A class of pyran derivatives containing fluorine and trifluoromethyl quaternary carbon centers, their preparation methods and applications

Abstract

This invention relates to a class of pyran derivatives containing fluorine and trifluoromethyl quaternary carbon centers, their preparation methods, and applications. The structure of the pyran derivatives is shown in formula (I). The pyran derivatives exhibit good inhibitory effects on tumor cell proliferation and can be used to prepare drugs for treating cancer. Furthermore, the method has the advantages of simplicity, mild reaction conditions, high yield, and good enantioselectivity.

Description

Technical Field

[0001] This invention belongs to the field of heterocyclic compounds. More specifically, it relates to a class of pyran derivatives containing fluorine and trifluoromethyl quaternary carbon centers, their preparation methods, and applications. Background Technology

[0002] Fluorine organic chemistry plays a vital role in many different but interconnected research areas, including the development of new materials with a wide range of applications, such as photovoltaic solar cells and materials used in positron emission tomography (PET). 18 F-labeled radioactive tracers 19 Magnetic resonance imaging (MRI) technology is also used in modern medical diagnostics. Furthermore, fluorine compounds can significantly alter the activity of drug molecules, enabling them to play an important role in the biomedical field.

[0003] For example, patent CN112920133A discloses a class of compounds with specific chemical structures possessing antitumor activity, specifically involving (E)-4-methyl-2-(4-(trifluoromethyl)styryl)oxazole compounds, their preparation methods, and applications. Pharmacological studies have shown that these compounds exhibit certain inhibitory activity against human non-small cell lung cancer A549 cells and can be used to prepare antitumor drugs. However, the number of existing fluorinated compounds used as drugs remains relatively small, making fluorination modification of these compounds and further re-evaluation of their biological activity a research hotspot.

[0004] Furthermore, developing new methods for preparing fluorinated compounds has become one of the most active areas of scientific research. However, traditional catalytic fluorination reactions suffer from harsh conditions, low atom utilization efficiency, and significant limitations in terms of functional group tolerance and substrate range. Currently, there are no publicly available or reported compounds with fluorine and trifluoromethyl quaternary carbon stereocenters and their synthesis, making the synthesis of compounds with chiral fluorine and trifluoromethyl groups extremely challenging. Summary of the Invention

[0005] To address the aforementioned problems in the prior art, the primary objective of this invention is to provide a class of pyran derivatives containing fluorine and a trifluoromethyl quaternary carbon center. These pyran derivatives possess a good inhibitory effect on tumor cell proliferation.

[0006] A second objective of this invention is to provide a method for preparing a class of pyran derivatives containing fluorine and trifluoromethyl quaternary carbon centers.

[0007] A third objective of this invention is to provide the use of a class of pyran derivatives containing fluorine and trifluoromethyl quaternary carbon centers in the preparation of medicaments for treating cancer.

[0008] A fourth object of the present invention is to provide a pharmaceutical composition comprising the above-described pyran derivative containing a fluorine and a trifluoromethyl quaternary carbon center.

[0009] The above-mentioned objectives of the present invention are achieved through the following technical solutions:

[0010] A class of pyran derivatives containing fluorine and trifluoromethyl quaternary carbon centers, with the structural formula shown in formula (I):

[0011]

[0012] Among them, R 1 Selected from aryl, substituted aryl, and heteroaryl; wherein the substituted aryl group is substituted by one or more substituents selected from halogen, halomethyl, alkyl, sulfone, alkoxy, nitro, heterocyclic, or ester group; R 2 Selected from aryl, substituted aryl, alkyl, cycloalkyl, or heteroaryl; wherein the substituted aryl group is substituted by one or more substituents selected from alkyl, halogen, or ester groups; R 3 Selected from aryl, alkyl, or substituted aryl groups; wherein the substituted aryl group is substituted by one or more substituents selected from halogens and halomethyl groups; A represents a five-membered or six-membered heterocycle substituted by one or more heteroatoms.

[0013] Preferably, the pyran derivative has the structural formula shown in formula (II) or formula (III) below:

[0014]

[0015] Among them, R 1 Selected from aryl, substituted aryl, and heteroaryl; wherein the substituted aryl group is substituted by one or more substituents selected from halogen, halomethyl, alkyl, sulfone, alkoxy, nitro, heterocyclic, or ester group; R 2 Selected from aryl, substituted aryl, alkyl, cycloalkyl, or heteroaryl; wherein the substituted aryl group is substituted by one or more substituents selected from alkyl, halogen, ester, or heteroaryl; R 3 Selected from aryl or substituted aryl groups; wherein the substituted aryl group is substituted by one or more substituents selected from halogens and halomethyl groups; R 4 It is an alkyl or aryl group; R 5 It is an aryl group.

[0016] Preferably, R 1 Selected from phenyl, naphthyl, substituted phenyl, or five-membered or six-membered heterocycles substituted with one or more heteroatoms; wherein the substituted phenyl is substituted with one or more substituents selected from halogen, trifluoromethyl, C1-C6 alkyl, C1-C3 sulfone, C1-C6 alkoxy, nitro, C1-C6 ester, or five-membered or six-membered heterocycles substituted with one or more heteroatoms; R 2 Selected from phenyl, naphthyl, substituted phenyl, C3-C8 cycloalkyl, C1-C6 alkyl, The substituted phenyl group is substituted by one or more substituents selected from halogens, C1-C6 alkyl groups, and C1-C6 ester groups; R 3 Selected from phenyl or substituted phenyl groups; wherein the substituted phenyl group is substituted by one or more substituents selected from halogens and trifluoromethyl groups; R 4 It is a C1-C6 alkyl or phenyl group; R 5 It is a phenyl group.

[0017] Preferably, the pyran derivative containing the fluorine and trifluoromethyl quaternary carbon center is selected from any of the following structures:

[0018]

[0019]

[0020] More preferably, the pyran derivative containing the fluorine and trifluoromethyl quaternary carbon center is selected from any of the following structures:

[0021]

[0022] Preferably, the present invention claims a method for preparing a pyran derivative containing a fluorine and a trifluoromethyl quaternary carbon center, comprising mixing a 5-enylthiazolidinone compound, an α-fluorinated β-ketodiol compound, an organic base and a first solvent, reacting, and then post-processing to obtain the compound shown in formula (II), or

[0023] A mixture of pyrazolinone compounds, α-fluorinated β-ketodiol compounds, an organic base, and a second solvent is reacted and then post-treated to obtain the compound shown in formula (III); its reaction formula is as follows:

[0024]

[0025] The method for preparing a class of pyran derivatives with fluorine and trifluoromethyl quaternary carbon centers provided by the present invention has the advantages of being simple, having mild reaction conditions, high yield, and good enantioselectivity.

[0026] Preferably, the organic base is a chiral amine catalyst. More specifically, the chiral amine catalyst includes, but is not limited to, 3-((3,5-bis(trifluoromethyl)phenyl)amino)-4-(((R)-(6-methoxyquinoline-4-yl)((1S,2R,4S,5R)-5-vinylquinoline-2-yl)methyl)amino)cyclobutane-3-en-1,2-dione, 1-(3,5-bis(trifluoromethyl)phenyl)-3-((R)-(6-methoxyquinoline-4-yl)((1S,2R,4S,5R)-5-vinylquinoline-2-yl)methyl)thiourea, 1-(3,5-bis(trifluoromethyl)phenyl)-3-((1R,2R)-2-(dimethylamino)cyclohexyl)urea, etc.

[0027] Preferably, the molar ratio of the 5-alkenylthiazolidinone compound, the α-fluorinated β-ketodiol compound, and the organic base is 0.1–10:1:0.01–1. More preferably, the molar ratio of the 5-alkenylthiazolidinone compound, the α-fluorinated β-ketodiol compound, and the organic base is 1–1.5:1:0.01–0.1. Most preferably, the molar ratio of the 5-alkenylthiazolidinone compound, the α-fluorinated β-ketodiol compound, and the organic base is 1.2:1:0.01.

[0028] Preferably, the molar ratio of the pyrazolone compound, the α-fluorinated β-ketodiol compound, and the organic base is 0.1–10:1:0.01–1. More preferably, the molar ratio of the pyrazolone compound, the α-fluorinated β-ketodiol compound, and the organic base is 1–1.5:1:0.01–0.1. Most preferably, the molar ratio of the pyrazolone compound, the α-fluorinated β-ketodiol compound, and the organic base is 1.2:1:0.01.

[0029] Preferably, the first solvent is selected from one or more of toluene, ethyl acetate, acetonitrile, chloroform, and tetrahydrofuran. More preferably, the first solvent is toluene.

[0030] Preferably, the second solvent is selected from one or more of dichloromethane, ethyl acetate, acetonitrile, chloroform, and tetrahydrofuran. More preferably, the second solvent is dichloromethane.

[0031] Preferably, when synthesizing the compound shown in formula (II), the reactants are mixed and reacted at room temperature. More specifically, the reactants are mixed and reacted at 22–28°C. At this reaction temperature, the product exhibits high yield and selectivity.

[0032] Preferably, when synthesizing the compound shown in formula (III), the starting materials are mixed and reacted at -3 to 3°C. At this reaction temperature, the product exhibits high yield and selectivity.

[0033] Furthermore, this invention claims protection for the use of a pyran derivative containing a fluorine and a trifluoromethyl quaternary carbon center in the preparation of a medicament for treating cancer.

[0034] Preferably, the cancer is lung cancer.

[0035] Furthermore, the present invention claims protection for a pharmaceutical composition comprising:

[0036] (a) 0.001-99.99% by weight of the pyran derivative containing a fluorine and trifluoromethyl quaternary carbon center as described in any one of claims 1-4, its optical isomers, cis-trans isomers, or pharmaceutically acceptable salts thereof, or combinations thereof; and

[0037] (b) Pharmaceutically acceptable carriers and / or excipients.

[0038] In some embodiments, the excipients include, but are not limited to, fillers, excipients, binders, disintegrants, surfactants, pH adjusters, flow aids, lubricants, or other suitable additives, etc.

[0039] Furthermore, the present invention seeks protection for the use of the above-described pharmaceutical composition in the preparation of a medicament for treating cancer.

[0040] In some embodiments, the pharmaceutical composition is prepared by filling the pharmaceutical composition containing the above-mentioned pyran derivative into capsules or tablets in the form of powder, granules, microcapsules, etc.

[0041] Furthermore, the present invention also claims protection for a method of treating cancer, comprising administering a subject a therapeutically effective amount of the above-mentioned pyran derivative or pharmaceutical composition.

[0042] Compared with existing technologies, the present invention has the following beneficial effects: The present invention discloses a class of pyran derivatives containing fluorine and trifluoromethyl quaternary carbon centers. These pyran derivatives exhibit good inhibitory effects on tumor cell proliferation and can be used to prepare drugs for treating cancer, possessing certain potential biological activity and market application value. Furthermore, the present invention also provides a method for preparing a class of pyran derivatives containing fluorine and trifluoromethyl quaternary carbon centers, which has the advantages of being simple, having mild reaction conditions, high yield, and good enantioselectivity. Detailed Implementation

[0043] The present invention will be further explained and described below with reference to specific embodiments, but the specific embodiments do not limit the present invention in any way. Unless otherwise specified, the reagents and methods involved in the embodiments are all commonly used reagents and methods in the art.

[0044] In this invention, unless otherwise specified in the context, the words, phrases, and symbols used below have the following meanings. The meanings of the following abbreviations and terms are consistent throughout the text:

[0045] The term "halogen" refers to fluorine, chlorine, bromine, and iodine. The term "halogen" preceding the group name indicates that the group is partially or completely halogenated, that is, replaced by F, Cl, Br, or I in any combination.

[0046] The term "heteroatoms" refers to nitrogen, sulfur, and oxygen atoms.

[0047] The term "alkyl" refers to a hydrocarbon group selected from saturated straight-chain or branched hydrocarbon groups. The alkyl group may have 1 to 12 carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, or similar groups.

[0048] The term "alkoxy group" is usually represented by RO- and consists of an alkyl group and an oxygen atom, where R is a hydrocarbon group selected from saturated straight-chain or branched hydrocarbon groups. The hydrocarbon group in the alkoxy group can have 1 to 6 carbon atoms.

[0049] The term "sulfone group" is usually represented by -SO2R and consists of an alkyl group, two oxygen atoms, and one sulfur atom. The R in the sulfone group is a hydrocarbon group, which is selected from saturated straight-chain or branched hydrocarbon groups. The hydrocarbon group in the alkoxy group can have 1 to 6 carbon atoms.

[0050] The term "ester group" refers to a substituent with the structural formula -COOR, where R in the ester group is a hydrocarbon group, selected from saturated straight-chain or branched hydrocarbon groups. The hydrocarbon group in the ester group can have 1 to 6 carbon atoms.

[0051] The term "cycloalkyl" refers to a hydrocarbon group selected from saturated or partially unsaturated cycloalkyl groups, including monocyclic or polycyclic groups. A cycloalkyl group may have 3 to 12 carbon atoms. For example, a cycloalkyl group may be a monocyclic group having 3 to 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-3-enyl, cyclohexene, 1-cyclohex-1-enyl, cyclohexadiene, cycloheptene, cyclooctene, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl, or similar groups. A cycloalkyl group may also be a bicyclic group having 4 to 12 carbon atoms, such as bicyclic systems of [4,5], [5,5], [5,6], and [6,6] rings, bridged bicyclic systems selected from bicyclic [2.2.1]heptane, bicyclic [2.2.2]octane, and bicyclic [3.2.2]nonane, or similar groups. The ring may be saturated or have at least one double bond, but is not fully conjugated and is not aromatic.

[0052] The term "aryl" refers to 5- and 6-membered carbocyclic aromatic rings, 7- to 12-membered bicyclic systems, and 10- to 15-membered tricyclic systems, wherein at least one ring in the bicyclic and tricyclic systems is a carbocyclic and an aromatic ring. Examples include (a) 5- and 6-membered carbocyclic aromatic rings, such as phenyl; (b) bicyclic systems such as 7- to 12-membered bicyclic systems, wherein at least one ring is a carbocyclic and an aromatic ring, such as naphthyl; and (c) tricyclic systems such as 10- to 15-membered tricyclic systems, wherein at least one ring is a carbocyclic and an aromatic ring, such as fluorene. However, aryl does not include heterocyclic groups or groups overlapping with heterocyclic aromatic groups, which are defined separately below. Thus, if one or more carbocyclic aromatic rings are fused with heterocyclic aromatic rings, the resulting ring system is a heterocyclic aromatic group as defined herein, not an aryl group.

[0053] The term "heteroaryl" refers to a 5- to 7-membered aromatic monocyclic ring, an 8- to 12-membered bicyclic ring, or an 11- to 14-membered bicyclic ring; it contains 1, 2, 3, or 4 heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon; wherein, at least one ring of the 8- to 12-membered bicyclic ring and the 11- to 14-membered bicyclic ring is aromatic. The heteroaryl group is further preferably a 5- to 6-membered aromatic monocyclic ring, for example, furan, pyrrole, thiophene, pyridine, pyran, etc., containing one heteroatom; or oxazole, imidazole, thiazole, isoxazole, pyrazole, isoxazole, pyrimidine, etc., containing two heteroatoms.

[0054] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic, bicyclic, and tricyclic ring selected from 4 to 12 members, containing at least one carbon atom in addition to one, two, three, or four heteroatoms selected from oxygen, sulfur, and nitrogen. It also refers to an aliphatic spirocyclic ring containing at least one heteroatom selected from N, O, and S, provided the bonding point is on the heterocycle. The ring may be saturated or contain at least one double bond. Examples include morpholine.

[0055] The term "cycloalkyl" refers to a hydrocarbon group selected from saturated or partially unsaturated cycloalkyl groups, including monocyclic or polycyclic groups. A cycloalkyl group may have 3 to 12 carbon atoms. For example, a cycloalkyl group may be a monocyclic group having 3 to 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-3-enyl, cyclohexene, 1-cyclohex-1-enyl, cyclohexadiene, cycloheptene, cyclooctene, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl, or similar groups. A cycloalkyl group may also be a bicyclic group having 4 to 12 carbon atoms, such as bicyclic systems of [4,5], [5,5], [5,6], and [6,6] rings, bridged bicyclic systems selected from bicyclic [2.2.1]heptane, bicyclic [2.2.2]octane, and bicyclic [3.2.2]nonane, or similar groups. The ring may be saturated or have at least one double bond, but is not fully conjugated and is not aromatic.

[0056] The compound may contain one asymmetric center and thus may exist as an enantiomer. When the compound has two or more asymmetric centers, they may also exist as diastereomers. Enantiomers and diastereomers belong to the broader category of stereoisomers. All these possible stereoisomers include substantially pure separated enantiomers (meaning the target stereoisomer contains no more than 10% by weight of any other stereoisomer), their racemic mixtures, and mixtures of diastereomers. Unless otherwise stated, the reference to one isomer applies to any possible isomer. When an isomer component is not specifically specified, all possible isomers are included.

[0057] The term "acceptable salt" refers to a salt whose cation or anion is known and which can be used to form a salt for purposes in the art. Suitable salts having a base, such as salts formed from compounds containing a carboxyl group, include salts of alkali metals (such as sodium and potassium), alkaline earth metals (such as calcium and magnesium), ammonium, and amines.

[0058] Suitable salts with anion addition, such as salts formed from compounds containing amino groups, include salts formed with inorganic acids, such as hydrochlorides, sulfates, sulfites, phosphates, hydrogen phosphates, and nitrates, as well as salts formed with organic acids such as acetic acid, malic acid, tartaric acid, citric acid, lactic acid, salicylic acid, and oxalic acid.

[0059] The term “treatment” refers to, for example, the prevention, suppression, and improvement of a disease, symptom, or condition in an individual.

[0060] The phrase “therapeutic effective amount” refers to the amount of an active compound or pharmaceutical agent that researchers, veterinarians, physicians or other clinicians seek to elicit a biological or medical response in a tissue, system, animal, individual or human.

[0061] Preparation of compound (II)

[0062]

[0063] Taking compound (II) as an example, its synthesis process is as follows:

[0064] (1) Take compound (1), compound (2) and sodium bicarbonate, and react them with dichloromethane / water at 0±3℃ to obtain compound (3); add triethylamine (4) to compound (3), and react with methanol at 65±3℃ to obtain compound (5) 5-enylthiazolidinone.

[0065] (2) Take the compound of formula (10), select a fluorine reagent, and react with acetonitrile / water as solvent at -20±3℃ to obtain the α-fluorinated β-ketodiol compound of formula (11);

[0066] (3) Take the 5-enylthiazolidinone compound of formula (5), the α-fluorinated β-ketodiol compound of formula (11) and an organic base, and react them with toluene as solvent at 25±3℃ to obtain the compound shown in formula (II).

[0067] Table 1 shows the structures of compounds with the general formula (II).

[0068]

[0069]

[0070]

[0071] The specific preparation processes for each of the (II) compounds are shown below.

[0072] Example 1: Preparation of compound II 01

[0073]

[0074] In the above reaction formula, R 1 It is a phenyl group, R 2 It is a phenyl group, R 3 It is a phenyl group.

[0075] (1) Add a solution of NaHCO3 (20 mmol in 20 mL of water) to a solution of CH2Cl2 (40 mL) containing 10 mmol of formula (1). After cooling to 0 °C in an ice-water bath, add 10 mmol of formula (2) dropwise to the stirred solution. Then stir the reaction mixture overnight at room temperature. Separate the organic phase of the reaction mixture and extract the aqueous phase with CH2Cl2 (50 mL x 2). Wash the combined organic phases with H2O (40 mL x 2), dry with anhydrous Na2SO4, and evaporate to dryness. Wash the solid residue with EtOH and filter to obtain formula (3). Dissolve 1 mmol of formula (3), 1.2 mmol of formula (4), and 2 mmol of Et3N in 20 mL of MeOH and heat under reflux at 65 °C for 3 hours, during which a precipitate gradually appears. After cooling to room temperature, filter the precipitate and wash with 20 mL of cold MeOH to obtain a 5-enylthiazolinone compound of formula (5).

[0076] (2) At -20°C, a solution of a selective fluoride reagent (11 mmol, Selectflour, CAS: 140681-55-6) in CH3CN / H2O (50 mL / 4 mL) was added dropwise to a stirred solution of formula (10) in acetonitrile (50 mL). The reaction mixture was stirred at -20°C for 12 hours. Water (80 mL) was added to the residue, and the resulting aqueous solution was extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine, dried over MgSO4, and concentrated by air separation. The residue was purified by distillation or recrystallization to give the product (11) α-fluorinated β-ketodiol compounds.

[0077] (3) In a clean reaction tube, add sequentially 0.12 mmol of α-fluorinated β-ketodiol compound of formula (11), 0.001 mmol of quinine squaring amide derivative catalyst, and 3-((3,5-bis(trifluoromethyl)phenyl)amino)-4-(((S)-(6-methoxyquinoline-4-yl)((1S,2S,4S,5R)-5-vinylquinoline-2-yl)methyl)amino)cyclobutane-3-en-1,2-dione ) and toluene (1 mL), followed by the addition of a 5-alkenylthiazolinone compound of formula (5) (0.1 mmol), and stirred at 25 °C for 48 h. The reaction of the starting alkenylthiazolinone compound was monitored by TLC. After the reaction was completed, the reaction solvent was removed under reduced pressure. The residue was loaded onto a silica gel column and eluted with hexane:ethyl acetate = 30:1. Thin-layer chromatography was performed, the eluates were combined, and the solvent was removed to obtain the thiazopyran compound of formula (II) containing fluorine and trifluoromethyl quaternary carbon centers.

[0078] Pale yellow solid, 95% yield, 98% ee value, high-resolution mass spectrometry (M+H) + 500.0933. 1 H NMR (400MHz, CDCl3) δ7.89 (dd, J=6.5, 3.2Hz, 2H), 7.49-7.38 (m, 4H), 7.33 (d, J=8. 1Hz,2H),7.26(s,5H),7.22(t,J=7.9Hz,2H),6.09(s,1H),5.04(d,J=29.0Hz,1H). 13 C NMR (100MHz, CDCl3) δ202.0,201.8,165.6,154.8,134.7,134.6,134.2,133.7,132.9,130.6,1 30.4,129.7,129.6,129.3,129.0,128.9,128.1,128.1,125.9,106.0,96.2,94.0,47.8,47.6. 19 F NMR (376MHz, CDCl3) δ-78.85,-78.89,-180.23,-180.26,-180.30,-180.34.

[0079] Example 2: Preparation of compound II 02

[0080] The preparation method is the same as that of compound Ⅱ 01, wherein R 1 =4-F-Ph, and the remaining experimental procedures are as described in Example 1.

[0081] Pale yellow solid, yield 73%, ee value 97%, mass spectrometry (M+H) + )518.0839.1 H NMR (400MHz, CDCl3) δ7.88 (dd, J=6.5, 3.1Hz, 2H), 7.49 (t, J=7.4Hz, 1H), 7.46-7.38 ( m,5H),7.30-7.24(m,4H),6.97(t,J=8.5Hz,2H),6.13(s,1H),5.04(d,J=28.8Hz,1H). 13 C NMR (100MHz, CDCl3) δ201.3,201.1,165.8,164.4,161.9,154.8,134.7,134.6,134.3,132.7,132.2,132 .2,132.1,132.1,130.7,129.7,129.6,129.0,128.3,128.3,125.9,105.9,96.7,96.3,94.1,47.0,46.8. 19 F NMR (376MHz, CDCl3) δ-78.89,-78.92,-111.68,-180.60,-180.64,-180.67,-180.71.

[0082] Example 3: Preparation of compound II 03

[0083] The preparation method is the same as that for compound II 01, R 1 =4-Cl-Ph, and the remaining experimental procedures are as described in Example 1.

[0084] Pale yellow solid, yield 84%, ee value 99%, mass spectrometry (M+H) + )534.0545. 1 H NMR (400MHz, CDCl3) δ7.86 (dd, J=6.5, 3.2Hz, 2H), 7.49 (t, J=7.4Hz, 1H), 7.43 (dt, J=4.6 ,1.8Hz,5H),7.31-7.24(m,3H),7.24-7.16(m,3H),6.40(s,1H),5.03(d,J=29.0Hz,1H). 13 CNMR(100MHz, CDCl3)δ200.5,200.2,165.9,154.7,134.8,134.8,134.3,132.6,132.4,131.7, 131.7,130.8,129.7,129.6,129.1,129.1,128.3,128.3,125.9,105.9,96.4,94.3,46.9,46.8. 19FNMR(376MHz, CDCl3)δ-78.83,-78.87,-180.50,-180.53.

[0085] Example 4: Preparation of compound II 04

[0086] The preparation method is the same as that for compound II 01, R 1 =4-Br-Ph, and the remaining experimental procedures are as described in Example 1.

[0087] Pale yellow solid, yield 77%, ee value 97%, mass spectrometry (M+H) + )578.0037. 1 H NMR (400MHz, CDCl3) δ7.85 (dd, J=6.7, 2.9Hz, 2H), 7.51-7.43 (m, 5H), 7.39 (d, J= 8.4Hz, 3H), 7.28 (d, J = 7.6Hz, 2H), 7.13 (d, J = 7.5Hz, 2H), 5.01 (d, J = 29.1Hz, 1H). 13 C NMR (100MHz, CDCl3) δ200.2,199.9,165.9,154.7,134.9,134.9,134.2,133.0,132.6,132. 0,130.8,129.6,129.6,129.1,128.3,128.3,126.0,123.5,105.9,96.4,94.3,46.9,46.7. 19 F NMR(376MHz, CDCl3)δ-78.86,-78.89,-180.50,-180.53,-180.57,-180.60

[0088] Example 5: Preparation of Compound II 05

[0089] The preparation method is the same as that for compound II 01, R 1 =4-CF3-Ph, and the remaining experimental procedures are as described in Example 1.

[0090] Pale yellow solid, yield 91%, ee value 84%, mass spectrometry (M+H) + )568.0805. 1H NMR (400MHz, CDCl3) δ7.90(dd,J=7.4,2.1Hz,2H),7.54(d,J=8.1Hz,2H),7.50(d,J=7.4Hz,1H),7.43(d d,J=8.1,2.6Hz,5H),7.38(d,J=8.2Hz,2H),7.24(d,J=8.2Hz,2H),5.92(s,1H),5.13(d,J=28.5Hz,1H). 13 C NMR (100MHz, CDCl3) δ200.2,199.9,166.1,154.8,138.0,134.7,134.7,134.4,132.5,130.9,129. 6,129.5,129.1,128.3,128.3,126.0,125.8,125.7,125.7,125.7,105.3,96.4,94.2,47.3,47.1. 19 F NMR (376MHz, CDCl3) δ-62.93,-78.81,-78.85,-180.29,-180.29,-180.32,-180.32.

[0091] Example 6: Preparation of Compound II 06

[0092] The preparation method is the same as that for compound II 01, R 1 =4-CH3-Ph, and the remaining experimental procedures are as described in Example 1.

[0093] Pale yellow solid, yield 74%, ee value 96%, mass spectrometry (M+H) + )514.1090. 1 H NMR (400MHz, CDCl3) δ7.89 (dd, J=6.5, 3.2Hz, 2H), 7.50-7.38 (m, 4H), 7.34 (d, J=8.2Hz, 2H), 7.23 (t, J=7. 9Hz, 2H), 7.17 (d, J = 7.3Hz, 2H), 7.08 (d, J = 7.8Hz, 2H), 6.10 (s, 1H), 5.00 (d, J = 29.1Hz, 1H), 2.28 (s, 3H). 13C NMR (100MHz, CDCl3) δ202.1,201.9,165.5,154.7,139.3,134.7,134.7,134.1,134.1,132.9,132.9,130.6, 130.6,130.2,130.2,129.8,129.7,129.5,129.0,128.1,128.1,125.9,106.4,96.2,94.0,47.4,47.2,21.1. 19 F NMR (376MHz, CDCl3) δ-78.86,-78.90,-180.31,-180.35,-180.38,-180.42.

[0094] Example 7: Preparation of Compound II 07

[0095] The preparation method is the same as that for compound II 01, R 1 =4-COOMe-Ph, and the remaining experimental procedures are as described in Example 1.

[0096] Pale yellow solid, yield 70%, ee value 96%, mass spectrometry (M+H) + )555.0981. 1 H NMR(400MHz, CDCl3)δ7.92(d,J=7.9Hz,2H),7.90-7.81(m,2H),7.50-7.39(m,6H) ),7.35(d,J=7.9Hz,2H),7.28-7.19(m,2H),5.12(d,J=29.1Hz,1H),3.88(s,3H). 13 C NMR (100MHz, CDCl3) δ199.9,199.7,166.4,165.9,154.7,139.0,134.9,134.8,134.2,132.6,130 .8,130.6,129.9,129.6,129.5,129.1,128.3,128.3,125.9,105.7,96.5,94.4,52.3,47.3,47.1. 19 F NMR (376MHz, CDCl3) δ-78.86,-78.90,-180.31,-180.35,-180.38,-180.42.

[0097] Example 8: Preparation of Compound II 08

[0098] The preparation method is the same as that for compound II 01, R 1 =4-C(CH3)3-Ph, and the remaining experimental procedures are as described in Example 1.

[0099] Pale yellow solid, yield 84%, ee value 95%, mass spectrometry (M+H) + )556.1557. 1 H NMR (400MHz, CDCl3) δ7.81 (dd, J=6.7, 3.0Hz, 2H), 7.33 (dd, J=6.7, 2.5Hz, 4H), 7.23 -7.16(m,2H),7.15-7.05(m,6H),6.23(s,1H),4.92(d,J=28.8Hz,1H),1.16(s,9H). 13 C NMR(100MHz, CDCl3)δ201.3,201.0,164.5,153.8,151.6,133.9,132.8,131.8,129.5,129.4,129.0 ,128.6,128.5,127.9,126.9,126.9,124.8,124.7,105.1,95.0,92.9,46.3,46.1,33.6,30.6,30.1. 19 F NMR (376MHz, CDCl3) δ-78.78,-78.82,-179.92,-179.95,-179.99,-180.02.

[0100] Example 9: Preparation of Compound II 09

[0101] The preparation method is the same as that of compound II 01, except that formula (5) is replaced with R. 1 =4-SO2CH3-Ph, and the remaining experimental procedures are as described in Example 1.

[0102] Pale yellow solid, yield 50%, ee value 89%, mass spectrometry (M+H) + )578.0743. 1 H NMR (400MHz, CDCl3) δ7.89 (dd, J=7.5, 1.9Hz, 2H), 7.84 (d, J=8.4Hz, 2H), 7.53-7.4 2(m,7H),7.26(d,J=15.8Hz,3H),5.93(s,1H),5.18(d,J=28.4Hz,1H),2.97(s,3H). 13 C NMR (100MHz, CDCl3) δ200.0,199.4,166.2,155.0,141.4,140.2,134.7,134.4,132.6,131. 5,131.5,131.0,129.7,129.6,129.1,128.4,128.4,127.8,125.9,104.5,47.6,47.4,44.4.19 F NMR (376MHz, CDCl3) δ-78.85,-78.89,-180.32,-180.35,-180.38,-180.42.

[0103] Example 10: Preparation of Compound II 10

[0104] The preparation method is the same as that for compound II 01, R 1 =4-morpholium-Ph, and the remaining experimental procedures are as described in Example 1.

[0105] Pale yellow solid, yield 62%, ee value 80%, mass spectrometry (M+H) + )585.1460. 1 H NMR (400MHz, CDCl3) δ7.89(d,J=9.6Hz,2H),7.51-7.38(m,4H),7.35(d,J=8.2Hz,2H),7.23(d,J=8.1Hz,2H),7.17( d,J=7.9Hz,2H),6.78(d,J=8.5Hz,2H),6.00(s,1H),4.98(d,J=29.0Hz,1H),3.92-3.72(m,4H),3.19-2.98(m,4H). 13 C NMR (100MHz, CDCl3) δ202.6,202.3,165.4,154.7,151.9,134.8,134.1,133.0,131.2,130.5, 129.8,129.7,129.0,128.1,125.8,124.2,115.4,106.6,96.2,94.1,66.7,48.8,47.1,46.9. 19 F NMR (376MHz, CDCl3) δ-78.87,-78.91,-180.38,-180.41,-180.45,-180.48.

[0106] Example 11: Preparation of Compound II 11

[0107] The preparation method is the same as that for compound II 01, R 1 =3-Cl-Ph, and the remaining experimental procedures are as described in Example 1.

[0108] Pale yellow solid, yield 67%, ee value 98%, mass spectrometry (M+H) + )534.0540. 1H NMR (400MHz, CDCl3) δ7.86-7.77(m,2H),7.46-7.33(m,6H),7.25-7.16(m,4H),7.14-7.05(m,2H),6.04(s,1H),4.95(d,J=28.6Hz,1H). 13 C NMR (100MHz, CDCl3) δ200.0,199.7,164.9,153.8,134.7,133.8,133.6,133.6,133.4,131.7,129.8,129. 4,129.3,129.0,128.7,128.6,128.4,128.0,127.5,127.3,127.3,124.9,104.2,95.2,93.0,46.4,46.2. 19 F NMR (376MHz, CDCl3) δ-78.86,-78.90,-180.25,-180.28,-180.31,-180.34.

[0109] Example 12: Preparation of Compound II 12

[0110] The preparation method is the same as that for compound II 01, R 1 =3-Br-Ph, and the remaining experimental procedures are as described in Example 1.

[0111] Pale yellow solid, yield 74%, ee value 98%, mass spectrometry (M+H) + )578.0038. 1 H NMR (400MHz, CDCl3) δ7.92-7.85(m,2H),7.53-7.46(m,2H),7.46-7.38(m,6H),7.31-7.26 (m,2H),7.20(d,J=7.5Hz,1H),7.12(t,J=7.8Hz,1H),6.06(s,1H),5.00(d,J=28.6Hz,1H). 13 C NMR (100MHz, CDCl3) δ201.0,200.8,165.9,154.8,136.0,134.6,134.6,134.4,133.2,132.7,132.4,130. 8,130.3,129.8,129.7,129.0,129.0,129.0,128.3,128.3,125.9,122.8,105.2,96.2,94.0,47.4,47.2. 19 F NMR (376MHz, CDCl3) δ-78.86,-78.89,-180.28,-180.31.

[0112] Example 13: Preparation of Compound II 13

[0113] The preparation method is the same as that for compound II 01, R 1 =3-CH3-Ph, and the remaining experimental procedures are as described in Example 1.

[0114] Pale yellow solid, yield 89%, ee value 96%, mass spectrometry (M+H) + )514.1092. 1 H NMR (400MHz, CDCl3) δ7.95-7.86(m,2H),7.50-7.39(m,4H),7.34(d,J=8.2Hz,2H),7.23(t,J=7.9H z,2H),7.18-7.12(m,1H),7.09(d,J=8.5Hz,3H),6.06(s,1H),4.99(d,J=29.0Hz,1H),2.24(s,3H). 13 CNMR(100MHz, CDCl3)δ202.3,202.0,165.5,154.8,138.7,134.7,134.2,133.5,132.9,131.0,130.6,130 .0,129.7,129.7,129.0,128.7,128.1,128.1,127.4,127.4,125.9,106.1,96.1,93.9,47.7,47.5,21.3. 19 F NMR (376MHz, CDCl3) δ-78.86,-78.89,-180.04,-180.07,-180.11,-180.15.

[0115] Example 14: Preparation of Compound II 14

[0116] The preparation method is the same as that for compound II 01, R 1 =3-OCH3-Ph, and the remaining experimental procedures are as described in Example 1.

[0117] Pale yellow solid, yield 89%, ee value 99%, mass spectrometry (M+H) + )530.1038. 1H NMR (400MHz, CDCl3) δ7.90(dd,J=6.5,3.1Hz,2H),7.46(s,1H),7.44-7.36(m,5H),7.26(d,J=3.6Hz,1H),7.24( d,J=8.2Hz,1H),7.17(t,J=7.8Hz,1H),6.90-6.78(m,3H),5.99(s,1H),5.04(s,0H),4.97(s,0H),3.70(s,3H). 13 C NMR (100MHz, CDCl3) δ201.8,201.8,165.7,159.8,154.8,135.1,134.2,132.9,130.6,1 29.9,129.8,129.7,129.0,128.2,125.9,122.7,115.8,115.0,105.8,55.4,47.8,47.6. 19 F NMR (376MHz, CDCl3) δ-78.9,-78.9,-179.8,-179.9,-179.9,-180.0.

[0118] Example 15: Preparation of Compound II 15

[0119] The preparation method is the same as that for compound II 01, R 1 =3-NO2-Ph, and the remaining experimental procedures are as described in Example 1.

[0120] Pale yellow solid, yield 64%, ee value 95%, mass spectrometry (M+H) + )545.0780. 1 H NMR (400MHz, CDCl3) δ8.14(d,J=8.2Hz,2H),7.89(dd,J=7.6,1.9Hz,2H),7.62(d,J=7.7Hz,1H ),7.53(d,J=8.2Hz,2H),7.50-7.40(m,5H),7.29(s,1H),7.25(s,1H),5.20(d,J=28.3Hz,1H). 13 C NMR (100MHz, CDCl3) δ166.3,155.0,148.2,136.3,136.3,136.1,134.7,132.5,131.0,129.9,1 29.7,129.7,129.1,128.5,128.5,126.0,125.2,125.2,124.2,104.5,96.3,94.2,47.4,47.2. 19F NMR(376MHz, CDCl3)δ-78.9,-78.9,-180.6,-180.7,-180.7,-180.7

[0121] Example 16: Preparation of Compound II 16

[0122] The preparation method is the same as that for compound II 01, R 1 =2-CH3-Ph, and the remaining experimental procedures are as described in Example 1.

[0123] Pale yellow solid, yield 64%, ee value 95%, mass spectrometry (M+H) + )514.1089. 1 H NMR(400MHz, CDCl3)δ7.90(dd,J=6.5,3.2Hz,2H),7.53-7.46(m,2H),7.46-7.39(m,5H),7.28(d,J=4.2Hz, 1H), 7.22 (dd, J=9.8, 2.1Hz, 2H), 7.06 (d, J=7.2Hz, 1H), 6.39 (s, 1H), 5.44 (d, J=29.1Hz, 1H), 2.28 (s, 3H). 13 C NMR (100MHz, CDCl3) δ202.1,201.9,165.5,154.7,136.7,134.4,134.4,134.3,132.9,132.6,131.5,131.5, 130.8,130.6,129.8,129.7,129.1,129.0,128.2,128.2,126.6,125.8,107.3,95.7,93.6,41.8,41.6,19.8. 19 F NMR (376MHz, CDCl3) δ-78.62,-78.66,-180.00,-180.04,-180.07,-180.11.

[0124] Example 17: Preparation of Compound II 17

[0125] The preparation method is the same as that for compound II 01, R 1 =2-naphyl, and the remaining experimental procedures are as described in Example 1.

[0126] Yellow solid, yield 68%, ee value 98%, mass spectrometry (M+H). + )555.1095. 1H NMR (400MHz, CDCl3) δ7.94-7.84(m,2H),7.83-7.69(m,4H),7.48(td,J=6.9,6.1,3.8Hz,2H),7.42(d,J=1.9Hz,2H),7.41 (d,J=1.7Hz,1H),7.37(d,J=10.4Hz,2H),7.35-7.29(m,2H),7.08(t,J=7.9Hz,2H),6.24(s,1H),5.24(d,J=29.2Hz,1H). 13 C NMR (100MHz, CDCl3) δ201.5,201.3,165.7,154.8,134.7,134.7,134.1,133.3,132.9,132.8,131.2,130.7,130.1,129 .7,129.6,129.0,128.7,128.1,128.1,127.6,127.3,127.3,126.9,126.6,125.9,106.4,96.6,96.3,94.4,47.8,47.6. 19 F NMR (376MHz, CDCl3) δ-78.78,-78.82,-179.87,-179.90,-179.93,-179.96.

[0127] Example 18: Preparation of Compound II 18

[0128] The preparation method is the same as that for compound II 01, R 1 =2,4-2CH3-Ph, and the remaining experimental procedures are as described in Example 1.

[0129] Pale yellow solid, yield 63%, ee value 97%, mass spectrometry (M+H) + )528.1250. 1 H NMR(400MHz, CDCl3)δ7.87(dd,J=6.5,3.1Hz,2H),7.48(t,J=7.4Hz,1H),7.44-7.36(m,5H),7.32(dd,J=8.0,4.2Hz,1H), 7.23(d,J=8.2Hz,2H),7.04(d,J=7.7Hz,1H),6.84(s,1H),6.16(s,1H),5.36(d,J=29.1Hz,1H),2.25(s,3H),2.20(s,3H). 13C NMR(100MHz, CDCl3)δ202.6,202.3,165.3,154.6,139.0,136.4,134.4,134.3,133.0,131.4,131.4,131.4, 130.5,129.9,129.8,129.4,128.9,128.2,128.2,127.4,125.8,107.5,95.7,93.5,41.6,41.5,21.0,19.7. 19 F NMR (376MHz, CDCl3) δ-78.65,-78.68,-180.11,-180.15,-180.18,-180.22.

[0130] Example 19: Preparation of Compound II 19

[0131] The preparation method is the same as that for compound II 01, R 1 =2,4-2Cl-Ph, and the remaining experimental procedures are as described in Example 1.

[0132] Pale yellow solid, yield 53%, ee value 98%, mass spectrometry (M+H) + )568.0187. 1 H NMR (400MHz, CDCl3) δ7.87 (dd, J=7.5, 2.0Hz, 2H), 7.55 (dt, J=10.0, 4.8Hz, 3H), 7.42 (dq, J=9 .0,3.3Hz,4H),7.31(t,J=7.9Hz,2H),7.26-7.21(m,2H),6.29(s,1H),5.71(d,J=28.5Hz,1H). 13 C NMR (100MHz, CDCl3) δ200.1,199.9,165.9,154.9,135.9,135.0,134.8,134.1,133.7,133.7,13 2.7,130.8,130.8,129.8,129.7,129.4,129.0,128.5,128.4,127.7,125.9,105.4,42.2,42.0. 19 F NMR (376MHz, CDCl3) δ-78.58,-78.62,-179.58,-179.62,-179.66,-179.69.

[0133] Example 20: Preparation of Compound II 20

[0134] The preparation method is the same as that for compound II 01, R 1=-thiophenyl, and the remaining experimental procedures are as described in Example 1.

[0135] Yellow solid, yield 83%, ee value 91%, mass spectrometry (M+H). + )506.0497. 1 H NMR (400MHz, CDCl3) δ7.96-7.85(m,2H),7.61-7.47(m,3H),7.42(dd,J=5.4,2.0Hz,5H),7.35-7.28(m, 2H),7.24(d,J=1.2Hz,1H),7.06(d,J=4.1Hz,1H),6.91(dd,J=5.3,3.6Hz,1H),5.41(d,J=27.9Hz,1H). 13 C NMR (100MHz, CDCl3) δ165.7,154.3,134.9,134.4,132.8,130.7,129.7,129.6,129.0,128.3,128.3,127.3,126.9,125.9,106.1,43.5,43.3. 19 F NMR (376MHz, CDCl3) δ-78.95,-78.99,-178.95,-178.98,-179.02,-179.06.

[0136] Example 21: Preparation of Compound II 21

[0137] The preparation method is the same as that for compound II 01, R 3 =4-Cl-Ph, and the remaining experimental procedures are as described in Example 1.

[0138] Pale yellow solid, yield 82%, ee value 91%, mass spectrometry (M+H) + )534.0540. 1 H NMR (400MHz, CDCl3) δ7.79(d,J=8.6Hz,2H),7.44(t,J=7.4Hz,1H),7.38(d,J=8.5Hz,2H),7. 33(d,J=7.9Hz,2H),7.27(s,5H),7.21(t,J=7.8Hz,2H),6.36(s,1H),5.04(d,J=29.2Hz,1H). 13C NMR (100MHz, CDCl3) δ201.4,201.2,164.2,154.9,136.7,134.8,134.8,134.1,133.6,131.3,1 30.4,129.7,129.6,129.4,129.3,128.9,128.1,128.1,127.1,106.8,96.2,94.1,47.6,47.4. 19 F NMR(376MHz, CDCl3)δ-78.79,-78.82,-180.14,-180.17,-180.20,-180.24.

[0139] Example 22: Preparation of compound II 22

[0140] The preparation method is the same as that for compound II 01, R 3 =4-CF3-Ph, and the remaining experimental procedures are as described in Example 1.

[0141] Pale yellow solid, yield 82%, ee value 91%, mass spectrometry (M+H) + )568.0811. 1 H NMR (400MHz, CDCl3) δ8.01(d,J=8.2Hz,2H),7.68(d,J=8.3Hz,2H),7.47(t,J=7.4Hz ,1H),7.37-7.26(m,7H),7.23(t,J=7.9Hz,2H),6.00(s,1H),5.06(d,J=28.9Hz,1H). 13 C NMR (100MHz, CDCl3) δ202.0,201.8,163.5,155.3,135.9,134.3,133.5,130.3,130.3,1 29.8,129.7,129.5,129.0,128.2,128.2,126.0,126.0,107.7,96.0,93.8,47.8,47.6. 19 F NMR (376MHz, CDCl3) δ-62.89,-78.88,-78.91,-180.24,-180.27,-180.31,-180.34.

[0142] Example 23: Preparation of Compound II 23

[0143] The preparation method is the same as that for compound II 01, R 2 =4-CH3-Ph, and the remaining experimental procedures are as described in Example 1.

[0144] Pale yellow solid, yield 76%, ee value 99%, mass spectrometry (M+H) + )514.1103. 1 H NMR (400MHz, CDCl3) δ7.89 (dd, J=6.5, 3.2Hz, 2H), 7.41 (dd, J=5.0, 1.8Hz, 3H), 7.34- 7.21(m,7H),7.02(d,J=8.2Hz,2H),6.18(s,1H),5.02(d,J=28.9Hz,1H),2.30(s,3H). 13 C NMR (100MHz, CDCl3) δ201.5,201.3,165.5,154.9,145.7,133.8,132.9,132.1,132.1,130.6,130.4, 130.4,130.0,129.9,129.3,129.0,129.0,128.9,128.8,125.9,106.0,96.1,93.9,47.8,47.6,21.8. 19 F NMR (376MHz, CDCl3) δ-78.92,-78.95,-180.12,-180.15,-180.19,-180.23.

[0145] Example 24: Preparation of Compound II 24

[0146] The preparation method is the same as that for compound II 01, R 2 =4-Cl-Ph, and the remaining experimental procedures are as described in Example 1.

[0147] Pale yellow solid, yield 62%, ee value 97%, mass spectrometry (M+H) + )534.0533. 1 H NMR (400MHz, CDCl3) δ7.89 (dd, J=6.5, 2.9Hz, 2H), 7.42 (dd, J=5.1, 1.6Hz, 3H), 7.37-7.26(m,7H),7.20(d,J=8.7Hz,2H),6.01(s,1H),5.03(d,J=29.2Hz,1H). 13 C NMR (100MHz, CDCl3) δ200.5,200.3,165.7,154.8,141.0,133.6,133.0,133.0,132.8,131.1,1 31.0,130.7,130.4,129.4,129.0,129.0,128.6,128.6,125.9,105.9,96.3,94.2,47.7,47.5. 19F NMR (376MHz, CDCl3) δ-78.82,-78.86,-179.97,-180.00,-180.04,-180.07.

[0148] Example 25: Preparation of Compound II 25

[0149] The preparation method is the same as that for compound II 01, R 2 =4-COOMe-Ph, and the remaining experimental procedures are as described in Example 1.

[0150] Pale yellow solid, yield 67%, ee value 97%, mass spectrometry (M+H) + )558.0989. 1 H NMR (400MHz, CDCl3) δ7.96-7.80(m,4H),7.42(dd,J=5.2,1.8Hz,3H),7.37-7.26(m,7H),5.06(d,J=29.1Hz,1H),3.90(s,3H). 13 C NMR (100MHz, CDCl3) δ201.5,201.2,165.8,154.7,138.0,138.0,134.3,133.5,132.8,130.7,130 .4,129.5,129.4,129.3,129.2,129.2,129.0,129.0,125.9,106.0,96.3,94.1,52.5,47.7,47.5. 19 F NMR (376MHz, CDCl3) δ-78.8,-78.8,-180.2,-180.3,-180.3,-180.3.

[0151] Example 26: Preparation of Compound II 26

[0152] The preparation method is the same as that for compound II 01, R 2 =4-(CH2)4CH3-Ph, and the remaining experimental procedures are as described in Example 1.

[0153] Pale yellow solid, yield 75%, ee value 94%, mass spectrometry (M+H) + )570.1736. 1H NMR (400MHz, CDCl3) δ7.95-7.85(m,2H),7.41(dd,J=5.1,1.8Hz,3H),7.32-7.23(m,7H),7.02(d,J=8.3Hz,2H),6. 15(s,1H),5.02(d,J=28.9Hz,1H),2.58-2.50(m,2H),1.60-1.49(m,2H),1.34-1.28(m,4H),0.87(t,J=7.0Hz,3H). 13 C NMR (100MHz, CDCl3) δ201.7,201.4,165.5,154.9,150.6,133.8,132.9,132.2,132.2,130.6,130.4,130.4,1 30.0,129.9,129.2,129.0,128.8,128.2,128.2,106.0,96.0,93.9,47.8,47.7,36.0,31.4,30.4,22.4,14.0. 19 F NMR (376MHz, CDCl3) δ-78.90,-78.94,-180.17,-180.20,-180.24,-180.27.

[0154] Example 27: Preparation of Compound II 27

[0155] The preparation method is the same as that for compound II 01, R 2 =2-naphyl, and the remaining experimental procedures are as described in Example 1.

[0156] Pale yellow solid, yield 75%, ee value 90%, mass spectrometry (M+H) + )570.1736. 1 H NMR (400MHz, CDCl3) δ7.91 (dd, J=6.5, 3.2Hz, 2H), 7.76 (d, J=8.1Hz, 1H), 7.73-7.67 (m, 2H), 7.64 (d, J=8.2Hz, 1H), 7.61-7. 53(m,1H),7.53-7.46(m,2H),7.46-7.39(m,3H),7.39-7.31(m,2H),7.31-7.26(m,3H),6.19(s,1H),5.10(d,J=28.8Hz,1H). 13C NMR (100MHz, CDCl3) δ201.8,201.6,165.6,154.9,135.7,133.9,133.0,132.9,132.8,131.8,131.7,130.6,130.5,1 30.5,130.2,129.5,129.4,129.0,128.9,128.1,127.6,126.8,125.9,124.4,124.4,105.9,96.2,94.1,47.9,47.7. 19 F NMR (376MHz, CDCl3) δ-78.78,-78.81,-179.25,-179.28,-179.32,-179.36.

[0157] Example 28: Preparation of Compound II 28

[0158] The preparation method is the same as that for compound II 01, R 2 =3-1,3-dioxindan, and the remaining experimental procedures are as described in Example 1.

[0159] Pale yellow solid, yield 86%, ee value 94%, mass spectrometry (M+H) + )544.0843. 1 H NMR (400MHz, CDCl3) δ7.85-7.77(m,2H),7.34(d,J=6.7Hz,3H),7.20(t,J=5.6Hz,5H),7.02(d,J= 8.4Hz,1H),6.87(s,1H),6.53(d,J=8.4Hz,1H),6.18(s,1H),5.90(s,2H),4.92(d,J=29.0Hz,1H). 13 CNMR (100MHz, CDCl3) δ199.1,198.8,165.5,154.9,153.1,147.7,133.8,132.9,130.6,130.3,129 .3,129.0,128.8,127.7,127.6,125.9,109.4,109.3,107.9,105.9,102.1,96.2,94.0,47.9,47.7. 19 F NMR (376MHz, CDCl3) δ-78.96,-78.99,-179.39,-179.43,-179.46,-179.50.

[0160] Example 29: Preparation of Compound II 29

[0161] The preparation method is the same as that for compound II 01, R2 =3-indole, and the remaining experimental procedures are as described in Example 1.

[0162] Pale yellow solid, yield 95%, ee value 93%, mass spectrometry (M+H) + )541.1206. 1 H NMR (400MHz, CD3OD) δ8.29(dd,J=6.2,2.9Hz,1H),7.87(dd,J=6.5,3.1Hz,2H),7.76(d,J=4.4Hz,1H),7.45(dd,J =5.1,1.7Hz,3H),7.33(ddd,J=14.5,5.7,2.3Hz,3H),7.19(ddd,J=11.6,5.6,2.5Hz,5H),5.27(d,J=31.2Hz,1H). 13 C NMR (100MHz, CD3OD) δ188.9,188.7,165.0,154.7,135.7,135.6,135.3,135.0,132.8,130.3,130. 3,128.8,128.2,127.9,126.5,125.3,123.3,122.4,121.6,111.4,108.0,96.4,94.3,45.9,45.7. 19 F NMR (376MHz, CD3OD) δ-80.24,-80.28,-180.37,-180.40,-180.44,-180.47.

[0163] Example 30: Preparation of Compound II 30

[0164] The preparation method is the same as that for compound II 01, R 2 =3-thiophenyl, and the remaining experimental procedures are as described in Example 1.

[0165] Pale yellow solid, yield 84%, ee value 88%, mass spectrometry (M+H) + )490.0738. 1 H NMR (400MHz, CDCl3) δ7.88 (dd, J=6.5, 2.7Hz, 2H), 7.62 (s, 1H), 7.46-7.38 (m, 3H), 7.24 (s,5H),7.03-6.98(m,1H),6.35(d,J=4.5Hz,1H),6.16(s,1H),5.00(d,J=29.6Hz,1H). 13C NMR (100MHz, CDCl3) δ185.3,185.0,165.7,154.7,149.6,133.5,132.8,130.6,130.1,1 30.1,129.1,129.0,128.6,125.9,125.7,125.5,113.1,105.9,94.4,92.3,47.1,46.9. 19 F NMR (376MHz, CDCl3) δ-79.14,-79.18,-183.27,-183.31,-183.34,-183.38.

[0166] Example 31: Preparation of Compound II 31

[0167] The preparation method is the same as that for compound II 01, R 2 =3-furanyl, and the remaining experimental procedures are as described in Example 1.

[0168] Pale yellow solid, yield 97%, ee value 95%, mass spectrometry (M+H) + )506.0519. 1 H NMR (400MHz, CDCl3) δ7.92(dd,J=6.8,3.3Hz,2H),7.71(d,J=5.2Hz,1H),7.61(dd,J=4.7,2.0Hz,1H) ,7.44(dd,J=5.3,2.0Hz,4H),7.26-7.23(m,4H),6.95(q,J=6.8,5.8Hz,1H),5.02(d,J=29.4Hz,1H). 13 C NMR (100MHz, CDCl3) δ191.5,191.3,165.6,154.8,139.4,138.3,138.2,137.2,137.1,133.5,132. 9,130.6,130.2,130.2,129.1,129.0,128.8,128.7,128.6,125.9,105.9,95.3,93.1,47.4,47.2. 19 F NMR (376MHz, CDCl3) δ-79.15,-79.19,-183.28,-183.32,-183.35,-183.39.

[0169] Example 32: Preparation of Compound II 32

[0170] The preparation method is the same as that for compound II 01, R 2 =cyclohexyl, and the remaining experimental procedures are as described in Example 1.

[0171] Pale yellow solid, yield 74%, ee value 84%, mass spectrometry (M+H) + )506.1417. 1 H NMR (400MHz, CDCl3) δ7.85 (dd, J=7.2, 2.5Hz, 2H), 7.47-7.27 (m, 7H), 7.15 (s, 1H), 5.55 (s, 1H) ),4.82(d,J=29.7Hz,1H),2.31(td,J=11.4,5.7Hz,1H),1.79-1.63(m,4H),1.36-1.20(m,6H). 13 C NMR (100MHz, CDCl3) δ213.2,212.9,165.4,154.3,134.2,132.8,130.6,12 9.4,129.0,125.8,106.7,47.6,46.3,46.1,31.5,29.7,27.5,26.2,25.3. 19 F NMR (376MHz, CDCl3) δ-79.34,-79.37,-187.00,-187.03,-187.07,-187.10.

[0172] Preparation of compound (III)

[0173]

[0174] Taking compound (III) as an example, its synthesis process is as follows:

[0175] (1) Take compounds of formula (6) and (7) and glacial acetic acid as solvents and react at 120±3℃ to obtain compound (8); add compound (4) and sodium acetate to compound (8) and react at 25±3℃ with glacial acetic acid as solvent to obtain pyrazolone compounds of formula (9).

[0176] (2) Take the compound of formula (10), select a fluorine reagent, and react with acetonitrile / water as solvent at -20±3℃ to obtain the α-fluorinated β-ketodiol compound of formula (11);

[0177] (3) Take pyrazolone compounds of formula (9), α-fluorinated β-ketodiol compounds of formula (11) and organic bases, and react them with dichloromethane as solvent at 0±3℃ to obtain the compound shown in formula (III).

[0178] Table 2 shows the structures of compounds with the general formula (III).

[0179]

[0180]

[0181] The specific preparation processes for each of the (III) compounds are shown below.

[0182] Example 33: Preparation of Compound III 01

[0183]

[0184] In the above reaction formula, R 1 It is a phenyl group, R 2 It is a phenyl group, R 4 It is methyl, R 5 It is a phenyl group.

[0185] (1) Add 0.1 mol of formula (6) to 40 mL of glacial acetic acid, then add 0.1 mol of formula (7), and reflux and stir for 3 hours. Separate the organic layer, and extract the aqueous layer with EtOAc (80 mL). Combine the organic layers, dry with anhydrous Na2SO4, and concentrate under reduced pressure to obtain pure formula (8), a pale yellow solid. Slowly add 5.5 mmol of compound (8) to 5 mmol of compound (4) and 1.5 mmol of sodium acetate, using glacial acetic acid as the solvent. Stir the mixture at room temperature for 15-30 minutes. After the reaction is complete, add ethyl acetate (50 mL). Filter the precipitate, and wash the filtrate with water (three times). Dry the combined organic layers on Na2SO4, and then concentrate under vacuum. After rapid purification by flash column chromatography on silica gel (petroleum ether / ethyl acetate 5:1), pyrazolone compounds of formula (9) are obtained.

[0186] (2) At -20°C, a solution of a selective fluoride reagent (11 mmol, Selectflour, CAS: 140681-55-6) in CH3CN / H2O (50 mL / 4 mL) was added dropwise to a stirred solution of formula (10) in acetonitrile (50 mL). The reaction mixture was stirred at -20°C for 12 hours. Water (80 mL) was added to the residue, and the resulting aqueous solution was extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine, dried over MgSO4, and concentrated by air separation. The residue was purified by distillation or recrystallization to give the product (11) α-fluorinated β-ketodiol compounds.

[0187] (3) In a clean reaction tube, 0.1 mmol of α-fluorinated β-ketodiol compound of formula (11), 0.001 mmol of 1,2-diphenylsquamamide derivative catalyst, 3-((3,5-bis(trifluoromethyl)phenyl)amino)-4-(((1R,2R)-2-(dimethylamino)-1,2-diphenylethyl)amino)cyclobutane-3-ene-1,2-dione) and 1 mL of dichloromethane were added sequentially, followed by 0.12 mmol of pyrazolone compound of formula (9). The mixture was stirred at 0 °C for 36 h. The reaction of the α-fluorinated β-ketodiol was monitored by TLC. After the reaction was completed, the reaction solvent was removed under reduced pressure. The residue was loaded onto a silica gel column and eluted with n-hexane:ethyl acetate = 30:1. Thin-layer chromatography was performed, the eluents were combined, and the solvent was removed to obtain the pyrazolopyran compound of formula (III) with fluorine and trifluoromethyl quaternary carbon centers.

[0188] White solid, yield 93%, ee value 99%, mass spectrometry (M+H). + )497.1479. 1 H NMR(400MHz, CDCl3)δ7.72(d,J=7.9Hz,2H),7.42(t,J=7.9Hz,5H),7.33-7.21 (m,5H),7.20-7.02(m,3H),6.73(s,1H),4.80(d,J=29.6Hz,1H),1.68(s,3H). 13 C NMR (100MHz, CDCl3) δ202.4,202.2,146.7,145.1,137.7,134.9,134.1,132.5,130. 5,129.8,129.7,129.1,128.8,128.1,128.1,126.3,120.6,95.9,46.6,46.4,13.6. 19 F NMR (376MHz, CDCl3) δ-78.84,-78.87,-180.43,-180.46,-180.50,-180.54.

[0189] Example 34: Preparation of Compound III O2

[0190] The preparation method is the same as that of compound III 01, R 1 =4-Cl-Ph, and the remaining experimental procedures are as described in Example 33.

[0191] White solid, yield 85%, ee value >99%, mass spectrometry (M+H). + )531.1087. 1H NMR (400MHz, CDCl3) δ7.76(d,J=7.9Hz,2H),7.52(t,J=7.4Hz,1H),7.46(t,J=7.9Hz,2H),7.39(d,J=8. 0Hz,3H),7.36-7.26(m,4H),7.07(d,J=39.9Hz,2H),6.12(s,1H),4.80(d,J=29.1Hz,1H),1.74(s,3H). 13 C NMR (100MHz, CDCl3) δ202.6,202.3,146.3,144.9,137.8,134.9,134.6,134.5,134.4, 131.7,131.1,129.9,129.8,129.2,128.3,126.4,120.6,95.3,94.1,46.3,46.1,13.8. 19 F NMR (376MHz, CDCl3) δ-78.97,-79.01,-180.78,-180.82,-180.85,-180.89.

[0192] Example 35: Preparation of Compound III O3

[0193] The preparation method is the same as that of compound III 01, R 1 =4-Br-Ph, and the remaining experimental procedures are as described in Example 33.

[0194] White solid, yield 75%, ee value 98%, mass spectrometry (M+H). + )575.0593. 1 H NMR (400MHz, CDCl3) δ7.68(d,J=7.7Hz,2H),7.44(t,J=7.4Hz,2H),7.38(t,J=8.0Hz,3H),7.30 (s,2H),7.22(d,J=7.4Hz,4H),6.88(s,1H),6.15(s,1H),4.71(d,J=29.1Hz,1H),1.66(s,3H). 13 C NMR (100MHz, CDCl3) δ201.4,201.1,145.2,143.9,136.7,133.6,133.5,133.4,131.0,13 0.6,128.8,128.7,128.2,127.3,125.4,122.0,95.2,94.2,93.0,76.3,45.3,45.1,12.8. 19F NMR (376MHz, CDCl3) δ-78.95,-78.98,-180.74,-180.78,-180.82,-180.85.

[0195] Example 36: Preparation of Compound III O4

[0196] The preparation method is the same as that of compound III 01, R 1 =4-CF3-Ph, and the remaining experimental procedures are as described in Example 33.

[0197] White solid, yield 70%, ee value 97%, mass spectrometry (M+H). + )565.1339. 1 H NMR (400MHz, CDCl3) δ7.72-7.67(m,2H),7.60-7.46(m,2H),7.45-7.36(m,4H),7.30- 7.19(m,4H),7.15(d,J=8.3Hz,2H),6.16(s,1H),4.81(d,J=28.9Hz,1H),1.65(s,3H). 13 C NMR (100MHz, CDCl3) δ201.1,200.9,145.1,144.0,136.7,135.8,133.7,133.4,133.4,130.0,129. 8,128.7,128.6,128.2,127.3,127.3,124.7,124.7,124.6,124.6,119.6,93.9,45.6,45.5,12.8. 19 FNMR(376MHz, CDCl3)δ-62.83,-78.92,-180.57,-180.61,-180.64,-180.68.

[0198] Example 37: Preparation of Compound III 05

[0199] The preparation method is the same as that of compound III 01, R 1 =4-OCH3-Ph, and the remaining experimental procedures are as described in Example 33.

[0200] White solid, yield 62%, ee value >99%, mass spectrometry (M+H). + )527.1581. 1H NMR(400MHz, CDCl3)δ7.77(dd,J=8.6,1.0Hz,2H),7.50-7.43(m,3H),7.42-7.32(m,3H),7.30-7.26(m,2H),7. 24(d,J=8.3Hz,1H),6.96(s,2H),6.65(s,1H),6.18(s,1H),4.77(d,J=29.4Hz,1H),3.75(s,3H),1.75(s,3H). 13 C NMR (100MHz, CDCl3) δ203.4,203.2,160.0,146.6,144.9,137.9,134.6,134.6,134.3,131 .5,129.9,129.9,129.2,128.2,126.2,124.2,120.5,95.9,77.3,55.3,46.2,46.0,13.8. 19 F NMR (376MHz, CDCl3) δ-78.99,-79.03,-180.77,-180.81,-180.84,-180.88.

[0201] Example 38: Preparation of Compound III 06

[0202] The preparation method is the same as that of compound III 01, R 1 =4-NO2-Ph, and the remaining experimental procedures are as described in Example 33.

[0203] White solid, yield 93%, ee value >99%, mass spectrometry (M+H). + )541.1231. 1 H NMR (400MHz, CDCl3) δ8.18(d,J=8.7Hz,1H),8.04(d,J=7.7Hz,1H),7.78-7.74(m,2H),7.52(d,J=7.5Hz,1H),7.47( dt,J=8.4,3.8Hz,5H),7.30(dd,J=13.0,7.5Hz,3H),7.25(s,1H),6.22(s,1H),4.96(d,J=28.8Hz,1H),1.69(s,3H). 13 C NMR (100MHz, CDCl3) δ201.2,200.9,148.1,145.9,144.9,140.4,137.6,135.0,134.4,131 .4,129.8,129.7,129.3,128.5,128.5,123.8,123.7,120.6,94.8,77.3,46.5,46.4,13.8.19 F NMR (376MHz, CDCl3) δ-78.90,-78.93,-180.60,-180.63,-180.67,-180.70.

[0204] Example 39: Preparation of Compound III 07

[0205] The preparation method is the same as that of compound III 01, R 1 =3-F-Ph, and the remaining experimental procedures are as described in Example 33.

[0206] White solid, yield 74%, ee value >99%, mass spectrometry (M+H). + )515.1381. 1 H NMR (400MHz, CDCl3) δ7.77(d,J=7.7Hz,2H),7.46(tt,J=16.2,7.9Hz,5H),7.29(t,J=7.5Hz,3H),7.25(s, 1H),7.20-7.12(m,1H),7.02-6.94(m,1H),6.88(s,1H),6.16(s,1H),4.84(d,J=26.1Hz,1H),1.75(s,3H). 13 C NMR (100MHz, CDCl3) δ202.5,202.3,146.3,144.9,137.8,134.6,130.4,130.3,1 29.9,129.8,129.2,128.3,128.3,126.4,126.1,120.6,113.0,95.2,46.4,13.7. 19 FNMR(376MHz, CDCl3)δ-78.96,-111.40,-112.37,-180.68.

[0207] Example 40: Preparation of Compound III 08

[0208] The preparation method is the same as that of compound III 01, R 1 =3-NO2-Ph, and the remaining experimental procedures are as described in Example 33.

[0209] White solid, 95% yield, ee value >99%, mass spectrometry (M+H). + )542.1318. 1H NMR (400MHz, CDCl3) δ8.04(d,J=9.1Hz,1H),7.95(dd,J=15.6,8.2Hz,1H),7.69(d,J=7.8Hz,3H),7.47-7.39(m,5H),7.37(d,J=7.1H z,1H),7.26(dd,J=14.5,7.7Hz,1H),7.21(d,J=4.1Hz,1H),7.17(d,J=8.0Hz,1H),6.17(s,1H),4.89(d,J=28.6Hz,1H),1.62(s,3H). 13 C NMR (100MHz, CDCl3) δ201.3,201.0,145.8,145.0,137.6,136.3,134.9,134.4,134.4,129. 8,129.8,129.7,129.2,128.5,128.5,126.6,125.1,123.8,120.7,94.7,46.6,46.4,13.8. 19 F NMR(376MHz, CDCl3)δ-78.92,-78.96,-180.97.

[0210] Example 41: Preparation of Compound III 09

[0211] The preparation method is the same as that of compound III 01, R 1 =2-CH3-Ph, and the remaining experimental procedures are as described in Example 33.

[0212] White solid, yield 75%, ee value >99%, mass spectrometry (M+H). + )511.1629. 1 H NMR (400MHz, CDCl3) δ7.79-7.75(m,2H),7.46(q,J=8.4,7.9Hz,4H),7.37(d,J=8.2Hz,2H),7.28(d,J=7.4Hz,1H),7.23(t ,J=7.9Hz,3H),7.19-7.14(m,1H),7.01(d,J=7.5Hz,1H),6.38(s,1H),5.17(d,J=29.6Hz,1H),2.21(s,3H),1.62(s,3H). 13C NMR (100MHz, CDCl3) δ203.4,203.2,146.4,145.0,137.9,136.7,134.5,134.2,134.2,131.5,131. 5,131.1,130.8,129.9,129.9,129.2,128.6,128.2,128.2,126.4,126.2,120.5,96.7,19.8,13.4. 19 F NMR (376MHz, CDCl3) δ-78.71,-78.75,-180.28,-180.32,-180.36,-180.40.

[0213] Example 42: Preparation of Compound III 10

[0214] The preparation method is the same as that of compound III 01, R 1 =2-Cl-Ph, and the remaining experimental procedures are as described in Example 33.

[0215] White solid, yield 75%, ee value 99%, mass spectrometry (M+H). + )549.9310. 1 H NMR (400MHz, CDCl3) δ7.77(dd,J=8.7,1.0Hz,2H),7.50(dd,J=10.2,1.9Hz,3H),7.48-7.40(m,3H),7.33- 7.26(m,3H),7.25(d,J=1.3Hz,1H),7.23-7.19(m,2H),6.57(s,1H),5.54(d,J=29.4Hz,1H),1.65(s,3H). 13 C NMR (100MHz, CDCl3) δ201.5,201.3,146.1,145.0,137.9,134.6,134.6,134.2,134.1,133.0,132.9,1 31.0,130.0,129.9,129.8,129.7,129.2,128.3,128.2,127.0,126.3,120.6,95.9,41.3,41.2,13.3. 19 F NMR (376MHz, CDCl3) δ-78.62,-78.66,-179.68,-179.72,-179.76,-179.80.

[0216] Example 43: Preparation of Compound III 11

[0217] The preparation method is the same as that of compound III 01, R 1=3,5-2CH3-Ph, and the remaining experimental procedures are as described in Example 33.

[0218] White solid, yield 94%, ee value 99%, mass spectrometry (M+H). + )525.1778. 1 H NMR (400MHz, CDCl3) δ7.78(d,J=1.1Hz,2H),7.50-7.42(m,3H),7.37(d,J=8.2Hz,2H),7.32(dd,J=8.0,4.4Hz,1H),7.28(d,J=7.4Hz,1 H),7.25-7.20(m,2H),7.04(d,J=7.1Hz,1H),6.82(s,1H),6.37(s,1H),5.12(d,J=29.7Hz,1H),2.25(s,3H),2.16(s,3H),1.63(s,3H). 13 C NMR (100MHz, CDCl3) δ196.2,195.8,146.5,138.2,138.0,136.4,134.4,134.2,131.4,130 .0,129.9,129.1,128.1,127.9,127.2,126.2,120.5,96.8,40.6,40.4,21.0,19.7,13.4. 19 F NMR (376MHz, CDCl3) δ-78.74,-78.78,-180.32,-180.36,-180.40,-180.44.

[0219] Example 44: Preparation of Compound III 12

[0220] The preparation method is the same as that of compound III 01, R 1 =3,4,5-3OCH3-Ph, and the remaining experimental procedures are as described in Example 33.

[0221] White solid, yield 62%, ee value 99%, mass spectrometry (M+H). + )587.1777. 1 H NMR (400MHz, CDCl3) δ7.79(d,J=7.8Hz,2H),7.49(dt,J=15.9,7.8Hz,3H),7.41(d,J=8.2Hz,2H),7.29(dd,J=7.6, 2.7Hz,3H),6.64(s,1H),6.38(s,1H),6.26(s,1H),4.74(d,J=28.9Hz,1H),3.78(s,6H),3.56(s,3H),1.86(s,3H).13 C NMR (100MHz, CDCl3) δ202.9,202.6,146.5,145.0,138.6,137.8,134.7,134.5,129.7,129.7,129.2,1 28.2,128.2,127.6,126.3,120.5,108.2,107.1,96.4,95.4,94.2,61.0,56.5,56.2,47.1,47.0,13.8. 19 F NMR (376MHz, CDCl3) δ-78.93,-78.96,-179.66,-179.70,-179.74,-179.78.

[0222] Example 45: Preparation of Compound III 13

[0223] The preparation method is the same as that of compound III 01, R 1 =thiophenyl, and the remaining experimental procedures are as described in Example 33.

[0224] White solid, yield 67%, ee value 99%, mass spectrometry (M+H). + )503.1040. 1 H NMR (400MHz, CDCl3) δ7.76(d,J=7.7Hz,2H),7.58-7.50(m,3H),7.46(t,J=8.0Hz,2H),7.37-7.28(m,3H),7.25 (d,J=5.4Hz,1H),7.00(d,J=2.9Hz,1H),6.95-6.84(m,1H),6.19(s,1H),5.16(d,J=28.4Hz,1H),1.82(s,3H). 13 C NMR (100MHz, CDCl3) δ202.6,202.3,146.7,144.3,137.8,134.7,134.5,129.8,129.7,1 29.3,129.2,128.3,128.3,127.0,127.0,126.8,126.3,120.6,96.0,42.5,42.3,13.3. 19 F NMR (376MHz, CDCl3) δ-79.05,-79.09,-178.90,-178.93,-178.96,-178.98.

[0225] Example 46: Preparation of Compound III 14

[0226] The preparation method is the same as that of compound III 01, R 4=-CH2CH3, and the remaining experimental procedures are as described in Example 33.

[0227] White solid, yield 79%, ee value >99%, mass spectrometry (M+H). + )511.1634. 1 H NMR (400MHz, CDCl3) δ7.79(d,J=7.7Hz,2H),7.43(dt,J=24.5,7.4Hz,5H),7.32-7.26(m,4H),7.21(t,J=7.8Hz,2H),7.11(dd,J=16.5 ,9.5Hz,2H),6.18(s,1H),4.81(d,J=29.3Hz,1H),2.18(dq,J=15.1,7.6Hz,1H),1.93(dq,J=15.0,7.5Hz,1H),0.97(t,J=7.5Hz,3H). 13 C NMR (100MHz, CDCl3) δ203.3,203.0,151.7,144.9,138.0,134.6,134.5,134.3,132.5,130 .4,129.9,129.8,129.1,128.8,128.7,128.1,126.2,120.6,94.8,47.0,46.8,21.6,12.5. 19 F NMR (376MHz, CDCl3) δ-78.97,-79.01,-180.26,-180.30,-180.33,-180.37.

[0228] Example 47: Preparation of Compound III 15

[0229] The preparation method is the same as that of compound III 01, R 1 =3-Cl-Ph; R 4 =-CH2CH3, and the remaining experimental procedures are as described in Example 33.

[0230] White solid, yield 82%, ee value 96%, mass spectrometry (M+H). + )545.9310. 1H NMR (400MHz, CDCl3) δ7.78(d,J=8.0Hz,2H),7.46(tt,J=13.7,7.4Hz,6H),7.29(dd,J=7.5,3.5Hz,4H),7.02(dd,J=38.2,8.1H z,2H),6.14(s,1H),4.79(t,J=27.2Hz,1H),2.17(dd,J=14.3,7.3Hz,1H),1.96(dd,J=13.6,6.5Hz,1H),0.99(t,J=7.5Hz,3H). 13 C NMR (100MHz, CDCl3) δ202.3,202.3,151.4,144.9,137.9,134.6,130.4,129 .9,129.8,129.2,128.5,128.3,126.3,120.7,94.3,46.7,46.5,21.6,12.4. 19 F NMR (376MHz, CDCl3) δ-78.96,-79.00,-180.26,-180.30,-180.40,-180.43.

[0231] Example 48: Preparation of Compound III 16

[0232] The preparation method is the same as that of compound III 01, R 1 =3-F,5-CH3-Ph; R 4 =-CH2CH3, and the remaining experimental procedures are as described in Example 33.

[0233] White solid, yield 76%, ee value >99%, mass spectrometry (M+H). + )541.1698. 1 H NMR (400MHz, CDCl3) δ7.78(d,J=7.6Hz,2H),7.51(s,1H),7.49(d,J=6.9Hz,1H) ,7.43(dd,J=13.2,7.3Hz,4H),7.28(d,J=5.6Hz,3H),7.25(s,1H),6.97-6.90( m,1H),6.72(dd,J=9.7,2.7Hz,1H),6.29(s,1H),5.14(d,J=29.1Hz,1H),2.21( s,3H),2.07(dd,J=15.0,7.5Hz,1H),1.89-1.74(m,1H),0.95(t,J=7.6Hz,3H). 13C NMR (100MHz, CDCl3) δ203.2,202.9,163.6,151.3,144.9,139.2,138.0,134.7,134.1,134.1,133.5,133.4,133.3,129 .9,129.8,129.2,128.3,127.0,126.2,120.6,117.3,117.1,113.6,113.4,100.0,95.5,40.6,40.4,21.4,19.8,12.4. 19 F NMR (376MHz, CDCl3) δ-78.77,-78.81,-113.44,-180.29,-180.33,-180.37,-180.41.

[0234] Example 49: Preparation of Compound III 17

[0235] The preparation method is the same as that of compound III 01, R 1 =4-F-Ph; R 4 =-CH2(CH3)2, and the remaining experimental procedures are as described in Example 33.

[0236] White solid, yield 83%, ee value >99%, mass spectrometry (M+H). + )541.1698. 1 H NMR (400MHz, CDCl3) δ7.80(d,J=7.7Hz,2H),7.48(dt,J=16.0,7.9Hz,4H),7.36(d,J=8.3Hz,2H),7.28(s,1H),7.25(d,J=3.1Hz,1H),7.15-7.0 2(m,2H),6.82(td,J=8.4,2.3Hz,1H),6.05(s,1H),4.82(d,J=28.9Hz,1H),2.09(p,J=6.9Hz,1H),1.15(d,J=6.8Hz,3H),0.96(d,J=6.9Hz,3H). 13 C NMR (100MHz, CDCl3) δ203.0,202.7,155.0,144.7,138.1,134.5,134.5,134.5,132.2,132.0,131.9,129.9,129 .8,129.1,128.6,128.5,128.3,126.2,120.6,116.2,115.9,115.5,115.3,94.2,46.6,46.4,27.3,22.6,19.5. 19F NMR (376MHz, CDCl3) δ-79.02,-79.06,-112.55,-180.24,-180.28,-180.31,-180.35.

[0237] Example 50: Preparation of Compound III 18

[0238] The preparation method is the same as that of compound III 01, except that formula (9) is replaced with R. 4 =-Ph, and the remaining experimental procedures are as described in Example 33.

[0239] White solid, yield 73%, ee value >99%, mass spectrometry (M+H). + )559.1635. 1 H NMR (400MHz, CDCl3) δ7.96-7.86(m,2H),7.50(t,J=8.0Hz,2H),7.44(t,J=7.2Hz,1H),7.37-7.29(m ,3H),7.26-7.15(m,4H),7.13-7.01(m,5H),7.01-6.91(m,3H),6.25(s,1H),5.14(d,J=28.8Hz,1H). 13 CNMR(100MHz, CDCl3)δ203.5,203.4,149.0,145.6,138.0,134.6,134.5,134.3,132.2,131.9,131.9,130.4, 130.4,130.0,129.9,129.2,128.4,128.1,128.1,127.6,127.6,127.5,126.6,121.0,94.7,47.5,47.4,26.9. 19 F NMR (376MHz, CDCl3) δ-78.92,-78.96,-179.80,-179.84,-179.88,-179.92.

[0240] Example 51: Preparation of Compound III 19

[0241] The preparation method is the same as that of compound III 01, R 1 =3-Br-Ph; R 4 =-Ph, and the remaining experimental procedures are as described in Example 33.

[0242] White solid, yield 73%, ee value >99%, mass spectrometry (M+H). + )559.1635. 1H NMR(400MHz, CDCl3)δ7.89(d,J=7.9Hz,2H),7.50(t,J=7.9Hz,3H),7.37-7.27(m,5H),7.23(s,1 H),7.16-7.02(m,5H),6.94(d,J=7.2Hz,2H),6.19(s,1H),5.11(d,J=28.5Hz,1H),4.82(s,1H). 13 C NMR (100MHz, CDCl3) δ202.6,202.4,148.9,145.5,137.8,134.7,134.5,134.4,132.0,131.9,131.4,1 31.2,129.9,129.9,129.2,128.3,128.3,127.9,127.7,127.5,126.8,122.4,121.0,94.3,47.0,46.8. 19 F NMR (376MHz, CDCl3) δ-78.93,-78.96,-180.08,-180.12,-180.15,-180.19.

[0243] Example 52: Preparation of Compound III 20

[0244] The preparation method is the same as that of compound III 01, R 2 =4-CH3-Ph, and the remaining experimental procedures are as described in Example 33.

[0245] White solid, yield 92%, ee value >99%, mass spectrometry (M+H). + )511.1643. 1 H NMR(400MHz, CDCl3) δ7.76(d,J=7.7Hz,2H),7.41(dt,J=29.1,7.5Hz,4H),7.31-7.22(m ,4H),7.20-6.93(m,4H),6.45(s,1H),4.78(d,J=29.5Hz,1H),2.31(s,3H),1.72(s,3H). 13 C NMR (100MHz, CDCl3) δ202.3,202.1,146.6,145.7,145.0,137.9,132.5,132.1,132.1,130 .5,130.1,130.0,129.1,128.9,128.9,128.7,126.2,120.6,95.7,94.1,46.8,21.8,13.7. 19F NMR (376MHz, CDCl3) δ-79.00,-79.04,-180.35,-180.39,-180.43,-180.47.

[0246] Example 53: Preparation of Compound III 21

[0247] The preparation method is the same as that of compound III 01, R 2 =4-Cl-Ph, and the remaining experimental procedures are as described in Example 33.

[0248] White solid, yield 92%, ee value >99%, mass spectrometry (M+H). + )531.1093. 1 H NMR (400MHz, CDCl3) δ7.75 (d, J=7.8Hz, 2H), 7.42 (dt, J=28.6, 7.6Hz, 4H), 7.33-7.27 (m, 2H ),7.27-7.22(m,3H),7.20-6.96(m,3H),6.28(s,1H),4.78(d,J=29.6Hz,1H),1.71(s,3H). 13 C NMR (100MHz, CDCl3) δ201.7,201.4,146.5,144.9,141.1,137.8,132.9,132.9,132.3,131.2, 131.1,130.4,129.2,129.0,128.9,128.6,126.3,120.6,100.0,95.6,94.3,46.7,46.5,13.7. 19 FNMR(376MHz, CDCl3)δ-78.92,-78.96,-180.23,-180.27,-180.30,-180.34.

[0249] Example 54: Preparation of Compound III 22

[0250] The preparation method is the same as that of compound III 01, R 2 =4-COOMe-Ph, and the remaining experimental procedures are as described in Example 33.

[0251] White solid, yield 83%, ee value >99%, mass spectrometry (M+H). + )555.1542. 1H NMR (400MHz, CDCl3) δ7.86 (d, J = 8.5Hz, 2H), 7.79-7.71 (m, 2H), 7.51-7.37 (m, 4H), 7.33-7.27 ( m,4H),7.11(d,J=36.1Hz,2H),6.23(s,1H),4.80(d,J=29.6Hz,1H),3.90(s,3H),1.71(s,3H). 13 C NMR (100MHz, CDCl3) δ202.6,202.3,165.8,144.9,137.9,137.9,137.7,134.4,132.2,130.5, 129.6,129.5,129.2,129.1,129.1,129.0,128.9,126.3,120.6,95.6,52.5,46.7,46.5,13.7. 19 F NMR (376MHz, CDCl3) δ-78.85,-78.89,-180.54,-180.57,-180.61,-180.65.

[0252] Example 55: Preparation of Compound III 23

[0253] The preparation method is the same as that of compound III 01, R 2 =4-(CH2)4CH3-Ph, and the remaining experimental procedures are as described in Example 33.

[0254] White solid, 90% yield, ee value >99%, mass spectrometry (M+H). + )567.2269. 1 H NMR (400MHz, CDCl3) δ7.77(d,J=7.9Hz,2H),7.42(dt,J=28.1,7.1Hz,4H),7.26(t,J=6.2Hz,4H),7.01(d,J=8.3Hz,4H),6.45(s ,1H),4.78(d,J=29.5Hz,1H),2.63-2.48(m,2H),1.72(s,3H),1.55(p,J=7.6Hz,2H),1.36-1.20(m,4H),0.87(t,J=7.0Hz,3H). 13C NMR (100MHz, CDCl3) δ202.4,202.2,150.6,146.5,145.0,137.9,132.5,132.2,132.2,130.5,13 0.1,130.0,129.1,128.7,128.2,126.2,120.6,95.7,46.8,46.6,36.0,31.4,30.4,22.4,13.7. 19 FNMR(376MHz, CDCl3)δ-78.98,-79.02,-180.40,-180.44,-180.48,-180.51.

[0255] Example 56: Preparation of Compound III 24

[0256] The preparation method is the same as that of compound III 01, R 2 =2-naphyl, and the remaining experimental procedures are as described in Example 33.

[0257] White solid, yield 88%, ee value 99%, mass spectrometry (M+H). + )547.1640. 1 H NMR (400MHz, CD3OD) δ7.80 (d, J = 8.2Hz, 1H), 7.77-7.63 (m, 5H), 7.59-7.44 (m, 5H), 7.44-7.00 (m, 6H), 5.08 (d, J = 31.2Hz, 1H), 1.71 (s, 3H). 13 C NMR (100MHz, CD3OD) δ196.6,196.6,147.0,145.5,137.6,135.0,133.7,133.6,133.5,131.8,130.7,130. 5,129.2,129.0,128.4,128.4,128.2,127.2,127.2,126.4,126.4,124.3,120.8,97.1,45.2,45.0,12.2. 19 F NMR (376MHz, CD3OD) δ-79.73,-79.77,-179.46.

[0258] Example 57: Preparation of Compound III 25

[0259] The preparation method is the same as that of compound III 01, R 2 =3-1,3-dioxindan, and the remaining experimental procedures are as described in Example 33.

[0260] White solid, yield 93%, ee value >99%, mass spectrometry (M+H).+ )541.1385. 1 H NMR (400MHz, DMSO-d6) δ10.14(s,1H),7.76(d,J=7.8Hz,2H),7.54(t,J=7.9Hz,2H),7.33(dd,J=12.9,5.2Hz,4H) ,7.21(s,2H),7.03(s,1H),6.86(d,J=8.2Hz,1H),6.74(s,1H),6.06(s,2H),4.99(d,J=32.2Hz,1H),1.59(s,3H). 13 C NMR (100MHz, DMSO-d6) δ195.7,195.6,151.8,145.1,138.2,133.7,129.8,129.0,128.7,126.6,120.4,108.3,102.6,97.5,44.9,44.7,13.8. 19 F NMR(376MHz, DMSO)δ-77.65,-77.68,-178.49.

[0261] Example 58: Preparation of Compound III 26

[0262] The preparation method is the same as that of compound III 01, R 2 =3-indole, and the remaining experimental procedures are as described in Example 33.

[0263] White solid, yield 93%, ee value >99%, mass spectrometry (M+H). + )536.1594. 1 H NMR (400MHz, DMSO-d6) δ11.88(s,1H),9.86(s,1H),8.25(s,1H),7.80(dd,J=10.9,5.7Hz,3H),7.54(t,J= 7.9Hz,2H),7.45-7.38(m,1H),7.36-7.30(m,1H),7.29-7.06(m,7H),5.08(d,J=32.8Hz,1H),1.57(s,3H). 13 C NMR(100MHz,DMSO-d6)δ187.5,187.2,146.6,145.2,138.3,135.7,135.3,135.0,134.5,129.8,128.6 ,128.2,126.8,126.5,123.7,122.8,121.9,120.3,114.3,112.6,98.1,97.6,95.5,43.9,43.8,13.8. 19F NMR(376MHz, DMSO-d6)δ-77.67,-77.70,-179.38,-179.42,-179.45,-179.48.

[0264] Example 59: Preparation of Compound III 27

[0265] The preparation method is the same as that of compound III 01, R 2 =2-funanyl, and the remaining experimental procedures are as described in Example 33.

[0266] White solid, 95% yield, ee value >99%, mass spectrometry (M+H). + )487.1277. 1 H NMR (400MHz, DMSO-d6) δ10.22(s,1H),7.97(s,1H),7.76(d,J=7.8Hz,2H),7.54(t,J=7.9Hz,2H),7.33(t,J=7.4 Hz,1H),7.31-7.15(m,5H),7.14-7.08(m,1H),6.56(dd,J=3.6,1.5Hz,1H),4.97(d,J=32.7Hz,1H),1.56(s,3H). 13 C NMR(100MHz,DMSO-d6)δ180.7,180.5,150.0,149.9,149.7,146.6,144.9,138.1,133.6,129.8 ,128.8,128.6,126.7,123.0,122.8,120.4,113.3,113.2,97.4,97.0,94.9,44.0,43.8,13.7. 19 F NMR(376MHz, DMSO-d6)δ-77.82,-77.86,-182.84,-182.88,-182.91,-182.95.

[0267] Example 60: Preparation of Compound III 28

[0268] The preparation method is the same as that of compound III 01, R 2 =2-thiophenyl, and the remaining experimental procedures are as described in Example 33.

[0269] White solid, yield 95%, ee value 98%, mass spectrometry (M+H). + )503.1046. 1H NMR (400MHz, DMSO-d6) δ10.22(s,1H),7.98(d,J=4.9Hz,1H),7.77(d,J=7.9Hz,2H),7.63(s,1H),7.54(t,J=7.9H z,2H),7.34(t,J=7.4Hz,1H),7.24(d,J=7.6Hz,5H),7.08(t,J=4.3Hz,1H),4.99(d,J=32.7Hz,1H),1.57(s,3H). 13 C NMR(101MHz,DMSO-d6)δ186.4,186.1,146.5,145.0,141.0,141.0,138.2,137.5,135.4,13 5.3,133.6,129.8,129.2,129.2,128.8,128.6,126.7,120.4,97.5,95.8,44.4,44.2,13.8. 19 F NMR(376MHz, DMSO-d6)δ-77.72,-77.75,-179.37,-179.40,-179.43,-179.47.

[0270] Example 61: Preparation of Compound III 29

[0271] The preparation method is the same as that of compound III 01, R 2 =cyclohexyl, and the remaining experimental procedures are as described in Example 33.

[0272] White solid, yield 83%, ee value 56%, mass spectrometry (M+H). + )503.1955. 1 H NMR (400MHz, DMSO-d6) δ10.24(s,1H),7.88(d,J=7.8Hz,2H),7.67(t,J=7.6Hz,2H),7. 48(d,J=12.2Hz,4H),7.31(s,2H),4.94(d,J=32.8Hz,1H),1.79(d,J=12.2Hz,1H),1.6 8(s,3H),1.60(d,J=10.4Hz,2H),1.44(dd,J=25.3,11.8Hz,2H),1.24(q,J=11.8Hz,1H ),1.06(dq,J=24.5,12.4,11.7Hz,2H),0.69(d,J=11.9Hz,1H),0.17(q,J=10.8Hz,1H). 13C NMR(100MHz,DMSO-d6)δ206.6,206.3,146.5,144.8,138.1,134.1,129.8,128.9,12 8.7,126.6,120.3,97.6,95.4,46.7,43.3,43.1,27.2,26.9,25.6,25.5,25.0,13.8. 19 F NMR(376MHz,DMSO-d6)δ-78.22,-78.26,-185.41.

[0273] Example 62: Activity evaluation of the compound

[0274] The MTT assay was used to detect the activity of compounds (II) and (III) prepared in the above examples in inhibiting the proliferation of tumor cells in vitro. The tumor cells studied were non-small cell lung cancer cell line A549.

[0275] The specific method is as follows: First, A549 cells are placed at a density of 5 × 10⁶ cells per well. 3 Cells were cultured at a density of [number] cells in 96-well plates for 16 hours. Compound I 01-32 was diluted with 0.5 mg / ml MTT to seven concentrations (3.125, 6.25, 12.5, 25, 50, 100, 200 μM) and added to the wells. Cells were incubated at 37°C for another 4 hours, and then 100 μL of DMSO was added to the wells. The wells were shaken at room temperature for 10 minutes to dissolve the purple solid formed. Cell viability was assessed using a microplate reader (Bio-Rad Laboratories, Inc.). The in vitro inhibitory activity of compounds (II) and (III) on tumor cell (A549) proliferation is shown in Table 3 below.

[0276] Table 3

[0277] serial number <![CDATA[IC 50 (μM)]]> serial number <![CDATA[IC 50 (μM)]]> serial number <![CDATA[IC 50 (μM)]]> serial number <![CDATA[IC 50 (μM)]]> II01 >50 II02 >50 II03 >50 II04 >50 II05 >50 II06 >50 II07 >50 II08 >50 II09 >50 II10 >50 II11 >50 II12 >50 II13 >50 II14 >50 II15 >50 II16 >50 II17 >50 II18 >50 II19 >50 II20 >50 II21 >50 II22 >50 II23 >50 II24 >50 II25 >50 II26 >50 II27 >50 II28 >50 II29 >50 II30 >50 II31 >50 II32 >50 III01 32.14 III02 25.09 III03 >50 III04 18.68 III05 20.12 III06 13.71 III07 36.91 III08 13.00 III09 >50 III10 >50 III11 >50 III12 >50 III13 >50 III14 >50 III15 >50 III16 >50 III17 17.23 III18 17.58 III19 19.71 III20 >50 III21 >50 III22 29.18 III23 >50 III24 >50 III25 41.41 III26 >50 III27 >50 III28 >50 III29 >50

[0278] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. A class of pyran derivatives containing fluorine and a trifluoromethyl quaternary carbon center, characterized in that, The pyran derivative containing a fluorine and a trifluoromethyl quaternary carbon center is selected from any of the following structures: 。 2. A method for preparing a pyran derivative containing a fluorine and a trifluoromethyl quaternary carbon center according to claim 1, characterized in that, A pyrazolinone compound, an α-fluorinated β-ketodiol compound, an organic base, and a second solvent are mixed, reacted, and then post-treated to obtain the compound; the compound is a compound of formula (III); The reaction formula is as follows: ； R 1 R 2 R 4 R 5 The group at the corresponding position of the compound described in claim 1 is consistent.

3. The preparation method according to claim 2, characterized in that, The organic base is a chiral amine catalyst.

4. The preparation method according to claim 2, characterized in that, The molar ratio of pyrazolinone compounds, α-fluorinated β-ketodiol compounds, and organic bases is 0.1~10:1:0.01~1.

5. The use of the fluorine-containing and trifluoromethyl quaternary carbon-centered pyran derivative of claim 1 in the preparation of a medicament for treating lung cancer.

6. A pharmaceutical composition, characterized in that, Include: (a) 0.001-99.99% by weight of the fluorine- and trifluoromethyl quaternary carbon-centered pyran derivatives of claim 1, their pharmaceutically acceptable salts, or combinations thereof; and (b) Pharmaceutically acceptable carriers and / or excipients.

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