Isobenzofuranone compounds, pharmaceutical compositions thereof and uses thereof

Abstract

The application discloses an isofuranone compound, a medicine combination and use thereof, and the isofuranone compound disclosed by the application can efficiently and selectively degrade hematopoietic progenitor kinase 1 protein, and has no degradation activity on other proteins in the same family. Compared with a small molecule inhibitor of hematopoietic progenitor kinase 1, the isofuranone compound can more efficiently stimulate T cell anti-tumor immune response, release effector cytokines, and has stronger anti-tumor activity.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to an isofuranone compound, its pharmaceutical composition, and its uses. Background Technology

[0002] Immunotherapy has revolutionized cancer treatment, bringing new hope to patients. In particular, immune checkpoint inhibitors targeting the PD-1 and CTLA-4 pathways have shown significant clinical efficacy. However, they are only effective for specific patient populations and specific types of tumors, with low tumor response rates (~30%), and most patients do not experience durable symptom relief and develop resistance after a period of use. Therefore, the discovery of new targets for tumor immunotherapy and the improvement of the clinical efficacy of immune checkpoint inhibitors are crucial for the application and promotion of tumor immunotherapy.

[0003] Hematopoietic progenitor kinase 1 (HPK1, MAP4K1) is a member of the MAP4K family, a Ste20 serine / threonine protein kinase. Besides HPK1, the MAP4K family includes five other members: MAP4K2, MAP4K3, MAP4K4, MAP4K5, and MAP4K6. HPK1 is primarily expressed on hematopoietic cells, such as T cells, B cells, neutrophils, dendritic cells (DCs), natural killer (NK) cells, and macrophages. Numerous studies have shown that HPK1 is a negative regulator of both T cell and B cell receptors. Upon TCR activation, HPK1 in the cytoplasm is recruited to the plasma membrane, where its amino acid residues Y381, S171, and T165 are phosphorylated, resulting in fully activated HPK1 kinase. Activated HPK1 phosphorylates amino acid residue S376 of its adaptor protein SLP76, providing a binding site for the negative regulator 14-3-3, promoting proteasomal degradation of SLP76, and ultimately disrupting the stability of the TCR signaling complex, thereby hindering downstream kinase signaling pathways that promote T cell activation and proliferation. In addition to TCR signaling, HPK1 also negatively regulates T cell signaling through the prostaglandin E2 (PGE2) receptor. Furthermore, under stimulation by growth factors, stress, inflammatory factors, and differentiation factors, HPK1 can also transmit immunosuppressive signals in B cells, NK cells, and dendritic cells. Additionally, a recent study showed that HPK1 kinase activity inhibits the immune function of various cells, including CD4+. + T cells, CD8 +T cells, NK cells, and dendritic cells were involved, and it was demonstrated that inhibiting HPK1 kinase activity was sufficient to induce an anti-tumor immune response. Furthermore, inhibiting HPK1 kinase activity further enhanced T cell effector function, significantly increasing the therapeutic effect of PD-L1 monoclonal antibodies. HPK1 gene deletion, HPK1 inhibitors, or HPK1 protac degraders all enhanced CAR-T cell-based immunotherapy, exhibiting better anti-tumor activity in various preclinical hematologic and solid tumor mouse models. Notably, neither HPK1 gene knockout nor inactivated kinase knock-in mice showed lethal inflammatory responses, whereas these were significantly observed in the absence of some other negative immune regulators, such as CTLA-4 and Cbl-b, indicating that HPK1 inhibitors have high safety profiles. In conclusion, HPK1 is a potentially effective new target for tumor immunotherapy, and the research and development of HPK1 inhibitors is of great significance for addressing key challenges currently facing tumor immunotherapy.

[0004] Currently, several HPK1 inhibitors with different structures have been reported, and four HPK1 inhibitors are in early clinical trials, including CFI-402411 from Treadwell Therapeutics, BGB-15025 from BeiGene, PRJ1-3024 from Zhuhai Yufan, and NDI-101150 from Nimbus Therapeutics. Despite the existence of multiple HPK1 inhibitors, none have yet been approved for marketing. The main challenge in HPK1 inhibitor development lies in the fact that while HPK1 family members have different functions, they share very high structural homology, making the design of highly selective inhibitors extremely difficult.

[0005] Compared to traditional drugs, PROTACs offer significant advantages: broader scope of action, higher activity, and the ability to target "undruggable" targets; improved selectivity, activity, and safety; and the ability to overcome drug resistance in tumors. PROTACs can achieve selectivity at certain targets that is difficult for small molecules to achieve. Therefore, developing HPK1 PROTAC molecules holds promise for solving the problems of low selectivity and dose-dependent efficacy of HPK1 inhibitors. Currently, HPK1 PROTAC molecules are rarely reported. Therefore, the research and development of HPK1 PROTAC molecules is urgent and has significant scientific and developmental value. Summary of the Invention

[0006] Objective: To address the low selectivity of small molecule HPK1 inhibitors, this invention leverages the advantage of PROTACs, which achieve selectivity difficult to attain with small molecules, to develop HPK1-targeting PROTAC molecules, providing a class of isofuranone-based HPK1 PROTAC degraders. The HPK1 PROTACF molecules of this invention can efficiently and selectively degrade HPK1 protein, while exhibiting no degradative activity against other proteins in the same family. Compared to small molecule HPK1 inhibitors, they can more efficiently stimulate T-cell anti-tumor immune responses, release effector cytokines, and possess stronger anti-tumor activity.

[0007] Technical solution: This invention provides a compound as shown in Formula I, or its enantiomers, diastereomers, racemates, cis-trans isomers, deuterated derivatives, metabolites, prodrugs, solvates, hydrates, pharmaceutically acceptable salts, or cocrystals, with the following general structural formula:

[0008] E——L——B (I)

[0009] In Formula I:

[0010] E is

[0011] R is -CH-, -C(CH3)-, or N;

[0012] Y represents deuterium, halogen, cyano, or C. 1-4 Alkyl, deuterated (C 1-4 Alkyl), halogenated (C) 1-4 Alkyl), deuterated (C) 1-4 alkoxy) or halogenated (C) 1-4 Alkyl groups);

[0013] M represents deuterium, halogen, and C. 1-4 Alkyl, deuterated (C 1-4 Alkyl) or halogenated (C) 1-4 alkyl);

[0014] a can be 0, 1, 2, 3, or 4;

[0015] b can be 0, 1, 2, or 3;

[0016] Q can be a single bond, -NH-, -CH2-, or -O-;

[0017] W is -CH2-, -C(CH3)2 or

[0018] L is L1 is connected to E, and L4 is connected to B;

[0019] L1 represents a single bond, -O-, or -NR. a-、-C≡C-、4-10 member monocyclic heterocyclic alkylene, 6-20 member spirocyclic heterocyclic alkylene, 6-18 member fused heterocyclic alkylene or 7-10 member bridged heterocyclic alkylene;

[0020] L2 is a single bond. -(CH2)r2-, -(CH2)r2NH-, (CH2)r3NH(C=O)-, -(CH2)r3(C=O)NH-, 4-10 member monocyclic heterocyclic alkylene, 6-20 member spirocyclic heterocyclic alkylene, 6-18 member fused-cyclic heterocyclic alkylene or 7-10 member bridged-cyclic heterocyclic alkylene;

[0021] L3 is a single bond, -(CH2)r4NH-, 4-10 member monocyclic heterocyclic alkylene, 6-20 member spirocyclic heterocyclic alkylene, 6-18 member fused-cyclic heterocyclic alkylene or 7-10 member bridged-cyclic heterocyclic alkylene;

[0022] L4 is a single bond or -(CH2)r5NR b -;

[0023] R a It is hydrogen or C 1-4 alkyl;

[0024] R b It is hydrogen or C 1-4 alkyl;

[0025] r2 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0026] r3 is 1, 2, 3, 4, 5, 6, 7 or 8;

[0027] r4 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0028] r5 can be 0, 1, 2, 3, 4, 5, or 6;

[0029] B is

[0030] X is Or “5-6 membered heteroaryl groups whose heteroatoms are selected from one or more of N, O and S, and whose number of heteroatoms is 1-3”;

[0031] Z is C 4-10 Alkylene, C 4-10 imide or C 4-10 The acetylenic group, the C 4-10 Alkylene, C 4-10 imidene group, C 4-10 One or two methylene groups of the alkynyl group are optionally and independently surrounded by O, -NH- or -N(C) 1-4 Alkyl groups are substituted.

[0032] In some implementations, R is -CH- or N;

[0033] In some implementations, Y is deuterium, fluorine, chlorine, cyano, methyl, trifluoromethyl, methoxy, or trifluoromethoxy.

[0034] In some implementations, M is deuterium, fluorine, methyl, or trifluoromethyl.

[0035] In some implementations, a is 0, 1, 2, or 3.

[0036] In some implementations, b is 0 or 1.

[0037] In some implementations, Q is a single bond or -NH-.

[0038] In some implementations, W is -CH2- or

[0039] In some implementation schemes, X is Imidazolyl, 1,3,4-Ixadiazolyl or 1,2,4-Ixadiazolyl.

[0040] In some implementations, Z is -OCH2CH2CH2CH2-, -OCH2CH2CH2CH2CH2-, -OCH2CH2OCH2CH2-, -OCH2CH2OCH2-, -OCH2CH2N(CH3)CH2-, or -CH2OCH2CH=CHCH2OCH2CH2-.

[0041] In some implementation schemes, X is The left side is connected to L, and the right side is connected to... Connected.

[0042] In some implementations, E is

[0043]

[0044] In some implementations, L1 is a single bond, -O-, -NH-, -N(CH3)-, -C≡C-,

[0045] L2 is a single bond, -(CH2)r2-, -(CH2)r2NH-, -(CH2)r3NH(C=O)-, -(CH2)r3(C=O)NH-,

[0046] L3 is a single bond, -(CH2)r4NH-,

[0047] L4 is a single bond, -(CH2)r5NH- or -(CH2)r5NCH3-.

[0048] n1 can be 1, 2, 3 or 4.

[0049] n2 is 1, 2, 3 or 4;

[0050] n3 can be 1, 2, or 3.

[0051] n4 can be 1, 2, or 3.

[0052] n5 can be 1, 2, or 3.

[0053] n6 can be 1, 2, or 3.

[0054] n7 can be 0, 1, 2, or 3.

[0055] n8 can be 0, 1, 2, or 3.

[0056] n9 can be 0, 1, 2, or 3.

[0057] n10 is 0, 1, 2 or 3.

[0058] Q 1 It can be CH or N.

[0059] Q 2 It can be CH or N.

[0060] Q 3 It can be CH or N.

[0061] R 1 It is hydrogen, halogen, -(C=O) or C 1-3 alkyl.

[0062] c can be 1, 2, 3 or 4.

[0063] r2 can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11.

[0064] r3 can be 1, 2, 3, 4, 5, or 6.

[0065] r4 can be 0, 1, 2, 3, 4, 5, 6, 7 or 8.

[0066] r5 can be 0, 1, 2, 3 or 4.

[0067] In some implementations, L1 is -O-, -NH-, -C≡C-, In some implementations, L2 is a single bond, -(CH2)r2-, -(CH2)r2NH-, -(CH2)r3NH(C=O)-, -(CH2)r3(C=O)NH-,

[0068] In some implementations, L3 is a single bond, -(CH2)r4NH-.

[0069] In some implementations, L4 is a single bond or -(CH2)r5NH-.

[0070] In some implementations, n1 is 1, 2, or 3.

[0071] In some implementations, n2 is 1, 2, or 3.

[0072] In some implementations, n3 is 1 or 2.

[0073] In some implementations, n4 is 1 or 2.

[0074] In some implementations, n5 is 1 or 2.

[0075] In some implementations, n6 is 1 or 2.

[0076] In some implementations, n7 is 1 or 2.

[0077] In some implementations, n8 is 1 or 2.

[0078] In some implementations, n9 is 0, 1, or 2.

[0079] In some implementations, n10 is 0, 1, or 2.

[0080] In some implementation schemes, Q 2 For CH, Q 3 Let N be the number of elements in the array.

[0081] In some implementation schemes, Q 2 For N, Q 3 For CH.

[0082] In some implementation schemes, R 1 It is hydrogen.

[0083] In some implementations, c is 0, 1, or 2.

[0084] In some implementations, r2 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0085] In some implementations, r3 is 1, 2, 3 or 4.

[0086] In some implementations, r4 is 0, 1, 2, 3, 4, 5, or 6.

[0087] In some implementations, r5 is 0, 1, 2, or 3.

[0088] In some implementations, L is -O-(CH2)r2NH- single bond - single bond -, -O-(CH2)r3NH(C=O)-(CH2)r4NH- single bond -, -O-(CH2)r3(C=O)NH-(CH2)r4NH- single bond -, -NH-(CH2)r2NH- single bond - single bond -, -NH-(CH2)r3NH(C=O)-(CH2)r4NH- single bond -, -NH-(CH2)r3(C=O)NH-(CH2)r4NH- single bond -, -NH-(CH2)r2- single bond - single bond -, -C≡C-(CH2)r2NH- single bond - single bond -, -C≡C-(CH2)r2- single bond - single bond -,

[0089]

[0090]

[0091] The left side is connected to E, and the right side is connected to B;

[0092] n1 is 1, 2, or 3;

[0093] n2 is 1, 2, or 3;

[0094] n3 is 1 or 2;

[0095] n4 is 1 or 2;

[0096] n5 is 1 or 2;

[0097] n6 is 1 or 2;

[0098] n7 is 1 or 2;

[0099] n8 is 1 or 2;

[0100] n9 can be 0, 1, or 2;

[0101] n10 is 0, 1, or 2;

[0102] Q 1 For CH or N;

[0103] Q 2 For CH or N;

[0104] Q 3 For CH or N;

[0105] R 1 It is hydrogen;

[0106] c is 0, 1, or 2;

[0107] r2 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0108] r3 can be 1, 2, 3, or 4;

[0109] r4 is 0, 1, 2, 3, 4, 5, or 6;

[0110] r5 can be 0, 1, 2, or 3.

[0111] In some implementation schemes,

[0112] L1 represents -O-, -NH-, -C≡C-,

[0113]

[0114] The left side is connected to E, and the right side is connected to L2;

[0115] In some implementation schemes,

[0116] L2 is a single bond, -(CH2)r2-, -(CH2)r2NH-, -(CH2)r3NH(C=O)-, -(CH2)r3(C=O)NH-,

[0117]

[0118] r2 is 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9;

[0119] r3 is 1, 2, or 3;

[0120] The left side is connected to L1, and the right side is connected to L3.

[0121] In some implementations, L3 is a single bond, -(CH2)r4NH-,

[0122]

[0123] It connects to L2 on the left and L4 on the right.

[0124] r4 can be 0, 1, 2, or 3.

[0125] In some implementations, L4 is a single bond or -(CH2)r5NH-.

[0126] r5 can be 0, 1, or 2.

[0127] In some implementations, L is

[0128]

[0129] The left side is connected to E, and the right side is connected to B;

[0130] r21 is 1, 2, 3, 4, 5, 6, 7 or 8;

[0131] r22 is 0, 1, 2, or 3;

[0132] r31 is 1, 2, or 3;

[0133] r41 is 1, 2, or 3;

[0134] r42 is 0, 1, 2, or 3;

[0135] r52 is either 0 or 1.

[0136] In some embodiments, the compound represented by Formula I is selected from compounds with any of the following structures:

[0137]

[0138]

[0139]

[0140]

[0141]

[0142]

[0143] This invention provides the use of a compound of Formula I or an enantiomer, diastereomer, racemate, cis-trans isomer, deuterated product, metabolite, prodrug, solvate, hydrate, pharmaceutically acceptable salt or cocrystal thereof in the preparation of a hematopoietic progenitor kinase 1 degrading agent.

[0144] This invention provides the use of a compound of Formula I or an enantiomer, diastereomer, racemate, cis-trans isomer, deuterated product, metabolite, prodrug, solvate, hydrate, pharmaceutically acceptable salt or eutectic thereof in the preparation of a medicament for the treatment and / or prevention of cancer.

[0145] In some implementations, the cancer is defined as cancer associated with abnormal activity or expression of hematopoietic progenitor cell kinase 1.

[0146] In some implementations, the cancer is one or more of the following: bone cancer, lung cancer, stomach cancer, colorectal cancer, endometrial cancer, breast cancer, prostate cancer, liver cancer, brain cancer, ovarian cancer, bladder cancer, gastrointestinal stromal tumor, cervical cancer, testicular cancer, kidney cancer, head and neck cancer, thyroid cancer, pancreatic cancer, esophageal cancer, lymphoma, leukemia, or skin cancer.

[0147] The present invention provides a pharmaceutical composition comprising any one of the compounds represented by Formula I or an enantiomer, diastereomer, racemate, cis-trans isomer, deuterated product, metabolite, prodrug, solvate, hydrate, pharmaceutically acceptable salt or cocrystal, and a pharmaceutically acceptable carrier or excipient.

[0148] In some embodiments, the amount of the compound of Formula I, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate, or hydrate thereof, in the pharmaceutical composition is a therapeutically effective amount.

[0149] This invention provides the use of a pharmaceutical composition in the preparation of a medicament for treating and / or preventing cancer.

[0150] In some implementations, the cancer is one or more of the following: bone cancer, lung cancer, stomach cancer, colorectal cancer, endometrial cancer, breast cancer, prostate cancer, liver cancer, brain cancer, ovarian cancer, bladder cancer, gastrointestinal stromal tumor, cervical cancer, testicular cancer, kidney cancer, head and neck cancer, thyroid cancer, pancreatic cancer, esophageal cancer, lymphoma, leukemia, or skin cancer.

[0151] The pharmaceutical excipients described herein may be those widely used in the pharmaceutical manufacturing field. Excipients primarily serve to provide a safe, stable, and functional pharmaceutical composition, and may also provide methods for enabling the active ingredient to dissolve at a desired rate after administration to a subject, or to promote the effective absorption of the active ingredient after administration to a subject. The pharmaceutical excipients may be inert fillers, or provide a function such as stabilizing the overall pH of the composition or preventing the degradation of the active ingredient. The pharmaceutical excipients may include one or more of the following: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, anti-adhesion agents, flow aids, wetting agents, gelling agents, absorption delay agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents, and sweeteners.

[0152] The pharmaceutical compositions of the present invention can be prepared using any method known to those skilled in the art, based on the disclosure. For example, conventional mixing, dissolving, granulation, emulsification, grinding, encapsulation, embedding, or lyophilization processes.

[0153] The pharmaceutical compositions of this invention can be administered in any form, including by injection (intravenous), mucosal, oral (solid and liquid formulations), inhalation, ocular, rectal, topical, or parenteral (infusion, injection, implantation, subcutaneous, intravenous, intra-arterial, intramuscular) administration. The pharmaceutical compositions of this invention can also be controlled-release or delayed-release dosage forms (e.g., liposomes or microspheres). Examples of solid oral formulations include, but are not limited to, powders, capsules, tablets, soft capsules, and tablets. Examples of liquid formulations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs, and solutions. Examples of topical formulations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops, or serum preparations. Examples of parenteral formulations include, but are not limited to, solutions for injection, dry formulations that can be dissolved or suspended in a pharmaceutically acceptable carrier, suspensions for injection, and emulsions for injection. Examples of other suitable formulations of the pharmaceutical composition include, but are not limited to, eye drops and other ophthalmic preparations; aerosols, such as nasal sprays or inhalers; liquid dosage forms suitable for parenteral administration; suppositories; and tablets.

[0154] The term "pharmaceutically acceptable salt" refers to a salt of the compounds of this invention, prepared by reacting a compound having specific substituents discovered in this invention with a relatively non-toxic acid or base. When the compounds of this invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the free form of such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts or similar salts. When the compounds of this invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the free form of such compounds with a sufficient amount of acid 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 (forming carbonates or bicarbonates), phosphoric acid (forming phosphates, monohydrogen phosphates, dihydrogen phosphates, sulfuric acid (forming sulfates or bisulfates), hydroiodic acid, phosphorous acid, etc.); and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, etc. Acids such as tartaric acid and methanesulfonic acid; organic acid salts also include salts of amino acids (such as arginine) and salts of organic acids such as glucuronic acid. Certain compounds of the present invention contain both basic and acidic functional groups, thus allowing them to be converted into any base or acid addition salt. Preferably, the salt is contacted with a base or acid in a conventional manner, followed by separation of the parent compound, thereby regenerating the free form of the compound. The free form of the compound differs from its various salt forms in certain physical properties, such as different solubilities in polar solvents.

[0155] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture of both. Non-aqueous media such as ethers, ethyl acetate, ethanol, isopropanol, or acetonitrile are generally preferred.

[0156] The term "enantiomer" refers to a stereoisomer that is a mirror image of another entity but cannot be superimposed. Examples of enantiomers include, but are not limited to, those shown below. and They are enantiomers.

[0157] The term "racemate" is a mixture of enantiomers. Examples of racemates include, but are not limited to, those listed below.

[0158] yes

[0159] Racemic mixture.

[0160] The term "diastereomer" refers to a stereoisomer that has the same atomic composition but different spatial arrangements and is not a mirror image of another molecule.

[0161] The term "cis-trans isomers" refers to isomers that are formed because the single bonds of double bonds or cyclic carbon atoms cannot rotate freely.

[0162] The term "deuterated product" refers to a molecule in which any hydrogen atom can be replaced by its isotope deuterium.

[0163] The term "metabolite" refers to a pharmaceutically active product produced in vivo by the metabolism of a compound of Formula I or a salt thereof. Such products can be generated, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, glucuronidation, enzymatic cleavage, etc., of the administered compound. Therefore, this invention includes metabolites of the compounds of this invention, including compounds produced by methods that expose the compounds of this invention to mammals for a sufficient period of time to obtain their metabolites.

[0164] The identification of metabolites is typically performed by preparing a radiolabeled isotope of the compound of the invention, administering it parenterally to an animal, such as a rat, mouse, guinea pig, monkey, or human, at a detectable dose (e.g., greater than about 0.5 mg / kg), allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours), and isolating the metabolites from urine, blood, or other biological samples. These products are readily isolated because they are labeled (others are isolated using antibodies capable of binding to antigenic epitopes present in the metabolites). The metabolite structure is determined in a conventional manner, for example, by MS, LC / MS, or NMR analysis. Typically, the analysis of metabolites is performed using methods known to those skilled in the art for routine drug metabolism studies. The metabolite products can be used for assays of therapeutic doses of the compound of the invention, provided they are not otherwise undetectable in vivo. The compounds of the invention may contain atomic isotopes in non-natural proportions on one or more atoms constituting the compound. For example, the compound may be radiolabeled with radioisotopes, such as tritium ( 3 H), Iodine-125 125 I) or C-14 14 C). All isotopic variations of the compounds of the present invention, regardless of radioactivity, are included within the scope of the present invention.

[0165] In addition to the salt form, the compounds provided by this invention also exist in prodrug form. The prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to transform into the compounds of this invention. Any compound that can be converted in vivo to provide a bioactive substance (i.e., the compound shown in Formula I) is a prodrug within the scope and spirit of this invention. For example, compounds containing a carboxyl group can form physiologically hydrolyzable esters, which act as prodrugs by hydrolysis in vivo to yield the compound shown in Formula I itself. The prodrugs are preferably administered orally because hydrolysis in many cases occurs primarily under the influence of digestive enzymes. Parenteral administration may be used when the ester itself is active or when hydrolysis occurs in the bloodstream.

[0166] Those skilled in the art will understand that, according to conventions used in the art, the use of "" in the structural formulas describing the functional groups in this application is appropriate. This refers to the connection of the corresponding group to other segments or groups in the compound shown in Formula I through this site.

[0167] The term "degrading agent" refers to a compound represented by Formula I or its enantiomers, diastereomers, cis-trans isomers, racemic mixtures, deuterated derivatives, metabolites, prodrugs, solvates, hydrates, pharmaceutically acceptable salts, or cocrystals that simultaneously bind to E3 ubiquitin ligase and hematopoietic progenitor kinase 1 protein, thereby bringing hematopoietic progenitor kinase 1 protein into close proximity with E3 ubiquitin ligase, and subsequently degrading hematopoietic progenitor kinase 1 protein under the action of E3 ubiquitin ligase.

[0168] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0169] The term "alkyl" refers to a straight-chain or branched alkyl group having a specified number of carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, and sec-butyl.

[0170] The term "alkoxy" refers to the group -O-alkyl, where alkyl is defined as described above.

[0171] The term "heterocyclic alkyl" refers to a saturated or partially saturated monocyclic or polycyclic group having heteroatoms, comprising 3-20 ring atoms, one or more of which are independently selected from heteroatoms N, O, or S, with the remaining ring atoms being carbon. Preferably, it has 3 to 20 ring atoms, of which 1-3 are heteroatoms. More preferably, it has 4-16 ring atoms, of which 1-2 are N, including 4-10-membered monocyclic heterocyclic alkyl, 6-16-membered spirocyclic heterocyclic alkyl, 6-15-membered cyclic heterocyclic alkyl, and 7-10-membered bridged cyclic heterocyclic alkyl. The term "heterocyclic alkylene" refers to a divalent group formed by removing another hydrogen atom from the above-mentioned "heterocyclic alkyl," including 4-10-membered monocyclic heterocyclic alkylene, 6-16-membered spirocyclic heterocyclic alkylene, 6-15-membered cyclic heterocyclic alkylene, and 7-10-membered bridged cyclic heterocyclic alkylene. Examples include, but are not limited to, those described above.

[0172]

[0173] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, as defined above. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl.

[0174] The term "haloalkoxy" refers to an alkoxy group that is substituted with one or more halogens, as defined above. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy groups.

[0175] The term "deuterated alkyl" refers to an alkyl group that is substituted with one or more deuterium atoms, as defined above. Examples of deuterated alkyl groups include, but are not limited to, -CD3.

[0176] The term "deuterated alkoxy" refers to an alkoxy group substituted with one or more deuterium groups, as defined above. Examples of deuterated alkoxy groups include, but are not limited to, -OCD3.

[0177] All hydrogen atoms described in this invention can be replaced by their isotope deuterium, and any hydrogen atom in the compounds of the embodiments of this invention can also be replaced by a deuterium atom.

[0178] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0179] The reagents and raw materials used in this invention are all commercially available.

[0180] Beneficial effects: The positive and progressive effects of the present invention are as follows: (1) The hematopoietic progenitor cell kinase 1 PROTAC molecule provided by the present invention can efficiently and selectively degrade various hematopoietic progenitor cell kinase 1 proteins, while having no degradation activity on other proteins in the same family, and has low toxicity. (2) The hematopoietic progenitor cell kinase 1 PROTAC molecule provided by the present invention has a good therapeutic effect on cancer. Attached Figure Description

[0181] Figure 1 Compound S10 in this example restores or enhances the tumor-killing effect of PBMC cells;

[0182] Figure 2 Compound S47 in this example is used to restore or enhance the killing effect of PBMC cells on tumor cells. Detailed Implementation

[0183] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0184] Synthesis of Intermediate 3 in Example 1

[0185]

[0186] a) Under argon protection, starting material 1 (8 g, 40.6 mmol), pinacol isopropenylborate (8.2 g, 48.72 mmol), K₂CO₃ (14 g, 101.52 mmol), and Pd(dppf)Cl₂ (292.68 mg, 0.4 mmol) were dissolved in 1,4-dioxane (200 mL) and water (40 mL). The mixture was stirred overnight at 95 °C. After the reaction was complete, the reaction solution was cooled to room temperature, diluted with water, and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered, concentrated, and purified by column chromatography to obtain intermediate 2 (5.56 g, 87%). MS (ESI, m / z): 159 (M + +1).

[0187] b) Intermediate 2 (5.5 g, 34.7 mmol) and Mn(Dpm)3 (2.1 g, 3.47 mmol) were dissolved in isopropanol (220 mL) and dichloromethane (10 mL) under oxygen conditions. Phenylsilane (7.52 g, 69.53 mmol) was added to the reaction system at 0 °C and stirred for 2 h. After the reaction was complete, the reaction was quenched with 20% Na2S2O3 aqueous solution, extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and concentrated to obtain crude 4-amino-2-(2-hydroxypropyl-2-yl)benzyl nitrile. MS (ESI, m / z): 177 (M + +1).

[0188] c) Crude 4-amino-2-(2-hydroxypropyl-2-yl)benzyl nitrile (34.7 mmol) was dissolved in DMF (70 mL) and water (70 mL), and solid NaHCO3 (11.67 g, 138.8 mmol) was added in portions. The mixture was stirred at 80 °C for 24 h. After the reaction was complete, the reaction solution was cooled to room temperature and filtered through diatomaceous earth, then washed with ethyl acetate. The mixture was extracted with ethyl acetate (30 mL × 3), the combined organic layers were washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and concentrated. Intermediate 3 (4.73 g, 77%) was purified by column chromatography. MS (ESI, m / z): 178 (M + +1).

[0189] Synthesis of Intermediate 7 in Example 2

[0190]

[0191] a) Dissolve starting material 4 (6 g, 27.14 mmol) in acetonitrile (70 mL), and add DIPEA (9 mL, 54.24 mmol) and (s)-2-amino-2-phenylethanol (4.08 g, 29.7 mmol) to the reaction system. Stir the reaction mixture at room temperature for 3 h. After the reaction is complete, filter the reaction mixture and concentrate the filtrate under reduced pressure. Purify by column chromatography to obtain intermediate 5 (6.95 g, 79%). MS (ESI, m / z): 322 (M + +1).

[0192] b) Intermediate 3 (2.95 g, 16.64 mmol) and intermediate 5 (5.35 mg, 16.64 mmol) were dissolved in isopropanol (42 mL). Hydrochloric acid (7 mL) was added dropwise to the reaction system, and the mixture was stirred overnight at 80 °C. After the reaction was complete, the reaction solution was cooled to room temperature, and the reaction was quenched by adding triethylamine. The mixture was extracted with ethyl acetate (30 mL × 3), and the combined organic layers were washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and concentrated to give intermediate 6 (6.5 g, 84%). MS (ESI, m / z): 463 (M + +1).

[0193] c) Dissolve intermediate 6 (6 g, 12.9 mmol) in tetrahydrofuran (50 mL), add 2 M NaOH aqueous solution (15 mL) to the reaction system, and stir overnight at 50 °C. After the reaction is complete, cool the reaction solution to room temperature, adjust the pH to 4 with 2 M HCl, and filter to obtain a white solid intermediate 7 (4.1 g, 73%). MS (ESI, m / z): 435 (M + +1).

[0194] Synthesis of Intermediate 12 in Example 3

[0195]

[0196] a) Following step a in the synthesis of intermediate 7, intermediate 9 can be obtained simply by changing the corresponding raw materials. MS (ESI, m / z): 327 (M + +1).

[0197] b) Following the synthesis step b of intermediate 7, intermediate 10 can be obtained simply by changing the corresponding raw materials. MS (ESI, m / z): 469 (M + +1).

[0198] c) Intermediate 10 (155 mg, 0.33 mmol), starting material 11a (135.2 mg, 0.52 mmol), Pd(PPh3)4 (42 mg, 0.036 mmol), and sodium bicarbonate (106 mg, 1.0 mmol) were added to a sealed tube and protected with argon. 1,4-Dioxane (20 mL) and water (4 mL) were added at room temperature, and the mixture was stirred at 100 °C for 12 h under argon atmosphere. After the reaction was complete, the reaction solution was cooled to room temperature, extracted with ethyl acetate (10 mL × 3), and the combined organic layers were washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography to obtain intermediate 12a (57 mg, 33%). Intermediate 12b can be obtained by simply changing the starting material and following the same preparation method. MS (ESI, m / z): 523 (M + +1).

[0199] Synthesis of Intermediate 13 in Example 4

[0200]

[0201] Intermediate 12b (74 mg, 0.12 mmol) was dissolved in dioxane (0.5 mL), and trifluoroacetic acid (0.5 mL) was added. The mixture was stirred at room temperature for 2 h, and the reaction solution was evaporated to dryness to obtain intermediate 13 (72 mg, 98%). MS (ESI, m / z): 611 (M + +1).

[0202] Synthesis of Intermediate 16 in Example 5

[0203]

[0204] a) 4-Cyano-1-butyne (1 g, 10.74 mmol) was dissolved in isopropanol (20 mL). Solid NaHCO3 (1.98 g, 23.63 mg) was added to the reaction system, and the mixture was stirred at room temperature for 15 min. Then, hydroxylamine hydrochloride (1.12 g, 16.11 mmol) was added, and the mixture was stirred at 80 °C for 3 h. After the reaction was complete, the reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to give intermediate 14a (1.35 g, 99%). MS (ESI, m / z): 113 (M + +1). By simply changing the corresponding raw materials, intermediate 14b can be prepared in the same way.

[0205] b) Intermediate 14b (600 mg, 4.76 mmol), compound 7 (1.88 g, 4.32 mmol), and HATU (2.71 g, 7.14 mmol) were dissolved in dichloromethane (40 mL). DIPEA (1.25 mL, 7.14 mmol) was added to the reaction mixture, and the mixture was stirred overnight at room temperature. After the reaction was complete, the reaction mixture was extracted with dichloromethane (30 mL × 3), the combined organic layers were washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography to obtain intermediate 15a (790 mg, 31%). MS (ESI, m / z): 529 (M + +1). Intermediate 15b can be obtained by simply changing the corresponding raw materials and following the same preparation method.

[0206] c) Intermediate 15a (790 mg, 1.46 mmol) was dissolved in pyridine (8 mL), and the mixture was stirred overnight at 100 °C. After the reaction was complete, the reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain intermediate 16a (230 mg, 30%). MS (ESI, m / z): 511 (M + +1). Intermediate 16b can be obtained by simply changing the corresponding raw materials and following the same preparation method.

[0207] Synthesis of Intermediate 13 in Example 6

[0208]

[0209] a) Compound 7 (400 mg, 0.46 mmol) was dissolved in anhydrous dichloromethane (3 mL). EDCI (210 mg, 0.55 mmol) was added to the reaction system, and the mixture was stirred at room temperature for 30 min. Then, tert-butyl hydrazide formate (213 mg, 0.8 mmol) was added, and the mixture was stirred at room temperature for 10 h. After the reaction was complete, the reaction solution was washed with 5% HCl (10 mL). The organic layer was washed with NaHCO3 (10 mL) and extracted with dichloromethane (30 mL × 3). The combined organic layers were washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography to obtain intermediate 17 (280 mg, 55%). MS (ESI, m / z): 549 (M + +1).

[0210] b) Intermediate 17 (200 mg, 0.36 mmol) was dissolved in dichloromethane (2 mL), and a solution of 1,4-dioxane hydrochloric acid (4 M, 0.3 mmol) was added dropwise to the reaction system. The mixture was stirred at room temperature for 1 h. After the reaction was complete, the reaction solution was filtered, and the filter cake was washed with dichloromethane and dried to obtain intermediate 18 (155 mg, 89%). MS (ESI, m / z): 485 (M + +1).

[0211] Synthesis of intermediates 20, 23, and 26 in Example 7

[0212]

[0213] a) Intermediate 18 (145 mg, 0.32 mmol) was dissolved in anhydrous DMF (2 mL). DIPEA (0.21 mL, 1.29 mmol) was added to the reaction system at 0 °C, and the mixture was stirred at room temperature for 30 min. Simultaneously, 5-hexyneic acid (32 mg, 0.32 mmol), EDCI (80 mg, 0.42 mmol), and HOBt (57 mg, 0.42 mmol) were added to the reaction system at room temperature, and the mixture was stirred at room temperature for 30 min. The two reaction systems were then mixed and stirred at room temperature for 10 h. After the reaction was complete, the mixture was extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered, and concentrated. Intermediate 19 (110 mg, 65%) was purified by column chromatography. MS (ESI, m / z): 543 (M + +1). By simply changing the corresponding raw materials, intermediates 21 and 24 can be prepared using the same method.

[0214] b) Intermediate 19 (90 mg, 0.17 mmol) was dissolved in anhydrous acetonitrile (3 mL). p-Toluenesulfonyl chloride (97.4 mL, 0.51 mmol) and DIPEA (56 μL, 0.34 mmol) were added to the reaction mixture, and the mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered, and concentrated. Intermediate 20 (110 mg, 65%) was purified by column chromatography. MS (ESI, m / z): 525 (M + +1). By simply changing the corresponding raw materials, intermediates 22 and 25 can be obtained using the same method.

[0215] c) Intermediates 23 and 26 can be prepared by referring to the synthesis method of intermediate 13 and simply by changing the corresponding raw materials.

[0216] Synthesis of intermediate 30 in Example 8

[0217]

[0218] a) Starting material 27 (1.8 g, 6.5 mmol), starting material 28 (2.5 g, 6.9 mmol), and triphenylphosphine (3.9 g, 14.8 mmol) were dissolved in toluene (50 mL), and then diisopropyl azodicarbonate (DIAD, 2.8 g, 13.9 mmol) was added dropwise. The mixture was stirred at 70 °C for 1 h. After the reaction was complete, the mixture was concentrated and purified by column chromatography to give compound 29 (2.3 g, 50.2%) as a pale yellow solid. MS (ESI, m / z): 640 (M + +1).

[0219] b) Compound 29 was dissolved in ethyl acetate (2 mL), and then a solution of 1,4-dioxane hydrochloric acid (4 M, 2 mL) was added to the reaction system. The mixture was stirred at room temperature for 12 h to obtain a white suspension. The reaction solution was filtered and washed with ethyl acetate. The filter cake was collected and dried to give a white solid intermediate 30 (1.1 g, 83%). MS (ESI, m / z): 326 (M + +1).

[0220] Synthesis of intermediate 33 in Example 9

[0221]

[0222] a) Intermediate 30 (1.25 g, 3.4 mmol) was dissolved in acetonitrile (5 mL), and DIPEA (1.2 g, 8.8 mmol) and starting material 8 (778.8 mg, 3.4 mmol) were added at 0 °C. The mixture was stirred at room temperature for 5 h. After the reaction was complete, the reaction solution was concentrated and purified by column chromatography to obtain intermediate 31 (1.0 g, 55%). MS (ESI, m / z): 516 (M + +1).

[0223] b) Intermediate 31 (1.0 g, 1.9 mmol) was dissolved in acetonitrile (5 mL), and this solution was added dropwise to an acetonitrile / water / HCl (4 M) solution (100:10:0.5 ( mL)) under reflux. The reaction mixture was stirred under reflux for 5 h. After the reaction was complete, the reaction mixture was concentrated and washed with methanol to obtain intermediate 32 (710.5 mg, 68%). MS (ESI, m / z): 480 (M + +1).

[0224] c) Prepare intermediates 33a and 33b by referring to step c of the synthesis of intermediate 12.

[0225] Synthesis of Intermediate 37 in Example 10

[0226]

[0227] a) Following step a of the synthesis of intermediate 30, intermediates 35a-35b can be obtained.

[0228] b) Intermediate 35a (1.9 g, 3.34 mmol) was dissolved in methanol (60 mL), and then stirred at room temperature for 12 h under 10% Pd / C (381 mg, 55% water content) and hydrogen atmosphere. The reaction solution was filtered and washed with methanol (30 mL). The solution was concentrated and filtered to obtain crude intermediate 36a. MS (ESI, m / z): 328 (M + +1). Intermediate 36b can be obtained by simply changing the corresponding raw materials and following the same preparation method.

[0229] c) Referring to step b of the synthesis of intermediate 30, intermediates 37a-37b can be prepared simply by changing the corresponding raw materials.

[0230] Synthesis of Intermediate 40 in Example 11

[0231]

[0232] a) Referring to step a of the synthesis of intermediate 33, intermediates 38a-38b can be prepared simply by changing the corresponding raw materials.

[0233] b) Referring to step b of the synthesis of intermediate 33, intermediates 39a-39b can be prepared simply by changing the corresponding raw materials.

[0234] c) Referring to step c of the synthesis of intermediate 33, intermediates 40a-40c can be prepared simply by changing the corresponding raw materials.

[0235] Synthesis of intermediates 44 and 47 in Example 12

[0236]

[0237] a) Dissolve starting material 28 (41 mg, 0.1 mmol) and starting material 41 (144 mg, 1.192 mmol) in anhydrous THF (2 mL), and reflux for 6 h by adding anhydrous THF solution of NaH (8 mg, 0.8 mmol). After the reaction is complete, cool the reaction solution to room temperature and quench with water (2 mL). Extract the reaction solution with dichloromethane (10 mL × 3), combine the organic layers, wash with saturated NaCl solution, dry with anhydrous Na2SO4, filter and concentrate, and purify by column chromatography to obtain intermediate 45 (20 mg, 50%). MS (ESI, m / z): 408 (M + +1). Intermediate 43 can be obtained by simply changing the corresponding raw materials and following the same preparation method.

[0238] b) Intermediates 44 and 46 can be prepared by simply changing the corresponding raw materials, referring to the synthesis method of intermediate 13.

[0239] c) Referring to step a of the synthesis of intermediate 33, intermediate 47 can be prepared simply by changing the corresponding raw materials.

[0240] Synthesis of Intermediate 50 in Example 13

[0241]

[0242] a) Following step a of the synthesis of intermediate 33, intermediate 48 can be obtained.

[0243] b) Intermediate 48 (29.4 mg, 0.052 mmol) was dissolved in dichloromethane (5 mL), and the pH was adjusted to 2.0-2.2 with 4 M HCl. HOVEYDA-GRUBBS catalyst (7 mg, 0.005 mmol) was added under nitrogen protection, in two portions every 1 h. The mixture was heated and stirred at 45 °C for 4 h. The reaction mixture was cooled. The reaction solution was extracted with dichloromethane (10 mL × 3), the combined organic layers were washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered, concentrated, and purified by column chromatography to obtain intermediate 49 (22.3 mg, 80%). MS (ESI, m / z): 536 (M + +1).

[0244] c) Following the synthesis step c of intermediate 12, intermediate 50 can be prepared simply by changing the corresponding raw materials.

[0245] Synthesis of intermediates 53, 55, and 57 in Example 14

[0246]

[0247] a) Dissolve starting material 51 (4.05 g, 14.66 mmol) in 1,4-dioxane (50 mL). Add N-Boc-ethylenediamine (3.06 g, 17.59 mmol) and DIPEA (3.16 mL, 19.06 mmol) to the reaction system and stir overnight at 90 °C. After the reaction is complete, cool the reaction solution to room temperature, concentrate under reduced pressure, dilute with water, extract with ethyl acetate (30 mL × 3), combine the organic layers, wash with saturated NaCl solution, dry with anhydrous Na2SO4, filter and concentrate, and purify by column chromatography to obtain intermediate 52a (1.59 g, 25%). MS (ESI, m / z): 417 (M + +1). By simply changing the corresponding raw materials and following the same preparation method, intermediates 53b-53d, 54, and 56a-56b can be obtained.

[0248] b) Referring to the synthesis method of intermediate 13, intermediates 53a-53d, 55, and 57a-57b can be prepared simply by changing the corresponding raw materials.

[0249] Synthesis of intermediate 59 in Example 15

[0250]

[0251] a) Dissolve starting material 55 (3.31 g, 10 mmol) in DMF (50 mL). Add N-tert-butoxycarbonyl-1,3-propanediamine (2.1 g, 12 mmol), DIPEA (5.2 mL, 30 mmol), and HATU (5.7 g, 15 mmol) to the reaction system. Stir at room temperature for 6 h. After the reaction is complete, extract with ethyl acetate (30 mL × 3). Combine the organic phases, wash with saturated NaCl solution, dry to anhydrous Na2SO4, filter, concentrate under reduced pressure, and purify by column chromatography to obtain intermediate 58 (3.17 g, 65%). MS (ESI, m / z): 488 (M + +1).

[0252] b) Prepare intermediate 59 using the same method as intermediate 13.

[0253] Synthesis of intermediates 62, 64, 66, 68, 70, and 72 in Example 16

[0254]

[0255] a) Referring to the synthesis step a of intermediate 53, intermediates 61, 63, 65a-65c, 67a-67b, 69, and 71 can be prepared simply by changing the corresponding raw materials.

[0256] b) Referring to the synthesis method of intermediate 13, intermediates 62, 64, 66a-66c, 68a-68b, 70, and 72 can be prepared simply by changing the corresponding raw materials.

[0257] Synthesis of Intermediate 74 in Example 17

[0258]

[0259] a) Referring to step a of the synthesis of intermediate 59, intermediate 73 can be prepared simply by changing the corresponding raw materials.

[0260] b) Referring to step b of the synthesis of intermediate 59, intermediate 74 can be prepared simply by changing the corresponding raw materials.

[0261] Synthesis of intermediates 76, 78, 80, 82, 84, 86, and 88 in Example 18

[0262]

[0263] a) Referring to the synthesis step a of intermediate 53, intermediates 75, 77, 79, 81, 83, 85, and 87 can be prepared simply by changing the corresponding raw materials.

[0264] b) Referring to the synthesis method of intermediate 13, intermediates 76, 78, 80, 82, 84, 86, and 88 can be prepared simply by changing the corresponding raw materials.

[0265] Synthesis of intermediates 90, 92, 94, 96, 98, and 100 in Example 19

[0266]

[0267] a) Referring to step a of the synthesis of intermediate 53, intermediates 89, 91a-91b, 93, 95, 97, and 99a-99b can be prepared simply by changing the corresponding raw materials.

[0268] b) Referring to the synthesis method of intermediate 13, intermediates 90, 92a-92b, 94, 96, 98, and 100a-100b can be prepared simply by changing the corresponding raw materials.

[0269] Synthesis of intermediates 102, 104, 106, 108, 110, and 112 in Example 20

[0270]

[0271] a) Referring to step a of the synthesis of intermediate 53, intermediates 101, 103, 105, 107, 109, and 111 can be prepared simply by changing the corresponding raw materials.

[0272] b) Referring to the synthesis method of intermediate 13, intermediates 102, 104, 106, 108, 110, and 112 can be prepared simply by changing the corresponding raw materials.

[0273] Synthesis of intermediates 114, 116, 118, 120, 122, 124, 126, and 128 in Example 21

[0274]

[0275] a) Referring to step a of the synthesis of intermediate 53, intermediates 113, 115, 117, 119, 121, 123, 125, and 127 can be prepared simply by changing the corresponding raw materials.

[0276] b) Referring to the synthesis method of intermediate 13, intermediates 114, 116, 118, 120, 122, 124, 126, and 128 can be prepared by simply changing the corresponding raw materials.

[0277] Synthesis of intermediate 133 in Example 22

[0278]

[0279] a) Referring to step a of the synthesis of intermediate 53, intermediate 130 can be prepared simply by changing the corresponding raw materials.

[0280] b) Referring to step a of the synthesis of intermediate 20, intermediate 132 can be prepared simply by changing the corresponding raw materials.

[0281] c) Prepare intermediate 133 by referring to the synthesis method of intermediate 13.

[0282] Synthesis of intermediate 133 in Example 23

[0283]

[0284] a) Under argon protection, starting material 134 (1.38 g, 4.3 mmol), N-Boc-aminopropyne (1 g, 6.4 mmol), Pd(pph3)2Cl2 (301 mg, 0.43 mmol), and cuprous iodide (164 mg, 0.86 mmol) were dissolved in DMF (15 mL). Triethylamine (13 mL, 0.1 mmol) was added to the reaction system, and the mixture was stirred overnight at 80 °C. After the reaction was complete, the reaction solution was cooled to room temperature, filtered with diatomaceous earth, and the filtrate was extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography to obtain intermediate 135a (619 mg, 35%). MS (ESI, m / z): 398 (M + +1). By simply changing the corresponding raw materials and following the same preparation method, intermediates 135b-135d, 137, and 139 can be obtained.

[0285] b) Intermediates 136a-136d, 138, and 140 were prepared using the same method as intermediate 13.

[0286] Synthesis of intermediate 143 in Example 24

[0287]

[0288] a) Referring to the synthesis method of intermediate 133, intermediate 142 can be obtained simply by changing the corresponding raw materials.

[0289] b) Referring to the synthesis method of intermediate 13, intermediate 143 can be obtained simply by changing the corresponding raw materials.

[0290] Synthesis of Intermediate 146 in Example 25

[0291]

[0292] a) Referring to the synthesis method of intermediate 133, intermediate 145 can be obtained simply by changing the corresponding raw materials.

[0293] b) Referring to the synthesis method of intermediate 13, intermediate 146 can be obtained simply by changing the corresponding raw materials.

[0294] Synthesis of Intermediate 149 in Example 25

[0295]

[0296] a) Referring to the synthesis method of intermediate 133, intermediate 148 can be obtained simply by changing the corresponding raw materials.

[0297] b) Referring to the synthesis method of intermediate 13, intermediate 149 can be obtained simply by changing the corresponding raw materials.

[0298] Synthesis of intermediates 153 and 158 in Example 26

[0299]

[0300] a) Dissolve starting material 150 (1.57 g, 5.71 mmol) in DMF (57 mL), add K2CO3 (1.19 g, 8.58 mmol) and starting material 151 (2.2 g, 5.71 mmol), stir at room temperature for 2 h, quench with water after the reaction is complete, extract with dichloromethane (30 mL × 3), combine the organic phases, wash with saturated NaCl solution, dry with anhydrous Na2SO4, filter to remove salt, concentrate under reduced pressure, and purify by column chromatography to obtain intermediate 152 (3.07 g, 93%). MS (ESI, m / z): 418 (M + +1). Intermediate 155 can be obtained by simply changing the corresponding raw materials and following the same preparation method.

[0301] b) Referring to the synthesis method of intermediate 13, intermediates 153 and 156 can be obtained simply by changing the corresponding raw materials.

[0302] c) Referring to step a of the synthesis of intermediate 59, intermediate 157 can be obtained simply by changing the corresponding raw materials.

[0303] d) Referring to the synthesis method of intermediate 13, intermediate 158 can be obtained simply by changing the corresponding raw materials.

[0304] Example 27 Synthesis of compounds 162 and 164

[0305]

[0306] a) Starting material 159 (105.3 mg, 0.34 mmol), K2CO3 (140 mg, 1 mmol), and starting material 160a (95 mg, 0.30 mmol) were dissolved in DMF (1 mL) and reacted overnight at 60 °C with stirring. After the reaction was complete, the reaction mixture was cooled, diluted with H2O, extracted with ethyl acetate (10 mL × 3), the organic phases were combined, washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered to remove salt, concentrated under reduced pressure, and purified by column chromatography to obtain intermediate 161a (12 mg, 8%). MS (ESI, m / z): 230 (M + +1). By simply changing the corresponding raw materials and following the same preparation method, intermediates 161b and 163 can be obtained.

[0307] b) Referring to the synthesis method of intermediate 13, intermediates 162a-162b and 164 can be obtained simply by changing the corresponding raw materials.

[0308] Example 28: Synthesis of compounds 168, 170, 172, 174, 176, 178, 180, 182, 184, 186, 188, 190, 192, and 194

[0309]

[0310] a) Referring to the synthesis step a of intermediate 162, intermediates 167, 169, 171, 173, 175, 177, 179, 181, 183, 185, 187, 189, 191, and 193 can be obtained by simply changing the corresponding raw materials.

[0311] b) Referring to the synthesis method of intermediate 13, intermediates 168, 170, 172, 174, 176, 178, 180, 182, 184, 186, 188, 190, 192, and 194 can be obtained by simply changing the corresponding raw materials.

[0312] Example 29 Synthesis of Compound 197

[0313]

[0314] a) Referring to the synthesis step a of intermediate 53, intermediate 196 can be obtained simply by changing the corresponding raw materials.

[0315] b) Referring to the synthesis method of intermediate 13, intermediate 197 can be obtained simply by changing the corresponding raw materials.

[0316] Example 30 Synthesis of Compound 200

[0317]

[0318] a) Following the synthesis step a of intermediate 53, intermediate 199 can be obtained simply by changing the corresponding raw materials.

[0319] b) Following the synthesis method of intermediate 13, intermediate 200 can be obtained simply by changing the corresponding raw materials.

[0320] Example 31 Synthesis of compounds 203, 206, and 209

[0321]

[0322] a) Referring to the synthesis step a of intermediate 16, intermediates 201a-201b, 204a-204b, and 205a-205b can be obtained by simply changing the corresponding raw materials.

[0323] b) Referring to the synthesis step b of intermediate 16, intermediates 202a-202b, 205a-205b, and 207a-207b can be obtained by simply changing the corresponding raw materials.

[0324] c) Referring to the synthesis method of intermediate 13, intermediates 203a-203b, 206a-206b, and 209a-209b can be obtained by simply changing the corresponding raw materials.

[0325] Example 32 Synthesis of Compound 210

[0326]

[0327] By referring to the synthesis method of intermediate 13, intermediate 210 can be obtained simply by changing the corresponding raw materials.

[0328] Example 33 Synthesis of compound S1

[0329]

[0330] Intermediate 14a (100 mg, 0.24 mmol), compound 7 (105.1 mg, 0.24 mmol), EDCI (69 mg, 0.36 mmol), and HOBt (48.6 mg, 0.36 mmol) were dissolved in DMF (2 mL). NMM (139 μL, 1.2 mmol) was added to the reaction mixture, and the mixture was stirred overnight at 25 °C. After the reaction was complete, the reaction solution was diluted with water (15 mL), and the filter cake was collected to obtain compound S1 (88 mg, 50%). ¹H NMR (500 MHz, DMSO-d6) δ 11.10 (s, 1H), 10.07 (s, 1H), 9.81 (s, 1H), 8.21 (s, 1H), 8.02 (d, J=7.6Hz, 1H), 7.96 (dd, J=7.4, 2.1Hz, 1H), 7.65 (dd, J=7 .4, 1.9Hz, 1H), 7.44 (dd, J=6.1, 2.0Hz, 2H), 7.38 (t, J=7.4Hz, 1H), 7.34-7.26 (m, 2H), 7.25-7.18 (m, 1H), 7.17-7.10 (m, 2 H), 6.95 (s, 1H), 6.75 (s, 1H), 5.13 (d, J = 2.8Hz, 2H), 4.56 (t, J = 5.5Hz, 1H), 4.27 (d, J = 5.4Hz, 2H), 3.75 (d, J = 12.5Hz, 1H) ), 3.64-3.57(m, 3H), 2.66(s, 1H), 2.54(s, 1H), 2.49(s, 1H), 1.99(s, 1H), 1.78(s, 3H), 1.73(s, 3H).MS (ESI, m / z): 733(M + +1).

[0331] Example 34 Synthesis of compound S2

[0332]

[0333] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S2. 1H NMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.07 (s, 1H), 9.81 (s, 1H), 8.07-7.99 (m, 2H), 7.90 (dd, J=7.3, 2.2Hz, 1H), 7.65 (dd, J=7.4, 1.9Hz, 1H), 7.47-7.41 (m , 2H), 7.39 (t, J=7.4Hz, 1H), 7.34-7.26 (m, 2H), 7.25-7.18 (m, 1H), 7.17-7.10 (m, 2H), 6.76 (s, 1H), 6.70 (s, 1H), 5.13 (d, J=2.8Hz, 2H ), 4.56 (t, J=5.5Hz, 1H), 4.28 (dd, J=12.4, 5.5Hz, 1H), 4.20 (dd, J=12.4, 5.5Hz, 1H), 3.39 (d, J=2.7Hz, 2H), 3.32 (d, J=12.4Hz, 1H), 3 .26 (d, J=12.5Hz, 1H), 2.66 (s, 1H), 2.54 (s, 1H), 2.49 (s, 1H), 1.97 (d, J=19.2Hz, 3H), 1.78 (s, 3H), 1.73 (s, 3H). MS (ESI, m / z): 747 (M + +1).

[0334] Example 35 Synthesis of compound S3

[0335]

[0336] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S3. 1H NMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.07 (s, 1H), 9.81 (s, 1H), 8.04-7.93 (m, 3H), 7.65 (dd, J=7.4, 1.9Hz, 1H), 7.47-7.35 (m, 3H), 7.34- 7.26 (m, 2H), 7.26-7.18 (m, 3H), 7.03 (s, 1H), 6.88 (s, 1H), 5.20-5.15 (m, 1H), 5.12 (s, 1H), 4.56 (t, J=5.5Hz, 1H), 4 .30 (dd, J=12.4, 5.4Hz, 1H), 4.20 (dd, J=12.4, 5.5Hz, 1H), 3.56 (s, 2H), 3.19 (s, 2H), 2.66 (s, 1H), 2.54 (s, 1H), 2.2 4 (d, J=0.9Hz, 2H), 1.78 (s, 3H), 1.73 (s, 3H), 1.65 (d, J=4.7Hz, 4H), 1.34 (s, 2H), 1.28 (s, 2H). MS (ESI, m / z): 789 (M + +1).

[0337] Example 36 Synthesis of compound S4

[0338]

[0339] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S4. 1H NMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.07 (s, 1H), 9.81 (s, 1H), 8.07-7.99 (m, 3H), 7.65 (dd, J=7.4, 1.9Hz, 1H), 7.49 (d, J=1.9Hz, 1H), 7.47-7.40 ( m, 2H), 7.34-7.26 (m, 2H), 7.25-7.18 (m, 1H), 7.17-7.10 (m, 2H), 6.70 (s, 1H), 6.55 (s, 1H), 5.13 (d, J=1.3Hz, 1H), 5.01 (s, 1H) ), 4.56 (t, J=5.5Hz, 1H), 4.28 (dd, J=12.4, 5.5Hz, 1H), 4.20 (dd, J=12.4, 5.5Hz, 1H), 3.46 (s, 2H), 3.32 (d, J=12.5Hz, 1H), 3. 24 (d, J=12.3Hz, 1H), 2.62 (d, J=11.5Hz, 2H), 2.24 (d, J=0.9Hz, 2H), 1.79 (d, J=10.1Hz, 5H), 1.73 (s, 3H). MS (ESI, m / z): 747 (M + +1).

[0340] Example 37 Synthesis of compound S5

[0341]

[0342] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S5. 1H NMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.07 (s, 1H), 9.81 (s, 1H), 8.18 (s, 1H), 8.02 (d, J=7.5Hz, 1H), 7.96 (dd, J=7.4, 2.1Hz, 1H), 7.65 (dd, J=7.4, 1.9Hz, 1H), 7.44 ( dd, J=6.1, 2.0Hz, 2H), 7.39 (t, J=7.5Hz, 1H), 7.34-7.26 (m, 2H), 7.25-7.18 (m, 1H), 7.17-7.10 (m, 2H), 6.88 (s, 1H), 6.70 (s, 1H), 5.15-5.10 ( m, 2H), 4.56 (t, J=5.5Hz, 1H), 4.28 (dd, J=12.4, 5.5Hz, 1H), 4.20 (dd, J=12.4, 5.5Hz, 1H), 3.49 (d, J=1.8Hz, 2H), 3.19 (d, J=1.2Hz, 2H), 2.66 ( s, 1H), 2.54 (s, 1H), 2.24 (d, J=0.9Hz, 2H), 1.78 (s, 3H), 1.73 (s, 3H), 1.66-1.54 (m, 4H), 1.34 (s, 2H), 1.32-1.24 (m, 6H). MS (ESI, m / z): 817 (M + +1).

[0343] Example 38 Synthesis of compound S6

[0344]

[0345] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S6. 1H NMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 9.10 (s, 1H), 8.34 (s, 1H), 8.02 (d, J=7.5Hz, 1H), 7.99-7.94 (m, 2H), 7.68-7.62 (m, 2H), 7.47-7.41 (m, 2H), 7. 34-7.27 (m, 3H), 7.26-7.18 (m, 3H), 7.03 (s, 1H), 6.12 (s, 1H), 5.20-5.15 (m, 1H), 5.12 (s, 1H), 4.56 (t, J=5.5Hz, 1H), 4.52- 4.43 (m, 2H), 4.30 (dd, J=12.4, 5.4Hz, 1H), 4.20 (dd, J=12.4, 5.5Hz, 1H), 3.36 (d, J=12.5Hz, 1H), 3.28 (d, J=12.5Hz, 1H), 3. 09-2.98 (m, 2H), 2.66 (s, 1H), 2.54 (s, 1H), 2.25 (d, J=11.2Hz, 2H), 1.78 (s, 3H), 1.72 (d, J=17.0Hz, 5H). MS (ESI, m / z): 804 (M + +1).

[0346] Example 39 Synthesis of compound S7

[0347]

[0348] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S7. 1 H NMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), 9.10 (s, 1H), 8.22 (s, 1H), 8.02 (d, J = 7.5Hz, 1H), 7.91 (d, J = 7.3Hz, 1H), 7.72 (s, 1H), 7.65 (dd, J=7.4, 1.9Hz, 1H), 7.52-7.41 (m, 4H), 7.34-7.26 (m, 2H), 7.26-7.18 (m, 3H), 6.55 (s, 1 H), 5.19-5.15 (m, 1H), 5.01 (s, 1H), 4.56 (t, J=5.5Hz, 1H), 4.33-4.25 (m, 2H), 3.45-3.36 (m, 4H), 3.36-3 .25 (m, 2H), 2.62 (d, J=11.4Hz, 4H), 2.24 (d, J=0.9Hz, 2H), 1.78 (s, 3H), 1.73 (s, 3H).MS (ESI, m / z): 804 (M + +1).

[0349] Example 40 Synthesis of compound S8

[0350]

[0351] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S8. 1 H NMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), 9.10 (s, 1H), 8.14 (s, 1H), 8.04-7.95 (m, 2H), 7.65 (dd, J=7.4, 1.9Hz, 1H), 7.48-7.41 (m, 2H), 7.34-7.26 (m, 2H), 7.26-7.18 (m, 4H), 7.07 (dd, J=7.5, 2.0Hz, 1H), 5.15-5 .10 (m, 2H), 4.56 (t, J = 5.5Hz, 1H), 4.42-4.31 (m, 2H), 4.22 (d, J = 2.0Hz, 2H), 3.68-3.58 (m, 2H), 2 .66 (s, 1H), 2.54 (s, 1H), 2.49 (s, 1H), 1.99 (s, 1H), 1.78 (s, 3H), 1.73 (s, 3H). MS (ESI, m / z): 734 (M + +1).

[0352] Example 41 Synthesis of compound S9

[0353]

[0354] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S9. 1H NMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), 8.97 (s, 1H), 8.04-7.94 (m, 3H), 7.78 (s, 1H), 7.65 (dd, J=7.4, 1.9Hz, 1H), 7.45 (d, J=2 .0Hz, 1H), 7.34-7.26 (m, 2H), 7.26-7.16 (m, 4H), 7.12 (dd, J=7.5, 2.0Hz, 1H), 7.03 (s, 1H), 5.20-5.15 (m, 1H), 5.1 2 (s, 1H), 4.59-4.52 (m, 3H), 4.30 (dd, J=12.4, 5.4Hz, 1H), 4.20 (dd, J=12.4, 5.5Hz, 1H), 3.39-3.29 (m, 2H), 3.13 ( s, 2H), 2.66 (s, 1H), 2.54 (s, 1H), 2.25 (d, J=11.2Hz, 2H), 1.78 (s, 3H), 1.72 (d, J=17.0Hz, 5H). MS (ESI, m / z): 805 (M + +1).

[0355] Example 42 Synthesis of compound S10

[0356]

[0357] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S10. 1 H NMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), 9.10 (s, 1H), 8.02 (d, J=7.5Hz, 1H), 7.96 (s, 1H), 7.82 (d, J=7.4Hz, 1H), 7.68-7 .62 (m, 2H), 7.47-7.41 (m, 2H), 7.34-7.26 (m, 2H), 7.26-7.18 (m, 4H), 5.18 (t, J=1.1Hz, 1H), 5.01 (s, 1H), 4 .56 (t, J=5.5Hz, 1H), 4.30 (dd, J=12.4, 5.4Hz, 1H), 4.20 (dd, J=12.4, 5.5Hz, 1H), 3.45-3.39 (m, 6H), 2.62 ( d, J=11.5Hz, 2H), 2.23 (d, J=3.8Hz, 2H), 1.80-1.71 (m, 7H), 1.63 (s, 2H), 1.59 (s, 2H). MS (ESI, m / z): 787 (M + +1).

[0358] Example 43 Synthesis of compound S11

[0359]

[0360] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S11. 1 H NMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), 9.12 (s, 1H), 8.26 (s, 1H), 8.02 (d, J = 7.5Hz, 1H), 7.86 (d, J = 7.5Hz, 1H), 7.65 (dd, J = 7.1, 1.9Hz, 2H), 7.45 (d, J=2.1Hz, 1H), 7.38 (dd, J=7.5, 2.0Hz, 1H), 7.34-7.26 (m, 2H), 7.26-7.18 (m, 3H), 7.03 (s, 1H), 5.19-5.15 (m, 1H), 5.01 (s, 1H), 4.5 6 (t, J=5.5Hz, 1H), 4.30 (dd, J=12.4, 5.4Hz, 1H), 4.20 (dd, J=12.4, 5.5Hz, 1H), 3.35 (s, 2H), 3.31 (s, 2H), 3.19 (s, 2H), 2.62 (d, J=11.5 Hz, 2H), 2.23 (d, J=3.8Hz, 2H), 1.94 (s, 1H), 1.86 (d, J=12.5Hz, 1H), 1.78 (s, 3H), 1.75-1.65 (m, 6H), 1.62 (s, 2H). MS (ESI, m / z): 801 (M + +1).

[0361] Example 44 Synthesis of compound S12

[0362]

[0363] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S12. 1H NMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), 9.12 (s, 1H), 8.07-7.99 (m, 2H), 7.86 (d, J=7.5Hz, 1H), 7.68-7.62 (m, 2H), 7.47-7.38 (m, 2H) , 7.34-7.26 (m, 2H), 7.26-7.18 (m, 3H), 7.03 (s, 1H), 5.19-5.15 (m, 1H), 5.01 (s, 1H), 4.56 (t, J=5.5Hz, 1H), 4.30 (dd, J= 12.4, 5.4Hz, 1H), 4.20 (dd, J=12.4, 5.5Hz, 1H), 3.34 (s, 2H), 3.22 (d, J=19.4Hz, 4H), 2.62 (d, J=11.5Hz, 2H), 2.23 (d, J= 3.8Hz, 2H), 2.06 (s, 1H), 1.78 (s, 3H), 1.72 (d, J=16.3Hz, 5H), 1.66 (d, J=12.3Hz, 4H), 1.42 (s, 2H). MS (ESI, m / z): 815 (M + +1).

[0364] Example 45 Synthesis of compound S13

[0365]

[0366] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S13. 1 H NMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), 9.12 (s, 1H), 8.08 (s, 1H), 8.02 (d, J=7.5Hz, 1H), 7.71-7.61 (m, 3H), 7.4 5(d, J=2.0Hz, 1H), 7.34-7.26(m, 2H), 7.26-7.18(m, 4H), 5.19-5.15(m, 1H), 5.01(s, 1H), 4.56(t, J =5.5Hz, 1H), 4.30 (dd, J = 12.4, 5.4Hz, 1H), 4.20 (dd, J = 12.4, 5.5Hz, 1H), 3.42 (s, 2H), 3.36 (s, 2H), 3.22 (s, 2H), 2.61 (d, J=6.4Hz, 2H), 2.23 (d, J=3.8Hz, 2H), 1.80-1.66 (m, 11H). MS (ESI, m / z): 805 (M + +1).

[0367] Example 46 Synthesis of compound S14

[0368]

[0369] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S14. 1 H NMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), 8.99 (s, 1H), 8.16 (s, 1H), 8.02 (d, J = 7.5Hz, 1H), 7.86 (d, J = 7.5Hz, 1H), 7.65 (dd, J = 7.1, 1.9 Hz, 2H), 7.45 (d, J=2.0Hz, 1H), 7.38 (dd, J=7.5, 2.0Hz, 1H), 7.34-7.26 (m, 2H), 7.26-7.18 (m, 4H), 5.18 (t, J=1.1Hz, 1H) , 5.01 (s, 1H), 4.56 (t, J=5.5Hz, 1H), 4.30 (dd, J=12.4, 5.4Hz, 1H), 4.20 (dd, J=12.4, 5.5Hz, 1H), 3.53-3.42 (m, 2H), 3.2 1 (d, J=6.6Hz, 4H), 2.65-2.57 (m, 4H), 2.54 (s, 4H), 2.23 (d, J=3.8Hz, 2H), 1.78 (s, 3H), 1.73 (s, 3H). MS (ESI, m / z): 805 (M + +1).

[0370] Example 47 Synthesis of compound S15

[0371]

[0372] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S15. 1H NMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), 9.12 (s, 1H), 8.26 (s, 1H), 8.02 (d, J=7.5Hz, 1H), 7.93 (dd, J=7.5, 2.0Hz, 1H), 7.65 (dd, J=7.4, 1.9 Hz, 1H), 7.48-7.41 (m, 2H), 7.38 (dd, J=7.5, 2.0Hz, 1H), 7.34-7.26 (m, 2H), 7.26-7.18 (m, 3H), 7.03 (s, 1H), 5.18 (t, J=1.1Hz, 1 H), 5.11 (s, 1H), 4.56 (t, J=5.5Hz, 1H), 4.30 (dd, J=12.4, 5.4Hz, 1H), 4.20 (dd, J=12.5, 5.5Hz, 1H), 3.38-3.31 (m, 3H), 3.25 (d, J=15.5Hz, 3H), 2.66 (s, 1H), 2.54 (s, 1H), 2.49 (s, 1H), 1.99 (s, 1H), 1.84-1.71 (m, 8H), 1.66-1.58 (m, 5H). MS (ESI, m / z): 801 (M + +1).

[0373] Example 48 Synthesis of compound S16

[0374]

[0375] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S16. 1 H NMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), 9.10 (s, 1H), 8.02 (d, J=7.5Hz, 1H), 7.83 (d, J=7.5Hz, 1H), 7.72-7.62 (m, 2H), 7 .60(d, J=2.0Hz, 1H), 7.47-7.41(m, 3H), 7.34-7.26(m, 2H), 7.26-7.18(m, 3H), 5.19-5.15(m, 1H), 5.01(s, 1 H), 4.56 (t, J=5.5Hz, 1H), 4.37 (d, J=12.3Hz, 1H), 4.30 (dd, J=12.4, 5.4Hz, 1H), 4.25-4.16 (m, 2H), 3.17 (s , 2H), 3.11 (s, 2H), 2.68-2.59 (m, 6H), 2.23 (d, J=3.8Hz, 2H), 1.78 (s, 3H), 1.73 (s, 3H). MS (ESI, m / z): 788 (M+ +1).

[0376] Example 49 Synthesis of compound S17

[0377]

[0378] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S17. 1 H NMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), 8.99 (s, 1H), 8.16 (s, 1H), 8.02 (d, J = 7.5Hz, 1H), 7.86 (d, J = 7.5Hz, 1H), 7.65 (dd, J = 7.1, 1.9 Hz, 2H), 7.45 (d, J=2.0Hz, 1H), 7.38 (dd, J=7.5, 2.0Hz, 1H), 7.34-7.26 (m, 2H), 7.26-7.18 (m, 4H), 5.18 (t, J=1.1Hz, 1H) , 4.90 (s, 1H), 4.56 (t, J=5.5Hz, 1H), 4.30 (dd, J=12.4, 5.4Hz, 1H), 4.20 (dd, J=12.4, 5.5Hz, 1H), 3.53-3.42 (m, 2H), 3.2 1 (d, J=6.6Hz, 4H), 2.65-2.57 (m, 4H), 2.54 (s, 4H), 2.23 (d, J=3.8Hz, 2H), 1.78 (s, 3H), 1.73 (s, 3H). MS (ESI, m / z): 802 (M + +1).

[0379] Example 50 Synthesis of compound S18

[0380]

[0381] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S18. 1H NMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), 8.99 (s, 1H), 8.16 (s, 1H), 8.02 (d, J = 7.5Hz, 1H), 7.86 (d, J = 7.5Hz, 1H), 7.65 (dd, J = 7.1, 1. 9Hz, 2H), 7.45 (d, J=2.0Hz, 1H), 7.38 (dd, J=7.5, 2.0Hz, 1H), 7.34-7.26 (m, 2H), 7.26-7.18 (m, 4H), 5.19-5.15 (m, 1H), 4 .90 (s, 1H), 4.56 (t, J=5.5Hz, 1H), 4.30 (dd, J=12.4, 5.4Hz, 1H), 4.20 (dd, J=12.4, 5.5Hz, 1H), 3.53-3.42 (m, 2H), 3.21 (d, J=6.6Hz, 4H), 2.65-2.57 (m, 4H), 2.54 (s, 4H), 2.23 (d, J=3.8Hz, 2H), 1.78 (s, 3H), 1.73 (s, 3H). MS (ESI, m / z): 802 (M + +1).

[0382] Example 51 Synthesis of compound S19

[0383]

[0384] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S19. 1H NMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), 9.10 (s, 1H), 8.26 (s, 1H), 8.02 (d, J = 7.5Hz, 1H), 7.82 (d, J = 7.4Hz, 1H), 7.65 (dd, J = 7.4, 1.9Hz, 1H), 7.60 (d, J=2.0Hz, 1H), 7.47-7.41 (m, 2H), 7.34-7.26 (m, 2H), 7.26-7.18 (m, 3H), 7.03 (s, 1H), 5.19-5.15 (m, 1H), 5.01 (s , 1H), 4.56 (t, J=5.5Hz, 1H), 4.30 (dd, J=12.4, 5.4Hz, 1H), 4.20 (dd, J=12.4, 5.5Hz, 1H), 3.50 (d, J=18.3Hz, 4H), 3.39 (s, 2H) , 2.62 (d, J=11.5Hz, 2H), 2.23 (d, J=3.8Hz, 2H), 2.03 (s, 1H), 1.93 (d, J=12.5Hz, 1H), 1.80-1.71 (m, 7H). MS (ESI, m / z): 773 (M + +1).

[0385] Example 52 Synthesis of compound S20

[0386]

[0387] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S20. 1H NMR (500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), 9.10 (s, 1H), 8.03 (dd, J=11.2, 7.5Hz, 2H), 7.96 (s, 1H), 7.65 (dd, J=7.1, 1.9Hz, 2H), 7.45 (d, J=2.1Hz, 1H), 7.36-7. 26(m, 3H), 7.26-7.18(m, 3H), 7.03(s, 1H), 5.19-5.15(m, 1H), 5.01(s, 1 H), 4.56 (t, J=5.5Hz, 1H), 4.30 (dd, J=12.4, 5.4Hz, 1H), 4.20 (dd, J=12. 4, 5.5Hz, 1H), 3.78 (d, J = 9.5Hz, 1H), 3.66 (d, J = 12.4Hz, 1H), 3.56 (d, J = 9.5Hz, 1H), 3.44 (d, J = 9.5Hz, 1H), 3.38 (d, J = 9.5Hz, 1H), 3.16 (d, J = 12. 4Hz, 1H), 2.62 (d, J=11.5Hz, 2H), 2.52 (s, 1H), 2.23 (d, J=3.8Hz, 2H), 1.78 (s, 3H), 1.73 (s, 3H), 1.68 (s, 1H), 1.63 (s, 1H). MS (ESI, rm / z): 773 (M + +1).

[0388] Example 53 Synthesis of compound S21

[0389]

[0390] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S21. 1H NMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), 9.12 (s, 1H), 8.33 (s, 1H), 8.02 (d, J = 7.5Hz, 1H), 7.83 (d, J = 7.5Hz, 1H), 7.62 (dd, J = 7.5, 2.0Hz, 1H), 7.47 (dd, J=18.4, 2.0Hz, 2H), 7.39 (dd, J=7.5, 1.8Hz, 1H), 7.37-7.29 (m, 2H), 7.29-7.17 (m, 3H), 7.03 (s, 1H), 5.18 (d, J=1.3Hz, 1H), 5.01 (s, 1H), 4.56 (t, J=5.5Hz, 1H), 4.30 (dd, J=12.4, 5.4Hz, 1H), 4.20 (dd, J=12.5, 5.5Hz, 1H), 3.72 (s, 4H), 3.34 (s, 2H), 2.77 (s, 4H), 2.65-2.55 (m, 4H), 2.23 (d, J=3.8Hz, 2H), 1.78 (d, J=4.2Hz, 5H), 1.73 (s, 3H). MS (ESI, m / z): 828 (M + +1).

[0391] Example 54 Synthesis of compound S22

[0392]

[0393] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S22. 1 H NMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), 9.12 (s, 1H), 8.02 (d, J=7.5Hz, 1H), 7.96 (s, 1H), 7.86 (d, J=7.5Hz, 1H), 7.65 (d d, J=7.1, 1.9Hz, 2H), 7.47-7.41 (m, 2H), 7.39 (dd, J=7.5, 2.0Hz, 1H), 7.34-7.26 (m, 2H), 7.26-7.18 (m, 3H) , 5.19-5.15 (m, 1H), 5.01 (s, 1H), 4.56 (t, J=5.5Hz, 1H), 4.36-4.26 (m, 2H), 4.25-4.16 (m, 2H), 3.71 (s, 4H) , 2.84 (s, 4H), 2.62 (d, J = 11.5Hz, 2H), 2.23 (d, J = 3.8Hz, 2H), 1.78 (s, 3H), 1.73 (s, 3H). MS (ESI, m / z): 800 (M ++1).

[0394] Example 55 Synthesis of compound S23

[0395]

[0396] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S23. 1 H NMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), 9.12 (s, 1H), 8.18 (s, 1H), 8.02 (d, J=7.4Hz, 1H), 7.83 (d, J=7.5Hz, 1H), 7.62 (dd, J=7.5, 2.0Hz, 1H), 7.47 (dd, J=1 8.4, 2.0Hz, 2H), 7.42-7.31 (m, 3H), 7.26-7.18 (m, 3H), 6.70 (s, 1H), 5.13 (q, J=0.8Hz, 1H), 5.01 (s, 1H), 4.56 (t, J=5.5Hz, 1H), 4.28 (dd, J=12. 4, 5.5Hz, 1H), 4.20 (dd, J=12.4, 5.5Hz, 1H), 3.72 (d, J=0.7Hz, 2H), 3.52-3.42 (m, 2H), 3.39-3.28 (m, 2H), 2.72-2.66 (m, 2H), 2.66-2.59 (m, 4H) , 2.59-2.53 (m, 1H), 2.50 (d, J=12.3Hz, 1H), 2.23 (d, J=3.8Hz, 2H), 1.90 (d, J=2.9Hz, 3H), 1.83-1.76 (m, 6H), 1.73 (s, 3H). MS (ESI, m / z): 856 (M + +1).

[0397] Example 56 Synthesis of compound S24

[0398]

[0399] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S24. 1H NMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), 9.12 (s, 1H), 8.25 (s, 1H), 8.15 (d, J = 7.5Hz, 1H), 7.83 (d, J = 7.5Hz, 1H), 7.65-7.58 (m, 2H), 7 .47-7.38(m, 2H), 7.37-7.29(m, 2H), 7.29-7.17(m, 3H), 7.03(s, 1H), 5.19-5.15(m, 1H), 5.01(s, 1H), 4.56(t, J=5.5Hz, 1 H), 4.30 (dd, J=12.4, 5.4Hz, 1H), 4.20 (dd, J=12.5, 5.5Hz, 1H), 3.56 (s, 2H), 3.47 (s, 2H), 3.37-3.27 (m, 2H), 2.65-2.56 (m, 7H), 2.52 (d, J=12.5Hz, 1H), 2.23 (d, J=3.8Hz, 2H), 2.05 (s, 4H), 1.97 (s, 4H), 1.80-1.71 (m, 8H). MS (ESI, m / z): 856 (M + +1).

[0400] Example 57 Synthesis of compound S25

[0401]

[0402] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S25. 1H NMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), 9.12 (s, 1H), 8.12 (s, 1H), 8.02 (d, J = 7.5Hz, 1H), 7.86 (d, J = 7.5Hz, 1H), 7.65 (dd, J = 7.4, 1.9Hz, 1H), 7.60 (d, J=2.0Hz, 1H), 7.47-7.38 (m, 2H), 7.34-7.26 (m, 2H), 7.26-7.18 (m, 3H), 7.03 (s, 1H), 5.18 (t, J=1.1Hz, 1H), 5.01 (s, 1H), 4.56 (t, J=5.5Hz, 1H), 4.30 (dd, J=12.4, 5.4Hz, 1H), 4.20 (dd, J=12.4, 5.5Hz, 1H), 3.73 (s, 4H), 3.30 (s, 2H), 2.62 (d, J=11.5Hz, 2 H), 2.23 (d, J=3.8Hz, 2H), 1.97 (s, 1H), 1.88 (d, J=12.5Hz, 1H), 1.78 (s, 3H), 1.76-1.69 (m, 4H), 1.54 (s, 4H). MS (ESI, m / z): 813 (M + +1).

[0403] Example 58 Synthesis of compound S26

[0404]

[0405] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S26. 1H NMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), 9.12 (s, 1H), 8.16 (s, 1H), 8.02 (d, J = 7.4Hz, 1H), 7.78 (d, J = 7.5Hz, 1H), 7.62 (dd, J = 7.5, 2.0Hz, 1H), 7.49 (d, J=2.0Hz, 1H), 7.46-7.38 (m, 2H), 7.38-7.31 (m, 2H), 7.26-7.18 (m, 3H), 6.95 (s, 1H), 5.14 (d, J=1.1Hz, 1H), 5.01 (s, 1H), 4.56 (t, J=5.5Hz, 1H), 4.28 (dd, J=12.4, 5.5Hz, 1H), 4.20 (dd, J=12.4, 5.5Hz, 1H), 3.88 (s, 2H), 3.80 (s, 2H), 3.43 (d, J=12.3Hz, 1 H), 3.37 (d, J=12.5Hz, 1H), 2.68-2.59 (m, 8H), 2.23 (d, J=3.8Hz, 2H), 1.90 (s, 4H), 1.78 (s, 3H), 1.73 (s, 3H). MS (ESI, m / z): 842 (M + +1).

[0406] Example 59 Synthesis of compound S27

[0407]

[0408] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S27. 1H NMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), 9.12 (s, 1H), 8.18 (s, 1H), 8.02 (d, J = 7.4Hz, 1H), 7.78 (d, J = 7.5Hz, 1H), 7.65-7.57 (m, 2H ), 7.47-7.38(m, 2H), 7.37-7.29(m, 2H), 7.29-7.17(m, 3H), 7.03(s, 1H), 5.18(d, J=1.4Hz, 1H), 5.01(s, 1H), 4.56(t, J=5.5Hz, 1H), 4.30 (dd, J=12.4, 5.4Hz, 1H), 4.20 (dd, J=12.5, 5.5Hz, 1H), 3.56 (s, 2H), 3.46 (s, 2H), 3.33 (s, 2H), 3.0 2 (s, 2H), 2.96 (s, 2H), 2.65-2.55 (m, 4H), 2.23 (d, J=3.8Hz, 2H), 1.92 (s, 4H), 1.80-1.71 (m, 8H). MS (ESI, m / z): 856 (M + +1).

[0409] Example 60 Synthesis of compound S28

[0410]

[0411] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S28. 1 H NMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), 9.12 (s, 1H), 8.02 (d, J=7.5Hz, 1H), 7.96 (s, 1H), 7.78 (d, J=7.5Hz, 1H), 7.65- 7.57(m, 2H), 7.47-7.38(m, 3H), 7.37-7.29(m, 2H), 7.29-7.17(m, 3H), 5.19-5.15(m, 1H), 5.01(s, 1H), 4. 59-4.49 (m, 2H), 4.30 (dd, J=12.4, 5.4Hz, 1H), 4.26-4.16 (m, 2H), 3.59 (s, 2H), 3.46 (s, 2H), 2.81 (s, 4H), 2.62 (d, J=11.5Hz, 2H), 2.23 (d, J=3.8Hz, 2H), 1.94 (s, 4H), 1.78 (s, 3H), 1.73 (s, 3H). MS (ESI, m / z): 828 (M + +1).

[0412] Example 61 Synthesis of compound S29

[0413]

[0414] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S29. 1 H NMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), 9.12 (s, 1H), 8.12 (s, 1H), 8.02 (d, J = 7.5Hz, 1H), 7.83 (d, J = 7.5Hz, 1H), 7.62 (dd, J = 7.5, 2.0Hz, 1 H), 7.49 (d, J = 2.0Hz, 1H), 7.46-7.39 (m, 2H), 7.37-7.29 (m, 2H), 7.29-7.17 (m, 4H), 5.19-5.15 (m, 1H), 5.01 (s, 1H), 4.56 (t, J=5.5Hz, 1H), 4.30 (dd, J=12.4, 5.4Hz, 1H), 4.20 (dd, J=12.4, 5.5Hz, 1H), 3.69-3.59 (m, 4H), 3.49 (s, 2H), 2.76 (d, J=9.5Hz, 2H), 2.71-2.64 (m, 3H), 2.64-2.58 (m, 3H), 2.23 (d, J=3.8Hz, 2H), 2.11 (s, 2H), 1.78 (s, 3H), 1.73 (s, 3H). MS (ESI, m / z): 828 (M + +1).

[0415] Example 62 Synthesis of compound S30

[0416]

[0417] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S30. 1H NMR(500MHz, DMSO-d6)δ 11.10(s, 1H), 10.2(s, 1H), 9.12(s, 1H), 8.20-8.12(m, 2H), 7.78(d, J=7.5Hz, 1H), 7.65-7.57(m, 2H), 7.47-7.38(m , 2H), 7.37-7.29 (m, 2H), 7.29-7.17 (m, 3H), 7.03 (s, 1H), 5.17 (t, J=1.0Hz, 1H), 5.01 (s, 1H), 4.56 (t, J=5.5Hz, 1H), 4.30 (dd, J=12.4, 5.4Hz, 1H), 4.20 (dd, J=12.5, 5.5Hz, 1H), 3.42 (s, 1H), 3.39-3.27 (m, 5H), 2.84 (s, 1H), 2.66-2.5 8 (m, 6H), 2.50 (d, J=12.5Hz, 1H), 2.23 (d, J=3.8Hz, 2H), 1.98-1.91 (m, 4H), 1.80-1.69 (m, 10H). MS (ESI, m / z): 870 (M + +1).

[0418] Example 63 Synthesis of compound S31

[0419]

[0420] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S31. 1 H NMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), 9.08 (s, 1H), 8.25 (s, 1H), 8.02 (d, J = 7.4Hz, 1H), 7.83 (d, J = 7.5Hz, 1H), 7.65-7.58 ( m, 2H), 7.45 (d, J=2.0Hz, 1H), 7.41-7.29 (m, 3H), 7.29-7.17 (m, 4H), 5.19-5.15 (m, 1H), 5.01 (s, 1H), 4.56 (t, J=5 .5Hz, 1H), 4.30 (dd, J=12.4, 5.4Hz, 1H), 4.20 (dd, J=12.5, 5.5Hz, 1H), 3.68 (s, 2H), 3.50 (s, 2H), 3.38 (s, 2H), 3. 03 (s, 1H), 2.65-2.53 (m, 8H), 2.45 (s, 4H), 2.24 (d, J=0.9Hz, 2H), 1.78 (s, 3H), 1.73 (s, 3H). MS (ESI, m / z): 857 (M + +1).

[0421] Example 64 Synthesis of compound S32

[0422]

[0423] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S32. 1 H NMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), 9.12 (s, 1H), 8.02 (d, J=7.4Hz, 1H), 7.96 (s, 1H), 7.83 (d, J=7.5Hz, 1H), 7.65- 7.58 (m, 2H), 7.47-7.41 (m, 2H), 7.41-7.29 (m, 3H), 7.29-7.17 (m, 3H), 5.18 (d, J=1.3Hz, 1H), 5.01 (s, 1H), 4.56 (t, J=5.5Hz, 1H), 4.30 (dd, J=12.4, 5.4Hz, 1H), 4.24-4.16 (m, 3H), 3.68 (s, 2H), 3.40 (s, 2H), 3.16 (s, 1H), 2.65-2.57 (m, 6H), 2.48 (s, 4H), 2.24 (d, J=0.9Hz, 2H), 1.78 (s, 3H), 1.73 (s, 3H). MS (ESI, m / z): 843 (M + +1).

[0424] Example 65 Synthesis of compound S33

[0425]

[0426] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S33. 1H NMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), 9.12 (s, 1H), 8.40 (s, 1H), 8.02 (d, J = 7.4Hz, 1H), 7.86 (d, J = 7.5Hz, 1H), 7.65-7.57 (m, 2H), 7. 47-7.39 (m, 2H), 7.37-7.29 (m, 2H), 7.29-7.17 (m, 3H), 7.03 (s, 1H), 5.18 (d, J=1.4Hz, 1H), 5.01 (s, 1H), 4.56 (t, J=5.5Hz , 1H), 4.30 (dd, J=12.4, 5.4Hz, 1H), 4.20 (dd, J=12.4, 5.5Hz, 1H), 3.46 (d, J=4.0Hz, 4H), 3.40 (s, 2H), 2.95 (s, 1H), 2.66- 2.59 (m, 4H), 2.55 (s, 2H), 2.23 (d, J=3.8Hz, 2H), 2.07 (s, 1H), 1.90-1.83 (m, 3H), 1.80-1.71 (m, 9H). MS (ESI, m / z): 856 (M + +1).

[0427] Example 66 Synthesis of compound S34

[0428]

[0429] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S34. 1H NMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), 9.08 (s, 1H), 8.18-8.12 (m, 2H), 7.77 (d, J=7.5Hz, 1H), 7.62 (dd, J=7.5, 2.0Hz, 1H), 7.55 (d, J=2. 0Hz, 1H), 7.47-7.38 (m, 2H), 7.37-7.29 (m, 2H), 7.29-7.17 (m, 4H), 5.19-5.15 (m, 1H), 5.01 (s, 1H), 4.56 (t, J=5.5Hz, 1H), 4.3 0 (dd, J=12.4, 5.4Hz, 1H), 4.20 (dd, J=12.5, 5.5Hz, 1H), 3.85 (s, 2H), 3.62 (s, 2H), 3.50 (s, 2H), 2.67 (s, 1H), 2.65-2.56 (m, 4 H), 2.48 (d, J=7.0Hz, 8H), 2.23 (d, J=3.8Hz, 2H), 1.89 (d, J=13.0Hz, 2H), 1.84-1.76 (m, 5H), 1.73 (s, 3H). MS (ESI, m / z): 897 (M + +1).

[0430] Example 67 Synthesis of compound S35

[0431]

[0432] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S35. 1H NMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), 9.12 (s, 1H), 8.15 (d, J=7.5Hz, 1H), 7.96 (s, 1H), 7.77 (d, J=7.5Hz, 1H), 7.62 (dd, J=7.5, 2.0Hz , 1H), 7.55 (d, J=2.0Hz, 1H), 7.47-7.38 (m, 3H), 7.37-7.29 (m, 2H), 7.29-7.17 (m, 3H), 5.19-5.15 (m, 1H), 5.01 (s, 1H), 4.56 (t, J=5.5Hz, 1H), 4.30 (dd, J=12.4, 5.4Hz, 1H), 4.24-4.16 (m, 3H), 3.53 (d, J=9.3Hz, 2H), 3.47 (d, J=9.5Hz, 2H), 2.87 (s, 1H ), 2.65-2.52 (m, 8H), 2.45 (s, 2H), 2.23 (d, J=3.8Hz, 2H), 2.10 (s, 2H), 1.78 (s, 3H), 1.77-1.67 (m, 7H). MS (ESI, m / z): 897 (M + +1).

[0433] Example 68 Synthesis of compound S36

[0434]

[0435] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S36. 1H NMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), 9.12 (s, 1H), 8.02 (d, J=7.4Hz, 1H), 7.81-7.74 (m, 2H), 7.65-7.57 (m, 2H), 7.47-7.38 ( m, 2H), 7.37-7.29 (m, 2H), 7.29-7.17 (m, 4H), 5.19-5.15 (m, 1H), 5.01 (s, 1H), 4.56 (t, J=5.5Hz, 1H), 4.30 (dd, J=12 .4, 5.4Hz, 1H), 4.24-4.16 (m, 2H), 3.35 (s, 2H), 3.31 (s, 2H), 3.19 (s, 2H), 2.85 (s, 2H), 2.62 (d, J=11.5Hz, 2H), 2.5 2 (s, 2H), 2.23 (d, J=3.8Hz, 2H), 1.99 (s, 1H), 1.87 (d, J=9.5Hz, 4H), 1.78 (s, 3H), 1.73 (s, 3H). MS (ESI, m / z): 842 (M + +1).

[0436] Example 69 Synthesis of compound S37

[0437]

[0438] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S37. 1H NMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), 9.12 (s, 1H), 8.18-8.12 (m, 2H), 7.82 (d, J=7.4Hz, 1H), 7.66-7.59 (m, 2H), 7.47-7.38 (m, 2H), 7.37-7.29 (m, 2H), 7.29-7.17 (m, 3H), 7.03 (s, 1H), 5.19-5.15 (m, 1H), 5.01 (s, 1H), 4.56 (t, J=5.5Hz, 1H), 4.30 (dd, J=12. 4, 5.4Hz, 1H), 4.20 (dd, J=12.5, 5.5Hz, 1H), 3.39 (s, 2H), 3.27-3.18 (m, 6H), 3.15 (s, 2H), 2.62 (d, J=11.5Hz, 2H), 2.42 (s , 1H), 2.23 (d, J=3.8Hz, 2H), 2.08 (s, 2H), 1.95 (s, 1H), 1.80-1.65 (m, 12H), 1.58 (s, 2H), 1.45 (s, 2H). MS (ESI, m / z): 926 (M + +1).

[0439] Example 70 Synthesis of compound S38

[0440]

[0441] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S38. 1H NMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), 9.12 (s, 1H), 8.02 (d, J=7.4Hz, 1H), 7.86 (d, J=7.5Hz, 1H), 7.62 (dd, J=7.5, 2.0Hz, 1H), 7.49 (d, J=2.0H z, 1H), 7.46-7.39 (m, 2H), 7.39-7.29 (m, 3H), 7.29-7.17 (m, 4H), 5.18 (d, J=1.4Hz, 1H), 5.01 (s, 1H), 4.56 (t, J=5.5Hz, 1H), 4.30 (d d, J=12.4, 5.4Hz, 1H), 4.20 (dd, J=12.4, 5.5Hz, 1H), 3.83 (s, 1H), 3.68 (d, J=9.5Hz, 1H), 3.62 (d, J=9.5Hz, 1H), 3.42-3.31 (m, 2H), 2.66-2.52 (m, 8H), 2.47 (d, J=12.5Hz, 1H), 2.23 (d, J=3.8Hz, 2H), 1.89 (s, 2H), 1.85-1.76 (m, 7H), 1.73 (s, 3H). MS (ESI, m / z): 856 (M + +1).

[0442] Example 71 Synthesis of compound S39

[0443]

[0444] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S39. 1H NMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), 9.12 (s, 1H), 8.18-8.12 (m, 2H), 7.83 (d, J=7.4Hz, 1H), 7.62 (dd, J=7.5, 2.0Hz, 1H), 7.51-7.41 (m, 3H), 7.37-7.29(m, 2H), 7.29-7.17(m, 4H), 5.19-5.15(m, 1H), 5.01(s, 1H), 4.56(t, J=5.5Hz, 1H), 4.30(dd, J=12.4, 5.4Hz, 1H) , 4.20 (dd, J=12.4, 5.5Hz, 1H), 3.43 (d, J=12.3Hz, 1H), 3.37 (d, J=12.5Hz, 1H), 3.22 (s, 4H), 2.67 (d, J=0.9Hz, 5H), 2.65-2.56 (m, 8H), 2.23 (d, J=3.8Hz, 2H), 1.96 (d, J=13.0Hz, 2H), 1.85 (d, J=13.0Hz, 2H), 1.78 (s, 3H), 1.73 (s, 3H). MS (ESI, rm / z): 897 (M + +1).

[0445] Example 72 Synthesis of compound S40

[0446]

[0447] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S40. 1H NMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), 9.12 (s, 1H), 8.18-8.12 (m, 2H), 7.83 (d, J=7.5Hz, 1H), 7.62 (dd, J=7.5, 2.0Hz, 1H), 7 .47 (dd, J=18.4, 2.0Hz, 2H), 7.41-7.29 (m, 3H), 7.29-7.17 (m, 4H), 5.18 (d, J=1.4Hz, 1H), 5.01 (s, 1H), 4.56 (t, J= 5.5Hz, 1H), 4.30 (dd, J=12.4, 5.4Hz, 1H), 4.20 (dd, J=12.4, 5.5Hz, 1H), 3.68 (s, 2H), 3.49 (s, 2H), 3.40 (s, 2H), 3. 11 (s, 1H), 2.76-2.55 (m, 12H), 2.24 (d, J=0.9Hz, 2H), 2.10 (s, 2H), 1.78 (s, 3H), 1.73 (s, 3H). MS (ESI, m / z): 883 (M + +1).

[0448] Example 73 Synthesis of compound S41

[0449]

[0450] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S41. 1 H NMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), 9.12 (s, 1H), 8.15 (d, J=7.5Hz, 1H), 7.83 (d, J=7.4Hz, 1H), 7.72 (s, 1H), 7.62 (dd, J=7.5, 2. 0Hz, 1H), 7.51-7.41 (m, 3H), 7.37-7.29 (m, 2H), 7.29-7.17 (m, 4H), 5.19-5.15 (m, 1H), 5.01 (s, 1H), 4.56 (t, J=5.5Hz, 1H ), 4.30 (dd, J=12.4, 5.4Hz, 1H), 4.26-4.16 (m, 3H), 3.28 (s, 2H), 3.22 (s, 2H), 2.69 (d, J=7.3Hz, 4H), 2.65-2.59 (m, 4H) , 2.53 (s, 2H), 2.46 (s, 1H), 2.23 (d, J = 3.8Hz, 2H), 1.78 (s, 3H), 1.74 (d, J = 1.8Hz, 5H), 1.67 (s, 2H). MS (ESI, m / z): 871 (M+ +1).

[0451] Example 74 Synthesis of compound S42

[0452]

[0453] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S42. 1 H NMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), 9.12 (s, 1H), 8.15 (d, J=7.5Hz, 1H), 7.86 (d, J=7.5Hz, 1H), 7.70 (s, 1H), 7.65-7 .57(m, 2H), 7.47-7.39(m, 3H), 7.37-7.29(m, 2H), 7.29-7.17(m, 3H), 5.19-5.15(m, 1H), 5.01(s, 1H), 4.56( t, J=5.5Hz, 1H), 4.30 (dd, J=12.4, 5.4Hz, 1H), 4.24-4.16 (m, 3H), 3.46 (d, J=4.0Hz, 4H), 2.80 (s, 1H), 2.65 -2.53 (m, 10H), 2.23 (d, J=3.8Hz, 2H), 1.87 (s, 2H), 1.78 (d, J=4.6Hz, 5H), 1.73 (s, 3H). MS (ESI, m / z): 871 (M + +1).

[0454] Example 75 Synthesis of compound S43

[0455]

[0456] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S43. 1H NMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), 9.10 (s, 1H), 8.33 (s, 1H), 8.02 (d, J=7.5Hz, 1H), 7.65 (dd, J=7.4, 1.9Hz, 1H), 7.52-7.38(m, 3H), 7.34-7.26(m, 3H), 7.26-7.18(m, 4H), 5.20-5.15(m, 1H), 4.70(t, J=5.5Hz, 1H ), 4.54 (d, J = 1.1Hz, 1H), 4.48-4.40 (m, 3H), 4.30 (dd, J = 12.3, 5.5Hz, 1H), 4.20 (dd, J = 12.4, 5.5Hz, 1H) ), 4.01 (s, 1H), 2.60 (s, 2H), 2.13 (s, 1H), 2.02 (s, 1H), 1.78 (s, 3H), 1.73 (s, 3H). MS (ESI, m / z): 714 (M + +1).

[0457] Example 76 Synthesis of compound S44

[0458]

[0459] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S44. 1 H NMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), 9.10 (s, 1H), 8.47 (s, 1H), 8.10 (d, J = 2.0Hz, 1H), 8.02 (d, J = 7.5Hz, 1H), 7.65 ( dd, J=7.4, 1.9Hz, 1H), 7.47-7.39 (m, 2H), 7.34-7.26 (m, 2H), 7.26-7.14 (m, 5H), 5.18 (t, J=1.1Hz, 1H), 4.7 3-4.61 (m, 3H), 4.57 (dd, J=5.0, 1.0Hz, 2H), 4.30 (dd, J=12.3, 5.5Hz, 1H), 4.20 (dd, J=12.4, 5.5Hz, 1H), 4. 01 (s, 1H), 2.60 (d, J=2.6Hz, 2H), 2.19 (s, 1H), 2.12 (s, 1H), 1.78 (s, 3H), 1.73 (s, 3H). MS (ESI, m / z): 714 (M + +1).

[0460] Example 77 Synthesis of compound S45

[0461]

[0462] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S45. 1 H NMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), 9.10 (s, 1H), 8.55 (s, 1H), 8.02 (d, J = 7.5Hz, 1H), 7.91 (d, J = 7.5Hz, 1H), 7.68- 7.62 (m, 2H), 7.47-7.39 (m, 2H), 7.34-7.26 (m, 2H), 7.26-7.18 (m, 4H), 5.19-5.15 (m, 1H), 4.70 (t, J=5.5Hz , 1H), 4.58-4.51 (m, 2H), 4.49-4.40 (m, 2H), 4.30 (dd, J=12.3, 5.5Hz, 1H), 4.20 (dd, J=12.4, 5.5Hz, 1H), 4. 01 (s, 1H), 2.60 (d, J=2.6Hz, 2H), 2.19 (s, 1H), 2.12 (s, 1H), 1.78 (s, 3H), 1.73 (s, 3H). MS (ESI, m / z): 714 (M + +1).

[0463] Example 78 Synthesis of compound S46

[0464]

[0465] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S46. 1H NMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), 9.10 (s, 1H), 8.38 (s, 1H), 8.02 (d, J=7.5Hz, 1H), 7.82 (dd, J=7.3, 2.0Hz, 1H), 7.65 (d d, J=7.4, 1.9Hz, 1H), 7.52 (t, J=7.5Hz, 1H), 7.47-7.39 (m, 2H), 7.34-7.26 (m, 2H), 7.26-7.18 (m, 4H), 5.18 (t, J= 1.1Hz, 1H), 4.70 (t, J=5.5Hz, 1H), 4.55 (d, J=12.3Hz, 1H), 4.49-4.42 (m, 2H), 4.34-4.26 (m, 2H), 4.20 (dd, J=12. 4, 5.5Hz, 1H), 4.01 (s, 1H), 2.60 (s, 2H), 2.13 (s, 1H), 2.02 (s, 1H), 1.78 (s, 3H), 1.73 (s, 3H). MS (ESI, m / z): 714 (M + +1).

[0466] Example 79 Synthesis of compound S47

[0467]

[0468] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S47. 1 H NMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), 9.10 (s, 1H), 8.25 (s, 1H), 8.02 (d, J=7.5Hz, 1H), 7.82 (dd, J=7.2, 2.3 Hz, 1H), 7.65 (dd, J=7.4, 1.9Hz, 1H), 7.53-7.43 (m, 3H), 7.34-7.26 (m, 2H), 7.26-7.18 (m, 4H), 5. 18 (t, J=1.1Hz, 1H), 4.56 (t, J=5.5Hz, 1H), 4.39 (s, 1H), 4.33-4.24 (m, 3H), 4.01 (s, 1H), 3.65-3. 53 (m, 2H), 2.71 (s, 2H), 2.19 (s, 1H), 2.12 (s, 1H), 1.78 (s, 3H), 1.73 (s, 3H). MS (ESI, m / z): 728 (M + +1).

[0469] Example 80 Synthesis of compound S48

[0470]

[0471] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S48. 1 H NMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), 9.10 (s, 1H), 8.14 (s, 1H), 8.02 (d, J = 7.5Hz, 1H), 7.82 (dd, J = 7.3, 2.0Hz, 1H), 7.65 (dd, J = 7.4, 1.9Hz, 1H), 7.53 (t, J=7.4Hz, 1H), 7.50-7.43 (m, 2H), 7.34-7.26 (m, 2H), 7.26-7.18 (m, 3H), 7.03 (s, 1H), 5.19-5.15 (m, 1H) , 4.56 (t, J=5.5Hz, 1H), 4.46 (d, J=11.5Hz, 2H), 4.30 (dd, J=12.4, 5.4Hz, 1H), 4.20 (dd, J=12.4, 5.5Hz, 1H), 4.01 (s, 1H), 3 .35 (d, J=2.9Hz, 2H), 2.79 (s, 2H), 2.59 (d, J=7.5Hz, 2H), 2.19 (s, 1H), 2.12 (s, 1H), 1.80-1.71 (m, 8H). MS (ESI, m / z): 742 (M + +1).

[0472] Example 81 Synthesis of compound S49

[0473]

[0474] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S49. 1H NMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), 9.10 (s, 1H), 8.14 (s, 1H), 8.02 (d, J = 7.5Hz, 1H), 7.82 (dd, J = 7.1, 2.2Hz, 1H), 7.65 (dd, J = 7.4, 1.9Hz, 1H), 7.52-7.43(m, 3H), 7.34-7.26(m, 2H), 7.26-7.18(m, 3H), 7.03(s, 1H), 5.19-5.15(m, 1H), 4.56(t, J=5.5Hz, 1H ), 4.47 (s, 1H), 4.34-4.26 (m, 2H), 4.20 (dd, J=12.4, 5.5Hz, 1H), 4.01 (s, 1H), 3.18 (d, J=0.8Hz, 2H), 2.64-2.56 (m, 4H), 2. 19 (s, 1H), 2.12 (s, 1H), 1.78 (s, 3H), 1.73 (s, 3H), 1.69-1.59 (m, 2H), 1.48 (s, 2H), 1.39-1.29 (m, 2H). MS (ESI, m / z): 770 (M + +1).

[0475] Example 82 Synthesis of compound S50

[0476]

[0477] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S50. 1H NMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), 9.12 (s, 1H), 8.18 (s, 1H), 8.02 (d, J=7.5Hz, 1H), 7.81 (dd, J=7.1, 2.4Hz, 1H), 7.62 (dd, J=7.5, 2.0Hz, 1 H), 7.55-7.43(m, 3H), 7.39-7.31(m, 2H), 7.26-7.18(m, 3H), 6.70(s, 1H), 5.13(q, J=0.8Hz, 1H), 4.56(t, J=5.5Hz, 1H), 4.46(d, J= 11.5Hz, 2H), 4-28 (dd, J=12.4, 5.5Hz, 1H), 4.20 (dd, J=12.4, 5.5Hz, 1H), 4.01 (s, 1H), 3.32 (s, 2H), 3.02 (s, 1H), 2.67 (s, 2H), 2.62 -2.53 (m, 5H), 2.50 (d, J=12.5Hz, 1H), 2.19 (s, 1H), 2.12 (s, 1H), 1.90 (s, 2H), 1.83 (s, 2H), 1.80-1.71 (m, 8H). MS (ESI, m / z): 825 (M + +1).

[0478] Example 83 Synthesis of compound S51

[0479]

[0480] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S51. 1H NMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), 8.97 (s, 1H), 8.14 (s, 1H), 8.02 (d, J=7.5Hz, 1H), 7.82 (dd, J=7.0, 2.4Hz, 1H), 7.65 (dd , J=7.4, 1.9Hz, 1H), 7.54-7.43 (m, 3H), 7.34-7.26 (m, 2H), 7.26-7.18 (m, 4H), 5.18 (t, J=1.1Hz, 1H), 4.56 (t, J=5. 5Hz, 1H), 4.47 (s, 1H), 4.34-4.26 (m, 2H), 4.20 (dd, J=12.4, 5.5Hz, 1H), 4.01 (s, 1H), 3.50 (s, 2H), 3.08 (s, 1H), 2. 72 (d, J=10.8Hz, 2H), 2.69-2.56 (m, 6H), 2.19 (s, 1H), 2.12 (s, 1H), 1.78 (s, 3H), 1.73 (s, 3H). MS (ESI, m / z): 783 (M + +1).

[0481] Example 84 Synthesis of compound S52

[0482]

[0483] Under argon protection, starting materials 16a (327 mg, 0.64 mmol), 3-(5-iodo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (159 mg, 0.43 mmol), Pd(pph3)2Cl2 (30.1 mg, 0.043 mmol), and cuprous iodide (16.4 mg, 0.086 mmol) were dissolved in DMF (2 mL). Triethylamine (1.3 mL, 0.01 mmol) was added to the reaction system, and the reaction was stirred overnight at 80 °C. After the reaction was complete, the reaction solution was cooled to room temperature, and the filtrate was extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography to obtain compound S54 (168 mg, 35%). 1HNMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), 9.03 (s, 1H), 8.02 (d, J=7.5Hz, 1H), 7.89 (d, J=7.5Hz, 1H), 7.68-7.62 (m, 2H), 7.58 (dd, J=7.5, 2.0Hz, 1H), 7.45 (d, J=2.0Hz, 1H), 7.34-7.26 (m, 2H), 7.25-7.17 (m, 1H), 7.17-7.10 (m, 2H), 6.70 (s, 1H), 5.16-5.12 (m, 1H) , 4.59-4.52 (m, 2H), 4.42 (d, J=1.1Hz, 1H), 4.28 (dd, J=12.4, 5.5Hz, 1H), 4.20 (dd, J=12.4, 5.5Hz, 1H), 4.01 (s, 1H), 2.96- 2.88 (m, 3H), 2.83 (d, J=12.5Hz, 1H), 2.60 (s, 2H), 2.19 (s, 1H), 2.12 (s, 1H), 1.78 (s, 3H), 1.73 (s, 3H). MS (ESI, m / z): 753 (M + +1).

[0484] Example 85 Synthesis of compound S53

[0485]

[0486] The synthesis method is the same as that for compound S52; only the corresponding raw materials need to be changed to obtain compound S53. 1HNMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), 9.03 (s, 1H), 8.02 (d, J = 7.5Hz, 1H), 7.82 (dd, J = 7.3, 2.0Hz, 1H), 7.65 (dd, J = 7.4, 1.9Hz, 1H) , 7.51 (t, J=7.4Hz, 1H), 7.46 (dd, J=7.8, 2.1Hz, 2H), 7.34-7.26 (m, 2H), 7.25-7.18 (m, 1H), 7.17-7.10 (m, 2H), 6.70 (s, 1 H), 5.13 (d, J=1.3Hz, 1H), 4.56 (t, J=5.5Hz, 1H), 4.39 (s, 1H), 4.32-4.24 (m, 2H), 4.20 (dd, J=12.4, 5.5Hz, 1H), 4.01 (s, 1H), 2.79 (s, 2H), 2.62-2.56 (m, 4H), 2.19 (s, 1H), 2.12 (s, 1H), 1.79 (d, J=8.1Hz, 5H), 1.73 (s, 3H). MS (ESI, m / z): 767 (M + +1).

[0487] Example 86 Synthesis of compound S54

[0488]

[0489] The synthesis method is the same as that for compound S52; only the corresponding raw materials need to be changed to obtain compound S54. 1 HNMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), 9.03 (s, 1H), 8.02 (d, J=7.5Hz, 1H), 7.89 (d, J=2.0Hz, 1H), 7.65 (dd, J=7 .4, 1.9Hz, 1H), 7.49-7.43(m, 2H), 7.34-7.26(m, 2H), 7-25-7.10(m, 4H), 6.70(s, 1H), 5.16-5.12(m , 1H), 4.60-4.52 (m, 3H), 4.28 (dd, J=12.4, 5.5Hz, 1H), 4.20 (dd, J=12.4, 5.5Hz, 1H), 4.01 (s, 1H), 2 .76 (s, 2H), 2.60 (d, J=5.2Hz, 4H), 2.19 (s, 1H), 2.12 (s, 1H), 1.80-1.68 (m, 8H). MS (ESI, m / z): 767 (M + +1).

[0490] Example 87 Synthesis of compound S55

[0491]

[0492] The synthesis method is the same as that for compound S52; only the corresponding raw materials need to be changed to obtain compound S55. 1 HNMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), 9.03 (s, 1H), 8.02 (d, J=7.5Hz, 1H), 7.66 (ddd, J=12.6, 7.5, 2.0Hz, 2H), 7.45 (d, J=2.0Hz, 1H), 7. 39-7.32 (m, 1H), 7.32-7.26 (m, 2H), 7.25-7.18 (m, 1H), 7.17-7.10 (m, 2H), 7.08 (ddt, J=7.5, 2.0, 0.9Hz, 1H), 6.70 (s, 1H), 5. 13 (d, J=1.3Hz, 1H), 4.59-4.52 (m, 2H), 4.42 (d, J=1.1Hz, 1H), 4.28 (dd, J=12.4, 5.5Hz, 1H), 4.20 (dd, J=12.4, 5.5Hz, 1H), 4. 01 (s, 1H), 2.79 (s, 2H), 2.62-2.56 (m, 4H), 2.19 (s, 1H), 2.12 (s, 1H), 1.79 (d, J=8.1Hz, 5H), 1.73 (s, 3H). MS (ESI, m / z): 767 (M + +1).

[0493] Example 88 Synthesis of compound S56

[0494]

[0495] The starting material 203b (89.8 mg, 0.147 mmol) was dissolved in 1,4-dioxane (2 mL). N-Boc-ethylenediamine (30.6 mg, 0.176 mmol) and DIPEA (31.6 μL, 0.19 mmol) were added to the reaction system, and the mixture was stirred overnight at 90 °C. After the reaction was complete, the reaction solution was cooled to room temperature, concentrated under reduced pressure, diluted with water, extracted with ethyl acetate (10 mL × 3), and the combined organic layers were washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered, concentrated, and purified by column chromatography to obtain compound S58 (28.34 mg, 25%). 1H NMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), 9.03 (s, 1H), 8.02 (d, J=7.5Hz, 1H), 7.93 (dd, J=7.4, 2.1Hz, 1H), 7.65 (dd, J=7.4, 1.9Hz, 1H), 7.5 0 (t, J=7.5Hz, 1H), 7.44 (dd, J=7.3, 2.1Hz, 2H), 7.34-7.26 (m, 2H), 7.25-7.18 (m, 1H), 7.17-7.08 (m, 3H), 6.70 (s, 1H), 5.13 ( d, J=8.1Hz, 2H), 4.56 (t, J=5.5Hz, 1H), 4.28 (dd, J=12.4, 5.5Hz, 1H), 4-20 (dd, J=12.4, 5.5Hz, 1H), 3.54 (s, 2H), 2.96-2.83 ( m, 2H), 2.66 (s, 1H), 2.54 (s, 1H), 2-24 (d, J=0.9Hz, 2H), 2.04 (d, J=1.4Hz, 2H), 1.78 (s, 3H), 1.73 (s, 3H). MS (ESI, m / z): 772 (M + +1).

[0496] Example 89 Synthesis of compound S57

[0497]

[0498] The synthesis method is the same as that for compound S56; only the corresponding raw materials need to be changed to obtain compound S57. 1HNMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), 9.03 (s, 1H), 8.02 (d, J=7.5Hz, 1H), 7.86 (d, J=7.5Hz, 1H), 7.68-7.60 (m, 2H), 7.51-7.43 (m, 2H), 7.34-7.26(m, 2H), 7.25-7.17(m, 1H), 7.17-7.10(m, 2H), 6.70(s, 1H), 6.48(s, 1H), 5.13(d, J=1.3Hz, 1H), 5.01(s, 1 H), 4.56 (t, J=5.5Hz, 1H), 4.28 (dd, J=12.4, 5.5Hz, 1H), 4.20 (dd, J=12.4, 5.5Hz, 1H), 3.65 (d, J=12.5Hz, 1H), 3.57 (d, J= 12.5Hz, 1H), 3.12 (s, 2H), 2.62 (d, J=11.5Hz, 2H), 2.24 (d, J=0.9Hz, 2H), 1.78 (s, 3H), 1.73 (s, 3H). MS (ESI, rm / z): 758 (M + +1).

[0499] Example 90 Synthesis of compound S58

[0500]

[0501] The synthesis method is the same as that for compound S56; only the corresponding raw materials need to be changed to obtain compound S58. 1HNMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), 9.08 (s, 1H), 8.02 (d, J=7.4Hz, 1H), 7.83 (d, J=7.5Hz, 1H), 7.62 (dd, J=7.5, 2.0Hz, 1H), 7.49 (d, J=2. 0Hz, 1H), 7.46-7.38 (m, 2H), 7.38-7.31 (m, 2H), 7.26-7.18 (m, 3H), 6.70 (s, 1H), 5.14 (d, J=1.2Hz, 1H), 5.01 (s, 1H), 4.56 (t, J=5 .5Hz, 1H), 4.28 (dd, J=12.4, 5.5Hz, 1H), 4.20 (dd, J=12.4, 5.5Hz, 1H), 3.20 (s, 4H), 2.79 (d, J=12.5Hz, 1H), 2.70 (d, J=12.5Hz, 1 H), 2.65-2.59 (m, 6H), 2.51 (d, J=2.5Hz, 2H), 2.23 (d, J=3.8Hz, 2H), 1.93 (s, 2H), 1.78 (s, 3H), 1.73 (s, 3H). MS (ESI, rm / z): 841 (M + +1).

[0502] Example 91 Synthesis of compound S59

[0503]

[0504] The synthesis method is the same as that for compound S56; only the corresponding raw materials need to be changed to obtain compound S59. 1HNMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), 9.08 (s, 1H), 8.02 (d, J=7.5Hz, 1H), 7.91 (d, J=7.5Hz, 1H), 7.65 (dd, J=7.1, 1.9Hz, 2H), 7.45 (d, J=2.0H z, 1H), 7.38 (dd, J=7.5, 2.0Hz, 1H), 7.34-7.26 (m, 2H), 7.25-7.18 (m, 1H), 7.17-7.10 (m, 2H), 6.70 (s, 1H), 5.16-5.12 (m, 1H), 5.01 (s, 1H), 4.56 (t, J=5.5Hz, 1H), 4.28 (dd, J=12.4, 5.5Hz, 1H), 4.20 (dd, J=12.4, 5.5Hz, 1H), 336 (s, 2H), 3.30 (s, 2H), 3.07 (s, 2H), 2 .62 (d, J=11.5Hz, 2H), 2.23 (d, J=3.8Hz, 2H), 1.96 (s, 2H), 1.91 (s, 1H), 1.78 (s, 3H), 1.73 (s, 3H), 1.46 (s, 2H). MS (ESI, m / z): 812 (M + +1).

[0505] Example 92 Synthesis of compound S60

[0506]

[0507] The synthesis method is the same as that for compound S56; only the corresponding raw materials need to be changed to obtain compound S60. 1HNMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), 9.08 (s, 1H), 8.02 (d, J=7.5Hz, 1H), 7.83 (d, J=7.5Hz, 1H), 7.65-7.57 (m, 2H), 7.47-7. 41 (m, 2H), 7.39-7.31 (m, 2H), 7.26-7.18 (m, 3H), 6.70 (s, 1H), 5.14 (d, J=1.2Hz, 1H), 5.01 (s, 1H), 4.56 (t, J=5.5H z, 1H), 4.28 (dd, J=12.4, 5.5Hz, 1H), 4.20 (dd, J=12.4, 5.5Hz, 1H), 3.33 (d, J=13.0Hz, 4H), 2.91 (s, 2H), 2.62 (d, J =11.5Hz, 2H), 2.23 (d, J = 3.8Hz, 2H), 1.80 (d, J = 17.9Hz, 4H), 1.75-1.67 (m, 7H), 1.64 (s, 2H). MS (ESI, m / z): 826 (M + +1).

[0508] Example 93 Synthesis of compound S61

[0509]

[0510] The synthesis method is the same as that for compound S52; only the corresponding raw materials need to be changed to obtain compound S61. 1 HNMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), 9.03 (s, 1H), 8.02 (d, J=7.5Hz, 1H), 7.82 (dd, J=7.5, 2.0Hz, 1H), 7.65 (dd, J=7.4, 1.9H z, 1H), 7.56 (t, J=7.5Hz, 1H), 7.47-7.41 (m, 2H), 7.34-7.26 (m, 2H), 7.26-7.18 (m, 3H), 7.03 (s, 1H), 5.19-5.15 (m , 1H), 4.56 (t, J=5.5Hz, 1H), 4.39 (s, 1H), 4.33-4.24 (m, 2H), 4.20 (dd, J=12.4, 5.5Hz, 1H), 4.01 (s, 1H), 2.97 (s, 2 H), 2.62-2.56 (m, 4H), 2.19 (s, 1H), 2.12 (s, 1H), 1.78 (s, 3H), 1.73 (s, 3H), 1.71-1.60 (m, 2H). MS (ESI, m / z): 767 (M + +1).

[0511] Example 94 Synthesis of compound S62

[0512]

[0513] The synthesis method is the same as that for compound S56; only the corresponding raw materials need to be changed to obtain compound S62. 1 HNMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), 9.03 (s, 1H), 8.02 (d, J=7.5Hz, 1H), 7.93 (t, J=4.8Hz, 1H), 7.65 (dd, J=7.4, 1.9Hz, 1H), 7.48- 7.40 (m, 3H), 7.34-7.26 (m, 2H), 7.26-7.18 (m, 3H), 7.10 (s, 1H), 7.03 (s, 1H), 5.17 (t, J=0.9Hz, 1H), 5.12 (s, 1H), 4.56 (t, J=5.5Hz, 1H), 4.30 (dd, J=12.4, 5.4Hz, 1H), 4.20 (dd, J=12.4, 5.5Hz, 1H), 3.54 (s, 2H), 3.05 (s, 2H), 2.66 (s, 1H), 2.54 (s, 1H), 2.24 (d, J=0.9Hz, 2H), 2.18 (d, J=12.5Hz, 1H), 2.08 (d, J=12.5Hz, 1H), 1.78 (s, 3H), 1.73 (s, 3H). MS (ESI, m / z): 772 (M + +1).

[0514] Example 95 Synthesis of compound S63

[0515]

[0516] The synthesis method is the same as that for compound S52; only the corresponding raw materials need to be changed to obtain compound S63. 1HNMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 9.26 (s, 1H), 8.37 (s, 1H), 8.10 (d, J=7.5Hz, 1H), 7.97 (s, 1H), 7.82 (dd, J=7.3, 2.0Hz, 1H), 7.62 (dd, J=7 .5, 2.0Hz, 1H), 7.52 (t, J=7.5Hz, 1H), 7.49-7.40 (m, 2H), 7.34-7.26 (m, 2H), 7.267.18 (m, 3H), 7.11 (s, 1H), 5.19 (q, J= 0.8Hz, 1H), 4.494.41 (m, 3H), 4.30 (dd, J=12.4, 5.5Hz, 1H), 4.20 (dd, J=12.4, 5.6Hz, 1H), 4.08 (s, 2H), 4.01 (s, 1H), 2. 78 (s, 2H), 2.59 (d, J=7.5Hz, 2H), 2.19 (s, 1H), 2.12 (s, 1H), 1.98 (s, 2H), 1.78 (s, 3H), 1.73 (s, 3H). MS (ESI, m / z): 765 (M + +1).

[0517] Example 96 Synthesis of compound S64

[0518]

[0519] The synthesis method is the same as that for compound S56; only the corresponding raw materials need to be changed to obtain compound S64. 1 HNMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 9.26 (s, 1H), 8.37 (s, 1H), 8.10 (d, J=7.5Hz, 1H), 7.99-7.89 (m, 2H), 7.62 (dd, J=7.5, 2.0Hz, 1H), 7.4 5-7.38 (m, 3H), 7.34-7.26 (m, 2H), 7.26-7.18 (m, 3H), 7.11 (s, 1H), 6.88 (s, 1H), 5.19 (q, J=0.8Hz, 1H), 5.12 (s, 1H), 4.44 (t, J=5.5Hz, 1H), 4.30 (dd, J=12.5, 5.5Hz, 1H), 4.244.15 (m, 3H), 3.46 (s, 2H), 2.66 (s, 1H), 2.54 (s, 1H), 2.49 (s, 1H), 2.14 (d, J=12.5Hz, 1H), 2.09 (d, J=12.3Hz, 1H), 1.99 (s, 1H), 1.78 (s, 3H), 1.73 (s, 3H). MS (ESI, m / z): 770 (M+ +1).

[0520] Example 97 Synthesis of compound S65

[0521]

[0522] The synthesis method is the same as that for compound S52; only the corresponding raw materials need to be changed to obtain compound S65. 1 HNMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 9.65 (s, 1H), 9.43 (s, 1H), 9.10 (s, 1H), 8.16 (s, 1H), 7.85-7.76 (m, 2H), 7.64 (d, J=7.5Hz, 1H), 7.59-7.49 (m, 2H), 7.46 ( dd, J=7.5, 2.0Hz, 1H), 7.29 (ddd, J=7.4, 2.0, 1.0Hz, 1H), 7.20-7.10 (m, 2H), 7.06-6.97 (m, 2H), 6.83 (dt, J=2.0, 0.9Hz, 1H), 5.11 (t, J= 0.7Hz, 1H), 4.55 (t, J=5.5Hz, 1H), 4.50-4.35 (m, 4H), 4.21 (d, J=1.1Hz, 2H), 4.08 (s, 2H), 4.01 (s, 1H), 2.96 (t, J=0.8Hz, 2H), 2.78 (s, 2 H), 2.59 (d, J=7.5Hz, 2H), 2.19 (s, 1H), 2.12 (s, 1H), 1.98 (s, 2H), 1.86 (d, J=0.9Hz, 2H), 1.81 (s, 1H), 1.76 (s, 1H). MS (ESI, m / z): 776 (M + +1).

[0523] Example 98 Synthesis of compound S66

[0524]

[0525] The synthesis method is the same as that for compound S56; only the corresponding raw materials need to be changed to obtain compound S66. 1HNMR(500MHz, DMSO-d6)δ 11.10(s, 1H), 9.65(s, 1H), 9.43(s, 1H), 9.12(s, 1H), 8.37(s, 1H), 7.87(s, 1H), 7.81 (dd, J=7.5, 2.0Hz, 1H), 7.64 (d, J=7.5Hz, 1H), 7.57 (dd, J=7.5, 2.0Hz, 1H), 7.39 (t, J =7.5Hz, 1H), 7.29 (ddd, J=7.4, 2.0, 1.0Hz, 1H), 7.24-7.10 (m, 3H), 7.02 (td, J=7.5, 2 .0Hz, 1H), 6.93 (dd, J=7.4, 2.0Hz, 1H), 6.83 (dt, J=1.9, 0.9Hz, 1H), 6.61 (s, 1H), 5.11 (t, J=0.7Hz, 1H), 4.55 (t, J=5.5Hz, 1H), 4.50-4.35 (m, 4H), 4.21 (d, J=1.1Hz, 2H), 4. 01 (s, 1H), 3.91 (s, 2H), 3.47 (d, J = 1.0Hz, 2H), 2.96 (t, J = 0.8Hz, 2H), 2.58 (d, J = 15.0H z, 2H), 2.19 (s, 1H), 2.12 (s, 1H), 1.97 (d, J=12.4Hz, 1H), 1.88-1.79 (m, 4H), 1.76 (s, 1H), 1.67 (s, 2H), 1.51 (d, J=12.3Hz, 1H), 1.44 (d, J=12.4Hz, 1H). MS (ESI, m / z): 795 (M + +1).

[0526] Example 99 Synthesis of compound S67

[0527]

[0528] The synthesis method is the same as that for compound S52; only the corresponding raw materials need to be changed to obtain compound S67. 1HNMR(500MHz, DMSO-d6)δ 11.10(s, 1H), 9.65(s, 1H), 9.43(s, 1H), 9.26(s, 1H), 8.16(s, 1H), 7.85-7.76(m, 2H), 7.59-7.43(m, 4H), 7.36(dd d, J=7.5, 2.0, 1.0Hz, 1H), 7.19 (td, J=7.5, 2.0Hz, 1H), 7.06-6.92 (m, 3H), 6.71 (dt, J=2.0, 1.0Hz, 1H), 5.08 (t, J= 0.8Hz, 1H), 4.58-4.42 (m, 6H), 4.39 (dd, J=11.5, 4.8Hz, 1H), 4.16 (d, J=1.3Hz, 2H), 4.08 (s, 2H), 4.01 (s, 1H), 3.8 1 (d, J=0.9Hz, 2H), 2.78 (s, 2H), 2.59 (d, J=7.5Hz, 2H), 2.19 (s, 1H), 2.12 (s, 1H), 1.98 (s, 2H). MS (ESI, m / z): 778 (M + +1).

[0529] Example 100 Synthesis of compound S68

[0530]

[0531] The synthesis method is the same as that for compound S56; only the corresponding raw materials need to be changed to obtain compound S68. 1HNMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 9.65 (s, 1H), 9.43 (s, 1H), 9.26 (s, 1H), 8.16 (s, 1H), 7.84-7.76 (m, 2H), 7.62 (d, J=2.0Hz, 1H), 7.57 (dd, J=7.5, 2.0Hz, 1H ), 7.48 (d, J=7.5Hz, 1H), 7.41 (dd, J=7.4, 1.9Hz, 1H), 7.36 (ddd, J=7.5, 2.1, 1.0Hz, 1H), 7.19 (td, J=7.5, 2.0Hz, 1H), 7.04 (s, 1H), 7.03 -6.92 (m, 2H), 6.71 (dt, J=2.0, 1.0Hz, 1H), 6.48 (s, 1H), 5.08 (d, J=0.7Hz, 1H), 5.01 (s, 1H), 4.58-4.49 (m, 2H), 4.46-4.34 (m, 3H), 4.20 -4.09 (m, 4H), 3.81 (d, J = 1.0Hz, 2H), 3.45 (s, 2H), 2.62 (d, J = 11.5Hz, 2H), 2.24 (d, J = 1.0Hz, 2H), 2.17-2.05 (m, 2H). MS (ESI, m / z): 783 (M + +1).

[0532] Example 101 Synthesis of compound S69

[0533]

[0534] The synthesis method is the same as that for compound S52; only the corresponding raw materials need to be changed to obtain compound S69. 1HNMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 9.65 (s, 1H), 9.52 (s, 1H), 9.43 (s, 1H), 8.16 (s, 1H), 7.85-7.76 (m, 2H), 7.61-7.49 (m, 3H), 7.46 (dd, J=7.5, 2.0Hz, 1H), 7. 36 (ddd, J=7.5, 2.0, 1.0Hz, 1H), 7.19 (td, J=7.5, 2.0Hz, 1H), 7.06-6.98 (m, 2H), 6.93 (dd, J=7.5, 2.0Hz, 1H), 6.82 (dd, J=1.8, 1.1Hz, 1H), 5.08 (d, J=0.7Hz, 1H), 4.55 (t, J=5.5Hz, 1H), 4.50-4.35 (m, 4H), 4.15 (d, J=10.2Hz, 2H), 4.08 (s, 2H), 4.01 (s, 1H), 3.66 (dd, J=2.0, 1.1Hz , 2H), 3.13 (d, J=0.9Hz, 2H), 2.78 (s, 2H), 2.59 (d, J=7.5Hz, 2H), 2.41 (s, 3H), 2.19 (s, 1H), 2.12 (s, 1H), 1.98 (s, 2H). MS (ESI, m / z): 783 (M + +1).

[0535] Example 102 Synthesis of compound S70

[0536]

[0537] The synthesis method is the same as that for compound S52; only the corresponding raw materials need to be changed to obtain compound S70. 1HNMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 9.65 (s, 1H), 9.43-9.40 (m, 2H), 8.37 (s, 1H), 7.97 (s, 1H), 7.81 (dd, J=7.1, 2.4Hz, 1H), 7.65-7.55 (m, 2H), 7.55-7.45 (m , 2H), 7.40 (ddt, J=7.6, 2.1, 1.1Hz, 1H), 7.32-7.16 (m, 3H), 6.94 (dt, J=2.0, 1.1Hz, 1H), 6.88 (s, 1H), 5.81 (d, J=6.0Hz, 2H), 5.07-5.03 (m, 1H), 4.57-4.49 (m, 2H), 4.49-4.41 (m, 3H), 4.35 (d, J=1.1Hz, 1H), 4.18 (d, J=1.0Hz, 1H), 4.10 (s, 4H), 4.08-3.99 (m, 3H), 3.97 (s, 1 H), 3.93 (s, 1H), 2.88 (d, J=1.0Hz, 2H), 2.78 (s, 2H), 2.59 (d, J=7.5Hz, 2H), 2.19 (s, 1H), 2.12 (s, 1H), 1.99 (s, 2H). MS (ESI, m / z): 832 (M + +1).

[0538] Example 103 Synthesis of compound S71

[0539]

[0540] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S71. 1H NMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 9.43 (s, 1H), 8.97 (s, 1H), 8.14 (s, 1H), 8.02 (d, J=7.5Hz, 1H), 7.65 (dd, J=7.4, 1.9Hz, 1H), 7.45 (d, J =2.0Hz, 1H), 7.34-7.26(m, 2H), 7.25-7.20(m, 1H), 7.20-7.10(m, 4H), 7.05-6.98(m, 2H), 6.95(s, 1H), 5.16-5.12(m , 1H), 4.56 (t, J=5.5Hz, 1H), 4.28 (dd, J=12.4, 5.5Hz, 1H), 4.23-4.16 (m, 2H), 3.53-3.42 (m, 2H), 3.22 (d, J=4.4Hz, 4 H), 2.60-2.53 (m, 6H), 2.49 (d, J=5.5Hz, 2H), 2.01 (d, J=12.5Hz, 2H), 1.78 (s, 3H), 1.73 (s, 3H). MS (ESI, m / z): 733 (M + +1).

[0541] Example 104 Synthesis of compound S72

[0542]

[0543] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S72. 1H NMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), 9.10 (s, 1H), 8.38 (s, 1H), 8.02 (d, J = 7.5Hz, 1H), 7.65 (dd, J = 7.4, 1.9Hz, 1H), 7.45 (d, J = 2.0Hz, 1H), 7.34-7.26 (m, 2H), 7.25-7.10 (m, 5H), 7.00-6.93 (m, 2H), 6.70 (s, 1H), 5.13 (d, J=1.3Hz, 1H), 4.56 (t, J=5.5Hz, 1H), 4.28 (dd, J= 12.4, 5.5Hz, 1H), 4.20 (dd, J=12.4, 5.5Hz, 1H), 3.85 (t, J=1.0Hz, 1H), 3.35 (d, J=6.2Hz, 4H), 3.26 (s, 2H), 2.49 (d, J=5.5Hz, 2H) , 2.01 (d, J=12.5Hz, 2H), 1.94 (s, 1H), 1.86 (d, J=12.5Hz, 1H), 1.78 (s, 3H), 1.75-1.62 (m, 6H), 1.60 (s, 2H). MS (ESI, m / z): 732 (M + +1).

[0544] Example 105 Synthesis of compound S73

[0545]

[0546] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S73. 1H NMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), 9.10 (s, 1H), 8.12 (s, 1H), 8.02 (d, J = 7.5Hz, 1H), 7.65 (dd, J = 7.4, 1.9Hz, 1H), 7.45 (d, J =2.0Hz, 1H), 7.34-7.26(m, 2H), 7.25-7.20(m, 1H), 7.20-7.10(m, 4H), 7.05-6.98(m, 2H), 6.70(s, 1H), 5.13(d, J=1. 3Hz, 1H), 4.56 (t, J=5.5Hz, 1H), 4.28 (dd, J=12.4, 5.5Hz, 1H), 4.23-4.16 (m, 2H), 3.33 (q, J=12.4Hz, 2H), 3.20 (s, 4 H), 2.61 (s, 4H), 2.51-2.43 (m, 4H), 2.01 (d, J=12.5Hz, 2H), 1.78 (d, J=4.2Hz, 5H), 1.73 (s, 3H). MS (ESI, m / z): 747 (M + +1).

[0547] Example 106 Synthesis of compound S74

[0548]

[0549] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S74. 1 H NMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), 8.97 (s, 1H), 8.16 (s, 1H), 8.02 (d, J=7.5Hz, 1H), 7.65 (dd, J=7.4, 1.9Hz, 1H), 7.45 (d, J=2. 0Hz, 1H), 7.34-7.26 (m, 2H), 7.25-7.18 (m, 1H), 7.16-7.10 (m, 4H), 6.95 (s, 1H), 5.13 (d, J=1.3Hz, 1H), 4.56 (t, J=5.5H z, 1H), 4.44 (s, 1H), 4.28 (dd, J=12.4, 5.5Hz, 1H), 4.20 (dd, J=12.4, 5.5Hz, 1H), 3.50 (d, J=1.8Hz, 2H), 3.31 (s, 2H), 3. 23 (s, 2H), 2.59 (d, J=2.4Hz, 6H), 2.50 (s, 2H), 2.12 (d, J=11.7Hz, 2H), 1.78 (s, 3H), 1.73 (s, 3H). MS (ESI, rm / z): 769 (M+ +1).

[0550] Example 107 Synthesis of compound S75

[0551]

[0552] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S75. 1 H NMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), 8.97 (s, 1H), 8.16 (s, 1H), 8.02 (d, J=7.5Hz, 1H), 7.65 (dd, J=7.4, 1.9Hz, 1H), 7.45 (d, J=2.0H z, 1H), 7.34-7.26 (m, 2H), 7.25-7.18 (m, 2H), 7.17-7.10 (m, 2H), 6.97-6.92 (m, 2H), 5.13 (d, J=1.3Hz, 1H), 4.56 (t, J=5.5 Hz, 1H), 4.44 (s, 1H), 4.28 (dd, J=12.4, 5.5Hz, 1H), 4.20 (dd, J=12.4, 5.5Hz, 1H), 3.50 (d, J=1.8Hz, 2H), 3.25 (s, 2H), 3.2 1 (s, 2H), 2.61-2.53 (m, 6H), 2.50 (d, J=2.4Hz, 2H), 2.12 (d, J=11.7Hz, 2H), 1.78 (s, 3H), 1.73 (s, 3H). MS (ESI, m / z): 785 (M + +1).

[0553] Example 108 Synthesis of compound S76

[0554]

[0555] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S76. 1H NMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), 8.97 (s, 1H), 8.25 (s, 1H), 8.02 (d, J = 7.5Hz, 1H), 7.65 (dd, J = 7.4, 1.9Hz, 1H), 7.53 (d, J = 1.0Hz, 1H), 7.4 5 (d, J=2.0Hz, 1H), 7.34-7.26 (m, 2H), 7.25-7.18 (m, 1H), 7.17-7.10 (m, 2H), 6.95 (d, J=1.8Hz, 2H), 5.13 (d, J=1.3Hz, 1H), 4.64 (d, J =1.1Hz, 1H), 4.56 (t, J = 5.5Hz, 1H), 4.28 (dd, J = 12.4, 5.5Hz, 1H), 4.20 (dd, J = 12.4, 5.5Hz, 1H), 3.53-3.42 (m, 2H), 3.14 (s, 2H), 3.1 0 (s, 2H), 2.60 (dd, J=18.4, 1.5Hz, 6H), 2.47 (d, J=8.8Hz, 2H), 2.06 (d, J=2.4Hz, 2H), 1.78 (s, 3H), 1.73 (s, 3H). MS (ESI, rm / z): 769 (M + +1).

[0556] Example 109 Synthesis of compound S77

[0557]

[0558] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S77. 1H NMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), δ 8.97 (s, 1H), 8.25 (s, 1H), 8.02 (d, J = 7.5Hz, 1H), 7.65 (dd, J = 7.4, 1.9Hz, 1H), 7.45 (d, J = 2.0Hz, 1H), 7.37 (d d, J=7.5, 1.1Hz, 1H), 7.34-7.26 (m, 2H), 7.25-7.18 (m, 1H), 7.17-7.10 (m, 2H), 7.03 (d, J=7.5Hz, 1H), 6.95 (s, 1H), 5.13 (d, J=1.3Hz, 1H) , 4.64 (d, J = 1.1Hz, 1H), 4.56 (t, J = 5.5Hz, 1H), 4.28 (dd, J = 12.4, 5.5Hz, 1H), 4.20 (dd, J = 12.4, 5.5Hz, 1H), 3.53-3.42 (m, 2H), 3.14 (s, 2H) ), 3.10 (s, 2H), 2.60 (dd, J=18.4, 1.5Hz, 6H), 2.47 (d, J=8.8Hz, 2H), 2.06 (d, J=2.4Hz, 2H), 1.78 (s, 3H), 1.73 (s, 3H). MS (ESI, m / z): 769 (M + +1).

[0559] Example 110 Synthesis of compound S78

[0560]

[0561] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S78. 1H NMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), δ 8.97 (s, 1H), 8.16 (s, 1H), 8.02 (d, J = 7.5Hz, 1H), 7.65 (dd, J = 7.4, 1.9Hz, 1H), 7.45 (d, J = 2.0Hz, 1H) ), 7.36 (d, J = 1.9Hz, 1H), 7.34-7.26 (m, 2H), 7.26-7.17 (m, 2H), 7.17-7.09 (m, 3H), 6.95 (s, 1H), 5.13 (d, J = 1.3Hz, 1H), 4.64 (d, J=1.1Hz, 1H), 4.56 (t, J=5.5Hz, 1H), 4.28 (dd, J=12.4, 5.5Hz, 1H), 4.20 (dd, J=12.4, 5.5Hz, 1H), 3.53-3.42 (m, 2H), 3.28 (s, 2H ), 3.23 (s, 2H), 2.60-2.53 (m, 6H), 2.47 (d, J = 8.8Hz, 2H), 2.04 (d, J = 7.5Hz, 2H), 1.78 (s, 3H), 1.73 (s, 3H). MS (ESI, m / z): 758 (M + +1).

[0562] Example 111 Synthesis of compound S79

[0563]

[0564] The synthesis method is the same as that for compound S56; only the corresponding raw materials need to be changed to obtain compound S79. 1HNMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), δ9.03 (s, 1H), 8.02 (d, J=7.5Hz, 1H), 7.65 (dd, J=7.4, 1.9Hz, 1H), 7.45 (d, J=2.0Hz, 1H), 7.34-7.24 (m, 3H), 7.24-7.19 (m, 1H), 7.17 (dd, J=2.0, 1.0Hz, 1H), 7.16-7.10 (m, 2H), 7.02 (d, J=7.5Hz, 1H), 6.70 (s, 1H), 5.16-5.12 (m, 1H), 4.59 -4.52 (m, 2H), 4.28 (dd, J=12.4, 5.5Hz, 1H), 4.20 (dd, J=12.4, 5.5Hz, 1H), 3.12 (d, J=6.8Hz, 4H), 2.98 (s, 2H), 2.88 (d, J=12.4Hz, 1H ), 2.81 (d, J = 12.5Hz, 1H), 2.62 (s, 4H), 2.49 (d, J = 5.5Hz, 2H), 2.01 (d, J = 4.6Hz, 2H), 1.78 (s, 3H), 1.73 (s, 3H). MS (ESI, m / z): 776 (M + +1).

[0565] Example 112 Synthesis of compound S80

[0566]

[0567] The synthesis method is the same as that for compound S56; only the corresponding raw materials need to be changed to obtain compound S80. 1HNMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 9.43 (s, 1H), δ 9.03 (s, 1H), 8.02 (d, J = 7.5Hz, 1H), 7.65 (dd, J = 7.4, 1.9Hz, 1H), 7.45 (d, J = 2.0Hz, 1H), 7.34- 7.24 (m, 3H), 7.24-7.18 (m, 1H), 7.17 (dd, J=2.0, 1.0Hz, 1H), 7.16-7.10 (m, 2H), 7.00 (d, J=7.5Hz, 1H), 6.70 (s, 1H), 5.16-5 .12 (m, 1H), 4.59-4.52 (m, 2H), 4.28 (dd, J=12.4, 5.5Hz, 1H), 4.20 (dd, J=12.4, 5.5Hz, 1H), 3.11 (d, J=3.8Hz, 4H), 3.05 (s, 2H), 2.71 (s, 2H), 2.61 (s, 4H), 2.49 (d, J=5.5Hz, 2H), 2.01 (d, J=4.6Hz, 2H), 1.78 (s, 3H), 1.73 (s, 3H). MS (ESI, m / z): 776 (M + +1).

[0568] Example 113 Synthesis of compound S81

[0569]

[0570] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S81. 1H NMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), δ 8.97 (s, 1H), 8.16 (s, 1H), 8.02 (d, J = 7.5Hz, 1H), 7.65 (dd, J = 7.4, 1.9Hz, 1H), 7.45 (d, J = 2. 0Hz, 1H), 7.34-7.18 (m, 5H), 7.17-7.10 (m, 2H), 6.97-6.89 (m, 3H), 5.18 (s, 1H), 5.13 (d, J=1.3Hz, 1H), 4.56 (t, J=5.5Hz , 1H), 4.34 (s, 1H), 4.28 (dd, J=12.4, 5.5Hz, 1H), 4.20 (dd, J=12.4, 5.5Hz, 1H), 3.53-3.42 (m, 2H), 3.28 (s, 2H), 3.22 (s, 2H), 2.58 (d, J=0.8Hz, 3H), 2.52 (d, J=15.0Hz, 5H), 2.29 (s, 1H), 1.79 (d, J=5.5Hz, 4H), 1.73 (s, 3H). MS (ESI, m / z): 748 (M + +1).

[0571] Example 114 Synthesis of compound S82

[0572]

[0573] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S82. 1H NMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), δ8.97 (s, 1H), 8.25 (s, 1H), 8.02 (d, J=7.5Hz, 1H), 7.65 (dd, J=7.4, 1.9Hz, 1H), 7.53-7.43 ( m, 2H), 7.34-7.26 (m, 2H), 7.25-7.18 (m, 2H), 7.17-7.10 (m, 2H), 6.94 (d, J=7.9Hz, 2H), 5.20-5.12 (m, 2H), 4.56 (t, J=5 .5Hz, 1H), 4.34 (s, 1H), 4.28 (dd, J=12.4, 5.5Hz, 1H), 4.20 (dd, J=12.4, 5.5Hz, 1H), 3.53-3.42 (m, 2H), 3.09 (d, J=2.4H z, 4H), 2.61 (d, J=2.6Hz, 5H), 2.58-2.52 (m, 3H), 2.29 (s, 1H), 1.79 (d, J=5.5Hz, 4H), 1.73 (s, 3H). MS (ESI, m / z): 766 (M + +1).

[0574] Example 115 Synthesis of compound S83

[0575]

[0576] The synthesis method is the same as that for compound S56; only the corresponding raw materials need to be changed to obtain compound S83. 1HNMR(500MHz, DMSO-d6)δ 11.10 (s, 1H) 9.43 (s, 1H), 8.02 (d, J = 7.5Hz, 1H), 7.65 (dd, J = 7.4, 1.9Hz, 1H), 7.53-7.43 (m, 2H), 7.34-7.26 (m, 2H), 7.25-7.18 ( m, 2H), 7.17-7.10 (m, 2H), 7.03 (d, J=7.5Hz, 1H), 6.70 (s, 1H), 5.18 (s, 1H), 5.13 (d, J=1.3Hz, 1H), 4.56 (t, J=5.5Hz, 1H), 4.34 (s , 1H), 4.28 (dd, J=12.4, 5.5Hz, 1H), 4.20 (dd, J=12.4, 5.5Hz, 1H), 3.06 (d, J=15.4Hz, 4H), 2.98 (s, 2H), 2.88 (d, J=12.5Hz, 1H), 2 .81 (d, J=12.5Hz, 1H), 2.61 (d, J=6.6Hz, 5H), 2.54 (s, 1H), 2.29 (s, 1H), 1.79 (d, J=5.5Hz, 4H), 1.73 (s, 3H). MS (ESI, m / z): 791 (M + +1).

[0577] Example 116 Synthesis of compound S84

[0578]

[0579] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S84. 1H NMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), δ 8.97 (s, 1H), 8.14 (s, 1H), 8.02 (d, J = 7.5Hz, 1H), 7.65 (dd, J = 7.4, 1.9Hz, 1H), 7.45 (d, J = 2. 0Hz, 1H), 7.34-7.26 (m, 2H), 7.25-7.16 (m, 3H), 7.16-7.05 (m, 4H), 6.95 (s, 1H), 5.13 (d, J=1.3Hz, 1H), 4.56 (t, J=5.5Hz, 1H), 4.28 (dd, J=12.4, 5.5Hz, 1H), 4.20 (dd, J=12.4, 5.5Hz, 1H), 3.533.42 (m, 2H), 3.22 (d, J=4.4Hz, 4H), 2.59 (d, J=3.8 Hz, 6H), 2.52 (s, 1H), 2.46 (s, 1H), 2.34 (s, 1H), 2.02 (s, 1H), 1.78 (s, 3H), 1.73 (s, 3H), 1.53 (s, 3H). MS (ESI, m / z): 747 (M + +1).

[0580] Example 117 Synthesis of Compound S85

[0581]

[0582] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S85. 1H NMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), δ8.97 (s, 1H), 8.16 (s, 1H), 8.02 (d, J=7.5Hz, 1H), 7.65 (dd, J=7.4, 1.9Hz, 1H), 7.45 (d, J=2.0 Hz, 1H), 7.42-7.36 (m, 2H), 7.34-7.26 (m, 2H), 7.25-7.18 (m, 1H), 7.17-7.10 (m, 2H), 6.99-6.93 (m, 3H), 5.16-5.12 (m, 1H) ), 4.56 (t, J=5.5Hz, 1H), 4.28 (dd, J=12.4, 5.5Hz, 1H), 4.20 (dd, J=12.4, 5.5Hz, 1H), 4.07 (d, J=13.9Hz, 2H), 3.53-3.42 ( m, 2H), 3.31 (s, 2H), 3.26 (s, 2H), 2.88 (s, 2H), 2.58 (s, 2H), 2.51 (s, 4H), 1.78 (s, 3H), 1.73 (s, 3H). MS (ESI, rm / z): 734 (M + +1).

[0583] Example 118 Synthesis of compound S86

[0584]

[0585] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S86. 1H NMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), δ8.97 (s, 1H), 8.288.23 (m, 2H), 8.02 (d, J=7.5Hz, 1H), 7.65 (dd, J=7.4, 1.9Hz, 1H), 7.45 (d, J=2.0 Hz, 1H), 7.38 (d, J=7.5Hz, 1H), 7.34-7.26 (m, 2H), 7.25-7.18 (m, 1H), 7.17-7.10 (m, 2H), 7.04 (dd, J=7.5, 2.0Hz, 1H), 6.95 (s, 1 H), 5.20-5.12 (m, 2H), 4.56 (t, J=5.5Hz, 1H), 4.34 (s, 1H), 4.28 (dd, J=12.4, 5.5Hz, 1H), 4.20 (dd, J=12.4, 5.5Hz, 1H), 3.50 (d, J=1.8Hz, 2H), 3.05 (d, J=13.0Hz, 3H), 2.61-2.52 (m, 7H), 2.29 (s, 1H), 1.79 (d, J=5.5Hz, 4H), 1.73 (s, 2H). MS (ESI, m / z): 816 (M + +1).

[0586] Example 119 Synthesis of compound S87

[0587]

[0588] The synthesis method is the same as that for compound S56; only the corresponding raw materials need to be changed to obtain compound S87. 1HNMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 9.43 (s, 1H), δ9.08 (s, 1H), 8.02 (d, J=7.5Hz, 1H), 7.65 (dd, J=7.4, 1.9Hz, 1H), 7.45 (d, J=2.0Hz, 1H), 7.39-7.2 6 (m, 4H), 7.25-7.18 (m, 1H), 7.17-7.10 (m, 2H), 6.91 (d, J = 1.8Hz, 1H), 6.70 (s, 1H), 5.18 (s, 1H), 5.13 (d, J = 1.3Hz, 1H), 4.56 (t , J=5.5Hz, 1H), 4.34 (s, 1H), 4.28 (dd, J=12.4, 5.5Hz, 1H), 4.20 (dd, J=12.5, 5.5Hz, 1H), 3.92 (s, 3H), 3.12 (s, 2H), 2.98 (s, 2H ), 2.82 (d, J=10.8Hz, 4H), 2.622.56 (m, 5H), 2.54 (s, 1H), 2.29 (s, 1H), 1.79 (d, J=5.5Hz, 4H), 1.73 (s, 3H). MS (ESI, m / z): 803 (M + +1).

[0589] Example 120 Synthesis of compound S88

[0590]

[0591] The synthesis method is the same as that for compound S56; only the corresponding raw materials need to be changed to obtain compound S88. 1HNMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 9.43 (s, 1H), δ9.03 (s, 1H), 8.02 (d, J=7.5Hz, 1H), 7.65 (dd, J=7.4, 1.9Hz, 1H), 7.53-7.43 (m, 2H), 7 .34-7.26 (m, 2H), 7.25-7.18 (m, 2H), 7.17-7.10 (m, 2H), 7.03 (d, J=7.5Hz, 1H), 6.70 (s, 1H), 5.205.12 (m, 2H), 4.5 6 (t, J=5.5Hz, 1H), 4.34 (s, 1H), 4.28 (dd, J=12.4, 5.5Hz, 1H), 4.20 (dd, J=12.4, 5.5Hz, 1H), 3.093.02 (m, 6H), 2.7 1 (s, 2H), 2.61 (d, J=3.5Hz, 5H), 2.54 (s, 1H), 2.29 (s, 1H), 1.79 (d, J=5.5Hz, 4H), 1.73 (s, 3H). MS (ESI, m / z): 791 (M + +1).

[0592] Example 121 Synthesis of compound S89

[0593]

[0594] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S89. 1 H NMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), δ8.99 (s, 1H), 8.16 (s, 1H), 8.02 (d, J=7.5Hz, 1H), 7.707.62 (m, 2H), 7.45 (d, J=2.0Hz, 1H), 7.36-7.26 (m, 3H), 7.26-7.18 (m, 4H), 6.85 (d, J=2.0Hz, 1H), 5.205.15 (m, 1H), 4.56 (t, J=5 .5Hz, 1H), 4.30 (dd, J=12.4, 5.4Hz, 1H), 4.24-4.16 (m, 2H), 3.53-3.42 (m, 2H), 3.20 (d, J=7.5Hz, 4H), 2. 62-2.56 (m, 8H), 2.19 (d, J=8.4Hz, 2H), 1.78 (d, J=3.1Hz, 6H), 1.73 (d, J=3.1Hz, 6H). MS (ESI, m / z): 816 (M + +1).

[0595] Example 122 Synthesis of compound S90

[0596]

[0597] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S90. 1 H NMR(500MHz, DMSO-d6)δ 11.10(s, 1H), 10.2(s, 1H), δ8.99(s, 1H), 8.16(s, 1H), 8.02(d, J=7.5Hz, 1H), 7.70-7.62(m, 2H), 7.45( d, J=2.0Hz, 1H), 7.36-7.26 (m, 3H), 7.26-7.18 (m, 4H), 6.89 (d, J=2.0Hz, 1H), 5.19-5.15 (m, 1H), 4.56 (t , J=5.5Hz, 1H), 4.33-4.25 (m, 2H), 4.20 (dd, J=12.5, 5.5Hz, 1H), 3.533.42 (m, 2H), 3.22 (s, 4H), 2.622.5 5 (m, 10H), 2.52 (d, J=4.9Hz, 2H), 2.19 (d, J=8.4Hz, 2H), 1.78 (s, 3H), 1.73 (s, 3H). MS (ESI, rm / z): 814 (M + +1).

[0598] Example 123 Synthesis of compound S91

[0599]

[0600] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S91. 1H NMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), δ9.10 (s, 1H), 8.33 (s, 1H), 8.01 (dd, J=7.3, 2.2Hz, 2H), 7.65 (dd, J=7.4, 1.9Hz, 1H), 7. 47-7.34 (m, 4H), 7.34-7.26 (m, 2H), 7.26-7.17 (m, 3H), 6.61 (s, 1H), 5.19-5.15 (m, 1H), 4.56 (t, J=5.5Hz, 1H), 4.35 (s, 1H), 4.33-4.25 (m, 2H), 3.75 (d, J = 12.5Hz, 1H), 3.65 (s, 2H), 3.60 (d, J = 12.3Hz, 1H), 2.58 (d, J = 15.0Hz, 2H), 2. 46 (d, J=4.9Hz, 2H), 2.30 (d, J=5.1Hz, 2H), 2.22 (s, 1H), 2.14 (s, 1H), 1.78 (s, 3H), 1.73 (s, 3H). MS (ESI, m / z): 745 (M + +1).

[0601] Example 124 Synthesis of compound S92

[0602]

[0603] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S92. 1 H NMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), δ9.08 (s, 1H), 8.188.12 (m, 2H), 7.83 (d, J=7.5Hz, 1H), 7.65-7.58 (m, 2H), 7.45 (d, J=2 .0Hz, 1H), 7.41-7.29(m, 3H), 7.29-7.17(m, 4H), 5.18(d, J=1.4Hz, 1H), 5.01(s, 1H), 4.56(t, J=5.5Hz, 1H), 4.30(d d, J=12.4, 5.4Hz, 1H), 4.20 (dd, J=12.4, 5.5Hz, 1H), 3.77 (s, 2H), 3.68 (s, 2H), 3.50 (s, 2H), 3.43 (s, 1H), 3.14 (d, J =1.3Hz, 3H), 2.662.56 (m, 10H), 2.46 (s, 4H), 2.24 (d, J = 0.9Hz, 2H), 1.78 (s, 3H), 1.73 (s, 3H). MS (ESI, m / z): 912 (M ++1).

[0604] Example 125 Synthesis of Compound S93

[0605]

[0606] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S93. 1 H NMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), δ9.08 (s, 1H), 8.18-8.12 (m, 2H), 7.86 (d, J=7.5Hz, 1H), 7.65-7.57 (m, 2H), 7.47-7.39 (m, 2H), 7.37-7.29 (m, 2H), 7.29-7.17 (m, 4H), 5.18 (d, J=1.3Hz, 1H), 5.01 (s, 1H), 4.56 (t, J=5.5Hz, 1H), 4.30 (dd, J=12.4, 5.4Hz, 1 H), 4.20 (dd, J=12.5, 5.5Hz, 1H), 3.53-3.45 (m, 6H), 3.03 (s, 1H), 2.87 (s, 2H), 2.80 (s, 1H), 2.68 (s, 2H), 2.65-2.57 (m, 4H) ), 2.55 (s, 4H), 2.46 (s, 4H), 2.23 (d, J = 3.8Hz, 2H), 1.85 (d, J = 17.0Hz, 4H), 1.78 (s, 3H), 1.73 (s, 3H). MS (ESI, rm / z): 940 (M + +1).

[0607] Example 126 Synthesis of compound S94

[0608]

[0609] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S94. 1H NMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), δ9.12 (s, 1H), 8.15 (d, J=7.5Hz, 1H), 8.10 (s, 1H), 7.83 (d, J=7.5Hz, 1H), 7.62 (dd, J=7.5, 2.0Hz, 1H), 7.47 (dd, J=18.4, 2.0Hz, 2H), 7.39 (dd, J=7.5, 1.8Hz, 1H), 7.37-7.29 (m, 2H), 7.29-7.17 (m, 4H), 5.18 (d, J=1.4Hz, 1H), 5.01 (s, 1H), 4.56 (t, J=5.5H z, 1H), 4.30 (dd, J=12.4, 5.4Hz, 1H), 4.20 (dd, J=12.4, 5.5Hz, 1H), 3.73 (s, 4H), 3.50 (s, 2H), 3.16 (d, J=15.9Hz, 3H), 3.02 (s, 1H), 2.81 (d, J=6.2Hz, 4H), 2.70-2.59 (m, 8H), 2.49 (s, 2H), 2.23 (d, J=3.8Hz, 2H), 1.78 (s, 3H), 1.73 (s, 3H), 1.67 (d, J=16.5Hz, 4H). MS (ESI, m / z): 952 (M + +1).

[0610] Example 127 Synthesis of compound S95

[0611]

[0612] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S95. 1H NMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), δ9.12 (s, 1H), 8.15 (d, J=7.5Hz, 1H), 8.10 (s, 1H), 7.83 (d, J=7.5Hz, 1H), 7.62 (dd, J=7.5, 2.0Hz, 1H), 7.47 (dd, J=18.4, 2.0Hz, 2H), 7.41-7.29 (m, 3H), 7.29-7.17 (m, 4H), 5.18 (d, J=1.4Hz, 1H), 5.01 (s, 1H), 4.56 (t, J=5.5Hz, 1H), 4. 30 (dd, J=12.4, 5.4Hz, 1H), 4.20 (dd, J=12.4, 5.5Hz, 1H), 3.68 (s, 2H), 3.50 (s, 2H), 3.39 (d, J=10.6Hz, 3H), 3.00 (s, 1H), 2.91 (s, 4H), 2.74 (s, 2H), 2.692.59 (m, 10H), 2.24 (d, J=0.9Hz, 2H), 1.78 (s, 3H), 1.73 (s, 3H), 1.63 (d, J=13.7Hz, 4H). MS (ESI, m / z): 952 (M + +1).

[0613] Example 128 Synthesis of compound S96

[0614]

[0615] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S96. 1H NMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), δ9.12 (s, 1H), 8.15 (d, J=7.5Hz, 1H), 8.10 (s, 1H), 7.83 (d, J=7.5Hz, 1H), 7.62 (dd, J=7.5, 2.0Hz, 1H), 7.47 (dd , J=18.4, 2.0Hz, 2H), 7.41-7.29 (m, 3H), 7.29-7.17 (m, 4H), 5.19-5.15 (m, 1H), 5.01 (s, 1H), 4.56 (t, J=5.5Hz, 1H), 4.30 (dd, J=12.4, 5.4H z, 1H), 4.20 (dd, J=12.4, 5.5Hz, 1H), 3.68 (s, 2H), 3.50 (s, 2H), 3.38 (s, 2H), 3.11 (s, 1H), 2.95 (s, 1H), 2.93-2.86 (m, 6H), 2.81 (d, J=9.5H z, 2H), 2.74 (d, J=9.5Hz, 2H), 2.68-2.59 (m, 6H), 2.26-2.20 (m, 4H), 1.78 (s, 3H), 1.73 (s, 3H), 1.66 (d, J=10.1Hz, 4H). MS (ESI, m / z): 966 (M + +1).

[0616] Example 129 Synthesis of compound S97

[0617]

[0618] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S97. 1H NMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), δ9.12 (s, 1H), 8.15 (d, J=7.5Hz, 1H), 7.96 (s, 1H), 7.83 (d, J=7.5Hz, 1H), 7.65-7.58 (m , 2H), 7.45 (d, J=2.1Hz, 1H), 7.41-7.29 (m, 3H), 7.29-7.17 (m, 4H), 5.195.15 (m, 1H), 5.01 (s, 1H), 4.60-4.52 (m, 2 H), 4.30 (dd, J=12.4, 5.4Hz, 1H), 4.26-4.16 (m, 2H), 3.68 (s, 2H), 3.40 (s, 2H), 3.16-3.10 (m, 3H), 3.05 (s, 1H), 2. 66-2.53 (m, 8H), 2.47 (d, J=2.6Hz, 4H), 2.24 (d, J=0.9Hz, 2H), 2.03 (s, 2H), 1.801.67 (m, 10H). MS (ESI, m / z): 952 (M + +1).

[0619] Example 130 Synthesis of compound S98

[0620]

[0621] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S98. 1 H NMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), δ9.12 (s, 1H), 8.188.12 (m, 2H), 7.83 (d, J=7.5Hz, 1H), 7.65-7.58 (m, 2H), 7.45 (d, J= 2.0Hz, 1H), 7.41-7.29 (m, 3H), 7.29-7.17 (m, 4H), 5.195.15 (m, 1H), 5.01 (s, 1H), 4.56 (t, J=5.5Hz, 1H), 4.30 (dd , J=12.4, 5.4Hz, 1H), 4.20 (dd, J=12.5, 5.5Hz, 1H), 3.77 (s, 2H), 3.49 (d, J=13.9Hz, 3H), 3.41 (d, J=12.9Hz, 2H), 2.93 (s, 4H), 2.682.59 (m, 8H), 2.24 (d, J=0.9Hz, 2H), 1.87 (s, 4H), 1.78 (s, 3H), 1.73 (s, 3H). MS (ESI, m / z): 897 (M + +1).

[0622] Example 131 Synthesis of compound S99

[0623]

[0624] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S99. 1 H NMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), δ9.12 (s, 1H), 8.188.12 (m, 2H), 7.83 (d, J=7.5Hz, 1H), 7.62 (dd, J=7.5, 2.0Hz, 1H), 7.47 (dd, J=18.4, 2.0Hz, 2H), 7.39 (dd, J=7.5, 1.8Hz, 1H), 7.37-7.29 (m, 2H), 7.29-7.17 (m, 4H), 5.18 (d, J=1.4Hz, 1H), 5.01 (s, 1H), 4.56 (t, J=5.5Hz, 1H), 4.30 (dd, J=12.4 . 63 (s, 3H), 2.62-2.56 (m, 4H), 2.49 (s, 2H), 2.23 (d, J=3.8Hz, 2H), 2.05 (s, 2H), 1.86 (d, J=12.8Hz, 2H), 1.81-1.71 (m, 8H). MS (ESI, m / z): 923 (M + +1).

[0625] Example 132 Synthesis of compound S100

[0626]

[0627] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S100. 1HNMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), δ9.10 (s, 1H), 8.02 (d, J=7.5Hz, 1H), 7.90 (dd, J=7.5, 2.0Hz, 1H), 7.68-7.62 (m, 2H) , 7.48-7.41 (m, 2H), 7.36-7.26 (m, 3H), 7.26-7.18 (m, 4H), 5.18 (t, J=1.1Hz, 1H), 5.11 (s, 1H), 4.56 (t, J=5.5Hz , 1H), 4.30 (dd, J=12.4, 5.4Hz, 1H), 4.20 (dd, J=12.4, 5.5Hz, 1H), 3.83 (s, 1H), 3.59 (d, J=6.2Hz, 4H), 2.66 (s, 1 H), 2.54 (s, 1H), 2.49 (s, 1H), 1.99 (s, 1H), 1.93 (s, 2H), 1.79 (d, J=2.9Hz, 5H), 1.73 (s, 3H). MS (ESI, m / z): 773 (M + +1).

[0628] Example 133 Synthesis of compound S101

[0629]

[0630] The synthesis method is the same as that for compound S1; only the corresponding raw materials need to be changed to obtain compound S101. 1 HNMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 10.2 (s, 1H), δ9.12 (s, 1H), 8.02 (d, J=7.5Hz, 1H), 7.85-7.79 (m, 2H), 7.65 (dd, J=7.4, 1.9Hz, 1H), 7.60 (d, J=2.0Hz, 1H), 7.47-7.41 (m, 2H), 7.34-7.26 (m, 2H), 7.26-7.18 (m, 4H), 5.195.15 (m, 1H), 4.90 (s, 1H), 4. 56 (t, J=5.5Hz, 1H), 4.30 (dd, J=12.4, 5.4Hz, 1H), 4.20 (dd, J=12.4, 5.5Hz, 1H), 4.00 (s, 1H), 3.85 (s, 2H), 3.73 ( s, 2H), 2.62 (d, J=11.5Hz, 2H), 2.23 (d, J=3.8Hz, 2H), 1.90 (s, 4H), 1.78 (s, 3H), 1.73 (s, 3H). MS (ESI, m / z): 785 (M + +1).

[0631] Example 134 Synthesis of compound S102

[0632]

[0633] Step 1: Synthesis of Compound 211

[0634] Compound 7 (434 mg, 1 mmol) and glycine tert-butyl hydrochloride (167 mg, 1 mmol) were dissolved in anhydrous DMF (5 mL). HATU (570 mg, 1.5 mmol) and DIPEA (646 mg, 5 mmol) were added to the solution. The mixture was stirred at room temperature for 5 h until complete. The reaction was quenched with water, extracted with ethyl acetate (10 mL × 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 211 (437 mg, 80%). MS (ESI, m / z): 548 (M + +1).

[0635] Step 2: Synthesis of Compound 212

[0636] Compound 211 (430 mg, 0.79 mmol) was dissolved in DCM (3 mL), and trifluoroacetic acid (1.5 mL) was added to the above solution. After the reaction was complete, the solvent and excess trifluoroacetic acid were removed under reduced pressure. The mixture was then slurried with diethyl ether, filtered, and dried to obtain compound 212, which was directly added to the next reaction without purification.

[0637] Step 3: Synthesis of compound S102

[0638] Compounds 212 (100 mg, 0.2 mmol) and 213 (55 mg, 0.2 mmol) were dissolved in anhydrous DMF (2 mL). HATU (114 mg, 0.3 mmol) and DIPEA (129 mg, 1 mmol) were added to the solution. The reaction was stirred at room temperature for 5 h until complete. The reaction was quenched with water, extracted with ethyl acetate (5 mL × 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound S102 (112 mg, 75%). 1H NMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 8.92 (s, 1H), 8.13 (dd, J=8.4, 1.8Hz, 1H), 7.98 (t, J=5.8Hz, 1H), 7.83 (d, J=8.4Hz, 1H), 7.49 (s, 1H), 7.3 5 (d, J=1.8Hz, 1H), 7.34-7.22 (m, 6H), 7.26-7.19 (m, 2H), 6.91-6.85 (m, 2H), 4.66 (dtt, J=9.0, 5.7, 0.9Hz, 1H), 4.20-4. 09 (m, 2H), 4.00 (ddd, J=11.9, 7.0, 5.7Hz, 1H), 3.86 (dd, J=16.7, 5.9Hz, 1H), 3.76 (t, J=5.3Hz, 4H), 3.70 (t, J=5.9Hz, 2H ), 3.34-3.21 (m, 4H), 2.98 (t, J=7.1Hz, 1H), 2.71 (td, J=5.9, 3.7Hz, 2H), 1.71 (s, 3H), 1.66 (s, 3H). MS (ESI, m / z): 748 (M + +1).

[0639] Example 135 Synthesis of compound S103

[0640]

[0641] The synthesis method is the same as that for compound S102; only the corresponding raw materials need to be changed to obtain compound S103. 1 HNMR (500MHz, DMSO-d6) δ 11.10 (s, 1H), 9.04 (s, 1H), 8.47 (t, J=4.4Hz, 1H), 8.13 (dd, J=8.5, 1.9Hz, 1H), 7.88 (d, J=8.4Hz, 1H), 7.35 (d, J=1.8Hz, 1H), 7.34-7.20 (m, 9H), 6.91-6.85 (m, 2H), 4.81-4.73(m, 1H), 4.44-4.27(m, 1H), 4.20-4.18(m, 1H), 3.82-3.75(m, 2H), 3.74-3.65(m, 4H) , 3.52-3.44 (m, 1H), 3.36-3.20 (m, 5H), 3.17 (t, J=7.1Hz, 1H), 2.71 (td, J=5.9, 3.7Hz, 2H), 2.66 (d t, J=14.8, 6.2Hz, 1H), 2.58 (dt, J=15.0, 6.2Hz, 1H), 1.67 (s, 3H), 1.63 (s, 3H). MS (ESI, m / z): 762 (M+ +1).

[0642] Example 136 Synthesis of compound S104

[0643]

[0644] The synthesis method is the same as that for compound S102; only the corresponding raw materials need to be changed to obtain compound S104. 1 HNMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 8.71 (s, 1H), 8.15 (dd, J=8.5, 1.9Hz, 1H), 7.84 (d, J=8.4Hz, 1H), 7.55 (s, 1H ), 7.35(d, J=1.8Hz, 1H), 7.34-7.23(m, 5H), 7.26-7.19(m, 3H), 6.91-6.85(m, 2H), 4.69(d tt, J=9.2, 5.7, 0.9Hz, 1H), 4.24-4.16 (m, 2H), 3.76-3.66 (m, 3H), 3.61-3.53 (m, 4H), 3.18 -3.13(m, 4H), 2.72(td, J=5.9, 2.8Hz, 2H), 1.73(s, 3H), 1.68(s, 3H).MS(ESI, m / z): 691(M + +1).

[0645] Example 137 Synthesis of compound S105

[0646]

[0647] The synthesis method is the same as that for compound S86; only the corresponding raw materials need to be changed to obtain compound S105. 1HNMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 9.01 (s, 1H), 8.13 (dd, J=8.4, 2.0Hz, 1H), 8.02 (t, J=4.4Hz, 1H), 7.90 (d, J= 8.4Hz, 1H), 7.44 (s, 1H), 7.35 (d, J=1.8Hz, 1H), 7.34-7.23 (m, 6H), 7.26-7.18 (m, 2H), 6.91 6.85 (m, 2H), 4.75 (dtt, J=9.1, 5.7, 0.9Hz, 1H), 4.294.15 (m, 2H), 3.70 (t, J=6 .0Hz, 2H), 3.50 (dtd, J=14.3, 6.3, 4.4Hz, 1H), 3.33-3.18 (m, 5H), 3.08 (t, J=7. 0Hz, 1H), 2.71 (td, J=5.9, 3.7Hz, 2H), 1.73-1.52 (m, 12H), 1.56-1.45 (m, 1H), 1 .43 (dt, J=12.9, 6.3Hz, 1H), 1.33 (dq, J=12.7, 6.5Hz, 1H). MS (ESI, m / z): 747 (M + +1).

[0648] Example 138 Synthesis of compound S106

[0649]

[0650] The synthesis method is the same as that for compound S86; only the corresponding raw materials need to be changed to obtain compound S106. 1HNMR(500MHz, DMSO-d6)δ 11.10 (s, 1H), 8.97 (s, 1H), 8.31 (t, J=4.3Hz, 1H), 8.15 (dd, J=8.4, 2.0Hz, 1H), 7.82 (d, J=8.4Hz, 1H), 7.47 (s, 1H), 735 (d, J=1.8Hz, 1H), 7.34-7.22 (m, 6H), 7.25-7.18 (m, 2H), 6.91-6.85 (m, 2H), 4.63 (dtt, J=9.2, 5.7, 1.0Hz, 1H), 4.25-4. 16 (m, 2H), 3.70 (t, J=6.0Hz, 2H), 3.35-3.21 (m, 5H), 3.12 (dtd, J=14.3, 5.8, 4.3Hz, 1H), 3.05 (t, J=7.0Hz, 1H), 2.71 (t d, J=5.9, 3.7Hz, 2H), 1.81-1.64 (m, 9H), 1.67-1.56 (m, 1H), 1.59-1.50 (m, 2H), 1.54-1.46 (m, 1H). MS (ESI, m / z): 733 (M + +1).

[0651] Example 139: Test of the HPK1 kinase activity of the compounds of the present invention.

[0652] The HPK1 kinase domain (1-307aa) was dissolved in a kinase buffer (20 mM HEPES pH 7.5, 10 mM MgCl2, 1 mM EGTA, 0.5 mM TCEP, 0.01% Brij-35, 0.05% BSA) and added to a 96-well plate to a final concentration of 20 nM. Then, serially diluted test compounds of the present invention (10 concentration points for each compound) were added. The HPK1 kinase was pre-incubated with the test compounds for 30 min. Then, 20 μL of substrate solution (final concentration of 0.5 mg / mL SLP76-SH2 domain and 10 μM ATP) was added to each well to initiate the enzymatic reaction. The reaction was incubated at room temperature for 1 h. The inhibition rate of the test compounds against HPK1 kinase activity at each concentration was determined according to the Luminescent Kinase Assay Kit (Beyotime Biotechnology Company) instructions. The IC50 of the inhibitory activity of the test compounds against HPK1 kinase was calculated using GraphPad fitting. 50 The experimental results are shown in Table 1. Compounds A and B were used as positive controls. The inhibitory activity of the compounds of this invention against HPK1 is comparable to or better than that of positive control compounds A and B.

[0653]

[0654]

[0655]

[0656] Example 140: Test of the degradation activity of the compounds of the present invention against HPK1 protein.

[0657] (1) Cell collection: Jurkat cells adhered to the culture wall for 12 h, and some of the compounds of the present invention were co-incubated with the cells for 24 h.

[0658] (2) Protein extraction: Discard the original culture medium, wash the cells three times with pre-cooled PBS, add an appropriate amount of lysis buffer, mix well and place on ice for lysis for 30 min, centrifuge at 12000 rpm for 5 min at 4℃, transfer the supernatant after centrifugation to a new centrifuge tube for quantification.

[0659] (3) Protein quantification: Protein was quantified using the BCA method. Solution A and solution B were mixed at a ratio of 50:1 to obtain the BCA working solution. 100 μL of BCA working solution, 9 μL of triple-distilled water, and 1 μL of protein sample were added to a 96-well plate, mixed, and incubated at 37°C for 30 min. The absorbance was measured using a full-wavelength microplate reader, and the protein concentration was calculated based on the standard curve. The quantified protein was mixed with 5× loading buffer at a ratio of 4:1, denatured in boiling water for 8 min, cooled on ice, and stored at -20°C for later use.

[0660] (4) Prepare SDS-PAGE gel. The voltage of the stacking gel is 90V and the voltage of the separating gel is 120V. At 4℃, the membrane is transferred at 100V for 1 hour. After the transfer is completed, the protein membrane is immediately placed in the prepared 5% BSA solution and shaken slowly on a shaker. The membrane is then blocked at room temperature for 1 hour.

[0661] (5) Refer to the instructions of HPK1 Antibody (4472SCST), GLK (D1L4G) Rabbit mAb (92427SCST), RabbitmAb (92711TCST), and β-actin Mouse Monoclonal antibody (BE0021 easybio) to dilute the primary antibody at an appropriate ratio, incubate overnight at 4°C with gentle shaking, and then wash three times with PBST for 10 min each time.

[0662] (6) Select Goat Anti-Rabbit IgG(H&L)-HRP Conjugated (BE0101easybio) or Goat Anti-Mouse IgG(H&L)-HRP Conjugated (BE0102 easybio) according to the primary antibody. Refer to the instructions of the secondary antibody, dilute the secondary antibody at an appropriate ratio, and incubate at room temperature with gentle shaking for 1 hour. Wash with PBST 3 times, 10 min each time.

[0663] (7) ECL luminescent solution was added, and the results were observed using a developer. The Western spectroscopy results were quantified using ImageJ software, and the degradation rates (HPK1 and GLK) were calculated by comparing with the control group without the compound. The experimental results are shown in Table 2. The compound of the present invention has excellent degradation activity against HPK1, but no significant degradation activity against GLK, indicating that the compound of the present invention has high selectivity and low toxicity.

[0664] Table 2. Degradation activities of the compounds of this invention on HPK1 and GLK proteins.

[0665]

[0666]

[0667] Example 141: Detection of Cytokine Release in T Cells

[0668] HPK1 kinase inhibits the release of T cell effector cytokines; therefore, the ability of the compound of this invention to enhance T cell cytokine release was detected by ELISA. Human PBMCs were thawed and resuspended in RPMI 1640 (Gibco) medium containing 10% bovine placental serum, and the cells were seeded in 96-well plates (1×10⁻⁶). 5 ( / well). Serially diluted compounds of the present invention were added to 96-well plates and incubated at 37°C, 5% CO2 for 1 h. PBMCs were activated with 100 μL of anti-CD3 / CD28 antibody (final concentration 1 μg / mL), and then incubated at 37°C, 5% CO2 for 48 h. The supernatant was diluted 8-fold with PBS, and 100 μL of the diluted supernatant was used to detect the release of IL-2 at each concentration of the compound of the present invention using a human IL-2 ELISA kit. The EC50 of the compound of the present invention was calculated using GraphPad fitting. 50 Values. The experimental results are shown in Table 3. The compounds of this invention can significantly enhance the release of IL-2 from PBMC cells, and are significantly superior to the HPK1 small molecule inhibitor (compound B). This indicates that the compounds of this invention can restore or enhance the ability of T cells to release factors by degrading HPK1 protein, thereby restoring or enhancing the anti-tumor immune response.

[0669] Table 3. Results of the activity test of the compounds of the present invention in stimulating PBMC to release IL-2.

[0670] serial number <![CDATA[EC 50 (nM)]]> serial number <![CDATA[EC 50 (nM)]]> S1 150 S49 82 S3 162 S53 79 S5 149 S60 82 S10 79 S61 87 S11 71 S62 80 S12 68 S63 79 S13 77 S71 59 S14 80 S72 60 S15 78 S74 63 S16 86 S81 72 S17 73 S85 69 S18 70 S103 70 S47 86 S106 65 S48 73 B 255

[0671] Example 142: Co-culture experiment of PBMCs and tumor cells

[0672] PBMC cells were stimulated with a mixed CD3 / CD28 antibody for 24 h. Then, MDA-MB-231 cells (triple-negative breast cancer) and CT-26 cells (mouse colon cancer) were co-cultured with CD3 / CD28 antibody-activated PBMC cells at an effector-to-target ratio of 1:10 for 6 h. The tumor-killing activity of PBMC cells in the co-culture system was detected by an LDH release assay. Cell membrane disruption caused by apoptosis or necrosis leads to the release of cytoplasmic enzymes into the culture medium, including the relatively stable enzyme lactate dehydrogenase (LDH). By detecting the activity of LDH released from ruptured cells into the culture medium, the tumor-killing effect of PBMCs can be quantitatively analyzed. Experimental results are as follows: Figure 1 and Figure 2 As shown, compared with the DMSO control group, the target compounds S10 and S47 can significantly promote the release of LDH, indicating that S10 and S47 significantly increase or restore the killing and lysis of tumor cells by PBMCs.

Claims

1. A compound of the general formula as described in Formula I, or a pharmaceutically acceptable salt thereof, characterized in that, Its structural formula is shown below. ； In Formula I: E is or ; R is either -CH- or -N-; Y can be deuterium, fluorine, chlorine, cyano, methyl, trifluoromethyl, methoxy, or trifluoromethoxy. M is deuterium, methyl, fluorine, or trifluoromethyl; a is 0, 1, or 2; b is 0 or 1; Q is a single bond or -NH-; W is -CH2-, -C(CH3)2 or ; L is ； ； ； The left side is connected to E, and the right side is connected to B; r21 is 1, 2, 3, 4, 5, 6, 7 or 8; r22 is 0, 1, 2, or 3; r31 is 1, 2, or 3; r41 is 1, 2, or 3; r42 is 0, 1, 2, or 3; r52 is either 0 or 1; B is or ; X is , The left side is connected to L, and the right side is connected to... or Connected; Z can be -OCH2CH2CH2CH2-, -OCH2CH2OCH2-, -OCH2CH2N(CH3)CH2-, or -CH2OCH2CH=CHCH2OCH2CH2-.

2. A compound as shown in Formula I, or a pharmaceutically acceptable salt thereof, characterized in that, Its structural formula is shown below: ； In Formula I: E is ； L is ； ； ； The left side is connected to E, and the right side is connected to B; r21 is 1, 2, 3, 4, 5, 6, 7 or 8; r22 is 0, 1, 2, or 3; r31 is 1, 2, or 3; r41 is 1, 2, or 3; r42 is 0, 1, 2, or 3; r52 is either 0 or 1; B is or ; X is , The left side is connected to L, and the right side is connected to... or Connected; Z can be -OCH2CH2CH2CH2-, -OCH2CH2OCH2-, -OCH2CH2N(CH3)CH2-, or -CH2OCH2CH=CHCH2OCH2CH2-.

3. A compound or a pharmaceutically acceptable salt thereof, characterized in that, The compounds are selected from compounds with any of the following structures: ； ； ； ； ； 。 4. A pharmaceutical composition, characterized in that, It contains a therapeutically effective amount of the compound as described in any one of claims 1-3 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

5. Use of a compound as described in any one of claims 1-3 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 4, in the preparation of a hematopoietic progenitor cell kinase 1 degrading agent.

6. Use of a compound as described in any one of claims 1-3 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 4, in the preparation of a medicament for treating and / or preventing cancer, wherein the cancer is breast cancer or colorectal cancer.

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