Preparation method for substituted 2-(pyrrolidin-3-yl)acetic acid derivative having reduced lp(a) levels

Abstract

A preparation method for a novel compound which reduces blood plasma Lp(a) levels, and an intermediate compound of the novel compound. The novel compound is biochemically effective and physiologically active.

Description

A method for preparing substituted 2-(pyrrolidine-3-yl)acetic acid derivatives with reduced Lp(a) levels Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and more particularly to compounds that are Lp(a) inhibitors, especially methods for preparing substituted 2-(pyrrolidine-3-yl)acetic acid derivatives and their intermediate compounds. Background Technology

[0002] Lipoprotein(a) (Lp(a)) are lipoprotein particles synthesized in the liver, consisting of cholesterol-rich low-density lipoprotein (LDL-C)-like particles attached to apolipoprotein(a). Lp(a) levels are primarily determined by genes, vary significantly among different populations, and are almost unaffected by lifestyle interventions.

[0003] Lp(a) is associated with an increased risk of coronary artery disease, ischemic stroke, aortic stenosis, heart failure, atrial fibrillation, and peripheral artery disease. Approximately 20% of the population has elevated serum Lp(a) levels (≥30 mg / dL). The increased risk of cardiovascular disease (CVD) associated with Lp(a) is primarily attributed to the dual procoagulant effect of Apo(a) (Apo(a) has a structure similar to plasminogen), and the atherogenic (AS) and pro-inflammatory effects of Apo B (apolipoprotein B) containing oxidized phospholipid components (OxPL). Lp(a) is a contributing factor not only to atherosclerotic cardiovascular disease (ASCVD) but also to calcific aortic valve disease. Elevated plasma Lp(a) levels are an independent risk factor for CVD.

[0004] For patients with elevated Lp(a) levels, approved treatment options are limited. Apheresis can be used to filter blood to remove LDL and Lp(a); however, the effects are temporary and usually require repetition every two weeks, and patient adherence is not good. Currently, there are no approved drug therapies for lowering Lp(a) levels. Therefore, it is essential to provide patients with CVD with pharmaceutically acceptable compounds and treatment options to lower plasma Lp(a) levels. Summary of the Invention

[0005] The purpose of this invention is to provide a method for preparing a novel compound that lowers plasma Lp(a) levels and an intermediate compound thereof. The novel compound is biochemically effective and physiologically active.

[0006] A first aspect of the present invention provides a method for synthesizing a compound of formula (I), or a stereoisomer, tautomer, isotopic derivative thereof, or a mixture thereof or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0007] Step (1): Formulas (I-1) and (I-2) undergo a substitution reaction to generate formula (I-3);

[0008] Step (2): Formula (I-3) undergoes an oxidative hydrolysis reaction (e.g., alkaline oxidation to remove the Evans chiral cofactor) to generate Formula (I-4);

[0009] Step (3): Deprotecting the group of formula (I-4) yields the compound of formula (I);

[0010] Where X is independently selected from halogens;

[0011] R1 and R2 are independently selected from hydrogen, deuterium, and C, respectively. 1-3 Alkoxy;

[0012] R3 is a protecting group;

[0013] R4 is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -CHO, nitro, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy group, -N(C 1-3 alkyl)2、-NH(C 1-3 Alkyl), -C(O)C 1-3 alkyl;

[0014] R5, R6, R7, R8, R9, R 10 They are selected independently from hydrogen and deuterium;

[0015] m is 0, 1, or 2;

[0016] n is 0, 1, 2, 3, 4, or 5;

[0017] Rings W1, W2, and W3 are each independently selected from C. 6-12 Aryl, 5-12 heteroaryl, C 6-14 Cycloalkyl, 5-12 membered heterocyclic groups; wherein the aryl, heteroaryl, cycloalkyl, or heterocyclic group is optionally selected by one or more elements independently selected from deuterium, halogen, -CN, -OH, -NH2, -CHO, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups, -N(C) 1-3 alkyl)2、-NH(C 1-3 Alkyl), -C(O)C 1-3Substituents of alkyl groups;

[0018] Z 11 Z 21 Z 31 Each is independently selected from the following bonds: -O-, -S-, -NH-, -Se-, -C. 1-4 alkylene-, -C 1-8 oxa-alkylene-, -C 1-4 Thionide-, -C 1-4 aziridine-, -C 1-4 Selenide-; the alkylene, oxaalkylene, thiaalkylene, aziridine, or selenide may optionally be selected from one or more of Z. 41 Substituents; Z 41 Independently selected from deuterium, halogen, oxo group, thio group, -CN, -OH, -NH2, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy; or any two Z 41 Together with the atoms they are attached to, they form C 3-6 cycloalkyl, 3-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl;

[0019] The heteroatoms in the heterocyclic group and heteroaryl group are independently selected from O, N or S, and the number of heteroatoms is 1, 2, 3 or 4.

[0020] In step (1), an alkaline reagent is included, which is selected from organic bases; preferably, the organic base is lithium bis(trimethylsilyl)amino, sodium bis(trimethylsilyl)amino, potassium bis(trimethylsilyl)amino, or N,N-diisopropylethylamine; preferably lithium bis(trimethylsilyl)amino.

[0021] Furthermore, step (1) includes a reaction solvent, which is tetrahydrofuran, toluene, diethyl ether, or tert-methyl ether; preferably, the reaction solvent is tetrahydrofuran.

[0022] Furthermore, in step (1), the reaction temperature is -78℃ to 30℃; preferably, the reaction temperature is -78℃ to 25℃; preferably, the reaction temperature is -78℃ to 0℃; preferably, the reaction temperature is -78℃ to -15℃; preferably, the reaction temperature is -35℃ to -15℃; preferably, the reaction temperature is -20±5℃.

[0023] Furthermore, in step (1), the reaction time is 1-24h; preferably, the reaction time is 2-18h; preferably, the reaction time is 6-10h; preferably, the reaction time is 8±0.5h.

[0024] Furthermore, in step (1), the reaction temperature is -78 to 30°C, and the reaction time is 1 to 24 hours; preferably, the reaction temperature is -78 to 25°C, and the reaction time is 2 to 18 hours; preferably, the reaction temperature is -20°C to room temperature, and the reaction time is 2 to 18 hours; preferably, the reaction temperature is 0°C to room temperature, and the reaction time is 2 to 18 hours.

[0025] Furthermore, step (1) is carried out under the protection of an inert gas, preferably nitrogen.

[0026] Further, step (1) includes column chromatography purification, wherein the eluent is dichloromethane, chloroform, methanol, ethanol, isopropanol or a mixture thereof; preferably, the eluent is dichloromethane, dichloromethane / methanol, dichloromethane / isopropanol, ethyl acetate / petroleum ether; preferably, the eluent and the ratio are dichloromethane:methanol = 50:1, ethyl acetate:petroleum ether = 1:2, dichloromethane:isopropanol = 30:1 to 50:1;

[0027] Furthermore, in step (1), the molar ratio of compound (I-1) to compound (I-2) is 1:4;

[0028] Furthermore, in step (1), the molar ratio of compound (I-1): compound (I-2): alkaline reagent (e.g., lithium bis(trimethylsilyl)amino) is 1:4:(3-5); preferably, the molar ratio of compound (I-1): compound (I-2): alkaline reagent (e.g., lithium bis(trimethylsilyl)amino) is 1:4:4.

[0029] In step (2), hydrogen peroxide is included, preferably an aqueous solution of hydrogen peroxide, and more preferably a 30% aqueous solution of hydrogen peroxide.

[0030] Furthermore, step (2) includes an alkaline reagent, which is an inorganic base; preferably, the inorganic base is lithium hydroxide or sodium hydroxide; preferably, lithium hydroxide.

[0031] Furthermore, step (2) includes a reaction solvent, which is a polar solvent; preferably, the polar solvent is tetrahydrofuran, methanol, ethanol, or acetonitrile; preferably, the polar solvent is tetrahydrofuran.

[0032] Furthermore, in step (2), the reaction temperature is 0-35℃; preferably, the reaction temperature is 0-room temperature; preferably, the reaction temperature is 0-25℃; preferably, the reaction temperature is 0-20℃; preferably, the reaction temperature is 5-15℃.

[0033] Furthermore, in step (2), the reaction time is 1-16 hours; preferably, the reaction time is 1-8 hours; preferably, the reaction time is 3-6 hours.

[0034] Furthermore, in step (2), the reaction temperature is 0-35℃ and the reaction time is 1-16h; preferably, the reaction temperature is 0-room temperature and the reaction time is 1-8h; preferably, the reaction temperature is 0-25℃ and the reaction time is 1-8h; preferably, the reaction temperature is 10±5℃ and the reaction time is 3-6h.

[0035] Furthermore, in step (2), the molar ratio of compound (I-3): 30% H2O2: lithium hydroxide monohydrate is 1:(9-12):(3-9); preferably, the molar ratio of compound (I-3): 30% H2O2: lithium hydroxide monohydrate is 1:9:4.5.

[0036] In step (3), an acid is included, which is hydrochloric acid-dioxane solution, trifluoroacetic acid, methanesulfonic acid, acetic acid, sulfuric acid, or hydrochloric acid; preferably, the acid is hydrochloric acid-dioxane solution or hydrochloric acid; preferably, the acid is concentrated hydrochloric acid.

[0037] Furthermore, step (3) includes a reaction solvent, which is tetrahydrofuran, 1,4-dioxane, or acetonitrile; preferably, the reaction solvent is 1,4-dioxane.

[0038] Furthermore, in step (3), the reaction temperature is 0-60℃; preferably, the reaction temperature is 0-55℃; preferably, the reaction temperature is 20-50℃.

[0039] Furthermore, in step (3), the reaction time is 1-16 hours; preferably, the reaction time is 1-8 hours; preferably, the reaction time is 2-8 hours.

[0040] Furthermore, in step (3), the reaction temperature is 0-35℃ and the reaction time is 1-16h; preferably, the reaction temperature is 20-35℃ and the reaction time is 2-8h.

[0041] In one embodiment of the invention, X is independently selected from fluorine, chlorine, bromine, preferably bromine.

[0042] In one embodiment of the present invention, R1 and R2 are independently selected from hydrogen, deuterium, and methyl, respectively.

[0043] In one embodiment of the invention, R3 is independently selected from tert-butoxycarbonyl (Boc), carboxybenzyl (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), trichloroethoxycarbonyl (Troc), trifluoroacetamyl (Tfa)benzamide (Bz), benzylamino (Bn), triphenylmethylamino (Tphm), p-toluenesulfonamide; preferably tert-butoxycarbonyl.

[0044] In one embodiment of the invention, R4 is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -CHO, nitro, amino, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Deuterated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Deuterated alkoxy group.

[0045] In one embodiment of the invention, R4 is independently selected from hydrogen, deuterium, nitro, amino, C 1-6 Alkoxy, C 1-6 Haloalkoxy groups; preferably, R4 is independently selected from hydrogen, deuterium, nitro, amino, C 1-4 Alkyl group; preferably, R4 is independently selected from hydrogen, nitro, methoxy, ethoxy, The preferred methoxy group is preferred.

[0046] In one embodiment of the present invention, m is 0 or 1, and n is 0 or 1.

[0047] In one embodiment of the present invention, m is 1 and n is 1; or m is 0 and n is 0.

[0048] In one embodiment of the invention, rings W1, W2, and W3 are each independently selected from phenyl and 5-6 membered monocyclic heteroaryl groups; the phenyl and heteroaryl groups are optionally selected by one or more independently selected from deuterium, halogens, -CN, -OH, -NH2, -CHO, C 1-3 Alkyl, C 1-3 Alkoxy, -N(C) 1-3 alkyl)2、-NH(C 1-3 Alkyl), -C(O)C 1-3 The alkyl group is substituted; the heteroatom in the heteroaryl group is O, N or S, and the number of heteroatoms is 1 or 2.

[0049] In one embodiment of the invention, rings W1, W2, and W3 are each independently selected from phenyl, pyridyl, and thiophene groups; the phenyl, pyridyl, and thiophene groups are optionally substituted by one or more substituents each independently selected from deuterium, fluorine, chlorine, bromine, -CN, -OH, -NH2, -CHO, methyl, ethyl, methoxy, ethoxy-N(CH3)2, -NH(CH3), and -C(O)CH3.

[0050] In one embodiment of the invention, rings W1, W2, and W3 are each independently selected from the following optionally substituted groups: The optional substitution refers to either being unsubstituted or substituted by one or more substituents, each independently selected from deuterium, fluorine, chlorine, bromine, -CN, -OH, -NH2, -CHO, methyl, ethyl, methoxy, ethoxy, -N(CH3)2, -NH(CH3), and -C(O)CH3.

[0051] In one embodiment of the invention, rings W1, W2, and W3 are each independently selected from the following optionally substituted groups: The optional substitution refers to either being unsubstituted or substituted by one or more substituents, each independently selected from deuterium, fluorine, chlorine, bromine, -CN, -OH, -NH2, -CHO, methyl, ethyl, methoxy, ethoxy, -N(CH3)2, -NH(CH3), and -C(O)CH3.

[0052] In one embodiment of the present invention, rings W1, W2, and W3 are each independently selected from... The aforementioned Optionally substituted by one or more substituents selected independently from fluorine, chlorine, bromine, methyl, ethyl, methoxy, and ethoxy.

[0053] In one embodiment of the present invention, W1, W2, and W3 are each independently selected from... Preferred

[0054] In one embodiment of the present invention, Z 11 Z 21 Z 31 Selected independently from -C 1-2 alkylene-, -C 1-3 oxa-alkylene-, -C 1-3 Thionide-, -C 1-3Aza-alkylene; the alkylene, oxa-alkylene, thia-alkylene, and azene-alkylene are optionally substituted by one or more substituents, each independently selected from deuterium, halogen, oxo, -CN, -OH, -NH2, methyl, and methoxy; preferably, the alkylene, oxa-alkylene, thia-alkylene, and azene-alkylene are optionally substituted by one or more substituents, each independently selected from deuterium and oxo.

[0055] In one embodiment of the present invention, Z 11 Z 21 and Z 31 The combination of the definition contains at least one heteroatom or heteroatom group, wherein the heteroatom or heteroatom group is selected from -O-, -S-, -Se-, -NH-, -CO-, -C(S)-; preferably -CO-.

[0056] In one embodiment of the present invention, Z 11 Z 21 and Z 31 The combination of definitions must contain at least one optional element. One of them; preferred * indicates the connection terminal with N.

[0057] In one embodiment of the present invention, Z 11 Z 21 and Z 31 The combination of the defined components contains 1-4 heteroatoms or heteroatom groups, wherein the heteroatoms or heteroatom groups are selected from -O-, -S-, -Se-, -NH-, -CO-, and -C(S)-, specifically 1, 2, 3, or 4; preferably 1-3 heteroatoms or heteroatom groups, specifically 1, 2, or 3; more preferably 2-4 heteroatoms or heteroatom groups, specifically 2, 3, or 4; more preferably 2 or 3 heteroatoms or heteroatom groups; the heteroatoms or heteroatom groups are preferably -O-, -S-, -NH-, or -CO-; the heteroatoms or heteroatom groups are more preferably -O- or -CO-; preferably, the heteroatoms or heteroatom groups contain at least -CO-.

[0058] In one embodiment of the present invention, Z 11 Z 21 Z 31 Selected independently from -CD2- and -C 1-2 Alkylene-, -OC 1-3 Alkylene-, -C(O)-, -C 1-2 Alkylene-C(O)-, -OC 1-2 Alkylene -C(O)-, -NH-C 1-2 Alkylene-C(O)-, -SC1-2 Alkylene-C(O)-, -OC 1-2 Alkylene-C(O)-C 1-2 alkylene-, -C 1-2 Alkylene-OC 1-2 Alkylene-, -NH-C 1-2 Alkylene-, -SC 1-2 alkylene-, -C 1-2 Alkylene-NH-C(O)-, -C 1-2 Alkylenes -OC(O)-, -NH-C(O)-, -OC(O)-, -SC(O)-.

[0059] In one embodiment of the present invention, Z 11 Z 21 Z 31 Each is independently selected from the following groups: bond, methylene, ethylene, -CD2-, -O-, -S-, -NH-, Preferred components include methylene, ethylene, and -CD2. * indicates the connection terminal with N.

[0060] In one embodiment of the present invention, Z 11 -CD2, -C 1-3 Alkylene-, -OC 1-3 Alkylene-; and Z 21 Selected from -OC 1-3 Alkylene-, -NH-C 1-3 Alkylene-, -SC 1-3 Alkylene-, -Se-C 1-3 alkylene-, -C 1-2 Alkylene-OC 1-3 Alkylene-; and Z 31 Selected from -C(O)-, -C 1-3 Alkylene-C(O)-, -OC 1-3 Alkylene -C(O)-, -NH-C 1-3 Alkylene-C(O)-, -SC 1-3 Alkylene-C(O)-, -OC 1-2 Alkylene-C(O)-C 1-3 alkylene-, -C 1-3 Alkylene-NH-C(O)-, -C 1-3 Alkylenes -OC(O)-, -NH-C(O)-, -OC(O)-, -SC(O)-, -C 1-3 Alkylene-C(S)-.

[0061] In one embodiment of the present invention, Z 11 -CD2, -C 1-3 Alkylene-, -OC 1-3 Alkylene-*; and Z 21 Selected from -OC 1-3 Alkylene-*, -NH-C 1-3 Alkylene-*, -SC 1-3 Alkylene-*, -Se-C 1-3 Alkylene-*, -C 1-2 Alkylene-OC 1-3 Alkylene-*; and Z 31 Selected from -C(O)-, -C 1-3 Alkylene-C(O)-*, -OC 1-3 Alkylene -C(O)-*, -NH-C 1-3 Alkylene-C(O)-*, -SC 1-3 Alkylene-C(O)-*, -OC 1-2 Alkylene-C(O)-C 1-3 Alkylene-*, -C 1-3 Alkylene -NH-C(O)-*, -C 1-3 Alkylenes -OC(O)-*, -NH-C(O)-*, -OC(O)-*, -SC(O)-*, -C 1-3 Alkylene-C(S)-*; * indicates the N-terminal junction.

[0062] In one embodiment of the present invention, Z 11 -CD2-, -C 1-2 Alkylene-, -OC 1-2 Alkylene-*; and Z 21 Selected from -OC 1-2 Alkylene-*, -NH-C 1-2 Alkylene-*, -SC 1-2 Alkylene-*, -Se-C 1-2 Alkylene-*, -CH2-OC 1-2 Alkylene-*; and Z 31 Selected from -C(O)-, -C 1-2 Alkylene-C(O)-*, -OC 1-2 Alkylene -C(O)-*, -NH-C 1-2 Alkylene-C(O)-*, -SC 1-2 Alkylene-C(O)-*, -C 1-2 Alkylene -NH-C(O)-*, -C 1-2 Alkylenes -OC(O)-*, -NH-C(O)-*, -OC(O)-*, -SC(O)-*, -C1-2 Alkylene-C(S)-*; more preferably, Z 31 Selected from -C 1-2 Alkylene-C(O)-*, -OC 1-2 Alkylene -C(O)-*, -NH-C 1-2 Alkylene-C(O)-*, -SC 1-2 Alkylene-C(O)-*, -C 1-2 Alkylene -NH-C(O)-*, -C 1-2 Alkylenes -OC(O)-*, -CH2NH-C(O)-*, -NH-C(O)-*, -OC(O)-*, -SC(O)-*, -C 1-2 Alkylene-C(S)-*; more preferably, Z 31 Selected from -C 1-2 Alkylenes -C(O)-*, -OCH2-C(O)-*, -CH2-OC(O)-*, -NH-C(O)-*, -OC(O)-*, -SC(O)-*; more preferably, Z 31 Selected from -CH2C(O)-*; * indicates the connection terminal with N.

[0063] In one embodiment of the present invention, Z 11 Selected from methylene, ethylene, -CD2, And Z 21 Selected from methylene, ethylene, -CD2, And Z 31 Selected from Further preferred Z 31 Selected from * indicates the connection terminal with N.

[0064] In one embodiment of the present invention, Z 11 Selected from methylene, ethylene, -CD2, And Z 21 Selected from methylene, ethylene, -CD2, And Z 31 Selected from * indicates the connection terminal with N.

[0065] A second aspect of the present invention provides a method for preparing (compound 7):

[0066] In one embodiment of the present invention, the preparation method of compound 7 includes the following steps:

[0067] Step (1-a): (a) undergoes a substitution reaction with (b1) to produce (c1);

[0068] Step (2-a): (c1) An oxidative hydrolysis reaction (e.g., alkaline oxidation to remove the Evans chiral cofactor) occurs to generate (d);

[0069] Step (3-a): (d) Deprotection of the protecting group to generate (compound 7).

[0070] In step (1-a), an alkaline reagent is included, which is selected from organic bases; preferably, the organic base is lithium bis(trimethylsilyl)amino, sodium bis(trimethylsilyl)amino, potassium bis(trimethylsilyl)amino, or N,N-diisopropylethylamine; preferably lithium bis(trimethylsilyl)amino.

[0071] Furthermore, step (1-a) includes a reaction solvent, which is tetrahydrofuran, toluene, diethyl ether, or tert-methyl ether; preferably, the reaction solvent is tetrahydrofuran.

[0072] Further, in step (1-a), the reaction temperature is -78℃ to 30℃; preferably, the reaction temperature is -78℃ to 25℃; preferably, the reaction temperature is -78℃ to 0℃; preferably, the reaction temperature is -78℃ to -15℃; preferably, the reaction temperature is -35℃ to -15℃; preferably, the reaction temperature is -20±5℃.

[0073] Furthermore, in step (1-a), the reaction time is 1-24 h; preferably, the reaction time is 2-18 h; preferably, the reaction time is 6-10 h; preferably, the reaction time is 8 ± 0.5 h.

[0074] Further, in step (1-a), the reaction temperature is -78 to 30°C, and the reaction time is 1 to 24 hours; preferably, the reaction temperature is -78 to 25°C, and the reaction time is 2 to 18 hours; preferably, the reaction temperature is -20°C to room temperature, and the reaction time is 2 to 18 hours; preferably, the reaction temperature is 0°C to room temperature, and the reaction time is 2 to 18 hours.

[0075] Furthermore, step (1-a) is carried out under the protection of an inert gas, preferably nitrogen.

[0076] Further, step (1-a) includes column chromatography purification, wherein the eluent is dichloromethane, chloroform, methanol, ethanol, isopropanol, or a mixture thereof; preferably, the eluent is dichloromethane, dichloromethane / methanol, dichloromethane / isopropanol, or ethyl acetate / petroleum ether; preferably, the eluent and the ratio are dichloromethane:methanol = 50:1, ethyl acetate:petroleum ether = 1:2, or dichloromethane:isopropanol = 30:1 to 50:1.

[0077] Furthermore, in step (1-a), the molar ratio of compound (a) to compound (b1) is 1:4;

[0078] Furthermore, in step (1-a), the molar ratio of compound (a): compound (b1): alkaline reagent (e.g., lithium bis(trimethylsilyl)amino) is 1:4:(3-5); preferably, the molar ratio of compound (a): compound (b1): alkaline reagent (e.g., lithium bis(trimethylsilyl)amino) is 1:4:4.

[0079] In step (2-a), hydrogen peroxide is included, preferably an aqueous solution of hydrogen peroxide, and more preferably a 30% aqueous solution of hydrogen peroxide.

[0080] Furthermore, step (2-a) includes an alkaline reagent, which is an inorganic base; preferably, the inorganic base is lithium hydroxide or sodium hydroxide; more preferably, lithium hydroxide.

[0081] Furthermore, step (2-a) includes a reaction solvent, which is a polar solvent; preferably, the polar solvent is tetrahydrofuran, methanol, ethanol, or acetonitrile; preferably, the polar solvent is tetrahydrofuran.

[0082] Furthermore, in step (2-a), the reaction temperature is 0-35℃; preferably, the reaction temperature is 0-room temperature; preferably, the reaction temperature is 0-25℃; preferably, the reaction temperature is 0-20℃; preferably, the reaction temperature is 5-15℃.

[0083] Furthermore, in step (2-a), the reaction time is 1-16 hours; preferably, the reaction time is 1-8 hours; preferably, the reaction time is 3-6 hours.

[0084] Furthermore, in step (2-a), the reaction temperature is 0-35℃ and the reaction time is 1-16h; preferably, the reaction temperature is 0-room temperature and the reaction time is 1-8h; preferably, the reaction temperature is 0-25℃ and the reaction time is 1-8h; preferably, the reaction temperature is 10±5℃ and the reaction time is 3-6h.

[0085] Furthermore, in step (2-a), the molar ratio of compound (c1): 30% H2O2: lithium hydroxide monohydrate is 1:(9-12):(3-9); preferably, the molar ratio of compound (c1): 30% H2O2: lithium hydroxide monohydrate is 1:9:4.5.

[0086] In step (3-a), an acid is included, wherein the acid is hydrochloric acid-dioxane solution, trifluoroacetic acid, methanesulfonic acid, acetic acid, sulfuric acid, or hydrochloric acid; preferably, the acid is hydrochloric acid-dioxane solution or hydrochloric acid; preferably, the acid is concentrated hydrochloric acid.

[0087] Furthermore, step (3-a) includes a reaction solvent, wherein the solvent is tetrahydrofuran, 1,4-dioxane, or acetonitrile; preferably, the reaction solvent is 1,4-dioxane.

[0088] Furthermore, in step (3-a), the reaction temperature is 0-60℃; preferably, the reaction temperature is 0-55℃; preferably, the reaction temperature is 20-50℃.

[0089] Furthermore, in step (3-a), the reaction time is 1-16 hours; preferably, the reaction time is 1-8 hours; preferably, the reaction time is 2-8 hours.

[0090] Furthermore, in step (3-a), the reaction temperature is 0-35℃ and the reaction time is 1-16h; preferably, the reaction temperature is 20-35℃ and the reaction time is 2-8h.

[0091] The preparation method of (a) includes the following steps:

[0092] Step (1-1): (a-1) and (2-bromoethyl)carbamate benzyl ester undergo a nucleophilic substitution reaction to generate (a-2);

[0093] Step (1-2): (a-2) Under hydrogen protection, a deprotection reaction occurs to produce (a-3);

[0094] Steps (1-3): (a-3) and (a-4) undergo a substitution reaction to generate compound (a-5);

[0095] Steps (1-4): (a-5) and (a-6) undergo a condensation reaction to form compound (a-7);

[0096] Steps (1-5): (a-7) undergoes a reduction reaction to produce compound (a-8);

[0097] Steps (1-6): (a-8) Halogenation (e.g., bromination) occurs to produce compound (a).

[0098] In step (1-1), an alkaline reagent is included, which is potassium carbonate, sodium carbonate, cesium carbonate, or potassium phosphate; preferably, the alkaline reagent is potassium carbonate.

[0099] Furthermore, step (1-1) includes a reaction solvent, which is N,N-dimethylformyl, dimethyl sulfoxide, or acetonitrile; preferably, the reaction solvent is N,N-dimethylformyl.

[0100] Furthermore, in step (1-1), the reaction temperature is 70-120℃ and the reaction time is 10-24h; preferably, the reaction temperature is 70-100℃ and the reaction time is 12-18h.

[0101] In step (1-2), a catalyst is included, and the catalyst is palladium on carbon;

[0102] Furthermore, in step (1-2), a reaction solvent is included, wherein the reaction solvent is methanol; the reaction temperature is 20-35℃, and the reaction time is 10-24h.

[0103] In step (1-3), an alkaline reagent is included; preferably, the alkaline reagent is potassium carbonate and potassium iodide, sodium carbonate, cesium carbonate, or potassium phosphate; preferably, the alkaline reagent is potassium carbonate and potassium iodide.

[0104] Furthermore, in steps (1-3), a reaction solvent is included, wherein the reaction solvent is acetonitrile, 1,4-dioxane, N,N-dimethylformyl, or dimethyl sulfoxide; preferably, the reaction solvent is acetonitrile.

[0105] Furthermore, in steps (1-3), the reaction temperature is 70-120℃ and the reaction time is 10-24h; preferably, the reaction temperature is 70-100℃ and the reaction time is 12-18h.

[0106] In step (1-4), an alkaline reagent is included, which is N,N-diisopropylethylamine, sodium carbonate, potassium carbonate, or triethylamine; preferably, the alkaline reagent is N,N-diisopropylethylamine.

[0107] Furthermore, steps (1-4) are carried out in the presence of a condensing agent selected from N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea;

[0108] Furthermore, in steps (1-4), a reaction solvent is included, wherein the reaction solvent is N,N-dimethylformamide or tetrahydrofuran, the reaction temperature is 0-65°C, and the reaction time is 1-4 h; preferably, the reaction solvent is N,N-dimethylformamide, the reaction temperature is 0-50°C, and the reaction time is 2-4 h.

[0109] In step (1-5), a reducing agent is included, which is lithium borohydride, sodium borohydride, or lithium aluminum hydride; preferably, the reducing agent is lithium borohydride.

[0110] Furthermore, in steps (1-5), a reaction solvent is included, the reaction solvent is tetrahydrofuran, the reaction temperature is 0-35℃, and the reaction time is 24-48h; preferably, the reaction temperature is 20-35℃ and the reaction time is 24-40h.

[0111] In step (1-6), a brominating agent is included, preferably phosphorus tribromide;

[0112] Furthermore, in steps (1-6), a reaction solvent is included, wherein the reaction solvent is a haloalkane; preferably dichloromethane;

[0113] Furthermore, in steps (1-6), the reaction temperature is 0-35℃ and the reaction time is 1-4h.

[0114] The preparation method of (b1) includes the following steps:

[0115] Step (2-1): (b1-1) undergoes a reduction reaction to produce compound (b1-2);

[0116] Step (2-2): (b1-2) undergoes a ring-closing reaction to produce (b1-3);

[0117] Steps (2-3): (b1-3) and (b1-4) generate (b1).

[0118] In step (2-1), a reducing agent is included, which is borane, lithium borohydride, sodium borohydride, or lithium aluminum hydride; preferably, the reducing agent is borane.

[0119] Furthermore, step (2-1) includes a reaction solvent, wherein the solvent is tetrahydrofuran;

[0120] Furthermore, in step (2-1), the reaction temperature is -10 to 35°C, and the reaction time is 0.5 to 12 hours; preferably, the reaction temperature is 0 to 35°C, and the reaction time is 1 to 10 hours.

[0121] In step (2-2), an alkaline reagent is included, wherein the alkaline reagent is NaH;

[0122] Furthermore, step (2-2) includes a reaction solvent, which is tetrahydrofuran;

[0123] Furthermore, in step (2-2), the reaction temperature is 20-70℃ and the reaction time is 1-12h; preferably, the reaction temperature is 10-50℃ and the reaction time is 2-8h.

[0124] In step (2-3), a condensation reagent is included, wherein the condensation reagent is 2,2-dimethylpropionyl chloride and lithium chloride;

[0125] Furthermore, in step (2-3), an alkaline reagent is included, wherein the alkaline reagent is triethylamine, N,N-diisopropylethylamine, sodium carbonate, potassium carbonate, or potassium phosphate; preferably, the alkaline condition is triethylamine.

[0126] Furthermore, in step (2-3), a reaction solvent is included, which is tetrahydrofuran, acetonitrile, or N,N-dimethylformamide; the reaction temperature is 0-40°C; and the reaction time is 1-12 h. Preferably, the reaction solvent is tetrahydrofuran; the reaction temperature is 0-35°C; and the reaction time is 2-6 h.

[0127] In one embodiment of the present invention, the preparation method of compound 7 includes the following steps:

[0128] Step (1-b): (a) undergoes a substitution reaction with (b2) to produce (c2);

[0129] Step (2-b): (c2) An oxidative hydrolysis reaction occurs (e.g., alkaline oxidation to remove the Evans chiral cofactor) to generate (d);

[0130] Step (3-b): (d) Deprotection of the protecting group to generate (compound 7).

[0131] In step (1-b), an alkaline reagent is included, which is selected from organic bases; preferably, the organic base is lithium bis(trimethylsilyl)amino, sodium bis(trimethylsilyl)amino, potassium bis(trimethylsilyl)amino, or N,N-diisopropylethylamine; preferably, the base is lithium bis(trimethylsilyl)amino.

[0132] Furthermore, step (1-b) includes a reaction solvent, which is tetrahydrofuran, toluene, diethyl ether, or tert-methyl ether; preferably, the reaction solvent is tetrahydrofuran.

[0133] Further, in step (1-b), the reaction temperature is -78 to 30°C, and the reaction time is 1 to 24 hours; preferably, the reaction temperature is -78 to 25°C, and the reaction time is 2 to 18 hours; preferably, the reaction temperature is -20°C to room temperature, and the reaction time is 2 to 18 hours; preferably, the reaction temperature is 0°C to room temperature, and the reaction time is 2 to 18 hours.

[0134] Furthermore, step (1-b) is carried out under the protection of an inert gas, preferably nitrogen.

[0135] In step (2-b), hydrogen peroxide is included, preferably an aqueous solution of hydrogen peroxide;

[0136] Furthermore, step (2-b) includes an alkaline reagent, which is an inorganic base; preferably, the inorganic base is lithium hydroxide or sodium hydroxide; more preferably, lithium hydroxide.

[0137] Furthermore, step (2-b) includes a reaction solvent, which is a polar solvent; preferably, the polar solvent is tetrahydrofuran, methanol, ethanol, or acetonitrile; preferably, the solvent is tetrahydrofuran.

[0138] Furthermore, in step (2-b), the reaction temperature is 0-35℃ and the reaction time is 1-16h; preferably, the reaction temperature is 0-room temperature and the reaction time is 1-8h; preferably, the reaction temperature is 0-25℃ and the reaction time is 1-8h.

[0139] In step (3-b), an acid is included, wherein the acid is hydrochloric acid-dioxane solution, trifluoroacetic acid, methanesulfonic acid, acetic acid, or sulfuric acid; preferably, the acid is hydrochloric acid-dioxane solution.

[0140] Furthermore, step (3-b) includes a reaction solvent, wherein the solvent is tetrahydrofuran, 1,4-dioxane, or acetonitrile; preferably, the reaction solvent is 1,4-dioxane.

[0141] Furthermore, in step (3-b), the reaction temperature is 0-35℃ and the reaction time is 1-16h; preferably, the reaction temperature is 20-35℃ and the reaction time is 2-8h.

[0142] The preparation method of (b2) includes the following steps:

[0143] Step (4-1): (b2-1) undergoes a reduction reaction (e.g., a reduction of deuteration) to produce (b2-2);

[0144] Step (4-2): (b2-2) A cyclization reaction occurs under the action of N,N'-carbonyldiimidazole to generate (b2-3);

[0145] Step (4-3): (b1-4) and (b2-3) undergo a condensation reaction in the presence of 2,2-dimethylpropionyl chloride and lithium chloride to generate (b2).

[0146] In step (4-1), a reducing agent is included, wherein the reducing agent is lithium aluminum deuterated hydride;

[0147] Furthermore, in step (4-1), a reaction solvent is included, wherein the solvent is tetrahydrofuran; the reaction temperature is -10 to 35°C, and the reaction time is 0.5 to 12 h.

[0148] In step (4-2), an alkaline reagent is included, wherein the alkaline reagent is cesium carbonate, potassium carbonate, or sodium carbonate; preferably, the alkaline reagent is cesium carbonate.

[0149] Furthermore, in step (4-2), the reaction temperature is 80-150℃ and the reaction time is 1-12h; preferably, the reaction temperature is 70-120℃ and the reaction time is 2-10h.

[0150] In step (4-3), an alkaline reagent is included, wherein the alkaline reagent is triethylamine, N,N-diisopropylethylamine, sodium carbonate, potassium carbonate, or potassium phosphate; preferably, the alkaline reagent is triethylamine.

[0151] Furthermore, in step (4-3), a reaction solvent is included, which is tetrahydrofuran, acetonitrile, or N,N-dimethylformamide; the reaction temperature is 0-35°C; and the reaction time is 1-12 h. Preferably, the reaction solvent is tetrahydrofuran; the reaction temperature is 10-30°C; and the reaction time is 2-10 h.

[0152] In one embodiment of the present invention, the preparation method of compound 7 includes the following steps:

[0153] Following the preparation method described above, (a) undergoes a substitution reaction with (b3) to generate (c3); (c3) undergoes an oxidative hydrolysis reaction (e.g., alkaline oxidation to remove the Evans chiral cofactor) to generate (d); and (d) undergoes deprotection to generate (compound 7).

[0154] In one embodiment of the present invention, the preparation method of compound 7 includes the following steps:

[0155] Following the preparation method described above, (a) undergoes a substitution reaction with (b4) to generate (c4); (c4) undergoes an oxidative hydrolysis reaction (e.g., alkaline oxidation to remove the Evans chiral cofactor) to generate (d); and (d) undergoes deprotection to generate (compound 7).

[0156] In one embodiment of the present invention, the preparation method of compound 7 includes the following steps:

[0157] Following the preparation method described above, (a) undergoes a substitution reaction with (b5) to generate (c5); (c4) undergoes an oxidative hydrolysis reaction (e.g., alkaline oxidation to remove the Evans chiral cofactor) to generate (d); and (d) undergoes deprotection to generate (compound 7).

[0158] In one embodiment of the present invention, the preparation method of compound 7 includes the following steps:

[0159] Following the preparation method described above, (a) undergoes a substitution reaction with (b6) to generate (c6); (c6) undergoes an oxidative hydrolysis reaction (e.g., alkaline oxidation to remove the Evans chiral cofactor) to generate (d); and (d) undergoes deprotection to generate (compound 7).

[0160] In one embodiment of the present invention, the preparation method of compound 7 includes the following steps:

[0161] Following the preparation method described above, (a) undergoes a substitution reaction with (b7) to generate (c7); (c7) undergoes an oxidative hydrolysis reaction (e.g., alkaline oxidation to remove the Evans chiral cofactor) to generate (d); and (d) undergoes deprotection to generate (compound 7).

[0162] A third aspect of the present invention provides a method for preparing compound 40, comprising the following steps:

[0163] (f) undergoes a substitution reaction with (b3) to generate (c8); (c8) undergoes an oxidative hydrolysis reaction (e.g., basic oxidation to remove the Evans chiral cofactor) to generate (h); (h) undergoes deprotection to generate (compound 40).

[0164] The preparation method of (f) includes the following steps:

[0165] Step (5-1): (f-1) reacts with ammonia to undergo a substitution reaction, producing (f-2);

[0166] Step (5-2): (f-2) undergoes a reduction reaction to produce (f-3);

[0167] Step (5-3): (f-3) undergoes a halogenation reaction (e.g., bromination) to produce (f).

[0168] In step (5-1), a reaction solvent is included, which is ethanol, methanol, tetrahydrofuran, or isopropanol; preferably, the reaction solvent is ethanol.

[0169] Furthermore, in step (5-1), the reaction temperature is 0-35℃ and the reaction time is 12-56h; preferably, the reaction temperature is 0-30℃ and the reaction time is 15-48h.

[0170] In step (5-2), a reducing agent is included, which is lithium aluminum hydride, sodium borohydride, or lithium borohydride; preferably, the reducing agent is lithium aluminum hydride.

[0171] Furthermore, in step (5-2), a reaction solvent is included, the reaction solvent is tetrahydrofuran, the reaction temperature is 0-35℃, and the reaction time is 1-4h; preferably, the reaction temperature is 0-30℃ and the reaction time is 2-4h.

[0172] In step (5-3), a brominating agent is included, preferably phosphorus tribromide.

[0173] Furthermore, step (5-3) includes a reaction solvent, which is a haloalkane; preferably dichloromethane.

[0174] Furthermore, in step (5-3), the reaction temperature is 0-35℃ and the reaction time is 8-18h.

[0175] A fourth aspect of the present invention provides a method for preparing compound 41, comprising the following steps:

[0176] (g) undergoes a substitution reaction with (b3) to generate (c9); (c9) undergoes an oxidative hydrolysis reaction (e.g., basic oxidation to remove the Evans chiral cofactor) to generate (j); (j) undergoes deprotection to generate (compound 41).

[0177] The preparation method of (g) includes the following steps:

[0178] Step (6-1): (g-1) and methyl 3-(bromomethyl)benzoate undergo a substitution reaction under alkaline conditions and in the presence of a reaction solvent to produce (g-2);

[0179] Step (6-2): (g-2) undergoes a reduction reaction under the action of a reducing agent and a reaction solvent to produce (g-3);

[0180] Step (6-3): (g-3) Under the action of halides, a halogenation reaction (e.g., bromination reaction) occurs to generate (g).

[0181] In step (6-1), an alkaline reagent is included, wherein the alkaline reagent is N,N-diisopropylethylamine, triethylamine, potassium carbonate, sodium carbonate, cesium carbonate, or potassium phosphate; preferably, the alkaline reagent is N,N-diisopropylethylamine.

[0182] Furthermore, step (6-1) includes a reaction solvent, which is acetonitrile, N,N-dimethylformamide, or dimethyl sulfoxide; preferably, the reaction solvent is acetonitrile.

[0183] Furthermore, in step (6-1), the reaction temperature is 50-100℃ and the reaction time is 1-8h; preferably, the reaction temperature is 40-100℃ and the reaction time is 2-6h.

[0184] In step (6-2), a reducing agent is included, which is lithium borohydride, sodium borohydride, or lithium aluminum hydride; preferably, the reducing agent is lithium borohydride.

[0185] Furthermore, step (6-2) includes a reaction solvent, which is tetrahydrofuran;

[0186] Furthermore, in step (6-2), the reaction temperature is 0-80℃ and the reaction time is 0.5-3h; preferably, the reaction temperature is 40-70℃ and the reaction time is 0.5-2h.

[0187] In step (6-3), a brominating reagent is included, preferably phosphorus tribromide.

[0188] Furthermore, step (6-3) includes a reaction solvent, which is a haloalkane; preferably dichloromethane.

[0189] Furthermore, in step (6-3), the reaction temperature is 0-35℃ and the reaction time is 0.5-4h.

[0190] The present invention also provides a compound represented by formula (I-1), a stereoisomer, tautomer, isotopic derivative thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0191] Among them, W1, W2, W3, Z 11 Z 21 Z 31,X,R5,R6,R7,R8,R9,R 10 The definition is as described in compound (I).

[0192] The present invention also provides a compound of formula (I-1-1), a stereoisomer, tautomer, isotopic derivative or mixture thereof, or a pharmaceutically acceptable salt thereof:

[0193] Wherein, X is defined as in compound (I).

[0194] The present invention also provides a compound represented by formula (I-2), a stereoisomer, tautomer, isotopic derivative or mixture thereof, or a pharmaceutically acceptable salt thereof:

[0195] Wherein, R1, R2, R3, R4, m, and n are defined as described in compound (I).

[0196] The condition is that the compound is not

[0197] The present invention also provides a compound of formula (I-2-1), wherein the stereoisomer, tautomer, isotopic derivative or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound:

[0198] The definitions of R1, R2, R3, and R4 are as described in compound (I).

[0199] The present invention also provides a compound represented by formula (I-3), a stereoisomer, tautomer, isotopic derivative thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

[0200] Among them, W1, W2, W3, Z 11 Z 21 Z 31 ,X,R1,R2,R3,R4,R5,R6,R7,R8,R9,R 10 The definitions of m and n are as described in compound (I).

[0201] In one embodiment of the invention, the intermediate of the substituted 2-(pyrrolidine-3-yl)acetic acid derivative may be selected from:

[0202] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0203] In one embodiment of the invention, the substituted 2-(pyrrolidine-3-yl)acetic acid derivative may be selected from:

[0204] definition

[0205] The terms “optional,” “arbitrary,” “optionally,” or “arbitrarily” refer to events or conditions that are subsequently described but are not required to occur, and the description includes both cases where said events or conditions occur and cases where said events or conditions do not occur.

[0206] The word "multiple" in "optionally replaced by one or more substituents selected independently from..." means 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; preferably 1, 2, 3 or 4; more preferably 1 or 2.

[0207] Unless otherwise specified, the term "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group, a straight-chain or branched group containing 1-20 carbon atoms, preferably containing 1-10 carbon atoms (i.e., C10). 1-10 Alkyl groups, more preferably containing 1-8 carbon atoms (C64- ... 1-8 Alkyl groups, more preferably containing 1-6 carbon atoms (i.e., C64-C ... 1-6 Alkyl), for example, "C 1-6 "Alkyl" refers to a group that is alkyl and has 1 to 6 carbon atoms in its carbon chain (specifically, 1, 2, 3, 4, 5, or 6). Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, n-octyl, etc.

[0208] Unless otherwise specified, the term "alkylene" refers to a monovalent saturated aliphatic hydrocarbon group, a straight-chain or branched group containing 1-20 carbon atoms, preferably containing 1-10 carbon atoms (i.e., C24-C24). 1-10 Alkylene), more preferably containing 1-8 carbon atoms (C 1-8 Alkylene), more preferably containing 1-6 carbon atoms (i.e., C64-C ... 1-6 Alkylene), for example, "C 1-6 "alkylene" refers to a group that is alkylene and has 1-6 carbon atoms in its carbon chain (specifically, 1, 2, 3, 4, 5, or 6). Examples include, but are not limited to, methylene, ethylene, n-propylene, n-pentylene, and n-hexylene. wait.

[0209] Unless otherwise specified, the term "cycloalkyl" refers to a monocyclic, bicyclic, or polycyclic cyclic saturated aliphatic hydrocarbon group having a specific number of carbon atoms, preferably containing 3-14 carbon atoms (i.e., C64-C64). 3-14 cycloalkyl groups, preferably containing 4-14 carbon atoms (i.e., C64-C ... 4-14 cycloalkyl groups, preferably containing 5-14 carbon atoms (i.e., C64-C ... 5-14 cycloalkyl), more preferably containing 6-14 carbon atoms (C 6-14 Cycloalkyl groups, more preferably 6-12 carbon atoms (C 6-12 (Cycloalkyl). Examples include, but are not limited to, cyclohexyl, spiro[3,5]nonyl, etc.

[0210] Unless otherwise specified, the term "oxaalkyl" refers to an alkyl residue in which one or more carbons (and associated hydrogens) are substituted with oxygen, such as "alkoxy" or "alkoxyalkyl". For example, C3 oxaalkylene includes -OC. 1-3 Alkoxy, -CH2OCH2CH3, -CH2CH2OCH3, etc. Examples include methoxy, ethoxy, propoxy, methoxypropyl, etc. The term oxaalkyl has the meaning understood in the art [see Nomenclature and Index of Chemical Substances for Chemical Extraction, published by the American Chemical Society, 196, but not limited to 127(a)], that is, it refers to a compound in which oxygen is bonded to its adjacent atoms by a single bond (forming an ether bond); it does not refer to the double oxygen bond found in the carbonyl group. The terms “thioalkyl” and “selenyl” are similar to “oxaalkyl”. The term “azaalkyl” refers to compounds containing the radicals “NH”, “-N(C)”, “-N(C)”, etc. 1-3 Alkyl groups of alkyl groups ()-”, for example, C3 azaalkylene groups include -NHCH2CH2CH3, -CH2NHCH2CH3, -CH2CH2NHCH3, -CH2CH2N(CH3)CH3, etc.

[0211] "Alkoxy" refers to -O-alkyl, and the alkyl group is defined as above, i.e., containing 1-20 carbon atoms, preferably 1-10 carbon atoms, more preferably 1-8 carbon atoms, and even more preferably 1-6 carbon atoms (specifically 1, 2, 3, 4, 5, or 6). Examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, tert-butoxy, pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, etc.

[0212] Unless otherwise specified, the terms “halogen” or “halogenated” refer to F, Cl, Br, and I.

[0213] Unless otherwise specified, the term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic, bicyclic, or polycyclic cyclic hydrocarbon substituent, which is a non-aromatic structure containing 3-20 ring atoms, wherein one, two, three, or more ring atoms are selected from N, O, S, or B, and the remaining ring atoms are C. Preferably, it contains 3-12 ring atoms, more preferably 3-10 ring atoms, or 3-8 ring atoms, or 3-6 ring atoms, or 4-6 ring atoms, or 5-6 ring atoms. The number of heteroatoms is preferably 1-4, more preferably 1-3 (i.e., 1, 2, or 3). Examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazoalkyl, tetrahydrofuranyl, dihydropyrrolidinyl, piperidinyl, piperazinyl, pyranyl, etc. Bicyclic or polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups.

[0214] Unless otherwise specified, the term "aryl" refers to an aromatic carbocyclic system containing 6-16 carbon atoms, or 6-14 carbon atoms, or 6-12 carbon atoms, or 6-10 carbon atoms, preferably 6-10 carbon atoms. The term "aryl" may be used interchangeably with the term "aromatic ring." Examples of aryl groups may include, but are not limited to, phenyl, naphthyl, anthraceneyl, phenanthryl, or pyreneyl.

[0215] Unless otherwise specified, the term "heteroaryl" refers to an aromatic monocyclic, bicyclic, or polycyclic cyclic system containing a 5-16 member structure, or a 5-14 member structure, a 5-12 member structure, a 5-10 member structure, a 5-8 member structure, or a 5-6 member structure, wherein one, two, three, or more ring atoms are heteroatoms and the remaining atoms are carbon atoms, the heteroatoms being independently selected from O, N, or S, and the number of heteroatoms is preferably one, two, or three. Polycyclic heteroaryl is a fused heteroaryl. Examples of heteroaryl groups may include, but are not limited to, furanyl, thiophene, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiazolyl, pyrrole, pyrazolyl, imidazole, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiodiazolyl, triazinyl, phthalazinyl, quinolinyl, isoquinolinyl, pteridinyl, purine, indoleyl, isoindoleyl, indazoleyl, benzofuranyl, benzothiophene, benzopyridyl, benzopyrimidinyl, and benzene. Pyrazinyl, benzimidazolyl, benziphthalazolyl, pyrrolo[2,3-b]pyridyl, imidazo[1,2-a]pyridyl, pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridyl, etc.

[0216] Unless otherwise specified, the terms "pharmaceutically acceptable salt" or "medicinal salt" refer to a salt that, within reasonable medical judgment, is suitable for contact with mammalian, particularly human, tissues without excessive toxicity, irritation, allergic reactions, etc., and is proportionate to a reasonable benefit / risk ratio. Medically acceptable salts of amines, carboxylic acids, and other types of compounds are well known in the art. The salts can be prepared in situ during the final isolation and purification of the compounds of this invention, or solely by reacting a free base or free acid with a suitable reagent.

[0217] Unless otherwise specified, the term "stereoisomer" refers to compounds having the same chemical structure but with different spatial arrangements of atoms or groups. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis / trans) isomers, and inhibited isomers. Any mixture of stereoisomers obtained can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physicochemical properties of the components, for example, by chromatography and / or fractional crystallization.

[0218] Unless otherwise specified, the term "tautomer" refers to structural isomers with different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium can be achieved in the tautomer. For example, proton tautomers (also called proton transfer tautomers) involve interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers involve interconversions via the rearrangement of some bonding electrons.

[0219] Unless otherwise specified, the term "isotope derivative" refers to compounds of the present invention that can exist in an isotopically traced or enriched form, containing one or more atoms whose atomic weights or mass numbers differ from the atomic weights or mass numbers of the most abundant atoms found in nature. Isotopes can be radioactive or non-radioactive. Commonly used isotopes for isotopic labeling are: hydrogen isotopes, 2 H and 3 H; Carbon isotopes: 13 C and 14 C; Chlorine isotopes: 35 Cl and 37 Cl; Fluorine isotopes: 18 F; Iodine isotopes: 123 I and 125 I; Nitrogen isotopes: 13 N and 15 N; oxygen isotopes: 15 O、 17 O and 18 O and sulfur isotopes 35S. These isotope-labeled compounds can be used to study the distribution of pharmaceutical molecules in tissues. Especially 3 H and 13 C, because they are easy to label and convenient to detect, are more widely used. Some heavy isotopes, such as deuterium (… 2 Substitution with H can enhance metabolic stability and prolong the half-life, thereby achieving the goal of reducing dosage and providing therapeutic advantages. Isotope-labeled compounds are generally synthesized from labeled starting materials using known synthetic techniques, just like non-isotope-labeled compounds.

[0220] Unless otherwise specified, the compounds of this invention also include their "solvates" or "solvents". The terms "solvate" and "solvent" refer to the physical association of the compound of this invention with one or more solvent molecules (organic or inorganic). This physical association includes hydrogen bonding. In some cases, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate can be separated. The solvent molecules in the solvate may be present in a regular and / or disordered arrangement. Solvates may contain stoichiometric or non-stoichiometric solvent molecules. "Solvate" encompasses both solution phases and separable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art. The term "hydrate" refers to a substance in which water molecules are bonded to cations or anions in a compound by coordinate or covalent bonds, or in which water ions do not directly bond to cations or anions but exist in a certain proportion at defined positions in a solid crystal lattice.

[0221] Unless otherwise specified, the compounds of this invention also include their “prodrugs.” The term “prodrug” refers to a drug that is converted into a parent drug in vivo. Prodrugs are generally useful because they can improve certain, undesirable physical or biological properties. Physical properties are generally related to solubility (excessive or insufficient lipid or water solubility) or stability, while problematic biological properties include metabolism that is too rapid or poor bioavailability, which may itself be related to physicochemical properties. For example, they can be bioavailable orally, whereas the parent drug cannot. Prodrugs also have improved solubility in pharmaceutical compositions compared to the parent drug. An example of a prodrug, but not limited thereto, can be any compound of this invention administered as an ester (“prodrug”) to facilitate transmembrane transport, where water solubility is detrimental to migration but beneficial once inside the cell, and which is subsequently metabolized and hydrolyzed into a carboxylic acid, i.e., the active entity. Another example of a prodrug can be a short peptide (polyamino acid) bound to an acid group, where the peptide is metabolized to exhibit the active moiety.

[0222] The term "oxo" refers to the substitution of two H atoms at the same substitution site by the same O atom to form a double bond.

[0223] The term "thioyl" refers to a double bond formed when two H atoms at the same substitution site are replaced by the same S atom.

[0224] The beneficial effects of the present invention are one or more of the following:

[0225] The method for preparing substituted 2-(pyrrolidine-3-yl)acetic acid derivatives with reduced Lp(a) levels described in this invention is rationally designed. It first uses methyl 3-hydroxybenzoate as the starting material, and then synthesizes the final product, substituted 2-(pyrrolidine-3-yl)acetic acid derivatives, through steps (1) substitution reaction, (2) oxidative hydrolysis reaction, and (3) deprotection. The purity of the obtained substituted 2-(pyrrolidine-3-yl)acetic acid derivatives is higher than 99.95%. The entire process has mild reaction conditions, high yield, low cost, and broad application prospects, which is conducive to large-scale industrial production and application. Detailed Implementation

[0226] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein can be applied to the methods of the present invention. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without inventive effort are within the scope of protection of the present invention. The preferred embodiments and materials shown herein are for illustrative purposes only.

[0227] The structures of the compounds of this invention were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS) and / or high-performance liquid chromatography (HPLC). The NMR measurements were performed using a Bruker 400MHz and / or Varian 400MHz instrument; the LC-MS instrument used was an Agilent 1260 Infinity II-6120 / 6125MSD; and the HPLC instrument used was a Waters UPCC (CA-352).

[0228] The starting materials used in the embodiments of the present invention are known and commercially available, or can be synthesized using or in accordance with methods known in the art.

[0229] Example 1: Preparation of compound 7:

[0230] Step 1: Synthesis of (a-2):

[0231] Dissolve (a-1) (11.0 g) in N,N-dimethylformamide (350 mL), add (2-bromoethyl)carbamate (37.3 g) and potassium carbonate (30.0 g). Stir at 90 °C under nitrogen protection for 16 hours, cool to room temperature, filter off the solid, add water and ethyl acetate to the filtrate, extract, combine the organic phases, dry the organic phase with anhydrous sodium sulfate, filter, concentrate to obtain crude product, and purify by column chromatography (petroleum ether:ethyl acetate = 4:1) to give the target compound (13.0 g). LCMS (ESI) [M+H] + =330.20.

[0232] Step 2: Synthesis of (a-3):

[0233] Dissolve (a-2) (12.0 g) in methanol (200 mL), and add 5% palladium on carbon (600 mg, 5%). Stir for 16 hours at room temperature under a hydrogen atmosphere. Filter off the palladium on carbon, evaporate the solvent from the filtrate to dryness, and purify by column chromatography (petroleum ether:ethyl acetate = 2:1) to give the target compound (6.5 g). LCMS (ESI) [M+H] + =196.14.

[0234] Step 3: Synthesis of (a-5):

[0235] Dissolve (a-3) (2.0 g) in acetonitrile (50 mL), then add (a-4) (2.1 g), potassium carbonate (2.83 g), and potassium iodide (170 mg). Stir at 90 °C under nitrogen protection for 16 hours. Cool the reaction solution to room temperature, filter off the solid, add water and ethyl acetate to the filtrate, extract, combine the organic phases, dry the organic phase with anhydrous sodium sulfate, filter, concentrate to obtain crude product, and purify by column chromatography (petroleum ether:ethyl acetate = 3:1) to give the target compound (1.1 g). LCMS (ESI) [M+H] + =344.23; 1 H NMR (400MHz, DMSO-d6) δ7.98(t,J=1.9Hz,1H),7.82(dt,J=7.8,1.5Hz,1H),7.63(dt,J=7.9,1.4Hz,1H),7.54(dt,J=7.8,1.2H z,1H),7.49–7.40(m,3H),7.23(ddd,J=8.2,2.7,1.1Hz,1H),4.09(t,J=5.6Hz,2H),3.92–3.79(m,8H),2.87(t,J=5.6Hz,2H).

[0236] Step 4: Synthesis of (a-7):

[0237] Dissolve (a-5) (1.1 g) in N,N-dimethylformamide (16 mL), add (a-6) (0.93 g), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (1.82 g), and N,N-diisopropylethylamine (1.24 g), and stir at room temperature for 2 hours. Add water and ethyl acetate to the reaction solution, extract, dry the organic phase with anhydrous sodium sulfate, filter, concentrate to obtain crude product, and purify by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain the target compound (1.5 g). LCMS (ESI) [M+H] + =520.36; 1 H NMR (400MHz, DMSO-d6) δ7.92–7.72(m,4H),7.60–7.31(m,7H),7.16(dd,J=8.2 ,3.7Hz,1H),4.90(s,2H),4.22–4.11(m,2H),3.89–3.74(m,11H),2.79(m,2H).

[0238] Step 5: Synthesis of (a-8):

[0239] Dissolve (a-7) (1.5 g) in tetrahydrofuran (20 mL), and slowly add lithium borohydride (564.5 mg) under ice bath conditions. Stir at room temperature for 48 hours, add a saturated ammonium chloride solution to the reaction mixture, extract with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, filter, concentrate to obtain crude product, and purify by column chromatography (dichloromethane:methanol = 20:1) to obtain the target compound (0.76 g). LCMS (ESI) [M+H] + =436.37; 1 H NMR(400MHz,DMSO-d6)δ7.33–7.03(m,9H),6.94–6.83(m,2H),6.82–6.70(m,1H),5.26–5.09 (m,3H),4.68(s,2H),4.53–4.36(m,6H),4.13–4.07(m,2H),3.80(s,2H),3.67–3.56(m,2H).

[0240] Step 6: Synthesis of (a):

[0241] (a-8) (0.76 g) was dissolved in dichloromethane (20 mL), and phosphorus tribromide (0.71 g) was slowly added under ice bath conditions, with stirring at room temperature for 2 hours. The reaction was quenched by adding saturated sodium bicarbonate solution under ice bath conditions, followed by the addition of dichloromethane and water, extraction, drying of the organic phase with anhydrous sodium sulfate, filtration, and concentration to obtain the target compound (1.03 g). LCMS(ESI)[M+H] +=622.11; 1 H NMR(400MHz,DMSO-d6)δ7.38–7.20(m,8H),7.17–7.14(m,1H),7.06–6.96(m,2H),6.92–6 .78(m,1H),4.83–4.56(m,8H),4.15–4.04(m,2H),3.96–3.90(m,1H),3.80–3.59(m,3H).

[0242] Step 7: Synthesis of (c3):

[0243] Under ice bath and nitrogen atmosphere, a solution of bis(trimethylsilyl)aminolithium (7.78 mL, 1.0 M in THF) was added dropwise to a tetrahydrofuran solution (b3) (3.02 g), and the mixture was stirred at 0 °C for 0.5 h. Then, a tetrahydrofuran solution (a) (1.08 g) was added, and the reaction temperature was slowly increased to room temperature. The mixture was stirred for 6 h, and the reaction was quenched by adding a saturated ammonium chloride solution. The mixture was extracted with ethyl acetate, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. This crude product was purified by column chromatography (dichloromethane:methanol = 50:1) to give the target compound (1.63 g). LCMS(ESI)[M+H] + =1546.81; 1 H NMR (400MHz, DMSO-d6) δ7.41–6.63(m,27H),4.66–3.72(m,16H),3.51–3.45(m,3H),3.35–3.20(m ,6H),3.17–2.56(m,16H),2.49–2.26(m,6H),2.00–1.80(m,3H),1.70–1.52(m,3H),1.38(s,27H).

[0244] Step 8: Synthesis of (d):

[0245] (c3) (0.83 g) was dissolved in tetrahydrofuran (5 mL), and lithium hydroxide monohydrate (58 mg) and an aqueous solution of hydrogen peroxide (82 mg, 30% purity) were added. The mixture was stirred at room temperature for 16 hours, then water and ethyl acetate were added, and extraction was performed. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a crude product. This crude product was purified by column chromatography (dichloromethane:methanol = 10:1) to give the target compound (450 mg). LCMS (ESI) [M+H-tert-butyl] + =969.81; 1H NMR (400MHz, DMSO-d6) δ12.34(s,2H),7.28–6.95(m,9H),6.86–6.68(m,3H),4.77–4.46(m,2H),4.10–3.95(m,2H),3.89–3.36(m,12 H),3.17–3.07(m,4H),2.98–2.83(m,3H),2.81–2.58(m,6H),2.33–2.14(m,3H),1.96–1.73(m,3H),1.68–1.53(m,3H),1.39(s,27H).

[0246] Step 9: Synthesis of Compound 7:

[0247] Dissolve (d) (300 mg) in 1,4-dioxane (5 mL), add hydrochloric acid / 1,4-dioxane solution (4.0 M, 5 mL), stir at room temperature for 2 hours, concentrate the reaction solution, and purify by preparative chromatography to obtain the target compound (110 mg). LCMS (ESI) [M+H] + =769.55; 1 HNMR(400MHz,Deuterium Oxide)δ7.29–7.13(m,3H),7.11–6.80(m,7H),6.72–6.60(m,2H),4.66–4.58(m,2H),4.12–3.97(m,2H),3.83– 3.67(m,3H),3.41–3.23(m,6H),3.18–3.07(m,3H),2.86–2.26(m,16H),2.09–1.95(m,3H),1.73–1.57(m,3H).

[0248] Example 2: Preparation of compound 40:

[0249] Step 1: Synthesis of (f-2):

[0250] Dissolve (f-1) (16 g) in ethanol (200 mL), add ammonia (612.0 mg), and stir the reaction mixture under nitrogen protection for 48 hours. The reaction was monitored by LCMS until complete. The solvent was evaporated to dryness, and the product (11 g) was purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 10:1). LCMS (ESI) [M+H] + =462.32; 1H NMR (400MHz, DMSO-d6) δ7.97(s,3H),7.84(d,J=9.3Hz,3H),7.63(d,J=7.8Hz,3H),7.49(t,J=7.6Hz,3H),3.86(s,9H),3.63(s,6H).

[0251] Step 2: Synthesis of (f-3):

[0252] Dissolve (f-2) (8 g) in THF (100 mL). Under ice bath conditions, slowly add 27.7 mL of a 2.5 M solution of lithium aluminum hydride in tetrahydrofuran. Slowly raise the reaction mixture to room temperature and stir for 2 hours. Monitor the reaction for completeness using LC-MS. Crudely quench the reaction by adding saturated ammonium chloride solution under ice bath conditions. Reduce the reaction mixture to dryness and purify using rapid chromatography (petroleum ether:ethyl acetate = 1:1) to obtain the product (6 g). LC-MS (ESI) [M+H] + =378.0; 1 HNMR (400MHz, DMSO-d6) δ7.35–7.24(m,9H),7.22–7.17(m,3H),5.16(t,J=6.6Hz,3H),4.49(d,J=3.7Hz,6H),3.51(s,6H).

[0253] Step 3: Synthesis of (f):

[0254] (f-3) (6 g) was dissolved in dichloromethane (20 mL), and phosphorus tribromide (4.3 g) was added under ice bath conditions. The reaction solution was slowly brought to room temperature and stirred for 16 hours. The reaction was monitored by LCMS to ensure complete reaction. The reaction was quenched by adding saturated ammonium chloride solution under ice bath conditions. The reaction solution was evaporated to dryness and purified by rapid chromatography (silica gel, petroleum ether:ethyl acetate = 10:1) to obtain the target compound (3.7 g). LCMS (ESI) [M+H] + =567.7; 1 H NMR (400MHz, DMSO-d6) δ7.41–7.37(m,9H),7.35–7.29(m,3H),4.52(s,6H),4.28(s,6H).

[0255] Step 4: Synthesis of (c8):

[0256] Dissolve (b3) (617.1 mg) in anhydrous tetrahydrofuran (5 mL). Under nitrogen atmosphere and an ice bath, add a tetrahydrofuran solution of bis(trimethylsilyl)aminolithium (1.6 mL, 1.0 M), stir for 0.5 hours, and then add (f) (200 mg). Slowly raise the reaction mixture to room temperature and stir for 16 hours; monitor the reaction for completeness using LCMS. Add saturated ammonium chloride solution and ethyl acetate to the reaction system. Extract and separate the liquid phase; dry the organic phase with anhydrous sodium sulfate, filter, and concentrate to obtain the target compound (160 mg, crude product). LCMS (ESI) [M+H] + =1488.7.

[0257] Step 5: Synthesis of (h):

[0258] A 0.1 mL (30%) aqueous solution of hydrogen peroxide was added in one step to 2 mL of tetrahydrofuran (150 mg C8), followed by 2 mL of water containing 37.8 mg lithium hydroxide monohydrate. The reaction mixture was heated to 25 °C and stirred for 2.5 hours. LCMS was used to confirm the completeness of the reaction. The reaction mixture was cooled in an ice bath, and hydrochloric acid (5 N) was added to adjust the pH to 3. The mixture was extracted and separated. The organic layer was washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Prep-HPLC was then used for purification (C8). 18 10 mmol / L TFA in H2O (acetonitrile) was used to obtain the target compound (70 mg). LCMS (ESI) [M+H] + =1057.7; 1 H NMR (400MHz, DMSO-d6) δ7.43–7.28(m,9H),7.24(dd,J=5.8,2.2Hz,3H),5.11(s,6H),3.50(s,5H),3.43(dd,J=10.8,5.5Hz,3H),3.33– 3.22(m,7H),3.18–3.04(m,3H),2.81(dd,J=10.5,7.7Hz,3H),2.48–2.34(m,9H),1.49(dt,J=16.4,8.8Hz,3H),1.36(d,J=9.5Hz,27H).

[0259] Step 6: Synthesis of Compound 40:

[0260] Dissolve (h)(70 mg) in dichloromethane (2 mL), add trifluoroacetic acid (0.2 mL), and stir the reaction solution at room temperature for 16 hours. Monitor the reaction until complete using LCMS. Concentrate to obtain the crude product, and then separate and purify it using Prep-HPLC (C 1810 mmol / L TFA in H2O (acetonitrile) was used to obtain the target compound (25 mg). LCMS (ESI) [M+H] + =711.60; 1 H NMR(400MHz, Deuterium Oxide)δ7.38–7.24(m,6H),7.22–7.05(m,6H),4.24(s,6H),3.56–3.46(m,3H),3.41–3.30(m,3H),3.25–3. 13(m,3H),3.02–2.90(m,3H),2.84–2.66(m,6H),2.53–2.36(m,6H),2.15–1.99(m,3H),1.76–1.59(m,3H).

[0261] Example 3: Preparation of compound 41:

[0262] Step 1: Synthesis of (g-2):

[0263] To a solution of 10 g of hydrochloride in 200 mL of acetonitrile, methyl 3-(bromomethyl)benzoate (24.72 g) and N,N-diisopropylethylamine (27.89 mL) were added. The reaction mixture was stirred at 70 °C for 4 hours. After concentration, the reaction mixture was purified by rapid chromatography (silica gel, ethyl acetate: petroleum ether = 1:3) to obtain the target compound (18 g). LCMS (ESI) [M+H] + =492.2. 1 H NMR (400MHz, CDCl3) δ8.05(s,2H),7.92(d,J=7.7Hz,2H),7.62(d,J=7.6Hz,3H),7.50(s,1H),7.39(t,J=7.7Hz,2H),7.31( t,J=8.0Hz,1H),7.05(dd,J=8.2,2.5Hz,1H),4.09(t,J=5.7Hz,2H),3.94–3.89(m,9H),3.78(s,4H),2.93(t,J=5.7Hz,2H).

[0264] Step 2: Synthesis of (g-3):

[0265] Lithium borohydride (1.42 g) was added to a solution of (g-2)(8 g) tetrahydrofuran (100 mL) under ice bath conditions. The reaction mixture was stirred at 60 °C for 1 hour. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The filtrate was purified by rapid chromatography (silica gel, ethyl acetate: petroleum ether = 1:1) to give the target compound (6.2 g). LCMS (ESI) [M+H] + =408.2. 1 H NMR (400MHz, CDCl3) δ7.44(s,2H),7.29–7.21(m,5H),7.18–7.14(m,2H),6.90–6.84(m,2H),6. 76–6.71(m,1H),4.65–4.56(m,6H),4.05(t,J=5.8Hz,2H),3.72(s,4H),2.92(t,J=5.8Hz,2H).

[0266] Step 3: Synthesis of (g):

[0267] Phosphorus tribromide (4.84 mL) was added to a solution of (g-3)(6 g) of dichloromethane (100 mL) under ice bath conditions. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with water under ice bath conditions and extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The filtrate was purified by rapid chromatography (silica gel, ethyl acetate / petroleum ether = 4:1) to give the target compound (6 g). LCMS (ESI) [M+H] + =593.9.1H NMR (400MHz, CDCl3) δ7.44–7.41(m,2H),7.33–7.26(m,6H),7.22(t,J=7.9Hz,1H),6.95(d,J=7.6Hz,1H),6.87–6.84(m ,1H),6.77(dd,J=8.3,1.9Hz,1H),4.49(s,4H),4.44(s,2H),4.03(t,J=5.9Hz,2H),3.70(s,4H),2.91(t,J=5.9Hz,2H).

[0268] Step 4: Synthesis of (c9):

[0269] Under ice bath and nitrogen protection, bis(trimethylsilyl)aminolithium (3.02 mL) was added dropwise to a solution of (b3) (1.17 g) tetrahydrofuran (10 mL). After stirring for 0.5 hours, a solution of (b3) (400 mg) tetrahydrofuran (2 mL) was slowly added dropwise, and the reaction mixture was slowly heated to room temperature and stirred for 3 hours. A saturated ammonium chloride aqueous solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The filtrate was then purified by rapid chromatography (silica gel, ethyl acetate: petroleum ether = 1:2) to give the target compound (300 mg). LCMS (ESI) [M+H] + =1518.7.

[0270] Step 5: Synthesis of 2-{3-[(2S)-2-[(3R)-1-[(tert-butoxy)carbonyl]pyrrolidine-3-yl]-2-carboxyethyl]phenoxy}-N,N-bis({3-[(2S)-2-[(3R)-1-[(tert-butoxy)carbonyl]pyrrolidine-3-yl]-2-carboxyethyl]phenyl}methyl)ethanolamine oxide:

[0271] A 0.12 mL (30%) aqueous solution of hydrogen peroxide was added in one step to 4 mL (600 mg) of tetrahydrofuran (C9), followed by 2 mL of lithium hydroxide monohydrate (149.18 mg) in water. The reaction temperature was raised to 25°C and stirred for 2.5 hours. The reaction was confirmed to be complete by LCMS. The reaction mixture was cooled in an ice bath, and hydrochloric acid (5 N) was added to bring the pH of the mixture to 3. The layers were separated, and the organic layer was washed with 8 mL of saturated sodium chloride aqueous solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by Prep-HPLC (C9). 18 The target compound (300 mg) was obtained by reacting 10 mmol / L LTFA in water (acetonitrile). LCMS (ESI) [M+H] + =1057.7.

[0272] Step 6: Composition of (j):

[0273] Zinc powder (92.76 mg) and ammonium chloride (75.89 mg) were added in one step to a solution of 2-{3-[(2S)-2-[(3R)-1-[(tert-butoxy)carbonyl]pyrrolidine-3-yl]-2-carboxyethyl]phenoxy}-N,N-bis({3-[(2S)-2-[(3R)-1-[(tert-butoxy)carbonyl]pyrrolidine-3-yl]-2-carboxyethyl]phenyl}methyl)ethanolamine oxide (300 mg) in tetrahydrofuran (4 mL) and water (4 mL). The mixture was stirred at room temperature for 2.5 hours. The reaction was confirmed to be complete by LCMS. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the target compound (150 mg, crude product). LCMS (ESI) [M+H] + =1041.7.

[0274] Step 7: Synthesis of Compound 41:

[0275] Hydrochloric acid / 1,4-dioxane (4 mL, 4.0 M) was added in a single batch to (j) (150 mg) of dioxane (4 mL), and the reaction mixture was stirred at room temperature for 1 hour. The reaction was confirmed to be complete by LCMS. An aqueous solution of sodium hydroxide (1 N) was added to adjust the pH to 7, and the solution was purified by Prep-HPLC (10 mmol / L ammonium bicarbonate in H₂O, acetonitrile) to obtain the target compound (52.31 mg). LCMS (ESI) [M+H] + =741.4; 1 HNMR(400MHz,D2O)δ7.26–7.07(m,9H),6.79(d,J=7.6Hz,1H),6.68(d,J=7.2Hz,2H),4.03(t,J=5.4Hz,2H),3.74–3.61(m ,4H),3.39–3.26(m,6H),3.19–3.07(m,3H),2.86–2.59(m,11H),2.43–2.28(m,6H),2.07–1.96(m,3H),1.71–1.57(m,3H).

[0276] Example 4: Preparation of compound 7:

[0277] Step 1: Synthesis of (b2-2):

[0278] Under ice bath conditions, 2.05 g of deuterated lithium aluminum hydride was slowly added to anhydrous tetrahydrofuran (80 mL) solution. After stirring for 5 minutes, 5 g of (2S)-2-amino-3-phenylpropionic acid was slowly added. Once the addition was complete, the reaction mixture was purged with nitrogen and then brought to room temperature with continued stirring for 16 hours. LC-MS showed the reaction was complete. The reaction mixture was cooled to below 10 °C, and then sodium sulfate decahydrate was slowly added to quench the reaction. The mixture was then filtered through diatomaceous earth. The filter cake was thoroughly washed with tetrahydrofuran, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (tetrahydrofuran: petroleum ether = 1:1) to obtain the target compound (2.3 g). LC-MS (ESI) [M+H] + =154.1; 1 H NMR(400MHz,DMSO-d6)δ7.31–7.24(m,2H),7.22–7.14(m,3H),4.52(br.s,1H) ,2.87–2.81(m,1H),2.70–2.63(m,1H),2.45–2.37(m,1H),1.55–1.19(m,2H).

[0279] Step 2: Synthesis of (b2-3):

[0280] (b2-2) (2.1 g), N,N'-carbonyldiimidazole (2.33 g), and cesium carbonate (446.56 mg) were placed in a round-bottom flask and heated to 120 °C with stirring for 4 hours. LCMS showed that the starting material was completely consumed and most of the product was formed. After the reaction solution cooled to room temperature, it was diluted with water (40 mL) and extracted with ethyl acetate (100 mL). The combined organic phases were washed with saturated brine (160 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (tetrahydrofuran: petroleum ether = 1:2) to give the target compound (1.9 g). LCMS (ESI) [M+H] + =180.0; 1 H NMR (400MHz, DMSO-d6) δ7.77(s,1H),7.33–7.28(m,2H),7.26–7.21(m,3H),4.06–4.01(m,1H),2.85–2.78(m,1H),2.77–2.71(m,1H).

[0281] Step 3: Synthesis of (b2):

[0282] Triethylamine (6.35 g) was added to 150 mL of solution (b1-4) under ice bath conditions. The reaction mixture was stirred for 5 minutes, followed by the addition of 3.78 g of 2,2-dimethylpropionyl chloride. The reaction mixture was allowed to react for another 15 minutes, after which anhydrous lithium chloride (1.33 g) and (b2-3) (4.5 g) were added, respectively. After the additions were complete, the reaction mixture was brought to room temperature and stirred for 16 hours. The reaction mixture was diluted with 200 mL of water and extracted with 750 mL of ethyl acetate. The combined organic phases were washed with 600 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:tetrahydrofuran = 3:1) to obtain the target compound (7.8 g). LCMS (ESI) [M+H-56] + =335.1; 1 H NMR (400MHz, DMSO-d6) δ7.34–7.29(m,2H),7.28–7.23(m,1H),7.21–7.17(m,2H),4.65(dd,J=7.4,3.4Hz,1H),3.53(dd,J=10.5,7.3Hz ,1H),3.32–3.27(m,1H),3.24–3.13(m,1H),3.03–2.85(m,5H),2.57–2.51(m,1H),2.06–1.94(m,1H),1.61–1.49(m,1H),1.40(s,9H).

[0283] Step 4: Synthesis of (c2):

[0284] A solution of bis(trimethylsilyl)aminolithium (1 M in THF, 7.2 mL) was added dropwise to a solution of tetrahydrofuran (b2) (2.8 g) under an ice bath and nitrogen atmosphere. The mixture was stirred at 0 °C for 0.5 h, then a solution of tetrahydrofuran (a) (1.0 g) was added, and the reaction temperature was slowly increased to room temperature with stirring for 6 h. The reaction was monitored by LCMS until complete. The reaction was quenched by adding a saturated ammonium chloride solution, extracted with ethyl acetate, and the organic layer was washed with a saturated sodium chloride solution. The organic matter was dried over anhydrous sodium sulfate, filtered, and the product (1.2 g) was obtained by dichloromethane:methanol = 50:1. LCMS (ESI) [M+H] + =1552.4; 1 H NMR (400MHz, DMSO-d6) δ7.41–6.65(m,27H),4.70–4.17(m,8H),3.95–3.69(m,3H),3.51–3.34(m, 9H),3.15–2.61(m,15H),2.48–2.27(m,6H),1.99–1.79(m,3H),1.74–1.55(m,3H),1.39(s,27H).

[0285] Step 5: Synthesis of (d):

[0286] Dissolve (c2) (1.0 g) in THF (5 mL), add lithium hydroxide monohydrate (121.3 mg) and an aqueous solution of hydrogen peroxide (98 mg, 30%). Stir overnight at room temperature. LCMS monitoring showed complete consumption of the starting material. The solvent was evaporated to dryness, and the extracted organic phase was dried over anhydrous sodium sulfate. Purification was performed by column chromatography (dichloromethane:methanol = 10:1) to give the product (250 mg). LCMS (ESI) [M+H] + =1069.2; 1 H NMR (400MHz, DMSO-d6) δ7.27–6.95(m,9H),6.82–6.64(m,3H),4.73–4.53(m,2H),4.06–3.92(m,2H),3.75–3.41(m,12H),3.1 6–3.04(m,4H),2.97–2.86(m,3H),2.82–2.62(m,6H),2.33–2.16(m,3H),1.93–1.75(m,3H),1.68–1.54(m,3H),1.39(s,27H).

[0287] Step 6: Synthesis of Compound 7

[0288] Dissolve (d)(250 mg) in 5 mL of 1,4-dioxane, add 5 mL of 4 M hydrochloric acid-dioxane solution, stir at room temperature for 2 h, and monitor the reaction for completeness by LC-MS. Adjust the pH to neutral under ice bath conditions, evaporate the solvent to dryness, and purify by Prep-HPLC (C 18 The target compound (83 mg) was obtained by reacting 10 mmol / L NH4HCO3 in water (MeCN).

[0289] LCMS(ESI)[M+H] + =769.53; 1 H NMR(400MHz, Deuterium Oxide)δ7.28–6.58(m,12H),4.66–4.57(m,2H),4.14–3.98(m,2H),3.91–3.63(m,4H),3.44 –3.21(m,6H),3.18–3.03(m,3H),2.89–2.21(m,15H),2.12–1.92(m,3H),1.74–1.53(m,3H).

[0290] Example 5: Preparation of compound 7:

[0291] Step 1: Synthesis of (b1-2):

[0292] (b1-1) (25.0 g) was dissolved in tetrahydrofuran (300.0 mL), and borane tetrahydrofuran (211.6 mL) was added at 0 °C. The reaction was stirred at room temperature for 3 hours. After the reaction was complete, the reaction solution was quenched with methanol (100.0 mL), concentrated under reduced pressure, diluted with water, extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate for 2 hours. The mixture was filtered and concentrated, and the concentrate was purified by column chromatography (petroleum ether:tetrahydrofuran = 3:1) to give the target compound (19.2 g). LCMS (ESI) [M+H-56] + =226.1; 1 H NMR (400MHz, DMSO-d6) δ7.10(d,J=8.6Hz,2H),6.82(d,J=8.5Hz,2H),6.53(d,J=8.5Hz,1H),4.71–4.59(m,1H),3.71 (s,3H),3.56–3.46(m,1H),3.32–3.28(m,1H),3.28–3.21(m,1H),2.77–2.68(m,1H),2.50–2.43(m,1H),1.32(s,9H).

[0293] Step 2: Synthesis of (b1-3):

[0294] Under ice bath conditions, a solution of (b1-2) (19.2 g) in tetrahydrofuran (200.0 mL) was slowly added dropwise to a solution of sodium hydride (13.65 g, 60%) in tetrahydrofuran (150.0 mL). The mixture was heated to 75 °C and stirred for 3 hours. LCMS analysis showed that the reaction proceeds were essentially complete. The mixture was then cooled under ice bath conditions, quenched with a saturated ammonium chloride solution, diluted with water, and extracted with ethyl acetate. The combined organic phases were washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate for 2 hours, concentrated under reduced pressure, and purified by rapid chromatography (petroleum ether:tetrahydrofuran = 1:1) to obtain the target compound (13.2 g). LCMS (ESI) [M+H] + =208.1; 1 HNMR(400MHz,DMSO-d6)δ7.75(s,1H),7.16(d,J=8.6Hz,2H),6.87(d,J=8.6Hz, 2H),4.24(t,J=7.6Hz,1H),4.03–3.95(m,2H),3.73(s,3H),2.80–2.66(m,2H).

[0295] Step 3: Synthesis of (b1):

[0296] Triethylamine (16.7 mL) was added to a tetrahydrofuran (100 mL) solution of (b1-4) (11.1 g) under ice bath conditions. Then, 2,2-dimethylpropionyl chloride (7.4 mL) was added and the mixture was stirred for 15 minutes. The reaction mixture was then added to a tetrahydrofuran (100 mL) solution of lithium chloride (2.57 g) and (b1-3) (10.03 g). After the addition was complete, the mixture was stirred at 25 °C for 2 hours. LCMS analysis showed that the reaction proceeds were essentially complete. The reaction mixture was diluted with water, extracted with ethyl acetate, and the organic phases were combined. The mixture was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate for 2 hours, concentrated under reduced pressure, and the concentrate was purified by rapid chromatography (petroleum ether:tetrahydrofuran = 3:1) to obtain the target compound (15 g). LCMS (ESI) [M+23] + =441.2; 1 HNMR(400MHz,DMSO-d6)δ7.11(d,J=8.5Hz,2H),6.87(d,J=8.5Hz,2H),4.67 –4.56(m,1H),4.31(t,J=8.5Hz,1H),4.22–4.12(m,1H),3.72(s,3H),3.53( t,J=7.8Hz,1H),3.32–3.29(m,1H),3.25–3.14(m,1H),3.01–2.77(m,5H),2 .51(d,J=0.6Hz,1H),2.00(d,J=7.5Hz,1H),1.59–1.48(m,1H),1.40(s,9H).

[0297] Step 4: Synthesis of (c1):

[0298] Add (b1) (3.0 g) to a tetrahydrofuran solution under nitrogen protection and cool to -10 °C. Add a solution of bis(trimethylsilyl)aminolithium (1 M in THF, 7.2 mL) dropwise to the reaction system. After the addition is complete, maintain the temperature at -10 °C and stir for 1.0 h. Lower the temperature of the reaction solution to -20 °C, add (a) (1.0 g), and maintain the temperature at -20 °C and stir for 4 h. Monitor the reaction of the starting material by LCMS until complete. Quench the reaction with a saturated ammonium chloride solution. Extract with ethyl acetate and wash the organic layer with a saturated sodium chloride solution. Dry the organic phase with anhydrous sodium sulfate for 2 h, filter, and perform silica gel column chromatography (dichloromethane:methanol = 50:1) to obtain the target product (1.8 g). 1H NMR(400MHz, DMSO-d6)δ7.32–7.06(m,6H),7.00(d,J=22.4Hz,3H),6.90–6.44(m,15H) ,4.52(d,J=39.9Hz,5H),4.24(dd,J=21.2,13.5Hz,6H),4.08–3.84(m,5H),3.80–3.58 (m,10H),3.55–3.33(m,9H),3.10(s,3H),2.92(q,J=18.8,14.5Hz,9H),2.65(dd,J=15 .3,5.6Hz,3H),2.39(s,6H),1.89(s,3H),1.61(d,J=12.6Hz,3H),1.48–1.31(m,27H).

[0299] Step 5: Synthesis of (d):

[0300] Dissolve (c1) (1.0 g) in THF (5 mL), add lithium hydroxide monohydrate (115.5 mg) and an aqueous solution of hydrogen peroxide (622.4 mg, 30% purity), and stir at 25 °C for 2 h. LCMS monitoring showed complete consumption of the starting material. Cool the reaction solution to 0 °C, quench with saturated sodium bisulfite solution, extract with methyl tert-butyl ether, wash with saturated sodium chloride aqueous solution, separate the layers, dry the organic phase with anhydrous sodium sulfate for 2 h, filter, concentrate the organic phase, and purify by silica gel column chromatography (dichloromethane:methanol = 10:1) to obtain the target product (600 mg). LCMS (ESI) [M+H-100] + =969.2; 1 H NMR (400MHz, DMSO-d6) δ7.27–6.95(m,9H),6.82–6.64(m,3H),4.73–4.53(m,2H),4.06–3.92(m,2H),3.75–3.41(m,12H),3.1 6–3.04(m,4H),2.97–2.86(m,3H),2.82–2.62(m,6H),2.33–2.16(m,3H),1.93–1.75(m,3H),1.68–1.54(m,3H),1.39(s,27H).

[0301] Step 6: Synthesis of Compound 7

[0302] Dissolve (d) (500 mg) in 5 mL of 1,4-dioxane, add 6 mL of 4M hydrochloric acid-dioxane solution, and stir at 25 °C for 2 hours. Monitor the reaction mixture by LCMS until complete. Concentrate the reaction solution to dryness under reduced pressure, adjust the pH to 7-8 with sodium hydroxide aqueous solution, and obtain the target product (250 mg) by Pre-hplc. LCMS(ESI)[M+H] + =769.2; 1 H NMR(400MHz, Deuterium Oxide)δ7.29–7.13(m,3H),7.11–6.80(m,7H),6.72–6.60(m,2H),4.66–4.58(m,2H),4.12–3.97(m,2H),3.83– 3.67(m,3H),3.41–3.23(m,6H),3.18–3.07(m,3H),2.86–2.26(m,16H),2.09–1.95(m,3H),1.73–1.57(m,3H).

[0303] Example 6: Preparation of compound 7:

[0304] According to the above preparation method, S-4-(4-(tert-butoxy)benzyl)oxazolidin-2-one and 2-[(3R)-1-[(tert-butoxy)carbonyl]pyrrolidine-3-yl]acetic acid undergo a condensation reaction in the presence of 2,2-dimethylpropionyl chloride and lithium chloride to generate (b4), and (a) undergoes a substitution reaction with (b4) to generate (c4);

[0305] (c4) Under the action of hydrogen peroxide and base, an alkaline oxidation reaction occurs to remove the Evans chiral cofactor to generate (d); d is deprotected to generate (compound 7).

[0306] Example 7: Preparation of compound 7:

[0307] Following the above preparation method, S-4-(4-(4-nitrobenzyl)oxazolidine-2-one and 2-[(3R)-1-[(tert-butoxy)carbonyl]pyrrolidine-3-yl]acetic acid undergo a condensation reaction in the presence of 2,2-dimethylpropionyl chloride and lithium chloride to generate (b5). (a) undergoes a substitution reaction with (b5) to generate (c5). (c5) undergoes alkaline oxidation in the presence of hydrogen peroxide and a base to remove the Evans chiral cofactor to generate (d). (d) undergoes deprotection to generate (compound 7).

[0308] Example 8: Preparation of compound 7:

[0309] Following the above preparation method, (S)-4-phenyloxazolidine-2-one and 2-[(3R)-1-[(tert-butoxy)carbonyl]pyrrolidine-3-yl]acetic acid undergo a condensation reaction in the presence of 2,2-dimethylpropionyl chloride and lithium chloride to generate (b6); (a) and (b6) undergo a substitution reaction to generate (c6); (c6) undergoes alkaline oxidation to remove the Evans chiral cofactor in the presence of hydrogen peroxide and a base to generate (d); (d) undergoes deprotection to generate (compound 7).

[0310] Example 9: Preparation of compound 7:

[0311] According to the above preparation method, (4S,5R)-5-methyl-4-phenyloxazolidine-2-one and 2-[(3R)-1-[(tert-butoxy)carbonyl]pyrrolidine-3-yl]acetic acid undergo a condensation reaction in the presence of 2,2-dimethylpropionyl chloride and lithium chloride to generate (b7), and (a) undergoes a substitution reaction with (b7) to generate (c7);

[0312] (c7) Under the action of hydrogen peroxide and base, an alkaline oxidation reaction occurs to remove the Evans chiral cofactor to generate (d); (d) deprotection group to generate (compound 7).

[0313] Example 10: Preparation of Compound 7:

[0314] Step 1: Synthesis of compound (c1):

[0315] Tetrahydrofuran (400 mL) and compound (b1) (152 g) were added to a reaction flask under nitrogen protection. The internal temperature of the reaction solution was controlled to be lowered to -20±5℃. A solution of bis(trimethylsilyl)aminolithium (1 M in THF, 348 mL) was slowly added dropwise to the reaction system. After the addition was complete, the mixture was stirred at -20±5℃ for 1.0 h. The internal temperature was controlled below -20℃. Then, a tetrahydrofuran solution of compound (a) (55 g) was added, and the mixture was stirred at -20℃±5℃ for 8±0.5 h. After the reaction was complete, the reaction was quenched with 23% ammonium chloride aqueous solution. The mixture was extracted with ethyl acetate and washed with saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and subjected to silica gel column chromatography (eluted sequentially with dichloromethane, dichloromethane and isopropanol = 50:1, and dichloromethane and isopropanol = 30:1) to obtain the target product (82.7 g).

[0316] Step 2: Synthesis of compound (d):

[0317] Compound (c1) (50 g) was dissolved in tetrahydrofuran (330 mL), cooled to 10 °C, and 29 g of 30% hydrogen peroxide aqueous solution was added. Purified water was added, and lithium hydroxide monohydrate (5.4 g) was dissolved in purified water. The internal temperature was controlled at 10 ± 5 °C, and the solution was slowly added dropwise to the reaction system. After the addition was complete, the reaction was stirred at 10 ± 5 °C for 6 ± 0.5 h. The reaction solution was cooled to 0 °C–5 °C, and the reaction was quenched with saturated sodium bisulfite solution. Ethyl acetate was added for extraction, and the organic phase was concentrated to dryness. Purified water and lithium hydroxide monohydrate (11 g) were added to the concentrate. The aqueous phase was extracted with methyl tert-butyl ether, and the aqueous phase was transferred to a reaction flask. The temperature was controlled at 0–5 °C, and 6 M hydrochloric acid aqueous solution was added dropwise to adjust the pH to 2–4. Ethyl acetate dissolved the solid, and the mixture was separated. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the target product (31.7 g).

[0318] Step 3: Synthesis of Compound 7:

[0319] Compound (d) (33.7 g), 1,4-dioxane (135 mL), purified water (27 mL), and concentrated hydrochloric acid (24.9 g) were added to a reaction flask. The mixture was heated to 50 °C and reacted for 2 h. After cooling to room temperature, the pH was adjusted to 6–7 with 20% sodium hydroxide aqueous solution. The mixture was washed with dichloromethane and concentrated to dryness under reduced pressure. The product was dissolved in trifluoroethanol, filtered, and the filter cake was washed with trifluoroethanol. The aqueous phase was concentrated to dryness under reduced pressure to obtain the target product (12.7 g).

[0320] Example 11: Screening of reaction conditions for compound 7:

[0321] (1) Screening of reaction conditions in the preparation of compound (c1): The preparation was carried out in the first step of the synthesis method in Example 10.

[0322] Screening of alkali dosage in the preparation of compound (c1): The nucleophilic substitution reaction temperature is -25℃ to -15℃, and the molar ratio of (a):(b1):bis(trimethylsilyl)aminolithium is controlled as follows.

[0323] Conclusion: In the preparation of compound (c1), the molar ratio of compound (a): compound (b1): bis(trimethylsilyl)aminolithium in the feed is 1:4:(3.95~4.20) which can meet the process requirements.

[0324] Screening of reaction temperature in the preparation of compound (c1)

[0325] Conclusion: In the preparation of compound (c1), the reaction temperature of -30±5℃ to -20±5℃ can meet the process requirements.

[0326] (2) Screening of reaction conditions in the preparation of compound (d): The preparation was carried out in step 2 of the synthesis method in Example 10.

[0327] Screening of reaction temperature and reaction time in the preparation of compound (d):

[0328] Conclusion: In the preparation of compound (d), the reaction temperature can be between 0 and 20℃ to meet the process requirements.

[0329] (3) Preparation of compound 7: It was prepared according to the third step of the synthesis method in Example 10.

[0330] Biological test evaluation

[0331] Test Example 1: Lp(a) Assembly Inhibition Screening ELISA Detection Experiment

[0332] 1. Reagents, consumables, and instruments

[0333] 2. Preparation of cell culture medium

[0334] 2.1 Complete cell culture medium

[0335] 2.2 Experimental Culture Medium

[0336] 3 Experimental Steps

[0337] 3.1 Cell Culture and Passaging

[0338] 1) Preheat the culture medium, DPBS, and trypsin in a 37℃ water bath.

[0339] 2) Digest cells with trypsin, transfer the cell suspension to a 15ml centrifuge tube, and centrifuge at 1000rpm for 5 minutes.

[0340] 3) Resuspend the cells in the culture medium and transfer the cell suspension to a new T75 cell culture flask.

[0341] 4) Incubate at 37℃ in a 5% CO2 incubator.

[0342] 3.2 Plate laying and chemical dosing

[0343] 1) Seed HepG2 cells overexpressing ApoA protein into 96-well plates, 100 μl per well, and culture overnight for adhesion.

[0344] 2) On the second day, replace the culture medium with fresh one, then add the diluted compound, and place the cell plate in a 5% CO2, 37°C constant temperature incubator for 24 hours.

[0345] 3.3 Preparation of cell culture supernatant

[0346] 1) Add 10 μl of 1.5 M EACA to each well.

[0347] 2) Centrifuge at 1000 rpm for 1 minute and transfer 100 μl of cell culture supernatant to a pre-coated ELISA plate.

[0348] 3.4 ELISA Experiment

[0349] 1) Add 100 μl of capture antibody to each well to pre-coat the ELISA plate and incubate overnight at 25°C.

[0350] 2) Add 300 μl of cleaning solution to each well and wash 5 times, one minute each time.

[0351] 3) Add 100 μl of blocking solution to each well and incubate at 25°C for 2 hours.

[0352] 4) Add 300 μl of cleaning solution to each well and wash 5 times, one minute each time.

[0353] 5) Add 100 μl of sample to each well and incubate at 25°C for 1 hour.

[0354] 6) Add 300 μl of cleaning solution to each well and wash 5 times, one minute each time.

[0355] 7) Add 100 μl of detection antibody to each well and incubate at 25°C for 1 hour.

[0356] 8) Add 300 μl of cleaning solution to each well and wash 5 times, one minute each time.

[0357] 9) Add 100 μl of substrate solution (Color Reagent A:Color Reagent B, 1:1) to each well and incubate at 25°C in the dark for 20 minutes.

[0358] 10) Add 50 μl of stop solution to each well, gently blow and aspirate several times with the pipette tip, and take the reading within five minutes.

[0359] 4.IC 50 Data Analysis

[0360] H = Ave (DMSO or H2O)

[0361] L = Ave (1uM Reference)

[0362] SD(H) = STDEV (DMSO or H2O)

[0363] SD(L) = STDEV(1uM Reference)

[0364] CV%(DMSO)=100*(SD_H / Ave_H)

[0365] CV%(1uM Reference)=100*SD_L / Ave_L

[0366] Z'=1-3*(SD_H+SD_L) / (Ave_H-Ave_L)

[0367] Inhibition%=(Ave_H-Sample) / (Ave_H-Ave_L)

[0368] Compound IC 50 Nonlinear fitting regression equation:

[0369] Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope))

[0370] X:cpd concentration

[0371] Y:inhibition%

[0372] Top and Bottom:Plateaus in same units as Y

[0373] logIC 50 Same log units as X

[0374] HillSlope:Slope factor or Hill slope

[0375] 5. Test Results

[0376] Experimental results show that the compounds of the present invention have a strong inhibitory effect on Lp(a) assembly. Exemplary compounds are shown in the table below.

Claims

1. A method for synthesizing a compound of formula (I), or a stereoisomer, tautomer, isotopic derivative thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that, Includes the following steps: Step (1): Formulas (I-1) and (I-2) undergo a substitution reaction to generate formula (I-3); Step (2): Formula (I-3) undergoes an oxidative hydrolysis reaction (e.g., alkaline oxidation to remove the Evans chiral cofactor) to generate Formula (I-4); Step (3): Deprotecting the group of formula (I-4) yields the compound of formula (I); Where X is independently selected from halogens; R1 and R2 are independently selected from hydrogen, deuterium, and C, respectively. 1-3 Alkoxy; R3 is a protecting group; R4 is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -CHO, nitro, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy group, -N(C 1-3 alkyl)2、-NH(C 1-3 Alkyl), -C(O)C 1-3 alkyl; R5, R6, R7, R8, R9, R 10 They are selected independently from hydrogen and deuterium; m is 0, 1, or 2; n is 0, 1, 2, 3, 4, or 5; Rings W1, W2, and W3 are each independently selected from C. 6-12 Aryl, 5-12 heteroaryl, C 6-14 Cycloalkyl, 5-12 membered heterocyclic groups; wherein the aryl, heteroaryl, cycloalkyl, or heterocyclic group is optionally selected by one or more elements independently selected from deuterium, halogen, -CN, -OH, -NH2, -CHO, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups, -N(C) 1-3 alkyl)2、-NH(C 1-3 Alkyl), -C(O)C 1-3 Substituents of alkyl groups; Z 11 Z 21 Z 31 Each is independently selected from the following bonds: -O-, -S-, -NH-, -Se-, -C. 1-4 alkylene-, -C 1-8 oxa-alkylene-, -C 1-4 Thionide-, -C 1-4 aziridine-, -C 1-4 Selenide-; the alkylene, oxaalkylene, thiaalkylene, aziridine, or selenide may optionally be selected from one or more of Z. 41 Substituents; Z 41 Independently selected from deuterium, halogen, oxo group, thio group, -CN, -OH, -NH2, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy; or any two Z 41 Together with the atoms they are attached to, they form C 3-6 cycloalkyl, 3-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl; The heteroatoms in the heterocyclic group and heteroaryl group are independently selected from O, N or S, and the number of heteroatoms is 1, 2, 3 or 4.

2. The method for synthesizing the compound of formula (I) according to claim 1, or the stereoisomers, tautomers, isotopic derivatives, or mixtures thereof, or pharmaceutically acceptable salts thereof, characterized in that: In step (1), an alkaline reagent is included, wherein the alkaline reagent is selected from organic bases; preferably, the organic base is lithium bis(trimethylsilyl)amino, sodium bis(trimethylsilyl)amino, potassium bis(trimethylsilyl)amino, or N,N-diisopropylethylamine; preferably lithium bis(trimethylsilyl)amino; or Step (1) includes a reaction solvent, which is tetrahydrofuran, toluene, diethyl ether, or tert-methyl ether; preferably, the reaction solvent is tetrahydrofuran; or In step (1), the reaction temperature is -78℃ to 30℃; preferably, the reaction temperature is -78℃ to 25℃; preferably, the reaction temperature is -78℃ to 0℃; preferably, the reaction temperature is -78℃ to -15℃; preferably, the reaction temperature is -35℃ to -15℃; preferably, the reaction temperature is -20±5℃; or In step (1), the reaction time is 1-24 hours; preferably, the reaction time is 2-18 hours; preferably, the reaction time is 6-10 hours; preferably, the reaction time is 8 ± 0.5 hours; or In step (1), the reaction temperature is -78 to 30°C, and the reaction time is 1 to 24 hours; preferably, the reaction temperature is -78 to 25°C, and the reaction time is 2 to 18 hours; preferably, the reaction temperature is -20°C to room temperature, and the reaction time is 2 to 18 hours; preferably, the reaction temperature is 0°C to room temperature, and the reaction time is 2 to 18 hours; or Step (1) is performed under the protection of an inert gas, preferably nitrogen; or Step (1) includes column chromatography purification, wherein the eluent is dichloromethane, chloroform, methanol, ethanol, isopropanol, or a mixture thereof; preferably, the eluent is dichloromethane, dichloromethane / methanol, dichloromethane / isopropanol, or ethyl acetate / petroleum ether; preferably, the eluent and the ratio are dichloromethane:methanol = 50:1, ethyl acetate:petroleum ether = 1:2, or dichloromethane:isopropanol = 30:1 to 50:1; or In step (1), the molar ratio of compound (I-1) to compound (I-2) is 1:4; or In step (1), the molar ratio of compound (I-1): compound (I-2): alkaline reagent (e.g., lithium bis(trimethylsilyl)amino) is 1:4:(3-5); preferably, the molar ratio of compound (I-1): compound (I-2): alkaline reagent (e.g., lithium bis(trimethylsilyl)amino) is 1:4:

4. and / or In step (2), hydrogen peroxide is included, preferably an aqueous solution of hydrogen peroxide, more preferably a 30% aqueous solution of hydrogen peroxide; or Step (2) includes an alkaline reagent, which is an inorganic base; preferably, the inorganic base is lithium hydroxide or sodium hydroxide; preferably, the alkaline reagent is lithium hydroxide; or Step (2) includes a reaction solvent, which is a polar solvent; preferably, the polar solvent is tetrahydrofuran, methanol, ethanol, or acetonitrile; preferably, the polar solvent is tetrahydrofuran; or In step (2), the reaction temperature is 0-35℃; preferably, the reaction temperature is 0-room temperature; preferably, the reaction temperature is 0-25℃; preferably, the reaction temperature is 0-20℃; preferably, the reaction temperature is 5-15℃; or In step (2), the reaction time is 1-16 hours; preferably, the reaction time is 1-8 hours; preferably, the reaction time is 3-6 hours; or In step (2), the reaction temperature is 0-35℃ and the reaction time is 1-16h; preferably, the reaction temperature is 0-room temperature and the reaction time is 1-8h; preferably, the reaction temperature is 0-25℃ and the reaction time is 1-8h; preferably, the reaction temperature is 10±5℃ and the reaction time is 3-6h; or In step (2), the molar ratio of compound (I-3): 30% H2O2: lithium hydroxide monohydrate is 1:(9-12):(3-9); preferably, the molar ratio of compound (I-3): 30% H2O2: lithium hydroxide monohydrate is 1:9:4.

5. and / or Step (3) includes an acid, which is hydrochloric acid-dioxane solution, trifluoroacetic acid, methanesulfonic acid, acetic acid, or sulfuric acid; preferably, the acid is hydrochloric acid-dioxane solution or hydrochloric acid; preferably, the acid is concentrated hydrochloric acid; or Step (3) includes a reaction solvent, wherein the solvent is tetrahydrofuran, 1,4-dioxane, or acetonitrile; preferably, the reaction solvent is 1,4-dioxane; or In step (3), the reaction temperature is 0-60℃; preferably, the reaction temperature is 0-55℃; preferably, the reaction temperature is 20-50℃; or In step (3), the reaction time is 1-16 hours; preferably, the reaction time is 1-8 hours; preferably, the reaction time is 2-8 hours; or In step (3), the reaction temperature is 0-35℃ and the reaction time is 1-16h; preferably, the reaction temperature is 20-35℃ and the reaction time is 2-8h.

3. A method for synthesizing the compound of formula (I) according to claim 1, or a stereoisomer, tautomer, isotopic derivative thereof, or a mixture thereof or a pharmaceutically acceptable salt thereof, characterized in that: X is independently selected from fluorine, chlorine, and bromine, with bromine being preferred; and / or R1 and R2 are independently selected from hydrogen, deuterium, and methyl, respectively; and / or R3 is independently selected from tert-butoxycarbonyl (Boc), carboxybenzyl (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), trichloroethoxycarbonyl (Troc), trifluoroacetamido (Tfa), benzamide (Bz), benzylamino (Bn), triphenylmethylamino (Tphm), p-toluenesulfonamide; preferably tert-butoxycarbonyl; and / or R4 is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -CHO, nitro, amino, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Deuterated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Deuterated alkoxy group; or R4 is independently selected from hydrogen, deuterium, nitro, amino, and C. 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups; or R4 is independently selected from hydrogen, deuterium, nitro, amino, and C. 1-4 alkoxy; or R4 is independently selected from hydrogen, nitro, methoxy, ethoxy, or R4 is a methoxy group; and / or m is 0 or 1, n is 0 or 1; or, m is 1 and n is 1; or m is 0 and n is 0; and / or Rings W1, W2, and W3 are each independently selected from phenyl and 5-6 membered monocyclic heteroaryl groups; the phenyl and heteroaryl groups are optionally selected by one or more independently selected from deuterium, halogens, -CN, -OH, -NH2, -CHO, C 1-3 Alkyl, C 1-3 Alkoxy, -N(C) 1-3 alkyl)2、-NH(C 1-3 Alkyl), -C(O)C 1-3 The alkyl group is substituted; the heteroatom in the heteroaryl group is O, N, or S, and the number of heteroatoms is one or two; or Rings W1, W2, and W3 are independently selected from phenyl, pyridyl, and thiophene, respectively; the phenyl, pyridyl, and thiophene groups are optionally substituted by one or more substituents independently selected from deuterium, fluorine, chlorine, bromine, -CN, -OH, -NH2, -CHO, methyl, ethyl, methoxy, ethoxy-N(CH3)2, -NH(CH3), and -C(O)CH3; or Rings W1, W2, and W3 are each independently selected from the following optionally substituted groups: The optional substitution refers to the substitution of a substance with or without substitution by one or more substituents, each independently selected from deuterium, fluorine, chlorine, bromine, -CN, -OH, -NH2, -CHO, methyl, ethyl, methoxy, ethoxy, -N(CH3)2, -NH(CH3), -C(O)CH3; or Rings W1, W2, and W3 are each independently selected from the following optionally substituted groups: The optional substitution refers to the substitution of a substance with or without substitution by one or more substituents, each independently selected from deuterium, fluorine, chlorine, bromine, -CN, -OH, -NH2, -CHO, methyl, ethyl, methoxy, ethoxy, -N(CH3)2, -NH(CH3), -C(O)CH3; or Rings W1, W2, and W3 are each independently selected from... The aforementioned Optionally substituted by one or more substituents, each independently selected from fluorine, chlorine, bromine, methyl, ethyl, methoxy, ethoxy; or W1, W2, and W3 are each independently selected from Preferred and / or Z 11 Z 21 Z 31 Selected independently from -C 1-2 alkylene-, -C 1-3 oxa-alkylene-, -C 1-3 Thionide-, -C 1-3 Aza-alkylene-; the alkylene, oxa-alkylene, thia-alkylene, and aza-alkylene are optionally substituted by one or more substituents, each independently selected from deuterium, halogen, oxo, -CN, -OH, -NH2, methyl, and methoxy; preferably, the alkylene, oxa-alkylene, thia-alkylene, and aza-alkylene are optionally substituted by one or more substituents, each independently selected from deuterium and oxo; or Z 11 Z 21 and Z 31 The combination of the defined components contains at least one heteroatom or heteroatom group, wherein the heteroatom or heteroatom group is selected from -O-, -S-, -Se-, -NH-, -CO-, -C(S)-; preferably -CO-; or Z 11 Z 21 and Z 31 The combination of definitions must contain at least one optional element. One of them; preferred * indicates the connection terminal to N; or Z 11 Z 21 and Z 31 The combination defined in the text contains 1-4 heteroatoms or heteroatom groups, wherein the heteroatoms or heteroatom groups are selected from -O-, -S-, -Se-, -NH-, -CO-, and -C(S)-, specifically 1, 2, 3, or 4; preferably 1-3 heteroatoms or heteroatom groups, specifically 1, 2, or 3; more preferably 2-4 heteroatoms or heteroatom groups, specifically 2, 3, or 4; even more preferably 2 or 3 heteroatoms or heteroatom groups; the heteroatoms or heteroatom groups are preferably -O-, -S-, -NH-, or -CO-; the heteroatoms or heteroatom groups are more preferably -O- or -CO-; preferably, the heteroatoms or heteroatom groups contain at least -CO-; or Z 11 Z 21 Z 31 Selected independently from -CD2- and -C 1-2 Alkylene-, -OC 1-3 Alkylene-, -C(O)-, -C 1-2 Alkylene-C(O)-, -OC 1- 2-alkylene-C(O)-, -NH-C 1-2 Alkylene-C(O)-, -SC 1-2 Alkylene-C(O)-, -OC 1-2 Alkylene-C(O)-C 1-2 alkylene-, -C 1-2 Alkylene-OC 1-2 Alkylene-, -NH-C 1-2 Alkylene-, -SC 1-2 alkylene-, -C 1-2 Alkylene-NH-C(O)-, -C 1-2 Alkylenes -OC(O)-, -NH-C(O)-, -OC(O)-, -SC(O)-; or Z 11 Z 21 Z 31 Each is independently selected from the following groups: bond, methylene, ethylene, -CD2-, -O-, -S-, -NH-, Preferred components include methylene, ethylene, and -CD2. * indicates the connection terminal to N; or Z 11 -CD2, -C 1-3 Alkylene-, -OC 1-3 Alkylene-; and Z 21 Selected from -OC 1-3 Alkylene-, -NH-C 1-3 Alkylene-, -SC 1-3 Alkylene-, -Se-C 1-3 alkylene-, -C 1-2 Alkylene-OC 1-3 Alkylene-; and Z 31 Selected from -C(O)-, -C 1-3 Alkylene-C(O)-, -OC 1-3 Alkylene -C(O)-, -NH-C 1-3 Alkylene-C(O)-, -SC 1-3 Alkylene-C(O)-, -OC 1-2 Alkylene-C(O)-C 1-3 alkylene-, -C 1-3 Alkylene-NH-C(O)-, -C 1- 3 alkylene groups -OC(O)-, -NH-C(O)-, -OC(O)-, -SC(O)-, -C 1-3 alkylene-C(S)-; or Z 11 -CD2, -C 1-3 Alkylene-, -OC 1-3 Alkylene-*; and Z 21 Selected from -OC 1-3 Alkylene-*, -NH-C 1-3 Alkylene-*, -SC 1-3 Alkylene-*, -Se-C 1-3 Alkylene-*, -C 1-2 Alkylene-OC 1-3 Alkylene-*; and Z 31 Selected from -C(O)-, -C 1-3 Alkylene-C(O)-*, -OC 1-3 Alkylene -C(O)-*, -NH-C 1-3 Alkylene-C(O)-*, -SC 1-3 Alkylene-C(O)-*, -OC 1-2 Alkylene-C(O)-C 1-3 Alkylene-*, -C 1-3 Alkylene -NH-C(O)-*, -C 1-3 Alkylenes -OC(O)-*, -NH-C(O)-*, -OC(O)-*, -SC(O)-*, -C 1-3 Alkylene-C(S)-*; * indicates the N-terminus; or Z 11 -CD2-, -C 1-2 Alkylene-, -OC 1-2 Alkylene-*; and Z 21 Selected from -OC 1-2 Alkylene-*, -NH-C 1-2 Alkylene-*, -SC 1-2 Alkylene-*, -Se-C 1-2 Alkylene-*, -CH2-OC 1-2 Alkylene-*; and Z 31 Selected from -C(O)-, -C 1-2 Alkylene-C(O)-*, -OC 1-2 Alkylene -C(O)-*, -NH-C 1-2 Alkylene-C(O)-*, -SC 1-2 Alkylene-C(O)-*, -C 1-2 Alkylene -NH-C(O)-*, -C 1-2 Alkylenes -OC(O)-*, -NH-C(O)-*, -OC(O)-*, -SC(O)-*, -C 1-2 Alkylene-C(S)-*; more preferably, Z 31 Selected from -C 1-2 Alkylene-C(O)-*, -OC 1- 2-alkylene-C(O)-*, -NH-C 1-2 Alkylene-C(O)-*, -SC 1-2 Alkylene-C(O)-*, -C 1-2 Alkylene -NH-C(O)-*, -C 1-2 Alkylenes -OC(O)-*, -CH2NH-C(O)-*, -NH-C(O)-*, -OC(O)-*, -SC(O)-*, -C 1-2 Alkylene-C(S)-*; more preferably, Z 31 Selected from -C 1-2 Alkylenes -C(O)-*, -OCH2-C(O)-*, -CH2-OC(O)-*, -NH-C(O)-*, -OC(O)-*, -SC(O)-*; more preferably, Z 31 Selected from -CH2C(O)-*; * indicates the connection terminal with N; or Z 11 Selected from methylene, ethylene, -CD2, And Z 21 Selected from methylene, ethylene, -CD2, And Z 31 Selected from Further preferred Z 31 Selected from * indicates the connection terminal to N; or Z 11 Selected from methylene, ethylene, -CD2, And Z 21 Selected from methylene, ethylene, -CD2, And Z 31 Selected from * indicates the connection terminal with N.

4. A method for synthesizing (compound 7), characterized in that, Includes the following steps: Step (1-a): (a) undergoes a substitution reaction with (b1) to produce (c1); Step (2-a): (c1) An oxidative hydrolysis reaction (e.g., alkaline oxidation to remove the Evans chiral cofactor) occurs to generate (d); Step (3-a): (d) Deprotection to generate (compound 7); or Step (1-b): (a) undergoes a substitution reaction with (b2) to produce (c2); Step (2-b): (c2) An oxidative hydrolysis reaction occurs (e.g., alkaline oxidation to remove the Evans chiral cofactor) to generate (d); Step (3-b): (d) Deprotection to generate (compound 7); or or or or or and / or Step (1-a) includes an alkaline reagent selected from organic bases; preferably, the organic base is lithium bis(trimethylsilyl)amino, sodium bis(trimethylsilyl)amino, potassium bis(trimethylsilyl)amino, or N,N-diisopropylethylamine; more preferably, lithium bis(trimethylsilyl)amino; or Step (1-a) includes a reaction solvent, which is tetrahydrofuran, toluene, diethyl ether, or tert-methyl ether; preferably, the reaction solvent is tetrahydrofuran; or In step (1-a), the reaction temperature is -78℃ to 30℃; preferably, the reaction temperature is -78℃ to 25℃; preferably, the reaction temperature is -78℃ to 0℃; preferably, the reaction temperature is -78℃ to -15℃; preferably, the reaction temperature is -35℃ to -15℃; preferably, the reaction temperature is -20±5℃; or In step (1-a), the reaction time is 1-24 h; preferably, the reaction time is 2-18 h; preferably, the reaction time is 6-10 h; preferably, the reaction time is 8 ± 0.5 h. In step (1-a), the reaction temperature is -78 to 30°C, and the reaction time is 1 to 24 hours; preferably, the reaction temperature is -78 to 25°C, and the reaction time is 2 to 18 hours; preferably, the reaction temperature is -20°C to room temperature, and the reaction time is 2 to 18 hours; preferably, the reaction temperature is 0°C to room temperature, and the reaction time is 2 to 18 hours; or Step (1-a) is carried out under the protection of an inert gas, preferably nitrogen; or Step (1-a) includes column chromatography purification, wherein the eluent is dichloromethane, chloroform, methanol, ethanol, isopropanol, or a mixture thereof; preferably, the eluent is dichloromethane, dichloromethane / methanol, dichloromethane / isopropanol, or ethyl acetate / petroleum ether; preferably, the eluent and its ratio are dichloromethane:methanol = 50:1, ethyl acetate:petroleum ether = 1:2, or dichloromethane:isopropanol = 30:1 to 50:1; or In step (1-a), the molar ratio of compound (a) to compound (b1) is 1:4; or In step (1-a), the molar ratio of compound (a): compound (b1): alkaline reagent (e.g., lithium bis(trimethylsilyl)amino) is 1:4:(3-5); preferably, the molar ratio of compound (a): compound (b1): alkaline reagent (e.g., lithium bis(trimethylsilyl)amino) is 1:4:

4. and / or In step (2-a), hydrogen peroxide is included, preferably an aqueous solution of hydrogen peroxide, more preferably a 30% aqueous solution of hydrogen peroxide; or Step (2-a) includes an alkaline reagent, which is an inorganic base; preferably, the inorganic base is lithium hydroxide or sodium hydroxide; more preferably, it is lithium hydroxide; or Step (2-a) includes a reaction solvent, which is a polar solvent; preferably, the polar solvent is tetrahydrofuran, methanol, ethanol, or acetonitrile; preferably, the polar solvent is tetrahydrofuran; or In step (2-a), the reaction temperature is 0-35℃; preferably, the reaction temperature is 0-room temperature; preferably, the reaction temperature is 0-25℃; preferably, the reaction temperature is 0-20℃; preferably, the reaction temperature is 5-15℃; or In step (2-a), the reaction time is 1-16 hours; preferably, the reaction time is 1-8 hours; preferably, the reaction time is 3-6 hours; or In step (2-a), the reaction temperature is 0-35℃, and the reaction time is 1-16h; preferably, the reaction temperature is 0-room temperature, and the reaction time is 1-8h; preferably, the reaction temperature is 0-25℃, and the reaction time is 1-8h; preferably, the reaction temperature is 10±5℃, and the reaction time is 3-6h; or In step (2-a), the molar ratio of compound (c1): 30% H2O2: lithium hydroxide monohydrate is 1:(9-12):(3-9); preferably, the molar ratio of compound (c1): 30% H2O2: lithium hydroxide monohydrate is 1:9:4.

5. and / or Step (3-a) includes an acid, which is hydrochloric acid-dioxane solution, trifluoroacetic acid, methanesulfonic acid, acetic acid, sulfuric acid, or hydrochloric acid; preferably, the acid is hydrochloric acid-dioxane solution or hydrochloric acid; preferably, the acid is concentrated hydrochloric acid; or Step (3-a) includes a reaction solvent, wherein the solvent is tetrahydrofuran, 1,4-dioxane, or acetonitrile; preferably, the reaction solvent is 1,4-dioxane; or In step (3-a), the reaction temperature is 0-60℃; preferably, the reaction temperature is 0-55℃; preferably, the reaction temperature is 20-50℃; or In step (3-a), the reaction time is 1-16 hours; preferably, the reaction time is 1-8 hours; preferably, the reaction time is 2-8 hours; or In step (3-a), the reaction temperature is 0-35℃ and the reaction time is 1-16h; preferably, the reaction temperature is 20-35℃ and the reaction time is 2-8h. and / or Step (1-b) includes an alkaline reagent selected from organic bases; preferably, the organic base is lithium bis(trimethylsilyl)amino, sodium bis(trimethylsilyl)amino, potassium bis(trimethylsilyl)amino, or N,N-diisopropylethylamine; preferably, the base is lithium bis(trimethylsilyl)amino; or Step (1-b) includes a reaction solvent, which is tetrahydrofuran, toluene, diethyl ether, or tert-methyl ether; preferably, the reaction solvent is tetrahydrofuran; or In step (1-b), the reaction temperature is -78 to 30°C, and the reaction time is 1 to 24 hours; preferably, the reaction temperature is -78 to 25°C, and the reaction time is 2 to 18 hours; preferably, the reaction temperature is -20°C to room temperature, and the reaction time is 2 to 18 hours; preferably, the reaction temperature is 0°C to room temperature, and the reaction time is 2 to 18 hours; or Step (1-b) is carried out under the protection of an inert gas, preferably nitrogen. and / or In step (2-b), hydrogen peroxide is included, preferably an aqueous solution of hydrogen peroxide; or Step (2-b) includes an alkaline reagent, which is an inorganic base; preferably, the inorganic base is lithium hydroxide or sodium hydroxide; more preferably, lithium hydroxide; or Step (2-b) includes a reaction solvent, which is a polar solvent; preferably, the polar solvent is tetrahydrofuran, methanol, ethanol, or acetonitrile; preferably, the solvent is tetrahydrofuran; or In step (2-b), the reaction temperature is 0-35℃ and the reaction time is 1-16h; preferably, the reaction temperature is 0-room temperature and the reaction time is 1-8h; preferably, the reaction temperature is 0-25℃ and the reaction time is 1-8h. and / or Step (3-b) includes an acid, wherein the acid is a hydrochloric acid-dioxane solution, trifluoroacetic acid, methanesulfonic acid, acetic acid, or sulfuric acid; preferably, the acid is a hydrochloric acid-dioxane solution; or Step (3-b) includes a reaction solvent, wherein the solvent is tetrahydrofuran, 1,4-dioxane, or acetonitrile; preferably, the reaction solvent is 1,4-dioxane; or In step (3-b), the reaction temperature is 0-35℃ and the reaction time is 1-16h; preferably, the reaction temperature is 20-35℃ and the reaction time is 2-8h.

5. The method for synthesizing (compound 7) according to claim 4, characterized in that: The preparation method of (a) includes the following steps: Step (1-1): (a-1) and (2-bromoethyl)carbamate benzyl ester undergo a nucleophilic substitution reaction to generate (a-2); Step (1-2): (a-2) Under hydrogen protection, a deprotection reaction occurs to produce (a-3); Steps (1-3): (a-3) and (a-4) undergo a substitution reaction to generate compound (a-5); Steps (1-4): (a-5) and (a-6) undergo a condensation reaction to form compound (a-7); Steps (1-5): (a-7) undergoes a reduction reaction to produce compound (a-8); Steps (1-6): (a-8) Halogenation occurs, producing compound (a); and / or In step (1-1), an alkaline reagent is included, wherein the alkaline reagent is potassium carbonate, sodium carbonate, cesium carbonate, or potassium phosphate; preferably, the alkaline reagent is potassium carbonate; or Step (1-1) includes a reaction solvent, which is N,N-dimethylformyl, dimethyl sulfoxide, or acetonitrile; preferably, the reaction solvent is N,N-dimethylformyl; or In step (1-1), the reaction temperature is 70-120℃ and the reaction time is 10-24h; preferably, the reaction temperature is 70-100℃ and the reaction time is 12-18h. and / or Steps (1-2) include a catalyst, wherein the catalyst is palladium on carbon; or In steps (1-2), a reaction solvent is included, and the reaction solvent is methanol; the reaction temperature is 20-35℃, and the reaction time is 10-24h; and / or Steps (1-3) include an alkaline reagent; preferably, the alkaline reagent is potassium carbonate and potassium iodide, sodium carbonate, cesium carbonate, or potassium phosphate; preferably, the alkaline reagent is potassium carbonate and potassium iodide; or Steps (1-3) include a reaction solvent, which is acetonitrile, 1,4-dioxane, N,N-dimethylformyl, or dimethyl sulfoxide; preferably, the reaction solvent is acetonitrile; or In steps (1-3), the reaction temperature is 70-120℃ and the reaction time is 10-24h; preferably, the reaction temperature is 70-100℃ and the reaction time is 12-18h. and / or Steps (1-4) include an alkaline reagent, which is N,N-diisopropylethylamine, sodium carbonate, potassium carbonate, or triethylamine; preferably, the alkaline reagent is N,N-diisopropylethylamine; or Steps (1-4) are carried out in the presence of a condensing agent selected from N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate; or In steps (1-4), a reaction solvent is included, wherein the reaction solvent is N,N-dimethylformamide or tetrahydrofuran, the reaction temperature is 0-65℃, and the reaction time is 1-4h; preferably, the reaction solvent is N,N-dimethylformamide, the reaction temperature is 0-50℃, and the reaction time is 2-4h. and / or Steps (1-5) include a reducing agent, which is lithium borohydride, sodium borohydride, or lithium aluminum hydride; preferably, the reducing agent is lithium borohydride; or In steps (1-5), a reaction solvent is included, the reaction solvent is tetrahydrofuran, the reaction temperature is 0-35℃, and the reaction time is 24-48h; preferably, the reaction temperature is 20-35℃ and the reaction time is 24-40h. and / or Steps (1-6) include a brominating agent, preferably phosphorus tribromide; or Steps (1-6) include a reaction solvent, which is a haloalkane; preferably dichloromethane; or In steps (1-6), the reaction temperature is 0-35℃ and the reaction time is 1-4h; and / or The preparation method of (b1) includes the following steps: Step (2-1): (b1-1) undergoes a reduction reaction to produce compound (b1-2); Step (2-2): (b1-2) undergoes a ring-closing reaction to produce (b1-3); Steps (2-3): (b1-3) and (b1-4) generate (b1); and / or Step (2-1) includes a reducing agent, which is borane, lithium borohydride, sodium borohydride, or lithium aluminum hydride; preferably, the reducing agent is borane; or In step (2-1), a reaction solvent is included, wherein the solvent is tetrahydrofuran; or In step (2-1), the reaction temperature is -10 to 35°C, and the reaction time is 0.5 to 12 hours; preferably, the reaction temperature is 0 to 35°C, and the reaction time is 1 to 10 hours. and / or Step (2-2) includes an alkaline reagent, wherein the alkaline reagent is NaH; or In step (2-2), a reaction solvent is included, wherein the solvent is tetrahydrofuran; or In step (2-2), the reaction temperature is 20-70℃ and the reaction time is 1-12h; preferably, the reaction temperature is 10-50℃ and the reaction time is 2-8h. and / or Steps (2-3) include a condensing agent, wherein the condensing agent is 2,2-dimethylpropionyl chloride and lithium chloride; or Steps (2-3) include an alkaline reagent, which is triethylamine, N,N-diisopropylethylamine, sodium carbonate, potassium carbonate, or potassium phosphate; preferably, the alkaline condition is triethylamine; or In step (2-3), a reaction solvent is included, which is tetrahydrofuran, acetonitrile, or N,N-dimethylformamide; the reaction temperature is 0-40℃; and the reaction time is 1-12h. Preferably, the reaction solvent is tetrahydrofuran, the reaction temperature is 0-35℃, and the reaction time is 2-6h. and / or The preparation method of (b2) includes the following steps: Step (4-1): (b2-1) undergoes a reduction reaction to produce (b2-2); Step (4-2): (b2-2) A cyclization reaction occurs under the action of N,N'-carbonyldiimidazole to generate (b2-3); Step (4-3): (b1-4) and (b2-3) undergo a condensation reaction in the presence of 2,2-dimethylpropionyl chloride and lithium chloride to generate (b2); and / or Step (4-1) includes a reducing agent, which is deuterated lithium aluminum hydride; or In step (4-1), a reaction solvent is included, wherein the solvent is tetrahydrofuran; the reaction temperature is -10 to 35°C, and the reaction time is 0.5 to 12 h; and / or Step (4-2) includes an alkaline reagent, which is cesium carbonate, potassium carbonate, or sodium carbonate; preferably, the alkaline reagent is cesium carbonate; or In step (4-2), the reaction temperature is 80-150℃ and the reaction time is 1-12h; preferably, the reaction temperature is 70-120℃ and the reaction time is 2-10h. and / or Step (4-3) includes an alkaline reagent, which is triethylamine, N,N-diisopropylethylamine, sodium carbonate, potassium carbonate, or potassium phosphate; preferably, the alkaline reagent is triethylamine; or In step (4-3), a reaction solvent is included, which is tetrahydrofuran, acetonitrile, or N,N-dimethylformamide. The reaction temperature is 0-35°C, and the reaction time is 1-12 h. Preferably, the reaction solvent is tetrahydrofuran, the reaction temperature is 10-30°C, and the reaction time is 2-10 h.

6. A method for synthesizing (compound 40), characterized in that, Includes the following steps: (f) undergoes a substitution reaction with (b3) to generate (c8); (c8) undergoes an oxidative hydrolysis reaction (e.g., basic oxidation to remove the Evans chiral cofactor) to generate (h); (h) undergoes deprotection to generate (compound 40); and / or The preparation method of (f) includes the following steps: Step (5-1): (f-1) reacts with ammonia to undergo a substitution reaction, producing (f-2); Step (5-2): (f-2) undergoes a reduction reaction to produce (f-3); Step (5-3): (f-3) undergoes a halogenation reaction to produce (f); and / or Step (5-1) includes a reaction solvent, which is ethanol, methanol, tetrahydrofuran, or isopropanol; preferably, the reaction solvent is ethanol; or Furthermore, in step (5-1), the reaction temperature is 0-35℃ and the reaction time is 12-56h; preferably, the reaction temperature is 0-30℃ and the reaction time is 15-48h. and / or Step (5-2) includes a reducing agent, which is lithium aluminum hydride, sodium borohydride, or lithium borohydride; preferably, the reducing agent is lithium aluminum hydride; or Furthermore, in step (5-2), a reaction solvent is included, the reaction solvent is tetrahydrofuran, the reaction temperature is 0-35℃, and the reaction time is 1-4h; preferably, the reaction temperature is 0-30℃ and the reaction time is 2-4h. and / or Step (5-3) includes a brominating agent, preferably phosphorus tribromide; or Step (5-3) includes a reaction solvent, which is a haloalkane; preferably dichloromethane; or In step (5-3), the reaction temperature is 0-35℃ and the reaction time is 8-18h.

7. A method for synthesizing (compound 41), characterized in that, Includes the following steps: (g) undergoes a substitution reaction with (b3) to generate (c9); (c9) undergoes an oxidative hydrolysis reaction (e.g., basic oxidation to remove the Evans chiral cofactor) to generate (j); (j) Deprotection of compound 41; and / or The preparation method of (g) includes the following steps: Step (6-1): (g-1) and methyl 3-(bromomethyl)benzoate undergo a substitution reaction under alkaline conditions and in the presence of a reaction solvent to produce (g-2); Step (6-2): (g-2) undergoes a reduction reaction under the action of a reducing agent and a reaction solvent to produce (g-3); Step (6-3): (g-3) undergoes a halogenation reaction under the action of halides to produce (g); and / or Step (6-1) includes an alkaline reagent, which is N,N-diisopropylethylamine, triethylamine, potassium carbonate, sodium carbonate, cesium carbonate, or potassium phosphate; preferably, the alkaline reagent is N,N-diisopropylethylamine; or Step (6-1) includes a reaction solvent, which is acetonitrile, N,N-dimethylformamide, or dimethyl sulfoxide; preferably, the reaction solvent is acetonitrile; or In step (6-1), the reaction temperature is 50-100℃ and the reaction time is 1-8h; preferably, the reaction temperature is 40-100℃ and the reaction time is 2-6h. and / or Step (6-2) includes a reducing agent, which is lithium borohydride, sodium borohydride, or lithium aluminum hydride; preferably, the reducing agent is lithium borohydride; or Step (6-2) includes a reaction solvent, wherein the reaction solvent is tetrahydrofuran; or In step (6-2), the reaction temperature is 0-80℃ and the reaction time is 0.5-3h; preferably, the reaction temperature is 40-70℃ and the reaction time is 0.5-2h. and / or Step (6-3) includes a brominating agent, preferably phosphorus tribromide; or Step (6-3) includes a reaction solvent, which is a haloalkane; preferably dichloromethane; or In step (6-3), the reaction temperature is 0-35℃ and the reaction time is 0.5-4h.

8. An intermediate for preparing the compound of formula (I) of claim 1, or a stereoisomer, tautomer, isotopic derivative or mixture thereof, or a pharmaceutically acceptable salt of the compound, characterized in that: The compound has a structure as shown in formula (I-1): Among them, W1, W2, W3, Z 11 Z 21 Z 31 ,X,R5,R6,R7,R8,R9,R 10 The definition is as defined in claim 1; or The compound has a structure as shown in formula (I-1-1): Wherein, X is defined as in claim 1; or The compound has a structure as shown in formula (I-2): The definitions of R1, R2, R3, R4, m, and n are as defined in claim 1. The condition is that the compound is not or The compound has a structure as shown in formula (I-2-1): The definitions of R1, R2, R3, and R4 are as defined in claim 1; or The compound has a structure as shown in formula (I-3): Among them, W1, W2, W3, Z 11 Z 21 Z 31 ,X,R1,R2,R3,R4,R5,R6,R7,R8,R9,R 10 The definitions of m and n are as described in compound (I).

9. The compound according to claim 8, or a stereoisomer, tautomer, isotopic derivative, or mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that: The compound is selected from:

10. A method for synthesizing the compound of formula (I) according to claim 1, or a stereoisomer, tautomer, isotopic derivative, or mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that: The compound is selected from:

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