Glutarimide compounds and their applications

Abstract

The present invention discloses a glutarimide compound and its application, specifically a compound represented by formula (VII-0) and a pharmaceutically acceptable salt thereof.

Description

[0001] The present invention claims the following priority:

[0002] CN202111050400X, application date: September 8, 2021;

[0003] CN2021113429975, application date: November 12, 2021;

[0004] CN2021113508407, application date: November 15, 2021;

[0005] CN2021113956259, application date: November 23, 2021;

[0006] CN2021115450152, application date: December 16, 2021;

[0007] CN2021116025367, application date: December 24, 2021;

[0008] CN2022110348171, application date: August 26, 2022. Technical Field

[0009] The present invention relates to a class of glutarimide compounds and applications thereof, and specifically to a compound represented by formula (VII-0) and a pharmaceutically acceptable salt thereof. Background Art

[0010] Interleukin-1 Receptor-Associated Kinase 4 (IRAK4) is a member of the intracellular serine / threonine kinase IRAK family and plays an important role in protein phosphorylation and cell signaling. IRAK4 is a key protein in the process of inflammation and immune response mediated by Toll-like receptors (TLR) and interleukin-1 receptor (IL-1R). As a key protein downstream of the signal transduction pathway of TLR and IL-1R, IRAK4 receives upstream signals to activate the downstream NF-κB and JNK signaling pathways. Therefore, IRAK4 is believed to play an important role in inflammatory response and immune regulation, and has become an important therapeutic target, attracting widespread research and development interest.

[0011] After folding, the IRAK4 protein forms a "pocket-like" structure that can bind to ATP, thereby realizing its protein phosphorylation function. Most of the current IRAK4 small molecule inhibitors competitively bind to the "pocket" region, thereby inhibiting its phosphorylation function for drug development. However, the function of IRAK4 is not only to phosphorylate proteins, but also to form a complex with myeloid differentiation factor (MyD88) to exert its function. IRAK4 requires its phosphorylation function for the activation of the JNK signaling pathway, but does not require its phosphorylation function for the activation of the NF-κB signaling pathway, indicating that IRAK4 not only has the function of a kinase, but also has the function of a scaffold protein that plays a role in the signaling pathway. Therefore, traditional small molecule kinase inhibitors targeting IRAK4 cannot completely block all the biological functions of IRAK4.

[0012] A new research method is to degrade IRAK4 and more thoroughly block all the biological functions of IRAK4. Proteolysis Targeting Chimera (PROTAC) is a technology that uses the ubiquitin-proteasome system to target specific proteins and induce their degradation in cells. The ubiquitin-proteasome system is the main pathway for intracellular protein degradation. Its normal physiological function is mainly responsible for clearing denatured, mutated or harmful proteins in cells. The degradation of more than 80% of proteins in cells depends on the ubiquitin-proteasome system. PROTAC uses the cell's own protein destruction mechanism to remove specific targeted proteins in cells. So far, 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 targeting IRAK4, by degrading IRAK4, removing IRAK4, and more thoroughly blocking all functions of IRAK4, and then fundamentally inhibiting the IRAK4 signaling pathway, so as to better exert anti-inflammatory and immunomodulatory effects. Summary of the invention

[0013] The present invention also provides a compound represented by formula (VII-0) or a pharmaceutically acceptable salt thereof,

[0014]

[0015] in,

[0016] L1 is selected from -(CH2)3- and -O(CH2)3-;

[0017] L2 is selected from -CR5R6- and O;

[0018] R1, R2, R3, R4, R5 and R6 are independently selected from H and halogen;

[0019] Alternatively, R1 and R2, R3 and R4, R5 and R6 optionally form a cyclopropyl group with the carbon atom to which they are attached;

[0020] R7 is selected from

[0021] R8 is selected from C 1-4 Alkyl, C 1-4 Haloalkyl, cyclopropyl and halocyclopropyl;

[0022] Ring A is selected from

[0023] X1 is selected from CH and N;

[0024] X2 is selected from NH, O, S and Se;

[0025] Ring B is selected from C 5-8 Cycloalkyl and 5-8 membered heterocycloalkyl, the C 5-8 Cycloalkyl and 5-8 membered heterocycloalkyl are each independently optionally substituted with 1, 2, 3 or 4 R a replace;

[0026] R a Selected from halogen, OH, NH2, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl and C 1-3 Haloalkoxy;

[0027] Ring C is selected from C 5-8 Cycloalkyl and 5-8 membered heterocycloalkyl, the C 5-8 Cycloalkyl and 5-8 membered heterocycloalkyl are each independently optionally substituted with 1, 2, 3 or 4 R b replace;

[0028] R b Selected from halogen, OH, NH2, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl and C 1-3 Halogenated alkoxy.

[0029] The present invention also provides a compound represented by formula (VII) or a pharmaceutically acceptable salt thereof,

[0030]

[0031] in,

[0032] L1 is selected from -(CH2)3- and -O(CH2)3-;

[0033] L2 is selected from -CR5R6- and O;

[0034] R1, R2, R3, R4, R5 and R6 are independently selected from H and halogen;

[0035] Or R1 and R2, R3 and R4, R5 and R6 optionally form a cyclopropyl group with the carbon atom to which they are attached;

[0036] R7 is selected from

[0037] T1 is selected from CH and N;

[0038] T2 is selected from CH and N;

[0039] T3 is selected from CH and N;

[0040] Ring A is selected from

[0041] X1 is selected from CH and N;

[0042] X2 is selected from NH, O, S and Se.

[0043] In some embodiments of the present invention, R1, R2, R3, R4, R5 and R6 are independently selected from H and F, and other variables are as defined in the present invention.

[0044] In some embodiments of the present invention, the above L1 is selected from Other variables are as defined in the present invention.

[0045] In some embodiments of the present invention, the above L2 is selected from -CH2- and O, and other variables are as defined in the present invention.

[0046] In some embodiments of the present invention, the above Selected from Other variables are as defined herein.

[0047] In some embodiments of the present invention, the above structural unit Selected from Other variables are as defined in the present invention.

[0048] In some embodiments of the present invention, the above R7 is selected from Other variables are as defined in the present invention.

[0049] In some embodiments of the present invention, the ring A is selected from Other variables are as defined in the present invention.

[0050] In some embodiments of the present invention, the ring A is selected from Other variables are as defined in the present invention.

[0051] The present invention also provides compounds represented by formula (VII-1), (VII-2), (VII-3), (VII-4), (VII-5) and (VII-6) or pharmaceutically acceptable salts thereof,

[0052]

[0053]

[0054] wherein X1, X2, R3, R4, T1 and L1 are as defined in the present invention.

[0055] The present invention also provides compounds represented by formula (VII-1R), (VII-1S), (VII-2R), (VII-2S), (VII-3R), (VII-3S), (VII-4R) and (VII-4S) or pharmaceutically acceptable salts thereof,

[0056]

[0057]

[0058]

[0059] wherein X1, X2, R3, R4, T1 and L1 are as defined in the present invention.

[0060] The present invention also provides compounds represented by formula (VII-1RT), (VII-1ST), (VII-2RT), (VII-2ST), (VII-3RT), (VII-3ST), (VII-5T) and (VII-6T) or pharmaceutically acceptable salts thereof,

[0061]

[0062]

[0063] wherein X1, X2, R3, R4, T1 and L1 are as defined in the present invention.

[0064] The present invention also provides a compound represented by the following formula or a pharmaceutically acceptable salt thereof:

[0065]

[0066]

[0067]

[0068]

[0069] wherein X1, X2, R3, R4, T1 and L1 are as defined in the present invention.

[0070] The present invention also provides a compound represented by formula (IV) or a pharmaceutically acceptable salt thereof,

[0071]

[0072] in,

[0073] L1 is selected from

[0074] L2 is selected from -CR5R6-;

[0075] R1, R2, R3, R4, R5 and R6 are independently selected from H and halogen;

[0076] Or R1 and R2, R3 and R4, R5 and R6 optionally form a cyclopropyl group with the carbon atom to which they are attached;

[0077] T1 is selected from CH and N;

[0078] Ring A is selected from

[0079] X1 is selected from CH and N;

[0080] X2 is selected from NH, O, S and Se.

[0081] In some embodiments of the present invention, R1, R2, R3, R4, R5 and R6 in formula (IV) are independently selected from H and F, and other variables are as defined in the present invention.

[0082] In some embodiments of the present invention, L1 in formula (IV) is selected from Other variables are as defined herein.

[0083] In some embodiments of the present invention, L2 in formula (IV) is selected from -CH2-, and other variables are as defined in the present invention.

[0084] In some embodiments of the present invention, the structural unit in formula (IV) Selected from Other variables are as defined herein.

[0085] In some embodiments of the present invention, the ring A in formula (IV) is selected from Other variables are as defined herein.

[0086] In some embodiments of the present invention, the ring A in formula (IV) is selected from Other variables are as defined in the present invention.

[0087] The present invention also provides a compound represented by (IV-1) or a pharmaceutically acceptable salt thereof,

[0088]

[0089] in,

[0090] X1 is selected from CH and N;

[0091] X2 is selected from NH, O, S and Se.

[0092] The present invention also provides compounds represented by formula (III-2) and (IV-2) or pharmaceutically acceptable salts thereof,

[0093]

[0094] wherein X1 is selected from CH and N;

[0095] L1, L2 and T1 are as defined in the present invention.

[0096] The present invention also provides a compound represented by formula (I-2) or (IV-2a) or a pharmaceutically acceptable salt thereof,

[0097]

[0098] wherein T2 is selected from CH and N;

[0099] L1, L2 and T1 are as defined in the present invention.

[0100] The present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

[0101]

[0102] in,

[0103] L1 is selected from

[0104] L2 is selected from -CR5R6-;

[0105] R1, R2, R3, R4, R5 and R6 are independently selected from H and halogen;

[0106] Or R1 and R2, R3 and R4, R5 and R6 optionally form a cyclopropyl group with the carbon atom to which they are attached;

[0107] T1 is selected from CH and N;

[0108] Ring A is selected from

[0109] X1 is selected from CH and N;

[0110] X2 is selected from CH2, NH, O, S and Se.

[0111] In some embodiments of the present invention, R1, R2, R3, R4, R5 and R6 in formula (I) are independently selected from H and F, and other variables are as defined in the present invention.

[0112] In some embodiments of the present invention, L1 in formula (I) is selected from Other variables are as defined herein.

[0113] In some embodiments of the present invention, L2 in formula (I) is selected from -CH2-, and other variables are as defined in the present invention.

[0114] In some embodiments of the present invention, the structural unit in formula (I) Selected from Other variables are as defined herein.

[0115] In some embodiments of the present invention, the ring A in formula (I) is selected from Other variables are as defined herein.

[0116] In some embodiments of the present invention, the ring A in formula (I) is selected from Other variables are as defined herein.

[0117] The present invention also provides compounds represented by formula (I-1) and (I-2) or pharmaceutically acceptable salts thereof,

[0118]

[0119] wherein X1 is selected from CH and N;

[0120] L1, L2 and T1 are as defined in the present invention.

[0121] The present invention provides a compound represented by formula (II) or a pharmaceutically acceptable salt thereof,

[0122]

[0123] in,

[0124] L1 is selected from

[0125] L2 is selected from -CR5R6-;

[0126] R1, R2, R3, R4, R5 and R6 are independently selected from H and halogen;

[0127] Or R1 and R2, R3 and R4, R5 and R6 optionally form a cyclopropyl group with the carbon atom to which they are attached;

[0128] T1 is selected from CH and N;

[0129] ELM is selected from

[0130] In some embodiments of the present invention, R1, R2, R3, R4, R5 and R6 in formula (II) are independently selected from H and F, and other variables are as defined in the present invention.

[0131] In some embodiments of the present invention, L1 in formula (II) is selected from Other variables are as defined in the present invention.

[0132] In some embodiments of the present invention, L2 in formula (II) is selected from -CH2-, and other variables are as defined in the present invention.

[0133] In some embodiments of the present invention, the structural unit in formula (II) Selected from Other variables are as defined in the present invention.

[0134] The present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

[0135]

[0136] in,

[0137] L1 is selected from

[0138] L2 is selected from -CR5R6-;

[0139] R1, R2, R3, R4, R5 and R6 are each independently selected from H or halogen;

[0140] Or R1 and R2, R3 and R4, R5 and R6 optionally form a cyclopropyl group with the carbon atom to which they are attached;

[0141] T1 is selected from CH and N;

[0142] Ring A is selected from

[0143] X1 is selected from CH or N;

[0144] X2 is selected from CH2, NH, O, S or Se.

[0145] In some embodiments of the present invention, R1, R2, R3, R4, R5 and R6 in formula (I) are independently selected from H and F, and other variables are as defined in the present invention.

[0146] In some embodiments of the present invention, L1 in formula (I) is selected from Other variables are as defined herein.

[0147] In some embodiments of the present invention, L2 in formula (I) is selected from -CH2-, and other variables are as defined in the present invention.

[0148] In some embodiments of the present invention, the structural unit in formula (I) Selected from Other variables are as defined herein.

[0149] In some embodiments of the present invention, the ring A in formula (I) is selected from Other variables are as defined herein.

[0150] In some embodiments of the present invention, the ring A in formula (I) is selected from Other variables are as defined herein.

[0151] The present invention also provides a compound represented by formula (III-1), (III-2) or (III-3) or a pharmaceutically acceptable salt thereof,

[0152]

[0153] wherein X1 is selected from CH and N;

[0154] L1, L2 and T1 are as defined in the present invention.

[0155] The present invention also provides a compound represented by formula (I-1), (I-2) or (III-3a) or a pharmaceutically acceptable salt thereof,

[0156]

[0157] wherein X1 is selected from CH and N;

[0158] L1, L2 and T1 are as defined in the present invention.

[0159] Some other solutions of the present invention are obtained by any combination of the above variables.

[0160] The present invention also provides the following compounds or pharmaceutically acceptable salts thereof:

[0161]

[0162]

[0163]

[0164]

[0165] In some embodiments of the present invention, the above compound is selected from:

[0166]

[0167]

[0168]

[0169]

[0170]

[0171] In some embodiments of the present invention, the above compound is selected from:

[0172]

[0173]

[0174]

[0175]

[0176] In some embodiments of the present invention, the above compound is selected from:

[0177]

[0178]

[0179]

[0180]

[0181]

[0182]

[0183]

[0184]

[0185] The present invention also provides the use of the compound of the present invention or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating a disease associated with interleukin-1 receptor associated kinase 4 protein degradation targeting chimera.

[0186] The present invention also provides a method for treating diseases associated with interleukin-1 receptor associated kinase 4 protein degradation targeting chimera, comprising administering a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to a mammal (preferably a human) in need of such treatment.

[0187] In some embodiments of the present invention, the above-mentioned disease associated with the interleukin-1 receptor-associated kinase 4 protein degradation targeted chimera is selected from inflammatory or immune diseases.

[0188] The present invention also provides the following synthetic route:

[0189]

[0190]

[0191] Technical Effects

[0192] The compounds of the present invention exhibit excellent target protein degradation in K562 IRAK4-HiBiT cells. The oral plasma systemic exposure of the compounds of the present invention is high. In rodent mice and non-rodent beagles and cynomolgus monkeys, the pharmacokinetic properties of the compounds of the present invention are excellent. The compounds of the present invention have therapeutic effects on the hind paw volume, hind paw arthritis index score and hind paw weight difference of acute gouty arthritis in rats induced by sodium urate, and are dose-dependent. The compounds of the present invention have an improvement effect on the pathological score, ear thickness increase and spleen weight of the imiquimod-induced mouse psoriasis model, and also have an inhibitory effect on inflammatory factors in the skin of the lesion, indicating that it has a therapeutic effect on the psoriasis model animal, and the therapeutic effect of the high dose (300mpk) is better than that of the medium and low doses (100mpk, 30mpk).

[0193] Definition and Description

[0194] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered to be uncertain or unclear in the absence of a special definition, but should be understood according to its ordinary meaning. When a trade name appears in this article, it is intended to refer to its corresponding commercial product or its active ingredient.

[0195] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0196] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention, prepared from a compound having a specific substituent found in the present invention and a relatively non-toxic acid or base. When 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 a base in a pure solution or a suitable inert solvent. Certain specific compounds of the present invention contain both basic and acidic functional groups and can be converted into either a base or acid addition salt.

[0197] Pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, the preparation method of such salts is: in water or an organic solvent or a mixture of the two, these compounds in free acid or base form are reacted with a stoichiometric amount of an appropriate base or acid to prepare.

[0198] The term "ubiquitin ligase" refers to a family of proteins that promote the transfer of ubiquitin to a specific substrate protein, targeting the substrate protein for degradation. For example, IAP, E3 ubiquitin ligase protein, which causes the attachment of ubiquitin to lysine on the target protein alone or in combination with E2 ubiquitin conjugating enzymes, and then targets a specific protein substrate for degradation by the proteasome. Therefore, the E3 ubiquitin ligase alone or in combination with the E2 ubiquitin conjugating enzyme is responsible for the transfer of ubiquitin to the target protein. In general, ubiquitin ligases involve polyubiquitination, so that the second ubiquitin is attached to the first ubiquitin; the third ubiquitin is attached to the second ubiquitin, and so on. Polyubiquitination marks proteins for degradation by the proteasome. However, there are some ubiquitination events that are limited to monoubiquitination, in which only a single ubiquitin is added to the substrate molecule by the ubiquitin ligase. Monoubiquitinated proteins are not targeted to the proteasome for degradation, but can be changed in their cellular location or function, for example, by binding to other proteins with a domain capable of binding ubiquitin. To complicate matters further, different lysines of ubiquitin can be targeted by E3 to make chains. The most common lysine is Lys48 on the ubiquitin chain. This is the lysine used to make polyubiquitin that is recognized by the proteasome.

[0199] The term "targeting chimera" refers to a bifunctional molecule comprising two small molecule ligands, one with high affinity for a target protein of interest, and a second for recruiting an E3 ligase that ubiquitinates and targets the protein for proteolysis by the 26S proteasome.

[0200] The therapeutic dosage of the compounds of the invention may be determined, for example, based on the specific use of the treatment, the manner in which the compound is administered, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of the compounds of the invention in the pharmaceutical composition may not be fixed, depending on a variety of factors, including dosage, chemical properties (e.g., hydrophobicity), and route of administration.

[0201] The term "treatment" means administering the compound or formulation of the present invention to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0202] (i) inhibiting a disease or disease state, i.e. arresting its development;

[0203] (ii) ameliorating a disease or condition, even if causing regression of the disease or condition.

[0204] The term "therapeutically effective amount" means an amount of a compound of the present invention that (i) treats a particular disease, condition, or disorder, (ii) alleviates, ameliorates, 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 described herein. The amount of a compound of the present invention that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art based on their own knowledge and this disclosure.

[0205] Unless otherwise required in the present invention, throughout the specification and the claims that follow, the word "comprise" and its English variations such as "comprises" and "comprising" should be interpreted as having an open and inclusive meaning, that is, "including but not limited to".

[0206] References to "one embodiment" or "an embodiment" or "in another embodiment" or "in certain embodiments" throughout this specification are intended to include in at least one embodiment the specific referenced elements, structures or features described in connection with that embodiment. Thus, the phrases "in one embodiment" or "in an embodiment" or "in another embodiment" or "in certain embodiments" appearing in different places throughout the specification do not necessarily all refer to the same embodiment. Furthermore, the specific elements, structures or features may be combined in any appropriate manner in one or more embodiments.

[0207] Unless otherwise stated, the term "isomer" is intended to include geometric isomers, cis-trans isomers, stereoisomers, enantiomers, optical isomers, diastereomers and tautomers.

[0208] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All of these isomers and their mixtures are included within the scope of the present invention.

[0209] Unless otherwise indicated, the term "enantiomer" or "optical isomer" refers to stereoisomers that are mirror images of one another.

[0210] Unless otherwise indicated, the term "cis-trans isomers" or "geometric isomers" arises from the inability of a ring carbon atom to rotate freely about double bonds or single bonds forming a ring.

[0211] Unless otherwise indicated, the term "diastereomer" refers to stereoisomers that have two or more chiral centers and that are not mirror images of each other.

[0212] Unless otherwise indicated, "(+)" indicates dextrorotatory, "(-)" indicates levorotatory, and "(±)" indicates racemic.

[0213] Unless otherwise specified, the key is a solid wedge. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond. and straight dashed key To express relative configuration, for example, represents trans-1,4-disubstituted cyclohexane, with represents a cis-1,4-disubstituted cyclohexane.

[0214] Unless otherwise indicated, the terms "enriched in one isomer", "isomerically enriched", "enriched in one enantiomer" or "enantiomerically enriched" mean that the content of one isomer or enantiomer is less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.

[0215] Unless otherwise indicated, the term "isomer excess" or "enantiomeric excess" refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomer or enantiomeric excess (ee value) is 80%.

[0216] Optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by conventional methods known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is usually accomplished by using chromatography, which uses a chiral stationary phase and is optionally combined with a chemical derivatization method (for example, a carbamate is generated from an amine).

[0217] The compounds of the invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125( 125 I) or C-14( 14 C). For another example, deuterium can be used to replace hydrogen to form a deuterated drug. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have the advantages of reducing toxic side effects, increasing drug stability, enhancing efficacy, and extending the biological half-life of drugs. All isotopic composition changes of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.

[0218] When the listed linking group does not indicate its linking direction, its linking direction is arbitrary, for example, The connecting group L is -MW-, in which case -MW- can connect ring A and ring B in the same direction as the reading order from left to right to form You can also connect ring A and ring B in the opposite direction of the reading order from left to right to form Combinations of linkers, substituents, and / or variations thereof are permissible only if such combinations result in stable compounds.

[0219] Unless otherwise specified, when a group has one or more connectable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When the chemical bond connection mode is non-positional and there are H atoms at the connectable sites, when the chemical bonds are connected, the number of H atoms at the site will decrease with the number of connected chemical bonds to become a group with the corresponding valence. The chemical bond connecting the site to other groups can be a straight solid bond. Straight dotted key or wavy line For example, the straight solid bond in -OCH3 indicates that it is connected to other groups through the oxygen atom in the group; The straight dashed bond in the group indicates that the two ends of the nitrogen atom in the group are connected to other groups; The wavy line in the phenyl group indicates that it is connected to other groups through the carbon atoms at positions 1 and 2 in the phenyl group. It means that any connectable site on the naphthalene ring can be connected to other groups through one chemical bond, including at least These 6 connection methods.

[0220] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0221] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include a variant of deuterium and hydrogen, as long as the valence state 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 replaced. Oxygen substitution does not occur on aromatic groups. The term "optionally substituted" means that it may be substituted or not substituted, and unless otherwise specified, the type and number of the substituents may be arbitrary on the basis of chemical achievable.

[0222] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, and each occurrence of R is an independent choice. In addition, combinations of substituents and / or variants thereof are permitted only if such combinations result in stable compounds.

[0223]

[0043] The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.

[0224] Unless otherwise specified, the term “C 1-4"Alkyl" is used to refer to a straight or branched chain saturated hydrocarbon group consisting of 1 to 4 carbon atoms. 1-4 Alkyl groups include C 1-2 , C 1-3 and C 2-3 Alkyl, etc.; it may be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). 1-4 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), and the like.

[0225] Unless otherwise specified, the term “C 1-3 "Alkyl" is used to refer to a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms. 1-3 Alkyl groups include C 1-2 and C 2-3 Alkyl, etc.; it may be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine).

[0226] Unless otherwise specified, the term “C 1-3 "Alkoxy" refers to those alkyl groups containing 1 to 3 carbon atoms which are attached to the rest of the molecule via an oxygen atom. 1-3 Alkoxy includes C 1-2 , C 2-3 , C3 and C2 alkoxy, etc. 1-3 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.

[0227] Unless otherwise specified, the term "haloalkyl" means that one or more hydrogen atoms of an alkyl group are replaced by halogen atoms, specifically including monohaloalkyl, dihaloalkyl and polyhaloalkyl. 1-3 "Haloalkyl" refers to monohaloalkyl and polyhaloalkyl groups containing 1 to 3 carbon atoms. 1-3 Haloalkyl includes C 1-2 , C 2-3 , C3, C2 and C1 haloalkyl, etc. 1-3 Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl and the like.

[0228] Unless otherwise specified, the term "haloalkyl" means that one or more hydrogen atoms of an alkoxy group are replaced by halogen atoms, specifically including monohaloalkoxy, dihaloalkoxy and polyhaloalkoxy. 1-3"Haloalkoxy" refers to monohaloalkoxy and polyhaloalkoxy groups containing 1 to 3 carbon atoms. 1-3 Haloalkoxy includes C 1-2 , C 2-3 , C3, C2 and C1 haloalkoxy, etc. 1-3 Examples of haloalkoxy include, but are not limited to, trifluoromethoxy, trichloromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, pentachloroethoxy, 3-bromopropoxy, and the like.

[0229] Unless otherwise specified, "ring" means substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl. The ring includes a monocyclic ring, and also includes bicyclic or polycyclic ring systems such as spirocyclic rings, cyclic rings and bridged rings. The number of atoms on the ring is usually defined as the number of ring members, for example, "5-7 membered ring" means 5 to 7 atoms arranged around. Unless otherwise specified, the ring optionally contains 1 to 3 heteroatoms. Therefore, "5-7 membered ring" includes, for example, phenyl, pyridyl and piperidyl; on the other hand, the term "5-7 membered heterocycloalkyl" includes pyridyl and piperidyl, but does not include phenyl. The term "ring" also includes a ring system containing at least one ring, each of which "rings" independently meets the above definition.

[0230] Unless otherwise specified, “C 5-8 "Cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of 5 to 8 carbon atoms, including monocyclic and bicyclic systems, wherein the bicyclic system includes spirocyclic, fused and bridged rings. 5-8 Cycloalkyl includes C 5-6 , C 5-7 , C 6-7 , C5, C6, C7, C8 cycloalkyl, etc.; which may be monovalent, divalent or polyvalent. 5-7 Examples of cycloalkyl groups include, but are not limited to, cyclopentyl, cyclohexyl, cycloheptyl, wait.

[0231] Unless otherwise specified, the term "5-8 membered heterocycloalkyl" by itself or in combination with other terms refers to a saturated cyclic group consisting of 5 to 8 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S, N, Si or Se, and the rest are carbon atoms, wherein the carbon atoms may be oxo-substituted (i.e., C(O)), the nitrogen atoms may be optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O)). p, p is 1 or 2). It includes monocyclic and bicyclic systems, wherein the bicyclic system includes spirocyclic, cyclic and bridged rings. In addition, with respect to the "5-8 membered heterocycloalkyl", heteroatoms may occupy the connection position of the heterocycloalkyl with the rest of the molecule. Examples of 5-8 membered heterocycloalkyls include, but are not limited to, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothien-2-yl and tetrahydrothien-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, 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.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, wait.

[0232] The structure of the compound of the present invention can be confirmed by conventional methods known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction (SXRD) is used to collect diffraction intensity data of the cultured single crystal using a Bruker D8 venture diffractometer, the light source is CuKα radiation, and the scanning mode is: After scanning and collecting relevant data, the crystal structure is further analyzed using the direct method (Shelxs97) to confirm the absolute configuration.

[0233] The compounds of the present invention can be prepared by a variety of synthetic 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 substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the embodiments of the present invention.

[0234] Compounds are named according to the conventional nomenclature in the art or using The software names were used, and commercially available compounds were named using the supplier's catalog names.

[0235] The solvent used in the present invention is commercially available.

[0236] The present invention uses the following abbreviations: Ph represents phenyl; Me represents methyl; Et represents ethyl; M represents moles per liter; Boc represents tert-butyloxycarbonyl, which is an amino protecting group; and room temperature represents 20 to 25°C. DETAILED DESCRIPTION

[0237] The present invention is described in detail below by way of examples, but it is not intended to impose any adverse limitations on the present invention. The present invention has been described in detail herein, and specific embodiments thereof are also disclosed therein. It will be apparent to those skilled in the art that various changes and modifications may be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention.

[0238] Reference Example 1

[0239]

[0240] Synthesis route:

[0241]

[0242] Step 1: Synthesis of intermediate BB-1-2

[0243] At room temperature and under nitrogen protection, compound BB-1-1 (40g, 416.29mmol) was dissolved in N,N-dimethylformamide (400mL), followed by the addition of benzyl bromide (74.76g, 437.10mmol, 51.92mL) and cesium carbonate (339.09g, 1.04mol), and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, water (1500mL) was added to the reaction solution, and extracted with ethyl acetate (5×1000mL). The organic phases were combined, washed with 10% brine (1000mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to remove the solvent. The obtained 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] + .

[0244] Step 2: Synthesis of intermediate BB-1-3

[0245] At room temperature and under nitrogen protection, the intermediate BB-1-2 (58g, 311.48mmol) was dissolved in dichloromethane (500mL), then cooled to 0°C, and diethylaminosulfur trifluoride (150.62g, 934.43mmol) was added. The reaction mixture was slowly heated to room temperature and stirred at room temperature for 16 hours. After the reaction was completed, it was cooled to 0°C, methanol (200mL) was slowly added dropwise to the reaction solution, and then water (1000mL) was added, and extracted with ethyl acetate (1000mL×3). The organic phases were combined, washed with saturated sodium bicarbonate solution (1000mL) and saturated brine (1000mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to remove the solvent. The obtained residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0-20 / 1, volume ratio) to obtain a crude product. Add petroleum ether (20 mL) to the obtained crude product, stir at room temperature for 2 hours, filter, rinse the filter cake with petroleum ether (10 mL), collect the filter cake, and dry it in vacuo to obtain intermediate BB-1-3. MS-ESI m / z: 209.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ: 7.40-7.32 (m, 4H), 7.24-7.22 (m, 2H), 6.73 (t, J = 55.2Hz, 1H), 6.51 (t, J = 1.0Hz, 1H), 5.33 (s, 2H).

[0246] Step 3: Synthesis of intermediate BB-1-4

[0247] At room temperature, the intermediate BB-1-3 (26.5 g, 127.28 mmol) was dissolved in methanol (300 mL), followed by the addition of palladium hydroxide / carbon (5 g, purity: 20%) and hydrochloric acid (2M, 25 mL), the reaction mixture was heated to 60 ° C, and stirred for 30 hours under a hydrogen (50 psi) atmosphere. After the reaction was completed, it was cooled to room temperature, filtered to remove insoluble matter, the filter cake was rinsed with methanol (800 mL), and the filtrate was decompressed to remove the solvent to obtain the intermediate BB-1-4. 1 H NMR (400MHz, DMSO_d6) δ: 11.41 (br s, 1H), 7.84 (d, J = 2.0Hz, 1H), 7.00 (t, J = 54.8Hz, 1H), 6.51 (J = 1.2Hz, 1H).

[0248] Step 4: Synthesis of intermediate BB-1-5

[0249] At 0°C, the intermediate BB-1-4 (30g, 254.06mmol) was dissolved in concentrated sulfuric acid (300mL, purity: 98%), and then concentrated nitric acid (68.950g, 711.24mmol, 49.25mL, purity: 65-68%) was added dropwise. The reaction mixture was stirred at 0°C for 10 minutes, and then heated to 115°C and stirred for 16 hours. After the reaction was completed, it was cooled to room temperature, and the reaction solution was slowly poured into ice water (1000mL) and extracted with ethyl acetate (500mL×3). The organic phases were combined, washed with saturated sodium bicarbonate solution (500mL) and saturated brine (500mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to remove the solvent to obtain the intermediate BB-1-5. MS-ESI m / z:164.1[M+H] + . 1 H NMR (400MHz, DMSO_d6) δ: 14.39 (s, 1H), 9.00 (s, 1H), 7.31 (t, J = 53.0Hz, 1H).

[0250] Step 5: Synthesis of intermediate BB-1-6

[0251] At room temperature and under nitrogen protection, cis-4-hydroxycyclohexanecarboxylic acid methyl ester (35g, 221.25mmol) was dissolved in dichloromethane (350mL), followed by the addition of triethylamine (22.39g, 221.25mmol, 30.79mL), cooled to 0°C, and then slowly added methanesulfonyl chloride (31.99g, 279.26mmol, 21.61mL). After the addition was complete, the reaction mixture was stirred at 0°C for 0.5 hours. After the reaction was completed, water (300mL) was slowly added and extracted with dichloromethane (300mL). The organic phase was washed with saturated brine (300mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to remove the solvent to obtain a crude product, which was directly used in the next step.

[0252] At room temperature, the crude product obtained above and intermediate BB-1-5 (13.5 g, 82.78 mmol) were dissolved in N, N-dimethylformamide (300 mL), followed by the addition of potassium carbonate (24 g, 173.65 mmol), and the reaction mixture was heated to 80 ° C and stirred for 16 hours. After the reaction was completed, it was cooled to room temperature, water (100 mL) was added, and extracted with ethyl acetate (40 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to remove the solvent. The obtained residue was separated by column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 3, volume ratio) to obtain intermediate BB-1-6. 1H NMR (400MHz, CDCl3) δ: 8.22 (s, 1H), 7.12 (t, J = 53.6Hz, 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).

[0253] Step 6: Synthesis of intermediate BB-1-7

[0254] At room temperature, wet palladium carbon (1.5 g, purity: 10%) was added to tetrahydrofuran (200 mL), followed by the addition of intermediate BB-1-6 (7.5 g, 24.73 mmol), and the reaction mixture was stirred at room temperature and hydrogen (15 psi) for 15 hours. After the reaction was completed, the insoluble matter was filtered out, the filter cake was rinsed with dichloromethane (50 mL × 2), and the filtrate was decompressed to remove the solvent. The obtained 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] + .

[0255] Step 7: Synthesis of intermediate BB-1

[0256] At room temperature and under nitrogen protection, the intermediate BB-1-7 (4 g, 14.64 mmol) was dissolved in a mixed solvent of tetrahydrofuran (40 mL) and methanol (5 mL), and then a tetrahydrofuran solution of lithium borohydride (2M, 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 completed, it was cooled to room temperature, water (20 mL) was slowly added, and it was extracted with ethyl acetate (100 mL × 5). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to remove the solvent to obtain the intermediate BB-1. 1 H NMR (400MHz, CDCl3) δ: 7.03 (s, 1H), 6.69 (t, J = 54.8Hz, 1H), 3.95 (tt, J = 4.0Hz, 12.0Hz, 1H), 3.51 (d, J = 6. 4Hz,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).

[0257] Reference Example 2

[0258]

[0259] Synthesis route:

[0260]

[0261] Step 1: Synthesis of intermediate BB-2-2

[0262] At room temperature, the 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), and then N,N-diisopropylethylamine (9.45 g, 73.13 mmol, 12.74 mL) was added. The reaction mixture was heated to 60 ° C and stirred for 3 hours. After the reaction was completed, it was cooled to room temperature and directly concentrated under reduced pressure to remove the solvent. The resulting residue was separated by column chromatography (eluent: first using dichloromethane and then using ethyl acetate) to obtain the intermediate BB-2-2. MS–ESI m / z: 289.2 [M+H] + .

[0263] Step 2: Synthesis of intermediate BB-2-3

[0264] At room temperature, the intermediate BB-2-2 (7g, 24.28mmol) and lithium hydroxide monohydrate (5.09g, 121.40mmol) were dissolved in a mixed solvent of methanol (70mL) and water (14mL), and the reaction mixture was heated to 60°C and stirred for 16 hours. After the reaction was completed, it was cooled to room temperature, and the solvent was directly removed by decompression and concentration. Water (150mL) was added to the residue, and the pH was adjusted to 5-6 with 1M dilute hydrochloric acid, and then extracted with ethyl acetate (150mL×6). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to remove the solvent to obtain the intermediate BB-2-3. 1 H NMR(400MHz, DMSO_d6)δ:11.62(s,1H),8.70(d,J=7.6Hz,1H),8.16(s,1H),6.85-6.30(m,1H),5. 09(d,J=75.2Hz,1H),4.73(s,1H),3.76(d,J=42.4Hz,2H),3.60-3.40(m,2H),1.99-1.90(m,2H).

[0265] Step 3: Synthesis of intermediate BB-2-4

[0266] At room temperature, the intermediate BB-2-3 (3.5 g, 11.80 mmol) was dissolved in acetonitrile (40 mL), and then N-methylimidazole (3.39 g, 41.29 mmol) and tetramethylchlorouronium hexafluorophosphate (3.97 g, 14.16 mmol) were added in sequence. The reaction mixture was stirred at room temperature for 1 hour, and then the intermediate BB-1 (3.47 g, 14.16 mmol) was added. The reaction mixture was stirred for 16 hours. After the reaction was completed, the reaction solution was filtered, the filter cake was rinsed with acetonitrile (3 mL), the filter cake was collected, and vacuum dried to obtain the intermediate BB-2-4. MS–ESI m / z: 488.3[M+H] + . 1 H NMR (400MHz, CDCl3) δ: 9.61 (s, 1H), 8.43 (d, J = 5.2Hz, 2H), 8.32 (d, J = 7.6Hz, 1H), 6.7 8(t,J=54.4Hz,1H),6.13(d,J=8.0Hz,1H),5.46(s,1H),4.80(s,1H),4.07(td,J=4.0 Hz,12.0Hz,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).

[0267] Step 4: Synthesis of intermediate BB-2

[0268] At room temperature and under nitrogen protection, the intermediate BB-2-4 (160 mg, 328.20 μmol) was dissolved in dichloromethane (5 mL), and then Dess-Martin oxidant (167.05 mg, 393.85 μmol) was added. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was filtered, the filter cake was rinsed with dichloromethane (2 ml), and the filtrate was dried with a nitrogen stream to obtain the intermediate BB-2, which was directly used in the next step. MS–ESI m / z: 486.3[M+H] + .

[0269] Reference Example 3

[0270]

[0271] Synthesis route:

[0272]

[0273] Step 1: Synthesis of intermediate BB-3-2

[0274] At room temperature and under nitrogen protection, compound BB-3-1 (200 g, 930.04 mmol) was dissolved in chloroform (1000 mL) and ethyl acetate (1000 mL), and copper bromide (415.45 g, 1.86 mol) was then added. The reaction mixture was heated to 90 ° C and stirred for 16 hours. After the reaction was completed, it was cooled to room temperature, filtered, and the filter cake was rinsed with dichloromethane (1.5 L) to obtain a solution of intermediate BB-3-2, which was directly used in the next step.

[0275] Step 2: Synthesis of intermediate BB-3-3

[0276] The solution (3.5L) of the intermediate BB-3-2 obtained above was cooled to 0°C, and then triethylamine (141.17g, 1.40mol, 194.18mL) was slowly added dropwise. After the addition was completed, the reaction mixture was slowly heated to room temperature and stirred for 2 hours. After the reaction was completed, water (2L) was added, the liquid was separated, and the aqueous phase was extracted with dichloromethane (500mL). The organic phases were combined, washed with saturated brine (1L×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to remove the solvent to obtain the intermediate BB-3-3.

[0277] Step 3: Synthesis of intermediate BB-3-4

[0278] At room temperature and under nitrogen protection, the intermediate BB-3-3 (198.1 g, 929.93 mmol) was dissolved in toluene (1.5 L), and then ethoxyformyl methylene triphenylphosphine (388.76 g, 1.12 mol) was added. The reaction mixture was heated to 130 ° C and stirred for 36 hours. After the reaction was completed, it was cooled to room temperature, concentrated under reduced pressure to remove the solvent, and methyl tert-butyl ether (700 mL × 3) was added to the residue, stirred at room temperature for 20 minutes, filtered, and the filter cake was rinsed with methyl tert-butyl ether (100 mL), and the filtrate was collected. The filtrate was decompressed to remove the solvent, and the residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0-70 / 1, volume ratio) to obtain intermediate BB-3-4. 1 H NMR(400MHz, CDCl3)δ:7.72(d,J=2.0Hz,1H),7.64(s,1H),7.41(dd,J=2.0Hz,8.8Hz,1H), 7.36(d,J=8.8Hz,1H), 4.21(q,J=7.0Hz,2H), 3.66(d,J=0.8Hz,2H), 1.30(t,J=7.2Hz,3H).

[0279] Step 4: Synthesis of intermediate BB-3

[0280] At room temperature, the intermediate BB-3-4 (5g, 17.66mmol) was dissolved in N,N-dimethylformamide (50mL), followed by the addition of acrylamide (1.51g, 21.19mmol) and potassium tert-butoxide (2.97g, 26.49mmol), and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was poured into 1M dilute hydrochloric acid (200mL) and extracted with ethyl acetate (100mL×2). The organic phases were combined, washed with 10% brine (150mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to remove the solvent. Ethyl acetate (30mL) was added to the resulting residue, stirred for 10 minutes, filtered, the filter cake was collected, and vacuum dried to obtain the intermediate BB-3. MS-ESI m / z:308.0[M+H] + ,310.1[M+H+2] + .

[0281] Reference Example 4

[0282]

[0283] Synthesis route:

[0284]

[0285] Step 1: Synthesis of intermediate BB-4-1

[0286] At room temperature and under nitrogen 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 added to a mixed solvent of toluene (100 mL) and water (20 mL) in sequence, and the reaction mixture was heated to 110°C and stirred for 16 hours. After the reaction was completed, it was cooled to room temperature, water (100 mL) was added, filtered, the filter cake was rinsed with ethyl acetate (100 mL), the filtrate was combined, the liquid was separated by standing, and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was decompressed to remove the solvent. The resulting residue was separated by column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 5, volume ratio) to obtain intermediate BB-4-1. 1H NMR (400MHz, CDCl3) δ: 7.71 (brs, 1H), 7.62 (s, 1H), 7.37 (d, J = 8.8Hz, 1H), 7.15 (dd, J = 2.0Hz, 8.8Hz ,1H),6.58(s,1H),4.20(q,J=7.2Hz,2H),3.67(q,J=1.2Hz,2H),1.53(s,9H),1.29(t,J=7.2Hz,3H).

[0287] Step 2: Synthesis of intermediate BB-4-2

[0288] At room temperature, the 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), followed by the addition of potassium tert-butoxide (1.8 g, 16.04 mmol), the reaction mixture was stirred at room temperature for 2 hours, potassium tert-butoxide (0.6 g, 5.35 mmol) was added, and the reaction mixture was stirred at room temperature for 0.5 hours. After the reaction was completed, the reaction solution was poured into 1M dilute hydrochloric acid (300 mL), stirred for 10 minutes, filtered, and the filter cake was washed with water (100 mL) and collected. The obtained filter cake was separated by column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 1, volume ratio) to obtain the intermediate BB-4-2. 1 H NMR (400MHz, CDCl3) δ: 8.32 (br s, 1H), 7.72 (br s, 1H), 7.53 (s, 1H), 7.39 (d, J = 8.8Hz, 1H), 7.12 (dd, J = 2.0Hz, 8.8Hz, 1H), 6.71 (br s,1H),3.97(t,J=7.6Hz,1H),2.82-2.63(m,2H),2.39-2.29(m,2H),1.53(s,9H).

[0289] Step 3: Synthesis of hydrochloride salt of intermediate BB-4

[0290] At room temperature, the intermediate BB-4-2 (2.3 g, 6.68 mmol) was dissolved in ethyl acetate (20 mL), and then a hydrochloric acid solution in ethyl acetate (4 M, 40 mL) was added, and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was filtered, the filter cake was rinsed with ethyl acetate (20 mL), the filter cake was collected, and vacuum dried to obtain the hydrochloride of the intermediate BB-4. 1H NMR(400MHz,D2O)δ:7.85(s,1H),7.67(d,J=8.8Hz,1H),7.56(d,J=1.6Hz,1H),7.34(dd,J=2.0Hz,8 .8Hz,1H),4.24(dd,J=5.2Hz,12.4Hz,1H),2.91-2.74(m,2H),2.50-2.37(m,1H),2.35-2.25(m,1H).

[0291] Reference Example 5

[0292]

[0293] Synthesis route:

[0294]

[0295] Step 1: Synthesis of intermediate BB-5-2

[0296] At room temperature and under nitrogen protection, compound BB-5-1 (200 g, 930.04 mmol) was dissolved in chloroform (1 L) and ethyl acetate (1 L), and copper bromide (415.45 g, 1.86 mol) was then added. The reaction mixture was heated to 90 ° C and stirred for 12 hours. After the reaction was completed, it was cooled to room temperature, filtered, and the filter cake was rinsed with dichloromethane (300 mL × 2). The filtrate was collected to obtain a solution of intermediate BB-5-2, which was directly used in the next step.

[0297] Step 2: Synthesis of intermediate BB-5-3

[0298] The solution of the 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 completed, the reaction mixture was slowly heated to room temperature and stirred for 1 hour. After the reaction was completed, water (600 mL) was added, the liquid was extracted, the organic phase was washed with saturated brine (1 L), dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to remove half of the solvent, toluene (500 mL) was added, and the residual low-boiling solvent was removed under reduced pressure to obtain a toluene solution of the intermediate BB-5-3.

[0299] Step 3: Synthesis of intermediate BB-5-4

[0300] At room temperature and under nitrogen protection, toluene (2L) was added to one-half of the toluene solution of the intermediate BB-5-3, followed by ethoxyformylmethylenetriphenylphosphine (161.90g, 464.73mmol), and the reaction mixture was heated to 130°C and stirred for 20 hours. After the reaction was completed, it was cooled to room temperature and the two batches were combined for treatment. The solvent was removed by concentration under reduced pressure, and methyl tert-butyl ether (800mL) was added to the residue, stirred at room temperature for 30 minutes, filtered, and the filter cake was rinsed with methyl tert-butyl ether (100mL×2). The filtrate was decompressed to remove the solvent, and the residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 100 / 1-10 / 1, volume ratio) to obtain intermediate BB-5-4. 1 H NMR (400MHz, CDCl3) δ: 7.94 (s, 1H), 7.88 (s, 1H), 7.56 (d, J = 8.4Hz, 1H), 7.44 (d, J=8.4Hz, 1H), 4.11 (q, J=7.2Hz, 2H), 3.79 (s, 2H), 1.19 (t, J=7.2Hz, 3H).

[0301] Step 4: Synthesis of intermediate BB-5

[0302] At room temperature, the intermediate BB-5-4 (5.00 g, 17.66 mmol) was dissolved in N, N-dimethylformamide (50 mL), followed by the addition of acrylamide (1.51 g, 21.19 mmol) and potassium tert-butoxide (2.97 g, 26.49 mmol), and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, it was poured into 1M dilute hydrochloric acid (100 mL) and extracted with ethyl acetate (30 mL × 2). The organic phases were combined, washed with 10% brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to remove the solvent. The obtained residue was separated by column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 1, volume ratio) to obtain the intermediate BB-5. MS-ESI m / z: 308.0 [M + H] + ,310.0[M+H+2] + . 1 H NMR(400MHz, DMSO_d6)δ:10.91(s,1H),7.94(s,1H),7.89(d,J=1.6Hz,1H),7.56(d,J=8.4Hz,1H),7.42(dd,J=1.6Hz,8.0Hz,1 H),4.15(dd,J=4.8Hz,12.0Hz,1H),2.80-2.68(m,1H),2.58(dt,J=4.0Hz,17.2Hz,1H),2.38-2.25(m,1H),2.15-2.05(m,1H).

[0303] Reference Example 6

[0304]

[0305] Synthesis route:

[0306]

[0307] Step 1: Synthesis of intermediate BB-6-1

[0308] At room temperature and under nitrogen protection, the intermediate BB-5-4 (10g, 35.32mmol), tert-butyl carbamate (4.97g, 42.39mmol), potassium phosphate (22.49g, 105.96mmol), tris(dibenzylideneacetone)dipalladium (646.88mg, 706.42μmol) and 2-di-tert-butylphosphine-2',4',6'-triisopropylbiphenyl (599.95mg, 1.41mmol) were dissolved in toluene (100mL) and water (20mL). The reaction mixture was heated to 110°C and stirred for 12 hours. After the reaction was completed, it was cooled to room temperature, water (100mL) was added, and it was extracted with ethyl acetate (70mL×3). The organic phases were combined, washed with saturated brine (70mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to remove the solvent. Add n-heptane (70 mL) to the residue, stir at room temperature for 10 minutes, filter, and collect the filter cake. Add n-heptane (50 mL) to the filter cake again, stir at room temperature for 10 minutes, filter, rinse the filter cake with n-heptane (10 mL × 3), collect the filter cake, and vacuum dry to obtain intermediate BB-6-1. MS-ESI m / z: 264.2 [M-55] + . 1 H NMR (400MHz, CDCl3) δ: 7.77 (s, 1H), 7.56 (s, 1H), 7.44 (d, J = 8.4Hz, 1H), 7.06 (dd, J = 1.6Hz, 8. 4Hz,1H),6.58(s,1H),4.19(q,J=7.0Hz,2H),3.66(s,2H),1.54(s,9H),1.27(t,J=7.2Hz,3H).

[0309] Step 2: Synthesis of intermediate BB-6-2

[0310] At room temperature, the 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), followed by the addition of potassium tert-butylate (6.20 g, 55.24 mmol), and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, 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 × 3). The organic phases were combined, washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to remove the solvent. Methyl tert-butyl ether (70 mL) was added to the resulting residue, stirred at room temperature for 0.5 hours, filtered, the filter cake was rinsed with methyl tert-butyl ether (10 mL × 3), the filter cake was collected, and vacuum dried to obtain the intermediate BB-6-2. 1 H NMR(400MHz, DMSO_d6)δ:10.88(s,1H),9.47(s,1H),7.78(s,2H),7.43(d,J=8.8Hz,1H),7.23(dd,J=1.4Hz,8.6Hz,1H),4 .07(dd,J=4.8Hz,12.0Hz,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).

[0311] Step 3: Synthesis of the hydrochloride salt of intermediate BB-6

[0312] At room temperature, the intermediate BB-6-2 (6.6 g, 19.17 mmol) was dissolved in dichloromethane (20 mL), and then a hydrochloric acid ethyl acetate solution (4 M, 150 mL) was added, and the reaction mixture was stirred at room temperature for 4 hours. After the reaction was completed, the solvent was removed under reduced pressure to obtain the hydrochloride salt of the intermediate BB-6. 1 H NMR(400MHz, DMSO_d6)δ:10.92(s,1H),10.06(s,2H),7.98(s,1H),7.66(d,J=8.4Hz,1H),7.57(d,J=1.6Hz,1H),7.21(dd,J=1 .8Hz,8.2Hz,1H),4.16(dd,J=4.8Hz,12.0Hz,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).

[0313] Reference Example 7

[0314]

[0315] Synthesis route:

[0316]

[0317] Step 1: Synthesis of intermediate BB-7-2

[0318] At room temperature and under nitrogen protection, the intermediate BB-7-1 (11.39 g, 52.97 mmol) was dissolved in chloroform (100 mL) and ethyl acetate (100 mL), and then copper bromide (23.66 g, 105.93 mmol) was added. The reaction mixture was heated to 110 ° C and stirred for 16 hours. After the reaction was completed, it was cooled to room temperature, filtered, and the filtrate was decompressed to remove the solvent, and then water (20 mL) was added to the residue and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to remove the solvent. The obtained residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0–100 / 1, volume ratio) to obtain the intermediate BB-7-2. 1 H NMR (400MHz, CDCl3) δ: 12.39 (s, 1H), 7.81 (dd, J = 1.2Hz, 8.0Hz, 1H), 7.76 (dd, J = 1.2Hz, 8.0Hz, 1H), 6.88 (t, J = 8.0Hz, 1H), 4.47 (s, 2H).

[0319] Step 2: Synthesis of intermediate BB-7-3

[0320] At 0°C, the 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 completed, the solvent was directly concentrated under reduced pressure to obtain the crude intermediate BB-7-3, which was directly used in the next step.

[0321] Step 3: Synthesis of intermediate BB-7-4

[0322] At room temperature and under nitrogen protection, the crude product of intermediate BB-7-3 (3.93 g, 18.45 mmol) was dissolved in toluene (80 mL), followed by the addition of ethoxyformyl methylene triphenylphosphine (9.64 g, 27.67 mmol), and the reaction mixture was heated to 130 ° C and stirred for 36 hours. After the reaction was completed, it 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 × 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to remove the solvent. The resulting residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0–100 / 1, volume ratio) to obtain intermediate BB-7-4. 1 H NMR (400MHz, CDCl3) δ: 7.72 (s, 1H), 7.52 (dd, J = 0.8Hz, 7.6Hz, 1H), 7.48 (dd, J = 0.8Hz, 7.6Hz, 1 H),7.15(t,J=7.6Hz,1H),4.20(q,J=7.2Hz,2H),3.70(d,J=0.8Hz,2H),1.28(t,J=7.2Hz,3H).

[0323] Step 4: Synthesis of intermediate BB-7

[0324] At 0℃ and nitrogen protection, the intermediate BB-7-4 (4.77g, 16.85mmol) was dissolved in N,N-dimethylformamide (30mL), followed by the addition of acrylamide (1.20g, 16.85mmol) and potassium tert-butoxide (1.89g, 16.85mmol), and the reaction mixture was stirred at 0℃ for 1 hour. After the reaction was completed, it was poured into a saturated ammonium chloride solution (50mL), and a large amount of white solid was produced. The solid was filtered and collected. The solid was slurried with methanol (20mL×2) at room temperature, filtered, the filter cake was collected, and vacuum dried to obtain the intermediate BB-7. 1 H NMR(400MHz, DMSO_d6)δ:10.92(s,1H),8.04(s,1H),7.62(dd,J=0.8Hz,7.6Hz,1H),7.56(d,J=7.6Hz,1H),7.21(t,J=7 .6Hz,1H),4.17(dd,J=4.8Hz,12.0Hz,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).

[0325] Reference Example 8

[0326]

[0327] Synthesis route:

[0328]

[0329] Step 1: Synthesis of intermediate BB-8-1

[0330] At room temperature and under nitrogen protection, the intermediate BB-7-4 (2g, 7.06mmol) was dissolved in toluene (50mL) and water (5mL), followed by the addition of tris(dibenzylideneacetone)dipalladium (647mg, 706.42μmol), 2-di-tert-butylphosphine-2',4',6'-triisopropylbiphenyl (450mg, 1.06mmol), potassium phosphate (6g, 28.26mmol) and tert-butyl carbamate (1.66g, 14.13mmol), and the reaction mixture was heated to 100°C and stirred for 16 hours. After the reaction was completed, it was cooled to room temperature, poured into water (20mL), and extracted with ethyl acetate (10mL×3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to remove the solvent. The resulting residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 0-10 / 1, volume ratio) to obtain intermediate BB-8-1. 1 H NMR(400MHz, 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=6.8Hz,2H),3.69(d,J=0.8Hz,2H),1.56(s,9H),1.28(t,J=7.2Hz,3H).

[0331] Step 2: Synthesis of the hydrochloride salt of intermediate BB-8

[0332] At room temperature, compound BB-8-1 (1.32 g, 4.13 mmol) was dissolved in ethyl acetate (3 mL), and then a hydrochloric acid solution in ethyl acetate (4 M, 15 mL) was added, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solvent was directly concentrated under reduced pressure to obtain the hydrochloride salt of intermediate BB-8.

[0333] Reference Example 9

[0334]

[0335] Synthesis route:

[0336]

[0337] Step 1: Synthesis of intermediate BB-9-2

[0338] 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-chloroacetoacetate (18.45 g, 112.07 mmol), and the internal temperature was controlled at 0-5°C. After the addition was completed, the reaction mixture was warmed to room temperature and stirred for 12 hours. Four batches were combined for processing. After the reaction was completed, the reaction solution was slowly poured into ice water (3 L) under stirring, stirred at room temperature for 10 minutes, filtered, the filter 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] + .

[0339] Step 2: Synthesis of intermediate BB-9-3

[0340] 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 combined for treatment. After the reaction was completed, it was cooled to room temperature, filtered, and the filter cake was washed with water (500 mL). The filter cake was collected and vacuum dried to obtain intermediate BB-9-3. 1 H NMR (400MHz, DMSO_d6) δ: 8.50 (d, J = 9.2Hz, 1H), 8.26 (d, J = 2.4Hz, 1H), 7.84 (s, 1H), 7.76 (d, J = 1.6Hz, 2H), 7.63 (dd, J = 2.0Hz, 8.8Hz, 1H), 3.50 (s, 2H).

[0341] Step 3: Synthesis of intermediate BB-9-4

[0342] At room temperature, the intermediate BB-9-3 (33.16 g, 101.37 mmol) was dissolved in ethanol (300 mL), and then concentrated sulfuric acid (27.19 g, 271.68 mmol, 14.78 mL, purity: 98%) was slowly added dropwise, and the reaction mixture was heated to 80 ° C and stirred for 12 hours. Two batches were combined for treatment. After the reaction was completed, it 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 × 2). The organic phases were combined and washed with aqueous sodium hydroxide solution (2M, 300 mL) and saturated brine (500 mL) in turn, dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to remove the solvent to obtain the intermediate BB-9-4. 1H NMR (400MHz, CDCl3) δ: 8.13-8.06 (m, 2H), 7.78 (s, 1H), 7.69-7.60 (m, 3H), 4.23 (q, J = 7.2Hz, 2H), 4.03 (s, 2H), 1.27 (t, J = 7.2Hz, 3H).

[0343] Step 4: Synthesis of intermediate BB-9-5

[0344] At room temperature and under nitrogen protection, the intermediate BB-9-4 (1g, 3.00mmol), tris(dibenzylideneacetone)dipalladium (275mg, 300.14μmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (191.18mg, 450.21mmol), potassium phosphate (2.55g, 12.01mmol) and tert-butyl carbamate (527.41mg, 4.50mmol) were dissolved in a mixed solvent of toluene (50mL) and water (5mL), and the reaction mixture was heated to 100°C and stirred for 12 hours. After the reaction was completed, it was cooled to room temperature, the reaction solution was poured into water (20mL), and extracted with ethyl acetate (10mL×3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to remove the solvent. The resulting residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 0–10 / 1, volume ratio) to obtain intermediate BB-9-5. MS-ESI m / z: 392.2 [M+Na] + . 1 H NMR (400MHz, CDCl3) δ: 8.14 (d, J = 9.2Hz, 1H), 8.12 (br s,1H),7.74(s,1H),7.67(d,J=9.2Hz,1H),7.62(d,J=8.8Hz,1H),7.45(dd,J=2.2Hz,9.0Hz,1H),6.64(br s,1H),4.22(q,J=7.0Hz,2H),4.04(s,2H),1.57(s,9H),1.27(t,J=7.2Hz,3H).

[0345] Step 5: Synthesis of intermediate BB-9-6

[0346] At 0℃ and nitrogen protection, the intermediate BB-9-5 (1.13g, 2.74mmol, purity: 89.57%) and acrylamide (234mg, 3.29mmol) were dissolved in N,N-dimethylformamide (10mL), and potassium tert-butoxide (368.93mg, 3.29mmol) was added, and the reaction mixture was stirred at 0℃ for 1 hour. After the reaction was completed, the reaction solution was slowly poured into a saturated aqueous ammonium chloride solution (30mL) and extracted with ethyl acetate (15mL×3). The organic phases were combined, washed with saturated brine (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to remove the solvent. Methanol (10mL) was added to the obtained residue, stirred at room temperature for 0.5 hours, filtered, the filter cake was collected, and vacuum dried to obtain the intermediate BB-9-6. MS-ESI m / z:417.0[M+Na-100] + . 1 H NMR(400MHz,CDCl3)δ:8.13(br s,1H),8.08(br s,1H),7.90(d,J=8.8Hz,1H),7.71(d,J=9.2Hz,1H),7.67-7.62(m,2H),7.48(dd,J=2.4Hz,8.8Hz,1H),6.67(br s,1H),4.47(dd,J=5.4Hz,8.6Hz,1H),2.85-2.71(m,2H),2.55-2.40(m,2H),1.57(s,9H).

[0347] Step 6: Synthesis of the hydrochloride salt of intermediate BB-9

[0348] At room temperature, the intermediate BB-9-6 (421 mg, 1.07 mmol) was dissolved in a hydrochloric acid / dioxane solution (4M, 20 mL), and the reaction mixture was stirred at room temperature for 12 hours. After the reaction was completed, the reaction solution was cooled and poured into a saturated ammonium chloride solution (100 mL), extracted with ethyl acetate (10 mL × 3), the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and dried. The residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1, volume ratio) to obtain the hydrochloride of the intermediate BB-9. MS-ESI m / z: 294.9 [M + H] + . 1H NMR(400MHz,DMSO_d6)δ:10.95(br s,1H),8.23(d,J=9.2Hz,1H),8.04(s,1H),7.88-7.81(m,3H),7.48-7.42(m,1H),4.66(dd,J=4 .4Hz,12.4Hz,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).

[0349] Reference Example 10

[0350]

[0351] Synthesis route:

[0352]

[0353] Synthesis of intermediate BB-10

[0354] At room temperature and under nitrogen protection, the intermediate BB-9-4 (1g, 3.00mmol) was dissolved in N,N-dimethylformamide (10mL), and then acrylamide (256mg, 3.60mmol) and potassium tert-butoxide (404.15mg, 3.60mmol) were added in sequence. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was slowly poured into a saturated aqueous ammonium chloride solution (100mL), stirred at room temperature for 1 hour, filtered, and the filter cake was collected. Methanol (20mL) was added to the obtained filter cake, stirred at room temperature for 0.5 hours, filtered, the filter cake was collected, and vacuum dried to obtain the intermediate BB-10. MS-ESI m / z: 357.7[M+H] + ,359.7[M+H+2] + . 1 HNMR (400MHz, CDCl3) δ: 8.15 (d, J = 2.0Hz, 1H), 8.06 (br s,1H),7.87(d,J=8.8Hz,1H),7.72-7.65(m,4H),4.47(dd,J=5.2Hz,9.6Hz,1H),2.89-2.74(m,2H),2.58-2.41(m,2H).

[0355] Reference Example 11

[0356]

[0357] Synthesis route:

[0358]

[0359] Step 1: Synthesis of intermediate BB-11-2

[0360] At room temperature and under nitrogen protection, triphenyl phosphite (149.14g, 480.67mmol) was dissolved in dichloromethane (1.3L), cooled to -70℃, and liquid bromine (83.80g, 524.37mmol, 27.03mL) was added dropwise. After the addition was completed, triethylamine (57.48g, 568.07mmol, 79.07mL) and compound BB-11-1 (77g, 436.98mmol) in dichloromethane (200mL) were added dropwise. After the addition was completed, the reaction mixture was slowly heated to room temperature and stirred for 15 hours. After the reaction was completed, the reaction solution was slowly poured into a saturated sodium sulfite aqueous solution (1.5L), stirred for 10 minutes, and extracted with dichloromethane (1L). The organic phase was washed with saturated brine (1L), dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to remove the solvent. The obtained residue was separated by column chromatography (eluent: petroleum ether) to obtain intermediate BB-11-2.

[0361] Step 2: Synthesis of intermediate BB-11-3

[0362] At room temperature and under nitrogen protection, the intermediate BB-11-2 (87g, 363.85mmol) was dissolved in toluene (1L), cooled to 0℃, and 2,3-dichloro-5,6-dicyanobenzoquinone (90.86g, 400.24mmol) was slowly added in batches. The reaction mixture was slowly heated to room temperature and stirred for 15 hours. After the reaction was completed, a saturated aqueous sodium sulfite solution (2L) was added dropwise, stirred for 10 minutes, and then a 1N aqueous sodium hydroxide solution (1L) was added, and extracted with ethyl acetate (500mL×3). The organic phases were combined, washed with saturated brine (1L), dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to remove the solvent. The obtained residue was added with petroleum ether (500ml), stirred for 10 minutes, filtered, and the filter cake was rinsed with petroleum ether (50mL×2). The filtrate was collected and concentrated to remove the solvent under reduced pressure. The obtained residue was separated by column chromatography (eluent: petroleum ether) to obtain the intermediate BB-11-3. 1 H NMR (400MHz, CDCl3) δ: 8.12 (d, J = 9.2Hz, 1H), 7.68 (d, J = 8.4Hz, 1H), 7.60 (d, J = 7.6Hz, 1H), 7.26-7.20 (m, 2H), 7.11 (d, J = 2.4Hz, 1H), 3.92 (s, 3H).

[0363] Step 3: Synthesis of intermediate BB-11-4

[0364] At room temperature and under nitrogen protection, the 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 warmed to room temperature and stirred for 3 hours. After the reaction was completed, 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 filtrate was decompressed to remove the solvent to obtain the intermediate BB-11-4. 1 H NMR (400MHz, CDCl3) δ: 8.15 (d, J=98.8Hz, 1H), 7.65-7.59 (m, 2H), 7.25 (t, J=7 .8Hz,1H),7.19(dd,J=2.4Hz,9.2Hz,1H),7.14(d,J=2.4Hz,1H),5.03(s,1H).

[0365] Step 4: Synthesis of intermediate BB-11-5

[0366] At room temperature, the intermediate BB-11-4 (20 g, 89.66 mmol) was dissolved in methanesulfonic acid (200 mL), and ethyl 4-chloroacetoacetate (22.14 g, 134.49 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 15 hours. After the reaction was completed, the reaction solution was poured into ice water (1 L), stirred at room temperature for 10 minutes, filtered, and the filter cake was rinsed with water (200 mL × 3), and the filter cake was collected and vacuum dried to obtain the intermediate BB-11-5. 1 H NMR(400MHz, DMSO_d6)δ:8.58(d,J=9.2Hz,1H),8.49(d,J=9.2Hz,1H),8.02(d,J=7.2H z,1H),7.74(d,J=9.2Hz,1H),7.65(dd,J=7.6Hz,8.4Hz,1H),6.93(s,1H),5.41(s,2H).

[0367] Step 5: Synthesis of intermediate BB-11-6

[0368] At room temperature, the intermediate BB-11-5 (29g, 89.63mmol) was added to an aqueous solution of sodium hydroxide (2M, 300mL), the reaction mixture was heated to 80°C, and the reaction mixture was stirred for 3 hours. After the reaction was completed, it was cooled to room temperature, water (200mL) was added, the pH was adjusted to 4 with 6M hydrochloric acid, and extracted with ethyl acetate (300mL×3). The organic phases were combined, washed with saturated brine (200mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to remove the solvent. Methyl tert-butyl ether (50mL) was added to the obtained residue, stirred at room temperature for 10 minutes, filtered, the filter cake was rinsed with methyl tert-butyl ether (10mL×2), the filter cake was collected, and vacuum dried to obtain the intermediate BB-11-6. MS-ESI m / z:305.0[M+H] + ,306.9[M+H+2] + . 1 H NMR(400MHz,DMSO_d6)δ:12.68(br s,1H),8.24(d,J=8.4Hz,1H),8.12(t,J=4.6Hz,2H),7.96(d,J=9.2Hz,1H),7.90(d,J=7.6Hz,1H),7.54(t,J=7.8Hz,1H),4.09(s,2H).

[0369] Step 6: Synthesis of intermediate BB-11-7

[0370] At room temperature, the intermediate BB-11-6 (18g, 58.99mmol) was dissolved in ethanol (180mL), and concentrated sulfuric acid (5.31g, 53.09mmol, 2.89mL, purity: 98%) was added. The reaction mixture was heated to 80°C and stirred for 15 hours. After the reaction was completed, it was cooled to room temperature, concentrated under reduced pressure to remove the solvent, and ethyl acetate (300mL) and saturated sodium bicarbonate aqueous solution (500mL) were added to the residue to extract the liquid. The organic phase was washed with saturated brine (300mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to remove the solvent. Petroleum ether (50mL) was added to the residue, stirred at room temperature for 10 minutes, filtered, and the filter cake was rinsed with petroleum ether (20mL×2), and the filter cake was collected and dried in vacuo to obtain the intermediate BB-11-7. 1 H NMR(400MHz, CDCl3)δ:8.22(t,J=8.4Hz,2H),7.84-7.78(m,2H),7.75(d,J=9.2Hz,1H),7.41( dd,J=7.6Hz,8.4Hz,1H),4.23(q,J=7.0Hz,2H),4.06(d,J=0.8Hz,2H),1.26(t,J=7.2Hz,3H).

[0371] Step 7: Synthesis of intermediate BB-11-8

[0372] At room temperature and under nitrogen protection, the intermediate BB-11-7 (5g, 15.01mmol), tris(dibenzylideneacetone)dipalladium (961.96mg, 1.05mmol), 2-di-tert-butylphosphine-2',4',6'-triisopropylbiphenyl (892.16mg, 2.10mmol), potassium phosphate (12.74g, 60.03mmol) and tert-butyl carbamate (2.64g, 22.51mmol) were dissolved in a mixed solvent of toluene (50mL) and water (10mL), and the reaction mixture was heated to 100°C and stirred for 15 hours. After the reaction was completed, it was cooled to room temperature, filtered, the filter cake was rinsed with ethyl acetate (30mL×3), the filtrate was washed with saturated brine (100mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to remove the solvent. Methyl tert-butyl ether (50 mL) was added to the residue, stirred at room temperature for 10 minutes, filtered, the filter cake was rinsed with methyl tert-butyl ether (10 mL×2), the filter cake was collected and dried in vacuo to obtain intermediate BB-11-8.

[0373] Step 8: Synthesis of intermediate BB-11-9

[0374] At room temperature and under nitrogen protection, the intermediate BB-11-8 (4.2g, 11.37mmol) and acrylamide (888.93mg, 12.51mmol) were dissolved in N,N-dimethylformamide (40mL), cooled to 0°C, potassium tert-butoxide (2.55g, 22.74mmol) dissolved in N,N-dimethylformamide (10mL) was added dropwise, the reaction mixture was warmed to room temperature, and stirred for 2 hours. After the reaction was completed, the reaction solution was poured into 0.2M hydrochloric acid (200mL) and extracted with ethyl acetate (100mL×3). The organic phases were combined, washed with saturated brine (100mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to remove the solvent. Dichloromethane (20mL) was added to the obtained residue, stirred at room temperature for 10 minutes, filtered, the filter cake was rinsed with dichloromethane (10mL), the filter cake was collected, and vacuum dried to obtain the intermediate BB-11-9. 1 H NMR(400MHz, DMSO_d6)δ:10.94(s,1H),9.28(s,1H),8.05-7.92(m,3H),7.79(d,J=9.6Hz,1H),7.58-7.47(m,2H),4.6 8(dd,J=4.4Hz,12.0Hz,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).

[0375] Step 9: Synthesis of the hydrochloride salt of intermediate BB-11

[0376] At room temperature, the intermediate BB-11-9 (1.3 g, 3.30 mmol) was dissolved in ethyl acetate (5 mL), and then a hydrochloric acid solution in ethyl acetate (4 M, 50 mL) was added, and the reaction mixture was stirred at room temperature for 3 hours. After the reaction was completed, the solvent was removed by concentration under reduced pressure to obtain the hydrochloride salt of the intermediate BB-11.

[0377] Reference Example 12

[0378]

[0379] Synthesis route:

[0380]

[0381] Synthesis of intermediate BB-12

[0382] At room temperature and under nitrogen protection, 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), followed by the addition of potassium tert-butoxide (370.47 mg, 3.30 mmol), and the reaction mixture was stirred at room temperature for 0.5 hours. After the reaction was completed, the reaction solution was poured into 0.1 M hydrochloric acid (10 mL) and extracted with dichloromethane (5 mL × 2). The organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to remove the solvent. Dichloromethane (5 mL) was added to the residue, stirred at room temperature for 1 hour, filtered, and the filter cake was rinsed with dichloromethane (1 mL). The filter cake was collected and dried in vacuo to obtain intermediate BB-12. MS-ESI m / z: 358.1 [M + H] + ,360.1[M+H+2] + .

[0383] Reference Example 13

[0384]

[0385] Synthesis route:

[0386]

[0387] Step 1: Synthesis of intermediate BB-13-2

[0388] At room temperature and under nitrogen protection, compound BB-13-1 (150g, 632.67mmol) was dissolved in dichloromethane (3L), and then acetyl chloride (49.66g, 632.67mmol, 45.15mL) was added. The reaction mixture was cooled to 5-15°C, and aluminum chloride (177.16g, 1.33mol) was added in batches. The reaction mixture was warmed to room temperature and stirred for 4 hours. Aluminum chloride (29.53g, 221.43mmol) was added and the reaction was continued to stir at room temperature for 12 hours. After the reaction was completed, the reaction solution was slowly poured into ice water (3L), extracted and separated, and the aqueous phase was extracted again with dichloromethane (2L×2). The organic phases were combined, washed with saturated brine (6L×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to remove the solvent to obtain intermediate BB-13-2. MS-ESI m / z:265.1[M+H] + ,267.1[M+H+2] + .

[0389] Step 2: Synthesis of intermediate BB-13-3

[0390] At room temperature and under nitrogen protection, the intermediate BB-13-2 (200g, 754.43mmol) and dimethyl carbonate (271.83g, 3.02mol, 254.04mL) were dissolved in tetrahydrofuran (2L), cooled to 0°C, and potassium tert-butoxide (507.93g, 4.53mol) was slowly added. The reaction mixture was heated to 70°C and stirred for 12 hours. After the reaction was completed, it was cooled to room temperature, concentrated under reduced pressure to remove the solvent, ice water (4L) was added to the residue, and pH was adjusted to 2-3 with 6M hydrochloric acid. A large amount of solid precipitated, filtered, and the filter cake was rinsed with water (1L) and methyl tert-butyl ether (1L) in turn. The filter cake was collected and dried in vacuo to obtain the intermediate BB-13-3. MS-ESI m / z: 291.0[M+H] + ,293.0[M+H+2] + . 1 H NMR(400MHz, DMSO_d6)δ:9.18(d,J=9.2Hz,1H),8.30(d,J=1.2Hz,1H),8.16(d,J=8.8Hz,1H),7.79(d,J=7.6Hz,1H),7.56(d,J=8.8Hz,1H),5.83(s,1H).

[0391] Step 3: Synthesis of intermediate BB-13-4

[0392] At room temperature, the intermediate BB-13-3 (200g, 687.06mmol), sodium acetate (309.99g, 3.78mol) and hydroxylamine hydrochloride (262.59g, 3.78mol) were dissolved in ethanol (2L), and the reaction mixture was heated to 80°C and stirred for 12 hours. After the reaction was completed, it was cooled to room temperature, poured into water (2L), concentrated under reduced pressure to remove the solvent, adjusted pH to 2-3 with 2M hydrochloric acid, and extracted with ethyl acetate / tetrahydrofuran = 1 / 1 (2L×3, volume ratio). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to remove the solvent. Methyl tert-butyl ether (600mL) was added to the residue, stirred at room temperature for 1 hour, filtered, the filter cake was collected, and vacuum dried to obtain the intermediate BB-13-4. MS-ESI m / z: 306.0[M+H] + ,308.0[M+H+2] + .

[0393] Step 4: Synthesis of intermediate BB-13-5

[0394] At room temperature, concentrated sulfuric acid (33.38 g, 333.49 mmol, 18.14 mL, purity: 98%) was dissolved in ethanol (1.3 L), and intermediate BB-13-4 (135 g, 373.32 mmol, purity: 84.65%) was added. The reaction mixture was heated to 75 ° C and stirred for 16 hours. After the reaction was completed, it was cooled to room temperature and concentrated under reduced pressure to remove the solvent. Ethanol (600 mL) was added to the residue, stirred at room temperature for 5 minutes, filtered, and the filter cake was rinsed with ethanol (100 mL × 2), the filter cake was collected, and vacuum dried to obtain intermediate BB-13-5. MS-ESI m / z: 334.1 [M + H] + ,336.0[M+H+2] + . 1 H NMR(400MHz, DMSO_d6)δ:8.47(d,J=1.6Hz,1H),8.19(d,J=9.2Hz,1H),8.08(d,J=8.8Hz,1H),8.00(d,J =9.2Hz, 1H), 7.89 (dd, J = 2.0Hz, 8.8Hz, 1H), 4.51 (s, 2H), 4.14 (q, J = 7.2Hz, 2H), 1.16 (t, J = 7.2Hz, 3H).

[0395] Step 5: Synthesis of intermediate BB-13-6

[0396] At room temperature and under nitrogen protection, the intermediate BB-13-5 (15 g, 44.89 mmol), tris(dibenzylideneacetone)dipalladium (1.44 g, 1.57 mmol), 2-di-tert-butylphosphine-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 added to a mixed solvent of toluene (150 mL) and water (30 mL) in sequence. The reaction mixture was heated to 100 ° C and stirred for 12 hours. After the reaction was completed, it was cooled to room temperature, water (100 mL) and ethyl acetate (150 mL) were added, and the liquid was extracted and separated. The aqueous phase was extracted again with ethyl acetate (200 mL × 3). The organic phases were combined, washed with saturated brine (200 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to remove the solvent. The obtained residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 20 / 1-1 / 1, volume ratio) to obtain intermediate BB-13-6. MS-ESI m / z: 371.2 [M+H] + . 1 H NMR(400MHz, CDCl3)δ:8.20(br s,1H),8.03(d,J=8.8Hz,1H),7.90(d,J=9.2Hz,1H),7.67(d,J=9.2Hz,1H),7.53(dd,J=2.0Hz,8 .8Hz,1H),6.75(s,1H),4.31(s,2H),4.21(q,J=7.2Hz,2H),1.57(s,9H),1.20(t,J=7.2Hz,3H).

[0397] Step 6: Synthesis of intermediate BB-13-7

[0398] At room temperature and under nitrogen protection, the intermediate BB-13-6 (7.3g, 19.71mmol) and acrylamide (1.54g, 21.68mmol) were dissolved in tetrahydrofuran (70mL), cooled to 0°C, potassium tert-butoxide (2.43g, 21.68mmol) was added, the reaction mixture was warmed to room temperature, and stirred for 1 hour. After the reaction was completed, the reaction solution was poured into 0.1M hydrochloric acid (30mL) and extracted with ethyl acetate (80mL×3). The organic phases were combined, washed with saturated brine (50mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to remove the solvent. Dichloromethane (5mL) was added to the obtained residue, stirred at room temperature for 5 minutes, filtered, the filter cake was rinsed with dichloromethane (3mL), the filter cake was collected, and vacuum dried to obtain the intermediate BB-13-7. MS-ESI m / z:396.2[M+H] + . 1H NMR(400MHz, DMSO_d6)δ:11.12(s,1H),9.66(s,1H),8.36(s,1H),8.13(d,J=8.8Hz,1H),8.07(d,J=8.8Hz,1H),7.85(d,J=9.2Hz,1H),7.68(dd, J=2.0Hz,8.8Hz,1H),5.00(dd,J=4.8Hz,11.6Hz,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).

[0399] Step 7: Synthesis of the hydrochloride salt of intermediate BB-13

[0400] At room temperature, the intermediate BB-13-7 (1 g, 2.53 mmol) was dissolved in ethyl acetate (5 mL), and then a hydrochloric acid solution in ethyl acetate (4 M, 20 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the filter cake was filtered and washed with ethyl acetate (3 mL × 3). The filter cake was collected and dried in vacuo to obtain the hydrochloride salt of the intermediate BB-13. MS-ESI m / z: 295.9 [M + H] + .

[0401] Reference Example 14

[0402]

[0403] Synthesis route:

[0404]

[0405] Synthesis of intermediate BB-14

[0406] At room temperature and under nitrogen protection, the intermediate BB-13-5 (3g, 8.98mmol) and acrylamide (701.92mg, 9.88mmol) were dissolved in tetrahydrofuran (70mL), cooled to 0°C, potassium tert-butylate (1.21g, 10.77mmol) was added in batches, the reaction mixture was warmed to room temperature, and stirred for 1 hour. After the reaction was completed, the reaction solution was poured into 1M hydrochloric acid (20mL) and extracted with ethyl acetate (40mL×3). The organic phases were combined, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to remove the solvent. Methyl tert-butyl ether (20mL) was added to the obtained residue, stirred at room temperature for 10 minutes, filtered, the filter cake was rinsed with methyl tert-butyl ether (5mL×2), the filter 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(400MHz, DMSO_d6)δ:11.14(s,1H),8.47(d,J=2.0Hz,1H),8.24-8.17(m,2H),8.01(d,J=9.2Hz,1H),7.85(dd ,J=2.0Hz,8.8Hz,1H),5.06(dd,J=4.8Hz,11.6Hz,1H),2.89-2.78(m,1H),2.70-2.56(m,2H),2.44-2.34(m,1H).

[0407] Reference Example 15

[0408]

[0409] Synthesis route:

[0410]

[0411] Step 1: Synthesis of intermediate BB-15-2

[0412] At room temperature and under nitrogen protection, triphenyl phosphite (193.69g, 624.25mmol) was dissolved in dichloromethane (1L), cooled to -70℃, and liquid bromine (108.83g, 681.00mmol, 35.11mL) was added dropwise. After the addition was completed, triethylamine (74.65g, 737.75mmol, 102.69mL) and compound BB-15-1 (100g, 567.50mmol) dissolved in dichloromethane (500mL) were added dropwise. After the addition was completed, the reaction mixture was slowly heated to room temperature and stirred for 15 hours. After the reaction was completed, it was poured into a saturated sodium sulfite aqueous solution (700mL), stirred for 10 minutes, and extracted with dichloromethane (800mL). The organic phase was washed with saturated brine (800mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to remove the solvent. The obtained residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 20 / 1-7 / 1, volume ratio) to obtain intermediate BB-15-2. 1 H NMR(400MHz, DMSO_d6)δ:7.33(d,J=8.0Hz,1H),6.84-6.75(m,2H),6.33(t,J=4.8Hz,1H),3.75(s,3H),2.76(t,J=8.0Hz,2H),2.32-2.25(m,2H).

[0413] Step 2: Synthesis of intermediate BB-15-3

[0414] At room temperature and under nitrogen protection, the 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 completed, it was cooled to 0-10 ° C, and a saturated aqueous sodium sulfite solution (1 L) and a 1M aqueous sodium hydroxide solution (1 L) were added dropwise, filtered, and the filter cake was rinsed with ethyl acetate (300 mL × 3). The filter cake was discarded and the filtrate was extracted with ethyl acetate (500 mL × 3). The organic phases were combined, washed with saturated brine (500 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to remove the solvent. The obtained residue was separated by column chromatography (eluent: petroleum ether) to obtain the intermediate BB-15-3. MS-ESI m / z:237.1[M+H] + ,239.1[M+H+2] + . 1 H NMR (400MHz, CDCl3) δ: 8.05 (d, J = 9.2Hz, 1H), 7.60 (d, J = 8.0Hz, 1H), 7.53 (d, J = 7.2Hz, 1H), 7.22-7.13 (m, 2H), 7.04 (s, 1H), 3.85 (s, 3H).

[0415] Step 3: Synthesis of intermediate BB-15-4

[0416] At room temperature and under nitrogen protection, acetic anhydride (21.53 g, 210.89 mmol, 19.75 mL) was placed in dichloromethane (400 mL), cooled to -60 ° C, and a boron trifluoride ether solution (63.68 g, 210.89 mmol, 55.38 mL, purity: 47%) was added dropwise. After stirring at -60 ° C for 10 minutes, a solution of intermediate BB-15-3 (25 g, 105.44 mmol) dissolved in dichloromethane (250 mL) was added dropwise. The reaction mixture was slowly warmed to room temperature and stirred for 12 hours. After the reaction was completed, ice water (200 mL) was added and extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to remove the solvent. The obtained residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 100 / 1-20 / 1) to obtain intermediate BB-15-4. MS-ESI m / z: 279.0 [M+H] + ,281.0[M+H+2] + . 1H NMR (400MHz, CDCl3) δ: 8.34 (d, J = 9.2Hz, 1H), 7.72 (d, J = 8.4Hz, 1H), 7.67 (dd, J = 0.8Hz, 7. 2Hz, 1H), 7.38 (d, J = 9.2Hz, 1H), 7.31 (dd, J = 7.6Hz, 8.8Hz, 1H), 4.01 (s, 3H), 2.65 (s, 3H).

[0417] Step 4: Synthesis of intermediate BB-15-5

[0418] At room temperature and under nitrogen protection, the 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, and stirred at 0 ° C for 1 hour. After the reaction was completed, the reaction solution was poured into ice water (300 mL) and extracted with dichloromethane (100 mL × 3). The organic phases were combined, washed with saturated brine (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to remove the solvent to obtain the intermediate BB-15-5. 1 H NMR (400MHz, CDCl3) δ: 13.05 (s, 1H), 8.41 (d, J = 9.2Hz, 1H), 8.04 (d, J = 8.8Hz, 1H), 7.70 (d d, J=0.8Hz, 7.6Hz, 1H), 7.40 (dd, J=7.6Hz, 8.4Hz, 1H), 7.25 (d, J=9.6Hz, 1H), 2.85 (s, 3H).

[0419] Step 5: Synthesis of intermediate BB-15-6

[0420] At room temperature and under nitrogen protection, the intermediate BB-15-5 (13g, 49.04mmol) and dimethyl carbonate (17.67g, 196.15mmol, 16.51mL) were dissolved in tetrahydrofuran (130mL), cooled to 0-10°C, potassium tert-butoxide (33.02g, 294.23mmol) was added in batches, the reaction mixture was heated to 70°C, and stirred for 12 hours. After the reaction was completed, it was cooled to room temperature, concentrated under reduced pressure to remove the solvent, ice water (200mL) was added to the residue, and extracted with methyl tert-butyl ether (70mL×2). The aqueous phase was adjusted to pH=2 with 6M hydrochloric acid, and a large amount of solid precipitated. It was filtered, the filter cake was washed with water (30mL×2), the filter cake was collected, and vacuum dried to obtain the intermediate BB-15-6. MS-ESI m / z:291.0[M+H] + ,293.0[M+H+2] + . 1H NMR(400MHz,DMSO_d6)δ:13.28(br s,1H),9.38(t,J=7.2Hz,1H),8.43(dd,J=6.8Hz,9.2Hz,1H),7.96(t,J=7.2Hz,1H),7.71-7.65(m,1H),7.63-7.56(m,1H),5.92-5.87(m,1H).

[0421] Step 6: Synthesis of intermediate BB-15-7

[0422] At room temperature, the intermediate BB-15-6 (22g, 75.58mmol), sodium acetate (43.40g, 529.03mmol) and hydroxylamine hydrochloride (36.76g, 529.03mmol) were dissolved in ethanol (400mL), the reaction mixture was heated to 80°C, and stirred for 12 hours. After the reaction was completed, it was cooled to room temperature and concentrated under reduced pressure to remove the solvent. Water (100mL) and methyl tert-butyl ether (50mL) were added to the residue, stirred at room temperature for 0.5 hours, filtered, and the filter cake was rinsed with methyl tert-butyl ether (20mL×3), the filter cake was collected, and vacuum dried to obtain the intermediate BB-15-7. MS-ESI m / z:306.0[M+H] + ,308.0[M+H+2] + . 1 H NMR (400MHz, DMSO_d6) δ: 8.40 (d, J = 9.2Hz, 1H), 8.27 (d, J = 8.4Hz, 1H), 8.05 (d, J = 9.2Hz, 1H), 7.96 (d, J = 7.6Hz, 1H), 7.62 (t, J = 8.0Hz, 1H), 4.25 (s, 2H).

[0423] Step 7: Synthesis of intermediate BB-15-8

[0424] At room temperature, the intermediate BB-15-7 (15g, 49.00mmol) was dissolved in ethanol (300mL), and concentrated sulfuric acid (1.29g, 12.87mmol, 0.7mL, purity: 98%) was added. The reaction mixture was heated to 80°C and stirred for 12 hours. After cooling to room temperature, concentrated sulfuric acid (4mL, purity: 98%) was added, and the reaction mixture was heated to 80°C and stirred for 3 hours. After the reaction was completed, it was cooled to room temperature and concentrated under reduced pressure to remove the solvent. A 0-10°C saturated sodium bicarbonate solution (100mL) was added to the residue, and extracted with ethyl acetate (70mL×3). The organic phases were combined, washed with saturated brine (70mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to remove the solvent to obtain the intermediate BB-15-8. MS-ESI m / z:334.0[M+H]+ ,336.0[M+H+2] + . 1 H NMR (400MHz, CDCl3) δ: 8.50 (d, J = 9.6Hz, 1H), 8.10 (d, J = 8.4Hz, 1H), 7.88 (dd, J = 0.8Hz, 7.6Hz, 1H), 7. 81(d,J=9.2Hz,1H),7.52(t,J=8.0Hz,1H),4.34(s,2H),4.22(q,J=7.2Hz,2H),1.21(t,J=7.2Hz,3H).

[0425] Step 8: Synthesis of intermediate BB-15-9

[0426] At room temperature and under nitrogen protection, the intermediate BB-15-8 (9.5 g, 28.43 mmol), tris(dibenzylideneacetone)dipalladium (1.30 g, 1.42 mmol), 2-di-tert-butylphosphine-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 added to a mixed solvent of toluene (90 mL) and water (30 mL) in sequence. The reaction mixture was heated to 100 ° C and stirred for 12 hours. After the reaction was completed, it was cooled to room temperature, water (200 mL) was added, and it was extracted with ethyl acetate (150 mL × 3). The organic phases were combined, washed with saturated brine (200 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to remove the solvent. The obtained 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(400MHz,DMSO_d6)δ:8.48(s,1H),8.28(d,J=9.2Hz,1H),7.95-7.87(m,2H),7.75 –7.60(m,2H),4.50(s,2H),4.14(q,J=7.2Hz,2H),1.50(s,9H),1.16(t,J=7.2Hz,3H).

[0427] Step 9: Synthesis of intermediate BB-15-10

[0428] At room temperature and under nitrogen protection, the intermediate BB-15-9 (2.5 g, 6.75 mmol) was dissolved in tetrahydrofuran (35 mL), followed by the addition of acrylamide (575.69 mg, 8.10 mmol) and potassium tert-butoxide (1.14 g, 10.12 mmol), and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was poured into 1M hydrochloric acid (30 mL) and extracted with ethyl acetate (45 mL × 3). The organic phases were combined, washed with saturated brine (40 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to remove the solvent. The resulting residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1-1 / 1, volume ratio) to obtain the intermediate BB-15-10. MS-ESI m / z: 396.2 [M + H] + . 1 H NMR(400MHz, DMSO_d6)δ:11.14(s,1H),9.46(s,1H),8.29(d,J=9.6Hz,1H),8.04(br d,J=7.6Hz,1H),7.93(d,J=9.2Hz,1H),7.75-7.59(m,2H),5.07(dd,J=4.8Hz,11 .2Hz,1H),2.97-2.79(m,1H),2.71-2.56(m,2H),2.43-2.31(m,1H),1.50(s,9H).

[0429] Step 10: Synthesis of the hydrochloride salt of intermediate BB-15

[0430] At room temperature, the intermediate BB-15-10 (1.5 g, 3.79 mmol) was added to a solution of hydrochloric acid in ethyl acetate (4 M, 15 mL), and the reaction mixture was stirred at room temperature for 12 hours. After the reaction was completed, the filter cake was filtered, and the filter cake was rinsed with ethyl acetate (30 mL). The filter cake was collected and dried in vacuo to obtain the hydrochloride salt of the intermediate BB-15. MS-ESI m / z: 296.1 [M+H] + . 1 H NMR(400MHz, DMSO_d6)δ:11.14(s,1H),8.34(d,J=9.6Hz,1H),8.04-7.94(m,2H),7.65(t,J=8.0Hz,1H),7.4 6(d,J=7.6Hz,1H),5.06(dd,J=4.8Hz,11.6Hz,1H),2.95-2.78(m,1H),2.69-2.56(m,2H),2.42-2.31(m,1H).

[0431] Example 1

[0432]

[0433] Synthesis route:

[0434]

[0435] Step 1: Synthesis of compound WX001-2

[0436] At room temperature, compound WX001-1 (6 g, 32.21 mmol) was dissolved in tetrahydrofuran (60 mL), followed by the addition of ethyl bromoacetate (6.46 g, 38.66 mmol, 4.28 mL) and triethylamine (3.91 g, 38.66 mmol, 5.38 mL), and the reaction mixture was stirred at room temperature for 4 hours. After the reaction was completed, water (200 mL) was added to the reaction solution, and it was extracted with ethyl acetate (150 mL × 2). The organic phases were combined, washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to remove the solvent. Petroleum ether (50 mL) was added to the obtained residue, stirred at room temperature for 5 minutes, filtered, the filter cake was rinsed with petroleum ether (30 mL), the filter cake was collected, and vacuum dried to obtain compound WX001-2.

[0437] Step 2: Synthesis of the hydrochloride salt of compound WX001-3

[0438] At room temperature, compound WX001-2 (5.5 g, 20.20 mmol) was dissolved in methanol (100 mL), followed by the addition of water (20 mL) and lithium hydroxide monohydrate (1.69 g, 40.39 mmol), and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the solvent was directly removed under reduced pressure, the pH was adjusted to 5-6 with 1M dilute hydrochloric acid, and the solvent was removed under reduced pressure. The residue was separated by a reverse 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 of compound WX001-3. MS–ESI m / z: 245.2 [M+H] + .

[0439] Step 3: Synthesis of compound WX001-4

[0440] At room temperature, the hydrochloride 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), followed by the addition of 2-(7-azabenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate (880.46 mg, 2.32 mmol), the reaction mixture was stirred at room temperature for 1 hour, the hydrochloride of compound BB-4 (0.5 g, 1.78 mmol) was added, and the reaction mixture was stirred at room temperature for 4 hours. After the reaction was completed, methyl tert-butyl ether (20 mL) was added, stirred for 5 minutes, filtered, and the filter 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 liquids were separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to remove the solvent and dried in vacuo to obtain a crude compound WX001-4, which was used directly in the next step without further purification. MS–ESI m / z: 471.3 [M+H] + .

[0441] Step 4: Synthesis of the hydrochloride salt of compound WX001-5

[0442] At room temperature, the crude product of compound WX001-4 (0.8 g, 1.70 mmol) was dissolved in dichloromethane (5 mL), and then a hydrochloric acid ethyl acetate solution (4 M, 20 mL) was added, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was filtered, the filter cake was rinsed with ethyl acetate (20 mL), the filter cake was collected, and vacuum dried to obtain the hydrochloride of compound WX001-5. 1 H NMR(400MHz,D2O)δ:7.78(s,1H),7.64(d,J=2.0Hz,1H),7.57(d,J=8.8Hz,1H),7.30(dd,J=2.0Hz,8.8Hz,1H),4.21( dd,J=5.2Hz,12.4Hz,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).

[0443] Step 5: Synthesis of the hydrochloride salt of compound WX001

[0444] At room temperature and under nitrogen protection, the intermediate BB-2 (75 mg, 154.48 μmol) was dissolved in N, N-dimethylformamide (2 mL), followed by the addition of the 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), the reaction mixture was stirred at room temperature for 2 hours, and then sodium triacetoxyborohydride (130.97 mg, 617.94 μmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, water (5 mL) and ethyl acetate (10 mL) were added to the reaction solution, and the liquid was separated, and the aqueous phase was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to remove the solvent. The obtained residue was separated by preparative HPLC (chromatographic column: Phenomenex luna C18 80*40mm*3μm; mobile phase: water (0.04% hydrochloric acid)-acetonitrile; acetonitrile%: 20%-38%, 7min) to obtain the hydrochloride salt of the target compound WX001. MS–ESI m / z: 840.5[M+H] + . 1 H NMR(400MHz,DMSO_d6)δ:10.94(s,1H),10.71(br s,1H),9.51(d,J=6.4Hz,1H),8.79(d,J=7.6Hz,1H),8.50–8.37(m,1H),8.26(d,J=5.2Hz,1H),7.93 (s,1H),7.91(s,1H),7.58(d,J=8.8Hz,1H),7.47(d,J=8.8Hz,1H),7.28–6.95(m,1H),6.90–6.42(m, 1H),5.18(d,J=79.2Hz,1H),4.77(d,J=20.0Hz,1H),4.34–4.09(m,6H),3.40–3.20(m,4H),3.06(s,2 H),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).

[0445] Example 2

[0446]

[0447] Synthesis route:

[0448]

[0449] Step 1: Synthesis of compound WX002-1

[0450] At room temperature, the hydrochloride 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), followed by the addition of 2-(7-azabenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate (812.61 mg, 2.14 mmol), the reaction mixture was stirred at room temperature for 1 hour, and then the hydrochloride of intermediate BB-6 (522.08 mg, 1.33 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was filtered, the filter cake was rinsed with N, N-dimethylformamide (5 mL), and then with methyl tert-butyl ether (20 mL), the filter cake was collected, and vacuum dried to obtain compound WX002-1. MS–ESI m / z: 471.3[M+H] + . 1 H NMR(400MHz, DMSO_d6)δ:10.88(s,1H),9.93(s,1H),8.06(d,J=1.2Hz,1H),7.8 3(s,1H),7.50(d,J=8.4Hz,1H),7.38(dd,J=1.2Hz,8.4Hz,1H),4.10(dd,J=4.8 Hz,12.0Hz,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).

[0451] Step 2: Synthesis of the hydrochloride salt of compound WX002-2

[0452] At room temperature, compound WX002-1 (0.8 g, 1.70 mmol) was dissolved in ethyl acetate (10 mL), and then a hydrochloric acid solution in ethyl acetate (4 M, 40 mL) was added. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was filtered, the filter cake was rinsed with ethyl acetate (5 mL), the filter cake was collected, and vacuum dried to obtain the hydrochloride salt of compound WX002-2. MS–ESI m / z: 371.3 [M+H] + . 1H NMR(400MHz,D2O)δ:7.75(d,J=1.6Hz,1H),7.66(s,1H),7.43(d,J=8.4Hz,1H),7.19(dd,J=1.2Hz,8.4Hz,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).

[0453] Step 3: Synthesis of the hydrochloride salt of compound WX002

[0454] At room temperature and under nitrogen protection, the intermediate BB-2 (75 mg, 154.48 μmol) was dissolved in N, N-dimethylformamide (2 mL), followed by the addition of the 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), the reaction mixture was stirred at room temperature for 2 hours, and then sodium triacetoxyborohydride (172.88 mg, 815.68 μmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, water (5 mL) and ethyl acetate (10 mL) were added to the reaction solution, and the liquid was separated, and the aqueous phase was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to remove the solvent. The residue was separated by preparative HPLC (chromatographic column: Phenomenex luna C18 80*40mm*3μm; mobile phase: water (0.04% hydrochloric acid)-acetonitrile; acetonitrile%: 15%-35%, 7min) to obtain the hydrochloride salt of the target compound WX002. MS–ESIm / z: 840.3[M+H] + . 1H NMR(400MHz, DMSO_d6)δ:10.96(s,1H),10.90(s,1H),9.51(d,J=6.0Hz,1H),8.79(d,J=7.6Hz,1H),8.50–8.37(m ,1H),8.26(d,J=5.6Hz,1H),8.06(s,1H),7.88(s,1H),7.56(d,J=8.4Hz,1H),7.38(d,J=8.0Hz,1H),7.28–6.95(m ,1H),6.90–6.41(m,1H),5.18(d,J=78.4Hz,1H),4.77(d,J=19.6Hz,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).

[0455] Example 3

[0456]

[0457] Synthesis route:

[0458]

[0459] Step 1: Synthesis of compound WX003-2

[0460] At room temperature and under nitrogen protection, 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, and then bromopropyne (5.32 g, 44.72 mmol) was added. The reaction mixture was slowly warmed to room temperature and stirred for 16 hours. After the reaction was completed, the reaction solution was slowly poured into ice water (100 mL) and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to remove the solvent. The obtained residue was separated by column chromatography (eluent: ethyl acetate / petroleum ether = 0 / 1–1 / 1, volume ratio) to obtain compound WX003-2. 1H NMR (400MHz, CDCl3) δ: 4.20 (d, J = 2.4Hz, 2H), 3.81-3.67 (m, 3H), 3.15-3.06 (m, 2H), 2.42(t,J=2.4Hz,1H),1.90-1.81(m,2H),1.59-1.49(m,2H),1.46(s,9H).

[0461] Step 2: Synthesis of compound WX003-3

[0462] At room temperature and under nitrogen protection, the intermediate BB-7 (1g, 3.25mmol) was dissolved in N,N-dimethylformamide (20mL), followed by the addition of compound WX003-2 (1.16g, 4.87mmol), cesium carbonate (3.17g, 9.74mmol), cuprous iodide (124mg, 694μmol) and dichlorobis(triphenylphosphine)palladium (456mg, 649μmol), the reaction mixture was heated to 80°C and stirred for 5 hours. After the reaction was completed, it was cooled to room temperature, poured into 1M hydrochloric acid (80mL), and extracted with ethyl acetate (10mL×3). The organic phases were combined, washed with saturated brine (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to remove the solvent. The residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1–1 / 1, volume ratio) to obtain compound WX003-3. 1 HNMR(400MHz, CDCl3)δ:7.98(s,1H),7.64(s,1H),7.49(dd,J=1.2Hz,7.6Hz,1H),7.44(dd,J=0.8Hz,7.6Hz,1H),7.24(t,J=7.6Hz,1H),4.53(s,2H),4 .00(t,J=7.6Hz,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).

[0463] Step 3: Synthesis of the hydrochloride salt of compound WX003-4

[0464] At room temperature, compound WX003-3 (990 mg, 2.12 mmol) was dissolved in ethyl acetate (5 mL), and then a solution of hydrochloric acid in ethyl acetate (4 M, 33 mL) was added, and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to a residual volume of 1-2 mL, filtered, and the filter cake was washed with ethyl acetate (12 mL × 2), and the filter cake was collected and dried in vacuo to obtain the hydrochloride of compound WX003-4.1 H NMR(400MHz, DMSO_d6)δ:10.92(s,1H),8.89-8.80(m,2H),8.00(s,1H),7.65(dd,J=0.8Hz, 7.6Hz,1H),7.43(d,J=7.6Hz,1H),7.26(t,J=7.6Hz,1H),4.55(s,2H),4.17(dd,J=4.8Hz,12 .4Hz,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),2.6 3-2.54(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).

[0465] Step 4: Synthesis of the hydrochloride salt of compound WX003

[0466] At room temperature, the intermediate BB-2 (149 mg, 307 μmol), the hydrochloride of compound WX003-4 (123.6 mg, 307 μmol) and potassium acetate (60 mg, 614 μmol) were added to a mixed solvent of tetrahydrofuran (5 mL) and N,N-dimethylformamide (1 mL) in sequence. The reaction mixture was stirred at room temperature for 0.5 hours, and then sodium triacetoxyborohydride (130 mg, 614 μmol) was added. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, water (1 mL) was added and the solvent was removed by concentration under reduced pressure. The obtained residue was separated by preparative HPLC (chromatographic column: Boston Green ODS 150*30mm*5μm; mobile phase: water (0.04% hydrochloric acid)-acetonitrile; acetonitrile%: 22%-42%, 10min) to obtain the hydrochloride of the target compound WX003. MS-ESI m / z:836.3[M+H] + . 1H NMR(400MHz, DMSO_d6)δ:10.93(s,1H),9.61-9.45(m,2H),8.80(d,J=7.6Hz,1H),8.41(d,J=2.8Hz,1H),8.27(dd,J=1.6Hz,5.6Hz, 1H),8.01(d,J=2.4Hz,1H),7.67(d,J=7.6Hz,1H),7.44(d,J=7.2Hz,1H),7.32-6.96(m,2H),6.92-6.43(m,1H),5.18(d,J=78.4Hz,1 H),4.77(d,J=20.0Hz,1H),4.58(d,J=2.8Hz,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),3.1 4-2.92(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).

[0467] Example 4

[0468]

[0469] Synthesis route:

[0470]

[0471] Step 1: Synthesis of compound WX004-1

[0472] At room temperature and under nitrogen protection, the 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 dichloride (387.25 mg, 551.72 μmol) and cesium carbonate (3.60 g, 11.03 mmol) were dissolved in N, N-dimethylformamide (15 mL), and the reaction mixture was heated to 80 ° C and stirred for 3 hours. After the reaction was completed, it was cooled to room temperature, poured into water (50 mL), and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to remove the solvent. The obtained 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 (400MHz, CDCl3) δ: 7.63 (s, 1H), 7.61 (s, 1H), 7.44 (d, J = 8.0Hz, 1H), 7.35 (dd, J = 1.2Hz, 8.0Hz, 1H), 4.45 (s, 2H), 3.99 (dd, J = 6.8Hz, 8. 8Hz,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).

[0473] Step 2: Synthesis of trifluoroacetate salt of compound WX004-2

[0474] 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, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the solvent was directly removed by concentration under reduced pressure. The obtained residue was separated by preparative HPLC (chromatographic column: Phenomenex luna C18 100*40mm*5μm; mobile phase: water (0.05% trifluoroacetic acid)-acetonitrile; acetonitrile%: 1%-45%, 8min) to obtain the trifluoroacetate salt of compound WX004-2. 1 H NMR(400MHz,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=8.0Hz,1H),7.32(dd,J=1.2Hz,8.4Hz,1H),4.47(s,2H),4.16(dd,J=4.8Hz,12.0Hz,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,17.2Hz,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).

[0475] Step 3: Synthesis of the hydrochloride salt of compound WX004

[0476] At room temperature, the intermediate BB-2 (70 mg, 144.19 μmol) and the trifluoroacetate 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), followed by the addition of potassium acetate (42.45 mg, 432.56 μmol). The reaction mixture was stirred at room temperature for 2 hours, and then sodium triacetyl borohydride (91.68 mg, 432.56 μmol) was added. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was directly separated by preparative HPLC (chromatographic column: Phenomenex Luna C18 80*40mm*3μm; mobile phase: water (0.04% hydrochloric acid)-acetonitrile; acetonitrile%: 28%-48%, 7min) to obtain the hydrochloride of the target compound WX004. MS-ESI m / z:836.3[M+H] + . 1 H NMR(400MHz,DMSO_d6)δ:10.92(s,1H),9.73(br s,1H),9.51(d,J=6.4Hz,1H),8.81-8.77(m,1H),8.40(d,J=4.0Hz,1H),8.26(d,J=5.6Hz,1H),8.02(s,1H),7.72( s,1H),7.61(d,J=8.0Hz,1H),7.33(d,J=8.4Hz,1H),7.27-6.95(m1H),6.91-6.43(m,1H),5.18(d,J=78.4Hz,1H),4 .76(d,J=19.6Hz,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).

[0477] Example 5

[0478]

[0479] Synthesis route:

[0480]

[0481] Step 1: Synthesis of compound WX005-1

[0482] At room temperature and under nitrogen protection, intermediate BB-3 (1g, 2.23mmol), compound WX003-2 (799.42mg, 3.34mmol), cuprous iodide (84.83mg, 445.40μmol), bis(triphenylphosphine)palladium dichloride (312.63mg, 445.40μmol) and cesium carbonate (2.90g, 8.91mmol) were added to N,N-dimethylformamide (20mL), and the reaction mixture was heated to 80°C and stirred for 5 hours. After the reaction was completed, it was cooled to room temperature, poured into water (100mL), and extracted with ethyl acetate (50mL×2). The organic phases were combined, washed with saturated brine (100mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The obtained 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] + .

[0483] Step 2: Synthesis of trifluoroacetate salt of compound WX005-2

[0484] 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 completed, the solvent was removed by concentration under reduced pressure. The obtained residue was separated by preparative HPLC (chromatographic column: Phenomenex Luna C18 100*40mm*5μm; mobile phase: water (0.05% trifluoroacetic acid)-acetonitrile; acetonitrile%: 1%-45%, 8min) to obtain the trifluoroacetate salt of compound WX005-2. 1 H NMR(400MHz,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=8.4Hz,1H),7.39(dd,J=1.6Hz,8.4Hz,1H),4.46(s,2H),4.15(dd,J= 4.8Hz,12.0Hz,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).

[0485] Step 3: Synthesis of the hydrochloride salt of compound WX005

[0486] At room temperature, the intermediate BB-2 (70 mg, 144.19 μmol) and the trifluoroacetate 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), followed by the addition of potassium acetate (42.45 mg, 432.56 μmol). The reaction mixture was stirred at room temperature for 2 hours, and then sodium triacetyl borohydride (91.68 mg, 432.56 μmol) was added. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the solvent was directly removed by concentration under reduced pressure. The residue was separated by preparative HPLC (chromatographic column: Phenomenex Luna 80*30mm*3μm; mobile phase: water (0.04% hydrochloric acid)-acetonitrile; acetonitrile%: 20%-35%, 8min) to obtain the hydrochloride of the target compound WX005. MS-ESI m / z:836.3[M+H] + . 1 H NMR(400MHz,DMSO_d6)δ:10.90(s,1H),9.68(s,1H),9.50(d,J=6.4Hz,1H),8.78(d,J=7.6Hz,1H),8.39(d,J=4.0Hz,1H),8.25(d,J =5.6Hz,1H),7.98(s,1H),7.76-7.72(m,1H),7.60(d,J=8.4Hz,1H),7.39(dd,J=1.6Hz,8.8Hz,1H),7.27-6.95(m,1H),6.90-6.43( m,1H),5.17(d,J=79.6Hz,1H),4.76(d,J=20.0Hz,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).

[0487] Example 6

[0488]

[0489] Synthesis route:

[0490]

[0491] Step 1: Synthesis of compound WX006-1

[0492] At room temperature, the hydrochloride of compound WX001-3 (1.3 g, 5.31 mmol) was dissolved in N, N-dimethylformamide (15 mL), followed by the addition of 2-(7-azabenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate (1.62 g, 4.25 mmol), N, N-diisopropylethylamine (1.37 g, 10.63 mmol) and the hydrochloride of intermediate BB-8 (906 mg, 3.54 mmol), and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was poured into water (150 mL) and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was freed from the solvent under reduced pressure. The resulting residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1-7 / 3, volume ratio) to obtain compound WX006-1. 1 H NMR(400MHz, 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 =7.2Hz,2H),3.71(d,J=1.2Hz,2H),3.59(m,4H),3.26(m,2H),2.65(m,4H),1.49(s,9H),1.28(t,J=7.2Hz,3H).

[0493] Step 2: Synthesis of compound WX006-2

[0494] At 0°C and under nitrogen protection, compound WX006-1 (1.53 g, 3.43 mmol) was dissolved in N, N-dimethylformamide (20 mL), and potassium tert-butoxide (462 mg, 4.12 mmol) and acrylamide (293 mg, 4.12 mmol) were added in sequence. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was slowly poured into a saturated aqueous ammonium chloride solution (30 mL) and extracted with ethyl acetate (15 mL × 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to remove the solvent. The residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1–1 / 1, volume ratio) to obtain compound WX006-2. 1H NMR(400MHz, 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=7.6Hz,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).

[0495] Step 3: Synthesis of the hydrochloride salt of compound WX006-3

[0496] At room temperature, compound WX006-2 (150 mg, 2.12 mmol) was dissolved in ethyl acetate (3 mL), and then a solution of hydrochloric acid in ethyl acetate (4 M, 15 mL) was added, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solvent was directly concentrated under reduced pressure to obtain the hydrochloride of compound WX006-3, which was used directly in the next step without further purification.

[0497] Step 4: Synthesis of the hydrochloride salt of compound WX006

[0498] At room temperature, the intermediate BB-2 (149 mg, 307 μmol) was dissolved in a mixed solvent of tetrahydrofuran (5 mL) and N,N-dimethylformamide (1 mL), followed by the addition of the hydrochloride of the compound WX006-3 (125 mg, 307 μmol) and potassium acetate (60 mg, 614 μmol), the reaction mixture was stirred at room temperature for 0.5 hours, and then sodium triacetoxyborohydride (130 mg, 614 μmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, water (1 mL) was added to quench, dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to remove the solvent, and the residue was separated by preparative HPLC (chromatographic column: Boston Green ODS 150*30mm*5μm; mobile phase: water (0.04% hydrochloric acid)-acetonitrile; acetonitrile%: 15%-35%, 10min) to obtain the hydrochloride of the target compound WX006. MS-ESI m / z:840.4[M+H] + . 1H NMR(400MHz, DMSO_d6)δ:10.93(s,1H),10.42(s,1H),9.52(d,J=7.2Hz,1H),8.78(d,J=8.0Hz,1H),8.41(d,J=4.4Hz,1H),8. 26(d,J=5.6Hz,1H),7.97(s,1H),7.73(d,J=7.6Hz,1H),7.41(d,J=7.6Hz,1H),7.32-6.96(m,3H),6.90-6.44(m,1H),5.17(d, J=81.2Hz,1H),4.77(d,J=20.4Hz,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),3.08-2.9 9(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).

[0499] Example 7

[0500]

[0501] Synthesis route:

[0502]

[0503] Step 1: Synthesis of compound WX007-1

[0504] At room temperature and under nitrogen protection, the intermediate BB-10 (300 mg, 838 μmol) was dissolved in N, N-dimethylformamide (10 mL), followed by the addition of compound WX003-2 (301 mg, 1.26 mmol), cesium carbonate (819 mg, 2.51 mmol), cuprous iodide (32 mg, 168 umol) and dichlorobis(triphenylphosphine)palladium (118 mg, 168 umol), the reaction mixture was heated to 80 ° C and stirred for 3 hours. After the reaction was completed, it was cooled to room temperature, poured into a saturated ammonium chloride solution (100 mL), and extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to remove the solvent. The residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1-1 / 1, volume ratio) to obtain compound WX007-1. MS-ESI m / z:539.3[M+Na] + . 1H NMR (400MHz, CDCl3) δ: 8.11 (d, J = 1.2Hz, 1H), 8.07 (br s,1H),7.93(d,J=8.8Hz,1H),7.76-7.67(m,3H),7.61(dd,J=1.6Hz,8.8Hz,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).

[0505] Step 2: Synthesis of the hydrochloride salt of compound WX007-2

[0506] At room temperature, compound WX007-1 (180 mg, 348 μmol) was dissolved in ethyl acetate (10 mL), and then a solution of hydrochloric acid in ethyl acetate (4 M, 10 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and ethyl acetate (10 mL) was added to the residue, which was concentrated again to a remaining 4-5 mL, filtered, and the filter cake was rinsed with ethyl acetate (5 mL × 2). The filter cake was collected and dried in vacuo to obtain the hydrochloride salt of compound WX007-2. MS-ESI m / z: 417.0 [M + H] + .

[0507] Step 3: Synthesis of the hydrochloride salt of compound WX007

[0508] At room temperature and under nitrogen protection, the intermediate BB-2 (149 mg, 307 umol) was dissolved in tetrahydrofuran (5 mL) and N,N-dimethylformamide (1 mL), followed by the addition of the hydrochloride of compound WX007-2 (139 mg, 307 μmol) and potassium acetate (90 mg, 921 μmol), and the reaction mixture was stirred at room temperature for 0.5 hours. Sodium triacetoxyborohydride (130 mg, 614 umol) was then added, and the reaction mixture was stirred at room temperature for 12 hours. After the reaction was completed, water (1 mL) was added, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was separated by preparative HPLC (chromatographic 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 (400MHz, DMSO_d6) δ: 10.95 (s, 1H), 9.51 (d, J = 4.4Hz, 1H), 9.45 (br s,1H),8.79(d,J=7.2Hz,1H),8.40(d,J=1.6Hz,1H),8.30-8.16(m,3H),8.06(s,1H),7.93-7.85(m,2H),7 .58(d,J=8.0Hz,1H),7.31-6.46(m,2H),5.18(d,J=79.2Hz,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).

[0509] Example 8

[0510]

[0511] Synthesis route:

[0512]

[0513] Step 1: Synthesis of compound WX008-1

[0514] At room temperature and under nitrogen protection, the hydrochloride of compound WX001-3 (387.74 mg, 1.59 mmol) was dissolved in N,N-dimethylformamide (10 mL), followed by the addition of 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (482.81 mg, 1.27 mmol), N,N-diisopropylethylamine (410.27 mg, 3.17 mmol) and the hydrochloride of intermediate BB-9 (350 mg, 1.06 mmol), and the reaction mixture was stirred at room temperature for 12 hours. After the reaction was completed, it was poured into water (50 mL) and extracted with ethyl acetate (10 mL×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 remove the solvent. The resulting residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1-1 / 1, volume ratio) to obtain compound WX008-1. MS-ESI m / z: 521.1 [M+H] + . 1H NMR(400MHz, CDCl3)δ:9.25(s,1H),8.28(s,1H),8.10(br s,1H),7.95(d,J=8.8Hz,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).

[0515] Step 2: Synthesis of the hydrochloride salt of compound WX008-2

[0516] At room temperature, compound WX008-1 (160 mg, 288 μmol) was dissolved in a 1,4-dioxane solution of hydrochloric acid (4M, 12 mL), and the reaction mixture was stirred at room temperature for 12 hours. After the reaction was completed, the solvent was removed under reduced pressure, ethyl acetate (20 mL) was added to the residue, and the solvent was removed under reduced pressure again to obtain the hydrochloride salt of compound WX008-2. MS-ESI m / z: 421.1 [M+H] + .

[0517] Step 3: Synthesis of the hydrochloride salt of compound WX008

[0518] At room temperature and under nitrogen protection, the intermediate BB-2 (140 mg, 288.37 μmol) was dissolved in tetrahydrofuran (5 mL) and N,N-dimethylformamide (1 mL), followed by the addition of the hydrochloride salt 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), and the reaction mixture was stirred at room temperature for 0.5 hours. Sodium triacetoxyborohydride (183 mg, 865 μmol) was then added, and the reaction mixture was stirred at room temperature for 4 hours. After the reaction was completed, water (20 mL) was added, and the mixture was extracted with ethyl acetate (15 mL × 3) to precipitate solids. The aqueous phase and organic phase were discarded, and the solids were dissolved with N,N-dimethylformamide (5 mL). The resulting solution was separated by preparative HPLC (chromatographic 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(400MHz,DMSO_d6)δ:10.95(s,1H),10.68(br s,1H),9.51(d,J=6.8Hz,1H),8.78(d,J=7.6Hz,1H),8.40(s,2H),8.25(d,J=5.6Hz,1H),8.17(d,J=8.8Hz,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=81.2Hz,1H),4.76(d,J=20.8Hz,1H ),4.66(dd,J=4.0Hz,11.6Hz,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).

[0519] Example 9

[0520]

[0521] Synthesis route:

[0522]

[0523] Step 1: Synthesis of compound WX009-1

[0524] At room temperature and under nitrogen protection, compound WX003-2 (400.87 mg, 1.68 mmol), intermediate BB-12 (0.3 g, 837.55 μmol), cuprous iodide (31.90 mg, 167.51 μmol), bistriphenylphosphine palladium dichloride (117.58 mg, 167.51 μmol) and N, N-diisopropylethylamine (216.50 mg, 1.68 mmol) were added to dimethyl sulfoxide (4 mL), and the reaction mixture was heated to 85 ° C and stirred for 2.5 hours. After the reaction was completed, it was cooled to room temperature, water (2 mL) was added, and extracted with ethyl acetate (5 mL × 2). The organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to remove the solvent. The obtained 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] + . 1H NMR(400MHz, CDCl3)δ:8.35(d,J=8.8Hz,1H),8.06(s,1H),7.99(d,J=8.4Hz,1H),7.76 (d,J=9.2Hz,1H),7.73-7.68(m,2H),7.54(dd,J=7.2Hz,8.8Hz,1H),4.60(s,2H),4.51 (dd,J=5.2Hz,8.8Hz,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).

[0525] Step 2: Synthesis of trifluoroacetate salt of compound WX009-2

[0526] At room temperature, compound WX009-1 (0.1 g, 193.58 μmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (617.19 mg, 5.41 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solvent was removed by concentration under reduced pressure to obtain the trifluoroacetate salt of compound WX009-2. MS-ESI m / z: 417.1 [M+H] + .

[0527] Step 3: Synthesis of the hydrochloride salt of compound WX009

[0528] Under nitrogen protection at room temperature, 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 sodium triacetylborohydride (117.87 mg, 556.14 μmol) was added. The reaction mixture was stirred at room temperature for 15 hours. After the reaction was completed, saturated ammonium chloride (10 mL) was added and extracted with ethyl acetate (5 mL × 2). There was a large amount of insoluble matter. The organic phase and the insoluble matter were concentrated under reduced pressure to remove the solvent. The obtained residue was separated and purified by preparative HPLC (chromatographic column: Phenomenex Luna 80*30mm*3μm; mobile phase: water (0.04% hydrochloric acid)-acetonitrile; acetonitrile%: 25%-45%, 8min) to obtain the hydrochloride of the target compound WX009. MS-ESIm / z: 886.4[M+H] + . 1H NMR (400MHz, CD3OD):8.54-8.48(m,1H),8.38-8.27(m,3H),8.21(d,J=8.8Hz,1H),7.89(s,1H),7.82-7.77(m,1H) ,7.69(d,J=7.2Hz,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)

[0529] Example 10

[0530]

[0531] Synthesis route:

[0532]

[0533] Step 1: Synthesis of compound WX010-1

[0534] At room temperature and under nitrogen protection, the hydrochloride 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 2-(7-benzotriazole oxide)-N, N, N, N-tetramethyluronium hexafluorophosphonate (344.86 mg, 906.99 μmol) were added. The reaction mixture was stirred at room temperature for 0.5 hours, and the hydrochloride of intermediate BB-11 (0.2 g, 604.66 μmol) was added. The reaction mixture was stirred at room temperature for 1.5 hours. After the reaction was completed, water (30 mL) was added and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with 10% brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to remove the solvent. The residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 2-0 / 1) to obtain compound WX010-1. MS-ESI m / z: 521.3 [M+H] + .

[0535] Step 2: Synthesis of the hydrochloride salt of compound WX010-2

[0536] At room temperature, compound WX010-1 (290 mg, 557.08 μmol) was dissolved in dichloromethane (2 mL), and a hydrochloric acid ethyl acetate solution (4 M, 5 mL) was added. The reaction mixture was stirred at room temperature for 12 hours. After the reaction was completed, the filter cake was filtered, and the filter cake was rinsed with ethyl acetate (10 mL). The filter cake was collected and dried in vacuo to obtain the hydrochloride salt of compound WX010-2. MS-ESI m / z: 421.2 [M+H] + . 1 H NMR(400MHz, 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=9.6Hz,1H),7.67-7.57(m,2H),4.71(dd,J=3.6 Hz,12.0Hz,1H),4.38(s,2H),3.70-3.55(m,4H),3.52-3.35(m,4H),2.9 7-2.82(m,1H),2.68-2.59(m,1H),2.48-2.37(m,1H),2.35-2.22(m,1H).

[0537] Step 3: Synthesis of the hydrochloride salt of compound WX010

[0538] At room temperature and under nitrogen protection, the intermediate BB-2 (190 mg, 391.36 μmol) and the hydrochloride 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. Sodium triacetoxyborohydride (331.78 mg, 1.57 mmol) was then added, and the reaction mixture was stirred at room temperature for 40 minutes. After the reaction was completed, 1M hydrochloric acid (4 mL) was added, and the solvent was removed by concentration under reduced pressure. The obtained residue was separated and purified by preparative HPLC (chromatographic column: Phenomenex Luna 80*30mm*3μm; mobile phase: water (0.04% hydrochloric acid)-acetonitrile; acetonitrile%: 10%-30%, 8 min) to obtain the hydrochloride of the target compound WX010. MS-ESI m / z:890.2[M+H] + . 1H NMR(400MHz, DMSO_d6)δ:10.96(s,1H),10.59(s,1H),9.51(d,J=6.4Hz,1H),8.79(d,J=8.0Hz,1H),8.41(d,J=4.0Hz,1H),8 .26(d,J=5.6Hz,1H),8.15-8.08(m,1H),8.08-8.00(m,2H),7.87(d,J=9.2Hz,1H),7.68-7.57(m,2H),7.26-6.96(m,1H),6. 90-6.40(m,1H),5.18(d,J=80.0Hz,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).

[0539] Embodiment 11

[0540]

[0541] Synthesis route:

[0542]

[0543] Step 1: Synthesis of compound WX011-1

[0544] At room temperature and under nitrogen protection, the 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), and bistriphenylphosphine palladium 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 in sequence. The reaction mixture was heated to 85 ° C and stirred for 2 hours. After the reaction was completed, it was cooled to room temperature, water (20 mL) was added, and it was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with 10% brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to remove the solvent. The residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0-6 / 1) to obtain compound WX011-1. 1H NMR (400MHz, CDCl3) δ: 8.53 (d, J = 9.2Hz, 1H), 8.11 (d, J = 8.0Hz, 1H), 7.78 (d, J = 9.2Hz, 1H), 7.75 (d, J = 7.6Hz, 1H), 7.63 (t, J = 8.0Hz, 1H), 4.59 (s, 2H) ,4.34(s,2H),4.22(q,J=7.0Hz,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=7.2Hz,3H)

[0545] Step 2: Synthesis of compound WX011-2

[0546] At room temperature and under nitrogen protection, 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 warmed to room temperature and stirred for 1.5 hours. After the reaction was completed, 1M hydrochloric acid was poured to adjust the pH to 3-4, water (20 mL) was added, and extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to remove the solvent. The obtained 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(400MHz, CDCl3)δ:8.58(d,J=9.2Hz,1H),8.13(s,1H),8.03(d,J=8.4Hz,1H),7.81( d,J=9.6Hz,1H),7.77(dd,J=0.8Hz,7.2Hz,1H),7.65(t,J=8.0Hz,1H),4.74(dd,J=4.8H z,8.4Hz,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).

[0547] Step 3: Synthesis of trifluoroacetate salt of compound WX011-3

[0548] At room temperature, compound WX011-2 (0.1 g, 193.21 μmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (61.72 mg, 541.29 μmol, 40.08 μL) was added, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solvent was removed by concentration under reduced pressure to obtain the trifluoroacetate salt of compound WX011-3.

[0549] Step 4: Synthesis of the hydrochloride salt of compound WX011

[0550] At room temperature and under nitrogen 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 added to a mixed solvent of glacial acetic acid (0.1 mL) and N,N-dimethylformamide (1 mL) in sequence, and the reaction mixture was stirred at room temperature for 2 hours, and then sodium triacetyl borohydride (117.87 mg, 556.14 μmol) was added, and the reaction mixture was stirred at room temperature for 15 hours. After the reaction was completed, saturated ammonium chloride (10 mL) was added, and the mixture was extracted with ethyl acetate (5 mL×2). There was a large amount of insoluble matter, and the organic phase and insoluble matter were concentrated under reduced pressure to remove the solvent. The obtained residue was separated and purified by preparative HPLC (chromatographic column: Phenomenex Luna 80*30mm*3μm; mobile phase: water (0.04% hydrochloric acid)-acetonitrile; acetonitrile%: 25%-45%, 8min) to obtain the hydrochloride salt of the target compound WX011. MS-ESI m / z: 887.4 [M+H] + . 1H NMR(400MHz,MeOD_d4)δ:8.59(d,J=9.2Hz,1H),8.51(t,J=7.6Hz,1H),8.37(d,J=9.2Hz,1H),8.33-8.26(m,2H),7.91(d,J =9.2Hz,1H),7.79(d,J=7.6Hz,1H),7.75-7.68(m,1H),7.06-6.72(m,1H),6.44(d,J=7.6Hz,1H),5.44(s,1H),5.01(d,J=4 .8Hz,10.4Hz,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).

[0551] Example 12

[0552]

[0553] Synthesis route:

[0554]

[0555] Step 1: Synthesis of compound WX012-1

[0556] At room temperature and under nitrogen protection, the hydrochloride of compound WX001-3 (93.09 mg, 331.57 μmol) was dissolved in N, N-dimethylformamide (2 mL), followed by the addition of N, N-diisopropylethylamine (194.78 mg, 1.51 mmol) and 2-(7-azabenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate (171.92 mg, 452.14 μmol), the reaction mixture was stirred at room temperature for 0.5 hours, and then the hydrochloride of intermediate BB-13 (0.1 g, 301.43 μmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, water (20 mL) was added to the reaction solution, and it was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with 10% brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to remove the solvent to obtain compound WX012-1. MS-ESI m / z: 522.3 [M+H] + .

[0557] Step 2: Synthesis of the hydrochloride salt of compound WX012-2

[0558] At room temperature, compound WX012-1 (150 mg, 287.60 μmol) was dissolved in ethyl acetate (1 mL), and then a hydrochloric acid solution in ethyl acetate (4 M, 2 mL) was added. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was filtered, the filter cake was rinsed with ethyl acetate (10 mL), the filter cake was collected, and vacuum dried to obtain the hydrochloride salt of compound WX012-2. MS-ESI m / z: 422.2 [M + H] + . 1 H NMR(400MHz,DMSO_d6)δ:11.25(s,1H),11.14(s,1H),9.85(s,2H),8.52(d, J=2.0Hz,1H),8.25(d,J=8.8Hz,1H),8.14(d,J=9.2Hz,1H),7.96-7.88(m,2 H),5.05(dd,J=4.4Hz,11.2Hz,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).

[0559] Step 3: Synthesis of the hydrochloride salt of compound WX012

[0560] At room temperature, the intermediate BB-2 (95 mg, 195.68 μmol) and the hydrochloride of compound WX012-2 (98.56 mg, 215.25 μmol) were dissolved in N, N-dimethylformamide (2 mL), followed by the addition of potassium acetate (57.61 mg, 587.04 μmol) and acetic acid (5.88 mg, 97.84 μmol), the reaction mixture was stirred at room temperature for 2 hours, and then sodium triacetoxyborohydride (165.89 mg, 782.72 μmol) was added, and the reaction mixture was stirred at room temperature for 10 hours. After the reaction was completed, a saturated ammonium chloride solution (20 mL) was added to the reaction solution, solids precipitated, filtered, and the filter cake was collected. The obtained filter cake was separated by preparative HPLC (chromatographic column: Phenomenex Luna 80*40mm*3μm; mobile phase: water (0.04% hydrochloric acid)-acetonitrile; acetonitrile%: 18%-38%, 7min) to obtain the hydrochloride salt of the target compound WX012. MS-ESI m / z: 891.5[M+H] + . 1H NMR(400MHz, DMSO_d6)δ:11.14(s,1H),11.06(s,1H),9.51(d,J=6.0Hz,1H),8.78(d,J=7.2Hz,1H),8.51(d,J=1 .6Hz,1H),8.40(d,J=3.6Hz,1H),8.26(d,J=5.6Hz,2H),8.14(d,J=9.2Hz,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=20.0Hz,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).

[0561] Embodiment 13

[0562]

[0563] Synthesis route:

[0564]

[0565] Step 1: Synthesis of compound WX013-1

[0566] At room temperature and under nitrogen protection, 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), bistriphenylphosphine palladium dichloride (117.25 mg, 167.05 μmol) and N, N-diisopropylethylamine (215.90 mg, 1.67 mmol) were added to dimethyl sulfoxide (4 mL), and the reaction mixture was heated to 85 ° C and stirred for 2.5 hours. After the reaction was completed, it was cooled to room temperature, water (2 mL) was added, and extracted with ethyl acetate (5 mL × 2). The organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to remove the solvent. The obtained 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] + . 1H NMR(400MHz, CDCl3)δ:8.13(br s,2H),7.97(t,J=9.2Hz,2H),7.73(dd,J=8.8Hz,15.2Hz,2H),4.72(dd,J=4.8Hz,8.4Hz,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).

[0567] Step 2: Synthesis of trifluoroacetate salt of compound WX013-2

[0568] At room temperature, compound WX013-1 (0.1 g, 193.21 μmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (616.00 mg, 5.40 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the solvent was removed by concentration under reduced pressure to obtain the trifluoroacetate salt of compound WX013-2. MS-ESI m / z: 418.2 [M+H] + .

[0569] Step 3: Synthesis of the hydrochloride salt of compound WX013

[0570] At room temperature and under nitrogen 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. Sodium triacetyl borohydride (117.87 mg, 556.14 μmol) was then added, and the reaction mixture was stirred at room temperature for 15 hours. After the reaction was completed, 1M hydrochloric acid (1 mL) was added, and the resulting solution was separated by preparative HPLC (chromatographic column: Phenomenex Luna 80*30mm*3μm; mobile phase: water (0.04% hydrochloric acid)-acetonitrile; acetonitrile%: 20%-40%, 8 min) to obtain the hydrochloride of the target compound WX013. MS-ESIm / z:887.4[M+H] + . 1H NMR (400MHz, 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 = 8.8Hz, 1H), 7.84 (d ,J=9.2Hz,1H),7.75-7.70(m,1H),7.04-6.72(m,1H),6.44(d,J=7.6Hz,1H),5.44(s,1H),4.96(dd,J=4.8Hz,10.4Hz,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=6.0Hz,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).

[0571] Embodiment 14

[0572]

[0573] Synthesis route:

[0574]

[0575] Step 1: Synthesis of compound WX014-1

[0576] At room temperature and under nitrogen protection, the hydrochloride of compound WX001-3 (465.44 mg, 1.66 mmol) was dissolved in N, N-dimethylformamide (10 mL), followed by the addition of N, N-diisopropylethylamine (973.92 mg, 7.54 mmol) and 2-(7-azabenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate (859.59 mg, 2.26 mmol), the reaction mixture was stirred at room temperature for 0.5 hours, and then the hydrochloride of intermediate BB-15 (0.5 g, 1.51 mmol) was added, and the reaction mixture was stirred at room temperature for 11.5 hours. After the reaction was completed, water (80 mL) was added and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with 10% brine (60 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to remove the solvent. The obtained residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 2-0 / 1, volume ratio) to obtain compound WX014-1. MS-ESI m / z: 522.2 [M+H] + .

[0577] Step 2: Synthesis of the hydrochloride salt of compound WX014-2

[0578] At room temperature, compound WX014-1 (520 mg, 997.00 μmol) was dissolved in dichloromethane (5 mL), and a hydrochloric acid ethyl acetate solution (4 M, 10 mL) was added. The reaction mixture was stirred at room temperature for 12 hours. After the reaction was completed, the filter cake was filtered, and the filter cake was rinsed with ethyl acetate (15 mL). The filter cake was collected and dried in vacuo to obtain the hydrochloride salt of compound WX014-2. MS-ESI m / z: 422.2 [M + H] + .

[0579] Step 3: Synthesis of the hydrochloride salt of compound WX014

[0580] At room temperature and under nitrogen protection, the intermediate BB-2 (190 mg, 391.36 μmol) and the hydrochloride 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. Sodium triacetoxyborohydride (331.78 mg, 1.57 mmol) was then added, and the reaction mixture was stirred at room temperature for 40 minutes. After the reaction was completed, 1M hydrochloric acid solution (4 mL) was added, and the solvent was removed by concentration under reduced pressure. The obtained residue was separated by preparative HPLC (chromatographic column: Phenomenex Luna 80*30mm*3μm; mobile phase: water (0.04% hydrochloric acid)-acetonitrile; acetonitrile%: 10%-30%, 8 min) to obtain the hydrochloride of the target compound WX014. MS-ESI m / z:891.3[M+H] + . 1 H NMR(400MHz, DMSO_d6)δ:11.15(s,1H),10.71(s,1H),9.51(d,J=6.4Hz,1H),8.78(d,J=7.6Hz,1H),8.41(d,J=3.6Hz,1H),8.3 6(d,J=9.2Hz,1H),8.26(d,J=5.6Hz,1H),8.17(d,J=5.6Hz,1H),8.00(d,J=9.2Hz,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=19.6Hz,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).

[0581] Embodiment 15

[0582]

[0583] Synthesis route:

[0584]

[0585] Step 1: Synthesis of compound WX015-2

[0586] At room temperature and under nitrogen protection, the hydrochloride of compound WX001-3 (9.7 g) was dissolved in N, N-dimethylformamide (50 mL), followed by the addition of N, N-diisopropylethylamine (8.55 g, 66.15 mmol) and 2-(7-azabenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate (16.35 g, 43.00 mmol), the reaction mixture was stirred at room temperature for 0.5 hours, and then compound WX015-1 (5 g, 33.08 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, water (200 mL) was added and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to remove the solvent. The obtained 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] + .

[0587] Step 2: Synthesis of compound WX015-3

[0588] At room temperature and under nitrogen protection, compound WX015-2 (4g, 10.60mmol) and dimethyl carbonate (3.82g, 42.39mmol, 3.57mL) were dissolved in tetrahydrofuran (50mL), potassium tert-butoxide (7.14g, 63.59mmol) was added, and the reaction mixture was heated to 90°C and stirred for 4 hours. After the reaction was completed, the solvent was removed by concentration under reduced pressure, ice water (50mL) was added to dissolve, and methyl tert-butyl ether (50mL×2) was used for extraction, and the aqueous phase was collected, and pH was adjusted to 7 with 6M 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(400MHz,D2O)δ:7.78(d,J=7.6Hz,1H),7.60(d,J=7.6Hz,1H),7.19(t,J=7.8Hz ,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).

[0589] Step 3: Synthesis of compound WX015-4

[0590] 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, the reaction mixture was heated to 80 ° C, and stirred for 5 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, the filter cake was rinsed with dichloromethane (50 mL × 2), the filtrate was concentrated to remove most of the solvent, water (100 mL) was added, and it was extracted with dichloromethane (50 mL × 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] + .

[0591] Step 4: Synthesis of compound WX015-5

[0592] 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, and the reaction mixture was stirred at 30°C for 1.5 hours, and anhydrous ethanol (2.75 g, 59.75 mmol) was added, and the reaction was continued for 1 hour. After the reaction was completed, it was poured into water (50 mL), separated, and the aqueous phase was extracted with dichloromethane (30 mL) again, and the organic phases were combined, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a 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 (400MHz, CDCl3) δ: 9.79 (s, 1H), 8.46 (d, J = 7.6Hz, 1H), 7.41 (d, J = 7.6Hz, 1H), 7.32 (t, J = 8.0Hz, 1H), 4.22 (q, J =7.0Hz,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=7.2Hz,3H).

[0593] Step 5: Synthesis of compound WX015-6

[0594] At room temperature and under nitrogen 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 tetrahydrofuran solution of potassium tert-butoxide (1M, 3.09 mL) was added dropwise. The reaction mixture was stirred at 0 ° C for 1.5 hours. After the reaction was completed, 0.05 M hydrochloric acid (70 mL) was added to the reaction solution, extracted with ethyl acetate (40 mL × 2), and the organic phases were combined. Washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The obtained crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1-1 / 1) to obtain compound WX015-6. MS-ESI m / z: 472.2 [M + H] + . 1 H NMR (400MHz, CDCl3) δ: 9.83 (s, 1H), 8.49 (d, J = 6.4Hz, 1H), 8.10 (s, 1H), 7.42 (d, J = 7.6Hz, 1H), 7.35 (t, J = 7.8Hz, 1H), 4.34 (dd, J = 5.0Hz ,9.0Hz,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).

[0595] Step 6: Synthesis of the hydrochloride salt of compound WX015-7

[0596] 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 completed, the solvent was removed by concentration under reduced pressure to obtain the hydrochloride salt of compound WX015-7. MS-ESI m / z: 372.1 [M+H] + .

[0597] Step 7: Synthesis of the hydrochloride salt of compound WX015

[0598] At room temperature and under nitrogen protection, the intermediate BB-2 (654.51 mg, 1.35 mmol) and the hydrochloride 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. Sodium triacetoxyborohydride (857.19 mg, 4.04 mmol) was then added, and the reaction mixture was stirred at room temperature for 1.5 hours. After the reaction was completed, 1M hydrochloric acid solution (10 mL) was added, and the solvent was removed by concentration under reduced pressure. The obtained residue was separated by preparative HPLC (chromatographic column: Phenomenex Luna 80*40mm*3μm; mobile phase: water (0.04% hydrochloric acid)-acetonitrile; acetonitrile%: 22%-37%, 7min) to obtain the hydrochloride of the target compound WX015. MS-ESI m / z:841.3[M+H] + . 1 H NMR (400MHz, DMSO_d6) δ: 11.50 (s, 1H), 11.12 (s, 2H), 9.50 (d, J = 6.0Hz, 1H), 8.78 (d, J = 7.6Hz, 1H), 8.40 (d, J = 3.6Hz, 1H), 8.26 (d, J = 5.6Hz, 1H),8.02(d,J=7.6Hz,1H),7.68(d,J=7.6Hz,1H),7.40(t,J=7.8Hz,1H),7.27-6.95(m,1H),6.90-6.41(m,1H),5.27(s,1H),5.08(s,1H),4.7 6(d,J=18.8Hz,1H),4.65(dd,J=4.8Hz,12.0Hz,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).

[0599] Step 8: Synthesis of compound WX015-8

[0600] At room temperature and under nitrogen protection, the intermediate BB-2-4 (80g, 164.10mmol) was dissolved in dichloromethane (1.6L), triphenylphosphine (51.65g, 196.92mmol) and imidazole (16.76g, 246.15mmol) were added, the reaction mixture was cooled to 0°C, elemental iodine (54.15g, 213.33mmol) was added, and the reaction mixture was stirred at room temperature for 14 hours. After the reaction was completed, the reaction solution was poured into a saturated aqueous sodium sulfite solution (600mL), stirred at room temperature until the solution was colorless, filtered, the filter cake was rinsed with dichloromethane (500mL×3), the mother liquor was separated, and the organic phase was collected. The organic phase was washed with saturated brine (500mL), 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 filter cake was rinsed with methanol (500 mL), the filter cake was collected, and vacuum dried to obtain compound WX015-8. MS-ESI m / z: 598.0 [M+H] + .

[0601] Step 9: Synthesis of compound WX015

[0602] At room temperature and under nitrogen protection, compound WX015-6 (3 g, 6.36 mmol) was dissolved in dichloromethane (30 mL), trifluoroacetic acid (9.24 g, 81.04 mmol, 6 mL) was added, and the reaction mixture was stirred at room temperature for 4 hours. After the reaction was completed, the solvent was removed by concentration under reduced pressure to obtain the trifluoroacetate salt of compound WX015-7. MS-ESI m / z: 372.0 [M+H] + .

[0603] At room temperature and under nitrogen protection, the trifluoroacetate 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 completed, the reaction solution was poured into acetone (4.3 L) and stirred at room temperature for 12 hours. Filter, rinse the filter cake with acetone (400 mL x 4), and collect the filter cake. The filter cake was dissolved in dichloromethane (1.5 L), concentrated under reduced pressure to remove the solvent, and the dissolution and concentration operation was repeated twice to obtain compound WX015. MS-ESI m / z: 841.3 [M + H] + . 1H NMR (400MHz, DMSO_d6) δ: 11.12 (s, 1H), 10.02 (s, 1H), 9.50 (d, J = 6.0Hz, 1H), 8.77 (d, J = 7.6Hz, 1H), 8.39 (d, J = 4.4Hz, 1H), 8.26 (d, J = 5. 6Hz,1H),8.10(d,J=7.6Hz,1H),7.59(d,J=8.0Hz,1H),7.36(t,J=8.0Hz,1H),7.27-6.94(m,1H),6.88-6.41(m,1H),5.17(d,J=84.4Hz, 1H),4.76(d,J=15.6Hz,1H),4.63(dd,J=4.8Hz,12.0Hz,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).

[0604] Example 16

[0605]

[0606] Synthesis route:

[0607]

[0608] Step 1: Synthesis of compound WX016-2

[0609] At room temperature and under nitrogen protection, add dichlorotitanocene (1.30 g, 5.02 mmol) and zinc powder (13.31 g, 203.55 mmol) to a dry reaction bottle, add tetrahydrofuran (100 mL) to dissolve, and dropwise add a solution of ethyl difluorobromoacetate (20.37 g, 100.38 mmol, 12.90 mL) in tetrahydrofuran (20 mL) (first dropwise add 1 / 10 of the solution, and after initiating the reaction (obviously heating up), dropwise add the remaining solution). After the addition is complete, continue stirring for 0.5 hours, filter, and add the filtrate to a solution of compound WX016-1 (10 g, 50.19 mmol) in tetrahydrofuran (50 mL), and stir to react for 12 hours. After the reaction was completed, 1M hydrochloric acid was added dropwise to adjust the pH to 3, ethyl acetate (100 mL) and water (100 mL) were added to dilute, the liquid was separated, the organic phase was collected, the aqueous phase was extracted with ethyl acetate (50 mL × 3), the organic phases were combined, washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained 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] + .

[0610] Step 2: Synthesis of compound WX016-3

[0611] At room temperature and under nitrogen protection, compound WX016-2 (1g, 3.09mmol), thionyl chloride (2.21g, 18.56mmol) and pyridine (1.47g, 18.56mmol) were added to dioxane (15mL), and the reaction mixture was stirred for 1.5 hours, and then 4-dimethylaminopyridine (37.78mg, 309.28μmol) was added, and the stirring reaction was continued for 12 hours. After the reaction was completed, water (20mL) was added to the reaction solution, and it was extracted with ethyl acetate (30mL×3), and the organic phase was washed with saturated brine (20mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The obtained residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 20 / 1-9 / 1, volume ratio) to obtain compound WX016-3. MS-ESI m / z: 206.2[M+H-100] + . 1 HNMR (400MHz, CDCl3) δ: 6.18 (s, 1H), 4.34 (q, J = 7.0Hz, 2H), 4.02 (d, J = 2.0Hz ,2H),3.54(t,J=5.6Hz,2H),2.25(s,2H),1.48(s,9H),1.36(t,J=7.2Hz,3H).

[0612] Step 3: Synthesis of compound WX016-4

[0613] At room temperature and under nitrogen protection, wet palladium hydroxide (0.5 g, 712.07 μmol, purity: 20%) was added to a hydrogenation bottle, followed by methanol (20 mL) and compound WX016-3 (1.5 g, 4.91 mmol), hydrogen was replaced three times, and the reaction mixture was stirred at 40 psi for 12 hours. After the reaction was completed, it was filtered, the filter cake was rinsed with methanol (50 mL × 4), the filtrate was collected, and the filtrate was concentrated under reduced pressure to remove the residual solvent. The obtained residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 20 / 1-10 / 1, volume ratio) to obtain compound WX016-4. MS-ESI m / z: 252.2 [M + H-56] + . 1 H NMR (400MHz, CDCl3) δ: 4.35 (q, J = 7.0Hz, 2H), 4.30-4.15 (m, 2H), 2.68 (t, J = 12.8Hz, 2H), 2.32-2.14 (m, 1H) ,1.73(d,J=12.8Hz,2H),1.49(d,J=4.8Hz,1H),1.47(s,9H),1.42(d,J=4.4Hz,1H),1.37(t,J=7.0Hz,3H).

[0614] Step 4: Synthesis of compound WX016-5

[0615] At room temperature and under nitrogen protection, compound WX016-4 (0.26 g, 845.99 μmol) was dissolved in a mixed solvent of ethanol (5 mL) and water (2 mL), and lithium hydroxide monohydrate (71.00 mg, 1.69 mmol) was added. The reaction mixture was stirred at room temperature for 12 hours. After the reaction was completed, it was concentrated under reduced pressure, and the residue was adjusted to pH = 2-3 with 1M hydrochloric acid, and solid precipitated. Filter, collect the filter cake, and vacuum dry to obtain compound WX016-5. MS-ESI m / z: 224.0 [M + H-56] + . 1 H NMR(400MHz, 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).

[0616] Step 5: Synthesis of compound WX016-6

[0617] At room temperature and under nitrogen protection, compound WX016-5 (0.12 g, 429.68 μmol) was dissolved in N, N-dimethylformamide (5 mL), 2-(7-azabenzotriazole)-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, and the reaction mixture was stirred for 0.5 hours, and then the hydrochloride of compound BB-8 (91.56 mg) was added, and the stirring reaction was continued for 12 hours. After the reaction was completed, water (20 mL) was added to the reaction solution, and it was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the residual solvent. The obtained residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1-2 / 1, volume ratio) to obtain compound WX016-6. MS-ESI m / z: 425.2 [M+H-56] + . 1 H NMR (400MHz, CDCl3) δ: 8.45 (s, 1H), 8.16 (d, J = 7.6Hz, 1H), 7.68 (s, 1H), 7.41 (dd, J = 1.0, 7.8Hz, 1H), 4.25-4.17 (m, 3H), 3.71 (d, J = 0 .8Hz,2H),2.72(t,J=12.2Hz,2H),2.57-2.42(m,1H),1.84(d,J=12.8Hz,2H),1.59-1.49(m,3H),1.47(s,9H),1.28(t,J=7.0Hz,3H).

[0618] Step 6: Synthesis of compound WX016-7

[0619] At room temperature and under nitrogen protection, compound WX016-6 (110 mg, 228.93 μmol) was dissolved in tetrahydrofuran (3 mL), acrylamide (19.53 mg, 274.71 μmol) was added, the reaction mixture was cooled to 0 ° C in an ice bath, and a tetrahydrofuran solution of potassium tert-butoxide (1M, 503.64 μL) was added dropwise. After the addition was completed, the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was poured into 0.1M hydrochloric acid (10 mL) and extracted with ethyl acetate (20 mL × 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 filter cake was rinsed with ethyl acetate (2 mL × 2), the filter cake was collected, and vacuum dried to obtain compound WX016-7. MS-ESI m / z:406.2[M+H-100]+ .

[0620] Step 7: Synthesis of the hydrochloride salt of compound WX016-8

[0621] At room temperature and under nitrogen protection, compound WX016-7 (70 mg, 138.47 μmol) was dissolved in ethyl acetate (1 mL), and a hydrochloric acid solution in ethyl acetate (3 mL, 4 M) was added. The reaction mixture was stirred at room temperature for 12 hours. After the reaction was completed, the filter cake was filtered, and the filter cake was washed with ethyl acetate (3 mL × 3). The filter cake was collected and dried in vacuo to obtain the hydrochloride salt of compound WX016-8. MS-ESI m / z: 406.2 [M + H] + . 1 H NMR(400MHz,DMSO_d6)δ:10.92(s,1H),10.80(s,1H),7.94(s,1H),7.53(dd, J=1.4,7.0Hz,1H),7.34-7.22(m,2H),4.17(dd,J=5.0,12.2Hz,1H),3.38(d, J=12.8Hz,2H),2.97(t,J=12.0Hz,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).

[0622] Step 8: Synthesis of the hydrochloride salt of compound WX016

[0623] At room temperature and under nitrogen protection, the hydrochloride salt of compound WX016-8 (50 mg) was dissolved in 1,2-dichloroethane (3 mL), and 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. The reaction mixture was stirred at room temperature for 2 hours, and then sodium triacetoxyborohydride (95.93 mg, 452.64 μmol) was added, and the stirring reaction was continued for 12 hours. After the reaction was completed, 1M hydrochloric acid (2 mL) was added to the reaction solution and stirred for 5 minutes, and the solvent was removed by concentration under reduced pressure. The residue was separated by preparative HPLC (chromatographic column: Phenomenex Luna80*30mm*3μm; mobile phase: water (0.04% hydrochloric acid)-acetonitrile; acetonitrile%: 15%-40%, 8min) to obtain the hydrochloride salt of the target compound WX016. MS-ESI m / z: 875.3 [M+H] + . 1H NMR(400MHz, DMSO_d6)δ:10.92(s,1H),10.84(s,1H),9.50(d,J=6.4Hz,2H),8.79(d,J=8.0Hz,1H),8.41(d,J =3.6Hz,1H),8.26(d,J=5.6Hz,1H),7.95(s,1H),7.53(d,J=7.6Hz,1H),7.38-6.94(m,3H),6.91-6.36(m,1H) ,5.36-5.04(m,1H),4.77(d,J=20.8Hz,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).

[0624] Embodiment 17

[0625]

[0626] Synthesis route:

[0627]

[0628] Step 1: Synthesis of compound WX017-1

[0629] At room temperature and under nitrogen protection, compound WX016-5 (0.7 g, 2.51 mmol) was dissolved in N, N-dimethylformamide (10 mL), 2-(7-azabenzotriazole)-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, and the reaction mixture was stirred at room temperature for 0.5 hours, and then compound WX015-1 (315.73 mg, 2.09 mmol) was added, and the stirring reaction was continued for 12 hours. After the reaction was completed, water (60 mL) was added to the reaction solution, and it was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The obtained residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1-5 / 1, volume ratio) to obtain compound WX017-1. MS-ESI m / z: 313.1 [M+H-100] + . 1H NMR (400MHz, CDCl3) δ: 12.94 (s, 1H), 8.74 (s, 1H), 8.59 (dd, J = 0.8, 8.0Hz, 1H), 7.57 (dd, J = 1.4, 8.2Hz, 1H), 6.98 (t, J = 8.0Hz, 1H ),4.29-4.17(m,2H),2.68(s,3H),2.53-2.40(m,1H),1.81(d,J=12.4Hz,2H),1.59-1.55(m,2H),1.53-1.48(m,2H),1.46(s,9H).

[0630] Step 2: Synthesis of compound WX017-2

[0631] At room temperature and under nitrogen protection, 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, 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 then heated to 80°C and stirred for 12 hours. After the reaction was completed, it was cooled to room temperature and concentrated under reduced pressure to remove the solvent to obtain compound WX017-2. MS-ESI m / z: 339.2 [M+H-100] + .

[0632] Step 3: Synthesis of compound WX017-3

[0633] At room temperature and under nitrogen protection, 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 completed, it 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 sodium bicarbonate aqueous solution, and extracted with dichloromethane / ethanol = 10 / 1 (30 mL×5), and the organic phase was washed with saturated brine (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] + .

[0634] Step 4: Synthesis of compound WX017-4

[0635] At room temperature and under nitrogen 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 completed, it was cooled to room temperature, water (30 mL) was added, and it was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (50 mL × 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 completed, water (30 mL) was added and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, 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 = 3 / 1-2 / 1, volume ratio) to obtain compound WX017-4. MS-ESI m / z: 382.1 [M+H-100] + . 1 H NMR(400MHz, CDCl3)δ:8.47(s,1H),8.42(d,J=8.0Hz,1H),7.53(d,J=8.0Hz,1H),7.37(t,J=7.8Hz,1H),4.27-4.19(m,3H),4.0 6(s,2H),2.79-2.66(m,2H),2.56-2.46(m,1H),1.83(d,J=12.4Hz,2H),1.59-1.50(m,3H),1.47(s,9H),1.27(t,J=7.2Hz,3H).

[0636] Step 6: Synthesis of compound WX017-5

[0637] At room temperature and under nitrogen 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 tetrahydrofuran solution of potassium tert-butoxide (1M, 1.87 mL) was added dropwise, and the reaction mixture was stirred at 0°C for 1 hour. After the reaction was completed, the reaction solution was poured into 0.3M hydrochloric acid (10 mL), extracted with ethyl acetate (20 mL×3), the organic phase was washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The obtained residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1-1 / 1, volume ratio) to obtain compound WX017-5. MS-ESI m / z: 407.1[M+H-100] + . 1 H NMR (400MHz, DMSO_d6) δ: 11.12 (s, 1H), 10.99 (s, 1H), 7.79 (d, J = 8.0Hz, 1H), 7.61 (d, J = 7.6Hz, 1H), 7.41 (t, J = 7.6Hz, 1H), 4.64 (dd, J = 4.8, 12. 0Hz,1H),4.11-4.06(m,1H),2.86-2.71(m,3H),2.68-2.53(m,3H),2.2 7-2.15(m,1H),1.81(d,J=12.4Hz,2H),1.40(s,9H),1.38-1.32(m,2H).

[0638] Step 7: Synthesis of the hydrochloride salt of compound WX017-6

[0639] At room temperature and under nitrogen protection, 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 completed, the filter cake was filtered, and the filter cake was washed with ethyl acetate (3 mL × 3). The filter cake was collected and dried in vacuo to obtain the hydrochloride salt of compound WX017-6. MS-ESI m / z: 407.1 [M + H] + . 1H NMR(400MHz, DMSO_d6)δ:11.13(s,1H),11.09(s,1H),8.74(s,2H),7.80(d,J= 8.0Hz,1H),7.62(d,J=7.2Hz,1H),7.42(t,J=7.8Hz,1H),4.65(dd,J=4.8,12.0 Hz,1H),3.38(d,J=11.6Hz,2H),2.97(t,J=12.6Hz,2H),2.85-2.71(m,2H),2. 70-2.53(m,3H),2.26-2.16(m,1H),1.96(d,J=14.0Hz,2H),1.83-1.64(m,2H).

[0640] Step 8: Synthesis of the hydrochloride salt of compound WX017

[0641] At room temperature and under nitrogen protection, the hydrochloride salt of compound WX017-6 (0.1 g) was dissolved in 1,2-dichloroethane (3 mL) and tetrahydrofuran (2 mL), and 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. The reaction mixture was stirred at room temperature for 2 hours, and then sodium triacetoxyborohydride (176.87 mg, 834.54 μmol) was added and stirred for 1 hour. After the reaction was completed, 1M hydrochloric acid (2 mL) was added and stirred for 5 minutes, and the solvent was removed by concentration under reduced pressure. The residue was separated by preparative HPLC (chromatographic column: Phenomenex C18 75*30mm*3μm; mobile phase: water (0.04% hydrochloric acid)-acetonitrile; acetonitrile%: 12%-42%, 8min) to obtain the hydrochloride of the target compound WX017. MS-ESI m / z: 876.4 [M+H] + . 1H NMR(400MHz, DMSO_d6)δ:11.13(s,2H),9.51(d,J=6.8Hz,1H),9.32(s,1H),8.79(d,J=7.6Hz,1H),8.43-8.20(m,1H), 7.81(d,J=8.0Hz,1H),7.64(d,J=7.6Hz,1H),7.43(t,J=7.8Hz,1H),7.31-6.94(m,1H),6.91-6.41(m,1H),5.30-5.03 (m,1H),4.77(d,J=21.6Hz,1H),4.65(dd,J=5.0,12.2Hz,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).

[0642] Embodiment 18

[0643]

[0644] Synthesis route:

[0645]

[0646] Step 1: Synthesis of compound WX018-1

[0647] At room temperature and under nitrogen protection, the intermediate BB-2-1 (1.10 g, 4.88 mmol) was dissolved in acetonitrile (10 mL), 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, and the reaction mixture was heated to 60 ° C and stirred for 2 hours. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and water (20 mL) was added to the obtained residue. The mixture was stirred at room temperature for 1 hour, and solids precipitated. It was filtered, and the filter cake was washed with water (20 mL×4). The filter cake was collected and dried in vacuo to obtain compound WX018-1. MS-ESI m / z: 303.2 [M+H] + . 1H NMR(400MHz, CDCl3)δ:8.35-8.25(m,2H),6.36(d,J=8.0Hz,1H),4.53(s,2H),4.35(q,J=7.4Hz,2H),4.23-3.71( m,1H),3.35(d,J=12.4Hz,2H),2.00(t,J=4.6Hz,2H),1.83(d,J=7.6Hz,2H),1.70(s,1H),1.39(t,J=7.2Hz,3H).

[0648] Step 2: Synthesis of compound WX018-2

[0649] At room temperature and under nitrogen protection, compound WX018-1 (1.4 g, 4.63 mmol) was dissolved in methanol (15 mL) and water (3 mL), and lithium hydroxide monohydrate (388.61 mg, 9.26 mmol) was added. The reaction mixture was heated to 60 ° C and stirred for 12 hours. After the reaction was completed, it was cooled to room temperature, concentrated under reduced pressure to remove methanol, and 1M hydrochloric acid was added to adjust the pH to 3-4. A large amount of white solid precipitated, filtered, and the filter cake was rinsed with water (10 mL × 2). The filter cake was collected and dried in vacuo to obtain compound WX018-2. MS-ESI m / z: 275.2 [M + H] + . 1 H NMR(400MHz, DMSO_d6)δ:11.70(s,1H),8.73(d,J=8.0Hz,1H),8.19(s,1H),6.76(d,J=8.0Hz,1H),4. 47(d,J=2.0Hz,2H),4.30-3.90(m,2H),3.15(d,J=12.4Hz,2H),1.89-1.80(m,2H),1.73-1.65(m,2H).

[0650] Step 3: Synthesis of compound WX018-3

[0651] At room temperature and under nitrogen protection, compound WX018-2 (0.2 g, 729.20 μmol) was dissolved in acetonitrile (4 mL), N, N, N, N-tetramethylchloroformamidine hexafluorophosphate (245.52 mg, 875.04 μmol) and N-methylimidazole (209.54 mg, 2.55 mmol, 203.44 μL) were added, 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 completed, the mixture was filtered, the filter cake was washed with acetonitrile (3 mL × 3), the filter cake was collected, and vacuum dried to obtain compound WX018-3. MS-ESI m / z: 502.2 [M + H] + .1 H NMR(400MHz,DMSO_d6)δ:9.41(s,1H),8.81(d,J=7.6Hz,1H),8.38(s,1H), 8.28(s,1H),7.27-6.95(m,1H),6.82(d,J=8.0Hz,1H),4.45(s,3H),4.25-4 .10(m,2H),3.25(d,J=6.0Hz,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).

[0652] Step 4: Synthesis of compound WX018-4

[0653] At room temperature and under nitrogen protection, 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, the reaction mixture was cooled to 0 ° C in an ice bath, elemental iodine (210.52 mg, 829.47 μmol) was added, and then the mixture was returned to room temperature and stirred for 12 hours. After the reaction was completed, the reaction solution was poured into a saturated aqueous sodium sulfite solution (30 mL) and extracted with dichloromethane (50 mL × 3). The organic phases were combined, washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The obtained residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1-0 / 1, volume ratio) to obtain compound WX018-4. MS-ESI m / z:612.1[M+H] + . 1 H NMR (400MHz, CDCl3) δ: 9.52 (s, 1H), 8.43 (d, J = 9.6Hz, 2H), 8.34 (d, J = 8.0Hz, 1H),6.77(t,J=54.2Hz,1H),6.37(d,J=8.0Hz,1H),4.56(d,J=2.4Hz,2H),4. 11-4.00(m,1H),3.45-3.32(m,2H),3.17(d,J=6.0Hz,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).

[0654] Step 5: Synthesis of the formate salt of compound WX018

[0655] At room temperature and under nitrogen protection, the trifluoroacetate of compound WX015-7 (268.38 mg) was dissolved in acetonitrile (4 mL), N,N-diisopropylethylamine (340.32 mg, 2.63 mmol, 458.66 μL) was added, 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 completed, it was cooled to room temperature, concentrated under reduced pressure to remove acetonitrile, water (20 mL) was added, and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The obtained residue was separated by preparative HPLC (chromatographic column: Phenomenex Luna 80*30mm*3μm; mobile phase: water (0.2% formic acid)-acetonitrile; acetonitrile%: 15%-40%, 8min) to obtain the formate salt of the target compound WX018. MS-ESI m / z: 855.5 [M+H] + . 1 H NMR(400MHz, DMSO_d6)δ:11.12(s,1H),10.02(s,1H),9.41(s,1H),8.81(d,J=8.0Hz,1H),8.38(s,1H),8.28(s,1H),8.15(s,1H),8 .10(d,J=7.6Hz,1H),7.59(dd,J=0.8,8.0Hz,1H),7.36(t,J=8.0Hz,1H),7.10(t,J=53.8Hz,1H),6.82(d,J=8.0Hz,1H),4.62(dd,J =4.8,11.6Hz,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).

[0656] Embodiment 19

[0657]

[0658] Synthesis route:

[0659]

[0660] Step 1: Synthesis of compound WX019-1

[0661] At room temperature and under nitrogen protection, the intermediate BB-2-1 (1.06 g, 4.71 mmol) was dissolved in acetonitrile (10 mL), and tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (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 completed, it was cooled to room temperature and concentrated under reduced pressure to remove the solvent. Water (20 mL) was added to the obtained residue and stirred at room temperature for 1 hour. Solids precipitated and filtered. The filter cake was washed with water (20 mL × 4), the filter cake was collected, and vacuum dried to obtain compound WX019-1. MS-ESI m / z: 402.3 [M + H] + . 1 H NMR(400MHz, CDCl3)δ:8.35-8.25(m,2H),6.39(d,J=8.0Hz,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=7.2Hz,3H).

[0662] Step 2: Synthesis of compound WX019-2

[0663] At room temperature and under nitrogen protection, compound WX019-1 (1.35 g, 3.36 mmol) was dissolved in methanol (10 mL) and water (2 mL), and lithium hydroxide monohydrate (282.23 mg, 6.73 mmol) was added. The reaction mixture was heated to 60 ° C and stirred for 2 hours. After the reaction was completed, it was cooled to room temperature, concentrated under reduced pressure to remove methanol, and 1M hydrochloric acid was added to adjust the pH to 3-4. A large amount of white solid precipitated, filtered, and the filter cake was rinsed with water (10 mL × 2). The filter cake was collected and dried in vacuo to obtain compound WX019-2. MS-ESI m / z: 374.2 [M + H] + . 1 H NMR(400MHz, DMSO_d6)δ:11.72(s,1H),8.74(d,J=7.6Hz,1H),8.19(s,1H),6.79(d,J=8.0Hz, 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).

[0664] Step 3: Synthesis of compound WX019-3

[0665] At room temperature and under nitrogen protection, compound WX019-2 (0.4 g, 1.07 mmol) was dissolved in acetonitrile (4 mL), N, N, N, N-tetramethylchloroformamidine hexafluorophosphate (360.67 mg, 1.29 mmol) and N-methylimidazole (307.83 mg, 3.75 mmol, 298.86 μL) were added, stirred for 0.5 hours, compound BB-1 (262.74 mg, 1.07 mmol) was added, and the reaction was continued to stir for 1 hour. After the reaction was completed, the filter cake was filtered, washed with acetonitrile (3 mL × 3), the filter cake was collected, and vacuum dried to obtain compound WX019-3. MS-ESI m / z: 601.4 [M + H] + . 1 H NMR(400MHz, DMSO_d6)δ:9.41(s,1H),8.83(d,J=8.0Hz,1H),8.39(s,1H),8.29(s,1H),7.14(t,J=53.8Hz,1H),6.84(d,J=8.0Hz,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,2 H),1.95-1.81(m,4H),1.80-1.62(m,4H),1.44(s,9H),1.18-1.02(m,2H).

[0666] Step 4: Synthesis of compound WX019-4

[0667] At room temperature and under nitrogen protection, 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 completed, the reaction solution was poured into a saturated aqueous sodium sulfite solution (30 mL) and extracted with dichloromethane (50 mL × 3). The organic phases were combined, washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The obtained residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1-0 / 1, volume ratio) to obtain compound WX019-4. MS-ESI m / z:711.3[M+H] + . 1H NMR (400MHz, CDCl3) δ: 9.52 (s, 1H), 8.44 (s, 1H), 8.41 (s, 1H), 8.35 (d, J = 8.0Hz, 1H), 6.78 (t,J=54.2Hz,1H),6.40(d,J=7.6Hz,1H),4.53-4.36(m,2H),4.11-4.01(m,1H),3.45-3.2 3(m,2H),3.17(d,J=6.0Hz,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).

[0668] Step 5: Synthesis of compound WX019-5

[0669] At room temperature and under nitrogen protection, the trifluoroacetate of compound WX015-7 (291.18 mg) was dissolved in acetonitrile (3 mL), N,N-diisopropylethylamine (369.24 mg, 2.86 mmol) was added, the reaction mixture was stirred for 5 minutes, 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 completed, it was cooled to room temperature, concentrated under reduced pressure to remove acetonitrile, water (20 mL) was added, and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The obtained residue was separated by column chromatography (eluent: dichloromethane / methanol = 5 / 1-1 / 1, volume ratio) to obtain compound WX019-5. MS-ESI m / z: 954.4 [M + H] + .

[0670] Step 6: Synthesis of the hydrochloride salt of compound WX019

[0671] At room temperature and under nitrogen protection, compound WX019-5 (0.3 g, 314.45 μmol) was dissolved in ethyl acetate (2 mL), and a solution of hydrochloric acid in ethyl acetate (8 mL, 4 M) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the filter cake was filtered, and the filter cake was washed with ethyl acetate (3 mL × 3) and collected. The filter cake was separated by preparative HPLC (chromatographic column: Phenomenex Luna80*30mm*3μm; mobile phase: water (0.04% hydrochloric acid)-acetonitrile]; acetonitrile%: 1%-30%, 8min) to obtain the hydrochloride of the target compound WX019. MS-ESI m / z: 854.4[M+H]+ . 1 H NMR(400MHz, DMSO_d6)δ:11.12(s,1H),10.69(s,1H),9.83(d,J=10.0Hz,1H),9.64(s,1H),9.37(s,1H),8.92(d,J=8.0Hz,1H),8.4 0(s,1H),8.33(s,1H),8.01(d,J=7.2Hz,1H),7.66(d,J=8.0Hz,1H),7.39(t,J=7.8Hz,1H),7.14(t,J=53.6Hz,1H),6.91(d,J=8.0H z,1H),4.64(dd,J=4.8,12.0Hz,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),3.1 3-2.97(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).

[0672] Embodiment 20

[0673]

[0674] Synthesis route:

[0675]

[0676] Step 1: Synthesis of compound WX020-2

[0677] At room temperature and under nitrogen protection, 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), and propargyl bromide (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 completed, saturated ammonium chloride (500 mL) was added to the reaction solution, and extracted with ethyl acetate (200 mL×3). The organic phases were combined, washed with saturated ammonium chloride (200 mL×2) and saturated brine (200 mL) in turn, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent to obtain compound WX020-2. MS-ESI m / z: 225.0[M+H] + . 1H NMR (400MHz, CDCl3) δ: 3.47 (t, J = 5.0Hz, 4H), 3.32 (d, J = 2.4Hz, 2H), 2.51 (t, J = 5.0Hz, 4H), 2.26 (t, J = 2.4Hz, 1H), 1.47 (s, 9H).

[0678] Step 2: Synthesis of compound WX020-5

[0679] At room temperature and under nitrogen protection, 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 completed, it was cooled to room temperature, concentrated under reduced pressure to remove the solvent, ice water (1000 mL) was added, and pH was adjusted to 2-3 with 6M hydrochloric acid. A white solid was precipitated, filtered, and the filter cake was rinsed with water (100 mL×2), and the filter cake was collected and dried in vacuo to obtain compound WX020-5. MS-ESI m / z: 240.9 [M+H] + ,243.7[M+H+2] + . 1 H NMR(400MHz, DMSO_d6)δ:12.80(s,1H),7.92(dd,J=1.4,7.8Hz,1H),7.81(dd,J=1.4,7.8Hz,1H),7.27(t,J=8.0Hz,1H),5.65(s,1H).

[0680] Step 3: Synthesis of compound WX020-6

[0681] At room temperature and under nitrogen 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), dichlorobis(triphenylphosphine)palladium (II) (4.37 g, 6.22 mmol) and triethylamine (25.19 g, 248.92 mmol) were dissolved in N,N-dimethylformamide (300 mL), and the reaction mixture was heated to 80 ° C and stirred for 3 hours. After the reaction was completed, it was cooled to 0-10 ° C, poured into ice water (1.2 L), adjusted to pH = 5-6 with 1M hydrochloric acid, extracted with ethyl acetate (300 mL × 3), and the aqueous phase was collected. The aqueous phase was concentrated under reduced pressure to obtain compound WX020-6. MS-ESI m / z: 385.1 [M + H] + .

[0682] Step 4: Synthesis of compound WX020-7

[0683] At room temperature and under argon protection, palladium hydroxide / carbon (7g, 24.92mmol, purity: 20%) and palladium / carbon (7g, 13.01mmol, purity: 10%) were suspended in methanol (700mL), compound WX020-6 (35g, 91.05mmol) was added, hydrogen was replaced three times, the hydrogen pressure was controlled at 30psi, and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, it was filtered, the filter cake was rinsed with methanol (200mL×5), and the filtrate was concentrated under reduced pressure to remove the solvent. Dichloromethane (50mL) and water (300mL) were added to the obtained crude product, solids were precipitated, filtered, the filter cake was rinsed with water (30mL×3), the filter cake was collected, and vacuum dried to obtain compound WX020-7. MS-ESI m / z:389.1[M+H] + . 1 H NMR(400MHz, DMSO_d6)δ:10.21(s,1H),7.71(d,J=8.0Hz,1H),7.56(d,J=7.2Hz,1H),7.29(t,J=7.6Hz,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=7.6Hz,2H),2.13-1.99(m,2H),1.40(s,9H).

[0684] Step 5: Synthesis of compound WX020-8

[0685] At room temperature and under argon 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 completed, it was cooled to room temperature, water (350 mL) was added, and it was extracted with methyl tert-butyl ether (100 mL×4), and the aqueous phase was collected; the organic phase was washed with 5% sodium bicarbonate aqueous solution (50 mL×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 extracted with a mixed solvent of dichloromethane and methanol (volume ratio: 10:1, 100 mL×4), and the organic phase was washed with saturated brine (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] + . 1H NMR(400MHz, DMSO_d6)δ:7.66(d,J=7.6Hz,1H),7.47(d,J=6.8Hz,1H),7.31(t,J=7.6Hz,1H),4.07( s,2H),3.49-3.39(m,4H),2.91(t,J=7.6Hz,2H),2.42-2.26(m,6H),1.95-1.79(m,2H),1.39(s,9H).

[0686] Step 6: Synthesis of compound WX020-9

[0687] At room temperature, compound WX020-8 (1.3 g, 3.22 mmol) was dissolved in anhydrous ethanol (20 mL), and concentrated sulfuric acid (632.03 mg, 6.44 mmol) was added. The reaction mixture was heated to 80 ° C and stirred for 12 hours. After the reaction was completed, it 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, and then di-tert-butyl dicarbonate (773.60 mg, 3.54 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, water (70 mL) was added and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The obtained residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1-0 / 1, volume ratio) to obtain compound WX020-9. MS-ESI m / z: 432.2 [M+H] + . 1 H NMR(400MHz, CDCl3)δ:7.54(d,J=7.6Hz,1H),7.35(d,J=6.8Hz,1H),7.24(d,J=7.6Hz,1H),4.22(q,J=7.2Hz,2H),4.04(s ,2H),3.51-3.35(m,4H),2.99(t,J=7.6Hz,2H),2.52-2.30(m,6H),2.03-1.91(m,2H),1.46(s,9H),1.27(t,J=7.0Hz,3H).

[0688] Step 7: Synthesis of compound WX020-10

[0689] At room temperature and under argon 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 tetrahydrofuran solution of potassium tert-butoxide (1M, 1.04 mL) was added dropwise. After the addition was complete, the mixture was stirred and reacted for 1 hour. After the reaction was completed, the reaction solution was poured into 0.1M hydrochloric acid (10.43 mL) and extracted with ethyl acetate (3 mL×3). The organic phases were combined, washed with saturated brine (3 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The 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 (400MHz, CDCl3) δ: 8.00 (s, 1H), 7.54 (d, J = 8.0Hz, 1H), 7.38 (d, J = 7.2Hz, 1H), 7.30-7.25 (m, 1H), 4.34 (dd, J = 5.2, 8.8Hz, 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).

[0690] Step 8: Synthesis of trifluoroacetate salt of compound WX020-11

[0691] At room temperature, compound WX020-10 (107 mg, 234.37 μmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (924.00 mg, 8.10 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the solvent was removed by concentration under reduced pressure to obtain the trifluoroacetate salt of compound WX020-11. MS-ESI m / z: 357.1 [M+H] + .

[0692] Step 9: Synthesis of the hydrochloride salt of compound WX020

[0693] At room temperature, the trifluoroacetate salt of compound WX020-11 (143.24 mg) was dissolved in acetonitrile (2 mL), N,N-diisopropylethylamine (199.04 mg, 1.54 mmol) was added, stirred for 5 minutes, compound WX015-8 (115 mg, 192.50 μmol) was added, and the reaction mixture was heated to 80°C, stirred and reacted for 16 hours. After the reaction was completed, it was cooled to room temperature and concentrated under reduced pressure to remove the solvent. The obtained residue was separated by preparative HPLC (chromatographic column: Phenomenex Luna 80*30mm*3μm; mobile phase: water (0.04% hydrochloric acid)-acetonitrile; acetonitrile%: 1%-35%, 8min) to obtain the hydrochloride salt of the target compound WX020. MS-ESI m / z: 826.6 [M+H] + . 1 H NMR(400MHz, DMSO_d6)δ:12.24-11.82(m,1H),11.76-11.36(m,1H),11.10(s,1H),9.50(d,J=6.4Hz,1H),8.78(d,J=7.6Hz,1H),8.39(d,J=4. 0Hz,1H),8.25(d,J=5.6Hz,1H),7.73(d,J=8.0Hz,1H),7.55(d,J=7.2Hz,1H),7.35(t,J=7.6Hz,1H),7.27-6.94(m,1H),6.91-6.40(m,1H),5.1 7(d,J=78.8Hz,1H),4.76(d,J=17.6Hz,1H),4.62(dd,J=4.8,12.0Hz,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).

[0694] Embodiment 21

[0695]

[0696] Synthesis route:

[0697]

[0698] Step 1: Synthesis of compound WX021-1

[0699] At room temperature and under nitrogen 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, and the mixture was cooled to 0°C in an ice bath, and methanesulfonyl chloride (7.25 g, 63.29 mmol) was added dropwise, and the mixture was stirred for 2 hours. After the reaction was completed, water (100 mL) was added, and the mixture was extracted with dichloromethane (100 mL × 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.

[0700] Step 2: Synthesis of compound WX021-2

[0701] At room temperature and under nitrogen 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), and compound WX021-1 (14.87 g, 53.22 mmol) was added. The reaction mixture was heated to 80 ° C and stirred for 15 hours. After the reaction was completed, it was cooled to room temperature, water (700 mL) was added, and extracted with ethyl acetate (300 mL × 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 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] + . 1 H NMR (400MHz, CDCl3) δ: 8.23 ​​(s, 1H), 7.12 (t, J = 53.4Hz, 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).

[0702] Step 3: Synthesis of compound WX021-3

[0703] At room temperature and under argon protection, compound WX021-2 (3.58 g, 10.34 mmol) was dissolved in tetrahydrofuran (90 mL), palladium carbon (1 g, purity: 10%) was added, hydrogen was replaced three times, and the pressure was maintained at 15 psi and stirred for 15 hours. After the reaction was completed, the filter was filtered, the filter cake was rinsed with methanol (50 mL×4), and the filtrate was concentrated under reduced pressure to obtain compound WX021-3. MS-ESI m / z: 261.0 [M+H-56] + .

[0704] Step 4: Synthesis of compound WX021-4

[0705] At room temperature and under nitrogen protection, the intermediate BB-2-3 (0.97 g, 3.73 mmol) was dissolved in acetonitrile (20 mL), tetramethyl chlorourea hexafluorophosphate (1.25 g, 4.47 mmol) and N-methylimidazole (1.07 g, 13.05 mmol) were added, stirred for 10 minutes, and compound WX021-3 (1.30 g, 4.10 mmol) was added. The reaction mixture was stirred at room temperature for 15 hours. After the reaction was completed, the solvent was removed by concentration under reduced pressure, saturated brine (50 mL) was added, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1-0 / 1, volume ratio) to obtain compound WX021-4. MS-ESI m / z: 559.3 [M + H] + . 1 H NMR (400MHz, CDCl3) δ: 9.61 (s, 1H), 8.43 (d, J = 10.0Hz, 2H), 8.31 (d, J = 7.6Hz, 1H), 6.77 (t, J = 54.4Hz, 1H), 6.12 (d, J = 8.0Hz, 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).

[0706] Step 5: Synthesis of the hydrochloride salt of compound WX021-5

[0707] At room temperature and under nitrogen protection, compound WX021-4 (0.51 g, 913.03 μmol) was dissolved in ethyl acetate (2 mL), and a hydrochloric acid solution in ethyl acetate (4 M, 20.40 mL) was added. The reaction mixture was stirred at room temperature for 15 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain the hydrochloride salt of compound WX021-5. MS-ESI m / z: 459.1 [M+H] + .

[0708] Step 6: Synthesis of compound WX021-7

[0709] At room temperature and under nitrogen protection, compound WX021-6 (200g, 1.32mol) was dissolved in ethanol (1.5L), di-tert-butyl dicarbonate (346.51g, 1.59mol) was added in batches, and the reaction mixture was heated to 60°C and stirred for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure to remove the solvent. Isopropanol (500mL) was added to the residue, cooled to 0°C, stirred for 1 hour, filtered, and the filter cake was rinsed with isopropanol (200mL), 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] + . 1 H NMR (400MHz, DMSO_d6) δ: 12.60 (s, 1H), 8.12 (s, 1H), 7.90 (d, J = 7.6Hz, 1H), 7.66 (d, J = 8.0Hz, 1H), 6.94 (d, J = 8.0Hz, 1H), 2.66 (s, 3H), 1.46 (s, 9H).

[0710] Step 7: Synthesis of compound WX021-8

[0711] At room temperature and under nitrogen protection, 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. Then the temperature was raised to 50 ° C for 1 hour, hydroxylamine hydrochloride (11.06 g, 159.19 mmol) was added, and the stirring reaction continued for 1 hour. After the reaction was completed, the reaction solution was cooled to room temperature, water (1.5 L) and methyl tert-butyl ether (1.5 L) were added, stirred for 5 minutes, separated, and the aqueous phase was extracted with methyl tert-butyl ether (500 mL × 2). The organic phases were combined, washed with 10% brine (500 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent to obtain compound WX021-8. MS-ESI m / z:211.1[M+H-56] + . 1 H NMR(400MHz, DMSO_d6)δ:12.27(s,1H),11.67(s,1H),7.82(s,1H),7.69(d,J=7. 2Hz, 1H), 7.23 (d, J = 8.0Hz, 1H), 6.86 (t, J = 8.0Hz, 1H), 2.27 (s, 3H), 1.46 (s, 9H).

[0712] Step 8: Synthesis of compound WX021-9

[0713] At room temperature and under nitrogen protection, 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 completed, the reaction solution was cooled to room temperature, water (1 L) was added, and it was extracted with a mixed solvent of methyl tert-butyl ether and petroleum ether (volume ratio 1 / 1, 500 mL×2), and the organic phase was washed with 10% brine (500 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent to obtain compound WX021-9. MS-ESI m / z: 249.1 [M+H] + . 1 H NMR(400MHz, CDCl3)δ:8.16(s,1H),7.30(s,1H),7.00(s,1H),2.59(s,3H),1.57(s,9H).

[0714] Step 9: Synthesis of compound WX021-10

[0715] At room temperature and under nitrogen protection, a tetrahydrofuran solution of lithium diisopropylamide (2M, 741.11 mL) was cooled to -68°C, and a tetrahydrofuran solution of dimethyl carbonate (36.72 g, 407.61 mmol, 34.31 mL) and compound WX021-9 (92 g, 370.55 mmol) (920 mL) was added dropwise. The addition was completed in about 30 minutes, and the temperature was controlled at -50°C to -68°C and stirred for 30 minutes. After the reaction was completed, the reaction solution was slowly poured into saturated ammonium chloride (1.5 L), extracted with ethyl acetate (500 mL × 3), and 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 to obtain compound WX021-10. MS-ESI m / z: 307.1 [M + H] + .

[0716] Step 10: Synthesis of compound WX021-11

[0717] At room temperature and under nitrogen protection, 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 potassium tert-butylate tetrahydrofuran solution (1M, 48.97 mL) was added dropwise. After the addition was complete, the mixture was stirred for 2 hours. After the reaction was completed, the reaction solution was poured into 1M hydrochloric acid (150 mL) and extracted with ethyl acetate (150 mL×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 a 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 filter cake was rinsed with methyl tert-butyl ether (50 mL), the filter cake was collected, and vacuum dried to obtain compound WX021-11. 1 H NMR(400MHz, DMSO_d6)δ:11.10(s,1H),9.55(s,1H),7.69(d,J=7.6Hz,1H),7.54(d,J=7.6Hz,1H),7.30(t,J=8.0Hz,1H) ,4.60(dd,J=5.0,11.8Hz,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).

[0718] Step 11: Synthesis of the hydrochloride salt of compound WX021-12

[0719] At room temperature, compound WX021-11 (9.4 g, 27.22 mmol) was dissolved in ethyl acetate (50 mL), and a solution of hydrochloric acid in ethyl acetate (4 M, 150 mL) was added, and the reaction mixture was stirred at room temperature for 12 hours. After the reaction was completed, the mixture was filtered, and the filter cake was rinsed with ethyl acetate (20 mL), and the filter cake was collected to obtain the hydrochloride salt of compound WX021-12. 1 H NMR(400MHz, DMSO_d6)δ:11.09(s,1H),8.32(s,2H),7.31(d,J=7.6Hz,1H),7.26-7.16(m,2H),4.59( dd,J=4.8,12.0Hz,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).

[0720] Step 12: Synthesis of compound WX021-13

[0721] At room temperature and under nitrogen protection, the hydrochloride of compound WX021-12 (300 mg) was dissolved in anhydrous dichloromethane (6 mL), cooled to 0-5 ° C in an ice bath, triethylamine (323.30 mg, 3.19 mmol) and chloroacetyl chloride (144.34 mg, 1.28 mmol) were added dropwise in sequence, stirred for 2 hours, slowly returned to room temperature and stirred for 2 hours. After the reaction was completed, water (20 mL) was added and extracted with dichloromethane (7 mL × 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 a residue. The obtained 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 completed, it was cooled to room temperature, water (30 mL) was added, and it was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained 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] + .

[0722] Step 13: Synthesis of compound WX021-14

[0723] At room temperature and under nitrogen protection, compound WX021-13 (247 mg, 555.71 μmol) was dissolved in tetrahydrofuran (4 mL), sulfuric acid (2M, 1 mL) was added, and the reaction mixture was heated to 70 ° C and stirred for 12 hours. After the reaction was completed, it was cooled to room temperature, water (20 mL) was added, and it was extracted with ethyl acetate (7 mL × 2), and 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 × 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] + .

[0724] Step 14: Synthesis of the hydrochloride salt of compound WX021

[0725] At room temperature and under nitrogen protection, the hydrochloride salt of compound WX021-5 (80 mg) and compound WX021-14 (64.40 mg, 161.64 μmol) 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. The reaction mixture was stirred at room temperature for 2 hours. Sodium acetate borohydride (102.77 mg, 484.92 μmol) was added and the stirring reaction was continued for 15 hours. After the reaction was completed, 1M hydrochloric acid (1 mL) was added to the reaction solution, and the organic solvent was removed by concentration under reduced pressure. The residue was separated by preparative HPLC (chromatographic column: Phenomenex Luna 80*30mm*3μm; mobile phase: water (0.04% hydrochloric acid)-acetonitrile; acetonitrile%: 1%-30%, 8min) to obtain the hydrochloride of the target compound WX021. MS-ESI m / z: 841.6 [M+H] + . 1 H NMR(400MHz, DMSO_d6)δ:11.13(s,2H),10.44(s,1H),10.12(s,1H),9.54(d,J=6.4Hz,1H),8.80(d,J=7.6Hz,1H),8.46(d,J=3.2Hz,1H), 8.27(d,J=5.6Hz,1H),8.01(d,J=7.6Hz,1H),7.69(d,J=8.0Hz,1H),7.41(t,J=8.0Hz,1H),7.32-7.00(m,1H),6.91-6.41(m,1H),5.31-5. 02(m,1H),4.77(d,J=20.8Hz,1H),4.65(dd,J=5.0,12.2Hz,1H),4.60-4.52(m,1H),4.41-4.23(m,2H),3.83-3.80(m,1H),3.76-3.62(m,4 H),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).

[0726] Embodiment 22

[0727]

[0728] Synthesis route:

[0729]

[0730] Step 1: Synthesis of compound WX022-1

[0731] Under nitrogen protection, compound WX020-5 (15 g, 62.23 mmol) was dissolved in N, N-dimethylformamide (250 mL), and cuprous iodide (1.19 g, 6.22 mmol), dichlorobis(triphenylphosphine) palladium (4.37 g, 6.22 mmol) and N, N-diisopropylethylamine (32.17 g, 248.92 mmol) were added. The reaction mixture was heated to 85 °C, and a solution of compound WX003-2 (59.57 g, 248.92 mmol) in N, N-dimethylformamide (50 mL) was added dropwise for 2 hours. After the addition was completed, the mixture was stirred and reacted for 1 hour. After the reaction was completed, the mixture was cooled to room temperature, poured into water (1000 mL), extracted with ethyl acetate (300 mL × 3), and the organic phase was discarded. The aqueous phase was collected, the pH was adjusted to 5-6 with 1M hydrochloric acid, and extracted with ethyl acetate (300 mL × 2). The organic phases were combined, washed with saturated brine (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] + .

[0732] Step 2: Synthesis of compound WX022-2

[0733] At room temperature and under argon protection, palladium / carbon (5g, purity: 10%) and palladium hydroxide / carbon (5g, purity: 20%) were added to methanol (400mL), compound WX022-1 (30g, 75.11mmol) was added, and the hydrogen balloon was replaced three times. The reaction mixture was stirred at room temperature for 24 hours. The reaction system was filtered, palladium / carbon (5g, purity: 10%) and palladium hydroxide / carbon (5g, purity: 20%) were added to the filtrate, the hydrogen pressure was set to 30psi, and the reaction was continued to stir at room temperature for 24 hours. After the reaction was completed, it was filtered, the filter cake was rinsed with methanol (50mL×3), and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase column (chromatographic column: DAC-150luna, flow rate: 650mL / min, mobile phase: pure water), the fraction was adjusted to pH=7-8 with saturated sodium bicarbonate aqueous solution, and most of the organic solvent was removed by concentration under reduced pressure, extracted with dichloromethane (100mL), and the organic phase was discarded. The aqueous phase was adjusted to pH 5-6 with 1M hydrochloric acid, extracted with dichloromethane (100 mL×2), the organic phase was 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] + . 1H NMR(400MHz, CDCl3)δ:11.06(s,1H),7.78(dd,J=1.4,7.8Hz,1H),7.44(dd,J=1.2,7.6Hz,1H),7.22(t,J=7.6Hz,1H),5.88(s,1H),3.72-3.62(m,2 H),3.47(t,J=6.2Hz,2H),3.44-3.36(m,1H),3.18-3.03(m,2H),2.94(t, J=7.4Hz,2H),2.03-1.91(m,2H),1.82-1.71(m,2H),1.54-1.41(m,11H).

[0734] Step 3: Synthesis of compound WX022-3

[0735] At room temperature and under nitrogen 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 stirring reaction was continued for 15 hours. After the reaction was completed, most of the organic solvent was removed by concentration under reduced pressure, and the pH was adjusted to 7-8 with sodium bicarbonate aqueous solution, extracted with methyl tert-butyl ether (50 mL × 2), and the organic phase was discarded. The aqueous phase was adjusted to pH 5-6 with 1N hydrochloric acid, extracted with dichloromethane (50 mL × 2), and 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] + .

[0736] Step 4: Synthesis of compound WX022-4

[0737] At room temperature and under nitrogen protection, compound WX022-3 (0.87 g, 2.08 mmol) was dissolved in ethanol (10 mL), and concentrated sulfuric acid (407.80 mg, 4.16 mmol, purity: 98%) was added dropwise. The reaction mixture was heated to 85 ° C and stirred for 15 hours. After the reaction was completed, it was concentrated under reduced pressure to obtain a 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 reaction was stirred for 3 hours. After the reaction was completed, it was extracted with ethyl acetate (10 mL × 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 obtained 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] + . 1 H NMR (400MHz, CDCl3) δ: 7.54 (dd, J = 0.8, 8.0Hz, 1H), 7.36 (d, J = 6.8Hz, 1H), 7.24 (d, J = 7.6Hz, 1H), 4.22 (q, J = 7.2Hz, 2H), 4.04 (s, 2H), 3.81-3.71 (m, 2H),3.50(t,J=6.2Hz,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=7.2Hz,3H).

[0738] Step 5: Synthesis of compound WX022-5

[0739] At room temperature and under nitrogen protection, compound WX022-4 (310 mg, 694.23 μmol) was dissolved in anhydrous tetrahydrofuran (6 mL), cooled to 0 ° C in an ice bath, and a tetrahydrofuran solution of lithium diisopropylamide (2M, 520.68 μL) was added dropwise. The mixture was stirred for 15 minutes, and acrylamide (59.21 mg, 833.08 μmol) in anhydrous tetrahydrofuran (2 mL) was added dropwise. The reaction mixture was stirred at room temperature for 12 hours. After the reaction was completed, the reaction solution was poured into 1M hydrochloric acid (10 mL) and extracted with ethyl acetate (5 mL × 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 residue was separated by thin layer chromatography (developing solvent: petroleum ether / ethyl acetate = 1 / 2, volume ratio) to obtain compound WX022-5. 1HNMR(400MHz, CDCl3)δ:8.19(s,1H),7.53(d,J=8.0Hz,1H),7.38(d,J=7.2Hz,1H) ,7.31-7.23(m,1H),4.34(dd,J=5.4,8.6Hz,1H),3.85-3.65(m,2H),3.50(t,J=6. 2Hz,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).

[0740] Step 6: Synthesis of trifluoroacetate salt of compound WX022-6

[0741] At room temperature and under nitrogen protection, compound WX022-5 (92 mg, 195.10 μmol) was dissolved in anhydrous dichloromethane (2 mL), trifluoroacetic acid (616.00 mg, 5.40 mmol, 0.4 mL) was added, and the reaction mixture was stirred at room temperature for 12 hours. After the reaction was completed, the trifluoroacetate salt of compound WX022-6 was obtained by concentration under reduced pressure. MS–ESI m / z: 372.0 [M+H] + .

[0742] Step 7: Synthesis of the hydrochloride salt of compound WX022

[0743] At room temperature and under nitrogen protection, the trifluoroacetate of compound WX022-6 (139.2 mg) was dissolved in acetonitrile (2 mL), 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 completed, the acetonitrile was removed by concentration under reduced pressure. The residue was separated by preparative HPLC (chromatographic column: Phenomenex Luna 80*30mm*3μm; mobile phase: water (0.04% hydrochloric acid)-acetonitrile; acetonitrile%: 25%-55%, 8min) to obtain the hydrochloride of the target compound WX022. MS-ESI m / z: 841.5[M+H] + . 1H NMR(400MHz,DMSO_d6)δ:11.10(s,1H),9.51(br d,J=6.4Hz,2H),8.78(d,J=7.6Hz,1H),8.40(d,J=4.0Hz,1H),8.25(d,J=5.6Hz,1H),7.69(d,J=8.0Hz,1H) ,7.49(t,J=7.2Hz,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=4.8,12.0Hz,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).

[0744] Embodiment 23

[0745]

[0746] Synthesis route:

[0747]

[0748] Step 1: Synthesis of compound WX023-1

[0749] At room temperature and under nitrogen protection, compound WX020-4 (10g, 46.50mmol) was dissolved in N,N-dimethylformamide (100mL), potassium carbonate (12.85g, 93.00mmol) was added, and the mixture was cooled to 0°C in an ice bath. Methyl iodide (19.80g, 139.50mmol) was slowly added. After the addition was complete, the mixture was slowly restored to room temperature and stirred for 3 hours. After the reaction was completed, the reaction solution was cooled to 0°C, ammonia water (10mL) was slowly added, stirred for 15 minutes, water (100mL) was added to the reaction solution, and extracted with ethyl acetate (100mL×3). The organic phases were combined, washed with saturated brine (200mL), 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] + . 1H NMR(400MHz, DMSO_d6)δ:7.83(dd,J=1.6,8.0Hz,1H),7.61(dd,J=1.6,7.6Hz,1H),7.18(t,J=7.8Hz,1H),3.80(s,3H),2.58(s,3H).

[0750] Step 2: Synthesis of compound WX023-2

[0751] At room temperature and under nitrogen protection, compound WX023-1 (10 g, 43.65 mmol) and allyl boric acid naphthalene 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] dichloropalladium dichloromethane (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 completed, it was cooled to room temperature, water (100 mL) was added to the reaction solution, and it was extracted with ethyl acetate (100 mL×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 a crude product. The crude product was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0-0 / 1, volume ratio) to obtain compound WX023-2. MS-ESI m / z: 191.2 [M+H] + . 1 H NMR(400MHz, DMSO_d6)δ:7.44(dd,J=1.6,7.6Hz,1H),7.38(dd,J=1.6,7.6Hz,1H),7.16(t,J=7.6Hz,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=6.4Hz,2H),2.56(s,3H).

[0752] Step 3: Synthesis of compound WX023-3

[0753] At room temperature and under nitrogen protection, 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), cooled to 0 ° C, sodium periodate (54.08 g, 252.84 mmol) and ruthenium trichloride (161.38 mg, 777.97 μmol) were added in batches, and the mixture was slowly returned to room temperature and stirred for 12 hours. After the reaction was completed, it was cooled to 0 ° C, and a saturated aqueous sodium sulfite solution (100 mL) was slowly added to the reaction solution, stirred at room temperature for 20 minutes, and the solution was adjusted to pH 5-6 with 2M hydrochloric acid, and extracted with ethyl acetate (500 mL × 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 (400MHz, CDCl3) δ: 10.04 (s, 1H), 7.55 (dd, J=1.6, 7.6Hz, 1H), 7.43 (dd, J= 1.2,7.6Hz,1H),7.16(t,J=7.6Hz,1H),3.94(s,2H),3.78(s,3H),2.64(s,3H).

[0754] Step 4: Synthesis of compound WX023-4

[0755] At room temperature and under nitrogen protection, compound WX023-3 (4.8 g, 23.05 mmol) was dissolved in N, N-dimethylformamide (50 mL), and N, N-diisopropylethylamine (8.94 g, 69.16 mmol) and 2-(7-azobenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate (9.64 g, 25.36 mmol) were added, stirred for 15 minutes, 1-tert-butyloxycarbonyl-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 completed, the reaction solution was poured into water (50 mL) and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with 15% brine (100 mL), then washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a 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] - . 1H NMR (400MHz, CDCl3) δ: 7.52 (dd, J=1.6, 7.6Hz, 1H), 7.42 (dd, J=1.6, 7.6Hz, 1H), 7.15 (t, J=7.6Hz, 1H), 5.78 (d, J=7.6Hz, 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).

[0756] Step 5: Synthesis of compound WX023-5

[0757] At room temperature and under nitrogen protection, 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 completed, a saturated sodium carbonate aqueous solution was added dropwise to the reaction solution 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 completed, 1M hydrochloric acid was used to adjust the pH to 7, and water (70 mL) and dichloromethane (20 mL) were added for extraction. The aqueous phase was extracted with dichloromethane (50 mL × 2). The organic phases were combined, washed with saturated brine (30 mL × 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] + .

[0758] Step 6: Synthesis of compound WX023-6

[0759] At room temperature and under nitrogen 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 completed, the mixture was concentrated under reduced pressure to obtain compound WX023-6. MS-ESI m / z: 303.3 [M+H-100] + .

[0760] Step 7: Synthesis of Compound WX023-7

[0761] At room temperature and under nitrogen protection, compound WX023-6 (2g, 4.97mmol) was dissolved in ethanol (60mL), glacial acetic acid (1.79g, 29.82mmol) was used to adjust pH = 6-7, hydroxylamine hydrochloride (2.59g, 37.27mmol) was added, and the reaction mixture was heated to 80°C and stirred for 8 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, the filter cake was rinsed with ethanol (10mL×2), water (15mL) was added to the filtrate, the filtrate was concentrated under reduced pressure to remove most of the solvent, and then extracted with dichloromethane (30mL×3). The organic phases were combined, washed with saturated brine (30mL), 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] + .

[0762] Step 8: Synthesis of compound WX023-8

[0763] At room temperature and under nitrogen protection, compound WX023-7 (1.2 g, 2.87 mmol) was dissolved in ethanol (10 mL), and concentrated sulfuric acid (563.87 mg, 5.75 mmol, 306.45 μL) was added. The reaction mixture was heated to 70 ° C and stirred for 6 hours. After the reaction was completed, the solvent was removed by concentration under reduced pressure, tetrahydrofuran (5 mL) was added, and the pH was adjusted to 7 with a saturated aqueous sodium carbonate solution, and then di-tert-butyl dicarbonate (750.68 mg, 3.44 mmol) was added. The reaction mixture was stirred for 2 hours at room temperature. After the reaction was completed, the pH was adjusted to 7 with 1M hydrochloric acid, and extracted with dichloromethane (20 mL × 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 a crude product. The crude product was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0-0 / 1, volume ratio) to obtain compound WX023-8. MS-ESI m / z:346.2[M+H-100] + . 1 H NMR (400MHz, CDCl3) δ: 7.65 (d, J = 8.0Hz, 1H), 7.52 (d, J = 6.8Hz, 1H), 7.33 (t, J = 7.6Hz, 1H), 5.64 (d, J = 7.6Hz, 1H), 4.23 (q, J = 7. 12Hz,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).

[0764] Step 9: Synthesis of trifluoroacetate salt of compound WX023-9

[0765] At room temperature and under nitrogen protection, compound WX023-8 (390 mg, 875.41 μmol) was dissolved in dichloromethane (4 mL), trifluoroacetic acid (2.46 g, 21.61 mmol, 1.6 mL) was added, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain the trifluoroacetate salt of compound WX023-9. MS-ESI m / z: 346.2 [M+H] + .

[0766] Step 10: Synthesis of compound WX023-10

[0767] At room temperature and under nitrogen protection, the trifluoroacetate of compound WX023-9 (450 mg) was dissolved in acetonitrile (5 mL), N, N-diisopropylethylamine (619.39 mg, 4.79 mmol) was added, the reaction mixture was stirred for 10 minutes, compound WX015-8 (520.56 mg, 871.37 μmol) was added, the reaction mixture was heated to 80 ° C and continued to react for 8 hours. After the reaction was completed, the reaction solution was cooled to room temperature, poured into a saturated aqueous ammonium chloride solution (10 mL), and extracted with a mixed solvent of dichloromethane and ethanol (volume ratio: 10:1, 10 mL×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 a crude product. The crude product was separated by a silica gel plate (developing solvent: dichloromethane / methanol = 8 / 1, volume ratio) to obtain compound WX023-10. MS-ESI m / z:815.2[M+H] + . 1H NMR(400MHz, DMSO_d6)δ:9.50(d,J=5.6Hz,1H),8.78(d,J=8.0Hz,1H),8.39(d,J=4.4Hz,1H),8.26(d,J=5.6Hz,1H),8.19(d,J= 6.8Hz,1H),7.69(d,J=8.0Hz,1H),7.51(d,J=7.4Hz,1H),7.34(t,J=7.6Hz,1H),7.27-6.95(m,1H),6.88-6.40(m,1H),5.17(d, J=82.8Hz,1H),4.77(d,J=16.8Hz,1H),4.19(s,2H),3.81(s,2H),3.75(s,2H),3.68-3.50(m,3H),3.44(d,J=9.6Hz,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).

[0768] Step 11: Synthesis of the formate salt of compound WX023

[0769] At room temperature and under nitrogen 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 (1M, 368.15 μL) were added in sequence, stirred for 4 hours, and then returned to room temperature and stirred for 4 hours. After the reaction was completed, the reaction solution was poured into a formic acid aqueous solution (0.1%, 5 mL), stirred for 2 minutes, and concentrated under reduced pressure to obtain a crude product. The crude product was first separated by preparative HPLC (chromatographic column: Phenomenex C18 75*30mm*3μm; mobile phase: water (0.2% formic acid)-acetonitrile; acetonitrile%: 1%-35%, 8min)), and then separated by preparative HPLC (chromatographic column: Phenomenex Luna 80*30mm*3μm; mobile phase: water (0.2% formic acid)-acetonitrile; acetonitrile%: 10%-30%, 8min) to obtain the formate salt of the target compound WX023. MS-ESI m / z: 840.3[M+H] + . 1H NMR(400MHz, DMSO_d6)δ:11.09(s,1H),9.50(d,J=6.4Hz,1H),8.78(d,J=7.6Hz,1H) ,8.38(d,J=4.4Hz,1H),8.26(d,J=6.0Hz,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=82.8Hz,1H),4.77(d,J=18.4Hz,1H),4.60(dd,J=5.2,12.0Hz,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=6.8Hz,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).

[0770] Embodiment 24

[0771]

[0772] Synthesis route:

[0773]

[0774] Step 1: Synthesis of compound WX024-1

[0775] At room temperature and under nitrogen protection, the hydrochloride of compound WX021-12 (300 mg) was dissolved in dichloromethane (6 mL), cooled to 0-5 ° C, triethylamine (323.30 mg, 3.19 mmol) and chloroacetyl chloride (144.34 mg, 1.28 mmol) were added dropwise in sequence, stirred and reacted for 2 hours, and then slowly returned to room temperature and stirred for 2 hours. After the reaction was completed, water (20 mL) was added to the reaction solution, and extracted with dichloromethane (7 mL × 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 directly used in the next step.

[0776] Step 2: Synthesis of compound WX024-3

[0777] At room temperature and under nitrogen protection, 4-hydroxypyridine (9g, 94.64mmol), compound WX024-2 (21.99g, 189.28mmol) and triphenylphosphine (24.82g, 94.64mmol) were dissolved in anhydrous tetrahydrofuran (200mL), cooled to 0-5°C, and diisopropyl azodicarboxylate (19.14g, 94.64mmol, 18.40mL) was added dropwise. After the addition was complete, the reaction mixture was slowly restored to room temperature and stirred for 12 hours. After the reaction was completed, water (500mL) was added to the reaction solution, and extracted with ethyl acetate (200mL×3). The organic phases were combined, washed with saturated brine (200mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The obtained residue was separated by column chromatography (eluent: dichloromethane / methanol = 50 / 1-30 / 1, volume ratio) to obtain compound WX024-3. MS-ESI m / z: 194.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ: 8.41 (d, J = 6.0Hz, 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).

[0778] Step 3: Synthesis of compound WX024-4

[0779] At room temperature and under argon 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, hydrogen was replaced three times, and the hydrogen pressure was maintained at 50 psi. The reaction mixture was heated to 50 ° C and stirred for 96 hours. After the reaction was completed, it was filtered, the filter cake was rinsed with methanol (200 mL × 7), the mother liquor was collected, and the solvent was removed by concentration under reduced pressure. The obtained residue was separated by column chromatography (eluent: dichloromethane / methanol = 100 / 1-30 / 1, volume ratio) to obtain compound WX024-4. MS-ESI m / z: 242.1 [M + H] + . 1H NMR(400MHz, 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).

[0780] Step 4: Synthesis of compound WX024-5

[0781] At room temperature and under nitrogen 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 stirred and reacted for 2 hours. After the reaction was completed, water (70 mL) was added to the reaction solution, and extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound WX024-5, which was directly used in the next step.

[0782] Step 5: Synthesis of compound WX024-6

[0783] At room temperature and under nitrogen protection, 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 in sequence, and the reaction mixture was heated to 80 ° C and stirred for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature, water (50 mL) was added, and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The obtained residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1-0 / 1, volume ratio) to obtain compound WX024-6. MS-ESI m / z: 387.1 [M + H] + . 1H NMR (400MHz, CDCl3) δ: 8.22 (s, 1H), 7.10 (t, J = 53.6Hz, 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).

[0784] Step 6: Synthesis of compound WX024-7

[0785] At room temperature and under nitrogen protection, 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 replaced with a hydrogen balloon three times. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, it was filtered, the filter cake was rinsed with methanol (50 mL × 5), and the filtrate was collected and concentrated under reduced pressure to remove the solvent. The obtained 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] + .

[0786] Step 7: Synthesis of compound WX024-8

[0787] At room temperature and under nitrogen protection, the intermediate BB-2-3 (143.70 mg, 552.17 μmol) was dissolved in acetonitrile (3 mL), and N,N,N,N-tetramethylchloroformamidine hexafluorophosphate (154.93 mg, 552.17 μmol) and N-methylimidazole (132.23 mg, 1.61 mmol) were added, stirred for 10 minutes, and compound WX024-7 (164 mg, 460.14 μmol) was added. The reaction mixture was stirred for 16 hours. After the reaction was completed, the reaction solution was poured into ice water (30 mL) and extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated on a silica gel plate (eluent: dichloromethane / methanol = 10 / 1, volume ratio) to obtain compound WX024-8. MS-ESI m / z:599.4[M+H] + .

[0788] Step 8: Synthesis of compound WX024-9

[0789] At room temperature and under nitrogen 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 completed, it was cooled to room temperature, adjusted to pH = 7 with 1 M hydrochloric acid, and concentrated under reduced pressure to remove the solvent to obtain compound WX024-9. MS-ESI m / z: 557.3 [M + H] + .

[0790] Step 9: Synthesis of compound WX024

[0791] At room temperature and under nitrogen 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 completed, the solvent was removed by concentration under reduced pressure. The obtained residue was first separated by preparative HPLC (chromatographic column: Phenomenex luna C18 80*40mm*3μm; mobile phase: water (0.04% hydrochloric acid)-acetonitrile]; acetonitrile%: 25%-50%, 7min), and then separated by preparative HPLC (chromatographic column: Phenomenex C18 75*30mm*3μm; mobile phase: water (10mM ammonium bicarbonate)-acetonitrile; acetonitrile%: 35%-55%, 8min) to obtain compound WX024. MS-ESI m / z: 842.5[M+H] + . 1H NMR(400MHz, DMSO_d6)δ:11.12(s,1H),11.08(d,J=6.4Hz,1H),10.02(s,1H),9.50(d,J=6.4Hz,1H),8.78(d,J=7.6Hz,1H),8.39(d,J =3.2Hz,1H),8.25(d,J=5.6Hz,1H),8.02(dd,J=2.8,7.2Hz,1H),7.69(d,J=7.6Hz,1H),7.41(t,J=7.8Hz,1H),7.27-6.95(m,1H),6.90 -6.40(m,1H),5.17(d,J=78.4Hz,1H),4.70(d,J=21.2Hz,1H),4.64(dd,J=5.0,J=12.2Hz,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).

[0792] Example 25 and Example 26

[0793]

[0794] Synthesis route:

[0795]

[0796] Synthesis of the hydrochloride salt of compound WX025 and the hydrochloride salt of compound WX026

[0797] The hydrochloride salt of compound WX006 (500 mg) was separated by supercritical fluid chromatography (separation conditions: chromatographic column: REGIS (S, S) WHELK-O1 (250 mm*25 mm, 10 μm); mobile phase: A: CO2; B: EtOH / ACN; B%: 70%-70%, 25 min. Analysis method: chromatographic 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). The sample with a retention time of 2.631 min was collected and separated by preparative HPLC (chromatographic column: Phenomenex Luna 80*40mm*3μm; mobile phase: water (0.04% hydrochloric acid)-acetonitrile; acetonitrile%: 5%-35%, 7min) to obtain the hydrochloride of compound WX025 (ee%: 99.10%). The sample with a retention time of 5.384 min was collected and separated by preparative HPLC (chromatographic column: Phenomenex Luna 80*40mm*3μm; mobile phase: water (0.04% hydrochloric acid)-acetonitrile; acetonitrile%: 5%-35%, 7min) to obtain the hydrochloride of compound WX026 (ee%: 98.94%).

[0798] The hydrochloride salt of compound WX025: 1 H NMR(400MHz, DMSO_d6)δ:11.18(s,1H),10.92(s,1H),10.58(s,1H),9.50(d,J=6.4Hz,1H),8.78(d,J=7.6Hz,1H),8.40(d, J=3.6Hz,1H),8.26(d,J=5.6Hz,1H),7.98(s,1H),7.73(d,J=7.6Hz,1H),7.41(d,J=7.6Hz,1H),7.27-6.96(m,2H),6.90-6. 41(m,1H),5.18(d,J=79.2Hz,1H),4.76(d,J=18.8Hz,1H),4.33-4.21(m,1H),4.17(dd,J=4.8Hz,12.0Hz,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).

[0799] Hydrochloride salt of compound WX026: 1H NMR(400MHz, DMSO_d6)δ:10.92(s,1H),10.44(s,1H),9.51(d,J=6.0Hz,1H),8.78(d,J=7.6Hz,1H),8.40(d,J=4.0Hz,1H),8. 25(d,J=5.6Hz,1H),7.97(s,1H),7.73(d,J=7.6Hz,1H),7.41(d,J=8.0Hz,1H),7.24(d,J=7.6Hz,1H),7.22-6.95(m,1H),6.90 -6.43(m,1H),5.17(d,J=79.2Hz,1H),4.77(d,J=19.6Hz,1H),4.32-4.20(m,1H),4.17(dd,J=4.8Hz,12.0Hz,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).

[0800] Example 27 and Example 28

[0801]

[0802] Synthesis route:

[0803]

[0804] Synthesis of the hydrochloride salt of compound WX027 and the hydrochloride salt of compound WX028

[0805] The hydrochloride salt of compound WX015 (500 mg) was separated by supercritical fluid chromatography (separation conditions: chromatographic 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. Analysis method: chromatographic 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). The sample with a retention time of 1.678 min was collected and separated by preparative HPLC (chromatographic column: Phenomenex luna C18 80*40mm*3μm; mobile phase: water (0.04% hydrochloric acid)-acetonitrile; acetonitrile%: 23%-43%, 7min) to obtain the hydrochloride of compound WX027 (ee%: 96.68%). The sample with a retention time of 2.265 min was collected and separated by preparative HPLC (chromatographic column: Phenomenex Luna 80*30mm*3μm; mobile phase: water (0.04% hydrochloric acid)-acetonitrile; acetonitrile%: 1%-30%, 8min) to obtain the hydrochloride of compound WX028 (ee%: 95.18%).

[0806] The hydrochloride salt of compound WX027: 1 H NMR(400MHz, DMSO_d6)δ:11.12(s,1H),10.49(s,1H),9.51(d,J=6.0Hz,1H),8.79(d,J=8.0Hz,1H),8.41(d,J=4.4Hz,1H),8.2 6(d,J=5.6Hz,1H),8.01(d,J=7.6Hz,1H),7.65(d,J=8.0Hz,1H),7.38(t,J=8.0Hz,1H),7.27-6.95(m,1H),6.90-6.44(m,1H),5 .18(d,J=78.0Hz,1H),4.76(d,J=20.4Hz,1H),4.64(dd,J=4.8Hz,12.0Hz,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).

[0807] The hydrochloride salt of compound WX028: 1H NMR(400MHz, DMSO_d6)δ:11.12(s,1H),10.47(s,1H),9.51(d,J=6.0Hz,1H),8.79(d,J=7.6Hz,1H),8.40(d,J=4.0Hz,1H) ,8.26(d,J=5.6Hz,1H),8.01(d,J=7.6Hz,1H),7.65(d,J=8.0Hz,1H),7.38(t,J=8.0Hz,1H),7.28-6.95(m,1H),6.90-6.43 (m,1H),5.18(d,J=79.2Hz,1H),4.76(d,J=20.8Hz,1H),4.64(dd,J=4.8Hz,12.0Hz,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).

[0808] Biological Testing

[0809] Experimental Example 1: Evaluation of target protein degradation in K562 IRAK4-HiBiT cells

[0810] Purpose of the experiment: This experiment detects the degradation effect of the test compound on the target protein IRAK4 in the K562 IRAK4-HiBiT cell line.

[0811] Experimental Materials:

[0812] 1. Cells and Culture Media

[0813] Cells: K562 IRAK4-HiBiT cells

[0814] Culture medium: RPMI 1640 + 10% FBS + 2mM GlutaMax + 1mM sodium pyruvate + penicillin / streptomycin

[0815] Positive control: 1000 nM; Negative control: 0.1% DMSO

[0816] 2. Reagents and consumables

[0817]

[0818] 3. Instruments

[0819]

[0820]

[0821] Experimental protocol:

[0822] Day 1

[0823] 1. Preparation of Compounds

[0824] (1) Dissolve the powder of the test compound in DMSO to 10 mM as the storage concentration, and manually pipette 9 μL of 10 mM test compound into the 1st and 13th columns of the LDV plate;

[0825] (2) Use a multidrop Combi to add 6 μL DMSO to columns 2-12 and 14-24;

[0826] (3) Use Bravo to dilute the test compound 3-fold (3 μL + 6 μL) from columns 1-11 and 13-23;

[0827] (4) According to the plate layout, use Echo to transfer 25nL of compound solution (columns 1-24 of LDV plate) to the experimental plate;

[0828] (5) Use Echo to transfer 25 nL of 1 mM positive control solution to the assay plate as a 100% degradation control (ie, LC, HPE), and transfer 25 nL of DMSO to the assay plate as a 0% control (ie, HC, ZPE).

[0829] 2. Cell Plating

[0830] (1) Discard the cell culture medium, wash once with DPBS, digest the cells with trypsin, count the cells, and prepare a cell suspension of 2×10 -5 cells / mL;

[0831] (2) Use MultiDrop Combi to add 25 μL / well of cell suspension to the experimental plate containing the test compound at medium speed;

[0832] (3) Place the experimental plate containing cells back into the incubator and culture at 37°C, 5% CO2 for 16 to 18 hours.

[0833] Day 2

[0834] (1) Use MultiDrop Combi to add 25 μL / well of detection reagent (NanoGlo lysis solution + substrate + LgBit protein) to the assay plate at high speed and shake for 10 minutes;

[0835] (2) Centrifuge at 2000 rpm for 1 min to remove bubbles;

[0836] (3). Read the plate using Envision, US Luminescence detection method.

[0837] 3. Data Analysis

[0838] 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 is the blank control. The inhibition rates of compounds at different concentrations were calculated in Excel, and then the inhibition curves were plotted and related parameters were calculated using XLFit software, including the minimum inhibition rate, maximum inhibition rate and DC. 50 .

[0839] The test results are shown in Table 1.

[0840] Table 1 Target protein degradation effect of the compounds of the present invention in K562 IRAK4-HiBiT cells

[0841]

[0842]

[0843] in conclusion:

[0844] The compound of the present invention exhibits excellent degradation effect of the target protein IRAK4 in K562 IRAK4-HiBiT cells.

[0845] Experimental Example 2: Pharmacokinetic evaluation of compounds in mice

[0846] Purpose:

[0847] In this study, CD-1 or C57BL / 6N male mice were used as test animals. The LC / MS / MS method was used to quantitatively determine the drug concentration in the plasma of mice at different time points after intravenous injection or oral administration of the test compound to evaluate the pharmacokinetic characteristics of the test drug in mice.

[0848] Experimental Materials:

[0849] CD-1 mice (male, 20-35 g, 7-10 weeks old, Beijing Weitong Lihua) or C57BL / 6N mice (male, 20-30 g, 7-10 weeks old, Beijing Weitong Lihua)

[0850] Experimental operation A:

[0851] The clear or suspended solution of the test compound was injected into CD-1 mice (overnight fasting) via the tail vein (solvent: 10% DMSO / 10% Solutol / 80% H2O) and administered to CD-1 mice (overnight fasting) by oral gavage. Blood was collected from the saphenous vein at 0h (before administration) and 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24h after intravenous administration, placed in EDTA-K2 anticoagulant tubes, the mixture was thoroughly vortexed and centrifuged at 3200g for 10 minutes at 4°C to obtain plasma; for oral gavage, blood was collected from the saphenous vein at 0.25, 0.5, 1, 2, 4, 8, and 24h after administration, placed in anticoagulant tubes added with EDTA-K2 (Jiangsu Kangjian Medical Supplies Co., Ltd.), the mixture was thoroughly vortexed and centrifuged at 3200g for 10 minutes at 4°C to obtain plasma. The blood drug concentration was determined by LC-MS / MS, and Phoenix WinNonlin TM Version 6.3 (Pharsight, Mountain View, CA) pharmacokinetic software was used to calculate relevant pharmacokinetic parameters using the non-compartmental linear logarithmic trapezoidal method.

[0852] Experimental operation B:

[0853] The clear or suspended solution of the test compound was injected into C57BL / 6N mice (overnight fasting) via the tail vein (vehicle: 5% DMSO / 10% solutol / 85% H2O), or administered to C57BL / 6N mice (overnight fasting). For intravenous administration, 50 μL of blood was collected from cheek puncture at 0h (before administration) and 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, 24h after administration, placed in an anticoagulant tube with sodium heparin, and the mixture was vortexed thoroughly and centrifuged at 6000g for 3 minutes at 2-8°C; for oral administration by gavage, blood was collected from cheek puncture at 0h (before administration) and 0.083, 0.25, 1, 2, 4, 6, 8, 24h after administration, placed in an anticoagulant tube with sodium heparin, and the mixture was vortexed thoroughly and centrifuged at 6000g for 3 minutes at 2-8°C. The plasma drug concentration was determined by LC-MS / MS, and the relevant pharmacokinetic parameters were calculated by the non-compartmental linear logarithmic trapezoidal method using Phoenix WinNonlin8.2.0 pharmacokinetic software.

[0854] The test results are shown in Table 2.

[0855] Table 2 Pharmacokinetic parameters of the compounds of the present invention in mice

[0856]

[0857]

[0858] Conclusion: The oral plasma systemic exposure (AUC 0-inf ) is higher. In rodent mice, its pharmacokinetic properties are better.

[0859] Experimental Example 3: Pharmacokinetic evaluation of compounds in beagle dogs

[0860] Purpose:

[0861] Male beagles were selected as test animals in this study. The LC / MS / MS method was used to quantitatively determine the drug concentration in the plasma of beagles at different time points after intravenous injection or oral administration of the test compound to evaluate the pharmacokinetic characteristics of the test drug in beagles.

[0862] Experimental Materials:

[0863] Beagle (male, 9-11 kg, Jiangsu Yadong Experimental Animal Research Institute Co., Ltd.).

[0864] Experimental operation:

[0865] The clear or suspended solution of the test compound was injected into the beagle dog via the tail vein (diet) (vehicle: 5% DMSO / 10% Solutol / 85% H2O) or administered to the beagle dog by gavage (diet). For intravenous administration, 1 mL of blood was collected from the forelimb vein at 0 h (before administration) and 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, 24 h after administration, EDTA-2K anticoagulated, the mixture was vortexed thoroughly and centrifuged at 2-8°C for 3 minutes at 6000 g; for oral gavage administration, 1 mL of blood was collected from the forelimb vein at 0 h (before administration) and 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, 24 h after administration, EDTA-2K anticoagulated, the mixture was vortexed thoroughly and centrifuged at 2-8°C for 3 minutes at 6000 g. The plasma drug concentration was determined by LC-MS / MS, and the relevant pharmacokinetic parameters were calculated by the non-compartmental linear logarithmic trapezoidal method using Phoenix WinNonlin8.2.0 pharmacokinetic software.

[0866] The test results are shown in Table 3.

[0867] Table 3 Pharmacokinetic parameters of the compounds of the present invention in beagle dogs

[0868]

[0869] Conclusion: The oral plasma systemic exposure (AUC 0-inf ) is higher. In non-rodent beagle dogs, its pharmacokinetic properties are better.

[0870] Experimental Example 4: Pharmacokinetic evaluation of the compound in cynomolgus monkeys

[0871] Purpose:

[0872] Male cynomolgus monkeys were used as test animals in this study. The LC / MS / MS method was used to quantitatively determine the drug concentration in the plasma of cynomolgus monkeys at different time points after intravenous injection or oral administration of the test compound to evaluate the pharmacokinetic characteristics of the test drug in cynomolgus monkeys.

[0873] Experimental Materials:

[0874] Cynomolgus monkeys (male, 2-5 kg, Hainan Jingang Biotechnology Co., Ltd.).

[0875] Experimental operation:

[0876] The clear solution of the test compound was slowly injected into the cynomolgus monkeys through the peripheral vein (administration) (vehicle: 5% DMSO / 10% Solutol / 85% H2O), or administered to the cynomolgus monkeys by gavage (administration). 0.5 mL of blood was collected from the peripheral vein at 0 h (before administration) and 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, 24 h after intravenous administration, placed in EDTA-2K anticoagulant tubes, centrifuged at 3200 g for 10 minutes at 2-8°C, and the supernatant was separated; 0.5 mL of blood was collected from the peripheral vein at 0 h (before administration) and 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, 24 h after oral gavage administration, placed in EDTA-2K anticoagulant tubes, centrifuged at 3200 g for 10 minutes at 2-8°C, and the supernatant was separated. Plasma drug concentrations were determined by LC-MS / MS, and relevant pharmacokinetic parameters were calculated by non-compartmental linear logarithmic trapezoidal method using Phoenix WinNonlin6.3 pharmacokinetic software.

[0877] The test results are shown in Table 4.

[0878] Table 4 Pharmacokinetic parameters of the compounds of the present invention in cynomolgus monkeys

[0879]

[0880] Conclusion: The oral plasma systemic exposure (AUC 0-inf ) is higher. In non-rodent cynomolgus monkeys, its pharmacokinetic properties are better.

[0881] Experimental Example 5: Study on the preventive and therapeutic effects of compounds on acute gouty arthritis induced by sodium urate in rats

[0882] Purpose:

[0883] To evaluate the preventive and therapeutic effects of the compounds on sodium urate-induced acute gouty arthritis in rats.

[0884] Experimental Materials:

[0885] Animals: 5-week-old male SD rats; Source: Zhejiang Weitonglihua Experimental Animal Technology Co., Ltd.

[0886] Experimental reagents:

[0887] Sodium urate: Sigma; Catalog number: BCCB4889;

[0888] DMSO: GENERAL-REAGENT, Catalog Number: P1908824;

[0889] Sterile water for injection: Guangdong Aixide Pharmaceutical Co., Ltd., catalog number: 200913203;

[0890] Solutol:BASF SE; Product Number: 35907288Q0;

[0891] Solvent: 10% DMSO+10% Solutol+80% H2O.

[0892] Experimental instruments:

[0893] Toe swelling meter: YLS-7B, Jinan Yiyan Technology

[0894] Incapacitance Testers, Linton

[0895] Experimental operation:

[0896] Experimental groups: After 3 days of adaptation, the basal hind paw volume, arthritis index score and bilateral hind paw pain threshold were measured for all animals, and 50 animals were selected and divided into 5 groups according to body weight, hind paw volume, arthritis index and bilateral hind paw pain threshold, with 10 animals in each group.

[0897] Table 5 Experimental grouping

[0898]

[0899] The day of drug administration was recorded as D-1, and the drug was administered orally twice a day for 6 consecutive days (D-1 to D4). On D0, one day after drug administration, one hour after the first administration, all rats except the blank control group were anesthetized with isoflurane, and 50 microliters (50 mg / mL) of sodium urate solution were injected into the joint cavity at the puncture point behind the outer side of the right ankle joint to create a model. Joint swelling will reach a peak in 8 to 12 hours (lasting to about 72 hours). The foot volume of the animals was measured before inflammation and 2, 5, 8, 11, 24, 48, 72 and 96 hours after inflammation, and the arthritis index (AI) score was performed; the pain threshold was measured before inflammation and 2, 24, 48, 72 and 96 hours after inflammation using a bipedal balance analgesia. At the peak of joint swelling (8 to 12 hours), key swelling photos of each group of animals were taken and retained.

[0900] Clinical observation: Observe the clinical symptoms of experimental animals once a day and record any abnormalities.

[0901] Foot volume measurement: Before measurement, use a marker to draw a line at the ankle joint of the rat to mark the position. After adding clean water to the instrument, the instrument value is reset to zero and ready for measurement. Put the rat's hind limbs into the water so that the marked line at the ankle joint is on the surface of the liquid. At this time, step on the pedal to read the value, which is the rat's foot volume. After the measurement is completed, step on the pedal again to reset to zero and prepare for the next measurement.

[0902] Arthritis Index (AI): The foot volume is measured and the swelling of the model foot is scored. Arthritis Index scoring criteria:

[0903] Table 6 Clinical scoring criteria for arthritis

[0904] Fraction degree 0 No swelling, normal appearance 1 Mild swelling of the ankle joint with visible bony landmarks 2 The ankle joint is obviously red and swollen, and the bone landmarks disappear, but the swelling is limited to the joint area 3 Swelling of toes other than the ankle

[0905] Statistics:

[0906] The experimental data were expressed as Mean±SD. The data were statistically analyzed using IBM SPSS Statistics 21. The data between the two groups were considered to be significantly different when p<0.05.

[0907] The results of the foot volume, arthritis index, and hindfoot weight-bearing difference tests are shown in Tables 7 , 8 , and 9 .

[0908] Table 7 Effects of the test substances on the paw volume in rats with acute gouty arthritis induced by sodium urate (n=10, )

[0909]

[0910]

[0911] *p<0.05, **p<0.01, ***p<0.001 vs. model group

[0912] Table 8 Effects of the test substances on the hind paw arthritis index in rats with acute gouty arthritis induced by sodium urate (n=10, )

[0913]

[0914] *p<0.05, **p<0.01, ***p<0.001 vs. model group

[0915] Table 9 Effects of the test substances on hind foot weight bearing in rats with acute gouty arthritis induced by sodium urate (n=10, )

[0916]

[0917]

[0918] *p<0.05, **p<0.01, ***p<0.001 vs. model group

[0919] Experimental conclusion:

[0920] The compound of the present invention has therapeutic effects on the hind paw volume, hind paw arthritis index score and hind paw weight-bearing difference of rats with acute gouty arthritis induced by sodium urate, and the effect is dose-dependent.

[0921] Experimental Example 6: Evaluation of the effectiveness of compounds on imiquimod-induced psoriasis mouse model

[0922] Purpose:

[0923] The compounds were evaluated for their efficacy in the imiquimod-induced psoriasis model in BALB / c mice.

[0924] Experimental Materials:

[0925] Animals: BALB / c mice, male, 18-20 g; Source: Zhejiang Weitong Lihua Experimental Animal Technology Co., Ltd.

[0926] Experimental reagents:

[0927] Imiquimod: 3M Health Care Limited, drug registration number: H20160079;

[0928] DMSO: Anergy Chemical, catalog number: E081359;

[0929] Solutol: Sigma-Aldrich, Catalog No.: 42966;

[0930] MC: Sigma-Aldrich, catalog number: M0202;

[0931] Tween 20: Sigma-Aldrich, catalog number: 9005-64-5;

[0932] Solvent: 10% DMSO+10% Solutol+80% H2O.

[0933] Experimental instruments:

[0934] Electronic balance: Sartorius, item number: QUINTIX124-1CN;

[0935] Electronic scale: Shanghai Yueping Instrument, item number: YP10001;

[0936] Ultrasonic cleaner: Kunshang, item number: KQ3200E;

[0937] Electronic oscillator: Scientific Industries, catalog number: SI-0256;

[0938] Anesthesia machine: Yuyan Instrument, item number: ABS-4.

[0939] Experimental operation:

[0940] Experimental grouping and dosing: 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, vehicle (model, G2) group, low-dose (30 mg / kg, BID, G3) group of the test compound, medium-dose (100 mg / kg, BID, G4) group of the test compound and high-dose (300 mg / kg, BID, G5) group of the test compound.

[0941] Model induction: The hair on the back skin of the experimental animals was shaved before applying imiquimod (surface area = 2×3 cm). Except for the normal group, imiquimod cream was applied topically to the shaved back (47 mg) and left ear (15 mg) at 62 mg / mouse every day for 8 consecutive days (from day 0 to day 7). The drug-treated groups (G2-G5) were dosed twice a day from day -1 to day 6, and the solvent or the test compound was administered by gavage, and only once on day 7. The dosage volume of each group was 10 mL / kg. (Note: The first application of imiquimod is stipulated as day 0; because it was administered one day in advance, the first administration was day -1).

[0942] Table 10 Experimental grouping

[0943]

[0944] Data collection and analysis:

[0945] Clinical scores: Clinical disease scores for erythema, scaling, and thickness were measured daily according to a grading system, and a cumulative score was calculated.

[0946] Table 11 Scoring system: erythema, scaling, thickness

[0947] Fraction Clinical symptoms 0 normal 1 slight 2 Mild 3 Moderate 4 Significant

[0948] Ear thickness: The thickness of the left ear was measured on days 0, 3, 5, and 7, for a total of 4 times, and the increase in ear thickness on day 7 relative to day 0 was calculated.

[0949] Spleen weight: The spleen weight was measured after the animals were sacrificed on day 7.

[0950] Inflammatory factors: On the 7th day, the animals were killed and the skin of the lesion site was obtained. The relative contents of interleukin-17, interleukin-6 and tumor necrosis factor-α were detected by fluorescent quantitative PCR.

[0951] Experimental results:

[0952] The experimental data were expressed as Mean ± SEM. The data were statistically analyzed using the one-way ANOVA method using Graphpad prism software. Data between the two groups were considered to be significantly different when p < 0.05.

[0953] The pathological scores, ear thickness increase, spleen weight and inflammatory factor test results of mice are shown in Tables 12 and 13.

[0954] Table 12 Effects of the test substances on pathological scores, ear thickness increase, and spleen weight in the imiquimod-induced psoriasis model in mice (n=6 or 9)

[0955]

[0956] *p<0.05, **p<0.01, ***p<0.001 vs. model group

[0957] Table 13 Effects of the test substances on the relative levels of inflammatory factors in the skin of mice with psoriasis induced by imiquimod (n=3 or 9)

[0958]

[0959] *p<0.05, **p<0.01, ***p<0.001 vs. model group

[0960] Experimental conclusion:

[0961] The compound of the present invention has an improving effect on the pathological score, ear thickness increase and spleen weight of the imiquimod-induced mouse psoriasis model, and also has an inhibitory effect on the inflammatory factors in the skin of the lesion, indicating that it has a therapeutic effect on the psoriasis model animal, and the therapeutic effect of the high dose (300 mpk) is better than that of the medium and low doses (100 mpk, 30 mpk).

Claims

1. The following compounds or pharmaceutically acceptable salts thereof, 2. The following compounds or pharmaceutically acceptable salts thereof, 3. Use of the compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating diseases associated with interleukin-1 receptor-associated kinase 4 protein degradation targeted chimera.

4. The use according to claim 3, wherein the disease associated with the interleukin-1 receptor-associated kinase 4 protein degradation targeted chimera is an inflammatory or immune disease.

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