Preparation method, intermediate and preparation method of fused pyridone compound serving as KRAS inhibitor

Abstract

The invention discloses a preparation method, an intermediate and a preparation method of a fused pyridone compound serving as a KRAS inhibitor. The KRAS inhibitor provided by the invention can be prepared through the following reaction. The preparation method disclosed by the invention has the advantages of short reaction route, low cost, high yield and mild and safe reaction, and has a good application prospect.

Description

[0001] This invention claims the following priority:

[0002] Application number CN2024107501438, application date: June 11, 2024;

[0003] Application number CN2025107415102, application date: June 4, 2025. Technical Field

[0004] This invention relates to a method for preparing fused pyridone compounds as KRAS inhibitors, intermediates, and the method for preparing them. Background Technology

[0005] The KRAS gene mutation rate in Asian populations is 10%–15%. KRAS is mutated in many cancers and is one of the major oncogenes. KRAS-mutant tumors are the most potentially targeted molecular subtype of non-small cell lung cancer (NSCLC), with a mutation rate of approximately 15%–25% in NSCLC. In NSCLC cases, KRAS mutations primarily occur at codons 12 and 13. The most common codon variation, accounting for approximately 39% of KRAS-mutant NSCLCs, is the KRAS-G12C mutation.

[0006] In lung adenocarcinoma, the KRAS gene positivity rate is 1 / 5 to 1 / 4, second only to EGFR positivity. The lack of targeted inhibitors makes treatment and prognosis extremely difficult for KRAS-positive non-small cell lung cancer patients. Lung cancer patients must undergo KRAS gene testing before receiving EGFR-TKI treatment; the decision to use EGFR-TKI targeted drugs as a clinical treatment measure is based on the test results. If the KRAS gene is mutated, molecular targeted therapy with EGFR-TKIs is not recommended.

[0007] Studies have shown that fused pyridone compounds can be used as KRAS inhibitors. Their traditional synthetic routes require the introduction of methoxy and demethoxy protection, involving multiple linear synthesis steps and resulting in low yields. Reactants... Introducing the compound using palladium-catalyzed coupling is costly; the synthesized intermediate compound Having two chiral axes is detrimental to quality control, the reaction is complex, and the yield is low; acryloyl chloride, as an acrylation reagent, is also detrimental to quality control, the reaction is complex, and the yield is low; performing chiral separation in the final step is detrimental to the quality control of the active pharmaceutical ingredient, and the compound... They are a pair of diastereomers, and chiral separation by supercritical chromatography (SFC) is required to obtain the final free base compound, which further increases the synthesis cost.

[0008] Other traditional synthetic methods introduce nitro groups onto fused pyridinones via nitration or reaction with nitroacetamide to prepare compounds containing... The intermediate compound of the structure is then further hydrogenated. Hydrogenation and cyclization synthesis Both nitration and hydrogenation reactions have relatively high risk factors.

[0009] Therefore, it is crucial to design a method for preparing KRAS inhibitors that is short in reaction, high in yield, mild and safe in reaction, and low in cost. Summary of the Invention

[0010] The technical problem this invention aims to solve is to overcome the technical defects of existing methods for preparing KRAS inhibitors and their intermediates, such as long synthetic routes, high costs, low yields, and high reaction risks. This invention provides a method for preparing fused pyridone compounds as KRAS inhibitors, as well as intermediates and their preparation methods. Compared with existing technologies, the preparation method provided by this invention has at least one of the following advantages: short reaction route, low cost, high yield, avoidance of nitration and hydrogenation reactions, mild and safe reaction, and good application prospects.

[0011] In one aspect of the present invention, a method for preparing a compound of formula A2 or an optical isomer thereof is provided, comprising the following steps:

[0012] Compound A2 is prepared by contacting compound A1 and compound Z1.

[0013]

[0014] R1 and R2 are independently selected from -H, -F, -Cl, -Br or -I, respectively;

[0015] R3 is selected from -F, -Cl, -Br, or -I;

[0016] R4 is selected from ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl.

[0017] In some embodiments of the present invention, R2 is preferably -Cl or -F; and / or R1 is preferably -Cl or -Br; and / or R3 is preferably -Cl or -F.

[0018] In some embodiments of the present invention, R4 is preferably ethyl, n-propyl, or isopropyl.

[0019] In some embodiments of the present invention, the preparation of the compound of formula A2 includes the following steps: first activating the carboxyl group of the compound of formula A1, and then contacting it with the compound of formula Z1 to carry out a ring-closing reaction to form an oxazole ring.

[0020] In this invention, the carboxyl activation in the above steps can be performed using reactions conventional in the art, such as acylation or azide reactions.

[0021] In some embodiments of the present invention, the preparation of the compound of formula A2 includes the following steps:

[0022] S1. The compound of formula A1 is subjected to an acylation reaction with an acylation reagent to prepare an acyl halide compound; or the compound of formula A1 is subjected to an azide reaction with an azide reagent to prepare an acyl azide intermediate;

[0023]

[0024] S2. The acyl halide compound or the acyl azide intermediate is subjected to a ring-closure reaction with the compound of formula Z1 to form an oxazole ring, thereby preparing the compound of formula A2.

[0025] In this invention, the conditions and operations in the acylation reaction, azide reaction in step S1 and the cyclization reaction in step S2 are all conventional conditions and operations in the art.

[0026] The following conditions and operations are particularly preferred in this invention:

[0027] In step S1, the preferred method for preparing the acyl halide compound is as follows: in a solvent, the compound of formula A1 and an acylating reagent are subjected to an acylation reaction to prepare the acyl halide compound;

[0028] The acylating agent is preferably one or more of oxalyl chloride and thionyl chloride;

[0029] The acylating agent is preferably oxalyl chloride;

[0030] The molar ratio of the compound of formula A1 to the acylation reagent is preferably 1:(0.5 to 1.5), including but not limited to 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, and 1:1.5.

[0031] The solvent is preferably one or more of ether solvents and halogenated hydrocarbon solvents. The ether solvent may be one or more of tetrahydrofuran, diethyl ether, and dioxane. The halogenated hydrocarbon solvent may be one or more of dichloromethane and trichloromethane. In a specific example of the present invention, the solvent is a mixture of tetrahydrofuran and dichloromethane.

[0032] The acylation reaction is carried out in the presence of a catalyst, preferably N,N-dimethylformamide.

[0033] The acylation reaction temperature can be a conventional reaction temperature for this type of reaction, such as room temperature. The acylation reaction temperature can be between 10°C and 30°C. Understandably, the acylation reaction temperature includes, but is not limited to, 10°C, 15°C, 20°C, 25°C, and 30°C.

[0034] The progress of the acylation reaction can be monitored using conventional monitoring methods in the art (e.g., LC-MS, TLC, HPLC, NMR, or GC), and the reaction endpoint is generally defined as the disappearance or cessation of reaction of compound A1. The preferred acylation reaction time is 1 to 6 hours, for example, 3 hours.

[0035] In step S2, the preferred method for preparing the compound of formula A2 is as follows: in a solvent and in the presence of a base, the acyl halide compound is subjected to a cyclization reaction with the compound of formula Z1 to prepare the compound of formula A2.

[0036] The molar ratio of the acyl halide compound to the compound of formula Z1 is preferably 1:(0.6 to 1.6), including but not limited to 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, and 1:1.6.

[0037] The base is preferably an organic amine base. The organic amine base may be triethylamine.

[0038] The solvent is preferably a nitrile solvent. The nitrile solvent may be acetonitrile.

[0039] The ring-closing reaction temperature can be a conventional reaction temperature for this type of reaction, such as room temperature. The ring-closing reaction temperature can be between 10°C and 30°C. Understandably, the ring-closing reaction temperature includes, but is not limited to, 10°C, 15°C, 20°C, 25°C, and 30°C.

[0040] The progress of the ring-closing reaction can be monitored using conventional monitoring methods in the art (e.g., LC-MS, TLC, HPLC, NMR, or GC), and the reaction endpoint is generally defined as the disappearance or cessation of the reaction of the acyl halide compound. The preferred ring-closing reaction time is 6 to 18 hours, for example, 12 hours.

[0041] In another aspect, the present invention also provides a compound of formula A2 or an optical isomer thereof:

[0042]

[0043] The definitions of R1 to R4 are as described above.

[0044] In some embodiments of the present invention, the compound of formula A2 is selected from...

[0045] In another aspect, the present invention also provides a method for preparing a compound of formula A3 or an optical isomer thereof, comprising the following steps:

[0046] Compound A2 was hydrolyzed to prepare compound A3.

[0047]

[0048] The definitions of R1 to R4 are as described above.

[0049] In this invention, the conditions and operations in the hydrolysis reaction in the above steps are all conventional conditions and operations in the art.

[0050] The following conditions and operations are particularly preferred in this invention:

[0051] The preferred method for preparing the compound of formula A3 is as follows: in a solvent, in the presence of a base, the compound of formula A2 is subjected to a hydrolysis reaction to prepare the compound of formula A3;

[0052] The alkali is preferably lithium hydroxide monohydrate.

[0053] The molar ratio of the compound of formula A2 to the base is preferably 1:(1.5 to 2.5), including but not limited to 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, 1:2.1, 1:2.2, 1:2.3, 1:2.4, and 1:2.5.

[0054] The solvent is preferably one or more of an ether solvent and water. The ether solvent may be tetrahydrofuran. In a specific example of the present invention, the solvent is a mixture of tetrahydrofuran and water.

[0055] The hydrolysis reaction temperature can be a conventional reaction temperature for this type of reaction, such as room temperature. The hydrolysis reaction temperature can be between 10℃ and 30℃. Understandably, the hydrolysis reaction temperature includes, but is not limited to, 10℃, 15℃, 20℃, 25℃, and 30℃.

[0056] The hydrolysis reaction can be monitored using conventional methods in the art (e.g., LC-MS, TLC, HPLC, NMR, or GC), with the reaction endpoint generally defined as the disappearance or cessation of reaction of compound A2. The hydrolysis reaction time is preferably 1 to 6 hours, for example, 3 hours.

[0057] In another aspect, the present invention also provides a method for preparing a compound of formula A4 or an optical isomer thereof, comprising the following steps:

[0058] S1. Hydrolyze compound A2 to prepare compound A3;

[0059] S2. The compounds of formula A3 and Z2 are subjected to an amidation reaction to prepare compound A4;

[0060]

[0061] The definitions of R1 to R4 are as described above;

[0062] R5 and R6 are independently selected from -H, -F, -Cl, and -C, respectively. 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl and C 1-6 The alkoxy group can be optionally surrounded by 1, 2 or 3 R groups. a replace;

[0063] Each occurrence of R7 is independently selected from -H, -F, -Cl, -Br, -I, hydroxyl, amino, nitro, cyano, and C. 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl and C 1-6 The alkoxy group can be optionally surrounded by 1, 2 or 3 R groups. a replace;

[0064] R a Each occurrence is independently selected from -H, -F, -Cl, -Br, -I, -OH, -NH2, -CH3, -CF3, -C2H5, -CN, -SF5, -CHO, -COOH, or -C(=O)NH2;

[0065] m is selected from 0, 1, or 2.

[0066] In some embodiments of the present invention, R5 is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl; and / or R6 is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.

[0067] In some embodiments of the present invention, in step S1 of the method for preparing compound A4 or its optical isomer, the conditions and operations for preparing compound A3 by hydrolyzing compound A2 are as described above.

[0068] In some embodiments of the present invention, in step S2 of the method for preparing the compound of formula A4 or its optical isomer, the preparation of the compound of formula A4 includes the following steps:

[0069] S21. The compound of formula A3 and the acylation reagent are subjected to an acylation reaction to prepare an acyl halide compound;

[0070] S22. The acyl halide compound is subjected to a substitution reaction with the compound of formula Z2 to prepare the compound of formula A4.

[0071] In this invention, the conditions and operations in the acylation reaction in step S21 and the substitution reaction in step S22 are conventional conditions and operations in the art.

[0072] The following conditions and operations are particularly preferred in this invention:

[0073] In step S21, the preferred method for preparing the acyl halide compound is as follows: in a solvent, the compound of formula A3 and an acylating reagent are subjected to an acylation reaction to prepare the acyl halide compound;

[0074] The acylation reagent is preferably oxalyl chloride.

[0075] The molar ratio of the compound of formula A3 to the acylation reagent is preferably 1:(0.5-2), including but not limited to 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, and 1:2.

[0076] The solvent is preferably an ether solvent. The ether solvent may be one or more of tetrahydrofuran, diethyl ether, and dioxane. In a specific example of the present invention, the solvent is tetrahydrofuran.

[0077] The acylation reaction is carried out in the presence of a catalyst, preferably N,N-dimethylformamide.

[0078] The acylation reaction temperature can be a conventional reaction temperature for this type of reaction, such as room temperature. The acylation reaction temperature can be between 10°C and 30°C. Understandably, the acylation reaction temperature includes, but is not limited to, 10°C, 15°C, 20°C, 25°C, and 30°C.

[0079] The progress of the acylation reaction can be monitored using conventional monitoring methods in the art (e.g., LC-MS, TLC, HPLC, NMR, or GC), and the reaction endpoint is generally defined as the disappearance or cessation of reaction of compound A1. The preferred acylation reaction time is 1 to 6 hours, for example, 3 hours.

[0080] In step S22, the preferred method for preparing the compound of formula A4 is as follows: in a solvent, in the presence of a base, the acyl halide compound is subjected to a substitution reaction with the compound of formula Z2 to prepare the compound of formula A4;

[0081] The molar ratio of the acyl halide compound to the compound of formula Z2 is preferably 1:(0.6 to 1.6), including but not limited to 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, and 1:1.6.

[0082] The base is preferably an organic amine base. The organic amine base may be N,N-diisopropylethylamine.

[0083] The solvent is preferably an ether solvent. The ether solvent may be one or more of tetrahydrofuran, diethyl ether, and dioxane. In a specific example of the present invention, the solvent is tetrahydrofuran.

[0084] The temperature of the substitution reaction can be a conventional reaction temperature for this type of reaction, such as room temperature. The temperature of the substitution reaction can be between 10°C and 30°C. Understandably, the temperature of the substitution reaction includes, but is not limited to, 10°C, 15°C, 20°C, 25°C, and 30°C.

[0085] The progress of the substitution reaction can be monitored using conventional monitoring methods in the art (e.g., LC-MS, TLC, HPLC, NMR, or GC), and the reaction endpoint is generally defined as the disappearance or cessation of the reaction of the acyl halide compound. The substitution reaction time is preferably 6 to 18 hours, for example, 12 hours.

[0086] In another aspect, the present invention also provides a compound of formula A4 or an optical isomer thereof:

[0087]

[0088] The definitions of R1~R3, R5~R7 and m are as described above.

[0089] In some embodiments of the present invention, the compound of formula A4 is selected from...

[0090] In another aspect, the present invention also provides a method for preparing a compound of formula E5 or an optical isomer thereof, comprising the following steps:

[0091] Compound E3 was subjected to an addition cyclization reaction with compound E4 to prepare compound E5.

[0092]

[0093] Among them, R1~R2, R5~R7 and m are defined as described above;

[0094] R 4aIt is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.

[0095] In this invention, the conditions and operations in the addition cyclization reaction in the above steps are all conventional conditions and operations in the art.

[0096] The following conditions and operations are particularly preferred in this invention:

[0097] The preferred method for preparing the E5 compound is as follows: in a solvent, the E3 compound and the E4 compound undergo an addition cyclization reaction to prepare the E5 compound;

[0098] The solvent is preferably a halocarbon solvent. The halocarbon solvent may be chloroform.

[0099] The molar ratio of the compound of formula E3 to the compound of formula E4 is preferably 1:(1.5 to 2.5), including but not limited to 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, 1:2.1, 1:2.2, 1:2.3, 1:2.4, and 1:2.5.

[0100] The temperature of the addition cyclization reaction can be a conventional reaction temperature for this type of reaction, such as room temperature. The temperature of the addition cyclization reaction can be 10℃ to 30℃. It is understood that the temperature of the addition cyclization reaction includes, but is not limited to, 10℃, 15℃, 20℃, 25℃, and 30℃.

[0101] The progress of the addition cyclization reaction can be monitored using conventional monitoring methods in the art (e.g., LC-MS, TLC, HPLC, NMR, or GC), and the reaction endpoint is generally defined as the disappearance or cessation of reaction of compounds of formula E3 and E4. The preferred reaction time is 6 to 24 hours, for example, 12 hours.

[0102] In another aspect, the present invention also provides a compound of formula E5 or an optical isomer thereof:

[0103]

[0104] Among them, R1~R2, R5~R7, m and R 4a The definition is as described above.

[0105] In some embodiments of the present invention, the compound of formula E5 is selected from...

[0106] In another aspect, the present invention also provides a method for preparing a compound of formula AA5 or an optical isomer thereof, comprising the following steps:

[0107] Compound A4 was subjected to a nucleophilic substitution reaction to prepare compound AA5.

[0108]

[0109] Alternatively, the E5 compound can be contacted with a base to undergo an amino-ester exchange reaction to prepare the AA5 compound;

[0110]

[0111] Among them, R1~R3, R5~R7, m and R 4a The definition is as described above.

[0112] In this invention, the conditions and operations in the nucleophilic substitution and amine ester exchange reactions in the above steps are all conventional conditions and operations in the art.

[0113] The following conditions and operations are particularly preferred in this invention:

[0114] The preferred method for preparing the AA5 compound is as follows: in a solvent, in the presence of a base, the A4 compound is subjected to a nucleophilic substitution reaction to cyclize and prepare the AA5 compound.

[0115] The base is an inorganic base. The inorganic base may be cesium carbonate or sodium hydroxide.

[0116] The base is an organic base. The organic base may be sodium tert-butoxide.

[0117] The solvent is an amide solvent. The amide solvent may be N,N-dimethylformamide.

[0118] The temperature of the nucleophilic substitution reaction can be a conventional reaction temperature for this type of reaction, such as room temperature. The temperature of the nucleophilic substitution reaction can be 10℃ to 30℃. Understandably, the temperature of the nucleophilic substitution reaction includes, but is not limited to, 10℃, 15℃, 20℃, 25℃, and 30℃.

[0119] The progress of the nucleophilic substitution reaction can be monitored using conventional monitoring methods in the art (e.g., LC-MS, TLC, HPLC, NMR, or GC), and the reaction endpoint is generally defined as the disappearance or cessation of reaction of compound A4. The preferred reaction time is 1 to 6 hours, for example, 4 hours.

[0120] The preferred method for preparing the AA5 compound is as follows: in a solvent and in the presence of a base, the E5 compound is subjected to an amine-ester exchange reaction to achieve cyclization and prepare the AA5 compound.

[0121] The base is an inorganic base. The inorganic base may be sodium hydroxide.

[0122] The solvent is preferably an ether solvent. The ether solvent may be tetrahydrofuran.

[0123] The molar ratio of the E3 compound to the base is preferably 1:(1.5 to 2.5), including but not limited to 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, 1:2.1, 1:2.2, 1:2.3, 1:2.4, and 1:2.5.

[0124] The temperature of the amino-ester exchange reaction can be a conventional reaction temperature for this type of reaction, such as room temperature. The temperature of the amino-ester exchange reaction can be 10℃ to 30℃. Understandably, the temperature of the amino-ester exchange reaction includes, but is not limited to, 10℃, 15℃, 20℃, 25℃, and 30℃.

[0125] The progress of the amino-ester exchange reaction can be monitored using conventional monitoring methods in the art (e.g., LC-MS, TLC, HPLC, NMR, or GC), and the reaction endpoint is generally defined as the disappearance or cessation of reaction of the E5 compound. The preferred reaction time is 1 to 6 hours, for example, 5 hours.

[0126] In another aspect, the present invention also provides a compound of formula A5 or an optical isomer thereof:

[0127]

[0128] Among them, R1~R2, R5~R7 and m are defined as described above; R 13 Selected from H or methyl.

[0129] In some embodiments of the present invention, the compound of formula A5 is selected from...

[0130] In some embodiments of the present invention, when R 13 When the methyl group is used, the compound of formula A5 is prepared by the following method:

[0131] S1. The compound of formula AA5 is subjected to a hydrolysis ring-opening reaction to prepare compound of formula A7'.

[0132]

[0133] S2. The compound of formula A7' is subjected to a cyclization reaction with substance P to prepare the compound of formula A5; wherein, substance P is selected from acetyl chloride, acetic anhydride or trimethyl orthoacetate.

[0134] In this invention, when R is mentioned above13 When the methyl group is used, the conditions and operations in the hydrolysis ring-opening reaction in step S1 and the cyclization reaction in step S2 of the preparation of compound A5 are conventional conditions and operations in the art.

[0135] The following conditions and operations are particularly preferred in this invention:

[0136] When R 13 When the methyl group is used, in step S1 of preparing compound A5, the preferred method for preparing compound A7' is as follows: in a solvent, the compound AA5 is subjected to a hydrolysis ring-opening reaction to prepare compound A7'.

[0137] The solvent is preferably one or more of an acid and an alcohol. The acid may be hydrochloric acid. The alcohol may be one or more of methanol and ethanol. In a specific example of the present invention, the solvent is a mixture of hydrochloric acid and methanol.

[0138] The temperature of the hydrolysis ring-opening reaction can be a conventional reaction temperature for this type of reaction, such as room temperature. The temperature of the hydrolysis ring-opening reaction can be 10℃ to 30℃. It is understood that the temperature of the hydrolysis ring-opening reaction includes, but is not limited to, 10℃, 15℃, 20℃, 25℃, and 30℃.

[0139] The progress of the hydrolysis ring-opening reaction can be monitored using conventional monitoring methods in the art (e.g., LC-MS, TLC, HPLC, NMR, or GC), and the reaction endpoint is generally defined as the disappearance or cessation of reaction of compound AA5. The preferred hydrolysis ring-opening reaction time is 1 to 6 hours, for example, 4 hours.

[0140] In another aspect, the present invention also provides a method for preparing a compound of formula A5-P or an optical isomer thereof, comprising the following steps:

[0141] Compound A5-P was prepared by coupling compound A5 with compound Z3-1.

[0142]

[0143] Among them, R1~R2, R5~R7, m and R 13 The definition is as described above;

[0144] R Z Selected from H;

[0145] R 10 R 11 Each group is independently selected from -H, -F, -Cl, -Br, -I, hydroxyl, amino, nitro, cyano, and C. 1-6 Alkyl or C 1-6Alkoxy, the C 1-6 Alkyl and C 1-6 The alkoxy group can be optionally surrounded by 1, 2 or 3 R groups. b replace;

[0146] R 12 Each occurrence is independently selected from -H, -F, -Cl, -Br, -I, hydroxyl, amino, nitro, cyano, and C. 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl and C 1-6 The alkoxy group can be optionally surrounded by 1, 2 or 3 R groups. b replace;

[0147] R b Each occurrence is independently selected from -H, -F, -Cl, -Br, -I, -OH, -NH2, -CH3, -CF3, -C2H5, -CN, -SF5, -CHO, -COOH, or -C(=O)NH2;

[0148] n is selected from 0, 1, 2 or 3.

[0149] In another aspect of the present invention, the present invention also provides a method for preparing a compound of formula A5-P or an optical isomer thereof, comprising the following steps: coupling a compound of formula A5 with a compound of formula Z3 to prepare a compound of formula A5-P;

[0150]

[0151] Wherein, the Z3 compound is a compound of formula Z3-1 or formula Z3-2;

[0152]

[0153] The definitions of R1 to R2 are as described above; the definitions of R5 to R7 and m are as described above; R 13 The definition is as described above;

[0154] R Z Each occurrence is independently selected from H or C. 1-6 Alkyl, the C 1-6 Alkyl groups may be optionally surrounded by 1, 2, or 3 R's. b replace;

[0155] R 10 R 11 Each group is independently selected from -H, -F, -Cl, -Br, -I, hydroxyl, amino, nitro, cyano, and C. 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl and C 1-6 The alkoxy group can be optionally surrounded by 1, 2 or 3 R groups.b replace;

[0156] R 12 Each occurrence is independently selected from -H, -F, -Cl, -Br, -I, hydroxyl, amino, nitro, cyano, and C. 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl and C 1-6 The alkoxy group can be optionally surrounded by 1, 2 or 3 R groups. b replace;

[0157] R b Each occurrence is independently selected from -H, -F, -Cl, -Br, -I, -OH, -NH2, -CH3, -CF3, -C2H5, -CN, -SF5, -CHO, -COOH, or -C(=O)NH2;

[0158] n is selected from 0, 1, 2 or 3.

[0159] In some embodiments of the present invention, R 10 Preferred radicals include -H, -F, -Cl, -Br, or hydroxyl groups; and / or R. 11 Preferred hydroxyl groups are -H, -F, -Cl, -Br, or hydroxyl groups.

[0160] In this invention, the conditions and operations in the coupling reaction of the above steps are all conventional conditions and operations in the art.

[0161] In another aspect, the present invention also provides a compound of formula A5-P or an optical isomer thereof:

[0162]

[0163] Among them, R2, R5~R7, m, R 13 R 10 ~R 12 The definition of n is as described above.

[0164] In some embodiments of the present invention, the compound of formula A5-P is selected from...

[0165] In another aspect, the present invention also provides a method for preparing a compound of formula A6, a compound of formula D6, or an optical isomer thereof, comprising the following steps:

[0166] The compound of formula A5 is contacted with substance L and chiral resolution is performed to prepare compound of formula A6 or compound of formula D6.

[0167]

[0168] Among them, R1~R2, R5~R7, m, R 13 The definition is as described above;

[0169] The substance L is one or more selected from S-binaphthol phosphate, D-3-bromocamphor-10-sulfonic acid, D-(+)-camphorsulfonic acid, S-3,3'-bis(triphenylsilyl)binaphthol phosphonate, S-3,3'-bis(3,5-bistrifluoromethoxyphenyl)-1,1'-bi-(2-naphthol) phosphate, and S-3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthol-2,2'-bisphosphate.

[0170] Or one or more of the following: R-binaphthol phosphate, L-3-bromocamphor-10-sulfonic acid, L-(+)-camphor sulfonic acid, R-3,3'-bis(triphenylsilyl)binaphthol phosphonate, R-3,3'-bis(3,5-bistrifluoromethoxyphenyl)-1,1'-bi-(2-naphthol) phosphate and R-3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthol-2,2'-bisphosphate.

[0171] In some embodiments of the present invention, the substance L may be S-binaphthol phosphate.

[0172] In some embodiments of the present invention, the substance L is preferably R-binaphthol phosphate.

[0173] In some embodiments of the present invention, the chiral splitting includes the following steps:

[0174] S1. A salt-forming reaction is carried out between compound A5 and substance L to prepare a salt-type intermediate compound;

[0175] S2. The salt-type intermediate compound is reacted with a free reagent to prepare compound A6 or compound D6.

[0176] In this invention, the conditions and operations in the salt formation reaction in step S1 and the free reaction in step S2 are conventional conditions and operations in the art.

[0177] The following conditions and operations are particularly preferred in this invention:

[0178] In the chiral resolution step S1, the preferred method for preparing the salt-type intermediate compound is as follows: in a solvent, the compound of formula A5 and substance L are subjected to a salt-forming reaction to prepare the salt-type intermediate compound;

[0179] The solvent may be one or more ketone solvents and water. The ketone solvent may be acetone. In a specific example of the present invention, the solvent is a mixture of acetone and water.

[0180] The solvent is preferably one or more of anisole and methanol; methanol can also be replaced by ethanol, ethyl acetate, methyl acetate, propyl acetate, or isopropyl acetate. In a specific example of the present invention, the solvent is a mixture of anisole and methanol.

[0181] The molar ratio of the compound of formula A5 to the substance L is preferably 1:(0.6 to 1.6), including but not limited to 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, and 1:1.6.

[0182] The temperature of the salt-forming reaction can be a conventional reaction temperature for this type of reaction. The temperature of the salt-forming reaction can be 10℃ to 50℃. Further, the preferred temperature of the salt-forming reaction is 10℃ to 40℃. It is understood that the temperature of the salt-forming reaction includes, but is not limited to, 10℃, 25℃, 30℃, 35℃, and 40℃.

[0183] The salt-forming reaction can be monitored using conventional methods in the art (e.g., LC-MS, TLC, HPLC, NMR, or GC), generally with the disappearance or cessation of the reaction of the free compound of formula A5 and the satisfactory chiral result of the resolved compound as the reaction endpoint. The preferred salt-forming reaction time is 3 to 60 hours. Further, the preferred salt-forming reaction time is 3 to 48 hours, for example, 4 hours.

[0184] In the chiral resolution step S2, the preferred method for preparing the compound of formula A6 or formula D6 is as follows: in a solvent, the salt-type intermediate compound is reacted with a free reagent to prepare the compound of formula A6 or formula D6.

[0185] The free reagent is preferably an acid or a base. The base can be sodium hydroxide or triethylamine. In one specific example of the invention, the free reagent is a 30% sodium hydroxide solution. In another specific example of the invention, the free reagent is triethylamine.

[0186] The preferred molar ratio of the salt-type intermediate compound to the free reagent is 1:(0.5-1.5), including but not limited to 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, and 1:1.5.

[0187] The solvent is preferably a halogenated hydrocarbon solvent or an ester solvent. The halogenated hydrocarbon solvent can be dichloromethane, and the ester solvent can be ethyl acetate.

[0188] The temperature of the free reaction can be the conventional reaction temperature for this type of reaction.

[0189] In another aspect, the present invention also provides a compound of formula A6, a compound of formula D6, substance N, or an optical isomer thereof, wherein substance N comprises the compound of formula A6 and the compound of formula D6:

[0190]

[0191] Among them, R1~R2, R5~R7, m, R 13 The definition is as described above.

[0192] In some embodiments of the present invention, the compound of formula A6 is selected from...

[0193] In some embodiments of the present invention, the compound of formula D6 is selected from...

[0194] In some embodiments of the present invention, the substance N is selected from a mixture of any of the following groups: mixtures mixtures mixtures mixtures mixtures mixtures mixtures A mixture.

[0195] In another aspect, the present invention also provides a method for preparing a compound of formula A6-P, a compound of formula D6-P, or an optical isomer thereof, comprising the following steps:

[0196] The A5-P compound and substance L are contacted and chiral resolution is performed to prepare the A6-P compound or the D6-P compound.

[0197]

[0198] or

[0199] Compound A6-P or compound D6 is prepared by coupling compound Z3-1 with compound D6-P.

[0200]

[0201] Among them, R1~R2, R5~R7, m, R 10 ~R 12 n, R 13The definition is as described above;

[0202] R Z Selected from H;

[0203] The definition of substance L is as described above;

[0204] The steps and conditions for chiral splitting are as described above.

[0205] In another aspect, the present invention also provides a method for preparing a compound of formula A6-P, a compound of formula D6-P, or an optical isomer thereof, comprising the following steps:

[0206] The A5-P compound and substance L are contacted and chiral resolution is performed to prepare the A6-P compound or the D6-P compound.

[0207]

[0208] or

[0209] Compound A6-P or compound D6 is prepared by coupling compound Z3 with compound Z3.

[0210]

[0211]

[0212] Wherein, the Z3 compound is a compound of formula Z3-1 or formula Z3-2;

[0213]

[0214] R Z Each occurrence is independently selected from H or C. 1-6 Alkyl, the C 1-6 Alkyl groups may be optionally surrounded by 1, 2, or 3 R's. b replace;

[0215] R1~R2, R5~R7, m, R 10 ~R 12 n, R 13 The definition is as described above;

[0216] The definition of substance L is as described above;

[0217] The steps and conditions for chiral splitting are as described above.

[0218] The following conditions and operations are particularly preferred in this invention:

[0219] The preferred method for preparing the compound of formula A6-P is as follows: in a solvent, in the presence of a palladium catalyst, a ligand and a base, the compound of formula A6 is coupled with the compound of formula Z3 to prepare the compound of formula A6-P.

[0220] The molar ratio of the compound of formula A6 to the compound of formula Z3 is preferably 1:(0.9 to 5), including but not limited to 1:0.9, 1:1, 1:1.2, 1:1.4, 1:1.6, 1:1.8, 1:2, 1:3, 1:4, and 1:5.

[0221] The solvent is preferably one or more of 1,4-dioxane, DMSO, DMF, tetrahydrofuran, toluene, acetonitrile, and water;

[0222] The alkali is preferably one or more selected from dipotassium hydrogen phosphate, cesium carbonate, potassium carbonate, sodium carbonate, and triethylamine.

[0223] The molar ratio of the compound of formula A6 to the base is preferably 1:(1 to 6), including but not limited to 1:1, 1:2, 1:3, 1:4, 1:5, and 1:6;

[0224] The palladium catalyst is preferably palladium acetate;

[0225] The molar ratio of the compound of formula A6 to the palladium catalyst is preferably 1:(0.001 to 0.5), including but not limited to 1:0.001, 1:0.005, 1:0.01, 1:0.05, 1:0.1, 1:0.2, 1:0.3, 1:0.4, and 1:0.5.

[0226] The ligand is preferably triphenylphosphine;

[0227] The molar ratio of the compound of formula A6 to the ligand is preferably 1:(0.001 to 0.5), including but not limited to 1:0.001, 1:0.005, 1:0.01, 1:0.05, 1:0.1, 1:0.2, 1:0.3, 1:0.4, and 1:0.5.

[0228] The temperature of the coupling reaction can be a conventional reaction temperature for this type of reaction. The temperature of the coupling reaction can be 40℃ to 100℃, including but not limited to 40℃, 50℃, 60℃, 70℃, 80℃, 90℃, and 100℃.

[0229] The process of the coupling reaction can be monitored using conventional monitoring methods in the art (e.g., LC-MS, TLC, HPLC, NMR or GC), and the reaction endpoint is generally defined as the disappearance or cessation of reaction of compound A6.

[0230] In another aspect, the present invention also provides a compound of formula A6-P, a compound of formula D6-P, a substance M or an optical isomer thereof, wherein the substance M comprises the compound of formula A6-P and the compound of formula D6-P:

[0231]

[0232] Among them, R2, R5~R7, m, R 10 ~R 12 n, R 13 The definition is as described above.

[0233] In some embodiments of the present invention, the compound of formula A6-P is selected from...

[0234] In some embodiments of the present invention, the compound of formula D6-P is selected from...

[0235] In some embodiments of the present invention, the substance M is selected from a mixture of any of the following groups: mixtures mixtures mixtures A mixture.

[0236] In another aspect, the present invention also provides a method for preparing a compound of formula A7', its optical isomer, or a pharmacologically acceptable salt thereof, comprising the following steps:

[0237] The compound of formula A5 is subjected to a hydrolytic ring-opening reaction to prepare the compound of formula A7' or its pharmacologically acceptable salt;

[0238]

[0239] Among them, R1~R2, R5~R7, m, R 13 The definition is as described above.

[0240] In this invention, the conditions and operations in the hydrolysis ring-opening reaction in the above steps are all conventional conditions and operations in the art.

[0241] The following conditions and operations are particularly preferred in this invention:

[0242] The preferred method for preparing the compound of formula A7' or its pharmacologically acceptable salt is as follows: in a solvent, the compound of formula A5 is subjected to a hydrolysis ring-opening reaction to prepare the compound of formula A7' or its pharmacologically acceptable salt;

[0243] The solvent is preferably one or more of an acid and an alcohol. The acid may be hydrochloric acid. The alcohol may be one or more of methanol and ethanol. In a specific example of the present invention, the solvent is a mixture of hydrochloric acid and methanol.

[0244] The temperature of the hydrolysis ring-opening reaction can be a conventional reaction temperature for this type of reaction, such as room temperature. The temperature of the hydrolysis ring-opening reaction can be 10℃ to 30℃. It is understood that the temperature of the hydrolysis ring-opening reaction includes, but is not limited to, 10℃, 15℃, 20℃, 25℃, and 30℃.

[0245] The progress of the hydrolysis ring-opening reaction can be monitored using conventional monitoring methods in the art (e.g., LC-MS, TLC, HPLC, NMR, or GC), and the reaction endpoint is generally defined as the disappearance or cessation of reaction of compound A5. The preferred hydrolysis ring-opening reaction time is 1 to 6 hours, for example, 4 hours.

[0246] In some embodiments of the present invention, the compound of formula A7' is prepared by neutralization reaction with a salt of formula A7' that is pharmacologically acceptable to the compound.

[0247] In another aspect, the present invention also provides a method for preparing a compound of formula A7, its optical isomer, or a pharmacologically acceptable salt thereof, comprising the following steps:

[0248] Path 1: Hydrolyze and ring-open the compound of formula A6 to prepare the compound of formula A7 or its pharmacologically acceptable salt;

[0249]

[0250] or

[0251] Pathway 2: Contact the compound of formula A7' or its pharmacologically acceptable salt with a chiral acid to perform chiral resolution and prepare the compound of formula A7 or its pharmacologically acceptable salt;

[0252]

[0253] Among them, R1~R2, R5~R7, m, R 13 The definition is as described above.

[0254] In this invention, the conditions and operations in the hydrolysis ring-opening reaction and chiral resolution in the above steps are all conventional conditions and operations in the art.

[0255] The following conditions and operations are particularly preferred in this invention:

[0256] In path 1, the preferred method for preparing the compound of formula A7 or its pharmacologically acceptable salt is as follows: in a solvent, the compound of formula A6 is subjected to a hydrolysis ring-opening reaction to prepare the compound of formula A7 or its pharmacologically acceptable salt;

[0257] The solvent is preferably one or more of an acid and an alcohol. The acid may be hydrochloric acid. The alcohol may be one or more of methanol and ethanol. In a specific example of the present invention, the solvent is a mixture of hydrochloric acid and methanol.

[0258] The temperature of the hydrolysis ring-opening reaction can be a conventional reaction temperature for this type of reaction, such as room temperature. The temperature of the hydrolysis ring-opening reaction can be 10℃ to 30℃. It is understood that the temperature of the hydrolysis ring-opening reaction includes, but is not limited to, 10℃, 15℃, 20℃, 25℃, and 30℃.

[0259] The progress of the hydrolysis ring-opening reaction can be monitored using conventional monitoring methods in the art (e.g., LC-MS, TLC, HPLC, NMR, or GC), and the reaction endpoint is generally defined as the disappearance or cessation of reaction of compound A6. The preferred hydrolysis ring-opening reaction time is 1 to 6 hours, for example, 4 hours.

[0260] In path 2, the preferred method for preparing the compound of formula A7 or its pharmacologically acceptable salt is as follows: in a solvent, the compound of formula A7' or its pharmacologically acceptable salt is contacted with a chiral acid to perform chiral resolution, thereby preparing the compound of formula A7 or its pharmacologically acceptable salt, or the compound of formula D7 or its pharmacologically acceptable salt.

[0261] The chiral acid is preferably S-binaphthol phosphate or R-binaphthol phosphate. It is understood that in this invention, the chiral acid can be resolved in different systems to obtain a compound of formula A7 or a pharmacologically acceptable salt thereof, or a compound of formula D7 or a pharmacologically acceptable salt thereof. Optionally, the chiral acid is S-binaphthol phosphate. More preferably, the chiral acid is R-binaphthol phosphate.

[0262] In some embodiments of the present invention, the compound of formula A7 is prepared by neutralization reaction of a salt of formula A7 that is pharmacologically acceptable to the compound.

[0263] In another aspect, the present invention also provides a method for preparing a compound of formula A7-P, its optical isomer, or a pharmacologically acceptable salt thereof, comprising the following steps:

[0264] Path 1: Hydrolyze and ring-open the compound of formula A6-P to prepare the compound of formula A7-P or its pharmacologically acceptable salt;

[0265]

[0266] or

[0267] Pathway 2: Prepare compound A7-P or its pharmacologically acceptable salt by coupling compound A7 or its pharmacologically acceptable salt with compound Z3-1;

[0268]

[0269] Among them, R Z Selected from H; R2, R5~R7, m, R 10 ~R 12 n, R 13 The definition is as described above.

[0270] In another aspect, the present invention also provides a method for preparing a compound of formula A7-P, its optical isomer, or a pharmacologically acceptable salt thereof, comprising the following steps:

[0271] Path 1: Hydrolyze and ring-open the compound of formula A6-P to prepare the compound of formula A7-P or its pharmacologically acceptable salt;

[0272]

[0273] or

[0274] Pathway 2: A compound of formula A7 or its pharmacologically acceptable salt is coupled with a compound of formula Z3 to prepare a compound of formula A7-P or its pharmacologically acceptable salt.

[0275]

[0276] Wherein, the Z3 compound is a compound of formula Z3-1 or formula Z3-2;

[0277]

[0278] R2, R5~R7, m, R 10 ~R 12 n, R Z R 13 The definition is as described above.

[0279] In this invention, the conditions and operations in the hydrolysis ring-opening reaction in path 1 and the coupling reaction in path 2 are conventional conditions and operations in the art.

[0280] In some embodiments of the present invention, the conditions and operation of the hydrolysis ring-opening reaction are as described above.

[0281] The following conditions and operations are particularly preferred in this invention:

[0282] The preferred method for preparing the compound of formula A7-P is as follows: in a solvent, the compound of formula A6-P is subjected to a hydrolysis ring-opening reaction to prepare the compound of formula A7-P or its pharmacologically acceptable salt;

[0283] The solvent is preferably one or more selected from ethanol hydrochloride, methanol hydrochloride, ethyl hydrochloride, and aqueous hydrochloric acid solution.

[0284] The temperature of the hydrolysis ring-opening reaction can be a conventional reaction temperature for this type of reaction, such as room temperature.

[0285] The progress of the hydrolysis ring-opening reaction can be monitored using conventional monitoring methods in the art (e.g., LC-MS, TLC, HPLC, NMR or GC), and the reaction endpoint is generally defined as the disappearance or cessation of reaction of compound A6-P.

[0286] In another aspect, the present invention also provides a method for preparing a compound of formula A7'-P, its optical isomer, or a pharmacologically acceptable salt thereof, comprising the following steps:

[0287] Path 1: Hydrolyze and ring-open the compound of formula A5-P to prepare the compound of formula A7'-P or its pharmacologically acceptable salt;

[0288]

[0289] or

[0290] Pathway 2: Prepare compound A7'-P or its pharmacologically acceptable salt by coupling compound A7' or Z3-1;

[0291]

[0292] Among them, R Z Selected from H; R2, R5~R7, m, R 10 ~R 12 n, R 13 The definition is as described above.

[0293] In another aspect, the present invention also provides a method for preparing a compound of formula A7'-P, its optical isomer, or a pharmacologically acceptable salt thereof, comprising the following steps:

[0294] Path 1: Hydrolyze and ring-open the compound of formula A5-P to prepare the compound of formula A7'-P or its pharmacologically acceptable salt;

[0295]

[0296] or

[0297] Pathway 2: Prepare compound A7'-P or its pharmacologically acceptable salt by coupling compound A7' with compound Z3;

[0298]

[0299] Wherein, the Z3 compound is a compound of formula Z3-1 or formula Z3-2;

[0300]

[0301] R2, R5~R7, m, R 10 ~R 12 n, R 13 The definition is as described above.

[0302] In this invention, the conditions and operations in the hydrolysis ring-opening reaction in path 1 and the coupling reaction in path 2 are conventional conditions and operations in the art.

[0303] In some embodiments of the present invention, the conditions and operation of the hydrolysis ring-opening reaction are as described above.

[0304] In another aspect, the present invention also provides a compound of formula A7, a compound of formula A7', a compound of formula A7-P, a compound of formula A7'-P, an optical isomer thereof, or a pharmacologically acceptable salt thereof:

[0305]

[0306] Among them, R1~R2, R5~R7, m, R 10 ~R 12 The definition of n is as described above.

[0307] In some embodiments of the present invention, the compound of formula A7 is selected from...

[0308] In some embodiments of the present invention, the compound of formula A7' is selected from...

[0309] In some embodiments of the present invention, the compound of formula A7-P is selected from...

[0310] In some embodiments of the present invention, the compound of formula A7'-P is preferably...

[0311] In another aspect, the present invention also provides a method for preparing a compound of formula A7-M, its optical isomer, or a pharmacologically acceptable salt thereof, comprising the following steps:

[0312] A compound of formula A7 or its pharmacologically acceptable salt is contacted with halomethane to carry out a nucleophilic substitution reaction to prepare a compound of formula A7-M or its pharmacologically acceptable salt.

[0313]

[0314] The definitions of R1~R2, R5~R7 and m are as described above.

[0315] In this invention, the conditions and operations in the nucleophilic substitution reactions in the above steps are all conventional conditions and operations in the art.

[0316] In another aspect, the present invention also provides a method for preparing a compound of formula A7-M, its optical isomer, or a pharmacologically acceptable salt thereof, comprising the following steps:

[0317] The compound of formula A7 or its pharmacologically acceptable salt is contacted with a carbonyl-containing compound to carry out a ring-closure reaction, thereby preparing the compound of formula A7-intermediate 1 or its pharmacologically acceptable salt.

[0318] The compound of formula A7-intermediate 1 or its pharmacologically acceptable salt is contacted with a methylating agent to carry out a methylation reaction, thereby preparing compound of formula A7-intermediate 2 or its pharmacologically acceptable salt;

[0319] The compound of formula A7-intermediate 2 or its pharmacologically acceptable salt is hydrolyzed to prepare compound of formula A7-M or its pharmacologically acceptable salt.

[0320]

[0321] The definitions of R1~R2, R5~R7 and m are as described above.

[0322] The following conditions and operations are particularly preferred in this invention:

[0323] The preferred method for preparing the compound of formula A7-intermediate 1 or its pharmacologically acceptable salt is as follows: in a solvent, in the presence of a base, the compound of formula A7 or its pharmacologically acceptable salt is contacted with a carbonyl-containing compound to carry out a ring-closing reaction to prepare the compound of formula A7-intermediate 1 or its pharmacologically acceptable salt.

[0324] The carbonyl compound may be triphosgene or carbon dioxide; the carbonyl compound is preferably triphosgene.

[0325] The molar ratio of the compound of formula A7 to the carbonyl-containing compound is preferably 1:(0.5 to 1.5), including but not limited to 1:0.5, 1:0.8, 1:0.9, 1:1, 1:1.1, 1:1.2, and 1:1.5.

[0326] The solvent is preferably one or more selected from tetrahydrofuran, acetonitrile, dichloromethane, chloroform, methyl tert-butyl ether and 1,4-dioxane;

[0327] Preferably, the base is one or more selected from N,N-diisopropylethylamine, pyridine, triethylamine and cesium carbonate;

[0328] The molar ratio of the compound of formula A7 to the base is preferably 1:(1.5 to 8), including but not limited to 1:1.5, 1:2, 1:3, 1:4, 1:5, 1:5.5, 1:6, 1:6.5, 1:7, and 1:8.

[0329] The ring-closing reaction temperature can be a conventional reaction temperature for this type of reaction. The ring-closing reaction temperature can be -30℃ to 30℃. It is understood that the ring-closing reaction temperature includes, but is not limited to, -30℃, -25℃, -20℃, -15℃, -10℃, 0℃, 10℃, 15℃, 20℃, 25℃, and 30℃.

[0330] The progress of the ring-closing reaction can be monitored using conventional monitoring methods in the art (e.g., LC-MS, TLC, HPLC, NMR or GC), and the reaction endpoint is generally defined as the disappearance or cessation of reaction of compound A7.

[0331] The preferred method for preparing the compound of formula A7-intermediate 2 or its pharmacologically acceptable salt is as follows: in a solvent, in the presence of a base, the compound of formula A7-intermediate 1 or its pharmacologically acceptable salt is contacted with a methylating agent to carry out a methylation reaction, thereby preparing the compound of formula A7-intermediate 2 or its pharmacologically acceptable salt.

[0332] The methylating agent is preferably one or more of halomethane and formaldehyde; further, the halomethane is preferably iodomethane;

[0333] The molar ratio of the compound of formula A7-intermediate 1 to the methylating agent is preferably 1:(0.9-6), including but not limited to 1:0.9, 1:1, 1:2, 1:3, 1:4, 1:5, and 1:6.

[0334] The solvent is preferably one or more selected from DMF, DMSO, NMP, acetonitrile, and tetrahydrofuran;

[0335] The alkali is preferably one or more selected from cesium carbonate, potassium carbonate, sodium carbonate, potassium phosphate, and DBU.

[0336] The molar ratio of the compound of formula A7-intermediate 1 to the base is preferably 1:(0.7-6), including but not limited to 1:0.7, 1:0.8, 1:0.9, 1:1, 1:2, 1:3, 1:4, 1:5, and 1:6.

[0337] The temperature of the methylation reaction can be the conventional reaction temperature for this type of reaction, such as room temperature;

[0338] The progress of the methylation reaction can be monitored using conventional monitoring methods in the art (e.g., LC-MS, TLC, HPLC, NMR or GC), and the reaction endpoint is generally defined as the disappearance or cessation of reaction of compound A7-intermediate 1.

[0339] The preferred method for preparing the compound of formula A7-M or its pharmacologically acceptable salt is as follows: in a solvent, in the presence of a base, the compound of formula A7-intermediate 2 or its pharmacologically acceptable salt is subjected to a hydrolysis reaction to prepare the compound of formula A7-M or its pharmacologically acceptable salt.

[0340] The solvent is preferably one or more of tetrahydrofuran, methanol, and ethanol;

[0341] The alkali is preferably one or more selected from lithium hydroxide, sodium hydroxide, and potassium hydroxide;

[0342] Wherein, the molar ratio of the compound of formula A7-intermediate 2 to the base is preferably 1:(1 to 8), including but not limited to 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, and 1:8;

[0343] The temperature of the hydrolysis reaction can be the conventional reaction temperature for this type of reaction, such as room temperature;

[0344] The progress of the hydrolysis reaction can be monitored using conventional monitoring methods in the art (e.g., LC-MS, TLC, HPLC, NMR or GC), and the reaction endpoint is generally defined as the disappearance or cessation of reaction of compound A7-intermediate 2.

[0345] In another aspect, the present invention also provides a method for preparing a compound of formula A7'-M, its optical isomer, or a pharmacologically acceptable salt thereof, comprising the following steps:

[0346] A compound of formula A7' or its pharmacologically acceptable salt is contacted with halomethane to carry out a nucleophilic substitution reaction to prepare a compound of formula A7'-M or its pharmacologically acceptable salt;

[0347]

[0348] The definitions of R1~R2, R5~R7 and m are as described above.

[0349] In this invention, the conditions and operations in the nucleophilic substitution reactions in the above steps are all conventional conditions and operations in the art.

[0350] In another aspect, the present invention also provides a method for preparing a compound of formula A7'-M, its optical isomer, or a pharmacologically acceptable salt thereof, comprising the following steps:

[0351] The compound of formula A7' or its pharmacologically acceptable salt is contacted with a carbonyl-containing compound to carry out a ring-closure reaction, thereby preparing the compound of formula A7'-intermediate 1 or its pharmacologically acceptable salt;

[0352] The A7'-intermediate 1 compound or its pharmacologically acceptable salt is contacted with a methylating agent to carry out a methylation reaction, thereby preparing the A7'-intermediate 2 compound or its pharmacologically acceptable salt;

[0353] The compound of formula A7'-intermediate 2 or its pharmacologically acceptable salt is hydrolyzed to prepare compound of formula A7'-M or its pharmacologically acceptable salt.

[0354]

[0355] The definitions of R1~R2, R5~R7 and m are as described above.

[0356] In this invention, the conditions and operations in the cyclization reaction, methylation reaction and hydrolysis reaction in the above steps are all conventional conditions and operations in the art.

[0357] In another aspect, the present invention also provides a method for preparing a compound of formula A7-PM, its optical isomer, or a pharmacologically acceptable salt thereof, comprising the following steps:

[0358] A7-P compound or its pharmacologically acceptable salt is prepared by contacting halomethane with a nucleophilic substitution reaction to carry out a nucleophilic substitution reaction.

[0359]

[0360] Among them, R2, R5~R7, m, R 10 ~R 12 The definition of n is as described above.

[0361] In this invention, the conditions and operations in the nucleophilic substitution reactions in the above steps are all conventional conditions and operations in the art.

[0362] In another aspect, the present invention also provides a method for preparing a compound of formula A7-PM, its optical isomer, or a pharmacologically acceptable salt thereof, comprising the following steps:

[0363] The compound of formula A7-P or its pharmacologically acceptable salt is contacted with a carbonyl-containing compound to carry out a ring-closure reaction, thereby preparing the compound of formula A7-P-intermediate 1 or its pharmacologically acceptable salt.

[0364] The compound of formula A7-P-intermediate 1 or its pharmacologically acceptable salt is contacted with a methylating agent to carry out a methylation reaction, thereby preparing compound of formula A7-P-intermediate 2 or its pharmacologically acceptable salt.

[0365] The compound of formula A7-P-intermediate 2 or its pharmacologically acceptable salt is prepared by hydrolysis.

[0366]

[0367] Among them, R2, R5~R7, m, R 10 ~R 12 The definition of n is as described above.

[0368] In this invention, the conditions and operations in the cyclization reaction, methylation reaction and hydrolysis reaction in the above steps are all conventional conditions and operations in the art.

[0369] The following conditions and operations are particularly preferred in this invention:

[0370] The preferred method for preparing the compound of formula A7-P-intermediate 1 or its pharmacologically acceptable salt is as follows: in a solvent, in the presence of a base, the compound of formula A7-P or its pharmacologically acceptable salt is contacted with a carbonyl-containing compound to carry out a ring-closing reaction, thereby preparing the compound of formula A7-P-intermediate 1 or its pharmacologically acceptable salt.

[0371] The carbonyl compound may be triphosgene or carbon dioxide; the carbonyl compound is preferably triphosgene.

[0372] The molar ratio of the compound of formula A7-P to the carbonyl-containing compound is preferably 1:(0.5 to 1.5), including but not limited to 1:0.5, 1:0.8, 1:0.9, 1:1, 1:1.1, 1:1.2, and 1:1.5.

[0373] The solvent is preferably one or more selected from tetrahydrofuran, acetonitrile, dichloromethane, chloroform, methyl tert-butyl ether and 1,4-dioxane;

[0374] Preferably, the base is one or more selected from N,N-diisopropylethylamine, pyridine, triethylamine and cesium carbonate;

[0375] The molar ratio of the compound of formula A7-P to the base is preferably 1:(1.5-8), including but not limited to 1:1.5, 1:2, 1:3, 1:4, 1:5, 1:5.5, 1:6, 1:6.5, 1:7, and 1:8.

[0376] The ring-closing reaction temperature can be a conventional reaction temperature for this type of reaction. The ring-closing reaction temperature can be -30℃ to 30℃. It is understood that the ring-closing reaction temperature includes, but is not limited to, -30℃, -25℃, -20℃, -15℃, -10℃, 0℃, 10℃, 15℃, 20℃, 25℃, and 30℃.

[0377] The progress of the ring-closing reaction can be monitored using conventional monitoring methods in the art (e.g., LC-MS, TLC, HPLC, NMR or GC), and the reaction endpoint is generally defined as the disappearance or cessation of the reaction of compound A7-P.

[0378] The preferred method for preparing the compound of formula A7-P-intermediate 2 or its pharmacologically acceptable salt is as follows: in a solvent, in the presence of a base, the compound of formula A7-P-intermediate 1 or its pharmacologically acceptable salt is contacted with a methylating agent to carry out a methylation reaction, thereby preparing the compound of formula A7-P-intermediate 2 or its pharmacologically acceptable salt.

[0379] The methylating agent is preferably one or more of halomethane and formaldehyde; further, the halomethane is preferably iodomethane;

[0380] The molar ratio of the compound of formula A7-P-intermediate 1 to the methylating agent is preferably 1:(0.9-6), including but not limited to 1:0.9, 1:1, 1:2, 1:3, 1:4, 1:5, and 1:6.

[0381] The solvent is preferably one or more selected from DMF, DMSO, NMP, acetonitrile, and tetrahydrofuran;

[0382] The alkali is preferably one or more selected from cesium carbonate, potassium carbonate, sodium carbonate, potassium phosphate, and DBU.

[0383] The molar ratio of the compound of formula A7-P-intermediate 1 to the base is preferably 1:(0.7-6), including but not limited to 1:0.7, 1:0.8, 1:0.9, 1:1, 1:2, 1:3, 1:4, 1:5, and 1:6.

[0384] The temperature of the methylation reaction can be the conventional reaction temperature for this type of reaction, such as room temperature;

[0385] The progress of the methylation reaction can be monitored using conventional monitoring methods in the art (e.g., LC-MS, TLC, HPLC, NMR or GC), and the reaction endpoint is generally defined as the disappearance or cessation of reaction of compound A7-P-intermediate 1.

[0386] Where R 10 and / or R 11 When the hydroxyl group is present, after contacting the compound of formula A7-P-intermediate 1 or its pharmacologically acceptable salt with a methylating agent to carry out a methylation reaction, the following steps are further included: subjecting the product of the methylation reaction to a demethylating agent to carry out a deprotection reaction to prepare compound of formula A7-P-intermediate 2 or its pharmacologically acceptable salt.

[0387] Furthermore, the demethylating agent is preferably one or more selected from aqueous solutions of hydrogen bromide, boron trichloride, and hydrochloric acid.

[0388] Furthermore, the temperature of the deprotection reaction can be a conventional reaction temperature for this type of reaction. The temperature of the deprotection reaction can be 80℃ to 120℃, including but not limited to 80℃, 85℃, 90℃, 95℃, 100℃, 105℃, 110℃, 115℃, and 120℃.

[0389] The preferred method for preparing the compound of formula A7-PM or its pharmacologically acceptable salt is as follows: in a solvent, in the presence of a base, the compound of formula A7-P-intermediate 2 or its pharmacologically acceptable salt is subjected to a hydrolysis reaction to prepare the compound of formula A7-PM or its pharmacologically acceptable salt.

[0390] The solvent is preferably one or more of tetrahydrofuran, methanol, and ethanol;

[0391] The alkali is preferably one or more selected from lithium hydroxide, sodium hydroxide, and potassium hydroxide;

[0392] Wherein, the molar ratio of the compound of formula A7-intermediate 2 to the base is preferably 1:(1 to 8), including but not limited to 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, and 1:8;

[0393] The temperature of the hydrolysis reaction can be the conventional reaction temperature for this type of reaction, such as room temperature;

[0394] The progress of the hydrolysis reaction can be monitored using conventional monitoring methods in the art (e.g., LC-MS, TLC, HPLC, NMR or GC), and the reaction endpoint is generally defined as the disappearance or cessation of reaction of compound A7-P-intermediate 2.

[0395] In another aspect, the present invention also provides a method for preparing a compound of formula A7-PM, its optical isomer, or a pharmacologically acceptable salt thereof, comprising the following steps:

[0396] The compound of formula A7 or its pharmacologically acceptable salt is contacted with a carbonyl-containing compound to carry out a ring-closure reaction, thereby preparing the compound of formula A7-PM-intermediate 1 or its pharmacologically acceptable salt.

[0397] The compound of formula A7-PM-intermediate 1 or its pharmacologically acceptable salt is contacted with a methylating agent to carry out a methylation reaction, thereby preparing compound of formula A7-PM-intermediate 2 or its pharmacologically acceptable salt;

[0398] Compound A7-PM-intermediate 2 or its pharmacologically acceptable salt is coupled with compound Z3 to prepare compound A7-PM-intermediate 3.

[0399] The compound of formula A7-PM-intermediate 3 or its pharmacologically acceptable salt is prepared by hydrolysis.

[0400]

[0401] Wherein, the Z3 compound is a compound of formula Z3-1 or formula Z3-2;

[0402]

[0403] R1~R2, R5~R7, m, R 10 ~R 12 R Z The definitions of and n are as described above.

[0404] In this invention, the conditions and operations in the cyclization reaction, methylation reaction, coupling reaction, and hydrolysis reaction in the above steps are all conventional conditions and operations in the art.

[0405] The following conditions and operations are particularly preferred in this invention:

[0406] The preferred method for preparing the compound of formula A7-PM-intermediate 1 or its pharmacologically acceptable salt is as follows: in a solvent, in the presence of a base, the compound of formula A7 or its pharmacologically acceptable salt is contacted with a carbonyl-containing compound to carry out a ring-closing reaction to prepare the compound of formula A7-PM-intermediate 1 or its pharmacologically acceptable salt.

[0407] The carbonyl compound may be selected from triphosgene or carbon dioxide, preferably triphosgene;

[0408] The molar ratio of the compound of formula A7 to the carbonyl-containing compound is preferably 1:(0.5 to 1.5), including but not limited to 1:0.5, 1:0.8, 1:0.9, 1:1, 1:1.1, 1:1.2, and 1:1.5.

[0409] The solvent is preferably one or more selected from tetrahydrofuran, acetonitrile, dichloromethane, chloroform, methyl tert-butyl ether and 1,4-dioxane;

[0410] Preferably, the base is one or more selected from N,N-diisopropylethylamine, pyridine, triethylamine and cesium carbonate;

[0411] The molar ratio of the compound of formula A7-P to the base is preferably 1:(1.5-8), including but not limited to 1:1.5, 1:2, 1:3, 1:4, 1:5, 1:5.5, 1:6, 1:6.5, 1:7, and 1:8.

[0412] The ring-closing reaction temperature can be a conventional reaction temperature for this type of reaction. The ring-closing reaction temperature can be -30℃ to 30℃. It is understood that the ring-closing reaction temperature includes, but is not limited to, -30℃, -25℃, -20℃, -15℃, -10℃, 0℃, 10℃, 15℃, 20℃, 25℃, and 30℃.

[0413] The progress of the ring-closing reaction can be monitored using conventional monitoring methods in the art (e.g., LC-MS, TLC, HPLC, NMR or GC), and the reaction endpoint is generally defined as the disappearance or cessation of reaction of compound A7.

[0414] The preferred method for preparing the compound of formula A7-PM-intermediate 2 or its pharmacologically acceptable salt is as follows: in a solvent, in the presence of a base, the compound of formula A7-PM-intermediate 1 or its pharmacologically acceptable salt is contacted with a methylating agent to carry out a methylation reaction, thereby preparing the compound of formula A7-PM-intermediate 2 or its pharmacologically acceptable salt.

[0415] The methylating agent may be selected from one or more of halomethane and formaldehyde, wherein the halomethane is preferably iodomethane;

[0416] The molar ratio of the compound of formula A7-P-intermediate 1 to the methylating agent is preferably 1:(0.9-6), including but not limited to 1:0.9, 1:1, 1:2, 1:3, 1:4, 1:5, and 1:6.

[0417] The solvent is preferably one or more selected from DMF, DMSO, NMP, acetonitrile, and tetrahydrofuran;

[0418] The alkali is preferably one or more selected from cesium carbonate, potassium carbonate, sodium carbonate, potassium phosphate, and DBU.

[0419] The molar ratio of the compound of formula A7-P-intermediate 1 to the base is preferably 1:(0.7-6), including but not limited to 1:0.7, 1:0.8, 1:0.9, 1:1, 1:2, 1:3, 1:4, 1:5, and 1:6.

[0420] The temperature of the methylation reaction can be the conventional reaction temperature for this type of reaction, such as room temperature;

[0421] The progress of the methylation reaction can be monitored using conventional monitoring methods in the art (e.g., LC-MS, TLC, HPLC, NMR or GC), and the reaction endpoint is generally defined as the disappearance or cessation of reaction of compound A7-PM-intermediate 1.

[0422] The preferred method for preparing the compound of formula A7-PM-intermediate 3 or its pharmacologically acceptable salt is as follows: in a solvent, in the presence of a palladium catalyst, a ligand and a base, the compound of formula A7-PM-intermediate 2 is coupled with the compound of formula Z3 to prepare the compound of formula A7-PM-intermediate 3.

[0423] The molar ratio of the compound of formula A7-PM-intermediate 2 to the compound of formula Z3 is preferably 1:(0.9-5), including but not limited to 1:0.9, 1:1, 1:1.2, 1:1.4, 1:1.6, 1:1.8, 1:2, 1:3, 1:4, and 1:5.

[0424] The solvent is preferably one or more of 1,4-dioxane, DMSO, DMF, tetrahydrofuran, toluene, acetonitrile, and water;

[0425] The base is selected from one or more of dipotassium hydrogen phosphate, cesium carbonate, potassium carbonate, sodium carbonate, and triethylamine;

[0426] The molar ratio of the compound of formula A7-PM-intermediate 2 to the base is preferably 1:(1 to 6), including but not limited to 1:1, 1:2, 1:3, 1:4, 1:5, and 1:6;

[0427] The palladium catalyst is preferably palladium acetate;

[0428] The molar ratio of the compound of formula A7-PM-intermediate 2 to the palladium catalyst is preferably 1:(0.005~0.5), including but not limited to 1:0.005, 1:0.01, 1:0.01, 1:0.05, 1:0.1, 1:0.2, 1:0.3, 1:0.4, and 1:0.5.

[0429] The ligand is preferably triphenylphosphine;

[0430] The preferred molar ratio of the compound of formula A7-PM-intermediate 2 to the ligand is 1:(0.005~0.5), including but not limited to 1:0.005, 1:0.01, 1:0.05, 1:0.1, 1:0.2, 1:0.3, 1:0.4, and 1:0.5.

[0431] The temperature of the coupling reaction can be a conventional reaction temperature for this type of reaction. The temperature of the coupling reaction can be 40℃ to 100℃, including but not limited to 40℃, 50℃, 60℃, 70℃, 80℃, 90℃, and 100℃.

[0432] The process of the coupling reaction can be monitored using conventional monitoring methods in the art (e.g., LC-MS, TLC, HPLC, NMR or GC), and the reaction endpoint is generally defined as the disappearance or cessation of reaction of compound A7-PM-intermediate 2.

[0433] The preferred method for preparing the compound of formula A7-PM or its pharmacologically acceptable salt is as follows: in a solvent, in the presence of an alkali, the compound of formula A7-PM-intermediate 3 or its pharmacologically acceptable salt is subjected to a hydrolysis reaction to prepare the compound of formula A7-PM or its pharmacologically acceptable salt.

[0434] The solvent is preferably one or more of tetrahydrofuran, methanol, and ethanol;

[0435] The alkali is preferably one or more selected from lithium hydroxide, sodium hydroxide, and potassium hydroxide;

[0436] The molar ratio of the compound of formula A7-PM-intermediate 3 to the base is preferably 1:(1 to 8), including but not limited to 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, and 1:8.

[0437] The temperature of the hydrolysis reaction can be the conventional reaction temperature for this type of reaction, such as room temperature;

[0438] The progress of the hydrolysis reaction can be monitored using conventional monitoring methods in the art (e.g., LC-MS, TLC, HPLC, NMR or GC), and the reaction endpoint is generally defined as the disappearance or cessation of reaction of compound A7-PM-intermediate 3.

[0439] In another aspect, the present invention also provides a method for preparing a compound of formula A7'-PM, its optical isomer, or a pharmacologically acceptable salt thereof, comprising the following steps:

[0440] A7'-P compound or its pharmacologically acceptable salt is prepared by contacting halomethane with a nucleophilic substitution reaction to carry out a nucleophilic substitution reaction.

[0441]

[0442] Among them, R2, R5~R7, m, R 10 ~R 12 The definition of n is as described above.

[0443] In this invention, the conditions and operations in the nucleophilic substitution reactions in the above steps are all conventional conditions and operations in the art.

[0444] In another aspect, the present invention also provides a method for preparing a compound of formula A7'-PM, its optical isomer, or a pharmacologically acceptable salt thereof, comprising the following steps:

[0445] The compound of formula A7'-P or its pharmacologically acceptable salt is contacted with a carbonyl-containing compound to carry out a ring-closure reaction, thereby preparing the compound of formula A7'-P-intermediate 1 or its pharmacologically acceptable salt.

[0446] The compound of formula A7'-P-intermediate 1 or its pharmacologically acceptable salt is contacted with a methylating agent to carry out a methylation reaction, thereby preparing compound of formula A7'-P-intermediate 2 or its pharmacologically acceptable salt;

[0447] The compound of formula A7'-P-intermediate 2 or its pharmacologically acceptable salt is prepared by hydrolysis.

[0448]

[0449] Among them, R2, R5~R7, m, R 10 ~R 12 The definition of n is as described above.

[0450] In this invention, the conditions and operations in the cyclization reaction, methylation reaction and hydrolysis reaction in the above steps are all conventional conditions and operations in the art.

[0451] In another aspect, the present invention also provides a compound of formula A7-M, a compound of formula A7'-M, a compound of formula A7-PM, a compound of formula A7'-PM, an optical isomer thereof, or a pharmacologically acceptable salt thereof:

[0452]

[0453] Among them, R1~R2, R5~R7, m, R 10 ~R 12 The definition of n is as described above.

[0454] In some embodiments of the present invention, the compound of formula A7-M is selected from...

[0455] In some embodiments of the present invention, the compound of formula A7'-M is selected from...

[0456] In some embodiments of the present invention, the compound of formula A7-PM is selected from...

[0457] In some embodiments of the present invention, the compound of formula A7'-PM is selected from...

[0458] In another aspect, the present invention also provides a method for preparing a compound of formula AA7, a compound of formula AA7', a compound of formula AA7-P, a compound of formula AA7'-P, a compound of formula AA7-M, a compound of formula AA7'-M, a compound of formula AA7-PM, a compound of formula AA7'-PM, an optical isomer thereof, or a pharmacologically acceptable salt thereof, comprising the following steps:

[0459] Compounds of formula A7, A7', A7-P, A7'-P, A7-M, A7'-M, A7-PM, or A7'-PM are prepared by subjecting compounds of formula A7, A7'-P, A7'-P, A7-M, A7'-M, A7-PM, or A7'-PM to hydroxyl protection reactions.

[0460]

[0461] Among them, R1~R2, R5~R7, m, R 10 ~R 12 The definition of n is as described above;

[0462] R 14-O-(S=O)2-R 15 -OC(=O)R 16 or -OR 17 ;

[0463] R 15 Selected from methyl or phenyl, wherein the methyl or phenyl group is optionally surrounded by 1, 2 or 3 R groups. d replace;

[0464] R 16 Selected from methyl or phenyl, wherein the methyl or phenyl group is optionally surrounded by 1, 2 or 3 R groups. d replace;

[0465] R 17 Selected from hydroxyl protecting groups;

[0466] R d Each time it appears, it is independently selected from H, F, methyl, or nitro.

[0467] In some embodiments of the present invention, the hydroxyl protecting group is a group used in the field of organic chemistry to protect hydroxyl groups, such as R. 17 It can be TBS, MOM or THP.

[0468] In some embodiments of the present invention, R 14 Preferred options are -O-TBS, -O-MOM, -OTs, -Oms, -OAc, or -OBz.

[0469] In this invention, the conditions and operations in the hydroxyl protection reaction in the above steps are all conventional conditions and operations in the art.

[0470] In another aspect, the present invention also provides a compound of formula AA7, a compound of formula AA7', a compound of formula AA7-P, a compound of formula AA7'-P, a compound of formula AA7-M, a compound of formula AA7'-M, a compound of formula AA7-PM, a compound of formula AA7'-PM, an optical isomer thereof, or a pharmacologically acceptable salt thereof:

[0471]

[0472] Among them, R1~R2, R5~R7, m, R 10 ~R 12 n, R 14 The definition is as described above;

[0473] In some embodiments of the present invention, R 14 Preferred options are -O-TBS, -O-MOM, -OTs, -Oms, -OAc, or -OBz.

[0474] In another aspect of the invention, the invention also provides the use of compound Z4 in the preparation of compounds of formula A8, A8', A8-P, A8'-P, A8-M, A8'-M, A8-PM, A8'-PM, A9, A9', A9-P, A9'-P, A9-M, A9'-M, A9-PM, A9'-PM, their optical isomers, or their pharmacologically acceptable salts.

[0475]

[0476]

[0477] Among them, R1~R2, R5~R7, m, R 10 ~R 12 The definition of n is as described above;

[0478] when When the dashed line represents a single bond, Y is CH(R9), Z is CH2, and W is selected from N(R8);

[0479] when When the dashed line in the diagram is absent, Y is a protecting group of H, R8, or hydroxyl, Z is H, and W is selected from NH or O.

[0480] R8 is selected from an amino protecting group, Ns, acryloyl group, or 3-chloropropionyl group;

[0481] R9 is selected from -H, -F, -Cl, -Br, -I, hydroxyl, amino, nitro, cyano, C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl and C 1-6 The alkoxy group can be optionally surrounded by 1, 2 or 3 R groups. c replace;

[0482] R c Each occurrence is independently selected from -H, -F, -Cl, -Br, -I, -OH, -NH2, -CH3, -CF3, -C2H5, -CN, -SF5, -CHO, -COOH, or -C(=O)NH2.

[0483] In some embodiments of the present invention, R9 is preferably -H, -F, -Cl, -Br, methyl, ethyl, or propyl.

[0484] In some embodiments of the present invention, the amino protecting group is a group used in the field of organic chemistry to protect amino groups, such as Boc.

[0485] In some embodiments of the present invention, the hydroxyl protecting group is a group used in the field of organic chemistry to protect hydroxyl groups, such as TBS, MOM, or THP.

[0486] In some embodiments of the present invention, the compound of formula Z4 is selected from...

[0487] When R9 is not -H, the compound of formula Z4 is

[0488] Furthermore, the compound of formula Z4-1 is selected from...

[0489] Furthermore, the compound of formula Z4-2 is selected from... Preferred

[0490] In some embodiments of the present invention, the preparation of the compound of formula Z4-1 includes the following steps:

[0491]

[0492] Compound Z4b was prepared by subjecting compound Z4a to an amino protection reaction with ditert-butyl dicarbonate.

[0493] The Z4b compound was subjected to an acylation and cyclization reaction with thionyl chloride to prepare the Z4-1 compound.

[0494] In this invention, the conditions and operations in the amino protection reaction and acylation cyclization reaction in the above steps are conventional conditions and operations in the art.

[0495] In another aspect, the present invention also provides a method for preparing a compound of formula A8, its optical isomer, or a pharmacologically acceptable salt thereof, comprising the following steps:

[0496] Pathway 1: Prepare compound A8 or its pharmacologically acceptable salt by amidation reaction of compound A7 or its pharmacologically acceptable salt with compound Z4;

[0497] or

[0498] Pathway 2: Perform a hydrolysis ring-opening reaction on compound A6, and after the hydrolysis ring-opening reaction is completed, add compound Z4 to perform an amidation reaction to prepare compound A8 or its pharmacologically acceptable salt.

[0499]

[0500] Among them, R1~R2, R5~R7, m, R 13 The definitions of W, Y, and Z are as described above.

[0501] In this invention, the conditions and operations in the amidation reaction in pathway 1, as well as the amidation reaction and hydrolysis ring-opening reaction in pathway 2, are all conventional conditions and operations in the art.

[0502] The following conditions and operations are particularly preferred in this invention:

[0503] In path 1, the preferred method for preparing the compound of formula A8 or its pharmacologically acceptable salt is as follows: in a solvent, the compound of formula A7 is contacted with the compound of formula Z4 to carry out an amidation reaction to prepare the compound of formula A8 or its pharmacologically acceptable salt.

[0504] The molar ratio of the compound of formula A7 to the compound of formula Z4 is preferably 1:(0.6 to 2), including but not limited to 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, and 1:2.

[0505] The molar ratio of the compound of formula A7 to the compound of formula Z4 is preferably 1:(1 to 6), including but not limited to 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:2, 1:3, 1:4, 1:5, and 1:6.

[0506] The solvent is preferably DMF. The amidation reaction can also be carried out in the presence of a base. The base is preferably one or more of N,N-diisopropylethylamine, pyridine, sodium bicarbonate, sodium carbonate, and triethylamine. The molar ratio of the compound of formula A7 to the base is preferably 1:(0.1-6), including but not limited to 1:0.1, 1:0.5, 1:1, 1:1.5, 1:1.8, 1:2, 1:2.2, 1:2.5, 1:3, 1:4, 1:5, and 1:6. Further, when Z4 is Z4-1, the molar ratio of the compound of formula A7 to the base is preferably 1:(0.3-0.7), more preferably 1:0.5. Even further, the structure of Z4-1 is...

[0507] Specifically, when Z4 is Z4-1, the amidation reaction can be carried out without the addition of a base. Further, the Z4-1 structure is...

[0508] The inventors have discovered that when Z4 is Z4-1, the amidation reaction can be carried out without the addition of a base, which can improve the yield of the reaction product. The inventors have also discovered that the amidation reaction can be carried out in the presence of a base, and the molar ratio of the compound of formula A7 to the base is limited to 1:(0.3 to 0.7), preferably 1:0.5, which can also improve the yield of the reaction product.

[0509] The temperature of the amidation reaction can be a conventional reaction temperature for this type of reaction, such as room temperature. The temperature of the amidation reaction can be 10℃ to 30℃. Understandably, the temperature of the amidation reaction includes, but is not limited to, 10℃, 15℃, 20℃, 25℃, and 30℃.

[0510] The progress of the amidation reaction can be monitored using conventional monitoring methods in the art (e.g., LC-MS, TLC, HPLC, NMR, or GC), and the reaction endpoint is generally defined as the disappearance or cessation of the reaction of the compound of formula A7. The amidation reaction time is preferably 6 to 18 hours, for example, 12 hours or 16 hours.

[0511] In route 2, the conditions for the hydrolysis ring-opening reaction are preferably the same as those for the preparation of compound A7 from compound A6; the conditions for the amidation reaction are preferably the same as those in route 1. It can be understood that the product obtained from the hydrolysis ring-opening reaction in route 2 can be directly added to compound Z4 for amidation reaction without separation, further shortening the synthesis time and saving costs.

[0512] In another aspect, the present invention also provides a method for preparing a compound of formula A8', its optical isomer, or a pharmacologically acceptable salt thereof, comprising the following steps:

[0513] Pathway 1: Prepare compound A8' or its pharmacologically acceptable salt by amidation reaction of compound A7' or its pharmacologically acceptable salt with compound Z4;

[0514] or

[0515] Pathway 2: Perform a hydrolysis ring-opening reaction on compound A5, and after the hydrolysis ring-opening reaction is completed, add compound Z4 to perform an amidation reaction to prepare compound A8' or its pharmacologically acceptable salt.

[0516]

[0517] Among them, R1~R2, R5~R7, m, R 13 The definitions of W, Y, and Z are as described above.

[0518] In this invention, the conditions and operations in the amidation reaction in pathway 1, as well as the amidation reaction and hydrolysis ring-opening reaction in pathway 2, are all conventional conditions and operations in the art.

[0519] The following conditions and operations are particularly preferred in this invention:

[0520] In path 1, the conditions for the amidation reaction are preferably as described above.

[0521] In route 2, the conditions for the hydrolysis ring-opening reaction are preferably the same as those for the preparation of compound A7' from compound A5; the conditions for the amidation reaction are preferably the same as those in route 1. It is understood that the product obtained from the hydrolysis ring-opening reaction in route 2 can be directly added to compound Z4 for amidation reaction without separation, further shortening the synthesis time and saving costs.

[0522] In another aspect, the present invention also provides a method for preparing a compound of formula A8-P, its optical isomer, or a pharmacologically acceptable salt thereof, comprising the following steps:

[0523] Pathway 1: Prepare compound A8-P or its pharmacologically acceptable salt by amidation reaction of compound A7-P or compound Z4;

[0524] or

[0525] Pathway 2: Perform a hydrolysis ring-opening reaction on compound A6-P, and after the hydrolysis ring-opening reaction is completed, add compound Z4 to perform an amidation reaction to prepare compound A8-P or its pharmacologically acceptable salt.

[0526]

[0527] Among them, R2, R5~R7, m, R 10 ~R 12 n, R 13 The definitions of W, Y, and Z are as described above.

[0528] In this invention, the conditions and operations in the amidation reaction in pathway 1, as well as the amidation reaction and hydrolysis ring-opening reaction in pathway 2, are all conventional conditions and operations in the art.

[0529] The following conditions and operations are particularly preferred in this invention:

[0530] In path 1, the conditions for the amidation reaction are preferably as described above.

[0531] The following conditions and operations are particularly preferred in this invention:

[0532] In path 1, the preferred method for preparing the compound of formula A8-P or its pharmacologically acceptable salt is as follows: in a solvent, the compound of formula A7-P is contacted with the compound of formula Z4 to carry out an amidation reaction to prepare the compound of formula A8-P or its pharmacologically acceptable salt.

[0533] The molar ratio of the compound of formula A7-P to the compound of formula Z4 is preferably 1:(1 to 6), including but not limited to 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:2, 1:3, 1:4, 1:5, and 1:6.

[0534] The solvent is preferably DMF;

[0535] The temperature of the amidation reaction can be a conventional reaction temperature for this type of reaction, such as room temperature. The temperature of the amidation reaction can be between 10°C and 30°C. It is understood that the temperature of the amidation reaction includes, but is not limited to, 10°C, 15°C, 20°C, 25°C, and 30°C.

[0536] The progress of the amidation reaction can be monitored using conventional monitoring methods in the art (e.g., LC-MS, TLC, HPLC, NMR, or GC), and the reaction endpoint is generally defined as the disappearance or cessation of the reaction of the compound of formula A7-P. The amidation reaction time is preferably 6 to 18 hours, for example, 12 hours or 16 hours.

[0537] In route 2, the conditions for the hydrolysis ring-opening reaction are preferably the same as those for the preparation of compound A7' from compound A5; the conditions for the amidation reaction are preferably the same as those in route 1. It is understood that the product obtained from the hydrolysis ring-opening reaction in route 2 can be directly added to compound Z4 for amidation reaction without separation, further shortening the synthesis time and saving costs.

[0538] In another aspect, the present invention also provides a method for preparing a compound of formula A8'-P, its optical isomer, or a pharmacologically acceptable salt thereof, comprising the following steps:

[0539] Pathway 1: Prepare compound A8'-P or its pharmacologically acceptable salt by amidation reaction with compound Z4;

[0540] or

[0541] Pathway 2: The compound of formula A5-P is subjected to a hydrolysis ring-opening reaction. After the hydrolysis ring-opening reaction is completed, the compound of formula Z4 is added to carry out an amidation reaction to prepare the compound of formula A8'-P or its pharmacologically acceptable salt.

[0542]

[0543] Among them, R2, R5~R7, m, R 10 ~R 12 n, R 13 The definitions of W, Y, and Z are as described above.

[0544] In this invention, the conditions and operations in the amidation reaction in pathway 1, as well as the amidation reaction and hydrolysis ring-opening reaction in pathway 2, are all conventional conditions and operations in the art.

[0545] The following conditions and operations are particularly preferred in this invention:

[0546] In path 1, the conditions for the amidation reaction are preferably as described above.

[0547] In route 2, the conditions for the hydrolysis ring-opening reaction are preferably the same as those for the preparation of compound A7' from compound A5; the conditions for the amidation reaction are preferably the same as those in route 1. It is understood that the product obtained from the hydrolysis ring-opening reaction in route 2 can be directly added to compound Z4 for amidation reaction without separation, further shortening the synthesis time and saving costs.

[0548] In another aspect, the present invention also provides a method for preparing a compound of formula A8-M, its optical isomer, or a pharmacologically acceptable salt thereof, characterized by comprising the following steps:

[0549] Compound A7-M or its pharmacologically acceptable salt is prepared by amidation reaction with compound Z4;

[0550]

[0551] The definitions of R1~R2, R5~R7, m, W, Y and Z are as described above.

[0552] In this invention, the conditions and operations in the amidation reaction in the above steps are all conventional conditions and operations in the art.

[0553] The following conditions and operations are particularly preferred in this invention:

[0554] The conditions for the amidation reaction are preferably as described above.

[0555] The following conditions and operations are particularly preferred in this invention:

[0556] The preferred method for preparing the compound of formula A8-M or its pharmacologically acceptable salt is as follows: in a solvent, in the presence of a base, the compound of formula A7-M or its pharmacologically acceptable salt is contacted with the compound of formula Z4 to carry out an amidation reaction, thereby preparing the compound of formula A8-M or its pharmacologically acceptable salt.

[0557] The molar ratio of the compound of formula A7-M to the compound of formula Z4 is preferably 1:(1 to 6), including but not limited to 1:1, 1:2, 1:3, 1:4, 1:5, and 1:6.

[0558] The solvent is preferably DMF;

[0559] The base is preferably one or more selected from N,N-diisopropylethylamine, pyridine, and triethylamine;

[0560] The molar ratio of the compound of formula A7-M to the base is preferably 1:(0.1 to 6), including but not limited to 1:0.1, 1:0.5, 1:1, 1:2, 1:3, 1:4, 1:5, and 1:6.

[0561] The temperature of the amidation reaction can be the conventional reaction temperature for this type of reaction, such as room temperature;

[0562] The progress of the amidation reaction can be monitored using conventional monitoring methods in the art (e.g., LC-MS, TLC, HPLC, NMR or GC), and the reaction endpoint is generally defined as the disappearance or cessation of reaction of compound A7-M.

[0563] In another aspect, the present invention also provides a method for preparing a compound of formula A8'-M, its optical isomer, or a pharmacologically acceptable salt thereof, characterized by comprising the following steps:

[0564] Compound A7'-M or its pharmacologically acceptable salt is prepared by amidation reaction with compound Z4;

[0565]

[0566] The definitions of R1~R2, R5~R7, m, W, Y and Z are as described above.

[0567] In this invention, the conditions and operations in the amidation reaction in the above steps are all conventional conditions and operations in the art.

[0568] The following conditions and operations are particularly preferred in this invention:

[0569] The conditions for the amidation reaction are preferably as described above.

[0570] In another aspect, the present invention also provides a method for preparing a compound of formula A8-PM, its optical isomer, or a pharmacologically acceptable salt thereof, comprising the following steps:

[0571] Compound A7-PM or its pharmacologically acceptable salt is prepared by amidation reaction with compound Z4;

[0572]

[0573] Among them, R2, R5~R7, m, R 10 ~R 12 The definitions of , n, W, Y and Z are as described above.

[0574] In this invention, the conditions and operations in the amidation reaction in the above steps are all conventional conditions and operations in the art.

[0575] The following conditions and operations are particularly preferred in this invention:

[0576] The conditions for the amidation reaction are preferably as described above.

[0577] The following conditions and operations are particularly preferred in this invention:

[0578] The preferred method for preparing the compound of formula A8-PM or its pharmacologically acceptable salt is as follows: in a solvent, in the presence of an alkali, the compound of formula A7-PM or its pharmacologically acceptable salt is contacted with the compound of formula Z4 to carry out an amidation reaction, thereby preparing the compound of formula A8-PM or its pharmacologically acceptable salt.

[0579] The molar ratio of the compound of formula A7-PM to the compound of formula Z4 is preferably 1:(1 to 6), including but not limited to 1:1, 1:2, 1:3, 1:4, 1:5, and 1:6.

[0580] The solvent is preferably DMF;

[0581] The base is preferably one or more selected from N,N-diisopropylethylamine, pyridine, and triethylamine;

[0582] The molar ratio of the compound of formula A7-PM to the base is preferably 1:(0.1 to 6), including but not limited to 1:0.1, 1:0.5, 1:1, 1:2, 1:3, 1:4, 1:5, and 1:6.

[0583] The temperature of the amidation reaction can be the conventional reaction temperature for this type of reaction, such as room temperature;

[0584] The progress of the amidation reaction can be monitored using conventional monitoring methods in the art (e.g., LC-MS, TLC, HPLC, NMR or GC), and the reaction endpoint is generally defined as the disappearance or cessation of the reaction of the compound of formula A7-PM.

[0585] In another aspect, the present invention also provides a method for preparing a compound of formula A8'-PM, its optical isomer, or a pharmacologically acceptable salt thereof, comprising the following steps:

[0586] Compound of formula A7'-PM or its pharmacologically acceptable salt is prepared by amidation reaction with compound of formula Z4;

[0587]

[0588] Among them, R2, R5~R7, m, R 10 ~R 12 The definitions of , n, W, Y and Z are as described above.

[0589] In this invention, the conditions and operations in the amidation reaction in the above steps are all conventional conditions and operations in the art.

[0590] The following conditions and operations are particularly preferred in this invention:

[0591] The conditions for the amidation reaction are preferably as described above.

[0592] In another aspect of the invention, the invention also provides a compound of formula A8, a compound of formula A8', a compound of formula A8-P, a compound of formula A8'-P, a compound of formula A8-M, a compound of formula A8'-M, a compound of formula A8-PM, a compound of formula A8'-PM, an optical isomer thereof, or a pharmacologically acceptable salt thereof:

[0593]

[0594] Among them, R1~R2, R5~R7, m, R 10 ~R 12 The definitions of , n, W, Y and Z are as described above.

[0595] In some embodiments of the present invention, the compound of formula A8 is selected from...

[0596] Furthermore, the compound of formula A8-1 is selected from...

[0597]

[0598] Furthermore, the compound of formula A8-2 is selected from...

[0599] In some embodiments of the present invention, the compound of formula A8' is selected from... Furthermore, the compound of formula A8'-1 is selected from...

[0600] Furthermore, the compound of formula A8'-2 is selected from...

[0601] In some embodiments of the present invention, the A8-M compound is selected from... Furthermore, the A8-M-1 compound is selected from...

[0602] Furthermore, the A8-M-2 compound is selected from...

[0603] In some embodiments of the present invention, the compound of formula A8'-M is selected from... Furthermore, the compound of formula A8'-M-1 is selected from...

[0604] Furthermore, the compound of formula A8'-M-2 is selected from...

[0605] In some embodiments of the present invention, the A8-P compound is selected from...

[0606] Furthermore, the A8-P-1 compound is preferably...

[0607] Furthermore, the A8-P-2 compound is selected from...

[0608] In some embodiments of the present invention, the compound of formula A8'-P is selected from...

[0609] Furthermore, the compound of formula A8'-P-1 is selected from...

[0610] Furthermore, the compound of formula A8'-P-2 is selected from...

[0611] In some embodiments of the present invention, the compound of formula A8-PM is selected from...

[0612] Furthermore, the compound of formula A8-PM-1 is selected from...

[0613] Furthermore, the compound of formula A8-PM-2 is selected from...

[0614] In some embodiments of the present invention, the compound of formula A8'-PM is selected from...

[0615] Furthermore, the compound of formula A8'-PM-1 is selected from...

[0616]

[0617] Furthermore, the compound of formula A8'-PM-2 is selected from...

[0618] In another aspect, the present invention also provides a method for preparing a compound of formula AA8, a compound of formula AA8', a compound of formula AA8-P, a compound of formula AA8'-P, a compound of formula AA8-M, a compound of formula AA8'-M, a compound of formula AA8-PM, a compound of formula AA8'-PM, an optical isomer thereof, or a pharmacologically acceptable salt thereof, comprising the following steps:

[0619] Compounds of formula AA7, AA7', AA7-P, AA7'-P, AA7-M, AA7'-M, AA7-PM, AA7'-PM, their optical isomers, or their pharmacologically acceptable salts are prepared by amidation reaction with compound Z4 to prepare compounds of formula AA8, AA8', AA8-P, AA8'-P, AA8-M, AA8'-M, AA8-PM, AA8'-PM, their optical isomers, or their pharmacologically acceptable salts.

[0620]

[0621]

[0622] Among them, R1~R2, R5~R7, m, R 10 ~R12 n, R 14 The definitions of W, Y, and Z are as described above;

[0623] The conditions for the amidation reaction are as described above.

[0624] In another aspect of the invention, the invention also provides a compound of formula AA8, a compound of formula AA8', a compound of formula AA8-P, a compound of formula AA8'-P, a compound of formula AA8-M, a compound of formula AA8'-M, a compound of formula AA8-PM, a compound of formula AA8'-PM, an optical isomer thereof, or a pharmacologically acceptable salt thereof:

[0625]

[0626] Among them, R1~R2, R5~R7, m, R 10 ~R 12 n, R 14 The definitions of W, Y, and Z are as described above.

[0627] In another aspect, the present invention also provides a method for preparing a compound of formula A9 or its optical isomer, comprising the following steps:

[0628] Pathway 1: Prepare compound A9 by cyclizing compound A8 or its pharmacologically acceptable salt;

[0629] or

[0630] Path 2: Perform a hydrolysis ring-opening reaction on compound A6, add compound Z4 after the hydrolysis ring-opening reaction, perform an amidation reaction, and perform a cyclization reaction after the amidation reaction to prepare compound A9.

[0631]

[0632] Among them, R1~R2, R5~R7, m, R 13 The definitions of W, Y, and Z are as described above.

[0633] In this invention, the conditions and operations in the cyclization reaction in path 1, as well as the hydrolysis ring-opening reaction, amidation reaction, and cyclization reaction in path 2, are all conventional conditions and operations in the art.

[0634] The following conditions and operations are particularly preferred in this invention:

[0635] In path 1, the preferred method for preparing the compound of formula A9 is as follows: in a solvent, in the presence of a base, the compound of formula A8 is contacted with TsCl to carry out a cyclization reaction to prepare the compound of formula A9;

[0636] Furthermore, the cyclization reaction is specifically divided into two steps: TsCl first undergoes a hydroxyl activation reaction with the compound of formula A8 to obtain an intermediate; then, the secondary amine within the intermediate molecule undergoes a nucleophilic substitution reaction with -OTs on the benzene ring, resulting in cyclization and yielding the compound of formula A9.

[0637]

[0638] The preferred molar ratio of the compound of formula A8 to TsCl is 1:(0.7-6), including but not limited to 1:0.7, 1:0.8, 1:0.9, 1:1, 1:2, 1:3, 1:4, 1:5, and 1:6.

[0639] The preferred molar ratio of the compound of formula A8 to TsCl is 1:(0.7 to 1.7), including but not limited to 1:0.7, 1:0.8, 1:0.9, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, and 1:1.7.

[0640] The preferred molar ratio of the compound of formula A8 to TsCl is 1:(1 to 6), including but not limited to 1:1, 1:2, 1:3, 1:4, 1:5, and 1:6.

[0641] The base is preferably an organic amine base. The organic amine base may be N,N-diisopropylethylamine.

[0642] The base is preferably one or more of N,N-diisopropylethylamine, pyridine, and triethylamine.

[0643] The molar ratio of the compound of formula A8 to the base is preferably 1:(1 to 6), including but not limited to 1:1, 1:2, 1:3, 1:4, 1:5, and 1:6.

[0644] The solvent is preferably a nitrile solvent. The nitrile solvent may be acetonitrile.

[0645] The solvent is preferably one or more selected from THF, dichloromethane, acetonitrile, DMF and DMSO.

[0646] Furthermore, the contact method between the compound of formula A8 and TsCl is to slowly add an acetonitrile solution of TsCl to the reaction system.

[0647] The cyclization reaction temperature can be a conventional reaction temperature for this type of reaction, such as room temperature. The cyclization reaction temperature can be between 10°C and 30°C. Understandably, the cyclization reaction temperature includes, but is not limited to, 10°C, 15°C, 20°C, 25°C, and 30°C.

[0648] The progress of the cyclization reaction can be monitored using conventional monitoring methods in the art (e.g., LC-MS, TLC, HPLC, NMR or GC), and the reaction endpoint is generally defined as the disappearance or cessation of the reaction of the compound of formula A8.

[0649] In pathway 2, the conditions for the hydrolysis ring-opening reaction and the amidation reaction are preferably as described above, and the conditions for the cyclization reaction are preferably as described above. It is understood that the product obtained from the hydrolysis ring-opening reaction in pathway 2 can be directly added to compound Z4 for amidation reaction without separation, and the product obtained from the amidation reaction can continue to undergo cyclization reaction without separation, further shortening the synthesis time and saving costs.

[0650] In another aspect, the present invention also provides a method for preparing a compound of formula A9' or its optical isomer, comprising the following steps:

[0651] Pathway 1: Prepare compound A9 by cyclizing compound A8' or its pharmacologically acceptable salt;

[0652] or

[0653] Path 2: Perform a hydrolysis ring-opening reaction on compound A5, add compound Z4 after the hydrolysis ring-opening reaction, perform an amidation reaction, and perform a cyclization reaction after the amidation reaction to prepare compound A9'.

[0654]

[0655] Among them, R1~R2, R5~R7, m, R 13 The definitions of W, Y, and Z are as described above.

[0656] In this invention, the conditions and operations in the cyclization reaction in path 1, as well as the hydrolysis ring-opening reaction, amidation reaction, and cyclization reaction in path 2, are all conventional conditions and operations in the art.

[0657] The following conditions and operations are particularly preferred in this invention:

[0658] In path 1, the conditions for the cyclization reaction are preferably as described above.

[0659] In Path 2, the conditions for the hydrolysis ring-opening reaction and the amidation reaction are preferably as described above, and the conditions for the cyclization reaction are preferably as described above. It is understood that the product obtained from the hydrolysis ring-opening reaction in Path 2 can be directly added to the Z4 compound for amidation reaction without separation, and the product obtained from the amidation reaction can continue to undergo cyclization reaction without separation, further shortening the synthesis time and saving costs.

[0660] In some embodiments of the present invention, the compound of formula A8 is a compound of formula A8-1, and a compound of formula A9-1 is prepared; or the compound of formula A8 is a compound of formula A8-2, and a compound of formula A9-2 is prepared.

[0661]

[0662] Alternatively, the compound of formula A9-2 can be contacted with an ethyl derivative and cyclized via nucleophilic substitution and reductive amination to prepare the compound of formula A9-1.

[0663]

[0664] Alternatively, the compound of formula A8' may be a compound of formula A8'-1, and a compound of formula A9'-1 may be prepared; or the compound of formula A8' may be a compound of formula A8'-2, and a compound of formula A9'-2 may be prepared.

[0665]

[0666] Alternatively, the compound of formula A9'-2 can be contacted with an ethyl derivative and cyclized via nucleophilic substitution and reductive amination to prepare the compound of formula A9'-1.

[0667]

[0668] The definitions of W, Y, R8, and R9 are as described above.

[0669] In another aspect, the present invention also provides a method for preparing a compound of formula A9-P or its optical isomer, comprising the following steps:

[0670] Pathway 1: Prepare compound A9-P by cyclizing compound A8-P or its pharmacologically acceptable salt;

[0671] or

[0672] Path 2: The A6-P compound is subjected to a hydrolysis ring-opening reaction. After the hydrolysis ring-opening reaction is completed, the Z4 compound is added to carry out an amidation reaction. After the amidation reaction is completed, a cyclization reaction is carried out to prepare the A9-P compound.

[0673]

[0674] Among them, R2, R5~R7, m, R 10 ~R 12 n, W, Y, Z, R 13 The definition is as described above.

[0675] In path 1, the conditions for the cyclization reaction are preferably as described above.

[0676] In path 1, the preferred method for preparing the compound of formula A9-P is as follows: in a solvent, in the presence of a base, the compound of formula A8-P is contacted with TsCl to carry out a cyclization reaction to prepare the compound of formula A9-P;

[0677] Furthermore, the cyclization reaction is specifically divided into two steps: TsCl first undergoes a hydroxyl activation reaction with the compound of formula A8-P to obtain an intermediate; then, the secondary amine within the intermediate molecule undergoes a nucleophilic substitution reaction with -OTs on the benzene ring, resulting in cyclization and obtaining the compound of formula A9-P.

[0678]

[0679] The molar ratio of the compound of formula A8-P to TsCl is preferably 1:(1 to 10), including but not limited to 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, and 1:10.

[0680] The base is preferably one or more of N,N-diisopropylethylamine, pyridine, and triethylamine.

[0681] The molar ratio of the compound of formula A8-P to the base is preferably 1:(2 to 12), including but not limited to 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, and 1:12.

[0682] The solvent is preferably one or more selected from THF, dichloromethane, acetonitrile, DMF and DMSO.

[0683] The cyclization reaction temperature can be a conventional reaction temperature for this type of reaction, such as room temperature.

[0684] The progress of the cyclization reaction can be monitored using conventional monitoring methods in the art (e.g., LC-MS, TLC, HPLC, NMR or GC), and the reaction endpoint is generally defined as the disappearance or cessation of the reaction of the compound of formula A8-P.

[0685] In Path 2, the conditions for the hydrolysis ring-opening reaction and the amidation reaction are preferably as described above, and the conditions for the cyclization reaction are preferably as described above. It is understood that the product obtained from the hydrolysis ring-opening reaction in Path 2 can be directly added to the Z4 compound for amidation reaction without separation, and the product obtained from the amidation reaction can continue to undergo cyclization reaction without separation, further shortening the synthesis time and saving costs.

[0686] In another aspect, the present invention also provides a method for preparing a compound of formula A9'-P or an optical isomer thereof, comprising the following steps:

[0687] Pathway 1: Prepare compound A9'-P by cyclizing compound A8'-P or its pharmacologically acceptable salt;

[0688] or

[0689] Path 2: The A5-P compound is subjected to a hydrolysis ring-opening reaction. After the hydrolysis ring-opening reaction is completed, the Z4 compound is added to carry out an amidation reaction. After the amidation reaction is completed, a cyclization reaction is carried out to prepare the A9'-P compound.

[0690]

[0691] Among them, R2, R5~R7, m, R 10 ~R 12 n, W, Y, Z, R 13 The definition is as described above.

[0692] In path 1, the conditions for the cyclization reaction are preferably as described above.

[0693] In pathway 2, the conditions for the hydrolysis ring-opening reaction and the amidation reaction are preferably as described above, and the conditions for the cyclization reaction are preferably as described above. It is understood that the product obtained from the hydrolysis ring-opening reaction in pathway 2 can be directly added to compound Z4 for amidation reaction without separation, and the product obtained from the amidation reaction can continue to undergo cyclization reaction without separation, further shortening the synthesis time and saving costs.

[0694] In some embodiments of the present invention, the compound of formula A8-P is a compound of formula A8-P-1, and a compound of formula A9-P-1 is prepared; or the compound of formula A8-P is a compound of formula A8-P-2, and a compound of formula A9-P-2 is prepared.

[0695]

[0696] Alternatively, the compound of formula A9-P-2 can be contacted with an ethyl derivative and cyclized through nucleophilic substitution and reductive amination to prepare the compound of formula A9-P-1.

[0697]

[0698] Alternatively, the compound of formula A8'-P may be a compound of formula A8'-P-1, and a compound of formula A9'-P-1 may be prepared; or the compound of formula A8'-P may be a compound of formula A8'-P-2, and a compound of formula A9'-P-2 may be prepared.

[0699]

[0700] Alternatively, the compound of formula A9'-P-2 can be contacted with an ethyl derivative and cyclized via nucleophilic substitution and reductive amination to prepare the compound of formula A9'-P-1.

[0701]

[0702] The definitions of W, Y, R8, and R9 are as described above.

[0703] In another aspect, the present invention also provides a method for preparing a compound of formula A9-M or its optical isomer, comprising the following steps:

[0704] Compound A9-M is prepared by cyclizing a compound of formula A8-M or its pharmacologically acceptable salt.

[0705]

[0706] The definitions of R1~R2, R5~R7, m, W, Y and Z are as described above.

[0707] The preferred method for preparing the compound of formula A9-M or its pharmacologically acceptable salt is as follows: in a solvent, in the presence of a base, the compound of formula A8-M or its pharmacologically acceptable salt is contacted with TsCl to carry out a cyclization reaction to prepare the compound of formula A9-M or its pharmacologically acceptable salt.

[0708] Furthermore, the cyclization reaction is specifically divided into two steps: TsCl first undergoes a hydroxyl activation reaction with the compound of formula A8-M or its pharmacologically acceptable salt to obtain an intermediate; then, the secondary amine in the intermediate molecule undergoes a nucleophilic substitution reaction with -OTs on the benzene ring to close the ring and obtain the compound of formula A9-M or its pharmacologically acceptable salt.

[0709] The molar ratio of the compound of formula A8-M to TsCl is preferably 1:(1 to 6), including but not limited to 1:1, 1:1.2, 1:1.5, 1:2, 1:3, 1:4, 1:5, and 1:6.

[0710] The solvent is preferably one or more selected from THF, dichloromethane, acetonitrile, DMF and DMSO;

[0711] The base is preferably one or more selected from N,N-diisopropylethylamine, pyridine, and triethylamine;

[0712] The molar ratio of the compound of formula A8-M to the base is preferably 1:(1 to 6), including but not limited to 1:1, 1:1.2, 1:1.5, 1:2, 1:3, 1:4, 1:5, and 1:6.

[0713] The cyclization reaction temperature can be a conventional reaction temperature for this type of reaction, such as room temperature.

[0714] The progress of the cyclization reaction can be monitored using conventional monitoring methods in the art (e.g., LC-MS, TLC, HPLC, NMR, or GC), and the reaction endpoint is generally defined as the disappearance or cessation of the reaction of the compound of formula A8-M. In another aspect of the invention, a method for preparing a compound of formula A9'-M or its optical isomers is also provided, comprising the following steps:

[0715] Compound A9'-M is prepared by cyclizing a compound of formula A8'-M or its pharmacologically acceptable salt.

[0716]

[0717] The definitions of R1~R2, R5~R7, m, W, Y and Z are as described above.

[0718] In some embodiments of the present invention, the compound of formula A8-M is a compound of formula A8-M-1, and a compound of formula A9-M-1 is prepared; or the compound of formula A8-M is a compound of formula A8-M-2, and a compound of formula A9-M-2 is prepared.

[0719]

[0720] Alternatively, the compound of formula A9-M-2 can be contacted with an ethyl derivative and cyclized via nucleophilic substitution and reductive amination to prepare the compound of formula A9-M-1.

[0721]

[0722] Alternatively, the compound of formula A8'-M may be a compound of formula A8'-M-1, and a compound of formula A9'-M-1 may be prepared; or the compound of formula A8'-M may be a compound of formula A8'-M-2, and a compound of formula A9'-M-2 may be prepared.

[0723]

[0724]

[0725] Alternatively, the compound of formula A9'-M-2 can be contacted with an ethyl derivative and cyclized via nucleophilic substitution and reductive amination to prepare the compound of formula A9'-M-1.

[0726]

[0727] The definitions of W, Y, R8, and R9 are as described above.

[0728] In another aspect, the present invention also provides a method for preparing a compound of formula A9-PM or its optical isomer, comprising the following steps:

[0729] Compound A9-PM was prepared by cyclizing a compound of formula A8-PM or its pharmacologically acceptable salt.

[0730]

[0731] Among them, R2, R5~R7, m, R 10 ~R 12 The definitions of , n, W, Y and Z are as described above.

[0732] The preferred method for preparing the A9-PM compound or its pharmacologically acceptable salt is as follows: in a solvent, in the presence of a base, the A8-PM compound or its pharmacologically acceptable salt is contacted with TsCl to carry out a cyclization reaction, thereby preparing the A9-PM compound or its pharmacologically acceptable salt.

[0733] Furthermore, the cyclization reaction is specifically divided into two steps: TsCl first undergoes a hydroxyl activation reaction with the compound of formula A8-PM or its pharmacologically acceptable salt to obtain an intermediate; then, the secondary amine in the intermediate molecule undergoes a nucleophilic substitution reaction with -OTs on the benzene ring to close the ring and obtain the compound of formula A9-PM or its pharmacologically acceptable salt.

[0734] The preferred molar ratio of the compound of formula A8-PM to TsCl is 1:(1 to 10), including but not limited to 1:1, 1:1.2, 1:1.5, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, and 1:10.

[0735] The solvent is preferably one or more selected from THF, dichloromethane, acetonitrile, DMF and DMSO;

[0736] The base is preferably one or more selected from N,N-diisopropylethylamine, pyridine, and triethylamine;

[0737] The molar ratio of the compound of formula A8-PM to the base is preferably 1:(1 to 12), including but not limited to 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, and 1:12.

[0738] The cyclization reaction temperature can be a conventional reaction temperature for this type of reaction, such as room temperature.

[0739] The progress of the cyclization reaction can be monitored using conventional monitoring methods in the art (e.g., LC-MS, TLC, HPLC, NMR or GC), and the reaction endpoint is generally defined as the disappearance or cessation of the reaction of the compound of formula A8-PM.

[0740] In another aspect, the present invention also provides a method for preparing a compound of formula A9'-PM or its optical isomer, comprising the following steps:

[0741] Compound A9'-PM is prepared by cyclizing a compound of formula A8'-PM or its pharmacologically acceptable salt.

[0742]

[0743] Among them, R2, R5~R7, m, R 10 ~R 12 The definitions of , n, W, Y and Z are as described above.

[0744] In some embodiments of the present invention, the compound of formula A8-PM is a compound of formula A8-PM-1, and a compound of formula A9-PM-1 is prepared; or the compound of formula A8-M is a compound of formula A8-PM-2, and a compound of formula A9-PM-2 is prepared.

[0745]

[0746] Alternatively, the compound of formula A9-PM-2 can be contacted with an ethyl derivative and cyclized via nucleophilic substitution and reductive amination to prepare the compound of formula A9-PM-1.

[0747]

[0748] Alternatively, the compound of formula A8'-PM may be a compound of formula A8'-PM-1, and a compound of formula A9'-PM-1 may be prepared; or the compound of formula A8'-PM may be a compound of formula A8'-PM-2, and a compound of formula A9'-PM-2 may be prepared.

[0749]

[0750]

[0751] Alternatively, the compound of formula A9'-PM-2 can be contacted with an ethyl derivative and cyclized via nucleophilic substitution and reductive amination to prepare the compound of formula A9'-PM-1.

[0752]

[0753] The definitions of W, Y, R8, and R9 are as described above.

[0754] In another aspect, the present invention also provides a method for preparing compounds of formula A9, A9', A9-P, A9'-P, A9-M, A9'-M, A9-PM, A9'-PM, or optical isomers thereof, comprising the following steps:

[0755] Compound AA8 was subjected to a dehydroxylation protection reaction to prepare compound A8, and then compound A8 was subjected to a cyclization reaction to prepare compound A9; wherein, when R 14 -O-(S=O)2-R 15 In this case, the method for preparing compound A9 does not involve the step of preparing compound A8 from compound AA8, but directly performs a cyclization reaction on compound AA8 to prepare compound A9.

[0756]

[0757] Compound of formula AA8' was subjected to a dehydroxylation protection reaction to prepare compound of formula A8', and then compound of formula A8' was subjected to a cyclization reaction to prepare compound of formula A9'; wherein, when R 14 -O-(S=O)2-R 15 In this case, the method for preparing compound A9' does not involve the step of preparing compound A8' from compound AA8', but directly performs a cyclization reaction on compound AA8' to prepare compound A9'.

[0758]

[0759] Compound AA8-P was subjected to a dehydroxylation protection reaction to prepare compound A8-P, and then compound A8-P was subjected to a cyclization reaction to prepare compound A9-P; wherein, when R 14 -O-(S=O)2-R 15 In this case, the method for preparing compound A9-P does not involve the step of preparing compound A8-P from compound AA8-P, but directly performs a cyclization reaction on compound AA8-P to prepare compound A9-P.

[0760]

[0761] The compound of formula AA8'-P was subjected to a dehydroxylation protection reaction to prepare compound A8'-P, and then the compound of formula A8'-P was subjected to a cyclization reaction to prepare compound A9'-P; wherein, when R 14 -O-(S=O)2-R 15In this case, the method for preparing compound A9'-P does not involve the step of preparing compound A8'-P from compound AA8'-P, but directly performs a cyclization reaction on compound AA8'-P to prepare compound A9'-P.

[0762]

[0763] Compound AA8-M was subjected to a dehydroxylation protection reaction to prepare compound A8-M, and then compound A8-M was subjected to a cyclization reaction to prepare compound A9-M; wherein, when R 14 -O-(S=O)2-R 15 In this case, the method for preparing compound A9-M does not involve the step of preparing compound A8-M from compound AA8-M, but directly performs a cyclization reaction on compound AA8-M to prepare compound A9-M.

[0764]

[0765] Compound AA8'-M was subjected to a dehydroxylation protection reaction to prepare compound A8'-M, and then compound A8'-M was subjected to a cyclization reaction to prepare compound A9'-M; wherein, when R 14 -O-(S=O)2-R 15 In this case, the method for preparing compound A9'-M does not involve the step of preparing compound A8'-M from compound AA8'-M, but directly performs a cyclization reaction on compound AA8'-M to prepare compound A9'-M;

[0766]

[0767] The compound of formula AA8-PM was subjected to a dehydroxylation protection reaction to prepare compound A8-PM, and then the compound of formula A8-PM was subjected to a cyclization reaction to prepare compound A9-PM; wherein, when R 14 -O-(S=O)2-R 15 In this case, the method for preparing compound A9-PM does not involve the step of preparing compound A8-PM from compound AA8-P, but directly performs a cyclization reaction on compound AA8-PM to prepare compound A9-PM.

[0768]

[0769] The compound of formula AA8'-PM was subjected to a dehydroxylation protection reaction to prepare compound A8'-PM, and then the compound of formula A8'-PM was subjected to a cyclization reaction to prepare compound A9'-PM; wherein, when R 14 -O-(S=O)2-R 15In this case, the method for preparing compound A9'-PM does not involve the step of preparing compound A8'-PM from compound AA8'-P, but directly performs a cyclization reaction on compound AA8'-PM to prepare compound A9'-PM.

[0770]

[0771] Among them, R1~R2, R5~R7, m, R 10 ~R 12 n, R 14 R 15 The definitions of W, Y, and Z are as described above.

[0772] Definitions and Explanations

[0773] Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

[0774] The term “pharmacologically acceptable” as used herein refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0775] The term "pharmacologically acceptable salt" refers to a salt of the compounds of this invention, prepared by reacting a compound with a specific substituent, as discovered in this invention, with a relatively non-toxic acid or base. When the compounds of this invention contain relatively acidic functional groups, base addition salts can be obtained by contacting a neutral form of such compound with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmacologically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts, or similar salts. When the compounds of this invention contain relatively basic functional groups, acid addition salts can be obtained by contacting a neutral form of such compound with a sufficient amount of acid in a solution or a suitable inert solvent. Examples of pharmacologically acceptable acid addition salts include inorganic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, trifluoroacetic acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; and also include salts of amino acids (such as arginine), and salts of organic acids such as glucuronic acid. Certain compounds of the present invention contain both basic and acidic functional groups, and thus can be converted into either a base or an acid addition salt.

[0776] The pharmacologically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture thereof.

[0777] As used herein, the term "and / or" encompasses any one of two or more of the related listed items, as well as any and all combinations of the related listed items. These arbitrary and all combinations include any two related listed items, any more related listed items, or a combination of all related listed items. For example, "A and / or B" includes three parallel options: A, B, and "a combination of A and B".

[0778] In this document, unless otherwise stated, "one or more" means any one of the listed items or any combination of the listed items. Similarly, "one or more" and other instances of "one or more" are to be understood in the same way unless otherwise stated.

[0779] In this document, terms such as "further," "even further," "especially," "for example," "as," "example," and "exemplary" are used for descriptive purposes to indicate a connection in the coverage of different technical solutions presented earlier and later. However, they should not be construed as limitations on the preceding technical solution or on the scope of protection of this document. Unless otherwise specified, A (as in B) indicates that B is a non-limiting example of A, and it can be understood that A is not limited to B.

[0780] In this article, "optionally," "optionally," and "optional" mean that something is optional, that is, it means that it is selected from either "with" or "without." If there are multiple "options" in a technical solution, unless otherwise specified, and there are no contradictions or mutual constraints, then each "option" is independent.

[0781] In this document, the terms "first aspect," "second aspect," "third aspect," and "fourth aspect," etc., are used for descriptive purposes only and should not be construed as indicating or implying relative importance or quantity, nor should they be construed as implicitly indicating the importance or quantity of the indicated technical features. Moreover, "first," "second," "third," and "fourth" serve only as a non-exhaustive enumeration and should be understood as not constituting a closed limitation on quantity.

[0782] In this article, the technical features described in an open-ended manner include both closed technical solutions composed of the listed features and open technical solutions that include the listed features.

[0783] In this document, when referring to numerical intervals (i.e., numerical ranges), unless otherwise specified, the distribution of selectable values ​​within a numerical interval is considered continuous, and includes the two endpoints (i.e., the minimum and maximum values) of the numerical interval, as well as every value between these two endpoints. Unless otherwise specified, when a numerical interval refers only to integers within that interval, it includes the two endpoint integers of the numerical range, as well as every integer between the two endpoints, which is equivalent to directly listing every integer. When multiple numerical ranges are provided to describe features or characteristics, these numerical ranges can be merged. In other words, unless otherwise specified, the numerical ranges disclosed herein should be understood to include any and all subranges included therein. The "numerical value" in this numerical interval can be any quantitative value, such as a number, percentage, ratio, etc. The term "numerical interval" can be broadly included to include percentage intervals, ratio intervals, proportion intervals, and other numerical interval types.

[0784] In this document, the term "room temperature" or "normal temperature" generally refers to 4°C to 35°C, for example, 20°C ± 5°C. In some embodiments of this document, "room temperature" or "normal temperature" refers to 10°C to 30°C. In some embodiments of this document, "room temperature" or "normal temperature" refers to 20°C to 30°C.

[0785] In this document, where the method involves multiple steps, unless otherwise explicitly stated herein, the execution of these steps is not strictly limited in order and can be performed in any order other than that described. Moreover, any step may include multiple sub-steps or multiple stages, which are not necessarily completed at the same time, but may be executed at different times, and their execution order is not necessarily sequential, but may be performed alternately or simultaneously with other steps or parts of the sub-steps or stages of other steps.

[0786] The compounds of this invention can exist in specific geometric or stereoisomeric forms. This invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this invention.

[0787] Unless otherwise stated, the terms "tautomer" or "tautomer form" refer to isomers with different functional groups in dynamic equilibrium at room temperature, capable of rapidly interconverting into each other. Tautomers can be chemically equilibrated if possible (e.g., in solution). For example, proton tautomers (also called prototropic tautomers) involve interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers involve interconversions involving the rearrangement of some bonding electrons. A specific example of keto-enol tautomerization is the interconversion between the tautomers pentane-2,4-dione and 4-hydroxypent-3-en-2-one.

[0788] The compounds of this invention may contain atomic isotopes in non-natural proportions on one or more atoms constituting the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium. 3 H), Iodine-125 125 I) or C-14 14C). For example, deuterium can be used to replace hydrogen to form deuterated drugs. The bond between deuterium and carbon is stronger than that between ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged drug biological half-life. All isotopic variations of the compounds of this invention, regardless of radioactivity, are included within the scope of this invention.

[0789] Those skilled in the art will understand that some compounds may contain one or more chiral centers, and thus have two or more stereoisomers. Therefore, the compounds of the present invention may exist as a single stereoisomer (e.g., enantiomer, diastereomer) and mixtures thereof in any proportion, such as racemates, and, where appropriate, as tautomers and geometric isomers.

[0790] As used in this article, "stereoisomer" refers to compounds that have the same chemical composition but differ in the spatial arrangement of atoms or groups. Stereoisomers include enantiomers, diastereomers, and conformational isomers.

[0791] The term "enantiomer" as used in this article refers to two stereoisomers of a compound that are non-overlapping mirror images of each other.

[0792] As used herein, the term "diastereomer" refers to a stereoisomer that has two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers possess different physical properties, such as melting point, boiling point, spectral properties, or biological activity. Mixtures of diastereomers can be separated using high-resolution analytical methods such as electrophoresis and chromatography such as HPLC.

[0793] As used in this article, "stereoisomer" refers to compounds that have the same chemical composition but differ in the spatial arrangement of atoms or groups. Stereoisomers include enantiomers, diastereomers, and conformational isomers.

[0794] The term "enantiomer" as used in this article refers to two stereoisomers of a compound that are non-overlapping mirror images of each other.

[0795] As used herein, the term "diastereomer" refers to a stereoisomer that has two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers possess different physical properties, such as melting point, boiling point, spectral properties, or biological activity. Mixtures of diastereomers can be separated using high-resolution analytical methods such as electrophoresis and chromatography such as HPLC.

[0796] The term "cis-trans isomers" as used in this article refers to molecules with the same molecular formula and chemical bonds that are arranged in different configurations. Cis isomers are molecules with two identical atoms or groups on the same side of the double bond, while trans isomers are molecules with two identical atoms or groups on opposite sides of the double bond.

[0797] Many organic compounds exist in optically active forms, meaning they possess the ability to rotate the plane of polarized light. In describing optically active compounds, the prefixes D and L, or R and S, are used to indicate the absolute configuration of the molecule with respect to its chiral center. The prefixes d and l, or (+) and (-), are used to indicate that the compound rotates the plane of polarized light, where (-) or l indicates that the compound is levorotatory. Compounds with the prefix (+) or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers can also be called enantiomers, and mixtures of such isomers are generally called enantiomeric mixtures. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur in chemical reactions or methods where there is no stereoselectivity or stereospecificity. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two non-optically active enantiomers. This invention includes all such possible isomers, including racemic mixtures, optically pure forms, and intermediate mixtures. If the compound contains a double bond, the substituent can be of E or Z configuration. If the compound contains a disubstituted cyclic hydrocarbon group, the cyclic hydrocarbon substituent can have a cis- or trans-configuration. That is, the compounds of the present invention include, but are not limited to, cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, racemic mixtures thereof, and other mixtures. The compounds of the present invention containing asymmetric carbon atoms can be isolated in optically active pure form or in the form of a mixture of two or more isomers. The optically active pure form can be resolved from a mixture of two or more isomers or synthesized using chiral starting materials or chiral reagents.

[0798] When the bonds with chiral carbon in the formula of this invention are depicted as a straight line... In this context, it should be understood that enantiomerically pure compounds and mixtures derived from the (R) and (S) configurations of chiral carbon are included within the scope of this formula. Unless otherwise specified, wedge-shaped solid lines represent the solid lines. and wedge-shaped dashed key The absolute configuration of the center of a solid is represented by a straight solid line key. and straight dashed key The relative configuration of the center of a solid.

[0799] Racemic mixtures can be used in their original form or resolved into individual isomers. Resolution yields stereochemically pure compounds or mixtures enriched with one or more isomers. Methods for isomer separation are well-known, including physical methods such as chromatography using chiral adsorbents. Chiral isomers can be prepared from chiral precursors. Alternatively, a single isomer can be chemically separated from a mixture by forming a diastereomeric salt with a chiral acid (e.g., a single enantiomer of 10-camphorsulfonic acid, camphoric acid, α-bromocamphoric acid, tartaric acid, diacetyltartaric acid, malic acid, pyrrolidone-5-carboxylic acid, etc.), the salt is fractionally crystallized, and one or both of the separated bases are then released. This process can optionally be repeated to obtain one or two isomers that substantially do not contain the other isomer, i.e., the desired stereoisomers with an optical purity of, for example, at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5% by weight. Alternatively, as is well known to those skilled in the art, a racemic compound can be covalently attached to a chiral compound (auxiliary compound) to obtain a diastereomeric isomer.

[0800] As used herein, the terms "tautomer" or "tautomer form" refer to structural isomers of different energies that can be interconverted via low-energy barriers. For example, proton tautomers (also known as proton transfer tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerization. Valence tautomers include interconversions via the recombination of some bonding electrons.

[0801] "Optional" or "optionally" means that the event or condition described below may occur but is not required to occur, and the description includes both the scenario in which said event or condition occurs and the scenario in which said event or condition does not occur.

[0802] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and hydrogen variants, provided that the valence state of the particular atom is normal and the substituted compound is stable. The term "optionally substituted" means that it may or may not be substituted, unless otherwise specified, and the type and number of substituents may be arbitrary on the basis of chemical feasibility.

[0803] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Therefore, for example, if a group is substituted by one, two, or three Rs, the group can optionally be substituted by up to three Rs, and each case has an independent option for R. Furthermore, combinations of substituents and / or their variants are only permitted if such combinations produce a stable compound. For example, Can be selected wait.

[0804] When one of the variables is selected as a single bond, it means that the two groups it connects to are directly connected, for example... When L2 represents a single bond, it means that the structure is actually A hyphen ("-") not between two letters or symbols indicates the connection site of a substituent. For example, C 1-6 Alkyl carbonyl group - refers to a carbonyl group connected to the rest of the molecule via a carbonyl group. 1-6 Alkyl groups. However, when the linking site of the substituent is obvious to those skilled in the art, such as halogen substituents, the "-" may be omitted.

[0805] When the listed substituents do not specify which atom they are attached to the substituted group, such substituents can be bonded to any of their atoms. For example, a pyridinium substituent can be attached to the substituted group by any carbon atom on the pyridine ring.

[0806] When the listed linking groups do not specify their linking direction, the linking direction is arbitrary, for example, The linking group L is at this time The phenyl and cyclopentyl groups can be connected in the same direction as the reading order from left to right to form the structure. Alternatively, the phenyl and cyclopentyl groups can be connected in the reverse order of reading from left to right to form the phenyl group. The combination of linking groups, substituents, and / or their variants is permitted only if such a combination produces a stable compound.

[0807] Unless otherwise specified, the term "alkyl" means a saturated hydrocarbon group containing a primary (normal) carbon atom, or a secondary carbon atom, or a tertiary carbon atom, or a quaternary carbon atom, or a combination thereof, which may represent a straight-chain and / or branched alkyl group, and may be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). Unless otherwise specifically stated in the specification, alkyl groups may optionally be substituted.

[0808] Unless otherwise specified, the term "C" 1-6 "alkyl" is used to denote a straight-chain or branched saturated hydrocarbon group consisting of 1 to 6 carbon atoms. The C 1-6 Alkyl groups include C 1-5 C 1-4 C 2-6 Alkyl groups, etc.; they can be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). C 1-6Examples of alkyl groups include, but are not limited to, methyl (“Me”), ethyl (“Et”), propyl such as n-propyl (“n-Pr”) or isopropyl (“i-Pr”), butyl such as n-butyl (“n-Bu”), isobutyl (“i-Bu”), sec-butyl (“s-Bu”) or tert-butyl (“t-Bu”), pentyl, hexyl, methylene, 1,2-ethylene, 1,3-propylene, 1,4-butylene, 1,5-pentylene, 1,6-hexylene, etc.

[0809] Unless otherwise specified, the term "C" 1-6 "Alkoxy" refers to alkyl groups containing 1 to 6 carbon atoms that are attached to the rest of the molecule by an oxygen atom. The C 1-6 Alkoxy groups include C 1-4 C 1-3 C 1-2 C 2-6 C 2-4 C6, C5, C4, and C3 alkoxy groups, etc. 1-6 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy and t-butoxy), pentoxy (including n-pentoxy, isopentoxy and neopentoxy), hexoxy, methyleneoxy, ethoxy, propoxy, butoxy, pentylooxy, etc.

[0810] Unless otherwise specified, the term "amino" can be monovalent (NH2) or divalent. Or multiple prices

[0811] Unless otherwise specified, the term "alkylamino" refers to an alkyl group attached to the remainder of a molecule by an amino group as defined above, wherein "alkyl" in "alkyl group" is defined as described above. Alkylamino groups may optionally be substituted unless specifically stated in the specification.

[0812] Unless otherwise specified, the term "alkylthio" refers to an alkyl group attached to the remainder of the molecule by a sulfur atom, wherein the "alkyl" in "alkyl group" is defined as described above. Unless specifically stated otherwise in the specification, the alkylthio group may optionally be substituted.

[0813] Those skilled in the art will understand that some compounds of formula (I) may contain one or more chiral centers, and thus have two or more stereoisomers. Therefore, the compounds of the present invention may exist as a single stereoisomer (e.g., enantiomer, diastereomer) and mixtures thereof in any proportion, such as racemates, and, where appropriate, as tautomers and geometric isomers.

[0814] As used in this article, "stereoisomer" refers to compounds that have the same chemical composition but differ in the spatial arrangement of atoms or groups. Stereoisomers include enantiomers, diastereomers, and conformational isomers.

[0815] As used in this article, "optical isomers" refers to molecules with different spatial arrangements, each exhibiting different optical rotations with respect to plane-polarized light. Optical isomers typically refer to enantiomers, meaning they are mirror images of each other. They have identical chemical structures but exhibit different directions of optical rotation due to their different spatial arrangements.

[0816] The term "enantiomer" as used in this article refers to two stereoisomers of a compound that are non-overlapping mirror images of each other.

[0817] As used herein, the term "diastereomer" refers to a stereoisomer that has two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers possess different physical properties, such as melting point, boiling point, spectral properties, or biological activity. Mixtures of diastereomers can be separated using high-resolution analytical methods such as electrophoresis and chromatography such as HPLC.

[0818] The term "cis-trans isomers" as used in this article refers to molecules with the same molecular formula and chemical bonds that are arranged in different configurations. Cis isomers are molecules with two identical atoms or groups on the same side of the double bond, while trans isomers are molecules with two identical atoms or groups on opposite sides of the double bond.

[0819] Many organic compounds exist in optically active forms, meaning they possess the ability to rotate the plane of polarized light. In describing optically active compounds, the prefixes D and L, or R and S, are used to indicate the absolute configuration of the molecule with respect to its chiral center. The prefixes d and l, or (+) and (-), are used to indicate that the compound rotates the plane of polarized light, where (-) or l indicates that the compound is levorotatory. Compounds with the prefix (+) or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers can also be called enantiomers, and mixtures of such isomers are generally called enantiomeric mixtures. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur in chemical reactions or methods where there is no stereoselectivity or stereospecificity. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two non-optically active enantiomers. This invention includes all such possible isomers, including racemic mixtures, optically pure forms, and intermediate mixtures. If the compound contains a double bond, the substituent can be of E or Z configuration. If the compound contains a disubstituted cyclic hydrocarbon group, the cyclic hydrocarbon substituent can have a cis- or trans-configuration. That is, the compounds of the present invention include, but are not limited to, cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, racemic mixtures thereof, and other mixtures. The compounds of the present invention containing asymmetric carbon atoms can be isolated in optically active pure form or in the form of a mixture of two or more isomers. The optically active pure form can be resolved from a mixture of two or more isomers or synthesized using chiral starting materials or chiral reagents.

[0820] When the bonds with chiral carbon in the formula of this invention are depicted as a straight line... In this context, it should be understood that enantiomerically pure compounds and mixtures derived from the (R) and (S) configurations of chiral carbon are included within the scope of this formula. Unless otherwise specified, wedge-shaped solid lines represent the solid lines. and wedge-shaped dashed key The absolute configuration of the center of a solid is represented by a straight solid line key. and straight dashed key The relative configuration of the center of a solid.

[0821] Racemic mixtures can be used in their original form or resolved into individual isomers. Resolution yields stereochemically pure compounds or mixtures enriched with one or more isomers. Methods for isomer separation are well-known, including physical methods such as chromatography using chiral adsorbents. Chiral isomers can be prepared from chiral precursors. Alternatively, a single isomer can be chemically separated from a mixture by forming a diastereomeric salt with a chiral acid (e.g., a single enantiomer of 10-camphorsulfonic acid, camphoric acid, α-bromocamphoric acid, tartaric acid, diacetyltartaric acid, malic acid, pyrrolidone-5-carboxylic acid, etc.), the salt is fractionally crystallized, and one or both of the separated bases are then released. This process can optionally be repeated to obtain one or two isomers that substantially do not contain the other isomer, i.e., the desired stereoisomers with an optical purity of, for example, at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5% by weight. Alternatively, as is well known to those skilled in the art, a racemic compound can be covalently attached to a chiral compound (auxiliary compound) to obtain a diastereomeric isomer.

[0822] As used herein, the terms "tautomer" or "tautomer form" refer to structural isomers of different energies that can be interconverted via low-energy barriers. For example, proton tautomers (also known as proton transfer tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerization. Valence tautomers include interconversions via the recombination of some bonding electrons.

[0823] The present application will be further described in detail 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 application. For experimental methods in the following embodiments where specific conditions are not specified, the guidance given in this application should be followed first, or experimental manuals or conventional conditions in the art can be used, or conditions recommended by the manufacturer can be followed, or experimental methods known in the art can be referenced. In the specific embodiments described below, the measurement parameters of raw material components may have slight deviations within the weighing accuracy range unless otherwise specified. For temperature and time parameters, acceptable deviations due to instrument testing accuracy or operational accuracy are allowed.

[0824] Undefined technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which this invention pertains. Detailed Implementation

[0825] The present application is described in detail below with reference to embodiments, but this does not imply any adverse limitations on the present application. The present application has been described in detail herein, and specific embodiments thereof have been disclosed. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific implementations of the present application without departing from the spirit and scope thereof.

[0826] Example 1

[0827]

[0828] Step 1:

[0829] Compound A1-1 (0.575 mol, 1.0 eq) was dissolved in a mixed solvent of 700 mL THF and 500 mL DCM. 1 mL DMF was added, and then oxalyl chloride (0.688 mol, 1.2 eq) was slowly added dropwise under an ice-water bath. The mixture was heated to room temperature and reacted for 3 hours. LC-MS showed that the starting material was completely converted. The solvent was removed by vacuum concentration, and 500 mL acetonitrile was added and distilled twice to obtain a concentrated acyl chloride solution.

[0830] Add ethyl isocyanate (0.603 mol, 1.05 eq) and 600 mL of acetonitrile to another three-necked flask, then add triethylamine (2.3 mol, 4.0 eq). Stir until dissolved, then slowly add an acetonitrile solution of acyl chloride (400 mL) under an ice-water bath and nitrogen protection. Let the mixture react overnight at room temperature. LC-MS confirmed complete conversion of the starting material. Concentrate under reduced pressure to remove most of the solvent, then add 2-methyltetrahydrofuran (800 mL) and saturated brine (800 mL). Stir to separate the layers. Extract the aqueous phase twice with 2-methyltetrahydrofuran (700 mL × 2). Combine the organic layers and concentrate under reduced pressure to obtain compound A2-1, which can be used directly in the next step.

[0831] Step 2:

[0832] Compound A2-1 was dissolved in a mixed solvent of 400 ml tetrahydrofuran and 400 ml water. Lithium hydroxide monohydrate (1.148 mol, 2.0 mol) was added, and the mixture was stirred at room temperature for 3 hours. LC-MS confirmed complete conversion of the starting material. Concentrated hydrochloric acid was added to adjust the pH of the reaction solution to approximately 9. The solution was concentrated under reduced pressure to remove most of the solvent. The resulting concentrate was stirred and slurried in 700 ml methyl tert-butyl ether for 1 hour, and then filtered. The resulting solid was dissolved in a mixed solvent of 500 ml tetrahydrofuran and 200 ml water. Acetic acid was added to adjust the pH of the reaction solution to 2-3, and the solution was concentrated under reduced pressure to remove the solvent. The resulting concentrate was stirred and slurried in 700 ml water for 2 hours, and then filtered. The filter cake was dried to obtain 127 g of compound A3-1, with a two-step yield of 75.4%. ¹H NMR (400 MHz, DMSO-d6) δ 8.64 (s, ¹H), 8.61 (s, ¹H).

[0833] Step 3:

[0834] Compound A3-1 (0.275 mol) was dissolved in 800 mL of tetrahydrofuran, 1 mL of DMF was added, and then oxalyl chloride (0.409 mol, 1.5 eq) was slowly added dropwise under an ice-water bath. The mixture was heated to room temperature and reacted for 3 hours. LC-MS showed that the starting material was completely converted. The solvent was removed by concentration under reduced pressure, and 500 mL of tetrahydrofuran was added and distilled twice to obtain a concentrated acyl chloride solution.

[0835] Add 0.33 mol (1.2 eq) of 3-isopropyl-5-methylpyridin-4-amine and 200 mL of tetrahydrofuran to another reaction flask, add DIPEA (0.55 mol, 2.0 eq) dropwise, and slowly add a tetrahydrofuran solution of acyl chloride (150 mL) under ice-water bath and nitrogen protection. Incubate overnight at room temperature. LC-MS confirms complete conversion of the starting material. Concentrate under reduced pressure to remove most of the solvent, then add 600 mL of ethyl acetate and 200 mL of water and stir to separate the layers. Extract the aqueous layer twice with ethyl acetate (300 mL × 2). Combine the organic layers, dry with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain compound A4-1, which can be used directly in the next step.

[0836] Step 4:

[0837] Compound A4-1 was dissolved in 500 ml DMF, and cesium carbonate (0.55 mol, 2.0 eq) was added. The mixture was stirred at room temperature for 4 hours. The reaction proceeds were completely converted by LC-MS. The solid was removed by diatomaceous earth filtration. The mother liquor was collected, and 800 ml ethyl acetate and 300 ml water were added. The mixture was stirred to separate the layers. The aqueous layer was extracted twice with ethyl acetate (500 ml × 2). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 71 g of compound A5-1 (0.1825 mol). The two-step yield was 66.3%. 1H NMR (400MHz, Chloroform-d) δ8.48 (s, 1H), 8.35 (d, J = 5.0Hz, 1H), 8.16 (s, 1H), 8. 05(s,1H),7.06-6.91(m,1H),3.23-3.11(m,1H),2.21(s,3H),1.30-1.09(m,6H).

[0838] Step 5:

[0839] Compound A5-1 (0.051 mol, 1.0 eq) and S-binaphthol phosphate (0.056 mol, 1.1 eq) were added to 200 ml of a 1 / 1, v / v mixture of acetone and water (Watson distilled water). The mixture was heated to 40 °C and stirred for 24 hours. Explosion occurred, and stirring became impossible. Therefore, 400 ml of the 1 / 1, v / v mixture of acetone and water was added, and stirring continued for another 24 hours. The reaction solution changed from a white suspension to a yellow suspension. The solution was filtered, washed, and dried to obtain a filter cake. The filter cake was dissolved in 300 ml of dichloromethane. Under ice-water bath conditions, 30% sodium hydroxide solution was added to adjust the pH of the solution to about 10. The mixture was stirred and separated into layers. The aqueous layer was extracted twice with dichloromethane (200 ml × 2 times). The organic layers were combined and washed successively with water and saturated brine. After drying with anhydrous sodium sulfate, the mixture was concentrated under reduced pressure to obtain compound A6-1 (0.01798 mol), with a yield of 35% and a chiral purity of 98.8%.

[0840] Step 6:

[0841] Compound A6-1 (0.051 mol, 1.0 eq) was dispersed in 2M hydrogen chloride / methanol (200 mL) and stirred at room temperature for 4 hours. LC-MS confirmed complete conversion of the starting material. The solvent was removed by concentration under reduced pressure, followed by vacuum drying to obtain compound A7-1 (0.047 mol), with a yield of 92.4%. ¹H NMR (400 MHz, Methanol-d⁴) δ 8.86 (d, J = 6.1 Hz, 1H), 8.77 (s, 1H), 8.11 (d, J = 6.1 Hz, 1H), 3.07 (m, 1H), 2.32 (s, 3H), 1.32 (dd, J = 19.5, 7.0 Hz, 6H).

[0842] Step 7:

[0843] Compound A7-1 (0.022 mol, 1.0 eq) was dissolved in 100 mL of pyridine, and 20 mL of DMF and compound Z4-1-1 (0.037 mol, 1.68 eq) were added. The reaction was carried out overnight at room temperature. LC-MS confirmed complete conversion of the starting material. The solvent was removed by concentration under reduced pressure, and the mixture was extracted with 400 mL of ethyl acetate and 200 mL of water to separate the layers. The aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 11 g of brown solid. The 11 g brown solid was dispersed in 200 mL of 1% sodium hydroxide solution and stirred for 30 minutes. The mixture was filtered, and the mother liquor was collected. 100 mL of toluene was added to the mother liquor, and the mixture was stirred to separate the layers. The aqueous layer was collected, and the pH of the aqueous layer was adjusted to approximately 2 with 10% citric acid aqueous solution. The acidic aqueous layer was extracted with dichloromethane (400 mL × 2 times). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound A8-1-1 (0.01436 mol), with a yield of 65.3%.

[0844] Synthesis of raw material Z4-1-1:

[0845]

[0846] Compound A (0.155 mol, 1.0 eq) was dissolved in a mixed solvent of methanol (160 ml) and water (160 ml). Then, under ice-water bath conditions, 50% sodium hydroxide solution was slowly added to adjust the pH of the reaction solution to approximately 10. Di-tert-butyl dicarbonate (0.232 mol, 1.5 eq) was added, and 50% sodium hydroxide solution was added again to maintain the pH at approximately 10. The reaction was carried out at room temperature for 3 hours. 200 ml of water and 200 ml of petroleum ether were added to the reaction solution, and the mixture was stirred to separate the layers. The organic layer was discarded. The pH of the aqueous layer was adjusted to approximately 3 with saturated citric acid solution. The acidic aqueous layer was extracted twice with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound B (white solid, 0.131 mol), with a yield of 84%.

[0847] Add 400 mL of acetonitrile and DMF (0.1956 mol, 1.5 eq) to a three-necked flask. Slowly add thionyl chloride (0.195 mol, 1.49 eq) under an ice-water bath and nitrogen protection. Stir the mixture at room temperature for 40 minutes. Dissolve compound B (0.131 mol, 1.0 eq) in 300 mL of acetonitrile and 21 g of pyridine. Slowly add this solution to the thionyl chloride mixture under an ice-water bath and nitrogen protection. React overnight at room temperature. Remove the solvent by vacuum concentration. Add 500 mL of ethyl acetate and 200 mL of water and stir to separate the layers. Extract the aqueous layer twice with ethyl acetate (500 mL × 2). Combine the organic layers, dry with anhydrous sodium sulfate, and concentrate under vacuum to obtain a solid. Stir the solid with 500 mL of n-heptane for 1 hour. Filter and dry to obtain compound Z4-1-1 (gray solid, 0.1147 mol), yield 87.8%. 1H NMR (400MHz, Chloroform-d) δ 4.51-4.16 (m, 3H), 4.11-3.93 (m, 1H), 3.42 (dd, J = 14.5, 6.2Hz, 1H), 2.82-2.77 (m, 1H), 1.44 (s, 9H), 1.20 (d, J = 6.5Hz, 3H).

[0848] Step 8:

[0849] Compound A8-1-1 (0.032 mol, 1.0 eq) was dissolved in 100 mL of acetonitrile, and 11.1 mL of DIPEA (0.0637 mol, 2.0 eq) was added. A 93 mL solution of TsCl (0.0382 mol, 1.2 eq) in acetonitrile was slowly added to the reaction solution. The mixture was stirred at room temperature for 1 hour. LC-MS confirmed complete conversion of the starting material. The reaction solution was concentrated under reduced pressure, dissolved in 100 mL of 2-methyltetrahydrofuran, washed twice with 100 mL of water, concentrated under reduced pressure, stirred and slurried with 100 mL of acetonitrile, filtered, and dried to obtain compound A9-1-1 (0.0216 mol), with a yield of 67% and a purity of 99.7%. 1H NMR(400MHz,Chloroform-d)δ8.61(d,J=4.9Hz,1H),8.25(d,J=8.8Hz,1H),8.13(s,1H),7.18(t,J=4.9Hz,1H),4.95(d,J=13.8Hz,1H),4. 68-4.26(m,1H),3.89-3.33(m,2H),3.22-2.81(m,2H),2.52-2.35(m,1H),1.96(d,J=15.7Hz,3H),1.56(d,J=6.7Hz,3H),1.52(s,9H),1.26 -1.00(m,6H).

[0850] Example 2

[0851]

[0852] Compound A5-1 (0.051 mol, 1.0 eq) and R-binaphthol phosphate (0.056 mol, 1.1 eq) were added to 720 mL of anisole and stirred at 10-20 °C for 3 h. Then, 36 mL of methanol was added and stirring continued for 1 h. A sample was taken (5 mL of the solid-liquid mixture was filtered, rinsed with 0.25 mL of anisole, and then rinsed with 1 mL of methyl ether; the solid and mother liquor were collected. The sampling and rinsing volumes can be scaled up proportionally). The ee value of the solid was determined; the ee value should be ≥92%. The conversion of the raw material A5-1 to ≤5% was determined by HPLC chirality of the mother liquor. If the reaction was not complete, samples were taken every 2 hours for monitoring until the reaction was complete. The filter cake was filtered and washed twice with a mixture of 440 ml anisole and 4 ml methanol, followed by two washes with 80 ml methyl tert-butyl ether. The resulting filter cake was then placed in a reaction vessel and 140 ml of n-heptane was added. The mixture was stirred for at least 2 hours, filtered, and washed twice with 30 ml of n-heptane. The filter cake was then dried. The filter cake was added to 200 ml of ethyl acetate at a controlled temperature of 10–20°C, and 15.6 g of triethylamine was added dropwise. The mixture was stirred for 1 hour until the reaction was complete. The filter cake was then filtered twice with 45 ml of ethyl acetate. The resulting filtrate was washed twice with sodium chloride aqueous solution at a controlled temperature of 10–20°C. The organic phase was rotary evaporated to a certain proportion, and n-heptane was added. The mixture was cooled, filtered, dried, and discharged to obtain compound A6-1 (0.023 mol), with a yield of 45% and a chiral purity of 98%.

[0853] Example 3

[0854]

[0855] Step 1:

[0856] Compound A7-1 (28.75 mmol) was dissolved in tetrahydrofuran (100 mL), and N,N-diisopropylethylamine (172.50 mmol) was added. The mixture was cooled to 0 °C. Triphosgene (31.63 mmol) was added in portions, and the mixture was brought to room temperature and stirred after the addition was complete. The reaction was monitored by sampling, and the reaction was confirmed to be complete. The reaction was quenched by adding ammonium chloride aqueous solution, and the mixture was stirred and clarified with ethyl acetate. The aqueous phase was extracted twice with EA, and the organic phases were combined, washed with saturated brine, dried, filtered, and concentrated to give A7-2-INT01 (11.5 g, 99% yield).

[0857] 1H NMR(400MHz,Chloroform-d)δ8.64(d,J=4.9Hz,1H),8.23(s,1H),7.19(d,J=4.9Hz ,1H),2.52–2.38(m,1H),1.95(s,3H),1.16(d,J=6.7Hz,3H),1.08(d,J=6.7Hz,3H). MS(ESI)m / z(M+H)+ =405.35.

[0858] Step 2:

[0859] The A7-2-INT01 obtained in step 1 was dispersed in DMF (100 mL), and cesium carbonate (57.50 mmol) was added and stirred at room temperature. Iodomethane (86.25 mmol) was added, and the mixture was stirred at room temperature for 2 h. The reaction was monitored and samples were taken; the reaction was complete. The aqueous phase was extracted twice with water / ethyl acetate (EA), and the organic phases were combined. The organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain A7-2-INT02 (11 g, 91% yield).

[0860] 1 H NMR(400MHz,Chloroform-d)δ8.62(d,J=4.9Hz,1H),8.21(s,1H),7.18(d,J=4.9Hz,1H),3 .71(s,3H),2.46–2.52(m,1H),1.96(s,3H),1.18(d,J=6.7Hz,3H),1.07(d,J=6.7Hz,3H). MS(ESI)m / z(M+H) + =419.36.

[0861] Step 3:

[0862] A7-2-INT02 (9.54 mmol) was dissolved in tetrahydrofuran (40 mL), and then dissolved in an aqueous solution of sodium hydroxide (38.16 mmol). The mixture was stirred at room temperature for 8 h, and samples were taken for monitoring until the reaction was complete. The reaction was quenched with an aqueous solution of citric acid, and the pH of the aqueous solution was adjusted to a weakly alkaline state. The aqueous phase was extracted twice with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated with ethyl acetate hydrochloride to give A7-M-2 (4 g, 97% yield). MS (ESI) m / z (M+H) + =393.37.

[0863] Step 4:

[0864] A7-M-2 (5.82 mmol) was dispersed in DMF (18.99 mL) solution, N,N-diisopropylethylamine (11.64 mmol) was added, followed by Z4-1-2 (11.64 mmol). The mixture was stirred at room temperature for 12 h, and samples were taken for monitoring. The reaction was complete. Water was added, and the aqueous phase was extracted twice with ethyl acetate. The organic phases were combined and washed three times with water. The organic phase was dried over anhydrous sodium sulfate, concentrated, and the resulting oil was directly added to the next step (3.0 g, yield 85%). MS (ESI) m / z (M+H) + =605.45.

[0865] Synthesis of raw material Z4-1-2:

[0866]

[0867] Compound E was dispersed in DCM (140 mL), cooled in an ice bath, and DMF (0.1–2.0 eq) was added. SOCl2 (65.38 mmol, 4.75 mL) was added dropwise, and the reaction was carried out at room temperature for 5 h. A sample was taken for control, and the reaction was complete. The reaction was quenched with water, the organic phase was separated, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to give Z4-1-2 (9.0 g, 80% yield). 1 HNMR (400MHz, DMSO-d6)δ

[0868] 4.04–3.99(m,1H),3.72–3.66(m,1H),3.52–3.39(m,2H),3.25–3.15(m,3H),1.36(s,9H).

[0869] Step 5:

[0870] Weigh out 4.95 mmol of A8-M-1-2 and dissolve it in 30 mL of THF. Add N,N-diisopropylethylamine (7.43 mmol) and TsCl (5.95 mmol) and stir at room temperature for 2 h. Monitor the reaction by taking a sample. Once the reaction is complete, add water and extract the aqueous phase twice with ethyl acetate. Combine the organic phases and wash the organic phase twice with brine. Dry the organic phase with anhydrous sodium sulfate, filter, concentrate, and perform column chromatography to obtain 2.5 g of A9-M-1-2 (83% yield).

[0871] 1H NMR (400MHz, Chloroform-d) δ8.62(d,J=4.9Hz,1H),8.19(s,1H),7.17(d,J=4.8Hz,1H),4.98(d,J=13.4Hz,1H),4.23(d,J=32.5Hz,1H),3. 48(s,3H),3.55-3.10(m,4H),2.96-2.82(m,1H),2.71-2.59(m,1H),1.89(s,3H),1.55(s,9H),1.22(d,J=6.7Hz,3H),1.18(d,J=6.7Hz,3H). MS(ESI)m / z(M+H) + =587.50.

[0872] Step 6:

[0873] 0.34 mmol of A9-M-1-2, 0.54 mmol of Z3-2-2 compound, 1.7 mmol of dipotassium hydrogen phosphate, 2% each of palladium acetate and triphenylphosphine were dispersed in 4 mL of 1,4-dioxane and 2 mL of water. The mixture was purged with nitrogen three times and heated to 80 °C for 12 hours. After sampling and analysis, the reaction was confirmed to be complete. The reaction solution was cooled to room temperature, and water and 20 mL of ethyl acetate were added. The aqueous phase was extracted twice with ethyl acetate, and the combined organic phases were used. The organic phase was washed with sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography to obtain A9-PM-1-2 (0.2 g, 89% yield). 1 H NMR(400MHz,Chloroform-d)δ8.60(d,J=4.9Hz,1H),8.32(s,1H),7.26–7.18( m,2H),6.73–6.61(m,2H),5.00(d,J=13.4Hz,1H),4.37–4.20(m,1H),3.58–3.4 6(m,4H),3.42-3.30(m,2H),3.28-3.15(m,1H),2.99-2.87(m,1H),2.83–2.70( m, 1H), 1.92 (s, 3H), 1.55 (s, 9H), 1.23 (d, J = 6.7Hz, 3H), 1.10 (d, J = 6.7Hz, 3H). MS(ESI)m / z(M+H) + =663.40.

[0874] Example 4

[0875]

[0876] Step 1:

[0877] A7-1 (2.57 mmol) was dispersed in DMF (10 mL) solution, N,N-diisopropylethylamine (5.14 mmol) was added, and Z4-1-2 (3.08 mmol) was added. The mixture was stirred at room temperature for 16 h, and samples were taken for monitoring. The reaction was complete. Water was added, and the aqueous phase was extracted twice with ethyl acetate. The organic phases were combined and washed three times with water. The organic phase was dried over anhydrous sodium sulfate, concentrated, and the resulting oil was directly added to the next step (1.3 g, yield 86%). MS (ESI) m / z (M+H) + =591.56.

[0878] Step 2:

[0879] Weigh out 0.34 mmol of A8-1-2 and dissolve it in 5 mL of THF. Add N,N-diisopropylethylamine (0.64 mmol) and TsCl (0.51 mmol) and stir at room temperature for 16 h. Monitor the reaction by taking a sample. Once the reaction is complete, add water and extract the aqueous phase twice with ethyl acetate. Combine the organic phases and wash the organic phase twice with brine. Dry the organic phase with anhydrous sodium sulfate, filter, concentrate, and perform column chromatography to obtain 0.19 g of A9-1-2 (98% yield).

[0880] 1 H NMR(400MHz,Chloroform-d)δ8.60(d,J=4.9Hz,1H),8.26(s,1H),8.18(s,1H) ,7.15(d,J=4.9Hz,1H),5.00(d,J=13.6Hz,1H),4.33–4.15(m,1H),3.72–3.57 (m,1H),3.39–3.29(m,1H),3.29–3.17(m,2H),3.08–2.94(m,1H),2.53–2.40( m, 1H), 1.93 (s, 3H), 1.51 (s, 9H), 1.16 (d, J = 6.7Hz, 3H), 1.10 (d, J = 6.7Hz, 3H). MS(ESI)m / z(M+H) + =573.57.

[0881] Step 3:

[0882] A9-1-2 (1.7 mmol) was dispersed in DMF (15 mL), and cesium carbonate (5.2 mmol) was added and stirred at room temperature. Iodomethane (8.7 mmol) was added, and the mixture was stirred at room temperature for 2 h. The reaction was monitored and the sample was taken to ensure complete reaction. The aqueous phase was extracted twice with water / ethyl acetate (EA), and the organic phases were combined. The organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain A9-M-1-2 (0.97 g, 95% yield).

[0883] 1H NMR (400MHz, Chloroform-d) δ8.62(d,J=4.9Hz,1H),8.19(s,1H),7.17(d,J=4.8Hz,1H),4.98(d,J=13.4Hz,1H),4.23(d,J=32.5Hz,1H),3. 48(s,3H),3.55-3.10(m,4H),2.96-2.82(m,1H),2.71-2.59(m,1H),1.89(s,3H),1.55(s,9H),1.22(d,J=6.7Hz,3H),1.18(d,J=6.7Hz,3H). MS(ESI)m / z(M+H)+ =587.40.

[0884] Step 4:

[0885] A9-M-1-2 (0.34 mmol), Z3-2-2 compound (0.54 mmol), dipotassium hydrogen phosphate (1.7 mmol), palladium acetate, and triphenylphosphine, 2% each, were dispersed in 1,4-dioxane (4 mL) and water (2 mL). The mixture was purged with nitrogen three times and heated to 80 °C for 12 hours. After sampling and confirming complete reaction, the reaction solution was cooled to room temperature, and water and ethyl acetate (20 mL) were added. The aqueous phase was extracted twice with ethyl acetate, and the combined organic phases were washed with sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography to obtain A9-PM-1-2 (0.2 g, 89% yield).

[0886] 1 H NMR(400MHz,Chloroform-d)δ8.60(d,J=4.9Hz,1H),8.32(s,1H),7.26–7.18( m,2H),6.73–6.61(m,2H),5.00(d,J=13.4Hz,1H),4.37–4.20(m,1H),3.58–3.4 6(m,4H),3.42-3.30(m,2H),3.28-3.15(m,1H),2.99-2.87(m,1H),2.83–2.70( m, 1H), 1.92 (s, 3H), 1.55 (s, 9H), 1.23 (d, J = 6.7Hz, 3H), 1.10 (d, J = 6.7Hz, 3H). MS(ESI)m / z(M+H) + =663.40.

[0887] Example 5

[0888]

[0889] Step 1:

[0890] A6-1 (3.4 mmol), Z3-2-2 compound (5.4 mmol), dipotassium hydrogen phosphate (17 mmol), palladium acetate, and triphenylphosphine, 2% each, were dispersed in 1,4-dioxane (40 mL) and water (20 mL). The mixture was purged with nitrogen three times and heated to 80 °C for 12 hours. After sampling and confirming complete reaction, the reaction solution was cooled to room temperature, and water and ethyl acetate (20 mL) were added. The aqueous phase was extracted twice with ethyl acetate, and the combined organic phases were washed with sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography to obtain A6-P-4 (2.3 g, 92% yield).

[0891] 1H NMR(400MHz,Chloroform-d)δ8.54(d,J=5.0Hz,1H),8.49(s,1H),8.32(s,1H),7.26–7.16(m,2H) ,6.74–6.60(m,2H),2.67–2.53(m,1H),2.04(s,3H),1.18(d,J=6.8Hz,3H),0.99(d,J=6.8Hz,3H). MS(ESI)m / z(M+H) + =465.20.

[0892] Step 2:

[0893] A6-P-4 (20.0 mmol) was dispersed in hydrochloric acid-ethanol and stirred at room temperature for 5 h. The reaction was then analyzed, and the reaction was found to be complete. A7-P-4 (10 g, 95% yield) was obtained by direct rotary evaporation.

[0894] 1 H NMR (400MHz, DMSO-d6) δ8.73(d,J=5.8Hz,1H),8.56(s,1H),7.92(t,J=5.6Hz,1H),7.26–7.14(m,1H),6.73(d,J=8.3Hz,1H),6.69 -6.58(m,3H),2.89 -2.74(m,1H),2.10(d,J=7.9Hz,3H),1.27(d,J=7.0Hz,3H),1.12(dd,J=11.0,6.9Hz,3H). MS(ESI)m / z(M+H) + =455.12.

[0895] Step 3:

[0896] A7-P-4 (4.4 mmol) was dissolved in tetrahydrofuran (20 mL), and N,N-diisopropylethylamine (26.38 mmol) was added. The mixture was cooled to 0 °C. Triphosgene (3.84 mmol) was added in portions, and the mixture was brought to room temperature and stirred after the addition was complete. The reaction was monitored by sampling until it was complete. The reaction was quenched by adding ammonium chloride aqueous solution, and the mixture was stirred and clarified with ethyl acetate. The aqueous phase was extracted twice with EA, and the organic phases were combined, washed with saturated brine, dried, filtered, concentrated, and subjected to column chromatography to obtain A7-PM-4-INT03 (2.10 g, 99% yield). MS (ESI) m / z (M+H) + =481.12.

[0897] Step 4:

[0898] A7-PM-4-INT03 (4.4 mmol) was dispersed in DMF (20 mL), and cesium carbonate (13.19 mmol) was added and stirred at room temperature. Iodomethane (21.98 mmol) was added, and the mixture was stirred at room temperature for 3 h. The reaction was monitored and the sample was taken to ensure complete reaction. The aqueous phase was extracted twice with water / ethyl acetate (EA), and the organic phases were combined. The organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography to obtain A7-PM-4-INT04 (1.9 g, yield 87%).

[0899] 1H NMR(400MHz,Chloroform-d)δ8.51(dd,J=4.9,3.5Hz,1H),8.25(d,J=1.1Hz,1H),7.31(td,J=8.4,6.6Hz,1H),7.16–7.04(m,1H),6.79–6. 60(m,2H),3.74(s,3H),3.67(d,J=7.6Hz,3H),2.66–2.50(m,1H),1.95(s,3H),1.20(dd,J=6.8,5.0Hz,3H),0.98(dd,J=13.7,6.7Hz,3H). MS(ESI)m / z(M+H) + =509.05.

[0900] Step 5:

[0901] A7-PM-4-INT04 (2.0 mmol) was dissolved in a 48% aqueous solution of hydrogen bromide, heated to 100 °C and refluxed overnight. The reaction was monitored by sampling until complete. The aqueous phase was adjusted to alkalinity with sodium carbonate solution, and the aqueous phase was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography to obtain A7-PM-4-INT05 (0.9 g, 90% yield).

[0902] 1H NMR(400MHz,Chloroform-d)δ8.54(d,J=4.9Hz,1H),8.32(s,1H),8.18(s,1H),7.25–7.13(m,2H),6.65(td,J =8.4,1.3Hz,2H),3.74(s,3H),2.50-2.62(m,1H),1.99(s,3H),1.18(d,J=6.7Hz,3H),0.99(d,J=6.7Hz,3H). MS(ESI)m / z(M+H) + =495.15.

[0903] Step 6:

[0904] A7-PM-4-INT05 (4.77 mmol) was dissolved in tetrahydrofuran (20 mL), and then dissolved in an aqueous solution of sodium hydroxide (19.08 mmol). The mixture was stirred at room temperature for 8 h, and samples were taken for monitoring until the reaction was complete. The reaction was quenched with an aqueous solution of citric acid, and the pH of the aqueous solution was adjusted to a slightly alkaline state. The aqueous phase was extracted twice with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated with ethyl acetate hydrochloride to give A7-PM-4 (1.9 g, 90% yield). MS (ESI) m / z (M+H) + =469.10.

[0905] Step 7:

[0906] A7-PM-4 (1.89 mmol) was dispersed in DMF (10.0 mL) solution, N,N-diisopropylethylamine (4.74 mmol) was added, and Z4-1-2 (2.84 mmol) was added. The mixture was stirred at room temperature for 3 h, and samples were taken for monitoring. The reaction was complete. The reaction solution was directly added to the next step. N,N-diisopropylethylamine (18 mmol) and TsCl (12 mmol) were added to the reaction mixture, and the mixture was stirred at room temperature for 3 h. Samples were taken for monitoring. The reaction was complete. Water was added, and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed three times with brine. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography to obtain A9-PM-1-2 (1.0 g, yield 80%).

[0907] 1 H NMR(400MHz,Chloroform-d)δ8.60(d,J=4.9Hz,1H),8.32(s,1H),7.26–7.18( m,2H),6.73–6.61(m,2H),5.00(d,J=13.4Hz,1H),4.37–4.20(m,1H),3.58–3.4 6(m,4H),3.42-3.30(m,2H),3.28-3.15(m,1H),2.99-2.87(m,1H),2.83–2.70( m, 1H), 1.92 (s, 3H), 1.55 (s, 9H), 1.23 (d, J = 6.7Hz, 3H), 1.10 (d, J = 6.7Hz, 3H). MS(ESI)m / z(M+H) + =663.40.

[0908] Example 6

[0909]

[0910] Step 1:

[0911] 3.4 mmol of A6-1, 5.4 mmol of compound Z3-2-2, 17 mmol of dipotassium hydrogen phosphate, 2% each of palladium acetate and triphenylphosphine were dispersed in 40 mL of 1,4-dioxane and 20 mL of water. The mixture was purged with nitrogen three times and heated to 80 °C for 12 hours. After sampling and confirming the reaction was complete, the reaction solution was cooled to room temperature, and water and 20 mL of ethyl acetate were added. The aqueous phase was extracted twice with ethyl acetate, and the combined organic phases were washed with an aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography to obtain A6-P-4 (2.3 g, 92% yield).

[0912] 1 H NMR(400MHz,Chloroform-d)δ8.54(d,J=5.0Hz,1H),8.49(s,1H),8.32(s,1H),7.26–7.16(m,2H) ,6.74–6.60(m,2H),2.67–2.53(m,1H),2.04(s,3H),1.18(d,J=6.8Hz,3H),0.99(d,J=6.8Hz,3H). MS(ESI)m / z(M+H) + =465.20.

[0913] Step 2:

[0914] A6-P-4 (20.0 mmol) was dispersed in hydrochloric acid-ethanol and stirred at room temperature for 5 h. The reaction was then analyzed and found to be complete. A7-P-4 (10 g, 95% yield) was obtained by direct rotary evaporation.

[0915] 1 H NMR (400MHz, DMSO-d6) δ8.73(d,J=5.8Hz,1H),8.56(s,1H),7.92(t,J=5.6Hz,1H),7.26–7.14(m,1H),6.73(d,J=8.3Hz,1H),6.69 -6.58(m,3H),2.89 -2.74(m,1H),2.10(d,J=7.9Hz,3H),1.27(d,J=7.0Hz,3H),1.12(dd,J=11.0,6.9Hz,3H). MS(ESI)m / z(M+H) + =455.21.

[0916] Step 3:

[0917] A7-P-4 (9.66 mmol) was dispersed in DMF (40.0 mL) solution, and Z4-1-2 (11.6 mmol) was added. The mixture was stirred at room temperature for 16 h, and samples were taken for monitoring. The reaction was complete. The reaction solution was directly added to the next step. N,N-diisopropylethylamine (91.7 mmol) and TsCl (62.8 mmol) were added to the reaction solution, and the mixture was stirred at room temperature for 2.5 h. Samples were taken for monitoring. The reaction was complete. Water was added, and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed three times with brine. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography to obtain A9-P-1-5 (yield 50%).

[0918] 1 H NMR(400MHz,Chloroform-d)δ8.53(d,J=5.0Hz,1H),8.38-8.22(m,2H),7.23–7 .09(m,2H),6.73–6.54(m,2H),4.99(d,J=16.0Hz,1H),4.34–4.14(m,1H),3.78 -3.60(m,1H),3.44–3.17(m,3H),3.05(t,J=11.2Hz,1H),2.67–2.45(m,1H ), 1.94 (s, 3H), 1.51 (s, 8H), 1.16 (d, J = 6.7Hz, 3H), 0.99 (d, J = 6.7Hz, 3H). MS(ESI)m / z(M+H) + =649.20.

[0919] Step 4:

[0920] A9-P-1-5 (1.5 mmol) was dispersed in DMF (10 mL), and cesium carbonate (4.6 mmol) was added and stirred at room temperature. Iodomethane (7.6 mmol) was added, and the mixture was stirred at room temperature for 3 h. The reaction was monitored and the sample was taken to ensure complete reaction. The aqueous phase was extracted twice with water / ethyl acetate (EA), and the organic phases were combined. The organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography to obtain A9-PM-5-INT01 (0.9 g, yield 87%).

[0921] 1H NMR(400MHz, Methanol-d4)δ8.46(d,J=1.9Hz,1H),8.38(d,J=5.0Hz,1H),7.41–7.28(m,1H),7 .26–7.16(m,1H),6.87-6.77(m,1H),6.75–6.63(m,1H),4.90(d,J=13Hz,1H),4.11(d,J=13.0H z,1H),3.86–3.73(m,1H),3.71-3.63(m,3H),3.47(s,3H),3.46–3.32(m,3H),2.90-2.74(m,2H ), 1.88 (d, J = 5.2Hz, 3H), 1.53 (s, 9H), 1.20 (dd, J = 6.8, 1.9Hz, 3H), 1.03 (dd, J = 6.8, 2.7Hz, 3H). MS(ESI)m / z(M+H) + =677.21. Step 5:

[0922] A9-PM-5-INT01 (0.73 mmol) was dissolved in a 48% aqueous solution of hydrogen bromide, heated to 100 °C and refluxed overnight. The reaction was monitored by sampling until complete. The aqueous phase was adjusted to alkalinity with sodium carbonate solution, and the aqueous phase was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography to obtain A9-TM-5 (0.37 g, 90% yield).

[0923] 1 H NMR (400MHz, Methanol-d4) δ8.48(s,1H),8.42(d,J=5.0Hz,1H),7.24(d,J=5.0Hz,1H ),7.18(td,J=8.4,6.7Hz,1H),6.62(d,J=8.3Hz,1H),6.60–6.51(m,1H),4.00(d,J=13 .3Hz,1H),3.94(d,J=3.8Hz,1H),3.52(s,4H),3.50–3.38(m,3H),2.91(t,J=11.3Hz, 1H), 2.82 (p, J = 6.8Hz, 1H), 1.91 (s, 3H), 1.20 (d, J = 6.7Hz, 3H), 1.05 (d, J = 6.7Hz, 3H). MS(ESI)m / z(M+H) + =563.40.

[0924] Example 7

[0925]

[0926] Step 1:

[0927] A7-1 was dissolved in tetrahydrofuran (100 mL), and N,N-diisopropylethylamine (172.50 mmol) was added. The mixture was cooled to 0 °C. Triphosgene (31.63 mmol) was added in portions, and the mixture was brought to room temperature and stirred after the addition was complete. The reaction was monitored by sampling, and the reaction was confirmed to be complete. The reaction was quenched by adding ammonium chloride aqueous solution, and the mixture was stirred and clarified with ethyl acetate. The aqueous phase was extracted twice with EA, and the organic phases were combined, washed with saturated brine, dried, filtered, and concentrated to obtain A7-2-INT01 (11.5 g, 99% yield).

[0928] 1H NMR(400MHz,Chloroform-d)δ8.64(d,J=4.9Hz,1H),8.23(s,1H),7.19(d,J=4.9Hz ,1H),2.52–2.38(m,1H),1.95(s,3H),1.16(d,J=6.7Hz,3H),1.08(d,J=6.7Hz,3H). MS(ESI)m / z(M+H) + =405.35.

[0929] Step 2:

[0930] A7-2-INT01 was dispersed in DMF (100 mL), and cesium carbonate (57.50 mmol) was added and stirred at room temperature. Iodomethane (86.25 mmol) was added, and the mixture was stirred at room temperature for 2 h. The reaction was monitored and samples were taken; the reaction was complete. The aqueous phase was extracted twice with water / ethyl acetate (EA), and the organic phases were combined. The organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain A7-2-INT02 (11 g, 91% yield).

[0931] 1 H NMR(400MHz,Chloroform-d)δ8.62(d,J=4.9Hz,1H),8.21(s,1H),7.18(d,J=4.9Hz,1H),3 .71(s,3H),2.46–2.52(m,1H),1.96(s,3H),1.18(d,J=6.7Hz,3H),1.07(d,J=6.7Hz,3H). MS(ESI)m / z(M+H) + =419.36.

[0932] Step 3:

[0933] A7-2-INT02 (11.69 mmol), compound Z3-2-2, dipotassium hydrogen phosphate (51.44 mmol), palladium acetate, and triphenylphosphine, 5% each, were dispersed in 1,4-dioxane (80 mL) and water (40 mL). The mixture was purged with nitrogen three times and heated to 80 °C for 12 hours. After sampling and analysis, the reaction was confirmed to be complete. The reaction solution was cooled to room temperature, and water and ethyl acetate (200 mL) were added. The aqueous phase was extracted twice with ethyl acetate, and the combined organic phases were used. The organic phase was washed with sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography to obtain A7-PM-4-INT05 (5 g, yield 86%).

[0934] 1 H NMR(400MHz,Chloroform-d)δ8.54(d,J=4.9Hz,1H),8.32(s,1H),8.18(s,1H),7.25–7.13(m,2H),6.65(td,J =8.4,1.3Hz,2H),3.74(s,3H),2.50-2.62(m,1H),1.99(s,3H),1.18(d,J=6.7Hz,3H),0.99(d,J=6.7Hz,3H). MS(ESI)m / z(M+H) + =495.15.

[0935] Step 4:

[0936] A7-PM-4-INT05 (4.0 mmol) was dissolved in tetrahydrofuran (15 mL), and an aqueous solution of sodium hydroxide (16 mmol) was added to dissolve it. The mixture was stirred at room temperature for 8 h, and samples were taken for monitoring. The reaction was complete. The solution was quenched with citric acid aqueous solution, and the pH of the aqueous solution was adjusted to a slightly alkaline state. The aqueous phase was extracted twice with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give A7-PM-4 (1.7 g, 90% yield). MS (ESI) m / z (M+H) + =469.14.

[0937] Step 5:

[0938] A7-PM-4 (3 mmol) was dispersed in DMF (8 mL) solution, N,N-diisopropylethylamine (3 mmol) was added, and Z4-1-2 (3.9 mmol) was added. The mixture was stirred at room temperature for 4 h, and samples were taken for monitoring. The reaction was complete. Water was added, and the aqueous phase was extracted twice with ethyl acetate. The organic phases were combined and washed three times with water. The organic phase was dried over anhydrous sodium sulfate, concentrated, and the resulting oil was directly added to the next step. (1.7 g, yield 85%). MS (ESI) m / z (M+H) + =681.36.

[0939] Step 6:

[0940] A8-PM-1-4 (2.4 mmol) was weighed and dissolved in THF (20 mL). N,N-diisopropylethylamine (4.2 mmol) and TsCl (3.3 mmol) were added, and the mixture was stirred at room temperature for 3 h. The reaction was monitored by sampling. Once complete, water was added, and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed twice with brine. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography to obtain A9-PM-1-2 (1.2 g, 70% yield).

[0941] 1 H NMR(400MHz,Chloroform-d)δ8.60(d,J=4.9Hz,1H),8.32(s,1H),7.26–7.18( m,2H),6.73–6.61(m,2H),5.00(d,J=13.4Hz,1H),4.37–4.20(m,1H),3.58–3.4 6(m,4H),3.42-3.30(m,2H),3.28-3.15(m,1H),2.99-2.87(m,1H),2.83–2.70( m, 1H), 1.92 (s, 3H), 1.55 (s, 9H), 1.23 (d, J = 6.7Hz, 3H), 1.10 (d, J = 6.7Hz, 3H). MS(ESI)m / z(M+H) + =663.40.

[0942] Example 8

[0943]

[0944] Step 1:

[0945] Under nitrogen protection, LiHMDS (bis-(trimethylsilyl)amine lithium) (4.0 eq) was added to a reaction flask and cooled to -10°C. Al-1 (1.0 eq) and 2-isopropyl-4-methylpyridin-3-amine S4 (1.1 eq) were dissolved in anhydrous tetrahydrofuran. The tetrahydrofuran solution of Al-1 and S4 was added dropwise to the LiHMDS reactor while maintaining the temperature at -5°C to 0°C. The reaction was maintained at -5°C to 0°C for 4 hours. Sampling was performed to monitor the reaction, which was confirmed to be complete. The reaction was quenched with water, the solvent was evaporated, and water and methyl tert-butyl ether were added. The pH was adjusted to approximately 6 with concentrated hydrochloric acid, resulting in the precipitation of a solid. Stirring was continued for another half hour. The solid was filtered, washed successively with methyl tert-butyl ether and water, and dried to obtain E3-1 (27.0 g, 90% yield).

[0946] 1H NMR (400MHz, DMSO-d6) δ9.91 (s, 1H), 8.34 (d, J = 4.8Hz, IH), 8.27 (s, 1H), 7.1 8(d,J=4.8Hz,1H),3.17-3.07(m,1H),2.13(s,3H),1.12(s,3H),1.11(s,3H). MS(ESI)m / z(M+H) + =340.50.

[0947] Step 2:

[0948] E4-1 (23.62 mmol) was dissolved in CHCl3 (40 mL), and E3-1 (11.81 mmol) was added to the solution. The reaction was carried out overnight at room temperature until the starting material was completely converted. The solvent was removed by concentration under reduced pressure, and the semi-solid was purified by column chromatography. The semi-solid was purified by slurrying with petroleum ether and methyl tert-butyl ether, filtered, washed, and dried to obtain E5-1 (3.85 g, yield 75%).

[0949] 1H NMR(400MHz,Chloroform-d)δ8.40(d,J=4.9Hz,1H),8.00(d,J=2.4Hz,2H),7.03(d,J=5.0Hz,1H),4 .43(q,J=7.1Hz,2H),3.48–3.05(m,1H),2.17(s,3H),1.40(t,J=7.2Hz,3H),1.21(d,J=6.8Hz,6H).

[0950] Step 3:

[0951] E5-1 (23.0 mmol) was dissolved in THF (100 mL), and then NaOH (45.9 mmol) was added. The mixture was stirred at room temperature for 5 hours until the starting material was completely converted. The solution was adjusted to neutral with acetic acid, and then extracted with ethyl acetate and water to separate the layers. The organic layers were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain A5-1 (9.0 g, 98% yield).

[0952] Example 9

[0953]

[0954] Compound A7-1 (0.022 mol, 1.0 eq) was dissolved in 20 mL of DMF, and compound Z4-1-1 (0.022 mol, 1.0 eq) was added. The reaction was carried out overnight at 32 °C. LC-MS confirmed complete conversion of the starting material. The mixture was extracted with 400 mL of ethyl acetate and 200 mL of water to separate the layers. The aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Column chromatography was used to obtain compound A8-1-1 (0.021 mol) in 95% yield.

[0955] Example 10

[0956]

[0957] Compound A7-1 (0.022 mol, 1.0 eq) was dissolved in 20 mL of DMF, compound Z4-1-1 (0.022 mol, 1.0 eq) was added, followed by sodium bicarbonate (0.011 mol, 0.5 eq). The reaction was carried out overnight at 32 °C. LC-MS confirmed complete conversion of the starting material. The mixture was extracted with 400 mL of ethyl acetate and 200 mL of water to separate the layers. The aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Column chromatography yielded compound A8-1-1 (0.021 mol), with a yield of 95%.

[0958] The exemplary embodiments of the present invention have been described above. It should be understood that the scope of protection of this application is not limited to the exemplary embodiments described above. Any modifications, equivalent substitutions, improvements, etc., made by those skilled in the art within the spirit and principles of the present invention should be included within the scope of protection of this application.

Claims

1. A method for preparing a compound of formula A2 or its optical isomer, characterized in that, Includes the following steps: Compound A2 is prepared by contacting compound A1 and compound Z1. R1 and R2 are independently selected from -H, -F, -Cl, -Br or -I, respectively; R3 is selected from -F, -Cl, -Br, or -I; R4 is selected from ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl.

2. The method for preparing the compound of formula A2 or its optical isomer according to claim 1, characterized in that, The preparation of the compound of formula A2 includes the following steps: An acylation reaction is carried out between the compound of formula A1 and an acylation reagent to prepare an acyl halide compound; or an azidation reaction is carried out between the compound of formula A1 and an azide reagent to prepare an acyl azide intermediate. The acyl halide compound or the acyl azide intermediate is subjected to a cyclization reaction with the compound of formula Z1 to form an oxazole ring, thereby preparing the compound of formula A2.

3. A compound of formula A2 or its optical isomer: in, The definitions of R1 to R4 are as described in claim 1; The compound of formula A2 is preferably...

4. A method for preparing a compound of formula A3 or its optical isomer, characterized in that, Includes the following steps: Compound A2 was hydrolyzed to prepare compound A3. The definitions of R1 to R4 are as described in claim 1.

5. A method for preparing a compound of formula A4 or its optical isomer, characterized in that, Includes the following steps: Compound A2 was hydrolyzed to prepare compound A3. Compound A4 was prepared by amidation of compound A3 and compound Z2. The definitions of R1 to R4 are as described in claim 1; R5 and R6 are independently selected from -H, -F, -Cl, and -C, respectively. 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl and C 1-6 The alkoxy group can be optionally surrounded by 1, 2 or 3 R groups. a replace; Each occurrence of R7 is independently selected from -H, -F, -Cl, -Br, -I, hydroxyl, amino, nitro, cyano, and C. 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl and C 1-6 The alkoxy group can be optionally surrounded by 1, 2 or 3 R groups. a replace; R a Each occurrence is independently selected from -H, -F, -Cl, -Br, -I, -OH, -NH2, -CH3, -CF3, -C2H5, -CN, -SF5, -CHO, -COOH, or -C(=O)NH2; m is selected from 0, 1, or 2.

6. The method for preparing the compound of formula A4 or its optical isomer according to claim 5, characterized in that, The preparation of the compound of formula A4 includes the following steps: The compound of formula A3 is subjected to an acylation reaction with an acylation reagent to prepare an acyl halide compound; The acyl halide compound was subjected to a substitution reaction with the compound of formula Z2 to prepare the compound of formula A4.

7. A compound of formula A4 or an optical isomer thereof: in, The definitions of R1 to R3 are as described in claim 1; the definitions of R5 to R7 and m are as described in claim 5; The compound of formula A4 is preferably...

8. A method for preparing a compound of formula E5 or its optical isomer, characterized in that, Includes the following steps: Compound E3 was subjected to an addition cyclization reaction with compound E4 to prepare compound E5. Wherein, the definitions of R1 to R2 are as described in claim 1; the definitions of R5 to R7 and m are as described in claim 5; R 4a It is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.

9. A compound of formula E5 or an optical isomer thereof: in, The definitions of R1 to R2 are as described in claim 1; the definitions of R5 to R7 and m are as described in claim 5; R 4a The definition is as described in claim 8; The E5 compound is preferably...

10. A method for preparing a compound of formula AA5 or its optical isomer, characterized in that, Includes the following steps: Compound A4 was subjected to a nucleophilic substitution reaction to prepare compound AA5. Alternatively, the E5 compound can be contacted with a base to undergo an amino-ester exchange reaction to prepare the AA5 compound; Wherein, R1 to R3 are defined as described in claim 1; R5 to R7 and m are defined as described in claim 5; R 4a The definition is as described in claim 8.

11. A compound of formula A5 or an optical isomer thereof: in, The definitions of R1 to R2 are as described in claim 1; the definitions of R5 to R7 and m are as described in claim 5; R 13 Selected from H or methyl; The compound of formula A5 is preferably...

12. The compound of formula A5 or its optical isomer according to claim 11, characterized in that, When R 13 When the methyl group is used, the compound of formula A5 is prepared by the following method: Compound A7' was prepared by hydrolysis and ring-opening reaction of compound AA5. Compound of formula A7' is subjected to a cyclization reaction with substance P to prepare compound of formula A5; wherein substance P is selected from acetyl chloride, acetic anhydride or trimethyl orthoacetate.

13. A method for preparing a compound of formula A5-P or its optical isomer, characterized in that, Includes the following steps: Compound A5-P was prepared by coupling compound A5 with compound Z3. Wherein, the Z3 compound is a compound of formula Z3-1 or formula Z3-2; The definitions of R1 to R2 are as described in claim 1; the definitions of R5 to R7 and m are as described in claim 5; R 13 The definition is as described in claim 11; R Z Each occurrence is independently selected from H or C. 1-6 Alkyl, the C 1-6 Alkyl groups may be optionally surrounded by 1, 2, or 3 R's. b replace; R 10 R 11 Each group is independently selected from -H, -F, -Cl, -Br, -I, hydroxyl, amino, nitro, cyano, and C. 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl and C 1-6 The alkoxy group can be optionally surrounded by 1, 2 or 3 R groups. b replace; R 12 Each occurrence is independently selected from -H, -F, -Cl, -Br, -I, hydroxyl, amino, nitro, cyano, and C. 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl and C 1-6 The alkoxy group can be optionally surrounded by 1, 2 or 3 R groups. b replace; R b Each occurrence is independently selected from -H, -F, -Cl, -Br, -I, -OH, -NH2, -CH3, -CF3, -C2H5, -CN, -SF5, -CHO, -COOH, or -C(=O)NH2; n is selected from 0, 1, 2 or 3.

14. A compound of formula A5-P or an optical isomer thereof: in, The definition of R2 is as described in claim 1; the definitions of R5 to R7 and m are as described in claim 5; R 13 The definition is as described in claim 11; R 10 ~R 12 The definition of n is as described in claim 13; The A5-P compound is preferably...

15. A method for preparing a compound of formula A6, a compound of formula D6, or an optical isomer thereof, characterized in that, Includes the following steps: The compound of formula A5 is contacted with substance L and chiral resolution is performed to prepare compound of formula A6 or compound of formula D6. Wherein, the definitions of R1 to R2 are as described in claim 1; the definitions of R5 to R7 and m are as described in claim 5; R 13 The definition is as described in claim 11; The substance L is one or more selected from S-binaphthol phosphate, D-3-bromocamphor-10-sulfonic acid, D-(+)-camphorsulfonic acid, S-3,3'-bis(triphenylsilyl)binaphthol phosphonate, S-3,3'-bis(3,5-bistrifluoromethoxyphenyl)-1,1'-bi-(2-naphthol) phosphate, and S-3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthol-2,2'-bisphosphate. Or one or more of the following: R-binaphthol phosphate, L-3-bromocamphor-10-sulfonic acid, L-(+)-camphor sulfonic acid, R-3,3'-bis(triphenylsilyl)binaphthol phosphonate, R-3,3'-bis(3,5-bistrifluoromethoxyphenyl)-1,1'-bi-(2-naphthol) phosphate and R-3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthol-2,2'-bisphosphate.

16. The method for preparing the compound of formula A6, the compound of formula D6, or their optical isomers according to claim 15, characterized in that, The chiral decomposition includes the following steps: A salt-forming intermediate compound is prepared by reacting compound A5 with substance L to form a salt. The salt-type intermediate compound is reacted with a free reagent to prepare compound A6 or compound D6.

17. A compound of formula A6, a compound of formula D6, substance N, or an optical isomer thereof, wherein substance N comprises the compound of formula A6 and the compound of formula D6: in, The definitions of R1 to R2 are as described in claim 1; the definitions of R5 to R7 and m are as described in claim 5; R 13 The definition is as described in claim 11; The compound of formula A6 is preferably... The D6 compound is preferably... The substance N is preferably a mixture of any of the following groups: mixtures mixtures mixtures mixtures mixtures mixtures mixtures A mixture.

18. A method for preparing a compound of formula A6-P, a compound of formula D6-P, or an optical isomer thereof, characterized in that, Includes the following steps: The A5-P compound and substance L are contacted and chiral resolution is performed to prepare the A6-P compound or the D6-P compound. or Compound A6-P or compound D6 is prepared by coupling compound Z3 with compound Z3. Wherein, the Z3 compound is a compound of formula Z3-1 or formula Z3-2; The definitions of R1 to R2 are as described in claim 1; the definitions of R5 to R7 and m are as described in claim 5; R Z R 10 ~R 12 The definition of n is as described in claim 13; R 13 The definition is as described in claim 11; The definition of substance L is as described in claim 15; The steps and conditions for chiral splitting are as described in claim 15 or 16.

19. A compound of formula A6-P, a compound of formula D6-P, a substance M, or an optical isomer thereof, wherein the substance M comprises the compound of formula A6-P and the compound of formula D6-P: in, The definition of R2 is as described in claim 1; the definitions of R5 to R7 and m are as described in claim 5; R 10 ~R 12 The definition of n is as described in claim 13; R 13 The definition is as described in claim 11; The A6-P compound is preferably... The D6-P compound is preferably... The substance M is preferably a mixture of any of the following groups: mixtures mixtures mixtures A mixture.

20. A method for preparing a compound of formula A7, a compound of formula A7', an optical isomer thereof, or a pharmacologically acceptable salt thereof, characterized in that, Includes the following steps: The compound of formula A5 is subjected to a hydrolytic ring-opening reaction to prepare the compound of formula A7' or its pharmacologically acceptable salt; or The A6 compound is subjected to a hydrolytic ring-opening reaction to prepare the A7 compound or its pharmacologically acceptable salt; or the A7' compound or its pharmacologically acceptable salt is contacted with a chiral acid to perform chiral resolution, thereby preparing the A7 compound or its pharmacologically acceptable salt. Wherein, the definitions of R1 to R2 are as described in claim 1; the definitions of R5 to R7 and m are as described in claim 5; R 13 The definition is as described in claim 11.

21. The method for preparing the compound of formula A7, the compound of formula A7', or their optical isomers according to claim 20, characterized in that, The compound of formula A7 is prepared by neutralization reaction of a salt of formula A7 that is pharmacologically acceptable to the compound of formula A7; and / or the compound of formula A7' is prepared by neutralization reaction of a salt of formula A7' that is pharmacologically acceptable to the compound of formula A7'.

22. A method for preparing a compound of formula A7-P, its optical isomer, or a pharmacologically acceptable salt thereof, characterized in that, Includes the following steps: The A6-P compound is subjected to a hydrolysis ring-opening reaction to prepare the A7-P compound or its pharmacologically acceptable salt. or Compound A7 or its pharmacologically acceptable salt is prepared by coupling compound Z3 with compound A7-P or its pharmacologically acceptable salt. Wherein, the Z3 compound is a compound of formula Z3-1 or formula Z3-2; The definition of R2 is as described in claim 1; the definitions of R5 to R7 and m are as described in claim 5; R Z R 10 ~R 12 The definition of n is as described in claim 13; R 13 The definition is as described in claim 11.

23. A method for preparing a compound of formula A7'-P, its optical isomer, or a pharmacologically acceptable salt thereof, characterized in that, Includes the following steps: The compound of formula A5-P is subjected to a hydrolytic ring-opening reaction to prepare the compound of formula A7'-P or its pharmacologically acceptable salt; or The A7' compound or its pharmacologically acceptable salt is coupled with the Z3 compound to prepare the A7'-P compound or its pharmacologically acceptable salt. Wherein, the Z3 compound is a compound of formula Z3-1 or formula Z3-2; The definition of R2 is as described in claim 1; the definitions of R5 to R7 and m are as described in claim 5; R Z R 10 ~R 12 The definition of n is as described in claim 13; R 13 The definition is as described in claim 11.

24. A compound of formula A7, a compound of formula A7', a compound of formula A7-P, a compound of formula A7'-P, an optical isomer thereof, or a pharmacologically acceptable salt thereof: in, The definitions of R1 to R2 are as described in claim 1; the definitions of R5 to R7 and m are as described in claim 5; R 10 ~R 12 The definition of n is as described in claim 13; The compound of formula A7 is preferably... The compound of formula A7' is preferably... The A7-P compound is preferably... The compound of formula A7'-P is preferably...

25. A method for preparing a compound of formula A7-M, a compound of formula A7'-M, its optical isomer, or a pharmacologically acceptable salt thereof, characterized in that, Includes the following steps: The compound of formula A7 or its pharmacologically acceptable salt is contacted with a carbonyl-containing compound to carry out a ring-closure reaction, thereby preparing the compound of formula A7-intermediate 1 or its pharmacologically acceptable salt. The compound of formula A7-intermediate 1 or its pharmacologically acceptable salt is contacted with a methylating agent to carry out a methylation reaction, thereby preparing compound of formula A7-intermediate 2 or its pharmacologically acceptable salt; The compound of formula A7-intermediate 2 or its pharmacologically acceptable salt is hydrolyzed to prepare compound of formula A7-M or its pharmacologically acceptable salt. or The compound of formula A7' or its pharmacologically acceptable salt is contacted with a carbonyl-containing compound to carry out a ring-closure reaction, thereby preparing the compound of formula A7'-intermediate 1 or its pharmacologically acceptable salt; The A7'-intermediate 1 compound or its pharmacologically acceptable salt is contacted with a methylating agent to carry out a methylation reaction, thereby preparing the A7'-intermediate 2 compound or its pharmacologically acceptable salt; The compound of formula A7'-intermediate 2 or its pharmacologically acceptable salt is hydrolyzed to prepare compound of formula A7'-M or its pharmacologically acceptable salt. The definitions of R1 to R2 are as described in claim 1; the definitions of R5 to R7 and m are as described in claim 5.

26. A method for preparing a compound of formula A7-PM, a compound of formula A7'-PM, its optical isomer, or a pharmacologically acceptable salt thereof, characterized in that, Includes the following steps: The compound of formula A7-P or its pharmacologically acceptable salt is contacted with a carbonyl-containing compound to carry out a ring-closure reaction, thereby preparing the compound of formula A7-P-intermediate 1 or its pharmacologically acceptable salt. The compound of formula A7-P-intermediate 1 or its pharmacologically acceptable salt is contacted with a methylating agent to carry out a methylation reaction, thereby preparing compound of formula A7-P-intermediate 2 or its pharmacologically acceptable salt. The compound of formula A7-P-intermediate 2 or its pharmacologically acceptable salt is prepared by hydrolysis. or The compound of formula A7 or its pharmacologically acceptable salt is contacted with a carbonyl-containing compound to carry out a ring-closure reaction, thereby preparing the compound of formula A7-PM-intermediate 1 or its pharmacologically acceptable salt. The compound of formula A7-PM-intermediate 1 or its pharmacologically acceptable salt is contacted with a methylating agent to carry out a methylation reaction, thereby preparing compound of formula A7-PM-intermediate 2 or its pharmacologically acceptable salt; Compound A7-PM-intermediate 2 or its pharmacologically acceptable salt is coupled with compound Z3 to prepare compound A7-PM-intermediate 3. The compound of formula A7-PM-intermediate 3 or its pharmacologically acceptable salt is prepared by hydrolysis. or The compound of formula A7'-P or its pharmacologically acceptable salt is contacted with a carbonyl-containing compound to carry out a ring-closure reaction, thereby preparing the compound of formula A7'-P-intermediate 1 or its pharmacologically acceptable salt. The compound of formula A7'-P-intermediate 1 or its pharmacologically acceptable salt is contacted with a methylating agent to carry out a methylation reaction, thereby preparing compound of formula A7'-P-intermediate 2 or its pharmacologically acceptable salt; The compound of formula A7'-P-intermediate 2 or its pharmacologically acceptable salt is prepared by hydrolysis. Wherein, the Z3 compound is a compound of formula Z3-1 or formula Z3-2; The definition of R2 is as described in claim 1; the definitions of R5 to R7 and m are as described in claim 5; R Z R 10 ~R 12 The definition of n is as described in claim 13.

27. A compound of formula A7-M, a compound of formula A7'-M, a compound of formula A7-PM, a compound of formula A7'-PM, an optical isomer thereof, or a pharmacologically acceptable salt thereof: in, The definitions of R1 to R2 are as described in claim 1; the definitions of R5 to R7 and m are as described in claim 5; R 10 ~R 12 The definition of n is as described in claim 13; The A7-M compound is preferably... The compound of formula A7'-M is preferably... The A7-PM compound is preferably... The A7'-PM compound is preferably...

28. A method for preparing a compound of formula AA7, a compound of formula AA7', a compound of formula AA7-P, a compound of formula AA7'-P, a compound of formula AA7-M, a compound of formula AA7'-M, a compound of formula AA7-PM, a compound of formula AA7'-PM, an optical isomer thereof, or a pharmacologically acceptable salt thereof, characterized in that, Includes the following steps: Compounds of formula A7, A7', A7-P, A7'-P, A7-M, A7'-M, A7-PM, or A7'-PM are prepared by subjecting compounds of formula A7, A7'-P, A7'-P, A7-M, A7'-M, A7-PM, or A7'-PM to hydroxyl protection reactions. Wherein, the definitions of R1 to R2 are as described in claim 1; the definitions of R5 to R7 and m are as described in claim 5; R 10 ~R 12 The definition of n is as described in claim 13; R 14 is -O-(S=O)2-R 15 、-OC(=O)R 16 or -O-R 17 ; R 15 Selected from methyl or phenyl, wherein the methyl or phenyl group is optionally surrounded by 1, 2 or 3 R groups. d replace; R 16 Selected from methyl or phenyl, wherein the methyl or phenyl group is optionally surrounded by 1, 2 or 3 R groups. d replace; R 17 Selected from hydroxyl protecting groups; R d Each time it appears, it is independently selected from H, F, methyl, or nitro.

29. A compound of formula AA7, a compound of formula AA7', a compound of formula AA7-P, a compound of formula AA7'-P, a compound of formula AA7-M, a compound of formula AA7'-M, a compound of formula AA7-PM, a compound of formula AA7'-PM, an optical isomer thereof, or a pharmacologically acceptable salt thereof: in, The definitions of R1 to R2 are as described in claim 1; the definitions of R5 to R7 and m are as described in claim 5; R 10 ~R 12 The definition of n is as described in claim 13; R 14 The definition is as described in claim 28; R 14 Preferred options are -O-TBS, -O-MOM, -OTs, -Oms, -OAc, or -OBz.

30. The use of a compound of formula Z4 in the preparation of compounds of formula A8, A8', A8-P, A8'-P, A8-M, A8'-M, A8-PM, A8'-PM, A9, A9', A9-P, A9'-P, A9-M, A9'-M, A9-PM, A9'-PM, their optical isomers, or their pharmacologically acceptable salts, in, The definitions of R1 to R2 are as described in claim 1; the definitions of R5 to R7 and m are as described in claim 5; R 10 ~R 12 The definition of n is as described in claim 13; when When the dashed line represents a single bond, Y is CH(R9), Z is CH2, and W is selected from N(R8); when When the dashed line in the diagram is absent, Y is a protecting group of H, R8, or hydroxyl, Z is H, and W is selected from NH or O. R8 is selected from an amino protecting group, Ns, acryloyl group, or 3-chloropropionyl group; R9 is selected from -H, -F, -Cl, -Br, -I, hydroxyl, amino, nitro, cyano, C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl and C 1-6 The alkoxy group can be optionally surrounded by 1, 2 or 3 R groups. c replace; R c Each occurrence is independently selected from -H, -F, -Cl, -Br, -I, -OH, -NH2, -CH3, -CF3, -C2H5, -CN, -SF5, -CHO, -COOH, or -C(=O)NH2.

31. The application according to claim 30, characterized in that, The Z4 compound is selected from... When R9 is not -H, the compound of formula Z4-1 is The Z4-1 compound is preferably... The Z4-2 compound is preferably...

32. The application according to claim 31, characterized in that, The preparation of the compound of formula Z4-1 includes the following steps: Compound Z4b was prepared by subjecting compound Z4a to an amino protection reaction with ditert-butyl dicarbonate. The Z4b compound was subjected to an acylation and cyclization reaction with thionyl chloride to prepare the Z4-1 compound.

33. A method for preparing a compound of formula A8, a compound of formula A8', its optical isomer, or a pharmacologically acceptable salt thereof, characterized in that, Includes the following steps: Compound A7 or its pharmacologically acceptable salt is prepared by amidation reaction with compound Z4 to prepare compound A8 or its pharmacologically acceptable salt. Alternatively, the compound of formula A6 may be subjected to a hydrolysis ring-opening reaction, and after the hydrolysis ring-opening reaction is completed, the compound of formula Z4 may be added to carry out an amidation reaction to prepare the compound of formula A8 or its pharmacologically acceptable salt. or Compound A7' or its pharmacologically acceptable salt is prepared by amidation reaction with compound Z4 to prepare compound A8' or its pharmacologically acceptable salt; Alternatively, the compound of formula A5 may be subjected to a hydrolysis ring-opening reaction, and after the hydrolysis ring-opening reaction is completed, the compound of formula Z4 may be added to carry out an amidation reaction to prepare the compound of formula A8' or its pharmacologically acceptable salt. Wherein, the definitions of R1 to R2 are as described in claim 1; the definitions of R5 to R7 and m are as described in claim 5; R 13 The definitions of are as described in claim 11; the definitions of W, Y, and Z are as described in claim 30.

34. A method for preparing a compound of formula A8-P, a compound of formula A8'-P, its optical isomer, or a pharmacologically acceptable salt thereof, characterized in that, Includes the following steps: Compound A7-P or its pharmacologically acceptable salt is prepared by amidation reaction with compound Z4; Alternatively, the compound of formula A6-P may be subjected to a hydrolysis ring-opening reaction, and after the hydrolysis ring-opening reaction is completed, the compound of formula Z4 may be added to carry out an amidation reaction to prepare the compound of formula A8-P or its pharmacologically acceptable salt. or Compound A7'-P or its pharmacologically acceptable salt is prepared by amidation reaction with compound Z4; Alternatively, the compound of formula A5-P may be subjected to a hydrolysis ring-opening reaction, and after the hydrolysis ring-opening reaction is completed, the compound of formula Z4 may be added to carry out an amidation reaction to prepare the compound of formula A8'-P or its pharmacologically acceptable salt. Wherein, R2 is defined as described in claim 1; R5 to R7 and m are defined as described in claim 5; R 10 ~R 12 The definition of n is as described in claim 13; R 13 The definitions of are as described in claim 11; the definitions of W, Y, and Z are as described in claim 30.

35. A method for preparing a compound of formula A8-M, a compound of formula A8'-M, its optical isomer, or a pharmacologically acceptable salt thereof, characterized in that, Includes the following steps: Compound A7-M or its pharmacologically acceptable salt is prepared by amidation reaction with compound Z4; or Compound A7'-M or its pharmacologically acceptable salt is prepared by amidation reaction with compound Z4; Wherein, the definitions of R1 to R2 are as described in claim 1; the definitions of R5 to R7 and m are as described in claim 5; and the definitions of W, Y, and Z are as described in claim 30.

36. A method for preparing a compound of formula A8-PM, a compound of formula A8'-PM, its optical isomer, or a pharmacologically acceptable salt thereof, characterized in that, Includes the following steps: Compound A7-PM or its pharmacologically acceptable salt is prepared by ring-opening reaction with compound Z4; or Compound of formula A7'-PM or its pharmacologically acceptable salt is prepared by amidation reaction with compound of formula Z4; Wherein, R2 is defined as described in claim 1; R5 to R7 and m are defined as described in claim 5; R 10 ~R 12 The definitions of n are as described in claim 13; the definitions of W, Y, and Z are as described in claim 30.

37. A compound of formula A8, a compound of formula A8', a compound of formula A8-P, a compound of formula A8'-P, a compound of formula A8-M, a compound of formula A8'-M, a compound of formula A8-PM, a compound of formula A8'-PM, an optical isomer thereof, or a pharmacologically acceptable salt thereof: in, The definitions of R1 to R2 are as described in claim 1; the definitions of R5 to R7 and m are as described in claim 5; R 10 ~R 12 The definitions of n are as described in claim 13; the definitions of W, Y, and Z are as described in claim 30.

38. The compound of formula A8, formula A8', formula A8-P, formula A8'-P, formula A8-M, formula A8'-M, formula A8-PM, formula A8'-PM, their optical isomers, or their pharmacologically acceptable salts according to claim 37, characterized in that, The compound of formula A8 is selected from The compound of formula A8-1 is preferably... The compound of formula A8-2 is preferably... The compound of formula A8' is selected from... The compound of formula A8'-1 is preferably... The compound of formula A8'-2 is preferably... The A8-M compound is selected from... The A8-M-1 compound is preferably... The A8-M-2 compound is preferably... The compound of formula A8'-M is selected from... The compound of formula A8'-M-1 is preferably... The compound of formula A8'-M-2 is preferably... The A8-P compound is selected from... The A8-P-1 compound is preferably... The A8-P-2 compound is preferably... The compound of formula A8'-P is selected from... The compound of formula A8'-P-1 is preferably... The compound of formula A8'-P-2 is preferably... The compound of formula A8-PM is selected from... The compound of formula A8-PM-1 is preferably... The compound of formula A8-PM-2 is preferably... The compound of formula A8'-PM is selected from... The compound of formula A8'-PM-1 is preferably... The compound of formula A8'-PM-2 is preferably...

39. A method for preparing a compound of formula AA8, a compound of formula AA8', a compound of formula AA8-P, a compound of formula AA8'-P, a compound of formula AA8-M, a compound of formula AA8'-M, a compound of formula AA8-PM, a compound of formula AA8'-PM, an optical isomer thereof, or a pharmacologically acceptable salt thereof, characterized in that, Includes the following steps: Compounds of formula AA7, AA7', AA7-P, AA7'-P, AA7-M, AA7'-M, AA7-PM, AA7'-PM, their optical isomers, or their pharmacologically acceptable salts are prepared by amidation reaction with compound Z4 to prepare compounds of formula AA8, AA8', AA8-P, AA8'-P, AA8-M, AA8'-M, AA8-PM, AA8'-PM, their optical isomers, or their pharmacologically acceptable salts. Wherein, the definitions of R1 to R2 are as described in claim 1; the definitions of R5 to R7 and m are as described in claim 5; R 10 ~R 12 The definition of n is as described in claim 13; R 14 The definition of is as described in claim 28; the definitions of W, Y and Z are as described in claim 30; the conditions for the amidation reaction are as described in any one of claims 33 to 36.

40. A compound of formula AA8, a compound of formula AA8', a compound of formula AA8-P, a compound of formula AA8'-P, a compound of formula AA8-M, a compound of formula AA8'-M, a compound of formula AA8-PM, a compound of formula AA8'-PM, an optical isomer thereof, or a pharmacologically acceptable salt thereof: in, The definitions of R1 to R2 are as described in claim 1; the definitions of R5 to R7 and m are as described in claim 5; R 10 ~R 12 The definition of n is as described in claim 13; R 14 The definitions of are as described in claim 28; the definitions of W, Y, and Z are as described in claim 30.

41. A method for preparing a compound of formula A9, a compound of formula A9', or an optical isomer thereof, characterized in that, Includes the following steps: Compound A9 is prepared by cyclizing a compound of formula A8 or its pharmacologically acceptable salt; or by hydrolyzing and ring-opening a compound of formula A6, adding a compound of formula Z4 after the hydrolysis and ring-opening reaction, performing an amidation reaction, and then performing a cyclization reaction after the amidation reaction. or Compound A9' is prepared by cyclizing a compound of formula A8' or its pharmacologically acceptable salt; or compound A5 is prepared by hydrolysis and ring-opening reaction, compound Z4 is added after the hydrolysis and ring-opening reaction is completed, amidation reaction is carried out, and cyclization reaction is carried out after the amidation reaction is completed, to prepare compound A9'. Wherein, the definitions of R1 to R2 are as described in claim 1; the definitions of R5 to R7 and m are as described in claim 5; R 13 The definitions of are as described in claim 11; the definitions of W, Y, and Z are as described in claim 30.

42. The method for preparing the compound of formula A9, the compound of formula A9', or their optical isomers according to claim 41, characterized in that, The compound of formula A8 is a compound of formula A8-1, and the compound of formula A9-1 is prepared; or the compound of formula A8 is a compound of formula A8-2, and the compound of formula A9-2 is prepared; Alternatively, the compound of formula A9-2 can be contacted with an ethyl derivative and cyclized via nucleophilic substitution and reductive amination to prepare the compound of formula A9-1. Alternatively, the compound of formula A8' may be a compound of formula A8'-1, and a compound of formula A9'-1 may be prepared; or the compound of formula A8' may be a compound of formula A8'-2, and a compound of formula A9'-2 may be prepared. Alternatively, the compound of formula A9'-2 can be contacted with an ethyl derivative and cyclized via nucleophilic substitution and reductive amination to prepare the compound of formula A9'-1. The definitions of W, Y, R8, and R9 are as described in claim 30.

43. A method for preparing a compound of formula A9-P, a compound of formula A9'-P, or an optical isomer thereof, characterized in that, Includes the following steps: Compound A9-P is prepared by cyclizing a compound of formula A8-P or its pharmacologically acceptable salt; or by hydrolyzing and ring-opening a compound of formula A6-P, adding a compound of formula Z4 after the hydrolysis and ring-opening reaction, performing an amidation reaction, and then performing a cyclization reaction after the amidation reaction. or Compound A9'-P is prepared by cyclizing a compound of formula A8'-P or its pharmacologically acceptable salt; or by hydrolyzing and ring-opening a compound of formula A5-P, adding a compound of formula Z4 after the hydrolysis and ring-opening reaction, performing an amidation cyclization reaction, and then performing a cyclization reaction after the amidation reaction. Wherein, R2 is defined as described in claim 1; R5 to R7 and m are defined as described in claim 5; R 10 ~R 12 The definitions of n are as described in claim 13; the definitions of W, Y, and Z are as described in claim 30; R 13 The definition is as described in claim 11.

44. The method for preparing the compound of formula A9-P, the compound of formula A9'-P, or their optical isomers according to claim 43, characterized in that, The compound of formula A8-P is a compound of formula A8-P-1, and the compound of formula A9-P-1 is prepared; Alternatively, the compound of formula A8-P may be an A8-P-2 compound, and a compound of formula A9-P-2 may be prepared. Alternatively, the compound of formula A9-P-2 can be contacted with an ethyl derivative and cyclized through nucleophilic substitution and reductive amination to prepare the compound of formula A9-P-1. Alternatively, the compound of formula A8'-P may be a compound of formula A8'-P-1, and a compound of formula A9'-P-1 may be prepared. Alternatively, the compound of formula A8'-P may be an A8'-P-2 compound, and a compound of formula A9'-P-2 may be prepared. Alternatively, the compound of formula A9'-P-2 can be contacted with an ethyl derivative and cyclized via nucleophilic substitution and reductive amination to prepare the compound of formula A9'-P-1. The definitions of W, Y, R8, and R9 are as described in claim 28.

45. A method for preparing a compound of formula A9-M, a compound of formula A9'-M, or an optical isomer thereof, characterized in that, Includes the following steps: Compound A9-M is prepared by cyclizing a compound of formula A8-M or its pharmacologically acceptable salt. or Compound A9'-M is prepared by cyclizing a compound of formula A8'-M or its pharmacologically acceptable salt. Wherein, the definitions of R1 to R2 are as described in claim 1; the definitions of R5 to R7 and m are as described in claim 5; and the definitions of W, Y, and Z are as described in claim 30.

46. ​​The method for preparing the compound of formula A9-M, the compound of formula A9'-M, or their optical isomers according to claim 45, characterized in that, The compound of formula A8-M is a compound of formula A8-M-1, and a compound of formula A9-M-1 is prepared; or the compound of formula A8-M is a compound of formula A8-M-2, and a compound of formula A9-M-2 is prepared. Alternatively, the compound of formula A9-M-2 can be contacted with an ethyl derivative and cyclized via nucleophilic substitution and reductive amination to prepare the compound of formula A9-M-1. Alternatively, the compound of formula A8'-M may be a compound of formula A8'-M-1, and a compound of formula A9'-M-1 may be prepared; or the compound of formula A8'-M may be a compound of formula A8'-M-2, and a compound of formula A9'-M-2 may be prepared. Alternatively, the compound of formula A9'-M-2 can be contacted with an ethyl derivative and cyclized via nucleophilic substitution and reductive amination to prepare the compound of formula A9'-M-1. The definitions of W, Y, R8, and R9 are as described in claim 30.

47. A method for preparing a compound of formula A9-PM, a compound of formula A9'-PM, or an optical isomer thereof, characterized in that, Includes the following steps: Compound A9-PM was prepared by cyclizing a compound of formula A8-PM or its pharmacologically acceptable salt. or Compound A9'-PM is prepared by cyclizing a compound of formula A8'-PM or its pharmacologically acceptable salt. Wherein, R2 is defined as described in claim 1; R5 to R7 and m are defined as described in claim 5; R 10 ~R 12 The definitions of n are as described in claim 13; the definitions of W, Y, and Z are as described in claim 30.

48. The method for preparing the compound of formula A9-PM, the compound of formula A9'-PM, or their optical isomers according to claim 47, characterized in that, The compound of formula A8-PM is a compound of formula A8-PM-1, and a compound of formula A9-PM-1 is prepared; or the compound of formula A8-M is a compound of formula A8-PM-2, and a compound of formula A9-PM-2 is prepared. Alternatively, the compound of formula A9-PM-2 can be contacted with an ethyl derivative and cyclized via nucleophilic substitution and reductive amination to prepare the compound of formula A9-PM-1. Alternatively, the compound of formula A8'-PM may be a compound of formula A8'-PM-1, and a compound of formula A9'-PM-1 may be prepared; or the compound of formula A8'-PM may be a compound of formula A8'-PM-2, and a compound of formula A9'-PM-2 may be prepared. Alternatively, the compound of formula A9'-PM-2 can be contacted with an ethyl derivative and cyclized via nucleophilic substitution and reductive amination to prepare the compound of formula A9'-PM-1. The definitions of W, Y, R8, and R9 are as described in claim 30.

49. A method for preparing a compound of formula A9, a compound of formula A9', a compound of formula A9-P, a compound of formula A9'-P, a compound of formula A9-M, a compound of formula A9'-M, a compound of formula A9-PM, a compound of formula A9'-PM, or an optical isomer thereof, characterized in that, Includes the following steps: Compound AA8 was subjected to a dehydroxylation protection reaction to prepare compound A8, and then compound A8 was subjected to a cyclization reaction to prepare compound A9; wherein, when R 14 -O-(S=O)2-R 15 In this case, the method for preparing compound A9 does not involve the step of preparing compound A8 from compound AA8, but directly performs a cyclization reaction on compound AA8 to prepare compound A9. Compound of formula AA8' was subjected to a dehydroxylation protection reaction to prepare compound of formula A8', and then compound of formula A8' was subjected to a cyclization reaction to prepare compound of formula A9'; wherein, when R 14 -O-(S=O)2-R 15 In this case, the method for preparing compound A9' does not involve the step of preparing compound A8' from compound AA8', but directly performs a cyclization reaction on compound AA8' to prepare compound A9'. Compound AA8-P was subjected to a dehydroxylation protection reaction to prepare compound A8-P, and then compound A8-P was subjected to a cyclization reaction to prepare compound A9-P; wherein, when R 14 -O-(S=O)2-R 15 In this case, the method for preparing compound A9-P does not involve the step of preparing compound A8-P from compound AA8-P, but directly performs a cyclization reaction on compound AA8-P to prepare compound A9-P. The compound of formula AA8'-P was subjected to a dehydroxylation protection reaction to prepare compound A8'-P, and then the compound of formula A8'-P was subjected to a cyclization reaction to prepare compound A9'-P; wherein, when R 14 -O-(S=O)2-R 15 In this case, the method for preparing compound A9'-P does not involve the step of preparing compound A8'-P from compound AA8'-P, but directly performs a cyclization reaction on compound AA8'-P to prepare compound A9'-P. Compound AA8-M was subjected to a dehydroxylation protection reaction to prepare compound A8-M, and then compound A8-M was subjected to a cyclization reaction to prepare compound A9-M; wherein, when R 14 -O-(S=O)2-R 15 In this case, the method for preparing compound A9-M does not involve the step of preparing compound A8-M from compound AA8-M, but directly performs a cyclization reaction on compound AA8-M to prepare compound A9-M. Compound AA8'-M was subjected to a dehydroxylation protection reaction to prepare compound A8'-M, and then compound A8'-M was subjected to a cyclization reaction to prepare compound A9'-M; wherein, when R 14 -O-(S=O)2-R 15 In this case, the method for preparing compound A9'-M does not involve the step of preparing compound A8'-M from compound AA8'-M, but directly performs a cyclization reaction on compound AA8'-M to prepare compound A9'-M; The compound of formula AA8-PM was subjected to a dehydroxylation protection reaction to prepare compound A8-PM, and then the compound of formula A8-PM was subjected to a cyclization reaction to prepare compound A9-PM; wherein, when R 14 -O-(S=O)2-R 15 In this case, the method for preparing compound A9-PM does not involve the step of preparing compound A8-PM from compound AA8-P, but directly performs a cyclization reaction on compound AA8-PM to prepare compound A9-PM. The compound of formula AA8'-PM was subjected to a dehydroxylation protection reaction to prepare compound A8'-PM, and then the compound of formula A8'-PM was subjected to a cyclization reaction to prepare compound A9'-PM; wherein, when R 14 -O-(S=O)2-R 15 In this case, the method for preparing compound A9'-PM does not involve the step of preparing compound A8'-PM from compound AA8'-P, but directly performs a cyclization reaction on compound AA8'-PM to prepare compound A9'-PM. Wherein, the definitions of R1 to R2 are as described in claim 1; the definitions of R5 to R7 and m are as described in claim 5; R 10 ~R 12 The definition of n is as described in claim 13; R 14 R 15 The definitions of are as described in claim 28; the definitions of W, Y, and Z are as described in claim 30.

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