Indolines compounds

Abstract

The application discloses a kind of indolines, and specifically discloses the application of the compound shown in formula (I) and its pharmaceutically acceptable salt in preparing drugs for treating related diseases.

Description

[0001] This application claims the following priority:

[0002] CN202110172933.9, application date: February 8, 2021;

[0003] CN202110934819.5, application date August 13, 2021;

[0004] CN202111076891.5, application date: September 14, 2021;

[0005] CN202111204272.X, application date October 15, 2021;

[0006] CN202111593525.7, application date December 23, 2021. Technical Field

[0007] This invention relates to a new class of indoline compounds, specifically to the use of compounds of formula (I) and their pharmaceutically acceptable salts in the preparation of medicaments for treating related diseases. Background Technology

[0008] PD-1, short for programmed death 1, is an important immunosuppressive molecule and a member of the CD28 superfamily. PD-L1, short for programmed cell death-ligand 1, is a 40kD transmembrane protein encoded by the CD274 gene. PD-L1 can be induced to express on the surface of T cells, B cells, dendritic cells, macrophages, mesenchymal stem cells, bone marrow-derived mast cells, and non-hematopoietic cells, and may be rapidly upregulated in tumor tissues and other tissues that respond to interferon and other inflammatory cytokines. Activation of the PD-1 / PD-L1 pathway suppresses the immune system in cancer, pregnancy, tissue transplantation, and autoimmune diseases. Furthermore, PD-L1 can bind to CD80, competitively inhibiting the CD80-ligand binding T cell activation pathway, becoming another mechanism by which PD-L1 suppresses T cell activity.

[0009] Under normal circumstances, the PD-1 / PD-L1 signaling pathway can prevent excessive inflammation and autoimmune diseases induced by the immune system's over-attack on tissues. Under abnormal conditions, such as in tumor tissues and chronically HBV-infected tissues, PD-L1 overexpression occurs. PD-1 / PD-L1 overexpression and signaling pathway activation inhibit the activation and proliferation of functional T cells, suppressing anti-tumor immune responses and causing the immune system to lose its inhibitory effect on tumor development, thereby accelerating tumor progression and deterioration. Several drugs targeting this pathway have been approved. Among them, PD-L1 monoclonal antibodies, such as Atezolizumab, have been approved for indications in urothelial carcinoma and non-small cell lung cancer, and more clinical studies are underway for tumor-related indications. However, compared to small molecules, large molecule drugs have significant drawbacks in areas such as tissue penetration, pharmacokinetic properties, cost, and administration methods. Therefore, the development of small molecule drugs targeting the PD-1 / PD-L1 signaling pathway remains an unmet clinical need with broad market prospects.

[0010] Currently, Bristol-Myers Squibb, Incyte Pharmaceuticals, and Gilead Sciences have all reported small-molecule PD-1 / PD-L1 inhibitors. Incyte Pharmaceuticals' patent WO2018119224 reports that this series of compounds exhibits good cellular activity, and compound INCB086550 has been approved for clinical trials. Nevertheless, there is still significant room for improvement in the pharmacological properties (in vitro activity and in vivo tumor growth inhibition activity, etc.) of these small-molecule compounds; therefore, the development of small-molecule inhibitors of the PD-1 / PD-L1 signaling pathway suggests even greater potential and prospects. Summary of the Invention

[0011] This invention provides compounds of formula (I) or pharmaceutically acceptable salts thereof.

[0012]

[0013] in,

[0014] Ring A is selected from

[0015] L1 and L2 are independently selected from -CH2- and -CH2-NH-CH2-, respectively;

[0016] Z and E are independently selected from CH and N, respectively;

[0017] Z1 is selected from O and S;

[0018] Z2 is selected from N and CR9;

[0019] X is selected from N and CR. 14 ;

[0020] Y is selected from N and CR. 15 ;

[0021] R1 is selected from H, CH3, and CHF2;

[0022] R2 is selected from CH3 and Cl;

[0023] R3, R4, R5, and R6 are independently selected from H and C, respectively. 1-6 Alkyl, OH, COOH and -C 1-3 Alkyl-COOH;

[0024] Alternatively, R3 and R4, together with the atoms they are bonded to, form an azacyclic butyl, pyrrolidinyl, oxazolyl, or piperidinyl group, wherein the azacyclic butyl, pyrrolidinyl, oxazolyl, and piperidinyl groups are each independently and optionally bonded by one, two, or three R groups. 16 replace;

[0025] Alternatively, R5 and R6, together with the atoms they are bonded to, form an azacyclic butyl, pyrrolidinyl, oxazolyl, or piperidinyl group, wherein the azacyclic butyl, pyrrolidinyl, oxazolyl, and piperidinyl groups are each independently and optionally bonded by one, two, or three R groups. 16 replace;

[0026] R7 is selected from H, F, Cl, CH3 and CHF2;

[0027] R8 is selected from -OCH3, -O-CH2-F, and -O-CH2-CN;

[0028] R9 is selected from H, F, and CN;

[0029] R 14 and R 15 Selected independently from H and C respectively 1-6 alkyl;

[0030] R 16 Selected independently from H and C respectively 1-6 Alkyl groups, OH, =O, COOH, and -C 1-3 Alkyl-COOH.

[0031] In some embodiments of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from...

[0032]

[0033] in,

[0034] Ring B and ring C are independently selected from aza-butyl, pyrrolidinyl, oxazolyl, and piperidinyl groups, respectively;

[0035] R 10 R11 R 12 and R 13 Selected independently from H and C respectively 1-4 Alkyl groups, OH, =O, COOH, and -C 1-3 Alkyl-COOH;

[0036] Rings A, Z, R1, and R2 are as defined in this invention.

[0037] In some embodiments of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from...

[0038]

[0039] in,

[0040] Ring B and ring C are independently selected from aza-butyl, pyrrolidinyl, oxazolyl, and piperidinyl groups, respectively;

[0041] R 10 R 11 R 12 and R 13 Selected independently from H and C respectively 1-4 Alkyl groups, OH, =O, COOH, and -C 1-3 Alkyl-COOH;

[0042] Z2 is selected from CH2 and O;

[0043] Z, Z1, Z2, E, R1, R2 and R8 are as defined in this invention.

[0044] In some embodiments of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from...

[0045]

[0046]

[0047] in,

[0048] Z3 is selected from -CH2- and -O-.

[0049] R 10 R 11 R 12 and R 13 Selected independently from H and C respectively 1-4 Alkyl groups, OH, =O, COOH, and -C 1-3 Alkyl-COOH,

[0050] Z, Z1, Z2, E, R1, R2 and R8 are as defined in this invention.

[0051] In some embodiments of the present invention, the above-mentioned compound or its pharmaceutically acceptable salt, wherein Z1 is selected from O, Z2 is selected from C (CN), and other variables are as defined in the present invention.

[0052] In some embodiments of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof, wherein X is selected from N, and other variables are as defined in the present invention.

[0053] In some embodiments of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof, wherein Y is selected from N, and other variables are as defined in the present invention.

[0054] In some embodiments of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof, wherein R1 is selected from CHF2, and other variables are as defined in the present invention.

[0055] In some embodiments of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof, wherein R3, R4, R5, and R6 are each independently selected from H, CH3, isopropyl, ... COOH and -C 1-3 Alkyl-COOH, other variables as defined in this invention.

[0056] In some embodiments of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof, wherein R7 is selected from H, and other variables are as defined in the present invention.

[0057] In some embodiments of the invention, the above-described compound or a pharmaceutically acceptable salt thereof, wherein ring A is selected from... Other variables are as defined in this invention.

[0058] In some embodiments of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof, wherein the structural unit Selected independently Other variables are as defined in this invention.

[0059] In some embodiments of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof, wherein the structural unit Selected independently Other variables are as defined in this invention.

[0060] In some embodiments of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof, wherein the structural unit Selected independently Other variables are as defined in this invention.

[0061] This invention also provides compounds of the following formula or pharmaceutically acceptable salts thereof.

[0062]

[0063]

[0064]

[0065]

[0066]

[0067]

[0068] In some embodiments of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from...

[0069]

[0070]

[0071]

[0072]

[0073]

[0074]

[0075]

[0076]

[0077] Some solutions in this invention are derived from arbitrary combinations of the above-mentioned variables.

[0078] In some embodiments of the present invention, the above-mentioned compounds or pharmaceutically acceptable salts thereof are used in the preparation of medicaments for treating diseases related to PD-L1.

[0079] In some embodiments of the present invention, the above-mentioned compounds or pharmaceutically acceptable salts thereof are used in the preparation of drugs for treating tumors.

[0080] In some embodiments of the present invention, the aforementioned tumor is colon cancer, melanoma, non-small cell lung cancer, hepatocellular carcinoma, or renal cell carcinoma.

[0081] Technical effect

[0082] The compounds of this invention are small-molecule inhibitors with good inhibitory activity against PD-L1, which differs significantly from existing treatment regimens (PD-L1 monoclonal antibody drugs). Small-molecule inhibitors are less expensive to produce than monoclonal antibody drugs, making them more suitable for large-scale production. Furthermore, the pharmacokinetic properties of small-molecule drugs differ significantly from those of large-molecule monoclonal antibody drugs, exhibiting a faster half-life and greater tissue distribution. Therefore, small-molecule PD-L1 inhibitors offer more flexible dosing regimens and more controllable side effects in clinical applications compared to large-molecule drugs. After multiple rounds of searching and evaluation, the compounds of this invention were unexpectedly found to possess excellent in vitro activity and pharmacokinetic properties, demonstrating high oral exposure in preclinical studies. Simultaneously, these compounds showed significant in vivo efficacy, exhibiting good inhibitory activity against tumors (such as colon cancer, melanoma, non-small cell lung cancer, hepatocellular carcinoma, or renal cell carcinoma). These properties support the oral use of this series of compounds for the treatment of PD-L1-positive diseases, demonstrating promising prospects for drug development and clinical application.

[0083] Definitions and Explanations

[0084] Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

[0085] The term “pharmaceutically acceptable” as used herein refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0086] The term "pharmaceutically acceptable salt" refers to a salt of the compounds of this invention, prepared by reacting a compound with a relatively non-toxic acid or base, as discovered in this invention, with a specific substituent. When the compounds of this invention contain relatively acidic functional groups, base addition salts can be obtained by contacting such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts, or similar salts. When the compounds of this invention contain relatively basic functional groups, acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; as well as salts of amino acids (such as arginine) and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups, and thus can be converted into either a base or an acid addition salt.

[0087] When the listed substituents do not specify which atom they are attached to the substituted group, such substituents can be bonded to any of their atoms. For example, a pyridinium substituent can be attached to the substituted group through any carbon atom on the pyridine ring.

[0088] When a substituent can be cross-bonded to two or more atoms on a ring, this substituent can bond with any atom on that ring, for example, structural units. This indicates that the substituent R can be substituted at any position on the cyclohexyl group or cyclohexadiene.

[0089] When the listed linking groups do not specify their linking direction, the linking direction is arbitrary, for example, The linker group L is -MW-. In this case, -MW- can connect ring A and ring B in the same direction as the reading order from left to right to form a ring. Alternatively, rings A and B can be connected in the opposite direction to the left-to-right reading order to form a ring. The combination of linking groups, substituents, and / or their variants is permitted only if such a combination produces a stable compound.

[0090] Unless otherwise specified, when a group has one or more connectable sites, any one or more sites of that group can be connected to other groups by chemical bonds. When the chemical bond connection is non-directional and the connectable site contains H atoms, the number of H atoms at that site will decrease accordingly with the number of chemical bonds connected, resulting in a group with a corresponding valence. The chemical bonds connecting the site to other groups can be straight solid line bonds. Straight dashed key or wavy line For example, a straight solid line bond in -OCH3 indicates that the oxygen atom in that group is connected to other groups; The straight dashed bond in the diagram indicates that the group is connected to other groups through both ends of the nitrogen atom in the group; The wavy lines in the text indicate that the phenyl group is connected to other groups through the carbon atoms at positions 1 and 2 of the phenyl group. This indicates that any connectable site on the piperidinyl group can be linked to other groups via a single chemical bond, including at least... Even if H atoms are drawn on -N- in these four connection methods, Still includes In this type of linkage, when a chemical bond is attached, the number of hydrogen atoms at that site is reduced by one, resulting in a monovalent piperidinyl group.

[0091] Unless otherwise specified, the term "C" 1-6 "alkyl" is used to denote a straight-chain or branched saturated hydrocarbon group consisting of 1 to 6 carbon atoms. The C 1-6 Alkyl groups include C 1-5 C 1-4 C 1-3 C 1-2 C 2-6 C 2-4 C6 and C5 alkyl groups, etc.; they can be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). 1-6 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, etc.

[0092] Unless otherwise specified, the term "C" 1-4 "alkyl" is used to denote a straight-chain or branched saturated hydrocarbon group consisting of 1 to 4 carbon atoms. The C 1-4 Alkyl groups include C 1-2 C 1-3 and C 2-3 Alkyl groups, etc.; they can be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). C1-4 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), etc.

[0093] Unless otherwise specified, the term "C" 1-3 "alkyl" is used to denote a straight-chain or branched saturated hydrocarbon group consisting of 1 to 3 carbon atoms. The C 1-3 Alkyl groups include C 1-2 and C 2-3 Alkyl groups, etc.; they can be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). C 1-3 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), etc.

[0094] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture thereof.

[0095] The compounds of the present invention can be prepared by a variety of synthetic methods 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 known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of the present invention.

[0096] The structures of the compounds of this invention can be confirmed by conventional methods well known to those skilled in the art. If this invention relates to the absolute configuration of a compound, that absolute configuration can be confirmed by conventional techniques in the art. For example, single-crystal X-ray diffraction (SXRD) is used, where the cultured single crystal is used to collect diffraction intensity data using a Bruker D8 venture diffractometer with CuKα radiation as the light source. The scanning method is as follows: After scanning and collecting relevant data, the crystal structure can be further analyzed using the direct method (Shelxs97) to confirm the absolute configuration.

[0097] The solvent used in this invention is commercially available.

[0098] The following abbreviations are used in this invention: Pd(PPh3)4 represents tetrakis(triphenylphosphine)palladium; Pd(dppf)Cl2·CH2Cl2 represents 1,1-bis(diphenylphosphine)ferrocene palladium dichloride dichloromethane complex; NaBH(OAc)3 represents sodium triacetylborohydride; DIAD represents diisopropyl azodicarbonate; Boc2O represents ditert-butyl dicarbonate; t-BuXPhos-Pd-G3 represents (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II)methanesulfonic acid; DIBAL-H represents diisobutylaluminum hydride; DMSO represents dimethyl sulfoxide.

[0099] Compounds are named according to conventional naming principles in the field or using Software naming conventions are used; commercially available compounds use supplier catalog names. Attached Figure Description

[0100] Figure 1 The compounds of this invention exhibit inhibitory activity against PD-1 / PD-L1 binding.

[0101] Figure 2 The tumor volume in the experimental animals.

[0102] Figure 3 The change in body weight of experimental animals.

[0103] Figure 4 The percentage of CD3+ T cells in mCD5+ cells.

[0104] Figure 5 The fluorescence intensity of PD-L1 in cells. Detailed Implementation

[0105] 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.

[0106] Example 1

[0107]

[0108]

[0109] Step A: A 2.5 M, 8.88 mL solution of n-butyllithium in n-hexane was added dropwise at -78 °C to a mixed solution of compound 1-1 (5 g, 18.49 mmol) and triisopropyl borate (4.17 g, 22.19 mmol) in 12.5 mL of 2-methyltetrahydrofuran and 50 mL of toluene. The reaction mixture was stirred at -78 °C for 1 hour, then slowly heated to 25 °C and reacted for 1 hour. The reaction was quenched with 80 mL of hydrochloric acid (1 mol / L), followed by extraction with 80 mL of water and ethyl acetate (80 mL × 3). The combined organic phases were washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was then stirred in 40 mL of ethyl acetate at 25 °C for 0.5 hours and filtered to obtain product 1-2.

[0110] Step B: Compounds 1-2 (3 g, 12.75 mmol), 1-3 (2.19 g, 12.75 mmol), potassium carbonate (3.52 g, 25.50 mmol), and Pd(PPh3)4 (1.47 g, 1.28 mmol) were added to a mixed solution of 30 mL dioxane and 6 mL water. The reaction system was purged with nitrogen three times and reacted at 85 °C under nitrogen protection for 12 hours. After cooling the reaction solution to room temperature, 20 mL of water was added, and the mixture was filtered through diatomaceous earth. The solution was then extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with triple-strength saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 0:1-1:0, v / v) to obtain compounds 1-4. MS (ESI) m / z: 328.2 [M+H] + .

[0111] Step C: Compounds 1-4 (1.29 g, 3.93 mmol), dibenzoyl borate (2.00 g, 7.87 mmol), potassium acetate (772.34 mg, 7.87 mmol), and Pd(dppf)Cl2·CH2Cl2 (321.33 mg, 393.48 μmol) were added to 20 mL of dioxane solution. The reaction system was purged with nitrogen three times and reacted at 85 °C under nitrogen protection for 6 hours. After cooling the reaction solution to room temperature, 15 mL of water was added, and the mixture was filtered through diatomaceous earth. The solution was then extracted with ethyl acetate (40 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 0:1-1:0, v / v) to obtain compounds 1-5. MS (ESI) m / z: 374.4 [M+H] + .

[0112] Step D: Compounds 1-7 (2 g, 8.21 mmol), compounds 1-6 (1.52 g, 9.86 mmol, 1.67 mL), sodium carbonate (2.18 g, 20.53 mmol), and Pd(PPh3)4 (474.59 mg, 410.70 μmol) in a mixed solution of tert-butanol (15 mL) and water (15 mL) were reacted at 80 °C for 2 hours under nitrogen protection. The reactants were diluted with water, extracted with ethyl acetate (40 mL × 3), and the combined organic phases were washed with saturated brine (30 mL × 3). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 0:1-1:0, v / v) to obtain compounds 1-8. MS (ESI) m / z: 191.1 [M+H] + .

[0113] Step E: Add potassium osmium tetroxide dihydrate (9.66 mg, 26.23 μmol) to a mixed solution of dioxane (20 mL) and water (20 mL) of compounds 1-8 (1 g, 5.25 mmol), stir at 25 °C for 30 minutes, and add sodium periodate (2.63 g, 12.30 mmol) in portions. Continue stirring the reaction mixture for 3 hours, quench with 50% sodium thiosulfate aqueous solution, and extract with dichloromethane (60 mL × 3). Wash the organic phase with saturated brine (30 mL × 3), dry with anhydrous sodium sulfate, filter, and concentrate to obtain crude compounds 1-9, which are directly used in the next step. MS (ESI) m / z: 193.3 [M+H + ].

[0114] Step F: A solution of compounds 1-9 (0.64 g, 3.32 mmol) and 1-10 (578.99 mg, 6.65 mmol) in dichloromethane (20 mL) was stirred at 25 °C for 30 min, and NaBH(OAc)3 (2.82 g, 13.29 mmol) was added. The reaction mixture was stirred at 25 °C for 12 h, diluted with water, and extracted with dichloromethane (50 mL × 3). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol:dichloromethane = 0:1-1:0, v / v) to obtain compounds 1-11. MS (ESI) m / z: 264.51 [M+H] + .

[0115] Step G: Compounds 1-11 (0.1 g, 379.19 μmol), 1-12 (78.86 mg, 398.15 μmol), and dioxane (4 M, 94.80 μL) of hydrogen chloride were heated to 120 °C and stirred for two hours in tert-butanol (4 mL). The reaction mixture was cooled to room temperature, quenched with sodium bicarbonate aqueous solution, and extracted with dichloromethane (40 mL × 3). The organic phase was washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by preparative thin-layer chromatography using silica gel plates (ethyl acetate) to obtain compounds 1-13. MS (ESI) m / z: 427.3 [M + H] +

[0116] Step H: Compounds 1-13 (106 mg, 249.22 μmol), compounds 1-5 (93.12 mg, 249.22 μmol), sodium carbonate (66.04 mg, 623.06 μmol), and Pd(PPh3)4 (28.80 mg, 24.92 μmol) in a dioxane (4 mL) and water (0.8 mL) solution were heated to 100 °C and stirred for 1 hour under nitrogen protection. After cooling to room temperature, 20 mL of water was added, and the mixture was filtered through diatomaceous earth. The solution was then extracted with ethyl acetate (40 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by preparative thin-layer chromatography using silica gel plates (ethyl acetate) to obtain compounds 1-14. MS (ESI) m / z: 592.1 [M+H] + .

[0117] Step I: A solution of compounds 1-14 (150 mg, 253.34 μmol) and compounds 1-15 (57.84 mg, 506.68 μmol) in dichloromethane (8 mL) was stirred at 25 °C for 30 minutes, and NaBH(OAc)3 (2.82 g, 13.29 mmol) was added. The reaction mixture was stirred at 25 °C for 1 hour, diluted with water, and extracted with dichloromethane (20 mL × 3). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: Phenomenex luna C18 250*50 mm*15 μm; mobile phase: [pure water (0.225% formic acid)-acetonitrile]; acetonitrile %: 12%-42%, 10 min) to obtain compound 1. 1H NMR (400MHz, DMSO-d6) δ = 8.83 (d, J = 2.0Hz, 1H), 8.21-8.17 (m, 2H), 7.83 (d, J = 7.6Hz, 1H), 7.72 (s, 1H), 7.65-7.59 (m, 2H), 7.52 (t, J = 7.6Hz, 1H),7.44(dd,J=2.0,7.6Hz,1H),7.40(d,J=5.6Hz,1H),7.28(d,J=7.2Hz,1H),7.19(t,J=8.0Hz,1H),6.81(d,J=6.8Hz,1H),4.71-4.54(m,2 H),4.30-4.15(m,1H),3.92(s,3H),3.80(d,J=7.6Hz,2H),3.72(d,J=2.0Hz,2H),3.67-3.60(m,2H),3.60(bs,4H),2.98(t,J=8.0Hz,2H),2. 77-2.73(m,1H),2.69-2.63(m,1H),2.56(d,J=6.0Hz,2H),2.30-2.37(m,1H),2.17-1.97(m,4H),1.78-1.50(m,2H),MS(ESI)m / z:690.5[M+H] + .

[0118] Example 2

[0119]

[0120]

[0121] Step A: Compound 1-13 (0.5 g, 1.18 mmol), dibenzoyl borate (597.052 mg, 2.35 mmol), potassium acetate (346.12 mg, 3.53 mmol), and Pd(dppf)Cl2·CH2Cl2 (96 mg, 117.56 μmol) were added to 10 mL of dioxane solution. The reaction system was purged with nitrogen three times and reacted at 100 °C under nitrogen protection for 3 hours. After cooling the reaction solution to room temperature, 10 mL of water was added, and the mixture was filtered through diatomaceous earth. The solution was then 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, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1 to 0:1, v / v) to obtain compound 2-1. MS (ESI) m / z: 473.3 [M+H] + .

[0122] Step B: Compound 2-2 (5 g, 24.10 mmol), dibenzoyl borate (7.34 g, 28.92 mmol), potassium acetate (4.73 g, 48.20 mmol), and Pd(dppf)Cl2·CH2Cl2 (1.97 g, 2.41 mmol) were added to 40 mL of dioxane solution. The reaction system was purged with nitrogen three times and reacted at 85 °C under nitrogen protection for 12 hours. After the reaction solution was cooled to room temperature, it was filtered through diatomaceous earth, and the filter cake was washed with 40 mL of dioxane solution. The filtrates were combined to obtain the crude compound 2-3.

[0123] Step C: Compound 2-4 (5.23 g, 24.08 mmol), potassium carbonate (8.32 g, 60.21 mmol), and Pd(dppf)Cl2·CH2Cl2 (1.97 g, 2.41 mmol) were added to a mixed solution of compound 2-3 (6.13 g, 24.08 mmol) and 16 mL of water in 80 mL of dioxane solution. The reaction system was purged with nitrogen three times and reacted at 85 °C under nitrogen protection for 4 hours. After cooling the reaction solution to room temperature, 20 mL of water was added, and the mixture was filtered through diatomaceous earth. The solution was then extracted with ethyl acetate (80 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0–0:1, v / v) to obtain compound 2-5. MS (ESI) m / z: 265.1 [M+H] + .

[0124] Step D: Trifluoromethanesulfonic anhydride (4.37 g, 15.47 mmol) was carefully added dropwise at -78 °C to a 60 mL dichloromethane solution of compounds 2-5 (3.15 g, 11.90 mmol) and N,N-diisopropylethylamine (9.23 g, 71.41 mmol). The reaction mixture was stirred at -78 °C for 0.5 hours, then quenched with 50 mL of saturated citric acid solution. After adding 20 mL of water, the mixture was extracted with dichloromethane (50 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0-0:1, v / v) to obtain compounds 2-6.

[0125] Step E: NaBH(OAc)3 (3.47 g, 16.38 mmol) was added to a dichloromethane (12 mL) solution of compounds 2-6 (1.3 g, 3.28 mmol) and 1-15 (748.07 mg, 6.55 mmol). The reaction mixture was stirred at 25 °C for 2 hours, diluted with 100 mL of water, and extracted with ethyl acetate (100 mL × 2). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0–0:1, v / v) to obtain compounds 2-7. MS (ESI) m / z: 495.1 [M+H] + .

[0126] Step F: Triethylamine (306.72 mg, 3.03 mmol) was added to a tetrahydrofuran (14 mL) solution of compounds 2-7 (0.5 g, 1.01 mmol) and di-tert-butyl dicarbonate (441.02 mg, 2.02 mmol). The reaction mixture was stirred at 25 °C for 2 hours. After adding 100 mL of water, the mixture was extracted with ethyl acetate (100 mL × 2). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0–0:1, v / v) to obtain compounds 2-8. MS (ESI) m / z: 595.1 [M+H] + .

[0127] Step G: A mixed solution of compound 2-8 (100 mg, 211.69 μmol), compound 2-1 (125.95 mg, 211.69 μmol), sodium carbonate (56.09 mg, 529.23 μmol), and Pd(PPh3)4 (24.46 mg, 21.17 μmol) in dioxane (2 mL) and water (0.4 mL) was purged three times with nitrogen. The mixture was heated to 100 °C under nitrogen protection and stirred for 1 hour. After cooling to room temperature, 10 mL of water was added, and the mixture was filtered through diatomaceous earth. The solution was then 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, and concentrated to obtain the crude product. The crude product was purified by preparative thin-layer chromatography using silica gel plates (ethyl acetate) to obtain compound 2-9. MS (ESI) m / z: 791.5 [M+H] + .

[0128] Step H: Trifluoroacetic acid (924.00 mg, 8.10 mmol) was added to a solution of compounds 2-9 (0.09 g, 113.73 μmol) in dichloromethane (1.8 mL). The reaction solution was stirred at 25 °C for 10 minutes and concentrated to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: Phenomenex Synergi C18 150*25 mm*10 μm; mobile phase: [pure water (0.225% formic acid)-acetonitrile]; acetonitrile %: 10%-40%, 10 min) to obtain compound 2. 1 H NMR (400MHz, DMSO-d6) δ = 8.89 (d, J = 2.0Hz, 1H), 8.56 (s, 1H), 8.31 (s, 1H), 8.22 (d, J = 5.6Hz, 1H), 8.13 (s, 1H), 7 .72-7.67(m,2H),7.65(d,J=8.0Hz,1H),7.60(t,J=7.6Hz,1H),7.57-7.53(m,1H),7.42(d,J=5.6Hz,1H),7.20(t ,J=8.0Hz,1H),6.83(d,J=7.2Hz,1H),5.15-4.94(m,1H),4.76-4.53(m,2H),4.29(s,3H),4.03(s,3H),3.90-3. 78(m,2H),3.04-2.95(m,6H),2.88-2.63(m,3H),2.21-2.03(m,4H),1.85-1.64(m,2H); MS(ESI)m / z:691.2[M+H] + .

[0129] Example 3

[0130]

[0131]

[0132] Step A: Compound 3-1 (10 g, 46.08 mmol) and compound 3-2 (64.16 g, 368.63 mmol) were stirred together at 60 °C for 12 hours, and then concentrated under reduced pressure to obtain compound 3-3. MS (ESI) m / z: 277.2 [M+H] + ]

[0133] Step B: Compound 3-3 (6.38 g, 23.03 mmol) and ammonia (28.83 g, 230.31 mmol, 31.68 mL, containing 28% amine) were stirred in a sealed container at 85°C for 5 hours. The crude product was concentrated, and 50 mL of a dichloromethane / methanol solution (10 / 10) was added. The mixture was stirred at 25°C for 1 hour, filtered, and the solid was collected and concentrated to obtain compound 3-4. MS (ESI) m / z: 276.2 [M+H] + ]

[0134] Step C: Compounds 3-4 (1.7 g, 6.16 mmol), 3-5 (1.9 g, 12.32 mmol), potassium phosphate (3.27 g, 15.40 mmol), and Pd(PPh3)4 (711.66 mg, 615.86 μmol) were added to a mixed solution of 20 mL dioxane and 20 mL water. The reaction system was purged with nitrogen three times, and the reaction was carried out at 100 °C under nitrogen protection for 12 hours. The reaction solution was concentrated to obtain the crude product. The crude product was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 0:1-1:0, V / V) to obtain compounds 3-6. MS (ESI) m / z: 224.3 [M+H] + .

[0135] Step D: Phosphorus oxychloride (1.44 g, 9.41 mmol) was added to 8 mL of acetonitrile solution containing compounds 3-6 (0.35 g, 1.57 mmol), N,N-dimethylaniline (285.06 mg, 2.35 mmol), and benzyltriethylammonium chloride (714.41 mg, 3.14 mmol). The reaction system was reacted at 75 °C for 2 hours, and the reaction solution was concentrated after cooling to room temperature. Then, compounds 1-12 (1.44 g, 9.41 mmol) were dissolved in 8 mL of isopropanol solution, and methanesulfonic acid (301.44 mg, 3.14 mmol) was added. The reaction system was reacted at 80 °C for 2 hours and then concentrated. The solution was then dissolved in 30 mL of ethyl acetate and 20 mL of sodium bicarbonate solution and extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 0:1-1:0, v / v) to give compounds 3-7. MS (ESI) m / z: 403.2 [M+H] + .

[0136] Step E: Add potassium osmium tetroxide dihydrate (913.77 μg, 2.48 μmol) and sodium periodate (265.23 mg, 1.24 mmol) to a mixed solution of compound 3-7 (0.1 g, 248.00 μmol) in tetrahydrofuran (4 mL) and water (1 mL). After reacting at 25 °C for 3 hours, quench the reaction with 20 mL of 50% sodium thiosulfate solution, then extract with dichloromethane (30 mL × 3). Combine the organic phases, wash with saturated brine (30 mL × 2), dry with anhydrous sodium sulfate, filter, and concentrate to obtain crude compound 3-8. MS (ESI) m / z: 405.2 [M+H] + .

[0137] Step F: A solution of compounds 3-8 (100 mg, 246.79 μmol) and 1-10 (43 mg, 493.59 μmol) in dichloromethane (6 mL) was stirred at 25 °C for 0.5 h, and NaBH(OAc)3 (209.22 mg, 987.18 μmol) was added. After stirring the reaction mixture at 25 °C for 2 hours, 10 mL of water was added, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phase was washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude compounds 3-9. MS (ESI) m / z: 478.3 [M+H] + .

[0138] Step G: Compounds 3-9 (90 mg, 188.95 μmol), compounds 1-5 (70.60 mg, 188.95 μmol), sodium carbonate (50.07 mg, 472.38 μmol), and Pd(PPh3)4 (65.50 mg, 56.69 μmol) in a dioxane (5 mL) and water (1 mL) solution were heated to 100 °C and stirred for 1 hour under nitrogen protection. The reaction mixture was diluted with 20 mL of water, filtered through diatomaceous earth, and then extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by preparative thin-layer chromatography using silica gel plates (petroleum ether: ethyl acetate = 1:1) to obtain compounds 3-10. MS (ESI) m / z: 643.5 [M+H] + .

[0139] Step H: A solution of compounds 3-10 (40 mg, 62.20 μmol) and 1-15 (14.20 mg, 124.40 μmol) in dichloromethane (2 mL) was stirred at 25 °C for 0.5 h, and NaBH(OAc)3 (65.91 mg, 311.00 μmol) was added. The reaction mixture was stirred at 25 °C for 0.5 h, diluted with 10 mL of water, and extracted with dichloromethane (20 mL × 5). The organic phase was washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: Phenomenex Synergi C18 150*25 mm*10 μm; mobile phase: [pure water (0.225% formic acid)-acetonitrile]; acetonitrile %: 14%-44%, 10 min) to obtain the formate salt of compound 3. 1 H NMR (400MHz, CD3OD) δ=8.98-8.86(m,1H),8.74(d,J=8.0Hz,1H),8.50(s,1H),8.14(s,1H),7.76(d,J=7.6Hz,1H ),7.61(d,J=7.6Hz,1H),7.53-7.45(m,1H),7.42-7.32(m,2H),7.26(d,J=7.2Hz,1H),7.14-6.98(m,1H),6.87- 6.51(m,1H),5.08-5.02(m,2H),4.41-4.38(m,1H),4.03(s,3H),3.98-3.80(m,5H),3.20-2.98(m,2H),2.95-2. 84(m,2H),2.83-2.72(m,2H),2.72-2.58(m,2H),2.44-2.11(m,4H),1.92-1.68(m,2H); MS(ESI)m / z:741.2[M+H] + .

[0140] Example 4: Compound 4

[0141]

[0142]

[0143] Step A: Compound 3-9 (0.2 g, 419.89 μmol), bis-pinacolborate (213.25 mg, 839.78 μmol), potassium acetate (123.62 mg, 1.26 mmol), and Pd(dppf)Cl2·CH2Cl2 (34.29 mg, 41.99 μmol) were added to 10 mL of dioxane solution. The reaction system was purged with nitrogen three times and reacted at 95 °C under nitrogen protection for 1 hour. After cooling the reaction solution to room temperature, 100 mL of water was added, followed by extraction with ethyl acetate (100 mL × 2). The combined organic phases were washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by thin-layer chromatography (dichloromethane:methanol = 10:1) to obtain compound 4-1. MS (ESI) m / z: 524.2 [M+H] + .

[0144] Step B: A mixed solution of compound 4-1 (90 mg, 171.96 μmol), compound 2-8 (112.54 mg, 189.15 μmol), sodium carbonate (36.45 mg, 343.92 μmol), and Pd(PPh3)4 (19.87 mg, 17.20 μmol) in dioxane (8 mL) and water (2 mL) was purged three times with nitrogen. The mixture was heated to 100 °C under nitrogen protection and stirred for 1 hour. After cooling to room temperature, 50 mL of the solution was added, followed by extraction with ethyl acetate (25 mL × 2). The combined organic phases were washed with saturated brine (25 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to obtain compound 4-2. MS (ESI) m / z: 842.3 [M+H] + .

[0145] Step C: Trifluoroacetic acid (3.08 g, 27.01 mmol) was added to a dichloromethane (6 mL) solution of compound 4-2 (80 mg, 94.97 μmol). The reaction solution was stirred at 25 °C for 30 minutes and concentrated to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [pure water (0.225% formic acid)-acetonitrile]; acetonitrile %: 13%-43%, 10 min) to obtain the formate salt of compound 4. 1H NMR (400MHz, DMSO-d6) δ=8.92(d,J=1.6Hz,1H),8.65(d,J=8.0Hz,1H),8.52(s,1H),8.18(d,J=1.6Hz,1H),8.14(s ,1H),7.72(dd,J=,1H),7.68(s,1H),7.61(t,1H),7.54(dd,1H),7.42(t,J=8.0Hz,1H),7.13-6.75(m,2H),5.00(br t,J=8.0Hz,2H),4.28-4.20(m,1H),4.10(s,2H),4.01(s,3H),3.98-3.82(m,3H),3 .79-3.69(m,1H),3.15-3.01(m,2H),2.85-2.70(m,4H),2.62-2.53(m,1H),2.46(br d,J=8.0Hz,2H),2.20-1.97(m,4H),1.80-1.68(m,1H),1.66-1.54(m,1H); MS(ESI)m / z:742.2[M+H] + .

[0146] Example 5: Compound 5

[0147]

[0148]

[0149] Step A: A mixed solution of compound 5-1 (500 mg, 2.31 mmol) and triethyl orthoformate (9.81 g, 66.21 mmol) was reacted at 110 °C for 5 hours. The reaction solution was concentrated to obtain crude compound 5-2.

[0150] Step B: Compound 5-2 (550 mg, 2.43 mmol), compound 3-5 (749.53 mg, 4.87 mmol), potassium phosphate (1.29 g, 6.08 mmol), and Pd(PPh3)4 (281.18 mg, 243.33 μmol) were added to a mixed solution of 20 mL dioxane and 4 mL water. The reaction system was purged with nitrogen three times, and the reaction was carried out at 85 °C under nitrogen protection for 12 hours. The reaction solution was concentrated to obtain crude compound 5-3. MS (ESI) m / z: 174.2 [M+H] + .

[0151] Step C: Phosphorus oxychloride (12.70 g, 82.81 mmol) was added to 25 mL of acetonitrile solution containing compound 5-3 (2.39 g, 13.80 mmol), N,N-dimethylaniline (2.51 g, 20.70 mmol), and benzyltriethylammonium chloride (6.29 g, 27.60 mmol). The reaction mixture was reacted at 75 °C for 2 hours. After concentration, ice and 30 mL of sodium bicarbonate solution were added, followed by extraction with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0-0:1, v / v) to obtain compound 5-4. MS (ESI) m / z: 192.1 [M+H] + .

[0152] Step D: Methanesulfonic acid (120.38 mg, 1.25 mmol) was added to 5 mL of isopropanol solution of compound 5-4 (120 mg, 626.25 μmol) and compound 1-12 (124.03 mg, 626.25 μmol). The system was reacted at 80 °C for 2 hours. Then, 20 mL of sodium bicarbonate solution was added and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude compound 5-5. MS (ESI) m / z: 353.0 [M+H] + .

[0153] Step E: Potassium osmium tetroxide dihydrate (2.37 mg, 6.43 μmol) and sodium periodate (687.30 mg, 3.21 mmol) were added to a mixed solution of compound 5-5 (227 mg, 6442.67 μmol) in tetrahydrofuran (25 mL) and water (5 mL). The reaction system was reacted at 25 °C for 12 hours, then quenched with 20 mL of 50% sodium thiosulfate solution, followed by extraction with dichloromethane (60 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by preparative thin-layer chromatography using silica gel plates (petroleum ether: ethyl acetate = 1:1) to obtain compound 5-6. MS (ESI) m / z: 355.3 [M+H] + .

[0154] Step F: A 6 mL solution of compounds 5-6 (90 mg, 253.39 μmol) and 5-7 (58.34 mg, 506.77 μmol) in dichloromethane was stirred at 25 °C for 0.5 h, and NaBH(OAc)3 (161.11 mg, 760.16 μmol) was added. The reaction system was stirred at 25 °C for 12 hours, then 10 mL of water was added, and the mixture was extracted with dichloromethane (50 mL × 5). The organic phase was washed with saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude compound 5-8. MS (ESI) m / z: 454.2 [M+H] + .

[0155] Step G: A mixed solution of compounds 5-8 (120 mg, 264.13 μmol), compounds 1-5 (128.30 mg, 343.37 μmol), sodium carbonate (69.99 mg, 660.33 μmol), and Pd(PPh3)4 (30.52 mg, 26.41 μmol) in dioxane (10 mL) and water (2 mL) was purged three times with nitrogen and heated to 100 °C under nitrogen protection, stirred for 1 hour. The reaction solution was filtered through diatomaceous earth, and the filter cake was washed with 100 mL of dichloromethane. The filtrates were combined and concentrated to obtain the crude product. The crude product was purified by preparative thin-layer chromatography using silica gel plates (dichloromethane:methanol = 5:1) to obtain compounds 5-9. MS (ESI) m / z: 621.1 [M+H] + .

[0156] Step H: A 2 mL solution of compounds 5-9 (45 mg, 72.45 μmol) and compounds 1-15 (16.54 mg, 144.91 μmol) in dichloromethane was stirred at 25 °C for 0.5 h. NaBH(OAc)3 (76.78 mg, 362.27 μmol) was added. The reaction system was stirred at 25 °C for 12 h, diluted with 10 mL of water, and extracted with dichloromethane (20 mL × 5). The organic phase was washed with saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [pure water (0.225% formic acid)-acetonitrile]; acetonitrile %: 8%-38%, 12 min) to obtain the formate salt of compound 5. 1H NMR (400MHz, DMSO-d6) δ = 8.84 (d, J = 2.0Hz, 1H), 8.74 (s, 1H), 8.52 (d, J = 8.0Hz, 1H), 8.23 ​​(s, 1H), 8.07 (d, J = 1.6Hz, 1H), 7.83 ( d,J=7.6Hz,1H),7.71(s,1H),7.65(dd,J=1.6,7.6Hz,1H),7.54(t,J=7.6Hz,1H),7.46(dd,J=2.0,7.6Hz,1H),7.38(t,J=7.6H z,1H),7.29(d,J=7.6Hz,1H),7.03(d,J=6.8Hz,1H),4.99-4.88(m,2H),3.93(s,3H),3.85(d,J=11.2Hz,2H),3.73(d,J=2.0Hz ,2H),3.10-2.92(m,4H),2.79-2.69(m,2H),2.62-2.55(m,4H),2.17-1.94(m,5H),1.78-1.60(m,1H); MS(ESI)m / z:719.2[M+H] + .

[0157] Example 6: Compound 6

[0158]

[0159]

[0160] Step A: Compound 6-1 (8 g, 35.09 mmol) was added to 40 mL of dioxane, followed by 20 mL of water and ammonia (18.01 g, 143.86 mmol, 28% purity). The reaction system was stirred at 25 °C for 10 minutes, and then sodium hydrosulfite (19.98 g, 114.74 mmol) was added in portions. The reaction was continued at 25 °C for 5 hours. The reaction solution was filtered through diatomaceous earth, and the filter cake was washed with 100 mL of ethyl acetate. The filtrate was then diluted with 20 mL of water and extracted with ethyl acetate (40 mL × 5). The combined organic phases were washed with saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0-0:1, v / v) to obtain compound 5-1.

[0161] Step B: A mixed solution of compound 5-1 (450 mg, 2.08 mmol) and triethyl orthoacetate (7.96 g, 49.10 mmol) was reacted at 120 °C for 5 hours. The reaction solution was concentrated to give crude compound 6-2. MS (ESI) m / z: 240.2 [M+H] + .

[0162] Step C: Compound 6-2 (690 mg, 2.87 mmol), compound 3-5 (885.37 mg, 5.75 mmol), potassium phosphate (1.53 g, 7.19 mmol), and Pd(PPh3)4 (332.15 mg, 287.43 μmol) were added to a mixed solution of 15 mL dioxane and 3 mL water. The reaction system was purged with nitrogen three times, and the reaction was carried out at 95 °C under nitrogen protection for 12 hours. The reaction solution was concentrated to obtain crude compound 6-3. MS (ESI) m / z: 188.3 [M+H] + .

[0163] Step D: Phosphorus oxychloride (10.81 g, 70.51 mmol) was added to 40 mL of acetonitrile solution containing compound 6-3 (2.2 g, 11.75 mmol), N,N-dimethylaniline (2.14 g, 17.63 mmol), and benzyltriethylammonium chloride (5.35 g, 23.50 mmol). The reaction mixture was reacted at 75 °C for 2 hours. After concentration, ice and 30 mL of sodium bicarbonate solution were added, followed by extraction with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0-0:1, v / v) to obtain compound 6-4. MS (ESI) m / z: 206.0 [M+H] + .

[0164] Step E: Methanesulfonic acid (214.98 mg, 2.24 mmol) was added to 10 mL of isopropanol solution of compounds 6-4 (230 mg, 1.12 mmol) and 1-12 (221.52 mg, 1.12 mmol). The reaction was carried out at 80 °C for 2 hours. Then, 30 mL of sodium bicarbonate solution was added and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by thin-layer chromatography using silica gel plates (petroleum ether: ethyl acetate = 1:1) to obtain compound 6-5. MS (ESI) m / z: 367.3 [M+H] + .

[0165] Step F: Potassium osmium tetroxide dihydrate (2.39 mg, 6.48 μmol) and sodium periodate (693.08 mg, 3.24 mmol) were added to a mixed solution of compound 6-5 (238 mg, 648.07 μmol) in tetrahydrofuran (25 mL) and water (5 mL). The reaction system was reacted at 25 °C for 5 hours, then quenched with 30 mL of 50% sodium thiosulfate solution, and extracted with dichloromethane (80 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude compound 6-6. MS (ESI) m / z: 369.3 [M+H] + .

[0166] Step G: A 15 mL solution of compound 6-6 (330 mg, 893.79 μmol) and compound 5-7 (205.80 mg, 1.79 mmol) in dichloromethane was stirred at 25 °C for 0.5 h, and NaBH(OAc)3 (568.29 mg, 2.68 mmol) was added. The reaction mixture was stirred at 25 °C for 12 hours, then 10 mL of water was added, and the mixture was extracted with dichloromethane (50 mL × 5). The organic phase was washed with saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude compound 6-7. MS (ESI) m / z: 468.2 [M+H] + .

[0167] Step H: A mixed solution of compounds 6-7 (657 mg, 1.40 mmol), compounds 1-5 (681.39 mg, 1.82 mmol), sodium carbonate (371.71 mg, 3.51 mmol), and Pd(PPh3)4 (162.10 mg, 140.28 μmol) in dioxane (15 mL) and water (3 mL) was purged three times with nitrogen and heated to 100 °C under nitrogen protection, stirred for 1 hour. The reaction solution was filtered through diatomaceous earth, and the filter cake was washed with 150 mL of dichloromethane. The filtrates were combined and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0-0:1, v / v) to obtain compounds 6-8. MS (ESI) m / z: 635.0 [M+H] + .

[0168] Step I: A 10 mL solution of compounds 6-8 (350 mg, 551.09 μmol) and compounds 1-15 (125.81 mg, 1.10 mmol) in dichloromethane was stirred at 25 °C for 0.5 h, and NaBH(OAc)3 (583.99 mg, 2.76 mmol) was added. The reaction system was stirred at 25 °C for 12 h, diluted with 10 mL of water, and extracted with dichloromethane (20 mL × 5). The organic phase was washed with saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: Phenomenex luna C18 150*40 mm*15 μm; mobile phase: [pure water (0.225% formic acid)-acetonitrile]; acetonitrile %: 70%-37%, 10 min) to obtain the formate of compound 6. 1H NMR (400MHz, DMSO-d6) δ = 8.73 (d, J = 1.6 Hz, 1H), 8.53 ( d, J = 8.4 Hz, 1H), 8.20 ( s, 1H), 7.95 ( d, J = 1.6 Hz, 1H), 7.85 ( d, J =7.6Hz,1H),7.72(s,1H),7.64(dd,J=1.6,7.6Hz,1H),7.53(t,J=7.6Hz,1H),7.44(dd,J=1.6,7.6Hz,1H),7.36(t,J= 7.6Hz,1H),7.30(d,J=7.6Hz,1H),7.00(d,J=7.2Hz,1H),4.89(t,J=8.0Hz,2H),3.94(s,3H),3.87-3.63(m,5H),3.0 9-2.90(m,3H),2.81-2.67(m,2H),2.66-2.55(m,7H),2.19-1.89(m,5H),1.78-1.62(m,1H); MS(ESI)m / z:733.2[M+H] + .

[0169] Example 7: Compound 7

[0170]

[0171] Step A: Boron tribromide (21.90 g, 87.42 mmol) was slowly added dropwise to a 60 mL dichloromethane solution of compound 1-3 (5 g, 29.14 mmol) at 0 °C. The mixture was reacted at 0 °C for 30 minutes, then quenched with 80 mL saturated sodium bicarbonate solution. After dilution with 30 mL of water, the mixture was extracted with dichloromethane (40 mL × 5). The combined organic phases were washed with saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0-0:1, v / v) to obtain compound 7-1.

[0172] Step B: Silver carbonate (6.16 g, 22.34 mmol) was added to 40 mL of an acetonitrile solution containing compound 7-1 (3.2 g, 20.31 mmol) and bromoacetonitrile (4.87 g, 40.62 mmol). The reaction system was stirred at 90 °C for 12 hours. The reaction solution was filtered through diatomaceous earth, and the filter cake was washed with 30 mL of ethyl acetate. Then, 20 mL of water was added to the filtrate for dilution, and the mixture was extracted with ethyl acetate (30 mL × 5). The combined organic phases were washed with saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1-5:1, v / v) to obtain compound 7-2.

[0173] Step C: Compound 7-2 (0.496 g, 2.52 mmol), compound 1-2 (652.95 mg, 2.78 mmol), potassium carbonate (697.41 mg, 5.05 mmol), and Pd(PPh3)4 (291.55 mg, 252.30 μmol) in dioxane (10 mL) and water (2 mL) were purged three times with nitrogen and heated to 85 °C under nitrogen protection, stirred for 5 hours. The reaction mixture was diluted with 20 mL of water and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0-0:1, v / v) to obtain compound 7-3. MS (ESI) m / z: 351.0 [M+H] + .

[0174] Step D: A 20 mL solution of compound 7-3 (630 mg, 1.79 mmol), bis(dppf)Cl2·CH2Cl2 (146.33 mg, 179.19 μmol) in dioxane was purged three times with nitrogen and heated to 85 °C under nitrogen protection, with stirring for 5 hours. The reaction solution was filtered through diatomaceous earth, and the filter cake was washed with 100 mL of ethyl acetate. The filtrates were combined and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0-0:1, v / v) to obtain compound 7-4. MS (ESI) m / z: 399.1 [M+H] + .

[0175] Step E: A mixed solution of compound 7-4 (100.43 mg, 251.93 μmol), compound 3-9 (100 mg, 209.94 μmol), sodium carbonate (55.63 mg, 524.86 μmol), and Pd(PPh3)4 (24.26 mg, 20.99 μmol) in dioxane (10 mL) and water (2 mL) was purged three times with nitrogen and heated to 100 °C under nitrogen protection, stirred for 1 hour. The reaction solution was filtered through diatomaceous earth, diluted with 20 mL of water, and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by preparative thin-layer chromatography using silica gel plates (dichloromethane:methanol = 10:1) to obtain compound 7-5. MS (ESI) m / z: 668.4 [M+H] + .

[0176] Step F: A 6 mL solution of compounds 7-5 (130 mg, 194.58 μmol) and 1-15 (44.42 mg, 389.17 μmol) in dichloromethane was stirred at 25 °C for 0.5 h, and NaBH(OAc)3 (206.20 mg, 972.92 μmol) was added. After stirring the reaction system at 25 °C for 1 hour, 10 mL of water was added for dilution, followed by extraction with dichloromethane (20 mL × 5). The organic phase was washed with saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: Phenomenex Synergi C18 150*25 mm*10 μm; mobile phase: [pure water (0.225% formic acid)-acetonitrile]; acetonitrile %: 9%-39%, 10 min) to obtain the formate salt of compound 7. 1 H NMR (400MHz, DMSO-d6) δ=8.92(d,J=2.0Hz,1H),8.66(d,J=8.0Hz,1H),8.18(s,1H),8.16(d,J=1.6Hz,1H),7.97(d,J=7.6H z,1H),7.74(dd,J=1.6,7.6Hz,1H),7.70(s,1H),7.58(t,J=7.6Hz,1H),7.53-7.47(m,2H),7.42(t,J=8.0Hz,1H),7.13-6. 76(m,2H),5.28(s,2H),5.00(t,J=8.0Hz,2H),4.26-4.21(m,1H),3.94-3.63(m,7H),3.09(t,J=8.0Hz,2H),2.79-2.64(m, 2H), 2.59 (d, J=6.0Hz, 2H), 2.42 (dd, J=3.2, 9.6Hz, 1H), 2.19-1.98 (m, 4H), 1.78-1.50 (m, 2H); MS (ESI) m / z: 766.5[M+H]+.

[0177] Example 8: Compound 8

[0178]

[0179]

[0180] Step A: A 15 mL solution of compounds 3-8 (200 mg, 493.59 μmol) and 5-7 (113.65 mg, 987.18 μmol) in dichloromethane was stirred at 25 °C for 0.5 h, and NaBH(OAc)3 (313.83 mg, 1.48 mmol) was added. The reaction mixture was stirred at 25 °C for 12 hours, diluted with 10 mL of water, and then extracted with dichloromethane (40 mL × 8). The organic phase was washed with saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude compound 8-1. MS (ESI) m / z: 504.3 [M+H] + .

[0181] Step B: A mixed solution of compound 8-1 (150 mg, 297.43 μmol), compound 7-4 (118.57 mg, 297.43 μmol), sodium carbonate (78.81 mg, 743.57 μmol), and Pd(PPh3)4 (34.37 mg, 29.74 μmol) in dioxane (15 mL) and water (3 mL) was purged three times with nitrogen and heated to 100 °C under nitrogen protection, stirred for 1 hour. The reaction solution was filtered through diatomaceous earth, and the filter cake was washed with 100 mL of ethyl acetate. The filtrates were combined and concentrated to obtain the crude product. The crude product was purified by preparative thin-layer chromatography using silica gel plates (dichloromethane:methanol = 5:1) to obtain compound 8-2. MS (ESI) m / z: 696.4 [M+H] + .

[0182] Step C: A 10 mL solution of compound 8-2 (80 mg, 114.93 μmol) and compound 1-15 (26.24 mg, 229.85 μmol) in dichloromethane was stirred at 25 °C for 0.5 h, and NaBH(OAc)3 (121.79 mg, 574.63 μmol) was added. After stirring the reaction system at 25 °C for 1 hour, 10 mL of water was added for dilution, followed by extraction with dichloromethane (20 mL × 5). The organic phase was washed with saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: Phenomenex Synergi C18 150*25 mm*10 μm; mobile phase: [pure water (0.225% formic acid)-acetonitrile]; acetonitrile %: 9%-39%, 10 min) to obtain the formate of compound 8. 1H NMR (400MHz, DMSO-d6) δ=8.92(d,J=2.0Hz,1H),8.66(d,J=8.0Hz,1H),8.20(s,1H),8.16(d,J=1.6Hz,1H),7.97(d,J=7.6 Hz,1H),7.74(dd,J=1.6,7.6Hz,1H),7.70(s,1H),7.58(t,J=7.6Hz,1H),7.53-7.46(m,2H),7.42(t,J=7.6Hz,1H),7.12-6 .76(m,2H),5.28(s,2H),5.01(t,J=8.0Hz,2H),3.92-3.82(m,2H),3.77(s,2H),3.69-3.62(m,1H),3.09(t,J=8.0Hz,2H) ,3.01-2.94(m,1H),2.80-2.70(m,2H),2.63-2.56(m,4H),2.21-1.93(m,5H),1.80-1.62(m,1H); MS(ESI)m / z:794.1[M+H] + .

[0183] Example 9: Compound 9

[0184]

[0185] Step A: A 10 mL solution of compounds 1-5 (0.5 g, 1.34 mmol) and 1-15 (305.50 mg, 1.34 mmol) in dichloromethane was stirred at 25 °C for 0.5 h, and NaBH(OAc)3 (1.42 g, 6.69 mmol) was added. The reaction mixture was stirred at 25 °C for 2 hours, diluted with 20 mL of water, and then extracted with dichloromethane (30 mL × 5). The organic phase was washed with saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude compound 9-1. MS (ESI) m / z: 472.4 [M+H] + .

[0186] Step B: Di-tert-butyl dicarbonate (138.78 mg, 635.89 μmol) and triethylamine (85.79 mg, 847.85 μmol) were added to 5 mL of dichloromethane solution of compound 9-1 (200 mg, 423.92 μmol). The reaction system was stirred at 25 °C for 2 hours, then diluted with 10 mL of water, and extracted with dichloromethane (20 mL × 3). The organic phase was washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by thin-layer chromatography (ethyl acetate) to obtain compound 9-2. MS (ESI) m / z: 572.2 [M + H] + .

[0187] Step C: A mixed solution of compound 9-2 (230 mg, 402.17 μmol), compound 3-8 (162.96 mg, 402.17 μmol), sodium carbonate (106.56 mg, 1.01 mmol), and Pd(PPh3)4 (46.47 mg, 40.22 μmol) in dioxane (5 mL) and water (1 mL) was purged three times with nitrogen and heated to 100 °C under nitrogen protection, stirred for 1 hour. The reaction solution was diluted with 20 mL of water, filtered through diatomaceous earth, and then extracted with ethyl acetate (40 mL × 3). The organic phase was washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by preparative thin-layer chromatography using silica gel plates (ethyl acetate) to obtain compound 9-3. MS (ESI) m / z: 770.5 [M+H] + .

[0188] Step D: Add NaBH(OAc)3 (41.28 mg, 194.75 μmol) to a dichloromethane (2 mL) solution of compound 9-3 (30 mg, 38.95 μmol) and compound 5-7 (8.97 mg, 77.90 μmol). Stir the reaction mixture at 25 °C for 1 hour, dilute with 50 mL of water, and extract with dichloromethane (50 mL × 2). Wash the organic phase with saturated brine (100 mL), dry with anhydrous sodium sulfate, filter, and concentrate to obtain crude product 9-4. The crude product is used directly in the next step. MS (ESI) m / z: 869.3 [M+H] + .

[0189] Step E: Trifluoroacetic acid (196.74 mg, 1.73 mmol) was added to a solution of compound 9-4 (30 mg, 34.51 μmol) in dichloromethane (2 mL). The reaction mixture was stirred at 25 °C for 1 hour and concentrated to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [pure water (0.225% formic acid)-acetonitrile]; acetonitrile %: 10%-40%, 10 min) to obtain compound 9. 1 H NMR (400MHz, DMSO-d6) δ = 8.92 (d, J = 2.0Hz, 1H), 8.65 (d, J = 8.0Hz, 1H), 8.17 (s, 1H), 7.88 (br s,1H),7.69-7.63(m,2H),7.56(t,J=7.6Hz,1H),7.51-7.46(m,1H),7.42(t,J=8.0Hz,1H),7.34(br d,J=8.0Hz,1H),7.11-6.79(m,2H),5.01(br t,J=8.0Hz,2H),3.96(s,3H),3.91-3.86(m,2H),3.08(br t,J=8.0Hz,2H),3.03-2.90(m,2H),2.81-2.73(m,2H),2.64-2.56(m,2H),2.24-2.07(m,4H),2.06-1.92(m,4H),1.24(br s,4H); MS(ESI)m / z:769.2[M+H] + .

[0190] Example 10: Compound 10

[0191]

[0192] Step A: A mixed solution of compound 4-1 (1 g, 1.91 mmol), compound 2-6 (758.01 mg, 1.91 mmol), sodium carbonate (607.53 mg, 5.73 mmol), and Pd(dppf)Cl2 (156.03 mg, 191.07 μmol) in tetrahydrofuran (32 mL) and water (8 mL) was purged three times with nitrogen and heated to 50 °C under nitrogen protection, stirred for 12 hours. The reaction solution was diluted with 20 mL of water, extracted with ethyl acetate (50 mL × 3), the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane = 0%–8%, v / v) to obtain compound 10-3. MS (ESI) m / z: 644.0 [M+H] + .

[0193] Step B: Compound 10-3 (40 mg, 62.11 μmol) and compound 5-7 (21.45 mg, 186.33 μmol) and A molecular sieve (40 mg) was added to a 5 mL solution of dichloromethane and stirred for 0.5 hours. NaBH(OAc)3 (65.81 mg, 310.55 μmol) was then added. The reaction system was stirred at 15 °C for 1.5 hours, then 2 mL of water was added. The mixture was filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [pure water (0.225% formic acid)-acetonitrile]; acetonitrile %: 10%-40%, 10 min) to obtain the formate salt of compound 10. 1 H NMR (400MHz, CD3OD) δ=8.96(d,J=2.0Hz,1H),8.77(d,J=8.0Hz,1H),8.53(s,1H),8.40(brs,1H),8.24(d,J=1.6Hz,1H),7.70 (dd,J=1.6,7.6Hz,1H),7.56(t,J=7.6Hz,1H),7.51-7.46(m,1H),7.40(t,J=8.0Hz,1H),7.08(d,J=7.6Hz,1H),6.86-6.53(m, 1H),5.06(brt,J=8.4Hz,2H),4.72-4.62(m,2H),4.52-4.43(m,1H),4.25-4.14(m,2H),4.12(s,3H),3.77(dd,J=6.0,11.2Hz, 1H),3.68-3.47(m,3H),3.26-3.02(m,5H),2.99-2.84(m,2H),2.48-2.19(m,3H),1.97-1.82(m,1H); MS(ESI)m / z:743.3[M+H] + .

[0194] Example 11: Compound 11

[0195]

[0196] Step A: Compound 10-3 (40 mg, 62.11 μmol) and Compound 11-1 (24.07 mg, 186.33 μmol) and A 5 mL solution of molecular sieve (40 mg) in dichloromethane was stirred for 0.5 hours, and then NaBH(OAc)3 (65.81 mg, 310.55 μmol) was added. The reaction system was stirred at 15 °C for 1.5 hours, and then 2 mL of water was added. The mixture was filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by preparative high performance liquid chromatography (HPLC) (column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [pure water (0.225% formic acid)-acetonitrile]; acetonitrile %: 11%-41%, 10 min) to obtain compound 11. 1 H NMR (400MHz, CD3OD) δ = 8.97 (d, J = 2.0Hz, 1H), 8.78 (d, J = 8.0Hz, 1H), 8.52 (s, 1H), 8.24 (d, J = 2.0Hz, 1H), 7.70 (dd, J = 1.6, 7. 6Hz,1H),7.57(t,J=7.6Hz,1H),7.52-7.46(m,1H),7.41(t,J=8.0Hz,1H),7.08(d,J=7.2Hz,1H),6.89-6.51(m,1H),5.08(br t,J=8.4Hz,2H),4.73-4.62(m,2H),4.50-4.42(m,1H),4.21-4.08(m,5H ),3.97(d,J=11.2Hz,1H),3.74-3.63(m,1H),3.62-3.51(m,1H),3.21(br d,J=12.8Hz,1H),3.16-3.02(m,4H),2.92-2.80(m,2H),2.56-2.44(m,1H),2.25(qd,J=7.2,14. 4Hz,1H),2.02(td,J=8.8,13.1Hz,1H),1.92-1.83(m,1H),1.40(s,3H); MS(ESI)m / z:757.2[M+H] + .

[0197] Example 12: Compound 12

[0198]

[0199] Step A: Compound 10-3 (40 mg, 62.11 μmol) and Compound 1-10 (16.23 mg, 186.33 μmol) and A 5 mL solution of molecular sieve (40 mg) in dichloromethane was stirred for 0.5 hours, and then NaBH(OAc)3 (65.81 mg, 310.55 μmol) was added. The reaction system was stirred at 15 °C for 1.5 hours, and then 2 mL of water was added. The mixture was filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [pure water (0.225% formic acid)-acetonitrile]; acetonitrile %: 9%-36%, 9 min) to obtain compound 12. 1 H NMR (400MHz, CD3OD) δ = 8.97-8.88 (m, 1H), 8.77 (br dd,J=5.0,8.1Hz,1H),8.46(d,J=2.4Hz,1H),8.19-8.10(m,1H),7.73-7.65(m,1H),7.60-7.52(m,1H),7.51-7.4 5(m,1H),7.41(dt,J=4.7,7.9Hz,1H),7.08(dd,J=3.1,7.6Hz,1H),6.87-6.54(m,1H),5.15-5.02(m,2H),4.60(br s,1H),4.41(br dd,J=2.9,6.6Hz,2H),4.12-4.02(m,5H),3.98-3.81(m,2H),3.20-2.99(m,4H),2.96-2.76 (m,4H),2.66-2.54(m,2H),2.27-2.11(m,2H),1.88-1.69(m,2H); MS(ESI)m / z:715.1[M+H] + .

[0200] Example 13: Compound 13

[0201]

[0202] Step A: Compound 10-3 (60 mg, 93.16 μmol) and Compound 13-1 (36.66 mg, 279.47 μmol) and 8 mL of dichloromethane solution containing 60 mg of molecular sieve was stirred for 0.5 hours, and NaBH(OAc)3 (98.72 mg, 465.79 μmol) was added. The reaction system was stirred at 15 °C for 1.5 hours, and then 2 mL of water was added. The mixture was filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by preparative high performance liquid chromatography (HPLC) (column: YMC Triart 30*150 mm*7 μm; mobile phase: [pure water (hydrochloric acid)-acetonitrile]; acetonitrile %: 31%-51%, 7 min) to obtain the hydrochloride salt of compound 13. 1H NMR (400MHz, DMSO-d6) δ=12.16-11.44(m,1H),9.54(br d,J=4.4Hz,1H),9.31-9.08(m,2H),8.75-8.56(m,3H),7.74(br d,J=7.6Hz,1H),7.68-7.54(m,2H),7.44(br t,J=7.6Hz,1H),7.14-6.82(m,2H),5.01(brt,J=8.0Hz,2H),4.71(br d,J=14.8Hz,2H),4.51-4.37(m,3H),4.04(s,3H),3.31-3.16(m,4H),3.09(br d,J=4.4Hz,3H),2.86-2.74(m,1H),2.39-2.26(m,1H),2.15-1.82(m,3H),0.93(br dd,J=7.2,9.6Hz,6H); MS(ESI)m / z:759.1[M+H] + .

[0203] Example 14: Compound 14

[0204]

[0205] Step A: Compound 10-3 (100 mg, 155.26 μmol) and Compound 14-1 (54.57 mg, 465.79 μmol) and 8 mL of dichloromethane solution containing 100 mg of molecular sieve was stirred for 0.5 hours, and NaBH(OAc)3 (164.53 mg, 776.31 μmol) was added. The reaction system was stirred at 15 °C for 1.5 hours, and then 2 mL of water was added. The mixture was filtered, and the filtrate was concentrated to obtain the crude product. Compound 14 was purified by preparative high performance liquid chromatography (column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [pure water (0.225% formic acid)-acetonitrile]; acetonitrile %: 15%-35%, 10 min). 1H NMR (400MHz, CD3OD) δ = 8.90 (d, J = 1.6Hz, 1H), 8.70 (br d,J=8.4Hz,1H),8.47-8.38(m,1H),8.19(d,J=1.2Hz,1H),7.64(dd,J=1.2,7.6Hz,1H),7.50(t,J=7.6Hz,1H),7.41(dd,J=1.2,7.6Hz,1H),7.34(br t,J=8.0Hz,1H),7.02(d,J=7.6Hz,1H),6.80-6.49(m,1H),4.51-4.39(m,3H),4.24-4.1 2(m,2H),4.08(s,3H),3.22-3.10(m,4H),3.05-2.86(m,4H),2.31-2.17(m,1H),1.90(br dd,J=5.6,7.6Hz,1H),1.28(s,6H); MS(ESI)m / z:745.1[M+H] + .

[0206] Example 15: Compound 15

[0207]

[0208] Step A: A solution of compound 10-3 (50.00 mg, 77.63 μmol), compound 15-1 (20.05 mg, 155.26 μmol), and molecular sieve (0.05 g) in dichloromethane (10 mL) was stirred at 25 °C for 0.5 h. NaBH(OAc)3 (49.36 mg, 232.89 μmol) was then added. The reaction mixture was stirred at 25 °C for 1 h, diluted with 20 mL of water, and extracted with dichloromethane (30 mL × 3). The organic phase was washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: Phenomenex Synergi C18 150*25 mm*10 μm; mobile phase: [pure water (formic acid)-acetonitrile]; acetonitrile %: 16%-36%, 10 min) to obtain compound 15. 1H NMR (400MHz, CD3OD) δ=8.96(s,1H),8.77(d,J=7.6Hz,1H),8.50(s,1H),8.23(s,1H),7.70(d,J=7.2Hz,1H),7.56(t ,J=7.2Hz,1H),7.52-7.45(m,1H),7.41(t,J=7.6Hz,1H),7.08(d,J=7.6Hz,1H),6.90-6.52(m,1H),5.05(s,3H),4.5 9-4.42(m,2H),4.15-4.10(m,4H),3.94-3.77(m,2H),3.27-3.19(m,1H),3.17-3.03(m,4H),2.95-2.77(m,3H),2.67 -2.55(m,1H),2.46-2.34(m,1H),2.31-2.08(m,3H),2.02-1.83(m,2H),1.41-1.28(m,1H); MS(ESI)m / z:757.0[M+H] + .

[0209] Example 16: Compound 16

[0210]

[0211]

[0212] Step A: A solution of compound 3-10 (60 mg, 93.30 μmol) and compound 11-1 (24.10 mg, 186.60 μmol) in dichloromethane (5 mL) was stirred at 25 °C for 0.5 h, and NaBH(OAc)3 (98.87 mg, 466.50 μmol) was added. The reaction mixture was stirred at 25 °C for 1 h, diluted with 10 mL of water, and extracted with dichloromethane (20 mL × 3). The organic phase was washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: Waters Xbridge 150*25 mm*5 μm; mobile phase: [pure water (ammonium bicarbonate)-acetonitrile]; acetonitrile %: 35%-65%, 9 min) to obtain compound 16. 1H NMR (400MHz, DMSO-d6) δ=8.92(d,J=2.0Hz,1H),8.65(d,J=8.0Hz,1H),8.17(d,J=1.6Hz,1H),7.79(d,J=7.6Hz,1H),7.67(dd,J=1.6 ,7.6Hz,1H),7.55(t,J=7.6Hz,1H),7.47(d,J=1.6Hz,1H),7.42(t,J=8.0Hz,1H),7.30(d,J=7.6Hz,1H),7.11-6.78(m,2H),5.00(br t,J=8.4Hz,2H),4.28-4.17(m,1H),3.99-3.79(m,6H),3.63(br d,J=4.0Hz,2H),3.12-2.97(m,4H),2.80-2.62(m,4H),2.46-2.24(m,4H),2.04( dd,J=6.8,13.2Hz,1H),1.65-1.53(m,2H),1.28(s,3H); MS(ESI)m / z:756.2[M+H] + .

[0213] Example 17: Compound 17

[0214]

[0215] Step A: A 10 mL solution of compound 7-5 (0.1 g, 149.68 μmol) and compound 5-7 (34.47 mg, 299.36 μmol) in dichloromethane was stirred at 25 °C for 0.5 h, and NaBH(OAc)3 (158.62 mg, 748.40 μmol) was added. After stirring the reaction system at 25 °C for 12 hours, 10 mL of water was added for dilution, followed by extraction with dichloromethane (20 mL × 5). The organic phase was washed with saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: Phenomenex Synergi C18 150*25 mm*10 μm; mobile phase: [pure water (0.225% formic acid)-acetonitrile]; acetonitrile %: 10%-40%, 10 min) to obtain the formate salt of compound 17. 1H NMR (400MHz, DMSO-d6) δ = 8.92 (d, J = 1.6Hz, 1H), 8.66 (d, J = 8.4Hz, 1H), 8.28-8.19 (m, 1H), 8.16 (d, J = 1.6Hz, 1H), 7.9 1(d,J=7.6Hz,1H),7.75(dd,J=1.6,7.6Hz,1H),7.58(t,J=7.6Hz,1H),7.53-7.46(m,2H),7.42(t,J=8.0Hz,1H),7.1 2-6.78(m,2H),5.28(s,2H),5.01(t,J=8.0Hz,2H),4.26-4.21(m,1H),3.96-3.78(m,3H),3.70-3.60(m,3H),3.09(t ,J=8.0Hz,2H),2.99-2.90(m,1H),2.81-2.56(m,6H),2.10-1.93(m,3H),1.68-1.51(m,1H); MS(ESI)m / z:767.1[M+H] + .

[0216] Example 18: Compound 18

[0217]

[0218] Step A: Add to a 20 mL solution of dichloromethane containing compound 3-8 (150 mg, 370.19 μmol) and compound 18-1 (74.89 mg, 740.38 μmol) Molecular sieve (150 mg) was stirred at 25 °C for 30 minutes, and NaBH(OAc)3 (235.38 mg, 1.11 mmol) was added. The reaction mixture was stirred at 25 °C for 1 hour, filtered through diatomaceous earth, and 20 mL of water was added. Extraction was then performed with dichloromethane (40 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 18-2. MS (ESI) m / z: 491.9 [M+H] + .

[0219] Step B: Compound 18-2 (0.17 g, 346.70 μmol), dibenzoyl borate (132.06 mg, 520.04 μmol), potassium acetate (85.06 mg, 866.74 μmol), and Pd(dppf)Cl2·CH2Cl2 (28.31 mg, 34.67 μmol) were added to 10 mL of dioxane solution. The reaction system was purged with nitrogen three times and reacted at 100 °C under nitrogen protection for 1 hour. After cooling the reaction solution to room temperature, it was filtered through diatomaceous earth. The filter cake was washed with dichloromethane (100 mL), and the combined organic phases were concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol:dichloromethane = 0–10%, v / v) to obtain compound 18-3. MS (ESI) m / z: 538.2 [M+H] + .

[0220] Step C: Compound 18-3 (65 mg, 120.95 μmol), compound 2-8 (75.56 mg, 127.00 μmol), sodium carbonate (32.05 mg, 302.38 μmol), and Pd(PPh3)4 (13.98 mg, 12.10 μmol) were added to a mixed solution of 5 mL dioxane and 1 mL water. The reaction system was purged with nitrogen three times and reacted at 100 °C under nitrogen protection for 1 hour. After cooling the reaction solution to room temperature, 20 mL of water was added, followed by extraction with dichloromethane (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated by silica gel plate chromatography (dichloromethane:methanol = 10:1, v / v) to obtain compound 18-4. MS (ESI) m / z: 856.2 [M+H] + .

[0221] Step D: Trifluoroacetic acid (1.54 g, 13.51 mmol) was added to a solution of compound 18-4 (0.1 g, 116.77 μmol) in dichloromethane (3 mL). The reaction mixture was stirred at 25 °C for 12 hours. The reaction mixture was concentrated to obtain a crude product, which was then purified by preparative high-performance liquid chromatography (HPLC) (column: Phenomenex Synergi C18 150*25 mm*10 μm; mobile phase: [pure water (0.225% formic acid)-acetonitrile]; acetonitrile %: 8%-38%, 10 min) to obtain compound 18. 1H NMR (400MHz, DMSO-d6) δ = 8.94 (d, J = 2.0Hz, 1H), 8.66 (d, J = 8.0Hz, 1H), 8.53 (s, 1H), 8.21 (s, 1H), 8.14 (s, 1H), 7.75-7. 67(m,2H),7.61(t,J=7.6Hz,1H),7.57-7.52(m,1H),7.42(t,J=8.0Hz,1H),7.14-6.79(m,2H),5.00(t,J=8.0Hz,2H),4. 80-4.52(m,1H),4.13(s,2H),4.01(s,3H),3.97-3.92(m,2H),3.79-3.71(m,2H),3.10-3.05(m,2H),2.85(d,J=5.6Hz, 2H),2.73-2.66(m,1H),2.64-2.57(m,2H),2.19-2.07(m,3H),1.85-1.69(m,3H),1.26(s,3H); MS(ESI)m / z:756.2[M+H] + .

[0222] Example 19: Compound 19

[0223]

[0224] Step A: Compound 19-1 (5 g, 26.87 mmol) was dissolved in methanol (30 mL), and hydrochloric acid (12 M, 6.72 mL) and water (15 mL) were added. The mixture was cooled, and at 0 °C, sodium nitrite (2.23 g, 32.25 mmol) dissolved in water (15 mL) was added dropwise to the reaction system. The mixture was stirred at 0 °C for 0.5 hours. Then, di-pinalanoic acid borate (20.47 g, 80.62 mmol) dissolved in methanol (30 mL) was added, and the mixture was stirred at 25 °C for 1 hour. The reaction solution was quenched with 50 mL of water, and then 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 concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0 to 0:1) to obtain compound 19-2.

[0225] Step B: Compound 19-2 (5.79 g, 19.50 mmol) and compound 19-3 (3.84 g, 18.57 mmol), sodium carbonate (3.94 g, 37.13 mmol), and Pd(dppf)Cl2·CH2Cl2 (1.52 g, 1.86 mmol) were added to 50 mL of dioxane and 10 mL of water. The reaction system was purged with nitrogen three times and reacted at 50 °C under nitrogen protection for 12 hours. After cooling the reaction solution to room temperature, 30 mL of water was added, and the mixture was filtered through diatomaceous earth. Then, it was extracted with ethyl acetate (80 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0~0:1, v / v) to obtain compound 19-4. MS (ESI) m / z: 342.9 [M+H + ].

[0226] Step C: Compound 19-4 (3.99 g, 11.69 mmol) and sodium methoxide (4.21 g, 23.38 mmol, 4.68 mL, 30% purity) were added to 40 mL of methanol. The mixture was stirred at 50 °C for 12 hours. Then 8 mL of water was added, and the mixture was stirred at 50 °C for 2 hours. After the reaction solution was cooled to room temperature, 30 mL of water was added, and the pH was adjusted to 5 with 12 M HCl. The mixture was filtered, and the filter cake was evaporated to obtain compound 19-5. MS (ESI) m / z: 322.7 [M+H + ].

[0227] Step D: Compound 19-5 (2 g, 6.19 mmol) and concentrated sulfuric acid (60.70 mg, 618.92 μmol) were added to 20 mL of methanol, and the mixture was stirred at 80 °C for 12 hours. The reaction mixture was evaporated to dryness to obtain the crude product, which was then separated by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0–0:1, v / v) to obtain compound 19-6. MS (ESI) m / z: 338.9 [M+H] + ]

[0228] Step E: Compound 19-6 (1.39 g, 4.12 mmol) was added to 25 mL of tetrahydrofuran, and diisobutylaluminum hydride (1 M, 10.31 mL) was added dropwise at -78 °C. The mixture was stirred at 0 °C for 1 hour. After the reaction solution was brought to room temperature, 50 mL of water was added, and then extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0 to 0:1, v / v) to obtain compound 19-7.

[0229] Step F: Compound 19-7 (1.33 g, 4.30 mmol) and triethylamine (870.64 mg, 8.60 mmol, 1.20 mL) were added to 25 mL of dichloromethane. The mixture was cooled, and methanesulfonyl chloride (1.59 g, 13.88 mmol, 1.07 mL) was added at 0 °C. The mixture was stirred at 0 °C for 1 hour. After the reaction solution reached room temperature, 40 mL of water was added, followed by extraction with dichloromethane (40 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0–0:1, v / v) to obtain compound 19-8. MS (ESI) m / z: 388.8 [M+H] + .

[0230] Step G: Compound 19-8 (0.2 g, 516.46 μmol), compound 19-9 (89.81 mg, 542.29 μmol), and triethylamine (209.04 mg, 2.07 mmol) were added to 25 mL of N,N-dimethylformamide. The mixture was stirred at 25 °C for 12 hours. 20 mL of water was added to the reaction mixture, followed by extraction with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by preparative thin-layer chromatography using silica gel plates (petroleum ether: ethyl acetate = 1:1) to obtain compound 19-10. MS (ESI) m / z: 422.0 [M+H] + .

[0231] Step H: Compound 19-10 (52.20 mg, 124.19 μmol), compound 4-1 (65 mg, 124.19 μmol), sodium carbonate (32.91 mg, 310.48 μmol), and Pd(PPh3)4 (14.35 mg, 12.42 μmol) in a dioxane (5 mL) and water (1 mL) solution were heated to 100 °C and stirred for 1 hour under nitrogen protection. The reaction solution was diluted with 20 mL of water, filtered through diatomaceous earth, and then extracted with dichloromethane (20 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by preparative thin-layer chromatography using silica gel plates (dichloromethane:methanol = 10:1) to obtain compound 19-11. MS (ESI) m / z: 643.5 [M+H] + MS(ESI) m / z: 737.1 [M+H] + .

[0232] Step I: Lithium hydroxide monohydrate (5.70 mg, 135.72 μmol) was added to a solution of compound 19-11 (0.05 g, 67.86 μmol) in methanol (5 mL) and water (1 mL). The reaction mixture was stirred at 50 °C for 1 hour. After cooling to room temperature, the mixture was concentrated. Then, it was dissolved in 10 mL of water, and the pH was adjusted to 5 using concentrated hydrochloric acid. The solution was then concentrated to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: Phenomenex Synergi C18 150*25 mm*10 μm; mobile phase: [water (formic acid)-acetonitrile]; acetonitrile %: 11%-41%, 10 min) to obtain compound 19. 1 H NMR (400MHz, DMSO-d6) δ = 8.92 (d, J = 2.0Hz, 1H), 8.65 (d, J = 8.0Hz, 1H), 8.36 (s, 1H), 8.16 (d, J = 2.0Hz, 1H), 7.5 3(dd,J=1.2,7.6Hz,1H),7.42(q,J=7.6Hz,2H),7.33(dd,J=1.2,7.6Hz,1H),7.09-6.78(m,2H),5.00(t,J=8.4H z,2H),4.30-4.15(m,1H),3.96(s,3H),3.91-3.76(m,4H),3.12-3.03(m,2H),2.97-2.86(m,3H),2.77-2.57(m ,6H),2.41(dd,J=3.2,9.6Hz,1H),2.16(s,3H),2.10-1.98(m,2H),1.63-1.55(m,1H); MS(ESI)m / z:723.1[M+H] + .

[0233] Example 20: Compound 20

[0234]

[0235]

[0236] Step A: Compound 19-8 (135 mg, 348.61 μmol), compound 20-1 (65.76 mg, 366.04 μmol), and triethylamine (141.10 mg, 1.39 mmol) were added to 2 mL of N,N-dimethylformamide solution. The mixture was reacted at 25 °C for 4 hours. After cooling the reaction solution to room temperature, 20 mL of water was added, followed by extraction with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by thin-layer chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound 20-2. MS (ESI) m / z: 435.9 [M+H] + .

[0237] Step B: A mixed solution of compound 20-2 (9.79 mg, 114.64 μmol), compound 4-1 (60 mg, 114.64 μmol), sodium carbonate (30.38 mg, 286.60 μmol), and Pd(PPh3)4 (13.25 mg, 11.46 μmol) in dioxane (5 mL) and water (1 mL) was purged three times with nitrogen. The mixture was heated to 100 °C under nitrogen protection and stirred for 1 hour. After cooling to room temperature, 20 mL of the solution was added, followed by extraction with dichloromethane (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to obtain compound 20-3. MS (ESI) m / z: 751.2 [M+H] + .

[0238] Step C: Lithium hydroxide monohydrate (7.82 mg, 186.46 μmol) was added to a solution of compound 20-3 (0.07 g, 93.23 μmol) in methanol (2 mL) and water (0.4 mL). The reaction mixture was stirred at 50 °C for 1 hour. After cooling to room temperature, the mixture was concentrated. Then, it was dissolved in 10 mL of water, and the pH was adjusted to 5 using 12 M HCl. The solution was then concentrated to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [water (formic acid)-acetonitrile]; acetonitrile %: 13%-43%, 10 min) to obtain compound 20. 1H NMR (400MHz, DMSO-d6) δ=8.91(d,J=1.6Hz,1H),8.65(d,J=8.4Hz,1H),8.37(s,1H),8.16(s,1H),7.54(d,J= 7.6Hz,1H),7.41(q,J=7.6Hz,2H),7.33(d,J=7.6Hz,1H),7.10-6.76(m,2H),5.00(t,J=7.6Hz,2H),4.30-4.1 6(m,1H),3.96(s,3H),3.92-3.78(m,4H),3.09-2.92(m,3H),2.77-2.65(m,4H),2.41(dd,J=3.2,9.6Hz,1H), 2.28-2.20(m,1H),2.16(s,3H),2.09-1.96(m,2H),1.64-1.46(m,2H),1.24(s,4H); MS(ESI)m / z:737.1[M+H] + .

[0239] Example 21: Compound 21

[0240]

[0241]

[0242] Step A: Compounds 3-8 (0.6 g, 1.48 mmol), compound 21-1 (365.99 mg, 2.96 mmol), acetic acid (444.61 mg, 7.40 mmol), and... A 15 mL solution of molecular sieve (0.6 g) in dichloromethane was stirred at 25 °C for 0.5 h, and NaBH(OAc)3 (941.50 mg, 4.44 mmol) was added. The reaction system was stirred at 25 °C for 12 hours, then filtered through diatomaceous earth. The filtrate was diluted with 20 mL of water, then extracted with dichloromethane (30 mL × 3). The organic phase was washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 1:0–4:1, v / v) to obtain compound 21-2. MS (ESI) m / z: 477.9 [M+H] + .

[0243] Step B: A 15 mL solution of compound 21-2 (559.78 mg, 2.20 mmol), bis-pinacol borate (0.7 g, 1.47 mmol), potassium acetate (360.57 mg, 3.67 mmol), and Pd(dppf)Cl2·CH2Cl2 (120.01 mg, 149.96 μmol) in dioxane was purged three times with nitrogen and heated to 100 °C under nitrogen protection, stirred for 1 hour. The reaction solution was filtered through diatomaceous earth, the filter cake was washed with 100 mL of dichloromethane, and the filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 1:0–4:1, v / v) to obtain compound 21-3. MS (ESI) m / z: 524.3 [M+H] + .

[0244] Step C: A mixed solution of compound 21-3 (200 mg, 382.13 μmol), compound 20-2 (165.97 mg, 382.13 μmol), sodium carbonate (101.26 mg, 955.33 μmol), and Pd(PPh3)4 (44.16 mg, 38.21 μmol) in dioxane (5 mL) and water (1 mL) was purged three times with nitrogen and heated to 100 °C under nitrogen protection, stirred for 1 hour. The reaction solution was diluted with 20 mL of water and extracted with dichloromethane (40 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by preparative thin-layer chromatography using silica gel plates (dichloromethane:methanol = 10:1) to obtain compound 21-4. MS (ESI) m / z: 751.0 [M+H] + .

[0245] Step D: Lithium hydroxide monohydrate (13.41 mg, 319.64 μmol) was added to a mixed solution of compound 21-4 (120 mg, 159.82 μmol) in methanol (5 mL) and water (1 mL). The reaction system was stirred at 50 °C for 0.5 hours and then concentrated. 10 mL of water was added for dilution, and the pH was adjusted to 5 with concentrated hydrochloric acid. The solution was then concentrated to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: Phenomenex luna C18 150*40 mm*15 μm; mobile phase: [pure water (0.225% formic acid)-acetonitrile]; acetonitrile %: 13%-43%, 10 min) to obtain the formate salt of compound 21. 1H NMR (400MHz, CD3OD) δ=8.90(s,1H),8.75(d,J=8.4Hz,1H),8.38(d,J=1.6Hz,2H),8.18(d,J=1.2Hz,1H),7.51(d,J=7.6Hz,1H),7 .41(q,J=7.6Hz,2H),7.34(d,J=7.2Hz,1H),7.04(d,J=7.6Hz,1H),6.88-6.53(m,1H),5.13-5.02(m,2H),4.67(d,J=1.6Hz,2H), 4.14(s,2H),4.10(s,3H),3.98(d,J=11.2Hz,1H),3.76-3.53(m,4H),3.45(d,J=8.0Hz,2H),3.23(d,J=11.2Hz,1H),3.18-3.04( m,1H),3.03-2.85(m,1H),2.57-2.42(m,1H),2.21(s,3H),2.06-1.99(m,1H),1.53(s,3H),1.41(s,3H); MS(ESI)m / z:737.0[M+H] + .

[0246] Example 22: Compound 22

[0247]

[0248] Step A: Compound 3-8 (0.5 g, 1.23 mmol), dibenzoyl borate (470.03 mg, 1.85 mmol), potassium acetate (363.31 mg, 3.70 mmol), and Pd(dppf)Cl2·CH2Cl2 (100.77 mg, 123.40 μmol) were added to 10 mL of dioxane solution. The reaction system was purged with nitrogen three times and reacted at 100 °C under nitrogen protection for 2 hours. After cooling the reaction solution to room temperature, 50 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL × 2). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 0–20%, v / v) to obtain compound 22-1. MS (ESI) m / z: 453.1 [M+H] + .

[0249] Step B: Compound 22-2 (2 g, 17.08 mmol) was dissolved in tetrahydrofuran (20 mL), and triphenylphosphine (4.93 g, 18.79 mmol) and DIAD (3.80 g, 18.79 mmol) were added. The mixture was stirred at 25 °C for 6 hours. Petroleum ether (100 mL) was added, the mixture was filtered, and the filter cake was collected and dried under reduced pressure. The mixture was then purified by preparative high-performance liquid chromatography (HPLC) (column: Phenomenexluna C18 (250*70 mm, 10 μm); mobile phase: [pure water (0.1% trifluoroacetic acid)-acetonitrile]; acetonitrile %: 10%-40%, 20 min) to obtain compound 22-3. MS (ESI) m / z: 247.1 [M+H] + .

[0250] Step C: Add hydrazine hydrate (2.54 g, 49.72 mmol) to an ethanol (30 mL) solution of compound 22-3 (2.8 g, 10.94 mmol). Stir the mixture at 50 °C for 0.5 h, then raise the temperature to 75 °C and continue stirring for 2 h. A white solid precipitates, which is filtered. The filtrate is concentrated, and ethanol (50 mL) is added. A white solid precipitates again. Filtering is continued, and the filtrate is concentrated to obtain compound 22-4.

[0251] Step D: To a methanol (10 mL) solution of compound 2-6 (256.24 mg, 645.89 μmol), NaBH(OAc)3 (405.89 mg, 6.46 mmol) and compound 22-4 (150 mg, 1.29 mmol) were added. The mixture was stirred at 25 °C for 5 hours. The reaction was quenched by adding water (10 mL) at 0 °C, extracted with dichloromethane (15 mL × 3), the combined organic phases were washed with saturated brine (15 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 22-5.

[0252] Step E: Add Boc₂O (263.56 mg, 1.21 mmol) and triethylamine (244.40 mg, 2.42 mmol) to a dichloromethane (10 mL) solution of compound 22-5 (400 mg, 805.08 μmol). Stir the mixture at 25 °C for 3 hours. Add saturated sodium bicarbonate (10 mL), extract with dichloromethane (20 mL × 2), combine the organic phases, wash with saturated brine (20 mL × 2), dry to anhydrous sodium sulfate, filter, and concentrate to obtain the crude product. Separate the crude product by silica gel column chromatography (petroleum ether: ethyl acetate = 50:1 to 0:1, v / v) to obtain compound 22-6.

[0253] Step F: Compound 22-1 (318.19 mg, 703.56 μmol), compound 22-6 (350 mg, 586.30 μmol), sodium carbonate (155.36 mg, 1.47 mmol), and Pd(dppf)Cl2·CH2Cl2 (47.88 mg, 58.63 μmol) were added to a mixed solution of 8 mL tetrahydrofuran and 2 mL water. The reaction system was purged with nitrogen three times and reacted at 50 °C under nitrogen protection for 12 hours. After cooling the reaction solution to room temperature, 20 mL of water was added, and the mixture was filtered through diatomaceous earth. The solution was then extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated by silica gel plate chromatography (petroleum ether:ethyl acetate = 2:3, v / v) to obtain compound 22-7. MS (ESI) m / z: 773.0 [M+H] + .

[0254] Step G: Add to a 20 mL solution of dichloromethane containing compound 22-7 (70 mg, 90.53 μmol) and compound 22-8 (37.34 mg, 362.14 μmol) Molecular sieve (100 mg) and acetic acid (543.68 μg, 9.05 μmol) were stirred at 25 °C for 30 minutes. NaBH(OAc)3 (76.75 mg, 362.14 μmol) was then added, and the reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel plate chromatography (methanol:dichloromethane = 1:10, v / v) to obtain compound 22-9. MS (ESI) m / z: 860.2 [M+H] + .

[0255] Step H: Trifluoroacetic acid (1.13 g, 9.90 mmol) was added to a dichloromethane (3 mL) solution of compound 22-9 (11 mg, 12.79 μmol), and the reaction solution was stirred at 25 °C for 20 min. The reaction solution was concentrated to obtain a crude product, which was purified by preparative high performance liquid chromatography (HPLC) (column: Phenomenex luna C18 150*50 mm*10 μm; mobile phase: [pure water (0.225% formic acid)-acetonitrile]; acetonitrile %: 10%-40%, 10 min) to obtain the formate salt of compound 22. 1H NMR (400MHz, CD3OD) δ = 8.85 (d, J = 2.0Hz, 1H), 8.67 (d, J = 8.0Hz, 1H), 8.33 (s, 1H ),8.09(d,J=2.0Hz,1H),7.57(dd,J=2.0,7.6Hz,1H),7.45(t,J=7.6Hz,1H),7.3 7(dd,J=2.0,7.6Hz,1H),7.31(t,J=8.0Hz,1H),6.97(dd,J=0.8,7.6Hz,1H),6. 76-6.45(m,2H),5.00(s,2H),4.42(s,1H),4.12(dd,J=5.6,8.8Hz,1H),4.01(br dd,J=3.2,4.0Hz,2H),3.99-3.97(m,3H),3.96(s,2H),3.94-3.86(m,1H),3.42(s,1H) ),3.12-2.88(m,6H),2.80-2.75(m,2H),2.62-2.57(m,2H); MS(ESI)m / z:760.1[M+H] + .

[0256] Example 23: Compound 23

[0257]

[0258] Step A: Compound 23-1 (3.5 g, 18.81 mmol) was dissolved in methanol (40 mL), and an aqueous solution of HCl (12 M, 4.70 mL) (20 mL) was added. The mixture was stirred at 0 °C, and an aqueous solution of sodium nitrite (1.56 g, 22.57 mmol) (10 mL) was added. The reaction mixture was stirred at 0 °C for 30 min, and a methanol solution of dipinacolborate (14.33 g, 56.44 mmol) (40 mL) was slowly added to the reaction mixture. The reaction mixture was stirred at 20 °C for 1 h, diluted with 100 mL of water, extracted with ethyl acetate (100 mL × 3), washed with saturated brine, dried over sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0 to 100:1) to give compound 23-2.

[0259] Step B: Compound 23-2 (1.5 g, 8.74 mmol), compound 1-3 (2.86 g, 9.62 mmol), Pd(PPh3)4 (1.01 g, 874.22 μmol), and potassium carbonate (2.42 g, 17.48 mmol) were mixed in a solution of dioxane (30 mL) and water (6 mL), purged with nitrogen, heated to 90 °C, and stirred for 10 hours. The reaction mixture was diluted with dichloromethane (50 mL), filtered through diatomaceous earth, and the filtrate was evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1–5:1, v / v) to give compound 23-3. MS (ESI) m / z: 308.0 [M+H + ].

[0260] Step C: A solution of compound 23-3 (1.4 g, 4.57 mmol), bis-pinacol borate (2.32 g, 9.15 mmol), dichloromethane, bis(triphenylphosphine)palladium dichloride (373.44 mg, 457 μmol), and potassium acetate (897 mg, 9.15 mmol) in dioxane was purged with nitrogen and heated to 85 °C under nitrogen protection with stirring for 5 hours. The reaction mixture was diluted with dichloromethane (50 mL), filtered through diatomaceous earth, and the filtrate was evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100:1–10:1, v / v) to give compound 23-4. MS (ESI) m / z: 354.3 [M+H] + ].

[0261] Step D: Compound 3-9 (750 mg, 1.57 mmol), compound 23-4 (556.17 mg, 1.57 mmol), sodium carbonate (417.22 mg, 3.94 mmol), and Pd(dppf)Cl2·CH2Cl2 (128.59 mg, 157.46 μmol) were added to a mixed solution of 32 mL dioxane and 8 mL water. The reaction system was purged with nitrogen three times and reacted at 100 °C under nitrogen protection for 2 hours. After cooling the reaction solution to room temperature, it was concentrated under vacuum, and after adding 30 mL of water, it was extracted with dichloromethane (30 mL × 2). The organic phases were combined and concentrated to obtain the crude product. The crude product was separated by silica gel column chromatography (methanol:dichloromethane = 0–6%, v / v) to obtain compound 23-5. MS (ESI) m / z: 623.1 [M+H] + .

[0262] Step E: Add to a 10 mL solution of dichloromethane containing compound 23-5 (100 mg, 160.60 μmol) and compound 23-6 (82.97 mg, 642.40 μmol). Molecular sieve (20 mg) was added, and the reaction solution was stirred at 25°C for 30 minutes. NaBH(OAc)3 (136.15 mg, 642.40 μmol) was then added, and the reaction solution was stirred at 25°C for 12 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: Waters Xbridge 150*25mm*5μm; mobile phase: [pure water (sodium bicarbonate)-acetonitrile]; acetonitrile %: 40%-70%, 7 minutes) to obtain compound 23. 1 H NMR (400MHz, CD3OD) δ = 9.03 (d, J = 2.0Hz, 1H), 8.78 (d, J = 8.0Hz, 1H), 8.36 (d, J = 2.0Hz, 1H), 7.93 (d, J =7.6Hz,1H),7.49-7.35(m,3H),7.33-7.20(m,2H),7.06(d,J=7.6Hz,1H),6.91-6.58(m,1H),5.10(br t,J=8.4Hz,2H),4.62-4.53(m,3H),4.48(s,2H),4.10(s,3H),3.85(br d,J=10.8Hz,1H),3.58-3.46(m,3H),3.41-3.35(m,2H),3.23(br d,J=12.0Hz,1H),3.18-3.08(m,2H),3.05-2.93(m,1H),2.56-2.44(m,1H),2.40-2 .27(m,1H),2.19(s,3H),2.11-1.99(m,2H),1.42(s,3H); MS(ESI)m / z:736.2[M+H] + .

[0263] Example 24: Compound 24

[0264]

[0265] Step A: Add to a 10 mL solution of dichloromethane containing compound 23-5 (100 mg, 160.60 μmol) and compound 24-1 (82.97 mg, 642.40 μmol) Molecular sieve (20 mg) was added, and the reaction solution was stirred at 25°C for 30 minutes. NaBH(OAc)3 (136.15 mg, 642.40 μmol) was then added, and the reaction solution was stirred at 25°C for 12 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: Waters Xbridge 150*25mm*5μm; mobile phase: [pure water (sodium bicarbonate)-acetonitrile]; acetonitrile %: 40%-70%, 7 minutes) to obtain compound 24. 1 H NMR (400MHz, CD3OD) δ = 8.95 (d, J = 2.0Hz, 1H), 8.75 (d, J = 8.0Hz, 1H), 8.17 (d, J = 2.0Hz, 1H), 7.91 (d, J = 7.6Hz, 1H), 7.51-7.4 4(m,1H),7.39(q,J=7.6Hz,2H),7.32-7.27(m,1H),7.22(d,J=7.6Hz,1H),7.04(d,J=7.2Hz,1H),6.90-6.52(m,1H),5.10(br t,J=8.0Hz,2H),4.70-4.50(m,3H),4.46-4.35(m,3H),4.10(s,3H),3.80-3.67(m,1H),3.59-3. 46(m,1H),3.19-3.06(m,1H),3.04-2.93(m,2H),2.93-2.82(m,2H),2.68-2.58(m,2H),2.42(br dd,J=4.4,7.6Hz,1H),2.25-2.14(m,4H),2.05(s,3H),2.02-1.92(m,1H),1.85-1.71(m,1H); MS(ESI)m / z:736.3 [M+H] + .

[0266] Example 25: Compound 25

[0267]

[0268] Step A: Compound 10-3 (40 mg, 62.11 μmol) and Compound 25-1 (27.05 mg, 186.33 μmol) and A molecular sieve (40 mg) was added to a 5 mL solution of dichloromethane and stirred for 0.5 hours. NaBH(OAc)3 (65.81 mg, 310.55 μmol) was then added. The reaction system was stirred at 15 °C for 1.5 hours, then 2 mL of water was added. The mixture was filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [pure water (0.225% formic acid)-acetonitrile]; acetonitrile %: 14%-44%, 10 min) to obtain compound 25. 1 H NMR (400MHz, CD3OD) δ = 9.00 (d, J = 2.0Hz, 1H), 8.84-8.74 (m, 1H), 8.55-8.46 ( m,1H),8.30(d,J=2.0Hz,1H),7.74-7.66(m,1H),7.62-7.54(m,1H),7.53-7. 47(m,1H),7.47-7.38(m,1H),7.13-7.04(m,1H),6.89-6.57(m,1H),5.15-5. 06(m,2H),4.54-4.44(m,3H),4.38-4.25(m,2H),4.16-4.08(m,3H),3.29(br d,J=6.8Hz,3H),3.22-2.96(m,5H),2.77-2.67(m,1H),2.34-2.23(m,1H),2.00-1.89(m,1 H),1.80-1.69(m,2H),1.43-1.34(m,1H),0.99(t,J=6.4Hz,6H); MS(ESI)m / z:773.1[M+H] + .

[0269] Example 26: Compound 26

[0270]

[0271] Step A: Compound 10-3 (40 mg, 62.11 μmol) and Compound 26-1 (27.05 mg, 186.33 μmol) and A molecular sieve (40 mg) was added to a 5 mL solution of dichloromethane and stirred for 0.5 hours. NaBH(OAc)3 (65.81 mg, 310.55 μmol) was then added. The reaction system was stirred at 15 °C for 1.5 hours, then 2 mL of water was added. The mixture was filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [pure water (0.225% formic acid)-acetonitrile]; acetonitrile %: 14%-44%, 10 min) to obtain compound 26. 1 H NMR (400MHz, CD3OD) δ = 8.94 (d, J = 2.0Hz, 1H), 8.77 (d, J = 8.0Hz, 1H), 8.50 (s, 1H), 8.19 (d, J = 1.6Hz, 1H), 7.69 (dd, J = 1.6, 7. 6Hz,1H),7.56(t,J=7.6Hz,1H),7.51-7.46(m,1H),7.40(t,J=8.0Hz,1H),7.07(d,J=7.6Hz,1H),6.87-6.53(m,1H),5.06(br t,J=8.0Hz,2H),4.48-4.41(m,3H),4.12(s,3H),4.09-3.97(m,2H),3.30-3.20(m,2H),3.17-3.04(m,2H),3.04-2.92(m,2H),2.82 -2.64(m,3H),2.23(qd,J=7.2,14.1Hz,1H),1.88-1.68(m,3H),1.43-1.26(m,1H),0.98(t,J=6.4Hz,6H); MS(ESI)m / z:773.1[M+H] + .

[0272] Example 27: Compound 27

[0273]

[0274] Step H: At 0°C, 20 mL of acetic acid solution containing 9.16 g, 145.30 mmol of nitric acid was added dropwise to 20 mL of acetic acid solution containing 10 g, 53.59 mmol of compound 27-1. The reaction system was stirred at 25°C for 2 hours, then diluted with 50 mL of water, filtered, and the filter cake was washed with 50 mL of water and dried to obtain crude compound 27-2.

[0275] Step I: Add sodium hydrosulfite (13.53 g, 77.72 mmol) to a mixed solution of compound 27-2 (3 g, 12.95 mmol) in 30 mL of methanol and 6 mL of water. Stir the reaction mixture at 70 °C for 12 hours. Filter the mixture, wash the filter cake with 100 mL of methanol, and concentrate the filtrate to obtain the crude product. Purify the crude product by silica gel column chromatography (dichloromethane:methanol = 1:0-4:1, v / v) to obtain compound 27-3. MS (ESI) m / z: 202.1 [M+H] + .

[0276] Step J: A 100 mL ethanol solution of compound 27-3 (4.2 g, 20.83 mmol) and compound 27-4 (3.94 g, 19.79 mmol) was stirred at 25 °C for 1 hour and concentrated. The solution was then dissolved in 100 mL of dichloromethane solution, and dichlorodicyanobenzoquinone (4.49 g, 19.79 mmol) was added. The reaction mixture was stirred at 25 °C for 12 hours, then quenched with 100 mL of saturated sodium sulfite solution and extracted with dichloromethane (80 mL × 3). The combined organic phases were washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: dichloromethane 1:0-0:1, v / v) to obtain compound 27-5. MS (ESI) m / z: 381.7 [M+H] + .

[0277] Step K: At -78°C, a 1 mol / L (40.04 mL) solution of DIBAL-H in toluene was added dropwise to a 120 mL solution of compound 27-5 (7.62 g, 20.02 mmol) in dichloromethane. The reaction mixture was stirred at 25°C for 2 hours, then quenched with 200 mL of saturated potassium sodium tartrate solution, and extracted with dichloromethane (100 mL × 3). The combined organic phases were washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 1:0-4:1, v / v) to obtain compound 27-6. MS (ESI) m / z: 354.0 [M+H] + .

[0278] Step L: A mixed solution of compound 4-1 (2.5 g, 4.78 mmol), compound 27-6 (1.68 g, 4.78 mmol), sodium carbonate (1.27 g, 11.94 mmol), and Pd(PPh3)4 (551.97 mg, 477.66 μmol) in dioxane (15 mL) and water (3 mL) was purged three times with nitrogen and heated to 100 °C under nitrogen protection, stirred for 12 hours. The reaction solution was diluted with 30 mL of water and filtered through diatomaceous earth. The filtrate was extracted with dichloromethane (50 mL × 3), the organic phases were combined and washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 1:0-3:1, v / v) to obtain compound 27-7. MS (ESI) m / z: 669.3 [M+H] + .

[0279] Step M: A mixed solution of compound 27-7 (2.7 g, 4.04 mmol), potassium ferrocyanide (1.70 g, 4.04 mmol), potassium acetate (79.20 mg, 807.03 μmol), and t-BuXPhos-Pd-G3 (320.54 mg, 403.52 μmol) in dioxane (30 mL) and water (30 mL) was purged three times with nitrogen and heated to 100 °C under nitrogen protection, stirred for 3 hours. The reaction solution was diluted with 20 mL of water and filtered through diatomaceous earth. The filtrate was extracted with dichloromethane (50 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 1:0-3:1, v / v) to obtain compound 27-8. MS(ESI) m / z: 660.0 [M+H] + .

[0280] Step N: Manganese dioxide (6.33 g, 72.76 mmol) was added to 40 mL of a dichloromethane solution of compound 27-8 (2.4 g, 3.64 mmol). The reaction mixture was stirred at 50 °C for 12 hours. The reaction solution was filtered through diatomaceous earth, and the filter cake was washed with 500 mL of dichloromethane. The filtrate was concentrated to obtain crude compound 27-9. MS (ESI) m / z: 658.3 [M+H] + .

[0281] Step O: A 30 mL solution of compound 27-9 (2.33 g, 3.54 mmol), compound 5-7 (815.77 mg, 7.09 mmol), and triethylamine (717.00 mg, 7.09 mmol) in dichloromethane was stirred at 45 °C for 1 hour, cooled to room temperature, and then NaBH(OAc)3 (1.5 g, 7.09 mmol) and acetic acid (319.12 mg, 5.31 mmol) were added. The mixture was stirred at 25 °C for 2 hours and then concentrated to obtain the crude product. The crude product was first purified by silica gel column chromatography (dichloromethane:methanol = 1:0-3:1, v / v), and then purified by preparative high performance liquid chromatography (column information: Phenomenex Synergi Max-RP 250*50mm*10μm; mobile phase: [pure water (0.225% formic acid)-acetonitrile]; acetonitrile %: 15%-45%, 20 min) to obtain compound 27. 1 H NMR (400MHz, DMSO-d6) δ = 8.90 (s, 1H), 8.66 (d, J = 8.4Hz, 1H), 8.19-8.07 (m, 3H), 7.8 7(s,1H),7.59-7.53(m,1H),7.53-7.49(m,1H),7.42(t,J=7.6Hz,1H),7.10-6.74(m, 2H),4.97(t,J=8.4Hz,2H),4.23(s,1H),3.94-3.73(m,7H),3.09-2.82(m,4H),2.81-2. 63(m,4H),2.52(s,3H),2.12-1.86(m,3H),1.61-1.58(m,1H); MS(ESI)m / z:757.3[M+H] + .

[0282] Example 28: Compound 28

[0283]

[0284] Step A: A 60 mL ethanol solution of compound 27-3 (3.0 g, 14.88 mmol) and compound 28-1 (3.10 g, 14.14 mmol) was stirred at 25 °C for 1 hour and concentrated. The solution was then dissolved in 60 mL of dichloromethane solution, and dichlorocyanobenzoquinone (3.21 g, 14.14 mmol) was added. The reaction mixture was stirred at 25 °C for 12 hours, then quenched with 30 mL of saturated sodium sulfite solution and extracted with dichloromethane (40 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: dichloromethane 1:0-0:1, v / v) to obtain compound 28-2. MS (ESI) m / z: 401.7 [M+H] + .

[0285] Step B: At -78°C, a 1 mol / L toluene solution of DIBAL-H (7.68 mL) was added dropwise to a 30 mL dichloromethane solution of compound 28-2 (1.4 g, 3.49 mmol). The reaction system was stirred at 25°C for 2 hours, then quenched with 50 mL of saturated potassium sodium tartrate solution, and extracted with dichloromethane (40 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0-0:1, v / v) to obtain compound 28-3. MS (ESI) m / z: 373.7 [M+H] + .

[0286] Step C: A mixed solution of compound 28-3 (570.18 mg, 1.53 mmol), compound 4-1 (0.8 g, 1.53 mmol), sodium carbonate (405.02 mg, 3.82 mmol), and Pd(PPh3)4 (176.63 mg, 152.85 μmol) in dioxane (15 mL) and water (3 mL) was purged three times with nitrogen and heated to 100 °C under nitrogen protection, stirred for 12 hours. The reaction solution was diluted with 20 mL of water and filtered through diatomaceous earth. The filtrate was extracted with dichloromethane (40 mL × 3), and the combined organic phases were washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 1:0-3:1, v / v) to obtain compound 28-4. MS (ESI) m / z: 688.9 [M+H] + .

[0287] Step D: A mixed solution of compound 28-4 (0.78 g, 1.13 mmol), potassium ferrocyanide (477.80 mg, 1.13 mmol), potassium acetate (22.20 mg, 226.24 μmol), and t-BuXPhos-Pd-G3 (89.86 mg, 113.12 μmol) in dioxane (10 mL) and water (10 mL) was purged three times with nitrogen and heated to 100 °C under nitrogen protection, stirred for 3 hours. The reaction solution was diluted with 20 mL of water and filtered through diatomaceous earth. The filtrate was extracted with dichloromethane (40 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 1:0-3:1, v / v) to obtain compound 28-5. MS(ESI) m / z: 679.9 [M+H] + .

[0288] Step E: Manganese dioxide (1.84 g, 21.17 mmol) was added to 30 mL of a dichloromethane solution of compound 28-5 (0.72 g, 1.06 mmol). The reaction mixture was stirred at 50 °C for 12 hours. The reaction solution was filtered through diatomaceous earth, and the filter cake was washed with 400 mL of dichloromethane. The filtrate was concentrated to obtain crude compound 28-6. MS (ESI) m / z: 677.9 [M+H] + .

[0289] Step F: A 15 mL solution of compound 28-6 (0.2 g, 294.95 μmol), compound 5-7 (67.91 mg, 589.90 mmol), and triethylamine (59.69 mg, 589.90 μmol) in dichloromethane was stirred at 45 °C for 1 hour, cooled to room temperature, and then NaBH(OAc)3 (125.02 mg, 589.90 μmol) and acetic acid (26.57 mg, 442.42 μmol) were added. The mixture was stirred at 25 °C for 12 hours and then concentrated to obtain the crude product. The crude product was first purified by preparative thin-layer chromatography using silica gel plates (dichloromethane:methanol = 10:1), and then purified by preparative high-performance liquid chromatography (column information: Phenomenex Synergi C18 150*25mm*10μm; mobile phase: [pure water (0.225% formic acid)-acetonitrile]; acetonitrile %: 16%-36%, 10 min) to obtain compound 28. 1H NMR (400MHz, DMSO-d6) δ = 8.90 (d, J = 1.6Hz, 1H), 8.66 (d, J = 8.4Hz, 1H), 8.19 (t, J = 4.8Hz, 1H), 8.16-8 .12(m,2H),7.92(s,1H),7.71(d,J=4.8Hz,2H),7.43(t,J=8.0Hz,1H),7.12-6.77(m,2H),4.98(t,J=8 .8Hz,2H),4.27-4.16(m,1H),3.90-3.71(m,6H),3.05(t,J=8.0Hz,2H),2.99-2.87(m,1H),2.76-2.6 3(m,4H),2.41(dd,J=3.6,9.6Hz,2H),2.09-1.93(m,3H),1.64-1.51(m,1H); MS(ESI)m / z:777.3[M+H] + .

[0290] Example 29: Compound 29

[0291]

[0292]

[0293] Step A: Compound 29-1 (5 g, 23.09 mmol), iron powder (12.89 g, 230.82 mmol), and a saturated solution of ammonium chloride (5 mL) were added to 100 mL of methanol solution. The reaction mixture was reacted at 75 °C for 2 hours. After cooling to room temperature, the reaction solution was filtered through diatomaceous earth. The filtrate was concentrated, and 20 mL of water was added. The mixture was extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude compound 29-2. MS (ESI) m / z: 186.9 [M + H] + .

[0294] Step B: Add 100 mL of dichloromethane solution to compound 29-3 (16.83 g, 78.24 mmol), add oxaloyl chloride (24.83 g, 195.61 mmol) at 0 °C, then add N,N-dimethylformamide (285.96 mg, 3.91 mmol) at 25 °C and react for 0.5 h under nitrogen protection at 25 °C. Concentrate the reaction solution under vacuum, add 100 mL of dichloromethane solution, then add 100 mL of dichloromethane solution of compound 29-2 (7.3 g, 39.12 mmol) and pyridine (15.47 g, 195.61 mmol) at 0 °C, and react for 0.5 h under nitrogen protection at 25 °C. 200 mL of water was added to the reaction solution, and the mixture was extracted with dichloromethane (200 mL × 2). The combined organic phases were concentrated under vacuum to obtain a crude product. Then, 200 mL of petroleum ether and 50 mL of ethyl acetate were added, and the mixture was stirred at room temperature for 0.5 hours. The mixture was filtered, and the filter cake was dried under vacuum to obtain compound 29-4. MS (ESI) m / z: 384.7 [M + H] + .

[0295] Step C: Sodium carbonate (635.45 mg, 6.00 mmol) was added to a solution of compound 29-4 (2.3 g, 6.00 mmol) in N,N-dimethylformamide (40 mL), and the mixture was stirred at 140 °C for 12 hours. After cooling, 300 mL of ethyl acetate was added, and the mixture was washed with water (200 mL × 2) and brine (100 mL). The solution was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1, v / v) to obtain compound 29-5. MS (ESI) m / z: 348.7 [M+H] + .

[0296] Step D: Under nitrogen protection, a toluene solution of DIBAL-H (1 mol / L, 4.61 mL) was slowly added dropwise to a dichloromethane (30 mL) solution of compound 29-5 (0.8 g, 2.30 mmol). The reaction mixture was stirred at -78 °C for 1 hour. Then, 20 mL of saturated sodium sulfate solution was slowly added to the reaction mixture. After the mixture returned to room temperature, it was stirred for 0.5 hours and then filtered through diatomaceous earth. The filtrate was extracted with dichloromethane (50 mL × 2). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1, v / v) to obtain compound 29-6. MS (ESI) m / z: 319.0 [M+H] + .

[0297] Step E: Compound 4-1 (655.96 mg, 1.25 mmol), Pd(PPh3)4 (144.83 mg, 125.33 μmol), and sodium carbonate (332.09 mg, 3.13 mmol) were added to a solution of compound 29-6 (0.4 g, 1.25 mmol) in dioxane (20 mL) and water (4 mL). The mixture was stirred at 100 °C under nitrogen protection for 4 hours. After cooling, the reaction solution was directly concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 10:1, v / v) to obtain compound 29-7. MS (ESI) m / z: 636.3 [M+H] + .

[0298] Step F: Manganese dioxide (1.64 g, 18.88 mmol) was added to a solution of compound 29-7 (0.6 g, 943.90 μmol) in dichloromethane (20 mL), and the mixture was stirred at 45 °C for 48 hours. After cooling, the reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated to obtain compound 29-8. MS (ESI) m / z: 634.0 [M+H] + .

[0299] Step G: Compound 5-7 (72.68 mg, 631.27 μmol) and triethylamine (70.27 mg, 694.39 μmol) were added to a dichloromethane solution (10 mL) of compound 29-8 (0.2 g, 315.23 μmol). The reaction solution was stirred at 45 °C under nitrogen protection for 1 hour. After the reaction solution was cooled to room temperature, NaBH(OAc)3 (147.17 mg, 694.39 μmol) and acetic acid (30.33 mg, 505.01 μmol) were added. The reaction solution was stirred at 25 °C under nitrogen protection for 12 hours. The reaction solution was concentrated under vacuum to obtain a crude product. The crude compound was purified by silica gel plate (dichloromethane / methanol = 10 / 1, v / v), and then purified by preparative high performance liquid chromatography (column information: Waters Xbridge 150*25mm*5μm; mobile phase: [pure water (ammonia)-acetonitrile]; acetonitrile %: 31%-61%, 9 min) to obtain compound 29. 1H NMR (400MHz, DMSO-d6)δ=12.07-11.56(m,1H),11.53-11.13(m,1H),9.19(br s,1H),8.70(d,J=8.4Hz,1H),8.66-8.58(m,3H),8.21(dd,J=1.6,7.7Hz,1H),7.63 -7.51(m,2H),7.45(t,J=8.0Hz,1H),7.15-6.81(m,2H),5.68-5.38(m,1H),5.00(br t,J=8.8Hz,2H),4.78-4.64(m,2H),4.60(br s,2H),4.45(br s,1H),3.66-3.47(m,4H),3.17(br s,4H),3.10-3.02(m,1H),2.99-2.87(m,1H),2.55(s,3H),2.37-1.80(m,4H); MS(ESI)m / z:733.2[M+H] + .

[0300] Example 30: Compound 30

[0301]

[0302] Step A: Add compound 23-6 (24.46 mg, 189.38 μmol) to a dichloromethane (10 mL) solution of compound 29-8 (60 mg, 94.69 μmol) and... Molecular sieve (20 mg) was added and stirred at 25 °C for 0.5 h. Then, sodium borohydride acetate (60.21 mg, 284.07 μmol) was added and the mixture was stirred at 25 °C for another 1 h. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated to obtain the crude product. The crude compound was purified by silica gel plate (dichloromethane:methanol = 10:1, v / v) to obtain the crude product. The crude product was purified by preparative high performance liquid chromatography (column information: Waters Xbridge 150*25mm*5μm; mobile phase: [pure water (ammonium bicarbonate)-acetonitrile]; acetonitrile %: 33%-63%, 8 min) to obtain compound 30. 1H NMR (400MHz, DMSO-d6) δ=8.91(d,J=2.0Hz,1H),8.67(d,J=8.4Hz,1H),8.34(d,J=2.0Hz,1H ),8.24-8.13(m,3H),7.59-7.48(m,2H),7.43(t,J=8.0Hz,1H),7.09-6.77(m,2H),4.99(br t,J=8.8Hz,2H),4.27-4.17(m,1H),3.92-3.82(m,2H),3.81-3.71(m,2H), 3.10-2.96(m,1H),2.96-2.90(m,2H),2.74(dd,J=6.0,9.6Hz,1H),2.69(br d,J=7.2Hz,1H),2.65-2.57(m,2H),2.54(s,3H),2.49-2.46(m, 1H),2.42(dd,J=3.6,9.6Hz,1H),2.35-2.32(m,1H),2.32-2.25(m,1H),2. 07-1.97(m,1H),1.63-1.54(m,2H),1.26(s,3H); MS(ESI)m / z:747.4[M+H] + .

[0303] Example 31: Compound 31

[0304]

[0305] Step A: Compound 29-4 (1 g, 2.61 mmol), phosphorus pentasulfide (1.16 g, 5.21 mmol), pyridine (20 mL), and xylene (80 mL) were added to a round-bottom flask and reacted at 140 °C for 12 hours. The solvent was concentrated under reduced pressure and separated by silica gel column chromatography (ethyl acetate / petroleum ether = 0%–20%, v / v) to give compound 31-1.

[0306] Step B: Add compound 31-1 (189 mg, 520.33 μmol) and dichloromethane (10 mL) to a round-bottom flask, cool to -78°C, and add a 1 mol / L toluene solution of DIBAL-H (1.04 mL) dropwise, keeping the temperature below -65°C. After the addition is complete, stir at -78°C for 3 hours. Carefully add saturated sodium sulfate solution (10 mL) while stirring, filter, and concentrate the filtrate to obtain compound 31-2, which can be used directly in the next step.

[0307] Step C: Compound 31-2 (80 mg, 238.65 μmol, 1 eq), compound 4-1 (124.91 mg, 238.65 μmol), sodium carbonate (63.24 mg, 596.63 μmol), and Pd(PPh3)4 (27.58 mg, 23.87 μmol) in a dioxane (10 mL) and water (2 mL) solution were heated to 100 °C and stirred for 12 hours under nitrogen protection. The reaction solution was filtered and concentrated to obtain the crude product. The crude product was purified by preparative thin-layer chromatography using silica gel plates (methanol / dichloromethane = 0%–10%, v / v) to obtain compound 31-3.

[0308] Step D: Add activated manganese dioxide (293.48 mg, 3.38 mmol) to a solution of compound 31-3 (110 mg, 168.78 μmol) in dichloromethane (10 mL) and stir at 45 °C for 48 hours. Filter, concentrate the filtrate to obtain compound 31-4, which can be used directly in the next step.

[0309] Step E: Triethylamine (37.38 mg, 369.39 μmol) was added to compounds 31-4 (80 mg, 123.13 μmol), compounds 1-22 (28.35 mg, 246.26 μmol), and dichloromethane (10 mL). The mixture was stirred at 45 °C for 1 hour. Then, NaBH(OAc)3 (78.29 mg, 369.39 μmol) and acetic acid (14.79 mg, 246.26 μmol) were added at 25 °C, and the mixture was stirred for another 12 hours. After the mixture was concentrated under reduced pressure, it was initially separated by preparative silica gel thin-layer chromatography (methanol / dichloromethane = 1 / 8), and further purified by preparative high-performance liquid chromatography (column: Phenomenex Synergi C18 150*25mm*10μm; mobile phase: [pure water (formic acid)-acetonitrile]; acetonitrile %: 13%-43%, 10 min) to obtain compound 31. 1H NMR (400MHz, DMSO-d6)δ=11.89-11.52(m,1H),11.43-11.13(m,1H),9.19(br d,J=16.0Hz,1H),8.92-8.76(m,2H),8.75-8.55(m,2H),7.85(d,J=7.2H z,1H),7.61-7.36(m,3H),7.16-6.79(m,2H),5.78-5.29(m,1H),5.00(br t,J=8.0Hz,2H),4.78-4.56(m,4H),4.52-4.39(m,1H),3.69-3.56(m,4H),3.28-3.17(m,4H),3.13-3.03 (m,1H),3.01-2.90(m,1H),2.39(s,3H),2.35-2.16(m,2H),2.11-1.83(m,2H); MS(ESI)m / z:749.3[M+H] + .

[0310] Example 32: Compound 32

[0311]

[0312]

[0313] Step A: At 0°C, 20 mL of acetic acid solution containing 9.16 g, 145.30 mmol of nitric acid was added dropwise to 20 mL of acetic acid solution containing 10 g, 53.59 mmol of compound 32-1. The reaction system was stirred at 25°C for 2 hours, then diluted with 50 mL of water, filtered, and the filter cake was washed with 50 mL of water and concentrated to obtain crude compound 32-2.

[0314] Step B: Add sodium hydrosulfite (13.53 g, 77.72 mmol) to a mixed solution of compound 32-2 (3 g, 12.95 mmol) in 30 mL of methanol and 6 mL of water. Stir the reaction mixture at 70 °C for 12 hours. Filter the mixture, wash the filter cake with 100 mL of methanol, and concentrate the filtrate to obtain the crude product. Purify the crude product by silica gel column chromatography (dichloromethane:methanol = 1:0-4:1, v / v) to obtain compound 32-3. MS (ESI) m / z: 202.1 [M+H] + .

[0315] Step C: A 100 mL ethanol solution of compound 32-3 (4.2 g, 20.83 mmol) and compound 32-4 (3.94 g, 19.79 mmol) was stirred at 25 °C for 1 hour and concentrated. The solution was then dissolved in 100 mL of dichloromethane solution, and dichlorodicyanobenzoquinone (4.49 g, 19.79 mmol) was added. The reaction mixture was stirred at 25 °C for 12 hours, then quenched with 100 mL of saturated sodium sulfite solution and extracted with dichloromethane (80 mL × 3). The combined organic phases were washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: dichloromethane 1:0-0:1, v / v) to obtain compound 32-5. MS (ESI) m / z: 381.7 [M+H] + .

[0316] Step D: At -78℃, a 1 mol / L toluene solution of DIBAL-H (40.04 mL) was added dropwise to a 120 mL dichloromethane solution of compound 32-5 (7.62 g, 20.02 mmol). The reaction system was stirred at 25℃ for 2 hours, then quenched with 200 mL of saturated potassium sodium tartrate solution, and extracted with dichloromethane (100 mL × 3). The combined organic phases were washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 1:0-4:1, v / v) to obtain compound 32-6. MS (ESI) m / z: 354.0 [M+H] + .

[0317] Step E: Under nitrogen protection, Pd(dppf)Cl2·CH2Cl2 (179.74 mg, 220.10 μmol) and potassium acetate (648.01 mg, 6.60 mmol) were added to 30 mL of dioxane solution containing compound 8-1 (1.11 g, 2.20 mmol) and bis(pinacol)boronic acid ester (1.12 g, 4.40 mmol). The reaction system was stirred at 100 °C for 1 hour. After cooling, the mixture was filtered through diatomaceous earth, and the filter cake was washed with 200 mL of dichloromethane. The filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 1:0-5:1, v / v) to obtain compound 32-7. MS (ESI) m / z: 552.2 [M+H] + .

[0318] Step F: Under nitrogen protection, sodium carbonate (192.22 mg, 1.81 mmol) and Pd(PPh3)4 (83.83 mg, 72.54 μmol) were added to a mixed solution of dioxane (10 mL) and water (2 mL) of compound 32-7 (0.4 g, 725.44 μmol). The mixture was purged three times with nitrogen and heated to 100 °C under nitrogen protection, with stirring for 1 hour. The reaction solution was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 1:0-3:1, v / v) to obtain compound 32-8. MS (ESI) m / z: 697.0 [M+H] + .

[0319] Step G: A mixed solution of compound 32-8 (0.515 g, 738.74 μmol), potassium ferrocyanide (468.06 mg, 1.11 mmol), potassium acetate (14.50 mg, 147.75 μmol), and t-BuXPhos-Pd-G3 (58.68 mg, 73.87 μmol) in dioxane (15 mL) and water (5 mL) was purged three times with nitrogen and heated to 100 °C under nitrogen protection, stirred for 3 hours. The reaction solution was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 1:0-3:1, v / v) to obtain compound 32-9. MS (ESI) m / z: 688.0 [M+H] + .

[0320] Step H: IBX (354.25 g, 1.27 mmol) was added to 15 mL of a dimethyl sulfoxide solution of compound 32-9 (0.435 g, 632.55 μmol). The reaction system was stirred at 25 °C for 12 hours. 20 mL of a saturated sodium thiosulfate solution was slowly added to the reaction solution. The mixture was extracted with dichloromethane (30 mL × 5). The combined organic phases were washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 1:0-3:1, v / v) to obtain compound 32-10. MS (ESI) m / z: 686.1 [M+H] + .

[0321] Step I: A 5 mL solution of compound 32-10 (0.15 g, 218.76 μmol) and compound 1-10 (38.12 mg, 437.52 μmol) in dichloromethane was stirred at 25 °C for 0.5 hours. Then, NaBH(OAc)3 (139.09 mg, 656.29 μmol) was added, and the reaction mixture was stirred at 25 °C for 12 hours. The reaction solution was concentrated to obtain a crude product. The crude product was first purified by silica gel column chromatography (dichloromethane:methanol = 1:0-2:1, v / v), and then purified by preparative high-performance liquid chromatography (HPLC) (column information: Phenomenex Synergi C18 150*25mm*10μm; mobile phase: [pure water (formic acid)-acetonitrile]; acetonitrile %: 11%-41%, 10 min) to obtain compound 32. 1 H NMR (400MHz, DMSO-d6) δ = 8.91 (d, J = 2.0Hz, 1H), 8.68 (d, J = 8.0Hz, 1H), 8.21-8.12 (m, 3H), 7.90 (d, J = 1.2Hz,1H),7.61-7.55(m,1H),7.55-7.51(m,1H),7.44(t,J=8.0Hz,1H),7.09-6.78(m,2H),5.00(br t,J=8.4Hz,2H),4.22(tt,J=3.2,6.6Hz,1H),3.90-3.81(m,3H),3.77(br d,J=12.0Hz,2H),3.03-2.92(m,3H),2.80-2.70(m,3H),2.69-2.65(m,1H),2.60(br t,J=6.8Hz,2H),2.54(br s,3H),2.40(brdd,J=3.2,9.6Hz,1H),2.07-1.95(m,3H),1.67-1.49(m,1H); MS(ESI)m / z:757.0[M+H] + .

[0322] Example 33: Compound 33

[0323]

[0324]

[0325] Step A: A 20 mL solution of compounds 3-8 (1.0 g, 2.47 mmol) and 5-7 (568.27 mg, 4.94 mmol) in dichloromethane was stirred at 25 °C for 0.5 hours. Then, NaBH(OAc)3 (1.57 g, 7.40 mmol) was added, and the reaction mixture was stirred at 25 °C for 1 hour. The mixture was diluted with 30 mL of water, extracted with dichloromethane (40 mL × 3), and the combined organic phases were washed with saturated brine (30 mL × 3). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 1:0-10:1, v / v) to obtain compound 33-1. MS (ESI) m / z: 504.2 [M+H] + .

[0326] Step B: Under nitrogen protection, Pd(dppf)Cl2·CH2Cl2 (179.74 mg, 220.10 μmol) and potassium acetate (648.01 mg, 6.60 mmol) were added to 30 mL of dioxane solution containing compound 33-1 (1.11 g, 2.20 mmol) and dipinacolborate (1.12 g, 4.40 mmol). The reaction system was stirred at 100 °C for 1 hour. After cooling, the mixture was filtered through diatomaceous earth. The filter cake was washed with 200 mL of dichloromethane, and the filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 1:0-5:1, v / v) to obtain compound 33-2. MS (ESI) m / z: 552.2 [M+H] + .

[0327] Step C: Under nitrogen protection, sodium carbonate (192.22 mg, 1.81 mmol) and Pd(PPh3)4 (83.83 mg, 72.54 μmol) were added to a mixed solution of dioxane (10 mL) and water (2 mL) of compound 33-2 (0.4 g, 725.44 μmol). The mixture was purged three times with nitrogen and heated to 100 °C under nitrogen protection, with stirring for 1 hour. The reaction solution was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 1:0-3:1, v / v) to obtain compound 33-3. MS (ESI) m / z: 697.0 [M+H] + .

[0328] Step D: A mixed solution of compound 33-3 (0.515 g, 738.74 μmol), potassium ferrocyanide (468.06 mg, 1.11 mmol), potassium acetate (14.50 mg, 147.75 μmol), and t-BuXPhos-Pd-G3 (58.68 mg, 73.87 μmol) in dioxane (15 mL) and water (5 mL) was purged three times with nitrogen and heated to 100 °C under nitrogen protection, stirred for 3 hours. The reaction solution was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 1:0-3:1, v / v) to obtain compound 33-4. MS (ESI) m / z: 688.0 [M+H] + .

[0329] Step E: IBX (354.25 g, 1.27 mmol) was added to 15 mL of a dimethyl sulfoxide solution of compound 33-4 (0.435 g, 632.55 μmol). The reaction system was stirred at 25 °C for 12 hours. 20 mL of a saturated sodium thiosulfate solution was slowly added to the reaction solution. The mixture was extracted with dichloromethane (30 mL × 5). The combined organic phases were washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 1:0-3:1, v / v) to obtain compound 33-5. MS (ESI) m / z: 686.1 [M+H] + .

[0330] Step F: A 5 mL solution of compound 33-5 (0.15 g, 218.76 μmol) and compound 33-6 (44.25 mg, 437.52 μmol) in dichloromethane was stirred at 25 °C for 0.5 hours. Then, NaBH(OAc)3 (139.09 mg, 656.29 μmol) was added, and the reaction mixture was stirred at 25 °C for 12 hours. The reaction solution was concentrated to obtain a crude product. The crude product was first purified by silica gel column chromatography (dichloromethane:methanol = 1:0-2:1, v / v), and then purified by preparative high-performance liquid chromatography (HPLC) (column information: Phenomenex Synergi C18 150*25mm*10μm; mobile phase: [pure water (formic acid)-acetonitrile]; acetonitrile %: 11%-41%, 10 min) to obtain compound 33. 1H NMR (400MHz, DMSO-d6) δ = 8.91 (d, J = 2.0Hz, 1H), 8.68 (d, J = 8.0Hz, 1H), 8.23-8.12 (m, 3H), 7 .93(d,J=1.2Hz,1H),7.64-7.50(m,2H),7.44(t,J=8.0Hz,1H),7.12-6.68(m,2H),5.00(br t,J=8.8Hz,2H),3.93-3.80(m,5H),3.03-2.94(m,3H),2.81-2.77(m,1H),2.76-2.69(m,2H),2.60(br t,J=6.8Hz,3H),2.54(br s,3H),2.06-1.95(m,2H),1.88-1.65(m,2H),1.32-1.19(m,4H); MS(ESI)m / z:771.0[M+H] + .

[0331] Experimental Example 1: PD-L1 Binding Experiment

[0332] Experimental materials:

[0333] PD1: The PD-L1 TR-FRET detection kit was purchased from BPS Biosciences. The Nivo multilabel analyzer was a PerkinElmer.

[0334] Experimental methods:

[0335] Dilute PD1-Eu, Dye-labeled acceptor, PD-L1-biotin, and the test compound using the buffer provided in the kit.

[0336] The test compound was diluted 5-fold to the 8th concentration, i.e., from 4 μM to 0.05 nM, with 4% DMSO, and a double-duplicate assay was performed. 5 μL of each concentration gradient of the test compound was added to the microplate. For the Max signal well, 5 μL of buffer containing 4% DMSO and 5 μL of PD-L1-biotin (60 nM) were added; for the Min signal well, only 5 μL of buffer was added. The plates were incubated at 25°C for 20 minutes. After incubation, 5 μL of diluted PD1-Eu (10 nM) and 5 μL of diluted dye-labeled acceptor were added to each well. The reaction system was incubated at 25°C for 90 minutes. After the reaction, time-resolved fluorescence signals were read using a multi-label analyzer.

[0337] Data Analysis:

[0338] The raw data were converted into inhibition rate using the equation (sample - Min) / (Max - Min)*100%, IC 50 The values ​​can be obtained by curve fitting using four parameters (obtained in GraphPad Prism using log(inhibitor) vs. response -- Variable slope mode). Table 1 provides the inhibitory activity of the compounds of this invention on PD1 / PD-L1 binding.

[0339] Table 1

[0340] Test compound <![CDATA[PD1 / PD-L1 binding IC 50 (nM)]]> 1 1.95

[0341] Experimental conclusion: The compounds of this invention exhibit good PD1 / PD-L1 binding inhibitory activity at the enzyme level.

[0342] Experiment Example 2: NFAT Combined Experiment

[0343] Experimental materials:

[0344] PD1: The PD-L1 TR-FRET assay kit was purchased from BPS Biosciences. Birght-Glo reagent was purchased from Promega. The Nivo multilabel analyzer was used (PerkinElmer).

[0345] Experimental methods:

[0346] TCR Activator / PD-L1 CHO cells with 80% confluence were seeded at 35,000 cells per well in a plate and incubated overnight at 37°C. The test compound was diluted 5-fold to the 8th concentration using a multipipeline, from 100 μmol to 1.28 nmol, with 100% DMSO, in duplicate. 147 μL of culture medium was added to the intermediate plate, and then 3 μL of the serially diluted compound was transferred to each well according to the corresponding position. At this point, the compound concentration was from 2 μmol to 0.0256 nmol, with 2% DMSO. The T-cell receptor / PD-L1 CHO cell supernatant was discarded, and 50 μL of the working solution of the compound was added to each well. The plate was incubated at 37°C for 30 minutes. After incubation, 50 μL of PD-1 / NFAT Reporter-Jurkat cell suspension at a density of 4 × 10⁵ / mL was added to each well, and the plate was incubated at 37°C for 5 hours. After incubation, add 100 μL Bright-Glo to each well, mix well, and then read the chemiluminescence signal using a Nivo multi-standard analyzer.

[0347] Data Analysis:

[0348] 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). The degree of inhibition of PD-1 / PD-L1 by the compound is calculated using the equation (Max-Min) / Min. The higher the fold increase, the stronger the inhibition of the PD-1 / PD-L1 pathway.

[0349] Experimental results: Figure 1 Table 2 provides the inhibitory activity of the compounds of the present invention against PD-1 / PD-L1 binding.

[0350] Table 2

[0351] Test compound <![CDATA[NFAT cell IC 50 (nM)]]> Relative DMSO activation factor 1 35 7.81 2 16 5.63 3 4.7 6.74 4 4.5 5.18 7 3.0 5.5 8 3.9 4.69 9 4.4 4.63 11 24.6 4.42 12 10.9 3.54 13 19.0 4.54 14 10.7 3.71 15 35.1 4.36 16 9.2 4.53 17 7.5 4.72 18 3.5 4.23 19 30.7 4.28 20 42.7 4.39 22 22.6 3.62 23 32.6 4.82 24 32.6 4.79 27 6.71 5.12 28 4.67 4.43 29 6.03 4.03 30 14.54 4.13 32 8.98 4.05 33 13.62 3.84

[0352] Experimental conclusion: The compound of this invention can effectively block the PD-1 / PD-L1 signaling pathway and restore T cell activity at the cellular level.

[0353] Experimental Example 3: Pharmacokinetic Study in Mice

[0354] Male C57BL / 6 mice were used as test animals. The plasma drug concentrations at different time points after gavage administration of the test compound were determined using LC / MS / MS. The pharmacokinetic behavior of the test compound in mice was investigated, and its pharmacokinetic characteristics were evaluated.

[0355] Test animals: Healthy male C57BL / 6 mice. Drug preparation: The solvent for group IV was 5% DMSO + 95% (20% hydroxypropyl-β-cyclodextrin); the solvent for group PO was 5% DMSO + 95% (20% HP-β-CD). Administration: The dosage of the test compound was 1 mg / kg for IV and 10 mg / kg or 30 mg / kg for PO (Note: Group PO was administered after fasting overnight).

[0356] Experimental procedure: After drug administration, whole blood was collected over a certain period of time to prepare plasma. Drug concentration was analyzed by LC-MS / MS, and pharmacokinetic parameters were calculated using Phoenix WinNonlin software (Pharsight, Inc., USA).

[0357] Experimental results are shown in Tables 3 and 4.

[0358] Table 3. Evaluation results of PK properties in vivo (Part 1)

[0359]

[0360] Table 4. Evaluation results of PK properties in vivo (II)

[0361]

[0362] Experimental conclusion: The compound of this invention has excellent pharmacokinetic properties, a long half-life in vivo, higher plasma exposure and bioavailability, and good drug-likeness.

[0363] Experiment Example 4: Pharmacodynamic Experiment of PD-L1 Antibody Drug Based on MC38-hPD-L1 Colon Cancer Animal Model of B-hPD-L1 Humanized Mice Experimental Methods:

[0364] 1. Cell Culture

[0365] Mouse colon cancer MC38 cells were purchased from Shunran Shanghai Biotechnology Co., Ltd. Biocytogen (Beijing) Pharmaceutical Technology Co., Ltd. genetically modified MC38 cells to express human PD-L1, naming it MC38-hPD-L1. These cells were adherent cells and cultured in a 37℃, 5% CO2 incubator using Dulbecco's Modified Eagle's Medium containing 10% inactivated fetal bovine serum.

[0366] 2. Inoculation and grouping of tumor cells

[0367] MC38-hPD-L1 cells resuspended in PBS were then subjected to a 5×10⁻⁶ ppm induction chamber. 5 0.1 mL / mouse was injected subcutaneously into the right side of B-hPD-L1 mice. The tumor volume was measured at 150 ± 50 mm. 3 Mice were selected based on tumor volume and body weight and randomly assigned to each experimental group, with 8 mice per group. Administration began on the day of grouping. The oral administration group received 5% DMSO + 95% (20% HP-β-CD dissolved in water) as the solvent, while the intraperitoneal injection group received 0.9% sodium chloride injection as the solvent. Specific administration protocols are shown in Table 5.

[0368] Table 5 Experimental Dosing Regimen for MC38-hPD-L1

[0369]

[0370] Note: a: The volume of administration is calculated based on the weight of the experimental animal at 10 μL / g; b: The dose is 20 mg / kg for the first 5 days after grouping, and the dose is adjusted to 50 mg / kg from day 6 onwards; c: po refers to oral administration, and ip refers to intraperitoneal injection; d: TIW refers to administration 3 times a week, and BID refers to administration twice a day.

[0371] 3. Drug evaluation indicators

[0372] Tumor volume inhibition rate (TGI) TV ): TGI TV (%) = [1 - (Ti - T0) / (Vi - V0)] × 100% (Ti: mean tumor volume in the treatment group on day i of administration, T0: mean tumor volume in the treatment group on day 0 of administration; Vi: mean tumor volume in the solvent control group on day i of administration, V0: mean tumor volume in the solvent control group on day 0 of administration)

[0373] Experimental results:

[0374] Atezolizumab (G2 group) TGI TV (%) = 88.4% (p<0.0001), TGI of compound 4 (G4 group) TV (%) = 86.1% (p<0.0001), TGI of compound 27 (G5 group) TV (%) = 86.1% (p < 0.0001), and the changes in tumor volume and body weight in the experimental animals are as follows: Figure 2 and Figure 3 As shown. Four hours after the last administration, tumor tissue from each group was collected for TILs (tumor-infiltrating lymphocytes) analysis. The TILs analysis results are shown below. Figure 4 and Figure 5 As shown.

[0375] Experimental conclusion:

[0376] The compounds of this invention can significantly inhibit tumor PD-L1 expression in mice, effectively activate immunity, and inhibit the growth of hPD-L1-positive MC38 tumors.

[0377] Experimental Example 5: Efficacy Experiment of Humanized PBMC+A375 Co-incubation Model

[0378] Objective: To evaluate the antitumor effect of the test drug in a human melanoma A375 mixed PBMC subcutaneous xenograft model.

[0379] Experimental Design:

[0380] 1. Cell culture:

[0381] A375 cells were cultured in DMEM medium containing 10% fetal bovine serum (FBS). A375 cells in the exponential growth phase were collected and resuspended in HBSS to a suitable concentration for subcutaneous tumor inoculation in NCG mice. Experimental A375 cells were cultured in Mitomycin C and then washed with PBS.

[0382] 2. Resuscitation and co-culture of peripheral blood mononuclear cells:

[0383] Purchase frozen PBMCs, thaw and count them, and add the obtained PBMCs to A375 cells treated with Mitomycin C. Co-culture the PBMCs and A375 cells in RPMI 1640 medium containing IL-2 and 10% FBS.

[0384] 3. Tumor cell inoculation:

[0385] After co-culturing PBMCs and A375 cells, PBMCs and freshly digested A375 cells were harvested and subcutaneously inoculated into the right side of NCG mice. Mice were then randomly assigned to groups based on their body weight and given the appropriate medication.

[0386] 4. Evaluation Indicators:

[0387] The inhibitory effect or complete curative ability of the test drug on the growth of human melanoma A375 mixed PBMC xenografts was detected and evaluated by tumor volume and tumor growth inhibition rate (TGI) (%).

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, ， in, Ring A is selected from and ; L1 and L2 are independently selected from -CH2- and -CH2-NH-CH2-, respectively; Z and E are independently selected from CH and N, respectively; Z1 is selected from O and S; Z2 is selected from N and CR9; X is N; Y is selected from N and CR. 15 ; R1 is selected from H, CH3, and CHF2; R2 is selected from CH3 and Cl; R3 and R4, together with the atoms they are bonded to, form an azahexacyclic butyl or pyrrolidinyl group, wherein the azahexacyclic butyl or pyrrolidinyl group is independently and optionally bonded by one, two, or three R atoms. 16 replace; R5 and R6 are independently selected from H and C, respectively. 1-6 Alkyl groups and COOH; Alternatively, R5 and R6, together with the atoms they are bonded to, form a pyrrolidinyl or oxazolyl group, wherein the pyrrolidinyl and oxazolyl groups are each optionally independently bounded by one, two, or three R atoms. 16 replace; R7 is H; R8 is selected from -OCH3, -O-CH2-F, and -O-CH2-CN; R9 is selected from H, F, and CN; R 15 Selected independently from H and C respectively 1-6 alkyl; R 16 Selected independently from H and C respectively 1-6 Alkyl groups, OH, =O, COOH, and -C 1-3 Alkyl-COOH.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, The compounds are selected from: ， in, Cycle B is selected from nitrogen-containing heterocyclic butyl and pyrrolidinyl compounds; The ring C is selected from pyrrolidinyl and oxazolyl; R 10 R 11 R 12 and R 13 Selected independently from H and C respectively 1-4 Alkyl groups, OH, =O, COOH, and -C 1-3 Alkyl-COOH; Rings A, Z, R1, and R2 are as defined in claim 1.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, The compounds are selected from: , and , in, Cycle B is selected from nitrogen-containing heterocyclic butyl and pyrrolidinyl compounds; The ring C is selected from pyrrolidinyl and oxazolyl; R 10 R 11 R 12 and R 13 Selected independently from H and C respectively 1-4 Alkyl groups, OH, =O, COOH, and -C 1-3 Alkyl-COOH; Z3 is selected from CH2 and O; Z, Z1, Z2, E, R1, R2 and R8 are as defined in claim 1.

4. The compound according to claim 1 or 3, or a pharmaceutically acceptable salt thereof, wherein, The compounds are selected from: , and , in, Z3 is selected from CH2 and O. R 10 R 11 R 12 and R 13 Selected independently from H and C respectively 1-4 Alkyl groups, OH, =O, COOH, and -C 1-3 Alkyl-COOH, Z, Z1, Z2, E, R1, R2 and R8 are as defined in claim 1 or 3.

5. The compound according to any one of claims 1, 2, and 3, or a pharmaceutically acceptable salt thereof, wherein, Z1 is selected from O, and Z2 is selected from C (CN).

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, Y is selected from N.

7. The compound according to any one of claims 1, 2, and 3, or a pharmaceutically acceptable salt thereof, wherein, R1 is selected from CHF2.

8. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, R5 and R6 are independently selected from H, CH3, isopropyl, and and COOH.

9. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein, Ring A is selected from , , , , and .

10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein, Structural unit Selected from , , , , , , and .

11. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein, Structural unit Selected from , , , , , , , , , and .

12. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein, Structural unit Selected from , , , , , , and .

13. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein, Structural unit Selected from , , , , , , , , , , and .

14. The compound according to claim 2 or 3, or a pharmaceutically acceptable salt thereof, wherein, Structural unit Selected from , , , , and .

15. The compound according to claim 2 or 3, or a pharmaceutically acceptable salt thereof, wherein, Structural unit Selected from , , , , , and .

16. A compound of the following formula or a pharmaceutically acceptable salt thereof, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

17. The compound of claim 16 or a pharmaceutically acceptable salt thereof, wherein, The compounds are selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

18. The use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 17 in the preparation of a medicament for treating PD-L1-related diseases, wherein the PD-L1-related diseases are colon cancer or melanoma.

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