Heterocyclic carboxamide compounds and pharmaceutical compositions and applications thereof

Abstract

The present invention discloses heterocyclic carboxamide compounds, pharmaceutical compositions, and applications thereof. The heterocyclic carboxamides of the present invention are capable of efficiently and selectively degrading hematopoietic progenitor cell kinase 1 (HPCK1), while lacking degradation activity against other proteins in the same family. Compared to HPCK1 small molecule inhibitors, these heterocyclic carboxamides are more efficient in stimulating T cell anti-tumor immune responses, releasing effector cytokines, and exhibiting stronger anti-tumor activity. #imgabs0#

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and in particular relates to a heterocyclic carboxamide hematopoietic progenitor cell kinase 1 degrader and an application thereof. Background Art

[0002] Immunotherapy has revolutionized cancer treatment and brought new hope to patients. In particular, immune checkpoint inhibitors targeting the PD-1 and CTLA-4 pathways have demonstrated significant clinical efficacy, but they are only effective in specific patient populations and tumor types, with low tumor response rates (~30%). Furthermore, most patients do not experience sustained symptom relief and develop drug resistance after a period of treatment. Therefore, the urgent need to discover new tumor immunotherapy targets and improve the clinical efficacy of immune checkpoints is crucial for the application and promotion of tumor immunotherapy.

[0003] Hematopoietic progenitor cell kinase 1 (HPK1, MAP4K1) is a member of the MAP4K family and a Ste20 serine / threonine protein kinase. In addition to HPK1, the MAP4K family includes five other members: MAP4K2, MAP4K3, MAP4K4, MAP4K5, and MAP4K6. HPK1 is primarily expressed in hematopoietic cells, such as T cells, B cells, neutrophils, dendritic cells (DCs), natural killer (NK) cells, and macrophages. Numerous studies have demonstrated that HPK1 is a negative regulator of both the T cell receptor and the B cell receptor. Following TCR activation, HPK1 in the cytoplasm is recruited to the plasma membrane, where it is phosphorylated at amino acid residues Y381, S171, and T165, resulting in fully kinase-activated HPK1. Activated HPK1 phosphorylates the amino acid residue S376 of its adaptor protein SLP76, providing a binding site for the negative regulatory factor 14-3-3, promoting the proteasomal degradation of SLP76, and ultimately destroying the stability of the TCR signaling complex, thereby hindering the downstream kinase signaling pathway that promotes T cell activation and proliferation. In addition to TCR signaling, HPK1 also negatively regulates T cell signaling through the prostaglandin E2 (PGE2) receptor. In addition, under the stimulation of growth factors, pressure, inflammatory factors and differentiation factors, HPK1 can also transmit immunosuppressive signals in B cells, NK cells and dendritic cells. In addition, a recent study showed that the kinase activity of HPK1 inhibits the immune function of multiple cells, including CD4 + T cells, CD8 +HPK1 is a key target for tumorigenesis and is a key component of cancer therapy. Studies have shown that HPK1 can inhibit T cells, NK cells, and dendritic cells, and that inhibiting HPK1 kinase activity is sufficient to induce antitumor immune responses. Furthermore, inhibiting HPK1 kinase activity further promotes T cell effector function, significantly enhancing the therapeutic efficacy of PD-L1 monoclonal antibodies. HPK1 gene deletion, HPK1 inhibitors, or HPK1 protac degraders can enhance CAR-T cell-based immunotherapy, demonstrating improved antitumor activity in various preclinical hematological and solid tumor mouse models. Notably, neither HPK1 knockout nor kinase-in mice exhibited lethal inflammatory responses, which are significantly evident in the absence of other negative immune regulators, such as CTLA-4 and Cbl-b, suggesting that HPK1 inhibitors have a high safety profile. In summary, HPK1 is a potentially effective new target for tumor immunotherapy, and the research and development of HPK1 inhibitors is crucial for addressing key challenges currently facing tumor immunotherapy.

[0004] Over a decade ago, researchers discovered that HPK1 could be a potential target for tumor immunotherapy. HPK1 inhibitors have been highly sought after by major pharmaceutical companies and research institutions, and various structures of HPK1 inhibitors have been reported. According to incomplete statistics, four HPK1 inhibitors are currently in early clinical development: Treadwell Therapeutics' CFI-402411, BeiGene's BGB-15025, Zhuhai Yufan's PRJ1-3024, and Nimbus Therapeutics' NDI-101150. Their structures have not yet been disclosed. Despite the numerous reports of HPK1 inhibitors, no such drugs have yet been marketed. The primary challenge in developing HPK1 inhibitors is that, despite the diverse functions of HPK1 family members, there is a high degree of structural homology, making the design of highly selective inhibitors challenging.

[0005] Compared to traditional drugs, PROTACs offer significant advantages: a wider range of action, higher activity, the ability to target undruggable targets; improved selectivity, activity, and safety; and the ability to overcome tumor drug resistance. PROTACs can achieve selectivity for certain targets that is difficult to achieve with small molecules. Therefore, the development of HPK1 PROTACs holds promise for addressing the issues of low selectivity and dose-dependent efficacy of HPK1 inhibitors. However, few HPK1 PROTACs have been reported. Therefore, the research and development of HPK1 PROTACs is urgent and holds significant scientific significance and development value. Summary of the Invention

[0006] To address the low selectivity of small-molecule HPK1 inhibitors, the present invention leverages the selectivity advantages of PROTACs, which are difficult to achieve with small molecules, to develop HPK1-targeting PROTAC molecules and provide a class of heterocyclic carboxamide-based HPK1 PROTAC degraders. The PROTACs of this invention are able to efficiently and selectively degrade HPK1 protein, while lacking degradation activity against other proteins in the same family. Compared to small-molecule HPK1 inhibitors, they are more efficient in stimulating T cell anti-tumor immune responses, releasing effector cytokines, and exhibiting stronger anti-tumor activity.

[0007] In order to achieve the above object, the present invention adopts the following technical solutions:

[0008] The present invention provides a heterocyclic carboxamide compound as shown in Formula I, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, the structure of which is shown below:

[0009]

[0010] In Formula 1:

[0011] R 1 For hydrogen, halogen, C 1-4 Alkoxy, halogenated (C 1-4 Alkoxy) or deuterated (C 1-4 alkoxy);

[0012] R2 is halogen, cyano, hydroxyl (C 1-4 Alkyl), halogenated (C 1-4 alkyl);

[0013] m is 0, 1, 2, or 3;

[0014] Q is N or C;

[0015] Y is N or C;

[0016] E is

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

[0018] R 3 C 1-6 alkyl;

[0019] R 4 for

[0020] R 5 is hydrogen or C 1-4 alkyl;

[0021] L is The "---" end indicates that it is connected to the E end. connected;

[0022] L1 is a single bond, -O-, or -NR 6 -、 The "---" end indicates that it is connected to the E end, and the "---" end indicates that it is connected to L2;

[0023] L2 is a single bond, The "---" end indicates that it is connected to L1, and the "---" end indicates that it is connected to L3;

[0024] L3 is a single bond,

[0025] R 6 is hydrogen or C 1-3 alkyl;

[0026] a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0027] b is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0028] c is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0029] d is 1, 2, 3, or 4;

[0030] e is 1, 2, 3, 4, 5, or 6;

[0031] f is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.

[0032] In some embodiments,

[0033] L is The "---" end indicates that it is connected to the E end. connected;

[0034] a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11;

[0035] b is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0036] c is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0037] d is 1, 2, or 3;

[0038] e is 1, 2, 3, 4, or 5;

[0039] f is 1, 2, 3, 4, 5, 6, 7, 8 or 10.

[0040] In some embodiments,

[0041] L is The "---" end indicates that it is connected to the E end. connected;

[0042] a is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0043] b is 1, 2, 3, 4, 5, 6 or 7;

[0044] c is 1, 2, 3, 4, 5, 6, 7, 8, or 9;

[0045] d is 1, 2, or 3;

[0046] e is 1, 2, 3, or 4;

[0047] f is 1, 2, 3, 4, 5, 6, 7 or 8.

[0048] In some embodiments,

[0049] E is

[0050]

[0051] In some embodiments, R 2 is fluorine, cyano, hydroxymethyl, methyl or trifluoromethyl.

[0052] In some embodiments, the heterocyclic carboxamide compound as shown in Formula I, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, has the structural formula shown in any of the following:

[0053]

[0054] Wherein, E, L, R1, R2 and a are as described above.

[0055] In some embodiments, the heterocyclic carboxamide compound represented by Formula I is selected from compounds with any of the following structures:

[0056]

[0057]

[0058]

[0059] The present invention provides a use of a heterocyclic carboxamide compound as shown in Formula I, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof in the preparation of a hematopoietic progenitor cell kinase 1 degrader.

[0060] The present invention provides a use of a heterocyclic carboxamide compound as shown in Formula I, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof in the preparation of a medicament for treating and / or preventing cancer.

[0061] In some embodiments, the cancer is one or more of bone cancer, lung cancer, stomach cancer, colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, bladder cancer, cervical cancer, testicular cancer, kidney cancer, head and neck cancer, thyroid cancer, esophageal cancer, lymphoma, leukemia, or skin cancer.

[0062] The present invention provides a pharmaceutical composition comprising a heterocyclic carboxamide compound as shown in Formula I, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, and a pharmaceutically acceptable carrier or excipient.

[0063] In some embodiments, in the pharmaceutical composition, the amount of the heterocyclic carboxamide compound as shown in Formula I, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof is a therapeutically effective amount.

[0064] The present invention provides an application of a pharmaceutical composition in preparing a hematopoietic progenitor cell kinase 1 degrader.

[0065] The present invention provides an application of a pharmaceutical composition in preparing a drug for treating and / or preventing cancer.

[0066] In some embodiments, the cancer is one or more of bone cancer, lung cancer, stomach cancer, colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, bladder cancer, cervical cancer, testicular cancer, kidney cancer, head and neck cancer, thyroid cancer, esophageal cancer, lymphoma, leukemia, or skin cancer.

[0067] The pharmaceutically acceptable carrier can be an excipient widely used in the field of pharmaceutical production. Excipients are primarily used to provide a safe, stable, and functional pharmaceutical composition. They can also provide methods to dissolve the active ingredient at a desired rate after administration to a subject, or to promote effective absorption of the active ingredient after administration of the composition to a subject. The pharmaceutical excipient can be an inert filler, or provide a certain function, such as stabilizing the overall pH value of the composition or preventing the degradation of the active ingredient in the composition. The pharmaceutical excipient can include one or more of the following excipients: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, anti-adhesive agents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents, and sweeteners.

[0068] The pharmaceutical compositions of the present invention can be prepared according to the disclosed content using any method known to those skilled in the art, such as conventional mixing, dissolving, granulating, emulsifying, grinding, encapsulating, embedding or lyophilizing processes.

[0069] The pharmaceutical compositions of the present invention can be administered in any form, including injection (intravenous), mucosal, oral (solid and liquid formulations), inhalation, ophthalmic, rectal, topical, or parenteral (infusion, injection, implant, subcutaneous, intravenous, intraarterial, intramuscular) administration. The pharmaceutical compositions of the present invention can also be in a controlled-release or sustained-release dosage form (e.g., liposomes or microspheres). Examples of solid oral formulations include, but are not limited to, powders, capsules, caplets, 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 formulations. Examples of formulations for parenteral administration include, but are not limited to, solutions for injection, dry powder 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 lozenges.

[0070] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, prepared by reacting the compounds of the present invention with relatively nontoxic acids or bases. When the compounds of the present 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 neat solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts, or similar salts. When the compounds of the present 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 neat 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, and the like; and organic acid salts such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, Citric acid, tartaric acid, methanesulfonic acid and similar acids; organic acid salts also include salts of amino acids (such as arginine, etc.), glucuronic acid and other organic acids. Certain specific compounds of the present invention contain basic and acidic functional groups and can be converted into any base or acid addition salt. Preferably, the salt is contacted with a base or acid in a conventional manner and the parent compound is separated to regenerate the free form of the compound. The free form of the compound differs from its various salt forms in certain physical properties, such as solubility in polar solvents.

[0071] The "pharmaceutically acceptable salts" of the present invention can be synthesized from parent compounds containing acid or basic groups by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of an appropriate base or acid in water or an organic solvent, or a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.

[0072] The term "isomers" refers to compounds that have the same chemical formula but different arrangements of the atoms.

[0073] The term "metabolite" refers to a pharmaceutically active product produced by the in vivo metabolism of a compound of Formula I or a salt thereof. Such a product may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, glucuronidation, enzymatic cleavage, or the like of the administered compound. Thus, the present invention includes metabolites of the compounds of the present invention, including compounds produced by methods in which a compound of the present invention is contacted with a mammal for a period of time sufficient to yield a metabolite thereof.

[0074] Metabolites are typically identified by preparing a radiolabeled isotope of a 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 conversion products from urine, blood, or other biological samples. These products are easily isolated because they are labeled (others are isolated by utilizing antibodies that can bind to antigenic epitopes present in the metabolites). Metabolite structures are determined in a conventional manner, for example, by MS, LC / MS, or NMR analysis. Typically, analysis of metabolites is performed using the same methods as conventional drug metabolism studies known to those skilled in the art. As long as the metabolite products are not otherwise undetectable in vivo, they can be used in assays for therapeutic dosing of the compounds of the invention. The compounds of the invention may contain unnatural ratios of atomic isotopes on one or more of the atoms that constitute the compound. For example, compounds may be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125( 125 I) or C-14( 14 C) All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0075] In addition to the form of salts, the compounds provided by the present invention also exist in prodrug form. The prodrugs of the compounds described herein are easily chemically changed under physiological conditions to be converted into the compounds of the present invention. Any compound that can be converted in vivo to provide a bioactive substance (i.e., a compound shown in Formula I) is a prodrug within the scope and spirit of the present invention. For example, a compound containing a carboxyl group can form a physiologically hydrolyzable ester, which acts as a prodrug by being hydrolyzed in vivo to obtain the compound shown in Formula I itself. The prodrug is preferably administered orally, because hydrolysis occurs primarily under the influence of digestive enzymes in many cases. When the ester itself is active or hydrolysis occurs in the blood, parenteral administration can be used.

[0076] Those skilled in the art will understand that according to the conventions used in the art, the structural formulas used in this application to describe groups and It means that the corresponding group is connected to other fragments and groups in the compound represented by formula I through this site.

[0077] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0078] The term "alkyl" refers to a straight or branched chain alkyl group having the specified number of carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.

[0079] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogen groups, as defined above. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy.

[0080] 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.

[0081] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

[0082] The reagents and raw materials used in the present invention are commercially available.

[0083] The present invention is beneficial in that:

[0084] (1) The heterocyclic carboxamide compounds provided by the present invention, namely the HPK1 PROTAC molecules, can efficiently and selectively degrade HPK1 protein, while having no degradation activity against proteins in the same family such as GLK.

[0085] (2) The HPK1 PROTAC molecule provided by the present invention more efficiently stimulates T cell anti-tumor immune response

[0086] (3) The HPK1 PROTAC molecule provided by the present invention has a good therapeutic effect on cancer. DETAILED DESCRIPTION

[0087] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples.

[0088] In the following examples, the experimental methods without specific conditions were carried out according to conventional methods and conditions, or selected according to the product instructions.

[0089] Example 1 Synthesis of Intermediates 2a-c

[0090]

[0091] 2,4-Dichloropyrimidine-5-carboxamide (1.92 g, 10 mmol) was dissolved in anhydrous ethanol (50 mL), and 2-aminobenzyl alcohol (1.23 g, 10 mmol) and DIPEA (5.24 mL, 30 mmol) were added. The mixture was refluxed for 3 h. After the reaction was complete, the reaction was quenched with water (150 mL). The product precipitated and the filter cake was collected by filtration, washed three times with purified water, and dried to obtain a white solid intermediate 2a (1.80 g, 65%). MS (ESI, m / z): 279 (M + +1). Intermediates 2b-c can be obtained by simply replacing the corresponding starting materials.

[0092] Example 2 Synthesis of Intermediate 10

[0093]

[0094] a) 3-Methoxy-phenylethylamine (50 g, 331 mmol) was dissolved in 1 M HCl aqueous solution, and 37% formaldehyde aqueous solution (107 g, 1.32 mol) was added. The mixture was reacted at 60°C for 1 h. After the reaction was complete, the mixture was cooled to 0°C and 50% NaOH aqueous solution (43.6 g, 1.10 mol) was slowly added. The mixture was stirred overnight, filtered, and washed with water to obtain a white solid intermediate 4 (48 g, 86%). MS (ESI, m / z): 339 (M + +1).

[0095] b) Compound 4 (48 g, 142 mmol) was dissolved in isopropanol (400 mL), concentrated hydrochloric acid (26 g) was added, and the mixture was allowed to react at room temperature overnight. After the reaction was complete, methyl tert-butyl ether (200 mL) was added and stirred for 2 h. The filter cake was collected by filtration and washed once with a mixed solution of isopropanol and methyl tert-butyl ether (1:1). The solid was dried to obtain a white solid, which was then dissolved in a saturated aqueous solution of NaHCO3 (400 mL) and stirred overnight. The solid was extracted with dichloromethane (200 mL x 3) to obtain intermediate 5 (37 g, 80%) as a light yellow oily liquid. MS (ESI, m / z): 164 (M + +1).

[0096] c) Compound 5 (16.3 g, 100 mmol) was dissolved in AcOH (100 mL), and a mixed solution of AcOH (100 mL) and fuming nitric acid (200 mL) was added dropwise at 0°C. The mixture was reacted at 0°C for 4 h. After the reaction was complete, water (300 mL) was slowly added at 0°C to quench the mixture. The pH was adjusted to alkaline, and the mixture was extracted with dichloromethane (200 mL×4). The mixture was concentrated under reduced pressure to obtain a crude intermediate 6. MS (ESI, m / z): 209 (M + +1).

[0097] d) The crude product of compound 6 (2.08 g) was dissolved in acetonitrile (50 mL), and a mixed solution of ethyl bromoacetate (1.75 g, 10.5 mmol) and DIPEA (8.7 mL, 50 mmol) was added at room temperature. The mixture was reacted at room temperature for 4 h. After the reaction was complete, water (30 mL) was added to quench the reaction. The mixture was extracted with ether (30 mL × 3), concentrated under reduced pressure, and purified by column chromatography to obtain intermediate 7 (1.18 g) as a colorless, transparent, oily liquid. MS (ESI, m / z): 295 (M + +1).

[0098] e) Compound 7 (2.94 g, 10 mmol) was dissolved in a mixed solvent of ethanol (18 mL) and water (6.3 mL). A mixed solution of ferrous sulfate heptahydrate (500 mg, 1.8 mmol) and reduced iron powder (494 mg, 8.82 mmol) was added at room temperature. The mixture was reacted at room temperature for 4 h. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by column chromatography to obtain a white solid intermediate 8a (2.11 g, 80%). MS (ESI, m / z): 265 (M + +1).

[0099] f) Compound 8 (2.64 g, 10 mmol) and intermediate 2a (2.65 g, 9.5 mmol) were dissolved in NMP (50 mL). 4 M HCl / Dioxane (6.3 mL, 25 mmol) was added at room temperature and the mixture was heated to 110° C. for 4 h. After the reaction was complete, the reaction was quenched with saturated NaHCO 3 solution (150 mL). The product precipitated and the filter cake was collected by filtration, washed three times with purified water, and dried to obtain intermediate 9 (3.14 g, 62%) as a brown solid. MS (ESI, m / z): 507 (M + +1).

[0100] g) Compound 9 (506 mg, 1 mmol) was dissolved in methanol (10 mL), and a 2M aqueous NaOH solution (1.5 mL, 3 mmol) was added. The mixture was reacted at room temperature for 2 h. After the reaction was complete, the mixture was concentrated under reduced pressure, slurried with purified water, filtered, washed, and dried to obtain a brown solid intermediate 10 (421 mg, 88%). MS (ESI, m / z): 479 (M + +1).

[0101] Example 3 Synthesis of Intermediates 14a-c

[0102]

[0103] a) The crude product of compound 6 (2.0 g) was dissolved in dichloromethane (25 mL), and TFAA (3 mL) was added at 0°C. The mixture was reacted at 0°C for 3 h. After the reaction was complete, 1 M aqueous KOH solution (20 mL) was added and stirred for 1 h to quench the reaction. The mixture was extracted with dichloromethane (30 mL × 3), concentrated under reduced pressure, and purified by column chromatography to obtain intermediate 11 (1.05 g) as a colorless, transparent, oily liquid. MS (ESI, m / z): 305 (M + +1).

[0104] b) Compound 11 (3.04 g, 10 mmol) was dissolved in a mixed solvent of ethanol (18 mL) and water (6.3 mL). A mixed solution of ferrous sulfate heptahydrate (500 mg, 1.8 mmol) and reduced iron powder (494 mg, 8.82 mmol) was added at room temperature. The mixture was reacted at room temperature for 4 hours. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by column chromatography to obtain a white solid intermediate 12 (2.24 g, 82%). MS (ESI, m / z): 275 (M + +1).

[0105] c) Compound 12 (2.72 g, 10 mmol) and intermediate 2 (2.65 g, 9.5 mmol) were dissolved in NMP (50 mL). 4 M HCl / Dioxane (6.3 mL, 25 mmol) was added at room temperature and the mixture was heated to 110° C. for 4 h. After the reaction was complete, the reaction was quenched with saturated NaHCO 3 solution (150 mL). The product precipitated and the filter cake was collected by filtration, washed three times with purified water, and dried to obtain intermediate 13a (3.2 g, 62%) as a brown solid. MS (ESI, m / z): 517 (M + +1). Intermediates 13b-c can be prepared by simply replacing the corresponding starting materials.

[0106] d) Compound 13a (516 mg, 1 mmol) was dissolved in methanol (10 mL), and K2CO3 (444.6 mg, 3.0 mmol) was added. The mixture was reacted at room temperature for 2 h. After the reaction was complete, the filtrate was filtered and concentrated under reduced pressure to obtain brown solid intermediate 14a (421 mg, 88%). MS (ESI, m / z): 421 (M + +1). Intermediates 14b-c can be prepared by simply replacing the corresponding starting materials.

[0107] Example 4 Synthesis of Intermediate 16

[0108]

[0109] a) Compound 5 (1.62 g, 9.94 mmol) was dissolved in trifluoroacetic acid (20 mL), and NBS (1.96 g, 11 mmol) was added. The mixture was allowed to react at room temperature for 1 h. After the reaction was complete, water was added to quench the mixture, and the pH was adjusted to alkaline with saturated NaHCO₃. The mixture was extracted with dichloromethane (20 mL × 5). The organic phases were combined and concentrated under reduced pressure to give the crude intermediate 15 (1.5 g, 63%). MS (ESI, m / z): 242 (M + +1).

[0110] b) Compound 15 (1.0 g, 4.15 mmol) was dissolved in dichloromethane (25 mL), and TFAA (3 mL) was added at 0°C. The mixture was reacted at 0°C for 3 h. After the reaction was complete, 1 M aqueous KOH solution (20 mL) was added and stirred for 1 h to quench the reaction. The mixture was extracted with dichloromethane (30 mL × 3), concentrated under reduced pressure, and purified by column chromatography to obtain intermediate 16 (545 mg, 39%) as a colorless, transparent, oily liquid. MS (ESI, m / z): 338 (M + +1).

[0111] Example 5 Synthesis of Intermediate 22

[0112]

[0113] a) Compound 17 (2.33 g, 10 mmol) was dissolved in tetrahydrofuran (30 mL), and H2O2 (330 mg, 11 mmol) was added. The mixture was allowed to react at room temperature overnight. After the reaction was complete, a saturated aqueous Na2S2O3 solution was added to quench the reaction. The mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with a saturated NaCl solution, dried over anhydrous Na2SO4, filtered to remove salt, and concentrated under reduced pressure to obtain intermediate 18 (1.75 g, 75%). MS (ESI, m / z): 250 (M + +1).

[0114] b) Compound 18 (2.50 g, 10 mmol) was dissolved in aqueous ammonia (20 mL) and reacted at room temperature overnight. After the reaction was complete, the mixture was concentrated under reduced pressure to obtain intermediate 19 (1.01 g, 50%). MS (ESI, m / z): 203 (M + +1).

[0115] c) Under nitrogen protection, compound 19 (2.33 g, 10 mmol) was dissolved in toluene (30 mL), and intermediate 16 (3.7 g, 11 mmol), Cs2CO3 (9.7 g, 30 mmol), Pd2(dba)3 (1.8 g, 2 mmol), and t-BuBrettPhos (2.4 g, 5 mmol) were added and reacted at 130°C for 3 h. After the reaction was complete, water was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered to remove salt, and concentrated under reduced pressure to obtain intermediate 20 (2.79 g, 65%). MS (ESI, m / z): 431 (M + +1).

[0116] d) Following the synthetic steps of intermediate 2a, intermediate 21 can be obtained by replacing the corresponding starting materials. MS (ESI, m / z): 518 (M + +1).

[0117] e) Following the synthetic step d of intermediates 14a-c, intermediate 22 was obtained. MS (ESI, m / z): 422 (M + +1).

[0118] Example 6 Synthesis of Intermediates 25a-e, 26a-d, and 28

[0119]

[0120] a) Under nitrogen protection, intermediate 23 (321 mg, 1 mmol), Pd(dppf)2Cl2 (70 mg, 0.1 mmol), 2-ethynol (84 mg, 1.5 mmol), and CuI (38 mg, 0.2 mmol) were dissolved in DMF (10 mL). Triethylamine (0.33 mL) was added and the mixture was stirred at 80°C overnight. After the reaction was complete, water was added to quench the reaction. The mixture was 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 24a (209 mg, 70%). MS (ESI, m / z): 313 (M + +1). Intermediates 24b-h and 27 can be obtained by simply replacing the corresponding reaction substrates.

[0121] b) Under nitrogen protection, intermediate 24a (312 mg, 1 mmol) was dissolved in tetrahydrofuran (2 mL), and triethylamine (207 μL, 1.5 mmol) and MsCl (172 mg, 1.5 mmol) were added at 0°C. The mixture was reacted at 0°C for 3 h and then directly dried to give intermediate 25a (343 mg, 88%). MS (ESI, m / z): 391 (M + +1). Intermediates 25b-f and 28 can be obtained by simply replacing the corresponding starting materials and following the same preparation method.

[0122] c) Starting material 24a (312 mg, 1 mmol) was dissolved in acetone and 2M Jones reagent (1 mL) was added dropwise at 0°C. The reaction was stirred at room temperature for 30 min. The reaction was monitored for completion by TLC. The mixture was extracted with ethyl acetate, dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford intermediate 26a (198 mg, 56%). MS (ESI, m / z): 355 (M + +1). Intermediates 26b-d were prepared by the same method by simply replacing the corresponding starting materials.

[0123] Example 7 Synthesis of Intermediates 31a-b

[0124]

[0125] a) The same synthesis step a as that of intermediate 25a was followed by replacing the corresponding raw materials and following the same preparation method to obtain intermediate 30a-b. 30a MS (ESI, m / z): 327 (M + +1).

[0126] b) The same synthesis step b as that of intermediate 25a was performed, except that the corresponding raw materials were replaced and the same preparation method was used to obtain intermediate 31a-b. 31a MS (ESI, m / z): 405 (M + +1).

[0127] Example 8 Synthesis of Intermediate 34

[0128]

[0129] a) The same synthetic step a as that of intermediate 25a was followed by replacing the corresponding raw materials and following the same preparation method to obtain intermediate 33. MS (ESI, m / z): 327 (M + +1).

[0130] b) The same synthesis step b as that of intermediate 25a was followed by replacing the corresponding raw materials and following the same preparation method to obtain intermediate 34. MS (ESI, m / z): 405 (M + +1).

[0131] Example 9 Synthesis of Intermediate 37

[0132]

[0133] a) The same synthetic step a as that of intermediate 25a was followed by replacing the corresponding raw materials and following the same preparation method to obtain intermediate 36. MS (ESI, m / z): 341 (M + +1).

[0134] b) The same synthesis step b as that of intermediate 25a was followed by replacing the corresponding raw materials and following the same preparation method to obtain intermediate 37. MS (ESI, m / z): 419 (M + +1).

[0135] Example 10 Synthesis of Intermediates 39a-f, 41a-c, and 43a-g

[0136]

[0137] a) Starting material 38 (2.0 g, 7.25 mmol) was dissolved in DMF (10 mL). 2-Bromoethylamine (1.08 g, 8.69 mmol) and DIPEA (2.84 mL, 9.43 mmol) were added to the reaction system and reacted at 90°C for 5 h. After the reaction was complete, the mixture was cooled to room temperature, diluted with water, and extracted with dichloromethane (10 mL x 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 39a (1.54 g, 56%). MS (ESI, m / z): 380 (M + +1). Intermediates 39b-g, 40a-c, and 42a-g can be obtained by simply replacing the corresponding starting materials and following the same preparation method.

[0138] b) Intermediate 40a (387.4 mg, 1 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (148 μL) was added, and the mixture was reacted at 25°C for 8 h, and then directly dried to obtain intermediate 41a (291 mg, 88%). MS (ESI, m / z): 332 (M + +1). Intermediates 41b-c can be prepared by the same method by simply replacing the corresponding starting materials.

[0139] c) Intermediate 42a (416 mg, 1 mmol) was dissolved in dichloromethane (0.2 mmol / mL) and methanol (1 mmol / mL). A 4M HCl solution in dioxane (0.5 mL) was added at 0°C and allowed to react at room temperature for 4 h. After completion of the reaction as monitored by TLC, the reaction solution was dried, slurried with isopropyl ether, and filtered to obtain intermediate 43a. MS (ESI, m / z): 317 (M + +1). Intermediates 43b-g can be prepared by the same method by simply replacing the corresponding starting materials.

[0140] Example 11 Synthesis of Intermediates 45a-c

[0141]

[0142] Bromoacetic acid (139 mg, 1 mmol) was added to the reaction flask, and thionyl chloride (1 mL) was added thereto. The reaction was stirred at 80°C for 5 h. After the reaction was completely cooled to room temperature, the mixture was dried and dissolved in dry tetrahydrofuran. Then, the starting material 44 (273 mg, 1 mmol) was added and the mixture was reacted at 50°C. After TLC monitoring, the reaction was completed. After cooling and filtration, the crude intermediate 45a was obtained. MS (ESI, m / z): 394 (M + +1). Intermediates 45b-c can be obtained by the same preparation method.

[0143] Example 12 Synthesis of Intermediates 46a-b

[0144]

[0145] The starting material 41a (3.31 g, 10 mmol) was dissolved in DMF (50 mL), and 2-bromoethylamine (1.49 g, 12 mmol), DIPEA (5.2 mL, 30 mmol), and HATU (5.7 g, 15 mmol) were added to the reaction system. The reaction was allowed to proceed at room temperature for 6 h. After the reaction was complete, the mixture was diluted with water and 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 46a (2.83 g, 65%). MS (ESI, m / z): 437 (M + +1). Intermediate 46b can be obtained by simply replacing the corresponding starting materials and following the same preparation method.

[0146] Example 13 Synthesis of Intermediates 48a-c

[0147]

[0148] a) The same synthetic steps as intermediate 46a were followed by replacing the corresponding raw materials and following the same preparation method to obtain intermediates 47a-c. 47a MS (ESI, m / z): 403 (M + +1).

[0149] b) The same synthesis step b as that of intermediate 25a was used, except that the corresponding raw materials were replaced and the same preparation method was used to obtain intermediates 48a-c. 48a MS (ESI, m / z): 481 (M + +1).

[0150] Example 14 Synthesis of Intermediates 50a-c, 53, and 55a-b

[0151]

[0152] a) Starting material 49 (1.57 g, 5.71 mmol) was dissolved in DMF (57 mL), and K2CO3 (1.19 g, 8.58 mmol) and 1,3-dibromopropane (1.15 g, 5.71 mmol) were added. The mixture was stirred at room temperature for 2 h. After the reaction was complete, water was added to quench the mixture, and the mixture was extracted with dichloromethane (30 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 50a (2.09 g, 93%). MS (ESI, m / z): 395 (M + +1). Intermediates 50b-c, 51, and 54a-b can be obtained by the same preparation method.

[0153] b) The starting material 51 (576 mg, 1 mmol) was dissolved in dichloromethane (5 mL), TFA (2 mmol) was added dropwise at 0°C, and the mixture was stirred at room temperature for 3 h. The mixture was concentrated under reduced pressure to obtain the intermediate 52 (470 mg, 90%). MS (ESI, m / z): 333 (M + +1).

[0154] c) Starting material 52 (332 mg, 1 mmol), 2-bromoethylamine (124 mg, 1 mmol), and HATU (570 mg, 1.5 mmol) were dissolved in DMF (5 mL). DIPEA (524 μL, 3 mmol) was added and the mixture was quenched with water after complete reaction. The mixture was extracted with dichloromethane (30 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 give intermediate 53 (393 mg, 90%). MS (ESI, m / z): 438 (M + +1).

[0155] d) The same synthesis step b as that of intermediate 25a was used, except that the corresponding raw materials were replaced and the same preparation method was used to obtain intermediate 55a-b. 55a MS (ESI, m / z): 485 (M + +1).

[0156] Example 15 Synthesis of Intermediate 57a-b

[0157]

[0158] The starting material 56 (498 mg, 1 mmol), 4-bromobutyric acid (200 mg, 1.2 mmol), HATU (562 mg, 1.5 mmol) and DIPEA (388 mg, 3 mmol) were dissolved in THF and stirred at room temperature for 2 h. After the reaction was complete, the mixture was extracted with ethyl acetate, dried over anhydrous Na2SO4, concentrated under reduced pressure and purified by column chromatography to obtain intermediate 57a (492 mg, 85%). MS (ESI, m / z): 579 (M + +1). Intermediate 57b can be obtained by the same preparation method.

[0159] Example 16 Synthesis of Intermediates 59a-b

[0160]

[0161] The same synthetic steps as intermediate 57a were followed by replacing the corresponding raw materials and following the same preparation method to obtain intermediate 59a-b. 59aMS (ESI, m / z): 579 (M + +1).

[0162] Example 17 Synthesis of Intermediate 62

[0163]

[0164] a) The same synthetic steps as intermediate 57a were followed by replacing the corresponding raw materials and following the same preparation method to obtain intermediate 61. MS (ESI, m / z): 612 (M + +1).

[0165] b) The same synthesis step b as that of intermediate 25a was followed by replacing the corresponding raw materials and following the same preparation method to obtain intermediate 62. MS (ESI, m / z): 690 (M + +1).

[0166] Example 18 Synthesis of Intermediate 65

[0167]

[0168] a) The same synthetic steps as intermediate 57a were followed by replacing the corresponding starting materials and following the same preparation method to obtain intermediate 64. MS (ESI, m / z): 646 (M + +1).

[0169] b) The same synthesis step b as that of intermediate 25a was followed by replacing the corresponding raw materials and following the same preparation method to obtain intermediate 65. MS (ESI, m / z): 724 (M + +1).

[0170] Example 19 Synthesis of Intermediate 68

[0171]

[0172] a) The same synthetic steps as intermediate 57a were followed by replacing the corresponding starting materials and following the same preparation method to obtain intermediate 67. MS (ESI, m / z): 515 (M + +1).

[0173] b) The same synthesis step b as that of intermediate 25a was followed by replacing the corresponding raw materials and following the same preparation method to obtain intermediate 68. MS (ESI, m / z): 593 (M + +1).

[0174] Example 20 Synthesis of Compound S1

[0175]

[0176] Raw material 14a (420 mg, 1 mmol) was dissolved in DMF (5 mL). To the solution were added 25a (585 mg, 1.5 mmol), DIPEA (0.53 mL, 3 mmol) and NaI (15 mg, 0.1 mmol). The mixture was reacted at 60°C for 5 h. After completion of the reaction, the mixture was concentrated under reduced pressure and purified by column chromatography to obtain compound S1 (250 mg, 35%). 1 H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.76(s,1H),8.69(s,1H),7.82(dd,J=7.2,2.3Hz,1H),7.5 3-7.43(m,2H),7.39(t,J=1.0Hz,1H),7.27-7.11(m,4H),7.09(s,1H),7.02(s,1H),6.86(t,J=1.0Hz,1H),5.40(t,J= 5.5Hz,1H),4.52(qdd,J=12.5,5.5,0.9Hz,2H),4.38(s,1H),4.28(s,1H),4.01(s,1H),3.93(s,3H),3.78(d,J=1.1Hz ,2H),3.10(s,2H),2.92-2.85(m,3H),2.78(s,1H),2.67-2.56(m,4H),2.17(s,1H),2.12(s,1H).MS(ESI,m / z):715(M + +1).

[0177] Example 21 Synthesis of Compound S2

[0178]

[0179] The synthesis method refers to Example 20, and compound S2 can be prepared by simply replacing the corresponding raw materials. 1H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.76(s,1H),8.69(s,1H),7.82(dd,J=7.1,2.2Hz,1H),7.52-7.43(m ,2H),7.39(t,J=1.0Hz,1H),7.27-7.16(m,3H),7.18-7.07(m,2H),7.02(s,1H),6.86(t,J=1.0Hz,1H),5.40(t,J=5.5Hz,1H),4 .52(qdd,J=12.5,5.5,0.9Hz,2H),4.38(s,1H),4.32(s,1H),4.01(s,1H),3.93(s,3H),3.84(d,J=1.1Hz,2H),2.90-2.85(m,3H ),2.78(d,J=4.9Hz,3H),2.57(d,J=9.5Hz,2H),2.52-2.41(m,2H),2.17(s,1H),2.12(s,1H),1.76(s,2H).MS(ESI,m / z):729(M + +1).

[0180] Example 22 Synthesis of Compound S3

[0181]

[0182] The synthesis method refers to Example 20, and compound S3 can be prepared by simply replacing the corresponding raw materials. 1 H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.76(s,1H),8.69(s,1H),7.82(dd,J=6.1,3.4Hz,1H),7.49 -7.37(m,3H),7.27-7.07(m,5H),7.02(s,1H),6.86(t,J=1.0Hz,1H),5.40(t,J=5.5Hz,1H),4.52(qdd,J=12.5,5.5,1.0 Hz,2H),4.38(s,1H),4.28(s,1H),4.01(s,1H),3.93(s,3H),3.78(d,J=1.1Hz,2H),2.90-2.85(m,3H),2.82(s,1H),2. 65-2.54(m,4H),2.49(s,2H),2.17(s,1H),2.12(s,1H),1.57-1.40(m,5H),1.37(d,J=12.5Hz,1H).MS(ESI,m / z):757(M+ +1).

[0183] Example 23 Synthesis of Compound S4

[0184]

[0185] The synthesis method refers to Example 20, and compound S4 can be prepared by simply replacing the corresponding raw materials. 1 H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.76(s,1H),8.69(s,1H),7.82(dd,J=7.1,2.2Hz,1H),7 .52-7.43(m,2H),7.39-7.33(m,2H),7.30-7.23(m,2H),7.21(d,J=2.8Hz,3H),6.86(t,J=1.0Hz,1H),5.41(t,J=5.5 Hz,1H),4.59-4.46(m,3H),4.32(s,1H),4.01(s,1H),3.92(s,3H),3.78(d,J=1.1Hz,2H),2.89-2.80(m,4H),2.64-2 .56(m,4H),2.53-2.42(m,2H),2.19(s,1H),2.12(s,1H),1.54-1.46(m,4H),1.37-1.24(m,6H).MS(ESI,m / z):785(M + +1).

[0186] Example 24 Synthesis of Compound S5

[0187]

[0188] The synthesis method refers to Example 20, and compound S5 can be prepared by simply replacing the corresponding raw materials. 1H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.76(s,1H),8.69(s,1H),7.82(dd,J=7.1,2.2Hz,1H),7. 52-7.43(m,2H),7.39-7.33(m,2H),7.30-7.23(m,2H),7.21(d,J=2.8Hz,3H),6.86(t,J=0.9Hz,1H),5.41(t,J=5.5Hz ,1H),4.59-4.45(m,3H),4.32(s,1H),4.01(s,1H),3.92(s,3H),3.78(d,J=1.1Hz,2H),2.89-2.80(m,4H),2.64-2.56 (m,4H),2.46(d,J=1.1Hz,2H),2.19(s,1H),2.12(s,1H),1.57-1.46(m,4H),1.35-1.21(m,10H).MS(ESI,m / z):813(M + +1).

[0189] Example 25 Synthesis of Compound S6

[0190]

[0191] Raw materials 14a (420 mg, 1 mmol) and 26a (368 mg, 1 mmol) were dissolved in DMF (5 mL). BOP (664 mg, 1.5 mmol) and DIPEA (0.53 mL, 3 mmol) were added to the solution. The mixture was reacted at room temperature overnight. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by column chromatography to obtain compound S6 (293 mg, 38%). 1H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.76(s,1H),8.69(s,1H),7.82(dd,J=7.2,2.3Hz,1H),7.51-7.40(m,2H) ,7.27-7.21(m,1H),7.21-7.18(m,2H),7.18-7.12(m,2H),7.10(d,J=10.8Hz,1H),7.02(s,1H),6.88(t,J=1.0Hz,1H),5.40(t,J=5. 5Hz,1H),4.61-4.46(m,4H),4.34(s,1H),4.21(s,1H),4.01(s,1H),3.93(s,3H),3.67(s,1H),3.62(s,1H),2.88(dd,J=5.0,1.0Hz, 2H),2.63-2.54(m,4H),2.27(s,2H),2.17(s,1H),2.12(s,1H),1.95(d,J=12.3Hz,1H),1.89(d,J=12.5Hz,1H).MS(ESI,m / z):757(M + +1).

[0192] Example 26 Synthesis of Compound S7

[0193]

[0194] The synthesis method refers to Example 25, and compound S7 can be prepared by simply replacing the corresponding raw materials. 1H NMR(500MHz,Chloroform-d)δ11.26(d,J=10.2Hz,1H),10.99(s,1H),8.67(d,J=3.2Hz,1H),8.07(s,1H),8.02(s,1H),7.89-7.78(m,2H),7 .71(d,J=9.0Hz,1H),7.63(t,J=8.5Hz,1H),7.57-7.40(m,2H),7.32(d,J=6.6Hz,1H),7.31-7.10(m,2H),6.81(d,J=5.2Hz,1H),5.25-5.09( m,2H),4.54-4.42(m,3H),4.32(d,J=18.5Hz,3H),3.81(d,J=7.8Hz,3H),3.63(d,J=5.8Hz,2H),2.90(s,1H),2.79(s,1H),2.69(s,1H),2.55 (m,J=7.3Hz,2H),2.44(dd,J=17.3,7.6Hz,2H),2.00(d,J=7.6Hz,1H),1.73(s,2H),1.65(s,2H),1.04(d,J=6.1Hz,2H).MS(ESI,m / z):771(M + +1).

[0195] Example 27 Synthesis of Compound S8

[0196]

[0197] The synthesis method refers to Example 25, and compound S8 can be prepared by simply replacing the corresponding raw materials. 1H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.76(s,1H),8.69(s,1H),7.82(dd,J=6.1,3.4Hz,1H),7. 49-7.41(m,2H),7.27-7.07(m,6H),7.02(s,1H),6.88(t,J=1.0Hz,1H),5.40(t,J=5.5Hz,1H),4.59-4.49(m,3H),4.4 9-4.43(m,1H),4.38(s,1H),4.28(s,1H),4.01(s,1H),3.92(s,3H),3.67(s,1H),3.62(s,1H),2.88(dd,J=5.0,1.0Hz ,2H),2.64-2.54(m,4H),2.27(s,2H),2.17(s,1H),2.12(s,1H),1.67-1.50(m,4H),1.34(s,2H).MS(ESI,m / z):785(M + +1).

[0198] Example 28 Synthesis of Compound S9

[0199]

[0200] The synthesis method refers to Example 25, and compound S8 can be prepared by simply replacing the corresponding raw materials. 1 H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.76(s,1H),8.69(s,1H),7.82(dd,J=6.1,3.4Hz,1H),7.49-7.41(m,2H ),7.27-7.18(m,3H),7.18-7.12(m,2H),7.10(d,J=10.8Hz,1H),7.02(s,1H),6.88(t,J=1.0Hz,1H),5.40(t,J=5.5Hz,1H),4.59-4. 43(m,4H),4.38(s,1H),4.28(s,1H),4.01(s,1H),3.92(s,3H),3.67(s,1H),3.62(s,1H),2.88(dd,J=5.0,1.0Hz,2H),2.61-2.48( m,4H),2.30(d,J=0.7Hz,2H),2.17(s,1H),2.12(s,1H),1.58(s,2H),1.49(d,J=2.2Hz,2H),1.29-1.23(m,6H).MS(ESI,m / z):813(M+ +1).

[0201] Example 29 Synthesis of Compound S10

[0202]

[0203] The synthesis method refers to Example 20, and compound S10 can be prepared by simply replacing the corresponding raw materials. 1 H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.76(s,1H),8.69(s,1H),7.88(d,J=7.5Hz,1H),7.62-7.53( m,2H),7.39(t,J=1.0Hz,1H),7.27-7.16(m,3H),7.18-7.07(m,2H),7.02(s,1H),6.86(t,J=1.0Hz,1H),5.40(t,J=5.5Hz ,1H),4.59-4.43(m,3H),4.33(d,J=0.9Hz,1H),4.01(s,1H),3.93(s,3H),3.84(d,J=1.1Hz,2H),2.90-2.85(m,3H),2.78 (d,J=4.9Hz,3H),2.59(d,J=10.1Hz,2H),2.52-2.41(m,2H),2.18(s,1H),2.12(s,1H),1.80(s,2H).MS(ESI,m / z):729(M + +1).

[0204] Example 30 Synthesis of Compound S11

[0205]

[0206] The synthesis method refers to Example 20, and compound S11 can be prepared by simply replacing the corresponding raw materials. 1H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.76(s,1H),8.69(s,1H),7.89(d,J=7.5Hz,1H),7.62-7.53(m,2 H),7.39(t,J=1.0Hz,1H),7.27-7.17(m,2H),7.17-7.07(m,3H),7.02(s,1H),6.86(t,J=1.0Hz,1H),5.40(t,J=5.5Hz,1H), 4.59-4.45(m,3H),4.33(d,J=0.9Hz,1H),4.01(s,1H),3.93(s,3H),3.78(d,J=1.1Hz,2H),2.90-2.85(m,3H),2.82(s,1H), 2.62-2.55(m,3H),2.54-2.47(m,3H),2.18(s,1H),2.12(s,1H),1.57-1.47(m,4H),1.42-1.31(m,2H).MS(ESI,m / z):757(M + +1).

[0207] Example 31 Synthesis of Compound S12

[0208]

[0209] The synthesis method refers to Example 20, and compound S12 can be prepared by simply replacing the corresponding raw materials. 1 H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.76(s,1H),8.69(s,1H),7.86(d,J=2.0Hz,1H),7.4 6(dd,J=7.5,2.0Hz,1H),7.39(t,J=1.0Hz,1H),7.27-7.04(m,6H),7.02(s,1H),6.86(t,J=1.0Hz,1H),5.40(t, J=5.5Hz,1H),4.60-4.46(m,4H),4.01(s,1H),3.93(s,3H),3.84(d,J=1.1Hz,2H),2.90-2.82(m,5H),2.78(s,1 H),2.59(d,J=10.1Hz,2H),2.52-2.41(m,2H),2.18(s,1H),2.12(s,1H),1.80-1.68(m,2H).MS(ESI,m / z):729(M + +1).

[0210] Example 32 Synthesis of Compound S13

[0211]

[0212] The synthesis method refers to Example 20, and compound S13 can be prepared by simply replacing the corresponding raw materials. 1 H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.76(s,1H),8.69(s,1H),7.56(dd,J=7.5,2.0Hz,1H),7 .39(t,J=1.0Hz,1H),7.34(t,J=7.5Hz,1H),7.27-7.16(m,3H),7.16-7.07(m,3H),7.02(s,1H),6.86(t,J=1.0Hz,1H ),5.40(t,J=5.5Hz,1H),4.59-4.45(m,3H),4.33(d,J=0.9Hz,1H),4.01(s,1H),3.93(s,3H),3.78(d,J=1.1Hz,2H) ,2.92-2.85(m,4H),2.60-2.47(m,6H),2.17(s,1H),2.12(s,1H),1.51(dd,J=17.2,1.1Hz,4H).MS(ESI,m / z):743(M + +1).

[0213] Example 33 Synthesis of Compound S14

[0214]

[0215] The synthesis method refers to Example 20, and compound S14 can be prepared by simply replacing the corresponding raw materials. 1H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.76(s,1H),8.69(s,1H),7.82(dd,J=6.5,3.0Hz,1H),7.51-7.42(m,2 H),7.39(t,J=1.0Hz,1H),7.27-7.07(m,5H),7.02(s,1H),6.86(t,J=0.9Hz,1H),5.40(t,J=4.9Hz,1H),4.52(dd,J=4.9,0.9Hz,2 H),4.38(s,1H),4.32(s,1H),4.01(s,1H),3.92(s,3H),3.86(d,J=0.9Hz,2H),3.04(s,1H),2.86(d,J=1.1Hz,2H),2.78(s,1H),2 .70(s,1H),2.64-2.54(m,8H),2.47(s,2H),2.17(s,1H),2.12(s,1H),1.91(s,2H),1.83(s,2H),1.72(s,2H).MS(ESI,m / z):812(M + +1).

[0216] Example 34 Synthesis of Compound S15

[0217]

[0218] Raw material 14a (420 mg, 1 mmol) was dissolved in DMF (5 mL), and raw material 39a (569 mg, 1.5 mmol) and K2CO3 (0.53 mL, 3 mmol) were added to the solution. The mixture was reacted at 60°C for 6 h. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by column chromatography to obtain compound S15 (259 mg, 36%). 1H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.76(s,1H),8.69(s,1H),7.93(dd,J=7.4,2.1Hz ,1H),7.45-7.33(m,3H),7.29(s,1H),7.27-7.16(m,3H),7.16-7.11(m,1H),7.09(s,1H),7.02(s,1H),6.86( t,J=1.0Hz,1H),5.40(t,J=5.5Hz,1H),5.10(s,1H),4.52(m,2H),3.93(s,3H),3.78(d,J=1.1Hz,2H),3.48(s ,2H),2.92-2.85(m,4H),2.66(d,J=19.2Hz,3H),2.55(s,1H),2.49(s,1H),1.99(s,1H).MS(ESI,m / z):720(M + +1).

[0219] Example 35 Synthesis of Compound S16

[0220]

[0221] The synthesis method refers to Example 34, and compound S16 can be prepared by simply replacing the corresponding raw materials. 1 H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.76(s,1H),8.69(s,1H),7.80(dd,J=7.4,2.1Hz,1H),7.52(dd, J=7.4,2.1Hz,1H),7.45(t,J=7.5Hz,1H),7.35(t,J=0.9Hz,1H),7.27-7.18(m,3H),7.21-7.07(m,2H),7.02(s,1H),6.90-6. 84(m,2H),5.40(t,J=5.5Hz,1H),5.10(s,1H),4.52(qdd,J=12.5,5.5,0.9Hz,2H),3.93(s,3H),3.86(d,J=0.9Hz,2H),3.49- 3.39(m,2H),2.92-2.84(m,3H),2.80(s,1H),2.63(s,1H),2.53-2.47(m,4H),1.99(s,1H),1.88(s,2H).MS(ESI,m / z):734(M + +1).

[0222] Example 36 Synthesis of Compound S17

[0223]

[0224] The synthesis method refers to Example 34, and compound S17 can be prepared by simply replacing the corresponding raw materials. 1 H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.76(s,1H),8.69(s,1H),7.93(dd,J=7.4,2.1Hz,1H),7.53-7. 41(m,2H),7.39(t,J=1.0Hz,1H),7.27-7.07(m,5H),7.02(s,1H),6.90-6.84(m,2H),5.40(t,J=5.5Hz,1H),5.10(s,1H),4 .52(qdd,J=12.5,5.5,1.0Hz,2H),3.93(s,3H),3.78(d,J=1.1Hz,2H),3.56(s,2H),2.89-2.80(m,4H),2.63(s,1H),2.55( s,2H),2.51(s,1H),2.24(d,J=0.9Hz,2H),1.64(s,2H),1.55(d,J=0.9Hz,2H),1.43(d,J=0.9Hz,2H).MS(ESI,m / z):762(M + +1).

[0225] Example 37 Synthesis of Compound S18

[0226]

[0227] The synthesis method refers to Example 34, and compound S18 can be prepared by simply replacing the corresponding raw materials. 1H NMR (500MHz, Chloroform-d) δ11.22(s,1H),11.11(s,1H),8.76(s,1H),8.69(s,1H),7.93(dd,J=7.5,2.0Hz,1H),7.53(dd,J=7. 5,2.0Hz,1H),7.45(t,J=7.4Hz,1H),7.39(t,J=1.0Hz,1H),7.27-7.17(m,2H),7.17-7.07(m,3H),7.02(s,1H),6.90-6.84(m,2H) ,5.40(t,J=5.5Hz,1H),5.10(s,1H),4.52(m,2H),3.92(s,3H),3.78(d,J=1.1Hz,2H),3.57-3.46(m,2H),2.90-2.85(m,3H),2.82 (s,1H),2.63(s,1H),2.53-2.41(m,3H),2.24(d,J=0.9Hz,2H),1.64(s,2H),1.50(s,2H),1.36-1.24(m,8H).MS(ESI,m / z):804(M + +1).

[0228] Example 38 Synthesis of Compound S19

[0229]

[0230] The synthesis method refers to Example 34, and compound S19 can be prepared by simply replacing the corresponding raw materials. 1H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.76(s,1H),8.69(s,1H),7.93(dd,J=7.5,2.0Hz,1H),7.53(dd,J=7 .5,2.0Hz,1H),7.45(t,J=7.4Hz,1H),7.39(t,J=1.0Hz,1H),7.27-7.17(m,2H),7.17-7.07(m,3H),7.02(s,1H),6.90-6.84(m,2 H),5.40(t,J=5.5Hz,1H),5.10(s,1H),4.52(m,2H),3.92(s,3H),3.78(d,J=1.1Hz,2H),3.56(s,2H),2.90-2.85(m,3H),2.82( s,1H),2.63(s,1H),2.57-2.45(m,3H),2.24(d,J=1.0Hz,2H),1.64(s,2H),1.54(s,2H),1.35-1.24(m,6H).MS(ESI,m / z):790(M + +1).

[0231] Example 39 Synthesis of Compound S20

[0232]

[0233] The synthesis method refers to Example 34, and compound S20 can be prepared by simply replacing the corresponding raw materials. 1H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.76(s,1H),8.69(s,1H),7.93(dd,J=7.3,2.2Hz,1H),7.56-7.46(m,2H) ,7.39(t,J=1.0Hz,1H),7.32-7.26(m,1H),7.24-7.17(m,1H),7.17-7.07(m,3H),7.02(s,1H),6.90-6.84(m,2H),5.40(t,J=5.5Hz, 1H),5.10(s,1H),4.52(m,2H),3.92(s,3H),3.78(d,J=1.1Hz,2H),3.57-3.46(m,2H),2.90-2.85(m,3H),2.82(s,1H),2.66(s,1H), 2.56-2.49(m,2H),2.46(d,J=12.4Hz,1H),2.24(d,J=1.0Hz,2H),1.64(s,2H),1.51(s,2H),1.36-1.21(m,12H).MS(ESI,m / z):832(M + +1).

[0234] Example 40 Synthesis of Compound S21

[0235]

[0236] The synthesis method refers to Example 25, and compound S21 can be prepared by simply replacing the corresponding raw materials. 1 H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.76(s,1H),8.69(s,1H),7.93(dd,J=7.5,2.0Hz, 1H),7.50(t,J=7.4Hz,1H),7.39(dd,J=7.5,2.0Hz,1H),7.27-7.07(m,7H),7.02(s,1H),6.88(t,J=1.0Hz,1H ),5.40(t,J=5.5Hz,1H),5.10(s,1H),4.59-4.43(m,4H),3.92(s,3H),3.69-3.60(m,4H),2.88(d,J=0.9Hz,2 H),2.63(s,1H),2.51(s,1H),2.32(s,2H),2.24(d,J=0.9Hz,2H),1.63(d,J=14.0Hz,4H).MS(ESI,m / z):776(M + +1).

[0237] Example 41 Synthesis of Compound S22

[0238]

[0239] The synthesis method refers to Example 25, and compound S22 can be prepared by simply replacing the corresponding raw materials. 1 H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.76(s,1H),8.69(s,1H),7.93(dd,J=7.5,2.0Hz,1H),7.53(dd,J=7.5,2.0Hz,1H ),7.48-7.41(m,1H),7.27-7.18(m,3H),7.18-7.12(m,2H),7.10(d,J=10.8Hz,1H),7.02(s,1H),6.88(t,J=1.0Hz,1H),6.74(s,1H),5.40(t, J=5.5Hz,1H),5.10(s,1H),4.59-4.49(m,3H),4.49-4.43(m,1H),3.92(s,3H),3.67(s,1H),3.62(s,1H),3.50-3.39(m,2H),2.88(dd,J=5.0 ,1.0Hz,2H),2.63(s,1H),2.51(s,1H),2.29-2.21(m,4H),1.66(s,2H),1.58(s,2H),1.34(s,2H),1.24(d,J=0.7Hz,2H).MS(ESI,m / z):804(M + +1).

[0240] Example 42 Synthesis of Compound S23

[0241]

[0242] The synthesis method refers to Example 25, and compound S23 can be prepared by simply replacing the corresponding raw materials. 1H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.76(s,1H),8.69(s,1H),7.93(dd,J=7.3,2.2Hz,1H),7.70(s,1H), 7.47-7.36(m,2H),7.27-7.07(m,6H),7.02(s,1H),6.86(t,J=1.0Hz,1H),6.75(s,1H),5.40(t,J=5.5Hz,1H),5.10(s,1H),4.5 2(m,2H),3.92(s,3H),3.84(d,J=0.9Hz,2H),3.73(d,J=12.5Hz,1H),3.62(d,J=12.5Hz,1H),3.38(s,2H),3.17(d,J=1.8Hz,2H ),2.98(s,1H),2.93(s,1H),2.86(dd,J=3.1,0.9Hz,2H),2.63(s,1H),2.50(d,J=7.3Hz,2H),1.99(s,1H).MS(ESI,m / z):777(M + +1).

[0243] Example 43 Synthesis of Compound S24

[0244]

[0245] The synthesis method refers to Example 25, and compound S24 can be prepared by simply replacing the corresponding raw materials. 1 H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.76(s,1H),8.69(s,1H),7.93(dd,J=7.5,2.0Hz,1H),7.64(s ,1H),7.53(dd,J=7.5,2.0Hz,1H),7.48-7.41(m,1H),7.27-7.07(m,7H),7.02(s,1H),6.86(t,J=0.9Hz,1H),5.40(t,J=5. 5Hz,1H),5.10(s,1H),4.52(m,2H),3.92(s,3H),3.84(d,J=0.9Hz,2H),3.56(s,2H),3.15(d,J=13.2Hz,4H),2.95(s,1H) ,2.90-2.84(m,3H),2.63(s,1H),2.51(s,1H),2.24(d,J=0.9Hz,2H),1.64(s,2H),1.54-1.44(m,2H).MS(ESI,m / z):805(M+ +1).

[0246] Example 44 Synthesis of Compound S25

[0247]

[0248] The synthesis method refers to Example 25, and compound S25 can be prepared by simply replacing the corresponding raw materials. 1 H NMR(500MHz,Chloroform-d)δ11.20(s,1H),11.09(s,1H),8.64(s,1H),8.03( s,1H),7.96(s,1H),7.77(d,J=6.2Hz,2H),7.60-7.51(m,2H),7.45(d,J=7.6Hz ,1H),7.32(s,1H),7.24(t,J=7.5Hz,1H),7.15(t,J=7.4Hz,1H),7.03(dd,J=14 .2,7.8Hz,2H),6.73(s,1H),6.50(t,J=5.8Hz,1H),5.17(t,J=5.2Hz,1H),5.04 (dd,J=12.9,5.4Hz,1H),4.48(d,J=5.1Hz,2H),3.79(s,3H),3.31-3.22(m,4H) ,3.16(q,J=6.6Hz,2H),3.05(s,2H),2.95-2.81(m,1H),2.77(d,J=5.9Hz,2H), 2.66(d,J=5.9Hz,2H),2.63(s,1H),2.51(s,1H),2.02(d,J=11.6Hz,1H),1.56( q,J=7.3Hz,2H),1.53-1.44(m,2H),1.33(d,J=7.6Hz,2H).MS(ESI,m / z):819(M + +1).

[0249] Example 45 Synthesis of Compound S26

[0250]

[0251] The synthesis method refers to Example 25, and compound S26 can be prepared by simply replacing the corresponding raw materials. 1H NMR(500MHz,Chloroform-d)δ11.20(s,1H),11.09(s,1H),8.64(s,1H),8.03(s,1H),7.93(dd,J=7.3,2.2Hz,1H),7.56-7.46( m,3H),7.32-7.23(m,2H),7.23-7.17(m,1H),7.17-7.07(m,3H),7.02(s,1H),6.90-6.84(m,2H),5.40(t,J=5.5Hz,1H),5.10( s,1H),4.52(m,2H),3.92(s,3H),3.84(d,J=0.9Hz,2H),3.57-3.46(m,2H),3.19-3.03(m,4H),2.95(s,1H),2.90-2.84(m,3H) ,2.66(s,1H),2.54(s,1H),2.24(d,J=0.9Hz,2H),1.66(d,J=0.7Hz,2H),1.49(s,2H),1.38-1.24(m,4H).MS(ESI,m / z):833(M + +1).

[0252] Example 46 Synthesis of Compound S27

[0253]

[0254] The synthesis method refers to Example 25, and compound S27 can be prepared by simply replacing the corresponding raw materials. 1 H NMR(500MHz,Chloroform-d)δ11.20(s,1H),11.09(s,1H),8.64(s,1H),8.03(s,1H),7.93(dd,J=7.3,2.2Hz,1H),7.56-7 .44(m,3H),7.32-7.07(m,6H),7.02(s,1H),6.90-6.84(m,2H),5.40(t,J=5.5Hz,1H),5.10(s,1H),4.52(m,2H),3.89(s,3 H),3.84(d,J=1.0Hz,2H),3.49(d,J=2.0Hz,2H),3.13(dd,J=15.3,1.4Hz,4H),2.95(s,1H),2.90-2.84(m,3H),2.66(s,1 H),2.54(s,1H),2.24(d,J=1.0Hz,2H),1.66(s,2H),1.48(s,2H),1.34(d,J=0.7Hz,4H),1.28(s,2H).MS(ESI,m / z):847(M+ +1).

[0255] Example 47 Synthesis of Compound S28

[0256]

[0257] The synthesis method refers to Example 25, and compound S28 can be prepared by simply replacing the corresponding raw materials. 1 H NMR(500MHz,Chloroform-d)δ11.20(s,1H),11.09(s,1H),8.64(s,1H),8.03(s,1H),7.93(dd,J=7.3,2.2Hz,1H),7.56-7 .46(m,3H),7.32-7.07(m,6H),7.02(s,1H),6.90-6.84(m,2H),5.40(t,J=5.5Hz,1H),5.10(s,1H),4.52(m,2H),3.89(s,3 H),3.84(d,J=0.9Hz,2H),3.57-3.46(m,2H),3.14(d,J=1.4Hz,2H),3.12-3.02(m,2H),2.95(s,1H),2.90-2.84(m,3H),2. 66(s,1H),2.54(s,1H),2.24(d,J=0.9Hz,2H),1.64(s,2H),1.47(d,J=2.9Hz,2H),1.35-1.22(m,8H).MS(ESI,m / z):861(M + +1).

[0258] Example 48 Synthesis of Compound S29

[0259]

[0260] The synthesis method refers to Example 25, and compound S29 can be prepared by simply replacing the corresponding raw materials. 1H NMR(500MHz,Chloroform-d)δ11.20(s,1H),11.09(s,1H),8.64(s,1H),8.03(s,1H),7.93(dd,J=7.3,2.2Hz,1H),7.56-7.4 6(m,3H),7.32-7.17(m,3H),7.17-7.07(m,3H),7.02(s,1H),6.90-6.84(m,2H),5.40(t,J=5.5Hz,1H),5.10(s,1H),4.52(m, 2H),3.89(s,3H),3.84(d,J=1.0Hz,2H),3.57-3.46(m,2H),3.13(dd,J=15.3,1.4Hz,4H),2.95(s,1H),2.90-2.84(m,3H),2 .66(s,1H),2.54(s,1H),2.24(d,J=1.0Hz,2H),1.64(s,2H),1.47(d,J=2.9Hz,2H),1.39-1.23(m,12H).MS(ESI,m / z):889(M + +1).

[0261] Example 49 Synthesis of Compound S30

[0262]

[0263] The synthesis method is similar to that of Example 25, and compound S30 can be obtained by simply replacing the corresponding raw materials. 1H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.05(s,1H),8.76(s,1H),8.69(s,1H),7.93(dd,J=7.5,2.0Hz,1H),7.44(dd,J =7.5,2.0Hz,1H),7.36(t,J=1.0Hz,1H),7.27-7.16(m,4H),7.17-7.11(m,1H),7.09(s,1H),7.02(s,1H),6.88(t,J=1.0Hz,1H ),5.99(s,1H),5.40(t,J=5.5Hz,1H),5.10(s,1H),4.59-4.46(m,2H),4.48-4.41(m,3H),4.35(d,J=12.3Hz,1H),3.93(s,3H ),3.76(d,J=5.1Hz,2H),2.89(dd,J=10.1,0.9Hz,2H),2.63(s,1H),2.51(s,1H),2.25(d,J=11.2Hz,2H).MS(ESI,m / z):734(M + +1).

[0264] Example 50 Synthesis of Compound S31

[0265]

[0266] The synthesis method refers to Example 34, and compound S31 can be prepared by simply replacing the corresponding raw materials. 1H NMR(500MHz,Chloroform-d)δ11.67(s,1H),11.55(s,1H),9.16(s,1H),8.76(s,1H),8.69(s,1H),7.93(dd,J=7.5,2.0Hz,1H), 7.78(dd,J=7.5,2.0Hz,1H),7.43(t,J=7.5Hz,1H),7.27-7.16(m,4H),7.17-7.11(m,1H),7.09(s,1H),7.02(s,1H),6.86(t,J=1 .0Hz,1H),5.40(t,J=5.5Hz,1H),5.10(s,1H),4.52(qdd,J=12.5,5.5,0.9Hz,2H),3.93(s,3H),3.84(d,J=0.9Hz,2H),3.32(s,2 H),2.97(s,1H),2.93(s,1H),2.85(dd,J=3.7,1.0Hz,2H),2.54(s,1H),2.48(s,1H),2.24(d,J=0.9Hz,2H).MS(ESI,m / z):734(M + +1).

[0267] Example 51 Synthesis of Compound S32

[0268]

[0269] The synthesis method refers to Example 34, and compound S32 can be prepared by simply replacing the corresponding raw materials. 1H NMR(500MHz,Chloroform-d)δ11.67(s,1H),11.22(s,1H),11.11(s,1H),8.76(s,1H),8.69(s,1H),7.89(dd,J=7.4,2.1Hz,1H), 7.57(dd,J=7.5,2.0Hz,1H),7.48(t,J=7.5Hz,1H),7.39(t,J=1.1Hz,1H),7.27-7.17(m,2H),7.17-7.07(m,3H),7.02(s,1H),6.8 6(t,J=1.0Hz,1H),5.40(t,J=5.5Hz,1H),5.10(s,1H),4.52(m,2H),4.02(d,J=1.1Hz,1H),3.92(d,J=1.7Hz,4H),2.98(s,1H),2 .93(s,1H),2.89(d,J=1.1Hz,2H),2.54(s,1H),2.52-2.43(m,5H),2.24(d,J=0.9Hz,2H),2.02-1.92(m,2H).MS(ESI,m / z):762(M + +1).

[0270] Example 52 Synthesis of Compound S33

[0271]

[0272] The synthesis method refers to Example 34, and compound S33 can be prepared by simply replacing the corresponding raw materials. 1H NMR(500MHz,Chloroform-d)δ11.67(s,1H),11.22(s,1H),11.11(s,1H),8.76(s,1H),8.69(s,1H),7.89(dd,J=7.4,2.1Hz,1H),7.57 (dd,J=7.5,2.0Hz,1H),7.48(t,J=7.5Hz,1H),7.39(t,J=1.0Hz,1H),7.27-7.17(m,2H),7.17-7.07(m,3H),7.02(s,1H),6.86(t,J=0. 9Hz,1H),5.40(t,J=5.5Hz,1H),5.10(s,1H),4.52(m,2H),3.92(s,3H),3.78(d,J=1.1Hz,2H),2.93(s,1H),2.90-2.85(m,3H),2.60- 2.52(m,3H),2.48(s,1H),2.42(d,J=0.7Hz,2H),2.24(d,J=0.9Hz,2H),1.65-1.50(m,4H),1.43(d,J=1.8Hz,2H).MS(ESI,m / z):790(M + +1).

[0273] Example 53 Synthesis of Compound S34

[0274]

[0275] The synthesis method refers to Example 34, and compound S34 can be prepared by simply replacing the corresponding raw materials. 1H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.76(s,1H),8.69(s,1H),7.96(dd,J=7.5,2.0Hz,1H),7.70 (s,1H),7.45-7.38(m,2H),7.30(t,J=7.5Hz,1H),7.27-7.09(m,5H),7.02(s,1H),6.95(s,1H),6.86(d,J=1.0Hz,1H), 5.40(t,J=5.5Hz,1H),5.10(s,1H),4.62(d,J=12.5Hz,1H),4.59-4.46(m,3H),3.92(s,3H),3.78(d,J=1.1Hz,2H),3.3 1-3.17(m,4H),2.93-2.85(m,3H),2.76(s,1H),2.63(s,1H),2.51(s,1H),2.25(d,J=11.2Hz,2H).MS(ESI,m / z):777(M + +1).

[0276] Example 54 Synthesis of Compound S35

[0277]

[0278] The synthesis method refers to Example 34, and compound S35 can be prepared by simply replacing the corresponding raw materials. 1H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.76(s,1H),8.69(s,1H),7.96(dd,J=7.5,2.0Hz,1H),7.64(s,1H),7.44(dd,J=7 .5,2.0Hz,1H),7.39(t,J=1.0Hz,1H),7.30(t,J=7.4Hz,1H),7.27-7.17(m,2H),7.17-7.07(m,3H),7.02(s,1H),6.86(t,J=0.9Hz,1H),6.12 (s,1H),5.40(t,J=5.5Hz,1H),5.10(s,1H),4.59-4.44(m,3H),4.36(d,J=12.5Hz,1H),3.92(s,3H),3.78(d,J=1.1Hz,2H),3.16(s,2H),2.9 0-2.85(m,3H),2.80(s,1H),2.63(s,1H),2.53-2.43(m,3H),2.25(d,J=11.2Hz,2H),1.69(s,2H),1.48(d,J=1.1Hz,2H).MS(ESI,m / z):805(M + +1).

[0279] Example 55 Synthesis of Compound S36

[0280]

[0281] The synthesis method refers to Example 20, and compound S36 can be prepared by simply replacing the corresponding raw materials. 1H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.76(s,1H),8.69(s,1H),7.93(dd,J=7.3,2.2Hz,1H),7.64(s,1H),7.51-7.41 (m,2H),7.39(t,J=1.0Hz,1H),7.27-7.17(m,2H),7.17-7.07(m,3H),7.02(s,1H),6.89-6.84(m,1H),6.75(s,1H),5.40(t,J=5.5Hz,1H), 5.10(s,1H),4.52(m,2H),4.02(d,J=1.1Hz,1H),3.92(d,J=1.0Hz,4H),3.51-3.38(m,4H),2.98(s,1H),2.93(s,1H),2.89(d,J=1.1Hz,2H ),2.63(s,1H),2.53-2.44(m,4H),2.26(d,J=1.1Hz,2H),1.99(s,1H),1.93(d,J=12.2Hz,1H),1.79(d,J=12.5Hz,1H).MS(ESI,m / z):805(M + +1).

[0282] Example 56 Synthesis of Compound S37

[0283]

[0284] The synthesis method refers to Example 20, and compound S37 can be prepared by simply replacing the corresponding raw materials. 1H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.76(s,1H),8.69(s,1H),7.96(dd,J=6.8,2.7Hz,1H),7.70(s,1H),7.54-7.45(m,2H),7. 39(t,J=1.0Hz,1H),7.29(m,1H),7.24-7.17(m,1H),7.17-7.07(m,3H),7. 02(s,1H),6.86(t,J=0.9Hz,1H),6.75(s,1H),5.40(t,J=5.5Hz,1H),5.10( s,1H),4.52(m,2H),3.92(s,3H),3.78(d,J=1.1Hz,2H),3.54(d,J=12.5Hz ,1H),3.50-3.42(m,2H),3.41(d,J=12.3Hz,1H),2.93(s,1H),2.90-2.85( m,3H),2.66(s,1H),2.58(s,2H),2.54(s,1H),2.49(s,1H),2.15(s,2H),1 .99(s,1H),1.59(dd,J=28.8,1.3Hz,4H),1.38(s,2H).MS(ESI,m / z):833(M + +1).

[0285] Example 57 Synthesis of Compound S38

[0286]

[0287] The synthesis method refers to Example 20, and compound S38 can be prepared by simply replacing the corresponding raw materials. 1H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.76(s,1H),8.69(s,1H),7.96(dd,J=6.8,2.7Hz,1H),7.66(s,1H),7.54-7.45(m,2H),7 .39(t,J=1.0Hz,1H),7.29(m,1H),7.24-7.17(m,1H),7.17-7.07(m,3H), 7.02(s,1H),6.86(t,J=0.9Hz,1H),6.75(s,1H),5.40(t,J=5.5Hz,1H),5. 10(s,1H),4.52(m,2H),3.89(s,3H),3.78(d,J=1.1Hz,2H),3.54(d,J=12 .5Hz,1H),3.50-3.38(m,3H),2.90-2.85(m,3H),2.82(s,1H),2.66(s,1H) ,2.54(d,J=5.0Hz,3H),2.49(s,1H),2.11(d,J=2.9Hz,2H),1.99(s,1H),1 .61-1.49(m,4H),1.34(s,2H),1.26(d,J=4.8Hz,4H).MS(ESI,m / z):861(M + +1).

[0288] Example 58 Synthesis of Compound S39

[0289]

[0290] The synthesis method refers to Example 34, and compound S39 can be prepared by simply replacing the corresponding raw materials. 1H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.76(s,1H),8.69(s,1H),7.78(dd,J=7.5,2.0Hz ,1H),7.43-7.33(m,2H),7.27-7.16(m,3H),7.16-7.11(m,1H),7.11-7.06(m,2H),7.02(s,1H),6.86(d,J=1. 0Hz,1H),5.40(t,J=5.5Hz,1H),5.10(s,1H),4.52(m,2H),4.21(s,2H),3.92(d,J=4.4Hz,5H),2.92-2.84(m ,3H),2.80(s,1H),2.62(d,J=11.4Hz,3H),2.50(d,J=7.3Hz,2H),2.00(d,J=8.3Hz,3H).MS(ESI,m / z):735(M + +1).

[0291] Example 59 Synthesis of Compound S40

[0292]

[0293] The synthesis method was similar to that of Example 34, except that the corresponding raw materials were replaced to obtain compound S40. H NMR (500 MHz, Chloroform-d) δ 11.22 (s, 1H), 11.11 (s, 1H), 8.76 (s, 1H), 8.69 (s, 1H), 7.84 (dd, J = 7.5, 2.0 Hz, 1H), 7.46-7.37 (m, 2H), 7.27-7.17 (m, 2H), 7.17-7.07 (m, 4H), 7.02 (s, 1H), 6.86 (t, J = 1.0 Hz, 1H), 5.40 (t, J = 5.5 Hz, 1H), 5.10 (s, 1 H),4.52(qdd,J=12.5,5.5,1.0Hz,2H),3.97(s,2H),3.92(s,3H),3.78(d,J=1.1Hz,2H),2.89-2.80(m,4H),2.69(d,J=1 2.5Hz,1H),2.66-2.59(m,2H),2.50(d,J=7.3Hz,2H),1.99(s,1H),1.94(s,2H),1.61-1.49(m,4H).MS(ESI,m / z):763(M + +1).

[0294] Example 60 Synthesis of Compound S41

[0295]

[0296] The synthesis method refers to Example 34, and compound S41 can be prepared by simply replacing the corresponding raw materials. 1 H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.76(s,1H),8.69(s,1H),7.84(dd,J=7.5,2.0Hz,1H), 7.46-7.37(m,2H),7.27-7.04(m,6H),7.02(s,1H),6.86(t,J=0.9Hz,1H),5.40(t,J=5.5Hz,1H),5.10(s,1H),4.5 2(m,2H),4.00(s,2H),3.92(s,3H),3.78(d,J=1.1Hz,2H),2.90-2.85(m,3H),2.82(s,1H),2.63(s,1H),2.59-2.4 7(m,4H),1.99(s,1H),1.79(d,J=1.8Hz,2H),1.52(s,2H),1.41(s,2H),1.31(d,J=1.7Hz,4H).MS(ESI,m / z):791(M + +1).

[0297] Example 61 Synthesis of Compound S42

[0298]

[0299] The synthesis method refers to Example 34, and compound S42 can be prepared by simply replacing the corresponding raw materials. 1H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.76(s,1H),8.69(s,1H),7.96(dd,J=7.4,2.1Hz,1H),7.70 (s,1H),7.40(t,J=1.0Hz,1H),7.27-7.07(m,7H),7.02(s,1H),6.86(t,J=1.0Hz,1H),5.40(t,J=5.5Hz,1H),5.10(s,1H ),4.59-4.46(m,4H),3.92(s,3H),3.78(d,J=1.1Hz,2H),3.29(d,J=12.5Hz,1H),3.19(dd,J=14.6,12.5Hz,2H),3.04(d ,J=12.5Hz,1H),2.90-2.85(m,3H),2.76(s,1H),2.63(s,1H),2.51(s,1H),2.25(d,J=11.2Hz,2H).MS(ESI,m / z):778(M + +1).

[0300] Example 62 Synthesis of Compound S43

[0301]

[0302] The synthesis method refers to Example 20, and compound S43 can be prepared by simply replacing the corresponding raw materials. 1H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),9.14(s,1H),8.75(s,1H),8.00(dd,J=7.5,2.0Hz,1H),7.39-7.32(m,3 H),7.30-7.23(m,2H),7.21(d,J=2.8Hz,3H),7.07(dd,J=7.5,2.0Hz,1H),6.86(t,J=0.9Hz,1H),5.41(t,J=5.5Hz,1H),5.12(s,1H ),4.59-4.46(m,2H),4.24(d,J=1.6Hz,2H),3.92(d,J=8.4Hz,5H),3.86-3.80(m,3H),3.80-3.71(m,3H),3.59(d,J=0.9Hz,2H),2. 86(dd,J=1.8,0.9Hz,2H),2.76(s,1H),2.68(d,J=16.7Hz,2H),2.54(d,J=1.3Hz,3H),2.25(d,J=11.2Hz,2H).MS(ESI,m / z):809(M + +1).

[0303] Example 63 Synthesis of Compound S44

[0304]

[0305] The synthesis method refers to Example 20, and compound S44 can be prepared by simply replacing the corresponding raw materials. 1H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.76(s,1H),8.69(s,1H),7.97(dd,J=7.5,2.0Hz,1H),7.46-7.38(m,2H ),7.29(ddt,J=7.3,2.1,1.0Hz,1H),7.24-7.07(m,5H),7.02(s,1H),6.86(t,J=0.9Hz,1H),5.40(t,J=5.5Hz,1H),5.10(s,1H),4. 52(qdd,J=12.5,5.5,1.1Hz,2H),4.28-4.17(m,2H),3.93-3.79(m,10H),3.79-3.73(m,3H),3.72-3.63(m,3H),3.58(d,J=12.5Hz, 1H),2.88(d,J=1.1Hz,2H),2.76(s,1H),2.68(d,J=16.7Hz,2H),2.54(d,J=1.3Hz,3H),2.25(d,J=11.2Hz,2H).MS(ESI,m / z):853(M + +1).

[0306] Example 64 Synthesis of Compound S45

[0307]

[0308] The synthesis method refers to Example 20, and compound S45 can be prepared by simply replacing the corresponding raw materials. 1H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.75(s,1H),8.45(s,1H),8.14(s,1H),7.73(s,1H),7.69-7.63(m,2H),7.37( t,J=1.0Hz,1H),7.35-7.17(m,8H),6.86(t,J=0.9Hz,1H),5.41(t,J=5.5Hz,1H),5.06(d,J=4.9Hz,1H),4.61-4.46(m,3H),4.31-4.25(m, 3H),4.01(d,J=4.9Hz,1H),3.89(s,3H),3.78(d,J=1.1Hz,2H),3.47(d,J=9.5Hz,1H),3.32(d,J=9.5Hz,1H),2.93(s,1H),2.89-2.84(m,3 H),2.62-2.52(m,2H),2.34(s,3H),2.14(s,2H),2.04(d,J=4.2Hz,2H),1.62-1.55(m,4H),1.38(s,2H),0.99(s,9H).MS(ESI,m / z):947(M + +1).

[0309] Example 65 Synthesis of Compound S46

[0310]

[0311] The synthesis method refers to Example 20, and compound S46 can be prepared by simply replacing the corresponding raw materials. 1H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.75(s,1H),8.45(s,1H),8.14(s,1H),7.71-7.63(m,3H),7.39-7.20(m,8H),7.20 (d,J=3.2Hz,1H),6.86(t,J=0.9Hz,1H),5.41(t,J=5.5Hz,1H),5.06(d,J=4.9Hz,1H),4.61-4.46(m,3H),4.28(dd,J=1.5,0.7Hz,3H),4.04-3 .98(m,2H),3.94-3.87(m,4H),3.42(d,J=9.3Hz,1H),3.31(d,J=9.5Hz,1H),2.98(s,1H),2.93(s,1H),2.88(d,J=0.9Hz,2H),2.56(d,J=12.5 Hz,1H),2.49(d,J=12.5Hz,1H),2.34(s,3H),2.30-2.19(m,2H),2.06-1.95(m,3H),1.88(d,J=12.5Hz,1H),0.99(s,9H).MS(ESI,m / z):919(M + +1).

[0312] Example 66 Synthesis of Compound S47

[0313]

[0314] The synthesis method refers to Example 20, and compound S47 can be prepared by simply replacing the corresponding raw materials. 1H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.75(s,1H),8.45( s,1H),7.81-7.71(m,4H),7.34(d,J=1.5Hz,2H),7.31-7.23(m,3H),7.23-7.1 7(m,2H),7.14-7.08(m,2H),6.86(t,J=0.9Hz,1H),5.41(t,J=5.5Hz,1H),5.2 0-5.15(m,1H),5.06(d,J=4.9Hz,1H),4.59-4.52(m,2H),4.50(ddd,J=12.5,5. 5,0.9Hz,1H),4.28(s,1H),4.05(d,J=1.0Hz,1H),4.01(d,J=4.9Hz,1H),3.95 (d,J=0.9Hz,1H),3.89(s,3H),3.47(d,J=9.5Hz,1H),3.36(d,J=9.3Hz,1H),2 .92-2.83(m,3H),2.74(s,1H),2.72-2.64(m,3H),2.61(d,J=12.5Hz,1H),2.3 4(s,3H),2.04(d,J=4.2Hz,2H),1.50(s,3H),0.99(s,9H).MS(ESI,m / z):919(M + +1).

[0315] Example 67 Synthesis of Compound S48

[0316]

[0317] The synthesis method refers to Example 20, and compound S48 can be prepared by simply replacing the corresponding raw materials. 1H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.75(s,1H),8.45(s,1H),7.81-7.73(m,3H),7.69(s,1H),7.39-7.33(m,2H),7.31-7.17( m,5H),7.14-7.08(m,2H),6.86(t,J=0.9Hz,1H),5.41(t,J=5.5Hz,1H),5. 20-5.15(m,1H),5.06(d,J=4.9Hz,1H),4.59-4.46(m,3H),4.27(s,1H),4.0 4-3.98(m,2H),3.94-3.87(m,4H),3.42(d,J=9.3Hz,1H),3.31(d,J=9.5Hz ,1H),2.98(s,1H),2.93(s,1H),2.88(d,J=0.9Hz,2H),2.56(d,J=12.5Hz,1 H),2.49(d,J=12.5Hz,1H),2.34(s,3H),2.30-2.19(m,2H),2.06-1.95(m, 3H),1.88(d,J=12.5Hz,1H),1.50(s,3H),0.99(s,9H).MS(ESI,m / z):933(M + +1).

[0318] Example 68 Synthesis of Compound S49

[0319]

[0320] The synthesis method refers to Example 20, and compound S49 can be prepared by simply replacing the corresponding raw materials. 1H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.75(s,1H),8.45(s,1H),7.82-7.76(m,2H),7.64(s,1H),7.52(s,1H),7.39-7.33(m,2H), 7.31-7.17(m,7H),6.86(t,J=0.9Hz,1H),6.75(s,1H),5.41(t,J=5.5Hz,1 H),5.07-5.00(m,2H),4.62(s,1H),4.52(qdd,J=12.5,5.5,1.0Hz,2H),4.0 9-4.03(m,2H),3.89(s,3H),3.78(d,J=1.1Hz,2H),3.47(d,J=9.5Hz,1H), 3.29(d,J=9.5Hz,1H),3.11(d,J=2.4Hz,2H),2.97-2.84(m,5H),2.80(s,1H ),2.55-2.43(m,2H),2.42-2.32(m,5H),2.26(s,3H),1.87(s,1H),1.69(s, 2H),1.48(d,J=1.4Hz,2H),1.12(s,3H),1.07(s,3H).MS(ESI,m / z):1014(M + +1).

[0321] Example 69 Synthesis of Compound S50

[0322]

[0323] The synthesis method refers to Example 20, and compound S50 can be prepared by simply replacing the corresponding raw materials. 1H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.75(s,1H),8.45(s,1H) ,7.85(s,1H),7.82-7.76(m,3H),7.64(s,1H),7.39-7.33(m,2H),7.31-7.24(m,5H), 7.24-7.17(m,2H),6.86(t,J=0.9Hz,1H),5.41(t,J=5.5Hz,1H),5.10-5.03(m,2H),4 .59-4.52(m,2H),4.50(ddd,J=12.5,5.5,0.9Hz,1H),4.28(s,1H),4.12(d,J=4.9Hz, 1H),3.89(s,3H),3.78(d,J=1.1Hz,2H),3.47(d,J=9.5Hz,1H),3.32(d,J=9.5Hz,1H ),3.11(d,J=2.4Hz,2H),2.94(d,J=12.3Hz,1H),2.91-2.84(m,4H),2.80(s,1H),2.5 7(d,J=4.9Hz,2H),2.52(d,J=12.5Hz,1H),2.46(d,J=12.3Hz,1H),2.34(s,3H),2.09 -2.01(m,4H),1.69(s,2H),1.48(d,J=1.4Hz,2H),0.99(s,9H).MS(ESI,m / z):1048(M + +1).

[0324] Example 70 Synthesis of Compound S51

[0325]

[0326] The synthesis method refers to Example 20, and compound S51 can be prepared by simply replacing the corresponding raw materials. 1H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.75(s,1H),7.58(s,1H),7.52(s,1H),7.42-7.31(m,6H),7.31-7.17(m,6H),6.86(t,J=0 .9Hz,1H),6.75(s,1H),5.41(t,J=5.5Hz,1H),5.10(q,J=0.8Hz,1H),5.04 (d,J=5.1Hz,1H),4.59-4.46(m,3H),4.09-4.03(m,2H),3.89(s,3H),3.78( d,J=1.1Hz,2H),3.47(d,J=9.5Hz,1H),3.29(d,J=9.5Hz,1H),3.11(d,J=2 .4Hz,2H),2.97-2.84(m,5H),2.80(s,1H),2.52(d,J=12.5Hz,1H),2.46(d ,J=12.3Hz,1H),2.39(d,J=16.9Hz,2H),2.26(s,3H),1.87(s,1H),1.69(s ,2H),1.48(d,J=1.4Hz,2H),1.12(s,3H),1.07(s,3H).MS(ESI,m / z):917(M + +1).

[0327] Example 71 Synthesis of Compound S52

[0328]

[0329] The synthesis method refers to Example 20, and compound S52 can be prepared by simply replacing the corresponding raw materials. 1H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.42(s,1H),8.27(s,1H),8.08(d,J=13.0Hz,2H),7.76 (dd,J=7.3,2.0Hz,1H),7.62-7.52(m,3H),7.47(t,J=7.5Hz,1H),7.42-7.33(m,2H),7.20(t,J=1.0Hz,1H),3.47(s ,1H),3.29(s,1H),3.22(s,1H),2.76(dd,J=18.3,1.0Hz,2H),2.63(d,J=1.1Hz,1H),2.56(d,J=1.1Hz,1H),2.40( s,2H),2.26(d,J=11.9Hz,2H),2.17(s,1H),2.12(s,1H),2.03(d,J=14.1Hz,3H),1.97(s,1H).MS(ESI,m / z):774(M + +1).

[0330] Example 72 Synthesis of Compound S53

[0331]

[0332] The synthesis method refers to Example 20, and compound S53 can be prepared by simply replacing the corresponding raw materials. 1 H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),9.26(s,1H),9.03(s,1H),7.82(dd,J=7.1,2.2Hz,1H),7.6 8(dd,J=7.5,2.0Hz,1H),7.62(t,J=7.4Hz,1H),7.52-7.43(m,2H),7.39-7.32(m,2H),7.25(s,1H),7.04(dd,J=7.4,2 .1Hz,1H),6.86(t,J=0.9Hz,1H),4.45(s,1H),4.32(s,1H),4.01(s,1H),3.92(s,3H),3.78(d,J=1.1Hz,2H),2.89-2. 80(m,4H),2.63-2.56(m,4H),2.55-2.45(m,2H),2.19(s,1H),2.12(s,1H),1.49(d,J=4.1Hz,4H).MS(ESI,m / z):799(M + +1).

[0333] Example 73 Synthesis of Compound S54

[0334]

[0335] The synthesis method refers to Example 34, and compound S54 can be prepared by simply replacing the corresponding raw materials. 1 H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.76(s,1H),8.69(s,1H),7.93(dd,J=7.3,2.2Hz,1H),7.63( dd,J=7.5,2.0Hz,1H),7.56-7.41(m,3H),7.39(t,J=1.0Hz,1H),7.12-7.04(m,2H),6.93(s,1H),6.90-6.84(m,2H),5.10 (s,1H),3.92(s,3H),3.78(d,J=1.1Hz,2H),3.57-3.46(m,2H),2.90-2.85(m,3H),2.82(s,1H),2.66(s,1H),2.56-2.49 (m,2H),2.46(d,J=12.5Hz,1H),2.24(d,J=0.9Hz,2H),1.64(s,2H),1.55(s,2H),1.36-1.24(m,6H).MS(ESI,m / z):846(M + +1).

[0336] Example 74 Synthesis of Compound S55

[0337]

[0338] The synthesis method refers to Example 20, and compound S55 can be prepared by simply replacing the corresponding raw materials. 1H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.76(s,1H),8.69(s,1H),7.82(dd,J=6.5,3.0Hz, 1H),7.55-7.42(m,3H),7.39(t,J=1.0Hz,1H),7.22(m,1H),7.08-7.00(m,3H),6.86(t,J=1.0Hz,1H),4.32(s ,1H),4.28(s,1H),4.01(s,1H),3.93(s,3H),3.78(d,J=1.1Hz,2H),2.92-2.85(m,4H),2.64-2.53(m,4H),2. 53-2.47(m,2H),2.24(d,J=0.9Hz,3H),2.17(s,1H),2.12(s,1H),1.50(d,J=4.3Hz,4H).MS(ESI,m / z):745(M + +1).

[0339] Example 75 Synthesis of Compound S56

[0340]

[0341] The synthesis method refers to Example 20, and compound S56 can be prepared by simply replacing the corresponding raw materials. 1H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.42(s,1H),8.27(s,1H),8.08(d,J=13.0Hz,2H),7.90(dd,J=7.4,2.1Hz,1H),7.72(dd,J=7.5, 2.0Hz,1H),7.64(t,J=7.5Hz,1H),7.45-7.38(m,2H),7.26(ddd,J=7.5,5.4,4 .1Hz,1H),7.20(t,J=1.0Hz,1H),7.18-7.10(m,2H),6.61(t,J=5.5Hz,1H),6. 15(s,1H),4.53(ddd,J=12.5,5.4,0.7Hz,1H),3.86(ddd,J=12.4,5.5,0.7Hz ,1H),3.24(s,1H),2.86(d,J=12.3Hz,1H),2.81-2.72(m,3H),2.63(d,J=1.1H z,1H),2.56(d,J=1.1Hz,1H),2.29-2.17(m,4H),2.04(s,1H),1.97(s,1H),1. 92(s,2H),1.78(q,J=12.4Hz,2H),1.56(d,J=3.5Hz,2H).MS(ESI,m / z):751(M + +1).

[0342] Example 76 Synthesis of Compound S57

[0343]

[0344] The synthesis method refers to Example 20, and compound S57 can be prepared by simply replacing the corresponding raw materials. 1H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),8.42(s,1H),8.27(s,1H),8.06(s,1H),7.58-7.49(m,2H),7.40(t,J=1.0Hz,1H),7. 33(ddd,J=11.8,7.3,2.2Hz,2H),7.23(td,J=7.5,2.0Hz,1H),7.18-7.08(m,2H),7.04(ddt,J=7.4,1.9,0.9Hz,1H),6.61(t,J=5.5Hz,1H),4.53 (ddd,J=12.4,5.5,1.1Hz,1H),3.86(ddd,J=12.4,5.5,1.1Hz,1H),3.47(s,1H),3.29(s,1H),3.22(s,1H),2.76(dd,J=18.3,1.0Hz,2H),2.63( d,J=1.1Hz,1H),2.61-2.54(m,3H),2.26(d,J=11.9Hz,2H),2.17(s,1H),2.12(s,1H),2.03(d,J=14.1Hz,3H),1.97(s,1H).MS(ESI,m / z):719(M + +1).

[0345] Example 77 Synthesis of Compound S58

[0346]

[0347] The synthesis method refers to Example 20, and compound S58 can be prepared by simply replacing the corresponding raw materials. 1H NMR(500MHz,Chloroform-d)δ11.22(s,1H),11.11(s,1H),9.25(s,1H),7.82(dd,J=7.3,2.0Hz,1H),7.52(t,J=7 .5Hz,1H),7.49-7.43(m,2H),7.39(t,J=1.0Hz,1H),7.35(s,1H),7.30-7.14(m,4H),6.90(t,J=1.0Hz,1H),5.42 (t,J=5.5Hz,1H),4.58-4.43(m,3H),4.32(s,1H),4.01(s,1H),3.93(s,3H),3.78(d,J=1.1Hz,2H),2.92-2.83(m ,4H),2.64-2.56(m,4H),2.55-2.45(m,2H),2.19(s,1H),2.12(s,1H),1.49(d,J=4.1Hz,4H).MS(ESI,m / z):744(M + +1).

[0348] Example 78: Activity test of the compounds of the present invention on HPK1 kinase

[0349] The HPK1 kinase domain (1-307aa) was dissolved in kinase buffer (20mM HEPES pH 7.5, 10mM MgCl2, 1mM EGTA, 0.5mM TCEP, 0.01% BriJ-35, 0.05% BSA) and added to a 96-well plate at a final concentration of 20nM. A serial dilution of the compound of the present invention to be tested was then added (10 concentration points for each compound). HPK1 kinase and the compound of the present invention were preincubated for 30min. The enzymatic reaction was then initiated by adding 20μL of substrate solution (final concentration of 0.5mg / mL SLP76-SH2 domain and 10μM ATP) to each well. The reaction was incubated at room temperature for 1h, and the inhibition rate of the compound of the present invention on HPK1 kinase activity at each concentration was determined according to the instructions of the Luminescent Kinase Assay Kit (Beyotime Biotechnology Company). The inhibitory activity IC of the compound of the present invention on HPK1 kinase was calculated using GraphPad fitting. 50 The experimental results are shown in Table 1.

[0350]

[0351] Table 1 Kinase inhibitory activity of the compounds of the present invention on HPK1 protein (IC 50 nM)

[0352]

[0353]

[0354] Compared with the positive control compound A, the compound of the present invention has substantially the same activity as the positive control, which indicates that the compound of the present invention substantially maintains the HPK1 inhibitory activity and has good binding to the HPK1 protein.

[0355] Example 79 Test of HPK1 protein degradation activity of some compounds of the present invention

[0356] (1) Cell collection: Jurkat cells were cultured for 12 h, and some compounds of the present invention (0.1 μM, 1 μM, 10 μM) were incubated with the cells for 12 h.

[0357] (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, place on ice for 30 minutes, centrifuge at 12000 rpm at 4°C for 5 minutes, transfer the supernatant after centrifugation into a new centrifuge tube, and prepare for quantification.

[0358] (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. After mixing, the mixture was 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 until use.

[0359] (4) Prepare SDS-PAGE gel, with the voltage of the stacking gel at 90 V and the voltage of the separation gel at 120 V. Transfer the membrane at 100 V for 1 h at 4°C. After transfer, immediately place the protein membrane in the pre-prepared 5% BSA solution, shake it slowly on a shaker, and block it at room temperature for 1 h.

[0360] (5) Refer to the instructions of HPK1 Antibody (4472SCST), GLK (D1L4G) Rabbit mAb (92427SCST), Rabbit mAb (92711TCST), and β-actin Mouse Monoclonal antibody (BE0021 easybio), dilute the primary antibody in an appropriate ratio, incubate at 4°C with slow shaking overnight, and then wash three times with PBST, 10 min each time.

[0361] (6) Select Goat Anti-Rabbit IgG (H&L)-HRP ConJugated (BE0101easybio) or Goat Anti-Mouse IgG (H&L)-HRP ConJugated (BE0102easybio) according to the primary antibody, refer to the instructions of the secondary antibody, dilute the secondary antibody according to the appropriate ratio, incubate at room temperature with slow shaking for 1 hour, and wash three times with PBST, 10 minutes each time.

[0362] (7) ECL luminescent solution was added, and the results were observed using a developer. The Western blot results were quantified using Image J software, and the degradation rates (HPK1 and GLK) were calculated by comparing with the control group without compound addition. The experimental results are shown in Table 2.

[0363] Table 2 Degradation activity of the compounds of the present invention on HPK1 HPK1 and GLK proteins

[0364]

[0365] The experimental results show that the compounds of the present invention have good degradation activity on HPK1 protein and are dose-dependent. The degradation rate of GLK protein by the compounds of the present invention is low at 1.0 μM, indicating that the compounds of the present invention can effectively and selectively reduce HPK1 protein.

[0366] Example 80 Detection of T cell cytokine release

[0367] HPK1 kinase inhibits the release of T cell effector cytokines, so the ELISA method was used to test whether the compounds of the present invention can enhance the release of T cell cytokines. Human PBMC cells were thawed and suspended in RPMI1640 (Gibco) medium containing 10% bovine placental serum. The cells were seeded in 96-well plates (1×10 5 / well). Serial dilutions of the compound of the present invention were added to a 96-well plate and incubated in a 37°C, 5% CO2 incubator for 1 hour. PBMCs were activated by adding 100 μL of anti-CD3 / CD28 antibody (final concentration 1 μg / mL), and then incubated in a 37°C, 5% CO2 incubator for 48 hours. The supernatant was diluted 8-fold with PBS, and 100 μL of the diluted supernatant was taken and the release of cytokine IL-2 at each concentration of the compound of the present invention was detected using a human IL-2 ELISA kit (4abio). The EC values ​​of the compound of the present invention were calculated using GraphPad fitting. 50 The experimental results are shown in Table 3.

[0368] Table 3 Test results of the activity of the compounds of the present invention in stimulating PBMC to release IL-2 cytokine

[0369] Compound number <![CDATA[EC 50 (nM)]]> S1 65 S3 45 S4 42 S17 23 S18 18 S19 15 S20 28 S38 45 S39 40 S40 56 S46 40 S48 58 A 140nM

[0370] The compounds of the present invention can significantly enhance the release of IL-2 from PBMC cells and are superior to the positive control compound A. This indicates that the compounds of the present invention can enhance the release of T cell effector cytokines by degrading HPK1 protein, thereby restoring or enhancing the anti-tumor immune response.

Claims

1. A heterocyclic carboxamide compound as shown in Formula I-1 or II-1 or a pharmaceutically acceptable salt thereof, whose structural formula is shown below: in: R 1 For hydrogen, halogen, C 1-4 Alkoxy, halogenated (C 1-4 Alkoxy) or deuterated (C 1-4 alkoxy); R2 is halogen, cyano, hydroxyl (C 1-4 Alkyl) or halo (C 1-4 alkyl); m is 0, 1, 2, or 3; E is W is -CH2-, -C(CH3)2 or R 3 C 1-6 alkyl; R 4 for R 5 is hydrogen or C 1-4 alkyl; L is The "---" end indicates that it is connected to the E end, and the "---" end indicates that it is connected to the connected; a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; b is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; c is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; d is 1, 2, 3, or 4; e is 1, 2, 3, 4, 5, or 6; f is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.

2. The heterocyclic carboxamide compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: L is The "---" end indicates that it is connected to the E end, and the "---" end indicates that it is connected to the connected; a is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; b is 1, 2, 3, 4, 5, 6 or 7; c is 1, 2, 3, 4, 5, 6, 7, 8, or 9; d is 1, 2, or 3; e is 1, 2, 3, or 4; f is 1, 2, 3, 4, 5, 6, 7 or 8.

3. The heterocyclic carboxamide compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: E is 4. The heterocyclic carboxamide compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: R 2 is fluorine, cyano, hydroxymethyl, methyl or trifluoromethyl.

5. The heterocyclic carboxamide compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The heterocyclic carboxamide compound is selected from the following compounds with any structure:

6. A pharmaceutical composition comprising a therapeutically effective amount of the heterocyclic carboxamide compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

7. Use of the heterocyclic carboxamide compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 in the preparation of a hematopoietic progenitor cell kinase 1 degrader.

8. Use of the heterocyclic carboxamide compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 in the preparation of a medicament for treating and / or preventing cancer.

9. Use of the pharmaceutical composition according to claim 8 in the preparation of a hematopoietic progenitor cell kinase 1 degrader.

10. Use of the pharmaceutical composition according to claim 8 in the preparation of a medicament for treating and / or preventing cancer.

Images