Enantioselective synthesis method and application of 1, 2, 4-triazinane derivative

Abstract

The invention discloses an enantioselective synthesis method and application of a 1, 2, 4-triazinane derivative, and belongs to the technical field of chemical medicines and organic synthesis. The invention provides a synthesis method of a 1, 2, 4-triazinane compound as shown in a general formula (III), and the 1, 2, 4-triazinane compound is prepared by taking a cyclohexadienone compound and azomethine as raw materials and reacting under the action of a specific chiral phosphoric acid catalyst. The method has the advantages of simplicity and convenience in operation, environment friendliness, wide substrate application range, high yield and the like. The 1, 2, 4-triazinane compound synthesized by the invention shows remarkable anti-hepatic fibrosis activity, and has a wide application prospect in the field of preparation of anti-hepatic fibrosis drugs.

Description

Technical Field

[0001] This invention belongs to the fields of chemical medicine and organic synthesis technology, specifically relating to an enantioselective synthesis method and application of 1,2,4-triazine derivatives. Background Technology

[0002] The 1,2,4-triazine structure, as an important core skeleton in heterocyclic chemistry, has attracted much attention in the field of medicinal chemistry due to its unique heterocyclic features and broad pharmacological potential. This skeleton is widely present in a variety of natural products and drug molecules with significant biological activity, exhibiting diverse pharmacological effects. For example: (1) Remdesivir, as a nucleoside analog, has excellent antiviral activity. In HAE cells, its half-maximal effective concentration (EC50) against SARS-CoV and MERS-CoV is significantly higher. 50 The EC50 value was 74 nM; in delayed brain tumor cells, the EC50 value against mouse hepatitis virus was 74 nM. 50 The value is 30 nM. (2) PF-06815189 is a highly effective phosphodiesterase 2A (PDE2A) inhibitor with an IC50 value of 30 nM. 50 Up to 0.4 nM. This compound is a potential clinical candidate for the treatment of neurological and cardiovascular diseases and can effectively reduce the risk of drug interactions. (3) HIV integrase inhibitors have a novel anti-HIV / AIDS mechanism of action, can be used in combination with other antiretroviral drugs to effectively treat HIV infection, and are less likely to develop drug resistance in clinical practice. (4) GPR139 agonist-2 can rescue social interaction deficits and improve cognitive function in a mouse model of schizophrenia, showing good potential for research on anti-schizophrenia drugs. (5) NLRP3-IN-71 is a selective NLRP3 inhibitor with oral activity that can cross the blood-brain barrier and can inhibit IL-1β secretion, which is suitable for research on neurodegenerative diseases. (6) Compounds with antifungal activity show strong inhibitory effects on wheat rust (the pathogen that causes wheat flour disease), showing significant activity in the control of wheat rust. In summary, given the significant bioactivity of 1,2,4-triazine compounds and their broad prospects in drug development, the development of rapid and efficient synthetic methods has become an important research direction in the fields of organic chemistry and medicinal chemistry.

[0003]

[0004] Given the compelling biological properties exhibited by 1,2,4-triazine derivatives, researchers have developed various synthetic methods to construct triazine skeletons over the past few decades. However, existing methods typically rely on expensive metal catalysts and phase-transfer catalysts, and suffer from drawbacks such as a lack of greenness in the synthetic process, a limited number of chiral centers in the product structures (compounds with three nitrogen-containing chiral centers and two consecutive chiral centers are rarely synthesized), and are mainly limited to the construction of bicyclic or tricyclic 1,2,4-triazine scaffolds, resulting in structurally homogeneous products lacking diversity. The synthetic difficulty increases significantly, especially for triazine derivatives with more diverse and complex spatial structures, and currently reported synthetic strategies are extremely limited, severely restricting drug development based on these skeletons.

[0005] To address the aforementioned problems, this invention develops a novel and efficient method for constructing 1,2,4-triazine alkyl frameworks, enriching the triazine alkyl compound library. Furthermore, it has been discovered that these compounds exhibit good anti-liver fibrosis activity and have potential application value. Summary of the Invention

[0006] This invention aims to address the shortcomings of existing technologies by providing a method for synthesizing 6 / 6 / 6 / 6-tetrafused 1,2,4-triazine compounds. These heterocyclic compounds possess novel structures, containing three chiral centers and exhibiting diverse three-dimensional configurations. Their complexity and diversity significantly enrich the types of heterocyclic compounds, providing new heterocyclic skeletons for drug molecule structure design research and offering applications in the preparation of anti-liver fibrosis drugs.

[0007] To achieve the above objectives, the present invention adopts the following technical solution: This invention first provides an enantioselective synthesis method for 1,2,4-triazine compounds, comprising the following steps:

[0008] In the formula, R is selected from: C1-C6 straight-chain or branched alkyl groups, C3-C6 cycloalkyl groups, R a Substituted alkynyl group, substituted or unsubstituted aryl group, substituted or unsubstituted aromatic heterocyclic group; the substitution on the aryl or aromatic heterocyclic group includes any one of mono- or tri-substituted, and the substituent is selected from H, halogen, C1-C8 straight-chain or branched alkyl group; R a It can be C3-C6 cycloalkyl, aryl, aromatic heterocyclic and silyl ether groups; a, b, and c represent R... 1 R 2 R 3 The number of substitutions, a is selected from 1-2, b is selected from 1-4, and c is selected from 1-5; R 1Selected from: H, C1-C6 straight-chain or branched alkyl groups, -CH=CH-CH=CH-; R 2 Selected from: H, halogens, C1-C6 alkoxy groups; R 3 Selected from: H, C1-C6 straight-chain or branched alkyl groups, C1-C6 alkoxy groups; In an organic solvent, using 4-aminocyclohexadienone compounds of formula (I) and azomethine imine compounds of formula (II) as substrates, a chiral phosphoric acid catalyst is used to react and yield 1,2,4-triazine compounds with the structure shown in formula (III).

[0009] In one embodiment of the present invention, the aryl group is selected from: phenyl, naphthyl.

[0010] In one embodiment of the present invention, the aromatic heterocyclic group is selected from: pyridinyl, 3-bromothiopheneyl, furanyl, 3-bromobenzothiopheneyl, and benzofuranyl.

[0011] In one embodiment of the present invention, R is specifically selected from: methyl, n-butyl, n-hexyl, cyclopropyl, , , , , , , , , , , , , , , , , , .

[0012] In one embodiment of the present invention, R 1 Specifically selected from: H, methyl.

[0013] In one embodiment of the present invention, R 2 Specifically selected from: H, F, and methoxy groups.

[0014] In one embodiment of the present invention, R 3 Specifically selected from: H, methyl, methoxy.

[0015] In one embodiment of the present invention, the molar ratio of the 4-aminocyclohexadienone compound represented by Formula I to the azomethine imine compound represented by Formula II is 1:(1-1.2).

[0016] In one embodiment of the present invention, the organic solvent is selected from any one or more of the following: dichloromethane (DCM), dichloroethane (DCE), chloroform (CHCl3), tetrahydrofuran (THF), diethyl ether (Et2O), acetonitrile (CH3CN), acetone, and toluene. Dichloroethane, dichloromethane, or toluene is preferred.

[0017] In one embodiment of the invention, the amount of organic solvent added, based on the amount of the 4-aminocyclohexadienone compound represented by Formula I, is 1 to 20 mL / mmol. Preferably, it is 20 mL / mmol.

[0018] In one embodiment of the present invention, the chiral phosphoric acid catalyst comprises any one or more of the following: BINOL framework chiral phosphoric acid catalyst ( R )-A1 ~( R )-A6, Spinol framework chiral phosphoric acid catalyst ( S )-B1 ~( S )-B3; .

[0019] In one embodiment of the present invention, a BINOL-based chiral phosphoric acid catalyst is preferred. R )-A2. The BINOL framework chiral phosphoric acid catalyst ( R The structure of )-A2 is shown below: .

[0020] In one embodiment of the present invention, the ratio of the amount of the 4-aminocyclohexadienone compound represented by Formula I to the amount of catalyst added is 1:(0.05~0.1), preferably 1:0.1.

[0021] In one embodiment of the present invention, the reaction temperature is -30°C. o C~0 ℃. Preferably -20~-10℃.

[0022] In one embodiment of the present invention, the reaction time is 15-72 h.

[0023] In one embodiment of the present invention, under air conditions, 4-aminocyclohexadienone compounds, azomethine imine compounds, and a chiral phosphoric acid catalyst are dissolved in an organic solvent and reacted at -20°C to -10°C for 24-72 hours. The reaction solution is then concentrated directly under reduced pressure, and the crude product is separated by silica gel column chromatography, eluted with petroleum ether and ethyl acetate, to obtain the 1,2,4-triazine compounds.

[0024] The present invention also provides 1,2,4-triazine compounds as shown in general formula (III) or pharmaceutically acceptable salts or deuterated derivatives thereof;

[0025] In the formula, R, R 1 R 2 R 3 The definitions of a, b, and c are the same as above.

[0026] In one embodiment of the present invention, the pharmaceutically acceptable salt is an inorganic salt or an organic salt; wherein the inorganic salt is selected from hydrochloride, hydrobromide, hydroiodide, perchlorate, sulfate, hydrogen sulfate, nitrate, phosphate, and acid phosphate; and the organic salt is selected from formate, acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, succinate, glutarate, fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, salicylate, p-toluenesulfonate, and ascorbate.

[0027] In one embodiment of the present invention, the 1,2,4-triazine compounds are specifically selected from: .

[0028] The present invention also provides a pharmaceutical composition for treating liver fibrosis, comprising a 1,2,4-triazine compound of the above general formula (III) or a pharmaceutically acceptable salt thereof, a deuterated derivative thereof, and pharmaceutical excipients.

[0029] This invention also provides the use of the 1,2,4-triazine compounds of the above general formula (III) or their pharmaceutically acceptable salts and deuterated derivatives in the preparation of medicaments for treating diseases associated with liver fibrosis. These diseases typically include hepatitis B, hepatitis C, metabolic-associated fatty liver disease (MAFLD), alcoholic liver disease (ALD), autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), hemochromatosis, Wilson's disease, α1-antitrypsin deficiency, biliary obstruction, drug-induced liver injury, cirrhosis, liver cancer, and heart failure.

[0030] Compared with the prior art, the present invention has the following beneficial effects: This invention provides a synthetic method with significant advantages: it can efficiently construct highly functionalized 1,2,4-triazine alkyl compounds with polynitrogenous and polycyclic structures. This method offers advantages such as simple operation, readily available raw materials, environmental friendliness, good substrate versatility, and excellent stereoselectivity; it also avoids the use of metal catalysts, resulting in high atom economy. The obtained product is a highly functionalized 1,2,4-triazole derivative, a nitrogen heterocyclic compound containing polynitrogenous and polycyclic structures, with three chiral centers (two of which are consecutive chiral centers), exhibiting excellent stereoselectivity. This invention greatly enriches the variety of triazine alkyl compounds containing 1,2,4-triazine alkyl skeletons, promoting the drug development of this class of skeleton compounds.

[0031] Furthermore, the 1,2,4-triazine compounds synthesized in this invention can effectively inhibit the expression of fibronectin (FN) in TGF-β1-induced LX-2 cells, exhibiting good anti-liver fibrosis activity. They have potential application prospects in the treatment of liver fibrosis-related diseases and can be considered as a class of active lead compounds with development potential, worthy of further in-depth research. Attached Figure Description

[0032] Figure 1 To evaluate the anti-hepatic fibrosis activity of TGF-β1 treatment in LX-2 fibroblasts after 48 hours of treatment using high-throughput screening. Figure A shows a schematic diagram illustrating high-throughput screening of hepatic fibrosis inhibitors by detecting cellular FN levels and cell viability. Figure B shows the effects of compounds P4 and P25 in reducing cellular FN levels, and Figure C shows the dose-dependent effect of compound P4.

[0033] Figure 2 This is a structural diagram of a chiral phosphoric acid framework catalyst, specifically a BINOL framework chiral phosphoric acid catalyst. R )-A1~( R )-A6, Spinol framework chiral phosphoric acid catalyst ( S )-B1 ~( S )-B3.

[0034] Figure 3 This is the X-ray single-crystal diffraction structure of P29. Detailed Implementation

[0035] The technical solution of the present invention will be further described in detail below with reference to specific embodiments.

[0036] This invention relates to the following chemical abbreviations: Me is methyl, n-Bu is n-butyl, n-Hexyl is n-hexyl, TBS is tert-butyldimethylsilyl, Ph is phenyl, OMe is methoxy, and Ts is p-toluenesulfonyl.

[0037] The 4-aminocyclohexadienone of Formula I involved in this invention (such as N1-N29 in the examples below) can be prepared according to existing literature, for example, literature Org. Lett. 2021 23, 7873-7877.

[0038] The azomethine imine of formula II involved in this invention (such as S1-S5 in the examples below) can be prepared according to existing literature, for example, literature Tetrahedron ,2015, 71, 4473-4477.

[0039] Example 1 The reaction formula for preparing 1,2,4-triazine compounds in this embodiment is as follows:

[0040] The preparation method is as follows: Under air conditions, N1 (0.1 mmol, 12.3 mg) and S1 (0.12 mmol, 35.9 mg) were dissolved in DCE (2.0 mL), and a chiral phosphoric acid catalyst was added. R )-A2 (0.01 mmol, 9.93 mg), -10 o The reaction was completed after 36 hours. The reaction solution was concentrated directly under reduced pressure, and the crude product was separated by silica gel column chromatography, eluted with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 1:1), to give product P1 (35.1 mg, 83%, 91% ee), which was a white solid.

[0041] Characterization data: = -160.4 (0.2, CHCl3); HPLC analysis of the product:Daicel Chiralcel OD-H column; 10% i -PrOH in hexanes; 1.0 mL / min; λ = 254 nm; retention times: 22.8 min (major), 25.9 min (minor). 1 H NMR (400 MHz, Chloroform- d ) δ 7.79 – 7.73 (m, 2H), 7.35 – 7.28 (m, 3H), 7.23 – 7.16 (m,2H), 7.12 (dd, J = 7.8, 1.2 Hz, 1H), 6.60 (d, J= 10.1 Hz, 1H), 6.34 (d, J = 1.1Hz, 1H), 5.98 (dd, J = 10.1, 0.9 Hz, 1H), 5.92 (s, 1H), 4.62 (dd, J = 13.4, 4.8Hz, 1H), 2.72 (dd, J = 15.8, 13.4 Hz, 1H), 2.58 (ddd, J = 15.8, 4.8, 1.0 Hz, 1H), 2.44 (s, 3H), 1.91 (d, J = 16.0 Hz, 1H), 1.77 (s, 3H). 13 C NMR (101 MHz, Chloroform- d ) δ 196.3, 151.8, 148.7, 145.5, 139.2, 134.4, 130.3, 130.2,128.7, 128.4, 128.2, 126.8, 126.0, 122.2, 61.8, 53.9, 50.0, 38.4, 23.8,21.8.HRMS(ESI) m / z calculated for C 22 H 23 N4O3S[M+H] + : 423.1485, found 423.1485. Examples 2-9 Referring to Example 1, the 4-aminocyclohexadienone compounds were replaced with N2-N9, and the reaction temperature and time were finely adjusted while other factors remained unchanged, to obtain the corresponding products P2-P9.

[0042]

[0043] P2 characterization data: 11H NMR (400 MHz, Chloroform-d) δ 7.80 – 7.73 (m, 2H), 7.36– 7.28 (m, 3H), 7.21 – 7.16 (m, 2H), 7.15 – 7.10 (m, 1H), 6.62 (d, J = 10.3Hz, 1H), 6.38 (d, J = 1.1 Hz, 1H), 6.03 (dd, J = 10.2, 0.9 Hz, 1H), 5.85 (d,J = 12.5 Hz, 1H), 4.70 (dd, J = 13.3, 4.8 Hz, 1H), 2.77 (dd, J = 15.8, 13.3Hz, 1H), 2.61 (ddd, J = 15.7, 4.9, 1.0 Hz, 1H), 2.44 (s, 3H), 2.27 (ddd, J =14.2, 11.8, 4.1 Hz, 1H), 2.02 (ddd, J = 14.2, 11.8, 4.3 Hz, 1H), 1.83 (d, J =12.7 Hz, 1H), 1.47 (dtdd, J = 10.8, 8.8, 7.7, 6.2 Hz, 3H), 1.40 – 1.32 (m,1H), 1.00 (t, J = 7.1 Hz, 3H). 13 13C NMR(101 MHz, Chloroform- d ) δ 196.4, 150.7,148.8, 145.5, 139.2, 134.6, 130.3, 130.2, 129.5, 128.4, 128.1, 126.7, 126.0,122.3, 61.9, 52.6, 52.1, 38.6, 34.3, 25.8, 23.1, 21.8, 14.2. Characterization data of P3: 1 1H NMR(400 MHz, Chloroform- d ) δ 7.79 – 7.72 (m, 2H), 7.35– 7.27 (m, 3H), 7.21 – 7.17 (m, 2H), 7.12 (d, J = 7.8 Hz, 1H), 6.62 (d, J = 10.2Hz, 1H), 6.38 (d, J = 1.0 Hz, 1H), 6.02 (dd,J = 10.2, 0.9 Hz, 1H), 5.84 (d, J =12.4 Hz, 1H), 4.70 (dd, J = 13.3, 4.8 Hz, 1H), 2.76 (dd, J = 15.8, 13.3 Hz, 1H),2.61 (ddd, J = 15.7, 4.8, 1.0 Hz, 1H), 2.44 (s, 3H), 2.26 (ddd, J = 13.6, 11.4,4.3 Hz, 1H), 2.01 (ddd, J = 13.6, 11.8, 3.6 Hz, 1H), 1.83 (d, J = 12.7 Hz, 1H),1.50 (td, J = 11.8, 11.0, 6.5 Hz, 1H), 1.37 (tt, J = 8.9, 7.2, 2.9 Hz, 6H), 1.25(s, 1H), 0.96 – 0.89 (m, 3H). 13 C NMR(101 MHz, Chloroform- d ) δ 196.4, 150.7,148.8, 145.5, 139.2, 134.6, 130.3, 130.2, 129.5, 128.4, 128.1, 126.7, 126.0,122.3, 61.9, 52.7, 52.1, 38.6, 34.6, 31.8, 29.7, 23.6, 22.7, 21.8, 14.2. P4 characterization data: = -32.7 (0.2, CHCl3); 1 H NMR(400 MHz, Chloroform- d ) δ7.81 – 7.74 (m, 2H), 7.35 – 7.28 (m, 3H), 7.25 – 7.16 (m, 2H), 7.11 (dd, J =7.9, 1.2 Hz, 1H), 6.37 (d, J = 1.0 Hz, 1H), 6.11 – 6.06 (m, 2H), 5.98 (d, J= 10.4 Hz, 1H), 4.84 (dd, J = 12.2, 4.9 Hz, 1H), 2.78 (dd, J = 15.9, 12.2 Hz, 1H), 2.66 (dd, J = 15.7, 5.0 Hz, 1H), 2.44 (s, 3H), 1.97 – 1.90 (m, 1H), 1.25 (d, J = 2.1 Hz, 1H), 0.82 – 0.70 (m, 3H), 0.40 – 0.31 (m, 1H). 13 C NMR(101 MHz, Chloroform- d ) δ 196.1, 148.8, 146.6, 145.6, 139.2, 134.4, 130.4, 130.3, 130.1, 128.4, 128. O, 126.7, 125.9, 122.8, 62.5, 56.0, 52.1, 39.3, 21.8, 15.8, 2.8, 1.7. HRMS(ESI) m / z calculated for C 24 H 25 N4O3S [M+H] + : 449.1642, found 449.1641. Characterization data of P5: = +138.6 (0.2, CHCl3); 11H NMR (400 MHz, Chloroform-d) δ 7.78 – 7.73 (m, 2H), 7.35 – 7.29 (m, 3H), 7.21 (ddd, J = 14.8, 7.5, 1.6 Hz, 2H), 7.14 (dd, J = 7.8, 1.3 Hz, 1H), 6.76 (d, J = 10.0 Hz, 1H), 6.35 (d, J = 1.2 Hz, 1H), 6.15 (s, 1H), 6.04 (dd, J = 10.0, 1.0 Hz, 1H), 4.89 (dd, J = 13.6, 4.6 Hz, 1H), 2.77 (dd, J = 15.9, 13.6 Hz, 1H), 2.61 (dd, J = 4.7, 1.0 Hz, 1H), 2.43 (s, 3H), 1.83 (s, 1H), 1.38 – 1.33 (m, 1H), 1.04 – 0.99 (m, 1H), 0.96 – 0.91 (m, 1H), 0.88 – 0.83 (m, 2H). 13 13C NMR (101 MHz, Chloroform-d) δ 195.7, 148.8, 147.6, 145.2, 139.3, 135.1, 130.3, 130.2, 128.7, 128.4, 127.9, 126.8, 126.0, 122.3, 92.5, 72.9, 63.2, 54.9, 50.6, 38.3, 21.8, 8.4, 8.3, -0.2. HRMS(ESI) m / z calculated for C 26 1 25 21H4N4O3S [M+H]+ + : 473.1642, found 473.1642. Characterization data of P6: 1 1H NMR (400 MHz, Chloroform- d ) δ 7.78 – 7.72 (m, 2H), 7.36 – 7.28 (m, 3H), 7.25 – 7.19 (m, 2H), 7.14 (dd, J J = 7.5, 1.0 Hz, 1H), 6.79 (d, J J = 10.0 Hz, 1H), 6.29 (d, J= 1.2 Hz, 1H), 6.23 (d, J = 5.1 Hz, 1H), 6.07 (dd, J =10.1, 0.9 Hz, 1H), 4.99 (dd, J = 13.6, 4.6 Hz, 1H), 2.78 (dd, J = 15.9, 13.6 Hz,1H), 2.59 (ddd, J = 15.8, 4.6, 1.0 Hz, 1H), 2.42 (s, 3H), 1.89 (d, J = 8.7 Hz,1H), 1.02 (s, 9H), 0.23 (d, J = 5.6 Hz, 6H). 13 C NMR(101 MHz, Chloroform- d ) δ195.6, 148.7, 147.1, 145.1, 139.3, 135.3, 130.3, 130.2, 129.1, 128.3, 127.8,126.9, 126.0, 122.3, 103.1, 92.4, 63.5, 54.1, 51.1, 38.2, 26.3, 21.8, 16.7, -4.7. Characterization data of P7: 1 H NMR(400 MHz, Chloroform- d ) δ 7.81 – 7.74 (m, 2H), 7.66– 7.60 (m, 2H), 7.40 – 7.37 (m, 2H), 7.37 – 7.30 (m, 2H), 7.26 – 7.22 (m,3H), 7.22 – 7.18 (m, 1H), 7.16 (dd, J = 7.9, 1.2 Hz, 1H), 6.88 (d, J = 10.0 Hz,1H), 6.46 (d, J = 1.3 Hz, 1H), 6.21 (d, J = 8.3 Hz, 1H), 6.10 (dd, J = 10.1, 0.9Hz, 1H), 5.07 (dd, J= 13.6, 4.6 Hz, 1H), 2.93 – 2.80 (m, 1H), 2.67 (ddd, J =15.9, 4.7, 1.0 Hz, 1H), 2.38 (s, 3H), 2.04 – 1.98 (m, 1H). 13 C NMR(101 MHz,Chloroform- d ) δ 195.5, 148.9, 146.9, 145.2, 139.3, 134.9, 132.3, 130.4,130.1, 129.3, 129.1, 128.5, 128.4, 127.9, 126.9, 126.1, 122.1, 121.8, 88.0,86.8, 63.4, 54.7, 51.1, 38.3, 21.8. Characterization data of P8: 1 H NMR(400 MHz, Chloroform- d ) δ 8.15 (d, J = 1.6 Hz, 1H),7.83 (dd, J = 6.6, 4.2 Hz, 3H), 7.78 (d, J = 8.1 Hz, 2H), 7.66 (dd, J = 8.5, 1.6Hz, 1H), 7.55 – 7.47 (m, 2H), 7.34 (td, J = 7.5, 1.7 Hz, 1H), 7.28 (d, J = 1.7Hz, 1H), 7.24 – 7.20 (m, 3H), 7.18 (d, J = 8.1 Hz, 1H), 6.93 (d, J = 10.0 Hz,1H), 6.50 (s, 1H), 6.26 (s, 1H), 6.13 (d, J = 10.0 Hz, 1H), 5.12 (dd, J = 13.5,4.6 Hz, 1H), 2.89 (dd, J = 15.9, 13.6 Hz, 1H), 2.71 (dd, J = 15.9, 4.6 Hz, 1H),2.35 (s, 3H), 2.02 (dd, J= 9.0, 5.0 Hz, 1H). 13 C NMR(101 MHz, Chloroform- d ) δ195.5, 148.9, 146.9, 145.2, 139.3, 134.9, 133.3, 133.0, 132.7, 130.4, 130.2,129.2, 128.6, 128.4, 128.2, 128.1, 127.9 (2C), 127.2, 126.9, 126.7, 126.1,122.2, 119.1, 88.4, 87.0, 63.5, 54.8, 51.2, 38.3, 21.8. Characterization data of P9: 1 H NMR(400 MHz, Chloroform- d ) δ 8.82 (dd, J = 2.2, 0.9 Hz,1H), 8.58 (dd,<0000’398>= 4.9, 1.7 Hz, 1H), 7.99 (dt, J = 7.9, 1.9 Hz, 1H), 7.80 – 7.74(m, 2H), 7.35 – 7.28 (m, 3H), 7.26 (t, J = 4.2 Hz, 3H), 7.20 (td, J = 7.4, 1.3Hz, 1H), 7.15 (dd, J = 7.8, 1.2 Hz, 1H), 6.89 (d, J = 10.‘0 Hz, 1H), 6.39 (d, J =1.2 Hz, 1H), 6.26 (d, J = 8.4 Hz, 1H), 6.13 (d, J = 9.8 Hz, 1H), 5.07 (dd, J =13.6, 4.6 Hz, 1H), 2.86 (dd, J = 15.9, 13.6 Hz, 1H), 2.67 (ddd, J = 15.9, 4.7,1.0 Hz, 1H), 2.41 (s, 3H), 2.09 (d, J = 9.5 Hz, 1H). 13 Note: There seems to be a small error in the original text where some of the tags like <0000’398> should probably be J . I've translated it as best as possible while maintaining the integrity of the tags.C NMR (101 MHz, Chloroform- d ) δ 195.3, 152.7, 149.5, 148.6, 146.3, 145.4, 139.7, 139.2, 134.7, 130.4,130.2, 129.5, 128.4, 127.9, 126.9, 126.1, 123.3, 122.0, 119.1, 90.1, 84.9,63.4, 54.5, 51.2, 38.2, 21.8. Examples 10-17 Referring to Example 1, the 4-aminocyclohexadienone compound was replaced with N10-17, and the reaction temperature and time were slightly adjusted while other factors remained unchanged, to obtain the corresponding product P10-17.

[0044]

[0045] P10 characterization data: = +186.9 (0.2, CHCl3); HPLC analysis of the product:Daicel Chiralcel OD-H column; 20% i -PrOH in hexanes; 1.0 mL / min; λ = 254 nm; retention times: 20.7 min (major), 34.4 min (minor). 1 H NMR (400 MHz, Chloroform- d ) δ 7.77 – 7.69 (m, 2H), 7.55 – 7.48 (m, 2H), 7.48 – 7.42 (m,1H), 7.37 – 7.32 (m, 3H), 7.30 (dd, J = 7.6, 1.6 Hz, 1H), 7.26 – 7.18 (m, 2H), 7.10 – 7.05 (m, 2H), 6.80 (d, J = 1.1 Hz, 1H), 6.34 (d, J = 10.0 Hz, 1H), 5.91(dd, J = 10.0, 0.9 Hz, 1H), 5.53 (d, J = 11.5 Hz, 1H), 5.48 (dd, J= 13.2, 4.7 Hz, 1H), 2.98 (dd, J = 15.7, 13.2 Hz, 1H), 2.85 (ddd, J = 15.6, 4.8, 1.0 Hz, 1H), 2.35 (s, 3H), 2.24 – 2.15 (m, 1H). 13 C NMR(101 MHz, Chloroform- d ) δ 196.2, 151.1, 149.4, 144.8, 139. / 139.3, 133.9, 130.4, 129.9, 129.6, 128.7, 128.2, 127.8, 127.4, 126.72, 126.65, 126.1, 122.0, 61.5, 56.3, 52.5, 39.3, 21.7. HRMS(ESI) m / z calculated for C 27 H 25 N4O3S [M+H] + : 485.1642, found 485.1639. Characterization data of P11: 1 H NMR(400 MHz, Chloroform- d ) δ 7.62 – 7.56 (m, 2H), / 7.32 (m, 3H), 7.32 – 7.27 (m, 3H), 7.25 – 7.21 (m, 1H), 7.19 (dd, J = 7.8, 1.3 Hz, 1H), 7.11 – 7.05 (m, 2H), 6.78 (d, J = 1.0 Hz, 1H), 6.32 (d, J = 10.0 Hz, 1H), 5.89 (dd, J = 10.0, 0.9 Hz, 1H), 5.55 (d, J = 12.5 Hz, 1H), 5.44 (dd, J = 13.2, 4.8 Hz, 1H), 3.02 – 2.93 (m, 1H), 2.83 (ddd, J = 15.6, 4.7, 1.0 Hz, 1H), 2.45 (s, 3H), 2.36 (s, 3H), 2.17 (d, J It should be noted that there are some possible inaccuracies in the original text, such as the incomplete "139. / 139.3" in line 8. This translation is based on the best understanding of the original text.= 12.6 Hz, 1H). 13 C NMR(101 MHz, Chloroform- d ) δ 196.3, 151.4, 149.4, 144.7, 139.3, 138.6, 136.3, 134.1, 130.3(2C), 129.8, 128.2, 127.8, 127.2, 126.7, 126.4, 126.1, 122.1, 61.5, 56.1, 52.5, 39.3, 21.8, 21.3. Characterization data of P12: 1 H NMR(400 MHz, Chloroform- d ) δ 7.67 – 7.60 (m, 2H), 7.48– 7.43 (m, 2H), 7.42 – 7.38 (m, 2H), 7.36 (ddd, J = 7.8, 7.1, 1.9 Hz, 1H), 7.30– 7.26 (m, 1H), 7.24 (dd, J = 7.2, 1.3 Hz, 1H), 7.20 (dd, J = 7.8, 1.3 Hz, 1H),7.15 – 7.11 (m, 2H), 6.80 – 6.75 (m, 1H), 6.29 (d, J = 10.0 Hz, 1H), 5.92 (dd, J = 10.0, 0.9 Hz, 1H), 5.53 (d, J = 12.7 Hz, 1H), 5.39 (dd, J = 13.2, 4.8 Hz, 1H),2.96 (dd, J = 15.7, 13.1 Hz, 1H), 2.83 (ddd, J = 15.7, 4.8, 1.0 Hz, 1H), 2.38 (s,3H), 2.21 (d, J = 12.7 Hz, 1H). 13 C NMR(101 MHz, Chloroform- d) δ 195.9, 150.5, 149.3, 145.0, 139.3, 138.1, 134.8, 134.1, 130.5, 129.9, 129.7, 128.8, 128.0, 127.8, 127.0, 126.8, 126.3, 121.8, 61.4, 56.1, 52.4, 39.2, 21.8. P13 characterization data: = +221.1 (0.2, CHCl3); HPLC analysis of the product: Daicel Chiralcel OD-H column; 20% i -PrOH in hexanes; 1.0 mL / min; λ = 254 nm; retention times: 12.9 min (major), 19.0 min (minor). 1 1H NMR(400 MHz, Chloroform- d ) δ 7.60 (d, J = 9.0 Hz, 2H), 7.57 (d, J = 9.1 Hz, 2H), 7.41 – 7.34 (m, 3H), 7.29 – 7.26 (m, 1H), 7.26 – 7.19 (m, 2H), 7.16 – 7.11 (m, 2H), 6.80 (d, J = 1.1 Hz, 1H), 6.28 (d, J = 10.0 Hz, 1H), 5.92 (dd, J = 10.0, 0.9 Hz, 1H), 5.51 (d, J = 12.7 Hz, 1H), 5.38 (dd, J = 13.1, 4.8 Hz, 1H), 2.96 (dd, J = 15.7, 13.1 Hz, 1H), 2.84 (ddd, J = 15.7, 4.8, 1.0 Hz, 1H), 2.39 (s, 3H), 2.18 (d, J = 12.8 Hz, 1H). 13 13C NMR(101 MHz, Chloroform- d) δ 195.9, 150.4, 149.3, 145.0, 139.3, 138.7, 134.1, 132.7, 130.5, 129.9, 129.2, 128.0, 127.7, 127.0, 126.8, 126.3, 123.0, 121.7, 61.5, 56.1, 52.4, 39.2, 21.8. HRMS(ESI) m / z calculated for C 27 H 24 BrN4O3S [M+H] + : 563.0747, found 563.0745, 565.0723. Characterization data of P14: = +274.1 (0.2, CHCl3); HPLC analysis of the product: Daicel Chiralpak AD-H column; 20% i -PrOH in hexanes; 1.0 mL / min; λ = 254 nm; retention times: 32.2 min (major), 44.3 min (minor). 1 1H NMR(400 MHz, Chloroform- d ) δ 7.76 (d, J = 8.7 Hz, 2H), 7.72 (d, J = 8.7 Hz, 2H), 7.70 – 7.66 (m, 2H), 7.54 – 7.48 (m, 2H), 7.44 – 7.38 (m, 1H), 7.36 (td, J = 4.7, 1.9 Hz, 2H), 7.32 (dd, J = 7.6, 1.7 Hz, 1H), 7.27 – 7.21 (m, 3H), 7.04 – 6.99 (m, 2H), 6.91 (d, J = 1.1 Hz, 1H), 6.36 (d, J = 10.0 Hz, 1H), 5.93 (dd, J = 9.9, 0.8 Hz, 1H), 5.53 – 5.49 (m, 1H), 5.47 (d, J = 4.7 Hz, 1H), 3.01 (dd,J = 15.6, 13.1 Hz, 1H), 2.89 (ddd, J = 15.6, 4.8, 1.0 Hz, 1H), 2.30 (s, 3H), 2.20 (d, J = 12.7 Hz, 1H). 13 C NMR(101 MHz, Chloroform- d ) δ 196.2, 150.9, 149.6, 144.7, 141.5, 140.1, 139.3, 138.4, 134.2, 130.5, 129.8, 129.1, 128.1, 128.0, 128.0, 127.8, 127.8, 127.2, 126.7, 126.2 (2C), 122.0, 61.6, 56.2, 52.7, 39.4, 21.7. HRMS(ESI) m / z calculated for C 33 H 29 N4O3S [M+H] + : 561.1955, found 561.1953. Characterization data of P15: = +164.2 (0.2, CHCl3); HPLC analysis of the product: Daicel Chiralpak AD-H column; 20% i-PrOH in hexanes; 1.0 mL / min; λ = 254 nm; retention times: 15.9 min (major), 25.0 min (minor). 1 H NMR(400 MHz, Chloroform- d ) δ 7.52 – 7.45 (m, 2H), 7.41 – 7.37 (m, 1H), 7.37 – 7.33 (m, 1H), 7.31 (dd, J = 8.7, 2.3 Hz, 2H), 7.28 – 7.24 (m, 2H), 7.24 – 7.19 (m, 2H), 7.08 – 7.03 (m, 2H), 6.85 (d, J = 1.0 Hz, 1H), 6.32 (d, J = 10.0 Hz, 1H), 5.90(dd, J= 10.0, 0.9 Hz, 1H), 5.48 – 5.46 (m, 1H), 5.45 – 5.43 (m, 1H), 2.98 (dd, J = 15.7, 13.2 Hz, 1H), 2.88 – 2.80 (m, 1H), 2.44 (s, 3H), 2.35 (s, 3H), 2.17(d, J = 12.5 Hz, 1H). 13 C NMR(101 MHz, Chloroform- d ) δ 196.3, 151.2, 149.5,144.6, 139.4, 139.33, 139. (原文此处有误,推测为139.26), 134.1, 130.4, 129.8, 129.5, 129.3, 128.1,128.0, 127.7, 126.7, 126.6, 126.2, 124.5, 122.1, 61.6, 56., (原文此处有误,推测为56.2), 52.8, 39.4,21.9, 21.7.HRMS(ESI) m / z calculated for C 28 H 27 N4O3S [M+H] + : 499.1798, found499.1795. Characterization data of P16: = +203.3 (0.2, CHCl3); HPLC analysis of the product:Daicel Chiralpak AD-H column; 20% i-PrOH in hexanes; 1.0 mL / min; λ = 254 nm;retention times: 24.1 min (major), 33.2 min (minor). 1 H NMR (400 MHz,Chloroform- d ) δ 7.43 (t, J = 8.2 Hz, 1H), 7.38 – 7.32 (m, 3H), 7.24 (d, J = 2.0Hz, 2H), 7.24 – 7.18 (m, 2H), 7.09 – 7.05 (m, 2H), 6.99 – 6.94 (m, 1H), 6.85(d, J = 1.1 Hz, 1H), 6.33 (d,J = 10.0 Hz, 1H), 5.90 (dd, J = 10.0, 0.8 Hz, 1H),5.49 – 5.45 (m, 1H), 5.45 – 5.41 (m, 1H), 3.87 (s, 3H), 2.97 (dd, J = 15.7,13.2 Hz, 1H), 2.84 (ddd, J = 15.6, 4.8, 1.0 Hz, 1H), 2.36 (s, 3H), 2.18 (d, J =12.7 Hz, 1H). 13 C NMR(101 MHz, Chloroform- d ) δ 196.2, 160.6, 151.0, 149.5,144.7, 141.2, 139.3, 134.0, 130.6, 130.4, 129.8, 128.1, 127.7, 126.73,126.67, 126.2, 122.0, 119.8, 114.1, 112.9, 61.6, 56.3, 55.4, 52.6, 39.3,21.7.HRMS(ESI) m / z calculated for C 28 H 27 N4O4S[M+H] + : 515.1748, found 515.1743. Characterization data of P17: = +170.8 (0.2, CHCl3); HPLC analysis of the product: Daicel Chiralpak AD-H column; 20% i-PrOH in hexanes; 1.0 mL / min; λ = 254 nm; retention times: 16.9 min (major), 27.4 min (minor). 1 H NMR(400 MHz,Chloroform- d ) δ 7.54 – 7.44 (m, 3H), 7.43 – 7.38 (m, 2H), 7.36 (td, J = 7.5,1.8 Hz, 1H), 7.32 – 7.27 (m, 1H), 7.22 (ddd, J= 15.3, 7.7, 1.3 Hz, 2H), 7.17 –7.10 (m, 3H), 6.76 (d, J = 1.1 Hz, 1H), 6.31 (d, J = 10.0 Hz, 1H), 5.93 (dd, J =9.9, 0.9 Hz, 1H), 5.53 (d, J = 12.6 Hz, 1H), 5.41 (dd, J = 13.1, 4.8 Hz, 1H),2.97 (dd, J = 15.7, 13.2 Hz, 1H), 2.84 (ddd, J = 15.7, 4.8, 1.0 Hz, 1H), 2.37 (s,3H), 2.22 (d, J = 12.7 Hz, 1H). 13 C NMR(101 MHz, Chloroform- d ) δ 195.9, 163.8 (d, J CF = 248.4 Hz), 150.3, 149.2, 145.1, 142.5 (d, J CF = 6.6 Hz), 139.2, 133.9,131.2 (d, J CF = 8.2 Hz), 130.5, 129.9, 128.1, 127.8, 127.1, 126.8, 126.2, 123.4(d, J CF = 2.76 Hz), 121.8, 115.7 (d, J CF = 21.2 Hz), 114.5 (d, J CF = 21.2 Hz), 61.5,56.2, 52.3, 39.2, 21.7. 19 F NMR(376 MHz, Chloroform- d ) δ -110.3 – -110.5 (m).HRMS(ESI) m / z calculated for C 27 H 24 FN4O3S [M+H] +: 503.1548, found 503.1547. Example 18 Referring to Example 1, the 4-aminocyclohexadienone compound was replaced with N18, and the reaction time was finely adjusted (-10). o (C reaction for 42 hours), with everything else unchanged, yielded the corresponding product P18 (80%, 97% ee, 13:1 dr).

[0046]

[0047] P18 characterization data: = +252.5 (0.2, CHCl3); HPLC analysis of the product:Daicel Chiralpak AD-H column; 20% i-PrOH in hexanes; 1.0 mL / min; λ = 254nm; retention times: 29.5 min (major), 39.1 min (minor). 1 H NMR (400 MHz, Chloroform- d ) δ 8.06 (d, J = 2.0 Hz, 1H), 7.98 – 7.91 (m, 2H), 7.86 – 7.83 (m,1H), 7.70 (d, J = 2.0 Hz, 1H), 7.62 – 7.57 (m, 2H), 7.39 (d, J = 1.7 Hz, 1H),7.36 – 7.29 (m, 2H), 7.27 (s, 1H), 7.11 (d, J = 8.3 Hz, 2H), 7.05 (d, J = 1.1 Hz, 1H), 6.56 (d, J = 8.0 Hz, 2H), 6.36 (d, J = 10.0 Hz, 1H), 5.95 (dd, J = 10.0, 0.9Hz, 1H), 5.57 (dd, J = 13.1, 4.9 Hz, 1H), 5.44 (d, J = 12.5 Hz, 1H), 3.04 (dd, J=15.7, 13.1 Hz, 1H), 2.97 – 2.90 (m, 1H), 2.24 (d, J = 12.5 Hz, 1H), 2.11 (s, 3H). 13 C NMR (101 MHz, Chloroform- d ) δ 196.2, 150.6, 149.8, 144.4, 139.4, 136.9,134.1, 133.7, 133.2, 130.5, 129.5, 129.4, 128.5, 127.8, 127.7, 127.5, 127.10,126.98, 127.0, 126.9, 126.8, 126.3, 124.4, 121.9, 61.6, 56.3, 53.3, 39.5,21.5.HRMS(ESI) m / z calculated for C 31 H 27 N4O3S [M+H] + : 535.1798, found 535.1794. Examples 19-22 Referring to Example 1, the 4-aminocyclohexadienone compounds were replaced with N19-N22, and the reaction temperature and time were slightly adjusted while other factors remained unchanged, to obtain the corresponding products P19-22.

[0048]

[0049] P19 characterization data: = +60.8 (0.2, CHCl3); HPLC analysis of the product:Daicel Chiralpak AD-H column; 20% i-PrOH in hexanes; 1.0 mL / min; λ = 254 nm; retention times: 21.5 min (major), 24.3 min (minor). 1 H NMR (400 MHz, Chloroform- d ) δ 7.74 (dd, J = 1.6, 0.9 Hz, 1H), 7.62 – 7.58 (m, 2H), 7.55 (t, J =1.7 Hz, 1H), 7.33 (ddd, J= 7.8, 7.0, 2.0 Hz, 1H), 7.25 – 7.19 (m, 3H), 7.17(ddd, J = 7.7, 6.0, 1.6 Hz, 2H), 6.63 (dd, J = 1.9, 0.9 Hz, 1H), 6.58 (d, J = 1.1Hz, 1H), 6.51 (d, J = 10.0 Hz, 1H), 5.93 (dd, J = 10.0, 0.9 Hz, 1H), 5.64 (d, J =12.2 Hz, 1H), 5.08 (dd, J = 13.2, 4.8 Hz, 1H), 2.89 (dd, J = 15.8, 13.2 Hz, 1H),2.77 (ddd, J = 15.7, 4.8, 1.1 Hz, 1H), 2.40 (s, 3H), 2.14 (d, J = 12.7 Hz, 1H). 13 CNMR(101 MHz, Chloroform- d ) δ 196.0, 150.8, 148.9, 145.2, 144.4, 142.1, 139.2,134.2, 130.3, 130.0, 128.3, 127.9, 127.0, 126.8, 126.2, 126.1, 122.0, 109.4,61.8, 52.7, 52.5, 38.8, 21.8.HRMS(ESI) m / z calculated for C 25 ; H 23 N4O4S [M+H] + :475.1435, found 475.1433. Characterization data of P20: = +23.1 (0.2, CHCl3); HPLC analysis of the product:Daicel Chiralpak AD-H column; 20% i-PrOH in hexanes; 1.0 mL / min; λ = 254 nm;retention times: 12.3 min (major), 21.0 min (minor).1 H NMR(400 MHz,Chloroform- d ) δ 8.11 (d, J = 7.6 Hz, 1H), 8.05 (s, 1H), 7.60 (d, J = 8.0 Hz, 1H),7.55 (d, J = 8.0 Hz, 2H), 7.45 – 7.40 (m, 1H), 7.38 (t, J = 7.2 Hz, 1H), 7.33(td, J = 7.6, 1.5 Hz, 1H), 7.21 (dd, J = 7.8, 5.3 Hz, 3H), 7.17 (d, J = 7.9 Hz,1H), 7.13 – 7.10 (m, 1H), 6.79 (d, J = 10.0 Hz, 1H), 6.57 (s, 1H), 5.99 (d, J =10.0 Hz, 1H), 5.50 (d, J = 12.8 Hz, 1H), 5.31 (dd, J = 13.2, 4.8 Hz, 1H), 2.98(dd, J = 15.8, 13.2 Hz, 1H), 2.84 (dd, J = 15.8, 4.7 Hz, 1H), 2.38 (s, 3H), 2.27(d, J = 12.9 Hz, 1H). 13 C NMR(101 MHz, Chloroform- d ) δ 195.8, 156.4, 149.3,148.9, 145.3, 145.1, 139.2, 134.3, 130.3, 130.1, 128.2, 128.2, 127.4, 126.9,126.0, 125.4, 125.3, 123.2, 122.1, 121.9, 119.2, 112.4, 62.6, 53.7, 51.8,38.7, 21.8.HRMS(ESI) m / z calculated for C 29 H 25 N4O4S [M+H] +: 525.1591, found 525.1591. P21 characterization data: = +137.0 (0.2, CHCl3); HPLC analysis of the product: Daicel Chiralpak AD-H column; 30% i-PrOH in hexanes; 1.0 mL / min; λ = 254 nm; retention times: 18.3 min (major), 27.2 min (minor). 1 1H NMR (400 MHz, Chloroform- d ) δ 7.54 – 7.48 (m, 2H), 7.40 – 7.29 (m, 3H), 7.25 – 7.20 (m, 2H), 7.17 – 7.12 (m, 2H), 7.07 (d, J J = 5.4 Hz, 1H), 6.86 (d, J J = 1.1 Hz, 1H), 6.28 (d, J J = 10.0 Hz, 1H), 6.12 – 6.06 (m, 2H), 6.06 – 6.05 (m, 1H), 2.90 (dd, J J = 15.5, 12.6 Hz, 1H), 2.84 (ddd, J J = 15.4, 5.6, 0.9 Hz, 1H), 2.38 (s, 3H), 2.28 (d, J J = 12.5 Hz, 1H). 13 13C NMR (101 MHz, Chloroform- d ) δ 195.8, 149.0, 146.4, 144.8, 139.2, 138.3, 134.2, 133.1, 130.6, 130.0, 128.4, 127.9, 127.8, 126.9, 126.6, 126.3, 121.4, 109.4, 61.4, 55.4, 50.7, 39.5, 21.8. HRMS(ESI) m / z calculated for C 25 21 22 11BrN4O3S2 [M+H] + : 569.0311, found 569.0299, 571.0276. P22 characterization data: = +290.3 (0.2, CHCl3); HPLC analysis of the product: Daicel Chiralcel OD-H column; 30% i -PrOH in hexanes; 1.0 mL / min; λ = 254 nm; retention times: 8.2 min (major), 16.7 min (minor). 1 1H NMR(400 MHz, Chloroform- d ) δ 7.94 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 7.9 Hz, 1H), 7.61 – 7.54 (m, 1H), 7.53 – 7.47 (m, 1H), 7.43 – 7.36 (m, 2H), 7.29 (dd, J = 7.6, 2.4 Hz, 3H), 7.24 (d, J = 7.8 Hz, 1H), 6.47 (d, J = 7.9 Hz, 2H), 6.31 – 6.19 (m, 2H), 6.10 (d, J = 9.9 Hz, 1H), 5.89 (d, J = 11.9 Hz, 1H), 3.03 – 2.95 (m, 1H), 2.94 (d, J = 3.2 Hz, 1H), 2.38 (d, J = 12.7 Hz, 1H), 2.09 (s, 3H). 13 13C NMR(101 MHz, Chloroform- d ) δ 195.7, 149.6, 145.2, 144.4, 140.6, 139.7, 139.2, 137.6, 134.5, 130.8, 129.5, 128.5, 127.8, 127.2, 126.9, 126.4, 126.3, 125.7, 123.5, 122.1, 121.2, 107.1, 61.9, 55.6, 51.5, 39.6, 21.6. HRMS(ESI) m / z calculated for C 29H 24 BrN4O3S2[M+H] + : 619.0468, found 619.0458, 621.0435. Example 23 Referring to Example 1, the 4-aminocyclohexadienone compound was replaced with N23 instead of N1, and the reaction time was finely adjusted (-10). o (C reaction for 27 hours), with other parameters unchanged, yielded the corresponding product P23 (yield 40%, 72% ee).

[0050]

[0051] P23 characterization data: = +140.7 (0.2, CHCl3); HPLC analysis of the product:Daicel Chiralpak AD-H column; 15% i-PrOH in hexanes; 1.0 mL / min; λ = 254 nm; retention times: 23.8 min (minor), 25.9 min (major). 1 H NMR (400 MHz, Chloroform- d ) δ 7.93 (dd, J = 7.9, 1.5 Hz, 1H), 7.84 – 7.76 (m, 2H), 7.67 (d, J =7.9 Hz, 1H), 7.63 – 7.54 (m, 1H), 7.42 – 7.31 (m, 3H), 7.29 – 7.26 (m, 1H),7.24 (q, J = 1.6 Hz, 1H), 7.16 (td, J = 7.4, 1.3 Hz, 1H), 7.08 – 7.03 (m, 1H), 6.34 (s, 1H), 6.00 (d, J = 10.3 Hz, 1H), 4.82 (dd, J = 13.5, 4.1 Hz, 1H), 3.06(dd, J = 15.2, 13.5 Hz, 1H), 2.82 (dd, J = 15.2, 4.1 Hz, 1H), 2.45 (s, 3H), 2.11(d, J= 12.3 Hz, 1H), 2.00 (s, 3H). 13 C NMR (101 MHz, Chloroform- d ) δ 194.9,148.8, 145.9, 145.4, 139.1, 135.0, 134.7, 130.34, 130.29, 130.0, 128.7,128.6, 128.4, 128.2, 126.6, 126.4, 125.8, 122.6, 62.7, 52.5, 39.7, 29.8,25.2, 21.8.HRMS(ESI) m / z calculated for C 26 H 25 N4O3S [M+H] + : 473.1642, found 473.1640. Example 24 Referring to Example 1, the 4-aminocyclohexadienone compound was replaced with N24 instead of N1, and the reaction time was finely adjusted (-10). o (C reacted for 25 hours), with everything else remaining unchanged, to obtain the corresponding product P24 (yield 47%, 91% ee).

[0052]

[0053] P24 characterization data: = -120.1 (0.2, CHCl3); HPLC analysis of the product:Daicel Chiralcel OD-H column; 20% i -PrOH in hexanes; 1.0 mL / min; λ = 254 nm; retention times: 12.9 min (minor), 16.5 min (major). 1 H NMR (400 MHz, Chloroform- d ) δ 7.79 – 7.73 (m, 2H), 7.35 – 7.27 (m, 3H), 7.23 – 7.16 (m,2H), 7.13 – 7.09 (m, 1H), 6.32 (d, J = 1.1 Hz, 1H), 5.86 (d, J = 9.9 Hz, 2H), 4.61 (dd, J= 13.6, 4.8 Hz, 1H), 2.71 (dd, J = 15.7, 13.6 Hz, 1H), 2.55 (dd, J =15.7, 4.8 Hz, 1H), 2.43 (s, 3H), 2.02 (d, J = 1.3 Hz, 3H), 1.87 (d, J = 12.7 Hz, 1H), 1.78 (s, 3H). 13 C NMR (101 MHz, Chloroform- d ) δ 195.3, 162.3, 148.7, 145.4,139.2, 134.6, 130.3, 130.1, 128.32, 128.28, 127.6, 126.6, 125.9, 122.3, 62.3,55.0, 52.7, 38.3, 21.8, 21.5, 19.3.HRMS(ESI) m / z calculated for C 23 H 25 N4O3S [M+H] + : 437.1642, found 437.1640. Example 25 The reaction formula for preparing 1,2,4-triazine compounds in this embodiment is as follows:

[0054] The preparation method is as follows: Under air conditions, N1 (0.1 mmol, 12.3 mg) and S2 (0.12 mmol, 38.0 mg) were dissolved in DCE (2.0 mL), and a chiral phosphoric acid catalyst was added. R )-A2 (0.01 mmol, 9.93 mg), -10 o The reaction was completed after 48 hours. The reaction solution was concentrated directly under reduced pressure, and the crude product was separated by silica gel column chromatography, eluted with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 2:1), to give product P25 (40.5 mg, 92%, 99% ee), which was a yellow solid.

[0055] Characterization data: = -96.6 (0.2, CHCl3); HPLC analysis of the product:Daicel Chiralpak IA column; 20% i-PrOH in hexanes; 1.0 mL / min; λ = 254 nm;retention times: 16.3 min (major), 25.3 min (minor). 1 H NMR(400 MHz,Chloroform- d ) δ 7.79 – 7.73 (m, 2H), 7.34 (d, J = 8.1 Hz, 2H), 7.09 (dd, J = 8.7,5.2 Hz, 1H), 7.00 (td, J = 8.4, 2.9 Hz, 1H), 6.93 (dd, J = 8.4, 2.9 Hz, 1H), 6.60(d, J = 10.1 Hz, 1H), 6.30 (d, J = 1.0 Hz, 1H), 6.00 (dd, J = 10.1, 0.9 Hz, 1H),5.89 (d, J = 12.6 Hz, 1H), 4.62 (dd, J = 13.2, 4.9 Hz, 1H), 2.71 (dd, J = 15.9,13.2 Hz, 1H), 2.59 (ddd, J = 15.8, 4.9, 1.0 Hz, 1H), 2.44 (s, 3H), 1.88 (d, J =12.8 Hz, 1H), 1.75 (s, 3H). 13 C NMR(101 MHz, Chloroform- d ) δ 196.2, 160.8 (d, J CF = 248.1 Hz), 151.6, 147.9, 145.6, 135.7, 134.4, 130.3, 128.8, 128.4, 127.8(d, J CF = 8.3 Hz), 123.8 (d, JCF = 7.9 Hz), 117.3 (d, J CF = 22.4 Hz), 114.6 (d, J CF =23.9 Hz), 61.7, 53.9, 50.1, 38.5, 23.8, 21.8. 19 F NMR (376 MHz, Chloroform- d ) δ-114.2 (q, J = 8.1 Hz).HRMS(ESI) m / z calculated for C 22 H 22 FN4O3S [M+H] + :441.1391, found 441.1390. Example 26 The reaction formula for preparing 1,2,4-triazine compounds in this embodiment is as follows:

[0056] The preparation method is as follows: Under air conditions, N1 (0.1 mmol, 12.3 mg) and S3 (0.12 mmol, 39.5 mg) were dissolved in DCE (2.0 mL), and a chiral phosphoric acid catalyst was added. R )-A2 (0.01 mmol, 9.93 mg), -10 o The reaction was completed after 60 hours. The reaction solution was concentrated directly under reduced pressure, and the crude product was separated by silica gel column chromatography, eluted with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 2:1), to give product P26 (38.5 mg, 85%, 91% ee), which was a yellow solid.

[0057] Characterization data: = -108.3 (0.2, CHCl3); HPLC analysis of the product:Daicel Chiralcel OD-H column; 10% i -PrOH in hexanes; 1.0 mL / min; λ = 254 nm; retention times: 35.1 min (major), 42.2 min (minor). 1 H NMR (400 MHz, Chloroform- d) δ 7.79 – 7.73 (m, 2H), 7.36 – 7.29 (m, 2H), 7.12 (d, J = 8.5 Hz, 1H), 6.75 (dd, J = 8.5, 2.6 Hz, 1H), 6.65 (d, J = 2.6 Hz, 1H), 6.60 (d, J = 10.1Hz, 1H), 6.34 (d, J = 1.1 Hz, 1H), 5.98 (dd, J = 10.1, 1.0 Hz, 1H), 5.86 (d, J =9.0 Hz, 1H), 4.62 (dd, J = 13.3, 4.8 Hz, 1H), 3.78 (s, 3H), 2.71 (dd, J = 15.8,13.4 Hz, 1H), 2.58 (ddd, J = 15.8, 4.9, 1.1 Hz, 1H), 2.44 (s, 3H), 1.83 (d, J =12.5 Hz, 1H), 1.75 (s, 3H). 13 C NMR (101 MHz, Chloroform- d ) δ 196.3, 161.0,151.8, 149.0, 145.5, 140.5, 134.4, 130.3, 129.0, 128.6, 128.4, 114.4, 113.6,109.9, 61.7, 55.6, 54.0, 50.0, 38.5, 23.9, 21.8.HRMS(ESI) m / z calculated forC 23 H 25 N4O4S [M+H] + : 453.1591, found 453.1590. Example 27 The reaction formula for preparing 1,2,4-triazine compounds in this embodiment is as follows:

[0058] The preparation method is as follows: Under air conditions, N1 (0.1 mmol, 12.3 mg) and S4 (0.12 mmol, 34.2 mg) were dissolved in DCE (2.0 mL), and a chiral phosphoric acid catalyst was added. R )-A2 (0.01 mmol, 9.93 mg), -20 o The reaction was completed after 48 hours. The reaction solution was concentrated directly under reduced pressure, and the crude product was separated by silica gel column chromatography, eluted with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 1:1), to give product P27 (35.2 mg, 86%, 88% ee), which was a white solid.

[0059] Characterization data: = -131.9 (0.2, CHCl3); HPLC analysis of the product:Daicel Chiralpak AD-H column; 15% i-PrOH in hexanes; 1.0 mL / min; λ = 254 nm; retention times: 21.9 min (minor), 26.0 min (major). 1 H NMR (400 MHz, Chloroform- d ) δ 7.92 – 7.86 (m, 2H), 7.70 – 7.62 (m, 1H), 7.55 (dd, J = 8.4, 7.1 Hz, 2H), 7.31 (ddd, J = 7.8, 6.5, 2.4 Hz, 1H), 7.24 – 7.17 (m, 2H), 7.14 –7.10 (m, 1H), 6.60 (d, J = 10.1 Hz, 1H), 6.35 (s, 1H), 5.99 (dd, J = 10.1, 0.9Hz, 1H), 5.91 (s, 1H), 4.63 (dd, J = 13.4, 4.8 Hz, 1H), 2.74 (dd, J = 15.8, 13.4Hz, 1H), 2.59 (ddd, J = 15.8, 4.8, 1.0 Hz, 1H), 1.92 (s, 1H), 1.77 (s, 3H). 13 CNMR (101 MHz, Chloroform-d ) δ 196.2, 151.7, 148.5, 139.2, 137.5, 134.3, 130.2,129.7, 128.7, 128.3, 128.2, 126.8, 126.0, 122.2, 61.9, 54.0, 50.1, 38.4,23.8.HRMS(ESI) m / z calculated for C 21 H 21 N4O3S [M+H] + : 409.1329, found 409.1328. Example 28 The reaction formula for preparing 1,2,4-triazine compounds in this embodiment is as follows:

[0060] The preparation method is as follows: Under air conditions, N1 (0.1 mmol, 12.3 mg) and S5 (0.12 mmol, 37.8 mg) were dissolved in DCE (2.0 mL), and a chiral phosphoric acid catalyst was added. R )-A2 (0.01 mmol, 9.93 mg), -20 o The reaction was completed after 48 hours. The reaction solution was concentrated directly under reduced pressure, and the crude product was separated by silica gel column chromatography, eluted with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 1:1), to give product P28 (41.3 mg, 94%, 96% ee), which was a white solid.

[0061] Characterization data: = -82.5 (0.2, CHCl3); HPLC analysis of the product:Daicel Chiralcel OD-H column; 20% i -PrOH in hexanes; 1.0 mL / min; λ = 254 nm; retention times: 15.9 min (major), 18.9 min (minor). 1 H NMR (400 MHz, Chloroform- d ) δ 7.83 – 7.77 (m, 2H), 7.30 (ddd, J = 7.9, 6.8, 2.1 Hz, 1H), 7.24– 7.16 (m, 2H), 7.12 (dd, J= 7.9, 1.2 Hz, 1H), 7.01 – 6.95 (m, 2H), 6.60 (d, J =10.1 Hz, 1H), 6.36 (d, J = 1.1 Hz, 1H), 5.98 (dd, J = 10.1, 0.9 Hz, 1H), 5.93 (d, J = 12.3 Hz, 1H), 4.62 (dd, J = 13.4, 4.8 Hz, 1H), 3.87 (s, 3H), 2.72 (dd, J =15.9, 13.3 Hz, 1H), 2.58 (ddd, J = 15.8, 4.8, 1.0 Hz, 1H), 1.90 (d, J = 12.6 Hz, 1H), 1.77 (s, 3H). 13 C NMR (101 MHz, Chloroform- d ) δ 196.3, 164.2, 151.8, 148.7,139.3, 130.7, 130.2, 128.6, 128.5, 128.2, 126.7, 125.9, 122.2, 114.8, 61.8,55.9, 54.0, 50.0, 38.5, 23.9.HRMS(ESI) m / z calculated for C 22 H 23 N4O4S [M+H] + :439.1435, found 439.1433. Example 29 The reaction formula for preparing 1,2,4-triazine compounds in this embodiment is as follows:

[0062] The preparation method is as follows: Under air conditions, N1 (0.1 mmol, 12.3 mg) and S6 (0.12 mmol, 39.2 mg) were dissolved in DCE (2.0 mL), and a chiral phosphoric acid catalyst was added. R )-A2 (0.01 mmol, 9.93 mg), -20 oThe reaction was completed after 48 hours. The reaction solution was concentrated directly under reduced pressure, and the crude product was separated by silica gel column chromatography, eluted with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 1:1), to give product P29 (39.2 mg, 87%, 99% ee), which was a yellow solid.

[0063] Characterization data: = -16.3 (0.2, CHCl3); HPLC analysis of the product:Daicel Chiralcel OD-H column; 10% i -PrOH in hexanes; 1.0 mL / min; λ = 254 nm; retention times: 12.7 min (major), 15.4 min (minor). 1 H NMR (400 MHz, Chloroform-d) δ 7.30 (td, J = 7.5, 1.7 Hz, 1H), 7.25 (d, J = 5.9 Hz, 1H), 7.19 (td, J = 7.4, 1.3 Hz, 1H), 7.10 (dd, J = 7.9, 1.3 Hz, 1H), 6.96 (s, 1H), 6.63 (d, J = 10.1 Hz, 1H), 6.18 (d, J = 1.0 Hz, 1H), 6.14 (d, J = 12.5 Hz, 1H), 6.00 (dd, J = 10.1, 0.8 Hz, 1H), 4.60 (dd, J = 13.0, 5.2 Hz, 1H), 2.73(dd, J = 16.0, 13.1 Hz, 1H), 2.68 – 2.61 (m, 1H), 2.53 (s, 6H), 2.30 (s, 3H), 1.91 (d, J = 12.9 Hz, 1H), 1.87 (s, 3H). 13 C NMR (101 MHz, Chloroform- d ) δ196.4, 152.2, 148.2, 144.4, 139.1, 132.5, 130.4, 130.2, 128.5, 128.2 (2C),126.7, 126.0, 121.8, 61.6, 53.6, 50.0, 38.0, 24.0 (2C), 21.2.HRMS(ESI) m / zcalculated for C24 H 27 N4O3S [M+H] + : 451.1798, found 451.1796. Example 30: Scale-up reaction Referring to Implementation Case 1, the preparation method is as follows: Under air conditions, N1 (3.0 mmol, 36.9 mg) and S1 (3.6 mmol, 1.08 g) are dissolved in DCE (60.0 mL), and a chiral phosphoric acid catalyst is added ( R )-A2 (0.3 mmol, 297.9 mg), -10 o The reaction was completed after 48 hours. The reaction solution was concentrated directly under reduced pressure, and the crude product was separated by silica gel column chromatography, eluted with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 1:1) to give product P1 (1.02 g, 80%, 91% ee), which was a white solid.

[0064] Stereomorphic characterization of the above products: Figure 1 The single-crystal structure diagram of product P29 and the corresponding X-ray single-crystal diffraction data are shown below:

[0065] Correspondingly, the other products P1 to P28 also have the same configuration.

[0066] Example 31: Investigation and Comparison of Catalysts Referring to Example 1, the catalyst shown in Table 1 was added, and the reaction solvent was replaced with DCM, while other aspects remained unchanged. The results of the corresponding reaction are shown in Table 1.

[0067] Table 1. Effect of catalyst on the preparation of 1,2,4-triazine derivatives

[0068] Correspondingly, the other products P1-P29 also have the same conditions.

[0069] Example 32: Investigation and Comparison of Solvents Referring to Example 1, the reaction solvent was replaced with other solvents shown in Table 2, while other aspects remained unchanged. The results of the corresponding reactions are shown in Table 2.

[0070] Table 2 Effect of solvent on the preparation of 1,2,4-triazine derivatives

[0071] Correspondingly, the other products P1-P29 also have the same conditions.

[0072] Example 33: Investigation and Comparison of Temperature Referring to Example 1, only the temperature was replaced with the other temperatures shown in Table 3, while everything else remained the same. The results of the corresponding reactions are shown in Table 3.

[0073] Table 3 Effect of temperature on the preparation of 1,2,4-triazine derivatives

[0074] Correspondingly, the other products P1-P29 also have the same conditions.

[0075] Example 34: Anti-liver fibrosis activity test of the compounds of the present invention To assess the potential liver fibrosis efficacy of these synthetic compounds, a human fibroblast LX-2 model treated with TGF-β1 was used, with the anti-liver fibrosis drug pirfenidone (PFD, 500 µM) as a positive control.

[0076] LX-2 cells were induced with 10 ng / mL TGF-β1 for 48 hours and then fixed. Cells were subsequently permeabilized, blocked, and stained with a 1:100 ratio of fibronectin antibody at 4 °C for 8 hours, followed by incubation with Alexa 647-labeled antibody and 2 μg / mL DAPI (for staining cell nuclei). Emissions of fibronectin and DAPI were collected sequentially at excitation wavelengths of 640 nm and 405 nm. Intracellular fluorescence signals were measured using an Image Xpress Micro confocal microscopy system. The average fibronectin intensity was obtained from approximately 5000 cells per sample.

[0077] The ability of seven compounds (P1, P4, P5, P9, P10, P19, and P25) in this invention to inhibit fibronectin (FN) expression was determined, and the results are as follows: Figure 1 As shown in Table 4: Table 4 Screening of FN Inhibitors

[0078] Note: The initial FN inhibition rate of the compound was determined at a concentration of 10 μM. The effect of a 10 μM concentration on FN expression was also shown. PFD (500 µM) was used as a positive control; it was a pirfenidone, an anti-hepatic fibrosis drug. Experimental results ( Figure 1 As shown in Table 4, most compounds effectively inhibited FN expression, with compound P4 showing the most significant inhibitory effect on fibronectin expression at a concentration of 10 µM, indicating that this compound has good liver fibrosis activity.

[0079] Compound P4 was selected to further investigate its anti-liver fibrosis effect. The experimental results (Table 5) showed that P4 significantly inhibited the expression of FN in a dose-dependent manner.

[0080] Table 5 shows the P4 dose-inhibition effect on FN levels.

[0081] In summary, the compounds provided by this invention show broad application prospects in the development of anti-liver fibrosis drugs.

[0082] The embodiments provided above are not intended to limit the scope of the invention, nor are the described steps intended to limit the order of execution. Any obvious modifications made to the invention by those skilled in the art based on existing common knowledge also fall within the scope of protection defined by the claims.

Claims

1. A method for the enantioselective synthesis of 1,2,4-triazine compounds, characterized in that, The process includes the following: In the formula, R is selected from: C1-C6 straight-chain or branched alkyl groups, C3-C6 cycloalkyl groups, R a Substituted alkynyl group, substituted or unsubstituted aryl group, substituted or unsubstituted aromatic heterocyclic group; the substitution on the aryl or aromatic heterocyclic group includes any one of mono- or tri-substituted, and the substituent is selected from H, halogen, C1-C8 straight-chain or branched alkyl group; R a It can be C3-C6 cycloalkyl, aryl, aromatic heterocyclic and silyl ether groups; a, b, and c represent R... 1 R 2 R 3 The number of substitutions, a is selected from 1-2, b is selected from 1-4, and c is selected from 1-5; R 1 Selected from: H, C1-C6 straight-chain or branched alkyl groups, -CH=CH-CH=CH-; R 2 Selected from: H, halogens, C1-C6 alkoxy groups; R 3 Selected from: H, C1-C6 straight-chain or branched alkyl groups, C1-C6 alkoxy groups; In an organic solvent, using 4-aminocyclohexadienone compounds of formula (I) and azomethine imine compounds of formula (II) as substrates, a chiral phosphoric acid catalyst is used to react and yield 1,2,4-triazine compounds with the structure shown in formula (III).

2. The synthesis method according to claim 1, characterized in that, The aryl group is selected from: phenyl, naphthyl; the aromatic heterocyclic group is selected from: pyridyl, 3-bromothiophene, furanyl, 3-bromobenzothiophene, benzofuranyl.

3. The synthesis method according to claim 1, characterized in that, The organic solvent is selected from any one or more of the following: dichloromethane, dichloroethane, chloroform, tetrahydrofuran, diethyl ether, acetonitrile, acetone, and toluene.

4. The synthesis method according to claim 1, characterized in that, The chiral phosphoric acid catalyst includes any one or more of the following: BINOL framework chiral phosphoric acid catalyst ( R )-A1 ~ ( R )-A6, Spinol framework chiral phosphoric acid catalyst ( S )-B1 ~ ( S )-B3; 。 5. The synthesis method according to claim 1, characterized in that, The molar ratio of the 4-aminocyclohexadienone compound shown in Formula I to the azomethine imine compound shown in Formula II is 1:(1-1.2); the molar ratio of the 4-aminocyclohexadienone compound shown in Formula I to the molar ratio of the amount of catalyst added is 1:(0.05~0.1).

6. 1,2,4-triazine compounds of general formula (III) or their pharmaceutically acceptable salts or deuterated derivatives; In the formula, R, R 1 R 2 R 3 The definitions of a, b, and c are the same as those in claim 1.

7. The 1,2,4-triazine compound or its pharmaceutically acceptable salt or deuterated derivative according to claim 6, characterized in that, The pharmaceutically acceptable salt is an inorganic or organic salt; wherein the inorganic salt is selected from hydrochloride, hydrobromide, hydroiodide, perchlorate, sulfate, hydrogen sulfate, nitrate, phosphate, and acid phosphate; and the organic salt is selected from formate, acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, succinate, glutarate, fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, salicylate, p-toluenesulfonate, and ascorbate.

8. The 1,2,4-triazine compound or its pharmaceutically acceptable salt or deuterated derivative according to claim 6, characterized in that, The 1,2,4-triazine compounds are specifically selected from: 。 9. A pharmaceutical composition for treating liver fibrosis, characterized in that, It contains the 1,2,4-triazine compounds of claim 6 or their pharmaceutically acceptable salts, deuterated derivatives, and pharmaceutical excipients.

10. The use of the 1,2,4-triazine compound of claim 6 or its pharmaceutically acceptable salts or deuterated derivatives in the preparation of a medicament for treating diseases associated with liver fibrosis.

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