Polysubstituted macrocyclic compounds, as well as methods for their preparation and use.

Abstract

The present invention provides a compound represented by general formula (I), or a racemic mixture thereof, or an isomer thereof, or a pharmaceutically acceptable salt thereof, and a method for treating several specific diseases or conditions using the same. [Formula 1] JPEG2026521953000041.jpg5364

Description

[Technical Field]

[0001] This invention belongs to the field of chemical drugs and provides polysubstituted macrocyclic compounds as inhibitors of selectivity factor XIa (abbreviated as FXIa), as well as methods for preparing and using the same. The invention also relates to pharmaceutical compositions containing these compounds and to the use of these compounds in drugs for treating diseases such as thromboembolism. [Background technology]

[0002] Cardiovascular and cerebrovascular diseases, including cerebrovascular disease, cerebral infarction, myocardial infarction, coronary heart disease, and arteriosclerosis, claim nearly 12 million lives worldwide each year, accounting for almost a quarter of all global deaths, making them the greatest enemy of human health. In China, more than 2.6 million people die from cardiovascular disease each year, and 75% of surviving patients suffer disabilities, with over 40% of those suffering severe disabilities. Cardiovascular and cerebrovascular diseases, diabetes, and thrombosis caused by their complications are urgent problems that need to be addressed today.

[0003] The human blood coagulation process consists of the intrinsic pathway, the extrinsic pathway, and the common pathway (Annu. Rev. Med. 2011. 62:41-57), and is a chain reaction in which the process is constantly strengthened and expanded by the sequential activation of multiple enzyme precursors. The blood coagulation cascade reaction is initiated by the intrinsic pathway (also called the contact activation pathway) and the extrinsic pathway (also called the tissue factor pathway) to produce FXa, which then proceeds through the common pathway to produce thrombin (FIIa), and finally forms fibrin.

[0004] The intrinsic pathway is when factor XII is activated and XIa-VIIIa-Ca 2+ - This process forms the PL complex and activates factor X, and the extrinsic coagulation pathway involves the release of tissue factor (TF) and TF-VIIa-Ca 2+This is the process of forming a complex and activating factor X. The common pathway refers to the process in which, after factor Xa is formed, the two pathways merge into one, activating prothrombin and ultimately producing fibrin. Here, FXI is necessary for maintaining the intrinsic pathway and plays a crucial role in the amplification of the blood coagulation cascade reaction. In the blood coagulation cascade reaction, thrombin can feedback-activate FXI, and activated FXI (FXIa) promotes the massive production of thrombin, thereby amplifying the blood coagulation cascade reaction. Therefore, FXI antagonists have been widely developed for the treatment of various thrombi.

[0005] Conventional anticoagulants such as warfarin, heparin, and low molecular weight heparin (LMWH), as well as newer drugs recently launched such as FXa inhibitors (rivaroxaban, apixaban, etc.) and thrombin inhibitors (dabigatran etexilate, hirudin, etc.), all have good effects in reducing thrombus formation and occupy a wide range of cardiovascular and cerebrovascular markets due to their remarkable efficacy. However, their side effects are also becoming increasingly prominent, and among them, "bleeding risk" is one of the most important issues (N Engl J Med1991;325:153-8, Blood.2003;101:4783-4788).

[0006] Studies have shown that in thrombosis models, inhibition of factor FXIa can effectively inhibit thrombus formation, but in more severe cases of thrombosis, the effect of FXIa is minimal (Blood. 2010;116(19):3981-3989). Clinical statistics show that increasing the amount of FXIa increases the incidence of VTE (Blood 2009;114:2878-2883), while severe FXIa deficiency reduces the risk of developing DVT (Thromb Haemost 2011;105:269-273).

[0007] Currently, patent applications disclosing compounds with FXIa inhibitory activity as novel targets for inhibiting thrombosis include WO9630396, WO9941276, WO2013093484, WO2004002405, WO2013056060, WO2017005725, WO2017 / 023992, and WO2018041122. [Overview of the Initiative]

[0008] This invention provides a series of macrocyclic derivatives, methods for preparing them, and their use in pharmaceuticals.

[0009] Specifically, in a first embodiment, the present invention provides a compound represented by general formula (I), or an isomer thereof, or a racemic mixture thereof, or a pharmaceutically acceptable salt thereof. [ka]

[0010] In a second embodiment, the present invention further provides a pharmaceutical composition comprising a therapeutically effective amount of any one of the compounds described above or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0011] In a third aspect, the present invention provides the use of a therapeutically effective amount of the above compound or a pharmaceutically acceptable salt thereof in a drug, specifically, as a selective factor XIa (FXIa) inhibitor in the preparation of drugs for treating diseases such as thromboembolism.

[0012] Specifically, the present invention is realized by the following technical proposal.

[0013] A compound represented by general formula (I), or its isomer, or its racemic mixture, or a pharmaceutically acceptable salt thereof, [ka] X is selected from hydrogen, halogen, and cyano groups, Y is selected from hydrogen, halogen, and cyano groups, Z is selected from hydrogen, halogen, and cyano groups, and at least two of X, Y, and Z are not hydrogen. W is selected from C or N. When W is N, R 1 does not exist. T1 and T2 are selected from C or N. When T1 is selected from N, R 2c does not exist. When T2 is selected from N, R 2b does not exist, and T1 and T2 are not N at the same time. Ring A is selected from a substituted or unsubstituted benzene ring and pyrazole ring. The substituents are selected from halogen, cyano group, alkyl group, and halogenated alkyl group. R 1 is selected from halogen, halogenated alkyl group, and cyano group. R 2a 、R 2b 、R 2c are independently selected from hydrogen, halogen, and alkoxy group. R 3 is selected from alkyl group, halogenated alkyl group, alkoxy group, -(CH2)n-cycloalkyl group, and -(CH2)n-heterocycloalkyl group, where n = 0 or 1. R 4 is selected from hydrogen and halogen.

[0014] As a preferred technical solution of the present invention, it is selected from the compounds represented by formula (Ia) or formula (Ib), or their isomers, or their racemates, or their pharmaceutically acceptable salts.

Chemical formula

[0015] As a preferred technical example of the present invention, the alkyl group is C 1-6 Selected from alkyl groups, the C 1-6 The alkyl group is selected from methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, sec-pentyl group, 1-ethylpropyl group, 2-methylbutyl group, tert-pentyl group, 1,2-dimethylpropyl group, isopentyl group, neopentyl group, n-hexyl group, isohexyl group, sec-hexyl group, tert-hexyl group, neohexyl group, 2-methylpentyl group, 1,2-dimethylbutyl group, and 1-ethylbutyl group.

[0016] As a preferred technical example of the present invention, the alkoxy group is C 1-6 Selected from alkoxy groups, the C 1-6The alkoxy group is selected from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, sec-pentoxy, 1-ethylpropoxy, 2-methylbutoxy, tert-pentoxy, 1,2-dimethylpropoxy, isopentoxy, neopentoxy, n-hexyloxy, isohexyloxy, sec-hexyloxy, tert-hexyloxy, neohexyloxy, 2-methylpentoxy, 1,2-dimethylbutoxy, and 1-ethylbutoxy.

[0017] As a preferred technical example of the present invention, the halogen is selected from fluorine, chlorine, bromine, and iodine.

[0018] In a preferred technical application of the present invention, the halogenated alkyl group means that one or more hydrogen atoms in the alkyl group are substituted with a halogen, and the halogen is selected from fluorine, chlorine, bromine, and iodine.

[0019] As a preferred technical example of the present invention, the cycloalkyl group is C 3-6 Selected from cycloalkyl groups, the C 3-6 The cycloalkyl group is selected from a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group, and the heterocycloalkyl group means that one or more carbon atoms of the cycloalkyl group are substituted with a heteroatom, the heteroatom is selected from nitrogen, oxygen, and sulfur, and there is one or more heteroatoms.

[0020] As a preferred technical example of the present invention, The aforementioned W is selected from C or N, and if W is N, R 1 It does not exist. X is selected from hydrogen and fluorine, Y is selected from hydrogen and fluorine, Z is selected from hydrogen and fluorine, and at least two of X, Y and Z are not hydrogen. T1 and T2 are selected from C or N, and if T1 is selected from N, R 2cIf there is no such thing as T2 being selected from N, then R 2b It does not exist, and T1 and T2 cannot be N at the same time. R 1 R is selected from chlorine, trifluoromethyl group, and difluoromethyl group. 2a , R 2b , R 2c R is independently selected from hydrogen, methoxy group, fluorine, and chlorine. 3 R is selected from methyl groups, 4 R is selected from hydrogen and fluorine. 5 The group is selected from a methyl group and a difluoromethyl group.

[0021] A preferred technical application of the present invention is that one or more hydrogen atoms of the compound are isotopic hydrogen ( 2 It is replaced by H).

[0022] As a preferred technical example of the present invention, the above-mentioned compound is selected from the compounds represented by the following formula. [ka] JPEG2026521953000006.jpg174108

[0023] As a preferred technical application of the present invention, a pharmaceutically acceptable salt of the compound is provided, where a pharmaceutically acceptable salt of the compound refers to one prepared from the compound, or an isomer thereof, or a racemic mixture thereof, and a pharmaceutically acceptable acid or base.

[0024] As a preferred technical example of the present invention, a pharmaceutical composition is provided comprising a therapeutically effective amount of the compound, or an isomer thereof, or a racemate thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0025] A preferred technical application of the present invention is to provide pharmaceutical uses of the compound, or its isomers, or its racemic mixture, or its pharmaceutically acceptable salts, specifically, use in the preparation of drugs for treating FXIa-related diseases, preferably in the preparation of drugs for treating thrombosis-related diseases.

[0026] For clarity, this specification defines common terms used to describe compounds.

[0027] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. Unless otherwise specified, any particular term or phrase should not be considered uncertain or ambiguous, but should be understood in its ordinary sense. Where a trade name is mentioned herein, it means the corresponding product or its active ingredient. As used herein, “pharmaceutically acceptable” means a compound, material, composition, and / or dosage form that, within the bounds of reliable medical judgment, is suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, and that is commensurate with an appropriate benefit-risk ratio.

[0028] The term "pharmaceutically acceptable salt" refers to a salt of the compound of the present invention, which is prepared from a compound having a specific substituent found in the present invention and a pharmaceutically acceptable acid or base.

[0029] In addition to salt forms, the compounds provided in this invention also exist in prodrug forms. The prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions and are converted into the compounds of the present invention. Furthermore, the prodrugs can be converted into the compounds of the present invention by chemical or biochemical methods in the in vivo environment.

[0030] Certain compounds of the present invention may exist in solvated forms, including non-solvated and hydrated forms. In general, the solvated forms are equivalent to the non-solvated forms and fall within the scope of the present invention.

[0031] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention intends that all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures, and other mixtures such as mixtures rich in enantiomers or diastereomers, are within the scope of the present invention. Substituents such as alkyl groups may have other chiral carbon atoms. All such isomers and mixtures thereof are within the scope of the present invention.

[0032] Optically active (R)- and (S)-isomers, as well as D and L isomers, can be prepared using chiral synthesis, chiral reagents, or conventional techniques. To obtain one enantiomer of a compound of the present invention, it is prepared by asymmetric synthesis or derivatization of a chiral auxiliary, in which case the resulting diastereomer mixture is separated and the auxiliary groups are cleaved to obtain the pure enantiomer of the desired type. Alternatively, if the molecule contains a basic functional group (e.g., an amino group) or an acidic functional group (e.g., a carboxyl group), a salt of the diastereomer is formed with a suitable optically active acid or base, and then the diastereomer is divided by a conventional method known in the art, after which the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomers is generally achieved by chromatography, which uses a chiral stationary phase and is optionally combined with chemical derivatization methods (e.g., formation of carbamates from amines).

[0033] The atoms of the compound molecules of the present invention are isotopes, and isotopic derivatization can typically result in effects such as extended half-life, reduced clearance, improved metabolic stability, and enhanced in vivo activity. Furthermore, embodiments include those in which at least one atom is substituted with an atom having the same number of atoms (number of protons) but a different mass number (total of protons and neutrons). Examples of isotopes contained in the compounds of the present invention include, 2 H, 3H, 13 C, 14 C, 15 N, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Contains hydrogen atoms, carbon atoms, nitrogen atoms, oxygen atoms, phosphorus atoms, sulfur atoms, fluorine atoms, and chlorine atoms, including Cl. In particular, radioactive isotopes that emit radiation upon decay, for example 3 H or 14 C can be used in local anatomical testing of pharmaceutical formulations or in vivo compounds. Stable isotopes can be used safely because their quantity does not decay or change and they are not radioactive. When the atoms constituting the molecule of the compound of the present invention are isotopes, they can be converted according to general methods by using the corresponding isotopic reagent in place of the reagent in the synthesis.

[0034] In the compound of the present invention, one or more atoms constituting the compound may contain atomic isotopes in non-natural ratios. For example, deuterium ( 2 H), Iodine-125( 125 I) or C-14 ( 14 Compounds can be labeled with radioactive isotopes such as C). All isotopic transformations of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.

[0035] Furthermore, one or more hydrogen atoms in the compound of the present invention are isotopic hydrogen ( 2 When substituted with H, the compounds of the present invention, after deuteration, exhibit effects such as extended half-life, reduced clearance, improved metabolic stability, and enhanced in vivo activity.

[0036] The method for preparing the isotope derivatives typically involves a phase-transfer catalytic method. For example, a preferred deuteration method uses a phase-transfer catalyst (e.g., tetraalkylammonium salt, NBu4HSO4). Exchanging methylene protons in a diphenylmethane compound using a phase-transfer catalyst results in higher deuterium uptake compared to reduction using a deuterated silane (e.g., triethyldeuterated silane) in the presence of an acid (e.g., methanesulfonic acid), or using a Lewis acid such as aluminum trichloride and sodium deuteborate.

[0037] The term "pharmaceutically acceptable carrier" refers to any pharmaceutical carrier or medium that can deliver an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and does not cause toxicity or side effects to the host or patient. Typical carriers include water, oil, vegetables and minerals, cream bases, detergent bases, ointment bases, etc. These bases include suspending agents, thickeners, transdermal absorption enhancers, etc. These formulations are well known to those skilled in the art in the fields of cosmetics or topical medicine. Further information regarding carriers can be found in Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.

[0038] The term "excipient" refers to a carrier, diluent, and / or medium necessary for preparing an effective pharmaceutical composition.

[0039] With respect to drugs or pharmacological activators, the term "effective dose" or "therapeutic dose" refers to a sufficient amount of the drug or agent that is non-toxic and can achieve the desired effect. With respect to oral dosage forms in this invention, the "effective dose" of one active substance in a composition refers to the amount required to achieve the desired effect when used in combination with another active substance in that composition. Determining the effective dose varies from person to person, depending on the subject's age and general circumstances, as well as the specific active substance. The appropriate effective dose in each case can be determined by a person skilled in the art through conventional testing.

[0040] The terms "active ingredient," "therapeutic agent," "active substance," or "activator" refer to chemical substances that can effectively treat a target disorder, disease, or condition.

[0041] "Optional" or "optional" means that the event or situation described thereafter may occur, but is not required, and that the description includes cases where the event or situation may or may not occur.

[0042] The compounds of the present invention can be prepared by various synthesis methods well known to those skilled in the art, and include, but are not limited to, the specific embodiments listed below, embodiments in combination with other chemical synthesis methods, and equivalent alternative forms well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present invention. [Modes for carrying out the invention]

[0043] The present invention will be described in more detail below with reference to examples, but the embodiments of the present invention are not limited thereto.

[0044] Example 1 (3S,7R)-3-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-6-oxopyrimidine-1(6H)-yl)-2 4 ,2 5 -difluoro-7-methyl-1 1 -(methyl-d3)-1 1 Synthesis of H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclonononaphane-8-one(1)

[0045] The specific synthesis route is as follows: [ka]

[0046] 6-(5-chloro-2-(4-chloro-1H-1,2,3-triazole-1-yl)phenyl)pyrimidine-4-(3H)-one (53.0 mg, 0.173 mmol) was dissolved in dried anhydrous 1,4-dioxane (6 mL), and then lithium bis(trimethylsilyl)amide (1 mol / L tetrahydrofuran solution, 0.173 mL, 0.173 mmol) was slowly added. The resulting reaction mixture was stirred at room temperature for 30 minutes. Then, (7R)-2 4 ,2 5 -difluoro-7-methyl-1 1 -(methyl-d3)-8-oxo-1 1 H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclononafane-3-yl-4-nitrobenzenesulfonate (90.3 mg, 0.173 mmol) was added and the mixture was reacted at 70°C for 16 hours.

[0047] After monitoring to indicate completion of the reaction, the mixture was cooled to room temperature. 25 mL of saturated ammonium chloride aqueous solution and 30 mL of ethyl acetate were added to the reaction mixture and separated. The resulting organic phase was washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 14 / 1). Further purification by preparative high-performance liquid chromatography yielded 17.9 mg of a white solid (3S,7R)-3-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazole-1-yl)phenyl)-6-oxopyrimidine-1(6H)-yl)-2 4 ,2 5 -difluoro-7-methyl-1 1 -(methyl-d3)-1 1 H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclononafane-8-one (yield: 16.5%) was obtained. LC-MS: RT=2.00min,[M+H] + = 627.99. 1H NMR(400MHz,DMSO-d6)δ9.23(s,1H),8.71(s,1H),8.27(s,1H),7.91(d,J=2.3H z,1H),7.86-7.80(m,2H),7.75(d,J=8.5Hz,1H),7.54(d,J=6.0Hz,1H),7.45(s, 1H),6.46(s,1H),5.63(d,J=12.3Hz,1H),2.46-2.36(m,2H),1.98-1.91(m,1H), 1.79-1.71(m,1H),1.51-1.37(m,2H),1.11-1.05(m,1H),1.02(d,J=6.7Hz,3H).

[0048] Example 2 (3R,7R)-3-(4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazole-1-yl)phenyl)-6-oxopyrimidine-1(6H)-yl)-2 4 ,2 5 -difluoro-7-methyl-1 1 -(methyl-d3)-1 1 Synthesis of H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclonononaphane-8-one(2)

[0049] The specific synthesis route is as follows: [ka]

[0050] 6-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazole-1-yl)phenyl)pyrimidine-4-(3H)-one (80.0 mg, 0.234 mmol) was dissolved in dried anhydrous 1,4-dioxane (8 mL), and then lithium bis(trimethylsilyl)amide (1 mol / L tetrahydrofuran solution, 0.234 mL, 0.234 mmol) was slowly added. The resulting reaction mixture was stirred at room temperature for 30 minutes. Then, (7R)-2 4 ,2 5 -difluoro-7-methyl-1 1 -(methyl-d3)-8-oxo-1 1H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclononafane-3-yl-4-nitrobenzenesulfonate (122 mg, 0.234 mmol) was added, and the mixture was reacted at 70°C for 16 hours.

[0051] After monitoring to indicate completion of the reaction, the mixture was cooled to room temperature. 25 mL of saturated ammonium chloride aqueous solution and 50 mL of ethyl acetate were added to the reaction mixture and separated. The resulting organic phase was washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 14 / 1). Further purification by preparative high-performance liquid chromatography yielded 33.2 mg of a white solid (3S,7R)-3-(4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazole-1-yl)phenyl)-6-oxopyrimidine-1(6H)-yl)-2 4 ,2 5 -difluoro-7-methyl-1 1 -(methyl-d3)-1 1 H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclononafane-8-one (yield: 21.4%) was obtained. LC-MS: RT=1.98min,[M+H] + = 662.08. 1 H NMR(400MHz,DMSO-d6)δ9.23(s,1H),9.15(s,1H),8.20(s,1H),7.94(d,J= 2.0Hz,1H),7.87-7.80(m,3H),7.53(d,J=5.9Hz,1H),7.45(s,1H),6.57(s ,1H),5.62(d,J=12.2Hz,1H),2.46-2.36(m,2H),1.927-1.87(m,1H),1.78 -1.69(m,1H),1.53-1.35(m,2H),1.09-1.04(m,1H),1.02(d,J=6.7Hz,3H).

[0052] Example 3 (3S,7R)-3-(4-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)-6-oxopyrimidine-1(6H)-yl)-2 4 ,2 5 -difluoro-7-methyl-1 1 -(methyl-d3)-1 1 Synthesis of H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclonononaphane-8-one(3) The specific synthesis route is as follows: [ka]

[0053] Step A: Synthesis of 4-chloro-3-fluoro-2-(6-methoxypyrimidine-4-yl)aniline (6-amino-3-chloro-2-fluorophenyl)boronic acid (1.60 g, 8.47 mmol), 4-chloro-6-methoxypyrimidine (1.80 g, 12.70 mmol), and potassium carbonate (2.30 g, 16.91 mmol) were dissolved in 1,4-dioxane (40 mL) and water (8 mL). Then, palladium catalyst (619 mg, 0.850 mmol) was added, and the mixture was reacted at 80°C for 1 hour with stirring under the protection of nitrogen gas. After complete reaction, water and ethyl acetate were added to the reaction mixture and separated. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 2) to obtain 1.20 g of a white solid, 4-chloro-3-fluoro-2-(6-methoxypyrimidine-4-yl)aniline (yield: 56.1%). LCMS:RT=2.29min,[M+H] + = 254.08.

[0054] Step B: Synthesis of 4-(3-chloro-6-(4-(tributylstannyl)-1H-1,2,3-triazole-1-yl)2-fluorophenyl)-6-methoxypyrimidine 4-chloro-3-fluoro-2-(6-methoxypyrimidine-4-yl)aniline (1.20 g, 4.74 mmol) was dissolved in acetonitrile (50 mL), tert-butyl nitrite (1.5 mL) was added at 0°C, and azidotrimethylsilane (1.5 mL) was slowly added dropwise. The mixture was stirred at room temperature for 1 hour to allow it to react. After monitoring by TLC to indicate completion of the reaction, the reaction was separated with water and ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The reaction mixture was dissolved in toluene (50 mL), tributylstannylacetylene (1.5 mL) was added, and the reaction mixture was stirred at 110 °C for 6 hours. After monitoring by TLC to indicate completion of the reaction, the product was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 6) to obtain 1.50 g of a pale yellow solid, 4-(3-chloro-6-(4-(tributylstannyl)-1H-1,2,3-triazole-1-yl)2-fluorophenyl)-6-methoxypyrimidine (yield: 54.1%). LCMS: RT = 2.23 min.

[0055] Step C: Synthesis of 4-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)2-fluorophenyl)-6-methoxypyrimidine 4-(3-chloro-6-(4-(tributylstannyl)-1H-1,2,3-triazole-1-yl)2-fluorophenyl)-6-methoxypyrimidine (1.50 g, 2.52 mmol) was dissolved in acetonitrile (15 mL), N-chlorosuccinimide (490 mg, 3.66 mmol) was added, and the reaction mixture was stirred at 90°C for 16 hours. After monitoring by TLC to indicate the completion of the reaction, the reaction solution was separated with water and ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 5) to obtain 800 mg of 4-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)2-fluorophenyl)-6-methoxypyrimidine as a pale yellow solid (yield: 93.1%). LCMS: RT = 2.08 min, [M+H] + = 340.10.

[0056] Step D: Synthesis of 4-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)2-fluorophenyl)pyrimidin-2(1H)-one After dissolving 4-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)2-fluorophenyl)-6-methoxypyrimidine (800 mg, 2.35 mmol) in isopropanol (15 mL), lithium chloride (1.44 g, 33.5 mmol) and p-toluenesulfonic acid monohydrate (2.73 g, 14.3 mmol) were added, and the reaction solution was stirred at 80 °C for 4 hours. The end of the reaction was monitored by TLC, water and ethyl acetate were added to the reaction solution for liquid separation, the obtained organic phase was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained residue was slurried (ethyl acetate / n-hexane = 1 / 10) to obtain 730 mg of 4-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)2-fluorophenyl)pyrimidin-2(1H)-one as a white solid (yield: 95.1%). LCMS: RT = 1.93 min, [M+H] + = 326.01.

[0057] Step E: (3S,7R)-3-(4-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)-6-oxopyrimidin-1(6H)-yl)-2 4 ,2 5 -difluoro-7-methyl-1 1 -(methyl-d3)-1 1Synthesis of H-9-aza-1(5,4)-pyrazolo-2(1,3)-benzannulen-8-one 4-(3-Chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)pyrimidin-2(1H)-one (100 mg, 0.310 mmol) was dissolved in dry 1,4-dioxane (10 mL), and then lithium bis(trimethylsilyl)amide (1 mol / L solution in tetrahydrofuran, 0.330 mL) was slowly added. The resulting reaction mixture was stirred at room temperature for 30 minutes. Then, (7R)-2 4 ,2 5 -difluoro-7-methyl-1 1 -(methyl-d3)-8-oxo-1 1 H-1(5,4)-pyrazolo-2(1,3)-benzannulen-3-yl 4-nitrobenzenesulfonate (100 mg, 0.190 mmol) was added, and the reaction mixture was stirred at 80 °C for 24 hours.

[0058] The reaction was monitored by TLC, cooled to room temperature, and saturated aqueous ammonium chloride solution (25 mL) and ethyl acetate (30 mL) were added to the reaction mixture for liquid separation. The obtained organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 10 / 1), and then by preparative high performance liquid chromatography to obtain 47.0 mg of a white solid, (3S,7R)-3-(4-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)-6-oxopyrimidin-1(6H)-yl)-2 4 ,2 5 -difluoro-7-methyl-1 1 -(methyl-d3)-1 1 H-9-aza-1(5,4)-pyrazolo-2(1,3)-benzannulen-8-one (yield: 39.0%) was obtained. LC-MS: RT = 1.93 min, [M+H] + = 646.01. 1H NMR(400MHz,DMSO-d6)δ9.24(s,1H),8.68(s,1H),8.33(s,1H),8.02(t,J=8.2Hz,1H),7.89-7.75(m,1H),7.68(dd,J=8.7,1.4Hz,1H),7.54(d,J=6.0 Hz,1H),7.45(s,1H),6.66(s,1H),5.69-5.60(m,1H),2.47-2.37(m,2H),2 .03-1.90(m,1H),1.80-1.70(m,1H),1.50-1.37(m,2H),1.13-0.97(m,4H).

[0059] Example 4 (3S,7R)-3-(4-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-triazole-1-yl)phenyl)-6-oxopyrimidine-1(6H)-yl)-2 4 ,2 5 -difluoro-7-methyl-1 1 -(methyl-d3)-1 1 Synthesis of H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclonononaphane-8-one(4) The specific synthesis route is as follows: [ka]

[0060] 6-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-triazole-1-yl)phenyl)pyrimidine-4-(3H)-one (80.0 mg, 0.222 mmol) was dissolved in dried anhydrous 1,4-dioxane (8 mL), and then lithium bis(trimethylsilyl)amide (1 mol / L tetrahydrofuran solution, 0.222 mL, 0.222 mmol) was slowly added. The resulting reaction mixture was stirred at room temperature for 30 minutes. Then, (7R)-2 4 ,2 5 -difluoro-7-methyl-1 1 -(methyl-d3)-8-oxo-1 1H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclononafane-3-yl-4-nitrobenzenesulfonate (116 mg, 0.222 mmol) was added and the mixture was reacted at 70°C for 16 hours.

[0061] After monitoring to indicate completion of the reaction, the mixture was cooled to room temperature. 25 mL of saturated ammonium chloride aqueous solution and 50 mL of ethyl acetate were added to the reaction mixture and separated. The resulting organic phase was washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 14 / 1). Further purification by preparative high-performance liquid chromatography yielded 27.3 mg of a white solid: (3S,7R)-3-(4-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-triazole-1-yl)phenyl)-6-oxopyrimidine-1(6H)-yl)-2 4 ,2 5 -difluoro-7-methyl-1 1 -(methyl-d3)-1 1 H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclononafane-8-one (yield: 18.1%) was obtained. LC-MS: RT=1.97min, [M+H] + = 680.03.

[0062] 1 H NMR(400MHz,DMSO-d6)δ9.23(s,1H),9.15(s,1H),8.26(s,1H),8.05(dd,J=8.7,7. 7Hz,1H),7.87-7.80(m,1H),7.77(dd,J=8.8,1.4Hz,1H),7.52(d,J=5.9Hz,1H),7. 45(s,1H),6.71(s,1H),5.64(d,J=12.2Hz,1H),2.46-2.36(m,2H),2.01-1.90(m,1 H),1.81-1.69(m,1H),1.54-1.37(m,2H),1.11-1.04(m,1H),1.01(d,J=6.7Hz,3H).

[0063] Example 5 (3S,7R)-3-(4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazole-1-yl)phenyl)-6-oxopyridazine-1(6H)-yl)-2 4 ,2 5 -difluoro-7-methyl-1 1 -(methyl-d3)-1 1 Synthesis of H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclonononaphane-8-one(5) The specific synthesis route is as follows: [ka]

[0064] 5-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazole-1-yl)phenyl)pyridazin-3(2H)-one (80.0 mg, 0.234 mmol) was dissolved in dried anhydrous 1,4-dioxane (8 mL), and then lithium bis(trimethylsilyl)amide (1 mol / L tetrahydrofuran solution, 0.234 mL, 0.234 mmol) was slowly added. The resulting reaction mixture was stirred at room temperature for 30 minutes. Then, (7R)-2 4 ,2 5 -difluoro-7-methyl-1 1 -(methyl-d3)-8-oxo-1 1 H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclononafane-3-yl-4-nitrobenzenesulfonate (122 mg, 0.234 mmol) was added, and the mixture was reacted at 70°C for 16 hours.

[0065] After monitoring to indicate completion of the reaction, the mixture was cooled to room temperature. 25 mL of saturated ammonium chloride aqueous solution and 50 mL of ethyl acetate were added to the reaction mixture and separated. The resulting organic phase was washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 14 / 1). Further purification by preparative high-performance liquid chromatography yielded 25.9 mg of a white solid (3S,7R)-3-(4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazole-1-yl)phenyl)-6-oxopyridazine-1(6H)-yl)-2 4 ,2 5 -difluoro-7-methyl-1 1 -(methyl-d3)-1 1 H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclononafane-8-one (yield: 16.7%) was obtained. LC-MS: RT=1.98min, [M+H] + = 662.07. 1 H NMR(400MHz,DMSO-d6)δ9.22(s,1H),9.19(s,1H),7.94(d,J=1.4Hz,1H),7.88(d,J=1.3Hz ,2H),7.81(ddd,J=11.2,7.1,2.0Hz,1H),7.50-7.42(m,3H),6.87(d,J=2.2Hz,1H),6.12( dd,J=12.4,3.3Hz,1H),2.44-2.34(m,1H),2.24-2.15(m,1H),1.91-1.81(m,1H),1.78-1. 66(m,1H),1.62-1.51(m,1H),1.43-1.32(m,1H),1.02(d,J=6.7Hz,3H),0.99-0.91(m,1H).

[0066] Example 6 (3S,7R)-3-(5-chloro-4-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-triazole-1-yl)phenyl)-6-oxopyridazine-1(6H)-yl)-2 4 ,2 5 -difluoro-7-methyl-1 1-(methyl-d3)-1 1 Synthesis of H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclonononaphane-8-one(6) The specific synthesis route is as follows: [ka] [ka]

[0067] Step A: Synthesis of 5-(6-amino-3-chloro-2-fluorophenyl)-2-benzyl-4-chloropyridazine-3(2H)-one (6-amino-3-chloro-2-fluorophenyl)boronic acid (1.80 g, 9.52 mmol; synthesis is described in patent WO2017023992A1), 2-benzyl-4,5-dichloropyridazine-3(2H)-one (2.66 g, 10.5 mmol), and sodium carbonate (2.02 g, 19.1 mmol) were dissolved in toluene (16 mL) and ethanol (4 mL). Then, tetrakis(triphenylphosphine)palladium (549 mg, 0.476 mmol) was added, and the mixture was reacted at 120°C with stirring for 1 hour under the protection of nitrogen gas.

[0068] After complete reaction, water and ethyl acetate were added to the reaction mixture and separated. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 2) to obtain 620 mg of a pale yellow solid, 5-(6-amino-3-chloro-2-fluorophenyl)-2-benzyl-4-chloropyridazine-3(2H)-one (yield: 17.9%). LCMS: RT = 2.29 min, [M + H] + =364.08.

[0069] Step B: Synthesis of 5-(6-azido-3-chloro-2-fluorophenyl)-2-benzyl-4-chloropyridazine-3(2H)-one 620 mg, 1.71 mmol of 5-(6-amino-3-chloro-2-fluorophenyl)-2-benzyl-4-chloropyridazine-3(2H)-one was dissolved in 10 mL of acetonitrile. At 0°C, 0.298 mL, 2.49 mmol of tert-butyl nitrite was added, and 0.336 mL, 2.56 mmol of azidotrimethylsilane was slowly added dropwise. The mixture was stirred at room temperature for 1 hour to allow the reaction to proceed. The reaction was monitored by TLC, the reaction mixture was placed in ice water, and the solution was separated with ethyl acetate. The organic phase was dried, and the mixture was dried by rotary evaporation to obtain 500 mg of the crude product, a pale yellow foamy solid, 5-(6-azido-3-chloro-2-fluorophenyl)-2-benzyl-4-chloropyridazine-3(2H)-one (yield: 75.2%), which was used directly in the next step. LCMS: RT=2.17 min, [M+H] + =390.03.

[0070] Step C: Synthesis of 2-benzyl-4-chloro-5-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-triazole-1-yl)phenyl)pyridazine-3(2H)-one Crude product of 5-(6-azido-3-chloro-2-fluorophenyl)-2-benzyl-4-chloropyridazine-3(2H)-one (500 mg, 1.28 mmol) was dissolved in acetonitrile (10 mL), and cuprous oxide (56.1 mg, 0.384 mmol) was added. Trifluoropropyne gas was slowly bubbled at room temperature until the reaction was complete.

[0071] The reaction mixture was separated with water and ethyl acetate, the organic phase was dried, and the crude product obtained by rotary evaporation was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 3) to obtain 190 mg of a pale yellow solid, 2-benzyl-4-chloro-5-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-triazole-1-yl)phenyl)pyridazin-3(2H)-one (yield: 30.7%). LCMS: RT=2.10 min, [M+H] + = 484.10.

[0072] Step D: Synthesis of 4-chloro-5-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-triazole-1-yl)phenyl)pyridazin-3(2H)-one 2-benzyl-4-chloro-5-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-triazole-1-yl)phenyl)pyridazine-3(2H)-one (190 mg, 0.496 mmol) was dissolved in toluene (8 mL), and then aluminum trichloride (52.1 mg, 1.24 mmol) and p-toluenesulfonic acid monohydrate (1.67 g, 8.79 mmol) were added and the mixture was reacted at 60°C for 1 hour.

[0073] The reaction was monitored by TLC, and sodium bicarbonate solution and ethyl acetate were added to the reaction mixture for liquid-liquid separation. The resulting organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate / n-hexane = 1 / 3) to obtain 86.0 mg of a pale yellow solid, 4-chloro-5-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-triazole-1-yl)phenyl)pyridazin-3(2H)-one (yield: 44.1%). LCMS: RT=1.82min,[M+H] + =394.04. 1 H NMR (400MHz, DMSO-d6) δ13.76 (s, 1H), 9.45 (d, J = 1.1Hz, 1H), 8.23-8.14 (m, 1H), 7.92 (s, 1H), 7.89 (dd, J = 8.8, 1.6Hz, 1H).

[0074] Step E: (3S,7R)-3-(5-chloro-4-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-triazole-1-yl)phenyl)-6-oxopyridazine-1(6H)-yl)-2 4 ,2 5 -difluoro-7-methyl-1 1 -(methyl-d3)-1 1Synthesis of H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclonononaphane-8-one 4-Chloro-5-(3-Chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-triazole-1-yl)phenyl)pyridazin-3(2H)-one (100 mg, 0.254 mmol) was dissolved in dried anhydrous 1,4-dioxane (8 mL), then lithium bis(trimethylsilyl)amide (1 mol / L tetrahydrofuran solution, 0.254 mL, 0.254 mmol) was slowly added, and the resulting reaction mixture was stirred at room temperature for 30 minutes. Then, (3R,7R)-2 4 ,2 5 -difluoro-7-methyl-1 1 -(methyl-d3)-8-oxo-1 1 H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclonononaphane-3-yl-4-nitrobenzenesulfonate (133 mg, 0.254 mmol) was added and the mixture was reacted at 70°C for 16 hours. After monitoring to indicate completion of the reaction, the mixture was cooled to room temperature, and saturated ammonium chloride aqueous solution (25 mL) and ethyl acetate (50 mL) were added to the reaction mixture and separated. The resulting organic phase was washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 14 / 1), followed by preparative high-performance liquid chromatography to obtain 26.4 mg of a white solid (3S,7R)-3-(5-chloro-4-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-triazole-1-yl)phenyl)-6-oxopyridazine-1(6H)-yl)-2 4 ,2 5 -difluoro-7-methyl-1 1 -(methyl-d3)-1 1 H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclononafane-8-one (yield: 14.6%) was obtained. LC-MS: RT=2.05min,[M+H] + = 713.98. 1H NMR(400MHz,DMSO-d6)δ9.29(d,J=1.0Hz,1H),9.25(s,1H),8.22-8.14(m,1H),7.92-7.80(m,3H),7.48(d,J=5.9Hz,1H),7.45(s,1H),6.10(d d,J=12.6,3.4Hz,1H),2.45-2.38(m,1H),2.28-2.18(m,1H),2.13-2.0 0(m,1H),1.78-1.68(m,1H),1.63-1.31(m,3H),1.02(d,J=6.4Hz,3H).

[0075] Example 7 (3S,7R)-3-(4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazole-1-yl)phenyl)-2-oxopyridine-1(2H)-yl)-2 4 ,2 5 -difluoro-7-methyl-1 1 -(methyl-d3)-1 1 Synthesis of H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclonononaphane-8-one(7) The specific synthesis route is as follows: [ka] [ka]

[0076] Step A: Synthesis of 5-bromo-2,3-difluorobenzoic acid 2,3-difluorobenzoic acid (50.0 g, 0.316 mol) and N-bromosuccinimide (61.9 g, 0.348 mol) were dissolved in concentrated sulfuric acid (150 mL), and the mixture was stirred at 60°C for 4 hours. After the reaction was complete, the reaction solution was cooled in an ice bath, then slowly poured into ice water (2 L) to precipitate a white solid, filtered, and the cake was washed three times with water. The mixture was dried under reduced pressure to obtain 66.4 g of white solid 5-bromo-2,3-difluorobenzoic acid (yield: 89.4%).

[0077] Step B: Synthesis of Methyl 5-Bromo-2,3-difluorobenzoate 5-Bromo-2,3-difluorobenzoic acid (22.0 g, 93.2 mmol) was dissolved in methanol (220 mL), concentrated sulfuric acid (10.1 mL) was added, and the mixture was stirred at 70 °C for 5 h. After the reaction was complete, the reaction solution was slowly poured into ice water to precipitate a white solid, which was filtered, and the cake was washed with water and dried under reduced pressure to obtain 23 g of methyl 5-bromo-2,3-difluorobenzoate as a slightly yellow solid (yield: 98.7%).

[0078] Step C: Synthesis of 2-(5-Bromo-2,3-difluorobenzoyl)cyclopentan-1-one At room temperature, cyclopentanone (47.2 g, 0.562 mol) and methyl 5-bromo-2,3-difluorobenzoate (117 g, 0.468 mol) were dissolved in tetrahydrofuran (800 mL), and a solution of potassium tert-butoxide in tetrahydrofuran (1 mol / L, 618 mL) was slowly added dropwise at -42 °C, controlling the internal temperature not to exceed -35 °C. The reaction was carried out at this temperature for 2 h under the protection of nitrogen gas. The completion of the reaction was monitored by TLC, and 2N hydrochloric acid solution (200 mL) was added to quench the reaction. Most of the tetrahydrofuran was removed by rotary evaporation from the mixture, and then the mixture was separated with ethyl acetate (500 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 9) to obtain 110 g of 2-(5-bromo-2,3-difluorobenzoyl)cyclopentan-1-one as a pale yellow oily liquid (yield: 77.8%).

[0079] Step D: Synthesis of 6-(5-Bromo-2,3-difluorophenyl)-6-oxohexanoic Acid At room temperature, 2-(5-bromo-2,3-difluorobenzoyl)cyclopentan-1-one (62.0 g, 0.205 mol) was placed in a mixed solution of 900 mL of acetonitrile and water (3:2), and reacted at 65 °C for 16 hours under the protection of nitrogen gas. After the reaction was cooled to room temperature, 500 mL of ethyl acetate was added to the reaction solution for liquid separation. The organic phase was further washed with water three times, dried, concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 2 / 11) to obtain 14.5 g of 6-(5-bromo-2,3-difluorophenyl)-6-oxohexanoic acid as a white solid (yield: 22.1%). LCMS: RT = 1.97 min, [M-H] - = 318.95.

[0080] Step E: Synthesis of methyl 6-(5-bromo-2,3-difluorophenyl)-6,6-dimethoxyhexanoate At room temperature, 6-(5-bromo-2,3-difluorophenyl)-6-oxohexanoic acid (14.5 g, 45.3 mmol) was placed in methanol (150 mL), and trimethyl orthoformate (21.6 g, 204 mmol) and chlorotrimethylsilane (9.45 g, 86.9 mmol) were added in sequence, and reacted at 50 °C for 3 hours under the protection of nitrogen gas.

[0081] After the reaction was completed, the reaction solution was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was added for quenching, and the mixture was extracted with dichloromethane (70 mL × 3 times). The organic phases were combined, the organic phase was washed with saturated aqueous sodium chloride solution (70 mL × 2 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 16.4 g of methyl 6-(5-bromo-2,3-difluorophenyl)-6,6-dimethoxyhexanoate as a white solid (yield: 95.3%). LCMS: RT = 2.23 min, [M+H] + -CH3O - = 348.95.

[0082] Step F: 6-(5-bromo-2,3-difluorophenyl)-6,6-dimethoxyhexanoic acid At 0°C, 30 mL of 4.5 mol sodium hydroxide solution was slowly added to a methanol (150 mL) solution of methyl 6-(5-bromo-2,3-difluorophenyl)-6,6-dimethoxyhexanoate (16.4 g, 43.1 mmol), and the mixture was reacted at room temperature for 2 hours.

[0083] After the reaction was complete, the reaction mixture was neutralized with saturated ammonium chloride solution, the mixture was extracted with ethyl acetate (70 mL x 3 times), the organic phase was combined, the organic phase was washed with saturated sodium chloride aqueous solution (70 mL x 2 times), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was slurryed with (n-hexane:ethyl acetate = 5:1) to obtain 13.0 g of a white solid, 6-(5-bromo-2,3-difluorophenyl)-6,6-dimethoxyhexanoic acid (yield: 82.8%). LCMS: RT = 2.07 min, [M + H] + -CH3O - = 334.94.

[0084] Step G: (R)-4-benzyl-3-(6-(5-bromo-2,3-difluorophenyl)-6,6-dimethoxyhexanoyl)oxazolidine-2-one 6-(5-bromo-2,3-difluorophenyl)-6,6-dimethoxyhexanoic acid (13.0 g, 35.6 mmol) and triethylamine (12.4 mL, 89.0 mmol) were dissolved in anhydrous tetrahydrofuran (250 mL). At 0°C, trimethylacetyl chloride (5.19 mL, 42.7 mmol) was added and the mixture was stirred for 0.5 hours. Lithium chloride (1.79 g, 42.7 mmol) was added and the mixture was stirred for 15 minutes. Then, (R)-4-benzyloxazolidine-2-one (7.57 g, 42.7 mmol) was added in several batches, and the mixture was allowed to react at room temperature for 4 hours. After monitoring to indicate completion of the reaction, water was added to quench the mixture, and most of the tetrahydrofuran was removed by rotary evaporation. The mixture was then extracted with ethyl acetate (40 mL x 2 times). The organic phase was combined and washed with saturated saline solution (80 mL x 3 times). After drying over anhydrous sodium sulfate, the mixture was purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate = 3:1) to obtain 16.6 g of a pale yellow oily substance, (R)-4-benzyl-3-(6-(5-bromo-2,3-difluorophenyl)-6,6-dimethoxyhexanoyl)oxazolidine-2-one (yield: 88.8%). LCMS: RT = 2.29 min, [M + H] + -CH3O - = 493.97.

[0085] Step H: Synthesis of (R)-4-benzyl-3-((R)-6-(5-bromo-2,3-difluorophenyl)-6,6-dimethoxy-2-methylhexanoyl)oxazolidine-2-one At -45°C, iodomethane (4.34 mL, 69.6 mmol) was added to tetrahydrofuran (200 mL) of (R)-4-benzyl-3-((R)-6-(5-bromo-2,3-difluorophenyl)-6,6-dimethoxy-2-methylhexanoyl)oxazolidine-2-one (16.6 g, 31.6 mmol), and after stirring for 10 minutes, a tetrahydrofuran solution of sodium bis(trimethylsilyl)amide (2 mol / L tetrahydrofuran solution, 20.6 mL) was slowly added, and the reaction was carried out at -45°C for 2 hours under the protection of nitrogen gas, while maintaining the internal temperature not to exceed -39°C.

[0086] The reaction was monitored, the reactants were quenched with saturated ammonium chloride solution (50 mL), most of the tetrahydrofuran was removed by rotary evaporation, and further extraction was performed with ethyl acetate (40 mL x 3 times). The organic phase was combined, dried over anhydrous sodium sulfate, and concentrated to obtain 17.0 g of the crude product (R)-4-benzyl-3-((R)-6-(5-bromo-2,3-difluorophenyl)-6,6-dimethoxy-2-methylhexanoyl)oxazolidine-2-one, a pale yellow oily substance, which was then used in the next step. LCMS: RT=2.30 min, [M+H] + -CH3O - = 508.17.

[0087] Step I: Synthesis of (R)-6-(5-bromo-2,3-difluorophenyl)-6,6-dimethoxy-2-methylhexanoic acid Crude product (17.0 g, 31.5 mmol) of (R)-4-benzyl-3-((R)-6-(5-bromo-2,3-difluorophenyl)-6,6-dimethoxy-2-methylhexanoyl)oxazolidine-2-one was dissolved in tetrahydrofuran (150 mL), and an aqueous hydrogen peroxide solution (W=30%, 6.4 mL, 63.1 mmol) was added at 0°C and the mixture was stirred for 30 minutes. Finally, lithium hydroxide (2.65 g, 63.1 mmol) was added and the mixture was reacted at room temperature for 2.0 hours.

[0088] The reaction was monitored, and the reaction was quenched by adding an aqueous sodium sulfite solution (50 mL, 126 mmol) at 0°C. Most of the tetrahydrofuran was removed from the mixture by rotary evaporation, and then the pH was adjusted to approximately 5 by neutralizing with an aqueous citric acid solution. Extraction was performed with ethyl acetate (30 mL x 3 times), the organic phase was combined, the organic phase was dried over anhydrous sodium sulfate, and finally, the mixture was purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate = 3:1) to obtain 5.70 g of a pale yellow oily substance, (R)-6-(5-bromo-2,3-difluorophenyl)-6,6-dimethoxy-2-methylhexanoic acid (two-step yield: 47.5%). LCMS: RT = 2.11 min, [M + H] + -CH3O- =348.96.

[0089] Step J: Synthesis of (R)-6-(2,3-difluoro-5-(1-(methyl-d3)-4-nitro-1H-pyrazole-5-yl)phenyl)-6,6-dimethoxy-2-methylhexanoic acid (R)-6-(5-bromo-2,3-difluorophenyl)-6,6-dimethoxy-2-methylhexanoic acid (5.70 g, 15.0 mmol), 1-(methyl-d3)-4-nitro-1H-pyrazole (1.95 g, 15.0 mmol), potassium carbonate (5.17 g, 37.5 mmol), and trimethylacetic acid (306 mg, 3.00 mmol) were dissolved in anhydrous 1,4-dioxane (60 mL). Then, n-butyldi(1-adamantyl)phosphine (537 mg, 1.50 mmol) and palladium acetate (336 mg, 1.50 mmol) were added, the mixture was purged with nitrogen gas, and the mixture was reacted at 100°C for 16 hours. After monitoring the completion of the reaction and cooling the reaction mixture, water was added, and the pH was adjusted to approximately 6 by neutralization with dilute hydrochloric acid. Extraction was performed with ethyl acetate (40 mL x 3 times), the organic phase was combined, and the organic phase was washed with saturated sodium chloride aqueous solution (50 mL x 2 times). Subsequently, it was dried over anhydrous sodium sulfate, and finally purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate = 2:1) to obtain 3.57 g of pale yellow foamy solid (R)-6-(2,3-difluoro-5-(1-(methyl-d3)-4-nitro-1H-pyrazole-5-yl)phenyl)-6,6-dimethoxy-2-methylhexanoic acid (yield: 55.3%). LCMS: RT = 1.99 min, [MH] - = 429.08.

[0090] Step K: Synthesis of (R)-6-(2,3-difluoro-5-(1-(methyl-d3)-4-amino-1H-pyrazole-5-yl)phenyl)-6,6-dimethoxy-2-methylhexanoic acid At room temperature, (R)-6-(2,3-difluoro-5-(1-(methyl-d3)-4-nitro-1H-pyrazole-5-yl)phenyl)-6,6-dimethoxy-2-methylhexanoic acid (3.57 g, 8.31 mmol) was dissolved in methanol (70 mL), and palladium / carbon (containing 10% palladium and 50% water, 714 mg) was added. The mixture was then purged with hydrogen gas, and a hydrogen gas balloon was attached. The reaction was carried out at 50°C for 6 hours. The completion of the reaction was monitored by TLC, the reaction mixture was cooled to room temperature, diatomaceous earth was added, and the mixture was filtered. The filtrate was dried and concentrated to obtain 3.20 g of a slightly reddish foamy solid (R)-6-(2,3-difluoro-5-(1-(methyl-d3)-4-amino-1H-pyrazole-5-yl)phenyl)-6,6-dimethoxy-2-methylhexanoic acid (yield: 96.3%). LCMS:RT=1.72min,[M+H] + = 401.13.

[0091] Step L:(R)-2 4 ,2 5 -difluoro-3,3-dimethoxy-7-methyl-1 1 -(methyl-d3)-1 1 Synthesis of H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclonononaphane-8-one At room temperature, a 300 mL solution of tetrahydrofuran containing (R)-6-(2,3-difluoro-5-(1-(methyl-d3)-4-amino-1H-pyrazole-5-yl)phenyl)-6,6-dimethoxy-2-methylhexanoic acid (3.20 g, 8.00 mmol) was slowly added dropwise to 100 mL of tetrahydrofuran containing chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (3.03 g, 10.8 mmol) and N,N-diisopropylethylamine (3.61 g, 28.0 mmol). After the addition was complete, the mixture was allowed to react at room temperature for 1 hour.

[0092] The reaction was monitored by TLC, the reaction mixture was diluted with saturated ammonium chloride solution, most of the tetrahydrofuran was removed from the mixture by rotary evaporation, the mixture was extracted with ethyl acetate (30 mL x 3 times), the organic phase was combined, the organic phase was dried over anhydrous sodium sulfate, and the product was concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: n-hexane:ethyl acetate = 1:9) to obtain 2.86 g of a pale yellow foamy solid (R)-2. 4 ,2 5 -difluoro-3,3-dimethoxy-7-methyl-1 1 -(methyl-d3)-1 1 H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclononafane-8-one (yield: 93.4%) was obtained. LCMS: RT=1.84min, [M+H] + = 383.13.

[0093] Step M:(R)-2 4 ,2 5 -difluoro-7-methyl-1 1 -(methyl-d3)-1 1 Synthesis of H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclonononaphane-3,8-zion (R)-2 4 ,2 5 -difluoro-3,3-dimethoxy-7-methyl-1 1 -(methyl-d3)-1 1 H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclononaphan-8-one (2.86 g, 7.46 mmol) was dissolved in acetonitrile (40 mL), and a dilute hydrochloric acid solution (4 mol / L aqueous solution, 6 mL) was added and the mixture was reacted at 50°C for 1 hour.

[0094] The reaction was monitored, and the solution was neutralized by adding saturated sodium bicarbonate aqueous solution. Extraction was performed with ethyl acetate (30 mL x 2 times), the organic phase was combined, the organic phase was dried over anhydrous sodium sulfate, and concentrated to obtain 2.20 g of a white solid (R)-2. 4 ,2 5 -difluoro-7-methyl-1 1 -(methyl-d3)-11 H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclonononaphane-3,8-dione (yield: 87.6%) was obtained. LCMS: RT=1.75min,[M+H] + = 337.11.

[0095] Step N: (7R)-2 4 ,2 5 -difluoro-3-hydroxy-7-methyl-1 1 -(methyl-d3)-1 1 Synthesis of H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclonononaphane-8-one (R)-2 4 ,2 5 -difluoro-7-methyl-1 1 -(methyl-d3)-1 1 H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclonononaphane-3,8-dione (2.20 g, 6.54 mmol) was dissolved in anhydrous methanol (25 mL), and sodium borohydride (373 mg, 9.82 mmol) was added in several batches at -70°C. The reaction was then allowed to proceed at the same temperature for 1 hour. After monitoring the completion of the reaction, saturated ammonium chloride aqueous solution was added to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL x 5 times). The organic phase was combined, dried over anhydrous sodium sulfate, and concentrated to obtain 1.52 g of a white solid (7R)-2 4 ,2 5 -difluoro-3-hydroxy-7-methyl-1 1 -(methyl-d3)-1 1 H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclononafane-8-one (yield: 68.7%) was obtained. LCMS: RT=1.62min, [M+H] + =339.04.

[0096] Step O: (7R)-2 4 ,2 5 -difluoro-7-methyl-1 1 -(methyl-d3)-8-oxo-1 1Synthesis of H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclonononaphane-3-yl-4-nitrobenzenesulfonate (7R)-2 4 ,2 5 -difluoro-3-hydroxy-7-methyl-1 1 -(methyl-d3)-1 1 H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclononaphan-8-one (1.52 g, 4.49 mmol) was added to anhydrous dichloromethane (30 mL), then triethylamine (907 mg, 8.98 mmol) and 4-dimethylaminopyridine (109 mg, 0.898 mmol) were added sequentially and the mixture was stirred for 10 minutes. Then p-nitrobenzenesulfonyl chloride (1.19 g, 5.39 mmol) was added in several batches, and the mixture was reacted at room temperature for 6 hours.

[0097] The reaction was monitored, diluted with 30 mL of sodium bicarbonate solution, extracted with dichloromethane (20 mL x 2 times), the organic phase was combined, the organic phase was dried over anhydrous sodium sulfate, and the residue obtained by concentrated under reduced pressure was purified by column chromatography (eluent: n-hexane:ethyl acetate = 1:15) to obtain 1.34 g of pale yellow solid (7R)-2. 4 ,2 5 -difluoro-7-methyl-1 1 -(methyl-d3)-8-oxo-1 1 H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclonononaphane-3-yl-4-nitrobenzenesulfonate (yield: 57.1%) was obtained. LCMS: RT=1.93min,[M+H] + = 524.02.

[0098] Step P: (3S,7R)-3-(4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazole-1-yl)phenyl)-2-oxopyridine-1(2H)-yl)-2 4 ,2 5 -difluoro-7-methyl-1 1 -(methyl-d3)-1 1Synthesis of H-9-aza-1(5,4)-pyrazolo-2(1,3)-benzannulenaphthalen-8-one 4-(5-Chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyridin-2(1H)-one (130 mg, 0.382 mmol) was dissolved in dry anhydrous 1,4-dioxane (10 mL), and then lithium bis(trimethylsilyl)amide (1 mol / L tetrahydrofuran solution, 0.382 mL, 0.382 mmol) was slowly added, and the resulting reaction solution was stirred at room temperature for 30 minutes. Then, (7R)-2 4 ,2 5 -difluoro-7-methyl-1 1 -(methyl-d3)-8-oxo-1 1 H-9-aza-1(5,4)-pyrazolo-2(1,3)-benzannulenaphthalen-3-yl 4-nitrobenzenesulfonate (200 mg, 0.382 mmol) was added, and the reaction was carried out at 70 °C for 16 hours.

[0099] After monitoring to indicate the completion of the reaction, it was cooled to room temperature, saturated aqueous ammonium chloride solution (25 mL) and ethyl acetate (50 mL) were added to the reaction solution for liquid separation, and the obtained organic phase was washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 14 / 1), and then purified by preparative high performance liquid chromatography to obtain 82.6 mg of a white solid (3S,7R)-3-(4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-2 4 ,2 5 -difluoro-7-methyl-1 1 -(methyl-d3)-1 1 H-9-aza-1(5,4)-pyrazolo-2(1,3)-benzannulenaphthalen-8-one (yield: 32.7%) was obtained. LC-MS: RT = 1.98 min, [M + H] + = 661.08. 1H NMR(400MHz,DMSO-d6)δ9.26(s,1H),9.08(s,1H),7.90-7.78(m,4H),7.52(d,J=6.0Hz,1H ),7.45(s,1H),7.31(d,J=7.2Hz,1H),6.30(d,J=2.0Hz,1H),5.89(d,J=12.4Hz,1H),5.67 (dd,J=7.2,2.1Hz,1H),2.44-2.34(m,1H),2.16-2.03(m,1H),1.90-1.80(m,1H),1.77-1. 67(m,1H),1.62-1.48(m,1H),1.43-1.33(m,1H),1.02(d,J=6.7Hz,3H),0.97-0.93(m,1H).

[0100] Example 8 (3S,7R)-3-(4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazole-1-yl)phenyl)-3-chloro-2-oxopyridine-1(2H)-yl)-2 4 ,2 5 -difluoro-7-methyl-1 1 -(methyl-d3)-1 1 Synthesis of H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclonononaphane-8-one(8) The specific synthesis route is as follows: [ka]

[0101] 4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazole-1-yl)phenyl)-3-chloropyridine-2(1H)-one (129 mg, 0.344 mmol) was dissolved in dried anhydrous 1,4-dioxane (10 mL), and then lithium bis(trimethylsilyl)amide (1 mol / L tetrahydrofuran solution, 0.181 mL, 0.181 mmol) was slowly added. The resulting reaction mixture was stirred at room temperature for 30 minutes. Then, (7R)-2 4 ,2 5 -difluoro-7-methyl-1 1-(methyl-d3)-8-oxo-1 1 H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclononafane-3-yl-4-nitrobenzenesulfonate (180 mg, 0.344 mmol) was added, and the mixture was reacted at 70°C for 16 hours.

[0102] After monitoring to indicate completion of the reaction, the mixture was cooled to room temperature. 25 mL of saturated ammonium chloride aqueous solution and 50 mL of ethyl acetate were added to the reaction mixture and separated. The resulting organic phase was washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 14 / 1). Further purification by preparative high-performance liquid chromatography yielded 50.6 mg of a white solid (3S,7R)-3-(4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazole-1-yl)phenyl)-3-chloro-2-oxopyridine-1(2H)-yl)-2 4 ,2 5 -difluoro-7-methyl-1 1 -(methyl-d3)-1 1 H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclononafane-8-one (yield: 21.2%) was obtained. LC-MS: RT=2.03min,[M+H] + = 694.97.

[0103] 1 H NMR(400MHz,DMSO-d6)δ9.29(s,1H),9.04(s,1H),7.95-7.83(m,3H),7.82(t,J=2.7Hz, 1H),7.57-7.53(m,1H),7.46(s,1H),7.45-7.42(m,1H),6.12(dd,J=7.2,2.0Hz,1H),5. 93(d,J=12.0Hz,1H),2.46-2.36(m,1H),2.25-2.09(m,1H),1.98-1.82(m,1H),1.79-1. 67(m,1H),1.65-1.50(m,1H),1.45-1.33(m,1H),1.08-1.01(m,3H),1.00-0.91(m,1H).

[0104] Example 9

[0105] (3S,7R)-3-(4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazole-1-yl)phenyl)-3-fluoro-2-oxopyridine-1(2H)-yl)-2 4 ,2 5 -difluoro-7-methyl-1 1 -(methyl-d3)-1 1 Synthesis of H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclonononaphane-8-one(9) The specific synthesis route is as follows: [ka]

[0106] 4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazole-1-yl)phenyl)-3-fluoropyridine-2(1H)-one (65.0 mg, 0.181 mmol) was dissolved in dried anhydrous 1,4-dioxane (8 mL), and then lithium bis(trimethylsilyl)amide (1 mol / L tetrahydrofuran solution, 0.181 mL, 0.181 mmol) was slowly added. The resulting reaction mixture was stirred at room temperature for 30 minutes. Then, (7R)-2 4 ,2 5 -difluoro-7-methyl-1 1 -(methyl-d3)-8-oxo-1 1 H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclononafane-3-yl-4-nitrobenzenesulfonate (94.9 mg, 0.181 mmol) was added and the mixture was reacted at 70°C for 16 hours.

[0107] After monitoring to indicate completion of the reaction, the mixture was cooled to room temperature. 25 mL of saturated ammonium chloride aqueous solution and 50 mL of ethyl acetate were added to the reaction mixture and separated. The resulting organic phase was washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 14 / 1). Further purification by preparative high-performance liquid chromatography yielded 24.9 mg of a white solid (3S,7R)-3-(4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazole-1-yl)phenyl)-3-fluoro-2-oxopyridine-1(2H)-yl)-2 4 ,2 5 -difluoro-7-methyl-1 1 -(methyl-d3)-1 1 H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclononafane-8-one (yield: 20.3%) was obtained. LC-MS: RT=2.00min,[M+H] + = 678.99.

[0108] 1 H NMR(400MHz,DMSO-d6)δ9.28(s,1H),9.19(s,1H),7.92-7.84(m,4H),7.55( d,J=5.8Hz,1H),7.46(s,1H),7.27(d,J=7.3Hz,1H),5.96-5.87(m,2H),2.44 -2.35(m,1H),2.20-2.08(m,1H),1.95-1.85(m,1H),1.78-1.68(m,1H),1.6 5-1.52(m,1H),1.44-1.34(m,1H),1.03(d,J=6.7Hz,3H),1.00-0.92(m,1H).

[0109] Example 10 (3S,7R)-3-(4-(5-chloro-2-(4-(difluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-2-oxopyridine-1(2H)-yl)-2 4 ,2 5 -difluoro-7-methyl-1 1 -(methyl-d3)-1 1Synthesis of H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclonononaphane-8-one(10) The specific synthesis route is as follows: [ka]

[0110] Step A: Synthesis of ethyl (Z)-4,4-difluoro-3-(2-tosylhydrazino)butanoate At room temperature, 10.0 g, 53.7 mmol of 4-methylbenzenesulfonyl hydrazide and 9.80 g, 59.1 mmol of ethyl 4,4-difluoro-3-oxobutanoate were dissolved in 100 mL of anhydrous ethanol and reacted at 65°C for 5 hours under the protection of nitrogen gas.

[0111] The reaction was monitored by TLC, and most of the solvent was removed by rotary evaporation. Water (200 mL) was added, followed by extraction with ethyl acetate (60 mL x 2 times). The organic phase was combined, washed with saturated brine (100 mL x 3 times), dried over anhydrous sodium sulfate, and finally concentrated to obtain 16.2 g of a white solid, ethyl (Z)-4,4-difluoro-3-(2-tosylhydrazino)butanoate (yield: 90.5%). LCMS: RT=1.73 min, [M+H] + =335.07.

[0112] Step B: Synthesis of 1-(2-bromo-4-chlorophenyl)-4-(difluoromethyl)-1H-1,2,3-triazole-5-carboxylate ethyl At room temperature, 2-bromo-4-chloroaniline (9.90 g, 48.5 mmol) and ethyl (Z)-4,4-difluoro-3-(2-tosylhydrazino)butanoate (16.2 g, 48.5 mmol) were added to toluene, followed by copper bromide (2.10 g, 9.70 mmol) and dimethyl sulfoxide (48.2 mL, 679 mmol). The mixture was reacted at 100°C for 6 hours under the protection of nitrogen gas. The reaction was monitored by TLC, and most of the solvent was removed by rotary evaporation. Water (200 mL) was added, and the mixture was further extracted with ethyl acetate (60 mL x 2 times). The organic phase was combined, washed with saturated saline solution (100 mL x 3 times), dried over anhydrous sodium sulfate, and finally purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate = 3:1) to obtain 13.1 g of a yellow solid, 1-(2-bromo-4-chlorophenyl)-4-(difluoromethyl)-1H-1,2,3-triazole-5-carboxylate ethyl (yield: 71.2%). LCMS: RT = 1.85 min, [MH] - =378.0.

[0113] Step C: 1-(2-bromo-4-chlorophenyl)-4-(difluoromethyl)-1H-1,2,3-triazole-5-carboxylic acid At 0°C, 1-(2-bromo-4-chlorophenyl)-4-(difluoromethyl)-1H-1,2,3-triazole-5-carboxylate ethyl (13.1 g, 34.5 mmol) was added to tetrahydrofuran / methanol / water = 60 mL / 20 mL / 40 mL, and then lithium hydroxide (1.70 g, 69.0 mmol) was added. The mixture was reacted at room temperature for 16 hours.

[0114] After monitoring by LC-MS to confirm the complete reaction of the starting materials, the majority of the solvent was removed by rotary evaporation. The pH was then adjusted to 4 with dichloromethane (100 mL) and dilute hydrochloric acid, and the mixture was extracted. The organic phase was combined and washed with saturated brine (80 mL x 2 times). The mixture was then dried over anhydrous sodium sulfate, and finally purified by silica gel column chromatography (eluent:dichloromethane:methanol = 15:1) to obtain 9.10 g of a pale yellow solid, 1-(2-bromo-4-chlorophenyl)-4-(difluoromethyl)-1H-1,2,3-triazole-5-carboxylic acid (yield: 75.2%). LC-MS: RT = 1.64 min, [MH] - = 350.11.

[0115] Step D: Synthesis of 1-(2-bromo-4-chlorophenyl)-4-(difluoromethyl)-1H-1,2,3-triazole At room temperature, 1-(2-bromo-4-chlorophenyl)-4-(difluoromethyl)-1H-1,2,3-triazole-5-carboxylic acid (9.10 g, 26.2 mmol) was added to N,N-dimethylformamide (50 mL), and then cuprous oxide (749 mg, 5.24 mmol) was added. The mixture was reacted at 120°C for 1 hour under the protection of nitrogen gas.

[0116] After monitoring by LC-MS to indicate the end of the reaction, the reaction mixture was cooled to room temperature, extracted with dichloromethane (80 mL x 3 times), and the organic phase was combined. The organic phase was washed with saturated sodium chloride aqueous solution (100 mL x 4 times), then dried over anhydrous sodium sulfate, and finally purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate = 4:1) to obtain 5.00 g of a yellow solid, 1-(2-bromo-4-chlorophenyl)-4-(difluoromethyl)-1H-1,2,3-triazole (yield: 62.5%). LC-MS: RT = 1.95 min, [M + H] + = 307.97.

[0117] Step E: Synthesis of 4-(5-chloro-2-(4-(difluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-2-methoxypyridine At room temperature, 1-(2-bromo-4-chlorophenyl)-4-(difluoromethyl)-1H-1,2,3-triazole (5.00 g, 16.2 mmol) and (2-methoxypyridine-4-yl)boronic acid (2.70 g, 17.8 mmol) were added to dioxane / water = 50 mL / 10 mL, and then potassium carbonate (5.60 g, 40.5 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (1.30 g, 1.80 mmol) were added, and the mixture was reacted at 80°C for 16 hours under the protection of nitrogen gas. After monitoring by LC-MS to indicate the end of the reaction, the majority of the solvent was removed by rotary evaporation, and the mixture was extracted with ethyl acetate (30 mL x 3 times) to combine the organic phase. The organic phase was washed with saturated sodium chloride aqueous solution (100 mL x 4 times), then dried over anhydrous sodium sulfate, and finally purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate = 3:1) to obtain 2.70 g of a yellow solid, 4-(5-chloro-2-(4-(difluoromethyl)-1H-1,2,3-triazole-1-yl)phenyl)-2-methoxypyridine (yield: 50.2%). LCMS: RT = 2.04 min, [M + H] + = 337.07.

[0118] Step F: Synthesis of 4-(5-chloro-2-(4-(difluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyridine-2-(1H)one 4-(5-chloro-2-(4-(difluoromethyl)-1H-1,2,3-triazole-1-yl)phenyl)-2-methoxypyridine (2.70 g, 8.00 mmol) was dissolved in isopropanol (40 mL), and then lithium chloride (2.20 g, 51.6 mmol) and p-toluenesulfonic acid monohydrate (4.90 g, 25.8 mmol) were added. The mixture was reacted overnight at 80°C with stirring. After detecting the absence of starting material residue by TLC, the reaction was neutralized by adding triethylamine (5 mL). The mixture was then concentrated under reduced pressure, the residue was dissolved in ethyl acetate (100 mL), and washed with saturated brine (50 mL x 3). The resulting organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 3 / 1) to obtain 1.50 g of a white solid, 4-(5-chloro-2-(4-(difluoromethyl)-1H-1,2,3-triazole-1-yl)phenyl)pyridine-2(1H)-one (yield: 58.0%). LCMS: RT = 1.73 min, [M + H] + =323.08.

[0119] Step G: (3S,7R)-3-(4-(5-chloro-2-(4-(difluoromethyl)-1H-1,2,3-triazole-1-yl)phenyl)-2-oxopyridine-1(2H)-yl)-2 4 ,2 5 -difluoro-7-methyl-1 1 -(methyl-d3)-1 1 Synthesis of H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclonononaphane-8-one 4-(5-chloro-2-(4-(difluoromethyl)-1H-1,2,3-triazole-1-yl)phenyl)pyridine-2(1H)-one (100 mg, 0.310 mmol) was dissolved in dry 1,4-dioxane (5 mL), then lithium bis(trimethylsilyl)amide (1 mol / L tetrahydrofuran solution, 0.310 mL, 0.310 mmol) was slowly added, and the resulting reaction mixture was stirred at room temperature for 30 minutes. Then, (7R)-2 4 ,2 5 -difluoro-7-methyl-11 -(methyl-d3)-8-oxo-1 1 H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclononafane-3-yl-4-nitrobenzenesulfonate (162 mg, 0.310 mmol) was added. The reaction was heated to 70°C and stirred at that temperature for 16 hours.

[0120] After monitoring by TLC to indicate completion of the reaction, the mixture was cooled to room temperature. The reaction solution was extracted with saturated ammonium chloride aqueous solution (4 mL) and ethyl acetate (20 mL), and the resulting organic phase was washed with saturated brine (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 4 / 1), followed by preparative high-performance liquid chromatography to obtain 33.0 mg of a white solid (3S,7R)-3-(4-(5-chloro-2-(4-(difluoromethyl)-1H-1,2,3-triazole-1-yl)phenyl)-2-oxopyridine-1(2H)-yl)-2 4 ,2 5 -difluoro-7-methyl-1 1 -(methyl-d3)-1 1 H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclononafane-8-one (yield: 15.0%) was obtained. LCMS: RT=1.93min, [M+H] + = 643.13. 1 H NMR(400MHz,DMSO-d6)δ9.25(s,1H),8.73(s,1H),7.90-7.70(m,4H),7.52(d,J=5.9Hz,1 H),7.45(s,1H),7.39-7.06(m,2H),6.29(d,J=2.0Hz,1H),5.90(d,J=12.2Hz,1H),5.69(d d,J=7.2,2.1Hz,1H),2.46-2.33(m,1H),2.17-2.01(m,1H),1.95-1.80(m,1H),1.80-1.6 4(m,1H),1.63-1.46(m,1H),1.45-1.31(m,1H),1.02(d,J=6.7Hz,3H),1.01-0.85(m,1H).

[0121] Example 11 (3S,7R)-3-(4-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-triazole-1-yl)phenyl)-6-oxopyrimidine-1(6H)-yl)-2 4 ,2 5 -difluoro-7-methyl-1 1 -difluoromethyl-1 1 Synthesis of H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclonononaphane-8-one(11) The specific synthesis route is as follows: [ka]

[0122] Step A: Synthesis of (R)-6-(2,3-difluoro-5-(1-difluoromethyl-4-nitro-1H-pyrazole-5-yl)phenyl)-6,6-dimethoxy-2-methylhexanoic acid Allyl palladium chloride dimer (318 mg, 0.87 mmol) and X-Phos (619 mg, 1.3 mmol) were dissolved in anhydrous 2-methyltetrahydrofuran (50 mL) and reacted at room temperature for 0.5 hours. Then, (R)-6-(5-bromo-2,3-difluorophenyl)-6,6-dimethoxy-2-methylhexanoic acid (3 g, 8.67 mmol), 1-difluoromethyl-4-nitro-1H-pyrazole (1.6 g, 9.54 mmol), and potassium pivalate (1.8 g, 13 mmol) were added, the mixture was purged with nitrogen gas, and the mixture was reacted at 80°C for 1.5 hours. After monitoring the completion of the reaction and cooling the reaction mixture, water was added, and the pH was adjusted to approximately 6 by neutralization with dilute hydrochloric acid. Extraction was performed with ethyl acetate (40 mL x 3 times), the organic phase was combined, and the organic phase was washed with saturated sodium chloride aqueous solution (50 mL x 2 times). Subsequently, the mixture was dried over anhydrous sodium sulfate, and finally purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 2 / 1) to obtain 3.2 g of pale yellow foamy solid (R)-6-(2,3-difluoro-5-(1-difluoromethyl-4-nitro-1H-pyrazole-5-yl)phenyl)-6,6-dimethoxy-2-methylhexanoic acid (yield: 80%). LCMS: RT = 2.04 min, [MH] - = 462.11.

[0123] Step B: Synthesis of (R)-6-(2,3-difluoro-5-(1-difluoromethyl-4-amino-1H-pyrazole-5-yl)phenyl)-6,6-dimethoxy-2-methylhexanoic acid At room temperature, (R)-6-(2,3-difluoro-5-(1-difluoromethyl-4-nitro-1H-pyrazole-5-yl)phenyl)-6,6-dimethoxy-2-methylhexanoic acid (3.2 g, 6.89 mmol) was dissolved in methanol (100 mL). Palladium / carbon (containing 10% palladium and 50% water, 1.28 g) was added, and the mixture was purged with hydrogen gas. A hydrogen gas balloon was then attached, and the reaction was carried out at 60°C for 2 hours. The completion of the reaction was monitored by TLC, the reaction mixture was cooled to room temperature, diatomaceous earth was added, and the mixture was filtered. The filtrate was dried and concentrated to obtain 3 g of a pale yellow foamy solid, (R)-6-(2,3-difluoro-5-(1-difluoromethyl-4-amino-1H-pyrazole-5-yl)phenyl)-6,6-dimethoxy-2-methylhexanoic acid. LCMS: RT=1.81 min, [M+H] + = 434.13.

[0124] Step C:(R)-2 4 ,2 5 -difluoro-3,3-dimethoxy-7-methyl-1 1 -difluoromethyl-1 1 Synthesis of H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclonononaphane-8-one At room temperature, a 600 mL solution of tetrahydrofuran containing (R)-6-(2,3-difluoro-5-(1-difluoromethyl-4-amino-1H-pyrazole-5-yl)phenyl)-6,6-dimethoxy-2-methylhexanoic acid (3 g, 6.91 mmol) was slowly added dropwise to a 500 mL solution of tetrahydrofuran containing N,N,N′,N′-tetramethylchloroformamidinium hexafluorophosphate (3.87 g, 13.82 mmol) and N,N-diisopropylethylamine (1.78 g, 13.84 mmol). After the addition was complete, the mixture was allowed to react at room temperature for 1 hour.

[0125] The reaction was monitored by TLC, the reaction mixture was diluted with saturated ammonium chloride solution, most of the tetrahydrofuran was removed from the mixture by rotary evaporation, the mixture was extracted with ethyl acetate (30 mL x 3 times), the organic phase was combined, the organic phase was dried over anhydrous sodium sulfate, and the mixture was concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: n-hexane:ethyl acetate = 1:10) to obtain 2.8 g of a pale yellow foamy solid (R)-2. 4 ,2 5 -difluoro-3,3-dimethoxy-7-methyl-1 1 -difluoromethyl-1 1 H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclonononaphane-8-one was obtained. LCMS: RT=1.88min,[M+H] + = 416.13.

[0126] Step D: (R)-2 4 ,2 5 -difluoro-7-methyl-1 1 -difluoromethyl-1 1 Synthesis of H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclonononaphane-3,8-zion (R)-2 4 ,2 5 -difluoro-3,3-dimethoxy-7-methyl-1 1 -difluoromethyl-1 1 H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclononaphan-8-one (2.8 g, 6.75 mmol) was dissolved in acetonitrile (40 mL), and a dilute hydrochloric acid solution (2 mol / L aqueous solution, 10 mL) was added and the mixture was reacted at 50°C for 3 hours.

[0127] The reaction was monitored, and the solution was neutralized by adding saturated sodium bicarbonate aqueous solution. Extraction was performed with ethyl acetate (30 mL x 2 times), the organic phase was combined, the organic phase was dried over anhydrous sodium sulfate, and concentrated to obtain 1.92 g of a white solid (R)-2. 4 ,2 5 -difluoro-7-methyl-1 1 -difluoromethyl-1 1H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclonononaphane-3,8-dione (yield: 78.3%) was obtained. LCMS: RT=1.75min,[M+H] + = 370.14.

[0128] Step E: (7R)-2 4 ,2 5 -difluoro-3-hydroxy-7-methyl-1 1 -difluoromethyl-1 1 Synthesis of H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclonononaphane-8-one (R)-2 4 ,2 5 -difluoro-7-methyl-1 1 -difluoromethyl-1 1 H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclonononaphane-3,8-dione (1.92 g, 5.19 mmol) was dissolved in anhydrous methanol (125 mL), and sodium borohydride (200 mg, 5.19 mmol) was added in several batches at -70°C, followed by a reaction at the same temperature for 1 hour.

[0129] The reaction was monitored, saturated ammonium chloride aqueous solution was added to quench the reaction, extraction was performed with ethyl acetate (30 mL x 5 times), the organic phase was combined, the organic phase was dried over anhydrous sodium sulfate, and concentrated to obtain 1.8 g of a white solid (7R)-2. 4 ,2 5 -difluoro-3-hydroxy-7-methyl-1 1 -difluoromethyl-1 1 H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclononafane-8-one (yield: 93%) was obtained. LCMS: RT=1.65min, [M+H] + = 372.11.

[0130] Step F: (7R)-2 4 ,2 5 -difluoro-7-methyl-1 1 -difluoromethyl-8-oxo-1 1Synthesis of H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclonononaphane-3-yl-4-nitrobenzenesulfonate (7R)-2 4 ,2 5 -difluoro-3-hydroxy-7-methyl-1 1 -difluoromethyl-1 1 H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclononaphan-8-one (400 mg, 1.08 mmol) was added to anhydrous dichloromethane (30 mL), then triethylamine (218 mg, 2.15 mmol) and 4-dimethylaminopyridine (131 mg, 1.08 mmol) were added sequentially and the mixture was stirred for 10 minutes. Then p-nitrobenzenesulfonyl chloride (357 mg, 1.61 mmol) was added in several batches and the mixture was reacted at room temperature for 10 minutes.

[0131] The reaction was monitored, diluted with 30 mL of sodium bicarbonate solution, extracted with dichloromethane (20 mL x 2 times), the organic phase was combined, the organic phase was dried over anhydrous sodium sulfate, and the residue obtained by concentrated under reduced pressure was purified by column chromatography (eluent: n-hexane / ethyl acetate = 1 / 10) to obtain 500 mg of a pale yellow solid (7R)-2. 4 ,2 5 -difluoro-7-methyl-1 1 -difluoromethyl-8-oxo-1 1 H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclonononaphane-3-yl-4-nitrobenzenesulfonate (yield: 83%) was obtained. LCMS: RT=1.98min, [M+H] + = 557.02.

[0132] Step G: (3S,7R)-3-(4-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-triazole-1-yl)phenyl)-6-oxopyrimidine-1(6H)-yl)-2 4 ,2 5 -difluoro-7-methyl-1 1 -difluoromethyl-1 1Synthesis of H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclonononaphane-8-one 6-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-triazole-1-yl)phenyl)pyrimidine-4-(3H)-one (130 mg, 0.36 mmol) was dissolved in dried anhydrous 1,4-dioxane (15 mL), and then lithium bis(trimethylsilyl)amide (1 mol / L tetrahydrofuran solution, 0.36 mL, 0.222 mmol) was slowly added. The resulting reaction mixture was stirred at room temperature for 30 minutes. Then, (7R)-2 4 ,2 5 -difluoro-7-methyl-1 1 -difluoromethyl-8-oxo-1 1 H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclononafane-3-yl-4-nitrobenzenesulfonate (200 mg, 0.36 mmol) was added and the mixture was reacted at 70°C for 16 hours.

[0133] After monitoring to indicate completion of the reaction, the mixture was cooled to room temperature. 25 mL of saturated ammonium chloride aqueous solution and 50 mL of ethyl acetate were added to the reaction mixture and separated. The resulting organic phase was washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 14 / 1). Further purification by preparative high-performance liquid chromatography yielded 62 mg of a white solid: (3S,7R)-3-(4-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-triazole-1-yl)phenyl)-6-oxopyrimidine-1(6H)-yl)-2 4 ,2 5 -difluoro-7-methyl-1 1 -difluoromethyl-1 1 H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclononaphan-8-one (yield: 24%) was obtained. LC-MS: RT=2.04min,[M+H] + = 712.94. 1H NMR(400MHz,DMSO-d6)δ9.42(s,1H),9.15(s,1H),8.33(s,1H),8.14-7.86(m,3H),7.78-7.74(m,1H),7.60(dt,J=18.1,7.0Hz,2H), 6.70(s,1H),5.63(d,J=12.4Hz,1H),2.48-2.37(m,2H),2.04-1.90(m,1H),1.83-1.72(m,1H),1.52-1.35(m,2H),1.11-0.95(m,4H).

[0134] Example 12 (3R,7R)-3-(4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazole-1-yl)phenyl)-6-oxopyrimidine-1(6H)-yl)-2 4 ,2 5 -difluoro-7-methyl-1 1 -difluoromethyl-1 1 Synthesis of H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclonononaphane-8-one(12)

[0135] The specific synthesis route is as follows: [ka]

[0136] 6-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazole-1-yl)phenyl)pyrimidine-4-(3H)-one (123 mg, 0.36 mmol) was dissolved in dried anhydrous 1,4-dioxane (15 mL), then lithium bis(trimethylsilyl)amide (1 mol / L tetrahydrofuran solution, 0.36 mL, 0.36 mmol) was slowly added, and the resulting reaction mixture was stirred at room temperature for 30 minutes. Then, (7R)-2 4 ,2 5 -difluoro-7-methyl-1 1 -difluoromethyl-8-oxo-1 1H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclononafane-3-yl-4-nitrobenzenesulfonate (200 mg, 0.36 mmol) was added and the mixture was reacted at 70°C for 16 hours.

[0137] After monitoring to indicate completion of the reaction, the mixture was cooled to room temperature. 25 mL of saturated ammonium chloride aqueous solution and 50 mL of ethyl acetate were added to the reaction mixture and separated. The resulting organic phase was washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 14 / 1). Further purification by preparative high-performance liquid chromatography yielded 50 mg of a white solid: (3R,7R)-3-(4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazole-1-yl)phenyl)-6-oxopyrimidine-1(6H)-yl)-2 4 ,2 5 -difluoro-7-methyl-1 1 -difluoromethyl-1 1 H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclononaphan-8-one (yield: 20%) was obtained. LC-MS: RT=2.04min,[M+H] + = 694.93. 1 H NMR(400MHz,DMSO-d6)δ9.42(s,1H),9.15(d,J=1.0Hz,1H),8.26(s,1H),8.09-7.75(m,5H),7.66-7.53(m,2H),6.56(s,1H) ),5.61(d,J=12.3Hz,1H),2.48-2.36(m,2H),2.02-1.86(m,1H),1.82-1.70(m,1H),1.54-1.35(m,2H),1.10-0.98(m,4H).

[0138] Example 13 (3S,7R)-3-(4-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)-6-oxopyrimidine-1(6H)-yl)-2 4 ,2 5 -difluoro-7-methyl-11 -difluoromethyl-1 1 Synthesis of H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclonononaphane-8-one(13) The specific synthesis route is as follows: [ka]

[0139] 4-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)2-fluorophenyl)pyrimidine-2(1H)-one (118 mg, 0.36 mmol) was dissolved in dry 1,4-dioxane (15 mL), then lithium bis(trimethylsilyl)amide (1 mol / L tetrahydrofuran solution, 0.36 mL) was slowly added, and the resulting reaction mixture was stirred at room temperature for 30 minutes. Then, (7R)-2 4 ,2 5 -difluoro-7-methyl-1 1 -difluoromethyl-8-oxo-1 1 H-1(5,4)-pyrazola-2(1,3)-benzenacyclononafane-3-yl-4-nitrobenzenesulfonate (200 mg, 0.36 mmol) was added, and the reaction mixture was stirred at 70°C for 24 hours.

[0140] The reaction was monitored using TLC, the temperature was lowered to room temperature, and saturated ammonium chloride aqueous solution (25 mL) and ethyl acetate (30 mL) were added to the reaction mixture and separated. The resulting organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 10 / 1), and then purified by preparative high-performance liquid chromatography to obtain 45 mg of a white solid (3S,7R)-3-(4-(3-chloro-6-(4-chloro-1H-1,2,3-triazole-1-yl)-2-fluorophenyl)-6-oxopyrimidine-1(6H)-yl)-2 4 ,2 5 -difluoro-7-methyl-1 1 -difluoromethyl-1 1H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclononafane-8-one (yield: 18%) was obtained. LC-MS: RT=1.98min, [M+H] + = 678.96. 1 H NMR(400MHz,DMSO-d6)δ9.43(s,1H),8.67(s,1H),8.39(s,1H),8.08-7.77(m,3H),7.68(dd,J=8.8,1.4Hz,1H),7.64-7.55(m,2H),6 .65(s,1H),5.64(d,J=11.8Hz,1H),2.48-2.38(m,2H),2.04-1.92(m,1H),1.84-1.73(m,1H),1.51-1.37(m,2H),1.12-0.99(m,4H).

[0141] Example 14 (3S,7R)-3-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-6-oxopyrimidine-1(6H)-yl)-2 4 ,2 5 -difluoro-7-methyl-1 1 -difluoromethyl-1 1 Synthesis of H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclonononaphane-8-one(14) The specific synthesis route is as follows: [ka]

[0142] 6-(5-chloro-2-(4-chloro-1H-1,2,3-triazole-1-yl)phenyl)pyrimidine-4-(3H)-one (110 mg, 0.36 mmol) was dissolved in dried anhydrous 1,4-dioxane (15 mL), and then lithium bis(trimethylsilyl)amide (1 mol / L tetrahydrofuran solution, 0.36 mL, 0.36 mmol) was slowly added. The resulting reaction mixture was stirred at room temperature for 30 minutes. Then, (7R)-2 4 ,2 5 -difluoro-7-methyl-1 1-difluoromethyl-8-oxo-1 1 H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclononafane-3-yl-4-nitrobenzenesulfonate (200 mg, 0.36 mmol) was added and the mixture was reacted at 70°C for 16 hours.

[0143] After monitoring to indicate completion of the reaction, the mixture was cooled to room temperature. 25 mL of saturated ammonium chloride aqueous solution and 30 mL of ethyl acetate were added to the reaction mixture and separated. The resulting organic phase was washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 14 / 1). Further purification by preparative high-performance liquid chromatography yielded 42 mg of a white solid (3S,7R)-3-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazole-1-yl)phenyl)-6-oxopyrimidine-1(6H)-yl)-2 4 ,2 5 -difluoro-7-methyl-1 1 -difluoromethyl-1 1 H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclononafane-8-one (yield: 18%) was obtained. LC-MS: RT=2.00min, [M+H] + = 660.95. 1 H NMR(400MHz,DMSO-d6)δ9.42(s,1H),8.71(s,1H),8.34(s,1H),8.08-7.87(m,3H),7.82(dd,J=8.5,2.4Hz,1H),7.75(t,J=7.8Hz,1H),7.60(dd,J=1 1.7,6.5Hz,2H),6.45(s,1H),5.70-5.54(m,1H),2.49-2.37(m,2H),2.01 -1.89(m,1H),1.1.82-1.71(m,1H),1.55-1.37(m,2H),1.10-0.97(m,4H).

[0144] Example 15 (3S,7R)-3-(4-chloro-2-fluoro-6-(4-trifluoromethyl)-1H-1,2,3-triazole-1-ylphenyl)-2-oxopyridine-1(2H)yl)-2 4 ,2 5 -difluoro-7-methyl-1 1 -methyl-d3-1 1 Synthesis of H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclonononaphane-8-one(15) The specific synthesis route is as follows: [ka]

[0145] Step A: Synthesis of 4-chloro-3-fluoro-2-(2-methoxypyridine-4-yl)aniline At room temperature, 6-amino-3-chloro-2-fluorophenylboronic acid (5.0 g, 26.5 mmol), 4-bromo-2-methoxypyridine (5.5 g, 29.1 mmol), and potassium carbonate (7.3 g, 53 mmol) were dissolved in 1,4-dioxane (100 mL) and water (27 mL). After adding [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (969 mg, 1.33 mmol), the system was replaced three times with N2 and reacted at 85°C for 16 hours.

[0146] The reaction was monitored by TLC, the reaction mixture was cooled to room temperature, filtered, the filtrate was concentrated, further diluted with ethyl acetate (30 mL), extracted with ethyl acetate (30 mL x 2 times), the organic phase was combined, the organic phase was washed with saturated sodium chloride aqueous solution (30 mL x 2 times), then dried over anhydrous sodium sulfate, and finally purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 10 / 1) to obtain 3.8 g of pale yellow solid 4-chloro-3-fluoro-2-(2-methoxypyridine-4-yl)aniline (yield: 57.1%). LCMS: RT = 2.05 min, [M + H] + = 253.02.

[0147] Step B: Synthesis of 4-(6-azido-3-chloro-2-fluorophenyl)-2-methoxypyridine At room temperature, 4-chloro-3-fluoro-2-(2-methoxypyridine-4-yl)aniline (660 mg, 2.62 mmol), tert-butyl nitrite (396 mg, 3.82 mmol), and azidotrimethylsilane (456 mg, 3.92 mmol) were dissolved in acetonitrile (14 mL) and reacted at room temperature for 1 hour under the protection of N2.

[0148] The reaction was monitored by TLC, and after cooling the reaction system to room temperature, the reaction mixture was quenched by adding saturated brine (20 mL) dropwise, and extracted with ethyl acetate (20 mL x 2 times). The organic phase was combined, washed with saturated brine (20 mL x 3 times), dried over anhydrous sodium sulfate, and finally purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 20 / 1) to obtain 694 mg of pale yellow solid 4-(6-azido-3-chloro-2-fluorophenyl)-2-methoxypyridine (yield: 96%). LCMS: RT = 1.95 min, [M + H] + = 279.03.

[0149] Step C: Synthesis of 4-(3-chloro-2-fluoro-6-(4-trifluoromethyl)-1H-1,2,3-triazole-1-yl)phenyl)-2-methoxypyridine At room temperature, 4-(6-azido-3-chloro-2-fluorophenyl)-2-methoxypyridine (694 mg, 2.49 mmol) and cuprous oxide (56 mg, 0.39 mmol) were dissolved in acetonitrile (14 mL). 3,3,3-trifluoro-1-propyne gas was introduced into the reaction system for 1 hour, and the reaction was carried out at room temperature for 3 hours.

[0150] The reaction was monitored by TLC, the reaction mixture was filtered, the filtrate was concentrated, and further diluted with ethyl acetate (20 mL). The organic phase was washed with saturated sodium chloride aqueous solution (20 mL x 2 times), then dried over anhydrous sodium sulfate, and finally purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 10 / 1) to obtain 460 mg of pale yellow solid 4-(3-chloro-2-fluoro-6-(4-trifluoromethyl)-1H-1,2,3-triazole-1-yl)phenyl)-2-methoxypyridine (yield: 49.8%). LCMS: RT = 2.09 min, [M + H] + = 327.97.

[0151] Step D: Synthesis of 4-(3-chloro-2-fluoro-6-(4-trifluoromethyl)-1H-1,2,3-triazole-1-ylphenyl)pyridine-2(1H)one At room temperature, 4-(3-chloro-2-fluoro-6-(4-trifluoromethyl)-1H-1,2,3-triazole-1-yl)phenyl)-2-methoxypyridine (460 mg, 1.24 mmol) was dissolved in isopropanol (6 mL), p-toluenesulfonic acid monohydrate (1.4 g, 7.42 mmol) and lithium chloride (736 mg, 17.4 mmol) were added, and the mixture was reacted at 75 °C for 16 hours under the protection of N2.

[0152] After monitoring by LC-MS to confirm the complete reaction of the starting materials, the reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated and further extracted with ethyl acetate (10 mL x 2 times). The organic phase was combined, washed first with saturated brine (10 mL x 3 times), then dried over anhydrous sodium sulfate, and finally purified by silica gel column chromatography (eluent: pure ethyl acetate) to obtain 430 mg of a white solid, 4-(3-chloro-2-fluoro-6-(4-trifluoromethyl)-1H-1,2,3-triazole-1-ylphenyl)pyridine-2(1H)one (yield: 96.8%). LCMS: RT=1.72 min, [M+H] + =359.02.

[0153] Step E: (3S,7R)-3-(4-chloro-2-fluoro-6-(4-trifluoromethyl)-1H-1,2,3-triazole-1-ylphenyl)-2-oxopyridine-1(2H)yl)-2 4 ,2 5 -difluoro-7-methyl-1 1 -methyl-d3-1 1 Synthesis of H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclonononaphane-8-one 4-(3-chloro-2-fluoro-6-(4-trifluoromethyl)-1H-1,2,3-triazole-1-ylphenyl)pyridine-2(1H)one (70 mg, 0.19 mmol) was dissolved in anhydrous 1,4-dioxane (7 mL), and then lithium bis(trimethylsilyl)amide (1 mol / L tetrahydrofuran solution, 0.21 mL, 0.21 mmol) was slowly added. The resulting reaction mixture was stirred at room temperature for 30 minutes. Then, (7R)-2 4 ,2 5 -difluoro-7-methyl-1 1 -methyl-d3-8-oxo-1 1 H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclononafane-3-yl-4-nitrobenzenesulfonate (100 mg, 0.19 mmol) was added and the mixture was reacted at 70°C for 24 hours.

[0154] After LC-MS monitoring indicated the completion of the reaction, the mixture was cooled to room temperature. 25 mL of saturated ammonium chloride aqueous solution and 50 mL of ethyl acetate were added to the reaction mixture and separated. The resulting organic phase was washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 14 / 1). Further purification by preparative high-performance liquid chromatography yielded 11 mg of a white solid (3S,7R)-3-(4-chloro-2-fluoro-6-(4-trifluoromethyl)-1H-1,2,3-triazole-1-ylphenyl)-2-oxopyridine-1(2H)yl)-2 4 ,2 5 -difluoro-7-methyl-1 1 -methyl-d3-11 H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclononafane-8-one was obtained. LCMS: RT=1.95min,[M+H] + = 679.07.

[0155] Example 16 (3S,7R)-3-(4-(3-chloro-2-fluoro-6-(4-trifluoromethyl)-1H-1,2,3-triazole-1-ylphenyl)-6-oxopyrimidine-1(6H)yl)-2 5 ,2 6 -difluoro-7-methyl-1 1 -(methyl-d3)-1 1 Synthesis of H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclonononaphane-8-one(16)

[0156] The specific synthesis route is as follows: [ka]

[0157] Step A: Synthesis of 2-(3-bromo-4,5-difluorobenzoyl)cyclopentan-1-one At room temperature, cyclopentanone (40.2 g, 478 mol) and methyl 3-bromo-4,5-difluorobenzoate (100 g, 398 mol) were dissolved in tetrahydrofuran (1000 mL). Lithium bis(trimethylsilyl)amide (1 mol / L solution of tetrahydrofuran, 419.2 mL, 419.2 mmol) was slowly added dropwise at -70°C. After the addition was complete, the temperature was allowed to rise naturally to -30°C. The mixture was then allowed to react at -30°C for 16 hours.

[0158] The reaction was monitored by TLC, and 150 mL of 2N dilute hydrochloric acid solution was added to quench the reaction. After liquid-liquid extraction, most of the tetrahydrofuran was removed from the organic phase by rotary evaporation. 500 mL of ethyl acetate was then added, followed by washing with saturated brine (100 mL x 1). The organic phase was dried over anhydrous sodium sulfate, and the resulting residue was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 9) to obtain 64 g of a pale yellow oily liquid, 2-(3-bromo-4,5-difluorobenzoyl)cyclopentan-1-one (yield: 53%).

[0159] Step B: Synthesis of 6-(3-bromo-4,5-difluorophenyl)-6-oxohexanoic acid At room temperature, 2-(3-bromo-4,5-difluorobenzoyl)cyclopentan-1-one (100 g, 0.33 mol) was added to a mixture of acetonitrile and water (1:1) in 1200 mL, followed by the addition of indium trifluoromethanesulfonate (18.6 g, 0.033 mol). The mixture was then heated to 80°C and reacted for 16 hours.

[0160] The reaction was monitored by TLC. After cooling the reaction to room temperature, solid sodium chloride was added to the reaction mixture, and after liquid-liquid extraction, the aqueous phase was extracted with ethyl acetate (300 mL x 2 times). The three organic phases were combined and dried, and the resulting residue was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 2 / 3) to obtain 68.5 g of a white solid, 6-(3-bromo-4,5-difluorophenyl)-6-oxohexanoic acid (yield: 65%). LCMS: RT = 1.97 min, [MH] - = 318.95.

[0161] Step C: Synthesis of (R)-1-(4-benzyl-2-oxoxazolidine-3-yl)-6-(3-bromo-4,5-difluorophenyl)hexane-1,6-dione 6-(3-bromo-4,5-difluorophenyl)-6-oxohexanoic acid (68.5 g, 214 mmol) and triethylamine (82.2 mL, 535 mmol) were dissolved in anhydrous tetrahydrofuran (1000 mL), and at 0°C, trimethylacetyl chloride (39.4 mL, 318 mmol) was added and the mixture was stirred for 0.5 hours to allow it to react. Lithium chloride (13.36 g, 318 mmol) was added and the mixture was stirred for 15 minutes, and then (R)-4-benzyloxazolidine-2-one (45.6 g, 257 mmol) was added all at once and the mixture was reacted at room temperature for 3 hours.

[0162] After monitoring to indicate completion of the reaction, saturated ammonium chloride aqueous solution (500 mL) was added to quench the reaction. After liquid-liquid separation, most of the tetrahydrofuran was removed from the organic phase by rotary evaporation, followed by the addition of ethyl acetate (500 mL), and then washing with saturated brine (100 mL x 1 time). The organic phase was then dried over anhydrous sodium sulfate, and finally purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate = 7:3) to obtain 95.5 g of a pale yellow oily substance, (R)-1-(4-benzyl-2-oxoxazolidine-3-yl)-6-(3-bromo-4,5-difluorophenyl)hexane-1,6-dione (yield: 93%). LCMS: RT = 2.29 min, [M + H] + -CH3O - = 493.97.

[0163] Step D: Synthesis of (R)-4-benzyl-3-(6-(3-bromo-4,5-difluorophenyl)-6,6-dimethoxyhexanoyl)oxazolidine-2-one Under room temperature conditions, (R)-1-(4-benzyl-2-oxoxazolidine-3-yl)-6-(3-bromo-4,5-difluorophenyl)hexane-1,6-dione (95.5 g, 199 mmol) was dissolved in methanol (955 mL), and trimethyl orthoformate (63.4 g, 597 mmol) and p-toluenesulfonic acid monohydrate (11.4 g, 59.7 mmol) were added in sequence, followed by a reaction at 70°C for 3 hours.

[0164] The end of the reaction was detected by TLC. After cooling the reaction mixture to room temperature, saturated sodium bicarbonate solution was added to adjust the pH to 9. Then, a large amount of methanol was removed by rotary evaporation, and the mixture was extracted with ethyl acetate (300 mL x 3 times). The organic phase was combined and washed with saturated sodium chloride aqueous solution (100 mL x 1 time). The mixture was then dried over anhydrous sodium sulfate, concentrated under reduced pressure, and finally purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate = 7:3) to obtain 83 g of a pale yellow oily substance, (R)-4-benzyl-3-(6-(3-bromo-4,5-difluorophenyl)-6,6-dimethoxyhexanoyl)oxazolidine-2-one (yield: 79%). LCMS: RT = 2.07 min, [M + H] + -CH3O - = 334.94.

[0165] Step E: Synthesis of (R)-4-benzyl-3-((R)-6-(3-bromo-4,5-difluorophenyl)-6,6-dimethoxy-2-methylhexanoyl)oxazolidine-2-one Iodomethane (21.6 mL, 374 mmol) was added to (R)-4-benzyl-3-(6-(3-bromo-4,5-difluorophenyl)-6,6-dimethoxyhexanoyl)oxazolidine-2-one (83 g, 158 mmol) in tetrahydrofuran (1000 mL). After three substitutions with N2, the internal temperature was lowered to -60°C, and a tetrahydrofuran solution of sodium bis(trimethylsilyl)amide (2 mol / L tetrahydrofuran solution, 118 mL) was slowly added while maintaining the internal temperature so as not to exceed -50°C. After the dropwise addition was complete, the reaction was allowed to proceed for 1 hour while maintaining the internal temperature at -60°C.

[0166] The reaction was monitored by TLC, and the reaction mixture was quenched with saturated ammonium chloride solution (400 mL). After liquid-liquid extraction, most of the tetrahydrofuran was removed from the organic phase by rotary evaporation. Ethyl acetate (600 mL) was then added, followed by washing with saturated brine (100 mL x 1 time). The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain 85 g of the crude product (R)-4-benzyl-3-((R)-6-(3-bromo-4,5-difluorophenyl)-6,6-dimethoxy-2-methylhexanoyl)oxazolidine-2-one, a pale yellow oily substance, which was then used in the next step. LCMS: RT=2.30 min, [M+H] + -CH3O - = 508.17.

[0167] Step F: Synthesis of (R)-6-(3-bromo-4,5-difluorophenyl)-6,6-dimethoxy-2-methylhexanoic acid Crude product (85 g, 158 mmol) of (R)-4-benzyl-3-((R)-6-(3-bromo-4,5-difluorophenyl)-6,6-dimethoxy-2-methylhexanoyl)oxazolidine-2-one was dissolved in tetrahydrofuran (850 mL), and an aqueous solution of hydrogen peroxide (W=30%, 35.7 g, 316 mmol) was added at 0°C and the mixture was stirred for 10 minutes. Finally, an aqueous solution of lithium hydroxide monohydrate (13.2 g, 316 mmol) (170 mL) was added, and the mixture was reacted at room temperature for 2.0 hours.

[0168] The reaction was monitored by TLC, and the reaction was quenched by adding an aqueous sodium sulfite solution (200 mL, 400 mmol) at 0°C. The mixture was then stirred at room temperature for 2 hours. Most of the tetrahydrofuran was removed from the mixture by rotary evaporation. The resulting residue was further adjusted to a pH of approximately 5 with solid citrate, then extracted with ethyl acetate (300 mL x 3 times). The organic phase was combined, dried over anhydrous sodium sulfate, and finally purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate = 4:1) to obtain 33 g of a pale yellow oily substance, (R)-6-(3-bromo-4,5-difluorophenyl)-6,6-dimethoxy-2-methylhexanoic acid (two-step yield: 55%). LCMS:RT=2.11min,[M+H] + -CH3O - =348.96.

[0169] Step G: Synthesis of (R)-6-(3,4-difluoro-5-(1-methyl-d3)-4-nitropyrazole-5-phenyl)-6,6-dimethoxy-2-methylhexanoic acid (R)-6-(3-bromo-4,5-difluorophenyl)-6,6-dimethoxy-2-methylhexanoic acid (25 g, 65 mmol), 1-(methyl-d3)-4-nitro-1H-pyrazole (8.6 g, 65 mmol), potassium carbonate (22.7 g, 163 mmol), and trimethylacetic acid (1.34 g, 13 mmol) were dissolved in anhydrous 1,4-dioxane (500 mL). Then, n-butyldi(1-adamantyl)phosphine (2.36 g, 6.5 mmol) and palladium acetate (1.47 mg, 6.5 mmol) were added, the mixture was purged with nitrogen gas, and the mixture was reacted at 110°C for 16 hours.

[0170] The reaction was monitored by TLC, and after cooling the reaction mixture, most of the dioxane was removed by rotation. Water was added, and the pH was adjusted to approximately 5 with solid citrate. Extraction was performed with ethyl acetate (400 mL x 3 times), the organic phase was combined, and the organic phase was washed with saturated sodium chloride aqueous solution (100 mL x 1 time). The mixture was then dried over anhydrous sodium sulfate, and finally purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate = 4:1) to obtain 18 g of pale yellow foamy solid (R)-6-(3,4-difluoro-5-(1-methyl-d3)-4-nitropyrazole-5-phenyl)-6,6-dimethoxy-2-methylhexanoic acid (yield: 64%). LCMS: RT = 1.99 min, [MH] - = 429.08.

[0171] Step H: Synthesis of (R)-6-(3-(4-amino-1-methyl-d3)-1H-pyrazole-5-yl)-4,5-difluorophenyl)-6,6-dimethoxy-2-methylhexanoic acid At room temperature, (R)-6-(3,4-difluoro-5-(1-methyl-d3)-4-nitropyrazole-5-phenyl)-6,6-dimethoxy-2-methylhexanoic acid (3.3 g, 7.6 mmol) was dissolved in methanol (99 mL), and then palladium / carbon (containing 10% palladium and 50% water, 1.32 g) was added. After purging with hydrogen gas, a hydrogen gas balloon was attached and the mixture was reacted at 60°C for 6 hours.

[0172] The reaction was monitored by TLC, the reaction mixture was cooled to room temperature, diatomaceous earth was added, and the solution was filtered. The filtrate was dried and concentrated to obtain 2.70 g of a slightly reddish, foamy solid (R)-6-(3-(4-amino-1-methyl-d3)-1H-pyrazole-5-yl)-4,5-difluorophenyl)-6,6-dimethoxy-2-methylhexanoic acid (yield: 90%). LCMS: RT=1.72 min, [M+H] + = 401.13.

[0173] Step I: (R)-2 5 ,2 6 -difluoro-3,3-dimethoxy-7-methyl-11 -(methyl-d3)-1 1 Synthesis of H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclonononaphane-8-one At room temperature, a 100 mL solution of tetrahydrofuran containing (R)-6-(3-(4-amino-1-methyl-d3)-1H-pyrazole-5-yl)-4,5-difluorophenyl)-6,6-dimethoxy-2-methylhexanoic acid (2.7 g, 6.75 mmol) was slowly added dropwise to a 400 mL solution of tetrahydrofuran containing N,N,N′,N′-tetramethylchloroformamidinium hexafluorophosphate (3.85 g, 13.50 mmol) and N,N-diisopropylethylamine (1.78 g, 13.50 mmol). After the addition was complete, the mixture was allowed to react at room temperature for 1 hour.

[0174] The reaction was monitored using TLC, the reaction mixture was diluted with an aqueous solution, most of the tetrahydrofuran was removed from the mixture by rotary evaporation, the mixture was extracted with ethyl acetate (50 mL x 3 times), the organic phase was combined, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 5 g of a pale yellow foamy solid (R)-2. 5 ,2 6 -difluoro-3,3-dimethoxy-7-methyl-1 1 -(methyl-d3)-1 1 The crude product H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclonononaphane-8-one was obtained and used directly in the next step. LCMS:RT=1.84min,[M+H] + = 383.13.

[0175] Step J:(R)-2 5 ,2 6 -difluoro-7-methyl-1 1 -(methyl-d3)-1 1 Synthesis of H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclonononaphane-3,8-zion (R)-2 5 ,2 6 -difluoro-3,3-dimethoxy-7-methyl-1 1 -(methyl-d3)-11 The crude product of H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclononaphan-8-one (5 g, 13 mmol) was dissolved in acetonitrile (45 mL), and a dilute hydrochloric acid solution (2 mol / L aqueous solution, 15 mL) was added and the mixture was reacted at 50°C for 4 hours.

[0176] The reaction was monitored by TLC, neutralized with saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate (30 mL x 2 times), the organic phase was combined, the organic phase was dried over anhydrous sodium sulfate, concentrated, and finally purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate = 1:4) to obtain 1.87 g of a white solid (R)-2. 5 ,2 6 -difluoro-7-methyl-1 1 -(methyl-d3)-1 1 H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclonononaphane-3,8-dione (two-step yield: 82%) was obtained. LCMS: RT=1.75min, [M+H] + = 337.11.

[0177] Step K: (7R)-2 5 ,2 6 -difluoro-3-hydroxy-7-methyl-1 1 -(methyl-d3)-1 1 Synthesis of H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclonononaphane-8-one (R)-2 5 ,2 6 -difluoro-7-methyl-1 1 -(methyl-d3)-1 1 H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclonononaphane-3,8-dione (1.87 g, 5.56 mmol) was dissolved in anhydrous methanol (36 mL), and sodium borohydride (211 mg, 5.56 mmol) was added in several portions at -70°C, followed by a reaction at the same temperature for 15 minutes.

[0178] The reaction was monitored by TLC, the reaction was quenched by adding saturated ammonium chloride aqueous solution, extracted with ethyl acetate (30 mL x 5 times), the organic phase was combined, the organic phase was dried over anhydrous sodium sulfate, and concentrated to obtain 900 mg of a white solid (7R)-2. 5 ,2 6 -difluoro-3-hydroxy-7-methyl-1 1 -(methyl-d3)-1 1 H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclononaphan-8-one (yield: 48%) was obtained. LCMS: RT=1.62min, [M+H] + =339.04.

[0179] Step L: (7R)-2 5 ,2 6 -difluoro-7-methyl-1 1 -(methyl-d3)-8-oxo-1 1 Synthesis of H-9-aza-1(5,4)-pyrazola-2(1,3)-benzoazepine-3-yl-4-nitrobenzenesulfonate (7R)-2 5 ,2 6 -difluoro-3-hydroxy-7-methyl-1 1 -(methyl-d3)-1 1 H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclononaphan-8-one (900 mg, 2.66 mmol) was added to anhydrous dichloromethane (50 mL), then triethylamine (672 mg, 6.66 mmol) and 4-dimethylaminopyridine (324 mg, 2.66 mmol) were added sequentially and the mixture was stirred for 10 minutes. Then p-nitrobenzenesulfonyl chloride (882 mg, 3.99 mmol) was added in several batches, and the mixture was reacted at room temperature for 4 hours.

[0180] The reaction was monitored by TLC, diluted with 30 mL of sodium bicarbonate solution, extracted with dichloromethane (20 mL twice), the organic phase was combined, the organic phase was dried over anhydrous sodium sulfate, and the residue obtained by concentrated under reduced pressure was purified by column chromatography (eluent: n-hexane:ethyl acetate = 1:15) to obtain 900 mg of a pale yellow solid (7R)-2 5 ,2 6 -difluoro-7-methyl-1 1 -(methyl-d3)-8-oxo-1 1 H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclonononaphane-3-yl-4-nitrobenzenesulfonate (yield: 65%) was obtained. LCMS: RT=1.93min, [M+H] + = 524.02.

[0181] Step M: (3S,7R)-3-(4-(3-chloro-2-fluoro-6-(4-trifluoromethyl)-1H-1,2,3-triazole-1-ylphenyl)-6-oxopyrimidine-1(6H)yl)-2 5 ,2 6 -difluoro-7-methyl-1 1 -(methyl-d3)-1 1 Synthesis of H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclonononaphane-8-one 6-(3-chloro-2-fluoro-6-(4-trifluoromethyl)-1H-1,2,3-triazole-1-yl)phenyl)pyrimidine-4(3H)one (160 mg, 0.44 mmol) was dissolved in dried anhydrous 1,4-dioxane (10 mL), and then lithium bis(trimethylsilyl)amide (1 mol / L tetrahydrofuran solution, 0.44 mL, 0.44 mmol) was slowly added. The resulting reaction mixture was stirred at room temperature for 30 minutes. Then, (7R)-2 5 ,2 6 -difluoro-7-methyl-1 1 -(methyl-d3)-8-oxo-1 1H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclononafane-3-yl-4-nitrobenzenesulfonate (230 mg, 0.44 mmol) was added and the mixture was reacted at 70°C for 16 hours.

[0182] The reaction was monitored using TLC, cooled to room temperature, and saturated ammonium chloride aqueous solution (25 mL) and ethyl acetate (50 mL) were added to the reaction mixture and separated. The resulting organic phase was washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 14 / 1), and then by preparative high-performance liquid chromatography to obtain 45 mg of a white solid (3S,7R)-3-(4-(3-chloro-2-fluoro-6-(4-trifluoromethyl)-1H-1,2,3-triazole-1-ylphenyl)-6-oxopyrimidine-1(6H)yl)-2 5 ,2 6 -difluoro-7-methyl-1 1 -(methyl-d3)-1 1 H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclononafane-8-one (yield: 15%) was obtained. LC-MS: RT=2.00min, [M+H] + = 679.99. 1 H NMR(400MHz,DMSO-d6)δ9.20(s,1H),9.19(s,1H),8.47(brs,1H),8.05(t,J=8.2Hz,1 H),7.77(dd,J=8.7,1.4Hz,1H),7.51(s,1H),7.42-7.37(m,2H),6.71(s,1H),5.54(d, J=12.6Hz,1H),2.56-2.52(m,1H),2.47-2.39(m,1H),2.39-2.28(m,1H),1.90-1.83(m ,1H),1.82-1.72(m,1H),1.45-1.33(m,1H),1.14-1.04(m,1H),0.95(d,J=6.7Hz,3H).

[0183] Example 17 (3S,7R)-3-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-6-oxopyrimidine-1(6H)-yl)-2 5 ,2 6 -difluoro-7-methyl-1 1 -(methyl-d3)-1 1 Synthesis of H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclonononaphane-8-one(17) The specific synthesis route is as follows: [ka]

[0184] 6-(5-chloro-2-(4-chloro-1H-1,2,3-triazole-1-yl)phenyl)pyrimidine-4(3H)one (100 mg, 0.325 mmol) was dissolved in dried anhydrous 1,4-dioxane (10 mL), and then lithium bis(trimethylsilyl)amide (1 mol / L tetrahydrofuran solution, 0.325 mL, 0.325 mmol) was slowly added. The resulting reaction mixture was stirred at room temperature for 30 minutes. Then, (7R)-2 5 ,2 6 -difluoro-7-methyl-1 1 -(methyl-d3)-8-oxo-1 1 H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclononafane-3-yl-4-nitrobenzenesulfonate (170 mg, 0.325 mmol) was added, and the mixture was reacted at 70°C for 16 hours.

[0185] The reaction was monitored using TLC, the mixture was cooled to room temperature, and saturated ammonium chloride aqueous solution (25 mL) and ethyl acetate (50 mL) were added to the reaction mixture and separated. The resulting organic phase was washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 14 / 1), and then by preparative high-performance liquid chromatography to obtain 19.7 mg of a white solid (3S,7R)-3-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazole-1-yl)phenyl)-6-oxopyrimidine-1(6H)-yl)-2 5 ,2 6 -difluoro-7-methyl-1 1 -(methyl-d3)-1 1 H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclononafane-8-one (yield: 9.7%) was obtained. LC-MS: RT=1.95min, [M+H] + = 627.98.

[0186] 1 H NMR(400MHz,DMSO-d6)δ9.20(s,1H),8.74(s,1H),8.48(s,1H),7.89(d,J=2.3Hz,1 H),7.82(dd,J=8.5,2.4Hz,1H),7.75(d,J=8.5Hz,1H),7.54-7.45(m,2H),7.45-7. 37(m,1H),6.40(s,1H),5.52(d,J=12.6Hz,1H),2.47-2.30(m,2H),1.95-1.82(m,1 H),1.82-1.69(m,1H),1.45-1.33(m,1H),1.17-1.02(m,2H),0.94(d,J=6.7Hz,3H).

[0187] Example 18 (3S,7R)-3-(4-(5-chloro-2-(4-trifluoromethyl)-1H-1,2,3-triazole-1-ylphenyl)-6-oxopyrimidine-1(6H)yl)-2 5 ,2 6 -difluoro-7-methyl-1 1 -(methyl-d3)-11 Synthesis of H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclonononaphane-8-one(18) The specific synthesis route is as follows: [ka]

[0188] 6-(5-chloro-2-(4-trifluoromethyl)-1H-1,2,3-triazole-1-yl)phenyl)pyrimidine-4(3H)one (200.0 mg, 0.59 mmol) was dissolved in dried anhydrous 1,4-dioxane (10 mL), and then lithium bis(trimethylsilyl)amide (1 mol / L tetrahydrofuran solution, 0.59 mL, 0.59 mmol) was slowly added. The resulting reaction mixture was stirred at room temperature for 30 minutes. Then, (7R)-2 5 ,2 6 -difluoro-7-methyl-1 1 -(methyl-d3)-8-oxo-1 1 H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclononafane-3-yl-4-nitrobenzenesulfonate (307 mg, 0.59 mmol) was added and the mixture was reacted at 70°C for 16 hours.

[0189] The reaction was monitored using TLC, the mixture was cooled to room temperature, and saturated ammonium chloride aqueous solution (25 mL) and ethyl acetate (30 mL) were added to the reaction mixture and separated. The resulting organic phase was washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 14 / 1), and then by preparative high-performance liquid chromatography to obtain 40.1 mg of a white solid (3S,7R)-3-(4-(5-chloro-2-(4-trifluoromethyl)-1H-1,2,3-triazole-1-ylphenyl)-6-oxopyrimidine-1(6H)yl)-2 5 ,2 6 -difluoro-7-methyl-1 1 -(methyl-d3)-1 1H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclononafane-8-one (yield: 10.2%) was obtained. LC-MS: RT=1.98min,[M+H] + = 662.00.

[0190] 1 H NMR(400MHz,DMSO-d6)δ9.26-9.14(m,2H),8.51-8.36(m,1H),7.93(d,1H ),7.89-7.79(m,2H),7.51(s,1H),7.48-7.36(m,2H),6.52(s,1H),5.53(d ,J=12.4Hz,1H),3.31(s,1H),2.47-2.36(m,2H),1.92-1.81(m,1H),1.81- 1.69(m,1H),1.46-1.33(m,1H),1.18-1.02(m,1H),0.95(d,J=6.7Hz,3H).

[0191] Example 19 (3S,7R)-3-(4-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)-6-oxopyrimidine-1(6H)yl)-2 5 ,2 6 -difluoro-7-methyl-1 1 -(methyl-d3)-1 1 Synthesis of H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclonononaphane-8-one(19) The specific synthesis route is as follows: [ka]

[0192] 6-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)pyrimidine-4(3H)one (70 mg, 0.215 mmol) was dissolved in dried 1,4-dioxane (7 mL), and then lithium bis(trimethylsilyl)amide (1 mol / L tetrahydrofuran solution, 0.215 mL) was slowly added. The resulting reaction mixture was stirred at room temperature for 30 minutes. Then, (7R)-2 5 ,2 6 -difluoro-7-methyl-1 1 -(methyl-d3)-8-oxo-1 1 H-1(5,4)-pyrazola-2(1,3)-benzenacyclononafane-3-yl-4-nitrobenzenesulfonate (170 mg, 323 mmol) was added, and the reaction mixture was stirred at 70°C for 16 hours.

[0193] The reaction was monitored using TLC, the mixture was cooled to room temperature, and saturated ammonium chloride aqueous solution (25 mL) and ethyl acetate (30 mL) were added to the reaction mixture and separated. The resulting organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 10 / 1), and then purified by preparative high-performance liquid chromatography to obtain 17.6 mg of a white solid (3S,7R)-3-(4-(3-chloro-6-(4-chloro-1H-1,2,3-triazole-1-yl)-2-fluorophenyl)-6-oxopyrimidine-1(6H)yl)-2 5 ,2 6 -difluoro-7-methyl-1 1 -(methyl-d3)-1 1 H-9-aza-1(5,4)-pyrazola-2(1,3)-benzenacyclononafane-8-one (yield: 12.7%) was obtained. LC-MS: RT=1.95min, [M+H] + = 646.01.

[0194] Examples 20-23 The compound represented by formula 20-23 below was prepared using the preparation method described in the above example. [ka]

[0195] Example 24: Detection of the biological activity of the compound of the present invention in inhibiting human blood coagulation factor XIa by spectrophotometric method 1. Experimental materials Enzyme: Human Factor XIa (ENZYME RESEARCH, catalog number HFXIa 1111a) Substrate: S-2366 TM :(CHROMOGENIX, catalog number 82109039) Buffer: 145mM NaCl, 5mM KCl, 1mg / mL PEG 8000, 30mM HEPES, PH7.4.

[0196] 2. Experimental Steps The 10 mM test compound dissolved in 100% DMSO was diluted with 100% DMSO to 1000, 200, 40, 8, 1.6, 0.32, 0.064, 0.0128, 0.00256, and 0.00128 μM. 98 μL (77.7 ng / mL) of FXIa enzyme solution was added to each well of a 96-well plate. 98 μL of buffer was added to the blank wells instead of FXIa enzyme solution, followed by 2 μL of the compound at different concentrations. DMSO was added to the blank and control wells instead of the compound. The mixtures were then homogenized using a shaker and incubated at 37°C for 20 minutes. Finally, 100 μL of 800 μM substrate was added to each well, and the absorbance was measured at 405 nm.

[0197] 3. Data Processing Curve fitting is performed using GraphPad Prism software, and IC 50 The value was calculated.

[0198] Example 25: Measurement of the in vitro anticoagulant effect of the compound of the present invention on human plasma. 1. Experimental materials aPTT lot number 220106600, calcium chloride lot number 210305600, needle washing solution lot number 211101300: manufactured by Shenzhen Mairui Biomedical Electronics Co., Ltd. Human mixed plasma was collected from healthy individuals using disposable venous blood collection tubes. Disposable human venous blood sample collection containers, lot number 211108, sodium citrate 9:1, manufactured by Liuyang Sanli Medical Technology Development Co., Ltd., were used to collect human blood. The sample was centrifuged at 3000 rpm for 10 minutes at room temperature, and the supernatant was taken and prepared for use. The supernatant was lot number 20220606.

[0199] 2. Experimental Steps A 10 mM test compound dissolved in 100% DMSO was diluted with 100% DMSO to 0.29, 0.59, 1.17, 2.34, 4.69, 9.38, 18.75, and 37.50 μM concentrations. 99 μL of human mixed plasma was added to each 1.5 ml centrifuge tube, followed by 1 μL of the compound at each different concentration. 1 μL of DMSO was added to the blank wells, and the mixtures were thoroughly mixed by repeatedly inverting them by hand. The samples were collected by centrifugation using a handheld centrifuge, incubated in a 37°C water bath in an electric thermostatic water bath for 10 minutes to ensure thorough mixing, and aPTT was detected using a fully automated blood coagulation analyzer according to a pre-set program.

[0200] 3. Data Processing Curve fitting was performed using Graphad Prism software to calculate EC1.5×.

[0201] The results for Examples 24 and 25 are shown in Table 1.

[0202] [Table 1]

[0203] Conclusion: The compounds of the present invention exhibit significant inhibitory activity against human FXIa and significant anticoagulant effects against human plasma.

[0204] Example 26: Pharmacokinetic experiment 1. Reagents and equipment Polyethylene glycol 400 (lot number GORKREUT, Satsuen Chemical Technology (Shanghai) Co., Ltd.), DMSO (lot number 20200319, Guangdong Guanghua Technology Co., Ltd.), physiological saline (lot number C20052604, Jiangxi Kelun Pharmaceutical Co., Ltd.). LC-MS equipment (Thermo Fisher Ultimate 3000 UPLC, TSQ QUANTUM ULTRA triple quadrupole mass spectrometer, AB SCIEX 5500 QTARP).

[0205] 2. Laboratory animals SD rats: Male, 180-250g, purchased from Guangdong Weitong Lihua Laboratory Animal Technology Co., Ltd.

[0206] 3. Preparation of the formulation The test powder was precisely weighed, completely dissolved in DMSO, then PEG-400 was added and uniformly mixed by vortex mixing. After that, physiological saline was added and uniformly mixed by vortex mixing to obtain a concentration of 0.5 mg / mL (DMSO:PEG-400:NS = 5:60:35, V / V / V), which was administered at a rate of 10 mL / kg for intragastric administration and 0.5 mL / kg for intravenous administration.

[0207] 4. Collection of blood samples After intravenous or intragastric administration to rats, 200 μL of venous blood was collected in heparinized EP tubes at 5 min (no sampling was performed for intragastric administration), 15 min, 30 min, 1 h, 2 h, 5 h, 7 h, and 24 h. The tubes were then centrifuged at 12000 rpm for 2 min, and the plasma was frozen and stored at -80°C for measurement.

[0208] 5, bioanalysis A precise amount of the test sample was weighed and dissolved in DMSO at a concentration of 1 mg / mL to prepare the stock solution. An appropriate amount of the compound stock solution was accurately aspirated and diluted with acetonitrile to prepare a series of standard solutions. 20 μL of each of the above series of standard solutions was accurately aspirated, 180 μL of blank plasma was added, and the mixture was vortexed to ensure uniformity. Plasma samples corresponding to plasma concentrations of 1, 3, 10, 30, 100, 300, 1000, 3000, and 5000 ng / mL were prepared, and dual-sample analysis was performed for each concentration to create standard curves. 20 μL of plasma was taken, 200 μL of acetonitrile solution of the internal standard propranolol (5 ng / mL) was added, and the mixture was vortexed to ensure uniformity. The mixture was then centrifuged at 4000 rpm for 5 minutes, and the supernatant was collected and analyzed by LC-MS. The LC-MS detection conditions were as follows. Column: Waters ACQUITY™ PREMIER HSS T3, 50*2.1mm, 1.8μm. Mobile phase A: water (0.1% formic acid), Mobile phase B: acetonitrile, Flow rate: 0.5 mL / min, Gradient elution is as shown in Table 2 below.

[0209] [Table 2]

[0210] 6. Data Processing After detecting blood drug concentrations using LC-MS, pharmacokinetic parameters after administration to rats were calculated using a non-compartment model with WinNonlin6.1 software, and the results are shown in Table 3 below.

[0211] [Table 3]

[0212] As can be seen from the experimental results in Table 3, the preferred compound of the present invention has good oral absorption, high absolute bioavailability and exposure levels, and is superior to the control compound.

[0213] Example 27: Detection of the biological activity of the compound of the present invention in inhibiting the human blood coagulation factor chymotrypsin by spectrophotometric method. 1. Experimental materials Enzyme: α-Chymotrypsin (Sigma, catalog number C8946) Substrate: S-2586 TM :(Sailor's organism, catalog number B2586) Buffer: 0.05M HEPES; 0.145M NaCl; 5mM KCl and0.1%PEG 8000, PH7.4

[0214] 2. Experimental Steps The 10 mM test compound dissolved in 100% DMSO was diluted with 100% DMSO to concentrations of 100, 33.33, 11.11, 3.704, 1.235, 0.412, 0.137, and 0.046 μM. 29.4 μL (20 nM) chymotrypsin enzyme solution was added to each well of a 384-well plate. 29.4 μL of buffer was added to the blank wells instead of the enzyme solution, followed by 0.6 μL of the compound at different concentrations. DMSO was added to the blank and control wells instead of the compound. The mixtures were then homogenized using a shaker and incubated at 37°C for 30 minutes. Finally, 30 μL of 200 μM substrate was added to each well, and the absorbance was measured at 405 nm.

[0215] 3. Data Processing Curve fitting is performed using GraphPad Prism software, and IC 50 The values ​​are calculated and shown in Table 4.

[0216] [Table 4]

[0217] Experimental conclusion: The compounds of the present invention exhibit weak inhibitory activity against chymotrypsin and superior selectivity for chymotrypsin.

[0218] Example 28: Detection of the biological activity of the compound of the present invention in inhibiting the human blood coagulation factor trypsin by spectrophotometric method.

[0219] 1. Experimental materials

[0220] Enzyme: Human trypsin (Sigma, catalog number T6424) Substrate: S-2222 TM :(CHROMOGENIX, catalog number 82031639) Buffer solution: 0.1M sodium phosphate; 0.2M NaCl and 0.5% PEG 8000, pH 7.4

[0221] 2. Experimental steps: The 10 mM test compound dissolved in 100% DMSO was diluted with 100% DMSO to concentrations of 10000, 3333, 1111, 370.4, 123.5, 41.2, 13.7, and 4.6 μM. 29.4 μL (0.8 nM) of trypsin enzyme solution was added to each well of a 384-well plate. 29.4 μL of buffer was added to the blank wells instead of the enzyme solution, followed by 0.6 μL of the compound at different concentrations. DMSO was added to the blank and control wells instead of the compound. The mixtures were then homogenized using a shaker and incubated at 37°C for 30 minutes. Finally, 30 μL of 40 μM substrate was added to each well, and the absorbance was measured at 405 nm.

[0222] 3. Data Processing Curve fitting is performed using GraphPad Prism software, and IC 50 The values ​​are calculated and shown in Table 5.

[0223] [Table 5]

[0224] Experimental conclusion: The compounds of the present invention exhibit weak inhibitory activity against trypsin and superior selectivity for trypsin.

[0225] Example 29: Detection of the biological activity of the compound of the present invention in inhibiting human blood coagulation factor FIIa by spectrophotometric method 1. Experimental materials Enzyme: Human FIIa (Enzyme Research Laboratories, catalog number HT1002a) Substrate: S-2366 TM :(CHROMOGENIX, catalog number 82109039) Buffer solution: 0.1M sodium phosphate; 0.2M NaCl and 0.5% PEG 8000, pH 7.4

[0226] 2. Experimental Steps The 10 mM test compound dissolved in 100% DMSO was diluted with 10000, 3333, 1111, 370.4, 123.5, 41.2, 13.7, and 4.6 μM with 100% DMSO. 29.4 μL (4 nM) of FIIa enzyme solution was added to each well of a 384-well plate. 29.4 μL of buffer was added to the blank wells instead of the enzyme solution, followed by 0.6 μL of the compound at different concentrations. DMSO was added to the blank and control wells instead of the compound. The mixtures were then homogenized using a shaker and incubated at 37°C for 30 minutes. Finally, 30 μL of 200 μM substrate was added to each well, and the absorbance was measured at 405 nm.

[0227] 3. Data Processing Curve fitting is performed using GraphPad Prism software, and IC 50 The values ​​are calculated and shown in Table 6.

[0228] [Table 6]

[0229] Experimental conclusion: The compound of the present invention exhibits weak inhibitory activity against blood coagulation factor FIIa and superior selectivity for blood coagulation factor FIIa.

[0230] The structural formula of the control compound is as follows: [ka]

[0231] The above embodiments are preferred embodiments of the present invention, and the embodiments of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principles of the present invention are all equivalent substitutions and are all within the scope of protection of the present invention.

Claims

1. A compound represented by general formula (I), or its isomer, or its racemic mixture, or a pharmaceutically acceptable salt thereof, 【Chemistry 1】 X is selected from hydrogen, halogen, and cyano groups, Y is selected from hydrogen, halogen, and cyano groups, Z is selected from hydrogen, halogen, and cyano groups, and at least two of X, Y, and Z are not hydrogen. W is selected from C or N, and if W is N, R １ It does not exist. T １ and T ２ is selected from C or N, and when T １ is selected from N, R ２ｃ does not exist, and when T ２ is selected from N, R ２ｂ does not exist, and T １ and T ２ are not N simultaneously Ring A is selected from substituted or unsubstituted benzene rings and pyrazole rings, and the substituents are selected from halogens, cyano groups, alkyl groups, and halogenated alkyl groups. R １ It is selected from halogens, alkyl halides, and cyano groups. R ２ａ , R ２ｂ , R ２ｃ These are independently selected from hydrogen, halogen, and alkoxy groups. R ３ These are alkyl groups, halogenated alkyl groups, alkoxy groups, -(CH ２ ) ｎ -Cycloalkyl group, -(CH ２ ) ｎ - Selected from heterocycloalkyl groups, where n = 0 or 1, R ４ It is characterized by being selected from hydrogen and halogens. A compound, or its isomer, or its racemic mixture, or a pharmaceutically acceptable salt thereof.

2. A compound represented by formula (Ia) or formula (Ib), or its isomer, or its racemic mixture, or a pharmaceutically acceptable salt thereof, is selected. 【Chemistry 2】 X is selected from hydrogen, halogen, and cyano groups, Y is selected from hydrogen, halogen, and cyano groups, Z is selected from hydrogen, halogen, and cyano groups, and at least two of X, Y, and Z are not hydrogen. T １ and T ２ is selected from C or N, T １ If selected from N, R ２ｃ It does not exist, T ２ If selected from N, R ２ｂ It does not exist, and T １ and T ２ It is not possible for something to be N at the same time. R １ It is selected from halogens, alkyl halides, and cyano groups. R ２ａ , R ２ｂ , R ２ｃ These are independently selected from hydrogen, halogen, and alkoxy groups. R ３ These are alkyl groups, halogenated alkyl groups, alkoxy groups, -(CH ２ ) n-cycloalkyl group, -(CH ２ ) Selected from n-heterocycloalkyl groups, where n = 0 or 1, R ４ It is selected from hydrogen or halogen, R ５ It is characterized by being selected from alkyl groups and halogenated alkyl groups. The compound described in claim 1, or its isomer, or its racemic mixture, or a pharmaceutically acceptable salt thereof.

3. The alkyl group is C １－６ Selected from alkyl groups, the C １－６ The alkyl group is selected from methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, sec-pentyl group, 1-ethylpropyl group, 2-methylbutyl group, tert-pentyl group, 1,2-dimethylpropyl group, isopentyl group, neopentyl group, n-hexyl group, isohexyl group, sec-hexyl group, tert-hexyl group, neohexyl group, 2-methylpentyl group, 1,2-dimethylbutyl group, and 1-ethylbutyl group. The alkoxy group is C １－６ Selected from alkoxy groups, the C １－６ The alkoxy group is characterized by being selected from methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, n-pentoxy group, sec-pentoxy group, 1-ethylpropoxy group, 2-methylbutoxy group, tert-pentoxy group, 1,2-dimethylpropoxy group, isopentoxy group, neopentoxy group, n-hexyloxy group, isohexyloxy group, sec-hexyloxy group, tert-hexyloxy group, neohexyloxy group, 2-methylpentoxy group, 1,2-dimethylbutoxy group, and 1-ethylbutoxy group. A compound according to claim 1 or 2, or an isomer thereof, or a racemic mixture thereof, or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1 or 2, or an isomer thereof, or a racemic mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that the halogen is selected from fluorine, chlorine, bromine, and iodine.

5. The halogenated alkyl group means that one or more hydrogen atoms in the alkyl group are substituted with a halogen, and the halogen is selected from fluorine, chlorine, bromine, and iodine, characterized in that the compound according to claim 1 or 2, or an isomer thereof, or a racemic mixture thereof, or a pharmaceutically acceptable salt thereof.

6. The cycloalkyl group is C ３－６ Selected from cycloalkyl groups, the C ３－６ The compound according to claim 1 or 2, or an isomer thereof, or a racemic mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the cycloalkyl group is selected from a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group, and the heterocycloalkyl group means that one or more carbon atoms of the cycloalkyl group are substituted with heteroatoms, the heteroatoms are selected from nitrogen, oxygen, or sulfur, and the heteroatoms are one or more.

7. The aforementioned W is selected from C or N, and if W is N, R １ It does not exist. X is selected from hydrogen and fluorine, Y is selected from hydrogen and fluorine, Z is selected from hydrogen and fluorine, and at least two of X, Y and Z are not hydrogen. T １ and T ２ is selected from C or N, T １ If selected from N, R ２ｃ It does not exist, T ２ If selected from N, R ２ｂ It does not exist, and T １ and T ２ It is not possible for something to be N at the same time. R １ R is selected from chlorine, trifluoromethyl group, and difluoromethyl group. ２ａ , R ２ｂ , R ２ｃ R is independently selected from hydrogen, methoxy group, fluorine, and chlorine. ３ R is selected from methyl groups, ４ R is selected from hydrogen and fluorine. ５ The group is characterized by being selected from a methyl group and a difluoromethyl group. A compound according to claim 1 or 2, or an isomer thereof, or a racemic mixture thereof, or a pharmaceutically acceptable salt thereof.

8. The aforementioned compounds are as follows: 1 to 23: 【Transformation 3】 【change】 【change】 A compound according to claim 1 or 2, or an isomer thereof, or a racemic mixture thereof, or a pharmaceutically acceptable salt thereof, characterized by being selected from the compounds shown in (1).

9. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 8, or an isomer thereof, or a racemic mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

10. Use of a compound according to any one of claims 1 to 8, or an isomer thereof, or a racemate thereof, or a pharmaceutically acceptable salt thereof, in the preparation of a drug for treating FXIa-related diseases, preferably in the preparation of a drug for treating thrombosis-related diseases.

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