A deuterated proliferating cell nuclear antigen inhibitor and its preparation method and application

Abstract

The present invention relates to a deuterium-substituted proliferating cell nuclear antigen inhibitor having a structure shown in formula I or any one or a combination thereof of a pharmaceutically acceptable salt, solvate or crystalline form thereof, wherein X=H, D; n=1-4 integers,

Description

Technical Field

[0001] The present invention relates to the field of biomedicine, and in particular to a deuterium-substituted proliferating cell nuclear antigen inhibitor, a preparation method thereof and an application thereof. Background Art

[0002] Malignant tumors seriously threaten human health and life, and their incidence rate is increasing year by year. According to the data of "Global Cancer Statistics 2015", the number of new cancer cases in the world in 2015 was about 14.1 million, and the number of deaths reached 8.2 million. In 2015, there were 4.29 million new cancer cases and 2.81 million deaths in China. It is estimated that by 2030, there will be nearly 26 million new cancer cases and nearly 17 million deaths each year. Surgery, radiotherapy and chemotherapy have become conventional means of tumor treatment, but they are all characterized by insufficient specificity, resulting in varying degrees of damage to normal tissues and organs while clearing tumor cells, and there are side effects and adverse reactions that are difficult for patients to accept, and even cause secondary malignant tumors.

[0003] Targeted therapy drugs (such as imatinib) are helpful in reducing the side effects and adverse reactions caused by chemotherapy drugs. However, drugs targeting oncogenes often show drug resistance due to mutations in cancer cell target genes, changes in target expression, or resistance caused by activation of alternative survival pathways. Proliferating Cell Nuclear Antigen (PCNA) has been widely used as a tumor progression marker and has become a new anticancer drug target.

[0004] WO2017049206A discloses a new broad-spectrum anticancer compound (AOH1996) targeting PCNA protein, which selectively inhibits tumor growth by regulating the cell growth cycle and can enhance the sensitivity of chemotherapeutic drugs (such as Cisplatin, etc.). WO2022232509A1 discloses a method for treating cancer using a PCNA inhibitor in combination with an EGFR inhibitor and a pharmaceutical composition thereof.

[0005]

[0006] The main purpose of the present invention is to develop new anti-tumor drugs with more significant efficacy, wider indications, and greener and more environmentally friendly production processes. Summary of the invention

[0007] The object of the present invention is to provide a proliferating cell nuclear antigen inhibitor having a structure shown in Formula I or any one or a combination thereof of a pharmaceutically acceptable salt, solvate or crystalline form thereof, wherein X = H, D; n = an integer of 1-4,

[0008]

[0009] In a preferred technical solution of the present invention, the pharmaceutically acceptable salt is selected from any one of an organic acid salt or an inorganic acid salt of the compound of formula I.

[0010] In a preferred technical solution of the present invention, the organic acid is selected from any one of maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, oxalic acid, propionic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, lactic acid, mandelic acid, phenylacetic acid, aspartic acid, stearic acid, palmitic acid, glycolic acid, glutamic acid, and benzenesulfonic acid, or a combination thereof.

[0011] In a preferred technical solution of the present invention, the inorganic acid is selected from any one of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and nitric acid, or a combination thereof.

[0012] Another object of the present invention is to provide a method for preparing a compound of formula I, which is prepared by reacting a compound of formula IV with naphthoylglycine in the presence of a condensing agent in a solvent.

[0013]

[0014] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the condensing agent is selected from N, N'-dicyclohexylcarbodiimide (DCC), N, N'-diisopropylcarbodiimide (DIC), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), 1,1-carbonyldiimidazole (CDI, carbonylimidazole), benzotriazol-1-yloxytriphosphonium hexafluorophosphate (BOP), benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), 2-(7-azobenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate (HATU), benzotriazole-N, N, N', N'-tetramethyluronium hexafluorophosphate (HBTU), O-benzotriazole-N, N, N', N'-tetramethyluronium hexafluorophosphate (HBTU), Triazole-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), O-[(ethoxycarbonyl)cyanomethylamine]-N,N,N',N'-tetramethylthiourea tetrafluoroborate (TOTU), 2-(2-pyridone-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU), ethyl methylphosphonic anhydride (EMPA), n-propylphosphonic anhydride (T3P), cyanuric chloride, 2-chloro-4,6-diphenyl-1,3,5-triazine (CDMT), 4-(4,6-dimethoxy-1,3,5,-triazine-2-yl)-4-methylmorpholine hydrochloride (DMTMM), boric acid, 3-nitrophenylboronic acid, methanesulfonyl chloride, p-toluenesulfonyl chloride, acetic anhydride, Boc anhydride (Boc 2O), pivaloyl chloride, ethyl chloroformate, isobutyl chloroformate, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), thionyl chloride, oxalyl chloride, phosphorus oxychloride, (chloromethylene) dimethylammonium chloride (Vilsmeier Reagent) or any one thereof or a combination thereof.

[0015] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the solvent is selected from any one of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, acetonitrile, acetone, 2-butanone, dichloromethane, 1,2-dichloroethane, ethyl acetate, isopropyl acetate, tert-butyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide or a combination thereof.

[0016] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the molar ratio of the compound of formula IV: naphthoylglycine: condensing agent is 1:1-2:1-2, preferably 1:1-1.2:1-1.5.

[0017] In a preferred embodiment of the present invention, a base is optionally added during the preparation of the compound of formula I.

[0018] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the base is selected from any one of triethylamine, diisopropylethylamine, pyridine, N-methylmorpholine (NMM), N-methylimidazole (NMI) or a combination thereof.

[0019] In the preferred technical scheme of the present invention, a condensation auxiliary agent is optionally added during the preparation of the compound of formula I.

[0020] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the condensation auxiliary agent is selected from any one of 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), N-hydroxy-5-norbornene-2,3-dicarboximide (HONB), and 3,4-dihydro-3-hydroxy-4-oxy-1,2,3-benzotriazine (HOOBt) or a combination thereof.

[0021] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the molar ratio of the compound of formula IV: naphthoylglycine: condensation agent: condensation aid: base is 1:1-2:1-2:0-2:0-10, preferably 1:1-1.2:1-1.5:1-2:1-2.

[0022] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the reaction temperature is 10°C-150°C, preferably 25°C-80°C, more preferably 25°C-60°C.

[0023] In the preferred technical scheme of the present invention, the compound of formula IV is prepared by reducing the compound of formula V in a solvent in the presence of a reducing agent.

[0024]

[0025] In the preferred technical scheme of the present invention, in the preparation of the compound of formula IV, the reducing agent is selected from any one of palladium carbon-hydrogen, palladium carbon-ammonium formate, palladium carbon-formic acid, palladium carbon-hydrazine hydrate, nickel-hydrogen, iron powder-dilute hydrochloric acid, sodium borohydride, potassium borohydride, and tin dichloride, or a combination thereof.

[0026] In a preferred technical solution of the present invention, in the preparation of the compound of formula IV, the solvent is selected from any one of methanol, ethanol, water or a combination thereof.

[0027] In the preferred technical scheme of the present invention, in the preparation of the compound of formula IV, the purity of palladium carbon in the reducing agent is 2%-15%, preferably 5%-10%.

[0028] In the preferred technical scheme of the present invention, in the preparation of the compound of formula IV, the purity of hydrazine hydrate in the reducing agent is 40%-85%, preferably 50%-80%.

[0029] In the preferred technical scheme of the present invention, in the preparation of the compound of formula IV, the molar ratio of the compound of formula V: hydrazine hydrate is 1:1-2.5, preferably 1:1.5-2.

[0030] In the preferred technical scheme of the present invention, in the preparation of the compound of formula IV, the reaction temperature is 25-100°C, preferably 30-80°C.

[0031] In the preferred technical scheme of the present invention, the compound of formula V is prepared by reacting the compound of formula IV with Xn-substituted o-halonitrobenzene (halogen is fluorine, chlorine, bromine or iodine) in a solvent in the presence of a base.

[0032]

[0033] In a preferred technical solution of the present invention, in the preparation of the compound of formula V, the base is selected from any one of sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, and cesium hydroxide, or a combination thereof.

[0034] In a preferred technical scheme of the present invention, in the preparation of the compound of formula V, the solvent is selected from any one of toluene, xylene, 2-methyltetrahydrofuran, dioxane, acetonitrile, acetone, 2-butanone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide or a combination thereof.

[0035] In the preferred technical scheme of the present invention, in the preparation of the compound of formula V, the molar ratio of the compound of formula VI: Xn-substituted o-halonitrobenzene: base is 1:1-2:1-5, preferably 1:1-1.5:1-2.5, and more preferably 1:1-1.2:1.2-2.

[0036] In the preferred technical scheme of the present invention, in the preparation of the compound of formula V, the reaction temperature is 20°C-150°C, preferably 30°C-110°C, and more preferably 50°C-80°C.

[0037] In the preferred technical scheme of the present invention, naphthoylglycine is prepared by reacting naphthoylglycine methyl ester in a solvent in the presence of a base.

[0038]

[0039] In the preferred technical scheme of the present invention, in the preparation of naphthoylglycine, the base is selected from any one of lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide or a combination thereof.

[0040] In the preferred technical scheme of the present invention, in the preparation of naphthoylglycine, the solvent is selected from any one of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, acetonitrile, acetone, 2-butanone, dichloromethane, 1,2-dichloroethane, ethyl acetate, isopropyl acetate, tert-butyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methanol, ethanol, isopropanol, and water, or a combination thereof.

[0041] In the preferred technical scheme of the present invention, in the preparation of naphthoylglycine, the molar ratio of naphthoylglycine methyl ester:base is 1:1-10, preferably 1:1-5.

[0042] In the preferred technical scheme of the present invention, in the preparation of naphthoylglycine, the reaction temperature is 20°C-65°C, preferably 25°C-50°C.

[0043] In the preferred technical scheme of the present invention, naphthoylglycine methyl ester is prepared by reacting 1-naphthoic acid and glycine methyl ester hydrochloride in a solvent in the presence of a condensing agent.

[0044]

[0045] In the preferred technical scheme of the present invention, in the preparation of naphthoylglycine methyl ester, the condensing agent is selected from N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), 1,1-carbonyldiimidazole (CDI), benzotriazol-1-yloxytriphosphonium hexafluorophosphate (BOP), benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), O-benzotriazole TBTU, O-[(ethoxycarbonyl) cyanomethylamine]-N,N,N',N'-tetramethylthiourea tetrafluoroborate (TOTU), 2-(2-pyridone-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU), ethyl methylphosphonic anhydride (EMPA), n-propylphosphonic anhydride (T3P), cyanuric chloride, 2-chloro-4,6-diphenyl-1,3,5-triazine (CDMT), 4-(4,6-dimethoxy-1,3,5,-triazine-2-yl)-4-methylmorpholine hydrochloride (DMTMM), boric acid, 3-nitrophenylboronic acid, methanesulfonyl chloride, p-toluenesulfonyl chloride, acetic anhydride, Boc anhydride (Boc 2 O), pivaloyl chloride, ethyl chloroformate, isobutyl chloroformate, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), thionyl chloride, oxalyl chloride, phosphorus oxychloride, (chloromethylene) dimethylammonium chloride (Vilsmeier Reagent) or any one thereof or a combination thereof.

[0046] In the preferred technical scheme of the present invention, in the preparation of naphthoylglycine methyl ester, the solvent is selected from any one of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, acetonitrile, acetone, 2-butanone, dichloromethane, 1,2-dichloroethane, ethyl acetate, isopropyl acetate, tert-butyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide, or a combination thereof.

[0047] In the preferred technical solution of the present invention, a base is optionally added during the preparation of naphthoylglycine methyl ester.

[0048] In the preferred technical scheme of the present invention, in the preparation of naphthoylglycine methyl ester, the base is selected from any one of triethylamine, diisopropylethylamine, pyridine, N-methylmorpholine (NMM), N-methylimidazole (NMI) or a combination thereof.

[0049] In the preferred technical solution of the present invention, a condensation aid is optionally added during the preparation of naphthoylglycine methyl ester.

[0050] In the preferred technical scheme of the present invention, in the preparation of naphthoylglycine methyl ester, the condensation auxiliary agent is selected from any one of 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), N-hydroxy-5-norbornene-2,3-dicarboximide (HONB), and 3,4-dihydro-3-hydroxy-4-oxy-1,2,3-benzotriazine (HOOBt) or a combination thereof.

[0051] In the preferred technical scheme of the present invention, in the preparation of naphthoylglycine methyl ester, the molar ratio of 1-naphthoic acid:glycine methyl ester hydrochloride:condensation agent is 1:1-2:1-2, preferably 1:1-1.2:1-1.5.

[0052] In the preferred technical scheme of the present invention, in the preparation of naphthoylglycine methyl ester, the molar ratio of 1-naphthoic acid: glycine methyl ester hydrochloride: condensation agent: condensation aid: base is 1:1-2:1-2:0-2:0-10, preferably 1:1-1.2:1-1.5:1-2:1-2.

[0053] In the preferred technical scheme of the present invention, in the preparation of naphthoylglycine methyl ester, the reaction temperature is 10°C-150°C, preferably 25°C-80°C, and more preferably 25°C-60°C.

[0054] Another object of the present invention is to provide another method for preparing the compound of formula I, comprising the following steps:

[0055]

[0056] 1) reacting a compound of formula VI with an Xn-substituted o-halonitrobenzene in a solvent in the presence of a base to obtain a compound of formula V;

[0057] 2) reacting the compound of formula V in the presence of a reducing agent in a solvent to obtain a compound of formula IV;

[0058] 3) 1-naphthoic acid and glycine methyl ester hydrochloride react in the presence of a condensing agent in a solvent to obtain naphthoylglycine methyl ester;

[0059] 4) naphthoylglycine methyl ester reacts in a solvent in the presence of a base to obtain naphthoylglycine;

[0060] 5) The compound of formula IV reacts with naphthoylglycine in the presence of a condensing agent in a solvent to obtain a compound of formula I.

[0061] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, there is no particular order in which the compound of formula IV and naphthoylglycine are prepared.

[0062] In a preferred technical scheme of the present invention, in the preparation of the compound of formula I, the base in step 1) is selected from any one of sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, and cesium hydroxide, or a combination thereof.

[0063] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the reaction solvent in step 1) is selected from any one of toluene, xylene, 2-methyltetrahydrofuran, dioxane, acetonitrile, acetone, 2-butanone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide or a combination thereof.

[0064] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the molar ratio of the compound of formula IV in step 1): Xn-substituted o-halonitrobenzene: base is 1:1-2:1-5, preferably 1:1-1.5:1-2.5, and more preferably 1:1-1.2:1.2-2.

[0065] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the reaction temperature in step 1) is 20°C-150°C, preferably 30°C-110°C, and more preferably 50°C-80°C.

[0066] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the reducing agent in step 2) is selected from any one of palladium carbon-hydrogen, palladium carbon-ammonium formate, palladium carbon-formic acid, palladium carbon-hydrazine hydrate, nickel-hydrogen, iron powder-dilute hydrochloric acid, sodium borohydride, potassium borohydride, and tin dichloride or a combination thereof.

[0067] In a preferred technical solution of the present invention, in the preparation of the compound of formula I, the solvent in step 2) is selected from any one of methanol, ethanol, water or a combination thereof.

[0068] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the purity of palladium carbon in the reducing agent in step 2) is 2%-15%, preferably 5%-10%.

[0069] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the purity of the hydrazine hydrate in the reducing agent in step 2) is 40%-85%, preferably 50%-80%.

[0070] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the molar ratio of the compound of formula V in step 2) to hydrazine hydrate is 1:1-2.5, preferably 1:1.5-2.

[0071] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the reaction temperature in step 2) is 25-100°C, preferably 30-80°C.

[0072] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the condensing agent in step 3) is selected from N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), 1,1-carbonyldiimidazole (CDI), benzotriazol-1-yloxytriphosphonium hexafluorophosphate (BOP), benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), O-benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), Triazole-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), O-[(ethoxycarbonyl)cyanomethylamine]-N,N,N',N'-tetramethylthiourea tetrafluoroborate (TOTU), 2-(2-pyridone-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU), ethyl methylphosphonic anhydride (EMPA), n-propylphosphonic anhydride (T3P), cyanuric chloride, 2-chloro-4,6-diphenyl-1,3,5-triazine (CDMT), 4-(4,6-dimethoxy-1,3,5,-triazine-2-yl)-4-methylmorpholine hydrochloride (DMTMM), boric acid, 3-nitrophenylboronic acid, methanesulfonyl chloride, p-toluenesulfonyl chloride, acetic anhydride, Boc anhydride (Boc 2 O), pivaloyl chloride, ethyl chloroformate, isobutyl chloroformate, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), thionyl chloride, oxalyl chloride, phosphorus oxychloride, (chloromethylene) dimethylammonium chloride (Vilsmeier Reagent) or any one thereof or a combination thereof.

[0073] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the solvent in step 3) is selected from any one of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, acetonitrile, acetone, 2-butanone, dichloromethane, 1,2-dichloroethane, ethyl acetate, isopropyl acetate, tert-butyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide or a combination thereof.

[0074] In a preferred technical solution of the present invention, in the preparation of the compound of formula I, a base is optionally added in step 3).

[0075] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the base in step 3) is selected from any one of triethylamine, diisopropylethylamine, pyridine, N-methylmorpholine (NMM), N-methylimidazole (NMI) or a combination thereof.

[0076] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, a condensation auxiliary is optionally added in step 3).

[0077] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the condensation auxiliary in step 3) is selected from any one of 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), N-hydroxy-5-norbornene-2,3-dicarboximide (HONB), and 3,4-dihydro-3-hydroxy-4-oxy-1,2,3-benzotriazine (HOOBt) or a combination thereof.

[0078] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the molar ratio of 1-naphthoic acid:glycine methyl ester hydrochloride:condensing agent in step 3) is 1:1-2:1-2, preferably 1:1-1.2:1-1.5.

[0079] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the molar ratio of 1-naphthoic acid: glycine methyl ester hydrochloride: condensation agent: condensation aid: base in step 3) is 1:1-2:1-2:0-2:0-10, preferably 1:1-1.2:1-1.5:1-2:1-2.

[0080] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the reaction temperature in step 3) is 10°C-150°C, preferably 25°C-80°C, and more preferably 25°C-60°C.

[0081] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the base in step 4) is selected from any one of lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide or a combination thereof.

[0082] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the solvent in step 4) is selected from any one of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, acetonitrile, acetone, 2-butanone, dichloromethane, 1,2-dichloroethane, ethyl acetate, isopropyl acetate, tert-butyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methanol, ethanol, isopropanol, and water, or a combination thereof.

[0083] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the molar ratio of naphthoylglycine methyl ester:base in step 4) is 1:1-10, preferably 1:1-5.

[0084] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the reaction temperature in step 4) is 20°C-65°C, preferably 25°C-50°C.

[0085] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the condensing agent in step 5) is selected from N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), 1,1-carbonyldiimidazole (CDI), benzotriazol-1-yloxytriphosphonium hexafluorophosphate (BOP), benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), O-benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), Triazole-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), O-[(ethoxycarbonyl)cyanomethylamine]-N,N,N',N'-tetramethylthiourea tetrafluoroborate (TOTU), 2-(2-pyridone-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU), ethyl methylphosphonic anhydride (EMPA), n-propylphosphonic anhydride (T3P), cyanuric chloride, 2-chloro-4,6-diphenyl-1,3,5-triazine (CDMT), 4-(4,6-dimethoxy-1,3,5,-triazine-2-yl)-4-methylmorpholine hydrochloride (DMTMM), boric acid, 3-nitrophenylboronic acid, methanesulfonyl chloride, p-toluenesulfonyl chloride, acetic anhydride, Boc anhydride (Boc 2 O), pivaloyl chloride, ethyl chloroformate, isobutyl chloroformate, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), thionyl chloride, oxalyl chloride, phosphorus oxychloride, (chloromethylene) dimethylammonium chloride (Vilsmeier Reagent) or any one thereof or a combination thereof.

[0086] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the solvent in step 5) is selected from any one of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, acetonitrile, acetone, 2-butanone, dichloromethane, 1,2-dichloroethane, ethyl acetate, isopropyl acetate, tert-butyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide or a combination thereof.

[0087] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, in step 5), the molar ratio of the compound of formula IV: naphthoylglycine: condensing agent is 1:1-2:1-2, preferably 1:1-1.2:1-1.5.

[0088] In a preferred technical solution of the present invention, in the preparation of the compound of formula I, a base is optionally added in step 5).

[0089] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the base in step 5) is selected from any one of triethylamine, diisopropylethylamine, pyridine, N-methylmorpholine (NMM), N-methylimidazole (NMI) or a combination thereof.

[0090] In a preferred technical solution of the present invention, in the preparation of the compound of formula I, a condensation auxiliary is optionally added in step 5).

[0091] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the condensation auxiliary agent in step 5) is selected from any one of 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), N-hydroxy-5-norbornene-2,3-dicarboximide (HONB), and 3,4-dihydro-3-hydroxy-4-oxy-1,2,3-benzotriazine (HOOBt) or a combination thereof.

[0092] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the molar ratio of the compound of formula IV in step 5): naphthoylglycine: condensation agent: condensation aid: base is 1:1-2:1-2:0-2:0-10, preferably 1:1-1.2:1-1.5:1-2:1-2.

[0093] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the reaction temperature in step 5) is 10°C-150°C, preferably 25°C-80°C, more preferably 25°C-60°C.

[0094] Another object of the present invention is to provide another method for preparing the compound of formula I, which is prepared by reacting the compound of formula II with 1-naphthoic acid in a solvent in the presence of a condensing agent.

[0095]

[0096] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the condensing agent is selected from N, N'-dicyclohexylcarbodiimide (DCC), N, N'-diisopropylcarbodiimide (DIC), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), 1,1-carbonyldiimidazole (CDI), benzotriazol-1-yloxytriphosphonium hexafluorophosphate (BOP), benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), 2-(7-azobenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate (HATU), benzotriazole-N, N, N', N'-tetramethyluronium hexafluorophosphate (HBTU), O-benzotriazole oxadiazole-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), O-[(ethoxycarbonyl)cyanomethylamine]-N,N,N',N'-tetramethylthiourea tetrafluoroborate (TOTU), 2-(2-pyridone-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU), ethyl methylphosphonic anhydride (EMPA), n-propylphosphonic anhydride (T3P), cyanuric chloride, 2-chloro-4,6-diphenyl-1,3,5-triazine (CDMT), 4-(4,6-dimethoxy-1,3,5,-triazine-2-yl)-4-methylmorpholine hydrochloride (DMTMM), boric acid, 3-nitrophenylboronic acid, methanesulfonyl chloride, p-toluenesulfonyl chloride, acetic anhydride, Boc anhydride (Boc 2 O), pivaloyl chloride, ethyl chloroformate, isobutyl chloroformate, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), thionyl chloride, oxalyl chloride, phosphorus oxychloride, (chloromethylene) dimethylammonium chloride (Vilsmeier Reagent) or any one thereof or a combination thereof.

[0097] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the solvent is selected from any one of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, acetonitrile, acetone, 2-butanone, dichloromethane, 1,2-dichloroethane, ethyl acetate, isopropyl acetate, tert-butyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide or a combination thereof.

[0098] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the molar ratio of the compound of formula II: 1-naphthoic acid: condensing agent is 1:1-2:1-2, preferably 1:1-1.2:1-1.5.

[0099] In a preferred embodiment of the present invention, a base is optionally added during the preparation of the compound of formula I.

[0100] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the base is selected from any one of triethylamine, diisopropylethylamine, pyridine, N-methylmorpholine (NMM), N-methylimidazole (NMI) or a combination thereof.

[0101] In the preferred technical scheme of the present invention, a condensation auxiliary agent is optionally added during the preparation of the compound of formula I.

[0102] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the condensation auxiliary agent is selected from any one of 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), N-hydroxy-5-norbornene-2,3-dicarboximide (HONB), and 3,4-dihydro-3-hydroxy-4-oxy-1,2,3-benzotriazine (HOOBt) or a combination thereof.

[0103] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the molar ratio of the compound of formula II: 1-naphthoic acid: condensation agent: condensation aid: base is 1:1-2:1-2:0-2:0-10, preferably 1:1-1.2:1-1.5:0-2:0-2.

[0104] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the reaction temperature is 10°C-150°C, preferably 25°C-80°C, more preferably 25°C-60°C.

[0105] In the preferred technical scheme of the present invention, the compound of formula II is prepared by deprotecting the compound of formula III in a solvent under acidic conditions.

[0106]

[0107] In the preferred technical scheme of the present invention, in the preparation of the compound of formula II, the acid is selected from any one of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, trifluoroacetic acid, a methanol solution of hydrogen chloride, an ethanol solution of hydrogen chloride, a dioxane solution of hydrogen chloride, and an ethyl acetate solution of hydrogen chloride, or a combination thereof.

[0108] In the preferred technical scheme of the present invention, in the preparation of the compound of formula II, the solvent is selected from any one of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, acetonitrile, acetone, 2-butanone, methanol, ethanol, isopropanol, dichloromethane, 1,2-dichloroethane, ethyl acetate, isopropyl acetate, tert-butyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, water or a combination thereof.

[0109] In the preferred technical scheme of the present invention, in the preparation of the compound of formula II, the molar ratio of the compound of formula III: acid is 1:1-10, preferably 1:1-5.

[0110] In the preferred technical scheme of the present invention, in the preparation of the compound of formula II, the reaction temperature is 20°C-60°C, preferably 25°C-50°C.

[0111] In the preferred technical scheme of the present invention, the compound of formula III is prepared by reacting the compound of formula IV with Boc glycine in a solvent in the presence of a condensing agent.

[0112]

[0113] In the preferred technical scheme of the present invention, in the preparation of the compound of formula III, the condensing agent is selected from N, N'-dicyclohexylcarbodiimide (DCC), N, N'-diisopropylcarbodiimide (DIC), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), 1,1-carbonyldiimidazole (CDI), benzotriazol-1-yloxytriphosphonium hexafluorophosphate (BOP), benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), 2-(7-azobenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate (HATU), benzotriazole-N, N, N', N'-tetramethyluronium hexafluorophosphate (HBTU), O-benzotriazole oxadiazole-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), O-[(ethoxycarbonyl)cyanomethylamine]-N,N,N',N'-tetramethylthiourea tetrafluoroborate (TOTU), 2-(2-pyridone-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU), ethyl methylphosphonic anhydride (EMPA), n-propylphosphonic anhydride (T3P), cyanuric chloride, 2-chloro-4,6-diphenyl-1,3,5-triazine (CDMT), 4-(4,6-dimethoxy-1,3,5,-triazine-2-yl)-4-methylmorpholine hydrochloride (DMTMM), boric acid, 3-nitrophenylboronic acid, methanesulfonyl chloride, p-toluenesulfonyl chloride, acetic anhydride, Boc anhydride (Boc 2 O), pivaloyl chloride, ethyl chloroformate, isobutyl chloroformate, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), thionyl chloride, oxalyl chloride, phosphorus oxychloride, (chloromethylene) dimethylammonium chloride (Vilsmeier Reagent) or any one thereof or a combination thereof.

[0114] In the preferred technical scheme of the present invention, in the preparation of the compound of formula III, the solvent is selected from any one of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, acetonitrile, acetone, 2-butanone, dichloromethane, 1,2-dichloroethane, ethyl acetate, isopropyl acetate, tert-butyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide, or a combination thereof.

[0115] In the preferred technical scheme of the present invention, in the preparation of the compound of formula III, the molar ratio of the compound of formula IV: Boc-glycine: condensing agent is 1:1-2:1-2, preferably 1:1-1.2:1-1.5.

[0116] In the preferred technical scheme of the present invention, a base is optionally added during the preparation of the compound of formula III.

[0117] In the preferred technical scheme of the present invention, in the preparation of the compound of formula III, the base is selected from any one of triethylamine, diisopropylethylamine, pyridine, N-methylmorpholine (NMM), N-methylimidazole (NMI) or a combination thereof.

[0118] In the preferred technical solution of the present invention, a condensation auxiliary is optionally added during the preparation of the compound of formula III.

[0119] In the preferred technical scheme of the present invention, in the preparation of the compound of formula III, the condensation aid is selected from any one of 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), N-hydroxy-5-norbornene-2,3-dicarboximide (HONB), and 3,4-dihydro-3-hydroxy-4-oxy-1,2,3-benzotriazine (HOOBt) or a combination thereof.

[0120] In the preferred technical scheme of the present invention, in the preparation of the compound of formula III, the molar ratio of the compound of formula IV: Boc-glycine: condensation agent: condensation aid: base is 1:1-2:1-2:0-2:0-10, preferably 1:1-1.2:1-1.5:1-2:1-2.

[0121] In the preferred technical scheme of the present invention, in the preparation of the compound of formula III, the reaction temperature is 10°C-150°C, preferably 25°C-80°C, and more preferably 25°C-60°C.

[0122] In the preferred technical scheme of the present invention, the compound of formula IV is prepared by reducing the compound of formula V in a solvent in the presence of a reducing agent.

[0123]

[0124] In the preferred technical scheme of the present invention, in the preparation of the compound of formula IV, the reducing agent is selected from any one of palladium carbon-hydrogen, palladium carbon-ammonium formate, palladium carbon-formic acid, palladium carbon-hydrazine hydrate, nickel-hydrogen, iron powder-dilute hydrochloric acid, sodium borohydride, potassium borohydride, and tin dichloride, or a combination thereof.

[0125] In a preferred technical solution of the present invention, in the preparation of the compound of formula IV, the solvent is selected from any one of methanol, ethanol, water or a combination thereof.

[0126] In the preferred technical scheme of the present invention, in the preparation of the compound of formula IV, the purity of palladium carbon in the reducing agent is 2%-15%, preferably 5%-10%.

[0127] In the preferred technical scheme of the present invention, in the preparation of the compound of formula IV, the purity of hydrazine hydrate in the reducing agent is 40%-85%, preferably 50%-80%.

[0128] In the preferred technical scheme of the present invention, in the preparation of the compound of formula IV, the molar ratio of the compound of formula V: hydrazine hydrate is 1:1-2.5, preferably 1:1.5-2.

[0129] In the preferred technical scheme of the present invention, in the preparation of the compound of formula IV, the reaction temperature is 25-100°C, preferably 30-80°C.

[0130] In the preferred technical scheme of the present invention, the compound of formula V is prepared by reacting the compound of formula IV with Xn-substituted o-halonitrobenzene in a solvent in the presence of a base.

[0131]

[0132] In a preferred technical solution of the present invention, in the preparation of the compound of formula V, the base is selected from any one of sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, and cesium hydroxide, or a combination thereof.

[0133] In a preferred technical scheme of the present invention, in the preparation of the compound of formula V, the solvent is selected from any one of toluene, xylene, 2-methyltetrahydrofuran, dioxane, acetonitrile, acetone, 2-butanone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide or a combination thereof.

[0134] In the preferred technical scheme of the present invention, in the preparation of the compound of formula V, the molar ratio of the compound of formula VI: Xn-substituted o-halonitrobenzene: base is 1:1-2:1-5, preferably 1:1-1.5:1-2.5, and more preferably 1:1-1.2:1.2-2.

[0135] In the preferred technical scheme of the present invention, in the preparation of the compound of formula V, the reaction temperature is 20°C-150°C, preferably 30°C-110°C, and more preferably 50°C-80°C.

[0136] Another object of the present invention is to provide a method for preparing the compound of formula I, comprising the following steps:

[0137]

[0138] 1) reacting a compound of formula VI with an Xn-substituted o-halonitrobenzene in a solvent in the presence of a suitable base to obtain a compound of formula V;

[0139] 2) reacting the compound of formula V in the presence of a reducing agent in a solvent to obtain a compound of formula IV;

[0140] 3) reacting the compound of formula IV with Boc glycine in the presence of a condensing agent in a solvent to obtain a compound of formula III;

[0141] 4) reacting the compound of formula III in the presence of an acid in a solvent to obtain a compound of formula II;

[0142] 5) The compound of formula II is reacted with 1-naphthoic acid in the presence of a condensing agent to obtain the compound of formula I.

[0143] In a preferred technical scheme of the present invention, in the preparation of the compound of formula I, the base in step 1) is selected from any one of sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, and cesium hydroxide, or a combination thereof.

[0144] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the solvent in step 1) is selected from any one of toluene, xylene, 2-methyltetrahydrofuran, dioxane, acetonitrile, acetone, 2-butanone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide or a combination thereof.

[0145] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the molar ratio of the compound of formula VI in step 1): Xn-substituted o-halonitrobenzene: base is 1:1-2:1-5, preferably 1:1-1.5:1-2.5, and more preferably 1:1-1.2:1.2-2.

[0146] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the reaction temperature of step 1) is 20°C-150°C, preferably 30°C-110°C, and more preferably 50°C-80°C.

[0147] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the reducing agent in step 2) is selected from any one of palladium carbon-hydrogen, palladium carbon-ammonium formate, palladium carbon-formic acid, palladium carbon-hydrazine hydrate, nickel-hydrogen, iron powder-dilute hydrochloric acid, sodium borohydride, potassium borohydride, and tin dichloride or a combination thereof.

[0148] In a preferred technical solution of the present invention, in the preparation of the compound of formula I, the solvent in step 2) is selected from any one of methanol, ethanol, water or a combination thereof.

[0149] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the purity of palladium carbon in the reducing agent in step 2) is 2%-15%, preferably 5%-10%.

[0150] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the purity of the hydrazine hydrate in the reducing agent in step 2) is 40%-85%, preferably 50%-80%.

[0151] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the molar ratio of the compound of formula V in step 2) to hydrazine hydrate is 1:1-2.5, preferably 1:1.5-2.

[0152] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the reaction temperature in step 2) is 25-100°C, preferably 30-80°C.

[0153] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the condensing agent in step 3) is selected from N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), 1,1-carbonyldiimidazole (CDI), benzotriazol-1-yloxytriphosphonium hexafluorophosphate (BOP), benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), O-benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), Triazole-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), O-[(ethoxycarbonyl)cyanomethylamine]-N,N,N',N'-tetramethylthiourea tetrafluoroborate (TOTU), 2-(2-pyridone-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU), ethyl methylphosphonic anhydride (EMPA), n-propylphosphonic anhydride (T3P), cyanuric chloride, 2-chloro-4,6-diphenyl-1,3,5-triazine (CDMT), 4-(4,6-dimethoxy-1,3,5,-triazine-2-yl)-4-methylmorpholine hydrochloride (DMTMM), boric acid, 3-nitrophenylboronic acid, methanesulfonyl chloride, p-toluenesulfonyl chloride, acetic anhydride, Boc anhydride (Boc 2 O), pivaloyl chloride, ethyl chloroformate, isobutyl chloroformate, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), thionyl chloride, oxalyl chloride, phosphorus oxychloride, (chloromethylene) dimethylammonium chloride (Vilsmeier Reagent) or any one thereof or a combination thereof.

[0154] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the solvent in step 3) is selected from any one of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, acetonitrile, acetone, 2-butanone, dichloromethane, 1,2-dichloroethane, ethyl acetate, isopropyl acetate, tert-butyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide or a combination thereof.

[0155] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the molar ratio of the compound of formula IV: Boc-glycine: condensing agent in step 3) is 1:1-2:1-2, preferably 1:1-1.2:1-1.5.

[0156] In a preferred technical solution of the present invention, in the preparation of the compound of formula I, a base is optionally added in step 3).

[0157] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the base in step 3) is selected from any one of triethylamine, diisopropylethylamine, pyridine, N-methylmorpholine (NMM), N-methylimidazole (NMI) or a combination thereof.

[0158] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, a condensation auxiliary is optionally added in step 3).

[0159] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the condensation auxiliary in step 3) is selected from any one of 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), N-hydroxy-5-norbornene-2,3-dicarboximide (HONB), and 3,4-dihydro-3-hydroxy-4-oxy-1,2,3-benzotriazine (HOOBt) or a combination thereof.

[0160] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the molar ratio of the compound of formula IV in step 3): Boc-glycine: condensation agent: condensation aid: base is 1:1-2:1-2:0-2:0-10, preferably 1:1-1.2:1-1.5:1-2:1-2.

[0161] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the reaction temperature of step 3) is 10°C-150°C, preferably 25°C-80°C, and more preferably 25°C-60°C.

[0162] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the acid in step 4) is selected from any one of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, trifluoroacetic acid, a methanol solution of hydrogen chloride, an ethanol solution of hydrogen chloride, a dioxane solution of hydrogen chloride, and an ethyl acetate solution of hydrogen chloride, or a combination thereof.

[0163] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the solvent in step 4) is selected from any one of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, acetonitrile, acetone, 2-butanone, methanol, ethanol, isopropanol, dichloromethane, 1,2-dichloroethane, ethyl acetate, isopropyl acetate, tert-butyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, water or a combination thereof.

[0164] In a preferred technical solution of the present invention, in the preparation of the compound of formula I, the molar ratio of the compound of formula III in step 4) to the acid is 1:1-10, preferably 1:1-5.

[0165] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, a solvent is optionally added in the preparation of the compound of formula II in step 4).

[0166] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the reaction temperature in step 4) is 20°C-60°C, preferably 25°C-50°C.

[0167] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the condensing agent in step 5) is selected from N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), 1,1-carbonyldiimidazole (CDI), benzotriazol-1-yloxytriphosphonium hexafluorophosphate (BOP), benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), O-benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), Triazole-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), O-[(ethoxycarbonyl)cyanomethylamine]-N,N,N',N'-tetramethylthiourea tetrafluoroborate (TOTU), 2-(2-pyridone-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU), ethyl methylphosphonic anhydride (EMPA), n-propylphosphonic anhydride (T3P), cyanuric chloride, 2-chloro-4,6-diphenyl-1,3,5-triazine (CDMT), 4-(4,6-dimethoxy-1,3,5,-triazine-2-yl)-4-methylmorpholine hydrochloride (DMTMM), boric acid, 3-nitrophenylboronic acid, methanesulfonyl chloride, p-toluenesulfonyl chloride, acetic anhydride, Boc anhydride (Boc 2O), pivaloyl chloride, ethyl chloroformate, isobutyl chloroformate, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), thionyl chloride, oxalyl chloride, phosphorus oxychloride, (chloromethylene) dimethylammonium chloride (Vilsmeier Reagent) or any one thereof or a combination thereof.

[0168] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the solvent in step 5) is selected from any one of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, acetonitrile, acetone, 2-butanone, dichloromethane, 1,2-dichloroethane, ethyl acetate, isopropyl acetate, tert-butyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide or a combination thereof.

[0169] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, in step 5), the molar ratio of the compound of formula II: 1-naphthoic acid: condensing agent is 1:1-2:1-2, preferably 1:1-1.2:1-1.5.

[0170] In a preferred technical solution of the present invention, in the preparation of the compound of formula I, in step 5), a base is optionally added.

[0171] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the base is selected from any one of triethylamine, diisopropylethylamine, pyridine, N-methylmorpholine (NMM), N-methylimidazole (NMI) or a combination thereof.

[0172] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, in step 5), a condensation aid is optionally added, and the condensation aid is selected from any one of 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), N-hydroxy-5-norbornene-2,3-dicarboximide (HONB), and 3,4-dihydro-3-hydroxy-4-oxy-1,2,3-benzotriazine (HOOBt) or a combination thereof.

[0173] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, in step 5), the molar ratio of the compound of formula II: 1-naphthoic acid: condensation agent: condensation aid: base is 1:1-2:1-2:0-2:0-10, preferably 1:1-1.2:1-1.5:1-2:1-2.

[0174] In the preferred technical scheme of the present invention, in the preparation of the compound of formula I, the reaction temperature in step 5) is 10°C-150°C, preferably 25°C-80°C, more preferably 25°C-60°C.

[0175] Another object of the present invention is to provide a compound of formula II, wherein X = H, D; n = an integer of 1-4,

[0176]

[0177] Another object of the present invention is to provide a method for preparing the compound of formula II, comprising the following steps:

[0178]

[0179] 1) reacting a compound of formula VI with an Xn-substituted o-halonitrobenzene in a solvent in the presence of a base to obtain a compound of formula V;

[0180] 2) reacting the compound of formula V in the presence of a reducing agent in a solvent to obtain a compound of formula IV;

[0181] 3) reacting the compound of formula IV with Boc glycine in the presence of a condensing agent in a solvent to obtain a compound of formula III;

[0182] 4) The compound of formula III is reacted in the presence of an acid in a solvent to obtain a compound of formula II.

[0183] In a preferred technical scheme of the present invention, in the preparation of the compound of formula II, the base in step 1) is selected from any one of sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, and cesium hydroxide, or a combination thereof.

[0184] In the preferred technical scheme of the present invention, in the preparation of the compound of formula II, the solvent in step 1) is selected from any one of toluene, xylene, 2-methyltetrahydrofuran, dioxane, acetonitrile, acetone, 2-butanone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide or a combination thereof.

[0185] In the preferred technical scheme of the present invention, in the preparation of the compound of formula II, the molar ratio of the compound of formula VI in step 1): Xn-substituted o-halonitrobenzene: base is 1:1-2:1-5, preferably 1:1-1.5:1-2.5, and more preferably 1:1-1.2:1.2-2.

[0186] In the preferred technical scheme of the present invention, in the preparation of the compound of formula II, the reaction temperature in step 1) is 20°C-150°C, preferably 50°C-110°C.

[0187] In the preferred technical scheme of the present invention, in the preparation of the compound of formula II, the reducing agent in step 2) is selected from any one of palladium carbon-hydrogen, palladium carbon-ammonium formate, palladium carbon-formic acid, palladium carbon-hydrazine hydrate, nickel-hydrogen, iron powder-dilute hydrochloric acid, sodium borohydride, potassium borohydride, and tin dichloride or a combination thereof.

[0188] In a preferred technical solution of the present invention, in the preparation of the compound of formula II, the solvent in step 2) is selected from any one of methanol, ethanol, water or a combination thereof.

[0189] In the preferred technical scheme of the present invention, in the preparation of the compound of formula II, the condensing agent in step 3) is selected from N, N'-dicyclohexylcarbodiimide (DCC), N, N'-diisopropylcarbodiimide (DIC), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), 1,1-carbonyldiimidazole (CDI), benzotriazol-1-yloxytriphosphonium hexafluorophosphate (BOP), benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), 2-(7-azobenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate (HATU), benzotriazole-N, N, N', N'-tetramethyluronium hexafluorophosphate (HBTU), O-benzotriazole-N, N, N', N'-tetramethyluronium hexafluorophosphate (HBTU), Triazole-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), O-[(ethoxycarbonyl)cyanomethylamine]-N,N,N',N'-tetramethylthiourea tetrafluoroborate (TOTU), 2-(2-pyridone-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU), ethyl methylphosphonic anhydride (EMPA), n-propylphosphonic anhydride (T3P), cyanuric chloride, 2-chloro-4,6-diphenyl-1,3,5-triazine (CDMT), 4-(4,6-dimethoxy-1,3,5,-triazine-2-yl)-4-methylmorpholine hydrochloride (DMTMM), boric acid, 3-nitrophenylboronic acid, methanesulfonyl chloride, p-toluenesulfonyl chloride, acetic anhydride, Boc anhydride (Boc 2 O), pivaloyl chloride, ethyl chloroformate, isobutyl chloroformate, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), thionyl chloride, oxalyl chloride, phosphorus oxychloride, (chloromethylene) dimethylammonium chloride (Vilsmeier Reagent) or any one thereof or a combination thereof.

[0190] In the preferred technical scheme of the present invention, in the preparation of the compound of formula II, the solvent in step 3) is selected from any one of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, acetonitrile, acetone, 2-butanone, dichloromethane, 1,2-dichloroethane, ethyl acetate, isopropyl acetate, tert-butyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide or a combination thereof.

[0191] In a preferred technical solution of the present invention, in the preparation of the compound of formula II, a base is optionally added in step 3).

[0192] In the preferred technical scheme of the present invention, in the preparation of the compound of formula II, the base in step 3) is selected from any one of triethylamine, diisopropylethylamine, pyridine, N-methylmorpholine (NMM), N-methylimidazole (NMI) or a combination thereof.

[0193] In the preferred technical scheme of the present invention, in the preparation of the compound of formula II, a condensation auxiliary agent is optionally added in step 3).

[0194] In the preferred technical scheme of the present invention, in the preparation of the compound of formula II, the condensation aid in step 3) is selected from any one of 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), N-hydroxy-5-norbornene-2,3-dicarboximide (HONB), and 3,4-dihydro-3-hydroxy-4-oxy-1,2,3-benzotriazine (HOOBt) or a combination thereof.

[0195] In the preferred technical scheme of the present invention, in the preparation of the compound of formula II, the molar ratio of the compound of formula IV in step 3): Boc-glycine: condensation agent: condensation aid: base is 1:1-2:1-2:0-2:0-10, preferably 1:1-1.2:1-1.5:0-2:0-2.

[0196] In the preferred technical scheme of the present invention, in the preparation of the compound of formula II, the reaction temperature of step 3) is 10°C-150°C, preferably 25°C-80°C, and more preferably 25°C-50°C.

[0197] In the preferred technical scheme of the present invention, in the preparation of the compound of formula II, the acid in step 4) is selected from any one of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, trifluoroacetic acid, a methanol solution of hydrogen chloride, an ethanol solution of hydrogen chloride, a dioxane solution of hydrogen chloride, and an ethyl acetate solution of hydrogen chloride, or a combination thereof.

[0198] In the preferred technical scheme of the present invention, in the preparation of the compound of formula II, the solvent in step 4) is selected from any one of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, acetonitrile, acetone, 2-butanone, methanol, ethanol, isopropanol, dichloromethane, 1,2-dichloroethane, ethyl acetate, isopropyl acetate, tert-butyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, water or a combination thereof.

[0199] In the preferred technical scheme of the present invention, in the preparation of the compound of formula II, the molar ratio of the compound of formula III in step 4) to the acid is 1:1-10, preferably 1:1-5.

[0200] In the preferred technical scheme of the present invention, in the preparation of the compound of formula II, the reaction temperature in step 4) is 20°C-100°C, preferably 25°C-50°C.

[0201] Another object of the present invention is to provide a compound of formula III, wherein X = H, D; n = an integer of 1-4,

[0202]

[0203] Another object of the present invention is to provide a method for preparing the compound of formula III, comprising the following steps:

[0204]

[0205] 1) reacting a compound of formula VI with an Xn-substituted o-halonitrobenzene in a solvent in the presence of a base to obtain a compound of formula V;

[0206] 2) reacting the compound of formula V in the presence of a reducing agent in a solvent to obtain a compound of formula IV;

[0207] 3) The compound of formula IV reacts with Boc glycine in the presence of a condensing agent in a solvent to obtain a compound of formula III.

[0208] In a preferred technical scheme of the present invention, in the preparation of the compound of formula III, the base in step 1) is selected from any one of sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, and cesium hydroxide, or a combination thereof.

[0209] In the preferred technical scheme of the present invention, in the preparation of the compound of formula III, the molar ratio of the compound of formula VI in step 1): Xn-substituted o-halonitrobenzene: base is 1:1-2:1-5, preferably 1:1-1.5:1-2.5, and more preferably 1:1-1.2:1.2-2.

[0210] In the preferred technical scheme of the present invention, in the preparation of the compound of formula III, the solvent in step 1) is selected from any one of toluene, xylene, 2-methyltetrahydrofuran, dioxane, acetonitrile, acetone, 2-butanone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide or a combination thereof.

[0211] In the preferred technical scheme of the present invention, in the preparation of the compound of formula III, the reaction temperature of step 1) is 20°C-150°C, preferably 50°C-110°C.

[0212] In the preferred technical scheme of the present invention, in the preparation of the compound of formula III, the reducing agent in step 2) is selected from any one of palladium carbon-hydrogen, palladium carbon-ammonium formate, palladium carbon-formic acid, palladium carbon-hydrazine hydrate, nickel-hydrogen, iron powder-dilute hydrochloric acid, sodium borohydride, potassium borohydride, and tin dichloride, or a combination thereof.

[0213] In a preferred technical solution of the present invention, in the preparation of the compound of formula III, the solvent in step 2) is selected from any one of methanol, ethanol, water or a combination thereof.

[0214] In the preferred technical scheme of the present invention, in the preparation of the compound of formula III, the condensing agent in step 3) is selected from N, N'-dicyclohexylcarbodiimide (DCC), N, N'-diisopropylcarbodiimide (DIC), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), 1,1-carbonyldiimidazole (CDI), benzotriazol-1-yloxytriphosphonium hexafluorophosphate (BOP), benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), 2-(7-azobenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate (HATU), benzotriazole-N, N, N', N'-tetramethyluronium hexafluorophosphate (HBTU), O-benzotriazole-N, N, N', N'-tetramethyluronium hexafluorophosphate (HBTU), Triazole-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), O-[(ethoxycarbonyl)cyanomethylamine]-N,N,N',N'-tetramethylthiourea tetrafluoroborate (TOTU), 2-(2-pyridone-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU), ethyl methylphosphonic anhydride (EMPA), n-propylphosphonic anhydride (T3P), cyanuric chloride, 2-chloro-4,6-diphenyl-1,3,5-triazine (CDMT), 4-(4,6-dimethoxy-1,3,5,-triazine-2-yl)-4-methylmorpholine hydrochloride (DMTMM), boric acid, 3-nitrophenylboronic acid, methanesulfonyl chloride, p-toluenesulfonyl chloride, acetic anhydride, Boc anhydride (Boc 2 O), pivaloyl chloride, ethyl chloroformate, isobutyl chloroformate, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), thionyl chloride, oxalyl chloride, phosphorus oxychloride, (chloromethylene) dimethylammonium chloride (Vilsmeier Reagent) or any one thereof or a combination thereof.

[0215] In the preferred technical scheme of the present invention, in the preparation of the compound of formula III, the solvent in step 3) is selected from any one of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, acetonitrile, acetone, 2-butanone, dichloromethane, 1,2-dichloroethane, ethyl acetate, isopropyl acetate, tert-butyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide or a combination thereof.

[0216] In a preferred technical solution of the present invention, in the preparation of the compound of formula III, a base is optionally added in step 3).

[0217] In the preferred technical scheme of the present invention, in the preparation of the compound of formula III, the base is selected from any one of triethylamine, diisopropylethylamine, pyridine, N-methylmorpholine (NMM), N-methylimidazole (NMI) or a combination thereof.

[0218] In the preferred technical scheme of the present invention, in the preparation of the compound of formula III, a condensation auxiliary agent is optionally added in step 3).

[0219] In the preferred technical scheme of the present invention, in the preparation of the compound of formula III, the condensation aid is selected from any one of 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), N-hydroxy-5-norbornene-2,3-dicarboximide (HONB), and 3,4-dihydro-3-hydroxy-4-oxy-1,2,3-benzotriazine (HOOBt) or a combination thereof.

[0220] In the preferred technical scheme of the present invention, in the preparation of the compound of formula III, the molar ratio of the compound of formula IV in step 3): Boc-glycine: condensation agent: condensation aid: base is 1:1-2:1-2:0-2:0-10, preferably 1:1-1.2:1-1.5:0-2:0-2.

[0221] Another object of the present invention is to provide a broad-spectrum anti-tumor pharmaceutical composition, which is composed of a compound of formula I or any one of its pharmaceutically acceptable salts, solvates, crystalline forms or a combination thereof and a pharmaceutically acceptable carrier.

[0222] In the preferred technical solution of the present invention, the amount or type of the pharmaceutically acceptable carrier in the composition is determined according to factors such as the physicochemical properties and content of the active ingredients in the composition, the type of preparation, the dissolution and bioavailability of the preparation, and the like.

[0223] In a preferred technical solution of the present invention, the pharmaceutical composition is in the form of an oral preparation, an injection, or an external preparation.

[0224] In a preferred technical solution of the present invention, the oral preparation is selected from any one of oral liquid preparations, tablets, capsules, granules, syrups, powders, dews, effervescents, suspensions, pills, pellets, mixtures, pastes, emulsions, liniments, dragees, solutions, lozenges, cachets, gels, and suspensions.

[0225] In the preferred technical solution of the present invention, the injection is selected from any one of a solution injection, an emulsion injection, a suspension injection, a sterile powder for injection, and a large infusion.

[0226] In the preferred technical scheme of the present invention, the external preparation is selected from any one of a gel, a paste, a plaster, a cream, an ointment, a liniment, a lotion, a suppository, a smear, a gel, an ointment, an aerosol, a dry powder inhaler, a spray, and a nebulizer.

[0227] In the preferred technical scheme of the present invention, the pharmaceutically acceptable carrier of the present invention is a commonly used excipient or auxiliary material in the art for preparing the preparation, selected from fillers (diluents), disintegrants, binders, emulsifiers, emulsifier aids, lyoprotectants, dispersants, pore-forming agents, lubricants (glidants or anti-adhesive agents), wetting agents, pH regulators (acid-base regulators), osmotic pressure regulators, solubilizers, antioxidants, antibacterial agents (bactericides), analgesics (anesthetics), suspending agents, flavoring agents, and any one or a combination of flavoring agents.

[0228] In the preferred technical scheme of the present invention, the filler is selected from any one or a combination of lactose, powdered sugar, dextrin, starch, sodium carboxymethyl starch, sodium starch glycolate, pregelatinized starch, modified starch, hydroxypropyl starch, potato starch, corn starch, cellulose, inorganic calcium salt, calcium chloride, calcium sulfate, calcium phosphate, calcium hydrogen phosphate, precipitated calcium carbonate, sorbitol, mannitol, microcrystalline cellulose, sodium carboxymethyl cellulose, ethyl cellulose, and hydroxypropyl methyl cellulose.

[0229] In a preferred technical solution of the present invention, the disintegrant is selected from any one or a combination of starch, sodium carboxymethyl starch, sodium starch glycolate, pregelatinized starch, modified starch, hydroxypropyl starch, potato starch, corn starch or its derivatives, cross-linked polyvinyl pyrrolidone, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, and cross-linked sodium carboxymethyl cellulose.

[0230] In the preferred technical scheme of the present invention, the adhesive is selected from any one of syrup, gum arabic, gelatin, sorbitol, tragacanth gum, cellulose, microcrystalline cellulose, sodium carboxymethyl cellulose, ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, gelatin slurry, starch slurry, polyvinyl pyrrolidone, sodium carboxymethyl starch, sodium starch glycolate, pregelatinized starch, modified starch, hydroxypropyl starch, potato starch, and corn starch, or a combination thereof.

[0231] In the preferred technical scheme of the present invention, the emulsifier is selected from any one of sodium stearate, potassium stearate, triethanolamine stearate, magnesium stearate, calcium stearate, sodium lauryl sulfate, sodium dodecylbenzene sulfonate, polysorbate (Tween), Span, benzyl alcohol, benzyl alcohol, tragacanth gum, gum arabic, Pluronic F-68, lecithin, and soybean lecithin, or a combination thereof.

[0232] In a preferred technical solution of the present invention, the auxiliary emulsifier is selected from any one of n-butanol, ethylene glycol, ethanol, propylene glycol, glycerol, and polyglycerol esters, or a combination thereof.

[0233] In a preferred technical solution of the present invention, the lyoprotectant is selected from any one of sucrose, lactose, galactose, glucose, trehalose, mannitol, sorbitol or a combination thereof.

[0234] In the preferred technical solution of the present invention, the solubilizing agent is selected from any one of Tween-80, Pluronic F-68, benzyl alcohol, benzyl alcohol, bile salt, deoxycholate, glycerol, propylene glycol, and polyethylene glycol, or a combination thereof.

[0235] In the preferred technical scheme of the present invention, the suspending agent is selected from any one of microcrystalline cellulose, sodium carboxymethyl cellulose, ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, syrup, glycerin, gelatin, gum arabic, tragacanth, sodium alginate, potassium alginate, pectin or a combination thereof.

[0236] In a preferred technical solution of the present invention, the wetting agent is selected from any one of sodium lauryl sulfate, polysorbate (Tween), water, alcohol, ester or a combination thereof.

[0237] In a preferred technical solution of the present invention, the lubricant is selected from any one of micro-powdered silica gel, magnesium stearate, talc, colloidal silicon dioxide, aluminum hydroxide, boric acid, hydrogenated vegetable oil, polyethylene glycol, and sodium lauryl sulfate, or a combination thereof.

[0238] In the preferred technical scheme of the present invention, the antioxidant is selected from any one of sodium sulfite, sodium bisulfite, sodium metabisulfite, sodium thiosulfate, vitamin C, vitamin E, dibutyl benzoic acid, butylated hydroxyanisole (BHA), dibutyl hydroxytoluene (BHT), propyl gallate (PG), niacinamide, acetylcysteic acid, and tert-butylhydroquinone (TBHQ) or a combination thereof.

[0239] In a preferred technical solution of the present invention, the bacteriostatic agent (bactericide) is selected from any one of phenol, cresol, chlorobutanol, benzyl alcohol or a combination thereof.

[0240] In a preferred technical solution of the present invention, the analgesic (anesthetic) is selected from any one of chlorobutanol, benzyl alcohol, lidocaine, procaine or a combination thereof.

[0241] In a preferred technical scheme of the present invention, the acid-base regulator (pH regulator) is selected from any one of hydrochloric acid, sodium hydroxide, potassium hydroxide, citric acid, sodium citrate, potassium citrate, malic acid, sodium malate, potassium malate, sodium dihydrogen phosphate, disodium hydrogen phosphate, calcium hydroxide, calcium lactate, sodium lactate, sodium phosphate, potassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, sodium bicarbonate, and sodium carbonate, or a combination thereof.

[0242] In a preferred technical solution of the present invention, the osmotic pressure regulator is selected from any one of sodium chloride, potassium chloride, glucose, phosphate and citrate.

[0243] In a preferred technical solution of the present invention, the flavoring agent is selected from any one of honey, syrup, acid, alkali, essence, sweetener, or a combination thereof.

[0244] In a preferred technical solution of the present invention, the pharmaceutical composition of the present invention is mixed with a pharmaceutically acceptable sustained-release preparation carrier or a controlled-release preparation carrier according to the preparation method of sustained-release preparation or controlled-release preparation in the art, such as adding a blocking agent coating or making a skeleton-type preparation, etc., and the compound of formula I of the present invention or any one of its pharmaceutically acceptable salts, solvates, crystalline forms or a combination thereof is microencapsulated to prepare a sustained-release preparation or a controlled-release preparation.

[0245] In the preferred technical solution of the present invention, the sustained-release preparation carrier or controlled-release preparation carrier is selected from any one of an oily admixture, a hydrophilic colloid, a water-insoluble blocker, an enteric blocker, and a biodegradable blocker or a combination thereof.

[0246] In the preferred technical solution of the present invention, the oily admixture is selected from any one of glyceryl monostearate, hydrogenated castor oil, mineral oil, polysiloxane, dimethylsiloxane or a combination thereof.

[0247] In the preferred technical scheme of the present invention, the hydrophilic colloid is selected from any one of methylcellulose (MC), sodium carboxymethylcellulose (CMC-Na), hydroxyethylcellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HMPC), polyvinyl pyrrolidone (PVP), gum arabic, tragacanth or carbopol, polyvinyl alcohol (PVA), pectin, alginate, chitosan, xanthan gum, guar gum, garnet, gelatin, agar, and galactomannan, or a combination thereof.

[0248] In the preferred technical solution of the present invention, the water-insoluble retarder is selected from any one of ethyl cellulose (EC), cellulose acetate (CA), polyethylene, polypropylene, polysiloxane, ethylene vinyl acetate copolymer (EVA), polymethyl methacrylate or a combination thereof.

[0249] In the preferred technical solution of the present invention, the enteric retarder is selected from any one of cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HMPCP), polyvinyl alcohol phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS) acrylic resin or a combination thereof.

[0250] In the preferred technical solution of the present invention, the biodegradable retarder is selected from any one of wax, fatty acid, fatty acid ester, fatty alcohol, carnauba wax, stearic acid, glyceryl monostearate, stearyl alcohol, and hexadecanol, or a combination thereof.

[0251] Another object of the present invention is to provide a pharmaceutical composition, which consists of a first composition containing a compound of formula I or any one of its pharmaceutically acceptable salts, solvates, crystalline forms or a combination thereof and a second composition containing other drugs.

[0252] In the preferred technical scheme of the present invention, the other drugs are selected from 13-cis retinoic acid, GM-CSF, IL-2, cisplatin, carboplatin, oxaloplatin, alkylating agents, cyclophosphamide, ifosfamide, melphalan, topoisomerase II inhibitors, etoposide, anthracycline antibiotics, doxorubicin, vinca alkaloids, vincristine, topotecan, irinotecan, osimertinib, gefitinib, osimertinib, gefitinib, afatinib, neratinib, erlotinib, rociletinib, omutinib, lazertinib, nazartinib, natinib, teritinib, abitinib, orafructinib, abrutinib, amivantambu, talocitinib , mobotimib, savalitinib, catinib, cetuximab, panitumumab, lapatinib, dacomitinib, nesituximab, vandetanib, icotinib, canertinib, allitinib, varlitimb, tesevatinib, pellitinib, sapitinib, any one of EAI045, TAK-285, AG-1478, AEE788, CUDC-101, WZ8040, WZ4002, WZ3146, AG-490, PD153035, or a combination thereof.

[0253] In a preferred technical solution of the present invention, the first composition and the second composition are administered sequentially, simultaneously or successively.

[0254] In a preferred technical solution of the present invention, the administration method of the pharmaceutical composition is selected from any one of oral administration, injection administration, mucosal administration, and skin administration.

[0255] Another object of the present invention is to provide the use of the compound of formula I in preparing a drug for inhibiting proliferating cell nuclear antigen-related diseases.

[0256] In a preferred technical solution of the present invention, the disease associated with inhibiting proliferating cell nuclear antigen is selected from diseases associated with excessive cell proliferation or diseases associated with abnormal PCNA activity levels, preferably any one of cancer, leukemia, sarcoma or their complications.

[0257] In the preferred technical scheme of the present invention, the cancer is selected from prostate cancer, large cell lung cancer, small cell lung cancer, liver cancer, breast cancer, ovarian cancer, pancreatic cancer, thyroid cancer, endocrine system cancer, brain cancer, adenocarcinoma, cervical cancer, colon cancer, head and neck cancer, kidney cancer, lung cancer, non-gastric cancer, uterine cancer, colorectal cancer, Hodgkin's disease, essential thrombocythemia, essential macroglobulinemia, bladder cancer, premalignant skin lesions, testicular cancer, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical carcinoma, medullary thyroid cancer, colorectal cancer, Colon cancer, papillary thyroid cancer, hepatocellular carcinoma, large cell lung cancer, pancreatic cancer, lymphoma, bladder cancer, head and neck cancer, skin cancer, testicular cancer, esophageal cancer, central nervous system (CNS) cancer, sympathetic nervous system (SNS) cancer, adrenal cancer, acinar carcinoma, acinar carcinoma, adenoid carcinoma, adenoid cystic carcinoma, adrenal cortical carcinoma, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, basaloid carcinoma, basosquamous cell carcinoma, bronchioloalveolar carcinoma, bronchiolar carcinoma, bronchial carcinoma, medullary carcinoma, cholangiocellular carcinoma, choriocarcinoma, colloid carcinoma, comedonal carcinoma , uterine cancer, cribriform cancer, armor-shaped cancer, skin cancer, columnar cancer, columnar cell carcinoma, ductal carcinoma, scirrhous cancer, embryonal carcinoma, medullary carcinoma, epidermoid carcinoma, adenoid epithelial carcinoma, exophytic carcinoma, ulcerative carcinoma, fibrocarcinoma, colloid carcinoma, colloid carcinoma, giant cell carcinoma, giant cell carcinoma, granular cell carcinoma, hair matrix carcinoma, blood cancer, hepatocellular carcinoma, Schüttel cell carcinoma, transparent carcinoma, adrenal carcinoma, immature embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Kronpecher's carcinoma, Kulczycki cell carcinoma, large cell carcinoma, lenticular carcinoma, lipomatous carcinoma, lymphoma Any of the following: cutaneous carcinoma, medullary carcinoma, melanoma, soft tissue carcinoma, mucinous carcinoma, mucoepidermoid carcinoma, myxomatous carcinoma, nasopharyngeal carcinoma, oat cell carcinoma, ossifying carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, acanthoid cell carcinoma, encephaloid carcinoma, renal cell carcinoma, reserve cell carcinoma, sarcomatoid carcinoma, Schneider's carcinoma, scirrhous carcinoma, scrotal carcinoma, signet ring cell carcinoma, simple carcinoma, small cell carcinoma, potato carcinoma, spheroid cell carcinoma, spindle cell carcinoma, medullary carcinoma, squamous cell carcinoma, rope-like carcinoma, angioectatic carcinoma, transitional cell carcinoma, nodular cutaneous carcinoma, sparse carcinoma, villous carcinoma, or their complications.

[0258] In the preferred technical scheme of the present invention, the leukemia is selected from acute non-lymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, non-leukemic leukemia, leukemic leukemia, basophilic leukemia, blast cell leukemia, bovine leukemia, chronic myeloid leukemia, cutaneous leukemia, embryonic leukemia, eosinophilic leukemia, Gross's leukemia, hairy cell leukemia, hemoblastic leukemia, hemoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenia any one of the following: leukemia, lymphocytic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenic leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myeloid leukemia, myelomonocytic leukemia, Negley's leukemia, plasma cell leukemia, multiple myeloma, plasma cell leukemia, promyelocytic leukemia, Liddle cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemic leukemia, undifferentiated cell leukemia, or their complications.

[0259] In the preferred technical scheme of the present invention, the sarcoma is selected from brain tumor, neuroblastoma, chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abernethy's sarcoma, liposarcoma, liposarcoma, alveolar soft tissue sarcoma, ameloblastic sarcoma, grape-like sarcoma, green carcinosarcoma, choriocarcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, immunoblastic sarcoma of B cells, lymphoma, immunoblastic sarcoma of T cells, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, Leukemic sarcoma, malignant mesenchymal sarcoma, periosteal sarcoma, reticular cell sarcoma, Rous sarcoma, plasma cystic sarcoma, synovial sarcoma or telangiectatic sarcoma, glioma, lymphoma (including B-acute lymphoblastic lymphoma, non-Hodgkin's lymphoma, Burkitt's lymphoma, small cell lymphoma, large cell lymphoma, Hodgkin's lymphoma, multiple myeloma, glioblastoma, olfactory neuroblastoma, melanoma, mesothelioma, rhabdomyosarcoma, non-Hodgkin's lymphoma, multiple myeloma, glioma, glioblastoma multiforme, primary brain tumor, malignant pancreatic insulinoma, malignant carcinoid tumor, lymphoma, pancreatic exocrine or endocrine tumor, any one of neuroblastoma or complications thereof.

[0260] In the preferred technical scheme of the present invention, the melanoma is selected from any one of acral lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Claudemann's melanoma, S91 melanoma, Harrington-Perkins melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungual melanoma, superficial spreading melanoma, or its complications.

[0261] The hydrogen spectrum of the compounds of the present invention ( 1 H-NMR detection method: the instrument is a 400 MHz nuclear magnetic resonance instrument (BrukerAdvance II 400MHz); tetramethylsilane (TMS) is used as the internal standard, and the data are collected at room temperature; the chemical shift (δ) is one part per million (ppm); single peaks are recorded as s, double peaks are recorded as d, triplet peaks are recorded as t, quartet peaks are recorded as q, multiple peaks are recorded as m, and broad single peaks are recorded as brs; the coupling constant is recorded as j, and the unit is Hz; the deuterated solvent is deuterated dimethyl sulfoxide (DMSO-d 6 ).

[0262] Mass spectrometry (MS) detection method for the compounds of the present invention: the instrument is Shimadzu LCMS2010EV, in positive direction, giving the ion peak of molecular weight hydrogenation (MH+).

[0263] Unless otherwise specified, when the present invention relates to the percentage between liquids, the percentage is volume / volume percentage; when the present invention relates to the percentage between liquids and solids, the percentage is volume / weight percentage; when the present invention relates to the percentage between solids and liquids, the percentage is weight / volume percentage, and the rest are weight / weight percentages.

[0264] Compared with the prior art, the present invention has the following beneficial effects:

[0265] 1. The proliferating cell nuclear antigen inhibitor compound of formula I of the present invention has significantly better tumor growth inhibition activity than AOH1996, and has the advantages of a broad anti-cancer spectrum, excellent safety and effectiveness, good stability, high bioavailability, and a wide range of applicable populations, providing a new medication option for clinical cancer patients.

[0266] 2. The preparation method of the compound of formula I of the present invention has the advantages of simple operation, better cost, green environmental protection, and suitability for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0267] Figure 1 The inhibitory activity of the proliferating cell nuclear antigen inhibitor of the present invention on tumor cell growth is studied. DETAILED DESCRIPTION

[0268] The present invention will be specifically described below in conjunction with embodiments; the embodiments of the present invention are only used to illustrate the technical solutions of the present invention and are not limited to the embodiments. Any changes, modifications, substitutions, combinations, and simplifications made without departing from the spirit, essence, and principles of the present invention shall be equivalent replacement methods and shall be included in the protection spirit and scope of the present invention.

[0269] Example 1 2-(3-methoxy-d 3 Preparation of -phenoxy)-nitrobenzene

[0270]

[0271] 1) In anhydrous, oxygen-free, stirring conditions, 3-methoxy-d 3 -phenol (50g, 393.21mmol), anhydrous potassium carbonate (110g, 795.89mmol) and N,N-dimethylformamide (200ml), mix evenly and heat to 80℃;

[0272] 2) After 30 minutes, o-fluoronitrobenzene (56 g, 396.88 mmol) was added dropwise; after the addition was complete, stirring was continued at 80° C. for 3 hours (TLC);

[0273] 3) The reaction mixture was cooled to room temperature, diluted with water (300 ml), and extracted with ethyl acetate (300 ml x 3);

[0274] 4) The ethyl acetate phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure at 50°C to remove ethyl acetate to obtain 2-(3-methoxy-d 3 -phenoxy)-nitrobenzene crude product (98g).

[0275] Example 2 2-(3-methoxy-d 3 Preparation of -phenoxy)-aniline

[0276]

[0277] 1) The 2-(3-methoxy-d 3 -phenoxy)-nitrobenzene crude product (98 g, -393.21 mmol) was dissolved in ethanol (300 ml), and 5% palladium carbon (10 g) was added; the temperature was raised to boiling under stirring;

[0278] 2) Slowly drop 80% hydrazine hydrate (54 g, 798.67 mmol); after the addition, stir and react for 5 hours under boiling conditions;

[0279] 3) The reaction mixture was cooled to room temperature, filtered through diatomaceous earth to remove palladium carbon, and the filter cake was washed with ethanol (50 ml x 3);

[0280] 4) The filtrate was collected and the ethanol was evaporated under reduced pressure at 50°C to obtain 2-(3-methoxy-d 3 -phenoxy)-aniline crude product (86 g).

[0281] Example 3 Preparation of Naphthalene-1-Carboxyylglycine Methyl Ester

[0282]

[0283] 1) At room temperature, in anhydrous and oxygen-free conditions, stir and mix 1-naphthoic acid (50 g, 290.39 mmol), glycine methyl ester hydrochloride (38 g, 302.67 mmol), triethylamine (32 g, 316.24 mmol) and tetrahydrofuran (150 ml);

[0284] 2) Add 1,3-cyclohexylcarbodiimide (DCC, 63 g, 305.34 mmol) to the above mixture and stir the mixture at room temperature for 10 hours (TLC);

[0285] 3) adding ethyl acetate (300 ml) to dilute, filtering, and removing the by-product 1,3-dicyclohexylurea (DCU);

[0286] 4) The filtrate was collected and ethyl acetate was evaporated under reduced pressure at 50°C to obtain crude naphthalene-1-formylglycine methyl ester (71 g).

[0287] Example 4 Preparation of Naphthalene-1-Carboxyl Glycine

[0288]

[0289] 1) At room temperature, the crude product of naphthalene-1-formylglycine methyl ester obtained in Example 3 was dissolved in methanol (300 ml, about 1 M), 2 M sodium hydroxide (151.5 ml, 303 mmol) was added, and the mixture was stirred for 20 hours;

[0290] 2) Remove the methanol by vacuum rotary evaporation at 45°C, add water and dilute to a clear transparent solution;

[0291] 3) Cool to 0°C, add concentrated hydrochloric acid to neutralize to pH 0-1 while stirring;

[0292] 4) Filter, wash the filter cake with water, and dry under reduced pressure at 50° C. The obtained crude naphthalene-1-formylglycine is crystallized from ethyl acetate-n-hexane to obtain a fine product (60 g, 90% yield, based on 50 g naphthoic acid).

[0293] Example 5 Naphthalene-1-carboxylic acid {[2-(3-methoxy-d 3Preparation of [-phenoxy)-phenylcarbamoyl]-methyl}-amide (BC2023D1)

[0294]

[0295] 1) At room temperature, anhydrous and oxygen-free conditions, naphthalene-1-formylglycine (43 g, 187.58 mmol) prepared in Example 4 was dissolved in N,N-dimethylformamide (150 ml), and carbonyl imidazole (32 g, 197.35 mmol) was added; the mixture was stirred at room temperature for 1 hour;

[0296] 2) The 2-(3-methoxy-d 3 -phenoxy)-aniline crude product (41 g, 188.70 mmol) was added to the above reaction mixture; after stirring for 1 hour at room temperature, it was kept stirring at 60°C for 20 hours (TLC);

[0297] 3) The reaction mixture was cooled to room temperature, diluted with ethyl acetate (500 ml), and washed with water (200 ml x 3), 0.1 N hydrochloric acid (200 ml x 2), saturated sodium bicarbonate (200 ml) and brine (200 ml) in sequence;

[0298] 4) The reaction solution after washing was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure at 50°C to remove ethyl acetate to obtain a crude compound (80 g), which was recrystallized from ethyl acetate to obtain a fine product (73 g, 91% yield).

[0299] 1 H NMR (400 MHz, DMSO-d 6 )δ9.61(s,1H),8.93(dd,J=8.4,1.5Hz,1H),8.37(dq,J=8.1,0.8Hz,1H),8.26(m,1H),8.21(d,J=8.3 Hz,1H),8.02(dd,J=7.1,1.2Hz,1H),7.95-8.00(m,1H),7.66(dd,J=8.2,7.0Hz,1H),7.49-7.59(m,2 H),7.29(t,J=8.6Hz,1H),7.15(td,J=7.8,1.5Hz,1H),7.13(ddd,J=8.8,7.6,1.7Hz,1H),6.95(dd,J =8.1,1.5Hz,1H),6.74(d,J=5.0Hz,1H),6.63-6.65(m,1H),6.51-6.55(m,1H),4.20(d,J=5.4Hz,2H).

[0300] 13C-NMR (101 MHz, DMSO-d 6 )δ169.20,168.11,160.62,157.63,146.66,134.20,133.10,130.40,129.99,129.76,129.59,128.11,126.6 8,126.21,125.55,125.31,124.87,124.64,123.74,122.59,118.55,110.44,109.29,104.72,55.23,43.36.

[0301] MS (ESI+) m / z: [M+Na] + Calculate for C 26 H 19 D 3 N 2 O 4 Na + 452.16; found 452.16.

[0302] Example 6 2-(3-methoxyphenoxy)nitrobenzene-3,4,5,6-d 4 Preparation

[0303]

[0304] 1) In anhydrous, oxygen-free, stirring condition, 3-methoxyphenol (320 mg, 2.58 mmol), anhydrous potassium carbonate (1.0 g, 7.24 mmol) and N,N-dimethylformamide (10 ml) were uniformly mixed and heated to 80°C;

[0305] 2) After 30 minutes, add 2-bromonitrobenzene-3,4,5,6-d 4 (500 mg, 2.43 mmol); After the addition, stirring was continued at 80°C for 3 hours (TLC);

[0306] 3) The reaction mixture was cooled to room temperature, diluted with water (30 ml), and extracted with ethyl acetate (30 ml x 3);

[0307] 4) The ethyl acetate phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure at 50°C to remove ethyl acetate. The residue was purified by a 200-300 mesh silica gel column to obtain 2-(3-methoxyphenoxy)-nitrobenzene-3,4,5,6-d 4 (601 mg, 99% yield).

[0308] Example 7 2-(3-methoxyphenoxy)-aniline-3,4,5,6-d4 Preparation

[0309]

[0310] 1) 2-(3-methoxyphenoxy)nitrobenzene-3,4,5,6-d 4 (600 mg, 2.41 mmol) was dissolved in ethanol (30 ml), and 5% palladium carbon (100 mg) was added; the temperature was raised to boiling under stirring;

[0311] 2) Slowly dropwise add 80% hydrazine hydrate (180 mg, 798.67 mmol) in ethanol (5 ml); after the addition is complete, stir and react for 5 hours under boiling conditions;

[0312] 3) The reaction mixture was cooled to room temperature, filtered through diatomaceous earth to remove palladium carbon, and the filter cake was washed with ethanol (50 ml x 3);

[0313] 4) The filtrate was collected and the ethanol was evaporated under reduced pressure at 50°C to obtain 2-(3-methoxyphenoxy)-aniline-3,4,5,6-d 4 Crude product (528mg).

[0314] Example 8 {[2-(3-methoxyphenoxy)-phenyl-3,4,5,6-d 4 Preparation of tert-butyl]-carbamoyl]-methyl}-carbamate

[0315]

[0316] 1) At room temperature, in anhydrous and oxygen-free conditions, dissolve Boc-glycine (436 mg, 2.49 mmol) in N,N-dimethylformamide (10 ml), add carbonyl imidazole (405 mg, 2.50 mmol); after addition, stir and react at room temperature for 1 hour;

[0317] 2) 2-(3-methoxyphenoxy)-aniline-3,4,5,6-d prepared in Example 7 4 The crude product (520 mg, about 2.37 mmol) was added to the above reaction mixture, stirred at room temperature for 1 hour, then heated to 60°C and stirred for 20 hours (TLC);

[0318] 3) The reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 ml), and washed with water (30 ml x 3), 0.1 N hydrochloric acid (30 ml x 2), saturated sodium bicarbonate (30 ml) and brine (30 ml) in sequence;

[0319] 4) The ethyl acetate phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure at 50°C to remove ethyl acetate. The resulting oil was purified by a 200-300 mesh silica gel column to obtain {[2-(3-methoxyphenoxy)-phenyl-3,4,5,6-d 4 -carbamoyl]-methyl}-carbamic acid tert-butyl ester (870 mg, 97% yield).

[0320] Example 9 2-amino-N-[2-(3-methoxyphenoxy)-phenyl-3,4,5,6-d 4 Preparation of ]-acetamide

[0321]

[0322] 1) The oily substance obtained in Example 8 (860 mg, about 2.28 mmol) was dissolved in dichloromethane (10 ml); trifluoroacetic acid (1.0 g, 8.77 mmol) was slowly added dropwise under stirring at 0-5°C, and the mixture was stirred at room temperature for 10 hours (TLC);

[0323] 2) After all volatiles were evaporated under reduced pressure, dichloromethane (30 ml) was added to dissolve and dilute, and then water (20 ml) was added and stirred at room temperature to mix evenly; while stirring, solid sodium carbonate was slowly added to adjust the pH to 7-8;

[0324] 3) Separate the organic phase and wash it with saturated sodium bicarbonate (30 ml) and brine (30 ml) in sequence;

[0325] 4) The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure to remove the solvent; 2-amino-N-[2-(3-methoxyphenoxy)-phenyl-3,4,5,6-d 4 The crude product of 1-acetamide (630 mg) was directly used in the next step without purification.

[0326] Example 10 Naphthalene-1-carboxylic acid {[2-(3-methoxyphenoxy)-phenyl-3,4,5,6-d 4 Preparation of [-carbamoyl]-methyl]-amide (BC2023D2)

[0327]

[0328] 1) At room temperature, in anhydrous and oxygen-free conditions, 1-naphthoic acid (415 mg, 2.41 mmol) was dissolved in N,N-dimethylformamide (10 ml), carbonyl imidazole (391 mg, 2.41 mmol) was added, and the mixture was stirred at room temperature for 1 hour;

[0329] 2) The crude product (630 mg, about 2.28 mmol) obtained in Example 9 was added to the above reaction mixture; after stirring at room temperature for 1 hour, the temperature was raised to 60° C. and the mixture was stirred and reacted for 20 hours (TLC);

[0330] 3) The reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 ml), and washed with water (20 ml x 3), 0.1 N hydrochloric acid (20 ml x 2), saturated sodium bicarbonate (20 ml) and brine (20 ml) in sequence;

[0331] 4) The washed ethyl acetate phase was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure at 50°C to remove ethyl acetate. The residue was purified by a 200-300 mesh silica gel column and then recrystallized from ethyl acetate to obtain the fine product, naphthalene-1-carboxylic acid {[2-(3-methoxyphenoxy)-phenyl-3,4,5,6-d 4 -carbamyl]-methyl}-amide (880 mg, 89.6% yield).

[0332] 1 H NMR (400 MHz, DMSO-d 6 )δ9.61(s,1H),8.93(dd,J=8.4,1.5Hz,1H),8.37(dq,J=8.1,0.8Hz,1H),8.27(m,1H), 8.21(d,J=8.3Hz,1H),8.02(dd,J=7.1,1.2Hz,1H),7.95-8.00(m,1H),7.66(dd,J=8.2 ,7.0Hz,1H),7.29(t,J=8.6Hz,1H),7.15(td,J=7.8,1.5Hz,1H),7.13(ddd,J=8.8,7.6 ,1.7Hz,1H),6.63-6.65(m,1H),6.51-6.55(m,1H),4.20(d,J=5.4Hz,2H),3.72(s,3H).

[0333] 13 C-NMR (101 MHz, DMSO-d 6 )δ169.20,168.11,160.62,157.63,146.66,134.20,133.10,130.40,129.99,129.76,129.59,128.11,126.6 8,126.21,125.55,125.31,124.87,124.64,123.74,122.59,118.55,110.44,109.29,104.72,55.23,43.36.

[0334] MS (ESI+) m / z: [M+Na] + Calculate for C 26 H 18 D 4 N 2 O 4 Na + 453.17; found 453.17.

[0335] Comparative Example Preparation of naphthalene-1-carboxylic acid {[2-(3-methoxy-phenoxy)-phenylcarbamoyl]-methyl}-amide

[0336]

[0337] According to the preparation method of Examples 1-5 of the present invention, m-methoxyphenol is used to replace 3-methoxy-d 3 -phenol, to obtain AOH1966 (purity 99.75%).

[0338] 1 H NMR (400 MHz, DMSO-d 6 )δ9.61(s,1H),8.93(dd,J=8.4,1.5Hz,1H),8.37(dq,J=8.1,0.8Hz,1H),8.26(brs,1H),8.21(d,J=8.3H z,1H),8.02(dd,J=7.1,1.2Hz,1H),7.96-7.98(m,1H),7.66(dd,J=8.2,7.0Hz,1H),7.50-7.59(m,2H),7. 299(t,J=8.6Hz,1H),7.15(td,J=7.8,1.5Hz,1H),7.13(ddd,J=8.8,7.6,1.7Hz,1H),6.95(dd,J=8.1,1.5 Hz,1H),6.75(d,J=5.0Hz,1H),6.63-6.65(m,1H),6.51-6.55(m,1H),4.21(d,J=5.4Hz,2H),3.72(s,3H).

[0339] 13 C-NMR (101 MHz, DMSO-d 6)δ169.23,168.13,160.63,157.65,146.67,134.21,133.11,130.41,130.01,129.78,129.62,128.12,126.6 9,126.22,125.57,125.33,124.87,124.64,123.76,122.60,118.57,110.48,109.30,104.75,55.23,43.40.

[0340] MS (ESI+) m / z: [M+Na] + Calculate for C 26 H 22 N 2 O 4 Na + 449.14; found 449.14.

[0341] Test Example 1 Study on the inhibitory activity of the compounds of the present invention on tumor cell growth

[0342] Cell lines: prostate cancer cell 22Rv.1, prostate cancer cell LNCap, large cell lung cancer NCI-H460, small cell lung cancer NCI-H82, liver cancer cell Hep G2, liver cancer cell HuH-7, breast cancer cell MCF-7, breast cancer cell MDA-MB-231, ovarian cancer cell OVCAR-3, ovarian cancer cell SK-OV-3, brain tumor cell BE(2)-C, neuroblastoma cell SK-N-AS, pancreatic cancer cell Miapaca-2, pancreatic cancer cell AsPc-1.

[0343] Culture medium and reagents: cell culture medium RPMI 1640, cell culture medium DMEM, cell culture medium EMEM, cell culture medium L-15, cell culture medium DMEM / F12, modified medium McCoy's 5A, Dulbecco's PBS buffer, fetal bovine serum FBS, antibiotics-antimycotics, 0.25% trypsin, dimethyl sulfoxide, L-glutamine, non-essential amino acids), insulin, hydroxyethylpiperazineethanesulfonic acid HEPES, sodium pyruvate, sodium bicarbonate, geneticin G418, puromycin.

[0344] Experimental equipment: Greiner CELLSTAR 96-well plate, flat-bottom black plate (with lid and transparent bottom); Promega CellTiter-Glo luminescent cell activity detection kit (Promega-G7573); 2104 EnVision plate reader, PerkinElmer.

[0345] Test group: the compound of formula I (BC2023D1) prepared in Example 5 of the present invention and the compound of formula I (BC2023D2) prepared in Example 10 were dissolved in DMSO and then gradiently diluted with culture medium to the required concentrations and used immediately after preparation;

[0346] Positive control: AOH1996 prepared in the comparative example was dissolved in DMSO and then graded diluted with culture medium to the required concentration and used immediately after preparation.

[0347] The study of the inhibitory activity of the compound on tumor cell growth includes the following steps:

[0348] 1. Place the tumor cell line at 37°C and 5% CO 2 Culture under the conditions, take cells in the logarithmic growth phase for plating, stain the cells with trypan blue and count the living cells, and adjust the cell concentration to the appropriate concentration;

[0349] 2. Add 90 μL of cell suspension to each well, add culture medium without cells to the blank control well, and place the culture plate at 37°C and 5% CO. 2 , cultured overnight at 100% (RH);

[0350] 3. Add 78 μL of cell culture medium and 2 μL of test medium to a 96-well plate; add 2 μL of DMSO to the vehicle control and blank control;

[0351] 4. Take 10 μL of compound working solution and add it to the cell culture plate; add 10 μL of DMSO-cell culture medium mixture to the solvent control and blank control; the final DMSO concentration is 0.25%, and culture at 37°C, 5% CO2 for 72 hours. Use Promega CellTiter-Glo luminescent cell activity detection kit (Promega-G7573) to detect tumor cell growth inhibition activity:

[0352] a) Thaw CellTiter-Glo buffer and place at room temperature;

[0353] b) Allow CellTiter-Glo Substrate to reach room temperature;

[0354] c) adding CellTiter-Glo buffer to CellTiter-Glo substrate to dissolve the substrate and prepare CellTiter-Glo working solution;

[0355] d) Slowly vortex to fully dissolve;

[0356] e) Take out the cell culture plate and place it for 30 minutes, add 50 μL CellTiter-Glo working solution to each well, wrap the cell plate with aluminum foil, shake the culture plate on an orbital shaker for 2 minutes, place it at room temperature for 10 minutes, and detect the luminescent signal on a 2104 EnVision plate reader.

[0357] Inhibition rate (IR) % = (1 – (RLU compound – RLU blank control) / (RLU solvent control – RLU blank control)) * 100%. Calculate the inhibition rate of compounds at different concentrations, and then use GraphPad Prism software to prepare inhibition curves and calculate IC 50 The results are shown in Table 1 and Figure 1 .

[0358] Table 1

[0359]

[0360]

Claims

1. A proliferating cell nuclear antigen inhibitor having the structure shown in Formula I or a pharmaceutically acceptable salt thereof, 。 2. The compound of Formula I according to claim 1, wherein the pharmaceutically acceptable salt is selected from any one of the organic acid salts or inorganic acid salts of the compound of Formula I.

3. The compound of Formula I according to claim 2, wherein the organic acid is selected from any one or a combination of maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, oxalic acid, propionic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, lactic acid, mandelic acid, phenylacetic acid, aspartic acid, stearic acid, palmitic acid, glycolic acid, glutamic acid, benzenesulfonic acid.

4. The compound of Formula I according to claim 2, wherein the inorganic acid is selected from any one or a combination of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid.

5. The preparation method of the compound of Formula I according to any one of claims 1-4, that is, the compound of Formula IV reacts with naphthoyl glycine in the presence of a condensing agent in a solvent to obtain it, 。 6. The preparation method according to claim 5, in the preparation of the compound of formula I, the condensing agent is selected from N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, 1,1 -Carbonyldiimidazole, benzotriazol-1-yloxytriphosphonium hexafluorophosphate, benzotriazol-1-yloxytripyrrolidino Phosphonium Hexafluorophosphoric acid, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate, O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate, O-[(ethoxycarbonyl)cyanomethylamine]-N,N,N',N'-tetramethylthiourea tetrafluoroborate, 2-(2-pyridone-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate, ethyl methylphosphonic anhydride, n-propylphosphonic acid any one or a combination thereof, of anhydride, cyanuric chloride, 2-chloro-4,6-diphenyl-1,3,5-triazine, 4-(4,6-dimethoxy-1,3,5,-triazine-2-yl)-4-methylmorpholine hydrochloride, boric acid, 3-nitrobenzeneboric acid, methanesulfonyl chloride, p-toluenesulfonyl chloride, acetic anhydride, Boc anhydride, pivaloyl chloride, ethyl chloroformate, isobutyl chloroformate, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, thionyl chloride, oxalyl chloride, phosphorus oxychloride, (chloromethylene) dimethylammonium chloride.

7. The preparation method according to claim 5, in the preparation of the compound of Formula I, the solvent is selected from any one or a combination of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, acetonitrile, acetone, 2-butanone, dichloromethane, 1,2-dichloroethane, ethyl acetate, isopropyl acetate, tert-butyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide.

8. The preparation method according to claim 5, in the preparation of the compound of Formula I, the molar ratio of the compound of Formula IV: naphthoyl glycine: condensing agent is 1:1-2:1-2.

9. The preparation method according to claim 8, in the preparation of the compound of Formula I, the molar ratio of the compound of Formula IV: naphthoyl glycine: condensing agent is 1:1-1.2:1-1.

5.

10. The preparation method according to claim 5, in the preparation of the compound of Formula I, an alkali is optionally added.

11. The preparation method according to claim 10, in the preparation of the compound of Formula I, the alkali is selected from any one or a combination of triethylamine, diisopropylethylamine, pyridine, N-methylmorpholine, N-methylimidazole.

12. The preparation method according to claim 5, in the preparation of the compound of Formula I, a condensation aid is optionally added.

13. The preparation method according to claim 12, in the preparation of the compound of Formula I, the condensation aid is selected from any one or a combination of 1-hydroxybenzotriazole, 1-hydroxy-7-azabenzotriazole, N-hydroxy-5-norbornene-2,3-dicarboximide, 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine.

14. The preparation method according to claim 5, in the preparation of the compound of Formula I, the molar ratio of the compound of Formula IV: naphthoyl glycine: condensing agent: condensation aid: alkali is 1:1-2:1-2:0-2:0-10.

15. The preparation method according to claim 14, in the preparation of the compound of Formula I, the molar ratio of the compound of Formula IV: naphthoyl glycine: condensing agent: condensation aid: alkali is 1:1-1.2:1-1.5:1-2:1-2.

16. The preparation method as claimed in claim 5, wherein in the preparation of the compound of formula I, the reaction temperature is 10°C-150°C.

17. The preparation method according to claim 16, wherein in the preparation of the compound of formula I, the reaction temperature is 25°C-80°C.

18. The preparation method according to claim 17, wherein in the preparation of the compound of formula I, the reaction temperature is 25°C-60°C.

19. The preparation method according to claim 5, wherein the compound of formula IV is prepared by reducing the compound of formula V in a solvent in the presence of a reducing agent. 。 20. The preparation method according to claim 19, wherein in the preparation of the compound of formula IV, the reducing agent is selected from any one of palladium carbon-hydrogen, palladium carbon-ammonium formate, palladium carbon-formic acid, palladium carbon-hydrazine hydrate, nickel-hydrogen, iron powder-dilute hydrochloric acid, sodium borohydride, potassium borohydride, and tin dichloride, or a combination thereof.

21. The preparation method according to claim 19, wherein in the preparation of the compound of formula IV, the solvent is selected from any one of methanol, ethanol, water or a combination thereof.

22. The preparation method according to claim 20, wherein in the preparation of the compound of formula IV, the purity of palladium carbon in the reducing agent is 2%-15%.

23. The preparation method according to claim 22, wherein in the preparation of the compound of formula IV, the purity of palladium carbon in the reducing agent is 5%-10%.

24. The preparation method according to claim 20, wherein in the preparation of the compound of formula IV, the purity of hydrazine hydrate in the reducing agent is 40%-85%.

25. The preparation method according to claim 24, wherein in the preparation of the compound of formula IV, the purity of hydrazine hydrate in the reducing agent is 50%-80%.

26. The preparation method according to claim 20, wherein in the preparation of the compound of formula IV, the molar ratio of the compound of formula V to hydrazine hydrate is 1:1-2.

5.

27. The preparation method according to claim 26, wherein in the preparation of the compound of formula IV, the molar ratio of the compound of formula V to hydrazine hydrate is 1:1.5-2.

28. The preparation method according to claim 19, wherein in the preparation of the compound of formula IV, the reaction temperature is 25-100°C.

29. The preparation method according to claim 28, wherein in the preparation of the compound of formula IV, the reaction temperature is 30-80°C.

30. The preparation method according to claim 19, wherein the compound of formula V is prepared by reacting the compound of formula IV with o-fluoronitrobenzene in a solvent in the presence of a base, 。 31. The preparation method according to claim 30, wherein in the preparation of the compound of formula V, the base is selected from any one of sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, and cesium hydroxide, or a combination thereof.

32. The preparation method as claimed in claim 30, wherein in the preparation of the compound of formula V, the solvent is selected from toluene, xylene, 2-methyltetrahydrofuran, dioxane, acetonitrile, acetone, 2-butanone, N, N -dimethylformamide, N , N - any one of dimethylacetamide, dimethyl sulfoxide or a combination thereof.

33. The preparation method as claimed in claim 30, wherein in the preparation of the compound of formula V, the molar ratio of the compound of formula VI: o-fluoronitrobenzene: base is 1:1-2:1-5.

34. The preparation method as claimed in claim 33, wherein in the preparation of the compound of formula V, the molar ratio of the compound of formula VI: o-fluoronitrobenzene: base is 1:1-1.5:1-2.

5.

35. In the preparation method according to claim 34, in the preparation of the compound of formula V, the molar ratio of the compound of formula VI: o-fluoronitrobenzene: base is 1: 1-1.2: 1.2-2.

36. In the preparation method according to claim 30, in the preparation of the compound of formula V, the reaction temperature is 20 °C - 150 °C.

37. In the preparation method according to claim 36, in the preparation of the compound of formula V, the reaction temperature is 30 °C - 110 °C.

38. In the preparation method according to claim 37, in the preparation of the compound of formula V, the reaction temperature is 50 °C - 80 °C.

39. In the preparation method according to claim 5, naphthoyl glycine is prepared by reacting methyl naphthoyl glycinate in the presence of a base in a solvent. 。 40. In the preparation method according to claim 39, in the preparation of naphthoyl glycine, the base is selected from any one or a combination of lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide.

41. In the preparation method according to claim 39, in the preparation of naphthoyl glycine, the solvent is selected from any one or a combination of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, acetonitrile, acetone, 2-butanone, dichloromethane, 1,2-dichloroethane, ethyl acetate, isopropyl acetate, tert-butyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methanol, ethanol, isopropanol, water.

42. In the preparation method according to claim 39, in the preparation of naphthoyl glycine, the molar ratio of methyl naphthoyl glycinate: base is 1: 1-10.

43. In the preparation method according to claim 42, in the preparation of naphthoyl glycine, the molar ratio of methyl naphthoyl glycinate: base is 1: 1-5.

44. In the preparation method according to claim 39, in the preparation of naphthoyl glycine, the reaction temperature is 20 °C - 65 °C.

45. In the preparation method according to claim 44, in the preparation of naphthoyl glycine, the reaction temperature is 25 °C - 50 °C.

46. In the preparation method according to claim 39, methyl naphthoyl glycinate is prepared by reacting 1-naphthoic acid with glycine methyl ester hydrochloride in the presence of a condensing agent in a solvent. 。 47. The preparation method according to claim 46, in the preparation of naphthoylglycine methyl ester, the condensing agent is selected from N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, 1,1 -Carbonyldiimidazole, benzotriazol-1-yloxytriphosphonium hexafluorophosphate, benzotriazol-1-yloxytripyrrolidino phosphonium Hexafluorophosphoric acid, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate, O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate, O-[(ethoxycarbonyl)cyanomethylamine]-N,N,N',N'-tetramethylthiourea tetrafluoroborate, 2-(2-pyridone-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate, ethyl methylphosphonic anhydride, n-propylphosphonic acid any one or a combination thereof, of anhydride, cyanuric chloride, 2-chloro-4,6-diphenyl-1,3,5-triazine, 4-(4,6-dimethoxy-1,3,5,-triazine-2-yl)-4-methylmorpholine hydrochloride, boric acid, 3-nitrobenzeneboric acid, methanesulfonyl chloride, p-toluenesulfonyl chloride, acetic anhydride, Boc anhydride, pivaloyl chloride, ethyl chloroformate, isobutyl chloroformate, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, thionyl chloride, oxalyl chloride, phosphorus oxychloride, (chloromethylene) dimethylammonium chloride.

48. In the preparation method according to claim 46, in the preparation of methyl naphthoyl glycinate, the solvent is selected from any one or a combination of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, acetonitrile, acetone, 2-butanone, dichloromethane, 1,2-dichloroethane, ethyl acetate, isopropyl acetate, tert-butyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide.

49. In the preparation method according to claim 46, in the preparation of methyl naphthoyl glycinate, a base is optionally added.

50. In the preparation method according to claim 49, in the preparation of methyl naphthoyl glycinate, the base is selected from any one or a combination of triethylamine, diisopropylethylamine, pyridine, N-methylmorpholine, N-methylimidazole.

51. In the preparation method according to claim 46, in the preparation of methyl naphthoyl glycinate, a condensation aid is optionally added.

52. The preparation method as claimed in claim 51, in the preparation of naphthoylglycine methyl ester, the condensation auxiliary agent is selected from any one of 1-hydroxybenzotriazole, 1-hydroxy-7-azabenzotriazole, N-hydroxy-5-norbornene-2,3-dicarboximide, and 3,4-dihydro-3-hydroxy-4-oxy-1,2,3-benzotriazine or a combination thereof.

53. The preparation method as claimed in claim 46, wherein in the preparation of naphthoylglycine methyl ester, the molar ratio of 1-naphthoic acid: glycine methyl ester hydrochloride: condensing agent is 1:1-2:1-2.

54. The preparation method as claimed in claim 53, wherein in the preparation of naphthoylglycine methyl ester, the molar ratio of 1-naphthoic acid: glycine methyl ester hydrochloride: condensing agent is 1:1-1.2:1-1.

5.

55. The preparation method as claimed in claim 51, in the preparation of naphthoylglycine methyl ester, the molar ratio of 1-naphthoic acid:glycine methyl ester hydrochloride:condensing agent:condensation auxiliary agent:base is 1:1-2:1-2:0-2:0-10.

56. The preparation method as claimed in claim 55, wherein in the preparation of naphthoylglycine methyl ester, the molar ratio of 1-naphthoic acid: glycine methyl ester hydrochloride: condensing agent: condensation aid: base is 1:1-1.2:1-1.5:1-2:1-2.

57. The preparation method as claimed in claim 46, wherein in the preparation of naphthoylglycine methyl ester, the reaction temperature is 10°C-150°C.

58. The preparation method as claimed in claim 57, wherein in the preparation of naphthoylglycine methyl ester, the reaction temperature is 25°C-80°C.

59. The preparation method as claimed in claim 58, wherein in the preparation of naphthoylglycine methyl ester, the reaction temperature is 25°C-60°C.

60. Another method for preparing a compound of formula I as claimed in any one of claims 1 to 4, comprising the following steps: ； 1) reacting a compound of formula VI with o-fluoronitrobenzene in the presence of a base in a solvent to obtain a compound of formula V; 2) reacting the compound of formula V in the presence of a reducing agent in a solvent to obtain a compound of formula IV; 3) 1-naphthoic acid and glycine methyl ester hydrochloride react in the presence of a condensing agent in a solvent to obtain naphthoylglycine methyl ester; 4) naphthoylglycine methyl ester reacts in a solvent in the presence of a base to obtain naphthoylglycine; 5) The compound of formula IV is reacted with naphthoylglycine in the presence of a condensing agent in a solvent to obtain a compound of formula I.

61. The method for preparing the compound of formula I as claimed in claim 60, wherein in the preparation of the compound of formula I, there is no particular order in which the compound of formula IV and naphthoylglycine are prepared.

62. The method for preparing a compound of formula I as claimed in claim 60, wherein in the preparation of the compound of formula I, the base in step 1) is selected from any one of sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, and cesium hydroxide, or a combination thereof.

63. The method for preparing the compound of formula I as claimed in claim 60, wherein in the preparation of the compound of formula I, the reaction solvent in step 1) is selected from toluene, xylene, 2-methyltetrahydrofuran, dioxane, acetonitrile, acetone, 2-butanone, N, N -dimethylformamide, N , N - any one of dimethylacetamide, dimethyl sulfoxide or a combination thereof.

64. The method for preparing the compound of formula I as claimed in claim 60, wherein in the preparation of the compound of formula I, the molar ratio of the compound of formula IV: o-fluoronitrobenzene: base in step 1) is 1:1-2:1-5.

65. The preparation method of the compound of formula I as claimed in claim 64. In the preparation of the compound of formula I, the molar ratio of the compound of formula IV: o-fluoronitrobenzene: base in step 1) is 1: 1 - 1.5: 1 - 2.

5.

66. The preparation method of the compound of formula I as claimed in claim 65. In the preparation of the compound of formula I, the molar ratio of the compound of formula IV: o-fluoronitrobenzene: base in step 1) is 1: 1 - 1.2: 1.2 - 2.

67. The preparation method of the compound of formula I as claimed in claim 60. In the preparation of the compound of formula I, the reaction temperature in step 1) is 20°C - 150°C.

68. The preparation method of the compound of formula I as claimed in claim 67. In the preparation of the compound of formula I, the reaction temperature in step 1) is 30°C - 110°C.

69. The preparation method of the compound of formula I as claimed in claim 68. In the preparation of the compound of formula I, the reaction temperature in step 1) is 50°C - 80°C.

70. The preparation method of the compound of formula I as claimed in claim 60. In the preparation of the compound of formula I, the reducing agent in step 2) is selected from any one or a combination of palladium-carbon - hydrogen, palladium-carbon - ammonium formate, palladium-carbon - formic acid, palladium-carbon - hydrazine hydrate, nickel - hydrogen, iron powder - dilute hydrochloric acid, sodium borohydride, potassium borohydride, stannous dichloride.

71. The preparation method of the compound of formula I as claimed in claim 60. In the preparation of the compound of formula I, the solvent in step 2) is selected from any one or a combination of methanol, ethanol, and water.

72. The preparation method of the compound of formula I as claimed in claim 70. In the preparation of the compound of formula I, the purity of palladium-carbon in the reducing agent in step 2) is 2% - 15%.

73. The preparation method of the compound of formula I as claimed in claim 72. In the preparation of the compound of formula I, the purity of palladium-carbon in the reducing agent in step 2) is 5% - 10%.

74. The preparation method of the compound of formula I as claimed in claim 70. In the preparation of the compound of formula I, the purity of hydrazine hydrate in the reducing agent in step 2) is 40% - 85%.

75. The preparation method of the compound of formula I as claimed in claim 74. In the preparation of the compound of formula I, the purity of hydrazine hydrate in the reducing agent in step 2) is 50% - 80%.

76. The preparation method of the compound of formula I as claimed in claim 70. In the preparation of the compound of formula I, the molar ratio of the compound of formula V: hydrazine hydrate in step 2) is 1: 1 - 2.

5.

77. The preparation method of the compound of formula I as claimed in claim 76. In the preparation of the compound of formula I, the molar ratio of the compound of formula V: hydrazine hydrate in step 2) is 1: 1.5 - 2.

78. The preparation method of the compound of formula I as claimed in claim 60. In the preparation of the compound of formula I, the reaction temperature in step 2) is 25 - 100°C.

79. The preparation method of the compound of formula I as claimed in claim 78. In the preparation of the compound of formula I, the reaction temperature in step 2) is 30 - 80°C.

80. The method for preparing the compound of formula I as claimed in claim 60, wherein in the preparation of the compound of formula I, the condensing agent in step 3) is selected from N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, 1,1 -Carbonyldiimidazole, benzotriazol-1-yloxytriphosphonium hexafluorophosphate, benzotriazol-1-yloxytripyrrolidino phosphonium Hexafluorophosphoric acid, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate, O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate, O-[(ethoxycarbonyl)cyanomethylamine]-N,N,N',N'-tetramethylthiourea tetrafluoroborate, 2-(2-pyridone-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate, ethyl methylphosphonic anhydride, n-propylphosphonic acid any one or a combination thereof, of anhydride, cyanuric chloride, 2-chloro-4,6-diphenyl-1,3,5-triazine, 4-(4,6-dimethoxy-1,3,5,-triazine-2-yl)-4-methylmorpholine hydrochloride, boric acid, 3-nitrobenzeneboric acid, methanesulfonyl chloride, p-toluenesulfonyl chloride, acetic anhydride, Boc anhydride, pivaloyl chloride, ethyl chloroformate, isobutyl chloroformate, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, thionyl chloride, oxalyl chloride, phosphorus oxychloride, (chloromethylene) dimethylammonium chloride.

81. The method for preparing a compound of formula I as claimed in claim 60, wherein in the preparation of the compound of formula I, the solvent in step 3) is selected from any one of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, acetonitrile, acetone, 2-butanone, dichloromethane, 1,2-dichloroethane, ethyl acetate, isopropyl acetate, tert-butyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide, or a combination thereof.

82. The method for preparing the compound of formula I as claimed in claim 60, wherein in the preparation of the compound of formula I, a base is optionally added in step 3).

83. The method for preparing a compound of formula I as claimed in claim 82, wherein in the preparation of the compound of formula I, the base in step 3) is selected from any one of triethylamine, diisopropylethylamine, pyridine, N-methylmorpholine, N-methylimidazole or a combination thereof.

84. The method for preparing the compound of formula I as claimed in claim 60, wherein in the preparation of the compound of formula I, a condensation auxiliary is optionally added in step 3).

85. The method for preparing a compound of formula I as claimed in claim 84, wherein in the preparation of the compound of formula I, the condensation aid in step 3) is selected from any one of 1-hydroxybenzotriazole, 1-hydroxy-7-azabenzotriazole, N-hydroxy-5-norbornene-2,3-dicarboximide, and 3,4-dihydro-3-hydroxy-4-oxy-1,2,3-benzotriazine or a combination thereof.

86. The method for preparing the compound of formula I as claimed in claim 60, wherein in the preparation of the compound of formula I, the molar ratio of 1-naphthoic acid:glycine methyl ester hydrochloride:condensing agent in step 3) is 1:1-2:1-2.

87. The method for preparing the compound of formula I as claimed in claim 84, wherein in the preparation of the compound of formula I, the molar ratio of 1-naphthoic acid:glycine methyl ester hydrochloride:condensing agent in step 3) is 1:1-1.2:1-1.

5.

88. The method for preparing the compound of formula I as claimed in claim 84, wherein in the preparation of the compound of formula I, the molar ratio of 1-naphthoic acid:glycine methyl ester hydrochloride:condensing agent:condensation auxiliary agent:base in step 3) is 1:1-2:1-2:0-2:0-10.

89. The method for preparing the compound of formula I as claimed in claim 88, wherein in the preparation of the compound of formula I, the molar ratio of 1-naphthoic acid:glycine methyl ester hydrochloride:condensing agent:condensation auxiliary agent:base in step 3) is 1:1-1.2:1-1.5:1-2:1-2.

90. The method for preparing the compound of formula I as claimed in claim 60, wherein in the preparation of the compound of formula I, the reaction temperature in step 3) is 10°C-150°C.

91. The method for preparing the compound of formula I as claimed in claim 90, wherein in the preparation of the compound of formula I, the reaction temperature in step 3) is 25°C-80°C.

92. The method for preparing the compound of formula I as claimed in claim 91, wherein in the preparation of the compound of formula I, the reaction temperature in step 3) is 25°C-60°C.

93. The preparation method of the compound of formula I as claimed in claim 60. In the preparation of the compound of formula I, the base in step 4) is selected from any one or a combination of lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide.

94. The preparation method of the compound of formula I as claimed in claim 60. In the preparation of the compound of formula I, the solvent in step 4) is selected from any one or a combination of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, acetonitrile, acetone, 2-butanone, dichloromethane, 1,2-dichloroethane, ethyl acetate, isopropyl acetate, tert-butyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methanol, ethanol, isopropanol, and water.

95. The preparation method of the compound of formula I as claimed in claim 60. In the preparation of the compound of formula I, the molar ratio of methyl naphthoyl glycinate to the base in step 4) is 1:1 - 10.

96. The preparation method of the compound of formula I as claimed in claim 95. In the preparation of the compound of formula I, the molar ratio of methyl naphthoyl glycinate to the base in step 4) is 1:1 - 5.

97. The preparation method of the compound of formula I as claimed in claim 60. In the preparation of the compound of formula I, the reaction temperature in step 4) is 20°C - 65°C.

98. The preparation method of the compound of formula I as claimed in claim 97. In the preparation of the compound of formula I, the reaction temperature in step 4) is 25°C - 50°C.

99. The method for preparing the compound of formula I as claimed in claim 60, wherein in the preparation of the compound of formula I, the condensing agent in step 5) is selected from N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, 1,1 -Carbonyldiimidazole, benzotriazol-1-yloxytriphosphonium hexafluorophosphate, benzotriazol-1-yloxytripyrrolidino phosphonium Hexafluorophosphoric acid, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate, O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate, O-[(ethoxycarbonyl)cyanomethylamine]-N,N,N',N'-tetramethylthiourea tetrafluoroborate, 2-(2-pyridone-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate, ethyl methylphosphonic anhydride, n-propylphosphonic acid any one or a combination thereof, of anhydride, cyanuric chloride, 2-chloro-4,6-diphenyl-1,3,5-triazine, 4-(4,6-dimethoxy-1,3,5,-triazine-2-yl)-4-methylmorpholine hydrochloride, boric acid, 3-nitrobenzeneboric acid, methanesulfonyl chloride, p-toluenesulfonyl chloride, acetic anhydride, Boc anhydride, pivaloyl chloride, ethyl chloroformate, isobutyl chloroformate, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, thionyl chloride, oxalyl chloride, phosphorus oxychloride, (chloromethylene) dimethylammonium chloride.

100. The preparation method of the compound of formula I as claimed in claim 60. In the preparation of the compound of formula I, the solvent in step 5) is selected from any one or a combination of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, acetonitrile, acetone, 2-butanone, dichloromethane, 1,2-dichloroethane, ethyl acetate, isopropyl acetate, tert-butyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide.

101. The preparation method of the compound of formula I as claimed in claim 60. In the preparation of the compound of formula I, in step 5), the molar ratio of the compound of formula IV to naphthoyl glycine to the condensing agent is 1:1 - 2:1 - 2.

102. The preparation method of the compound of formula I as claimed in claim 101. In the preparation of the compound of formula I, in step 5), the molar ratio of the compound of formula IV to naphthoyl glycine to the condensing agent is 1:1 - 1.2:1 - 1.

5.

103. The preparation method of the compound of formula I as claimed in claim 60. In the preparation of the compound of formula I, a base is optionally added in step 5).

104. The preparation method of the compound of formula I as claimed in claim 103. In the preparation of the compound of formula I, the base in step 5) is selected from any one or a combination of triethylamine, diisopropylethylamine, pyridine, N-methylmorpholine, and N-methylimidazole.

105. The preparation method of the compound of formula I as claimed in claim 60. In the preparation of the compound of formula I, a condensation aid is optionally added in step 5).

106. The method for preparing a compound of formula I as claimed in claim 105, wherein in the preparation of the compound of formula I, the condensation aid in step 5) is selected from any one of 1-hydroxybenzotriazole, 1-hydroxy-7-azabenzotriazole, N-hydroxy-5-norbornene-2,3-dicarboximide, and 3,4-dihydro-3-hydroxy-4-oxy-1,2,3-benzotriazine or a combination thereof.

107. The method for preparing a compound of formula I as claimed in claim 60, wherein in the preparation of the compound of formula I, the molar ratio of the compound of formula IV: naphthoylglycine: condensation agent: condensation aid: base in step 5) is 1:1-2:1-2:0-2:0-10.

108. The method for preparing a compound of formula I as claimed in claim 107, wherein in the preparation of the compound of formula I, the molar ratio of the compound of formula IV in step 5): naphthoylglycine: condensation agent: condensation aid: base is 1:1-1.2:1-1.5:1-2:1-2.

109. The method for preparing the compound of formula I as claimed in claim 60, wherein in the preparation of the compound of formula I, the reaction temperature in step 5) is 10°C-150°C.

110. The method for preparing the compound of formula I as claimed in claim 109, wherein in the preparation of the compound of formula I, the reaction temperature in step 5) is 25°C-80°C.

111. The method for preparing the compound of formula I as claimed in claim 110, wherein in the preparation of the compound of formula I, the reaction temperature in step 5) is 25°C-60°C.

112. A broad-spectrum anti-tumor pharmaceutical composition, which is composed of a compound of formula I or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 4 and a pharmaceutically acceptable carrier.

113. The pharmaceutical composition of claim 112, wherein the amount or type of the pharmaceutically acceptable carrier in the composition is determined according to the physicochemical properties and content of the active ingredient in the composition, the type of preparation, and the dissolution and bioavailability of the preparation.

114. The pharmaceutical composition of claim 112, wherein the pharmaceutical composition is in the form of an oral preparation, an injection, or an external preparation.

115. The pharmaceutical composition of claim 114, wherein the oral preparation is selected from any one of tablets, capsules, granules, syrups, dews, effervescents, suspensions, pills, pellets, mixtures, pastes, emulsions, dragees, solutions, lozenges, cachets, and suspensions.

116. The pharmaceutical composition of claim 112, wherein the injection is selected from any one of a solution injection, an emulsion injection, a suspension injection, and sterile powder for injection.

117. The pharmaceutical composition of claim 112, wherein the external preparation is selected from any one of a gel, a patch, a cream, a liniment, a lotion, a suppository, an smear, a gel, an ointment, an aerosol, a dry powder inhaler, a spray, and a nebulizer.

118. The pharmaceutical composition of claim 112, wherein the pharmaceutically acceptable carrier of the present invention is a common excipient or adjuvant used in the art for preparing the preparation, selected from any one or a combination of fillers, disintegrants, binders, emulsifiers, co-emulsifiers, lyoprotectants, dispersants, pore-forming agents, lubricants, wetting agents, pH regulators, osmotic pressure regulators, solubilizers, antioxidants, antibacterial agents, analgesics, suspending agents, flavoring agents, and fragrance agents.

119. The pharmaceutical composition of claim 118, wherein the filler is selected from any one of lactose, powdered sugar, dextrin, starch, sodium carboxymethyl starch, sodium starch glycolate, pregelatinized starch, modified starch, hydroxypropyl starch, potato starch, corn starch, cellulose, inorganic calcium salt, calcium chloride, calcium sulfate, calcium phosphate, calcium hydrogen phosphate, precipitated calcium carbonate, sorbitol, mannitol, microcrystalline cellulose, sodium carboxymethyl cellulose, ethyl cellulose, and hydroxypropyl methyl cellulose or a combination thereof.

120. The pharmaceutical composition of claim 118, wherein the disintegrant is selected from any one of starch, sodium carboxymethyl starch, sodium starch glycolate, pregelatinized starch, modified starch, hydroxypropyl starch, potato starch, corn starch or derivatives thereof, cross-linked polyvinyl pyrrolidone, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, and cross-linked sodium carboxymethyl cellulose or a combination thereof.

121. The pharmaceutical composition of claim 118, wherein the binder is selected from any one of syrup, gum arabic, gelatin, sorbitol, gum tragacanth, cellulose, microcrystalline cellulose, sodium carboxymethyl cellulose, ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, gelatin slurry, starch slurry, polyvinyl pyrrolidone, sodium carboxymethyl starch, sodium starch glycolate, pregelatinized starch, modified starch, hydroxypropyl starch, potato starch, and corn starch, or a combination thereof.

122. The pharmaceutical composition of claim 118, wherein the emulsifier is selected from any one of sodium stearate, potassium stearate, triethanolamine stearate, magnesium stearate, calcium stearate, sodium lauryl sulfate, sodium dodecylbenzene sulfonate, polysorbate, Span, benzyl alcohol, gum tragacanth, gum arabic, Pluronic F-68, lecithin, and soybean lecithin, or a combination thereof.

123. The pharmaceutical composition of claim 118, wherein the co-emulsifier is selected from any one of n-butanol, ethylene glycol, ethanol, propylene glycol, glycerol, polyglycerol esters, or a combination thereof.

124. The pharmaceutical composition of claim 118, wherein the lyoprotectant is selected from any one of sucrose, lactose, galactose, glucose, trehalose, mannitol, sorbitol, or a combination thereof.

125. The pharmaceutical composition of claim 118, wherein the solubilizing agent is selected from any one of Tween-80, Pluronic F-68, benzyl alcohol, benzyl alcohol, cholate, deoxycholate, glycerol, propylene glycol, and polyethylene glycol, or a combination thereof.

126. The pharmaceutical composition of claim 118, wherein the suspending agent is selected from any one of microcrystalline cellulose, sodium carboxymethyl cellulose, ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, syrup, glycerin, gelatin, gum arabic, gum tragacanth, sodium alginate, potassium alginate, pectin, or a combination thereof.

127. The pharmaceutical composition of claim 118, wherein the wetting agent is selected from any one of sodium lauryl sulfate, polysorbate, water, alcohol, ester, or a combination thereof.

128. The pharmaceutical composition of claim 118, wherein the lubricant is selected from any one of micronized silica gel, magnesium stearate, talc, colloidal silicon dioxide, aluminum hydroxide, boric acid, hydrogenated vegetable oil, polyethylene glycol, and sodium lauryl sulfate, or a combination thereof.

129. The pharmaceutical composition of claim 118, wherein the antioxidant is selected from any one of sodium sulfite, sodium bisulfite, sodium metabisulfite, sodium thiosulfate, vitamin C, vitamin E, dibutyl benzoic acid, butylated hydroxyanisole, dibutyl hydroxytoluene, propyl gallate, niacinamide, acetylcysteine, and tert-butylhydroquinone, or a combination thereof.

130. The pharmaceutical composition of claim 118, wherein the bacteriostatic agent is selected from any one of phenol, cresol, chlorobutanol, benzyl alcohol, or a combination thereof.

131. The pharmaceutical composition of claim 118, wherein the analgesic is selected from any one of chlorobutanol, benzyl alcohol, lidocaine, procaine, or a combination thereof.

132. The pharmaceutical composition of claim 118, wherein the pH adjusting agent is selected from any one of hydrochloric acid, sodium hydroxide, potassium hydroxide, citric acid, sodium citrate, potassium citrate, malic acid, sodium malate, potassium malate, monosodium phosphate, disodium hydrogen phosphate, calcium hydroxide, calcium lactate, sodium lactate, sodium phosphate, potassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, sodium bicarbonate, and sodium carbonate, or a combination thereof.

133. The pharmaceutical composition of claim 118, wherein the osmotic pressure regulator is selected from any one of sodium chloride, potassium chloride, glucose, phosphate, and citrate.

134. The pharmaceutical composition of claim 118, wherein the flavoring agent is selected from any one of honey, syrup, acid, alkali, essence, sweetener, or a combination thereof.

135. Use of the compound of formula I as claimed in any one of claims 1 to 4 for preparing a medicament for inhibiting proliferating cell nuclear antigen-related diseases.

136. The use as claimed in claim 135, wherein the disease associated with the inhibition of proliferating cell nuclear antigen is selected from diseases associated with excessive cell proliferation or diseases associated with abnormal PCNA activity levels.

137. The use according to claim 136, wherein the proliferating cell nuclear antigen-inhibiting related disease is any one of cancer and sarcoma or their complications.

138. The use according to claim 136, wherein the disease associated with the inhibition of proliferating cell nuclear antigen is leukemia or its complications.

139. The use according to claim 138, wherein the cancer is selected from any one of prostate cancer, liver cancer, breast cancer, ovarian cancer, lung cancer, pancreatic cancer or complications thereof.

140. The use according to claim 138, wherein the sarcoma is selected from any one of brain tumor, neuroblastoma or complications thereof.

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