, the compound according to claim 9, or a pharmaceutically acceptable salt thereof. 【Chemistry 35】 【Transformation 36】

12. The compound is selected from the following formulas, the compound according to claim 9, or a pharmaceutically acceptable salt thereof. 【Chemistry 37】 【Transformation 38】 【Chemistry 39】

13. Use of a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof in the preparation of a pharmacopoeia for the treatment of a disease associated with an interleukin-1 receptor-related kinase 4 proteolysis-inducing chimeric molecule.

14. The use according to claim 13, wherein the disease associated with the interleukin-1 receptor-related kinase 4 proteolytic chimeric molecule is an inflammatory disease or an immune disease.

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