Aromatic heterocyclic compounds, pharmaceutical compositions containing them, and their use

Abstract

The present invention discloses a compound as shown in formula I and its composition and use, wherein A, X, Y, L, M and W are as defined herein. The compounds disclosed in the present invention can be used for treating diseases related to overactivation or overexpression of JAK3 kinase, such as autoimmune diseases, lung injury, organ transplant rejection diseases, etc. In vitro experiments show that the series of compounds have good JAK3 kinase inhibitory activity and have good prospects for use in the medical field. JPEG2024531433000089.jpg124149

Description

[Technical Field]

[0001] The present invention belongs to the field of pharmaceutical technology and relates to one or more aromatic heterocyclic compounds having inhibitory activity of Janus kinase (JAK). The present invention further relates to a pharmaceutical composition containing the said compound as an active ingredient and the use thereof. [Background technology]

[0002] Janus kinase (JAK) is a cytoplasmic tyrosine protein kinase that is responsible for the transmission of many inflammation-related cytokine signals from cytokine membrane receptors to STAT transcription factors. Abnormalities in JAK / STAT signaling are associated with many diseases, including organ transplant rejection, multiple sclerosis, rheumatoid arthritis, type 1 diabetes, lupus, psoriasis, asthma, food allergies, atopic dermatitis and rhinitis, and skin rashes. It has also been reported to be closely related to the onset and progression of solid and hematological malignancies and myeloproliferative disorders (lung cancer, breast cancer, chronic idiopathic myelofibrosis, polycythemia, essential thrombocythemia, etc.).

[0003] First-generation JAK inhibitors exhibit broad inhibitory activity against JAK kinase family subtypes and have good therapeutic effects in inflammatory diseases, tumors, and hematological disorders. However, the JAK kinase family broadly mediates signaling of multiple cytokines, many of which have functions closely related to the body's normal physiological functions. Pan-JAK inhibitors have been associated with side effects in clinical use, including anemia, neutropenia, infection, lymphopenia, and hyperlipidemia. Tofacitinib carries a risk of infection and thrombosis, and the FDA has issued a black box warning for it. Ruxolitinib has also received a black box warning for platelet abnormalities.

[0004] Second-generation selective JAK inhibitors generally act primarily on specific subtypes of the JAK family, controlling disease progression and reducing the occurrence of adverse events. Currently marketed JAK selective inhibitors include Celgene's JAK2 inhibitor Fedratinib, AbbVie's JAK1 selective inhibitor upadacitinib, and Gilead's JAK1 inhibitor Filgotinib. While JAK1 inhibitors have shown remarkable therapeutic effects in treating immune diseases, they still belong to the broad-spectrum immunosuppressant class, have limited selectivity, and carry a high safety risk. Both the marketed JAK1 inhibitors Upadacitinib and Baricitinib have black-bordered warnings, and the marketed JAK2 inhibitor Fedratinib has been associated with serious adverse events such as Wernicke's encephalopathy and orbital inflammatory reactions.

[0005] JAK3 is primarily expressed in hematopoietic cells, including bone marrow cells, thymocytes, NK cells, and activated B lymphocytes and T lymphocytes. Because its physiological effects stem solely from the signaling pathways of the general γ cytokine receptor family, it acts with high selectivity on JAK3 kinase, avoiding unnecessary side effects. Therefore, improving the activity and selectivity of JAK3 kinase inhibitors can further enhance their clinical efficacy, offering significant clinical advantages over currently used Pan-JAK inhibitors and selective JAK1 and JAK2 inhibitors. Currently, while PF-06651600 is in late-stage clinical development and has received FDA Breakthrough Therapy approval for the treatment of alopecia areata, other highly selective JAK3 kinase inhibitors remain in the early stages of academic research and clinical development. PF-06651600 irreversibly inhibits the TEC kinase family (BTK, BMX, ITK, RLK, TEC), and the therapeutic effect of PF-06651600 on autoimmune diseases largely stems from its inhibition of the TEC kinase family. Clinical Phase 2a data indicate that adverse events occurring during treatment with PF-06651600 were infections, skin and subcutaneous tissue disorders. Simultaneously, many patients experienced thrombocytopenia, which may be related to PF-06651600's inhibitory effect on the TEC kinase family. (Robinson MF, Damjanov N., Stamenkovic B. et al. Efficacy and Safety of PF-06651600 (Ritlecitinib), a Novel JAK3 / TEC Inhibitor, in Patients With Moderate-to-Severe Rheumatoid Arthritis and an Inadequate Response to Methotrexate. Arthritis Rheumatol. 2020, 72(10), 1621-1631.)

[0006] Therefore, improving the activity and selectivity of JAK inhibitors against JAK3 kinase and reducing off-target effects is of crucial importance in addressing the current issues of low therapeutic efficacy and safety problems associated with the use of JAK inhibitors. [Overview of the Initiative]

[0007] This invention provides aromatic heterocyclic compounds with good Janus kinase (JAK) inhibitory activity, exhibiting both excellent activity and selectivity for JAK3 kinase. The present invention provides compositions and formulations containing the above-mentioned aromatic heterocyclic compounds.

[0008] The present invention also provides the use of the above-mentioned compounds, compositions, or formulations in the manufacture of drugs for preventing or treating diseases caused by abnormalities in the JAK-STAT signaling pathway. The compounds of the present invention are used as JAK kinase inhibitors for clinical use in the treatment and prevention of abnormalities in kinase activity associated with autoimmune diseases, inflammatory diseases, and other diseases. This invention employs the following technical solutions. The present invention provides compounds having the structure of general formula I, optical isomers thereof, deuterated compounds thereof, or pharmaceutically acceptable salts thereof.

[0009] JPEG0007831797000001.jpg124149 Here, Ring A is a 5-membered aromatic heterocycle containing 1 to 3 heteroatoms selected from O, N, and S.

[0010] M is a substituent of ring A, and M is selected from deletion, hydrogen, C1-C4 alkanoyl group, C1-C4 alkyl group, deuterated C1-C4 alkyl group, C1-C4 alkanesulfonyl group or C4-C6 heterocycloalkyl group, where C4-C6 heterocycloalkyl group contains one heteroatom selected from O, N, and S.

[0011] L is JPEG0007831797000002.jpg35132

[0012] selected from, where R a , R b , R c , R d , R e , R f , R g , R h are each independently selected from hydrogen, a cyano group, a hydroxy group, a halogen, a C1-C4 alkoxy group, a C1-C4 alkyl group, a monosubstituted C1-C4 alkyl group, a C1-C4 alkanoyl group, a C1-C4 alkylthio group, a C1-C4 alkanesulfonyl group, the substituent in the monosubstituted C1-C4 alkyl group is selected from a C1-C3 alkylthio group, a C1-C3 alkanesulfonyl group, a C1-C3 alkanoyl group, a halogen, a cyano group, k is an integer from 1 to 5, q is an integer from 0 to 4, r is an integer from 0 to 3, p and m are each independently selected from integers from 1 to 4, when k is greater than 1, that is, when L is an alkyl group segment containing two or more Cs, R a or R b are the same or different (that is, R a at different carbon atoms may be different or the same, R b at different carbon atoms may be the same or different, that is, R a are independent of each other, R b are independent of each other), when p is greater than 1, R e or R f are the same or different (as described above), when m is greater than 1, R g or R h are the same or different (as described above),

[0013] W is a covalent bond target, and the covalent bond target refers to a chemical group that can form a covalent bond with a nucleophile, and W is JPEG0007831797000003.jpg39168

[0014] or selected from nitrile groups, where R1 and R2 are independently selected from hydrogen, deuterium, halogen, cyano group, C1-C4 alkyl group, and halomethyl group, and R3 is hydrogen, deuterium, halogen, cyano group, C1-C4 alkyl group, and halomethyl group. JPEG0007831797000004.jpg38151

[0015] n and t are selected independently from integers 1 to 3, and R4 and R j , R k , R m Each is independently selected from hydrogen or a C1-C4 alkyl group, R5 is a halomethyl group, and R6 is a vinyl group or a halomethyl group. X is selected from N or CH, and Y is selected from hydrogen, a C1-C4 alkyl group, or a C1-C4 alkanoyl group. According to the compound of general formula (I), the present invention preferably relates to a compound having any of the following structures: Ring A is a 5-membered aromatic heterocycle having 1-3 heteroatoms selected from the N atom.

[0016] M is a substituent of ring A, and M is selected from hydrogen, a deuterated methyl group, a C1-C4 alkanoyl group, a C1-C4 alkyl group, or a C4-C6 heterocycloalkyl group, where the C4-C6 heterocycloalkyl group contains one heteroatom, and the heteroatom is an oxygen atom.

[0017] L is JPEG0007831797000005.jpg45168

[0018] Selected from, here R a , R b , R c , R d , R e , R f , R g , R hEach of the following is independently selected from hydrogen, a C1-C4 alkyl group, and a monosubstituted C1-C4 alkyl group, the substituent on the monosubstituted C1-C4 alkyl group is selected from a C1-C3 alkylthio group, a C1-C3 alkanesulfonyl group, and a cyano group, k is an integer from 1 to 4, q is an integer from 0 to 3, r is an integer from 0 to 2, p is 1 or 2, and m is 3 or 4.

[0019] W is JPEG0007831797000006.jpg33129

[0020] or selected from nitrile groups, where R1 and R2 are independently selected from hydrogen, deuterium, halogen, cyano group, and C1-C4 alkyl group, and R3 is hydrogen, deuterium, halogen, cyano group, C1-C4 alkyl group, and halomethyl group. JPEG0007831797000007.jpg43169

[0021] n and t are selected independently from integers 1 to 3, R j , R k , R m Each of the following is independently selected from hydrogen, a methyl group, or an ethyl group; R4 is selected from hydrogen or a methyl group; R5 is a halomethyl group; and R6 represents a vinyl group. X is selected from N or CH, and Y is selected from hydrogen or a C1-C4 alkanoyl group.

[0022] The present invention more preferably has a structure represented by general formula II, or an optical isomer thereof, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof. JPEG0007831797000008.jpg121138 Here,

[0023] Ring A is a five-membered heterocycle containing two double bonds, where Z is N or C, Q is N or NR7, and T is CH, N, or NR8. When Z and T are both N, Q is N, where R7 and R8 are independently hydrogen, a deuterated methyl group, a C1-C4 alkanoyl group, a C1-C4 alkyl group, or a C4-C6 heterocycloalkyl group, where the C4-C6 heterocycloalkyl group contains one heteroatom, and the heteroatom is an oxygen atom.

[0024] L is JPEG0007831797000009.jpg46165

[0025] Selected from, here R a , R b , R c , R d , R e , R f , R g , R h Each of the following is independently selected from hydrogen, a C1-C4 alkyl group, and a monosubstituted C1-C4 alkyl group, the substituent on the monosubstituted C1-C4 alkyl group is selected from a C1-C3 alkylthio group, a C1-C3 alkanesulfonyl group, and a cyano group, k is an integer from 1 to 4, q is an integer from 0 to 3, r is an integer from 0 to 2, p is 1 or 2, and m is 3 or 4.

[0026] W is JPEG0007831797000010.jpg29128

[0027] or selected from nitrile groups, where R1 and R2 are independently selected from hydrogen, deuterium, halogen, cyano group, and C1-C4 alkyl group, and R3 is hydrogen, deuterium, halogen, cyano group, C1-C4 alkyl group, and halomethyl group. JPEG0007831797000011.jpg41165

[0028] n and t are selected independently from integers 1 to 3, R j , R k , Rm Each of the following is independently selected from hydrogen, a methyl group, or an ethyl group; R4 is selected from hydrogen or a methyl group; R5 is a halomethyl group; and R6 represents a vinyl group. X is selected from N or CH, and Y is selected from hydrogen or a C1-C4 alkanoyl group.

[0029] The present invention more preferably has a structure represented by general formula III-1, III-2, III-3, or III-4, or an optical isomer thereof, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof. JPEG0007831797000012.jpg52170

[0030] L is JPEG0007831797000013.jpg37130

[0031] Selected from, here R a , R b , R c , R d , R e , R f , R g , R h Each of the following is independently selected from hydrogen, a C1-C4 alkyl group, and a monosubstituted C1-C4 alkyl group, the substituent on the monosubstituted C1-C4 alkyl group is selected from a methylthio group, a methylsulfonyl group, and a cyano group, k is an integer from 1 to 4, q is an integer from 0 to 3, r is an integer from 0 to 2, p is 1, and m is 3 or 4.

[0032] W is JPEG0007831797000014.jpg40167

[0033] or selected from nitrile groups, where R1 is hydrogen, deuterium, halogen, cyano group, or methyl group, R2 is hydrogen, deuterium, cyano group, or methyl group, and R3 is hydrogen, deuterium, halogen, cyano group, methyl group, or trifluoromethyl group. The filename is JPEG0007831797000015.jpg43160, where n and t are 2, and R j , Rk , R m R4 is a methyl group, R5 is a hydrogen or methyl group, R6 is a halomethyl group, and R6 represents a vinyl group. X is selected from N or CH, and Y is selected from hydrogen or an acetyl group.

[0034] Preferably, L is JPEG0007831797000016.jpg47166

[0035] Selected from, where R a , R b Each of these is independently selected from H, methyl group, isopropyl group, methylthio group-substituted ethyl group, and methylsulfonyl group-ethyl group, and R c , R d , R e , R f Each is independently selected from H and methyl groups, and R g , R h Each is independently selected from H and methyl groups, k is 1, 2, 3, or 4, q is 1, r is 0, p is 1, and m is 3 or 4.

[0036] R7 and R8 are independently hydrogen, a methyl group, an isopropyl group, an acetyl group, a deuterated methyl group, and a C4-C6 heterocycloalkyl group, respectively, where the C4-C6 heterocycloalkyl group contains one heteroatom, and the heteroatom is an oxygen atom. Specifically, preferably, The A ring is selected from a five-membered heterocycle having two double bonds, and the heteroatoms are two adjacent N atoms, preferably A is selected from a pyrazole ring.

[0037] In the above general formula I, JPEG0007831797000017.jpg5098 is selected from the following structures: JPEG0007831797000018.jpg81170

[0038] Preferably, Ra is a methyl group, H, an ethyl group, an isopropyl group, a methylthio group, an ethyl group, or a methylsulfonyl group. R7 is preferably a methyl group, H, an acetyl group, or an isopropyl group.

[0039] Preferably, W is JPEG0007831797000019.jpg65170 That is the case.

[0040] Preferably, in general formula I, the N adjacent to W is defined as N-1, and in L, if a carbon atom adjacent to N-1 has a substitution other than H (for example, the substituent is a methyl group or an isopropyl group), then the carbon atom has a chiral structure.

[0041] The present invention further preferably relates to a compound having any of the following structures: JPEG0007831797000020.jpg237170JPEG0007831797000021.jpg254170It is its optical isomer, its deuterated compound, or its pharmaceutically acceptable salt. The present invention further provides a pharmaceutical composition comprising one or more of the above general formulas I, II, or III-1 to III-4, or the above specific compounds.

[0042] A drug formulation comprising at least one active ingredient and one or more pharmaceutically acceptable carriers or excipients, wherein the active ingredient is selected from one or more of the compounds of general formula I, general formula II, or general formulas III-1 to III-4, or the specific compounds described above, or their optical isomers, or their deuterated compounds or pharmaceutically acceptable salts. The present invention provides the use of the compound described in general formula I, its optical isomer, its deuterated compound, or its pharmaceutically acceptable salt in the manufacture of drugs for preventing or treating diseases caused by abnormalities in the JAK-STAT signaling pathway. More preferably, the use is in diseases caused by hyperactivation or overexpression of JAK3 kinase. The aforementioned diseases include, but are not limited to, autoimmune diseases and lung injuries. Autoimmune diseases refer to one or more of the following: alopecia areata, lupus, multiple sclerosis, amyotrophic lateral sclerosis, rheumatoid arthritis, type 1 diabetes mellitus, autoimmune hemolytic anemia, rheumatoid arthritis, psoriasis, complications associated with organ transplantation, atopic dermatitis, autoimmune thyroid disease, ulcerative colitis, Crohn's disease, Sjögren's syndrome, systemic scleroderma, mixed connective tissue disease, vitiligo, autoimmune kidney disease, autoimmune liver disease, and chronic obstructive pulmonary disease. Preferably, the disease caused by the abnormality of the JAK-STAT signaling pathway is lung injury, and the lung injury is radiation-induced lung injury and acute lung injury.

[0043] Definitions and Explanations: The following terms and phrases used herein are intended to have the meanings set forth below unless otherwise specified. Unless otherwise specifically defined, any particular term or phrase should not be considered uncertain or ambiguous, but should be understood in its ordinary sense. Where trade names appear herein, they are intended to refer to the corresponding product or its active ingredient.

[0044] The term "pharmaceutically acceptable" means a compound, material, composition, and / or dosage form that is suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, within the bounds of reliable medical judgment, and that is commensurate with a reasonable benefit / risk ratio.

[0045] The term "pharmaceutically acceptable salt" refers to a salt of the compound of the present invention, which is prepared from a compound having a specific substituent discovered in the present invention and a relatively non-toxic acid or base. If the compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting a sufficient amount of base with the neutral form of such compound in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonium, or magnesium salts or similar salts. If the compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting a sufficient amount of acid with the neutral form of such compound in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, hydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, and phosphorous acid, as well as organic acid salts containing similar acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid, and further include salts of amino acids (such as arginine) and salts of organic acids such as glucuronic acid. Certain compounds of the present invention contain basic and acidic functional groups and can be converted into any base addition salt or acid addition salt.

[0046] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing an acidic or basic group by conventional chemical methods. Generally, such salts are prepared by reacting the free acidic or basic form of these compounds with a stoichiometric amount of a suitable base or acid in water, an organic solvent, or a mixture thereof.

[0047] The term "isomer" refers to the fact that the compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all these mixtures, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as mixtures rich in enantiomers or diastereomers, all of which are within the scope of the present invention. There may be yet another asymmetric carbon atom in substituents such as alkyl groups. All such isomers and their mixtures are included within the scope of the present invention.

[0048] Unless otherwise specified, the term "enantiomer" or "optical isomer" refers to stereoisomers that are mirror images of each other. Unless otherwise specified, the term system of "cis-trans isomer" or "geometric isomer" is caused by the fact that the double bond or the single bond of the ring-forming carbon atom cannot rotate freely. Unless otherwise specified, the term "diastereomer" refers to stereoisomers in which the molecule has two or more chiral centers and there is no mirror-image relationship between molecules. Unless otherwise specified, "(D)" or "(+)" represents dextrorotation, "(L)" or "(-)" represents levorotation, and "(DL)" or "(±)" represents a racemate. Unless otherwise specified, JPEG0007831797000022.jpg131701 represents the absolute configuration of one stereocenter.

[0049] "Select" or "selectively" means that the event or situation described thereafter may occur, but does not necessarily occur, and the description means including both the case where the event or situation occurs and the case where it does not occur.

[0050] The term "substituted" means that any one or more hydrogen atoms in a particular atom are substituted by a substituent, and may include deuterium and hydrogen isomers, provided that the valence of the particular atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e., =0), it means that two hydrogen atoms are substituted. Oxygen substitution does not occur in aromatic groups. The term "selectively substituted" means that the atom may be substituted or unsubstituted, and unless otherwise specified, the type and number of substituents are arbitrary as long as they are chemically feasible.

[0051] When any variable (e.g., R) appears one or more times in the composition or structure of a compound, its definition in each situation is independent. Therefore, for example, if a group is substituted with 0 to 2 Rs, the group may be selectively substituted with up to 2 Rs, and in each situation, the multiple Rs are independent of each other, may be the same, or may be different. Furthermore, combinations of substituents and / or their isomers are permitted only if the combination produces a stable compound.

[0052] If one of the variables is selected from a bond, it indicates that the two groups it is bonded to are directly bonded; for example, if L in ALZ represents a bond, it indicates that the structure is actually AZ.

[0053] If it is not indicated which atom a substituent is bonded to in the group being substituted, such substituent may be bonded to any of those atoms; for example, a phenyl group as a substituent may be bonded to the group being substituted via any one carbon atom of the phenyl ring.

[0054] The term "covalent target" refers to a chemical group that can form a covalent bond with a nucleophile. JPEG0007831797000023.jpg35170 This includes, but is not limited to, these items.

[0055] Unless otherwise specified, the term "alkyl group" is used to refer to a linear or branched saturated hydrocarbon group, which may be monosubstituted (e.g., -CH2F) or polysubstituted (e.g., -CF3), and may be monovalent (e.g., methyl group), divalent (methylene group), or polyvalent (e.g., methine group). Examples of alkyl groups include methyl group (Me), ethyl group (Et), propyl group (e.g., n-propyl group and isopropyl group), butyl group (e.g., n-butyl group, isobutyl group, s-butyl group, t-butyl group), pentyl group (e.g., n-pentyl group, isopentyl group, neopentyl group), etc.

[0056] Unless otherwise specified, a cycloalkyl group comprises any stable cyclic or polycyclic hydrocarbon group, where any carbon atom is saturated, may be monosubstituted or polysubstituted, and may be monovalent, divalent, or polyvalent. Examples of such cycloalkyl groups include, but are not limited to, cyclopropyl groups, norbornane, [2.2.2]bicyclooctane, and [4.4.0]bicyclodecane.

[0057] Unless otherwise specified, the term "halogen" means a fluorine (F), chlorine (Cl), bromine (Br), or iodine (I) atom, either by itself or as part of another substituent.

[0058] Unless otherwise specified, "alkoxy group" refers to an alkyl group bonded to the rest of the molecule via an oxygen atom, and the alkyl group has the meaning described in this invention. Unless otherwise specified, C 1-5 The alkoxy group includes C1, C2, C3, C4, and C5 alkoxy groups. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, and S-pentyloxy groups. The alkoxy group may be selectively substituted with one or more substituents described in the present invention. Unless otherwise specified, the term "aromatic ring" means a polyunsaturated aromatic cycloalkane, which may be monosubstituted or polysubstituted. Unless otherwise specified, the term "aromatic heterocycle" means an aromatic ring containing 1 to 4 heteroatoms selected from N, O, and S.

[0059] In vitro experiments demonstrate that the compounds provided by the present invention possess good JAK3 kinase inhibitory activity and selectivity, and have promising prospects for use in the pharmaceutical field. [Brief explanation of the drawing]

[0060] [Figure 1] The compound exhibits immunosuppressive activity against the SRBC mouse model. [Figure 2] This study demonstrates the immunosuppressive effect of the compound on a mouse model of collagen-induced arthritis. [Figure 3] The compound exhibits immunosuppressive effects on a mouse model of inflammatory bowel disease induced by dextran sulfate sodium (DSS). [Figure 4] This study demonstrates the inhibitory effect of the compound on TNF-α levels in mice with acute radiation-induced lung injury. [Figure 5] The compound reduces the number of inflammatory cell infiltrations in the lungs of mice with acute radiation-induced lung injury. [Modes for carrying out the invention]

[0061] The feasibility of the present invention will be illustrated below with reference to examples, and those skilled in the art should understand that modifications or substitutions made to corresponding technical features based on the teachings of the prior art still fall within the scope of protection of the present invention.

[0062] Example 1 Synthesis of intermediate (R)-1e JPEG0007831797000024.jpg27170

[0063] Step 1: Under nitrogen gas protection, pyrazole-3-formaldehyde 1a (20 g, 208.1 mmol) and (R)-2-aminopropanol (18.7 g, 249.7 mmol) are added sequentially to a 100 ml three-necked flask containing 150 mL of methanol, and the mixture is reacted at room temperature for 3 hours. Slowly and gradually add sodium borohydride (19.7 g, 520.4 mmol), and the reaction is continued at room temperature for 2 hours. After the reaction is complete, 20 ml of water is added, and di-tert-butyl dicarbonate (59.1 g, 270.6 mmol) is slowly added dropwise under an ice bath, and the reaction is continued at room temperature for 24 hours. After the reaction is complete, the reaction mixture is poured into 200 mL of water, extracted three times with ethyl acetate, the organic layers are combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product is purified by silica gel column chromatography to obtain 40.3 g of the colorless oily intermediate (R)-1b in 75% yield. ESI(M+H) + = 256.

[0064] Step 2: Under ice bath conditions, dissolve intermediate (R)-1b (40 g, 156.7 mmol) in 200 ml of tetrahydrofuran, add triphenylphosphine (61.6 g, 235 mmol) and diethyl azodicarboxylate (40.9 g, 235 mmol) in sequence, and react at room temperature for 6 hours. After the reaction is complete, pour the reaction mixture into 200 ml of water, extract three times with ethyl acetate, combine the organic layers, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the resulting crude product by silica gel column chromatography to obtain 19 g of intermediate (R)-1c, a colorless oily substance, with a yield of 51%. ESI(M+H) + = 238.

[0065] Step 3: Dissolve intermediate (R)-1c (19 g, 80.1 mmol) in 200 ml of dichloromethane under ice bath, add N-bromosuccinimide (15.7 g, 88.1 mmol), and react at room temperature for 1 hour. After the reaction is complete, add 100 ml of saturated sodium bicarbonate aqueous solution, extract three times with dichloromethane, combine the organic layers, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the resulting crude product by silica gel column chromatography to obtain 23 g of intermediate (R)-1d, a colorless oily substance, with a yield of 92%. ESI(M+H) + = 316.

[0066] Step 4: Under nitrogen gas protection, intermediate (R)-1d (23 g, 72.7 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (5.3 g, 7.3 mmol), bis(pinacolate)diborone ((Bpin)2, 27.7 g, 109.1 mmol), and potassium acetate (28.6 g, 290.9 mmol) are sequentially added to a 1 L three-necked flask containing 150 mL of DMSO. The reaction system is thoroughly stirred at 95°C and allowed to react overnight. After the reaction is complete, the mixture is cooled to room temperature, the reaction solution is poured into 100 mL of water, extracted three times with ethyl acetate, the organic layers are combined and washed twice with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product is purified by silica gel column chromatography to obtain 13 g of intermediate (R)-1e, a colorless oil, in yield of 50%. ESI(M+H) + = 364. Example 2 Synthesis of intermediate (S)-1e JPEG0007831797000025.jpg29170

[0067] Replace (R)-2-aminopropanol with (S)-2-aminopropanol in Example 1, and refer to the synthesis method of Example 1 to obtain intermediate (S)-1e. The yield was 40% (4 steps), and ESI(M+H) + = 364. Example 3 Synthesis of intermediate 2d JPEG0007831797000026.jpg38170

[0068] Replace (R)-2-aminopropanol with aminoethanol in Example 1, and refer to the synthesis method of (R)-1d in Example 1 to obtain intermediate 2d. The yield was 34% (3 steps), and ESI(M+H) + = 302. Example 4 Synthesis of intermediate (S)-3e JPEG0007831797000027.jpg32170

[0069] Replace (R)-2-aminopropanol with (R)-1-amino-2-propanol in Example 1, and refer to the synthesis method of Example 1 to obtain intermediate (S)-3e. The yield was 45% (4 steps), and ESI(M+H) + = 364. Example 5 Synthesis of intermediate (R)-3e JPEG0007831797000028.jpg32170

[0070] Replace (R)-2-aminopropanol in Example 1 with (S)-1-amino-2-propanol, and refer to the synthesis method of Example 1 to obtain intermediate (R)-3e. The yield was 39% (4 steps), and ESI(M+H) + = 364. Example 6 Synthesis of intermediate (R)-4e JPEG0007831797000029.jpg31170

[0071] Replace (R)-2-aminopropanol with (R)-3-aminobutanol in Example 1, and refer to the synthesis method of Example 1 to obtain intermediate (R)-4e. The yield was 49% (4 steps), and ESI(M+H) + = 378. Example 7 Synthesis of intermediate (R)-5e JPEG0007831797000030.jpg33170

[0072] Replace (R)-2-aminopropanol in Example 1 with (R)-(-)-2-amino-3-methyl-1-butanol, and refer to the synthesis method of Example 1 to obtain intermediate (R)-5e. The yield was 49% (4 steps), and ESI(M+H) + = 392. Example 8 Synthesis of intermediate (S)-5e JPEG0007831797000031.jpg33170

[0073] Replace (R)-2-aminopropanol in Example 1 with (S)-(-)-2-amino-3-methyl-1-butanol, and refer to the synthesis method of Example 1 to obtain intermediate (S)-5e. The yield was 50% (4 steps), and ESI(M+H) + = 392. Example 9 Synthesis of intermediate (S,S)-6d JPEG0007831797000032.jpg42170

[0074] Step 1: Under nitrogen gas protection, add pyrazole-3-formaldehyde 1a (10 g, 104.1 mmol) and (1S, 2S)-2-aminocyclopentanol hydrochloride (17.2 g, 124.8 mmol) in order to a 100 ml three-necked flask containing 100 ml of methanol, and react at room temperature for 3 hours. Sodium borohydride (9.8 g, 260.2 mmol) was slowly added little by little, and the reaction was continued at room temperature for 2 hours. After the reaction was complete, 20 ml of water was added, and 31.8 g (145.7 mmol) of di-tert-butyl dicarbonate was slowly added dropwise under ice bath conditions. The reaction was continued at room temperature for 24 hours. After the reaction was complete, the reaction mixture was poured into 200 ml of water, extracted three times with ethyl acetate, and the organic layers were combined. The mixture was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography to obtain 20 g of the colorless oily intermediate (S,S)-6b in yield of 68%. ESI(M+H) + = 282

[0075] Step 2: Under ice bath, dissolve intermediate (S,S)-6b (20 g, 71.8 mmol) in 200 ml of tetrahydrofuran, add triphenylphosphine (27.9 g, 106.6 mmol) and diethyl azodicarboxylate (18.6 g, 106.6 mmol) in sequence, and react at room temperature for 6 hours. After the reaction is complete, pour the reaction mixture into 100 mL of water, extract three times with ethyl acetate, combine the organic layers, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the resulting crude product by silica gel column chromatography to obtain 12 g of intermediate (S,S)-6c, a colorless oily substance, in yield of 66%. ESI (M+H)+ = 264.

[0076] Step 3: Dissolve intermediate (S,S)-6c (12 g, 45.5 mmol) in 100 ml of dichloromethane under ice bath, add N-bromosuccinimide (8.9 g, 50.1 mmol), react at room temperature for 1 hour, add 500 ml of saturated sodium bicarbonate aqueous solution, extract three times with dichloromethane, combine the organic layers, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the resulting crude product by silica gel column chromatography to obtain 10 g of intermediate (S,S)-6d, a colorless oily substance, with a yield of 92%. ESI(M+H) + = 342. Example 10 Synthesis of intermediate 7e JPEG0007831797000033.jpg35170

[0077] Replace (R)-2-aminopropanol in Example 1 with 1-aminocyclopropanemethanol, and follow the synthesis method of Example 1 to obtain intermediate 7e. The yield was 54% (4 steps), and ESI(M+H) + = 376. Example 11 Synthesis of intermediate 8f JPEG0007831797000034.jpg52170

[0078] Step 1: Dissolve compound 8a (20 g, 100 mmol) in 200 ml of DCM, add triethylamine (14 ml, 100 mmol), stir the reaction mixture at room temperature for 30 min, then add acetic acid (5.7 ml, 100 mmol) and p-anisaldehyde (14.3 g, 105 mmol), stir in an external bath at 40°C for 1 hour, add Na(OAc)3BH (29.7 g, 140 mmol), stir in an external bath at 40°C and react overnight. After the reaction is complete, rotate dry the solvent, add water (150 ml), adjust the pH to 8-9 with 3N NaOH solution, extract the aqueous phase three times with EA (50 ml), combine with the organic phase, dry with saturated NaCl solution and anhydrous Na2SO4, concentrate under reduced pressure, and purify the resulting crude product by silica gel column chromatography to obtain 22.6 g of 8b, with a yield of 80%. ESI(M+H) + = 284.

[0079] Step 2: Dissolve compound 1a (9.67 g, 101 mmol) in 200 ml of DCM, add acetic acid (3.8 ml, 67 mmol) and compound 8b (19.1 g, 67 mmol), stir in an external bath at 40°C for 1 hour, add Na(OAc)3BH (19.9 g, 94 mmol), stir in an external bath at 40°C and react overnight. After the reaction is complete, rotate dry the solvent, add water (150 ml), adjust the pH to 8-9 with 3N NaOH solution, extract the aqueous phase three times with EA (50 ml), combine with the organic phase, dry with saturated NaCl solution and anhydrous Na2SO4, concentrate under reduced pressure, and purify the resulting crude product by silica gel column chromatography to obtain 17.5 g of 8c, with a yield of 72%. ESI(M+H)+=364.

[0080] Step 3: Add lithium aluminum hydride (1.4 g, 38 mmol) to a 500 ml three-necked flask, dissolve compound 8c (8.8 g, 25 mmol) in 150 ml of anhydrous THF and add it to an isobaric dropping funnel, pour 100 ml of anhydrous THF into the three-necked flask under an N2 atmosphere, add the THF solution of compound 8c dropwise under ice bath stirring, gradually raise the temperature to room temperature after the dropwise addition is complete, stir and react for 3 hours. After the reaction is complete, gradually add sodium sulfate decahydrate to the reaction system until no more solids are formed, filter, wash the filtrate multiple times with DCM, combine the filtrates, rotary dry, freeze-dry, and the resulting crude product is added directly to the next step without further purification.

[0081] Step 4: Dissolve the crude reaction product from the previous step in 200 ml of THF, add triphenylphosphine (9.8 g, 37.5 mmol), stir to dissolve, slowly add DEAD (6.5 g, 37.5 mmol) dropwise at -10°C, and after the addition is complete, slowly raise the temperature to room temperature and stir, allowing to react overnight. After the reaction is complete, concentrate under reduced pressure to remove the solvent, add water, extract multiple times with EA, combine the organic phases, dry over saturated NaCl solution and anhydrous Na2SO4, concentrate under reduced pressure, and purify the resulting crude product by silica gel column chromatography to obtain 4 g of 8d, with a yield of 51%. ESI(M+H) + = 318.

[0082] Step 5: Dissolve compound 8d (4g, 12.8 mmol) in 6 ml of trifluoroacetic acid, slowly add 2 ml of concentrated sulfuric acid dropwise, stir under reflux and react for 1 hour. After the reaction is complete, slowly pour the reaction mixture into ice water, adjust the pH to 8-9 with 3N NaOH, extract the aqueous phase multiple times with EA, combine with the organic phase, dry with saturated NaCl solution and anhydrous Na2SO4, concentrate under reduced pressure, and the resulting crude product is added directly to the next step without further purification.

[0083] Step 6: Dissolve the crude reaction product from the previous step in a 1:1 mixed solvent of THF and water, add di-tert-butyl dicarbonate (2.8 g, 32 mmol), NaOH (1.5 g, 38 mmol), and DMAP (159 mg, 1.3 mmol), and stir at room temperature and react overnight. After the reaction is complete, concentrate under reduced pressure to remove the solvent, add water, extract multiple times with EA, combine the organic phases, dry over saturated NaCl solution and anhydrous Na2SO4, concentrate under reduced pressure, and purify the resulting crude product by silica gel column chromatography to obtain 3.0 g of 8e, with a yield of 78%. ESI(M+H) + = 298.

[0084] Step 7: Dissolve compound 8e (946 mg, 3 mmol) in 8 ml of DCM, slowly add NBS (737 mg, 4 mmol) in an ice bath, and slowly raise the temperature to room temperature while stirring to allow the reaction to proceed. After the reaction is complete, stop the reaction, add water, extract multiple times with DCM, combine the organic phases, dry with saturated NaCl solution and anhydrous Na2SO4, concentrate under reduced pressure, and purify the resulting crude product by silica gel column chromatography to obtain 1.0 g of compound 8f, with a yield of 90%. ESI(M+H) + = 376. Example 12 Synthesis of intermediate SM1 JPEG0007831797000035.jpg59170

[0085] Step 1: Dissolve intermediate SM1-1 (50 g, 253.7 mmol) in 300 ml of acetone, then add sodium hydroxide (20.3 g, 507.5 mmol), and slowly add p-toluenesulfonyl chloride (58.1 g, 304.5 mmol) little by little. React at room temperature for 3 hours, then remove organic solvent by reducing pressure. Add 200 ml of water to the remaining reaction mixture, wash and extract three times with dichloromethane, combine the organic layers, dry over anhydrous sodium sulfate, concentrate under reduced pressure, recrystallize the resulting crude product with acetonitrile / water, and filter by suction to obtain 75 g of white solid SM1-2. The yield is 84%, and ESI(M+H) + = 351.

[0086] Step 2: Under nitrogen gas protection, intermediate SM1-2 (75 g, 213.5 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (15.5 g, 21.3 mmol), bis(pinacolate)diborone (81.3 g, 320.3 mmol), and potassium acetate (83.8 g, 854.2.9 mmol) are sequentially added to a 3 L three-necked flask containing 1 L of DMSO. The reaction system is thoroughly stirred at 95°C and allowed to react overnight. After the reaction is complete, the mixture is cooled to room temperature, the reaction solution is poured into 1 L of water, extracted three times with ethyl acetate, the organic layers are combined and washed twice with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product is purified by silica gel column chromatography to obtain 70 g of intermediate SM1 as a white solid in 93% yield. ESI(M+H) + = 399. Example 13 Synthesis of intermediate SM2 JPEG0007831797000036.jpg52126

[0087] Step: Dissolve intermediate SM2-1 (30g, 195.2 mmol) in 200 ml of acetone, then add sodium hydroxide (15.6g, 390.7 mmol), and slowly add p-toluenesulfonyl chloride (40.9g, 214.8 mmol) little by little. React at room temperature for 3 hours, then remove organic solvent by reducing pressure. Add 100 mL of water to the remaining reaction mixture, wash and extract three times with dichloromethane, combine the organic layers, dry over anhydrous sodium sulfate, concentrate under reduced pressure, recrystallize the resulting crude product with acetonitrile / water, and filter by suction to obtain 48 g of white solid SM2. The yield is 90%, and ESI(M+H) + = 308. Example 14 Synthesis of intermediate SM3 JPEG0007831797000037.jpg64130

[0088] Step: Under nitrogen gas protection, intermediate SM1-1 (25 g, 126.8 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (9.3 g, 12.6 mmol), bis(pinacolate)diborone (64.4 g, 253.7 mmol), and potassium acetate (37.3 g, 380.6 mmol) were sequentially added to a 3 L three-necked flask containing 300 mL of DMSO. The reaction system was thoroughly stirred at 95 °C and allowed to react overnight. After the reaction was complete, the mixture was cooled to room temperature, the reaction solution was poured into 1 L of water, extracted three times with ethyl acetate, the organic layers were combined and washed twice with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography to obtain 20 g of intermediate SM1 as a white solid in 64% yield. ESI(M+H) + = 245 Example 15 Synthesis of intermediate (R)-1e-IM3 JPEG0007831797000038.jpg50170

[0089] Step 1: Under nitrogen gas protection, intermediate (R)-1d (10 g, 25.1 mmol), tetrakis(triphenylphosphine)palladium (2.9 g, 2.5 mmol), intermediate SM1 (10 g, 25.1 mmol), and potassium carbonate (13.8 g, 100.4 mmol) are sequentially added to a 200 ml three-necked flask containing 100 ml of 1,4-dioxane. The reaction system is thoroughly stirred at 95 °C and allowed to react overnight. After the reaction is complete, the mixture is cooled to room temperature, the reaction solution is poured into 50 mL of water, extracted three times with ethyl acetate, the organic layers are combined and washed twice with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product is purified by silica gel column chromatography to obtain 10 g of intermediate (R)-1e-IM1 as a pale yellow solid with a yield of 83%. ESI(M+H) + = 508.

[0090] Step 2: Intermediate (R)-1e-IM1 (10 g, 19.7 mmol) and sodium hydroxide (1.58 g, 39.4 mmol) were successively added to a 500 mL three-necked flask containing 200 mL of methanol. The reaction system was stirred well at 50 °C for 3 hours for reaction. After the reaction was completed, it was cooled to room temperature. The reaction solution was poured into water and extracted three times with dichloromethane. The combined organic layers were washed twice with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography to obtain 5.5 g of white solid intermediate (R)-1e-IM2, with a yield of 78%. ESI(M+H) + = 354.

[0091] Step 3: Intermediate (R)-1e-IM2 (5 g, 14.1 mmol) was dissolved in dichloromethane, an equal volume of trifluoroacetic acid was added, and the reaction was carried out overnight at room temperature. After the reaction was completed, the pH was adjusted to 8 - 9, and it was extracted three times with dichloromethane. The combined organic layers were washed twice with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography to obtain 3 g of white solid intermediate (R)-1e-IM3, with a yield of 83%. ESI(M+H) + = 254. JPEG0007831797000039.jpg103170 Example 16 Synthesis of Intermediate (S)-1e-IM3

[0092] In Example 15, intermediate (R)-1d was replaced with intermediate (S)-1d, and referring to the synthesis method of Example 15, intermediate (S)-1e-IM3 was obtained, with a yield of 49% (3 steps), and ESI(M+H) + = 254. Example 17 Synthesis of Intermediate 2e-IM3

[0093] In Example 15, intermediate (R)-1d was replaced with intermediate 2d, and referring to the synthesis method of Example 15, intermediate 2e-IM3 was obtained, with a yield of 50% (3 steps), and ESI(M+H) + = 240. Example 18 Synthesis of intermediate (S)-3e-IM3

[0094] In Example 15, intermediate (R)-1d was replaced with intermediate (S)-1d, and intermediate SM1 was replaced with intermediate SM2. Following the synthesis method of Example 15, intermediate (S)-3e-IM3 was obtained, with a yield of 53% (3 steps), and ESI(M+H) + = 255. Example 19 Synthesis of intermediate (R)-3e-IM3

[0095] In Example 15, intermediate (R)-1d was replaced with intermediate (R)-1e, and intermediate SM1 was replaced with intermediate SM2. Following the synthesis method of Example 15, intermediate (R)-3e-IM3 was obtained, with a yield of 57% (3 steps), and ESI(M+H) + = 255. Example 20 Synthesis of intermediate (S)-4e-IM3

[0096] In Example 15, intermediate (R)-1d was replaced with intermediate (S)-3e, and intermediate SM1 was replaced with intermediate SM2. Following the synthesis method of Example 15, intermediate (S)-4e-IM3 was obtained, with a yield of 65% (3 steps), and ESI(M+H) + = 255. Example 21 Synthesis of intermediate (R)-4e-IM3

[0097] In Example 15, intermediate (R)-1d was replaced with intermediate (R)-3e, and intermediate SM1 was replaced with intermediate SM2. Following the synthesis method of Example 15, intermediate (R)-4e-IM3 was obtained, with a yield of 45% (3 steps), and ESI(M+H) + = 255. Example 22 Synthesis of intermediate (R)-5e-IM3

[0098] In Example 15, intermediate (R)-1d was replaced with intermediate (R)-4e, and intermediate SM1 was replaced with intermediate SM2. Following the synthesis method of Example 15, intermediate (R)-5e-IM3 was obtained, with a yield of 42% (3 steps), and ESI(M+H)+ = 269. Example 23 Synthesis of Intermediate (S)-6e-IM3

[0099] Replace (R)-1d in Example 15 with (S)-5e, replace SM1 with SM2, refer to the synthesis method of Example 15, obtain intermediate (S)-6e-IM3, and the yield is 48% (3 steps), ESI(M+H) + = 283. Example 24 Synthesis of Intermediate (R)-6e-IM3

[0100] Replace (R)-1d in Example 15 with (R)-5e, replace intermediate SM1 with intermediate SM2, refer to the synthesis method of Example 15, obtain intermediate (R)-6e-IM3, and the yield is 42% (3 steps), ESI(M+H) + = 283. Example 25 Synthesis of Intermediate (S,S)-7d -IM3

[0101] Replace (R)-1d in Example 15 with (S,S)-6d, replace intermediate SM1 with intermediate SM2, refer to the synthesis method of Example 15, obtain intermediate (S,S)-7d-IM3, and the yield is 43% (3 steps), ESI(M+H) + = 280. Example 26 Synthesis of Intermediate 8d -IM5 JPEG0007831797000040.jpg34170

[0102] [[ID=ID=33]]Step 1: Add intermediate 8d-IM1 (20 g, 89.1 mmol) and hydrazine (4.2 g, 133.7 mmol) in sequence to a 500 mL three-necked flask containing 200 mL of methanol, stir the reaction system thoroughly at 70 °C for 4 hours for reaction. After the reaction is completed, cool to room temperature and concentrate under reduced pressure. Purify the obtained crude product by silica gel column chromatography to obtain 18 g of white solid intermediate 8d-IM2, and the yield is 85%. ESI(M+H) + = 239.

[0103] Step 2: Add intermediate 8d-IM2 (15 g, 62.9 mmol), copper bromide (14.1 g, 62.9 mmol), and isoamyl nitrite (8.8 g, 75.5 mmol) in order to a 500 mL three-necked flask containing 200 mL of acetonitrile. Stir the reaction system thoroughly at 60°C and allow to react for 4 hours. After the reaction is complete, cool to room temperature, pour the reaction mixture into water, extract three times with dichloromethane, combine the organic layers, wash twice with saturated sodium chloride, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the resulting crude product by silica gel column chromatography to obtain 10 g of intermediate 8d-IM3 as a yellow solid in 52% yield. ESI(M+H) + = 302.

[0104] Step 3: Under nitrogen gas protection, intermediate 8d-IM3 (10 g, 33.1 mmol), tetrakis(triphenylphosphine)palladium (3.8 g, 3.3 mmol), intermediate SM3 (12.1 g, 49.1 mmol), and potassium carbonate (13.8 g, 100.4 mmol) are sequentially added to a 200 ml three-necked flask containing 100 ml of 1,4-dioxane. The reaction system is thoroughly stirred at 95°C and allowed to react overnight. After the reaction is complete, the mixture is cooled to room temperature, the reaction solution is poured into 100 ml of water, extracted three times with ethyl acetate, the organic layers are combined and washed twice with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product is purified by silica gel column chromatography to obtain 7 g of intermediate 8d-IM4 as a pale yellow solid. The yield is 63%, and the ESI (M+H) + = 340.

[0105] Step 4: Dissolve intermediate 8d-IM4 (7 g, 20.6 mmol) in dichloromethane, add an equal volume of trifluoroacetic acid, and react overnight at room temperature. After the reaction is complete, adjust the pH to 8-9, extract three times with dichloromethane, combine the organic layers, wash twice with saturated sodium chloride, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the resulting crude product by silica gel column chromatography to obtain 5 g of intermediate 8d-IM5 as a white solid in 71% yield. ESI(M+H) + = 240.

[0106] Example 27 Synthesis of intermediate 9f-IM3 JPEG0007831797000041.jpg47167

[0107] Step 1: Add intermediate 8d-IM3 (20 g, 66.1 mmol), sodium hydride (3.2 g, 132.3 mmol), and iodomethane (11.2 g, 79.4 mmol) in sequence to a 500 mL three-necked flask containing 100 mL of DMF. Stir the reaction system thoroughly at 0°C and allow to react for 2 hours. After the reaction is complete, pour the reaction mixture into water, extract three times with dichloromethane, combine the organic layers, wash twice with saturated sodium chloride, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the resulting crude product by silica gel column chromatography to obtain 15 g of intermediate 9f-IM1 as a yellow solid in 71% yield. ESI(M+H) + = 316.

[0108] Step 2: Under nitrogen gas protection, intermediate 9f-IM1 (15 g, 47.4 mmol), tetrakis(triphenylphosphine)palladium (5.4 g, 4.7 mmol), intermediate SM3 (17.3 g, 71.1 mmol), and potassium carbonate (19.6 g, 142.3 mmol) are sequentially added to a 200 ml three-necked flask containing 100 ml of 1,4-dioxane. The reaction system is thoroughly stirred at 95°C and allowed to react overnight. After the reaction is complete, the mixture is cooled to room temperature, the reaction solution is poured into 100 ml of water, extracted three times with ethyl acetate, the organic layers are combined and washed twice with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product is purified by silica gel column chromatography to obtain 12 g of intermediate 9f-IM2 as a pale yellow solid with a yield of 75%. ESI(M+H) + = 354.

[0109] Step 3: Dissolve intermediate 9f-IM2 (12 g, 20.6 mmol) in dichloromethane, add an equal volume of trifluoroacetic acid, and react overnight at room temperature. After the reaction is complete, adjust the pH to 8-9, extract three times with dichloromethane, combine the organic layers, wash twice with saturated sodium chloride, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the resulting crude product by silica gel column chromatography to obtain 5 g of intermediate 9f-IM3 as a white solid in 58% yield. ESI(M+H) + = 254.

[0110] Example 28 Synthesis of 10g intermediate IM3 JPEG0007831797000042.jpg40170

[0111] Step 1: Add intermediate 8d-IM3 (20 g, 66.1 mmol), R-3-hydroxytetrahydrofuran (7 g, 79.4 mmol), triphenylphosphine (26 g, 99.2 mmol), and diethyl azodicarboxylate (17.2 g, 99.2 mmol) in order to a 500 mL three-necked flask containing 100 mL of THF. Stir the reaction system thoroughly at room temperature and allow to react for 2 hours. After the reaction is complete, pour the reaction mixture into water, extract three times with ethyl acetate, combine the organic layers, wash twice with saturated sodium chloride, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the resulting crude product by silica gel column chromatography to obtain 18 g of the yellow solid intermediate 10 g-IM1 in 75% yield. ESI(M+H) + = 372

[0112] Step 2: Under nitrogen gas protection, intermediate 10g-IM1 (18g, 48.4 mmol), tetrakis(triphenylphosphine)palladium (5.6g, 4.8 mmol), intermediate SM3 (17.7g, 72.5 mmol), and potassium carbonate (20g, 145 mmol) are sequentially added to a 500 ml three-necked flask containing 300 ml of 1,4-dioxane. The reaction system is thoroughly stirred at 95°C and allowed to react overnight. After the reaction is complete, the mixture is cooled to room temperature, the reaction solution is poured into 200 ml of water, extracted three times with ethyl acetate, the organic layers are combined and washed twice with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product is purified by silica gel column chromatography to obtain 14 g of intermediate 10g-IM2 as a pale yellow solid. The yield is 73%, and the ESI (M+H) + = 410.

[0113] Step 3: Dissolve 10g of intermediate IM2 (12g, 20.6 mmol) in dichloromethane, add an equal volume of trifluoroacetic acid, and react overnight at room temperature. After the reaction is complete, adjust the pH to 8-9, extract three times with dichloromethane, combine the organic layers, wash twice with saturated sodium chloride, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the resulting crude product by silica gel column chromatography to obtain 6g of the white solid intermediate 10g-IM3 in 57% yield. ESI(M+H) + = 310.

[0114] Example 29 Synthesis of intermediate 11h-IM1 JPEG0007831797000043.jpg71131

[0115] Referring to the synthesis method of intermediate (S,S)-6d in Example 9, (1S,2S)-2-aminocyclopentanol hydrochloride was replaced with (1R,2R)-2-aminocyclopentanol to obtain intermediate 1-1. Then, referring to the synthesis method of intermediate (S,S)-7d-IM3 in Example 25, intermediate (S,S)-6d was replaced with intermediate 1-1 to obtain 11h-IM1, with a yield of 34%. ESI(M+H) + = 280.

[0116] Example 30 Synthesis of intermediate 12I-IM1 JPEG0007831797000044.jpg69123

[0117] Referring to the synthesis method of intermediate (S,S)-6d in Example 9, (1S,2S)-2-aminocyclopentanol hydrochloride was replaced with (1R,2R)-2-aminocyclohexanol to obtain intermediate 1-2. Then, referring to the synthesis method of intermediate (S,S)-7d-IM3 in Example 25, intermediate (S,S)-6d was replaced with intermediate 1-2 to obtain 12I-IM1, with a yield of 25%. ESI(M+H) + = 294.

[0118] Example 31 Synthesis of intermediate 13J-IM1 JPEG0007831797000045.jpg88162

[0119] Referring to the synthesis method of intermediate (R)-1d in Example 1, (R)-2-aminopropanol was replaced with (S)-3-aminobutanol to obtain intermediates 1-4. Then, referring to the synthesis method of intermediate (R)-1e-IM3 in Example 15, intermediate R-1d was replaced with intermediates 1-3 to obtain 13J-IM1, with a yield of 28%. ESI(M+H) + = 268.

[0120] Example 32 Synthesis of intermediate 14K-IM3 JPEG0007831797000046.jpg46149

[0121] Step 1: Under nitrogen gas protection, intermediate (S)-1e (22.7 g, 62.7 mmol), tetrakis(triphenylphosphine)palladium (4.8 g, 4.1 mmol), intermediate 14K-IM1 (10 g, 41.8 mmol), and potassium carbonate (17.3 g, 125.4 mmol) are sequentially added to a 500 ml three-necked flask containing 200 ml of 1,4-dioxane. The reaction system is thoroughly stirred at 95 °C and allowed to react overnight. After the reaction is complete, the mixture is cooled to room temperature, the reaction solution is poured into 100 mL of water, extracted three times with ethyl acetate, the organic layers are combined and washed twice with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product is purified by silica gel column chromatography to obtain 11 g of intermediate 14K-IM2 as a pale yellow solid. The yield is 66%, and the ESI (M+H) + = 396.

[0122] Step 2: Dissolve intermediate 14K-IM2 (11 g, 20.6 mmol) in dichloromethane, add an equal volume of trifluoroacetic acid, and react overnight at room temperature. After the reaction is complete, adjust the pH to 8-9, extract three times with dichloromethane, combine the organic layers, wash twice with saturated sodium chloride, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the resulting crude product by silica gel column chromatography to obtain 6 g of intermediate 14K-IM3 as a yellow solid in 73% yield. ESI(M+H) + = 296.

[0123] Example 33 Synthesis of intermediate 15L-IM4 JPEG0007831797000047.jpg45169

[0124] Step 1: Dissolve intermediate 15L-IM1 (20g, 95.5 mmol) in dichloromethane, then add NBS and react at room temperature for 1 hour. After the reaction is complete, extract three times with dichloromethane, combine the organic layers, wash twice with saturated sodium chloride, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the resulting crude product by silica gel column chromatography to obtain 21g of intermediate 15L-IM2 as a yellow solid. The yield is 77%. ESI(M+H)+ = 288.

[0125] Step 2: Under nitrogen gas protection, intermediate 15L-IM2 (21g, 72.8 mmol), tetrakis(triphenylphosphine)palladium (8.4g, 7.2 mmol), intermediate SM3 (26.6g, 109.3 mmol), and potassium carbonate (30g, 218.1 mmol) are sequentially added to a 500 ml three-necked flask containing 300 ml of 1,4-dioxane. The reaction system is thoroughly stirred at 95°C and allowed to react overnight. After the reaction is complete, the mixture is cooled to room temperature, the reaction solution is poured into 100 ml of water, extracted three times with ethyl acetate, the organic layers are combined and washed twice with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product is purified by silica gel column chromatography to obtain 15 g of intermediate 15L-IM3 as a pale yellow solid. The yield is 65%, and the ESI(M+H) + = 326.

[0126] Step 3: Dissolve intermediate 15L-IM3 (11g, 20.6 mmol) in dichloromethane, add an equal volume of trifluoroacetic acid, and react overnight at room temperature. After the reaction is complete, adjust the pH to 8-9, extract three times with dichloromethane, combine the organic layers, wash twice with saturated sodium chloride, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the resulting crude product by silica gel column chromatography to obtain 5g of intermediate 15L-IM3 as a yellow solid. The yield is 50%. ESI(M+H) + = 226.

[0127] Example 34 Synthesis of intermediate 16M-IM1 JPEG0007831797000048.jpg99119

[0128] Referring to the synthesis method of intermediate 15L-IM4 in Example 33, 15L-IM1 was replaced with (S)-6-methyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate tert-butyl ester, and 3 g of intermediate 16M-IM1 was obtained in a 3-step reaction with a yield of 54%. ESI(M+H) += 240.

[0129] Example 35 Synthesis of intermediate 17N-IM3 JPEG0007831797000049.jpg48169

[0130] Step 1: Add intermediate 15L-IM2 (15g, 52 mmol), sodium hydride (2.5g, 104 mmol), and iodomethane (7.3g, 52 mmol) in sequence to a 500 mL three-necked flask containing 100 mL of DMF. Stir the reaction system thoroughly at 0°C and allow to react for 2 hours. After the reaction is complete, pour the reaction mixture into water, extract three times with dichloromethane, combine the organic layers, wash twice with saturated sodium chloride, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the resulting crude product by silica gel column chromatography to obtain 10 g of intermediate 17N-IM1 as a yellow solid. The yield is 66%. ESI(M+H) + = 302.

[0131] Step 2: Under nitrogen gas protection, intermediate 17N-IM1 (10 g, 33 mmol), tetrakis(triphenylphosphine)palladium (3.8 g, 3.3 mmol), intermediate SM3 (12.1 g, 49.6 mmol), and potassium carbonate (13.7 g, 99.3 mmol) are sequentially added to a 200 ml three-necked flask containing 100 ml of 1,4-dioxane. The reaction system is thoroughly stirred at 95°C and allowed to react overnight. After the reaction is complete, the mixture is cooled to room temperature, the reaction solution is poured into 100 ml of water, extracted three times with ethyl acetate, the organic layers are combined and washed twice with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product is purified by silica gel column chromatography to obtain 5 g of intermediate 17N-IM2 as a pale yellow solid with a yield of 45%. ESI(M+H) + = 340.

[0132] Step 3: Dissolve intermediate 17N-IM2 (5 g, 20.6 mmol) in dichloromethane, add an equal volume of trifluoroacetic acid, and react overnight at room temperature. After the reaction is complete, adjust the pH to 8-9, extract three times with dichloromethane, combine the organic layers, wash twice with saturated sodium chloride, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the resulting crude product by silica gel column chromatography to obtain 2 g of intermediate 17N-IM3 as a white solid in 57% yield. ESI(M+H) + = 240.

[0133] Example 36 Synthesis of intermediate 18O-IM4 JPEG0007831797000050.jpg43170

[0134] Step 1: Add intermediate 18O-IM1 (20 g, 63.2 mmol), sodium hydride (3.0 g, 126 mmol), and iodomethane (10.7 g, 75.9 mmol) in order to a 500 mL three-necked flask containing 100 mL of DMF. Stir the reaction system thoroughly at 0°C and allow to react for 2 hours. After the reaction is complete, pour the reaction mixture into water, extract three times with dichloromethane, combine the organic layers, wash twice with saturated sodium chloride, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the resulting crude product by silica gel column chromatography to obtain 15 g of intermediate 18O-IM2 as a yellow solid in 75% yield. ESI(M+H) + = 330.

[0135] Step 2: Under nitrogen gas protection, intermediate 18O-IM2 (15 g, 45.4 mmol), tetrakis(triphenylphosphine)palladium (5.2 g, 4.5 mmol), intermediate SM3 (16.6 g, 68.1 mmol), and potassium carbonate (18.8 g, 136.2 mmol) are sequentially added to a 200 ml three-necked flask containing 100 ml of 1,4-dioxane. The reaction system is thoroughly stirred at 95°C and allowed to react overnight. After the reaction is complete, the mixture is cooled to room temperature, the reaction solution is poured into 100 ml of water, extracted three times with ethyl acetate, the organic layers are combined and washed twice with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product is purified by silica gel column chromatography to obtain 10 g of intermediate 18O-IM3 as a pale yellow solid in 60% yield. ESI(M+H) + = 368.

[0136] Step 3: Dissolve intermediate 18O-IM3 (7 g, 20.6 mmol) in dichloromethane, add an equal volume of trifluoroacetic acid, and react overnight at room temperature. After the reaction is complete, adjust the pH to 8-9, extract three times with dichloromethane, combine the organic layers, wash twice with saturated sodium chloride, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the resulting crude product by silica gel column chromatography to obtain 5.5 g of intermediate 18O-IM4 as a white solid, with a yield of 76%. ESI(M+H) + = 268.

[0137] Example 37 Synthesis of intermediate 19P-IM1 JPEG0007831797000051.jpg89118

[0138] Referring to the synthesis method of intermediate 18O-IM4 in Example 36, the iodomethane in step 1 was replaced with 2-iodopropane, and 4 g of intermediate 19P-IM1 was obtained in a 3-step reaction with a yield of 64%. ESI(M+H) + = 296.

[0139] Example 38 Synthesis of intermediate 20Q-IM1 JPEG0007831797000052.jpg66137

[0140] Referring to the synthesis method of intermediate (R)-1d in Example 1, (R)-2-aminopropanol was replaced with aminopropanol to obtain intermediates 1-4. Then, referring to the synthesis method of intermediate (R)-1e-IM3 in Example 15, (R)-1d was replaced with intermediates 1-4 to obtain 20Q-IM1, with a yield of 30%. ESI(M+H) + = 254.

[0141] Example 39 Synthesis of intermediate 21R-IM1 JPEG0007831797000053.jpg65131

[0142] Referring to the synthesis method of intermediate (R)-1d in Example 1, intermediates 1-5 were obtained by replacing (R)-2-aminopropanol with aminobutanol. Then, referring to the synthesis method of intermediate (R)-1e-IM3 in Example 15, intermediate (R)-1d was replaced with intermediates 1-5 to obtain 21R-IM1, with a yield of 34%. ESI(M+H) + = 268.

[0143] JPEG0007831797000054.jpg71145 Example 40 Synthesis of Intermediate 22S-IM1

[0144] Referring to the synthesis method of intermediate (R)-1d in Example 1, (R)-2-aminopropanol was replaced with aminobutanol to obtain the intermediate. Then, referring to the synthesis method of intermediate (R)-1e-IM3 in Example 15, intermediate (R)-1d was replaced with intermediate (S)-3d to obtain 21R-IM1, with a yield of 34%. ESI(M+H) + = 254. Example 41 Synthesis of intermediate 23T-IM1

[0145] Referring to the synthesis method of intermediate (R)-1e-IM3 in Example 15, intermediate (R)-1d was replaced with 7d to obtain 23T-IM1, with a yield of 24% and ESI(M+H) + = 266. Example 42 Synthesis of intermediate 24U-IM1

[0146] Referencing the synthesis method of intermediate (R)-1e-IM3 in Example 15, intermediate (R)-1d was replaced with 8f to obtain intermediate 24U-IM1, with a yield of 24%. ESI(M+H) + = 314.

[0147] Example 43 Synthesis of intermediate 25V-IM4 JPEG0007831797000055.jpg45170

[0148] Step 1: Referring to Step 1 of Example 15, intermediate (R)-1d was replaced with intermediate 8f to obtain intermediate 25V-IM1, with a yield of 54% and ESI(M+H) + = 568.

[0149] Step 2: Dissolve intermediate 25V-IM1 (186 mg, 0.33 mmol) in DCM, slowly add m-CPBA (170 mg, 0.98 mmol) under ice bath, slowly raise the temperature to room temperature, stir, and react for 3 hours. After the reaction is complete, stop the reaction with saturated sodium thiosulfate and sodium bicarbonate solution, add water, extract multiple times with DCM, combine the organic phases, dry with saturated NaCl solution and Na2SO4, concentrate under reduced pressure, and purify the resulting crude product by silica gel column chromatography to obtain 158 mg of intermediate 25V-IM2, with a yield of 82%. ESI(M+H) + = 600.

[0150] Step 3: Referring to Step 2 of Example 15, intermediate (R)-1e-IM1 is replaced with intermediate 25V-IM2 to obtain intermediate 25V-IM3, with a yield of 69% and ESI(M+H) + = 446.

[0151] Step 4: Referring to Step 3 of Example 15, intermediate (R)-1e-IM2 is replaced with intermediate 25V-IM3 to obtain intermediate 25V-IM4, with a yield of 73% and ESI(M+H)+ = 346. JPEG0007831797000056.jpg111166 Synthesis of Intermediate 26W-IM1 in Example 44

[0152] Refer to the synthesis method of Intermediate 9f-IM3 in Example 27, replace iodomethane with deuterated iodomethane to obtain 26W-IM1, the yield is 43%, ESI(M+H) + = 257. Synthesis of Intermediate 27X-IM1 in Example 45

[0153] Refer to the synthesis method of Intermediate 9f-IM3 in Example 27, replace iodomethane with acetyl chloride to obtain Intermediate 27X-IM1, the yield is 38%, and ESI(M+H)+ = 282.

[0154] Synthesis of Intermediate 28Y-IM3 in Example 46 JPEG0007831797000057.jpg51170

[0155] Refer to the synthesis method of Intermediate 18O-IM4 in Example 36, replace iodomethane in Step 1 with 2-iodopropane, and replace Intermediate 18O-IM1 in Step 1 with 15L-IM2, and obtain 1.8 g of Intermediate 28Y-IM3 through a 3-step reaction, the yield is 24%. ESI(M+H) + = 268.

[0156] Synthesis of Intermediate 29Z-IM3 in Example 47 JPEG0007831797000058.jpg45170

[0157] Refer to the synthesis method of Intermediate 18O-IM4 in Example 36, replace Intermediate 18O-IM1 in Step 1 with 8d-IM3, and obtain 1.3 g of Intermediate 29Z-IM3 through a 3-step reaction, the yield is 27%. ESI(M+H) + = 282.

[0158] Synthesis of Intermediate 3OA-IM3 in Example 48 JPEG0007831797000059.jpg43170

[0159] Step 1: Add intermediate 8d-IM3 (10 g, 33.1 mmol), sodium hydride (1.59 g, 66.2 mmol), and iodomethane (9.4 g, 66.2 mmol) in sequence to a 500 mL three-necked flask containing 100 mL of DMF. Stir the reaction system thoroughly at 0°C and allow to react for 2 hours. After the reaction is complete, pour the reaction mixture into water, extract three times with dichloromethane, combine the organic layers, wash twice with saturated sodium chloride, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the resulting crude product by silica gel column chromatography to obtain 2 g of intermediate 30A-IM1 as a yellow solid in 20% yield. ESI(M+H) + = 316.

[0160] Step 2: Under nitrogen gas protection, intermediate 30A-IM1 (2 g, 6.3 mmol), tetrakis(triphenylphosphine)palladium (0.7 g, 0.6 mmol), intermediate SM3 (2.3 g, 9.5 mmol), and potassium carbonate (2.6 g, 18.9 mmol) are sequentially added to a 200 ml three-necked flask containing 100 ml of 1,4-dioxane. The reaction system is thoroughly stirred at 95°C and allowed to react overnight. After the reaction is complete, the mixture is cooled to room temperature, the reaction solution is poured into 100 ml of water, extracted three times with ethyl acetate, the organic layers are combined and washed twice with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product is purified by silica gel column chromatography to obtain 1.5 g of intermediate 30A-IM2 as a pale yellow solid with a yield of 68%. ESI(M+H) + = 354.

[0161] Step 3: Dissolve intermediate 30A-IM2 (1.5 g, 20.6 mmol) in dichloromethane, add an equal volume of trifluoroacetic acid, and react overnight at room temperature. After the reaction is complete, adjust the pH to 8-9, extract three times with dichloromethane, combine the organic layers, wash twice with saturated sodium chloride, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the resulting crude product by silica gel column chromatography to obtain 0.7 g of intermediate 30A-IM3 as a white solid. The yield is 70%. ESI(M+H) + = 254.

[0162] Example 49 Synthesis of compound YZ001001 JPEG0007831797000060.jpg65135

[0163] Step: Intermediate (R)-1e-IM3 (100 mg, 0.39 mmol) was dissolved in 20 ml of dichloromethane, then triethylamine (119.8 mg, 1.2 mmol) was added, and acryloyl chloride (42.9 mg, 0.47 mmol) was slowly added under an ice bath. After reacting at room temperature for 3 hours, saturated sodium bicarbonate aqueous solution was added, and the mixture was washed and extracted three times with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography to obtain 60 mg of compound YZ001001 as a white solid in 50% yield. 1 H NMR (400 MHz, MeOD): δ 8.22 (d, J = 5.1 Hz, 1H), 8.02 (s, 1H), 7.45 (d, J = 3.5 Hz, 1H), 7.10 (d, J = 5.1 Hz, 1H), 6.87 (s, 1H), 6.64 (d, J = 3.5 Hz, 1H), 6.28 (d, J = 16.8 Hz, 1H), 5.82 (d, J = 10.6 Hz, 1H), 5.40 (s, 1H), 4.87 - 4.85 (m, 3H), 4.39 (s, 1H), 4.30 (d, J = 12.9 Hz, 1H), 1.29 (d, J = 6.3 Hz, 3H). ESI(M+H) + =308.

[0164] JPEG0007831797000061.jpg218170JPEG0007831797000062.jpg207170 Example 50 Synthesis of compound YZ001002

[0165] Referring to the steps of Example 49, intermediate (R)-1e-IM3 in Example 49 was replaced with intermediate 2e-IM3 to obtain compound YZ001002, with a yield of 47%. 1 H NMR (400 MHz, MeOD): δ 8.25 (d, J = 5.1 Hz, 1H), 8.02 (s, 1H), 7.48 (d, J = 3.5 Hz, 1H), 7.09 (d, J = 5.0 Hz, 1H), 7.02 - 6.73 (m, 1H), 6.68 (d, J = 2.9 Hz, 1H), 6.39 - 6.24 (m, 1H), 5.95 - 5.74 (m, 1H), 5.17 - 5.06 (m, 2H), 4.43 - 4.32 (m, 2H), 4.30 - 4.21 (m, 2H). ESI(M+H) + =294. Example 51 Synthesis of compound YZ001003

[0166] Referring to the steps of Example 49, compound YZ001003 was obtained in 50% yield by replacing acryloyl chloride with acetyl chloride in Example 49. 1 H NMR (400 MHz, MeOD): δ 8.24 (d, J = 4.5 Hz, 1H), 8.05 (s, 1H), 7.52 - 7.44 (m, 1H), 7.16 - 7.07 (m, 1H), 6.67 (d, J = 3.5 Hz, 1H), 5.56 - 4.89 (m, 2H), 4.82 - 4.73 (m, 1H), 4.55 - 4.27 (m, 2H), 2.25 (d, J = 38.1 Hz, 3H), 1.39 - 1.26 (m, 3H). ESI(M+H) + =296. Example 52 Synthesis of compound YZ001004

[0167] Step: Intermediate (R)-1e-IM3 (100 mg, 0.39 mmol) is dissolved in 20 ml of dichloromethane, then N,N-diisopropylethylamine (204.1 mg, 1.6 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (195.1 mg, 0.51 mmol), and 2-fluoroacrylic acid (46.2 mg, 0.51 mmol) are added and the mixture is reacted at room temperature for 3 hours. Then saturated sodium bicarbonate aqueous solution is added, and the mixture is washed and extracted three times with dichloromethane. The organic layers are combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product is purified by silica gel column chromatography to obtain 80 mg of compound YZ001004 as a white solid, with a yield of 66%. 1 H NMR (400 MHz, DMSO-d6): δ 11.77 (s, 1H), 8.27 (d, J = 4.9 Hz, 1H), 8.07 (s, 1H), 7.55 - 7.47 (m, 1H), 7.05 (d, J = 5.0 Hz, 1H), 6.65 (dd, J = 3.4, 1.8 Hz, 1H), 5.42 (s, 1H), 5.34 (dd, J = 32.2, 4.2 Hz, 1H), 4.91 (s, 1H), 4.35 (dt, J = 38.6, 8.6 Hz, 2H), 2.72 (s, 2H), 1.30 (s, 3H).ESI(M+H) + =326. Example 53 Synthesis of compound YZ001005

[0168] Referring to the steps of Example 52, compound YZ001005 was obtained in 52% yield by replacing 2-fluoroacrylic acid in Example 52 with trans-4-dimethylaminocrotonate salt. 1H NMR (400 MHz, DMSO-d6): δ 11.76 (s, 1H), 8.26 (d, J = 4.9 Hz, 1H), 8.05 (s, 1H), 7.57 - 7.49 (m, 1H), 7.07 (s, 1H), 6.64 (dd, J = 3.4, 1.8 Hz, 1H), 5.31 (d, J = 17.0 Hz,1H), 4.92 (s, 1H), 4.60 (s, 2H), 4.28 (s, 2H), 3.19 (d, J = 9.6 Hz, 1H), 3.08 (s, 2H), 2.18 (d, J = 1.4 Hz, 6H), 1.23 (s, 3H). ESI(M+H) + =365. Example 54 Synthesis of compound YZ001006

[0169] Referring to the steps of Example 52, compound YZ001006 was obtained in 80% yield by replacing 2-fluoroacrylic acid with (2E)-4-(1-piperidinyl)-2-butenic acid in Example 52. 1 H NMR (400 MHz, DMSO-d6): δ 11.75 (s, 1H), 8.26 (d, J = 4.9 Hz, 1H), 8.05 (s, 1H), 7.58 - 7.44 (m, 1H), 7.07 (d, J = 4.2 Hz, 1H), 6.74 - 6.60 (m, 2H), 5.30 (d, J = 17.1 Hz, 1H), 4.91 (s, 1H), 4.60 (s, 1H), 4.27 (d, J = 12.3 Hz, 2H), 3.14 (s, 2H), 2.36 (d, J = 1.9 Hz, 4H), 1.52 (s, 4H), 1.41 (s, 3H), 1.23 (d, J = 6.2 Hz, 2H). ESI(M+H) + =405. Example 55 Synthesis of compound YZ001007

[0170] Referring to the steps of Example 52, 2-fluoroacrylic acid in Example 52 was replaced with (E)-buta-2-enoic acid to obtain compound YZ001007, with a yield of 70%. 1 H NMR (400 MHz, DMSO-d6): δ 11.75 (s, 1H), 8.26 (dd, J = 4.9, 2.5 Hz, 1H), 8.06 (d, J = 4.7 Hz, 1H), 7.55 - 7.50 (m, 1H), 7.08 (s, 1H), 6.79 (dd, J = 14.8, 6.7 Hz, 1H), 6.65 (dd, J = 3.4, 1.8 Hz, 2H), 5.41 - 5.06 (m, 2H), 4.71 (dd, J = 12.8, 5.2 Hz, 1H), 4.26 (d, J = 12.3 Hz, 2H), 1.89 (d, J = 6.2 Hz, 3H), 1.22 (s, 3H). ESI(M+H) + =322. Example 56 Synthesis of compound YZ001008

[0171] Referring to the steps of Example 52, compound YZ001008 was obtained in 68% yield by replacing 2-fluoroacrylic acid with 2-methacrylic acid in Example 52. 1 H NMR (400 MHz, DMSO-d6): δ 11.75 (s, 1H), 8.25 (d, J = 4.9 Hz, 1H), 8.06 (s, 1H), 7.52 (t, J = 2.9 Hz, 1H), 7.04 (d, J = 4.9 Hz, 1H), 6.64 (dd, J = 3.2, 1.7 Hz, 1H), 5.28 (s, 1H), 5.16 (s, 1H), 4.93 - 4.56 (m, 2H), 4.48 - 4.36 (m, 1H), 4.28 (dd, J = 40.4, 8.4 Hz, 2H), 1.93 (s, 3H), 1.30 (d, J = 6.9 Hz, 3H). ESI(M+H) + =322. Example 57 Synthesis of compound YZ001009

[0172] Referring to the steps of Example 52, compound YZ001009 was obtained in 78% yield by replacing 2-fluoroacrylic acid with 4,4,4-trifluorobutenoic acid in Example 52. 1 H NMR (400 MHz, DMSO-d6): δ 11.76 (s, 1H), 8.27 (d, J = 4.6 Hz, 1H), 8.06 (s, 1H), 7.52 (s, 2H), 7.06 (d, J = 4.6 Hz, 1H), 6.85 (dd, J = 15.4, 7.1 Hz, 1H), 6.64 (dd, J = 3.4, 1.8 Hz, 1H), 5.36 (d, J = 17.9 Hz, 1H), 4.90 (s, 1H), 4.45 (dt, J = 70.9, 15.2 Hz, 2H), 1.27 (d, J = 6.4 Hz, 3H).ESI(M+H) + =376. Example 58 Synthesis of compound YZ001010

[0173] Referring to the steps of Example 52, compound YZ001010 was obtained in 58% yield by replacing 2-fluoroacrylic acid with 2-butyric acid in Example 52. 1 H NMR (400 MHz, DMSO-d6): δ 11.76 (s, 1H), 8.27 (dd, J = 7.4, 5.0 Hz, 1H), 8.07 (s, 1H), 7.53 (dd, J = 7.3, 4.4 Hz, 1H), 7.05 (t, J = 5.1 Hz, 1H), 6.65 (dd, J = 3.2, 1.8 Hz, 1H), 5.34 (dd, J = 50.6, 17.3 Hz, 1H), 5.16 - 5.08 (m, 1H), 4.58 (d, J = 17.8 Hz, 1H), 4.46 - 4.20 (m, 2H), 2.12 (s, 3H), 1.28 (d, J = 6.2 Hz, 3H).ESI(M+H) + =320. Example 59 Synthesis of compound YZ001011

[0174] Referring to the steps of Example 49, acryloyl chloride in Example 49 was replaced with methanesulfonyl chloride to obtain Compound YZ001011 in a yield of 40%. 1 H NMR (400 MHz, DMSO-d6): δ 11.76 (s, 1H), 8.26 (d, J = 4.9 Hz, 1H), 8.08 (s, 1H), 7.59 - 7.43 (m, 1H), 7.05 (d, J = 5.0 Hz, 1H), 6.66 (dd, J = 3.4, 1.8 Hz, 1H), 4.81 (dd, J = 39.0, 16.6 Hz, 2H), 4.57 (s, 1H), 4.42 - 4.17 (m, 2H), 3.11 (s, 3H), 1.33 (d, J = 6.9 Hz, 3H). ESI(M+H) + =332. Example 60 Synthesis of Compound YZ001012

[0175] Referring to the steps of Example 49, acryloyl chloride in Example 49 was replaced with cyclopropanesulfonyl chloride to obtain Compound YZ001012 in a yield of 46%. 1 H NMR (400 MHz, DMSO-d6): δ 11.77 (s, 1H), 8.26 (d, J = 4.9 Hz, 1H), 8.08 (s, 1H), 7.57 - 7.50 (m, 1H), 7.04 (d, J = 5.0 Hz, 1H), 6.66 (dd, J = 3.4, 1.8 Hz, 1H), 4.83 (s, 2H), 4.57 (dd, J = 8.7, 3.4 Hz, 1H), 4.40 (dd, J = 13.0, 5.0 Hz, 2H), 2.86 - 2.77 (m, 1H), 1.39 (d, J = 6.9 Hz, 3H), 1.06 - 0.98 (m, 2H), 0.96 - 0.86 (m, 2H). ESI(M+H) + =358. Example 61 Synthesis of Compound YZ001013

[0176] Referring to the steps of Example 49, compound YZ001013 was obtained in 53% yield by replacing acryloyl chloride with chloroacetyl chloride in Example 49. 1 H NMR (400 MHz, DMSO-d6): δ 11.76 (s, 1H), 8.26 (d, J = 4.6 Hz, 1H), 8.07 (s, 1H), 7.53 (s, 1H), 7.07 (s, 1H), 6.66 (s, 1H), 5.79 (s, ESI(M+H) + =330. Example 62 Synthesis of compound YZ001014

[0177] Referring to the steps of Example 52, compound YZ001014 was obtained in 52% yield by replacing 2-fluoroacrylic acid with 1-trifluoromethylcyclopropane-1-carboxylic acid in Example 52. 1 H NMR (400 MHz, DMSO-d6): δ 11.77 (s, 1H), 8.26 (d, J = 4.9 Hz, 1H), 8.08 (s, 1H), 7.56 - 7.51 (m, 1H), 7.05 (d, J = 5.0 Hz, 1H), 6.65 (dd, J = 3.4, 1.8 Hz, 1H), 5.38 (d, J = 17.5 Hz, 1H), 5.20 - 5.06 (m, 1H), 4.68 (s, 1H), 4.36 (d, J = 9.1 Hz, 1H), 4.26 (d, J = 12.7 Hz, 1H), 1.39 (s, 4H), 1.36 (s, 3H). ESI(M+H) + =390. Example 63 Synthesis of compound YZ001015

[0178] Referring to the steps of Example 52, compound YZ001015 was obtained in 65% yield by replacing 2-fluoroacrylic acid with trifluoroacetic acid in Example 52. 1 H NMR (400 MHz, DMSO-d6): δ 11.71 (d, J = 62.5 Hz, 1H), 8.27 (d, J = 4.9 Hz, 1H), 8.08 (d, J = 8.3 Hz, 1H), 7.54 (d, J = 2.5 Hz, 1H), 7.04 (dd, J = 19.1, 4.9 Hz, 1H), 6.64 (d, J = 11.8 Hz, 1H), 5.32 (d, J = 17.7 Hz, 1H), 5.11 (dd, J = 52.8, 16.5 Hz, 1H), 4.77 (d, J = 10.0 Hz, 1H), 4.44 (dd, J = 13.1, 4.1 Hz, 1H), 4.33 (dd, J = 13.1, 6.9 Hz, 1H), 1.32 (t, J = 9.4 Hz, 3H). ESI(M+H) + =350. Example 64 Synthesis of compound YZ001016

[0179] Referring to the steps of Example 52, compound YZ001016 was obtained in 75% yield by replacing 2-fluoroacrylic acid with brominated nitrile in Example 52. 1 H NMR (400 MHz, DMSO-d6): δ 11.77 (s, 1H), 8.26 (t, J = 11.7 Hz, 1H), 8.08 (s, 1H), 7.56 - 7.46 (m, 1H), 7.00 (t, J = 5.9 Hz, 1H), 6.66 (dd, J = 3.3, 1.7 Hz, 1H), 4.91 (dd, J = 38.5, 16.2 Hz, 2H), 4.47 (dt, J = 9.6, 4.8 Hz, 1H), 4.11 - 4.00 (m, 1H), 3.94 (ddd, J = 15.5, 7.8, 4.6 Hz, 1H), 1.46 (t, J = 5.4 Hz, 3H). ESI(M+H) + =279. Example 65 Synthesis of compound YZ001017

[0180] Referring to the steps of Example 49, compound YZ001017 was obtained in 43% yield by replacing acryloyl chloride with propylene sulfonyl chloride in Example 49. 1 H NMR (400 MHz, DMSO-d6): δ 11.70 (d, J = 59.9 Hz, 1H), 8.25 (t, J = 5.3 Hz, 1H), 8.07 (s, 1H), 7.66 (t, J = 6.0 Hz, 1H), 7.63 (s, 1H), 7.61 - 7.57 (m, 1H), 7.01 (dd, J = 12.4, 6.9 Hz, 1H), 6.21 - 6.16 (m, 1H), 6.11 (d, J = 9.9 Hz, 1H), 4.80 - 4.72 (m, 2H), 4.56 - 4.47 (m, 1H), 4.35 (dd, J = 13.0, 4.9 Hz, 1H), 4.26 - 4.15 (m, 1H), 1.31 (t, J = 8.3 Hz, 3H). ESI(M+H)+=344. Example 66 Synthesis of compound YZ001018

[0181] Referring to the steps of Example 49, intermediate (R)-1e-IM3 in Example 49 was replaced with intermediate (R)-3e-IM3 to obtain compound YZ001018 in 59% yield. 1 H NMR (400 MHz, DMSO-d6): δ 12.13 (s, 1H), 8.76 (s, 1H), 8.48 (s, 1H), 7.60 - 7.56 (m, 1H), 7.03 (dd, J = 3.4, 1.6 Hz, 1H), 6.22 (dd, J = 16.7, 2.1 Hz, 1H), 5.81 (d, J = 10.5 Hz, 2H), 4.95 (s, 1H), 4.73 (d, J = 7.5 Hz, 1H), 4.38 (s, 1H), 4.26 (d, J = 12.7 Hz, 1H), 1.20 (d, J = 5.6 Hz, 3H).ESI(M+H) + =309. Example 67 Synthesis of compound YZ001019

[0182] Referring to the steps of Example 52, 2-fluoroacrylic acid in Example 52 was replaced with trans-4-dimethylaminocrotonate, and (R)-1e-IM3 was replaced with (R)-3e-IM3 to obtain compound YZ001019 in 76% yield. 1 H NMR (400 MHz, DMSO-d6): δ 12.13 (s, 1H), 8.75 (s, 1H), 8.47 (s, 1H), 7.60 - 7.50 (m, 1H), 7.03 (d, J = 2.2 Hz, 1H), 6.71 (d, J = 5.2 Hz, 2H), 5.70 (s, 1H), 4.92 (s, 1H), 4.79 - 4.63 (m, 1H), 4.38 (s, 1H), 4.28 (s, 1H), 3.10 (d, J = 4.0 Hz, 2H), 2.21 (s, 6H), 1.20 (d, J = 6.1 Hz, 3H).ESI(M+H) + =366. Example 68 Synthesis of compound YZ001020

[0183] Referring to the steps of Example 52, compound YZ001020 was obtained in 80% yield by replacing 2-fluoroacrylic acid with propiolic acid in Example 52. 1 H NMR (400 MHz, CDCl3): δ 11.74 (s, 1H), 8.23 ​​(d, J = 3.3 Hz, 1H), 8.04 (s, 1H), 7.56 (dd, J = 9.5, 5.3 Hz, 1H), 7.51 (d, J = 2.6 Hz, 1H), 7.02 (d, J = 4.9 Hz, 1H), 6.62 (s, 1H), 5.24 (d, J = 17.8 Hz, 1H), 4.60 (dd, J = 38.5, 20.8 Hz, 1H), 4.48 - 4.20 (m, 2H), 3.14 (s, 1H), 1.30 (s, 3H).ESI(M+H) + =306. Example 69 Synthesis of compound YZ001021

[0184] Referring to the steps of Example 49, the intermediate (R)-1e-IM3 in Example 49 was replaced with intermediate (S)-1e-IM3 to obtain compound YZ001021 in 78% yield. 1 H NMR (400 MHz, DMSO-d6): δ 11.72 (d, J = 34.0 Hz, 1H), 8.27 (d, J = 4.9 Hz, 1H), 8.06 (s, 2H), 7.54 - 7.51 (m, 1H), 7.08 (s, 1H), 6.66 (dd, J = 3.2, 1.7 Hz, 1H), 6.19 (dt, J = 24.2, 12.1 Hz, 1H), 5.77 (dd, J = 17.3, 13.3 Hz, 1H), 5.33 (d, J = 17.2 Hz, 1H), 4.98 (dd, J = 13.6, 7.1 Hz, 2H), 4.28 (d, J = 12.2 Hz, 2H), 1.16 (d, J = 6.6 Hz, 3H). ESI(M+H) + =308. Example 70 Synthesis of compound YZ001022

[0185] Referring to the steps of Example 49, intermediate (R)-1e-IM3 in Example 49 was replaced with intermediate (S)-1e-IM3, and acryloyl chloride was replaced with trans-4-dimethylaminocrotonate to obtain compound YZ001022 in 82% yield. 1H NMR (400 MHz, DMSO-d6): δ 11.85 - 11.49 (m, 1H), 8.26 (m, 1H), 8.06 (d, J = 6.6 Hz, 1H), 7.56 - 7.49 (m, 1H), 7.08 (s, 1H), 6.70 (d, J = 5.3 Hz, 2H), 6.65 (dd, J = 3.4, 1.8 Hz, 1H), 5.32 (d, J = 16.8 Hz, 1H), 4.92 (s, 1H), 4.38 (d, J = 7.2 Hz, 1H), 4.27 (d, J = 12.5 Hz, 1H), 3.07 (s, 2H), 2.24 - 2.13 (m, 6H), 1.28 - 1.18 (m, 3H).ESI(M+H) + =365. Example 71 Synthesis of compound YZ001023

[0186] Referring to the steps of Example 49, intermediate (R)-1e-IM3 in Example 49 was replaced with intermediate (S)-1e-IM3, and acryloyl chloride was replaced with (2E)-4-(1-piperidinyl)-2-butenoic acid to obtain compound YZ001023 in 86% yield. 1 H NMR (400 MHz, DMSO-d6): δ 11.80 - 11.64 (m, 1H), 8.26 (d, J = 4.9 Hz, 1H), 8.01 (d, J = 35.2 Hz, 1H), 7.58 - 7.48 (m, 1H), 7.06 (d, J = 4.2 Hz, 1H), 6.70 (s, 2H), 6.64 (dd, J = 3.4, 1.8 Hz, 1H), 5.30 (d, J = 17.0 Hz, 1H), 4.90 (s, 1H), 4.52 (d, J = 53.5 Hz, 1H), 4.36 (s, 1H), 4.28 (s, 1H), 3.11 (s, 2H), 2.36 (s, 4H), 1.50 (s, 4H), 1.40 (s, 2H), 1.26 - 1.18 (m, 3H). ESI(M+H) + =405. Example 72 Synthesis of compound YZ001024

[0187] Referring to the steps of Example 49, intermediate (R)-1e-IM3 in Example 49 was replaced with intermediate (S)-3e-IM3 to obtain compound YZ001024 in 48% yield. 1 H NMR (400 MHz, DMSO-d6): δ 12.07 (d, J = 53.5 Hz, 1H), 8.76 (s, 1H), 8.53 (d, J = 36.6 Hz, 1H), 7.63 (d, J = 30.5 Hz, 1H), 6.99 (d, J = 35.4 Hz, 1H), 6.18 (t, J = 30.5 Hz, 1H), 5.80 (d, J = 19.6 Hz, 2H), 4.94 (s, 1H), 4.74 (s, 1H), 4.34 (d, J = 28.4 Hz, 1H), 4.27 (d, J = 11.7 Hz, 1H), 1.22 (d, J = 14.8 Hz, 3H). ESI(M+H) + =309. Example 73 Synthesis of compound YZ001025

[0188] Referring to the steps of Example 52, 2-fluoroacrylic acid in Example 52 was replaced with trans-4-dimethylaminocrotonate, and (R)-1e-IM3 was replaced with (S)-3e-IM3 to obtain compound YZ001025 in 66% yield. 1 H NMR (400 MHz, DMSO-d6): δ 12.13 (s, 1H), 8.85 (s, 1H), 8.57 (s, 1H), 7.60 - 7.40 (m, 1H), 7.13 (d, J = 2.2 Hz, 1H), 6.61 (d, J = 5.2 Hz, 2H), 5.60 (s, 1H), 4.92 (s, 1H), 4.79 - 4.63 (m, 1H), 4.38 (s, 1H), 4.38 (s, 1H), 3.20 (d, J = 4.0 Hz, 2H), 2.31 (s, 6H), 1.40 (d, J = 6.3 Hz, 3H).ESI(M+H) + =366. Example 74 Synthesis of compound YZ001026

[0189] Referring to the steps of Example 49, intermediate (R)-1e-IM3 in Example 49 was replaced with intermediate (R)-4e-IM3 to obtain compound YZ001026 in 58% yield. 1 H NMR (400 MHz, DMSO-d6): δ 12.21 (s, 1H), 8.76 (s, 1H), 8.45 (s, 1H), 7.63 - 7.50 (m, 1H), 7.01 (dd, J = 3.4, 1.5 Hz, 1H), 6.26 (d, J = 16.8 Hz, 1H), 5.82 (dd, J = 10.5, 2.1 Hz, 1H), 5.28 (d, J = 11.8 Hz, 1H), 4.52 (s, 1H), 4.24 (d, J = 10.8 Hz, 1H), 4.11 (d, J = 16.0 Hz, 1H), 3.99 (d, J = 5.9 Hz, 1H), 1.49 (d, J = 6.1 Hz, 3H). ESI(M+H) + =309. Example 75 Synthesis of compound YZ001027

[0190] Referring to the steps of Example 52, 2-fluoroacrylic acid in Example 52 was replaced with trans-4-dimethylaminocrotonate, and (R)-1e-IM3 was replaced with (R)-4e-IM3 to obtain compound YZ001027 in 76% yield. 1H NMR (400 MHz, DMSO-d6): δ 12.15 (s, 1H), 8.76 (s, 1H), 8.45 (s, 1H), 7.59 (s, 1H), 7.02 (d, J = 2.7 Hz, 1H), 6.89 - 6.64 (m, 2H), 5.41 - 5.21 (m, 2H), 4.52 (s, 1H), 4.23 (d, J = 12.4 Hz, 1H), 3.95 (dd, J = 14.0, 5.9 Hz, 1H), 3.18 (d, J = 4.8 Hz, 2H), 2.25 (s, 6H), 1.50 (d, J = 6.0 Hz, 3H). ESI(M+H) + =366. Example 76 Synthesis of compound YZ001028

[0191] Referring to the steps of Example 49, the intermediate (R)-1e-IM3 in Example 49 was replaced with intermediate S)-4e-IM3 to obtain compound YZ001028 in 58% yield. 1 H NMR (400 MHz, DMSO-d6): δ 12.21 (s, 1H), 8.76 (s, 1H), 8.45 (s, 1H), 7.64 - 7.51 (m, 1H), 7.01 (d, J = 1.9 Hz, 1H), 6.26 (d, J = 16.6 Hz, 1H), 5.82 (dd, J = 10.4, 2.1 Hz, 1H), 5.28 (d, J = 11.8 Hz, 1H), 4.52 (s, 1H), 4.24 (d, J = 11.7 Hz, 1H), 4.11 (d, J = 11.4 Hz, 1H), 3.97 (dd, J = 14.1, 5.8 Hz, 1H), 3.61 (d, J = 4.1 Hz, 1H), 1.49 (d, J = 6.2 Hz, 3H). ESI(M+H) + =309. Example 77 Synthesis of compound YZ001029

[0192] Referring to the steps of Example 52, 2-fluoroacrylic acid in Example 52 was replaced with trans-4-dimethylaminocrotonate, and (R)-1e-IM3 was replaced with (R)-5e-IM3 to obtain compound YZ001029 in 36% yield. 1 H NMR (400 MHz, DMSO-d6): δ 12.20 (s, 1H), 8.78 (s, 1H), 8.26 (s, 1H), 7.63 - 7.58 (m, 1H), 6.94 (d, J = 2.6 Hz, 1H), 6.52 (s, 2H), 4.82 (d, J = 6.1 Hz, 1H), 4.71 (d, J = 17.8 Hz, 1H), 4.59 (dd, J = 14.5, 6.7 Hz, 1H), 4.39 (d, J = 16.8 Hz, 1H), 4.18 - 4.05 (m, 2H), 3.15 (d, J = 5.5 Hz, 1H), 2.23 (s, 2H), 1.84 (s, 6H), 1.25 (s, 3H).ESI(M+H) + =380. Example 78 Synthesis of compound YZ001030

[0193] Referring to the steps of Example 49, intermediate (R)-1e-IM3 in Example 49 was replaced with intermediate (R)-6e-IM3 to obtain compound YZ001030 in 59% yield. 1 H NMR (400 MHz, CDCl3): δ 11.15 (s, 1H), 8.85 (s, 1H), 8.25 (s, 1H), 7.41 (s, 1H), 6.83 (s, 1H), 6.80 - 6.73 (m, 1H), 6.43 (d, J = 16.2 Hz, 1H), 5.85 (d, J = 10.5 Hz, 1H), 4.97 (dd, J = 12.6, 4.7 Hz, 2H), 4.74 - 4.50 (m, 2H), 4.23 (dd, J = 13.5, 4.2 Hz, 1H), 1.89 - 1.78 (m, 1H), 1.07 (s, 3H), 0.97 (s, 3H). ESI(M+H) + =337. Example 79 Synthesis of compound YZ001031

[0194] Referring to the steps of Example 52, 2-fluoroacrylic acid in Example 52 was replaced with trans-4-dimethylaminocrotonate, and (R)-1e-IM3 was replaced with (R)-6e-IM3 to obtain compound YZ001031 in 78% yield. 1 H NMR (400 MHz, CDCl3): δ 11.14 (s, 1H), 8.85 (s, 1H), 8.25 (s, 1H), 7.41 (s, 1H), 6.83 (s, 1H), 6.81 - 6.74 (m, 1H), 6.45 (d, J = 16.2 Hz, 1H), 4.98 (dd, J = 12.6, 4.7 Hz, 2H), 4.74 - 4.50 (m, 2H), 4.23 (dd, J = 13.5, 4.2 Hz, 1H), 2.86 (d, J = 4.0 Hz, 2H), 1.99 (s, 6H), 1.89 - 1.78 (m, 1H), 0.97 (s, 6H). ESI(M+H) + =394. Example 80 Synthesis of compound YZ001032

[0195] Referring to the steps of Example 52, intermediate (R)-1e-IM3 in Example 52 was replaced with intermediate (R)-6e-IM3, and 2-fluoroacrylic acid was replaced with (2E)-4-(1-piperidinyl)-2-butenoic acid to obtain compound YZ001032 in 87% yield. ESI(M+H) + = 434. Example 81 Synthesis of compound YZ001033

[0196] Referring to the steps of Example 49, intermediate (R)-1e-IM3 in Example 49 was replaced with intermediate (S)-6e-IM3 to obtain compound YZ001033 in 60% yield. 1H NMR (400 MHz, CDCl3): δ 11.13 (s, 1H), 8.84 (s, 1H), 8.25 (s, 1H), 7.40 (s, 1H), 6.83 (s, 1H), 6.80 - 6.73 (m, 1H), 6.43 (d, J = 16.2 Hz, 1H), 5.85 (d, J = 10.5 Hz, 1H), 4.97 (dd, J = 12.6, 4.7 Hz, 2H), 4.74 - 4.50 (m, 2H), 4.23 (dd, J = 13.5, 4.2 Hz, 1H), 1.89 - 1.78 (m, 1H), 1.05 (s, 3H), 0.93 (s, 3H). ESI(M+H) + =337. Example 82 Synthesis of compound YZ001034

[0197] Referring to the steps of Example 52, 2-fluoroacrylic acid in Example 52 was replaced with trans-4-dimethylaminocrotonate, and (R)-1e-IM3 was replaced with (S)-6e-IM3 to obtain compound YZ001034 in 80% yield. 1 H NMR (400 MHz, CDCl3): δ 11.13 (s, 1H), 8.85 (s, 1H), 8.23 ​​(s, 1H), 7.41 (s, 1H), 6.83 (s, 1H), 6.82 - 6.74 (m, 1H), 6.45 (d, J = 16.2 Hz, 1H), 4.98 (dd, J = 12.6, 4.7 Hz, 2H), 4.74 - 4.50 (m, 2H), 4.23 (dd, J = 13.5, 4.2 Hz, 1H), 2.86 (d, J = 4.0 Hz, 2H), 1.99 (s, 6H), 1.89 - 1.78 (m, 1H), 0.97 (s, 6H). ESI(M+H) + =394. Example 83 Synthesis of compound YZ001035

[0198] Referring to the steps of Example 52, intermediate (R)-1e-IM3 in Example 52 was replaced with intermediate (S)-6e-IM3, and 2-fluoroacrylic acid was replaced with (2E)-4-(1-piperidinyl)-2-butenoic acid to obtain compound YZ001035 in 83% yield. ESI(M+H) + = 434. Example 84 Synthesis of compound YZ001039

[0199] Referring to the steps of Example 49, the intermediate (R)-1e-IM3 in Example 49 was replaced with intermediate 23T-IM1 to obtain compound YZ001039 in 41% yield. 1 H NMR (400 MHz, CDCl3): δ 10.19 (s, 1H), 8.35 (d, J = 2.8 Hz, 1H), 8.09 - 7.92 (m, 1H), 7.45 (d, J = 0.4 Hz, 1H), 7.06 (d, J = 2.9 Hz, 1H), 6.96 - 6.81 (m, 1H), 6.73 (d, J = 0.6 Hz, 1H), 6.49 (d, J = 16.9 Hz, 1H), 5.86 (d, J = 7.2 Hz, 1H), 4.53 - 3.98 (m,2H), 3.07 - 2.61 (m, 2H), 1.26 - 1.06 (m, 2H), 1.02 - 0.48 (m, 2H). ESI(M+H)+=320. Example 85 Synthesis of compound YZ001045

[0200] Referring to the steps of Example 49, the intermediate (R)-1e-IM3 in Example 49 was replaced with the intermediate (S,S)-7d-IM3 to obtain compound YZ001045 in 48% yield. 1H NMR (400 MHz, DMSO-d6): δ 11.75 (s, 1H), 8.27 (d, J = 4.9 Hz, 1H), 8.06 (s, 1H), 7.74 - 7.67 (m, 1H), 7.61 - 7.57 (m, 1H), 7.53 (d, J = 2.6 Hz, 1H), 7.05 (d, J = 4.7 Hz, 1H), 6.65 (s, 1H), 6.18 (d, J = 16.8 Hz, 1H), 5.44 (s, 1H), 5.08 (s, 1H), 4.66 (s, 2H), 2.27 - 2.16 (m, 2H), 2.02 (s, 1H), 1.96 - 1.89 (m, 1H), 1.71 (dd, J = 13.6, 5.8 Hz, 2H). ESI(M+H) + =334. Example 86 Synthesis of compound YZ001047

[0201] Referring to the steps of Example 52, 2-fluoroacrylic acid in Example 52 was replaced with trans-4-dimethylaminocrotonate, and (R)-1e-IM3 was replaced with (S,S)-7d-IM3 to obtain compound YZ001047 in 86% yield. 1 H NMR (400 MHz, DMSO-d6): δ 11.75 (s, 1H), 8.26 (d, J = 4.9 Hz, 1H), 8.05 (s, 1H), 7.73 - 7.62 (m, 1H), 7.58 (d, J = 7.5 Hz, 1H), 7.54 - 7.49 (m, 1H), 7.04 (d, J = 4.9 Hz, 1H), 6.64 (d, J = 1.6 Hz, 1H), 5.45 (d, J = 17.2 Hz, 1H), 5.06 (s, 1H), 4.70 (s, 1H), 4.56 (d, J = 18.0 Hz, 1H), 3.16 (s, 2H), 2.35 (s, 2H), 2.24 (s, 6H), 2.01 (s, 2H), 1.81 - 1.68 (m, 2H). ESI(M+H) + =391. Example 87 Synthesis of compound YZ001048

[0202] Referring to the steps of Example 52, intermediate (R)-1e-IM3 in Example 52 was replaced with intermediate (R)-6e-IM3 to obtain compound YZ0010048, with a yield of 70%. 1 H NMR (400 MHz, CDCl3): δ 11.15 (s, 1H), 8.84 (s, 1H), 8.23 ​​(s, 1H), 7.41 (s, 1H), 6.83 (s, 1H), 5.32 (t, J = 4 Hz, 0.5H), 5.20 (d, J = 4 Hz, 0.5H), 5.13 (d, J = 16 Hz, 1H), 4.97 (dd, J = 12.6, 4.7 Hz, 2H), 4.74 - 4.50 (m, 2H), 4.23 (dd, J = 13.5, 4.2 Hz, 1H), 1.89 - 1.78 (m, 1H), 1.07 (s, 3H), 0.97 (s, 3H). ESI(M+H) + =355. Example 88 Synthesis of compound YZ001049

[0203] Referring to the steps of Example 52, the intermediate (R)-1e-IM3 in Example 52 was replaced with the intermediate (S)-6e-IM3 to obtain compound YZ0010049, with a yield of 68%. 1 H NMR (400 MHz, CDCl3): δ 11.13 (s, 1H), 8.81 (s, 1H), 8.25 (s, 1H), 7.40 (s, 1H), 6.83 (s, 1H), 5.30 (t, J = 4 Hz, 0.5H), 5.24 (d, J = 4 Hz, 0.5H), 5.16 (d, J = 16 Hz, 1H), 4.97 (dd, J = 12.6, 4.7 Hz, 2H), 4.71 - 4.45 (m, 2H), 4.23 (dd, J = 13.5, 4.2 Hz, 1H), 1.84 - 1.73 (m, 1H), 1.05 (s, 3H), 0.93 (s, 3H). ESI(M+H) + =355. Example 89 Synthesis of compound YZ001050

[0204] Referring to the steps of Example 52, intermediate (R)-1e-IM3 in Example 52 was replaced with intermediate (S)-6e-IM3, and 2-fluoroacrylic acid was replaced with 2-butyric acid to obtain compound YZ0010050, with a yield of 67%. 1 H NMR (400 MHz, CDCl3): δ 11.12 (s, 1H), 8.84 (s, 1H), 8.25 (s, 1H), 7.40 (s, 1H), 6.83 (s, 1H), 4.97 (dd, J = 12.6, 4.7 Hz, 2H), 4.74 - 4.50 (m, 2H), 4.23 (dd, J = 13.5, 4.2 Hz, 1H), 2.03 (d, J = 48 Hz, 3H), 1.89 - 1.78 (m, 1H), 1.05 (s, 3H), 0.93 (s, 3H). ESI(M+H) + =349. Example 90 Synthesis of compound YZ001051

[0205] Referring to the steps of Example 52, the intermediate (R)-1e-IM3 in Example 52 was replaced with the intermediate (S,S)-7d-IM3 to obtain compound YZ001051 in 86% yield. 1 H NMR (400 MHz, DMSO-d6): δ 11.77 (s, 1H), 8.26 (d, J = 4.9 Hz, 1H), 8.07 (s, 1H), 7.75 - 7.67 (m, 1H), 7.57 (dd, J = 9.6, 4.7 Hz, 1H), 7.52 (s, 1H), 7.02 (d, J = 4.9 Hz, 1H), 6.64 (dd, J = 3.2, 1.6 Hz, 1H), 5.39 (d, J = 6.3 Hz, 2H), 5.25 (d, J = 4.2 Hz, 1H), 4.73 (s, 1H), 2.30 (s, 1H), 2.04 (d, J = 6.5 Hz, 2H), 1.76 - 1.57 (m, 2H).ESI(M+H) + =352. Example 91 Synthesis of compound YZ001052

[0206] Referring to the steps of Example 49, the intermediate (R)-1e-IM3 in Example 49 was replaced with intermediate 9f-IM5 to obtain compound YZ001052 in 76% yield. 1 H NMR (400 MHz, DMSO-d6): δ 11.69 (s, 1H), 8.30 (d, J = 4.9 Hz, 1H), 7.49 (s, 1H), 7.13 - 7.07 (m, 1H), 7.02 (d, J = 4.8 Hz, 1H), 6.98 - 6.89 (m, 1H), 6.16 (d, J = 15.2 Hz, 1H), 5.76 (d, J = 12.0 Hz, 1H), 4.83 (d, J = 13.9 Hz, 2H), 3.93 (d, J = 5.6 Hz, 2H), 3.86 (s, 3H), 2.86 (s, 2H).ESI(M+H) + =308. Example 92 Synthesis of compound YZ001053

[0207] Referring to the steps of Example 52, the intermediate 2-fluoroacrylic acid in Example 52 was replaced with the intermediate 2-butyric acid, and (R)-1e-IM3 was replaced with (S)-3e-IM3 to obtain compound YZ001053 in 76% yield. 1 H NMR (400 MHz, DMSO-d6): δ 12.16 (s, 1H), 8.76 (s, 1H), 8.51 (s, 1H), 7.60 (d, J = 2.4 Hz, 1H), 7.05 (s, 1H), 5.15 (d, J = 5.2 Hz, 1H), 4.68 (d, J = 19.5 Hz, 1H), 4.32 (d, J = 13.1 Hz, 1H), 2.92 (s, 1H), 2.76 (s, 1H), 2.13 (s, 3H), 1.27 (s, 3H). ESI(M+H) + =321. Example 93 Synthesis of compound YZ001054

[0208] Referring to the steps of Example 52, the intermediate (R)-1e-IM3 in Example 52 was replaced with intermediate 9f-IM5 to obtain compound YZ001054 in 45% yield. 1 H NMR (400 MHz, DMSO-d6): δ 11.71 (s, 1H), 8.30 (d, J = 4.9 Hz, 1H), 7.98 (s, 1H), 7.52 - 7.44 (m, 1H), 7.00 (s, 1H), 5.36 (s, 2H), 4.80 (s, 2H), 3.87 (s, 2H), 2.92 (s, 2H). 2.72 (s, 3H), ESI(M+H) + =326. Example 94 Synthesis of compound YZ001055

[0209] Referring to the steps of Example 49, the intermediate (R)-1e-IM3 in Example 49 was replaced with intermediate 12I-IM1 to obtain compound YZ001055 in 32% yield. 1 H NMR (400 MHz, DMSO-d6): δ 11.77 (s, 1H), 8.26 (d, J = 4.7 Hz, 1H), 8.10 (s, 1H), 7.54 - 7.49 (m, 1H), 7.07 (s, 2H), 6.65 (s, 1H), 6.22 (d, J = 16.7 Hz, 1H), 5.31 (d, J = 17.9 Hz, 1H), 4.71 - 4.38 (m, 2H), 3.71 - 3.58 (m, 1H), 3.20 - 3.09 (m, 1H), 1.65 (d, J = 24.2 Hz, 2H), 1.52 (d, J = 12.4 Hz, 2H), 1.32 (d, J = 6.6 Hz, 4H). ESI(M+H) + =348. Example 95 Synthesis of compound YZ001056

[0210] Referring to the steps of Example 52, the intermediate (R)-1e-IM3 in Example 52 was replaced with intermediate 12I-IM1 to obtain compound YZ001054 in 65% yield. 1H NMR (400 MHz, DMSO-d6): δ 11.77 (s, 1H), 8.26 (d, J = 4.9 Hz, 1H), 8.12 (s, 1H), 7.56 - 7.49 (m, 1H), 7.07 (d, J = 4.7 Hz, 1H), 6.65 (dd, J = 3.3, 1.7 Hz, 1H), 5.42 (s, 1H), 5.34 (dd, J = 30.3, 4.1 Hz, 1H), 4.69 - 4.32 (m, 2H), 3.01 - 2.86 (m, 1H), 2.71 (s, 1H), 1.86 (s, 2H), 1.62 (dd, J = 79.8, 11.7 Hz, 6H). ESI(M+H) + =366. Example 96 Synthesis of Compound YZ001057

[0211] Referring to the steps of Example 49, the intermediate (R)-1e-IM3 in Example 49 was replaced with intermediate 11h-IM1 to obtain compound YZ001057 in 45% yield. 1 H NMR (400 MHz, DMSO-d6): δ 11.75 (s, 1H), 8.27 (d, J = 4.9 Hz, 1H), 8.06 (s, 1H), 7.73 - 7.63 (m, 1H), 7.60 - 7.55 (m, 1H), 7.54 - 7.49 (m, 1H), 7.05 (d, J = 4.8 Hz, 1H), 6.68 - 6.57 (m, 1H), 6.18 (d, J = 16.6 Hz, 1H), 5.45 (d, J = 16.6 Hz, 1H), 5.08 (s, 1H), 4.60 (dd, J = 42.7, 24.3 Hz, 2H), 2.25 (dd, J = 34.5, 28.5 Hz, 2H), 2.01 (s, 2H), 1.78 - 1.55 (m, 2H). ESI(M+H) + =334. Example 97 Synthesis of compound YZ001058

[0212] Referring to the steps of Example 52, the intermediate (R)-1e-IM3 in Example 52 was replaced with intermediate 11h-IM1 to obtain compound YZ001058 in 55% yield. 1 H NMR (400 MHz, DMSO-d6): δ 11.77 (s, 1H), 8.27 (d, J = 4.9 Hz, 1H), 8.07 (s, 1H), 7.63 - 7.40 (m, 1H), 7.03 (d, J = 4.9 Hz, 1H), 6.65 (dd, J = 3.2, 1.7 Hz, 1H), 5.39 (s, 1H), 5.26 (d, J = 4.2 Hz, 1H), 3.65 (d, J = 3.9 Hz, 1H), 3.17 (dd, J = 7.4, 4.3 Hz, 1H), 2.72 (s, 2H), 2.39 - 2.18 (m, 2H), 2.05 (d, J = 5.9 Hz, 2H), 1.76 - 1.54 (m, 2H). ESI(M+H) + =352. Example 98 Synthesis of compound YZ001059

[0213] Referring to the steps of Example 49, intermediate (R)-1e-IM3 in Example 49 was replaced with intermediate 13J-IM1 to obtain compound YZ001059 in 60% yield. 1 H NMR (400 MHz, DMSO-d6): δ 11.89 - 11.55 (m, 1H), 8.24 (t, J = 10.8 Hz, 1H), 7.78 (d, J = 9.6 Hz, 1H), 7.50 (s, 1H), 7.23 (d, J = 4.4 Hz, 1H), 7.05 - 6.76 (m, 1H), 6.61 (s, 1H), 6.10 (d, J = 16.0 Hz, 1H), 5.26 (dd, J = 33.6, 16.6 Hz, 1H), 4.51 (dd, J = 37.0, 13.5 Hz, 2H), 4.13 (d, J = 11.3 Hz, 1H), 2.33 (s, 2H), 1.32 (d, J = 5.9 Hz, 2H), 1.26 (s, 3H). ESI(M+H) + =322. Example 99 Synthesis of compound YZ001060

[0214] Referring to the steps of Example 52, intermediate (R)-1e-IM3 in Example 52 was replaced with intermediate 13J-IM1 to obtain compound YZ001060 in 53% yield. 1 H NMR (400 MHz, DMSO-d6): δ 11.73 (s, 1H), 8.24 (d, J = 4.9 Hz, 1H), 7.78 (s, 1H), 7.54 - 7.42 (m, 1H), 7.17 (s, 1H), 6.62 (s, 1H), 5.31 (d, J = 22.4 Hz, 1H), 5.05 (d, J = 14.7 Hz, 1H), 4.61 - 4.47 (m, 2H), 3.64 (dd, J = 6.6, 2.6 Hz, 1H), 2.71 (s, 2H), 2.33 (s, 2H), 1.38 (s, 3H).ESI(M+H) + =340. Example 100 Synthesis of compound YZ001063

[0215] Referring to the steps of Example 49, the intermediate (R)-1e-IM3 in Example 49 was replaced with intermediate 14K-IM3 to obtain compound YZ001063 in 45% yield. 1 H NMR (400 MHz, DMSO-d6): δ 12.61 (s, 1H), 8.53 (s, 1H), 8.34 (d, J = 4.9 Hz, 1H), 7.56 (s, 1H), 7.13 (d, J = 4.9 Hz, 1H), 6.15 (d, J = 16.7 Hz, 1H), 5.74 (s, 1H), 4.97 (d, J = 6.2 Hz, 1H), 4.77 (d, J = 17.1 Hz, 2H), 4.26 - 4.17 (m, 2H), 2.41 (d, J = 2.4 Hz, 3H), 1.26 (s, 3H).ESI(M+H) + =350. Example 101 Synthesis of compound YZ001064

[0216] Referring to the steps of Example 52, the intermediate (R)-1e-IM3 in Example 52 was replaced with intermediate 14K-IM3 to obtain compound YZ001064 in 34% yield. 1 H NMR (400 MHz, DMSO-d6): δ 12.65 (s, 1H), 8.56 (d, J = 2.5 Hz, 1H), 8.34 (d, J = 4.9 Hz, 1H), 7.57 (s, 1H), 7.13 (d, J = 4.9 Hz, 1H), 5.39 - 5.30 (m, 2H), 5.23 (d, J = 4.1 Hz, 1H), 4.72 (d, J = 17.1 Hz, 2H), 4.26 (t, J = 14.9 Hz, 2H), 2.42 (s, 3H), 1.32 (d, J = 6.7 Hz, 3H).ESI(M+H) + =368. Example 102 Synthesis of compound YZ001065

[0217] Referring to the steps of Example 49, the intermediate (R)-1e-IM3 in Example 49 was replaced with intermediate 8d-IM5 to obtain compound YZ001065 in 55% yield. 1 H NMR (400 MHz, DMSO-d6): δ 13.03 (s, 1H), 11.68 (s, 1H), 8.31 (s, 1H), 7.50 (s, 1H), 7.18 - 7.07 (m, 1H), 6.96 (dd, J = 16.7, 10.6 Hz, ESI(M+H) + =294. Example 103 Synthesis of compound YZ001066

[0218] Referring to the steps of Example 52, the intermediate (R)-1e-IM3 in Example 52 was replaced with intermediate 8d-IM5 to obtain compound YZ001066 in 43% yield. 1H NMR (400 MHz, DMSO-d6): δ 11.77 (s, 1H), 8.32 (d, J = 4.7 Hz, 1H), 7.53 (s, 1H), 7.09 (s, 1H), 6.95 (d, J = 7.8 Hz, 1H), 5.36 (s, 1H), 4.79 (s, 1H), 3.88 (d, J = 5.4 Hz, 2H), 3.44 (s, 2H), 2.90 (s, 2H). ESI(M+H) + =312. Example 104 Synthesis of compound YZ001067

[0219] Referring to the steps of Example 52, intermediate (R)-1e-IM3 in Example 52 was replaced with intermediate 8d-IM5, and 2-fluoroacrylic acid was replaced with trans-4-dimethylaminocrotonate to obtain compound YZ001067 in 38% yield. 1 H NMR (400 MHz, DMSO-d6): δ 11.74 (s, 1H), 8.48 (d, J = 3.1 Hz, 1H), 8.31 (d, J = 1.2 Hz, 1H), 8.29 (d, J = 1.2 Hz, 1H), 7.52 (s, 1H), 7.31 (dd, J = 8.4, 4.3 Hz, 1H), 7.10 (d, J = 4.8 Hz, 1H), 4.80 (s, 2H), 3.91 (s, 2H), 3.28 (dd, J = 11.2, 5.7 Hz, 2H), 3.06 (s, 2H). 2.34 (s, 6H).ESI(M+H) + =351. Example 105 Synthesis of Compound YZ001068

[0220] Referring to the steps of Example 52, intermediate (R)-1e-IM3 in Example 52 was replaced with intermediate 11h-IM1, and 2-fluoroacrylic acid was replaced with trans-4-dimethylaminocrotonate to obtain compound YZ001068 in 48% yield. 1H NMR (400 MHz, DMSO-d6): δ 11.76 (s, 1H), 8.26 (d, J = 4.9 Hz, 1H), 8.06 (s, 1H), 7.77 - 7.59 (m, 1H), 7.53 - 7.49 (m, 1H), 7.04 (d, J = 4.9 Hz, 1H), 6.81 (d, J = 14.6 Hz, 1H), 6.67 - 6.61 (m, 1H), 5.46 (d, J = 17.6 Hz, 1H), 5.07 (s, 1H), 4.76 - 4.48 (m, 2H), 3.07 (dd, J = 8.8, 4.2Hz, 2H), 2.35 (d, J = 1.8 Hz, 2H), 2.19 (s, 6H), 2.04 - 1.91 (m, 2H), 1.71 (m, 2H). ESI(M+H) + =391. Example 106 Synthesis of Compound YZ001069

[0221] Referring to the steps of Example 52, intermediate (R)-1e-IM3 in Example 52 was replaced with intermediate 13J-IM1, and 2-fluoroacrylic acid was replaced with trans-4-dimethylaminocrotonate to obtain compound YZ001069 in 38% yield. 1 H NMR (400 MHz, DMSO-d6): δ 11.76 (d, J = 26.3 Hz, 1H), 8.27 (dd, J = 13.4, 4.9 Hz, 1H), 7.78 (d, J = 9.5 Hz, 1H), 7.56 - 7.47 (m, 1H), 7.23 (d, J = 4.9 Hz, 1H), 6.98 (d, J = 4.9 Hz, 1H), 6.62 (d, J = 10.9 Hz, 2H), 5.53 - 5.21 (m, 1H), 4.83 (s, 1H), 4.65 (d, J = 17.4 Hz, 2H), 4.12 (d, J = 12.7 Hz, 1H), 3.11 (d, J = 5.3 Hz, 2H), 2.33 (d, J = 5.9 Hz, 2H), 2.21 (d, J = 5.9 Hz, 6H). 1.69 (s, 3H). ESI(M+H)+ =379. Example 107 Synthesis of compound YZ001070

[0222] Referring to the steps of Example 52, intermediate (R)-1e-IM3 in Example 52 was replaced with intermediate 9f-IM5, and 2-fluoroacrylic acid was replaced with trans-4-dimethylaminocrotonate to obtain compound YZ001070 in 48% yield. 1 H NMR (400 MHz, DMSO-d6): δ 11.69 (s, 1H), 8.30 (d, J = 4.7 Hz, 1H), 7.66 - 7.42 (m, 1H), 7.08 (d, J = 4.9 Hz, 1H), 7.01 (dd, J = 3.3, 2.0 Hz, 1H), 6.83 (d, J = 15.1 Hz, 1H), 6.71 - 6.58 (m, 1H), 4.81 (s, 2H), 3.93 (s, 2H), 3.86 (s, 3H), 3.26 (d, J = 6.3 Hz, 2H), 2.87 (s, 2H), 2.32 (s, 6H).ESI(M+H) + =365. Example 108 Synthesis of compound YZ001071

[0223] Referring to the steps of Example 52, compound YZ001071 was obtained in 57% yield by replacing (R)-1e-IM3 with 23T-IM1 in Example 52. 1H NMR (400 MHz, CDCl3): δ 10.39 (s, 1H), 8.29 (d, J = 2.8 Hz, 1H), 8.08 - 7.94 (m, 1H), 7.46 (d, J = 0.4 Hz, 1H), 7.09 (d, J = 2.6 Hz, 1H), 6.96 - 6.81 (m, 1H), 6.78 (d, J = 0.6 Hz, 1H), 6.52 (t, J = 4 Hz, 0.5H), 5.78 (d, J = 16 Hz, 1H), 4.56 - 3.99 (m,2H), 3.08 - 2.63 (m, 2H), 1.27 - 1.05 (m, 2H), 1.01 - 0.49 (m, 2H).ESI(M+H) + =338. Example 109 Synthesis of compound YZ001072

[0224] Referring to the steps of Example 49, the intermediate (R)-1e-IM3 in Example 49 was replaced with intermediate 24U-IM1 to obtain compound YZ001072 in 32% yield. 1 H NMR (400 MHz, CDCl3): δ 8.47 (d, J = 3.8 Hz, 1H), 7.88 (d, J = 7.6 Hz, 1H), 7.77 (d, J = 4.0 Hz, 1H), 7.32 (s, 1H), 6.71 (d, J = 0.6 Hz, 1H),6.63 (d, J = 4.0 Hz, 1H), 6.45 (d, J = 16.8 Hz, 1H), 5.84 (d, J = 7.2 Hz, 1H),1.70 (s, 3H), 1.51 - 1.43 (m, 1H), 1.37 (d, J = 6.4 Hz, 2H), 1.33 (s, 2H), 1.26 - 1.23 (m, 1H), 0.92 (t, J = 6.6 Hz, 2H), 0.90 - 0.85 (m, 1H). ESI(M+H) + =368. Example 110 Synthesis of compound YZ001073

[0225] Referring to the steps of Example 52, the intermediate (R)-1e-IM3 in Example 52 was replaced with intermediate 24U-IM1 to obtain compound YZ001073 in 56% yield. 1 H NMR (400 MHz, CDCl3): δ 8.26 (s, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.54 (d, J =3.9 Hz, 1H), 7.37 (s, 1H), 6.71 (d, J = 0.6 Hz, 1H), 6.49 (t, J = 3.8 Hz, 0.5H), 5.89 (d, J = 4 Hz, 0.5H), 5.78 (d, J = 16 Hz, 1H), 1.70 (s, 3H), 1.51 - 1.43 (m, 1H), 1.37 (d, J = 6.6 Hz, 2H), 1.33 (s, 2H), 1.26 - 1.23 (m, 1H), 0.92 (t, J = 6.8 Hz, 2H), 0.90 - 0.85 (m, 1H). ESI(M+H) + =386. Example 111 Synthesis of compound YZ001074

[0226] Referring to the steps of Example 49, the intermediate (R)-1e-IM3 in Example 49 was replaced with intermediate 25V-IM4 to obtain compound YZ001074 in 39% yield. 1 H NMR (400 MHz, CDCl3): δ 8.50 (d, J = 3.8 Hz, 1H), 7.85 (d, J = 7.6 Hz, 1H), 7.79 (d, J = 4.0 Hz, 1H), 7.31 (s, 1H), 6.69 (d, J = 0.6 Hz, 1H),6.60 (d, J = 4.0 Hz, 1H), 6.47 (d, J = 16.4 Hz, 1H), 5.83 (d, J = 7.0 Hz, 1H),2.53 (s, 3H), 2.31 (d, J = 6.4 Hz, 2H), 1.51 - 1.43 (m, 1H), 1.31 (s, 2H), 1.21 - 1.19 (m, 1H), 1.15 (t, J = 6.6 Hz, 2H), 0.92 - 0.86 (m, 1H). ESI(M+H)+ =400. Example 112 Synthesis of compound YZ001075

[0227] Referring to the steps of Example 52, the intermediate (R)-1e-IM3 in Example 52 was replaced with intermediate 25V-IM4 to obtain compound YZ001075 in 61% yield. 1 H NMR (400 MHz, CDCl3): δ 8.26 (d, J = 4.0 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 3.8 Hz, 1H), 7.28 (s, 1H), 6.57 (s, 1H), 6.36 (t, J = 3.8 Hz, 0.5H), 5.85 (d, J = 4 Hz, 0.5H), 5.76 (d, J = 14 Hz, 1H),2.56 (s, 3H), 2.34 (d, J = 6.4 Hz, 2H), 1.53 - 1.44 (m, 1H), 1.32 (s, 2H), 1.23 - 1.19 (m, 1H), 1.15 (t, J = 6.6 Hz, 2H), 0.90 - 0.84 (m, 1H). ESI(M+H) + =418. Example 113 Synthesis of compound YZ001076

[0228] Referring to the steps of Example 49, intermediate (R)-1e-IM3 in Example 49 was replaced with intermediate 15L-IM4 to obtain compound YZ001076 in 45% yield. 1 H NMR (400 MHz, DMSO-d6): δ 13.31 (d, J = 43.4 Hz, 1H), 11.85 (d, J = 85.5 Hz, 1H), 8.31 (s, 1H), 7.65 (s, 1H), 7.25 (s, 1H), 6.81 (d, J = ESI(M+H) +=280. Example 114 Synthesis of compound YZ001077

[0229] Referring to the steps of Example 52, the intermediate (R)-1e-IM3 in Example 52 was replaced with intermediate 15L-IM4 to obtain compound YZ001077 in 52% yield. 1 H NMR (400 MHz, DMSO-d6): δ 13.43 (s, 1H), 12.00 (s, 1H), 9.10 - 8.63 (m, 1H), 8.31 (s, 1H), 7.64 (s, 1H), 7.28 (s, 1H), 5.43 (dd, J = 17.4, 3.6 Hz, 1H), 5.09 (s, 1H), 2.92 (s, 2H), 2.75 (s, 2H). ESI(M+H) + =298. Example 115 Synthesis of compound YZ001083

[0230] Referring to the steps of Example 49, the intermediate (R)-1e-IM3 in Example 49 was replaced with intermediate 18O-IM4 to obtain compound YZ001083 in 44% yield. 1 H NMR (400 MHz, DMSO-d6): δ 11.71 (s, 1H), 8.30 (s, 1H), 7.53 - 7.37 (m, 1H), 7.15 (s, 1H), 7.05 (s,1H), 6.94 (d, J = 10.7 Hz, 1H), 6.13 (dd, J = 16.7, 2.1 Hz, 1H), 5.72 (s, 1H), 5.39 (d, J = 16.4 Hz, 1H), 4.85 (s, 1H), 4.22 (d, J = 16.3 Hz, 1H), 3.87 (s, 3H), 2.96 (dd, J = 37.6, 16.3 Hz, 1H), 2.79 (d, J = 15.1 Hz, 1H), 1.26 (d, J = 2.5 Hz, 3H). ESI(M+H) + =322. Example 116 Synthesis of compound YZ001084

[0231] Referring to the steps of Example 52, the intermediate (R)-1e-IM3 in Example 52 was replaced with intermediate 18O-IM4 to obtain compound YZ001084 in 46% yield. 1 H NMR (400 MHz, DMSO-d6): δ 11.73 (s, 1H), 8.30 (d, J = 4.9 Hz, 1H), 7.59 - 7.40 (m, 1H), 7.11 (s, 1H), 7.02 (s, 1H), 5.39 - 5.10 (m, ESI(M+H) + =340. Example 117 Synthesis of compound YZ001085

[0232] Referring to the steps of Example 49, intermediate (R)-1e-IM3 in Example 49 was replaced with intermediate 19P-IM1 to obtain compound YZ001085 in 44% yield. 1 H NMR (400 MHz, DMSO-d6): δ 11.69 (s, 1H), 8.31 (s, 1H), 7.50 (d, J = 2.5 Hz,1H), 7.13 (s, 1H), 7.07 (s, 1H), 6.96 (dd, J = 16.7, 10.6 Hz, 1H), 6.13 (dd, J = 16.7, 2.1 Hz,1H), 5.73 (d, J = 10.5 Hz, 1H), 5.38 (d, J = 16.4 Hz, 1H), 4.83 (s, 1H), 4.58 - 4.51 (m, 1H), 3.01 (s, 1H), 2.81 (d, J = 14.8 Hz, 1H), 1.49 (t, J = 6.9 Hz, 6H), 1.25 (s, 3H). ESI(M+H) + =350. Example 118 Synthesis of compound YZ001086

[0233] Referring to the steps of Example 52, the intermediate (R)-1e-IM3 in Example 52 was replaced with intermediate 19P-IM1 to obtain compound YZ001086 in 56% yield. 1 H NMR (400 MHz, DMSO-d6): δ 11.89 (s, 1H), 8.37 (s, 1H), 7.57 (d, J = 2.3 Hz, 1H), 7.19 (s, 1H), 7.11 (s, 1H), 5.41 - 5.30 (m, 2H), 5.22 (d, J = 4.1 Hz, 1H), 4.61 - 4.51 (m, 1H), 4.41 (s, 1H), 3.06 (s, 1H), 2.87 (d, J = 16.1 Hz, 1H), 1.51 (d, J = 6.5 Hz, 6H), 1.31 (d, J = 6.7 Hz, 3H).ESI(M+H) + =368. Example 119 Synthesis of compound YZ001087

[0234] Referring to the steps of Example 49, the intermediate (R)-1e-IM3 in Example 49 was replaced with intermediate 10g-IM3 to obtain compound YZ001087 in 32% yield. 1 H NMR (400 MHz, DMSO-d6): δ 12.03 (s, 1H), 8.39 (d, J = 4.1 Hz, 1H), 7.65 (s, 1H), 7.10 (d, J = 15.5 Hz, 1H), 6.94 (dd, J = 16.6, 10.5 Hz, 1H), 6.34 (d, J = 16.3 Hz, 1H), 6.13 (dd, J = 16.7, 1.9 Hz, 1H), 5.76 - 5.69 (m, 1H), 4.88 (s, 1H), 4.44 (d, J = 32.8 Hz, 2H), 3.91 (d, J = 6.5 Hz, 4H), 3.78 (d, J = 5.2 Hz, 2H), 2.83 (s, 2H), 2.27 - 2.12 (m, 2H). ESI(M+H) + =364. Example 120 Synthesis of compound YZ001088

[0235] Referring to the steps of Example 52, the intermediate (R)-1e-IM3 in Example 52 was replaced with intermediate 10g-IM3 to obtain compound YZ001088 in 45% yield. 1 H NMR (400 MHz, DMSO-d6): δ 12.05 (s, 1H), 8.39 (d, J = 3.9 Hz, 1H), 7.65 (s, 1H), 7.11 (dd, J = 19.4, 4.7 Hz, 1H), 6.32 (d, J = 16.9 Hz, 1H), 5.32 (s, 2H), 4.87 (s, 1H), 4.42 (d, J = 19.5 Hz,2H), 3.90 (s, 4H), 3.78 (d, J = 5.2 Hz, 2H), 2.88 (s, 2H), 2.22 (d, J = 4.7 Hz, 2H).ESI(M+H) + =382. Example 121 Synthesis of compound YZ001091

[0236] Referring to the steps of Example 49, the intermediate (R)-1e-IM3 in Example 49 was replaced with intermediate 16M-IM1 to obtain compound YZ001091 in 65% yield. 1 H NMR (400 MHz, DMSO-d6): δ 13.26 (s, 1H), 11.80 (s, 1H), 9.11 (s, 1H), 8.46 - 8.06 (m, 1H), 7.56 (s,1H), 7.17 (s, 1H), 6.79 (td, J = ESI(M+H) + =294. Example 122 Synthesis of compound YZ001093

[0237] Referring to the steps of Example 49, the intermediate (R)-1e-IM3 in Example 49 was replaced with intermediate 20Q-IM1 to obtain compound YZ001093 in 44% yield. 1H NMR (400 MHz, DMSO-d6): δ 11.71 (s, 1H), 8.26 (d, J = 4.9 Hz, 1H), 7.70 (d, J = 6.9 Hz, 1H), 7.57 - 7.47 (m, 2H), 6.99 - 6.79 (m, 1H), 6.53 - 6.45 (m, 1H), 6.10 (dd, J = 16.6, 2.2 Hz, 1H), 5.76 - 5.67 (m, 1H), 4.92 (s, 2H), 4.56 (s, 2H), 3.96 (d, J = 4.8 Hz, 2H), 1.99 (s, 2H).ESI(M+H) + =308. Example 123 Synthesis of compound YZ001094

[0238] Referring to the steps of Example 52, the intermediate (R)-1e-IM3 in Example 52 was replaced with intermediate 20Q-IM1 to obtain compound YZ001094 in 35% yield. 1 H NMR (400 MHz, DMSO-d6): δ 11.73 (s, 1H), 8.25 (d, J = 4.9 Hz, 1H), 7.73 (s, 1H), 7.60 - 7.43 (m, 1H), 7.38 (s, 1H), 6.50 (s, 1H), 5.36 - 5.21 (m, 1H), 4.95 (s, 2H), 4.64 - 4.46 (m, 2H), 3.90 (s, 2H), 2.06 (s, 2H). ESI(M+H) + =326. Example 124 Synthesis of compound YZ001095

[0239] Referring to the steps of Example 49, the intermediate (R)-1e-IM3 in Example 49 was replaced with intermediate 21R-IM1 to obtain compound YZ001095 in 64% yield. 1H NMR (400 MHz, DMSO-d6): δ 11.75 (s, 1H), 8.89 (s, 1H), 8.22 (t, J = 5.1 Hz, 1H), 7.87 (d, J = 11.0 Hz, 1H), 7.51 (dd, J = 5.5, 2.7 Hz, 1H), 6.96 (t, J = 5.6 Hz, 1H), 6.54 - 6.47 (m, 1H), 6.18 (dd, J = 16.7, 2.3 Hz, 1H), 5.74 (dd, J = 10.4, 2.3 Hz, 1H), 4.86 (s, 2H), 3.68 - 3.56 (m, 4H), 3.15 (dd, J = 7.4, 4.2 Hz, 4H). ESI(M+H) + =322. Example 125 Synthesis of compound YZ001096

[0240] Referring to the steps of Example 52, the intermediate (R)-1e-IM3 in Example 52 was replaced with intermediate 21R-IM1 to obtain compound YZ001096 in 55% yield. 1 H NMR (400 MHz, DMSO-d6): δ 11.74 (s, 1H), 8.20 (d, J = 4.9 Hz, 1H), 7.88 (d, J = 8.8 Hz, 1H), 7.53 - 7.40 (m, 1H), 6.87 (d, J = 4.9 Hz, 1H), 6.55 - 6.34 (m, 1H), 5.29 (s, 1H), 4.96 (s, 1H), 4.89 (s, 2H), 4.46 (s, 2H), 3.42 (d, J = 4.8 Hz, 2H), 1.86 (d, J = 3.5 Hz, 2H), 1.76 (s, 2H).ESI(M+H) + =340. Example 126 Synthesis of compound YZ001099

[0241] Referring to the steps of Example 49, the intermediate (R)-1e-IM3 in Example 49 was replaced with intermediate 22S-IM1 to obtain compound YZ001099 in 54% yield. 1H NMR (400 MHz, DMSO-d6): δ 11.77 (s, 1H), 8.27 (d, J = 4.8 Hz, 1H), 8.04 (s, 1H), 7.63 - 7.43 (m, 1H), 7.00 (dd, J = 11.2, 5.2 Hz, 2H), 6.65 (dd, J = 3.3, 1.6 Hz, 1H), 6.23 (d, J = 16.9 Hz, 1H), 5.82 (d, J = 10.6 Hz, 1H), 5.01 (d, J = 4.6 Hz, 2H), 4.49 (d, J = 4.4 Hz, 2H), 3.94 (dd, J = 14.1, 6.5 Hz, 1H), 1.51 (d, J = 6.3 Hz, 3H). ESI(M+H) + =308. Example 127 Synthesis of compound YZ001100

[0242] Referring to the steps of Example 52, the intermediate (R)-1e-IM3 in Example 52 was replaced with intermediate 22S-IM1 to obtain compound YZ001100 in 35% yield. 1 H NMR (400 MHz, DMSO-d6): δ 11.78 (s, 1H), 8.27 (d, J = 4.9 Hz, 1H), 8.02 (d, J = 31.4 Hz, 1H), 7.69 - 7.45 (m, 1H), 6.97 (d, J = 4.8 Hz, 1H), 6.69 - 6.49 (m, 1H), 5.02 (s, 2H), 4.62 - 4.43 (m, 1H), 4.36 - 4.15 (m, 1H), 3.88 (dd, J = 13.9, 6.6 Hz, 1H), 2.91 (s, 1H), 2.76 (s, 1H), 1.53 (d, J = 6.5 Hz, 3H). ESI(M+H) + =326. Example 128 Synthesis of compound YZ001103

[0243] Referring to the steps of Example 49, the intermediate (R)-1e-IM3 in Example 49 was replaced with intermediate 26W-IM1 to obtain compound YZ001103 in 80% yield. 1 H NMR (400 MHz, DMSO-d6): δ 11.67 (s, 1H), 8.27 (d, J = 5.1 Hz, 1H), 7.46 (d, J = 2.9 Hz, 1H), 7.05 (d, J = 5.0 Hz, 1H), 7.00 - 6.96 (m, 1H), 6.14 (dd, J = 16.5, 2.3 Hz, 1H), 5.76 (s, 1H), 5.75 - 5.64 (m, 1H), 4.79 (s, 2H), 3.90 (d, J = 6.1 Hz, 2H), 2.83 (s, 2H). ESI(M+H) + =311. Example 129 Synthesis of compound YZ001104

[0244] Referring to the steps of Example 52, the intermediate (R)-1e-IM3 in Example 52 was replaced with intermediate 26W-IM1 to obtain compound YZ001104 in 53% yield. 1 H NMR (400 MHz, DMSO-d6): δ 11.69 (s, 1H), 8.27 (d, J = 5.0 Hz, 1H), 7.48 (dd, J = 3.4, 2.5 Hz, 1H), 7.06 - 6.95 (m, 2H), 5.26 (dd, J = 49.9, 4.1 Hz, 2H), 4.76 (s, 2H), 3.87 (t, J = 6.0 Hz, 2H), 2.89 (s, 2H). ESI(M+H) + =329. Example 130 Synthesis of compound YZ001107

[0245] Referring to the steps of Example 52, the intermediate (R)-1e-IM3 in Example 52 was replaced with intermediate (S)-1e-IM3 to obtain compound YZ001107 in 45% yield. 1H NMR (400 MHz, DMSO-d6): δ 11.75 (s, 1H), 8.23 ​​(s, 1H), 8.05 (s, 1H), 7.51 (dd, J = 3.5, 2.5 Hz, 1H), 7.03 (s, 1H), 6.62 (s, 1H), 5.39 (s, 1H), 5.31 (dd, J = 32.1, 4.1 Hz, 1H), 5.22 (d, J = 17.4 Hz, 1H), 4.84 (d, J = 35.8 Hz, 2H), 4.39 - 4.23 (m, 2H), 1.28 (d, J = 6.9 Hz, 3H).ESI(M+H) + =326. Example 131 Synthesis of compound YZ001108

[0246] Referring to the steps of Example 49, the intermediate (R)-1e-IM3 in Example 49 was replaced with intermediate 27X-IM1 to obtain compound YZ001108 in 45% yield. 1 H NMR (400 MHz, DMSO-d6): δ 11.84 (s, 1H), 8.34 (s, 1H), 7.55 (s, 1H), 7.19 (s, 1H), 6.98 (s, 1H), 6.94 - 6.86 (m, 1H), 6.13 - 6.06 (m, 1H), 5.74 - 5.65 (m, 1H), 4.79 (s, 2H), 3.84 (s, 2H), 3.12 (s, 2H), 2.71 (s, 3H). ESI(M+H) + =336. Example 132 Synthesis of compound YZ001109

[0247] Referring to the steps of Example 52, the intermediate (R)-1e-IM3 in Example 52 was replaced with intermediate 27X-IM1 to obtain compound YZ001109 in 53% yield. 1H NMR (400 MHz, DMSO-d6): δ 11.89 (s, 1H), 8.37 (d, J = 4.9 Hz, 1H), 7.60 (t, J = 3.0 Hz, 1H), 7.24 - 7.14 (m, 1H), 7.00 (dd, J = 3.4, 1.9 ESI(M+H) + =354. Example 133 Synthesis of compound YZ001115

[0248] Referring to the steps of Example 49, the intermediate (R)-1e-IM3 in Example 49 was replaced with intermediate 28Y-IM3 to obtain compound YZ001115 in 58% yield. 1 H NMR (400 MHz, DMSO-d6): δ 11.99 (s, 1H), 8.34 (dd, J = 4.8, 1.1 Hz, 1H), 7.61 (d, J = 1.2 Hz, 1H), 7.13 (dd, J = 4.8, 1.0 Hz, 1H), 6.65 (ddd, J = 36.7, 16.7, 10.3 Hz, 1H), 6.36 (ddd, J = 14.6, 3.4, 1.8 Hz, 1H), 6.21 (ddd, J = 16.7, 8.8, 2.4 Hz, 1H), 5.84 - 5.57 (m, 1H), 4.76 (d, J = 52.0 Hz, 2H), 4.51 (d, J = 48.8 Hz, 3H), 1.37 (d, J = 6.5 Hz, 6H). ESI(M+H) + =322. Example 134 Synthesis of compound YZ001117

[0249] Referring to the steps of Example 49, the intermediate (R)-1e-IM3 in Example 49 was replaced with intermediate 29Z-IM3 to obtain compound YZ001117 in 60% yield. 1H NMR (400 MHz, DMSO-d6): δ 11.96 (s, 1H), 8.31 (d, J = 4.8 Hz, 1H), 7.57 (s, 1H), 7.01 (d, J = 4.8 Hz, 1H), 6.86 (dd, J = 16.6, 10.5 Hz, 1H), 6.41 - 6.18 (m, 1H), 6.06 (dd, J = 16.7, 2.4 Hz, 1H), 5.66 (dd, J = 10.5, 2.4 Hz, 1H), 4.66 - 4.18 (m, 3H), 3.84 (d, J = 6.8 Hz, 2H), 2.76 (s, 2H), 1.28 (d, J = 6.6 Hz, 5H). ESI(M+H) + =336. Example 135 Synthesis of compound YZ001118

[0250] Referring to the steps of Example 49, the intermediate (R)-1e-IM3 in Example 49 was replaced with intermediate 30A-IM3 to obtain compound YZ001118 in 41% yield. 1 H NMR (400 MHz, DMSO-d6): δ 11.95 (s, 1H), 8.31 (d, J = 4.9 Hz, 1H), 7.58 (s, 1H), 7.07 (d, J = 4.9 Hz, 1H), 6.87 (dd, J = 16.7, 10.5 Hz, 1H), 6.31 (dd, J = 3.5, 1.8 Hz, 1H), 6.07 (dd, J = 16.7, 2.3 Hz, 1H), 5.66 (dd, J = 10.5, 2.3 Hz, 1H), 4.43 (d, J = 17.3 Hz, 2H), 3.85 (s, 2H), 3.68 (s, 3H), 2.73 (s, 2H). ESI(M+H) + =336. Example 136: JAK3 kinase inhibitory activity of the compound according to the present invention (developed by Sandia Pharmaceutical Technology (Shanghai) Co., Ltd., which was commissioned to conduct the experiment) Objective of the experiment:

[0251] The mobility shift assay method is used to detect the in vitro inhibitory activity of the test compounds (listed below) against JAK3 kinase enzyme activity. Cerdulatinib (supplier: selleckchem, catalog number: S7634) is used as the positive control compound. Experimental method: 1. Preparation of the compound Dissolve the compound in 100% DMSO to prepare a 10 mM stock solution, and store it in the dark in a refrigerator at -20°C. 2. Kinase reaction process (1) Prepare 1 × Kinase buffer.

[0252] (2) Preparation of concentration gradients of compounds: The test concentration of the test compounds (including the compounds in the examples and PF-06651600) is 10,000 nM, which is diluted 10-fold to 10 different concentrations and measured in single wells. Dilution is performed stepwise in a 384-well plate to a 100-fold final concentration solution. Next, 250 nL is transferred to a 384 reaction plate using Echo550 and prepared for use. 250 nL of 100% DMSO is added to the negative control well and the positive control well, respectively. (3) Prepare a kinase solution to a final concentration of 2.5 times the original concentration using 1 × Kinase buffer.

[0253] (4) Add 10 μL of 2.5x final concentration kinase solution to the compound well and the positive control well, respectively, and add 10 μL of 1× Kinase buffer to the negative control well. (5) Centrifuge at 1000 rpm for 30 seconds, shake evenly, and then incubate at room temperature for 10 minutes. (6) Prepare a mixed solution of ATP and Kinase substrate 22 at a final concentration of 25 / 15 times using 1 × Kinase buffer.

[0254] (7) Add 15 μL of a 25 / 15-fold final concentration mixed solution of ATP and substrate to the compound well, positive control well, and negative control well of the 384 reaction plate, respectively, and start the reaction. (8) Centrifuge the 384-well plate at 1000 rpm for 30 seconds, shake uniformly, and then incubate at room temperature for 30 minutes. (9) Add 30 μL of reaction stop solution to stop the kinase reaction, then centrifuge at 1000 rpm for 30 seconds and shake uniformly. (10) Read the conversion rate using Caliper EZ Reader. 3. Data Analysis (1) Calculation formula

[0255] % Inhibition = (Conversion%_max-Conversion%_sample) / (Conversion%_max- Conversion%_min)× 100

[0256] Here, Conversion%_sample is the reading of the sample conversion rate, Conversion%_min is the mean value of the negative control wells and represents the reading of the conversion rate of wells without enzyme activity, Conversion%_max is the mean value of the positive control wells and represents the reading of the conversion rate of wells without compound inhibition, and %Inhibition represents the percentage inhibition rate. (2) Fitting of dose-response curves

[0257] The IC50 value for the enzyme activity of each compound is obtained by fitting a dose-response curve using the log(inhibitor) vs. response -Variable slope function of the analysis software GraphPad Prism 5, with the log value of concentration on the X-axis and the percentage inhibition rate on the Y-axis. The calculation formula is Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC50 - X) * HillSlope)).

[0258] Experimental results: JPEG0007831797000063.jpg172170

[0259] Compared to the positive control PF-06651600, the compounds in this application have different core structures, and the structural differences are remarkably pronounced. As can be seen from the data in the table above, most of the compounds in this application have superior JAK3 in vitro kinase inhibitory activity compared to PF-06651600, and the inhibitory activity against JAK3 kinase of some compounds is more than 10 times that of PF-06651600, demonstrating a significant technical advantage in kinase inhibitory activity. As can be seen from the comparison between comparative examples YZ001003 and YZ001001, both have the same molecular skeleton, but the only difference is that a covalent target is bound to the NH group of YZ001001, while a non-covalent target is bound to the NH group of YZ001003. The former has good JAK3 kinase inhibitory activity, while the latter basically has no inhibitory activity. As can be seen from the comparison between comparative examples YZ001011, YZ001012 and YZ001017, both have the same molecular skeleton, but the only difference is that a covalent target is bound to the NH group of YZ001017, while a non-covalent target is bound to the NH group of YZ001011 and YZ001012. The JAK3 inhibitory activity of YZ001017 is far superior to that of YZ001011 and YZ001012. The above comparison shows that the covalent target of the compound in this application is very important for the inhibitory activity of JAK3 kinase, and the applicant speculates that the covalent target can form a covalent bond with the JAK3 kinase Cys909 amino acid. Example 137 Kinase selectivity experiment Objective of the experiment:

[0260] The Mobility Shift Assay method will be used to detect the in vitro inhibitory activity of the test compounds (listed below) against other subtypes of the JAK kinase family (JAK1, JAK2, TYK2) and to investigate the kinase selectivity of the compounds. PF-06651600 will be used as the positive control compound. Experimental method: The experimental method for JAK3 kinase inhibitory activity is the same as described above.

[0261] Experimental results: As can be seen from the data in the table above, the compounds of this application have good selectivity for other subtypes of the JAK family. Example 138: Cell Activity Experiment Objective of the experiment:

[0262] Based on the mechanism of the JAK-STAT pathway, we stimulate hPBMC cells using the cytokine IL-15 and evaluate the effect of compounds on the JAK-STAT pathway using the phosphorylation level of downstream STAT5 as a detection indicator. Experimental method: 1. Counting and seeding PBMC cells: Seed 90 μL of PBMCs into a 96-well plate (PBMC cell density of 80,000 / well).

[0263] 2. Treatment of the test compound: Immediately after seeding the cells, the test compound is administered. The test drug is administered at 5 μL / well (final concentrations of 1, 0.5, 0.1, 0.05, 0.01, and 0.005 μM) and incubated in a 37°C incubator for 45 minutes. 3. Cytokine IL-15 stimulation: Stimulate with 5 μL of IL-15 and incubate at 37°C for 30 minutes.

[0264] 4. Protein sample collection: Collect cells in a centrifuge tube and centrifuge for 5 minutes. Discard the supernatant after centrifugation and lyse the cells with 1× Cell Extraction Buffer PTR. 5. p-STAT5 detection: Detect according to the requirements of the ELISA kit.

[0265] Experimental results: IC5 of compounds in response to IL-15 stimulation in PBMCs 50 value JPEG0007831797000065.jpg41170

[0266] As can be seen from the data in the table above, the compounds of this invention have a good effect in inhibiting the JAK3-STATs signaling pathway at the cellular level, and some compounds have ICs equivalent to or lower than those of positive drugs.50 This indicates. Example 139: Measurement of In-Vehicle Exposure Levels in Animals Objective of the experiment: The exposure level of YZ001054 in the plasma of IG:SD Rat was measured at a dose of 20 mg / kg. Experimental method:

[0267] Preparation of standard curves and quality control samples: Dilute the stock solution of each compound with 50% methanol water to create standard working solutions at concentrations of 20, 40, 100, 200, 400, 1000, 2000, 4000, and 10000 ng / mL, and quality control working solutions at concentrations of 60, 600, and 8000 ng / mL, respectively. 47.5 μL of plasma from each blank rat was taken, and 2.50 μL of standard curve working solution and quality control working solution were added to prepare standard curves with compound concentrations of 1.00, 2.00, 5.00, 10.00, 20.00, 50.00, 100.00, 200.00, and 500.00 ng / mL, as well as quality control samples with concentrations of 3.00, 30.00, and 400.00 ng / mL. 200 μL of acetonitrile (containing an internal standard of verapamil 2 ng / mL) was added to each, and after vortexing for 3 minutes, the mixture was centrifuged at 20000 rcf and 4°C for 10 minutes. The supernatant was then taken and analyzed by LC-MS / MS.

[0268] Preparation of plasma sample for measurement: Take 50 μL of plasma sample, add 200 μL of acetonitrile (containing internal standard verapamil 2 ng / mL), vortex for 3 minutes, then centrifuge at 20000 rcf and 4°C for 10 minutes, and take the supernatant for LC-MS / MS analysis. JPEG0007831797000066.jpg79170 Experimental results: As can be seen from the data in the table above, the compound of this application has a certain level of exposure in the body, making it possible to develop it for oral administration. Example 140: Immunosuppressive effect of the compound on delayed-type hypersensitivity (DTH) in mice. Objective of the experiment:

[0269] The immunosuppressive activity of YZ001052, YZ001054, YZ001065, and YZ001085 will be measured in an SRBC mouse model. PF-06651600 will be used as the positive control compound. Experimental method: Drug preparation: Weigh the compound and add a 0.5% CMC-Na solution to prepare a drug suspension (dosage: 10 mg / mL).

[0270] Induction and administration of delayed-type hypersensitivity response (DTH): Thirty male Balb / c mice were weighed and randomly divided into six groups of five mice each, according to their body weight. The experimental cycle totaled seven days. On day 0, sheep red blood cells (SRBCs) were subcutaneously injected to induce sensitization. From day 0 to day 6, 100 mg / kg was force-administered orally (once daily). On day 6, SRBCs were injected into the right hind foot of each mouse to induce a challenge. On day 7, measurements and photographs were taken, and the experiment was concluded.

[0271] Pharmacodynamic detection indices for the disease model: Detection and observation indices are the degree of foot swelling and thickness measurement in SRBC-inducible model mice. The thickness of the right foot is measured before the SRBC injection challenge on day 6 to establish a baseline. At the end of the experiment, the thickness of the right foot is measured again, and the difference in foot thickness before and after the two injections is calculated.

[0272] Statistical analysis: Experimental data are presented as mean ± standard deviation (Mean ± SD). All data were statistically analyzed using the T-test, with P < 0.05 considered to indicate a statistically significant difference. The results are shown in Figure 1. Experimental results:

[0273] As can be seen in Figure 1, the thickness of the right foot of mice after SRBC induction (model group) significantly increased, and the thickness of the right foot of mice after drug treatment (containing compounds YZ001052, YZ001054, YZ001065, and YZ001085) all showed varying degrees of improvement. This indicates that compounds YZ001052, YZ001054, YZ001065, and YZ001085 have a significant immunosuppressive effect against delayed-type hypersensitivity reactions in mice induced by SRBC, and their efficacy is comparable to that of PF-06651600. Example 142: Immunosuppressive effect of a compound on a mouse model of collagen-induced arthritis 1. Construction of a mouse model of collagen-induced arthritis (mCIA) Experimental objective: To test the immunosuppressive activity of YZ001052 in an mCIA model. PF-06651600 will be used as the positive control compound.

[0274] Experimental method: 32 female DBA / 1J mice were randomly divided into four groups: a blank control group, a model group, a model + YZ001052 administration group, and a model + PF-06651600 administration group. After successful modeling of arthritis, YZ001052 or PF-06651600 was administered as drug therapy at a dose of 50 mg / kg once daily. Complete and incomplete Freund's adjuvant were mixed in equal proportions with chicken type II collagen solution to form emulsifiers. Except for the blank control group, on Day 0, the mixture of complete Freund's adjuvant and chicken type II collagen solution was subcutaneously injected into the tail root and thigh joint of the mice. 100 μL was subcutaneously injected into the tail root of each mouse, and 50 μL was subcutaneously injected into the thigh joint of each mouse (primary immunization). On day 21, mice are subcutaneously injected with a 200 μL mixture of incomplete Freund's adjuvant and chicken type II collagen solution as an additional injection (second immunization). Arthritis is considered to have developed if the clinical score of at least one foot is ≥2 points. Measurement of foot thickness: The thickness of the left and right hind feet of the mice, i.e., the degree of foot swelling, is measured and recorded using calipers, and the measurement frequency is once every 3 days.

[0275] Experimental results: As can be seen in Figure 2, after the second immunization, the model group mice experienced a continuous worsening of inflammation in the foot area, with swelling gradually spreading throughout the entire foot, and a significant increase in arthritis score on day 16. After treatment with YZ001052 or PF-06651600, the degree of swelling in the feet of the CIA mice improved to varying degrees, and the arthritis score significantly decreased (compared to the model group).

[0276] Consistent with arthritis scores, significant swelling occurred in the paws of the model mice. However, after treatment with YZ001052 or PF-06651600, varying degrees of improvement in the swelling of the mice's paws were observed. These results indicate that YZ001052 or PF-06651600 can improve the symptoms of rheumatoid arthritis. Example 143: Immunosuppressive effect of compounds on a mouse model of inflammatory bowel disease induced by dextran sulfate sodium (DSS)

[0277] Experimental objective: To test the immunosuppressive activity of YZ001052 in a mouse model of inflammatory bowel disease induced by DSS. PF-06651600 will be used as the positive control compound.

[0278] Experimental Method: 32 female C57BL / 6 mice were randomly divided into four groups: a blank control group, a model group, a model + YZ001052 administration group, and a model + PF-06651600 administration group. Administration of YZ001052 and PF-06651600 was simultaneous with the start of the modeling process, with a dose of 50 mg / kg once daily. 50 g of DSS was weighed, and 1000 mL of sterile water was added to prepare a 5% DSS solution, which was then filtered through a 0.22 μm filter. From day 0, the blank group was given drinking water without DSS, while the other experimental groups were given drinking water containing 5% DSS. All mice were sacrificed on day 8. After the experiment, the colorectum was collected, photographed, and its length measured for statistical analysis.

[0279] Experimental results: As shown in Figure 3, the colorectal length of the model group mice was significantly reduced compared to the normal control group, indicating that the colorectal region of inflammatory bowel disease mice is severely damaged. Compared to the model group mice, the colorectal length of the YZ001052-treated mice was significantly increased, indicating that treatment with YZ001052 mitigates colorectal damage in inflammatory bowel disease mice, and the results are superior to those of PF-06651600. Example 144 Immunosuppressive effect of compounds on a radiation-induced lung injury mouse model 1. Construction of a mouse model of acute radiation lung injury. (1) Animal grouping and administration

[0280] Eighteen female C57BL / 6 mice were randomly divided into three groups: a blank control group, a simple irradiation group, and an irradiation + drug YZ001052 (30 mg / kg qd) therapy group, with six mice in each group. (2) Modeling method

[0281] Mice were anesthetized by intraperitoneal injection of 1% pentobarbital sodium, and a single whole-lung irradiation of 22.5 Gy using 220 kV X-rays was administered using the Small Animal Radiation Research Platform (SARRP). After irradiation, the mice were kept in normal conditions. 2. Indicator detection

[0282] Three weeks after modeling, the mice were anesthetized, the lung tissue was dissected and exposed, the left lung was ligated, an open tracheostomy was performed, the lungs were washed with cold PBS, and bronchoalveolar lavage fluid (BALF) was collected, frozen at 4°C, and centrifuged.

[0283] After collecting the supernatant, the content of the inflammatory cytokine TNF-α was measured by ELISA. As shown in Figure 4, TNF-α levels in the bronchoalveolar lavage fluid of the model mice were significantly increased after irradiation induction. The drug YZ001052 has a good inhibitory effect on TNF-α levels.

[0284] To count white blood cells (WBCs), the bronchoalveolar lavage pellet was resuspended in 200 μL of PBS. As shown in Figure 5, the number of white blood cells in the bronchoalveolar lavage fluid of the model mice significantly increased after irradiation induction. The drug YZ001052 significantly reduced the number of inflammatory cell infiltrations in the lungs of mice induced by irradiation.

Claims

1. A compound having a structure represented by the following general formula I, an optical isomer thereof, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, The compound having the structure represented by the above general formula I is selected from the compounds having the structures shown in the following general formulas III-1, III-2, III-3, or III-4. L is selected from, where R ４ , R ｂ , R ｃ , R ｄ , R ｅ , R ｆ , R ｇ , R ｈ are each independently hydrogen, C １ -C ４ alkyl group, monosubstituted C １ -C ４ alkyl group, and the substituent in the monosubstituted C １ -C ４ alkyl group is selected from a methylthio group, a methylsulfonyl group, and a cyano group, k is an integer of 1 to 4, q is an integer of 0 to 3, r is an integer of 0 to 2, p is 1, and m is 3 or 4, W is Or selected from nitrile groups, where R １ R consists of hydrogen, deuterium, halogen, cyano group, and methyl group. ２ R is hydrogen, deuterium, a cyano group or a methyl group, ３ hydrogen, deuterium, halogen, cyano group, methyl group, trifluoromethyl group, And n and t are 2, R ｊ , R ｋ , R ｍ R is a methyl group, ４ R is a hydrogen or methyl group, ５ R is a halomethyl group, ６ represents a vinyl group, X is selected from N or CH, and Y is selected from hydrogen or acetyl group. R ７ is hydrogen, deuterated methyl group, C １ -C ４ Alkanoyl group, C １ -C ４ Alkyl alkyl group or C ４ -C ６ It is a heterocycloalkyl group, C ４ -C ６ An aromatic heterocyclic compound characterized in that the heterocycloalkyl group contains one heteroatom, and the heteroatom is an oxygen atom.

2. In the above general formulas III-1, III-2, III-3, or III-4, L is Selected from, here, R ａ , R ｂ Each of these is independently selected from H, methyl group, isopropyl group, methylthio group-substituted ethyl group, and methylsulfonyl group-ethyl group, and R ｃ , R ｄ , R ｅ , R ｆ Each is independently selected from H and methyl groups, and R ｇ , R ｈ Each is independently selected from H and methyl groups, k is 1, 2, 3, or 4, q is 1, r is 0, p is 1, and m is 3 or 4. R ７ C is hydrogen, methyl group, isopropyl group, acetyl group, deuterated methyl group, C ４ -C ６ It is a heterocycloalkyl group, where C ４ -C ６ The aromatic heterocyclic compound according to claim 1, characterized in that the heterocycloalkyl group contains one heteroatom, and the heteroatom is an oxygen atom.

3. is selected from the following structures: Here, R ７ is hydrogen, deuterated methyl group, C １ -C ４ Alkanoyl group, C １ -C ４ Alkyl alkyl group or C ４ -C ６ It is a heterocycloalkyl group, C ４ -C ６ A heterocycloalkyl group contains one heteroatom, and the heteroatom is an oxygen atom. R ａ is hydrogen, C １ -C ４ Alkyl alkyl groups, monosubstituted C １ -C ４ Selected from alkyl groups, the monosubstituted C １ -C ４ The substituents in alkyl groups are C １ -C ３ Alkylthio group, C １ -C ３ Selected from an alkanesulfonyl group and a cyano group, The aforementioned W is, The aromatic heterocyclic compound according to claim 1, characterized in that it is such.

4. The aromatic heterocyclic compound according to claim 1, characterized in that in the general formulas III-1, III-2, III-3, or III-4, the N adjacent to W is defined as N-1, and in L, if a substitution other than H exists on the carbon atom adjacent to N-1, the carbon atom has a chiral structure.

5. The following compounds The aromatic heterocyclic compound according to claim 1, characterized by being selected from its optical isomer, its deuterated compound, or its pharmaceutically acceptable salt.

6. A pharmaceutical composition characterized by containing the compound described in any one of claims 1 to 5.

7. The pharmaceutical composition comprises at least one active ingredient and one or more pharmaceutically acceptable carriers or excipients, wherein the active ingredient is selected from any one of the compounds described in claims 1 to 5, optical isomers thereof, deuterated compounds thereof, or pharmaceutically acceptable salts thereof.

8. Use of the compound according to any one of claims 1 to 5 in the manufacture of a drug for preventing or treating a disease caused by abnormalities in the JAK-STAT signaling pathway.

9. The use according to claim 8, characterized in that the JAK-STAT signaling pathway abnormality refers to the abnormal expression of JAK3 or a change in the JAK-STAT signaling pathway due to such abnormal expression.

10. The use according to claim 8, characterized in that the disease is selected from one or more autoimmune diseases.

11. The use according to claim 8, characterized in that the disease is selected from one or more of the following: alopecia areata, lupus, multiple sclerosis, amyotrophic lateral sclerosis, rheumatoid arthritis, rheumatoid arthritis, psoriasis, complications associated with organ transplantation, atopic dermatitis, autoimmune thyroid disease, ulcerative colitis, Crohn's disease, Sjögren's syndrome, vitiligo, autoimmune kidney disease, autoimmune liver disease, and chronic obstructive pulmonary disease.

12. The use according to claim 8, characterized in that the disease caused by the abnormality of the JAK-STAT signaling pathway is lung injury, and the lung injury is radiation-induced lung injury and acute lung injury.

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