Aza-di-peri-cyclic compounds, pharmaceutical compositions thereof and uses thereof

Abstract

The application belongs to the field of pharmaceutical chemistry, and relates to an azadipolyheterocyclic compound and a pharmaceutical composition and application thereof, the compound being an azadipolyheterocyclic compound as shown in formula I, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, metabolite or prodrug thereof, wherein R1-R3 and X, Y, A and B are as defined in the specification. The compound and the pharmaceutical composition containing the same have good MAT2a inhibitory activity, and can be used as a MAT2a inhibitor and for preparing a drug for treating and / or preventing a disease caused by overexpression of MAT2a, such as cancer, and are widely used in the field of medicine. The azadipolyheterocyclic compound in the application has excellent biological activity and drugability, and has great prospects for drug development.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry, specifically relating to a class of azadiane polycyclic fused ring compounds, pharmaceutical compositions containing such compounds, and their applications in the pharmaceutical field. Background Technology

[0002] Methionine adenosine transferase (MAT), also known as S-adenosylmethionine synthase, plays a crucial role in cell growth and survival. Recent studies have shown that approximately 15% of cancer patients have MTAP deficiency, accounting for more than 10% in non-small cell lung cancer, pancreatic cancer, glioma, head and neck cancer, bladder cancer, melanoma, and other solid tumors. MTAP gene deletion can induce intracellular MTA accumulation, which inhibits the activity of protein arginase methyltransferase 5 (PRMT5), leading to increased resistance of cancer cells to key enzymes in SAM synthesis and causing abnormalities in RNA splicing, gene expression, and genome stability. Research has identified the MAT subtype MAT2A as a "synthetic lethal" target in MTAP-deficient tumors. These findings have encouraged the initiation of drug discovery efforts targeting MAT2A to treat MTAP-deficient cancers.

[0003] Since the 1960s, methionine analogs have been used as lead compounds to discover substrate-competitive inhibitors of MAT2A, but these efforts have failed due to insufficient affinity and selectivity. It wasn't until 2017 that Pfizer researchers discovered the first variant MAT2A inhibitor—PF-9366—but its activity needs further improvement. Currently, most research on MAT2A inhibitors is in the preclinical stage, with only one inhibitor, AG-270, having entered clinical trials. Therefore, developing novel and highly effective MAT2A inhibitors is crucial. This invention discloses a series of novel MAT2A inhibitors with a zazadicyclic multi-fused ring as the parent core, exhibiting extremely high in vivo antitumor efficacy and metabolic activity. Summary of the Invention

[0004] The problem the invention aims to solve

[0005] The present invention aims to provide a class of novel azadiacetic polycyclic fused ring compounds for use as MAT2a inhibitors, which exhibit good inhibitory activity against tumor cells, have good drug-like properties, and have broad prospects for drug development.

[0006] Solution for solving the problem

[0007] In a first aspect, the present invention provides a compound of Formula I or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, metabolite or prodrug thereof:

[0008]

[0009] Among them, Z 1 Selected from C=O, CH, or N; Z 2 It is C or N; A is selected from C3-C 10 Aryl, 5- to 6-membered monocyclic heteroaryl or bicyclic heteroaryl, wherein each of the aryl, monocyclic heteroaryl and bicyclic heteroaryl is optionally substituted by one or more independent R3s;

[0010] B is selected from hydrogen and C3-C. 10 Aryl, 5- to 6-membered monocyclic heterocyclic rings;

[0011] X and Y are each independently selected from C or N;

[0012] R1 and R2 are each independently selected from hydrogen, halogen, cyano, hydroxyl, amino, -NH(R4), -C(=O)-NH(R4), C1-C6 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, 3 to 8-membered heterocyclic alkyl, C1-C3 alkoxy and C1-C6 haloalkyl, or R1 and R2 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl or heterocycle;

[0013] R3 is selected from hydrogen, halogen, cyano, hydroxyl, amino, -NH(R4), -C(=O)-NH(R4), C1-C6 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, 3 to 8-membered heterocyclic alkyl, C1-C3 alkoxy and C1-C6 haloalkyl;

[0014] R4 can be independently selected from hydrogen, halogen, cyano, hydroxyl, amino, carbamoyl, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, 3- to 14-membered heterocycloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C6-C 10 Aryl, 5- to 6-membered monocyclic heteroaryl or 9- to 10-membered bicyclic heteroaryl, wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, haloalkoxy, aryl, monocyclic heteroaryl and bicyclic heteroaryl are each optionally substituted by at least one R5.

[0015] Each R5 is independently selected from hydrogen, chlorine, fluorine, cyano, hydroxyl, amino, isopropyl, cyclopropyl, methyl, difluoromethyl, trifluoromethyl, methoxy, trifluoromethoxy, ethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, and phenyl.

[0016] Preferably, Z 1 Selected from CH or N, and Z 2 For C; or Z 1 For C=O and Z2 Let N be the number of elements; where Z is the number of elements. 1 For C=O and Z 2 The chemical structural formula for N is as follows:

[0017]

[0018] Z 1 Selected from CH or N, and Z 2 The chemical structural formula of C is as follows:

[0019]

[0020] More preferably, it is a compound as shown in any one of formulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, II-1, II-2, or II-3.

[0021]

[0022] More preferably, it is a compound as shown in any one of Formulas 1-41:

[0023]

[0024]

[0025]

[0026] Those skilled in the art can select the groups and substituents described in the above-mentioned general formula of the compounds to provide stable compounds, or pharmaceutically acceptable salts thereof, or stereoisomers thereof, or tautomers thereof, or hydrates thereof, or solvates thereof, or metabolites thereof, or prodrugs thereof, including but not limited to the compounds described in the embodiments of the present invention.

[0027] In a second aspect, the present invention provides a pharmaceutical composition comprising an effective dose of one or more of the following compounds: a compound of formula I, I-1, I-2, I-3, I-4, I-5, II-1 or II-2, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, a hydrate thereof, a solvate thereof, a metabolite thereof, or a prodrug thereof.

[0028] Preferably, the pharmaceutical composition further comprises at least one pharmaceutically acceptable excipient.

[0029] More preferably, the excipients include at least one pharmaceutically acceptable excipient.

[0030] Thirdly, the use of any of the compounds provided by the present invention, or pharmaceutically acceptable salts thereof, or stereoisomers thereof, or tautomers thereof, or hydrates thereof, or solvates thereof, or metabolites thereof, or prodrugs thereof, or pharmaceutical compositions thereof, in the preparation of medicaments for the prevention and / or treatment of diseases caused by MAT2a overexpression.

[0031] Fourthly, the use of any of the compounds provided by the present invention, or pharmaceutically acceptable salts thereof, or stereoisomers thereof, or tautomers thereof, or hydrates thereof, or solvates thereof, or metabolites thereof, or prodrugs thereof, or pharmaceutical compositions thereof, in the preparation of MAT2a inhibitor drugs.

[0032] Fifthly, in some embodiments of the present invention, the use of the above-mentioned compounds provided by the present invention, or pharmaceutically acceptable salts thereof, or stereoisomers thereof, or tautomers thereof, or hydrates thereof, or solvates thereof, or metabolites thereof, or prodrugs thereof, or pharmaceutical compositions thereof, in the preparation of medicaments for treating and / or preventing cancer.

[0033] Preferably, the compounds described in this invention can be used to treat and / or prevent cancer, wherein the cancers that can be used to treat and / or prevent include, but are not limited to, one or more of pancreatic cancer, colorectal cancer, and lung cancer.

[0034] The effects of the invention

[0035] This invention provides a series of novel azadiacetic polycyclic fused-ring compounds. Enzyme and cell activity assays have demonstrated that these compounds exhibit excellent cell proliferation inhibitory activity. In in vitro experiments, they showed an IC50 inhibitory effect on cell proliferation. 50 With values ​​reaching the nM level, it can be well applied in various tumors. Simultaneously, the compounds of this invention exhibit very good inhibitory activity against the substrate MAT2a, reaching the nM level, making them suitable for preparation as MAT2a inhibitors for the prevention and / or treatment of diseases or conditions related to MAT2a activation, such as cancers (including but not limited to colorectal cancer, pancreatic cancer, and lung cancer). Detailed Implementation

[0036] General terms and definitions

[0037] Unless otherwise stated, the terms used in this invention have the following meanings.

[0038] "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight-chain and branched groups with 1 to 20 carbon atoms, such as straight-chain and branched groups with 1 to 18 carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. In this invention, "alkyl" can be a monovalent, divalent, or trivalent group. Non-limiting examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, and their various branched isomers. Non-limiting examples also include, but are not limited to, methylene, methine, ethylene, methine, propylene, methine, butylene, methine, and their various branched isomers. Furthermore, in this invention, "alkyl" may be optionally substituted or unsubstituted.

[0039] "Alkoxy" refers to the "-O-alkyl" group, where "alkyl" is defined as described above.

[0040] "Alkenyl" refers to an unsaturated aliphatic hydrocarbon group, comprising straight-chain and branched groups with 1 to 20 carbon atoms and at least one carbon-carbon double bond, such as straight-chain and branched groups with 1 to 18 carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. In this invention, "alkenyl" can be a monovalent, divalent, or trivalent group. Non-limiting examples include, but are not limited to, vinyl (-CH=CH2), propen-1-yl (-CH=CH-CH3), propen-2-yl (-C(CH3)=CH2), buten-1-yl (-CH=CH-CH2-CH3), buten-2-yl (-C(C2H5)=CH2), 1-methylpropen-1-yl (-C(CH3)=CH-CH3), and their various branched isomers. Non-limiting examples also include, but are not limited to, 1,1-vinylene (=C=CH2), 1,2-vinylene (-CH=CH-), 1,1-propenylidene (=C=CH-CH3), 1,2-propenylidene (-CH=C(CH3)-), 1,3-propenylidene (-CH=CH-CH2-), and their various branched isomers. Furthermore, in this invention, the "alkenyl" may be optionally substituted or unsubstituted.

[0041] "Alynyl" refers to an unsaturated aliphatic hydrocarbon group comprising 1 to 20 carbon atoms and at least one carbon-carbon triple bond, in both straight-chain and branched groups. For example, it can be a straight-chain or branched group with 1 to 18 carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. In this invention, "alkynyl" can be a monovalent, divalent, or trivalent group. Non-limiting examples include, but are not limited to, ethynyl (-C≡CH), propynyl (-C≡CH-CH3), and butynyl. Pentyne And its various branched isomers, etc. Non-limiting examples also include, but are not limited to, ethynylene (C≡C-) and propynylene. Butyrynethin And its various branched isomers. Furthermore, in this invention, the "alkynyl group" may be optionally substituted or unsubstituted.

[0042] "Heteroalkyl" refers to a saturated aliphatic hydrocarbon group, including straight-chain and branched groups of 2 to 20 atoms, for example, straight-chain and branched groups of 2 to 18 atoms, 2 to 12 atoms, 2 to 8 atoms, 2 to 6 atoms, or 2 to 4 atoms, wherein one or more atoms are selected from nitrogen, oxygen, or S(O). m (Where m is 0, 1, or 2) heteroatoms, with the remainder being carbon. In this invention, "heteroalkyl" can be a monovalent, divalent, or trivalent group. Non-limiting examples include, but are not limited to, methoxymethyl (2-oxapropyl), methylthiomethyl (2-thiopropyl), methylaminomethyl (2-azapropyl), and their various branched isomers. Furthermore, in this invention, "heteroalkyl" can be optionally substituted or unsubstituted.

[0043] "Cycloalkyl" refers to a saturated or partially unsaturated, monocyclic or polycyclic aliphatic hydrocarbon group comprising 3 to 12 ring atoms, for example, 3 to 12, 3 to 10, or 3 to 6 ring atoms (i.e., 3 to 6 membered rings). Non-limiting examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc. In this invention, "cycloalkyl" may be optionally substituted or unsubstituted.

[0044] "Heterocyclic alkyl" refers to a saturated or partially unsaturated, monocyclic or polycyclic aliphatic hydrocarbon group comprising 3 to 20 ring atoms, for example, 3 to 16, 3 to 12, 3 to 10, or 3 to 6 ring atoms, wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O). m(where m is 0, 1, or 2) heteroatoms, with the remaining ring atoms being carbon. Preferably, the heterocyclic alkyl group comprises 3 to 12 ring atoms, wherein 1 to 4 ring atoms are heteroatoms; more preferably, it comprises 3 to 10 ring atoms; most preferably, it comprises 5 or 6 ring atoms, wherein 1 to 4, preferably 1 to 3, and more preferably 1 to 2 are heteroatoms. Non-limiting examples of monocyclic heterocyclic alkyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and homopiperazinyl. Non-limiting examples of polycyclic heterocyclic alkyl groups include, but are not limited to, spirocyclic or bridged heterocyclic alkyl groups.

[0045] "Halogen" refers to fluorine, chlorine, bromine and iodine, with fluorine, chlorine and bromine being preferred.

[0046] "Halogenated alkyl" or "halogenated alkoxy" means that an alkyl or alkoxy group is replaced by one or more identical or different halogen atoms. Preferred examples of alkyl or alkoxy groups include, but are not limited to, trifluoromethyl, trifluoroethyl, and trifluoromethoxy.

[0047] "Cyano" refers to the "-CN" group.

[0048] "Hydroxy group" refers to the "-OH" group.

[0049] "Amino" refers to the "-NH2" group.

[0050] "Carbamoyl" refers to the "-(C=O)-NH2" group.

[0051] "Aryl" refers to a monocyclic, bicyclic, or tricyclic carbocyclic system containing 6-14 ring atoms, wherein at least one ring system is aromatic, and each ring system comprises a ring of 3-7 atoms with one or more bonding sites connected to the rest of the molecule. Examples include, but are not limited to, phenyl, naphthyl, and anthracene. Preferably, the aryl group is a carbocyclic system with 6-10 or 6-7 ring atoms.

[0052] "Heteroaryl" refers to a monocyclic, bicyclic, or tricyclic system containing 5-14 ring atoms, wherein at least one ring system is aromatic, and at least one ring system contains one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein each ring system contains a ring of 5-7 atoms and has one or more bonding sites connected to the rest of the molecule. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound." Examples include, but are not limited to: furanyl, imidazolyl, 2-pyridyl, 3-pyridyl, thiazolyl, purinyl, and quinolinyl. Preferably, the heteroaryl is a ring system with 5-10 ring atoms.

[0053] "Optional" or "optionally" means that the event or environment described below may but does not have to occur, and the description includes the possibility that the event or environment may or may not occur. For example, "optionally alkyl-substituted heterocyclic group" means that the alkyl group may but is not required to be present, and the description includes the possibility that the heterocyclic group is substituted with an alkyl group and the possibility that the heterocyclic group is not substituted with an alkyl group.

[0054] "Substituted" refers to one or more hydrogen atoms in a group, preferably up to five, and more preferably one to three hydrogen atoms that are independently substituted by the corresponding number of substituents.

[0055] "Pharmaceutically acceptable salt" refers to a salt prepared from the compounds of this invention with a relatively non-toxic acid or base. When the compounds of this invention contain a relatively acidic functional group (e.g., a carboxyl or sulfonic acid group), a base addition salt can be obtained by contacting it with a sufficient amount of base in a pure solution or a suitable inert solvent in its free form. Non-limiting examples of pharmaceutically acceptable base addition salts include, but are not limited to, sodium, potassium, ammonium, calcium, magnesium, organic amine, or similar salts. When the compounds of this invention contain a relatively basic functional group (e.g., an amino or guanidine group), an acid addition salt can be obtained by contacting it with a sufficient amount of acid in a pure solution or a suitable inert solvent in its free form. Non-limiting examples of pharmaceutically acceptable acid addition salts include, but are not limited to, inorganic acid salts (e.g., hydrochlorides, hydrobroms, hydroiodates, nitrates, carbonates, bicarbonates, phosphates, monohydrogen phosphates, dihydrogen phosphates, phosphites, sulfates, hydrogen sulfates, etc.), organic acid salts (e.g., acetates, propionates, isobutyrates, malonates, succinates, octanoates, maleates, fumarates, citrates, tartrates, lactates, mandelates, benzoates, phthalates, methanesulfonates, benzenesulfonates, p-toluenesulfonates, glucuronic acid, etc.), and amino acid salts (e.g., arginine salts). Specific forms of pharmaceutically acceptable salts can also be found in Berge et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66:1-19. Certain compounds of this invention contain both basic and acidic functional groups, and thus can be converted into either a basic addition salt or an acid addition salt. Preferably, the salt is contacted with a base or acid in a conventional manner, and then the parent compound is separated, thereby regenerating the neutral form of the compound. The parent form of the compound differs from its various salt forms in certain physical properties, such as different solubilities in polar solvents. According to embodiments of the invention, the pharmaceutically acceptable salt of the compound as shown in Formula I is preferably an acid addition salt, preferably a hydrochloride, hydrobromide, phosphate, or sulfate, more preferably a hydrochloride.

[0056] "Pharmaceutical composition" means a composition that is pharmaceutically usable and comprises one or more compounds as shown in Formula I or in a pharmaceutically acceptable form thereof (e.g., salt, hydrate, solvate, stereoisomer, tautomer, metabolite, prodrug, etc.), and other components (e.g., pharmaceutically acceptable excipients).

[0057] In this invention, "pharmaceuticalally acceptable excipients" refer to auxiliary materials widely used in the pharmaceutical manufacturing field. The primary purpose of using excipients is to provide a pharmaceutical composition that is safe to use, stable in nature, and / or has specific functionalities, and also to provide a method for enabling the active ingredient to dissolve at a desired rate or promote the effective absorption of the active ingredient in the body of the administered subject after administration of the drug. Pharmaceutically acceptable excipients can be inert fillers or functional ingredients that provide a certain function to the pharmaceutical composition (e.g., stabilizing the overall pH of the composition or preventing the degradation of the active ingredient in the composition). Non-limiting examples of pharmaceutically acceptable excipients include, but are not limited to, binders, suspending agents, emulsifiers, diluents (or 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, sweeteners, etc.

[0058] The pharmaceutical compositions of this invention can be prepared using any method known to those skilled in the art. For example, conventional mixing, dissolving, granulation, emulsification, grinding, encapsulation, embedding, and / or lyophilization processes.

[0059] In this invention, the purpose of using the pharmaceutical composition is to promote drug delivery to the organism, facilitating the absorption of the active ingredient and thereby exerting its biological activity. The pharmaceutical compositions of this invention can be administered in any form, including injection (intra-arterial, intravenous, intramuscular, intraperitoneal, subcutaneous), mucosal, oral (oral solid dosage forms, oral liquid dosage forms), rectal, inhalation, implantation, and topical (e.g., ocular) administration. Non-limiting examples of oral solid dosage forms include, but are not limited to, powders, capsules, lozenges, granules, tablets, etc. Non-limiting examples of oral or mucosal liquid dosage forms include, but are not limited to, suspensions, tinctures, elixirs, solutions, etc. Non-limiting examples of topical dosage forms include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops, or serum preparations. Non-limiting examples of parenteral dosage forms include, but are not limited to, solutions for injection, dry powders for injection, suspensions for injection, emulsions for injection, etc. The pharmaceutical compositions of this invention can also be formulated into controlled-release or delayed-release dosage forms (e.g., liposomes or microspheres).

[0060] Preferably, the compounds of the present invention or pharmaceutical compositions comprising them are administered orally or intravenously to the individual in need. Depending on the specific circumstances of the recipient, other administration methods may also be used or even preferred. For example, percutaneous administration would be a very important method of administration for patients who are forgetful or irritable with oral medications. In the present invention, the administration method can be varied or adjusted in any applicable manner to meet the needs of the properties of the drug, the convenience of the patient and healthcare personnel, and other relevant factors.

[0061] The compounds of the present invention, or their pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, tautomers, metabolites, or prodrugs, or pharmaceutical compositions comprising thereof, possess excellent MAT2a enzyme activity and cell proliferation inhibitory activity, and can be used as MAT2a inhibitors for the prevention and / or treatment of diseases or conditions caused by MAT2a overexpression, exhibiting good clinical and pharmaceutical applications. Preferably, non-limiting examples of diseases or conditions caused by MAT2a overexpression are cancers, including but not limited to pancreatic cancer, colorectal cancer, and lung cancer.

[0062] The technical solution of the present invention will be described below with reference to specific embodiments. The following embodiments are provided to further illustrate the present invention, and are not intended to limit the scope of the present invention. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope of the invention.

[0063] The compounds of this invention can be prepared by synthetic methods well known to those skilled in the art, including but not limited to the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of this invention. The known starting materials used in this invention can be synthesized by methods known in the art or purchased through conventional commercial means (e.g., from companies such as Shaoyuan Chemical Technology and Beijing Coupling Technology). Unless otherwise specified, all reactions are carried out under an argon or nitrogen atmosphere. Hydrogenation reactions are typically performed under vacuum and purged with hydrogen, repeated three times. The reaction temperature is room temperature, ranging from 20°C to 30°C. Monitoring of the reaction progress can be achieved by synthetic methods well known to those skilled in the art, including but not limited to thin-layer chromatography (TLC). Qingdao Ocean GF254 silica gel plates are used for TLC. The developing solvent system includes, but is not limited to, A: dichloromethane and methanol system; B: petroleum ether and ethyl acetate system. The volume ratio of the solvent can be adjusted according to the polarity of the compound.

[0064] The separation and purification of the compounds of this invention can be achieved through synthetic methods well known to those skilled in the art, including but not limited to column chromatography (CC), high-performance liquid chromatography (HPLC), and ultra-high-performance liquid chromatography (UPLC). Column chromatography generally uses Qingdao Ocean 200-300 mesh silica gel as the carrier. The eluent system includes, but is not limited to, A: dichloromethane and methanol; B: petroleum ether and ethyl acetate. The volume ratio of the solvent can be adjusted according to the polarity of the compound, and a small amount of acidic or basic anti-tailing reagent can also be added for adjustment. HPLC chromatograms are determined using an Agilent 1200DAD HPLC system (column: Sunfire C18, 150×4.6mm, 5μm) or a Waters 2695-2996 HPLC system (column: Gimini C18, 150×4.6mm, 5μm).

[0065] The structural identification of the compounds of this invention can be achieved by methods well known to those skilled in the art, including but not limited to nuclear magnetic resonance (NMR) and mass spectrometry (MS). NMR spectra were determined using a Bruker AVANCE-400 or Agilent DD2600 NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), or deuterated methanol (CD3OD) as the solvent, and tetramethylsilane (TMS) as the internal standard. Chemical shifts were expressed in 10⁻⁶ increments. -6 (ppm) were measured. MS spectra were determined using an Agilent SQD (ESI) mass spectrometer (model: 6110) or a Shimadzu SQD (ESI) mass spectrometer (model: 2020).

[0066] The present invention will be described in detail below with reference to examples, but this does not imply any adverse limitation on the invention. The compounds of the present invention can be prepared by various synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of the present invention. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope of the invention. The following synthetic schemes describe the steps for preparing the compounds disclosed in the present invention. Unless otherwise stated, each substituent has the definition as described in the present invention.

[0067] Preparation and functional verification of target compounds

[0068] Example 1: Preparation of Compound 1

[0069]

[0070] The synthetic route for compound 1 is as follows:

[0071]

[0072] Preparation method:

[0073] Step 1: Synthesize compound B1

[0074] Compound A1 (200 mg) was dissolved in acetonitrile (5 mL), followed by the addition of potassium carbonate (382 mg) and iodoethane (360 mg). The mixture was then stirred at 60 °C for 8 hours. After TLC analysis, the reaction mixture was filtered, and the filtrate was desolvated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate 10:1 to 1:1 (v / v)) to give compound B1 (250 mg, colorless oil, yield 98.92%).

[0075] MS(ESI): m / z 273.0 [M+1] +

[0076] Step 2: Synthesize compound D1

[0077] Compound B1 (250 mg) and compound C1 (150 mg) were dissolved in dioxane (4 mL), and cesium carbonate (600 mg), tris(dibenzylacetone)palladium (40 mg), and 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (55 mg) were added. The reaction mixture was purged with nitrogen three times and stirred at 100 °C for 8 hours. After TLC analysis, the reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (10 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered to remove the desiccant, dissolved under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate from 10:1 to 3:1 (v / v)) to give compound D1 (250 mg, white oil, yield 77.4%).

[0078] MS(ESI): m / z 352.1[M+1] +

[0079] Step 3: Synthesize compound E1

[0080] Compound D1 (250 mg) was dissolved in tetrahydrofuran (6 mL), and lithium aluminum hydride (51 mg) was added in portions at 0 °C. The mixture was then stirred at room temperature for 2 hours. After the reaction was complete as shown by TLC, water (1 mL) was added dropwise to the reaction mixture at 0 °C, and the mixture was stirred at 0 °C for 30 minutes. Anhydrous sodium sulfate was then added and the mixture was dried. The mixture was filtered, and the filtrate was desolvated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate from 10:1 to 1:1 (v / v)) to give compound E1 (190 mg, pale yellow solid, yield 85.91%).

[0081] MS(ESI): m / z 310.1 [M+1] +

[0082] Step 4: Synthesize compound F1

[0083] Compound E1 (190 mg) was dissolved in dichloromethane (4 mL), and activated manganese dioxide (470 mg) was added. The mixture was then stirred at room temperature for 16 hours. After the reaction was complete as shown by TLC, the reaction solution was filtered, and the filter cake was washed with dichloromethane (5 mL × 2). The filtrate was desolvated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate from 10:1 to 5:1 (v / v)) to give compound F1 (154 mg, pale yellow solid, yield 82%).

[0084] MS(ESI): m / z 308.1 [M+1] +

[0085] Step 5: Synthesize compound G1

[0086] Compound F1 (120 mg) was added to anhydrous dioxane (3 mL), and sodium hydride (78 mg, 60%) was added in portions at 0 °C. The mixture was stirred at 0 °C for 10 minutes, followed by the addition of chloroacetyl chloride (144 mg) dropwise at 0 °C. The reaction mixture was then stirred at 100 °C for 16 hours under nitrogen protection. TLC showed that the reaction was complete. The reaction was slowly quenched with water (10 mL) at 0 °C, followed by extraction with dichloromethane (20 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and dissolved under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate from 20:1 to 5:1 (v / v)) to give crude product compound G1 (120 mg, yellow oil, 40% purity).

[0087] MS(ESI): m / z 366.1 [M+1] +

[0088] Step 6: Synthesize Compound 1

[0089] Compound G1 (100 mg) and compound H1 (50 mg) were dissolved in dioxane (2 mL) and water (0.5 mL). Cesium carbonate (180 mg) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (22 mg) were added. The reaction solution was purged with nitrogen three times and stirred at 90 °C for 5 hours. After the reaction was completed by TLC, the reaction solution was concentrated under reduced pressure. The residue was purified by prep-HPLC (10 μm 100A 30 × 250 mm; mobile phase A: 0.1% ammonium bicarbonate in water, mobile phase B: acetonitrile, gradient: 1.1–6 min, 10%–90%; 6–11 min, 90%) to obtain compound 1 (20 mg, yellowish-brown solid).

[0090] MS(ESI): m / z 462.2 [M+1] +

[0091] 1 H NMR(300MHz, DMSO-d6)δ(ppm)8.37(s,1H),8.19(s,1H),8.09(t,J=1.3Hz,1H),7.79(d,J=8.7Hz,1H),7.60–7.55(m,2H),7.48–7.36(m,4 H),7.40(t,J=73.7Hz,1H),6.93(dd,J=8.7,2.3Hz,1H),5.89(d,J=2.3Hz,1H),4.16(s,3H),3.92(q,J=6.9Hz,2H),1.24(t,J=6.9Hz,3H).

[0092] Example 2: Preparation of Compound 2

[0093]

[0094] The synthetic route for compound 2 is as follows:

[0095]

[0096] Preparation method:

[0097] Step 1: Synthesize compound B2

[0098] Compound A2 (2.0 g) was dissolved in 1,4-dioxane (18 mL). A solution of compound C1 (1.65 g) in 1,4-dioxane (2 mL) was added dropwise to the above reaction solution under ice bath conditions. Then, N,N-diisopropylethylamine (2.67 g) was added dropwise under ice bath conditions, followed by stirring at room temperature for 10 minutes. After the reaction was complete as shown by TLC, the reaction solution was desolvated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate from 100:0 to 10:1 (v / v)) to give compound B2 (2.82 g, yellow solid, yield: 86.7%).

[0099] MS(ESI): m / z 317.0 [M+1] +

[0100] Step 2: Synthesize compound C2

[0101] Compound B2 (2.5 g) was dissolved in anhydrous ethanol (25 mL), and sodium ethoxide (538 mg) was added at 0 °C. The reaction was then carried out at 80 °C for 16 hours. After the reaction was completed by TLC, the reaction solution was desolvated under reduced pressure, and the residue was slurried with water (25 mL), filtered, and the filter cake was dried to give compound C2 (2.4 g, yellow solid, yield: 93.2%).

[0102] MS(ESI): m / z 327.1 [M+1] +

[0103] Step 3: Synthesize compound D2

[0104] Compound C2 (2.4 g) was dissolved in ethanol (30 mL), and 10% wet palladium / carbon (240 mg) was added. The mixture was then stirred overnight at room temperature under a hydrogen balloon. After the reaction was complete as shown by TLC, the reaction solution was filtered through diatomaceous earth, and the filtrate was desolvated under reduced pressure to give compound D2 (2.06 g, black solid, yield: 94.1%).

[0105] MS(ESI): m / z 297.1 [M+1] +

[0106] Step 4: Synthesize compound F2

[0107] Compound D2 (1 g) was dissolved in dichloromethane (15 mL) and pyridine (10 mL), and then a solution of compound E2 (0.689 g) in dichloromethane (5 mL) was added dropwise under ice bath conditions. The mixture was stirred at 50 °C for 16 hours. After the reaction was complete as shown by TLC, the reaction solution was diluted with water (20 mL), and the pH was adjusted to 3 with hydrochloric acid (6 mol / L) under ice bath conditions. The mixture was then extracted with dichloromethane (50 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and dissolved under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate from 10:0 to 1:1 (v / v)) to give compound F2 (1.05 g, reddish-white solid, yield: 88.81%).

[0108] MS(ESI): m / z 351.1[M+1] +

[0109] Step 5: Synthesize compound G2

[0110] Compound F2 (500 mg) was dissolved in toluene (10 mL), and phosphorus oxychloride (655.7 mg) and N,N-diisopropylethylamine (553 mg) were added sequentially under ice bath conditions. The mixture was then stirred at 100 °C for 4 hours. After the reaction was complete as shown by TLC, the reaction solution was desolvated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate from 20:0 to 3:1 (v / v)) to give compound G2 (225 mg, yellow solid, yield: 43.7%).

[0111] MS(ESI): m / z 369.1 [M+1] +

[0112] Step 6: Synthesize compound 2

[0113] The synthesis method is the same as that of compound 1. The synthesis of compound 2 is the same as that of compound 1. In step 6 of the synthesis of compound 1 in Example 1, compound H2 was used instead of compound H1 in Example 1 to synthesize compound 2.

[0114] MS(ESI): m / z 465.1 [M+1] +

[0115] 1H NMR (300MHz, DMSO-d6) δ (ppm) 9.07 (s, 1H), 8.87 (d, J = 1.4Hz, 1H), 8.52 (s, 1H), 8.09 (dd, J = 9.2, 1.7Hz, 1H), 7.67 (dt, J = 9.1, 1.0 Hz,1H),7.53–7.48(m,2H),7.40–7.36(m,2H),7.38(t,J=75.0Hz,1H),4.24(t,J=7.0Hz,2H),4.18(s,3H),1.23(t,J=7.0Hz,3H).

[0116] Example 3: Preparation of Compound 3

[0117]

[0118] The synthetic route for compound 3 is as follows:

[0119]

[0120] Preparation method:

[0121] Step 1: Synthesize compound C3

[0122] Compound A3 (500 mg) was dissolved in N,N-dimethylformamide (5 mL), and sodium hydride (260 mg, 60% purity) was added in portions at 0 °C. The mixture was then stirred at room temperature for 30 minutes. Subsequently, a solution of compound B3 (960 mg) in N,N-dimethylformamide (2 mL) was added dropwise to the above reaction solution at 0 °C. After the addition was complete, the mixture was stirred at room temperature for 30 minutes. After the reaction was complete as indicated by TLC, the reaction solution was slowly poured into a saturated ammonium chloride solution (20 mL) at 0 °C, and then extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and dissolved under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate from 100:0 to 3:1 (v / v)) to give compound C3 (800 mg, pale yellow solid, yield 58.1%).

[0123] MS(ESI): m / z 314.0 [M+1] + .

[0124] Step 2: Synthesize compound D3

[0125] Compound C3 (500 mg) was dissolved in formic acid (10 mL), and then iron powder (425 mg) was added at room temperature. After the addition was complete, the mixture was stirred at 80 °C for 1 hour. After the reaction was complete as shown by TLC, the reaction solution was poured into ice water (20 mL), and sodium bicarbonate was added to adjust the pH to 8. The mixture was then extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and dissolved under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate from 5:1 to 0:1 (v / v)) to give compound D3 (350 mg, pale yellow solid, yield 82.6%).

[0126] MS(ESI): m / z 266.0 [M+1] + .

[0127] Step 3: Synthesize compound E3

[0128] Compound D3 (100 mg) was dissolved in 1,4-dioxane (1 mL), followed by the sequential addition of pinacol diborate (150 mg), potassium acetate (100 mg), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (20 mg). After the addition was complete, the reaction mixture was purged with nitrogen three times and stirred at 90 °C for 5 hours. TLC showed that the reaction was complete. The reaction mixture was then diluted with water (10 mL) and extracted with dichloromethane:methanol (10 mL × 3, 10:1). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and dissolved under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate from 5:1 to 0:1 (v / v)) to give compound E3 (100 mg, brown oil, yield 84.0%).

[0129] MS(ESI): m / z 314.2 [M+1] +

[0130] 1 H NMR (300MHz, Chloroform-d) δ7.89-7.67(m,3H),4.27-4.13(m,2H),3.89(s,2H),3.07-2.92(m,2H),2.56(s,3H),1.38(s,12H).

[0131] Step 4: Synthesize compound G3

[0132] Compound F3 (5.0 g) was dissolved in 1,4-dioxane (50 mL), and triethylamine (4.35 g) and compound C1 (3.42 g) were added sequentially at room temperature. The mixture was then stirred at 60 °C for 16 hours. After TLC analysis, the reaction mixture was poured into water (50 mL) and extracted with dichloromethane (50 mL × 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, dissolved under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate from 100:0 to 10:1 (v / v)) to give compound G3 (6.6 g, off-white solid, 90.0% yield).

[0133] MS(ESI): m / z 356.1 [M+1] +

[0134] Step 5: Synthesize compound H3

[0135] Compound G3 (6.6 g) was dissolved in tetrahydrofuran (60 mL), and lithium aluminum hydride (1.4 g) was added in portions at 0 °C. The mixture was then stirred at room temperature for 3 hours. After the reaction was complete as shown by TLC, water (1.32 mL), 20% sodium hydroxide solution (2.64 mL), and water (3.96 mL) were slowly added dropwise to the reaction mixture at 0 °C, and the mixture was stirred at room temperature for 30 minutes. The mixture was filtered, and the filter cake was washed with dichloromethane (10 mL × 3). The filtrate was dried over anhydrous sodium sulfate, and the desiccant was removed by filtration. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate from 10:1 to 3:1 (v / v)) to give compound H3 (5.06 g, pale yellow solid, yield 87.24%).

[0136] MS(ESI): m / z 314.1 [M+1] +

[0137] Step 6: Synthesize compound I3

[0138] Compound H3 (5.06 g) was dissolved in dichloromethane (50 mL), and activated manganese dioxide (14.1 g) was added. The mixture was then stirred at room temperature for 16 hours. After the reaction was complete as shown by TLC, the reaction solution was filtered, and the filter cake was washed with dichloromethane (10 mL × 3). The filtrate was desolvated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate from 20:1 to 5:1 (v / v)) to give compound I3 (4.13 g, pale yellow solid, yield 82.11%).

[0139] MS(ESI): m / z 312.1[M+1]

[0140] Step 7: Synthesize compound J3

[0141] Compound I3 (1.0 g) was added to anhydrous dioxane (10 mL), and sodium hydride (640 mg, 60% purity) was added in portions at 0 °C. The mixture was stirred at 0 °C for 10 minutes, followed by the addition of chloroacetyl chloride (1.09 g) dropwise to the reaction mixture at 0 °C. After the addition was complete, the reaction mixture was stirred at 100 °C for 16 hours under nitrogen protection. TLC showed that the reaction was complete. The reaction was slowly quenched with water (20 mL) at 0 °C, and then extracted with dichloromethane (30 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and dissolved under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate from 20:1 to 5:1 (v / v)) to give compound J3 (300 mg, yellow solid, yield 25.42%).

[0142] MS(ESI): m / z 370.0 [M+1] +

[0143] 1 H NMR (300MHz, Chloroform-d) δ8.66(d,J=1.1Hz,1H),7.93(d,J=1.1Hz,1H),7.30-7.26(m,4H),6.61(t,J=73.4Hz,1H),2.20(d,J=1.1Hz,3H).

[0144] Step 8: Synthesize compound K3

[0145] Compound J3 (1.2 g) was added to dichloromethane (12 mL), and m-chloroperoxybenzoic acid (2.0 g) was added at 0 °C. The mixture was then stirred at room temperature for 1.5 h. After the reaction was complete as shown by TLC, the reaction was quenched with saturated sodium thiosulfate (20 mL) at 0 °C, and then stirred at room temperature for 30 min. The reaction mixture was extracted with dichloromethane (30 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered to remove the desiccant, dissolved under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate from 10:1 to 1:1 (v / v)) to give compound K3 (1.17 g, pale yellow solid, 80% purity).

[0146] MS(ESI): m / z 402.0 [M+1] +

[0147] Step 9: Synthesize compound L3

[0148] Sodium tert-butoxide (861 mg) was added to anhydrous ethanol (10 mL) at 0 °C, and the mixture was stirred at 0 °C for 10 minutes. Then, compound K3 (1.2 g) was added to the reaction mixture. After the addition was complete, the reaction was stirred at room temperature for 1 hour. TLC showed that the reaction was complete. The reaction mixture was then poured into ice water (20 mL) and extracted with dichloromethane (20 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered to remove the desiccant, dissolved under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate from 10:1 to 3:1 (v / v)) to give compound L3 (728 mg, white solid, 66% yield).

[0149] MS(ESI): m / z 368.1 [M+1] +

[0150] Step 10: Synthesize compound 3

[0151] Compound E3 (100 mg) and compound L3 (83 mg) were dissolved in 1,4-dioxane (0.8 mL) and water (0.2 mL). Cesium carbonate (150 mg) and dichloro[1,1'-bis(o-tert-butylphosphine)ferrocenepalladium(II) (17 mg) were added. The reaction solution was purged with nitrogen three times and stirred at 105 °C for 5 hours. After the reaction was completed by TLC, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: EA:MeOH from 1:0 to 10:1 (v / v)) to obtain crude product. Then, compound 3 (50 mg, pale yellow solid, yield 41.9%) was prepared and purified by prep-HPLC (10 μm 100A 30 × 250 mm; mobile phase A: 0.1% ammonium bicarbonate in water, mobile phase B: acetonitrile, gradient: 1.1-6 min, 10%-90%; 6-10 min, 90%).

[0152] MS(ESI): m / z 519.2 [M+1] + .

[0153] 1H NMR(300MHz,DMSO-d6)δ(ppm)9.00(s,1H),8.26(s,1H),7.87(s,1H),7.60(d d,J=8.4,1.4Hz,1H),7.52(dd,J=8.4,1.4Hz,1H),7.45(d,J=8.9Hz,2H),7.36 (t,J=73.8Hz,1H),7.34(d,J=8.7Hz,2H),4.19(q,J=6.9Hz,2H),4.15–4.10(m ,2H),3.79(s,2H),2.95(t,J=5.0Hz,2H),2.46(s,3H),1.20(t,J=7.0Hz,3H).

[0154] Example 4: Preparation of Compound 4

[0155]

[0156] Compound 4 was synthesized by referring to the synthesis steps of compound 3 in Example 3, except that in step 10, compound E3 in Example 3 was replaced with 7-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-3,4-dihydro-5-oxa-1,2a-diazaacenaphthene to obtain compound 4.

[0157] MS(ESI): m / z 492.1 [M+1] +

[0158] 1 H NMR (300MHz, DMSO-d6) δ (ppm) 8.97 (s, 1H), 8.25 (s, 1H), 8.20 (s, 1H), 7.55 (d, J = 0.9Hz, 1H), 7.48-7.42 (m, 2H), 7.37 (t, J =75.0Hz,1H),7.36-7.32(m,2H),7.02(d,J=0.9Hz,1H),4.55-4.43(m,4H),4.18(q,J=6.0Hz,2H),1.20(t,J=6.0Hz,3H).

[0159] Example 5: Preparation of Compound 5

[0160]

[0161] Compound 5 was synthesized by referring to the synthesis steps of Compound 3 in Example 3, wherein in step 10, 8-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-2,3,3a,4-tetrahydro-1H-benzo[b]pyrrole[1,2-d][1,4]oxazine was used instead of Compound E3 in Example 3 to synthesize Compound 5.

[0162] MS(ESI): m / z 507.2 [M+1] +

[0163] 1 H NMR (300MHz, DMSO-d6) δ8.93 (ppm) (s, 1H), 8.09 (s, 1H), 7.41 (d, J = 8.8Hz, 2H), 7.37 (t, J = 75.0 Hz,1H),7.32(d,J=8.8Hz,2H),7.25(dd,J=8.3,2.0Hz,1H),7.20(d,J=1.9Hz,1H),6.59(d,J=8 .4Hz,1H),4.46(dd,J=10.1,3.3Hz,1H),4.16(q,J=7.0Hz,2H),3.49(t,J=9.0Hz,2H),3.36-3. 30(m,1H),3.15(q,J=9.2Hz,1H),2.11–1.91(m,3H),1.49–1.34(m,1H),1.19(t,J=7.0Hz,3H).

[0164] Example 6: Preparation of Compound 6

[0165]

[0166] The synthesis of compound 6 was performed following the steps of compound 3 in Example 3, except that in step 10, compound E3 in Example 3 was replaced with 4,4,5,5-tetramethyl-2-(2H-spirocyclic[benzofuran-3,1'-cyclopropyl]-5-yl)-1,3,2-dioxacyclopentaborane to obtain compound 6.

[0167] MS(ESI): m / z 478.2 [M+1] +

[0168] 1H NMR(300MHz, DMSO-d6)δ(ppm)8.94(d,J=2.0Hz,1H),8.13(d,J=1.6Hz,1H),7.45–7.37(m,3H),7.37–7.30(m,2H),7.34(t,J=80 .7Hz,1H),7.13(s,1H),6.82(d,J=8.5Hz,1H),4.51(s,2H),4.17(q,J=6.9Hz,2H),1.19(t,J=7.0Hz,3H),1.06(d,J=9.8Hz,4H).

[0169] Example 7: Preparation of Compound 7

[0170]

[0171] Compound 7 was synthesized by referring to the synthesis steps of Compound 3 in Example 3, wherein in step 10, Compound E3 in Example 3 was replaced with 1'-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)-3-hydrospirocyclic [benzo[b][1,4]dioxin-2,4'-piperidine] to obtain Compound 7.

[0172] MS(ESI): m / z 551.3 [M+1] + .

[0173] 1 H NMR(300MHz,DMSO-d6)δ(ppm)8.94(s,1H),8.18(s,1H),7.45-7.39(m,2H),7.36 (t,J=73.9Hz,1H),7.36–7.30(m,2H),7.26(d,J=2.1Hz,1H),7.21(dd,J=8.4,2. 2Hz,1H),6.92(d,J=8.4Hz,1H),4.16(q,J=7.0Hz,2H),4.01(s,2H),2.59-2.52( m,2H),2.41–2.27(m,2H),2.23(s,3H),1.73-1.65(m,4H),1.19(t,J=7.0Hz,3H).

[0174] Example 8: Preparation of Compound 8

[0175]

[0176] Compound 8 was synthesized by referring to the synthesis steps of Compound 3 in Example 3, wherein in step 10, 2-methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine was used instead of Compound E3 in Example 3 to obtain Compound 8.

[0177] MS(ESI): m / z 519.2 [M+1] +

[0178] 1 H NMR(400MHz,DMSO-d6)δ(ppm)9.01(s,1H),8.25(s,1H),7.93(s,1H),7.64-7.53(m,2H),7.52-7.44(m,2H),7.41- 7.31(m,2H),7.38(t,J=72.0Hz,1H),4.28-4.12(m,4H),3.79(s,2H),3.02-2.93(m,2H),2.34(s,3H),1.23(m,3H).

[0179] Example 9: Preparation of Compound 9

[0180]

[0181] Compound 9 was synthesized by referring to the synthesis steps of Compound 3 in Example 3, wherein in step 10, 2-methyl-9-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1,2,3,4-tetrahydropyrazolo[1,2-b]inazole was used instead of Compound E3 in Example 3 to obtain Compound 9.

[0182] MS(ESI): m / z 519.2 [M+1] +

[0183] 1 H NMR(600MHz, DMSO-d6)δ(ppm)8.97(s,1H),8.22(s,1H),8.03(d,J=1.6Hz,1H),7.57–7.51(m,2H),7.45–7.40(m,2H),7.34(t,J=73.9Hz,1H ),7.34–7.29(m,2H),4.39(t,J=5.5Hz,2H),4.17(q,J=7.0Hz,2H),3.94(s,2H),2.97(t,J=5.5Hz,2H),2.48(s,3H),1.19(t,J=7.0Hz,3H).

[0184] Example 10: Preparation of Compound 10

[0185]

[0186] The synthesis of compound 10 was performed following the synthesis steps of compound 3 in Example 3, except that in step 10, compound E3 in Example 3 was replaced with 2-methyl-9-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-3,4-dihydropyrazolo[1,2-b]indazole-1(2-hydro)-one to obtain compound 10.

[0187] MS(ESI): m / z 533.2 [M+1] +

[0188] 1 H NMR (600MHz, DMSO-d6) δ (ppm) 9.00 (s, 1H), 8.37 (s, 1H), 8.27 (s, 1H), 7.77 (d, J = 9.0Hz, 1H), 7.67-7.60 (m, 1H), 7.45 (d, J = 8.6Hz, 2H), 7.34 (t, J=73.8Hz,1H),7.33(d,J=8.4Hz,2H),4.71(t,J=6.3Hz,2H),4.17(q,J=7.0Hz,2H),3.88(t,J=6.3Hz,2H),3.05(s,3H),1.19(t,J=7.3Hz,3H).

[0189] Example 11: Preparation of Compound 11

[0190]

[0191] The synthetic route for compound 11 is as follows:

[0192]

[0193] Preparation method:

[0194] Step 1: Synthesize compound B11

[0195] Compound A11 (5.0 g) was dissolved in water (50 mL) and ethyl acetate (50 mL), sodium carbonate (15.0 g) was added, and benzyl chloroformate (10.2 g) was added dropwise at 0 °C. The mixture was then stirred at room temperature for 16 hours. After the reaction was complete as shown by TLC, the reaction solution was diluted with water (300 mL) and extracted with ethyl acetate (200 mL × 3). The combined organic phases were washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and dissolved under reduced pressure. The residue was slurried (petroleum ether:ethyl acetate = 20:1 (v / v), 100 mL) to give compound B11 (8.0 g, white solid, yield 68.4%).

[0196] MS(ESI): m / z 235.1 [M+1] +

[0197] Step 2: Synthesize compound C11

[0198] Compound B11 (2.0 g) was dissolved in N,N-dimethylformamide (20 mL), and sodium hydride (512 mg, 60%) was added in portions at 0 °C, followed by stirring at 30 °C for 30 min. Subsequently, a solution of B3 (1.9 g) in N,N-dimethylformamide (10 mL) was added dropwise to the above reaction solution at 0 °C under ice bath conditions, and the mixture was stirred at room temperature for 30 min. After the reaction was complete as shown by TLC, the reaction solution was cooled to 0 °C and the reaction was slowly quenched with saturated ammonium chloride solution (100 mL), followed by ethyl acetate (80 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered to remove the drying agent, dissolved under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate from 10:1 to 3:1 (v / v)) to give compound C11 (1.0 g, orange-yellow solid, yield 27%).

[0199] MS(ESI): m / z 434.0 [M+1] +

[0200] Step 3: Synthesize compound D11

[0201] Compound C11 (2.0 g) was dissolved in formic acid (40 mL), and iron powder (1.04 g) was added. The mixture was then stirred at 100 °C for 16 hours. After the reaction was complete as shown by TLC, the mixture was cooled to 0 °C, diluted with water (80 mL), and the pH was slowly adjusted to 8 with sodium bicarbonate. The mixture was then extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and dissolved under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate from 10:1 to 1:1 (v / v)) to give compound D11 (1.3 g, pale yellow solid, yield 73.1%).

[0202] MS(ESI): m / z 386.0 388.0 [M+1] +

[0203] Step 4: Synthesize compound E11

[0204] Compound D11 (500 mg) was dissolved in 1,4-dioxane (5 mL), followed by the addition of pinacol diborate (490 mg), potassium acetate (380 mg), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (110 mg). The mixture was stirred at 100 °C for 3 hours under nitrogen protection. After the reaction was complete as indicated by TLC, the reaction mixture was diluted with water (30 mL) and extracted with dichloromethane (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and dissolved under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate from 1:1 to 0:1 (v / v)) to give compound E11 (640 mg, brown gelatinous solid, crude product).

[0205] MS(ESI): m / z 434.2 [M+1] +

[0206] Step 5: Synthesize compound F11

[0207] Compound L3 (450 mg) and compound E11 (640 mg) were dissolved in 1,4-dioxane (10 mL) and water (1 mL), followed by the addition of cesium carbonate (1.2 g) and dichloro[1,1'-bis(o-tert-butylphosphine)ferrocenepalladium(II) (80 mg), and then stirred at 110 °C for 2 hours. After the reaction was complete as indicated by LCMS, the reaction mixture was diluted with water (30 mL) and then extracted with dichloromethane (30 mL × 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered to remove the desiccant, dissolved under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate from 1:1 to 0:1 (v / v)) to give compound F11 (580 mg, brown gelatinous solid, yield 74.6%).

[0208] MS(ESI): m / z 639.2 [M+1] +

[0209] Step 6: Synthesize compound G11

[0210] Compound F11 (580 mg) was dissolved in trifluoroethanol (5 mL), and 10% wet palladium on carbon (60 mg) was added. The mixture was then stirred at 40 °C for 3 hours under a hydrogen balloon. After the reaction was complete as shown by LCMS, the reaction solution was filtered through diatomaceous earth. The filtrate was desolvated under reduced pressure to obtain the crude product compound G11 (500 mg, brown solid).

[0211] MS(ESI): m / z 505.2 [M+1] +

[0212] Step 7: Synthesize compound 11

[0213] Compound G11 (77 mg) was dissolved in dichloromethane (2 mL), and triethylamine (46 mg) and acetic anhydride (24 mg) were added at room temperature. The mixture was then stirred at room temperature for 30 minutes. After the reaction was complete as shown by TLC, the reaction mixture was poured into water (10 mL) and then extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and dissolved under reduced pressure. The residue was purified by prep-HPLC (100 × 20.0 mm, DS-5 μm, 8 nm; mobile phase A: 0.1% ammonium bicarbonate in water, mobile phase B: acetonitrile, gradient: 1.1–8 min, 10%–90%; 8–9 min, 90%) to give compound 11 (23 mg, white solid, 28% yield).

[0214] MS(ESI): m / z 547.2 [M+1] +

[0215] 1 H NMR(600MHz,323K,DMSO-d6)δ(ppm)8.97(s,1H),8.22(s,1H),7.89(d,J=1.7Hz,1H),7.61(d,J=8.4Hz,1H),7.55(d,J=8.5Hz,1H),7.44–7.41(m, 2H),7.35–7.30(m,2H),7.28(t,J=73.9Hz,1H),4.94-4.87(m,2H),4.24 -4.12(m,4H),4.02(t,J=5.6Hz,2H),2.15(s,3H),1.19(t,J=7.0Hz,3H).

[0216] Example 12: Preparation of Compound 12

[0217]

[0218] The synthesis of compound 12 was performed following the steps of compound 11 in Example 11, except that in step seven, bromoacetonitrile was used instead of acetic anhydride in Example 11 to synthesize compound 12.

[0219] MS(ESI): m / z 544.2 [M+H] +

[0220] 1 H NMR (300MHz, DMSO-d6) δ (ppm) 9.00 (s, 1H), 8.26 (s, 1H), 7.88 (d, J = 1.8Hz, 1H), 7.62 (d, J = 6.0Hz, 1H), 7.53 (dd, J1 = 3.0Hz, J2 = 6.0Hz, 1H), 7.48–7 .42(m,2H),7.32-7.37(m,2H),7.36(t,J=72.0Hz,1H),4.13-4.24(m,4H) ,4.05(s,2H),3.96(s,2H),3.12(t,J=6.0Hz,2H),1.20(t,J=9.0Hz,3H).

[0221] Example 13: Preparation of Compound 13

[0222]

[0223] The synthesis of compound 13 follows the steps outlined in Example 11, specifically step seven, which involves the following reaction:

[0224] Compound G11 (100 mg) was dissolved in 1,2-dichloroethane (0.5 mL), acetone (115 mg) and acetic acid (1 drop) were added, and the mixture was stirred at 65 °C for 1 hour. The mixture was then cooled to 0 °C, and sodium cyanoborohydride (25 mg) was added. The reaction mixture was stirred again at 65 °C for 1 hour. LC-MS showed that after the reaction was complete, the reaction mixture was cooled to room temperature, diluted with water (10 mL), and ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and dissolved under reduced pressure. The residue was purified by prep-HPLC (100 × 20.0 mm, DS-5 μm, 8 nm; mobile phase A: 0.1% ammonium bicarbonate in water, mobile phase B: acetonitrile, gradient: 1.1–8 min, 10%–90%; 8–9 min, 90%) to give compound 13 (10 mg, yellow solid, yield 9.2%).

[0225] MS(ESI): m / z 547.2 [M+1] +

[0226] 1 H NMR (300MHz, DMSO-d6) δ (ppm) 8.99 (s, 1H), 8.25 (s, 1H), 7.85 (d, J = 1.7Hz, 1H), 7.59(d,J=8.6Hz,1H),7.51(dd,J=8.4,1.7Hz,1H),7.48-7.41(m,2H),7.36(t, J=72.0Hz,1H),7.36-7.32(m,2H),4.18(q,J=7.0Hz,2H),4.08(t,J=5.4Hz,2H) ,3.88(s,2H),3.04-2.89(m,3H),1.20(t,J=7.0Hz,3H),1.09(d,J=6.5Hz,6H).

[0227] Example 14: Preparation of Compound 14

[0228]

[0229] The synthesis of compound 14 follows the steps outlined in Example 11, specifically step seven, which involves the following reaction:

[0230] Compound G11 (80.0 mg) was dissolved in N,N-dimethylformamide (1 mL), followed by the addition of oxetane-3-methylene-4-methylbenzenesulfonic acid (152 mg), potassium iodide (5 mg), and N,N-diisopropylethylamine (62.0 mg). The mixture was stirred at 80 °C for 5 hours. After the reaction was complete as indicated by LC-MS, the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and dissolved under reduced pressure. The residue was purified by prep-HPLC (100 × 20.0 mm, DS-5 μm, 8 nm; mobile phase A: 0.1% ammonium bicarbonate in water, mobile phase B: acetonitrile, gradient: 1.1–8 min, 10%–90%; 8–9 min, 90%) to give compound 14 (10 mg, pale yellow solid, yield 11.0%).

[0231] MS(ESI): m / z 575.2 [M+1] +

[0232] 1 H NMR(300MHz,DMSO-d6)δ(ppm)8.99(s,1H),8.25(s,1H),7.87-7.82(m,1H),7.62-7.56(m,1H), 7.51(dd,J=8.5,1.6Hz,1H),7.47-7.41(m,2H),7.37(t,J=75.0Hz,1H),7.36-7.31(m,2H),4.6 7(dd,J=7.8,5.9Hz,2H),4.31(t,J=6.0Hz,2H),4.18(q,J=7.0Hz,2H),4.14-4.03(m,2H),3.80 (s,2H),3.30-3.24(m,1H),2.97(t,J=5.5Hz,2H),2.91(d,J=7.4Hz,2H),1.20(t,J=7.0Hz,3H).

[0233] Example 15: Preparation of Compound 15

[0234]

[0235] The synthesis of compound 15 was performed following the steps of compound 14 in Example 14, except that in step seven, compound 1-bromo-2-methylethyl ether was used instead of oxetane-3-methylene-4-methylbenzenesulfonic acid in Example 14 to synthesize compound 15.

[0236] MS(ESI): m / z 563.2 [M+1] +

[0237] 1 H NMR (300MHz, DMSO-d6) δ (ppm) 9.00 (s, 1H), 8.26 (s, 1H), 7.86 (d, J = 1.6Hz, 1H), 7.60 (d, J=8.3Hz,1H),7.52(dd,J=8.4,1.6Hz,1H),7.47–7.41(m,2H),7.36(t,J=72.0Hz,1H),7. 36-7.33(m,2H),4.18(q,J=7.0Hz,2H),4.14–4.03(m,2H),3.89(s,2H),3.55(t,J=5.5H z,2H),3.27(s,3H),3.05(t,J=5.4Hz,2H),2.77(t,J=5.5Hz,2H),1.20(t,J=7.0Hz,3H).

[0238] Example 16: Preparation of Compound 16

[0239]

[0240] The synthetic route for compound 16 is as follows:

[0241]

[0242] Preparation method:

[0243] Step 1: Synthesize compound A16

[0244] Compound K3 (150 mg) was dissolved in anhydrous THF (4 mL), and 2,2-difluoroethanol (33.7 mg) was added. Then, potassium tert-butoxide (53.9 mg) was added in portions under ice bath conditions. After the addition was complete, the mixture was stirred overnight at 50 °C. After the reaction was complete as shown by TLC, the reaction solution was desolvated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate from 10:1 to 1:1 (v / v)) to give compound A16 (75 mg, pale yellow solid, yield: 50%).

[0245] MS(ESI): m / z 404.0 [M+1] +

[0246] Step 2: Synthesize compound 16

[0247] The synthesis method refers to step 10 of the synthesis steps of compound 3 in Example 3, and compound A16 is used instead of compound L3 in Example 3 to synthesize compound 16.

[0248] MS(ESI): m / z 555.2 [M+1] +

[0249] 1 H NMR(400MHz,DMSO-d6)δ(ppm)9.04(s,1H),8.29(s,1H),7.88(s,1H),7.61(d ,J=8.5Hz,1H),7.53(d,J=8.1Hz,1H),7.51–7.42(m,2H),7.41–7.28(m,2H),7 .36(t,J=72.0Hz,1H),6.29(tt,J=54.6,3.5Hz,1H),4.45(td,J=14.8,3.5Hz ,2H),4.13(t,J=5.5Hz,2H),3.77(s,2H),2.94(t,J=5.5Hz,2H),2.45(s,3H).

[0250] Example 17: Preparation of Compound 17

[0251]

[0252] The synthesis of compound 17 follows the same steps as in Example 16, except that in the first step, trifluoroethylamine was used instead of 2,2-difluoroethanol in Example 16 to synthesize compound 17.

[0253] MS(ESI): m / z 572.2 [M+1] +

[0254] 1 H NMR(400MHz,DMSO-d6)δ(ppm)8.86–8.78(m,1H),8.29(s,0.5H),8.13(s,1H) ),8.00(s,0.5H),7.84(s,1H),7.58(d,J=8.4Hz,1H),7.50(d,J=7.8Hz,1H) ,7.45-7.37(d,J=9.3Hz,2H),7.34(t,J=74.0Hz,1H),7.33(d,J=8.4Hz,2H) ,4.18-4.09(m,3H),3.80-3.69(m,3H),2.93(t,J=5.5Hz,2H),2.44(s,3H).

[0255] Example 18: Preparation of Compound 18

[0256]

[0257] The synthesis of compound 18 was performed following the synthesis steps of compound 3 in Example 3, except that methanol was used instead of ethanol in step nine of Example 3 to synthesize compound 18.

[0258] MS(ESI): m / z 505.2[M+1]+.

[0259] 1 H NMR(400MHz, DMSO-d6)δ(ppm)9.00(s,1H),8.26(s,1H),7.86(d,J=1.6Hz,1H),7.59(d,J=8.4Hz,1H),7.52(dd,J=8.4,1.6Hz,1H),7 .47–7.42(m,2H),7.35(t,J=74.1Hz,1H),7.35–7.31(m,2H),4.12(t,J=5.4Hz,2H),3.75(s,5H),2.93(t,J=5.4Hz,2H),2.44(s,3H).

[0260] Example 19: Preparation of Compound 19

[0261]

[0262] The synthetic route for compound 19 is as follows:

[0263]

[0264] Step 1: Synthesize compound A19

[0265] Compound K3 (120 mg) was dissolved in anhydrous tetrahydrofuran (2 mL), and ethylamine hydrochloride (30 mg) and N,N-diisopropylethylamine (100 mg) were added. The mixture was then stirred at 50 °C for 2 hours. After the reaction was complete as shown by TLC, saturated ammonium chloride (10 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (10 mL × 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and dissolved under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate from 10:1 to 1:1 (v / v)) to give compound A19 (108 mg, yellow solid, yield 98.59%).

[0266] MS(ESI): m / z 367.1 [M+1] +

[0267] Step 2: Synthesize compound 19

[0268] The synthesis method refers to step 10 of the synthesis steps of compound 3 in Example 3, and compound A19 is used instead of compound L3 in Example 3 to synthesize compound 19.

[0269] MS(ESI): m / z 518.2 [M+1] +

[0270] 1 H NMR(300MHz,DMSO-d6)δ(ppm)8.77-8.65(m,1H),8.06(s,1H),7.82(s,1H),7. 79-7.75(m,1H),7.56(d,J=8.6Hz,1H),7.48(d,J=8.5Hz,1H),7.39(d,J=8.5H z,2H),7.35–7.27(m,2H),7.34(t,J=74.0Hz,1H),4.11(t,J=5.5Hz,2H),3.75 (s,2H),3.31-3.24(m,1H),2.97-2.88(m,3H),2.44(s,3H),1.11–0.80(m,3H).

[0271] Example 20: Preparation of Compound 20

[0272]

[0273] The synthesis of compound 20 follows the same steps as the synthesis of compound 3 in Example 3, except that in step nine, cyclopropanol was used instead of ethanol in Example 3 to synthesize compound 20.

[0274] MS(ESI): m / z 531.2 [M+1] +

[0275] 1 H NMR(300MHz, DMSO-d6)δ(ppm)9.02(s,1H),8.27(s,1H),7.86(d,J=1.6Hz,1H),7.60(d,J=8.4Hz,1H),7.52(dd,J=8.5,1.6Hz,1H),7.48–7.4 0(m,2H),7.38–7.30(m,2H),7.35(t,J=73.8Hz,1H),4.18-4.07(m,3H),3.76(s,2H),2.93(t,J=5.6Hz,2H),2.44(s,3H),0.69-0.61(m,4H).

[0276] Example 21: Preparation of compound 21

[0277]

[0278] The synthesis of compound 21 was performed following the synthesis steps of compound 3 in Example 3, except that isopropanol was used instead of ethanol in step nine of Example 3 to synthesize compound 21.

[0279] MS(ESI): m / z 533.2 [M+1]+

[0280] 1 H NMR (300MHz, DMSO-d6) δ (ppm) 8.99 (s, 1H), 8.25 (s, 1H), 7.86 (d, J = 1.6Hz, 1H ),7.60(d,J=8.4Hz,1H),7.52(dd,J=8.4,1.6Hz,1H),7.48–7.42(m,2H),7.37 -7.32(m,2H),7.36(t,J=73.9Hz,1H),4.91(p,J=6.2Hz,1H),4.13(t,J=5.5Hz ,2H),3.76(s,2H),2.93(t,J=5.5Hz,2H),2.44(s,3H),1.19(d,J=6.2Hz,6H).

[0281] Example 22: Preparation of compound 22

[0282]

[0283] The synthetic route for compound 22 is as follows:

[0284]

[0285] Preparation method:

[0286] Step 1: Synthesize compound A22

[0287] Compound K3 (120 mg) was dissolved in anhydrous tetrahydrofuran (3 mL), and a tetrahydrofuran solution of cyclopropylmagnesium bromide (0.9 mL, 0.5 mol / L) was added dropwise at 0 °C, followed by stirring at 0 °C for 15 minutes. After TLC showed the reaction was complete, the reaction was quenched at 0 °C with saturated ammonium chloride (10 mL), and extracted with dichloromethane (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, dissolved under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate from 10:1 to 1:1 (v / v)) to give compound A22 (98 mg, white solid, yield 90.23%).

[0288] MS(ESI): m / z 364.1 [M+1] +

[0289] Step 2: Synthesize compound 22

[0290] The synthesis method refers to step 10 of the synthesis steps of compound 3 in Example 3, and compound A22 is used instead of compound L3 in Example 3 to synthesize compound 22.

[0291] MS(ESI): m / z 515.2 [M+1] +

[0292] 1 H NMR (600MHz, DMSO-d6) δ (ppm) 8.99 (s, 1H), 8.24 (s, 1H), 7.87 (d, J = 1.7Hz, 1H), 7 .58(d,J=8.3Hz,1H),7.52(dd,J=8.5,1.7Hz,1H),7.45–7.40(m,2H),7.35(t,J= 74.0Hz,1H),7.34–7.30(m,2H),4.11(t,J=5.7Hz,2H),3.75(s,2H),2.92(t,J=5 .6Hz,2H),2.43(s,3H),2.00-1.95(m,1H),0.98-0.93(m,2H),0.85-0.80(m,2H).

[0293] Example 23: Preparation of compound 23

[0294]

[0295] The synthesis of compound 23 follows the same steps as in Example 19, where in the first step, aziridine hydrochloride is used instead of ethylamine hydrochloride to synthesize compound 23.

[0296] MS(ESI): m / z 530.2 [M+1] +

[0297] 1 H NMR(300MHz, DMSO-d6)δ(ppm)8.75(s,1H),8.10(s,1H),7.83(d,J=1.6Hz,1H),7.61–7.53(m,1H),7.49(dd,J=8.4,1.6Hz,1H),7.42 –7.35(m,2H),7.34(t,J=73.9Hz,1H),7.33–7.26(m,2H),4.16–3.59(m,8H),2.92(t,J=5.5Hz,2H),2.44(s,3H),2.27-2.14(m,2H).

[0298] Example 24: Preparation of compound 24

[0299]

[0300] The synthesis of compound 24 follows the same steps as in Example 19, where pyrrolidine is used instead of ethylamine hydrochloride in the first step to synthesize compound 24.

[0301] MS(ESI): m / z 544.2[M+1]+

[0302] 1 H NMR (300MHz, DMSO-d6) δ (ppm) 8.76 (s, 1H), 8.09 (s, 1H), 7.83 (d, J = 1.6Hz, 1H), 7 .56(d,J=8.5Hz,1H),7.49(dd,J=8.4,1.5Hz,1H),7.42–7.37(m,2H),7.35(t,J= 74.0Hz,1H),7.34–7.28(m,2H),4.10(d,J=5.8Hz,2H),3.75(s,2H),3.55-3.47( m,2H),3.09-3.01(m,2H),2.93(d,J=5.6Hz,2H),2.44(s,3H),1.90–1.76(m,4H).

[0303] Example 25: Preparation of Compound 25

[0304]

[0305] The synthesis of compound 25 follows the same steps as in Example 19. In the first step, morpholine is used to replace the hydrochloride of ethylamine to synthesize compound 25.

[0306] MS(ESI): m / z 560.2 [M+1] +

[0307] 1H NMR(400MHz, DMSO-d6)δ(ppm)8.81(s,1H),8.12(s,1H),7.85(s,1H),7.57(d,J=8.4Hz,1H),7.53–7.47(m,1H),7.41(d,J=8.8Hz,2H),7.34(t,J= 76.0Hz,1H),7.32(d,J=8.8Hz,2H),4.12(t,J=5.4Hz,2H),3.76(s,2H),3 .58-3.51(m,4H),3.25-3.15(m,4H),2.93(t,J=5.4Hz,2H),2.44(s,3H).

[0308] Example 26: Preparation of Compound 26

[0309]

[0310] Compound 26 was synthesized by referring to the synthesis steps of compound 3 in Example 3, wherein in step 10, compound E3 in Example 3 was replaced with 6-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-3,4-dihydro-5-oxo-1,2a-diazanaphthene to obtain compound 26.

[0311] MS(ESI): m / z 492.1 [M+1] +

[0312] 1 H NMR(400MHz,DMSO-d6)δ(ppm)8.98(s,1H),8.23(s,1H),8.13(s,1H),7.45–7.41(m,2H),7.35(t,J=72.0Hz,1 H),7.33(d,J=8.8Hz,2H),7.24-7.22(m,2H),4.51-4.43(m,4H),4.18(q,J=7.0Hz,2H),1.20(t,J=7.0Hz,3H).

[0313] Example 27: Preparation of Compound 27

[0314]

[0315] Synthetic route of compound 27:

[0316]

[0317] Preparation method:

[0318] Step 1: Synthesize compound C27

[0319] Compound A27 (150 mg) was dissolved in N,N-dimethylformamide (2 mL), and copper acetate (90 mg), pyridine (150 mg), and compound B27 (90 mg) were added. The mixture was then stirred at 40 °C for 16 hours under an oxygen balloon. After the reaction was complete as shown by TLC, the reaction mixture was slowly poured into a 1N hydrochloric acid aqueous solution (10 mL) at 0 °C, and then extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered to remove the drying agent, dissolved under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate from 100:0 to 5:1 (v / v)) to give compound C27 (111 mg, brown solid, yield 51.1%).

[0320] MS(ESI): m / z 459.0 [M+1] + .

[0321] Step 2: Synthesize compound D27

[0322] Compound C27 (90 mg) was dissolved in dioxane (2 mL) and water (0.2 mL), and compound E11 (90 mg), cesium carbonate (126 mg), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (18 mg) were added. The mixture was then stirred at 100 °C for 3 hours under nitrogen protection. After the reaction was complete as indicated by TLC, the reaction mixture was poured into water (15 mL) and then extracted with dichloromethane (10 mL × 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, dissolved under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate: methanol from 1:0 to 10:1 (v / v)) to give compound D27 (108 mg, brown solid, 86% yield).

[0323] MS(ESI): m / z 638.2 [M+1] + .

[0324] Step 3: Synthesize compound 27

[0325] Compound D27 (70 mg) was dissolved in methanol (2 mL), and then 10% palladium on carbon (7 mg) was added. The mixture was stirred at room temperature for 3 hours under a hydrogen balloon. After the reaction was complete as shown by TLC, 0.5 mL of 30% formaldehyde aqueous solution was added to the reaction solution, and the mixture was stirred at room temperature for another 16 hours under a hydrogen balloon. After the reaction was complete as shown by LCMS, the reaction solution was filtered, dissolved under reduced pressure, and the residue was purified by prep-HPLC (10 μm 100A 30 × 250 mm; mobile phase A: 0.1% ammonium bicarbonate in water, mobile phase B: acetonitrile, gradient: 1.1–6 min, 10%–90%; 6–10 min, 90%) to give compound 27 (7 mg, pale yellow solid).

[0326] MS(ESI): m / z 518.2 [M+1] +

[0327] 1H NMR (300MHz, DMSO-d6) δ (ppm) 8.22 (s, 1H), 8.15 (d, J=8.4Hz, 1H), 7.90 (d, J= 1.5Hz,1H),7.61–7.50(m,2H),7.45–7.38(m,2H),7.35–7.31(m,2H),7.34(d, J=73.2Hz,1H),6.71(d,J=8.4Hz,1H),4.12(t,J=5.6Hz,2H),3.93(q,J=7.0Hz ,2H),3.76(s,2H),2.93(t,J=5.6Hz,2H),2.44(s,3H),1.08(t,J=7.0Hz,3H).

[0328] Example 28: Preparation of Compound 28

[0329]

[0330] Synthetic route of compound 28:

[0331]

[0332] Preparation method:

[0333] Step 1: Synthesize compound A28

[0334] Compound F3 (3.0 g) was dissolved in tetrahydrofuran (30 mL), and p-methoxybenzylamine (2.1 g) and triethylamine (3.9 g) were added. The mixture was then stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and dissolved under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate from 10:1 to 3:1 (v / v)) to give compound A28 (4.0 g, off-white solid, yield 93.1%).

[0335] MS(ESI): m / z 334.1 [M+1] +

[0336] Step 2: Synthesizing compound B28

[0337] Compound A28 (4.0 g) was dissolved in anhydrous tetrahydrofuran (30 mL), and lithium aluminum hydride (1.8 g) was added in portions at room temperature. The mixture was then stirred at 50 °C for 3 hours. After the reaction was complete as shown by TLC, the reaction mixture was cooled to 0 °C, and water (1.8 mL), 15% sodium hydroxide aqueous solution (1.8 mL), and water (5.4 mL) were slowly added dropwise under ice bath conditions. Then ethyl acetate (150 mL) was added, and the mixture was stirred at room temperature for 15 minutes. The mixture was filtered, and the filtrate was desolvated under reduced pressure to give compound B28 (3.0 g, yellow solid, yield 85.8%).

[0338] MS(ESI): m / z 292.1 [M+1] +

[0339] Step 3: Synthesize compound C28

[0340] Compound B28 (3.0 g) was dissolved in dichloromethane (30 mL), and activated manganese dioxide (9.0 g) was added. The mixture was then stirred at 30 °C for 16 hours. After the reaction was complete as shown by TLC, the reaction solution was filtered, the filtrate was desolvated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate from 10:1 to 1:1 (v / v)) to give compound C28 (2.1 g, white solid, yield 70.5%).

[0341] MS(ESI): m / z 290.1 ​​[M+1] +

[0342] Step 4: Synthesize compound D28

[0343] Compound C28 (2.1 g) was dissolved in anhydrous tetrahydrofuran (20 mL), potassium tert-butoxide (2.1 g) was added, followed by the addition of triethyl phosphoroacetate (3.3 g) at 0 °C, and then stirred at room temperature for 16 hours. After the reaction was complete as indicated by TLC, the reaction mixture was diluted with water (80 mL) and extracted with ethyl acetate (80 mL × 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and dissolved under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 3 / 1 (v / v)) to give compound D28 (2.1 g, yellow oil, yield 80.5%).

[0344] MS(ESI): m / z 360.1 [M+1] +

[0345] Step 5: Synthesize compound E28

[0346] Compound D28 (2.1 g) was dissolved in anhydrous ethanol (20 mL). A solution of sodium hydride (450 mg, 60%) in anhydrous ethanol (5 mL) was added dropwise to the reaction solution under ice bath conditions, and the mixture was stirred at 75 °C for 1 hour. After the reaction was complete as shown by TLC, the reaction solution was cooled to room temperature, and a saturated ammonium chloride solution (80 mL) was slowly added, followed by extraction with ethyl acetate (80 mL × 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, dissolved under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate from 5:1 to 1:1 (v / v)) to give compound E28 (1.0 g, off-white solid, yield 55.0%).

[0347] MS(ESI): m / z 312.1[M+1] + .

[0348] Step 6: Synthesize compound F28

[0349] Compound E28 (1.0 g) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (1 mL) was added. The mixture was then stirred at 35 °C for 5 hours. After the reaction was complete as shown by TLC, the reaction solution was cooled to room temperature, diluted with water (50 mL), and the pH was adjusted to 8 with sodium bicarbonate. The solution was then extracted with dichloromethane:methanol (50 mL × 6, 10:1). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and dissolved under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate from 5:1 to 1:1 (v / v)) to give compound F28 (400 mg, off-white solid, 65.1%).

[0350] MS(ESI): m / z 192.1 [M+1] +

[0351] Step 7: Synthesize compound G28

[0352] Compound F28 (400 mg) was dissolved in N,N-dimethylformamide (8 mL), and N-bromosuccinimide (480 mg) was added. The mixture was then stirred at 50 °C for 2 hours. After the reaction was complete as shown by TLC, the reaction solution was cooled to room temperature and diluted with water (50 mL). A yellow solid precipitated out. The solution was filtered, and the filter cake was washed with water (10 mL). The filter cake was then dried to give compound G28 (400 mg, yellow solid, 70.8%).

[0353] MS(ESI): m / z 270.0 [M+1] +

[0354] 1H NMR (300MHz, DMSO-d6) δ (ppm) 11.06 (s, 1H), 8.83 (s, 1H), 8.45 (s, 1H), 4.39 (q, J = 7.1Hz, 2H), 1.33 (t, J = 7.1Hz, 3H).

[0355] Step 8: Synthesize compound I28

[0356] Compound G28 (100 mg) was dissolved in dichloromethane (2 mL), and compound H28 (114 mg), copper acetate (112 mg), and triethylamine (113 mg) were added. The mixture was then stirred at 30 °C for 16 hours under an oxygen balloon. After the reaction was complete as shown by TLC, the reaction solution was evaporated to dryness, and the residue was purified by prep-TLC to give compound I28 (35.0 mg, grayish-white solid, 25.1%).

[0357] MS(ESI): m / z 377.0 [M+1] +

[0358] Step 9: Synthesize compound 28

[0359] Compound I28 (30.0 mg) was dissolved in 1,4-dioxane (1 mL) and water (0.1 mL), and compound E3 (29.9 mg), cesium carbonate (52.0 mg), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (7 mg) were added. The mixture was then stirred at 90 °C for 16 hours under nitrogen protection. After the reaction was complete as shown by TLC, the reaction solution was cooled to room temperature, diluted with water (10 mL), and then extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered to remove the desiccant, dissolved under reduced pressure, and the residue was purified by prep-TLC to obtain the crude compound. Further purification was performed by prep-HPLC (100 × 20.0 mm, DS-5 μm, 8 nm; mobile phase A: 0.1% FA in water, mobile phase B: acetonitrile, gradient: 1.1–8 min, 10%–90%; 8–9 min, 90%) to obtain compound 28 (10 mg, pale yellow solid, 26.0%).

[0360] MS(ESI): m / z 484.2 [M+1] +

[0361] 1H NMR (300MHz, DMSO-d6) δ (ppm) 9.00 (s, 1H), 8.26 (s, 1H), 8.18 (d, J = 3.0Hz, 1H), 7.90 (s, 1H), 7.77 (dd, J1 = 3.0, J2 = 9.06Hz, 1H), 7.62 (s, 1H) ),7.52(s,1H),7.00(d,J=9.0Hz,1H),4.26–4.05(m,4H),3.92(s,3H),3.76(s,2H),2.98-2.88(m,2H),2.44(s,3H),1.22(t,J=6.0Hz,3H).

[0362] Example 29: Preparation of compound 29

[0363]

[0364] The synthesis of compound 29 was performed following the steps of compound 28 in Example 28, except that in step 8, p-chlorophenylboronic acid was used instead of compound H28 in Example 28 to synthesize compound 29.

[0365] MS(ESI): m / z 487.2 [M+1] +

[0366] 1 H NMR(600MHz, DMSO-d6)δ(ppm)8.98(s,1H),8.24(s,1H),7.84(d,J=1.3Hz,1H),7.63–7.56(m,3H),7.50(dd,J=8.4,1.6Hz,1H),7.44 –7.38(m,2H),4.16(q,J=7.0Hz,2H),4.11(t,J=5.5Hz,2H),3.74(s,2H),2.91(t,J=5.5Hz,2H),2.42(s,3H),1.19(t,J=7.0Hz,3H).

[0367] Example 30: Preparation of compound 30

[0368]

[0369] The synthesis of compound 30 was performed following the steps of compound 28 in Example 28, except that in step 8, p-cyanobenzoic acid was used instead of compound H28 in Example 28, and in step 9, 2-methyl-9-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1,2,3,4-tetrahydropyrazolo[1,2-b]inazole was used instead of compound E3, thus obtaining compound 30.

[0370] MS(ESI): m / z 478.2 [M+1] + .

[0371] 1 H NMR(300MHz,DMSO-d6)δ(ppm)9.00(s,1H),8.27(s,1H),8.11–8.01(m,3H),7.72–7.60(m,2H),7.59-7.51(m,2H),4 .41(t,J=5.3Hz,2H),4.16(q,J=7.0Hz,2H),3.95(s,2H),2.98(t,J=5.4Hz,2H),2.48(s,3H),1.19(t,J=7.0Hz,3H).

[0372] Example 31: Preparation of compound 31

[0373]

[0374] The synthesis of compound 31 was performed following the steps of compound 28 in Example 28, except that in step 8, p-trifluoromethylphenylboronic acid was used instead of compound H28 in Example 28, and in step 9, 2-methyl-9-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1,2,3,4-tetrahydropyrazolo[1,2-b]inazole was used instead of compound E3, thus obtaining compound 31.

[0375] MS(ESI): m / z 521.2 [M+1] + .

[0376] 1 H NMR (300MHz, DMSO-d6) δ (ppm) 9.00 (s, 1H), 8.27 (s, 1H), 8.05 (s, 1H), 7.94 (d, J = 8.2Hz, 2H), 7.66 (d, J = 8.1Hz, 2H), 7.56 ( s,2H),4.40(d,J=5.6Hz,2H),4.17(q,J=7.0Hz,2H),3.95(s,2H),3.02-2.92(m,2H),2.48(s,3H),1.19(t,J=7.0Hz,3H).

[0377] Example 32: Preparation of compound 32

[0378]

[0379] The synthesis of compound 32 was performed following the steps of compound 19 in Example 19, except that in the second step, compound E3 was replaced with 2-methyl-9-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1,2,3,4-tetrahydropyrazolo[1,2-b]inazole to obtain compound 32.

[0380] MS(ESI): m / z 518.2 [M+1] +

[0381] 1 H NMR(300MHz,DMSO-d6)δ(ppm)8.74-8.67(m,1H),8.05(s,1H),7.99(s,1H),7.76(br.s,0.5H),7.52(s,2H),7.47(br.s,0.5H),7.41–7.36(m,2H),7 .34-7.29(m,2H),7.34(t,J=74.3Hz,1H),4.40(t,J=5.5Hz,2H),3.95(s,2 H),3.29-3.21(m,1H),3.04-2.85(m,3H),2.48(s,3H),1.11–0.82(m,3H).

[0382] Example 33: Preparation of compound 33

[0383]

[0384] Synthetic route of compound 33:

[0385]

[0386] Step 1: Synthesize compound B33

[0387] The crude compound A33 was dissolved in dioxane (5 mL) and water (0.5 mL), then compound L3 (251 mg), potassium carbonate (671 mg), and 1,1'-bis(di-tert-butylphosphine)ferrocene dichloropalladium (45 mg) were added. The mixture was stirred at 110 °C for 3 hours under nitrogen protection. After the reaction was complete as shown by TLC, the reaction mixture was poured into ice water (20 mL) and extracted with dichloromethane (15 mL × 3). The combined organic phases were washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, dissolved under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate from 1:0 to 0:1 (v / v)) to give compound B33 (184 mg, pale yellow solid).

[0388] MS(ESI): m / z 605.2 [M+1] + .

[0389] Step 2: Synthesize compound C33

[0390] Compound B33 (184 mg) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (2.5 mL) and stirred at room temperature for 0.5 hours. After the reaction was complete, the solution was removed under reduced pressure to give crude compound C33.

[0391] MS(ESI): m / z 505.2 [M+1] + .

[0392] Step 3: Synthesize compound 33

[0393] The crude compound C33 and sodium acetate (50 mg) were dissolved in methanol (2 mL), followed by the addition of 30% formaldehyde aqueous solution (55 mg) and stirring at room temperature for 1 hour. Sodium cyanoborohydride (38 mg) was then added, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete as shown by TLC, the reaction mixture was poured into water (20 mL) and extracted with dichloromethane (15 mL × 3). The combined organic phases were washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered to remove the desiccant, dissolved under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate from 1:0 to 0:1 (v / v)) to obtain the crude product, which was then purified by prep-HPLC (100 × 20.0 mm, DS-5 μm, 8 nm; mobile phase A: 0.1% ammonium bicarbonate in water, mobile phase B: acetonitrile, gradient: 1.1–8 min, 10%–90%; 8–9 min, 90%) to obtain compound 33 (25 mg, yellow solid).

[0394] MS(ESI): m / z 519.2 [M+1] + .

[0395] 1 H NMR(300MHz, DMSO-d6)δ(ppm)8.99(s,1H),8.67(t,J=1.4Hz,1H),8.42(s,1H),7.54(d,J=1.4Hz,2H),7.48–7.42(m,2H),7.38– 7.32(m,2H),7.36(t,J=74.9Hz,1H),4.19(q,J=7.0Hz,2H),3.69(s,2H),2.80-2.72(m,4H),2.45(s,3H),1.20(t,J=7.0Hz,3H).

[0396] Example 34: Preparation of compound 34

[0397]

[0398] Synthetic route of compound 34:

[0399]

[0400] Preparation method:

[0401] Step 1: Synthesize compound B34

[0402] Compound A34 (5.5 g) was dissolved in 1,2-dichloroethane (50 mL), and oxalyl chloride (4.05 g) was added. The mixture was stirred at 80 °C for 1 hour. After the reaction was complete as shown by TLC, the reaction solution was cooled to 0 °C, and compound C1 (9.22 g) was added dropwise to the above reaction solution. After the addition was complete, the mixture was stirred at 0 °C for 1 hour. After the reaction was complete as shown by TLC, the reaction solution was filtered, and the filter cake was washed with dichloromethane (10 mL × 2) and then dried under reduced pressure to give compound B34 (13.2 g, off-white solid, purity 65%).

[0403] MS(ESI): m / z 376.0 [M+1] + .

[0404] Step 2: Synthesize compound C34

[0405] 5.0 g of compound B34 was dissolved in anhydrous N,N-dimethylformamide (50 mL), and 1.6 g of 60% sodium hydride (60% purity) was added in portions at 0 °C. After the addition was complete, the mixture was stirred at room temperature for 1 hour under nitrogen protection. After the reaction was complete as indicated by TLC, the reaction solution was slowly added dropwise to a saturated aqueous solution of ammonium chloride (50 mL) at 0 °C, and then extracted with ethyl acetate (60 mL × 4). The combined organic phases were washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered to remove the drying agent, dissolved under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate from 100:0 to 1:1 (v / v)) to give compound C34 (3.8 g, off-white solid, 65% purity).

[0406] MS(ESI): m / z 340.0 [M+1] + .

[0407] Step 3: Synthesize compound 34

[0408] Compound C34 (1.0 g) was dissolved in N,N-dimethylformamide (10 mL), and copper acetate (280 mg), triethylamine (894 mg), and compound D34 (520 mg) were added sequentially. The mixture was then stirred for 16 hours under an oxygen balloon at 40 °C. After the reaction was complete as shown by TLC, the reaction mixture was slowly poured into a 1N hydrochloric acid aqueous solution (10 mL) at 0 °C, and then extracted with ethyl acetate (10 mL × 2). The combined organic phases were washed with saturated potassium carbonate solution (10 mL × 3), followed by washing with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, dissolved under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate from 100:0 to 0:1 (v / v)) to give compound 34 (320 mg, yellow solid, yield 23.4%). Compound 34 (8 mg, white solid) was purified by prep-HPLC (100 × 20.0 mm, DS-5 μm, 8 nm; mobile phase A: 0.1% ammonium bicarbonate in water, mobile phase B: acetonitrile, gradient: 1.1–8 min, 10%–90%; 8–9 min, 90%).

[0409] MS(ESI): m / z 470.1 [M+1] +

[0410] 1 H NMR (300MHz, DMSO-d6) δ (ppm) 8.45 (d, J = 8.1Hz, 1H), 8.41 (s, 1H), 7.69 (dd, J = 1.9, 0.8Hz, 1H), 7.65 (d, J = 9.1Hz, 1H), 7.53 –7.46(m,2H),7.43(d,J=8.1Hz,1H),7.37–7.29(m,2H),7.35(t,J=74.7Hz,1H),7.16(dd,J=9.1,1.9Hz,1H),4.18(s,3H).

[0411] Example 35: Preparation of compound 35

[0412]

[0413] Synthetic route of compound 35:

[0414]

[0415] Preparation method:

[0416] Step 1: Synthesize compound 35

[0417] Compound 34 (110 mg) was dissolved in dioxane (2 mL), and cyclopropionic acid A35 (100 mg), tripotassium phosphate trihydrate (187 mg), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (22 mg) were added. The mixture was then stirred at 100 °C for 3 hours under nitrogen protection. After the reaction was complete as shown by TLC, the reaction solution was poured into ice water (15 mL) and then extracted with dichloromethane (10 mL × 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered to remove the desiccant, dissolved under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate: methanol from 1:0 to 10:1 (v / v)) to give the crude product. The crude product was then purified by prep-HPLC (100 × 20.0 mm, DS-5 μm, 8 nm; mobile phase A: 0.1% ammonium bicarbonate in water, mobile phase B: acetonitrile, gradient: 1.1–8 min, 10%–90%; 8–9 min, 90%) to give compound 35 (17 mg, yellow solid).

[0418] MS(ESI): m / z 476.2 [M+1] + .

[0419] 1 H NMR(300MHz, DMSO-d6)δ(ppm)8.40(s,1H),8.25(d,J=7.9Hz,1H),7.68(d,J=1.8Hz,1H),7.63(d,J=9.0Hz,1H),7.48–7.39(m,2H),7.33- 7.25(m,3H),7.32(t,J=75.6Hz,1H),7.15(dd,J=9.1,2.0Hz,1H),4.18(s,3H),2.15–2.05(m,1H),0.96-0.87(m,2H),0.66-0.55(m,2H).

[0420] Example 36: Preparation of compound 36

[0421]

[0422] Synthetic route of compound 36:

[0423]

[0424] Preparation method:

[0425] Step 1: Synthesize compound 36

[0426] Compound 34 (100 mg) was dissolved in isopropanol (2 mL), and ethylamine hydrochloride (35 mg) and N,N-diisopropylethylamine (83 mg) were added. The mixture was then stirred at 80 °C for 3 hours. After the reaction was complete as shown by TLC, the reaction mixture was poured into ice water (15 mL) and then extracted with dichloromethane (10 mL × 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and dissolved under reduced pressure. The residue was slurryed with ethyl acetate:petroleum ether = 1:1 (v / v) to give compound 36 (39 mg, white solid).

[0427] MS(ESI): m / z 479.2 [M+1] + .

[0428] 1 H NMR(300MHz, DMSO-d6)δ(ppm)8.38(s,1H),7.87(d,J=8.7Hz,1H),7.73(br.s,1H),7.66–7.57(m,2H),7.49–7.41(m,2H),7.32–7.23( m,2H),7.28(t,J=76.4Hz,1H),7.11(dd,J=9.1,2.0Hz,1H),6.33(d,J=8.7Hz,1H),4.18(s,3H),2.98-2.85(m,2H),0.95-0.81(m,3H).

[0429] Example 37: Preparation of compound 37

[0430]

[0431] Synthetic route of compound 37:

[0432]

[0433] Preparation method:

[0434] Step 1: Synthesize compound A37

[0435] Compound 34 (160 mg) was dissolved in dioxane (2 mL), and trimethylsilylacetylene (320 mg), triethylamine (138 mg), cuprous iodide (12.8 mg), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (24 mg) were added. After the addition was complete, the mixture was stirred at 60 °C for 3 hours under nitrogen protection. After the reaction was complete as indicated by TLC, the reaction mixture was poured into ice water (15 mL) and then extracted with dichloromethane (10 mL × 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, dissolved under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate from 1:0 to 1:1 (v / v)) to give compound A37 (100 mg, brown solid, 55% yield).

[0436] MS(ESI): m / z 532.2 [M+1] + .

[0437] Step 2: Synthesize compound 37

[0438] Compound A37 (100 mg) was dissolved in acetonitrile (2 mL), and then cesium fluoride (86 mg) was added. The mixture was stirred at 60 °C for 0.5 h. After the reaction was complete as shown by TLC, the reaction mixture was poured into ice water (10 mL) and then extracted with dichloromethane (10 mL × 3). The combined organic phases were washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and dissolved under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate from 1:0 to 0:1 (v / v)) to give the crude product. The crude product was then purified by prep-HPLC (100 × 20.0 mm, DS-5 μm, 8 nm; mobile phase A: 0.1% ammonium bicarbonate in water, mobile phase B: acetonitrile, gradient: 1.1–8 min, 10%–90%; 8–9 min, 90%) to give compound 37 (17 mg, white solid).

[0439] MS(ESI): m / z 460.1 [M+1] +

[0440] 1 H NMR(300MHz, DMSO-d6)δ(ppm)8.52-8.33(m,2H),7.73–7.43(m,6H),7.40-7.28(m,2H),7.22–7.10(m,1H),4.60(s,1H),4.19(s,3H).

[0441] Example 38: Preparation of compound 38

[0442]

[0443] Synthetic route of compound 38:

[0444]

[0445] Preparation method:

[0446] Step 1: Synthesize compound A38

[0447] Compound C34 (150 mg) was dissolved in N,N-dimethylacetamide (3 mL), followed by the addition of zinc cyanide (104 mg), triethylamine (134 mg), zinc powder (58 mg), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (36 mg). After the addition was complete, the mixture was stirred at 120 °C for 4 hours under nitrogen protection. After the reaction was complete as indicated by TLC, the reaction mixture was poured into ice water (15 mL) and then extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and dissolved under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate from 1:0 to 1:1 (v / v)) to give compound A38 (100 mg, brown solid, yield 68.2%).

[0448] MS(ESI): m / z 331.1[M+1] +

[0449] Step 2: Synthesize compound 38

[0450] Compound A38 (100 mg) was dissolved in N,N-dimethylformamide (2 mL), and copper acetate (27.8 mg), triethylamine (92.2 mg), pyridine (23 mg), and compound D34 (53 mg) were added sequentially. The mixture was then stirred at 40 °C for 16 hours under an air balloon. After the reaction was complete as shown by TLC, the reaction mixture was slowly poured into a 1N hydrochloric acid aqueous solution (10 mL) at 0 °C, and then extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered to remove the desiccant, dissolved under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate from 100:0 to 0:1 (v / v)). The purified compound 38 (7 mg, white solid) was obtained by prep-HPLC (100 × 20.0 mm, DS-5 μm, 8 nm; mobile phase A: 0.1% ammonium bicarbonate in water, mobile phase B: acetonitrile, gradient: 1.1–8 min, 10%–90%; 8–9 min, 90%).

[0451] MS(ESI): m / z 461.1 [M+1] + .

[0452] 1 H NMR(300MHz,DMSO-d6)δ(ppm)8.66(d,J=7.7Hz,1H),8.42(s,1H),7.94(dd,J=7.9,1.6Hz,1H),7.72–7.63(m, 2H),7.53–7.45(m,2H),7.39–7.31(m,2H),7.36(t,J=74.0Hz,1H),7.16(dd,J=9.1,1.9Hz,1H),4.19(s,3H).

[0453] Example 39: Preparation of compound 39

[0454]

[0455] Synthetic route of compound 39:

[0456]

[0457] Preparation method:

[0458] Step 1: Synthesize compound A39

[0459] Compound D11 (8 g) was dissolved in dioxane (100 mL), and tris(dibenzylacetone)dipalladium (950 mg), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (1.2 g), cesium carbonate (13.5 g), and benzophenone imine (4.13 g) were added. The mixture was then stirred at 100 °C for 16 hours under nitrogen protection. After the reaction was complete as shown by TLC, the reaction solution was cooled to room temperature, filtered through diatomaceous earth, and the filtrate was desolvated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate from 1:1 to 0:1 (v / v)) to give compound A39 (8.1 g, yellow-brown solid, yield 80.3%).

[0460] MS(ESI): m / z 487.2 [M+1] + .

[0461] Step 2: Synthesize compound B39

[0462] Compound A39 (8.1 g) was dissolved in dioxane (40 mL), and hydrochloric acid aqueous solution (20 mL, 4 mol / L) was added dropwise. The mixture was then stirred at room temperature for 30 minutes. After the reaction was complete, the reaction solution was extracted with sodium bicarbonate at pH 8 and then with ethyl acetate (80 mL × 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and dissolved under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate from 1:1 to 0:1 (v / v)) to give compound B39 (4.1 g, yellow solid, 76% yield).

[0463] MS(ESI): m / z 323.1[M+1] + .

[0464] Step 3: Synthesize compound D39

[0465] Compound B39 (300 mg) was dissolved in N,N-dimethylformamide (5 mL), and 4-dimethylaminopyridine (727 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (713 mg) and compound C39 (430 mg) were added. The mixture was then stirred at room temperature for 1 hour. After the reaction was complete as shown by TLC, the reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and dissolved under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate from 1:1 to 0:1 (v / v)) to give compound D39 (401 mg, yellow solid, 85% yield).

[0466] MS(ESI): m / z 506.2 [M+1] + .

[0467] Step 4: Synthesize compound E39

[0468] Compound D39 (700 mg) was dissolved in dimethyl sulfoxide (5 mL), and 4-methoxybenzylamine (190 mg) and cesium fluoride (630 mg) were added. The mixture was then stirred at 130 °C for 1 hour under nitrogen protection. After the reaction was complete as shown by TLC, the reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and dissolved under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate from 1:1 to 0:1 (v / v)) to give compound E39 (410 mg, yellow solid, 49% yield).

[0469] MS(ESI): m / z 607.3 [M+1]+ .

[0470] Step 5: Synthesize compound F39

[0471] Compound E39 (410 mg) was dissolved in trifluoroacetic acid (3 mL) and stirred at 40 °C for 2 hours. After the reaction was complete, the reaction solution was removed under reduced pressure. The residue was extracted with saturated sodium bicarbonate at pH 8 and then with ethyl acetate (20 mL × 5). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate from 1:1 to 0:1 (v / v)) to give compound F39 (230 mg, white solid, 70% yield).

[0472] MS(ESI): m / z 487.2 [M+1] + .

[0473] Step 6: Synthesize compound G39

[0474] Compound F39 (230 mg) was dissolved in toluene (3 mL), and 4-dimethylaminopyridine (173 mg) and triphosgene (70 mg) were added at room temperature. The mixture was then stirred at 120 °C for 1 hour under nitrogen protection. After the reaction was complete as shown by TLC, the reaction solution was cooled to room temperature and quenched with water (10 mL), followed by extraction with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and dissolved under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate from 1:1 to 0:1 (v / v)) to give compound G39 (150 mg, white solid, 62% yield).

[0475] MS(ESI): m / z 513.2 [M+1] + .

[0476] 1 H NMR (300MHz, DMSO-d6) δ (ppm) 11.94 (br.s, 1H), 8.12 (d, J = 8.3Hz, 1H), 7.64 (d, J = 8.1Hz, 1H), 7.54 (s, 1H), 7.42-7.32 (m, 5H), 7.13 (d, J = 7.8Hz, 1H),6.64(d,J=8.4Hz,1H),5.16(s,2H),4.95-4.80(m,2H),4.41(q,J=6 .9Hz,2H),4.23-4.13(m,2H),4.03-3.95(m,2H),1.35(t,J=6.9Hz,3H).

[0477] Step 7: Synthesize compound H39

[0478] Compound G39 (150 mg) was dissolved in N,N-dimethylformamide (3 mL), and compound C1 (220 mg), copper acetate (106 mg), triethylamine (88 mg), and pyridine (69 mg) were added at room temperature. The mixture was then stirred at 60 °C for 12 hours under an oxygen balloon. After the reaction was complete as shown by TLC, the reaction mixture was cooled to room temperature and diluted with water (10 mL), followed by extraction with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered to remove the drying agent, dissolved under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate from 1:1 to 0:1 (v / v)) to give compound H39 (70 mg, white solid, 37% yield).

[0479] MS(ESI): m / z 655.2 [M+1] + .

[0480] Step 7: Synthesize compound 39

[0481] Compound H39 (70 mg) was dissolved in methanol (2 mL), and 10% wet palladium / carbon (10 mg) of the compound was added. The mixture was then stirred at room temperature for 2 hours under a hydrogen balloon. 0.1 mL of 37% formaldehyde aqueous solution was added to the reaction mixture, and stirring was continued at room temperature for another 2 hours under a hydrogen balloon. LCMS showed that after the reaction was complete, the reaction mixture was filtered, and the filtrate was desolvated under reduced pressure. The residue was purified by prep-HPLC (100 × 20.0 mm, DS-5 μm, 8 nm; mobile phase A: 0.1% ammonium bicarbonate in water, mobile phase B: acetonitrile, gradient: 1.1–8 min, 10%–90%; 8–9 min, 90%) to give compound 39 (12 mg, white solid).

[0482] MS(ESI): m / z 535.2 [M+1] + .

[0483] 1H NMR(300MHz, DMSO-d6)δ(ppm)8.27(d,J=8.5Hz,1H),7.62(d,J=8.5Hz,1H),7.55–7.49(m,3H),7.35–7.28(m,2H),7.32(t,J=73.8Hz,1H),7.16(dd,J= 8.5,1.9Hz,1H),6.70(d,J=8.5Hz,1H),4.15-4.08(m,2H),3.97(q,J=7.0H z,2H),3.78(s,2H),2.97-2.89(m,2H),2.45(s,3H),1.08(t,J=7.0Hz,3H).

[0484] Example 40: Preparation of Compound 40

[0485]

[0486] Synthetic route of compound 40:

[0487]

[0488] Preparation method:

[0489] Step 1: Synthesize compound B40

[0490] Compound A40 (7.0 g) was dissolved in tetrahydrofuran (70 mL), and ethanolamine (3.8 g) and acetic acid (1.9 g) were added. The mixture was then stirred at 45 °C for 1 hour. After cooling to room temperature, sodium cyanoborohydride (3.9 g) was added in portions. The mixture was then stirred at 40 °C for 16 hours. After the reaction was complete as shown by TLC, the reaction mixture was cooled to room temperature, and water (70 mL), sodium bicarbonate (5.3 g), and di-tert-butyl dicarbonate (14.0 g) were added. The mixture was then stirred at room temperature for 2 hours. After the reaction was complete as shown by TLC, the mixture was diluted with water (100 mL) and extracted with ethyl acetate (150 mL × 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, dissolved under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1 to 1 / 1 (v / v)) to give compound B40 (8.0 g, yellow solid, yield 69.5%).

[0491] MS(ESI): m / z 370.1 372.1 [M+1] + .

[0492] Step 2: Synthesize compound C40

[0493] Compound B40 (4.0 g) was dissolved in dichloromethane (40 mL), and triethylamine (3.3 g) was added. After the addition was complete, methanesulfonyl chloride (1.4 g) was added dropwise under ice bath conditions. The mixture was stirred at room temperature for 30 minutes after the addition was complete. TLC showed that the reaction was complete. The solvent was removed under reduced pressure to give crude compound C40 (4.8 g, brownish-green solid).

[0494] MS(ESI): m / z 448.1 [M+1] + .

[0495] Step 3: Synthesize compound D40

[0496] Compound C40 (4.8 g) was dissolved in N,N-dimethylformamide (50 mL), and cesium carbonate (6.5 g) and potassium iodide (166 mg) were added. After the addition was complete, the mixture was stirred at 80 °C for 2 hours. After the reaction was complete as shown by TLC, the reaction solution was cooled to room temperature, diluted with water (200 mL), and extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and dissolved under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1 to 1 / 1 (v / v)) to give compound D40 (800 mg, white solid, yield 21.2%).

[0497] MS(ESI): m / z 352.1[M+1] + .

[0498] 1 H NMR (300MHz, DMSO-d6) δ (ppm) 8.05 (d, J=1.9Hz, 1H), 7.53 (dd, J=9.1, 0.7Hz, 1H), 7.31 (dd, J= 9.1,1.9Hz,1H),4.92(s,2H),4.41(t,J=5.4Hz,2H),3.91(dd,J=6.3,4.5Hz,2H),1.45(s,9H).

[0499] Step 4: Synthesize compound E40

[0500] Compound D40 (800 mg) was dissolved in 1,4-dioxane (10 mL), and benzophenone imine (600 mg), cesium carbonate (1.48 g), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (266 mg), and tris(dibenzylacetone)dipalladium (200 mg) were added. The mixture was then purged three times with nitrogen and stirred at 100 °C for 16 hours. After the reaction was complete as shown by TLC, water (100 mL) was added for dilution, followed by extraction with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and dissolved under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1 to 1 / 1 (v / v)) to give compound E40 (800 mg, yellow solid, yield 77.8%).

[0501] MS(ESI): m / z 453.2 [M+1] + .

[0502] Step 5: Synthesize compound F40

[0503] Compound E40 (800 mg) was dissolved in 1,4-dioxane (10 mL), followed by the addition of hydrochloric acid aqueous solution (10 mL, 1 mol / L), and then stirred at room temperature for 30 minutes. After the reaction was complete as shown by TLC, the pH of the reaction solution was adjusted to 7–8 with saturated sodium bicarbonate solution, and then extracted with ethyl acetate (40 mL × 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and dissolved under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 5 / 1 to 0 / 1 (v / v)) to give compound F40 (400 mg, yellow solid, yield 78.5%).

[0504] MS(ESI): m / z 289.2 [M+1] +

[0505] Step 6: Synthesize compound G40

[0506] Compound F40 (400 mg) and compound C39 (300 mg) were dissolved in N,N-dimethylformamide (5 mL), followed by the addition of 4-dimethylaminopyridine (727 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (713 mg). The mixture was stirred at room temperature for 1 hour. After the reaction was complete as indicated by TLC, the reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and dissolved under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate from 1:1 to 0:1 (v / v)) to give compound G40 (570 mg, yellow solid, 87% yield).

[0507] MS(ESI): m / z 472.2 [M+1] +

[0508] Step 7: Synthesize compound H40

[0509] Compound G40 (870 mg) was dissolved in dimethyl sulfoxide (10 mL), and 4-methoxybenzylamine (253 mg) and cesium fluoride (840 mg) were added. The mixture was then stirred at 130 °C for 1 hour under nitrogen protection. After the reaction was complete as shown by TLC, the reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and dissolved under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate from 1:1 to 0:1 (v / v)) to give compound H40 (590 mg, yellow solid, yield 55.8%).

[0510] MS(ESI): m / z 573.3 [M+1] + .

[0511] Step 8: Synthesize compound I40

[0512] Compound H40 (590 mg) was dissolved in trifluoroacetic acid (5 mL), and then stirred at 40 °C for 1 hour. After the reaction was complete (TLC), the reaction solution was directly dissolved under reduced pressure. The residue was dissolved in dichloromethane (5 mL), and then triethylamine (650 mg) and di-tert-butyl dicarbonate (270 mg) were added. The mixture was stirred at room temperature for 1 hour. After the reaction was complete (LCMS), the reaction solution was dissolved under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate from 1:1 to 0:1 (v / v)) to give compound I40 (400 mg, yellow solid, yield 85.8%).

[0513] MS(ESI): m / z 453.2 [M+1] +.

[0514] Step 9: Synthesize compound J40

[0515] Compound I40 (500 mg) was dissolved in toluene (5 mL), and 4-dimethylaminopyridine (405 mg) and triphosgene (164 mg) were added sequentially at room temperature. The mixture was then stirred at 120 °C for 1 hour under nitrogen protection. After the reaction was complete as shown by TLC, the reaction mixture was cooled to room temperature and quenched with water (10 mL), followed by extraction with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, dissolved under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate from 1:1 to 0:1 (v / v)) to give compound J40 (170 mg, white solid, 32% yield).

[0516] MS(ESI): m / z 479.2 [M+1] + .

[0517] Step 10: Synthesize compound K40

[0518] Compound J40 (160 mg) was dissolved in N,N-dimethylformamide (2 mL), and compound C1 (126 mg), copper acetate (61 mg), triethylamine (51 mg), and pyridine (40 mg) were added sequentially at room temperature. The mixture was then stirred at 60 °C for 12 hours under an oxygen balloon. After the reaction was complete as shown by TLC, the reaction mixture was cooled to room temperature and diluted with water (10 mL), followed by extraction with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered to remove the drying agent, dissolved under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate from 1:1 to 0:1 (v / v)) to give compound K40 (140 mg, yellow solid, 68% yield).

[0519] MS(ESI): m / z 621.2 [M+1] + .

[0520] Step 11: Synthesize compound L40

[0521] Compound K40 (140 mg) was dissolved in dichloromethane (1.5 mL) and trifluoroacetic acid (0.5 mL), and stirred at room temperature for 1 hour. LCMS showed that after the reaction was complete, the reaction solution was desolvated under reduced pressure to give compound L40 (100 mg, yellow oil, yield 85%).

[0522] MS(ESI): m / z 521.2 [M+1] + .

[0523] Step 12: Synthesize compound 40

[0524] Compound L40 (140 mg) was dissolved in methanol (2 mL), and formaldehyde aqueous solution (0.2 mL) and sodium acetate (44 mg) were added. The mixture was stirred at room temperature for 30 minutes. Then, sodium cyanoborohydride (34 mg) was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed as indicated by LCMS, the reaction solution was diluted with water (5 mL) and extracted with dichloromethane (15 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and dissolved under reduced pressure. The residue was purified by prep-HPLC (100 × 20.0 mm, DS-5 μm, 8 nm; mobile phase A: 0.1% ammonium bicarbonate in water, mobile phase B: acetonitrile, gradient: 1.1–8 min, 10%–90%; 8–9 min, 90%) to give compound 40 (35 mg, off-white solid).

[0525] MS(ESI): m / z 535.2 [M+1] + .

[0526] 1 H NMR (300MHz, DMSO-d6) δ8.27(d,J=8.5Hz,1H),7.64–7.58(m,2H),7.56–7.47(m,2H),7.35–7.28(m,2H),7.32(t,J=73.9Hz,1H),7.17(dd ,J=9.0,2.0Hz,1H),6.70(d,J=8.5Hz,1H),4.48-4.40(m,2H),4.04–3.90(m,4H),3.05-2.97(m,2H),2.48(s,3H),1.08(t,J=7.0Hz,3H).

[0527] Example 41: Preparation of compound 41

[0528]

[0529] Synthetic route of compound 41:

[0530]

[0531] Preparation method:

[0532] Step 2: Synthesize compound B41

[0533] Compound C39 (1.5 g) was dissolved in anhydrous N,N-dimethylformamide (15 mL). Compound A41 (1.1 g), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (4.2 g), and N,N-diisopropylethylamine (1.9 g) were added under ice bath conditions, followed by stirring for 0.5 h. After TLC showed the reaction was complete, the reaction mixture was added to water (30 mL) under ice bath conditions and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and dissolved under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate from 10:1 to 3:1 (v / v)) to give compound B41 (900 mg, yellow solid, 37% yield).

[0534] MS(ESI): m / z 331.1[M+1] +

[0535] Step 3: Synthesize compound C41

[0536] Compound B41 (900 mg) was dissolved in dioxane (9 mL), followed by the addition of compound C1 (430 mg), cesium carbonate (1.77 g), tris(dibenzylacetone)dipalladium (62 mg), and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (77 mg). The mixture was stirred at 100 °C for 16 hours under nitrogen protection. After the reaction was complete as indicated by TLC, the reaction solution was desolvated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1:1 (v / v)) to give compound C41 (400 mg, yellow solid, yield 32%).

[0537] MS(ESI): m / z 454.2 [M+1] + .

[0538] Step 4: Synthesize compound 41

[0539] Compound C41 (100 mg) was dissolved in anhydrous 1,4-dioxane (2 mL), and triethylamine (44 mg) and N,N'-carbonyldiimidazole (43 mg) were added at room temperature. The mixture was then stirred overnight at 65 °C. After the reaction was complete as shown by TLC, the reaction mixture was poured into water (10 mL) and then extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and dissolved under reduced pressure. The residue was purified by prep-HPLC (10 μm 100A 30 × 250 mm; mobile phase A: 0.1% FA in water, mobile phase B: acetonitrile, gradient: 1.1–8 min, 10%–90%; 6–9 min, 90%) to obtain compound 41 (8 mg, off-white solid).

[0540] MS(ESI): m / z 480.1 [M+1] + .

[0541] 1 H NMR (300MHz, DMSO-d6) δ (ppm) 8.41 (s, 1H), 8.27 (d, J = 8.5Hz, 1H), 7.68 (dd, J = 1.9, 0.8Hz, 1H), 7.64 (dd, J = 9.0, 0.9Hz, 1H), 7.51 (d, J = 8.9Hz, 2H), 7.32 (t,J=74.0Hz,1H),7.31(d,J=8.7Hz,2H),7.15(dd,J=9.1,1.9Hz,1H),6.70 (d,J=8.5Hz,1H),4.18(s,3H),3.97(q,J=7.0Hz,2H),1.08(t,J=7.0Hz,3H).

[0542] Experimental Example 1: MAT2a Enzyme Inhibitory Activity Test

[0543] The inhibitory activity of the example compounds against MAT2 was tested using a Kinase Assay. The lower IC50 value... 50 The value indicates the high potency of the compound as a MAT2a inhibitor in the following assay setup. The procedure is as follows:

[0544] Prepare a standard buffer solution: a buffer consisting of 50 mM Hepes, 50 mM KCl, 10 mM MgCl2, and 10 mM DTT (pH = 7.5); add 4 μL (100 nM) of diluted enzyme buffer to each well of a 384-well plate, followed by 2 μL of diluted example compound solution (final concentration 0.128 nM–10 μM) and mix well; after incubating at 25°C for 15 min, add 4 μL of mixed substrate (50 μM ATP, 100 μM l-methionine) to each well; incubate at 25°C for another 60 min, then add 10 μL of kinase- The enzymatic reaction was terminated using Luminescent Kinase Reagent (Promega Corporation, USA), and the remaining ATP was measured. Plates were incubated at 25°C for 20 min, and the luminescence of each well was recorded using a multi-mode microplate reader. The IC50 values ​​of the compounds were fitted using XLfit 5.5.0 software based on the inhibition rates at different concentrations. 50 .

[0545] The inhibitory activity of the compounds prepared in this invention against MAT2a is shown in Table 1, where + represents >1 μM, ++ represents 100 nM-1 μM, +++ represents 10 nM-100 nM, ++++ represents <10 nM, and ND represents not tested.

[0546] Table 1. IC50 of the inhibitory activity of the compounds of the present invention against MAT2a 50 data

[0547]

[0548]

[0549] As shown in Table 1, the compounds of the present invention have good inhibitory effects on MAT2a, with most compounds having an inhibitory effect of less than 100 nM, indicating good prospects for clinical application.

[0550] Experimental Example 2: HCT-116 wt and HCT-116 MTAP- Cell antiproliferative activity test

[0551] 1. Experimental materials:

[0552] DLD-1 cells were purchased from Wuhan Pronosai Life Science Technology Co., Ltd.; 1640 culture medium was purchased from Biological Industries; fetal bovine serum was purchased from Biosera; and Advanced Phospho-ERK1 / 2 (THR202 / TYR204) KIT was purchased from Cisbio.

[0553] 2. Experimental Methods:

[0554] HCT-116 wt and HCT-116 MTAP- Cells were seeded in 384-well cell culture plates, with 40 μL of cell suspension per well, each well containing 400 HCT-116 cells. wt Or HCT-116 MTAP- Cells and cell culture plates were placed in a CO2 incubator and incubated overnight at 37°C. The test compound was diluted to 2 mM with 100% DMSO as the first concentration, and then further diluted 5-fold to the eighth concentration (from 2 mM to 0.026 μM) using a pipette. 1 μL of the compound was added to 39 μL of cell starvation medium, mixed well, and then 10 μL of the compound solution was added to the corresponding well of the cell culture plate. At this point, the compound concentration was 10 μM to 0.128 nM, and the DMSO concentration was 0.5%. The cell culture plates were returned to the CO2 incubator for another 4 days. 40 μL of CTG reagent was added to each well, and the plates were returned to the CO2 incubator for another hour. The values ​​were then read using a multi-mode microplate reader. The IC50 of the compound was fitted using the accompanying software based on the inhibition rate at different concentrations. 50 .

[0555] 3. Data Analysis:

[0556] The original data were converted into inhibition rate using the equation (Sample-Min) / (Max-Min)*100%, IC 50 The value can be obtained by curve fitting using four parameters (obtained in GraphPad Prism using log(inhibitor) vs. response -- Variable slope mode).

[0557] The compound prepared in this invention is effective against HCT-116. MTAP- The inhibitory activity of the compounds prepared in this invention against HCT-116 is shown in Table 2. wt The inhibitory activity of the cells is shown in Table 3.

[0558] Where - represents >10uM, + represents >1uM, ++ represents 100nM-1uM, +++ represents 10nM-100nM, ++++ represents <10nM, and ND represents untested.

[0559] Table 2. Effects of the compounds of the present invention on HCT-116 MTAP- Cell inhibitory activity test results IC 50 data

[0560] Compound 1 ++ Compound 15 +++ Compound 29 ++ Compound 2 ++ Compound 16 +++ Compound 30 + Compound 3 +++ Compound 17 ++ Compound 31 ++ Compound 4 ++ Compound 18 ++ Compound 32 +++ Compound 5 + Compound 19 +++ Compound 33 ++ Compound 6 ++ Compound 20 +++ Compound 34 ++ Compound 7 + Compound 21 +++ Compound 35 ++ Compound 8 +++ Compound 22 +++ Compound 36 ++ Compound 9 +++ Compound 23 + Compound 37 ++ Compound 10 +++ Compound 24 + Compound 38 + Compound 11 ++ Compound 25 + Compound 39 ++ Compound 12 +++ Compound 26 + Compound 40 ++ Compound 13 +++ Compound 27 +++ Compound 41 ++ Compound 14 +++ Compound 28 ++

[0561] Table 3. Effects of the compounds of the present invention on HCT-116 wtCell inhibitory activity test results IC 50 data

[0562]

[0563]

[0564] As shown in Tables 2 and 3, the compounds of the present invention are effective against HCT-116. MTAP- It has a good inhibitory effect on cells, and also on HCT-116. wt The cell inhibition was greater than 1 μM, indicating that the example compound has high cell selectivity. Therefore, the compound of the present invention has good prospects for clinical application.

[0565] Although embodiments of the present invention have been shown and described above, it is to be understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Without departing from the principles and spirit of the present invention, those skilled in the art can make changes, modifications, substitutions, and variations to the above embodiments within the scope of the present invention, and all such changes, modifications, substitutions, and variations are covered within the scope of the present invention.

Claims

1. A nitrogen-based dianone polycyclic fused ring compound, characterized in that, The compound is any of the compounds shown below, or a pharmaceutically acceptable salt thereof. 。 2. A pharmaceutical composition, characterized in that, It contains an effective dose of one or more of the compound as described in claim 1, or a pharmaceutically acceptable salt thereof.

3. The pharmaceutical composition according to claim 2, characterized in that, The pharmaceutical composition also contains at least one pharmaceutically acceptable excipient.

4. Use of a compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for the prevention and / or treatment of diseases caused by MAT2a overexpression.

5. Use of a compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a MAT2a inhibitor medicament.

6. Use of a compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for treating and / or preventing cancer.

7. The use according to claim 6, characterized in that, The cancers include one or more of pancreatic cancer, colorectal cancer, and lung cancer.

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