Polysubstituted macrocyclic compound as well as preparation method and application thereof

Abstract

Provided are a compound represented by general formula (I), or a racemate thereof, or an isomer thereof, or a pharmaceutically acceptable salt thereof, and methods of using the same to treat a variety of specific diseases or conditions. # imgabs0 #

Description

A polysubstituted macrocyclic compound and its preparation method and application Technical Field

[0001] The present invention belongs to the field of chemical pharmaceutical technology and provides polysubstituted macrocyclic compounds, their preparation methods, and their use as selective inhibitors of Factor XIa (FXIa). The present invention also relates to pharmaceutical compositions containing these compounds and their use in pharmaceuticals for treating diseases such as thromboembolism. Background Art

[0002] Globally, cardiovascular diseases such as cerebrovascular disease, stroke, myocardial infarction, coronary heart disease, and arteriosclerosis claim nearly 12 million lives annually, accounting for nearly a quarter of the world's total mortality and becoming the number one threat to human health. In China, over 2.6 million people die from cardiovascular disease each year, and 75% of those who survive suffer a disability, with over 40% experiencing severe disability. Thrombosis caused by cardiovascular disease, diabetes, and their complications has become a pressing issue that needs to be addressed.

[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). It is a chain reaction that is continuously strengthened and amplified through the sequential activation of multiple zymogens. The coagulation cascade is initiated by the intrinsic pathway (also known as the contact activation pathway) and the extrinsic pathway (also known as the tissue factor pathway) to produce FXa, which then generates thrombin (FIIa) through the common pathway, ultimately forming fibrin.

[0004] The intrinsic pathway is the activation of factor XII to form XIa-VIIIa-Ca 2+ The extrinsic coagulation pathway is the process of releasing tissue factor (TF) to TF-VIIa-Ca 2+ The common pathway involves the formation of a complex and the activation of factor X. Following the formation of factor Xa, the two pathways merge to activate prothrombin and ultimately generate fibrin. FXI is essential for maintaining the intrinsic pathway and plays a key role in amplifying the coagulation cascade. During the coagulation cascade, thrombin can feedback activate FXI. Activated FXI (FXIa) in turn promotes the production of thrombin, thereby amplifying the coagulation cascade. Consequently, FXI antagonists have been widely developed for the treatment of various thrombosis conditions.

[0005] Traditional anticoagulants, such as warfarin, heparin, and low molecular weight heparin (LMWH), as well as new drugs launched in recent years, such as FXa inhibitors (rivaroxaban, apixaban, etc.) and thrombin inhibitors (dabigatran etexilate, hirudin, etc.), are all effective in reducing thrombosis and occupy a large part of the cardiovascular market with their significant effectiveness. However, their side effects are also becoming increasingly significant, among which "bleeding risk" is one of the most serious problems (N Engl J Med 1991; 325: 153-8, Blood. 2003; 101: 4783-4788).

[0006] Studies have found that in thrombosis models, inhibiting FXIa can effectively inhibit thrombosis, but in more severe 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 those with severe FXIa deficiency have a reduced risk of DVT (Thromb Haemost 2011; 105: 269–273).

[0007] FXIa is an emerging target for inhibiting thrombosis. Patent applications disclosing compounds with FXIa inhibitory activity include WO9630396, WO9941276, WO2013093484, WO2004002405, WO2013056060, WO2017005725, WO2017 / 023992, WO2018041122, etc.

[0008] Summary of the Invention

[0009] The present invention provides a series of macrocyclic derivatives, preparation methods thereof and medical applications thereof.

[0010] Specifically, in a first aspect, the present application provides a compound represented by general formula (I), or its isomer, racemate, or pharmaceutically acceptable salt:

[0011] In a second aspect, the present invention further provides a pharmaceutical composition comprising a therapeutically effective amount of any one of the above-mentioned compounds or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0012] In a third aspect, the present invention also provides a medical use of a therapeutically effective amount of the above-mentioned compound or a pharmaceutically acceptable salt thereof, specifically, its use in the preparation of a medicament for treating a disease condition as a selective inhibitor of Factor XIa (FXIa), and its use in a medicament for treating diseases such as thromboembolism.

[0013] Specifically, the present invention is achieved through the following technical solutions:

[0014] A compound represented by general formula (I), or its isomer, racemate, or pharmaceutically acceptable salt,

[0015] wherein X is selected from hydrogen, halogen, and cyano; Y is selected from hydrogen, halogen, and cyano; Z is selected from hydrogen, halogen, and cyano; and at least two of X, Y, and Z are not hydrogen;

[0016] W is selected from C or N. When W=N, R 1 does not exist;

[0017] T1 and T2 are selected from C or N. When T1 is selected from N, R 2c Not present, when T2 is selected from N, R 2b Does not exist, and T1 and T2 cannot be N at the same time;

[0018] Ring A is selected from substituted or unsubstituted benzene ring, pyrazole ring, wherein the substituent is selected from halogen, cyano, alkyl, haloalkyl;

[0019] R 1 is selected from halogen, haloalkyl, and cyano;

[0020] R 2a 、R 2b 、R 2c independently selected from hydrogen, halogen, alkoxy;

[0021] R 3 Selected from alkyl, haloalkyl, alkoxy, -(CH2)n-cycloalkyl, -(CH2)n-heterocycloalkyl, n=0 or 1;

[0022] R 4 Selected from hydrogen and halogen.

[0023] As a preferred technical solution of the present invention, a compound represented by formula (Ia) or formula (Ib), or an isomer, racemate, or pharmaceutically acceptable salt thereof is selected from:

[0024] or

[0025] wherein X is selected from hydrogen, halogen, and cyano; Y is selected from hydrogen, halogen, and cyano; Z is selected from hydrogen, halogen, and cyano; and at least two of X, Y, and Z are not hydrogen;

[0026] T1 and T2 are selected from C or N. When T1 is selected from N, R 2c Not present, when T2 is selected from N, R 2b Does not exist, and T1 and T2 cannot be N at the same time;

[0027] R 1 is selected from halogen, haloalkyl, and cyano;

[0028] R 2a 、R 2b 、R 2c independently selected from hydrogen, halogen, alkoxy;

[0029] R 3 Selected from alkyl, haloalkyl, alkoxy, -(CH2)n-cycloalkyl, -(CH2)n-heterocycloalkyl, n=0 or 1;

[0030] R 4 is selected from hydrogen or halogen;

[0031] R 5 Selected from alkyl and halogenated alkyl.

[0032] As a preferred technical solution of the present invention, the alkyl group is selected from C 1-6 The alkyl group, the C 1-6 The alkyl group is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, 1-ethylpropyl, 2-methylbutyl, tert-pentyl, 1,2-dimethylpropyl, isopentyl, neopentyl, n-hexyl, isohexyl, sec-hexyl, tert-hexyl, neohexyl, 2-methylpentyl, 1,2-dimethylbutyl, and 1-ethylbutyl.

[0033] As a preferred technical solution of the present invention, the alkoxy group is selected from C 1-6 Alkoxy, the C 1-6 The 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-hexoxy, isohexoxy, sec-hexoxy, tert-hexoxy, neohexoxy, 2-methylpentoxy, 1,2-dimethylbutoxy, and 1-ethylbutoxy.

[0034] As a preferred technical solution of the present invention, the halogen is selected from fluorine, chlorine, bromine and iodine.

[0035] As a preferred technical solution of the present invention, the haloalkyl group refers to an alkyl group in which one or more hydrogen atoms are replaced by halogen atoms, and the halogen atoms are selected from fluorine, chlorine, bromine and iodine.

[0036] As a preferred technical solution of the present invention, the cycloalkyl group is selected from C 3-6 The cycloalkyl group, the C 3-6 The cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; the heterocycloalkyl group refers to a cycloalkyl group in which one or more carbon atoms are replaced by heteroatoms, and the heteroatoms are selected from nitrogen, oxygen and sulfur, and the heteroatoms are one or more.

[0037] As a preferred technical solution of the present invention,

[0038] The W is selected from C or N. When W=N, R 1 does not exist;

[0039] 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;

[0040] T1 and T2 are selected from C or N. When T1 is selected from N, R 2c Not present, when T2 is selected from N, R 2b Does not exist, and T1 and T2 cannot be N at the same time;

[0041] R 1 Selected from chlorine, trifluoromethyl, difluoromethylene; R 2a 、R 2b 、R 2c are independently selected from hydrogen, methoxy, fluorine, chlorine; R 3 Selected from methyl; R 4 is selected from hydrogen, fluorine; R 5 Selected from methyl and difluoromethylene.

[0042] As a preferred technical solution of the present invention, one or more hydrogen atoms of the compound are replaced by isotope deuterium ( 2 H) substitution.

[0043] As a preferred technical solution of the present invention, the compound is selected from:

[0044] As a preferred technical solution of the present invention, a pharmaceutically acceptable salt of the compound is provided. The pharmaceutically acceptable salt of the compound refers to a compound, or an isomer thereof, or a racemate thereof, prepared with a pharmaceutically acceptable acid or base.

[0045] As a preferred technical solution of the present invention, a pharmaceutical composition is provided, comprising a therapeutically effective amount of the aforementioned compound, or an isomer thereof, or a racemate thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0046] As a preferred technical solution of the present invention, provided is the medical use of the compound, or its isomer, or its racemate, or its pharmaceutically acceptable salt, specifically, its use in the preparation of a drug for treating FXIa-related diseases, preferably a drug for treating thrombosis-related diseases.

[0047] For the sake of clarity, general terms used in the description of the compounds are defined herein.

[0048] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered as undefined or unclear in the absence of a specific definition, but should be understood according to its ordinary meaning. When a trade name appears in this article, it is intended to refer to its corresponding commercial product or its active ingredient. The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms that are suitable for use in contact with human and animal tissues within the scope of sound medical judgment without excessive toxicity, irritation, allergic reaction or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0049] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention, which is prepared by reacting a compound having a specific substituent discovered in the present invention with a pharmaceutically acceptable acid or base.

[0050] In addition to the form of salts, the compounds provided by the present invention also exist in prodrug form. The prodrugs of the compounds described herein easily undergo chemical changes under physiological conditions to be converted into the compounds of the present invention. In addition, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an in vivo environment.

[0051] Certain compounds of the present invention may exist in unsolvated forms as well as solvated forms, including hydrates. In general, the solvated forms are equivalent to the unsolvated forms and are encompassed within the scope of the present invention.

[0052] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are encompassed within the scope of the present invention.

[0053] Optically active (R)- and (S)-isomers, as well as D and L isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are resolved by conventional methods known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is typically accomplished using chromatography, which employs a chiral stationary phase and is optionally combined with a chemical derivatization method (e.g., carbamate formation from an amine).

[0054] The atoms of the molecules of the compounds of the present invention are isotopes, and isotope derivatization can generally extend half-life, reduce clearance, stabilize metabolism, and increase in vivo activity. In addition, an embodiment is included in which at least one atom is replaced by an atom having the same atomic number (number of protons) and a different mass number (protons and neutrons). Examples of isotopes included in the compounds of the present invention include hydrogen atoms, carbon atoms, nitrogen atoms, oxygen atoms, phosphorus atoms, sulfur atoms, fluorine atoms, chlorine atoms, which respectively include 2 H. 3 H. 13 C. 14 C. 15 N. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 36 In particular, radioactive isotopes that emit radiation as they decay, such as 3 H or 14C can be used for local anatomy testing of pharmaceutical preparations or compounds in vivo. Stable isotopes neither decay nor change with their amount nor are they radioactive, so they can be used safely. When the atoms constituting the molecules of the compounds of the present invention are isotopes, the isotopes can be converted according to general methods by replacing the reagents used in the synthesis with reagents containing the corresponding isotopes.

[0055] The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, the compounds may be labeled with radioactive isotopes, such as deuterium ( 2 H), iodine-125( 125 I) or C-14( 14 C) All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0056] Furthermore, the compounds of the present invention may have one or more hydrogen atoms replaced by deuterium isotopes ( 2 After deuteration, the compounds of the present invention have the effects of extending half-life, reducing clearance rate, stabilizing metabolism and improving in vivo activity.

[0057] The preparation method of the isotopic derivative generally includes a phase transfer catalytic method. For example, a preferred deuteration method uses a phase transfer catalyst (e.g., a tetraalkylammonium salt, NBu4HSO4). The use of a phase transfer catalyst to exchange the methylene protons of the diphenylmethane compound results in a higher deuterium incorporation than reduction with a deuterated silane (e.g., triethyldeuterated monosilane) in the presence of an acid (e.g., methanesulfonic acid) or with a Lewis acid such as aluminum trichloride using sodium deuterated borate.

[0058] The term "pharmaceutically acceptable carrier" refers to any formulation 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 has no toxic side effects on the host or patient. Representative carriers include water, oils, vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, viscosity increasing agents, transdermal enhancers, etc. Their preparations are well known to those skilled in the art of cosmetics or topical medicine. For additional information about carriers, reference can be made to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.

[0059] The term "excipient" generally refers to a carrier, diluent and / or vehicle required to formulate an effective pharmaceutical composition.

[0060] With respect to a drug or pharmacologically active agent, the term "effective amount" or "therapeutically effective amount" refers to a non-toxic amount of the drug or agent sufficient to achieve the intended effect. For the oral dosage forms of the present invention, an "effective amount" of an active substance in the composition means the amount required to achieve the intended effect when used in combination with another active substance in the composition. The determination of an effective amount varies from person to person, depending on the age and general condition of the recipient, as well as the specific active substance. The appropriate effective amount in each individual case can be determined by those skilled in the art through routine experimentation.

[0061] The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that is effective in treating a target disorder, disease, or condition.

[0062] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0063] The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present invention. DETAILED DESCRIPTION

[0064] The present application is further described in detail below with reference to examples, but the implementation methods of the present application are not limited thereto.

[0065] Example 1

[0066] Synthesis of (3S,7R)-3-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-6-oxopyrimidin-1(6H)-yl)-2 4 ,2 5 -difluoro-7-methyl-1 1 -deuterated methyl-1 1 H-9-Aza-1(5,4)-pyrazole-2(1,3)-benzocyclononanoic acid-8-one (1)

[0067] The specific synthetic route is as follows:

[0068] 6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-(3H)-one (53.0 mg, 0.173 mmol) was dissolved in dry 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, and the resulting reaction solution was stirred at room temperature for 30 minutes. Then, (7R)-2 4 ,2 5 -difluoro-7-methyl-1 1 -deuterated methyl-8-oxo-1 1 H-9-Aza-1(5,4)-pyrazol-2(1,3)-benzazepin-3-yl 4-nitrobenzenesulfonate (90.3 mg, 0.173 mmol) was reacted at 70°C for 16 hours.

[0069] After monitoring showed that the reaction was complete, the reaction mixture was cooled to room temperature. Saturated aqueous ammonium chloride solution (25 ml) and ethyl acetate (30 ml) were added to the reaction mixture for separation. The resulting organic phase was washed with saturated brine. 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 / petroleum ether = 14 / 1) and then purified by preparative high performance liquid chromatography to obtain 17.9 mg of a white solid (3S,7R)-3-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-6-oxopyrimidin-1(6H)-yl) ...2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-6-oxopyrim 4 ,2 5 -difluoro-7-methyl-1 1 -deuterated methyl-1 1 H-9-Aza-1(5,4)-pyrazol-2(1,3)-benzocyclononanoic acid-8-one (yield: 16.5%). LC-MS: RT = 2.00 min, [M+H] + =627.99. 1 H 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).

[0070] Example 2

[0071] Synthesis of (3R,7R)-3-(4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-6-oxopyrimidin-1(6H)-yl) ... 4 ,2 5 -difluoro-7-methyl-1 1 -deuterated methyl-1 1 H-9-Aza-1(5,4)-pyrazole-2(1,3)-benzocyclononanoic acid-8-one (2)

[0072] The specific synthetic route is as follows:

[0073] 6-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-(3H)-one (80.0 mg, 0.234 mmol) was dissolved in dry 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, and the resulting reaction solution was stirred at room temperature for 30 minutes. Then, (7R)-2 4 ,2 5 -difluoro-7-methyl-1 1 -deuterated methyl-8-oxo-1 1 H-9-Aza-1(5,4)-pyrazol-2(1,3)-benzazepin-3-yl 4-nitrobenzenesulfonate (122 mg, 0.234 mmol) was reacted at 70°C for 16 hours.

[0074] After monitoring showed that the reaction was complete, the reaction mixture was cooled to room temperature. Saturated aqueous ammonium chloride solution (25 ml) and ethyl acetate (50 ml) were added to the reaction mixture for separation. The resulting organic phase was washed with saturated brine. 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 / petroleum ether = 14 / 1) and then purified by preparative high performance liquid chromatography to obtain 33.2 mg of a white solid (3S,7R)-3-(4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-6-oxopyrimidin-1(6H)-yl) ... 4 ,2 5 -difluoro-7-methyl-1 1 -deuterated methyl-1 1 H-9-Aza-1(5,4)-pyrazol-2(1,3)-benzocyclononanoic acid-8-one (yield: 21.4%). LC-MS: RT = 1.98 min, [M+H] + =662.08. 1H 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).

[0075] Example 3

[0076] Synthesis of (3S,7R)-3-(4-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)-6-oxopyrimidin-1(6H)-yl)-2-fluorophenyl 4 , 2 5 -difluoro-7-methyl-1 1 -deuterated methyl-1 1 H-9-Aza-1(5,4)-pyrazol-2(1,3)-phenylcyclononane-8-one (3)

[0077] The specific synthetic route is as follows:

[0078] Step A: Synthesis of 4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)aniline

[0079] (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). Palladium catalyst (619 mg, 0.850 mmol) was then added. The mixture was stirred at 80°C for 1 hour under nitrogen. After the reaction was complete, the reaction mixture was separated by adding water and ethyl acetate. 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 afford 1.20 g of 4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)aniline as a white solid (yield: 56.1%). LCMS: RT = 2.29 min, [M+H] + =254.08.

[0080] Step B: Synthesis of 4-(3-chloro-6-(4-(tributyltinyl)-1H-1,2,3-triazol-1-yl)2-fluorophenyl)-6-methoxypyrimidine

[0081] 4-Chloro-3-fluoro-2-(6-methoxypyrimidin-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. Azidotrimethylsilane (1.5 ml) was slowly added dropwise and the reaction was stirred at room temperature for 1 hour.

[0082] After TLC monitoring, the reaction was complete, and the mixture was separated with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The mixture was dissolved in toluene (50 ml), and tributyltin acetylene (1.5 ml) was added. The reaction mixture was stirred at 110°C for 6 hours.

[0083] After the reaction was complete as monitored by TLC, the mixture was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 6) to afford 1.50 g of 4-(3-chloro-6-(4-(tributylstannyl)-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)-6-methoxypyrimidine as a pale yellow solid (yield: 54.1%). LCMS: RT = 2.23 min.

[0084] Step C: Synthesis of 4-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)2-fluorophenyl)-6-methoxypyrimidine

[0085] 4-(3-Chloro-6-(4-(tributyltinyl)-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)-6-methoxypyrimidine (1.50 g, 2.52 mmol) was dissolved in acetonitrile (15 ml), and N-chlorosuccinimide (490 mg, 3.66 mmol) was added. The reaction solution was stirred at 90°C for 16 hours.

[0086] After the reaction was complete as monitored by TLC, the reaction solution was partitioned between water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 5) to afford 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.

[0087] Step D: Synthesis of 4-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)2-fluorophenyl)pyrimidin-2(1H)-one

[0088] 4-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)-6-methoxypyrimidine (800 mg, 2.35 mmol) was dissolved in isopropanol (15 ml), followed by the addition of lithium chloride (1.44 g, 33.5 mmol) and p-toluenesulfonic acid monohydrate (2.73 g, 14.3 mmol). The reaction mixture was stirred at 80°C for 4 hours. TLC confirmed the reaction was complete. Water and ethyl acetate were added to the reaction mixture for separation. The resulting organic phase was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was slurried (ethyl acetate / n-hexane = 1 / 10) to afford 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.

[0089] Step E: Synthesis of (3S,7R)-3-(4-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)-6-oxopyrimidin-1(6H)-yl)-2-fluorophenyl 4 , 2 5 -difluoro-7-methyl-1 1 -deuterated methyl-1 1 H-9-Aza-1(5,4)-pyrazol-2(1,3)-phenylcyclononane-8-one

[0090] 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 tetrahydrofuran solution, 0.330 ml) 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 -deuterated methyl-8-oxo-1 1 H-1(5,4)-pyrazol-2(1,3)-phenylcyclononan-3-yl 4-nitrobenzenesulfonate (100 mg, 0.190 mmol) was added, and the reaction solution was stirred at 80°C for 24 hours.

[0091] After TLC monitoring showed that the reaction was complete, the temperature was cooled to room temperature. Saturated aqueous ammonium chloride solution (25 ml) and ethyl acetate (30 ml) were added to the reaction solution and the layers were separated. The obtained organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained 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 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-fluorophenyl)-3 ... 4 , 2 5 -difluoro-7-methyl-1 1 -deuterated methyl-1 1 H-9-Aza-1(5,4)-pyrazol-2(1,3)-phenylcyclononane-8-one (yield: 39.0%). LC-MS: RT = 1.93 min, [M+H] + =646.01. 1 H 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).

[0092] Example 4

[0093] Synthesis of (3S,7R)-3-(4-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-6-oxopyrimidin-1(6H)-yl)-2-nitropropane 4 ,2 5 -difluoro-7-methyl-1 1 -deuterated methyl-1 1 H-9-Aza-1(5,4)-pyrazole-2(1,3)-benzocyclononanoic acid-8-one (4)

[0094] The specific synthetic route is as follows:

[0095] 6-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-(3H)-one (80.0 mg, 0.222 mmol) was dissolved in dry 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, and the resulting reaction solution was stirred at room temperature for 30 minutes. Then, (7R)-2 4 ,2 5 -difluoro-7-methyl-1 1 -deuterated methyl-8-oxo-1 1 H-9-Aza-1(5,4)-pyrazol-2(1,3)-benzazepin-3-yl 4-nitrobenzenesulfonate (116 mg, 0.222 mmol) was reacted at 70°C for 16 hours.

[0096] After monitoring showed that the reaction was complete, the reaction mixture was cooled to room temperature. Saturated aqueous ammonium chloride solution (25 ml) and ethyl acetate (50 ml) were added to the reaction mixture for separation. The resulting organic phase was washed with saturated brine. 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 / petroleum ether = 14 / 1) and then purified by preparative high performance liquid chromatography to obtain 27.3 mg of a white solid (3S,7R)-3-(4-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-6-oxopyrimidin-1(6H)-yl)-2 ... 4 ,2 5 -difluoro-7-methyl-1 1 -deuterated methyl-1 1 H-9-Aza-1(5,4)-pyrazol-2(1,3)-benzocyclononanoic acid-8-one (yield: 18.1%). LC-MS: RT = 1.97 min, [M+H] + =680.03.

[0097] 1H 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).

[0098] Example 5

[0099] Synthesis of (3S,7R)-3-(4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-6-oxopyridazin-1(6H)-yl)-2-nitropropene 4 ,2 5 -difluoro-7-methyl-1 1 -deuterated methyl-1 1 H-9-Aza-1(5,4)-pyrazole-2(1,3)-benzocyclononanoic acid-8-one (5)

[0100] The specific synthetic route is as follows:

[0101] 5-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyridazin-3(2H)-one (80.0 mg, 0.234 mmol) was dissolved in dry 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, and the resulting reaction solution was stirred at room temperature for 30 minutes. Then, (7R)-2 4 ,2 5 -difluoro-7-methyl-1 1 -deuterated methyl-8-oxo-1 1 H-9-Aza-1(5,4)-pyrazol-2(1,3)-benzazepin-3-yl 4-nitrobenzenesulfonate (122 mg, 0.234 mmol) was reacted at 70°C for 16 hours.

[0102] After monitoring indicated the reaction was complete, the reaction mixture was cooled to room temperature. Saturated aqueous ammonium chloride solution (25 ml) and ethyl acetate (50 ml) were added to the reaction mixture for separation, and the resulting organic phase was washed with saturated brine. 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 / petroleum ether = 14 / 1) and then by preparative high performance liquid chromatography to obtain 25.9 mg of a white solid (3S,7R)-3-(4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-6-oxopyridazin-1(6H)-yl)-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-6-oxopyridazin ... 4 ,2 5 -difluoro-7-methyl-1 1 -deuterated methyl-1 1 H-9-Aza-1(5,4)-pyrazol-2(1,3)-benzocyclononanoic acid-8-one (yield: 16.7%). LC-MS: RT = 1.98 min, [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).

[0103] Example 6

[0104] Synthesis of (3S,7R)-3-(5-chloro-4-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-6-oxopyridazin-1(6H)-yl)-2 ...2-yl 4 ,2 5 -difluoro-7-methyl-1 1 -deuterated methyl-1 1 H-9-Aza-1(5,4)-pyrazole-2(1,3)-benzocyclononanoic acid-8-one (6)

[0105] The specific synthetic route is as follows:

[0106] Step A: Synthesis of 5-(6-amino-3-chloro-2-fluorophenyl-2-benzyl-4-chloropyridazin-3(2H)-one

[0107] (6-Amino-3-chloro-2-fluorophenyl)boronic acid (1.80 g, 9.52 mmol, synthesis see patent WO2017023992A1), 2-benzyl-4,5-dichloropyridazin-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), and then tetrakis(triphenylphosphine)palladium (549 mg, 0.476 mmol) was added. After nitrogen protection, the reaction was stirred at 120 degrees Celsius for 1 hour.

[0108] After the reaction was complete, the reaction mixture was separated by adding water and ethyl acetate. 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-chloropyridazin-3(2H)-one (yield: 17.9%). LCMS: RT = 2.29 min, [M+H] + =364.08.

[0109] Step B: Synthesis of 5-(6-azido-3-chloro-2-fluorophenyl)-2-benzyl-4-chloropyridazin-3(2H)-one

[0110] 5-(6-Amino-3-chloro-2-fluorophenyl)-2-benzyl-4-chloropyridazin-3(2H)-one (620 mg, 1.71 mmol) was dissolved in acetonitrile (10 ml). Tert-butyl nitrite (0.298 ml, 2.49 mmol) was added at 0°C, and trimethylsilyl azide (0.336 ml, 2.56 mmol) was slowly added dropwise. The mixture was stirred at room temperature for 1 hour. The reaction was monitored for completion by TLC. The reaction solution was poured into ice water, separated with ethyl acetate, and the organic phase was dried and spin-dried to obtain 500 mg of crude light yellow foamy solid 5-(6-azido-3-chloro-2-fluorophenyl)-2-benzyl-4-chloropyridazin-3(2H)-one (yield: 75.2%), which was used directly in the next step. LCMS: RT = 2.17 min, [M+H] + =390.03.

[0111] Step C: Synthesis of 2-benzyl-4-chloro-5-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyridazin-3(2H)-one

[0112] The crude product of 5-(6-azido-3-chloro-2-fluorophenyl)-2-benzyl-4-chloropyridazin-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. Trifluoropropane gas was slowly bubbled into the mixture at room temperature until the reaction was complete.

[0113] The reaction mixture was partitioned between water and ethyl acetate, and the organic phase was dried and spin-dried to obtain a crude product, which was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 3) to afford 190 mg of 2-benzyl-4-chloro-5-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyridazin-3(2H)-one as a pale yellow solid (yield: 30.7%). LCMS: RT = 2.10 min, [M+H] + =484.10.

[0114] Step D: Synthesis of 4-chloro-5-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyridazin-3(2H)-one

[0115] 2-Benzyl-4-chloro-5-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyridazin-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 reacted at 60°C for 1 hour.

[0116] The reaction was complete as monitored by TLC. The reaction mixture was separated by adding sodium bicarbonate solution and ethyl acetate. The resulting organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / n-hexane = 1 / 3) to obtain 86.0 mg of 4-chloro-5-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyridazin-3(2H)-one as a pale yellow solid (yield: 44.1%). LCMS: RT = 1.82 min, [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).

[0117] Step E: Synthesis of (3S,7R)-3-(5-chloro-4-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-6-oxopyridazin-1(6H)-yl)-2- 4 ,2 5 -difluoro-7-methyl-1 1 -deuterated methyl-1 1 H-9-Aza-1(5,4)-pyrazol-2(1,3)-benzocyclononanoic acid-8-one

[0118] 4-Chloro-5-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyridazin-3(2H)-one (100 mg, 0.254 mmol) was dissolved in dry anhydrous 1,4-dioxane (8 ml), and then lithium bis(trimethylsilyl)amide (1 mol / L tetrahydrofuran solution, 0.254 ml, 0.254 mmol) was slowly added, and the resulting reaction solution was stirred at room temperature for 30 minutes. Then, (3R,7R)-2 4 ,2 5 -difluoro-7-methyl-1 1 -deuterated methyl-8-oxo-1 1 H-9-aza-1(5,4)-pyrazol-2(1,3)-benzazepin-3-yl 4-nitrobenzenesulfonate (133 mg, 0.254 mmol) was reacted at 70°C for 16 hours. After monitoring indicated the reaction was complete, the mixture was cooled to room temperature. Saturated aqueous ammonium chloride (25 mL) and ethyl acetate (50 mL) were added to the reaction mixture for separation, and the resulting organic phase was washed with saturated brine. 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 / petroleum ether = 14 / 1) and then 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-triazol-1-yl)phenyl)-6-oxopyridazin-1(6H)-yl)-2-(3S,7R)-3-(5-chloro-4-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-6-oxopyridazin-2-yl)-1- ... 4 ,2 5 -difluoro-7-methyl-1 1 -deuterated methyl-1 1 H-9-Aza-1(5,4)-pyrazol-2(1,3)-benzocyclononanoic acid-8-one (yield: 14.6%). LC-MS: RT = 2.05 min, [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).

[0119] Example 7

[0120] Synthesis of (3S,7R)-3-(4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-6-oxopyrimidin-1(2H)-yl)-2 4 ,2 5 -difluoro-7-methyl-1 1 -deuterated methyl-1 1 H-9-Aza-1(5,4)-pyrazole-2(1,3)-benzocyclononanoic acid-8-one (7)

[0121] The specific synthetic route is as follows:

[0122] Step A: Synthesis of 5-bromo-2,3-difluorobenzoic acid

[0123] 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 stirred at 60°C for 4 hours. After the reaction was complete, the reaction solution was cooled in an ice bath and slowly poured into ice water (2 L). A white solid precipitated, which was filtered. The filter cake was washed three times with water and dried under reduced pressure to yield 66.4 g of 5-bromo-2,3-difluorobenzoic acid as a white solid (yield: 89.4%).

[0124] Step B: Synthesis of methyl 5-bromo-2,3-difluorobenzoate

[0125] 5-Bromo-2,3-difluorobenzoic acid (22.0 g, 93.2 mmol) was dissolved in methanol (220 ml), and concentrated sulfuric acid (10.1 ml) was added. The mixture was stirred at 70°C for 5 hours. After the reaction was complete, the reaction solution was slowly poured into ice water to precipitate a white solid. This solid was filtered, and the filter cake was washed with water and dried under reduced pressure to yield 23 g of methyl 5-bromo-2,3-difluorobenzoate as a slightly yellow solid (yield: 98.7%).

[0126] Step C: Synthesis of 2-(5-bromo-2,3-difluorobenzoyl)cyclopentan-1-one

[0127] 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). A solution of potassium tert-butoxide in tetrahydrofuran (1 mol / L, 618 ml) was slowly added dropwise at -42°C, maintaining the internal temperature at -35°C. The reaction was allowed to proceed at this temperature for 2 hours under nitrogen. TLC monitoring indicated the reaction was complete, and the mixture was quenched by adding 2N dilute hydrochloric acid (200 ml). The mixture was vortexed to remove most of the tetrahydrofuran and then partitioned with ethyl acetate (500 ml). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a residue which 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 light yellow oily liquid (yield: 77.8%).

[0128] Step D: Synthesis of 6-(5-bromo-2,3-difluorophenyl)-6-oxohexanoic acid

[0129] 2-(5-Bromo-2,3-difluorobenzoyl)cyclopentan-1-one (62.0 g, 0.205 mol) was added to 900 mL of a mixture of acetonitrile and water (3:2) at room temperature and reacted at 65°C under nitrogen for 16 hours. After cooling to room temperature, 500 mL of ethyl acetate was added to the reaction mixture for separation. The organic phase was then washed three times with water, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 2 / 11) to yield 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, [MH] - =318.95.

[0130] Step E: Synthesis of methyl 6-(5-bromo-2,3-difluorophenyl)-6,6-dimethoxyhexanoate

[0131] At room temperature, 6-(5-bromo-2,3-difluorophenyl)-6-oxohexanoic acid (14.5 g, 45.3 mmol) was added to methanol (150 ml), and trimethyl orthoformate (21.6 g, 204 mmol) and trimethylchlorosilane (9.45 g, 86.9 mmol) were added in sequence. The mixture was reacted at 50 degrees Celsius under nitrogen protection for 3 hours.

[0132] After the reaction was complete, the reaction mixture was cooled to room temperature and quenched with saturated aqueous sodium bicarbonate. The mixture was extracted with dichloromethane (70 mL x 3 times). The organic phases were combined, washed with saturated aqueous sodium chloride (70 mL x 2 times), then dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 16.4 g of crude 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.

[0133] Step F: 6-(5-Bromo-2,3-difluorophenyl)-6,6-dimethoxyhexanoic acid

[0134] At 0°C, 30 mL of 4.5 M sodium hydroxide solution was slowly added to a solution of methyl 6-(5-bromo-2,3-difluorophenyl)-6,6-dimethoxyhexanoate (16.4 g, 43.1 mmol) in methanol (150 mL) and the mixture was reacted at room temperature for 2 hours.

[0135] After the reaction, the reaction mixture was neutralized with saturated ammonium chloride solution, and the mixture was extracted with ethyl acetate (70 mL × 3 times). The organic phases were combined, washed with saturated sodium chloride aqueous solution (70 mL × 2 times), then dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was slurried with (n-hexane:ethyl acetate = 5:1) to obtain 13.0 g of 6-(5-bromo-2,3-difluorophenyl)-6,6-dimethoxyhexanoic acid as a white solid (yield: 82.8%). LCMS: RT = 2.07 min, [M+H] + -CH3O - =334.94.

[0136] Step G: (R)-4-Benzyl-3-(6-(5-bromo-2,3-difluorophenyl)-6,6-dimethoxyhexanoyl)oxazolidin-2-one

[0137] Dissolve 6-(5-bromo-2,3-difluorophenyl)-6,6-dimethoxyhexanoic acid (13.0 g, 35.6 mmol) and triethylamine (12.4 mL, 89.0 mmol) in anhydrous tetrahydrofuran (250 mL). Add trimethylacetyl chloride (5.19 mL, 42.7 mmol) at 0°C and stir for 0.5 hours. Add lithium chloride (1.79 g, 42.7 mmol) and continue stirring for 15 minutes. Then, add (R)-4-benzyloxazolidin-2-one (7.57 g, 42.7 mmol) in portions and allow to react at room temperature for 4 hours. Monitor the reaction for completion, quench with water, remove most of the tetrahydrofuran, and extract with ethyl acetate (40 mL x 2). The organic phases were combined and washed with saturated brine (80 ml x 3 times), then dried over anhydrous sodium sulfate, and finally purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate = 3:1) to obtain 16.6 g of (R)-4-benzyl-3-(6-(5-bromo-2,3-difluorophenyl)-6,6-dimethoxyhexanoyl)oxazolidin-2-one as a pale yellow oil (yield: 88.8%). LCMS: RT = 2.29 min, [M+H] + -CH3O - =493.97.

[0138] Step H: Synthesis of (R)-4-benzyl-3-((R)-6-(5-bromo-2,3-difluorophenyl)-6,6-dimethoxy-2-methylhexanoyl)oxazolidin-2-one

[0139] To a solution of (R)-4-benzyl-3-((R)-6-(5-bromo-2,3-difluorophenyl)-6,6-dimethoxy-2-methylhexanoyl)oxazolidin-2-one (16.6 g, 31.6 mmol) in tetrahydrofuran (200 ml) was added iodomethane (4.34 ml, 69.6 mmol) at -45°C. The mixture was stirred for 10 minutes, and then a solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (2 mol / L tetrahydrofuran solution, 20.6 ml) was slowly added. The reaction was carried out at -45°C under nitrogen protection for 2 hours, maintaining the internal temperature at no more than -39°C.

[0140] After monitoring the reaction for completion, the reaction solution was quenched with saturated ammonium chloride solution (50 mL), most of the tetrahydrofuran was removed by vortexing, and the mixture was extracted with ethyl acetate (40 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give 17.0 g of crude (R)-4-benzyl-3-((R)-6-(5-bromo-2,3-difluorophenyl)-6,6-dimethoxy-2-methylhexanoyl)oxazolidin-2-one as a pale yellow oil. The crude product was used directly in the next step. LCMS: RT = 2.30 min, [M+H] + -CH3O - =508.17.

[0141] Step I: Synthesis of (R)-6-(5-bromo-2,3-difluorophenyl)-6,6-dimethoxy-2-methylhexanoic acid

[0142] The crude product of (R)-4-benzyl-3-((R)-6-(5-bromo-2,3-difluorophenyl)-6,6-dimethoxy-2-methylhexanoyl)oxazolidin-2-one (17.0 g, 31.5 mmol) was dissolved in tetrahydrofuran (150 ml). Aqueous hydrogen peroxide solution (W = 30%, 6.4 ml, 63.1 mmol) was added at 0°C and stirred for 30 minutes. Finally, lithium hydroxide (2.65 g, 63.1 mmol) was added and the reaction was allowed to react at room temperature for 2.0 hours.

[0143] The reaction was monitored for completion and quenched by the addition of aqueous sodium sulfite (50 mL, 126 mmol) at 0°C. The mixture was vortexed to remove most of the tetrahydrofuran and then neutralized with aqueous citric acid to adjust the pH to approximately 5. The mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate = 3:1) to afford 5.70 g of (R)-6-(5-bromo-2,3-difluorophenyl)-6,6-dimethoxy-2-methylhexanoic acid as a pale yellow oil (yield over two steps: 47.5%). LCMS: RT = 2.11 min, [M+H] + -CH3O - =348.96.

[0144] Step J: Synthesis of (R)-6-(2,3-difluoro-5-(1-deuteromethyl-4-nitro-1H-pyrazol-5-yl)phenyl)-6,6-dimethoxy-2-methylhexanoic acid

[0145] (R)-6-(5-Bromo-2,3-difluorophenyl)-6,6-dimethoxy-2-methylhexanoic acid (5.70 g, 15.0 mmol), 1-deuterated methyl-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), and n-butyldi(1-adamantyl)phosphine (537 mg, 1.50 mmol) and palladium acetate (336 mg, 1.50 mmol) were added. After nitrogen substitution, the mixture was reacted at 100°C for 16 hours. After monitoring the reaction for completion, the reaction solution was cooled, water was added, and the pH was adjusted to approximately 6 with dilute hydrochloric acid. The solution was extracted with ethyl acetate (40 ml x 3 times). The organic phases were combined, washed with saturated aqueous sodium chloride (50 ml x 2 times), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate = 2:1) to obtain 3.57 g of (R)-6-(2,3-difluoro-5-(1-deuteromethyl-4-nitro-1H-pyrazol-5-yl)phenyl)-6,6-dimethoxy-2-methylhexanoic acid as a pale yellow foamy solid (yield: 55.3%). LCMS: RT = 1.99 min, [MH] - =429.08.

[0146] Step K: Synthesis of (R)-6-(2,3-difluoro-5-(1-deuteromethyl-4-amino-1H-pyrazol-5-yl)phenyl)-6,6-dimethoxy-2-methylhexanoic acid

[0147] At room temperature, (R)-6-(2,3-difluoro-5-(1-deuteromethyl-4-nitro-1H-pyrazol-5-yl)phenyl)-6,6-dimethoxy-2-methylhexanoic acid (3.57 g, 8.31 mmol) was dissolved in methanol (70 mL). Palladium / carbon (10% palladium in 50% water, 714 mg) was added, the atmosphere was replaced with hydrogen, and then a hydrogen balloon was added to react at 50°C for 6 hours. The reaction was monitored by TLC. The reaction solution was cooled to room temperature, filtered through celite, and the filtrate was dried and concentrated to afford 3.20 g of (R)-6-(2,3-difluoro-5-(1-deuteromethyl-4-amino-1H-pyrazol-5-yl)phenyl)-6,6-dimethoxy-2-methylhexanoic acid as a reddish foamy solid (yield: 96.3%). LCMS: RT = 1.72 min, [M+H] + =401.13.

[0148] Step L: Synthesis of (R)-2 4 ,2 5 -difluoro-3,3-dimethoxy-7-methyl-1 1 -deuterated methyl-1 1H-9-Aza-1(5,4)-pyrazol-2(1,3)-benzocyclononan-8-one

[0149] At room temperature, a solution of (R)-6-(2,3-difluoro-5-(1-deuteromethyl-4-amino-1H-pyrazol-5-yl)phenyl)-6,6-dimethoxy-2-methylhexanoic acid (3.20 g, 8.00 mmol) in tetrahydrofuran (300 mL) was slowly added dropwise to a solution of N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (3.03 g, 10.8 mmol) and N,N-diisopropylethylamine (3.61 g, 28.0 mmol) in tetrahydrofuran (100 mL). After the addition was complete, the mixture was reacted at room temperature for 1 hour.

[0150] The reaction was completed by TLC monitoring. The reaction solution was diluted with saturated ammonium chloride solution. The mixture was vortexed to remove most of the tetrahydrofuran and extracted with ethyl acetate (30 ml × 3 times). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product which was purified by column chromatography (eluent: n-hexane: ethyl acetate = 1:9) to obtain 2.86 g of a light yellow foamy solid (R)-2 4 ,2 5 -difluoro-3,3-dimethoxy-7-methyl-1 1 -deuterated methyl-1 1 H-9-Aza-1(5,4)-pyrazol-2(1,3)-benzocyclononane-8-one (yield: 93.4%). LCMS: RT = 1.84 min, [M+H] + =383.13.

[0151] Step M: Synthesis of (R)-2 4 ,2 5 -difluoro-7-methyl-1 1 -deuterated methyl-1 1 H-9-Aza-1(5,4)-pyrazole-2(1,3)-benzocyclononane-3,8-dione

[0152] (R)-2 4 ,2 5 -difluoro-3,3-dimethoxy-7-methyl-1 1 -deuterated methyl-1 1 H-9-aza-1(5,4)-pyrazol-2(1,3)-benzocyclononane-8-one (2.86 g, 7.46 mmol) was dissolved in acetonitrile (40 ml), and dilute hydrochloric acid solution (4 mol / L aqueous solution, 6 ml) was added and reacted at 50°C for 1 hour.

[0153] The reaction was monitored for completion, and saturated aqueous sodium bicarbonate solution was added to neutralize the mixture, and the mixture was extracted with ethyl acetate (30 ml x 2 times). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give 2.20 g of a white solid (R)-2 4 ,2 5 -difluoro-7-methyl-1 1 -deuterated methyl-1 1 H-9-Aza-1(5,4)-pyrazole-2(1,3)-benzocyclononane-3,8-dione (yield: 87.6%). LCMS: RT = 1.75 min, [M+H] + =337.11.

[0154] Step N: Synthesis of (7R)-2 4 ,2 5 -difluoro-3-hydroxy-7-methyl-1 1 -deuterated methyl-1 1 H-9-Aza-1(5,4)-pyrazol-2(1,3)-benzazepin-8-one

[0155] (R)-2 4 ,2 5 -difluoro-7-methyl-1 1 -deuterated methyl-1 1 H-9-aza-1(5,4)-pyrazole-2(1,3)-benzocyclononane-3,8-dione (2.20 g, 6.54 mmol) was dissolved in anhydrous methanol (25 ml). Sodium borohydride (373 mg, 9.82 mmol) was added in batches at -70 degrees Celsius and the mixture was reacted at the same temperature for 1 hour. The reaction was monitored for completion and quenched by adding saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate (30 ml x 5 times). The organic phases were 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 -deuterated methyl-1 1 H-9-Aza-1(5,4)-pyrazol-2(1,3)-benzazepine-8-one (yield: 68.7%). LCMS: RT = 1.62 min, [M+H] + =339.04.

[0156] Step O: Synthesis of (7R)-2 4 ,2 5 -difluoro-7-methyl-1 1 -deuterated methyl-8-oxo-1 1 H-9-Aza-1(5,4)-pyrazol-2(1,3)-benzazepin-3-yl 4-nitrobenzenesulfonate

[0157] (7R)-2 4 ,2 5 -difluoro-3-hydroxy-7-methyl-1 1 -deuterated methyl-1 1 H-9-aza-1(5,4)-pyrazol-2(1,3)-benzazepine-8-one (1.52 g, 4.49 mmol) was added to anhydrous dichloromethane (30 ml), and triethylamine (907 mg, 8.98 mmol) and 4-dimethylaminopyridine (109 mg, 0.898 mmol) were added in sequence and stirred for 10 minutes. Then, p-nitrobenzenesulfonyl chloride (1.19 g, 5.39 mmol) was added in batches and reacted at room temperature for 6 hours.

[0158] After monitoring the reaction, 30 ml of sodium bicarbonate solution was added for dilution, and the mixture was extracted with dichloromethane (20 ml × 2 times). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (eluent: n-hexane: ethyl acetate = 1:15) to obtain 1.34 g of a light yellow solid (7R)-2 4 ,2 5 -difluoro-7-methyl-1 1 -deuterated methyl-8-oxo-1 1 H-9-Aza-1(5,4)-pyrazol-2(1,3)-benzazepin-3-yl 4-nitrobenzenesulfonate (yield: 57.1%). LCMS: RT = 1.93 min, [M+H] + =524.02.

[0159] Step P: Synthesis of (3S,7R)-3-(4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-6-oxopyrimidin-1(2H)-yl)-2 4 ,2 5 -difluoro-7-methyl-1 1 -deuterated methyl-1 1 H-9-Aza-1(5,4)-pyrazol-2(1,3)-benzocyclononanoic acid-8-one

[0160] 4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-2(3H)-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-deuterated methyl-8-oxo-1 1 H-9-Aza-1(5,4)-pyrazol-2(1,3)-benzazepin-3-yl 4-nitrobenzenesulfonate (200 mg, 0.382 mmol) was reacted at 70°C for 16 hours.

[0161] After monitoring showed that the reaction was complete, the reaction mixture was cooled to room temperature. Saturated aqueous ammonium chloride solution (25 ml) and ethyl acetate (50 ml) were added to the reaction mixture for separation. The resulting organic phase was washed with saturated brine. 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 / 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)-6-oxopyrimidin-1(2H)-yl) ... 4 ,2 5 -difluoro-7-methyl-1 1 -deuterated methyl-1 1 H-9-Aza-1(5,4)-pyrazol-2(1,3)-benzocyclononanoic acid-8-one (yield: 32.7%). LC-MS: RT = 1.98 min, [M+H] + =661.08. 1 H 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).

[0162] Example 8

[0163] Synthesis of (3S,7R)-3-(4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-3-chloro-6-oxopyrimidin-1(2H)-yl)-2 4 ,2 5 -difluoro-7-methyl-1 1 -deuterated methyl-11 H-9-Aza-1(5,4)-pyrazole-2(1,3)-benzocyclononanoic acid-8-one (8)

[0164] The specific synthetic route is as follows:

[0165] 4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-3-chloropyrimidin-2(3H)-one (129 mg, 0.344 mmol) was dissolved in dry 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, and the resulting reaction solution was stirred at room temperature for 30 minutes. Then, (7R)-2 4 ,2 5 -difluoro-7-methyl-1 1 -deuterated methyl-8-oxo-1 1 H-9-Aza-1(5,4)-pyrazol-2(1,3)-benzazepin-3-yl 4-nitrobenzenesulfonate (180 mg, 0.344 mmol) was reacted at 70°C for 16 hours.

[0166] After monitoring showed that the reaction was complete, the reaction mixture was cooled to room temperature. Saturated aqueous ammonium chloride solution (25 ml) and ethyl acetate (50 ml) were added to the reaction mixture for separation. The resulting organic phase was washed with saturated brine. 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 / petroleum ether = 14 / 1) and then purified by preparative high performance liquid chromatography to obtain 50.6 mg of a white solid (3S,7R)-3-(4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-3-chloro-6-oxopyrimidin-1(2H)-yl) ... 4 ,2 5 -difluoro-7-methyl-1 1 -deuterated methyl-1 1 H-9-Aza-1(5,4)-pyrazol-2(1,3)-benzocyclononanoic acid-8-one (yield: 21.2%). LC-MS: RT = 2.03 min, [M+H] + =694.97.

[0167] 1H 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).

[0168] Example 9

[0169] Synthesis of (3S,7R)-3-(4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-3-fluoro-6-oxopyrimidin-1(2H)-yl)-2 4 ,2 5 -difluoro-7-methyl-1 1 -deuterated methyl-1 1 H-9-Aza-1(5,4)-pyrazole-2(1,3)-benzocyclononanoic acid-8-one (9)

[0170] The specific synthetic route is as follows:

[0171] 4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-3-fluoropyrimidin-2(3H)-one (65.0 mg, 0.181 mmol) was dissolved in dry 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, and the resulting reaction solution was stirred at room temperature for 30 minutes. Then, (7R)-2 4 ,2 5 -difluoro-7-methyl-1 1 -deuterated methyl-8-oxo-1 1 H-9-Aza-1(5,4)-pyrazol-2(1,3)-benzazepin-3-yl 4-nitrobenzenesulfonate (94.9 mg, 0.181 mmol) was reacted at 70°C for 16 hours.

[0172] After monitoring showed that the reaction was complete, the reaction mixture was cooled to room temperature. Saturated aqueous ammonium chloride solution (25 ml) and ethyl acetate (50 ml) were added to the reaction mixture for separation. The resulting organic phase was washed with saturated brine. 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 / petroleum ether = 14 / 1) and then purified by preparative high performance liquid chromatography to obtain 24.9 mg of a white solid (3S,7R)-3-(4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-3-fluoro-6-oxopyrimidin-1(2H)-yl) ...2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-3-fluoro-6-oxopyrimidin-1(2H)-yl)-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1- 4 ,2 5 -difluoro-7-methyl-1 1 -deuterated methyl-1 1 H-9-Aza-1(5,4)-pyrazol-2(1,3)-benzocyclononanoic acid-8-one (yield: 20.3%). LC-MS: RT = 2.00 min, [M+H] + =678.99.

[0173] 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).

[0174] Example 10

[0175] Synthesis of (3S,7R)-3-(4-(5-chloro-2-(4-(difluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-2 4 ,2 5 -difluoro-7-methyl-1 1 -deuterated methyl-1 1 H-9-Aza-1(5,4)-pyrazole-2(1,3)-benzocyclononanoic acid-8-one (10)

[0176] The specific synthetic route is as follows:

[0177] Step A: Synthesis of ethyl (Z)-4,4-difluoro-3-(2-toluenesulfonylhydrazinyl)butyrate

[0178] At room temperature, 4-methylbenzenesulfonylhydrazide (10.0 g, 53.7 mmol) and ethyl 4,4-difluoro-3-oxobutanoate (9.80 g, 59.1 mmol) were dissolved in anhydrous ethanol (100 ml) and reacted at 65°C under nitrogen protection for 5 hours.

[0179] TLC monitoring indicated the reaction was complete. Most of the solvent was removed by vortexing, and water (200 mL) was added. The mixture was then extracted with ethyl acetate (60 mL x 2). The organic phases were combined, washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, and concentrated to yield 16.2 g of ethyl (Z)-4,4-difluoro-3-(2-toluenesulfonylhydrazinyl)butanoate as a white solid (yield: 90.5%). LCMS: RT = 1.73 min, [M+H] + =335.07.

[0180] Step B: Synthesis of ethyl 1-(2-bromo-4-chlorophenyl)-4-(difluoromethyl)-1H-1,2,3-triazole-5-carboxylate

[0181] 2-Bromo-4-chloroaniline (9.90 g, 48.5 mmol) and ethyl (Z)-4,4-difluoro-3-(2-tosylhydrazinyl)butanoate (16.2 g, 48.5 mmol) were added to toluene at room temperature. Copper bromide (2.10 g, 9.70 mmol) and dimethyl sulfoxide (48.2 mL, 679 mmol) were then added. The mixture was reacted at 100°C under nitrogen for 6 hours. TLC monitoring indicated the reaction was complete, and most of the solvent was removed by vortexing. Water (200 mL) was added, and the mixture was extracted with ethyl acetate (60 mL x 2). The organic phases were combined and washed with saturated brine (100 ml x 3 times), then 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 ethyl 1-(2-bromo-4-chlorophenyl)-4-(difluoromethyl)-1H-1,2,3-triazole-5-carboxylate as a yellow solid (yield: 71.2%). LCMS: RT = 1.85 min, [MH] - =378.0.

[0182] Step C: 1-(2-Bromo-4-chlorophenyl)-4-(difluoromethyl)-1H-1,2,3-triazole-5-carboxylic acid

[0183] At 0°C, ethyl 1-(2-bromo-4-chlorophenyl)-4-(difluoromethyl)-1H-1,2,3-triazole-5-carboxylate (13.1 g, 34.5 mmol) was added to tetrahydrofuran / methanol / water = 60 ml / 20 ml / 40 ml, and lithium hydroxide (1.70 g, 69.0 mmol) was added, and the reaction was carried out at room temperature for 16 hours.

[0184] LC-MS monitoring indicated complete reaction of the starting material. Most of the solvent was removed by direct vortexing, followed by the addition of dichloromethane (100 mL). The pH was adjusted to 4 with dilute hydrochloric acid, and extraction was performed. The organic phases were combined and washed twice with saturated brine (80 mL), then dried over anhydrous sodium sulfate. Finally, the product was purified by silica gel column chromatography (eluent: dichloromethane:methanol = 15:1) to yield 9.10 g of 1-(2-bromo-4-chlorophenyl)-4-(difluoromethyl)-1H-1,2,3-triazole-5-carboxylic acid as a pale yellow solid (yield: 75.2%). LCMS: RT = 1.64 min, [MH] - =350.11.

[0185] Step D: Synthesis of 1-(2-bromo-4-chlorophenyl)-4-(difluoromethyl)-1H-1,2,3-triazole

[0186] 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. Under nitrogen protection, the mixture was reacted at 120°C for 1 hour.

[0187] LC-MS monitoring indicated the reaction was complete. After cooling the reaction solution to room temperature, dichloromethane (80 mL x 3) was added for extraction. The organic phases were combined and washed with saturated aqueous sodium chloride (100 mL x 4), then dried over anhydrous sodium sulfate. Finally, purification by silica gel column chromatography (eluent: n-hexane:ethyl acetate = 4:1) afforded 5.00 g of 1-(2-bromo-4-chlorophenyl)-4-(difluoromethyl)-1H-1,2,3-triazole as a yellow solid (yield: 62.5%). LCMS: RT = 1.95 min, [M+H] + =307.97.

[0188] Step E: Synthesis of 4-(5-chloro-2-(4-(difluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-2-methoxypyridine

[0189] At room temperature, 1-(2-bromo-4-chlorophenyl)-4-(difluoromethyl)-1H-1,2,3-triazole (5.00 g, 16.2 mmol) and (2-methoxypyridin-4-yl)boronic acid (2.70 g, 17.8 mmol) were added to dioxane / water = 50 ml / 10 ml, followed by potassium carbonate (5.60 g, 40.5 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (1.30 g, 1.80 mmol). The mixture was reacted at 80 degrees Celsius for 16 hours under nitrogen protection. LC-MS monitoring indicated the reaction was complete, and most of the solvent was removed by vortexing. The mixture was then extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride (100 mL x 4), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate = 3:1) to afford 2.70 g of 4-(5-chloro-2-(4-(difluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-2-methoxypyridine as a yellow solid (yield: 50.2%). LCMS: RT = 2.04 min, [M+H] + =337.07.

[0190] Step F: Synthesis of 4-(5-chloro-2-(4-(difluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyridin-2-(1H)one

[0191] 4-(5-chloro-2-(4-(difluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-2-methoxypyridine (2.70 g, 8.00 mmol) was dissolved in isopropanol (40 mL), followed by the addition of lithium chloride (2.20 g, 51.6 mmol) and p-toluenesulfonic acid monohydrate (4.90 g, 25.8 mmol). The reaction was stirred at 80°C overnight. After TLC confirmed the absence of residual starting material, triethylamine (5 mL) was added to neutralize the reaction, and 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 4-(5-chloro-2-(4-(difluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyridin-2-(1H)one as a white solid (yield: 58.0%). LCMS: RT = 1.73 min, [M+H] + =323.08.

[0192] Step G: Synthesis of (3S,7R)-3-(4-(5-chloro-2-(4-(difluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-2 4 ,25 -difluoro-7-methyl-1 1 -deuterated methyl-1 1 H-9-Aza-1(5,4)-pyrazol-2(1,3)-benzocyclononanoic acid-8-one

[0193] 4-(5-chloro-2-(4-(difluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyridin-2-(1H)one (100 mg, 0.310 mmol) was dissolved in dry 1,4-dioxane (5 mL), and then lithium bis(trimethylsilyl)amide (1 mol / L tetrahydrofuran solution, 0.310 mL, 0.310 mmol) was slowly added and the resulting reaction was stirred at room temperature for 30 minutes. Then (7R)-2 4 ,2 5 -difluoro-7-methyl-1 1 -deuterated methyl-8-oxo-1 1 H-9-Aza-1(5,4)-pyrazol-2(1,3)-benzazepin-3-yl 4-nitrobenzenesulfonate (162 mg, 0.310 mmol) The reaction was warmed to 70° C. and stirred at this temperature for 16 hours.

[0194] After TLC monitoring indicated the reaction was complete, the mixture was cooled to room temperature. Saturated aqueous ammonium chloride (4 ml) and ethyl acetate (20 ml) were added to the reaction mixture for extraction. The resulting organic phase was washed with saturated brine (10 ml x 3). 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 / petroleum ether = 4 / 1) and then 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-triazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-2-(4-(difluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-2-oxopyridin-1(2H)-yl)-2-(4-(difluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-2-oxopyridin-2 ... 4 ,2 5 -difluoro-7-methyl-1 1 -deuterated methyl-1 1 H-9-Aza-1(5,4)-pyrazol-2(1,3)-benzocyclononanoic acid-8-one (yield: 15.0%). LCMS: RT = 1.93 min, [M+H] + =643.13. 1H 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).

[0195] Example 11

[0196] Synthesis of (3S,7R)-3-(4-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-6-oxopyrimidin-1(6H)-yl)-2-nitropropane 4 ,2 5 -difluoro-7-methyl-1 1 -Difluoromethyl-1 1 H-9-Aza-1(5,4)-pyrazole-2(1,3)-benzocyclononanoic acid-8-one (11)

[0197] The specific synthetic route is as follows:

[0198] Step A: Synthesis of (R)-6-(2,3-difluoro-5-(1-difluoromethyl-4-nitro-1H-pyrazol-5-yl)phenyl)-6,6-dimethoxy-2-methylhexanoic acid

[0199] Diallylpalladium dichloride (318 mg, 0.87 mmol) and X-Phos (619 mg, 1.3 mmol) were dissolved in anhydrous dimethyltetrahydrofuran (50 ml) and reacted at room temperature for 0.5 hour. 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. After nitrogen substitution, the reaction was carried out at 80°C for 1.5 hours. After monitoring the reaction completion, the reaction solution was cooled, water was added, and the pH was adjusted to approximately 6 with dilute hydrochloric acid. Extraction was performed with ethyl acetate (40 ml x 3 times). The organic phases were combined, washed with saturated aqueous sodium chloride (50 ml x 2 times), 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 (R)-6-(2,3-difluoro-5-(1-difluoromethyl-4-nitro-1H-pyrazol-5-yl)phenyl)-6,6-dimethoxy-2-methylhexanoic acid as a pale yellow foamy solid (yield: 80%). LCMS: RT = 2.04 min, [MH] - =462.11.

[0200] Step B: Synthesis of (R)-6-(2,3-difluoro-5-(1-difluoromethyl-4-amino-1H-pyrazol-5-yl)phenyl)-6,6-dimethoxy-2-methylhexanoic acid

[0201] At room temperature, (R)-6-(2,3-difluoro-5-(1-difluoromethyl-4-nitro-1H-pyrazol-5-yl)phenyl)-6,6-dimethoxy-2-methylhexanoic acid (3.2 g, 6.89 mmol) was dissolved in methanol (100 mL). Palladium / carbon (10% palladium in 50% water, 1.28 g) was added, the atmosphere was replaced with hydrogen, and a hydrogen balloon was added to react at 60°C for 2 hours. The reaction was monitored by TLC. The reaction solution was cooled to room temperature, filtered through celite, and the filtrate was dried and concentrated to yield 3 g of (R)-6-(2,3-difluoro-5-(1-difluoromethyl-4-amino-1H-pyrazol-5-yl)phenyl)-6,6-dimethoxy-2-methylhexanoic acid as a pale yellow foamy solid. LCMS: RT = 1.81 min, [M+H] + =434.13.

[0202] Step C: Synthesis of (R)-2 4 ,2 5 -difluoro-3,3-dimethoxy-7-methyl-1 1 -Difluoromethyl-1 1 H-9-Aza-1(5,4)-pyrazol-2(1,3)-benzocyclononan-8-one

[0203] At room temperature, a solution of (R)-6-(2,3-difluoro-5-(1-difluoromethyl-4-amino-1H-pyrazol-5-yl)phenyl)-6,6-dimethoxy-2-methylhexanoic acid (3 g, 6.91 mmol) in tetrahydrofuran (600 mL) was slowly added dropwise to a solution of N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (3.87 g, 13.82 mmol) and N,N-diisopropylethylamine (1.78 g, 13.84 mmol) in tetrahydrofuran (500 mL). After the addition was complete, the mixture was reacted at room temperature for 1 hour.

[0204] The reaction was completed by TLC monitoring. The reaction solution was diluted with saturated ammonium chloride solution. The mixture was vortexed to remove most of the tetrahydrofuran and extracted with ethyl acetate (30 ml × 3 times). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product which was purified by column chromatography (eluent: n-hexane: ethyl acetate = 1:10) to obtain 2.8 g of a light 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)-pyrazol-2(1,3)-benzocyclononane-8-one. LCMS: RT = 1.88 min, [M+H] + =416.13.

[0205] Step D: Synthesis of (R)-2 4 ,2 5 -difluoro-7-methyl-1 1 -Difluoromethyl-1 1 H-9-Aza-1(5,4)-pyrazole-2(1,3)-benzocyclononane-3,8-dione

[0206] (R)-2 4 ,2 5 -difluoro-3,3-dimethoxy-7-methyl-1 1 -Difluoromethyl-1 1 H-9-aza-1(5,4)-pyrazol-2(1,3)-benzocyclononane-8-one (2.8 g, 6.75 mmol) was dissolved in acetonitrile (40 ml), and dilute hydrochloric acid solution (2 mol / L aqueous solution, 10 ml) was added and reacted at 50°C for 3 hours.

[0207] After monitoring the reaction, saturated sodium bicarbonate aqueous solution was added to neutralize the mixture, and the mixture was extracted with ethyl acetate (30 ml × 2 times). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain 1.92 g of a white solid (R)-2 4 ,2 5 -difluoro-7-methyl-11 -Difluoromethyl-1 1 H-9-Aza-1(5,4)-pyrazole-2(1,3)-benzocyclononane-3,8-dione (yield: 78.3%). LCMS: RT = 1.75 min, [M+H] + =370.14.

[0208] Step E: Synthesis of (7R)-2 4 ,2 5 -difluoro-3-hydroxy-7-methyl-1 1 -Difluoromethyl-1 1 H-9-Aza-1(5,4)-pyrazol-2(1,3)-benzazepin-8-one

[0209] (R)-2 4 ,2 5 -difluoro-7-methyl-1 1 -Difluoromethyl-1 1 H-9-Aza-1(5,4)-pyrazole-2(1,3)-benzocyclononane-3,8-dione (1.92 g, 5.19 mmol) was dissolved in anhydrous methanol (125 ml). Sodium borohydride (200 mg, 5.19 mmol) was added portionwise at -70°C and the mixture was reacted at the same temperature for 1 hour.

[0210] After monitoring the reaction, saturated aqueous ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate (30 ml × 5 times). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give 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)-pyrazol-2(1,3)-benzazepine-8-one (yield: 93%). LCMS: RT = 1.65 min, [M+H] + =372.11.

[0211] Step F: Synthesis of (7R)-2 4 ,2 5 -difluoro-7-methyl-1 1 -Difluoromethyl-8-oxo-1 1 H-9-Aza-1(5,4)-pyrazol-2(1,3)-benzazepin-3-yl 4-nitrobenzenesulfonate

[0212] (7R)-2 4 ,2 5 -difluoro-3-hydroxy-7-methyl-1 1 -Difluoromethyl-11 H-9-aza-1(5,4)-pyrazol-2(1,3)-benzazepine-8-one (400 mg, 1.08 mmol) was added to anhydrous dichloromethane (30 ml), and triethylamine (218 mg, 2.15 mmol) and 4-dimethylaminopyridine (131 mg, 1.08 mmol) were added in sequence and stirred for 10 minutes. Then, p-nitrobenzenesulfonyl chloride (357 mg, 1.61 mmol) was added in batches and reacted at room temperature for 10 minutes.

[0213] The reaction was monitored for completion, and 30 ml of sodium bicarbonate solution was added for dilution, and the mixture was extracted with dichloromethane (20 ml x 2 times). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (eluent: n-hexane / ethyl acetate = 1 / 10) to obtain 500 mg of a light yellow solid (7R)-2 4 ,2 5 -difluoro-7-methyl-1 1 -Difluoromethyl-8-oxo-1 1 H-9-Aza-1(5,4)-pyrazol-2(1,3)-benzazepin-3-yl 4-nitrobenzenesulfonate (yield: 83%). LCMS: RT = 1.98 min, [M+H] + =557.02.

[0214] Step G: Synthesis of (3S,7R)-3-(4-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-6-oxopyrimidin-1(6H)-yl)-2 4 ,2 5 -difluoro-7-methyl-1 1 -Difluoromethyl-1 1 H-9-Aza-1(5,4)-pyrazol-2(1,3)-benzocyclononanoic acid-8-one

[0215] 6-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-(3H)-one (130 mg, 0.36 mmol) was dissolved in dry 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, and the resulting reaction solution 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)-pyrazol-2(1,3)-benzazepin-3-yl 4-nitrobenzenesulfonate (200 mg, 0.36 mmol) was reacted at 70°C for 16 hours.

[0216] After monitoring showed that the reaction was complete, the reaction mixture was cooled to room temperature. Saturated aqueous ammonium chloride solution (25 ml) and ethyl acetate (50 ml) were added to the reaction mixture for separation. The resulting organic phase was washed with saturated brine. 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 / petroleum ether = 14 / 1) and then purified by preparative high performance liquid chromatography to obtain 62 mg of a white solid (3S,7R)-3-(4-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-6-oxopyrimidin-1(6H)-yl)-2 ... 4 ,2 5 -difluoro-7-methyl-1 1 -Difluoromethyl-1 1 H-9-Aza-1(5,4)-pyrazol-2(1,3)-benzocyclononanoic acid-8-one (yield: 24%). LC-MS: RT = 2.04 min, [M+H] + =712.94. 1 H 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).

[0217] Example 12

[0218] Synthesis of (3R,7R)-3-(4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-6-oxopyrimidin-1(6H)-yl) ... 4 ,2 5 -difluoro-7-methyl-1 1 -Difluoromethyl-1 1 H-9-Aza-1(5,4)-pyrazole-2(1,3)-benzocyclononanoic acid-8-one (12)

[0219] The specific synthetic route is as follows:

[0220] 6-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-(3H)-one (123 mg, 0.36 mmol) was dissolved in dry 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 solution 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)-pyrazol-2(1,3)-benzazepin-3-yl 4-nitrobenzenesulfonate (200 mg, 0.36 mmol) was reacted at 70°C for 16 hours.

[0221] After monitoring showed that the reaction was complete, the reaction mixture was cooled to room temperature. Saturated aqueous ammonium chloride solution (25 ml) and ethyl acetate (50 ml) were added to the reaction mixture for separation. The resulting organic phase was washed with saturated brine. 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 / petroleum ether = 14 / 1) and then purified by preparative high performance liquid chromatography to obtain 50 mg of a white solid (3R,7R)-3-(4-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-6-oxopyrimidin-1(6H)-yl) ... 4 ,2 5 -difluoro-7-methyl-1 1 -Difluoromethyl-1 1 H-9-Aza-1(5,4)-pyrazol-2(1,3)-benzocyclononanoic acid-8-one (yield: 20%). LC-MS: RT = 2.04 min, [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).

[0222] Example 13

[0223] Synthesis of (3S,7R)-3-(4-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)-6-oxopyrimidin-1(6H)-yl)-2-fluorophenyl 4 , 2 5 -difluoro-7-methyl-1 1 -Difluoromethyl-1 1 H-9-Aza-1(5,4)-pyrazol-2(1,3)-phenylcyclononane-8-one (13)

[0224] The specific synthetic route is as follows:

[0225] 4-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)2-fluorophenyl)pyrimidin-2(1H)-one (118 mg, 0.36 mmol) was dissolved in dry 1,4-dioxane (15 ml), and then lithium bis(trimethylsilyl)amide (1 mol / L tetrahydrofuran solution, 0.36 ml) 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 -Difluoromethyl-8-oxo-1 1 H-1(5,4)-pyrazol-2(1,3)-phenylcyclononan-3-yl 4-nitrobenzenesulfonate (200 mg, 0.36 mmol) was added, and the reaction solution was stirred at 70°C for 24 hours.

[0226] After TLC monitoring showed that the reaction was complete, the temperature was cooled to room temperature. Saturated aqueous ammonium chloride solution (25 ml) and ethyl acetate (30 ml) were added to the reaction solution and the layers were separated. The obtained organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained 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-triazol-1-yl)-2-fluorophenyl)-6-oxopyrimidin-1(6H)-yl)-2-fluorophenyl)-3 ... 4 , 2 5 -difluoro-7-methyl-1 1 -Difluoromethyl-1 1 H-9-Aza-1(5,4)-pyrazol-2(1,3)-phenylcyclononane-8-one (yield: 18%). LC-MS: RT = 1.98 min, [M+H] + =678.96. 1H 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).

[0227] Example 14

[0228] Synthesis of (3S,7R)-3-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-6-oxopyrimidin-1(6H)-yl)-2 4 ,2 5 -difluoro-7-methyl-1 1 -Difluoromethyl-1 1 H-9-Aza-1(5,4)-pyrazole-2(1,3)-benzocyclononanoic acid-8-one (14)

[0229] The specific synthetic route is as follows:

[0230] 6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-(3H)-one (110 mg, 0.36 mmol) was dissolved in dry 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, and the resulting reaction solution 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)-pyrazol-2(1,3)-benzazepin-3-yl 4-nitrobenzenesulfonate (200 mg, 0.36 mmol) was reacted at 70°C for 16 hours.

[0231] After monitoring showed that the reaction was complete, the reaction mixture was cooled to room temperature. Saturated aqueous ammonium chloride solution (25 ml) and ethyl acetate (30 ml) were added to the reaction mixture for separation. The resulting organic phase was washed with saturated brine. 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 / petroleum ether = 14 / 1) and then purified by preparative high performance liquid chromatography to obtain 42 mg of a white solid (3S,7R)-3-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-6-oxopyrimidin-1(6H)-yl) ... 4 ,2 5 -difluoro-7-methyl-1 1 -Difluoromethyl-1 1 H-9-Aza-1(5,4)-pyrazol-2(1,3)-benzocyclononanoic acid-8-one (yield: 18%). LC-MS: RT = 2.00 min, [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).

[0232] Example 15

[0233] Synthesis of (3S,7R)-3-(4-chloro-2-fluoro-6-(4-trifluoromethyl)-1H-1,2,3-triazol-1-ylphenyl)-2-oxopyridin-1(2H)yl)-2 4 , 2 5 -difluoro-7-methyl-1 1 -methyl-d3-1 1 H-9-Aza-1(5,4)-pyrazol-2(1,3)-phenylcyclononaphthalene-8-one (15)

[0234] The specific synthetic route is as follows:

[0235] Step A: Synthesis of 4-chloro-3-fluoro-2-(2-methoxypyridin-4-yl)aniline

[0236] 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 with N2 three times and reacted at 85 °C for 16 hours.

[0237] TLC monitoring indicated the reaction was complete. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated and diluted with ethyl acetate (30 mL). Extraction was performed with ethyl acetate (30 mL x 2). The organic phases were combined and washed with saturated aqueous sodium chloride (30 mL x 2), then dried over anhydrous sodium sulfate. Finally, the mixture was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 10 / 1) to obtain 3.8 g of 4-chloro-3-fluoro-2-(2-methoxypyridin-4-yl)aniline as a pale yellow solid (yield: 57.1%). LCMS: RT = 2.05 min, [M+H] + =253.02.

[0238] Step B: Synthesis of 4-(6-azido-3-chloro-2-fluorophenyl)-2-methoxypyridine

[0239] At room temperature, 4-chloro-3-fluoro-2-(2-methoxypyridin-4-yl)aniline (660 mg, 2.62 mmol), tert-butyl nitrite (396 mg, 3.82 mmol) and trimethylsilyl azide (456 mg, 3.92 mmol) were dissolved in acetonitrile (14 ml) and reacted at room temperature under N2 protection for 1 hour.

[0240] TLC monitoring indicated the reaction was complete. After the reaction system cooled to room temperature, saturated brine (20 mL) was added dropwise to the reaction mixture to quench the reaction, followed by extraction with ethyl acetate (20 mL x 2). The organic phases were combined, washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 20 / 1) to yield 694 mg of 4-(6-azido-3-chloro-2-fluorophenyl)-2-methoxypyridine as a pale yellow solid (yield: 96%). LCMS: RT = 1.95 min, [M+H] + =279.03.

[0241] Step C: Synthesis of 4-(3-chloro-2-fluoro-6-(4-trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-2-methoxypyridine

[0242] 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 system for 1 hour, and the reaction was allowed to proceed at room temperature for 3 hours.

[0243] TLC monitoring indicated the reaction was complete. The reaction mixture was filtered, the filtrate concentrated, and then diluted with ethyl acetate (20 mL). The organic phase was washed with saturated aqueous sodium chloride (20 mL x 2), dried over anhydrous sodium sulfate, and finally purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 10 / 1) to provide 460 mg of 4-(3-chloro-2-fluoro-6-(4-trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-2-methoxypyridine as a pale yellow solid (yield: 49.8%). LCMS: RT = 2.09 min, [M+H] + =327.97.

[0244] Step D: Synthesis of 4-(3-chloro-2-fluoro-6-(4-trifluoromethyl)-1H-1,2,3-triazol-1-ylphenyl)pyridin-2(1H)one

[0245] At room temperature, 4-(3-chloro-2-fluoro-6-(4-trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-2-methoxypyridine (460 mg, 1.24 mmol) was dissolved in isopropanol (6 ml), and p-toluenesulfonic acid monohydrate (1.4 g, 7.42 mmol) and lithium chloride (736 mg, 17.4 mmol) were added. Under N2 protection, the reaction was carried out at 75°C for 16 hours.

[0246] LC-MS monitoring indicated complete reaction of the starting material. The reaction mixture was cooled to room temperature, filtered, and the filtrate concentrated and extracted with ethyl acetate (10 mL x 2). The organic phases were combined, washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, and finally purified by silica gel column chromatography (eluent: pure ethyl acetate) to yield 430 mg of 4-(3-chloro-2-fluoro-6-(4-trifluoromethyl)-1H-1,2,3-triazol-1-ylphenyl)pyridin-2(1H)-one as a white solid (yield: 96.8%). LCMS: RT = 1.72 min, [M+H] + =359.02.

[0247] Step E: Synthesis of (3S,7R)-3-(4-chloro-2-fluoro-6-(4-trifluoromethyl)-1H-1,2,3-triazol-1-ylphenyl)-2-oxopyridin-1(2H)yl)-2 4 , 2 5 -difluoro-7-methyl-1 1-methyl-d3-1 1 H-9-Aza-1(5,4)-pyrazol-2(1,3)-phenylcyclononaphthalene-8-one

[0248] 4-(3-chloro-2-fluoro-6-(4-trifluoromethyl)-1H-1,2,3-triazol-1-ylphenyl)pyridin-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, 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)-pyrazolol-2(1,3)-phenylcyclononaphthalen-3-yl 4-nitrobenzenesulfonate (100 mg, 0.19 mmol) was reacted at 70°C for 24 hours.

[0249] After LC-MS monitoring indicated the reaction was complete, the mixture was cooled to room temperature. Saturated aqueous ammonium chloride (25 ml) and ethyl acetate (50 ml) were added to the reaction solution for separation, and the resulting organic phase was washed with saturated brine. 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 / petroleum ether = 14 / 1) and then by preparative high performance liquid chromatography to obtain 11 mg of a white solid (3S,7R)-3-(4-chloro-2-fluoro-6-(4-trifluoromethyl)-1H-1,2,3-triazol-1-ylphenyl)-2-oxopyridin-1(2H)yl)-2-oxopyridin-2 4 , 2 5 -difluoro-7-methyl-1 1 -methyl-d3-1 1 H-9-Aza-1(5,4)-pyrazol-2(1,3)-phenylcyclononaphthalene-8-one. LCMS: RT = 1.95 min, [M+H] + =679.07.

[0250] Example 16

[0251] Synthesis of (3S,7R)-3-(4-(3-chloro-2-fluoro-6-(4-trifluoromethyl)-1H-1,2,3-triazol-1-ylphenyl)-6-oxopyridin-1(6H)yl)-2-nitropropene 5 , 2 6 -difluoro-7-methyl-1 1 -(deuterated methyl)-1 1H-9-Aza-1(5,4)-pyrazole-2(1,3)-phencyclononane-8-one (16)

[0252] The specific synthetic route is as follows:

[0253] Step A: Synthesis of 2-(3-bromo-4,5-difluorobenzoyl)cyclopentan-1-one

[0254] 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 tetrahydrofuran solution, 419.2 ml, 419.2 mmol) was slowly added dropwise at -70°C. After completion of the addition, the temperature was naturally raised to -30°C. The reaction was then continued at -30°C for 16 hours.

[0255] TLC monitoring indicated completion of the reaction, and the mixture was quenched by the addition of 2N dilute hydrochloric acid solution (150 ml). After separation, the organic phase was vortexed to remove most of the tetrahydrofuran, and ethyl acetate (500 ml) was added. The mixture was then washed with saturated brine (100 ml x 1). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a residue which was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 9) to obtain 64 g of 2-(3-bromo-4,5-difluorobenzoyl)cyclopentan-1-one as a light yellow oily liquid (yield: 53%).

[0256] Step B: Synthesis of 6-(3-bromo-4,5-difluorophenyl)-6-oxohexanoic acid

[0257] 2-(3-Bromo-4,5-difluorobenzoyl)cyclopentan-1-one (100 g, 0.33 mol) was added to a mixture of 1200 ml of acetonitrile and water (1:1) at room temperature, followed by indium trifluoromethanesulfonate (18.6 g, 0.033 mol), and the mixture was heated to 80 degrees Celsius and reacted for 16 hours.

[0258] TLC monitoring indicated the reaction was complete. After cooling to room temperature, solid sodium chloride was added to the reaction mixture. After separation, the aqueous phase was extracted with ethyl acetate (300 ml x 2). The three organic phases were combined, dried, and 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 6-(3-bromo-4,5-difluorophenyl)-6-oxohexanoic acid as a white solid (yield: 65%). LCMS: RT = 1.97 min, [MH] - =318.95.

[0259] Step C: Synthesis of (R)-1-(4-benzyl-2-oxooxazolidin-3-yl)-6-(3-bromo-4,5-difluorophenyl)hexane-1,6-dione

[0260] 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). Trimethylacetyl chloride (39.4 ml, 318 mmol) was added at 0°C and stirred for 0.5 hours. Lithium chloride (13.36 g, 318 mmol) was added and stirring continued for 15 minutes. (R)-4-benzyloxazolidin-2-one (45.6 g, 257 mmol) was then added in one portion and the mixture was allowed to react at room temperature for 3 hours.

[0261] The reaction was monitored for completion and quenched by adding saturated aqueous ammonium chloride (500 ml). After separation, the organic phase was vortexed to remove most of the tetrahydrofuran, and ethyl acetate (500 ml) was added, followed by washing with saturated brine (100 ml x 1). 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 light yellow oily substance (R)-1-(4-benzyl-2-oxooxazolidin-3-yl)-6-(3-bromo-4,5-difluorophenyl)hexane-1,6-dione (yield: 93%). LCMS: RT = 2.29 min, [M+H] + -CH3O - =493.97.

[0262] Step D: Synthesis of (R)-4-benzyl-3-(6-(3-bromo-4,5-difluorophenyl)-6,6-dimethoxyhexanoyl)oxazolidin-2-one

[0263] At room temperature, (R)-1-(4-benzyl-2-oxooxazolidin-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, and then the mixture was reacted at 70 degrees for 3 hours.

[0264] The reaction was complete as determined by TLC. After the reaction mixture was cooled to room temperature, saturated sodium bicarbonate solution was added to adjust the pH to 9. The excess methanol was then removed by vortexing. The mixture was extracted with ethyl acetate (300 ml x 3 times). The organic phases were combined and washed with saturated sodium chloride aqueous solution (100 ml x 1 time), then dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate = 7:3) to obtain 83 g of (R)-4-benzyl-3-(6-(3-bromo-4,5-difluorophenyl)-6,6-dimethoxyhexanoyl)oxazolidin-2-one as a pale yellow oil (yield: 79%). LCMS: RT = 2.07 min, [M+H] + -CH3O - =334.94.

[0265] Step E: Synthesis of (R)-4-benzyl-3-((R)-6-(3-bromo-4,5-difluorophenyl)-6,6-dimethoxy-2-methylhexanoyl)oxazolidin-2-one

[0266] Iodomethane (21.6 ml, 374 mmol) was added to a solution of (R)-4-benzyl-3-(6-(3-bromo-4,5-difluorophenyl)-6,6-dimethoxyhexanoyl)oxazolidin-2-one (83 g, 158 mmol) in tetrahydrofuran (1000 ml). After nitrogen substitution three times, the internal temperature was lowered to -60°C. A solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (2 mol / L tetrahydrofuran, 118 ml) was slowly added, maintaining the internal temperature below -50°C. After the addition was complete, the internal temperature was maintained at -60°C for 1 hour.

[0267] The reaction was monitored by TLC to determine completion. Saturated ammonium chloride solution (400 mL) was added to the reaction mixture to quench the reaction. After separation, the organic phase was vortexed to remove most of the tetrahydrofuran, and ethyl acetate (600 mL) was added. The mixture was then washed with saturated brine (100 mL x 1). The organic phase was dried over anhydrous sodium sulfate and concentrated to yield 85 g of crude (R)-4-benzyl-3-((R)-6-(3-bromo-4,5-difluorophenyl)-6,6-dimethoxy-2-methylhexanoyl)oxazolidin-2-one as a pale yellow oil, which was used directly in the next step. LCMS: RT = 2.30 min, [M+H] + -CH3O - =508.17.

[0268] Step F: Synthesis of (R)-6-(3-bromo-4,5-difluorophenyl)-6,6-dimethoxy-2-methylhexanoic acid

[0269] The crude product of (R)-4-benzyl-3-((R)-6-(3-bromo-4,5-difluorophenyl)-6,6-dimethoxy-2-methylhexanoyl)oxazolidin-2-one (85 g, 158 mmol) was dissolved in tetrahydrofuran (850 ml). Aqueous hydrogen peroxide solution (W=30%, 35.7 g, 316 mmol) was added at 0°C and stirred for 10 minutes. Finally, an aqueous solution (170 ml) of lithium hydroxide monohydrate (13.2 g, 316 mmol) was added, and the mixture was reacted at room temperature for 2.0 hours.

[0270] The reaction was monitored for completion by TLC. Aqueous sodium sulfite (200 mL, 400 mmol) was added at 0°C to quench the reaction, followed by stirring at room temperature for 2 hours. The mixture was vortexed to remove most of the tetrahydrofuran, and the resulting residue was adjusted to pH 5 with solid citric acid. The mixture was then extracted with ethyl acetate (300 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate = 4:1) to yield 33 g of (R)-6-(3-bromo-4,5-difluorophenyl)-6,6-dimethoxy-2-methylhexanoic acid as a pale yellow oil (yield: 55% for both steps). LCMS: RT = 2.11 min, [M+H] + -CH3O - =348.96.

[0271] Step G: Synthesis of (R)-6-(3,4-difluoro-5-(1-methyl-d3)-4-nitropyrazole-5-phenyl)-6,6-dimethoxy-2-methylhexanoic acid

[0272] (R)-6-(3-Bromo-4,5-difluorophenyl)-6,6-dimethoxy-2-methylhexanoic acid (25 g, 65 mmol), 1-deuterated methyl-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), and n-butyldi(1-adamantyl)phosphine (2.36 g, 6.5 mmol) and palladium acetate (1.47 mg, 6.5 mmol) were added. After nitrogen substitution, the mixture was reacted at 110°C for 16 hours.

[0273] The reaction was monitored for completion by TLC. After cooling, the reaction solution was spun off most of the dioxane, then water was added and the pH was adjusted to approximately 5 with solid citric acid. The solution was extracted with ethyl acetate (400 ml x 3). The organic phases were combined, washed with saturated aqueous sodium chloride (100 ml x 1), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate = 4:1) to provide 18 g of (R)-6-(3,4-difluoro-5-(1-methyl-d3)-4-nitropyrazole-5-phenyl)-6,6-dimethoxy-2-methylhexanoic acid (yield: 64%) as a pale yellow foamy solid. LCMS: RT = 1.99 min, [MH] - =429.08.

[0274] Step H: Synthesis of (R)-6-(3-(4-amino-1-methyl-d3)-1H-pyrazol-5-yl)-4,5-difluorophenyl)-6,6-dimethoxy-2-methylhexanoic acid

[0275] 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 palladium / carbon (10% palladium containing 50% water, 1.32 g) was added. After hydrogen replacement, a hydrogen balloon was added and the reaction was carried out at 60°C for 6 hours.

[0276] The reaction was monitored for completion by TLC. The reaction solution was cooled to room temperature, filtered through celite, and the filtrate was dried and concentrated to yield 2.70 g of a reddish foamy solid (R)-6-(3-(4-amino-1-methyl-d3)-1H-pyrazol-5-yl)-4,5-difluorophenyl)-6,6-dimethoxy-2-methylhexanoic acid (yield: 90%). LCMS: RT = 1.72 min, [M+H] + =401.13.

[0277] Step I: Synthesis of (R)-2 5 ,2 6 -difluoro-3,3-dimethoxy-7-methyl-1 1 -(deuterated methyl)-1 1 H-9-Aza-1(5,4)-pyrazol-2(1,3)-benzocyclononan-8-one

[0278] At room temperature, a solution of (R)-6-(3-(4-amino-1-methyl-d3)-1H-pyrazol-5-yl)-4,5-difluorophenyl)-6,6-dimethoxy-2-methylhexanoic acid (2.7 g, 6.75 mmol) in tetrahydrofuran (100 ml) was slowly added dropwise to a solution of N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (3.85 g, 13.50 mmol) and N,N-diisopropylethylamine (1.78 g, 13.50 mmol) in tetrahydrofuran (400 ml). After the addition was complete, the mixture was reacted at room temperature for 1 hour.

[0279] The reaction was completed by TLC monitoring. The reaction solution was diluted with aqueous solution. The mixture was vortexed to remove most of the tetrahydrofuran and extracted with ethyl acetate (50 ml × 3 times). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 5 g of a light yellow foam solid (R)-2 5 ,2 6 -difluoro-3,3-dimethoxy-7-methyl-1 1 -(deuterated methyl)-1 1 The crude product of H-9-aza-1(5,4)-pyrazol-2(1,3)-benzocyclononane-8-one was directly used in the next step. LCMS: RT = 1.84 min, [M+H] + =383.13.

[0280] Step J: Synthesis of (R)-2 5 ,2 6 -difluoro-7-methyl-1 1 -(deuterated methyl)-1 1 H-9-Aza-1(5,4)-pyrazole-2(1,3)-benzocyclononane-3,8-dione

[0281] (R)-2 5 ,2 6 -difluoro-3,3-dimethoxy-7-methyl-1 1 -(deuterated methyl)-1 1 The crude product of H-9-aza-1(5,4)-pyrazol-2(1,3)-benzocyclononane-8-one (5 g, 13 mmol) was dissolved in acetonitrile (45 ml), and dilute hydrochloric acid solution (2 mol / L aqueous solution, 15 ml) was added and reacted at 50 °C for 4 hours.

[0282] The reaction was monitored by TLC, and saturated aqueous sodium bicarbonate solution was added to neutralize the mixture, and the mixture was extracted with ethyl acetate (30 ml x 2 times). The organic phases were combined, 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 white solid (R)-2 5 ,2 6-difluoro-7-methyl-1 1 -(deuterated methyl-d3)-1 1 H-9-Aza-1(5,4)-pyrazole-2(1,3)-benzocyclononane-3,8-dione (two-step yield: 82%). LCMS: RT = 1.75 min, [M+H] + =337.11.

[0283] Step K: Synthesis of (7R)-2 5 ,2 6 -difluoro-3-hydroxy-7-methyl-1 1 -(deuterated methyl)-1 1 H-9-Aza-1(5,4)-pyrazol-2(1,3)-benzazepin-8-one

[0284] (R)-2 5 ,2 6 -difluoro-7-methyl-1 1 -(deuterated methyl)-1 1 H-9-Aza-1(5,4)-pyrazole-2(1,3)-benzocyclononane-3,8-dione (1.87 g, 5.56 mmol) was dissolved in anhydrous methanol (36 ml). Sodium borohydride (211 mg, 5.56 mmol) was added in portions at -70°C and the mixture was reacted at the same temperature for 15 minutes.

[0285] The reaction was monitored by TLC, and saturated aqueous ammonium chloride was added to quench the reaction, and the mixture was extracted with ethyl acetate (30 ml × 5 times). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give 900 mg of a white solid (7R)-2 5 ,2 6 -difluoro-3-hydroxy-7-methyl-1 1 -(deuterated methyl)-1 1 H-9-Aza-1(5,4)-pyrazol-2(1,3)-benzazepine-8-one (yield: 48%). LCMS: RT = 1.62 min, [M+H] + =339.04.

[0286] Step L: Synthesis of (7R)-2 5 ,2 6 -difluoro-7-methyl-1 1 -(deuterated methyl)-8-oxo-1 1 H-9-Aza-1(5,4)-pyrazol-2(1,3)-benzazepin-3-yl 4-nitrobenzenesulfonate

[0287] (7R)-2 5 ,2 6-difluoro-3-hydroxy-7-methyl-1 1 -(deuterated methyl)-1 1 H-9-aza-1(5,4)-pyrazol-2(1,3)-benzazepine-8-one (900 mg, 2.66 mmol) was added to anhydrous dichloromethane (50 ml), and triethylamine (672 mg, 6.66 mmol) and 4-dimethylaminopyridine (324 mg, 2.66 mmol) were added in sequence and stirred for 10 minutes. Then, p-nitrobenzenesulfonyl chloride (882 mg, 3.99 mmol) was added in batches and reacted at room temperature for 4 hours.

[0288] The reaction was monitored by TLC, and 30 ml of sodium bicarbonate solution was added for dilution, and the mixture was extracted with dichloromethane (20 ml x 2 times). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue which was purified by column chromatography (eluent: n-hexane: ethyl acetate = 1:15) to obtain 900 mg of a light yellow solid (7R)-2 5 ,2 6 -difluoro-7-methyl-1 1 -(deuterated methyl)-8-oxo-1 1 H-9-Aza-1(5,4)-pyrazol-2(1,3)-benzazepin-3-yl 4-nitrobenzenesulfonate (yield: 65%). LCMS: RT = 1.93 min, [M+H] + =524.02.

[0289] Step M: Synthesis of (3S,7R)-3-(4-(3-chloro-2-fluoro-6-(4-trifluoromethyl)-1H-1,2,3-triazol-1-ylphenyl)-6-oxopyridin-1(6H)yl)-2 5 , 2 6 -difluoro-7-methyl-1 1 -(deuterated methyl)-1 1 H-9-Aza-1(5,4)-pyrazol-2(1,3)-phencyclnonanoin-8-one

[0290] 6-(3-chloro-2-fluoro-6-(4-trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4(3H)one (160 mg, 0.44 mmol) was dissolved in dry 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, and the resulting reaction solution was stirred at room temperature for 30 minutes. Then (7R)-2 5 ,2 6 -difluoro-7-methyl-1 1 -(deuterated methyl)-8-oxo-1 1H-9-Aza-1(5,4)-pyrazol-2(1,3)-benzazepin-3-yl 4-nitrobenzenesulfonate (230 mg, 0.44 mmol) was reacted at 70°C for 16 hours.

[0291] After TLC monitoring showed that the reaction was complete, the mixture was cooled to room temperature. Saturated aqueous ammonium chloride solution (25 ml) and ethyl acetate (50 ml) were added to the reaction solution for separation. The resulting organic phase was washed with saturated brine. 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 / petroleum ether = 14 / 1) and then purified 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-triazol-1-ylphenyl)-6-oxopyridin-1(6H)yl)-2-[3-(4-(3-chloro-2-fluoro-6-(4-trifluoromethyl)-1H-1,2,3-triazol-1-ylphenyl)-6-oxopyridin-2-yl)-1-[ ... 5 , 2 6 -difluoro-7-methyl-1 1 -(deuterated methyl)-1 1 H-9-Aza-1(5,4)-pyrazol-2(1,3)-phenanthenonanoin-8-one (yield: 15%). LC-MS: RT = 2.00 min, [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).

[0292] Example 17

[0293] Synthesis of (3S,7R)-3-(4-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-6-oxopyridin-1(6H)-yl)-2 5 , 2 6 -difluoro-7-methyl-1 1 -(methyl-d3)-1 1 H-9-Aza-1(5,4)-pyrazolo-2(1,3)-phenylcyclononaphthalene-8-one (17)

[0294] The specific synthetic route is as follows:

[0295] 6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4(3H)one (100 mg, 0.325 mmol) was dissolved in dry 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, and the resulting reaction solution was stirred at room temperature for 30 minutes. Then (7R)-2 5 ,2 6 -difluoro-7-methyl-1 1 -(deuterated methyl)-8-oxo-1 1 H-9-Aza-1(5,4)-pyrazol-2(1,3)-benzazepin-3-yl 4-nitrobenzenesulfonate (170 mg, 0.325 mmol) was reacted at 70°C for 16 hours.

[0296] After TLC monitoring showed that the reaction was complete, the mixture was cooled to room temperature. Saturated aqueous ammonium chloride solution (25 ml) and ethyl acetate (50 ml) were added to the reaction solution for separation. The resulting organic phase was washed with saturated brine. 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 / petroleum ether = 14 / 1) and then purified 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-triazol-1-yl)phenyl)-6-oxopyridin-1(6H)-yl)-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)-6-oxopyridin-2-yl)-1 ... 5 , 2 6 -difluoro-7-methyl-1 1 -(methyl-d3)-1 1 H-9-Aza-1(5,4)-pyrazolo-2(1,3)-phenylcyclononaphthalene-8-one (yield: 9.7%). LC-MS: RT = 1.95 min, [M+H] + =627.98.

[0297] 1H 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).

[0298] Example 18

[0299] Synthesis of (3S,7R)-3-(4-(5-chloro-2-(4-trifluoromethyl)-1H-1,2,3-triazol-1-ylphenyl)-6-oxopyridin-1(6H)yl)-2-nitropropene 5 , 2 6 -difluoro-7-methyl-1 1 -(methyl-d3)-1 1 H-9-Aza-1(5,4)-pyrazol-2(1,3)-phenylcyclononaphthalene-8-one (18)

[0300] The specific synthetic route is as follows:

[0301] 6-(5-chloro-2-(4-trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4(3H)one (200.0 mg, 0.59 mmol) was dissolved in dry 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, and the resulting reaction solution was stirred at room temperature for 30 minutes. Then (7R)-2 5 ,2 6 -difluoro-7-methyl-1 1 -(deuterated methyl)-8-oxo-1 1 H-9-Aza-1(5,4)-pyrazol-2(1,3)-benzazepin-3-yl 4-nitrobenzenesulfonate (307 mg, 0.59 mmol) was reacted at 70°C for 16 hours.

[0302] After TLC monitoring indicated that the reaction was complete, the mixture was cooled to room temperature. Saturated aqueous ammonium chloride solution (25 ml) and ethyl acetate (30 ml) were added to the reaction solution for separation. The resulting organic phase was washed with saturated brine. 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 / 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-triazol-1-ylphenyl)-6-oxopyridin-1(6H)yl)-2-(4-(5-chloro-2-(4-trifluoromethyl)-1H-1,2,3-triazol-1-ylphenyl)-6-oxopyridin ... 5 , 2 6 -difluoro-7-methyl-1 1 -(methyl-d3)-1 1 H-9-Aza-1(5,4)-pyrazol-2(1,3)-phenylcyclononaphthalene-8-one (yield: 10.2%). LC-MS: RT = 1.98 min, [M+H] + =662.00.

[0303] 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).

[0304] Example 19

[0305] Synthesis of (3S,7R)-3-(4-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)-6-oxopyridin-1(6H)yl)-2-fluorophenyl 5 , 2 6 -difluoro-7-methyl-1 1 -(methyl-d3)-1 1 H-9-Aza-1(5,4)-pyrazol-2(1,3)-phenylcyclononaphthalene-8-one (19)

[0306] The specific synthetic route is as follows:

[0307] 6-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)pyrimidin-4(3H)one (70 mg, 0.215 mmol) was dissolved in dry 1,4-dioxane (7 ml), and then lithium bis(trimethylsilyl)amide (1 mol / L tetrahydrofuran solution, 0.215 ml) was slowly added, and the resulting reaction solution was stirred at room temperature for 30 minutes. Then, (7R)-2 5 , 2 6 -difluoro-7-methyl-1 1 -(deuterated methyl)-8-oxo-1 1 H-1(5,4)-pyrazol-2(1,3)-phenylcyclononan-3-yl 4-nitrobenzenesulfonate (170 mg, 323 mmol), the reaction solution was stirred at 70°C for 16 hours.

[0308] After TLC monitoring showed that the reaction was complete, the mixture was cooled to room temperature. Saturated aqueous ammonium chloride solution (25 ml) and ethyl acetate (30 ml) were added to the reaction solution and the layers were separated. The obtained organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained 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-triazol-1-yl)-2-fluorophenyl)-6-oxopyridin-1(6H)-yl)-2-fluorophenyl)-3-(4-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)-6-oxopyridin-1(6H)-yl)-2-fluorophenyl)-3-(4-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)-3 ... 5 , 2 6 -difluoro-7-methyl-1 1 -(methyl-d3)-1 1 H-9-Aza-1(5,4)-pyrazol-2(1,3)-phenylcyclononaphthalene-8-one (yield: 12.7%). LC-MS: RT = 1.95 min, [M+H] + =646.01.

[0309] Examples 20-23

[0310] According to the preparation method of the above embodiment, the following compounds 20-23 were prepared:

[0311] Example 24: Absorption spectroscopy to detect the biological activity of the compounds of the present invention in inhibiting human coagulation factor XIa

[0312] 1. Experimental Materials

[0313] Enzyme: Human Factor XIa (ENZYME RESEARCH, Product No. HFXIa 1111a)

[0314] Substrate: S-2366TM :(CHROMOGENIX, product number 82109039)

[0315] Buffer: 145 mM NaCl, 5 mM KCl, 1 mg / mL PEG 8000, 30 mM HEPES, pH 7.4.

[0316] 2. Experimental steps

[0317] A 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, and then 2 μL of compounds of different concentrations were added. DMSO was added to the blank and control wells, mixed with a shaker, and incubated at 37°C for 20 min.

[0318] Finally, 100 μL of 800 μM substrate was added to each well, and the absorbance was measured at 405 nm.

[0319] 3 Data processing

[0320] GraphPad Prism software was used for curve fitting and IC 50 value.

[0321] Example 25: Determination of the anticoagulant effect of the compounds of the present invention on human plasma in vitro

[0322] 1. Experimental Materials

[0323] aPTT lot number 220106600, calcium chloride lot number 210305600, and needle wash lot number 211101300: manufactured by Shenzhen Mindray Bio-Medical Electronics Co., Ltd. Human pooled plasma was collected from healthy individuals using disposable venous blood collection tubes (lot number 211108, manufactured by Liuyang Sanli Medical Technology Development Co., Ltd.). Sodium citrate (9:1 ratio) was used to collect human blood and centrifuged at 3000 rpm for 10 minutes at room temperature. The supernatant was then collected and used for later use. (lot number 20220606)

[0324] 2. Experimental steps

[0325] 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. 99 μL of mixed human plasma was added to each 1.5 ml centrifuge tube, followed by 1 μL of the compound of varying solubility. 1 μL of DMSO was added to the blank well, and the mixture was mixed by inverting repeatedly by hand. The samples were collected by centrifugation in a handheld centrifuge and incubated in an electric constant temperature water bath at 37°C for 10 min to mix. The aPTT was detected using a fully automatic coagulation analyzer according to the pre-set program.

[0326] 3. Data processing

[0327] Graphad Prism software was used for curve fitting and EC1.5× was calculated.

[0328] The results of Examples 24 and 25 are shown in Table 1:

[0329] Table 1:

[0330] Conclusion: The compounds of the present invention have significant inhibitory activity against human FXIa and significant anticoagulant effect on human plasma.

[0331] Example 26: Pharmacokinetic Experiment

[0332] 1. Reagents and instruments

[0333] Polyethylene glycol 400 (lot number GORKREUT, Sane Chemical Technology (Shanghai) Co., Ltd.), DMSO (lot number 20200319, Guangdong Guanghua Technology Co., Ltd.), and normal saline (lot number C20052604, Jiangxi Kelun Pharmaceutical Co., Ltd.) were used. LC-MS instruments (Thermo Fisher Ultimate 3000 UPLC, TSQ QUANTUM ULTRA triple quadrupole mass spectrometer, AB SCIEX 5500 QTARP) were used.

[0334] 2. Experimental Animals

[0335] SD rats: male, 180-250 g, purchased from Guangdong Weitonglihua Experimental Animal Technology Co., Ltd.

[0336] 3. Preparation

[0337] Accurately weigh the test sample powder, completely dissolve it in DMSO, add PEG-400, mix thoroughly by vortexing and ultrasonicating, then add normal saline and mix thoroughly by vortexing and ultrasonicating to a concentration of 0.5 mg / mL (DMSO:PEG-400:NS=5:60:35, V / V / V). Administer 10 mL / kg by gavage and 0.5 mL / kg by intravenous administration.

[0338] 4. Blood sample collection

[0339] After intravenous or oral administration, 200 μL of venous blood was collected from rats at 5 min (not collected by oral administration), 15 min, 30 min, 1 h, 2 h, 5 h, 7 h, and 24 h into heparinized EP tubes, centrifuged at 12000 rpm for 2 min, and plasma was frozen at -80°C for testing.

[0340] 5. Biological analysis

[0341] Accurately weigh a certain amount of test sample and dissolve it in DMSO to 1 mg / mL as a stock solution. Accurately draw an appropriate amount of compound stock solution and add acetonitrile to dilute it to make a standard series solution. Accurately draw 20 μL of each of the above standard series solutions, add 180 μL of blank plasma, vortex to mix, and prepare plasma samples equivalent to plasma concentrations of 1, 3, 10, 30, 100, 300, 1000, 3000 and 5000 ng / mL. Perform double sample analysis for each concentration to establish a standard curve. Take 20 μL of plasma, add 200 μL of acetonitrile solution of internal standard propranolol (5 ng / mL), vortex to mix, centrifuge at 4000 rpm for 5 minutes, and take the supernatant for LC-MS analysis. The LC-MS detection conditions are as follows:

[0342] Chromatographic column: Waters ACQUITY™ PREMIER HSS T3, 50*2.1 mm, 1.8 μm.

[0343] Mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile, flow rate: 0.5 mL / min, gradient elution see Table 2 below:

[0344] Table 2

[0345] 6. Data processing

[0346] After LC-MS detection of blood drug concentration, WinNonlin6.1 software was used to calculate the pharmacokinetic parameters of beagle dogs after administration using a non-compartmental model. The results are shown in Table 3 below.

[0347] Table 3: Pharmacokinetic parameters of the compounds of the present invention in dogs (iv and PO administration)

[0348] From the experimental results in Table 3, it can be seen that the preferred compounds of the present invention are better absorbed orally, have higher absolute bioavailability and exposure, and are superior to the control compounds.

[0349] Example 27: Absorption spectroscopy to detect the biological activity of the compounds of the present invention against human coagulation factor Chymotrypsin

[0350] 1. Experimental Materials

[0351] Enzyme: α-Chymotrypsin (Sigma, Cat. No. C8946)

[0352] Substrate: S-2586 TM :(Boatman Biological, product number B2586)

[0353] Buffer: 0.05 M HEPES; 0.145 M NaCl; 5 mM KCl and 0.1% PEG 8000, pH 7.4

[0354] 2. Experimental steps

[0355] A 10 mM test compound dissolved in 100% DMSO was diluted with 100% DMSO to 100, 33.33, 11.11, 3.704, 1.235, 0.412, 0.137, and 0.046 μM; 29.4 μL (20 nM) of 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, and then 0.6 μL of compounds of different concentrations were added. DMSO was added to the blank and control wells, mixed with an oscillator, and incubated at 37°C for 30 min.

[0356] Finally, 30 μL of 200 μM substrate was added to each well, and the absorbance was measured at 405 nm.

[0357] 3. Data processing

[0358] GraphPad Prism software was used for curve fitting and IC 50 The values ​​are shown in Table 4.

[0359] Table 4. Inhibitory effects of compounds on Chymotrypsin

[0360] Experimental conclusion: The inhibitory effect of the compound of the present invention on Chymotrypsin is relatively weak, suggesting that the compound has better selectivity for Chymotrypsin.

[0361] Example 28: Absorption spectroscopy to detect the biological activity of the compounds of the present invention in inhibiting human coagulation factor Trypsin

[0362] 1. Experimental Materials

[0363] Enzyme: Human Trypsin (Sigma, Cat. No. T6424)

[0364] Substrate: S-2222 TM :(CHROMOGENIX, product number 82031639)

[0365] Buffer: 0.1 M sodium phosphate; 0.2 M NaCl and 0.5% PEG 8000, pH 7.4

[0366] 2. Experimental steps:

[0367] A 10 mM test compound dissolved in 100% DMSO was diluted with 100% DMSO to 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, and then 0.6 μL of compounds of different concentrations were added. DMSO was added to the blank and control wells, mixed with an oscillator, and incubated at 37°C for 30 min.

[0368] Finally, 30 μL of 40 μM substrate was added to each well, and the absorbance was measured at 405 nm.

[0369] 3. Data processing

[0370] GraphPad Prism software was used for curve fitting and IC 50 See Table 5 for the values.

[0371] Table 5. Inhibitory effects of compounds on Trypsin

[0372] Experimental conclusion: The inhibitory effect of the compound of the present invention on Trypsin is relatively weak, suggesting that the compound has better selectivity for Trypsin.

[0373] Example 29: Absorption spectroscopy to detect the biological activity of the compounds of the present invention against human coagulation factor FIIa

[0374] 1. Experimental Materials

[0375] Enzyme: Human FIIa (Enzyme Research Laboratories, Cat. No. HT1002a)

[0376] Substrate: S-2366 TM :(CHROMOGENIX, product number 82109039)

[0377] Buffer: 0.1M sodium phosphate; 0.2M NaCl and 0.5% PEG 8000, pH 7.4

[0378] 2. Experimental steps

[0379] A 10 mM test compound dissolved in 100% DMSO was diluted with 100% DMSO to 10000, 3333, 1111, 370.4, 123.5, 41.2, 13.7, and 4.6 μM; 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, and then 0.6 μL of compounds of different concentrations were added. DMSO was added to the blank and control wells, mixed with an oscillator, and incubated at 37°C for 30 min.

[0380] Finally, 30 μL of 200 μM substrate was added to each well, and the absorbance was measured at 405 nm.

[0381] 3. Data processing

[0382] GraphPad Prism software was used for curve fitting and IC 50 See Table 6 for the values.

[0383] Table 6. Inhibitory effect of compounds on coagulation factor FIIa

[0384] Experimental conclusion: The inhibitory effect of the compound of the present invention on coagulation factor FIIa is relatively weak, suggesting that the compound has better selectivity for coagulation factor FIIa.

[0385] The structural formula of the control compound is as follows:

[0386] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be considered as equivalent replacement methods and are included in the scope of protection of the present invention.

Claims

1. A compound represented by general formula (I), or an isomer, a racemate, or a pharmaceutically acceptable salt thereof, characterized in that: wherein X is selected from hydrogen, halogen, and cyano, Y is selected from hydrogen, halogen, and cyano, Z is selected from hydrogen, halogen, and cyano, and at least two of X, Y, and Z are not hydrogen; W is selected from C or N. When W=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 cannot be N at the same time; Ring A is selected from substituted or unsubstituted benzene ring, pyrazole ring, wherein the substituent is selected from halogen, cyano, alkyl, haloalkyl; R 1 is selected from halogen, haloalkyl, cyano; R 2a , R 2b , R 2c independently selected from hydrogen, halogen, alkoxy; R 3 Selected from alkyl, haloalkyl, alkoxy, -(CH2) n -cycloalkyl, -(CH2) n -heterocycloalkyl, n=0 or 1; R 4 Selected from hydrogen and halogen.

2. The compound according to claim 1, or its isomer, or its racemate, or its pharmaceutically acceptable salt, characterized in that: A compound selected from the group consisting of a compound represented by formula (Ia) or formula (Ib), or an isomer, a racemate, or a pharmaceutically acceptable salt thereof: wherein X is selected from hydrogen, halogen, and cyano, Y is selected from hydrogen, halogen, and cyano, Z is selected from hydrogen, halogen, and cyano, and at least two of X, Y, and Z are not hydrogen; 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 cannot be N at the same time; R 1 is selected from halogen, haloalkyl, cyano; R 2a , R 2b , R 2c independently selected from hydrogen, halogen, alkoxy; R 3 Selected from alkyl, haloalkyl, alkoxy, -(CH2)n-cycloalkyl, -(CH2)n-heterocycloalkyl, n=0 or 1; R 4 is selected from hydrogen or halogen; R 5 Selected from alkyl and halogenated alkyl.

3. The compound according to claim 1 or 2, or its isomer, racemate, or pharmaceutically acceptable salt thereof, characterized in that: The alkyl group is selected from C 1-6 The alkyl group, the C 1-6 The alkyl group is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, 1-ethylpropyl, 2-methylbutyl, tert-pentyl, 1,2-dimethylpropyl, isopentyl, neopentyl, n-hexyl, isohexyl, sec-hexyl, tert-hexyl, neohexyl, 2-methylpentyl, 1,2-dimethylbutyl, and 1-ethylbutyl; The alkoxy group is selected from C 1-6 Alkoxy, the C 1-6 The 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.

4. The compound according to claim 1 or 2, or its isomer, racemate, or pharmaceutically acceptable salt thereof, characterized in that: The halogen is selected from fluorine, chlorine, bromine and iodine.

5. The compound according to claim 1 or 2, or its isomer, racemate, or pharmaceutically acceptable salt thereof, characterized in that: The haloalkyl group refers to a group in which one or more hydrogen atoms on the alkyl group are replaced by halogen atoms, wherein the halogen atoms are selected from fluorine, chlorine, bromine and iodine.

6. The compound according to claim 1 or 2, or its isomer, racemate, or pharmaceutically acceptable salt thereof, characterized in that: The cycloalkyl group is selected from C 3-6 The cycloalkyl group, the C 3-6 The cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; the heterocycloalkyl group refers to a cycloalkyl group in which one or more carbon atoms are replaced by heteroatoms selected from nitrogen, oxygen and sulfur, and the heteroatoms are one or more.

7. The compound according to claim 1 or 2, or its isomer, racemate, or pharmaceutically acceptable salt thereof, characterized in that: The W is selected from C or N. When W=N, R 1 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. 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 cannot be N at the same time; R 1 is selected from chloro, trifluoromethyl, difluoromethylene; R 2a , R 2b , R 2c R is independently selected from hydrogen, methoxy, fluorine, and chlorine; 3 is selected from methyl; R 4 is selected from hydrogen, fluorine; R 5 Selected from methyl and difluoromethylene.

8. The compound according to claim 1 or 2, or its isomer, racemate, or pharmaceutically acceptable salt thereof, characterized in that: The compound is selected from:

9. A pharmaceutical composition, characterized in that The invention comprises a therapeutically effective amount of the compound according to any one of claims 1 to 8, or an isomer thereof, or a racemate thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

10. The medical use of the compound according to any one of claims 1 to 8, or its isomer, racemate, or pharmaceutically acceptable salt, specifically, its use in the preparation of a drug for treating FXIa-related diseases, preferably a drug for treating thrombosis-related diseases.

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