Cryptotanshinone derivative as well as preparation method and medical application thereof

Abstract

The invention discloses a cryptotanshinone derivative as well as a preparation method and medical application thereof. The invention specifically discloses a cryptotanshinone derivative as shown in a formula I. The cryptotanshinone derivative has good inhibitory activity on triple-negative breast cancer cells.

Description

TECHNICAL FIELD

[0001] The present application relates to a cryptotanshinone derivative, a preparation method and medical uses thereof. BACKGROUND

[0002] Breast cancer is the second most common cause of death in female cancer patients. According to the expression status of hormone receptors, breast cancer can be divided into five molecular subtypes, of which triple negative breast cancer (TNBC) accounts for 15-20% of the incidence of breast cancer. TNBC is the only subtype of breast cancer lacking targeted treatment due to its negative expression of estrogen receptor (ER), progesterone receptor (PR) and epidermal growth factor receptor 2 (ERBB2). Compared with other breast cancer subtypes, TNBC has high metastasis rate, low survival rate and poor prognosis. At present, the systemic treatment regimen for TNBC mainly uses drugs containing taxanes and anthracyclines for chemotherapy, but studies have shown that existing chemotherapy drugs have developed resistance. Therefore, it is urgent to find new TNBC treatment drugs.

[0003] Salvia miltiorrhiza Bge. of Labiatae. Cryptotanshinone (structure shown below) is one of the main liposoluble components of Salvia miltiorrhiza extract. It has anticancer, anti-inflammatory, immunomodulatory, neuroprotective and anti-fibrosis biological activities. Studies have shown that CTS can inhibit the growth of breast cancer cells and promote their apoptosis through competitive binding of ERa, mediation of JAK2 / STAT4 stimulation of the immune system and induction of endoplasmic reticulum stress.

[0004] SUMMARY

[0005] The technical problem to be solved by the present application is to overcome the structural simplicity of the drugs for treating triple negative breast cancer in the prior art, and therefore the present application provides a cryptotanshinone derivative, a preparation method and medical uses thereof. The cryptotanshinone derivative shows one or more of the following advantages over the lead compound cryptotanshinone: (1) better anti-triple negative breast cancer activity, (2) further optimization of drug properties, such as increased metabolic stability and / or better absorption characteristics.

[0006] The present application solves the above technical problems by the following technical solutions.

[0007] The present application provides a cryptotanshinone derivative as shown in formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof for use in the preparation of a drug for treating triple negative breast cancer.

[0008]

[0009] wherein the dotted line "-----" in ring A is a single or double bond;

[0010] R 1 , R 2 together form =X1, wherein X1is CH2, O, S or NH;

[0011] or R 1 , R 2 are each independently hydrogen;

[0012] R 3 is independently hydrogen or -O-R 3-1 ;

[0013] R 3-1 is independently 5-6 membered heteroaryl or 5-6 membered heteroaryl substituted with one or more R 3-1-1 ; the number of heteroatoms in said 5-6 membered heteroaryl is 1, 2 or 3, each heteroatom being independently N, O or S;

[0014] R 3-1-1 is independently halogen, -CN, C 1-6 haloalkyl, C 2-6 alkenyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -S-C 1-6 alkyl, -SO-C 1-6 alkyl or -SO2-C 1-6 alkyl;

[0015] R in ring C; a end is connected to ring B and b end is connected to ring D;

[0016] X2is O or N-O-R 4 ;

[0017] X3is O;

[0018] R 4 is independently hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, -(C 1-4 alkylene) n- C 1-6 alkoxy, -(C 1-4 alkylene) n -C 1-6 haloalkoxy or -(C 1-4 alkylene) n -C6-C 10 aryl; n is 0 or 1; said -(C 1-4 alkylene) n -C6-C10 C6-C10aryl in the aryl group is substituted with one or more R 10 C6-C10aryl is substituted with one or more R 4-1 C6-C10aryl is substituted with one or more R

[0019] R 4-1 is independently hydrogen, halogen, -CN, -NO2, C 1-6 alkyl, C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 haloalkoxy;

[0020] when is X2is O and X3is O, R 3 is -O-R 3-1 .

[0021] In some embodiments, when R 1 , R 2 together form =X1, X1is O.

[0022] In some embodiments, R 1 , R 2 are each independently hydrogen.

[0023] In some embodiments, R 3 is hydrogen.

[0024] In some embodiments, R 3-1 is independently 5-6 membered heteroaryl substituted with one or more R 3-1-1 , the number of heteroatoms in the 5-6 membered heteroaryl group is 1, 2, or 3, each heteroatom is independently N, O, or S.

[0025] In some embodiments, R 3-1-1 is independently halogen, -CN, C 1-6 haloalkyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -S-C 1-6 alkyl, -SO-C 1-6 alkyl, or -SO2-C 1-6 alkyl.

[0026] In some embodiments, R 4 is independently hydrogen, C 1-6 alkyl, -(C 1-4 alkylene) n -C6-C 10 aryl; n is 0 or 1; the -(C 1-4 alkylene) n -C6-C 10 aryl group is substituted with one or more R10 Aryl is substituted by one or more R 4-1 ; preferably hydrogen, -(C 1-4 Alkylene) n -C6-C 10 aryl.

[0027] In some embodiments, R 4-1 is independently hydrogen, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 haloalkoxy; preferably hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 haloalkoxy.

[0028] In some embodiments, R 3 is hydrogen;

[0029] In ring C, is

[0030] X2is N-OR 4 ;

[0031] X3is O.

[0032] In some embodiments, R 3 is hydrogen;

[0033] In ring C, is a is attached to ring B and b is attached to ring D.

[0034] In some embodiments, R 3 is -O-R 3-1 ;

[0035] In ring C, is

[0036] X2is O;

[0037] X3is O.

[0038] In some embodiments,

[0039] The dashed line “-----” in ring A is a single or double bond;

[0040] R 1 and R 2 together form =X1, wherein X1is O;

[0041] or R 1 and R 2 are each independently hydrogen;

[0042] R 3 It is hydrogen;

[0043] In ring C for End a is connected to ring B, and end b is connected to ring D;

[0044] X2 is 0 or N-OR 4 ;

[0045] X3 is 0;

[0046] R 4 Independently hydrogen, -(C 1-4 Alkylene) n -C6-C 10 Aryl; n is 0 or 1; the -(C 1-4 Alkylene) n -C6-C 10 C6-C in aryl 10 aryl is formed by one or more R 4-1 Replaced;

[0047] R 4-1 Independently hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Halogenated alkoxy groups; preferably, R 4-1 Independently hydrogen, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Halogenated alkoxy groups.

[0048] In some schemes, R 3-1 In the context, the 5-6 membered heteroaryl group and the group surrounded by one or more R 3-1-1 The heteroatom of the substituted 5-6-membered heteroaryl group is independently N or O, and the number of heteroatoms is independently one or two; preferably, it is a 5-6-membered heteroaryl group containing an N atom; more preferably, it is pyridyl or pyrimidinyl, for example,

[0049] In some schemes, R 3-1-1 In this context, the halogen is independently F, Cl, Br or I, preferably F, Cl or Br.

[0050] In some schemes, R 3-1-1 In, the C 2-6 The alkenyl group can be vinyl, 1-propenyl, 2-propenyl, 1-methylvinyl, butenyl, or pentenyl.

[0051] In some schemes, R 3-1-1 In, the C 1-6Haloalkyl, C 1-6 Alkyl, -SC 1-6 Alkyl, -SO-C 1-6 Alkyl groups and -SO2-C 1-6 C in alkyl 1-6 The alkyl group is independently methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl.

[0052] In some schemes, R 3-1-1 In, the C 1-6 Halogenated alkyl groups and C 1-6 The number of halogens in a haloalkoxy group can be 1, 2, or 3, for example, 3.

[0053] In some schemes, R 3-1-1 In, the C 1-6 Halogenated alkyl groups and C 1-6 The halogen in the haloalkoxy group is independently fluorinated, chlorinated, brominated or iodinated, preferably fluorinated.

[0054] In some schemes, R 3-1-1 In, the C 1-6 Alkoxy and C 1-6 C in haloalkoxy 1-6 The alkoxy group is independently methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, or tert-butoxy, preferably methoxy.

[0055] In some schemes, R 4 In, the C 1-6 Alkyl and C 1-6 C in haloalkyl 1-6 The alkyl group is independently methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl or ethyl.

[0056] In some schemes, R 4 In, the -(C 1-4 Alkylene) n -C 1-6 Alkoxy, -(C 1-4 Alkylene) n -C 1-6 Halogenated alkoxy groups and -(C 1-4 Alkylene) n -C6-C 10 C in aryl 1-4 The alkylene group is independently -CH2-, -CH2CH2-, -CH(CH3)-, -CH(CH3)CH2- or -C(CH3)2-, for example -CH2-.

[0057] In some schemes, R 4 In, the -(C1-4 Alkylene) n- C 1-6 Alkoxy and -(C 1-4 Alkylene) n -C 1-6 C in haloalkoxy 1-6 The alkoxy group is independently methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, or tert-butoxy.

[0058] In some schemes, R 4 In, the C 1-6 Halogenated alkyl groups and -(C 1-4 Alkylene) n- C 1-6 The number of halogens in a haloalkoxy group can be 1, 2, or 3 independently.

[0059] In some schemes, R 4 In, the C 1-6 Halogenated alkyl groups and -(C 1-4 Alkylene) n -C 1-6 The halogen in a haloalkoxy group can be fluorinated, chlorinated, brominated, or iodinated independently.

[0060] In some schemes, R 4 In, the -(C 1-4 Alkylene) n -C6-C 10 C6-C in aryl 10 The aryl group can be phenyl or naphthyl, for example, phenyl.

[0061] In some schemes, R 4-1 In this context, the halogen is independently F, Cl, Br or I, preferably F, Cl or Br, for example F or Br.

[0062] In some schemes, R 4-1 In, the C 1-6 Alkyl and C 1-6 C in haloalkyl 1-6 The alkyl group is independently methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably tert-butyl.

[0063] In some schemes, R 4-1 In, the C 1-6 Halogenated alkyl and C 1-6 The number of halogens in a haloalkoxy group can be 1, 2, or 3 independently, for example, 2 or 3.

[0064] In some schemes, R 4-1 In, the C 1-6 Halogenated alkyl and C 1-6The halogen in haloalkyl is independently fluoro, chloro, bromo or iodo, preferably fluoro.

[0065] In some embodiments, R 4-1 In some embodiments, the C 1-6 The C 1-6 The alkoxy is independently methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy or t-butoxy, preferably methoxy.

[0066] In some embodiments, R 3-1-1 is independently F, Cl, Br, CN, CF3, CH3, OCH3,

[0067] In some embodiments, R 3-1 is independently

[0068] In some embodiments, R 4-1 is independently H, F, CN, CF3, OCF3, OCHF2, Cl, Br or t-butyl, preferably F, CN, CF3, OCF3, OCHF2, Br or t-butyl.

[0069] In some embodiments, R 4 is independently H, methyl, ethyl,

[0070]

[0071] In some embodiments, the C is independently

[0072]

[0073] In some embodiments, the cryptotanshinone derivative of Formula I is selected from any one of the following structures:

[0074]

[0075] In some embodiments, R 3-1 , R 4 and X are as defined above, and the “ ” bond represents a “ ” bond or a “ ” bond.

[0076] In some embodiments, preferably, the cryptotanshinone derivative of Formula I-1 is R 3-1 is as defined above.

[0077] In some embodiments, the tanshinone derivative of Formula I is selected from any one of the following structures:

[0078]

[0079]

[0080]

[0081]

[0082] The present application provides a tanshinone derivative of Formula II, a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

[0083]

[0084] wherein the definitions of “-----”, R 1 , R 2 , R 3 and are as described above; and

[0085] The tanshinone derivative of Formula II is not any one of the following structures: In some embodiments, the tanshinone derivative of Formula II is selected from any one of the following structures:

[0086]

[0087]

[0088]

[0089] The present application also provides a preparation method of the tanshinone derivative of Formula II, which is Method A, Method B, Method C or Method D:

[0090] Method A, when the tanshinone derivative of Formula II is a compound of Formula III-1, comprises the following steps:

[0091] In a solvent, in the presence of an organic base, the compound of Formula II-1 is subjected to an oximation reaction with hydroxylamine hydrochloride as shown below to obtain the compound of Formula III-1; wherein R 4 is hydrogen; the definitions of “-----”, R 1 , R 2 and R 3 in ring A are as described above;

[0092]

[0093] Method B, when the cryptotanshinone derivative as shown in Formula II is one or more of the compounds as shown in Formula III-2, includes the following steps:

[0094] carrying out an oxidation reaction as shown below in a solvent on a compound as shown in Formula II-2 with an oxidizing agent to obtain a compound as shown in Formula III-2;

[0095] wherein R 1 , R 2 are taken together to form =X1, X1 is O; R 4 are as previously described;

[0096]

[0097] Method C, when the cryptotanshinone derivative as shown in Formula II is one or more of the compounds as shown in Formula III-3, III-4, and III-5, includes the following steps:

[0098] carrying out a reaction as shown below in a solvent on a compound as shown in Formula II-3 with R 4 -H in the presence of an inorganic base to obtain a compound as shown in Formula III-3, III-4, and III-5;

[0099] wherein R 4 are as previously described, and R 4 is not hydrogen;

[0100]

[0101] Method D, when the cryptotanshinone derivative as shown in Formula II is a compound as shown in Formula III-6, includes the following steps:

[0102] carrying out a reaction as shown below in a solvent on a compound as shown in Formula II-4 with R 3-1 -OH in the presence of an oxidizing agent to obtain a compound as shown in Formula III-6;

[0103] wherein R 3-1 are as previously described;

[0104]

[0105] In Method A, the solvent is selected from conventional organic solvents for such reactions in the art, and is preferably an alcoholic solvent, such as ethanol.

[0106] In some embodiments, in Method A, the organic base is pyridine, piperidine, or piperazine, such as pyridine.

[0107] In some embodiments, in method A, the reaction temperature is 60°C-100°C, for example, 80°C.

[0108] In some schemes, in method A, the reaction time is 16-32 hours, for example, 24 hours.

[0109] In some embodiments, in method A, the molar ratio of the compound as shown in formula II-1 to the organic base is 1:(4-10), preferably 1:5.

[0110] In some embodiments, in method A, the molar ratio of the compound as shown in formula II-1 to the hydroxylamine hydrochloride is 1:(4-10), preferably 1:5.

[0111] In some embodiments, in method A, the molar volume ratio of the compound as shown in formula II-1 to the solvent is 0.1-0.4 mol / L, preferably 0.23 mol / L.

[0112] In Method B, the solvent is selected from conventional organic solvents used in such reactions in the art, preferably ether solvents, such as 1,4-dioxane.

[0113] In some embodiments, specifically method B, the oxidant is selenium dioxide.

[0114] In some embodiments, in method B, the reaction temperature is 100°C-120°C, for example, 100°C.

[0115] In some embodiments, in method B, the molar ratio of the compound as shown in formula II-2 to the oxidant is 1:(1-5), preferably 1:2.

[0116] In some embodiments, in method B, the molar volume ratio of the compound as shown in formula II-2 to the solvent is 0.01-0.1 mol / L, preferably 0.02 mol / L.

[0117] In method C, the solvent is selected from conventional organic solvents used in such reactions in the art, preferably ketone solvents, such as acetone.

[0118] In some embodiments, in method C, the inorganic base is potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, sodium acetate, potassium acetate, sodium phosphate, or potassium phosphate, preferably potassium carbonate.

[0119] In some embodiments, in method C, the reaction temperature is 25°C-80°C, preferably 40°C-70°C, for example 55°C.

[0120] In some embodiments, in method C, the molar ratio of the compound as shown in formula II-3 to the inorganic base is 1:(1-3), preferably 1:1.9.

[0121] In some embodiments, in method C, the molar ratio of the compound of formula II-3 to the R 4 the molar ratio of -H to -OH is 1:(1-3), preferably 1:1.7.

[0122] In method D, the solvent is selected from conventional organic solvents for such reactions in the art, preferably halogenated aromatic hydrocarbons, such as chlorobenzene.

[0123] In some embodiments, in method D, the oxidizing agent is oxygen, tert-butyl hydroperoxide, di-tert-butyl peroxide, 2,2,6,6-tetramethylpiperidine oxide (TEMPO), or manganese dioxide, preferably 2,2,6,6-tetramethylpiperidine oxide (TEMPO).

[0124] In some embodiments, in method D, the reaction temperature is 90-130 °C, preferably 110-130 °C, for example 120 °C.

[0125] In some embodiments, in method D, the reaction time is 16-32 h, for example 24 h.

[0126] In some embodiments, in method D, the molar ratio of the compound of formula II-4 to the oxidizing agent is 1:(1-3), preferably 1:2.

[0127] In some embodiments, in method D, the molar ratio of the compound of formula II-4 to the R 3-1 the molar ratio of -H to -OH is 1:(1-3), preferably 1:1.7.

[0128] In some embodiments, in method D, the molar volume ratio of the compound of formula II-4 to the solvent is 0.01-0.1 mol / L, preferably 0.02 mol / L.

[0129] The present application provides a pharmaceutical composition comprising a cryptotanshinone derivative of formula II or a pharmaceutically acceptable salt thereof as described above, and at least one pharmaceutical excipient.

[0130] Definitions of Terms

[0131] The term "stereoisomer" refers to a cis-trans isomer or an optical isomer, a cis-trans isomer is an isomer caused by the inability of a double bond or a single bond of a ring-forming carbon atom to rotate freely, and an optical isomer is a stereoisomer with different optical properties caused by the absence of inversion symmetry in the molecule.

[0132] The term "pharmaceutically acceptable salt" refers to a salt of a compound prepared by reaction of the compound with a pharmaceutically acceptable acid or base. When a compound contains relatively acidic functionalities, base addition salts can be obtained by contacting the compound in a suitable inert solvent with a sufficient amount of the pharmaceutically acceptable base to produce the salt. Pharmaceutically acceptable base addition salts include, but are not limited to, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, bismuth salts, ammonium salts, and the like.

[0133] The term "alkyl" refers to a straight or branched chain, saturated, monovalent hydrocarbon group having the specified number of carbon atoms (e.g., C1-C6). Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, and the like. The term "alkyl" refers to a straight or branched chain, saturated, monovalent hydrocarbon group having the specified number of carbon atoms (e.g., C1-C6). Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, and the like.

[0134] The term "multiple" refers to 2, 3, 4, or 5.

[0135] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0136] The term "alkyl" refers to a straight or branched chain, saturated, monovalent hydrocarbon group having the specified number of carbon atoms (e.g., C1-C6). Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, and the like.

[0137] The term "alkoxy" refers to the group Rx-O-, where Rx is an alkyl group as defined above.

[0138] The term "alkenyl" refers to a straight or branched chain, unsaturated, monovalent hydrocarbon group having the specified number of carbon atoms (e.g., C2-C6) with one or more (e.g., 1, 2, or 3) carbon-carbon sp2bonds. Alkenyl groups include, but are not limited to, ethenyl (i.e., vinyl), propenyl, i-propenyl, butenyl, i-butenyl, s-butenyl, butadienyl, and the like. The term "alkenyl" refers to a straight or branched chain, unsaturated, monovalent hydrocarbon group having the specified number of carbon atoms (e.g., C2-C6) with one or more (e.g., 1, 2, or 3) carbon-carbon sp2bonds. Alkenyl groups include, but are not limited to, ethenyl (i.e., vinyl), propenyl, i-propenyl, butenyl, i-butenyl, s-butenyl, butadienyl, and the like.

[0139] The term "alkylene" refers to a saturated, divalent hydrocarbon radical derived from a straight chain or branched chain alkyl group by removal of two hydrogen atoms; that is, one hydrogen from each of the two carbon atoms. Examples of alkylene groups include methylene (-CH2-), ethylene {including -CH2CH2- or -CH(CH3)-}, isopropylene {including -CH(CH3)CH2- or -C(CH3)2-}, and the like.

[0140] The term "aryl" refers to a cyclic group consisting solely of carbon atoms, having the specified number of ring atoms (e.g., C6-Ci2), which is either single ring or multiple rings, and which is either annulated or fused, and having at least one ring that is aromatic (complies with Hückel's rule). The aryl group is attached to the rest of the molecule through a ring atom of the aryl radical. Aryl groups include, but are not limited to, phenyl, naphthyl, and the like. 10 ) of carbon atoms. Aryl groups are attached to the rest of the molecule through a ring atom of the aryl radical. Aryl groups include, but are not limited to, phenyl, naphthyl, and the like.

[0141] The term "heteroaryl" refers to a cyclic group having a specified number of ring atoms (e.g., 5-10 membered), a specified number of heteroatoms (e.g., 1, 2, or 3), a specified type of heteroatoms (one or more of N, O, and S), which is monocyclic or polycyclic, and at least one ring has aromaticity (complying with Huckel's rule). The heteroaryl is attached to the rest of the molecule through a ring that has aromaticity or a ring that does not have aromaticity. Heteroaryl includes, but is not limited to, furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidyl, indolyl, and the like.

[0142] On the basis of common general knowledge in the art, the above-mentioned preferred conditions can be combined arbitrarily, i.e. to obtain each preferred example of the present application.

[0143] The reagents and raw materials used in the present application are commercially available.

[0144] The positive progress effect of the present application is that the present application provides a novel cryptotanshinone derivative, a preparation method and application thereof. The cryptotanshinone derivative of the present application has good inhibitory activity on triple-negative breast cancer cells. DETAILED DESCRIPTION

[0145] The present application will be further described by way of examples below, but the present application is not limited in the scope of the examples. The experimental methods in the following examples are not specified, and are selected according to conventional methods and conditions, or according to the instructions of the goods.

[0146] Specific experimental scheme one:

[0147]

[0148] Synthesis route of a4

[0149] Preparation of compound a1

[0150] Compound cryptotanshinone (200 mg, 0.675 mmol) was dissolved in 4 mL of chlorobenzene, followed by the addition of propionic acid (101 μL, 1.35 mmol), TEMPO (127 mg, 0.804 mmol), and the reaction was placed at 120°C for 24 h. After completion of the reaction was monitored by TLC, it was cooled to room temperature, and the solvent was removed by rotary evaporation at 80°C. Purification by column chromatography (PE:EA = 3:1-1:1) gave a pair of chiral isomers of crude product a1 (205.2 mg, 82.6%). 1H NMR (500 MHz, Chloroform-d) δ 7.72 (d, J = 8.2 Hz, 1H), 7.65 (d, J = 8.2 Hz, 1H), 6.47 (t, J = 3.7 Hz, 1H), 4.89 (t, J = 9.5 Hz, 1H), 4.37 (dd, J = 9.3, 6.0 Hz, 1H), 3.59 (dp, J = 9.6, 6.7 Hz, 1H), 2.34 - 2.14 (m, 3H), 2.03 - 1.85 (m, 2H), 1.57 - 1.50 (m, 1H), 1.39 (s, 3H), 1.34 (d, J = 6.8 Hz, 3H), 1.26 (s, 3H), 1.11 (t, J = 7.5 Hz, 3H). 13 CNMR (125 MHz, Chloroform-d) δ 183.28, 175.04, 173.24, 170.26, 152.78, 137.42, 133.22, 129.11, 127.13, 125.09, 118.59, 81.56, 66.99, 34.92, 34.64, 32.17, 31.53, 31.22, 27.49, 24.55, 18.81, 9.16.

[0151] Preparation of compound a2

[0152] The crude product a1 (205.2 mg, 0.557 mmol) was dissolved in 5 mL of methanol, sodium hydroxide (89.2 mg, 2.230 mmol) was added at 0 °C, and the reaction was carried out at 65 °C. After completion of the reaction was monitored by TLC, water and concentrated hydrochloric acid were added to neutralize the sodium hydroxide that did not participate in the reaction, and the organic phase was collected by extraction with ethyl acetate. The crude product was dissolved in 5 mL of anhydrous ethanol, and concentrated sulfuric acid was slowly added at 0 °C. The reaction was carried out at room temperature for about 45 min, and after completion of the reaction was monitored by TLC, the excess concentrated sulfuric acid was neutralized with saturated aqueous sodium bicarbonate solution, and the organic layer was collected by extraction with ethyl acetate. The final product a2 (79.5 mg, 40.0%) was obtained by concentration and purification by column chromatography (PE:EA = 3:1-1:1). 1H NMR (500 MHz, Chloroform-d) δ 7.86 (dt, J = 10.3, 1.8 Hz, 1H), 7.52 (d, J = 7.9 Hz, 1H), 7.47 (d, J = 7.9 Hz, 1H), 6.30 (dt, J = 10.2, 4.6 Hz, 1H), 4.88 (t, J = 9.5 Hz, 1H), 4.35 (dd, J = 9.3, 6.0 Hz, 1H), 3.59 (dp, J = 9.6, 6.5 Hz, 1H), 2.26 (dd, J = 4.6, 1.9 Hz, 2H), 1.34 (d, J = 6.8 Hz, 3H), 1.27 (s, 3H), 1.27 (s, 3H). 13 C NMR (125 MHz, Chloroform-d) δ 184.90, 175.71, 170.72, 150.66, 136.58, 134.01, 129.36, 126.14, 124.59, 124.33, 124.02, 118.51, 81.47, 37.71, 34.61, 34.33, 28.36, 28.32, 18.77.

[0153] Preparation of compound a3

[0154] a2 (200 mg, 0.67 mmol) was placed in a 25 mL round bottom flask, dissolved in 3 mL of anhydrous ethanol, followed by the addition of hydroxylamine hydrochloride (239 mg, 3.44 mmol), anhydrous pyridine (277 μL, 3.44 mmol), the reaction was moved to 80 °C for 24 h, TLC monitoring reaction was completed, filtered, the filtrate was collected and rotary evaporated, purified by column chromatography (PE:EA = 8:1-1:1) to give a light yellow solid product a3 (119 mg, 54.1%). 1 H NMR (500 MHz, Chloroform-d) δ 7.63 (d, J = 8.1 Hz, 1H), 7.57 (dt, J = 10.0, 1.8 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 6.13 (dt, J = 9.8, 4.7 Hz, 1H), 4.94 (t, J = 9.4 Hz, 1H), 4.42 (dd, J = 9.3, 5.8 Hz, 1H), 3.67 (ddq, J = 12.6, 9.5, 6.6 Hz, 1H), 2.35 - 2.20 (m, 2H), 1.40 (d, J = 6.8 Hz, 3H), 1.30 (d, J = 13.5 Hz, 6H). 13C NMR (126 MHz, CDCI3) δ 180.23, 173.56, 152.68, 149.55, 133.13, 130.17, 128.60, 128.18, 126.24, 125.06, 122.29, 117.98, 83.43, 78.71, 78.45, 78.20, 38.85, 36.22, 35.63, 29.74, 29.72, 20.18.

[0155] Preparation of compound a4

[0156] Put a3 (20 mg, 0.065 mmol) in a 25 mL three-necked flask, add selenium dioxide (14.6 mg, 0.132 mmol) under argon protection, add 1,4-dioxane 3 mL as solvent, reflux at 100 °C, TLC monitor the completion of the reaction, cool to room temperature, spin evaporation to remove the solvent, PTLC (PE:EA = 1:1) purification, orange solid product a4 (2.3 mg, 6.3%) was obtained. 1 H NMR (600 MHz, Chloroform-d) δ 9.03 (d, J = 10.5 Hz, 1H), 7.72 (d, J = 0.8 Hz, 2H), 6.41 (d, J = 10.5 Hz, 1H), 4.95 (t, J = 9.5 Hz, 1H), 4.42 (dd, J = 9.3, 6.2 Hz, 1H), 3.65 (dt, J = 6.8, 3.4 Hz, 1H), 1.50 (d, J = 2.4 Hz, 3H), 1.42 - 1.37 (m, 6H). 13 C NMR (151 MHz, CDCI3) δ 139.14, 131.43, 128.62, 125.83, 81.78, 77.24, 77.03, 76.82, 34.76, 27.70, 27.55, 18.76.

[0157] Specific experimental scheme two

[0158]

[0159] Preparation of compound a5

[0160] Put cryptotanshinone (200 mg, 0.675 mmol) in a 25 mL round-bottom flask, add 3 mL of anhydrous ethanol to dissolve it, then add hydroxylamine hydrochloride (239 mg, 3.442 mmol), anhydrous pyridine (277 μL, 3.442 mmol), move the reaction liquid to 80 °C for 24 h, TLC monitor the completion of the reaction, filter, collect the filtrate and spin evaporation, column chromatography (PE:EA = 8:1-1:1) purification, light yellow solid product a5 (119 mg, 54.1%) was obtained.1 H NMR (500 MHz, Chloroform-d) δ 7.65 - 7.60 (m, 1H), 7.52 (d, J = 8.3 Hz, 1H), 4.94 (t, J = 9.4 Hz, 1H), 4.42 (dd, J = 9.3, 5.8 Hz, 1H), 3.67 (dqd, J = 9.6, 6.8, 5.7 Hz, 1H), 3.16 (t, J = 6.2 Hz, 2H), 1.77 - 1.66 (m, 4H), 1.39 (d, J = 6.8 Hz, 3H), 1.34 (d, J = 3.8 Hz, 6H). 13 C NMR (126 MHz, CDC13) δ 180.31, 173.67, 153.83, 150.13, 139.27, 131.99, 129.32, 123.38, 121.53, 117.73, 83.38, 78.71, 78.46, 78.20, 39.87, 36.85, 35.60, 34.62, 33.80, 33.75, 32.87, 31.62, 21.55, 20.20.

[0161] Preparation of compounds b1-b22

[0162]

[0163] a5 (20 mg, 0.0643 mmol) was placed in a 25 mL round bottom flask, dissolved in acetone, followed by addition of anhydrous potassium carbonate (16.8 mg, 0.1222 mmol), methyl iodide (15.5 mg, 0.1093 mmol), the reaction was reacted at 55 °C, TLC monitored the completion of the reaction, water washed, ethyl acetate extraction, combined organic phase, PTLC (PE:EA = 5:1) purification, colorless solid product b1-1 (8 mg, 40.4%). 1 H NMR (600 MHz, Chloroform-d) δ 8.08 (d, J = 5.4 Hz, 1H), 7.89 (t, J = 7.4 Hz, 1H), 7.55 (t, J = 7.4 Hz, 1H), 4.95 (d, J = 7.9 Hz, 1H), 4.39 (d, J = 7.6 Hz, 1H), 4.02 (q, J = 8.0, 7.5 Hz, 1H), 3.73 (d, J = 7.1 Hz, 2H), 2.06 - 1.98 (m, 2H), 1.79 (s, 2H), 1.55 - 1.50 (m, 3H), 1.48 - 1.38 (m, 6H). 13C NMR (151 MHz, CDC13) δ 155.56, 147.95, 145.51, 144.62, 132.13, 130.21, 125.36, 124.26, 119.83, 117.44, 109.41, 79.58, 77.28, 77.07, 76.86, 38.73, 36.40, 34.59, 31.88, 31.82, 30.46, 19.68, 19.22.

[0164] The following compounds are b-2 series for trans structure, b-3 series for cis structure.

[0165] b1-2: light yellow solid, yield 23.9%. 1 H NMR (600 MHz, Chloroform-d) δ 7.49 - 7.45 (m, 1H), 7.43 (d, J = 8.2 Hz, 1H), 4.80 (t, J = 9.2 Hz, 1H), 4.27 (dd, J = 9.0, 6.2 Hz, 1H), 4.14 (s, 3H), 3.56 (dp, J = 9.5, 6.7 Hz, 1H), 3.09 (dd, J = 6.7, 5.1 Hz, 2H), 1.74 - 1.68 (m, 4H), 1.35 (d, J = 6.8 Hz, 3H), 1.32 (s, 6H). 13 C NMR (151 MHz, CDC13) δ 155.56, 147.95, 145.51, 144.62, 132.13, 130.21, 125.36, 124.26, 119.83, 117.44, 109.41, 79.58, 77.28, 77.07, 76.86, 38.73, 36.40, 34.59, 31.88, 31.82, 30.46, 19.68, 19.22.

[0166] b1-3: light yellow solid, yield 19.1%. 1 H NMR (600 MHz, Chloroform-d) δ 7.46 (s, 2H), 4.83 - 4.77 (m, 1H), 4.27 (d, J = 19.3 Hz, 1H), 4.16 (s, 3H), 3.56 - 3.52 (m, 1H), 2.91 (s, 1H), 2.36 (d, J = 23.5 Hz, 1H), 1.82 - 1.68 (m, 4H), 1.35 - 1.25 (m, 9H). 13C NMR (151 MHz, CDC13) δ 152.99, 149.74, 139.02, 129.64, 128.79, 127.86, 122.50, 122.29, 121.66, 121.55, 81.08, 80.90, 77.26, 77.05, 76.84, 64.57, 63.48, 60.41, 39.37, 38.80, 35.09, 35.06, 35.01, 34.89, 32.69, 32.37, 32.32, 31.93, 31.49, 31.26, 29.70, 29.36, 22.70, 20.23, 19.79, 18.71, 14.21, 1.03.

[0167] Referring to the preparation method of compound b1-1, methyl iodide is replaced by ethyl bromide to obtain compounds b2-1, b2-2 and b2-3.

[0168]

[0169] b2-1: colorless solid, yield 14.3%. 1 H NMR (600 MHz, Chloroform-d) δ 7.84 (d, J = 8.7 Hz, 1H), 7.49 (d, J = 8.8 Hz, 1H), 4.93 (t, J = 8.8 Hz, 1H), 4.37 (dd, J = 8.5, 6.7 Hz, 1H), 4.03 - 3.94 (m, 1H), 3.69 (t, J = 6.4 Hz, 1H), 3.49 (t, J = 6.5 Hz, 1H), 2.70 (s, 3H), 1.51 (dd, J = 11.7, 6.8 Hz, 4H), 1.37 (d, J = 4.9 Hz, 3H), 1.25 (s, 6H). 13 C NMR (151 MHz, CDC13) δ 152.99, 149.74, 139.02, 129.64, 128.79, 127.86, 122.50, 122.29, 121.66, 121.55, 81.08, 80.90, 77.26, 77.05, 76.84, 64.57, 63.48, 60.41, 39.37, 38.80, 35.09, 35.06, 35.01, 34.89, 32.69, 32.37, 32.32, 31.93, 31.49, 31.26, 29.70, 29.36, 22.70, 20.23, 19.79, 18.71, 14.21, 1.03.

[0170] b2-2: light yellow solid, yield 49.5%. 1H NMR (600 MHz, Chloroform-d) δ 7.49 - 7.40 (m, 2H), 4.79 (t, J = 9.2 Hz, 1H), 4.44 (s, 1H), 4.37 (qd, J = 7.1, 4.7 Hz, 1H), 4.27 (dd, J = 9.0, 6.0 Hz, 1H), 3.56 (dp, J = 9.6, 6.6 Hz, 1H), 3.07 (t, J = 5.1 Hz, 2H), 1.69 (qd, J = 8.6, 4.2 Hz, 4H), 1.42 - 1.30 (m, 12H). 13 C NMR (151 MHz, CDC13) δ 177.69, 168.69, 150.63, 149.64, 148.94, 138.98, 136.92, 131.83, 129.75, 128.56, 127.73, 122.45, 122.24, 121.48, 117.55, 81.03, 80.86, 77.26, 77.05, 76.83, 72.45, 72.02, 39.48, 38.82, 37.59, 35.11, 35.09, 35.02, 34.92, 32.40, 32.34, 31.73, 31.46, 29.71, 20.31, 19.79, 18.79, 15.03, 14.61, 14.13.

[0171] b2-3: light yellow solid, yield 15.9%. 1 H NMR (600 MHz, Chloroform-d) δ 7.44 (d, J = 14.8 Hz, 2H), 4.86 - 4.76 (m, 1H), 4.50 - 4.33 (m, 2H), 4.30 - 4.24 (m, 1H), 3.56 (ddt, J = 14.6, 10.3, 7.3 Hz, 1H), 3.07 (t, J = 5.2 Hz, 1H), 2.45 - 2.24 (m, 1H), 1.71 (ddt, J = 21.0, 9.2, 4.4 Hz, 4H), 1.39 - 1.27 (m, 12H). 13 C NMR (151 MHz, CDC13) δ 177.70, 168.69, 150.64, 149.64, 148.94, 138.98, 136.92, 131.84, 128.56, 127.73, 122.45, 122.24, 121.48, 117.55, 81.04, 80.86, 77.24, 77.03, 76.82, 72.45, 72.02, 39.48, 38.82, 35.11, 35.09, 35.02,

[0172] 34.92, 32.40, 32.34, 31.94, 31.73, 31.46, 29.71, 29.37, 20.31, 19.79, 18.79, 15.02, 14.61.

[0173] Referring to the preparation method of compound b1-1, bromobenzene is replaced with methyl iodide to obtain compounds b3-1, b3-2 and b3-3.

[0174]

[0175] b3-1: colorless solid, yield 8.1%. 1 H NMR (600 MHz, Chloroform-d) δ 8.27 (d, J = 7.6 Hz, 2H), 7.88 (d, J = 8.7 Hz, 1H), 7.55 - 7.49 (m, 3H), 7.47 (t, J = 7.3 Hz, 1H), 4.98 (t, J = 8.8 Hz, 1H), 4.41 (dd, J = 8.5, 6.7 Hz, 1H), 4.14 - 4.05 (m, 1H), 3.85 (t, J = 6.4 Hz, 2H), 2.02 (td, J = 6.2, 3.0 Hz, 2H), 1.82 - 1.77 (m, 2H), 1.40 (d, J = 4.7 Hz, 6H), 1.33 (s, 3H). 13 C NMR (151 MHz, CDCl3) δ 158.57, 155.33, 146.10, 144.40, 132.71, 130.10, 128.77, 128.17, 126.74, 124.16, 119.75, 109.43, 79.58, 77.23, 77.02, 76.81, 38.86, 36.46, 34.60, 31.92, 31.86, 31.45, 30.43, 30.20, 29.71, 22.70, 19.83, 19.27.

[0176] b3-2: light yellow solid, yield 34.9%. 1H NMR (600 MHz, Chloroform-d) δ 7.44 (d, J = 8.1 Hz, 3H), 7.40 (d, J = 8.2 Hz, 1H), 7.37 - 7.33 (m, 2H), 7.30 (d, J = 7.2 Hz, 1H), 5.34 (s, 2H), 4.79 (t, J = 9.3 Hz, 1H), 4.26 (dd, J = 9.0, 6.1 Hz, 1H), 3.58 - 3.52 (m, 1H), 2.80 (t, J = 6.2 Hz, 2H), 1.65 - 1.52 (m, 4H), 1.34 (d, J = 6.8 Hz, 3H), 1.28 (d, J = 4.4 Hz, 6H). 13 C NMR (151 MHz, CDC13) δ 177.68, 168.79, 150.64, 149.71, 149.53, 139.22, 137.81, 137.16, 136.13, 131.50, 128.73, 128.56, 128.40, 128.35, 128.30, 127.86, 127.81, 122.45, 122.33, 121.46, 117.49, 81.08, 80.87, 78.51, 78.25, 77.26, 77.05, 76.84, 39.33, 38.75, 35.10, 35.05, 34.96, 34.92, 32.35, 32.29, 31.54, 31.41, 30.21, 29.72, 20.13, 19.63, 18.78.

[0177] b3-3: light yellow solid, yield 19.4%. 1 H NMR (600 MHz, Chloroform-d) δ 7.44 (d, J = 8.1 Hz, 3H), 7.40 (d, J = 8.2 Hz, 1H), 7.37 - 7.33 (m, 2H), 7.30 (d, J = 7.2 Hz, 1H), 5.34 (s, 2H), 4.79 (t, J = 9.3 Hz, 1H), 4.26 (dd, J = 9.0, 6.1 Hz, 1H), 3.58 - 3.52 (m, 1H), 2.80 (t, J = 6.2 Hz, 2H), 1.65 - 1.52 (m, 4H), 1.34 (d, J = 6.8 Hz, 3H), 1.28 (d, J = 4.4 Hz, 6H). 13C NMR (151 MHz, CDC13) δ 139.22, 128.73, 128.56, 128.40, 128.35, 128.30, 127.86, 122.44, 81.08, 80.87, 78.51, 77.24, 77.03, 76.82, 39.32, 38.75, 35.09, 34.96, 34.92, 32.36, 31.41, 29.71, 20.13, 19.62, 18.78.

[0178] The preparation method of reference compound b1-1 is referred to, and iodomethane is replaced by 2-fluorobenzyl bromide to obtain compounds b4-1, b4-2 and b4-3.

[0179]

[0180] b4-1: colorless solid, yield 1.9%. 1 H NMR (600 MHz, Chloroform-d) δ 8.29 (td, J = 7.6, 1.9 Hz, 1H), 7.88 (d, J = 8.7 Hz, 1H), 7.59 - 7.50 (m, 1H), 7.49 - 7.42 (m, 1H), 7.37 - 7.27 (m, 2H), 4.99 (t, J = 8.8 Hz, 1H), 4.41 (dd, J = 8.5, 6.9 Hz, 1H), 4.10 (dp, J = 9.2, 6.8 Hz, 1H), 3.83 (t, J = 6.4 Hz, 2H), 2.02 (dddd, J = 15.5,

[0181] 9.6, 6.3, 2.9 Hz, 2H), 1.79 (dt, J = 9.3, 3.5 Hz, 2H), 1.57 (d, J = 6.9 Hz, 3H), 1.40 (d, J = 4.6 Hz, 6H). 13 CNMR (151 MHz, CDC13) δ 130.10, 124.28, 119.78, 109.38, 79.66, 77.23, 77.02, 76.81, 38.84, 36.44, 34.61, 31.92, 31.87, 30.38, 29.71, 19.82, 19.19.

[0182] b4-2: light yellow solid, yield 62.3%. 1H NMR (600 MHz, Chloroform-d) δ 7.53 (td, J = 7.5, 1.8 Hz, 1H), 7.46 - 7.36 (m, 3H), 7.12 (dt, J = 24.4, 7.5 Hz, 1H), 7.05 (dd, J = 10.0, 8.2 Hz, 1H), 5.42 (d, J = 3.2 Hz, 2H), 4.79 (t, J = 9.2 Hz, 1H), 4.27 (dd, J = 9.1, 6.0 Hz, 1H), 3.56 (dp, J = 9.7, 6.6 Hz, 1H), 2.84 (t, J = 6.2 Hz, 2H), 1.65 - 1.57 (m, 4H), 1.34 (d, J = 6.8 Hz, 3H), 1.29 (d, J = 4.8 Hz, 6H). 13 C NMR (151 MHz, CDC13) δ 177.66, 168.87, 161.48, 159.85, 150.70, 149.79, 149.75, 137.23, 131.35, 130.52, 130.50, 129.60, 129.54, 127.90, 124.12, 124.09, 124.08, 124.06, 122.36, 121.50, 117.47, 115.27, 115.25, 115.10, 80.89, 77.27, 77.06, 76.85, 71.59, 38.74, 35.09, 35.05, 32.34, 32.29, 31.39, 20.13, 18.79.

[0183] b4-3: light yellow solid, yield 17.8%. 1 H NMR (600 MHz, Chloroform-d) δ 7.46 - 7.34 (m, 3H), 7.31 (tdd, J = 7.4, 5.3, 1.8 Hz, 1H), 7.10 (t, J = 7.5 Hz, 1H), 7.05 (t, J = 9.1 Hz, 1H), 5.56 - 5.38 (m, 2H), 4.80 (dd, J = 15.6, 6.3 Hz, 1H), 4.36 - 4.23 (m, 1H), 3.56 (ddt, J = 14.6, 10.9, 7.0 Hz, 1H), 2.84 (t, J = 6.2 Hz, 1H), 2.31 (s, 1H), 1.62 (dt, J = 23.3, 5.9 Hz, 4H), 1.35 (q, J = 6.2, 3.8 Hz, 3H), 1.30 - 1.25 (m, 6H). 13C NMR (151 MHz, CDCI3) δ 177.66, 161.87, 160.22, 150.70, 149.76, 139.31, 131.33, 131.30, 130.37, 130.32, 129.58, 128.62, 127.89, 124.08, 124.05, 123.41, 123.32, 122.46, 121.49, 115.41, 115.27, 81.09, 77.24, 77.03, 76.82, 71.87, 39.32, 34.97, 34.91, 32.35, 32.29, 31.22, 19.62, 18.79.

[0184] The preparation method of reference compound b1-1 is referred to, and iodomethane is replaced by 4-fluorobenzyl bromide to obtain compounds b5-1, b5-2 and b5-3.

[0185]

[0186] b5-1: colorless solid, yield 12.7%. 1 H NMR (600 MHz, Chloroform-d) δ 8.28 - 8.23 (m, 2H), 7.87 (d, J = 8.7 Hz, 1H), 7.53 (d, J = 8.7 Hz, 1H), 7.20 (t, J = 8.6 Hz, 2H), 4.98 (t, J = 8.8 Hz, 1H), 4.41 (dd, J = 8.5, 6.7 Hz, 1H), 4.08 (dp, J = 9.4, 6.9 Hz, 1H), 3.82 (t, J = 6.4 Hz, 2H), 2.02 (dqd, J = 12.5, 6.3, 5.8, 2.6 Hz, 2H), 1.82 - 1.77 (m, 2H), 1.57 (d, J = 6.9 Hz, 3H), 1.40 (d, J = 4.9 Hz, 6H). 13 C NMR (151 MHz, CDCI3) δ 177.66, 161.87, 160.22, 150.70, 149.76, 139.31, 131.33, 131.30, 130.37, 130.32, 129.58, 128.62, 127.89, 124.08, 124.05, 123.41, 123.32, 122.46, 121.49, 115.41, 115.27, 81.09, 77.24, 77.03, 76.82, 71.87, 39.32, 34.97, 34.91, 32.35, 32.29, 31.22, 19.62, 18.79.

[0187] b5-2: light yellow solid, yield 70.9%. 1H NMR (600 MHz, Chloroform-d) δ 7.52 - 7.39 (m, 4H), 7.04 (t, J = 8.8 Hz, 2H), 5.29 (s, 2H), 4.87 - 4.76 (m, 1H), 4.27 (d, J = 9.0 Hz, 1H), 3.61 - 3.52 (m, 1H), 2.80 (d, J = 6.8 Hz, 2H), 1.70 - 1.58 (m, 4H), 1.31 (dd, J = 29.0, 5.6 Hz, 9H). 13 C NMR (151 MHz, CDC13) δ 177.67, 168.85, 163.37, 161.74, 150.69, 149.68, 137.08, 133.61, 131.41, 130.20, 130.15, 127.89, 122.36, 121.53, 117.47, 115.39, 115.29, 115.25, 115.15, 80.88, 77.44, 77.26, 77.05, 76.84, 38.74, 35.08, 35.05, 32.34, 32.28, 31.56, 20.13, 18.76.

[0188] b5-3: light yellow solid, yield 11.9%. 1 H NMR (600 MHz, Chloroform-d) δ 7.43 (dd, J = 12.1, 3.9 Hz, 3H), 7.34 (dd, J = 8.4, 5.4 Hz, 1H), 7.03 (dt, J = 15.0, 8.6 Hz, 2H), 5.44 - 5.27 (m, 2H), 4.80 (dd, J = 16.7, 7.4 Hz, 1H), 4.33 - 4.24 (m, 1H), 3.61 - 3.50 (m, 1H), 3.01 - 2.69 (m, 2H), 1.65 - 1.58 (m, 4H), 1.32 - 1.21 (m, 9H). 13 C NMR (151 MHz, CDC13) δ 161.93, 149.76, 139.15, 130.76, 130.71, 130.20, 128.64, 127.90, 122.47, 121.65, 115.40, 115.30, 115.25, 115.16, 81.11, 77.67, 77.24, 77.03, 76.81, 39.33, 34.97, 34.91, 32.36, 31.44, 19.63, 18.76.

[0189] Referring to the preparation method of compound bl-1, replacing iodomethane with 2,6-difluorobenzyl bromide to obtain compounds b6-1, b6-2 and b6-3.

[0190]

[0191] b6-1: colorless solid, yield 8.1%. 1 H NMR (600 MHz, Chloroform-d) δ 7.89 (d, J = 8.7 Hz, 1H), 7.55 (d, J = 8.8 Hz, 1H), 7.44 (tt, J = 8.6, 6.0 Hz, 1H), 7.08 (dd, J = 9.4, 7.2 Hz, 2H), 4.99 (t, J = 8.8 Hz, 1H), 4.42 (dd, J = 8.5, 6.8 Hz, 1H), 4.15 - 4.04 (m, 1H), 3.79 (t, J = 6.4 Hz, 2H), 2.03 - 1.96 (m, 2H), 1.80 - 1.75 (m, 2H), 1.55 (d, J = 7.3 Hz, 6H), 1.39 (d, J = 4.7 Hz, 3H). 13 C NMR (151 MHz, CDC13) δ 124.35, 119.78, 112.33, 112.16, 79.70, 77.23, 77.02, 76.81, 38.80, 36.40, 34.61, 31.91, 31.86, 30.35, 29.71, 19.75, 19.19.

[0192] b6-2: light yellow solid, yield 64.7%. 1 H NMR (600 MHz, Chloroform-d) δ 7.41 (q, J = 8.2 Hz, 2H), 7.32 - 7.27 (m, 1H), 6.90 (t, J = 7.6 Hz, 2H), 5.45 - 5.37 (m, 2H), 4.77 (td, J = 9.2, 1.1 Hz, 1H), 4.24 (ddd, J = 9.0, 6.0, 1.1 Hz, 1H), 3.53 (dp, J = 9.1, 6.6 Hz, 1H), 2.85 (t, J = 6.3 Hz, 2H), 1.68 - 1.52 (m, 4H), 1.32 (d, J = 6.8 Hz, 3H), 1.29 (d, J = 6.9 Hz, 6H). 13C NMR (151 MHz, CDC13) δ 177.54, 168.65, 163.04, 162.98, 161.37, 161.31, 150.57, 149.68, 131.24, 130.55, 127.82, 122.40, 121.43, 117.46, 113.63, 113.50, 113.38, 111.34, 111.17, 80.84, 77.26, 77.05, 76.84, 65.53, 38.81, 35.10, 35.05, 32.35, 32.29, 31.09, 20.14, 18.78.

[0193] b6-3: light yellow solid, yield 23.3%. 1 H NMR (600 MHz, Chloroform-d) δ 7.37 - 7.31 (m, 2H), 7.23 (tq, J = 10.2, 5.1, 3.7 Hz, 1H), 6.83 (t, J = 7.7 Hz, 2H), 5.47 - 5.38 (m, 2H), 4.72 (d, J = 21.3 Hz, 1H), 4.24 - 4.15 (m, 1H), 3.49 - 3.43 (m, 1H), 2.78 (t, J = 6.3 Hz, 1H), 1.60 - 1.51 (m, 4H), 1.28 - 1.21 (m, 3H), 1.17 (s, 6H). 13 C NMR (151 MHz, CDC13) δ 177.54, 168.65, 163.04, 162.98, 161.37, 161.31, 150.57, 149.68, 131.24, 130.55, 127.82, 122.40, 121.43, 117.46, 113.63, 113.50, 113.38, 111.34, 111.17, 80.84, 77.26, 77.05, 76.84, 65.53, 38.81, 35.10, 35.05, 32.35, 32.29, 31.09, 20.14, 18.78.

[0194] Referring to the preparation method of compound bl-1, methyl iodide is replaced by 3,5-difluorobenzyl bromide to obtain compounds b7-1, b7-2 and b7-3.

[0195]

[0196] b7-1: colorless solid, yield 4.1%. 1H NMR (600 MHz, Chloroform-d) δ 7.88 (d, J = 8.7 Hz, 1H), 7.83 - 7.70 (m, 2H), 7.55 (d, J = 8.7 Hz, 1H), 6.90 (tt, J = 8.8, 2.4 Hz, 1H), 4.99 (t, J = 8.8 Hz, 1H), 4.42 (dd, J = 8.5, 6.7 Hz, 1H), 4.07 (dq, J = 8.8, 6.8 Hz, 1H), 3.79 (t, J = 6.4 Hz, 1H), 3.66 (d, J = 1.3 Hz, 1H), 2.02 (ddd, J = 12.6, 10.5, 6.0 Hz, 2H), 1.81 - 1.74 (m, 2H), 1.57 (d, J = 6.8 Hz, 3H), 1.40 (d, J = 4.8 Hz, 6H). 13 C NMR (151 MHz, CDC13) δ 156.13, 146.39, 144.89, 132.75, 132.53, 131.00, 125.35, 124.51, 119.87, 117.59, 109.62, 109.58, 109.44, 109.25, 105.45, 105.28, 105.11, 79.69, 77.23, 77.02, 76.81, 38.78, 36.36, 34.63, 34.12, 31.89, 31.84, 31.45, 30.40, 29.71, 29.19, 29.13, 27.86, 25.88, 19.75, 19.29, 14.03.

[0197] b7-2: light yellow solid, yield 47.3%. 1 H NMR (600 MHz, Chloroform-d) δ 7.49 - 7.40 (m, 2H), 6.95 (h, J = 4.5 Hz, 1H), 6.84 (h, J = 4.6 Hz, 1H), 6.73 (ddt, J = 11.3, 8.9, 2.4 Hz, 1H), 5.28 (s, 2H), 4.82 (t, J = 9.3 Hz, 1H), 4.28 (dd, J = 9.1, 6.1 Hz, 1H), 3.57 (dp, J = 9.4, 6.6 Hz, 1H), 2.82 (t, J = 6.1 Hz, 2H), 1.82 - 1.54 (m, 4H), 1.38 - 1.26 (m, 9H). 13C NMR (151 MHz, CDCI3) δ 177.73, 169.18, 163.83, 162.18, 150.87, 150.33, 141.95, 141.89, 141.83, 139.12, 137.14, 131.18, 128.90, 128.11, 122.43, 121.66, 117.44, 110.73, 110.71, 110.67, 110.57, 110.54, 103.30, 103.13, 102.96, 80.98, 77.24, 77.03, 76.82, 76.68, 38.69, 35.06, 32.31, 31.53, 20.06, 18.72.

[0198] b7-3: light yellow solid, yield 29.3%. 1 H NMR (600 MHz, Chloroform-d) δ 7.47 (s, 2H), 6.99 - 6.67 (m, 3H), 5.45 - 5.25 (m, 2H), 4.88 - 4.78 (m, 1H), 4.35 - 4.25 (m, 1H), 3.61 - 3.49 (m, 1H), 2.99 - 2.79 (m, 1H), 2.37 (s, 1H), 1.82 - 1.58 (m, 4H), 1.44 - 1.21 (m, 9H). 13 C NMR (151 MHz, CDCI3) δ 177.73, 169.18, 163.83, 162.18, 150.87, 150.33, 141.95, 141.89, 141.83, 139.12, 137.14, 131.18, 128.90, 128.11, 122.43, 121.66, 117.44, 110.73, 110.71, 110.67, 110.57, 110.54, 103.30, 103.13, 102.96, 80.98, 77.24, 77.03, 76.82, 76.68, 38.69, 35.06, 32.31, 31.53, 20.06, 18.72.

[0199] Referring to the preparation method of compound b1-1, methyl iodide is replaced by 2-cyanobenzyl bromide to obtain compounds b8-1, b8-2 and b8-3.

[0200]

[0201] b8-1 : colorless solid, yield 5.5%. 1H NMR (600 MHz, Chloroform-d) δ 8.40 (d, J = 8.0 Hz, 1H), 7.87 (dd, J = 18.3, 8.2 Hz, 2H), 7.73 (t, J = 7.7 Hz, 1H), 7.59 - 7.51 (m, 2H), 5.01 (t, J = 8.9 Hz, 1H), 4.43 (dd, J = 8.5, 7.1 Hz, 1H), 4.11 (ddt, J = 13.7, 9.2, 6.3 Hz, 1H), 3.86 (t, J = 6.4 Hz, 2H), 2.03 (ddd, J = 12.6, 6.9, 3.4 Hz, 2H), 1.82 - 1.77 (m, 2H), 1.61 (d, J = 6.8 Hz, 3H), 1.40 (d, J = 4.7 Hz, 6H). 13 C NMR (151 MHz, CDC13) δ 156.55, 155.10, 146.37, 145.05, 135.11, 133.02, 132.66, 129.90, 129.66, 128.54, 125.44, 124.64, 119.82, 117.72, 109.95, 109.30, 79.81, 77.24, 77.02, 76.81, 38.78, 36.38, 34.65, 31.90, 31.85, 30.38, 29.71, 19.77, 19.11.

[0202] b8-2: light yellow solid, yield 59.5%. 1 H NMR (600 MHz, Chloroform-d) δ 7.73 (d, J = 7.8 Hz, 1H), 7.68 - 7.52 (m, 3H), 7.46 - 7.37 (m, 3H), 5.58 (d, J = 4.1 Hz, 2H), 4.81 (t, J = 9.2 Hz, 1H), 4.28 (dd, J = 9.1, 6.0 Hz, 1H), 3.57 (dp, J = 9.5, 6.7 Hz, 1H), 2.83 (t, J = 6.2 Hz, 2H), 1.69 - 1.53 (m, 4H), 1.35 (d, J = 6.8 Hz, 3H), 1.29 (d, J = 3.8 Hz, 6H). 13C NMR (151 MHz, CDCI3) δ 177.71, 169.14, 150.90, 150.47, 141.53, 139.78, 139.26, 137.33, 133.06, 132.88, 132.56, 131.08, 128.90, 128.80, 128.15, 128.13, 121.62, 117.41, 111.15, 80.96, 77.26, 77.05, 76.83, 75.12, 39.25, 38.64, 35.06, 32.31, 31.38, 20.06, 19.67, 18.78.

[0203] b8-3: light yellow solid, yield 5.8%. 1 H NMR (600 MHz, Chloroform-d) δ 7.54 (dd, J = 22.5, 8.7 Hz, 6H), 5.23 - 5.05 (m, 2H), 4.89 - 4.76 (m, 1H), 4.30 (dt, J = 14.9, 8.4 Hz, 1H), 3.91 - 3.85 (m, 3H), 1.81 (d, J = 10.9 Hz, 2H), 1.64 (d, J = 6.2 Hz, 2H), 1.53 (d, J = 9.1 Hz, 3H), 1.35 - 1.26 (m, 6H). 13 C NMR (151 MHz, CDCI3) δ 177.71, 169.14, 150.90, 150.47, 141.53, 139.78, 139.26, 137.33, 133.06, 132.88, 132.56, 131.08, 128.90, 128.80, 128.15, 128.13, 121.62, 117.41, 111.15, 80.96, 77.26, 77.05, 76.83, 75.12, 39.25, 38.64, 35.06, 32.31, 31.38, 20.06, 19.67, 18.78.

[0204] Referring to the preparation method of compound b1-1, replace iodomethane with 3-cyanobromobenzyl to obtain compounds b9-2 and b9-3.

[0205]

[0206] b9-2: light yellow solid, yield 43.4%. 1H NMR (600 MHz, Chloroform-d) δ 7.75 - 7.67 (m, 1H), 7.62 - 7.55 (m, 2H), 7.50 - 7.40 (m, 3H), 5.44 - 5.30 (m, 2H), 4.81 (t, J = 9.3 Hz, 1H), 4.28 (dd, J = 9.1, 6.1 Hz, 1H), 3.57 (dp, J = 8.9, 6.3 Hz, 1H), 2.77 (t, J = 6.1 Hz, 2H), 1.71 - 1.54 (m, 4H), 1.35 (d, J = 6.8 Hz, 3H), 1.29 (d, J = 3.7 Hz, 6H). 13 C NMR (151 MHz, CDC13) δ 177.72, 169.15, 150.87, 150.41, 139.48, 137.05, 132.49, 131.85, 131.60, 131.55, 131.14, 129.31, 128.94, 128.15, 122.45, 121.70, 118.71, 117.42, 112.50, 80.98, 77.26, 77.04, 76.83, 76.68, 39.34, 38.66, 35.06, 32.31, 32.26, 31.57, 20.10, 18.74.

[0207] b9-3: light yellow solid, yield 12.0%. 1 H NMR (600 MHz, Chloroform-d) δ 7.72 - 7.57 (m, 3H), 7.51 - 7.40 (m, 3H), 5.49 - 5.31 (m, 2H), 4.88 - 4.76 (m, 1H), 4.31 - 4.26 (m, 1H), 3.56 (dddd, J = 16.7, 12.8, 9.8, 5.3 Hz, 1H), 2.95 - 2.73 (m, 1H), 2.45 - 2.29 (m, 1H), 1.76 - 1.55 (m, 4H), 1.44 - 1.33 (m, 3H), 1.32 - 1.24 (m, 6H). 13 C NMR (151 MHz, CDC13) δ 149.93, 139.03, 138.00, 132.67, 131.86, 131.71, 131.61, 131.55, 129.30, 128.94, 128.16, 122.54, 118.51, 112.64, 81.18, 77.24, 77.03, 76.82, 39.34, 35.01, 34.88, 32.40, 31.48, 20.10, 19.66, 18.73.

[0208] The preparation method of reference compound b1-1 was referred to, and iodomethane was replaced by 3-trifluoromethylbenzyl bromide to obtain compounds b10-1, b10-2 and b10-3.

[0209]

[0210] b10-1: colorless solid, yield 30.3%. 1 H NMR (600 MHz, Chloroform-d) δ 8.59-8.39 (m, 2H), 7.89 (d, J = 8.7 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.59 (dq, J = 49.8, 10.2, 9.0 Hz, 2H), 4.99 (t, J = 8.8 Hz, 1H), 4.43 (dd, J = 8.5, 6.6 Hz, 1H), 4.09 (dq, J = 9.1, 6.7 Hz, 1H), 3.82 (t, J = 6.4 Hz, 2H), 2.03 (dtd, J = 14.1, 7.6, 7.1, 3.2 Hz, 2H), 1.84-1.75 (m, 2H), 1.58 (d, J = 6.8 Hz, 3H), 1.40 (d, J = 5.1 Hz, 6H). 13 C NMR (151 MHz, CDCl3) δ 157.02, 155.90, 146.34, 144.76, 132.75, 132.60, 129.79, 129.35, 128.96, 126.45, 126.42, 125.37, 124.42, 123.37, 123.35, 119.84, 117.54, 109.34, 79.67, 77.24, 77.03, 76.81, 38.81, 36.39, 34.64, 31.85, 30.42, 29.71, 19.78, 19.36.

[0211] b10-2: light yellow solid, yield 29.2%. 1 H NMR (600 MHz, Chloroform-d) δ 7.71-7.38 (m, 6H), 5.35 (s, 2H), 4.80 (t, J = 9.3 Hz, 1H), 4.27 (dd, J = 9.1, 6.1 Hz, 1H), 3.56 (dp, J = 9.7, 6.6 Hz, 1H), 2.73 (t, J = 6.2 Hz, 1H), 2.43-2.24 (m, 1H), 1.59-1.52 (m, 2H), 1.35 (d, J = 6.8 Hz, 3H), 1.28 (d, J = 3.0 Hz, 6H). 13C NMR (151 MHz, CDCI3) δ 177.73, 168.99, 150.79, 150.18, 138.93, 137.12, 131.65, 131.29, 128.95, 128.81, 128.03, 125.09, 124.71, 122.41, 121.58, 117.43, 80.93, 77.24, 77.03, 76.82, 39.25, 38.66, 35.07, 35.03, 32.31, 32.27, 20.00, 18.71.

[0212] b10-3: light yellow solid, yield 29.5%. 1 H NMR (600 MHz, Chloroform-d) δ 7.62 - 7.38 (m, 6H), 5.40 (d, J = 54.5 Hz, 2H), 4.81 (dd, J = 15.8, 6.5 Hz, 1H), 4.38 - 4.25 (m, 1H), 3.56 (dtd, J = 13.8, 7.4, 7.0, 3.7 Hz, 1H), 2.98 - 2.71 (m, 1H), 2.52 - 2.23 (m, 1H), 1.76 - 1.55 (m, 4H), 1.37 - 1.20 (m, 9H). 13 C NMR (151 MHz, CDCI3) δ 177.73, 168.99, 150.79, 150.18, 138.93, 137.12, 131.65, 131.29, 128.95, 128.81, 128.03, 125.09, 124.71, 122.41, 121.58, 117.43, 80.93, 77.24, 77.03, 76.82, 39.25, 38.66, 35.07, 35.03, 32.31, 32.27, 20.00, 18.71.

[0213] Referring to the preparation method of compound b1-1, replace iodomethane with 4- trifluoromethylbenzyl bromide to obtain compounds b11-1, b11-2 and b11-3.

[0214]

[0215] b11-1: colorless solid, yield 14.8%. 1H NMR (600 MHz, Chloroform-d) δ 8.36 (d, J = 8.1 Hz, 2H), 7.89 (d, J = 8.7 Hz, 1H), 7.76 (d, J = 8.1 Hz, 2H), 7.55 (d, J = 8.6 Hz, 1H), 4.99 (t, J = 8.8 Hz, 1H), 4.43 (dd, J = 8.5, 6.6 Hz, 1H), 4.08 (dt, J = 9.1, 6.8 Hz, 1H), 3.82 (t, J = 6.4 Hz, 2H), 2.03 (ddt, J = 12.6, 9.4, 4.3 Hz, 2H), 1.83 - 1.78 (m, 2H), 1.58 (d, J = 6.8 Hz, 3H), 1.40 (d, J = 5.1 Hz, 6H). 13 C NMR (151 MHz, CDC13) δ 157.03, 156.02, 146.46, 144.81, 132.74, 126.82, 125.77, 125.74, 124.45, 119.88, 117.57, 109.30, 79.67, 77.24, 77.02, 76.81, 38.80, 36.38, 34.63, 31.90, 31.85, 30.42, 19.79, 19.30.

[0216] b11-2: light yellow solid, yield 48.7%. 1 H NMR (600 MHz, Chloroform-d) δ 7.64 - 7.54 (m, 4H), 7.43 (dd, J = 24.3, 9.1 Hz, 2H), 5.39 (d, J = 11.2 Hz, 2H), 4.84 - 4.78 (m, 1H), 4.30 - 4.25 (m, 1H), 3.60 - 3.53 (m, 1H), 2.73 (t, J = 6.3 Hz, 2H), 1.61 (t, J = 5.6 Hz, 2H), 1.54 (q, J = 6.0 Hz, 2H), 1.35 (d, J = 6.8 Hz, 3H), 1.31 - 1.27 (m, 6H). 13 C NMR (151 MHz, CDC13) δ 177.71, 169.03, 150.79, 150.10, 142.00, 139.10, 137.11, 131.26, 130.10, 129.89, 128.80, 128.55, 128.20, 128.04, 125.34, 125.32, 121.61, 117.43, 80.93, 77.25, 77.12, 77.04, 76.83, 38.68, 35.07, 35.04, 32.30, 32.26, 31.45, 20.01, 18.75.

[0217] b11-3: light yellow solid, yield 31.2%. 1 H NMR (600 MHz, Chloroform-d) δ 7.64 - 7.39 (m, 6 H), 5.53 - 5.35 (m, 2 H), 4.87 - 4.78 (m, 1 H), 4.33 - 4.25 (m, 1 H), 3.59 - 3.51 (m, 1 H), 2.96 - 2.68 (m, 1 H), 2.35 (s, 1 H), 1.61 (t, J = 4.6 Hz, 4 H), 1.35 (d, J = 6.8 Hz, 3 H), 1.31 - 1.24 (m, 6 H). 13 CNMR (151 MHz, CDC13) δ 169.03, 149.83, 140.33, 139.10, 128.80, 128.55, 128.20, 125.38, 125.36, 123.15, 122.52, 121.73, 81.14, 77.24, 77.12, 77.03, 76.82, 39.33, 34.99, 34.90, 32.39, 31.45, 20.02, 19.65.

[0218] Referring to the preparation method of compound b1-1, methyl iodide is replaced by 3,5-di(trifluoromethyl)benzyl bromide to obtain compounds b12-1, b12-2 and b12-3.

[0219]

[0220] b12-1: colorless solid, yield 28.7%. 1 H NMR (600 MHz, Chloroform-d) δ 8.63 (d, J = 1.6 Hz, 2 H), 7.97 - 7.75 (m, 2 H), 7.57 (d, J = 8.7 Hz, 1 H), 4.99 (t, J = 8.8 Hz, 1 H), 4.44 (dd, J = 8.5, 6.6 Hz, 1 H), 4.06 (dp, J = 9.3, 6.8 Hz, 1 H), 3.79 (t, J = 6.4 Hz, 2 H), 2.04 (ddp, J = 10.6, 7.2, 4.2, 3.7 Hz, 2 H), 1.83 - 1.79 (m, 2 H), 1.59 (d, J = 6.9 Hz, 3 H), 1.41 (d, J = 5.5 Hz, 6 H). 13CNMR (151 MHz, CDC13) δ 156.54, 155.47, 146.64, 145.15, 132.82, 132.53, 132.29, 130.15, 126.31, 125.40, 124.70, 124.06, 123.01, 122.25, 119.95, 117.72, 109.23, 79.76, 77.24, 77.02, 76.81, 38.74, 36.29, 34.66, 31.88, 31.84, 30.40, 19.72, 19.42.

[0221] b12-2: light yellow solid, yield 27.5%. 1 H NMR (600 MHz, Chloroform-d) δ 7.90 (s, 1H), 7.82 (d, J = 6.9 Hz, 1H), 7.76 (s, 1H), 7.51 - 7.40 (m, 2H), 5.51 (s, 1H), 5.39 (s, 1H), 4.82 (t, J = 9.3 Hz, 1H), 4.28 (dd, J = 9.1, 6.3 Hz, 1H), 3.57 (dp, J = 9.9, 6.8 Hz, 1H), 2.71 (t, J = 6.2 Hz, 1H), 1.99 (s, 1H), 1.77 - 1.50 (m, 4H), 1.36 (d, J = 6.8 Hz, 3H), 1.28 (s, 6H). 13 C NMR (151 MHz, CDC13) δ 177.75, 169.26, 150.93, 140.59, 139.03, 138.95, 137.04, 131.92, 131.88, 131.70, 131.65, 131.08, 129.09, 128.39, 128.27, 128.15, 124.18, 122.57, 122.49, 122.38, 122.04, 121.85, 121.74, 117.37, 81.02, 77.24, 77.03, 76.82, 76.21, 39.23, 38.58, 35.02, 34.97, 32.24, 31.42, 19.92, 18.63.

[0222] b12-3: light yellow solid, yield 33.4%. 1H NMR (600 MHz, Chloroform-d) δ 7.92 - 7.72 (m, 3H), 7.48 (s, 2H), 5.45 (d, J = 76.0 Hz, 2H), 4.88 - 4.76 (m, 1H), 4.38 - 4.25 (m, 1H), 3.61 - 3.49 (m, 1H), 2.90 (s, 1H), 2.49 - 2.29 (m, 1H), 1.95 (s, 2H), 1.73 - 1.60 (m, 2H), 1.42 - 1.31 (m, 3H), 1.30 - 1.24 (m, 6H). 13 C NMR (151 MHz, CDC13) δ 150.05, 139.01, 138.96, 131.93, 131.70, 129.11, 128.16, 122.55, 122.25, 122.06, 81.23, 77.24, 77.02, 76.81, 76.31, 39.23, 34.98, 34.85, 32.24, 31.56, 29.71, 19.58, 18.63.

[0223] The preparation method of reference compound b1-1 was referred to, and iodomethane was replaced by 3-trifluoromethoxybenzyl bromide to obtain compounds b13-2 and b13-3.

[0224]

[0225] b13-2: light yellow solid, yield 20.0%. 1 H NMR (600 MHz, Chloroform-d) δ 7.49 - 7.31 (m, 3H), 7.28 (d, J = 7.9 Hz, 1H), 7.22 - 7.13 (m, 2H), 5.37 (d, J = 52.5 Hz, 2H), 4.81 (dd, J = 16.5, 7.2 Hz, 1H), 4.28 (ddd, J = 16.4, 13.1, 9.4 Hz, 1H), 3.61 - 3.50 (m, 1H), 2.97 - 2.74 (m, 1H), 2.35 (d, J = 33.6 Hz, 1H), 1.61 (tt, J = 34.5, 26.7, 9.6 Hz, 4H), 1.41 - 1.24 (m, 9H). 13C NMR (151 MHz, CDCI3) δ 149.92, 149.29, 139.15, 138.55, 129.85, 129.81, 128.80, 126.76, 122.45, 121.73, 121.59, 121.28, 120.86, 120.67, 120.23, 119.57, 81.17, 77.29, 77.24, 77.03, 76.82, 39.25, 34.97, 34.88, 32.27, 31.47, 31.44, 19.60, 18.70.

[0226] b13-3: light yellow solid, yield 32.1%. 1 H NMR (600 MHz, Chloroform-d) δ 7.49 - 7.34 (m, 4H), 7.28 (d, J = 8.5 Hz, 1H), 7.20 - 7.13 (m, 1H), 5.32 (s, 2H), 4.81 (t, J = 9.3 Hz, 1H), 4.28 (dd, J = 9.1, 6.1 Hz, 1H), 3.57 (dp, J = 9.3, 6.5 Hz, 1H), 2.76 (t, J = 6.2 Hz, 1H), 2.18 (s, 1H), 1.64 - 1.49 (m, 4H), 1.35 (d, J = 6.8 Hz, 2H), 1.28 (d, J = 2.6 Hz, 6H). 13 C NMR (151 MHz, CDCI3) δ 149.92, 149.29, 139.15, 138.55, 129.85, 129.81, 128.80, 126.76, 122.45, 121.73, 121.59, 121.28, 120.86, 120.67, 120.23, 119.57, 81.17, 77.29, 77.24, 77.03, 76.82, 39.25, 34.97, 34.88, 32.27, 31.47, 31.44, 19.60, 18.70.

[0227] Referring to the preparation method of compound b1-1, replacing iodomethane with 2-trifluoromethoxybenzyl bromide to obtain compounds b14-1, b14-2 and b14-3.

[0228]

[0229] b14-1: colorless solid, yield 2.9%. 1H NMR (600 MHz, Chloroform-d) δ 8.40 (dd, J = 7.5, 2.0 Hz, 1H), 7.89 (d, J = 8.7 Hz, 1H), 7.60 - 7.40 (m, 4H), 4.99 (t, J = 8.8 Hz, 1H), 4.42 (dd, J = 8.5, 6.8 Hz, 1H), 4.08 (dp, J = 9.4, 6.9 Hz, 1H), 3.83 (t, J = 6.4 Hz, 2H), 2.04 - 1.97 (m, 2H), 1.81 - 1.76 (m, 2H), 1.56 (d, J = 6.8 Hz, 3H), 1.40 (d, J = 5.3 Hz, 6H). 13 C NMR (151 MHz, CDC13) δ 155.88, 155.02, 144.67, 132.80, 132.34, 131.07, 130.55, 127.35, 124.34, 122.91, 122.18, 119.79, 117.53, 109.33, 79.70, 77.23, 77.02, 76.81, 38.83, 36.39, 34.61, 31.85, 30.38, 29.71, 19.73, 18.99.

[0230] b14-2: light yellow solid, yield 55.0%. 1 H NMR (600 MHz, Chloroform-d) δ 7.49 - 7.28 (m, 5H), 7.24 (d, J = 7.5 Hz, 1H), 5.52 - 5.41 (m, 2H), 4.81 (q, J = 9.2, 7.2 Hz, 1H), 4.29 (td, J = 9.1, 8.5, 4.5 Hz, 1H), 3.56 (ddd, J = 12.8, 9.3, 6.4 Hz, 1H), 2.84 (t, J = 6.1 Hz, 2H), 1.72 - 1.54 (m, 4H), 1.35 (d, J = 6.8 Hz, 3H), 1.30 - 1.26 (m, 6H). 13 C NMR (151 MHz, CDC13) δ 177.73, 169.09, 150.82, 150.04, 149.85, 147.28, 139.29, 137.25, 131.32, 130.69, 129.89, 129.74, 128.93, 128.71, 127.98, 126.98, 126.74, 122.39, 121.55, 120.36, 120.22, 117.47, 80.95, 77.25, 77.04, 76.83, 72.23, 39.27, 35.05, 34.95, 32.32, 31.31, 31.23, 19.60, 18.77.

[0231] b14-3: light yellow solid, yield 33.0%. 1 H NMR (600 MHz, Chloroform-d) δ 7.50 - 7.28 (m, 4H), 7.24 (d, J = 7.7 Hz, 2H), 5.58 - 5.42 (m, 2H), 4.88 - 4.78 (m, 1H), 4.35 - 4.26 (m, 1H), 3.60 - 3.47 (m, 1H), 3.02 - 2.80 (m, 1H), 2.55 (s, 1H), 1.76 - 1.53 (m, 4H), 1.42 - 1.32 (m, 3H), 1.30 - 1.24 (m, 6H). 13 C NMR (151 MHz, CDC13) δ 177.75, 169.15, 149.88, 147.28, 139.30, 130.91, 129.75, 128.94, 128.72, 127.98, 126.97, 126.74, 122.37, 121.56, 120.22, 81.16, 77.24, 77.03, 76.82, 72.50, 39.27, 38.68, 34.95, 34.87, 32.27, 31.23, 19.60, 18.76.

[0232] Referring to the preparation method of compound b1-1, methyl iodide is replaced by 3-difluoromethoxybenzyl bromide to obtain compounds b15-1, b15-2 and b15-3.

[0233]

[0234] b15-1: colorless solid, yield 6.1%. 1 H NMR (600 MHz, Chloroform-d) δ 8.17 - 8.02 (m, 1H), 7.88 (d, J = 8.7 Hz, 1H), 7.58 - 7.52 (m, 1H), 7.29 (dd, J = 8.4, 5.4 Hz, 1H), 7.16 (t, J = 2.0 Hz, 1H), 7.01 (dd, J = 8.1, 2.5 Hz, 1H), 6.67 - 6.48 (m, 1H), 4.96 (t, J = 8.7 Hz, 1H), 4.42 (dd, J = 8.4, 6.3 Hz, 1H), 4.04 (q, J = 7.2 Hz, 1H), 3.74 (q, J = 7.2 Hz, 1H), 3.59 (t, J = 6.3 Hz, 1H), 1.67 (s, 4H), 1.40 (d, J = 4.0 Hz, 3H), 1.30 - 1.28 (m, 6H). 13C NMR (151 MHz, CDC13) δ 130.46, 126.34, 124.07, 120.28, 118.31, 118.07, 79.55, 77.23, 77.02, 76.81, 41.42, 37.14, 36.91, 34.44, 32.79, 31.65, 30.08, 29.74, 29.34, 27.13, 24.50, 19.74.

[0235] b15-2: light yellow solid, yield 56.0%. 1 H NMR (600 MHz, Chloroform-d) δ 7.48 - 7.27 (m, 4H), 7.19 (d, J = 7.1 Hz, 1H), 7.06 (dd, J = 8.1, 2.5 Hz, 1H), 6.49 (td, J = 73.9, 19.3 Hz, 1H), 5.36 (d, J = 48.5 Hz, 2H), 4.90 - 4.79 (m, 1H), 4.31 - 4.24 (m, 1H), 3.62 - 3.53 (m, 1H), 3.02 - 2.76 (m, 1H), 2.11 (s, 1H), 1.77 - 1.52 (m, 4H), 1.35 (d, J = 6.8 Hz, 3H), 1.30 - 1.25 (m, 6H). 13 CNMR (151 MHz, CDC13) δ 169.09, 151.22, 151.20, 149.89, 139.16, 138.48, 129.85, 128.77, 127.99, 125.38, 125.07, 122.46, 121.58, 119.46, 119.31, 119.08, 115.83, 114.11, 81.15, 77.49, 77.24, 77.03, 76.82, 39.29, 34.98, 34.88, 32.27, 31.47, 29.71, 19.62, 18.71.

[0236] b15-3: light yellow solid, yield 30.2%. 1H NMR (600 MHz, Chloroform-d) δ 7.48 - 7.39 (m, 2H), 7.38 - 7.27 (m, 2H), 7.19 (dd, J = 4.7, 2.8 Hz, 1H), 7.12 - 7.03 (m, 1H), 6.49 (td, J = 73.9, 19.7 Hz, 1H), 5.32 (s, 2H), 4.80 (t, J = 9.3 Hz, 1H), 4.27 (dd, J = 9.1, 6.1 Hz, 1H), 3.56 (tdd, J = 10.4, 8.3, 5.2 Hz, 1H), 2.80 (t, J = 6.2 Hz, 2H), 1.73 - 1.52 (m, 4H), 1.35 (d, J = 6.8 Hz, 3H), 1.29 (d, J = 3.1 Hz, 6H). 13 C NMR (151 MHz, CDC13) δ 177.73, 169.05, 151.21, 150.78, 149.99, 140.15, 139.15, 137.13, 131.34, 129.83, 128.76, 127.98, 125.37, 125.05, 122.36, 121.57, 119.46, 119.30, 119.07, 118.82, 117.45, 115.94, 114.22, 80.93, 77.33, 77.25, 77.03, 76.82, 39.28, 38.69, 35.06, 35.04, 32.32, 31.49, 20.07, 18.71.

[0237] The preparation method of reference compound b1-1 was referred to, and iodomethane was replaced with 4-chlorobenzybromide to obtain compounds b16-1, b16-2 and b16-3.

[0238]

[0239] b16-1: colorless solid, yield 12.5%. 1 H NMR (600 MHz, Chloroform-d) δ 8.22 - 8.15 (m, 2H), 7.87 (d, J = 8.7 Hz, 1H), 7.56 - 7.45 (m, 3H), 4.98 (t, J = 8.8 Hz, 1H), 4.41 (dd, J = 8.5, 6.7 Hz, 1H), 4.06 (dp, J = 9.4, 6.8 Hz, 1H), 3.81 (t, J = 6.4 Hz, 2H), 2.01 (ddt, J = 12.4, 9.2, 4.5 Hz, 2H), 1.82 - 1.77 (m, 2H), 1.56 (d, J = 6.9 Hz, 3H), 1.40 (d, J = 5.5 Hz, 6H). 13C NMR (151 MHz, CDC13) δ 157.57, 155.57, 146.16, 144.55, 136.07, 132.68, 132.67, 129.06, 127.94, 126.65, 125.30, 124.28, 119.80, 117.43, 109.34, 79.60, 77.24, 77.03, 76.82, 38.83, 36.41, 34.62, 31.91, 31.86, 30.42, 19.81, 19.29.

[0240] b16-2: light yellow solid, yield 47.0%. 1 H NMR (600 MHz, Chloroform-d) δ 7.46 - 7.27 (m, 6 H), 5.29 (d, J = 2.1 Hz, 2 H), 4.80 (t, J = 9.2 Hz, 1 H), 4.27 (dd, J = 9.1, 6.1 Hz, 1 H), 3.55 (dp, J = 9.5, 6.6 Hz, 1 H), 2.78 (t, J = 6.2 Hz, 2 H), 1.66 - 1.51 (m, 4 H), 1.31 (dd, J = 32.4, 5.4 Hz, 9 H). 13 C NMR (151 MHz, CDC13) δ 177.69, 168.95, 150.74, 149.81, 137.11, 136.37, 133.72, 131.36, 130.06, 129.64, 128.60, 128.53, 127.94, 122.36, 121.56, 117.46, 80.91, 77.30, 77.26, 77.05, 76.84, 38.73, 35.07, 35.05, 32.33, 32.28, 31.53, 20.11, 18.76.

[0241] b16-3: light yellow solid, yield 35.3%. 1 H NMR (600 MHz, Chloroform-d) δ 7.63 - 7.27 (m, 6 H), 5.33 (d, J = 46.2 Hz, 2 H), 4.99 - 4.76 (m, 1 H), 4.46 - 4.21 (m, 1 H), 3.55 (s, 1 H), 2.83 (d, J = 67.0 Hz, 1 H), 2.27 (d, J = 61.6 Hz, 1 H), 1.77 - 1.51 (m, 4 H), 1.48 - 1.20 (m, 9 H). 13C NMR (151 MHz, CDCI3) δ 149.77, 139.11, 134.73, 134.17, 130.06, 129.64, 128.69, 128.60, 128.53, 122.48, 121.66, 81.11, 77.48, 77.26, 77.05, 76.84, 39.34, 34.98, 34.91, 32.39, 31.44, 19.65.

[0242] The preparation method of reference compound b1-1 was referred to, and iodomethane was replaced by 3-chlorobenzyl to obtain compounds b17-1, b17-2 and b17-3.

[0243]

[0244] b17-1: colorless solid, yield 15.2%. 1 H NMR (600 MHz, Chloroform-d) δ 8.23 (d, J = 2.2 Hz, 1H), 8.14 (dt, J = 6.7, 2.0 Hz, 1H), 7.88 (d, J = 8.7 Hz, 1H), 7.54 (d, J = 8.7 Hz, 1H), 7.52 - 7.41 (m, 2H), 4.98 (t, J = 8.8 Hz, 1H), 4.42 (dd, J = 8.5, 6.7 Hz, 1H), 4.16 - 4.02 (m, 1H), 3.81 (t, J = 6.4 Hz, 2H), 2.02 (dtd, J = 12.5, 6.7, 3.4 Hz, 2H), 1.82 - 1.75 (m, 2H), 1.57 (d, J = 6.9 Hz, 3H), 1.40 (d, J = 5.6 Hz, 6H). 13 C NMR (151 MHz, CDCI3) δ 149.77, 139.11, 134.73, 134.17, 130.06, 129.64, 128.69, 128.60, 128.53, 122.48, 121.66, 81.11, 77.48, 77.26, 77.05, 76.84, 39.34, 34.98, 34.91, 32.39, 31.44, 19.65.

[0245] b17-2: light yellow solid, yield 35.3%. 1H NMR (600 MHz, Chloroform-d) δ 7.47 - 7.39 (m, 3H), 7.34 - 7.27 (m, 3H), 5.28 (s, 2H), 4.80 (t, J = 9.3 Hz, 1H), 4.27 (dd, J = 9.1, 6.1 Hz, 1H), 3.56 (dp, J = 9.7, 6.7 Hz, 1H), 2.78 (t, J = 6.1 Hz, 2H), 1.69 - 1.55 (m, 4H), 1.35 (d, J = 6.8 Hz, 3H), 1.29 (d, J = 3.6 Hz, 6H). 13 C NMR (151 MHz, CDC13) δ 177.70, 169.00, 150.77, 149.95, 139.88, 137.16, 134.21, 131.33, 129.71, 128.75, 128.44, 128.35, 128.02, 127.98, 126.40, 122.37, 121.56, 117.45, 80.93, 77.36, 77.25, 77.04, 76.83, 39.33, 38.73, 35.08, 32.33, 32.28, 31.60, 20.11, 18.75.

[0246] b17-3: light yellow solid, yield 27.1%. 1 H NMR (600 MHz, Chloroform-d) δ 7.50 - 7.39 (m, 2H), 7.32 (s, 1H), 7.30 - 7.21 (m, 3H), 5.33 (d, J = 55.6 Hz, 2H), 4.90 - 4.74 (m, 1H), 4.38 - 4.23 (m, 1H), 3.62 - 3.49 (m, 1H), 2.98 - 2.73 (m, 1H), 2.44 - 2.26 (m, 1H), 1.80 - 1.48 (m, 4H), 1.39 - 1.24 (m, 9H). 13 C NMR (151 MHz, CDC13) δ 150.76, 149.86, 139.15, 138.22, 134.29, 129.71, 128.75, 128.46, 128.44, 128.35, 126.49, 126.40, 122.48, 121.70, 81.13, 77.35, 77.25, 77.04, 76.83, 39.33, 34.99, 34.90, 32.39, 31.45, 19.63.

[0247] Referring to the preparation method of compound bl-1, iodomethane is replaced by 2-chlorobenzybromide to obtain compounds b18-1, b18-2 and b18-3.

[0248]

[0249] b18-1: colorless solid, yield 6.0%. 1 H NMR (600 MHz, Chloroform-d) δ 8.23 (dd, J = 7.3, 2.1 Hz, 1H), 7.89 (d, J = 8.7 Hz, 1H), 7.61 - 7.52 (m, 2H), 7.47 - 7.34 (m, 2H), 5.00 (t, J = 8.8 Hz, 1H), 4.42 (dd, J = 8.5, 6.9 Hz, 1H), 4.09 (dt, J = 9.1, 6.8 Hz, 1H), 3.83 (t, J = 6.4 Hz, 2H), 2.05 - 1.97 (m, 2H), 1.84 - 1.75 (m, 2H), 1.57 (d, J = 6.9 Hz, 3H), 1.40 (d, J = 5.0 Hz, 3H), 1.26 (s, 3H). 13 C NMR (151 MHz, CDC13) δ 144.62, 131.40, 131.20, 130.75, 126.85, 124.30, 119.78, 79.67, 77.23, 77.02, 76.81, 38.83, 36.43, 34.61, 31.92, 30.37, 29.71, 19.82, 19.18.

[0250] b18-2: light yellow solid, yield 61.0%. 1 H NMR (600 MHz, Chloroform-d) δ 7.58 (dd, J = 7.7, 1.7 Hz, 1H), 7.48 - 7.39 (m, 2H), 7.36 (dt, J = 8.0, 2.1 Hz, 1H), 7.28 (td, J = 7.5, 1.3 Hz, 1H), 7.23 (td, J = 7.7, 1.9 Hz, 1H), 5.47 (d, J = 2.4 Hz, 2H), 4.81 (t, J = 9.2 Hz, 1H), 4.29 (dd, J = 9.1, 5.9 Hz, 1H), 3.58 (dp, J = 9.6, 6.7 Hz, 1H), 2.88 (t, J = 6.1 Hz, 2H), 1.69 - 1.59 (m, 3H), 1.36 (d, J = 6.7 Hz, 3H), 1.29 (d, J = 4.6 Hz, 6H). 13C NMR (151 MHz, CDCI3) δ 177.70, 168.93, 150.76, 150.04, 137.23, 135.58, 132.61, 131.36, 129.37, 129.17, 128.76, 127.96, 126.85, 122.37, 121.54, 117.50, 80.93, 77.26, 77.05, 76.84, 75.15, 38.72, 35.08, 35.06, 32.34, 32.29, 31.43, 20.12, 18.83.

[0251] b18-3: light yellow solid, yield 23.6%. 1 H NMR (600 MHz, Chloroform-d) δ 7.52 - 7.31 (m, 4H), 7.22 (dtd, J=14.8, 7.5, 1.7 Hz, 2H), 5.64 - 5.44 (m, 2H), 4.89 - 4.76 (m, 1 H), 4.36 - 4.25 (m, 1 H), 3.57 (ddt, J=19.5, 16.7, 7.7 Hz, 1 H), 3.12 - 2.82 (m, 1 H), 2.35 (s, 1 H), 1.75 - 1.47 (m, 4H), 1.40 - 1.24 (m, 9H). 13 C NMR (151 MHz, CDCI3) δ 177.70, 168.93, 150.76, 150.04, 137.23, 135.58, 132.61, 131.36, 129.37, 129.17, 128.76, 127.96, 126.85, 122.37, 121.54, 117.50, 80.93, 77.26, 77.05, 76.84, 75.15, 38.72, 35.08, 35.06, 32.34, 32.29, 31.43, 20.12, 18.83.

[0252] Referring to the preparation method of compound b1-1, methyl iodide is replaced by 4-bromobenzyl bromide to obtain compounds b19-1, b19-2 and b19-3.

[0253]

[0254] b19-1 : colorless solid, yield 4.8%. 1H NMR (600 MHz, Chloroform-d) δ 8.22 - 8.11 (m, 2H), 7.88 (d, J = 8.7 Hz, 1H), 7.66 - 7.62 (m, 2H), 7.54 (d, J = 8.7 Hz, 1H), 4.98 (t, J = 8.8 Hz, 1H), 4.42 (dd, J = 8.5, 6.7 Hz, 1H), 4.08 (dtd, J = 12.0, 7.6, 7.2, 3.8 Hz, 1H), 3.81 (t, J = 6.4 Hz, 2H), 2.06 - 1.97 (m, 2H), 1.83 - 1.77 (m, 2H), 1.57 (d, J = 6.8 Hz, 3H), 1.40 (d, J = 4.6 Hz, 6H). 13 C NMR (151 MHz, CDC13) δ 157.64, 155.63, 146.19, 144.59, 132.70, 132.02, 128.15, 127.10, 125.31, 124.44, 124.31, 119.81, 117.45, 109.35, 79.62, 77.23, 77.02, 76.81, 38.83, 36.42, 34.62, 31.85, 30.42, 29.71, 19.80, 19.30.

[0255] b19-2: light yellow solid, yield 36.3%. 1 H NMR (600 MHz, Chloroform-d) δ 7.47 (s, 4H), 7.33 - 7.29 (m, 1H), 7.25 (d, J = 15.1 Hz, 1H), 5.27 (d, J = 2.0 Hz, 2H), 4.80 (t, J = 9.3 Hz, 1H), 4.27 (dd, J = 9.0, 6.1 Hz, 1H), 3.56 (dp, J = 9.4, 6.6 Hz, 1H), 2.76 (s, 2H), 1.70 - 1.53 (m, 4H), 1.32 (dd, J = 32.2, 5.4 Hz, 9H). 13 C NMR (151 MHz, CDC13) δ 177.69, 168.97, 150.75, 149.84, 137.12, 136.90, 131.57, 131.49, 131.35, 129.95, 127.95, 122.36, 121.87, 121.56, 117.45, 80.92, 77.24, 77.03, 76.82, 38.73, 35.07, 35.06, 32.33, 32.28, 31.51, 20.11, 18.75.

[0256] b19-3: light yellow solid, yield 24.9%.1 H NMR (600 MHz, Chloroform-d) δ 7.49 - 7.42 (m, 4H), 7.23 (d, J = 8.2 Hz, 2H), 5.40 - 5.25 (m, 2H), 4.83 - 4.77 (m, 1H), 4.31 - 4.24 (m, 1H), 3.59 - 3.52 (m, 1H), 2.96 - 2.77 (m, 1H), 2.32 (s, 1H), 1.74 - 1.56 (m, 4H), 1.36 - 1.26 (m, 9H). 13 C NMR (151 MHz, CDC13) δ 149.79, 139.11, 135.26, 131.56, 131.49, 130.33, 129.95, 128.71, 122.48, 122.34, 81.12, 80.91, 77.24, 77.02, 76.81, 39.34, 35.07, 34.99, 34.91, 32.39, 31.44, 29.71, 19.65.

[0257] Referring to the preparation method of compound b1-1, methyl iodide is replaced with 3-bromobenzyl to obtain compounds b20-1, b20-2 and b20-3.

[0258]

[0259] b20-1: colorless solid, yield 15.1%. 1 H NMR (600 MHz, Chloroform-d) δ 8.39 (t, J = 1.8 Hz, 1H), 8.20 (dt, J = 7.8, 1.3 Hz, 1H), 7.88 (d, J = 8.7 Hz, 1H), 7.63 - 7.53 (m, 2H), 7.38 (t, J = 7.9 Hz, 1H), 4.99 (t, J = 8.8 Hz, 1H), 4.42 (dd, J = 8.5, 6.7 Hz, 1H), 4.09 (ddq, J = 13.6, 9.1, 7.0 Hz, 1H), 3.81 (t, J = 6.4 Hz, 2H), 2.03 (dtd, J = 12.5, 6.0, 2.8 Hz, 2H), 1.85 - 1.77 (m, 2H), 1.57 (d, J = 6.9 Hz, 3H), 1.40 (d, J = 5.0 Hz, 6H). 13CNMR (151 MHz, CDC13) δ 156.96, 155.77, 146.28, 144.68, 132.91, 132.75, 132.63, 130.34, 130.08, 129.45, 125.23, 124.36, 122.88, 119.82, 117.48, 109.34, 79.65, 77.23, 77.02, 76.81, 38.82, 36.40, 34.63, 31.91, 31.85, 30.43, 19.79, 19.33.

[0260] b20-2: light yellow solid, yield 37.6%. 1 H NMR (600 MHz, Chloroform-d) δ 7.59 (d, J = 1.9 Hz, 1H), 7.50 - 7.36 (m, 4H), 7.22 (dt, J = 16.5, 7.7 Hz, 1H), 5.27 (s, 2H), 4.80 (t, J = 9.2 Hz, 1H), 4.27 (dd, J = 9.1, 6.1 Hz, 1H), 3.56 (dq, J = 16.1, 6.7 Hz, 1H), 2.78 (t, J = 6.1 Hz, 2H), 1.74 - 1.56 (m, 4H), 1.35 (dd, J = 6.8, 1.3 Hz, 3H), 1.29 (d, J = 3.5 Hz, 6H). 13 C NMR (151 MHz, CDC13) δ 177.70, 168.97, 150.77, 149.98, 140.18, 137.17, 131.41, 131.38, 130.95, 130.02, 130.00, 127.98, 126.93, 122.39, 121.56, 117.44, 80.92, 77.24, 77.03, 76.82, 39.33, 38.74, 35.08, 32.34, 32.29, 31.60, 20.14, 18.75.

[0261] b20-3: light yellow solid, yield 4.7%. 1 H NMR (600 MHz, Chloroform-d) δ 7.50 - 7.36 (m, 5H), 7.21 (q, J = 8.4, 7.8 Hz, 1H), 5.32 (d, J = 58.3 Hz, 2H), 4.81 (t, J = 9.3 Hz, 1H), 4.31 - 4.25 (m, 1H), 3.61 - 3.53 (m, 1H), 2.78 (t, J = 6.2 Hz, 2H), 1.71 - 1.55 (m, 4H), 1.40 - 1.28 (m, 9H). 13C NMR (151 MHz, CDCI3) δ 139.15, 138.49, 131.39, 131.28, 130.96, 130.00, 128.76, 126.97, 122.45, 81.13, 77.24, 77.02, 76.81, 39.33, 35.00, 34.90, 32.40, 31.46, 29.71, 19.63, 18.75.

[0262] The preparation method of reference compound b1-1 is referred to, and 2-bromobenzyl is used to replace methyl iodide to obtain compounds b21-1, b21-2 and b21-3.

[0263]

[0264] b21-1: colorless solid, yield 16.1%. 1 H NMR (600 MHz, Chloroform-d) δ 8.18 (dd, J = 7.8, 1.7 Hz, 1H), 7.89 (d, J = 8.7 Hz, 1H), 7.79 (dd, J = 15.5, 8.0 Hz, 1H), 7.55 - 7.44 (m, 2H), 7.36 - 7.29 (m, 1H), 5.00 (t, J = 8.8 Hz, 1H), 4.42 (dd, J = 8.5, 6.9 Hz, 1H), 4.09 (dt, J = 9.0, 6.8 Hz, 1H), 3.84 (t, J = 6.4 Hz, 2H), 2.00 (ddd, J = 12.4, 10.3, 5.9 Hz, 2H), 1.79 (tt, J = 9.2, 3.3 Hz, 2H), 1.58 (d, J = 6.8 Hz, 3H), 1.40 (d, J = 5.4 Hz, 6H). 13 C NMR (151 MHz, CDCI3) δ 139.15, 138.49, 131.39, 131.28, 130.96, 130.00, 128.76, 126.97, 122.45, 81.13, 77.24, 77.02, 76.81, 39.33, 35.00, 34.90, 32.40, 31.46, 29.71, 19.63, 18.75.

[0265] b21-2: light yellow solid, yield 39.6%. 1H NMR (600 MHz, Chloroform-d) δ 7.60 - 7.52 (m, 2H), 7.48 - 7.40 (m, 2H), 7.37 - 7.30 (m, 1H), 7.15 (qd, J = 7.6, 6.5, 1.5 Hz, 1H), 5.44 (d, J = 2.1 Hz, 2H), 4.80 (t, J = 9.2 Hz, 1H), 4.28 (dd, J = 9.1, 5.9 Hz, 1H), 3.57 (dp, J = 9.5, 6.6 Hz, 1H), 2.88 (t, J = 6.1 Hz, 2H), 1.71 - 1.53 (m, 4H), 1.36 (d, J = 6.8 Hz, 3H), 1.29 (d, J = 4.4 Hz, 6H). 13 C NMR (151 MHz, CDCl3) δ 177.70, 168.96, 150.76, 150.14, 137.24, 137.19, 132.69, 132.41, 131.35, 129.65, 129.44, 129.01, 127.97, 127.46, 122.38, 122.25, 121.55, 77.35, 77.28, 77.07, 76.86, 39.33, 38.71, 35.07, 32.29, 31.45, 29.29, 20.12, 18.84.

[0266] b21-3: light yellow solid, yield 11.7%. 1 H NMR (600 MHz, Chloroform-d) δ 7.55 (dt, J = 8.1, 1.9 Hz, 1H), 7.45 (s, 2H), 7.34 (td, J = 6.2, 5.0, 1.4 Hz, 1H), 7.26 - 7.23 (m, 1H), 7.16 (td, J = 7.6, 1.8 Hz, 1H), 5.52 (s, 2H), 4.84 - 4.78 (m, 1H), 4.31 - 4.26 (m, 1H), 3.60 - 3.49 (m, 1H), 3.09 - 2.85 (m, 1H), 2.29 (d, J = 76.3 Hz, 1H), 1.72 - 1.56 (m, 4H), 1.37 - 1.26 (m, 9H). 13CNMR (151 MHz, CDC13) δ 150.77, 149.80, 139.36, 135.89, 132.69, 132.41, 130.26, 129.64, 129.43, 129.01, 128.67, 127.97, 127.39, 123.43, 122.46, 121.54, 81.10, 77.55, 77.25, 77.04, 76.83, 39.34, 34.98, 34.91, 32.40, 31.44, 31.35, 19.64, 18.84.

[0267] The preparation method of reference compound b1-1 is referred to, and 4-tert-butylbromobenzene is used to replace methyl iodide to obtain compounds b22-2 and b22-3.

[0268]

[0269] b22-2: light yellow solid, yield 32.0%. 1 H NMR (600 MHz, Chloroform-d) δ 7.45-7.28 (m, 6H), 5.49-5.27 (m, 2H), 4.79 (t, J = 9.2 Hz, 1H), 4.26 (dd, J = 9.0, 6.1 Hz, 1H), 3.55 (dp, J = 9.6, 6.7 Hz, 1H), 2.79 (t, J = 6.2 Hz, 2H), 1.67-1.54 (m, 4H), 1.36-1.24 (m, 18H). 13 C NMR (151 MHz, CDC13) δ 150.77, 149.80, 139.36, 135.89, 132.69, 132.41, 130.26, 129.64, 129.43, 129.01, 128.67, 127.97, 127.39, 123.43, 122.46, 121.54, 81.10, 77.55, 77.25, 77.04, 76.83, 39.34, 34.98, 34.91, 32.40, 31.44, 31.35, 19.64, 18.84.

[0270] b22-3: light yellow solid, yield 32%. 1H NMR (600 MHz, Chloroform-d) δ 7.45 - 7.28 (m, 6H), 5.46 - 5.29 (m, 2H), 4.86 - 4.76 (m, 1H), 4.34 - 4.23 (m, 1H), 3.57 - 3.53 (m, 1H), 2.97 - 2.76 (m, 1H), 2.30 (s, 1H), 1.68 - 1.52 (m, 4H), 1.36 - 1.22 (m, 18H). 13 C NMR (151 MHz, CDC13) δ 177.64, 168.71, 151.36, 149.66, 139.24, 134.77, 133.16, 128.63, 128.48, 128.29, 127.75, 125.31, 125.25, 122.42, 121.42, 117.51, 81.06, 78.38, 77.25, 77.04, 76.83, 39.30, 38.10, 34.95, 34.61, 31.38, 31.32, 19.62, 18.78.

[0271] Specific Experimental Protocol Three

[0272]

[0273] Preparation of compound c1-1:

[0274] In a 25 ml round bottom flask was added Cryptotanshinone (20 mg, 0.0675 mmol), 3 mL chlorobenzene to dissolve it, followed by 2-fluoro-5-hydroxypyridine (13 mg, 0.1147 mmol), TEMPO (21 mg, 0.1350 mmol), 120 °C for 24 h, TLC monitored the completion of the reaction, after cooling, 80 °C rotary evaporation to remove the solvent, PTLC (PE:EA = 3:1) purification, orange product c1-1 (5.5 mg, 20.0%) was obtained. 1 H NMR (500 MHz, Chloroform-d) δ 7.93 (dd, J = 3.1, 1.6 Hz, 1H), 7.81 - 7.74 (m, 1H), 7.75 - 7.69 (m, 2H), 6.90 (dd, J = 8.9, 3.4 Hz, 1H), 6.47 (t, J = 3.1 Hz, 1H), 4.91 (t, J = 9.5 Hz, 1H), 4.39 (dd, J = 9.4, 5.9 Hz, 1H), 3.60 (dp, J = 9.6, 6.7 Hz, 1H), 2.18 - 2.03 (m, 2H), 1.86 (tt, J = 13.9, 3.0 Hz, 2H), 1.46 (s, 3H), 1.36 - 1.32 (m, 3H), 1.28 (s, 3H). 13C NMR (126 MHz, CDC13) δ 184.80, 176.19, 171.81, 160.42, 158.57, 153.96, 153.11, 153.07, 138.57, 137.62, 137.50, 134.98, 130.85, 130.79, 130.15, 128.82, 126.93, 120.06, 111.34, 111.02, 83.09, 78.71, 78.45, 78.20, 70.92, 36.47, 36.07, 32.95, 32.74, 32.69, 31.12, 23.95, 20.23, 1.42.

[0275] Preparation of compound c1-2-c13-2:

[0276] c1-2: orange solid, yield 28.7%. 1 H NMR (500 MHz, Chloroform-d) δ 7.94 (dd, J = 3.1, 1.6 Hz, 1H), 7.78 (d, J = 8.3 Hz, 1H), 7.76 - 7.69 (m, 2H), 6.90 (dd, J = 8.8, 3.4 Hz, 1H), 6.47 (d, J = 3.3 Hz, 1H), 4.91 (t, J = 9.5 Hz, 1H), 4.39 (dd, J = 9.4, 5.9 Hz, 1H), 3.61 (dp, J = 9.7, 6.6 Hz, 1H), 2.18 - 2.03 (m, 2H), 1.88 (tt, J = 14.0, 3.1 Hz, 1H), 1.51 (dt, J = 13.5, 3.7 Hz, 1H), 1.45 (s, 3H), 1.33 (d, J = 6.8 Hz, 3H), 1.30 (s, 3H).13C NMR (126 MHz, CDC13) δ 184.83, 176.21, 171.79, 160.41, 158.56, 153.97, 153.12, 153.09, 138.61, 137.62, 137.50, 135.00, 130.78, 130.71, 130.12, 128.83, 126.93, 120.14, 111.30, 110.97, 83.08, 78.71, 78.45, 78.20, 70.91, 36.47, 36.05, 32.99, 32.75, 32.61, 23.95, 20.24.

[0277] Following the procedure for the preparation of reference compound c1-1, replacing 2-fluoro-5-hydroxypyridine with 2-fluoro-4-hydroxypyridine, compounds c2-1 and c2-2 were obtained.

[0278]

[0279] c2-1: orange solid, yield 30.2%. 1 H NMR (500 MHz, Chloroform-d) δ 8.20 (d, J = 5.7 Hz, 1H), 8.03 (d, J = 5.8 Hz, 1H), 7.92 (t, J = 8.2 Hz, 1H), 7.86 - 7.78 (m, 2H), 7.76 - 7.70 (m, 1H), 4.91 (d, J = 8.6 Hz, 1H), 4.41 - 4.38 (m, 1H), 4.12 (q, J = 7.2 Hz, 1H), 3.60 (t, J = 6.9 Hz, 1H), 2.25 (d, J = 11.2 Hz, 2H), 2.02 - 1.94 (m, 2H), 1.49 - 1.37 (m, 9H).

[0280] c2-2: orange solid, yield 23%. 1 H NMR (500 MHz, Chloroform-d) δ 8.20 (d, J = 5.8 Hz, 1H), 7.80 (d, J = 8.3 Hz, 1H), 7.72 (d, J = 8.2 Hz, 1H), 6.97 (d, J = 2.3 Hz, 1H), 6.87 (s, OH), 4.91 (t, J = 9.5 Hz, 1H), 4.39 (dd, J = 9.4, 6.0 Hz, 1H), 4.11 (q, J = 7.1 Hz, 1H), 3.61 (dp, J = 9.7, 6.6 Hz, 1H), 2.25 - 2.15 (m, 1H), 2.02 - 1.94 (m, 2H), 1.56 - 1.51 (m, 1H), 1.44 (s, 3H), 1.33 (d, J = 6.8 Hz, 3H), 1.30 (s, 3H). 13 C NMR (126 MHz, CDC13) δ 184.59, 176.00, 171.68, 167.12, 153.97, 153.90, 151.70, 137.64, 135.08, 129.96, 128.89, 127.14, 120.24, 112.69, 112.37, 83.12, 78.71, 78.46, 78.21, 70.07, 61.85, 36.38, 36.05, 32.96, 32.88, 32.50, 24.23, 20.19, 15.63.

[0281] Referring to the preparation method of compound c1-1, 2-fluoro-5-hydroxypyridine was replaced by 2-chloro-5-hydroxypyridine to obtain compounds c3-1 and c3-2.

[0282]

[0283] c3-1: orange solid, yield 30.4%. 1 H NMR (500 MHz, Chloroform-d) δ 8.12 (d, J = 3.1 Hz, 1H), 7.78 (d, J = 8.2 Hz, 1H), 7.71 (d, J = 8.2 Hz, 1H), 7.54 (dd, J = 8.7, 3.1 Hz, 1H), 7.27 (d, J = 8.8 Hz, 1H), 6.51 - 6.48 (m, 1H), 4.90 (t, J = 9.5 Hz, 1H), 4.38 (dd, J = 9.4, 5.9 Hz, 1H), 3.59 (dp, J = 9.7, 6.6 Hz, 1H), 2.18 - 2.11 (m, 1H), 2.05 (td, J = 13.6, 2.8 Hz, 1H), 1.89 (tt, J = 14.2, 3.1 Hz, 1H), 1.55 - 1.48 (m, 1H), 1.45 (s, 3H), 1.35 (d, J = 6.8 Hz, 3H), 1.28 (s, 3H). 13 C NMR (126 MHz, CDC13) δ 182.81, 174.20, 169.86, 152.60, 152.05, 142.06, 138.68, 136.40, 133.10, 128.20, 126.95, 125.80, 125.09, 124.18, 118.21, 81.20, 76.82, 76.57, 76.31, 68.51, 34.55, 34.19, 31.04, 30.87, 30.76, 22.13, 18.35.

[0284] c3-2: orange solid, yield 30.8%. 1 H NMR (500 MHz, Chloroform-d) δ 8.12 (d, J = 3.1 Hz, 1H), 7.78 (d, J = 8.2 Hz, 1H), 7.71 (d, J = 8.2 Hz, 1H), 7.54 (dd, J = 8.7, 3.1 Hz, 1H), 7.27 (d, J = 8.8 Hz, 1H), 6.51 - 6.48 (m, 1H), 4.90 (t, J = 9.5 Hz, 1H), 4.38 (dd, J = 9.4, 5.9 Hz, 1H), 3.59 (dp, J = 9.7, 6.6 Hz, 1H), 2.18 - 2.11 (m, 1H), 2.05 (td, J = 13.6, 2.8 Hz, 1H), 1.89 (tt, J = 14.2, 3.1 Hz, 1H), 1.55 - 1.48 (m, 1H), 1.45 (s, 3H), 1.35 (d, J = 6.8 Hz, 3H), 1.28 (s, 3H). 13C NMR (126 MHz, CDC13) δ 182.85, 174.24, 169.86, 152.62, 152.06, 142.06, 138.69, 136.44, 133.13, 128.17, 126.96, 125.74, 125.09, 124.15, 118.27, 81.20, 76.82, 76.57, 76.32, 68.51, 34.55, 34.16, 31.09, 30.89, 30.68, 22.14, 18.33.

[0285] The preparation method of reference compound c1-1 was referred to, 2-fluoro-5- hydroxypyridine was replaced by 2,3-dichloro-5-hydroxypyridine to obtain compounds c4-1 and c4-2.

[0286]

[0287] c4-1: orange solid, yield 34.7%. 1 H NMR (500 MHz, Chloroform-d) δ 8.05 (d, J = 2.7 Hz, 1H), 7.79 (d, J = 8.2 Hz, 1H), 7.72 (d, J = 8.2 Hz, 1H), 7.61 (d, J = 2.7 Hz, 1H), 6.48 - 6.44 (m, 1H), 4.91 (t, J = 9.5 Hz, 1H), 4.39 (dd, J = 9.4, 5.9 Hz, 1H), 3.60 (dp, J = 9.5, 6.6 Hz, 1H), 2.16 (ddt, J = 14.5, 5.3, 2.6 Hz, 1H), 2.03 (d, J = 9.9 Hz, 1H), 2.01 - 1.88 (m, 2H), 1.45 (s, 3H), 1.35 (d, J = 6.8 Hz, 3H), 1.29 (s, 3H). 13 C NMR (126 MHz, CDC13) δ 182.85, 174.24, 169.86, 152.62, 152.06, 142.06, 138.69, 136.44, 133.13, 128.17, 126.96, 125.74, 125.09, 124.15, 118.27, 81.20, 76.82, 76.57, 76.32, 68.51, 34.55, 34.16, 31.09, 30.89, 30.68, 22.14, 18.33.

[0288] c4-2: orange solid, yield 26.3%. 1H NMR (500 MHz, Chloroform-d) δ 8.05 (d, J = 2.7 Hz, 1H), 7.79 (d, J = 8.3 Hz, 1H), 7.72 (d, J = 8.2 Hz, 1H), 7.62 (d, J = 2.7 Hz, 1H), 6.48 - 6.45 (m, 1H), 4.91 (t, J = 9.5 Hz, 1H), 4.39 (dd, J = 9.4, 6.0 Hz, 1H), 3.61 (dp, J = 9.6, 6.7 Hz, 1H), 2.16 (ddt, J = 14.3, 5.3, 2.2 Hz, 1H), 2.03 (d, J = 10.3 Hz, 1H), 2.01 - 1.89 (m, 2H), 1.45 (s, 3H), 1.33 (d, J = 6.8 Hz, 3H), 1.29 (s, 3H). 13 C NMR (126 MHz, CDC13) δ 184.65, 176.02, 171.69, 154.86, 153.89, 141.45, 138.29, 137.79, 135.08, 131.79, 129.97, 128.92, 127.13, 127.07, 120.23, 83.12, 78.71, 78.45, 78.20, 70.78, 61.84, 36.41, 36.07, 32.96, 32.79, 32.50, 24.06, 20.19, 15.62.

[0289] The preparation method of reference compound c1-1 was referred to, 2-fluoro-5- hydroxypyridine was replaced with 2-bromo-5-hydroxypyridine to obtain compounds c5-1 and c5-2.

[0290]

[0291] c5-1: orange solid, yield 20.3%. 1 H NMR (500 MHz, Chloroform-d) δ 8.05 (d, J = 2.7 Hz, 1H), 7.79 (d, J = 8.3 Hz, 1H), 7.72 (d, J = 8.2 Hz, 1H), 7.62 (d, J = 2.7 Hz, 1H), 6.48 - 6.45 (m, 1H), 4.91 (t, J = 9.5 Hz, 1H), 4.39 (dd, J = 9.4, 6.0 Hz, 1H), 3.61 (dp, J = 9.6, 6.7 Hz, 1H), 2.16 (ddt, J = 14.3, 5.3, 2.2 Hz, 1H), 2.03 (d, J = 10.3 Hz, 1H), 2.01 - 1.89 (m, 2H), 1.45 (s, 3H), 1.33 (d, J = 6.8 Hz, 3H), 1.29 (s, 3H). 13C NMR (126 MHz, CDC13) δ 182.80, 174.18, 169.85, 153.10, 152.05, 139.39, 137.78, 136.36, 133.09, 131.67, 128.20, 127.93, 127.80, 126.96, 125.71, 125.09, 118.22, 81.21, 76.81, 76.56, 76.30, 68.43, 34.55, 34.19, 31.04, 30.88, 30.75, 29.24, 22.13, 18.36.

[0292] c5-2: orange solid, yield 22.2%. 1 H NMR (500 MHz, Chloroform-d) δ 8.12 (d, J = 3.0 Hz, 1H), 7.79 (d, J = 8.3 Hz, 1H), 7.71 (d, J = 8.2 Hz, 1H), 7.49 - 7.39 (m, 2H), 6.52 - 6.48 (m, 1H), 4.91 (t, J = 9.5 Hz, 1H), 4.39 (dd, J = 9.4, 6.0 Hz, 1H), 3.61 (dp, J = 9.6, 6.6 Hz, 1H), 2.18 - 2.00 (m, 3H), 1.94 - 1.87 (m, 1H), 1.45 (s, 3H), 1.33 (d, J = 6.8 Hz, 3H), 1.29 (s, 3H). 13 CNMR (126 MHz, CDC13) δ 184.72, 176.11, 171.72, 155.02, 153.94, 141.30, 138.29, 135.01, 133.55, 130.05, 129.77, 128.86, 127.52, 126.98, 120.17, 83.08, 78.70, 78.45, 78.19, 70.31, 36.43, 36.06, 32.97, 32.78, 32.56, 24.03, 20.22.

[0293] Referring to the preparation method of compound cl-1, 2-fluoro-5-hydroxypyridine was replaced by 3-bromo-5-hydroxypyridine to obtain compounds c6-1 and c6-2.

[0294]

[0295] c6-1: orange solid, yield 8.9%. 1H NMR (500 MHz, Chloroform-d) δ 8.29 - 8.25 (m, 2H), 7.78 (d, J = 8.3 Hz, 1H), 7.71 (d, J = 8.2 Hz, 1H), 7.64 (d, J = 2.2 Hz, 1H), 6.50 (d, J = 3.2 Hz, 1H), 4.90 (t, J = 9.5 Hz, 1H), 4.38 (dd, J = 9.4, 5.9 Hz, 1H), 3.59 (dp, J = 9.7, 6.7 Hz, 1H), 2.21 - 2.14 (m, 1H), 2.08 - 1.98 (m, 2H), 1.91 (tt, J = 14.3, 3.1 Hz, 1H), 1.45 (s, 3H), 1.34 (d, J = 6.7 Hz, 3H), 1.28 (s, 3H). 13 C NMR (126 MHz, CDC13) δ 184.57, 176.03, 171.70, 155.63, 153.94, 144.21, 139.46, 138.06, 135.00, 130.05, 128.85, 127.02, 126.75, 122.10, 120.14, 83.09, 78.72, 78.47, 78.21, 70.15, 61.83, 36.42, 36.07, 32.93, 32.80, 32.61, 23.99, 20.25, 15.62.

[0296] c6-2: orange solid, yield 15.9%. 1 H NMR (500 MHz, Chloroform-d) δ 8.27 (dd, J = 4.7, 2.2 Hz, 2H), 7.78 (d, J = 8.3 Hz, 1H), 7.71 (d, J = 8.2 Hz, 1H), 7.65 (q, J = 2.8, 2.2 Hz, 1H), 6.52 - 6.49 (m, 1H), 4.90 (t, J = 9.5 Hz, 1H), 4.38 (dd, J = 9.4, 6.0 Hz, 1H), 3.60 (dp, J = 9.6, 6.7 Hz, 1H), 2.25 - 2.14 (m, 1H), 2.08 - 1.97 (m, 2H), 1.92 (tt, J = 14.3, 3.0 Hz, 1H), 1.44 (s, 3H), 1.32 (d, J = 6.8 Hz, 3H), 1.29 (s, 3H). 13C NMR (126 MHz, CDC13) δ 184.60, 176.08, 171.74, 155.65, 153.96, 144.16, 139.40, 138.09, 135.04, 129.99, 128.85, 127.04, 126.72, 122.08, 120.19, 83.09, 78.73, 78.48, 78.22, 70.14, 61.83, 36.41, 36.05, 32.98, 32.81, 32.53, 23.98, 22.48, 20.20, 15.62.

[0297] Following the procedure for the preparation of Reference Compound c1-1, replacing 2-fluoro-5-hydroxypyridine with 3-cyano-5-hydroxypyridine, Reference Compounds c7-1 and c7-2 were obtained.

[0298]

[0299] c7-1: Orange solid, yield 16.1%. 1 H NMR (500 MHz, Chloroform-d) δ 8.51 (d, J = 2.9 Hz, 1H), 8.48 (d, J = 1.7 Hz, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.74 (d, J = 8.3 Hz, 1H), 7.69 (dd, J = 2.9, 1.7 Hz, 1H), 6.54 (d, J = 3.3 Hz, 1H), 4.95 - 4.88 (m, 1H), 4.40 (dd, J = 9.4, 5.9 Hz, 1H), 3.60 (dp, J = 9.8, 6.7 Hz, 1H), 2.18 - 2.12 (m, 1H), 2.05 - 2.02 (m, 1H), 2.01 - 1.93 (m, 2H), 1.46 (s, 3H), 1.35 (d, J = 6.8 Hz, 3H), 1.30 (s, 3H). 13 C NMR (126 MHz, CDC13) δ 184.60, 176.08, 171.74, 155.65, 153.96, 144.16, 139.40, 138.09, 135.04, 129.99, 128.85, 127.04, 126.72, 122.08, 120.19, 83.09, 78.73, 78.48, 78.22, 70.14, 61.83, 36.41, 36.05, 32.98, 32.81, 32.53, 23.98, 22.48, 20.20, 15.62.

[0300] c7-2: Orange solid, yield 21.1%. 1H NMR (500 MHz, Chloroform-d) δ 8.52 (d, J = 2.9 Hz, 1H), 8.47 (d, J = 1.7 Hz, 1H), 7.80 (s, 1H), 7.74 (d, J = 8.3 Hz, 1H), 7.69 (dt, J = 3.8, 1.9 Hz, 1H), 6.54 (d, J = 3.3 Hz, 1H), 4.92 (t, J = 9.5 Hz, 1H), 4.40 (dd, J = 9.4, 6.0 Hz, 1H), 4.12 (q, J = 7.1 Hz, OH), 3.61 (dp, J = 9.7, 6.7 Hz, 1H), 2.16 (dt, J = 13.8, 2.9 Hz, 1H), 2.06 - 1.96 (m, 3H), 1.46 (s, 3H), 1.34 (d, J = 6.7 Hz, 3H), 1.31 (s, 3H). 13 C NMR (126 MHz, CDC13) δ 184.68, 175.95, 171.75, 154.92, 153.92, 145.59, 145.04, 137.59, 135.15, 129.94, 128.96, 127.22, 125.69, 120.26, 118.10, 111.66, 83.16, 78.71, 78.45, 78.20, 73.37, 70.41, 61.85, 40.30, 36.41, 36.26, 36.06, 32.95, 32.84, 32.47, 32.18, 31.12, 24.07, 22.49, 20.18, 15.62.

[0301] Referring to the preparation method of compound c1-1, 2-fluoro-5-hydroxypyridine was replaced by 2-trifluoromethyl-4-hydroxypyridine to obtain compounds c8-1 and c8-2.

[0302]

[0303] c8-1: orange solid, yield 36.3%. 1H NMR (500 MHz, Chloroform-d) δ 8.56 (d, J = 5.7 Hz, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.74 (d, J = 8.3 Hz, 1H), 7.25 (d, J = 2.4 Hz, 1H), 7.14 (dd, J = 5.7, 2.5 Hz, 1H), 6.61 (d, J = 3.0 Hz, 1H), 4.92 (td, J = 9.5, 3.4 Hz, 1H), 4.40 (dd, J = 9.4, 5.8 Hz, 1H), 3.64 - 3.54 (m, 1H), 2.22 (ddd, J = 12.3, 5.3, 3.4 Hz, 1H), 2.03 - 1.98 (m, 2H), 1.59 - 1.52 (m, 1H), 1.46 (d, J = 1.5 Hz, 3H), 1.34 (d, J = 6.8 Hz, 3H), 1.30 (d, J = 2.9 Hz, 3H). 13 C NMR (126 MHz, CDC13) δ 184.57, 175.88, 171.77, 166.44, 154.00, 152.86, 137.46, 135.13, 129.99, 128.91, 127.23, 120.22, 114.51, 110.61, 83.17, 78.71, 78.46, 78.20, 70.13, 36.39, 36.06, 36.04, 32.89, 32.87, 32.55, 32.47, 24.19, 20.25, 20.15.

[0304] c8-2: orange solid, yield 39.2%. 1 H NMR (500 MHz, Chloroform-d) δ 8.57 (d, J = 5.5 Hz, 1H), 7.81 (d, J = 8.2 Hz, 1H), 7.74 (d, J = 8.2 Hz, 1H), 7.25 (d, J = 2.1 Hz, 1H), 7.15 (dd, J = 5.9, 2.4 Hz, 1H), 6.62 (s, 1H), 4.92 (t, J = 9.5 Hz, 1H), 4.40 (dd, J = 9.4, 6.0 Hz, 1H), 3.61 (dp, J = 9.9, 6.7 Hz, 1H), 2.24 - 2.19 (m, 1H), 2.03 - 1.99 (m, 2H), 1.60 - 1.49 (m, 1H), 1.46 (s, 3H), 1.33 (d, J = 6.8 Hz, 3H), 1.31 (s, 3H). 13C NMR (126 MHz, CDC13) δ 184.61, 175.96, 171.74, 166.43, 153.99, 152.92, 137.50, 135.15, 129.93, 128.92, 127.22, 120.26, 114.43, 110.61, 83.15, 78.71, 78.45, 78.20, 70.11, 36.39, 36.05, 32.95, 32.88, 32.48, 24.19, 20.16.

[0305] The preparation method of reference compound c1-1 was referred to, 2-fluoro-5- hydroxypyridine was replaced with 2-methyl-5-hydroxypyridine to obtain compound c9.

[0306]

[0307] c9: orange solid, yield 82.0%. 1 H NMR (500 MHz, Chloroform-d) δ 8.18 - 8.16 (m, 1H), 7.77 (d, J = 8.3 Hz, 1H), 7.69 (d, J = 8.2 Hz, 1H), 7.20 (d, J = 6.3 Hz, 1H), 7.05 (s, 1H), 6.51 (q, J = 3.4 Hz, 1H), 4.90 (t, J = 9.5 Hz, 1H), 4.38 (ddd, J = 9.1, 5.9, 2.8 Hz, 1H), 3.65 - 3.53 (m, 1H), 2.50 (d, J = 1.5 Hz, 3H), 2.18 - 2.02 (m, 2H), 1.86 (dddd, J = 20.4, 13.9, 6.2, 3.1 Hz, 1H), 1.49 (d, J = 3.5 Hz, 1H), 1.44 (d, J = 1.6 Hz, 3H), 1.34 - 1.25 (m, 6H). 13 C NMR (126 MHz, CDC13) δ 184.61, 175.96, 171.74, 166.43, 153.99, 152.92, 137.50, 135.15, 129.93, 128.92, 127.22, 120.26, 114.43, 110.61, 83.15, 78.71, 78.45, 78.20, 70.11, 36.39, 36.05, 32.95, 32.88, 32.48, 24.19, 20.16.

[0308] The preparation method of reference compound c1-1 was referred to, 2-fluoro-5-hydroxypyridine was replaced by 2-methoxy-5-hydroxypyridine to obtain compounds c10-1 and c10-2.

[0309]

[0310] c10-1: orange solid, yield 6.4%. 1 H NMR (500 MHz, Chloroform-d) δ 7.96 (d, J = 3.0 Hz, 1H), 7.76 (d, J = 8.2 Hz, 1H), 7.70 - 7.64 (m, 2H), 6.74 (d, J = 8.9 Hz, 1H), 6.43 - 6.38 (m, 1H), 4.90 (t, J = 9.5 Hz, 1H), 4.37 (dd, J = 9.3, 5.9 Hz, 1H), 3.90 (s, 3H), 3.65 - 3.54 (m, 1H), 2.18 - 2.02 (m, 3H), 1.85 - 1.75 (m, 1H), 1.45 (s, 3H), 1.35 (d, J = 6.7 Hz, 3H), 1.27 (s, 3H). 13 C NMR (126 MHz, CDCl3) δ 184.83, 176.38, 171.79, 160.52, 154.00, 149.99, 139.21, 137.15, 134.84, 130.68, 130.30, 128.73, 126.71, 119.95, 112.60, 83.01, 78.71, 78.46, 78.21, 70.96, 54.98, 36.50, 36.08, 32.97, 32.79, 32.72, 23.86, 20.22.

[0311] c10-2: orange solid, yield 6.0%. 1 H NMR (500 MHz, Chloroform-d) δ 7.95 (d, J = 3.0 Hz, 1H), 7.76 (d, J = 8.3 Hz, 1H), 7.70 - 7.62 (m, 2H), 6.73 (d, J = 8.9 Hz, 1H), 6.41 (d, J = 3.7 Hz, 1H), 4.94 - 4.85 (m, 1H), 4.38 (dd, J = 9.4, 5.8 Hz, 1H), 3.89 (s, 3H), 3.59 (dp, J = 9.8, 6.6 Hz, 1H), 2.18 - 2.02 (m, 3H), 1.81 (tt, J = 15.3, 3.9 Hz, 1H), 1.44 (s, 3H), 1.32 (d, J = 6.8 Hz, 3H), 1.27 (s, 3H). 13C NMR (126 MHz, CDC13) δ 184.87, 176.38, 171.79, 160.51, 154.01, 150.01, 139.25, 137.13, 134.86, 130.61, 130.29, 128.73, 126.71, 120.04, 112.56, 83.01, 78.72, 78.47, 78.22, 70.95, 61.84, 54.97, 36.50, 36.04, 33.01, 32.74, 32.69, 23.86, 20.28, 15.62.

[0312] The preparation method of reference compound c1-1 was referred to, 2-fluoro-5- hydroxypyridine was replaced with 2-chloro-5-hydroxypyrimidine to obtain compounds c11-1 and c11-2.

[0313]

[0314] c11-1: orange solid, yield 45.4%. 1 H NMR (400 MHz, Chloroform-d) δ 8.43 (d, J = 1.9 Hz, 2H), 7.81 (d, J = 8.3 Hz, 1H), 7.75 (d, J = 8.2 Hz, 1H), 6.54 (d, J = 3.3 Hz, 1H), 4.93 (td, J = 9.5, 1.8 Hz, 1H), 4.41 (dd, J = 9.5, 5.9 Hz, 1H), 3.67 - 3.54 (m, 1H), 2.27 - 2.14 (m, 1H), 2.13 - 1.84 (m, 3H), 1.61 - 1.48 (m, 1H), 1.37 - 1.30 (m, 9H).

[0315] c11-2: orange solid, yield 42.2%. 1 H NMR (400 MHz, Chloroform-d) δ 8.44 (s, 2H), 7.81 (d, J = 8.3 Hz, 1H), 7.74 (d, J = 8.3 Hz, 1H), 6.54 (d, J = 3.2 Hz, 1H), 4.93 (t, J = 9.6 Hz, 1H), 4.41 (dd, J = 9.4, 6.0 Hz, 1H), 3.62 (dp, J = 9.5, 6.6 Hz, 1H), 2.22 - 2.11 (m, 1H), 2.08 - 1.93 (m, 2H), 1.65 - 1.54 (m, 1H), 1.35 (s, 2H), 1.34 (s, 4H), 1.31 (s, 3H).

[0316] The preparation method of reference compound c1-1 was referred to, and 2-fluoro-5- hydroxypyridine was replaced by 2-bromo-5-hydroxypyrimidine to obtain compounds c12-1 and c12-2.

[0317]

[0318] c12-1: orange solid, yield 22.5%. 1 H NMR (500 MHz, Chloroform-d) δ 8.38 (s, 2H), 7.81 (d, J = 8.3 Hz, 1H), 7.74 (d, J = 8.2 Hz, 1H), 6.53 (d, J = 3.4 Hz, 1H), 4.92 (t, J = 9.5 Hz, 1H), 4.40 (dd, J = 9.4, 5.9 Hz, 1H), 3.66 - 3.55 (m, 1H), 2.16 (d, J = 12.5 Hz, 1H), 2.07 - 1.93 (m, 2H), 1.59 - 1.53 (m, 1H), 1.38 - 1.23 (m, 9H). 13 C NMR (126 MHz, CDC13) δ 184.64, 175.85, 171.75, 153.86, 153.10, 148.90, 143.83, 137.39, 135.13, 129.99, 128.97, 127.29, 120.25, 83.19, 78.70, 78.45, 78.19, 70.76, 36.40, 36.08, 32.87, 32.78, 32.50, 31.12, 24.04, 20.24.

[0319] c12-2: orange solid, yield 31.6%. 1 H NMR (500 MHz, Chloroform-d) δ 8.38 (s, 2H), 7.81 (d, J = 8.3 Hz, 1H), 7.74 (d, J = 8.2 Hz, 1H), 6.53 (d, J = 3.4 Hz, 1H), 4.92 (t, J = 9.5 Hz, 1H), 4.40 (dd, J = 9.4, 5.9 Hz, 1H), 3.66 - 3.55 (m, 1H), 2.16 (d, J = 12.5 Hz, 1H), 2.07 - 1.93 (m, 2H), 1.59 - 1.53 (m, 1H), 1.38 - 1.23 (m, 9H). 13C NMR (126 MHz, CDC13) δ 184.66, 175.91, 171.69, 153.84, 153.12, 148.86, 143.81, 137.41, 135.14, 129.95, 128.98, 127.28, 120.28, 83.16, 78.71, 78.45, 78.20, 70.74, 36.40, 36.07, 32.92, 32.80, 32.43, 31.12, 24.05, 20.15.

[0320] The preparation method of reference compound c1-1 was referred to, 2-fluoro-5- hydroxypyridine was replaced by 2-methylthio-5-hydroxy pyrimidine to obtain compounds c13-1 and c13-2.

[0321]

[0322] c13-1: orange solid, yield 40.8%. 1 H NMR (500 MHz, Chloroform-d) δ 8.44 (s, 2H), 7.79 (d, J = 8.2 Hz, 1H), 7.72 (d, J = 8.2 Hz, 1H), 6.50 (d, J = 3.3 Hz, 1H), 4.91 (t, J = 9.5 Hz, 1H), 4.39 (dd, J = 9.4, 5.9 Hz, 1H), 3.60 (dp, J = 9.5, 6.8 Hz, 1H), 2.57 (s, 3H), 2.17 (ddt, J = 14.6, 4.3, 2.8 Hz, 1H), 2.04 (td, J = 13.7, 2.7 Hz, 1H), 1.92 (tt, J = 14.2, 3.1 Hz, 1H), 1.56 - 1.49 (m, 1H), 1.45 (s, 3H), 1.35 (d, J = 6.9 Hz, 3H), 1.29 (s, 3H). 13 C NMR (126 MHz, CDC13) δ 184.66, 175.91, 171.69, 153.84, 153.12, 148.86, 143.81, 137.41, 135.14, 129.95, 128.98, 127.28, 120.28, 83.16, 78.71, 78.45, 78.20, 70.74, 36.40, 36.07, 32.92, 32.80, 32.43, 31.12, 24.05, 20.15.

[0323] c13-2: orange solid, yield 44.2%. 1H NMR (500 MHz, Chloroform-d) δ 8.44 (s, 2H), 7.79 (d, J = 8.3 Hz, 1H), 7.71 (d, J = 8.2 Hz, 1H), 6.53 - 6.48 (m, 1H), 4.91 (t, J = 9.5 Hz, 1H), 4.39 (dd, J = 9.4, 6.0 Hz, 1H), 3.66 - 3.55 (m, 1H), 2.56 (s, 3H), 2.16 (ddt, J = 14.7, 4.6, 2.8 Hz, 1H), 2.10 - 1.99 (m, 1H), 1.93 (tt, J = 14.2, 3.0 Hz, 1H), 1.57 - 1.50 (m, 1H), 1.45 (s, 3H), 1.33 (d, J = 6.8 Hz, 3H), 1.29 (s, 3H). 13 C NMR (126 MHz, CDC13) δ 184.00, 175.41, 171.02, 164.16, 153.21, 149.52, 146.97, 137.44, 134.34, 129.41, 128.23, 126.38, 119.53, 82.43, 78.04, 77.79, 77.53, 69.83, 35.76, 35.40, 32.29, 32.11, 31.85, 23.33, 19.54, 15.29.

[0324]

[0325] Preparation of compound c14-1:

[0326] In a 25 ml round bottom flask, c13-1 (20 mg, 0.0459 mmol) was added, dissolved in 2 mL of dichloromethane, then m-CPBA (8.7 mg, 0.0505 mmol) was added at 0 °C. The reaction was moved to room temperature for about 1 h, after TLC monitoring was completed, the solvent was removed by rotary evaporation, and PTLC (PE:EA = 1:3) purification was performed to obtain orange product c14-1 (3.3 mg, 16.0%). 1 H NMR (500 MHz, Methanol-d4) δ 8.77 (s, 2H), 7.98 (d, J = 8.3 Hz, 1H), 7.82 (d, J = 8.2 Hz, 1H), 6.66 (d, J = 3.3 Hz, 1H), 4.99 (t, J = 9.6 Hz, 1H), 4.46 (dd, J = 9.5, 6.2 Hz, 1H), 3.56 (dq, J = 16.2, 7.0 Hz, 1H), 2.97 (s, 3H), 2.29 - 1.98 (m, 4H), 1.47 (s, 3H), 1.35 - 1.30 (m, 6H). 13C NMR (126 MHz, MeOD) δ 184.48, 176.15, 172.82, 163.57, 153.94, 147.28, 137.32, 135.23, 130.13, 128.70, 126.99, 119.78, 83.32, 71.45, 49.53, 49.36, 49.19, 49.02, 48.85, 48.68, 48.51, 40.10, 36.04, 35.79, 32.75, 31.80, 31.17, 23.96, 18.74.

[0327] c14-2: orange solid, yield 36.0%. 1 H NMR (500 MHz, Methanol-d4) δ 8.77 (s, 2H), 7.98 (d, J = 8.3 Hz, 1H), 7.82 (d, J = 8.3 Hz, 1H), 6.67 (d, J = 3.2 Hz, 1H), 4.99 (t, J = 9.6 Hz, 1H), 4.46 (dd, J = 9.5, 6.2 Hz, 1H), 3.55 (dp, J = 9.8, 6.7 Hz, 1H), 2.97 (d, J = 0.9 Hz, 3H), 2.25 - 2.03 (m, 3H), 1.63 (dt, J = 13.5, 3.6 Hz, 1H), 1.47 (s, 3H), 1.36 - 1.30 (m, 6H). 13 C NMR (126 MHz, MeOD) δ 184.48, 176.15, 172.82, 163.57, 153.94, 147.28, 137.32, 135.23, 130.13, 128.70, 126.99, 119.78, 83.32, 71.45, 49.53, 49.36, 49.19, 49.02, 48.85, 48.68, 48.51, 40.10, 36.04, 35.79, 32.75, 31.80, 31.17, 23.96, 18.74.

[0328]

[0329] Preparation of compound c15-1:

[0330] In a 25 ml round bottom flask was added c13-1 (9.2 mg, 0.0211 mmol), 2 mL of dichloromethane to dissolve it, then added m-CPBA (8.0 mg, 0.0464 mmol) at 0 °C. The reaction was moved to room temperature for 16-20 h, after TLC monitoring was complete, the solvent was removed by rotary evaporation, PTLC (DCM:MeOH = 20:1) purification, to get the orange product c15-1 (5.6 mg, 33%). 1 H NMR (500 MHz, Chloroform-d) δ 8.63 (d, J = 4.0 Hz, 1H), 8.51 (s, 1H), 7.85 - 7.73 (m, 2H), 6.75 - 6.64 (m, 1H), 4.97 - 4.89 (m, 1H), 4.40 (ddd, J = 10.1, 7.9, 5.3 Hz, 1H), 3.60 (dp, J = 9.9, 6.5 Hz, 1H), 3.34 (d, J = 4.9 Hz, 3H), 2.28 - 2.17 (m, 2H), 2.04 (d, J = 3.0 Hz, 2H), 1.49 - 1.44 (m, 3H), 1.36 - 1.31 (m, 6H).

[0331] c15-2: Orange solid, yield 28.6%. 1 H NMR (500 MHz, Chloroform-d) δ 8.64 (s, 2H), 7.83 (d, J = 8.3 Hz, 1H), 7.76 (d, J = 8.3 Hz, 1H), 6.67 (d, J = 3.3 Hz, 1H), 4.93 (t, J = 9.6 Hz, 1H), 4.40 (dd, J = 9.5, 6.1 Hz, 1H), 3.61 (dp, J = 9.4, 6.6 Hz, 1H), 3.33 (s, 3H), 2.26 - 2.17 (m, 1H), 2.12 - 1.97 (m, 2H), 1.66 - 1.57 (m, 1H), 1.32 (d, J = 5.9 Hz, 4H), 1.29 - 1.23 (m, 5H). 13 CNMR (126 MHz, CDC13) δ 183.45, 174.47, 170.42, 157.54, 153.74, 152.62, 145.40, 135.54, 134.01, 128.60, 127.77, 126.21, 119.06, 81.93, 77.41, 77.16, 76.91, 69.86, 40.35, 35.12, 34.78, 31.60, 31.51, 31.07, 30.32, 29.83, 22.91, 18.83.

[0332] The preparation method of reference compound c1-1 is referred to, 2-fluoro-5-hydroxypyridine is replaced by 2-methyl-5-hydroxypyrimidine to obtain compounds c16-1 and c16-2.

[0333]

[0334] c16: orange solid, yield 39.6%. 1 H NMR (500 MHz, Chloroform-d) δ 8.45 (d, J = 2.0 Hz, 2H), 7.80 - 7.74 (m, 1H), 7.70 (d, J = 8.2 Hz, 1H), 6.54 (d, J = 3.2 Hz, 1H), 4.89 (td, J = 9.5, 1.4 Hz, 1H), 4.37 (ddd, J = 9.4, 6.0, 2.2 Hz, 1H), 3.64 - 3.54 (m, 1H), 2.67 (d, J = 3.1 Hz, 3H), 2.25 - 2.13 (m, 1H), 1.44 (d, J = 1.5 Hz, 3H), 1.36 - 1.22 (m, 9H). 13 C NMR (126 MHz, CDCl3) δ 182.72, 182.69, 174.16, 174.12, 169.81, 169.79, 159.63, 151.99, 151.98, 149.21, 149.19, 144.55, 144.52, 144.22, 136.21, 136.17, 133.12, 133.09, 128.20, 128.15, 126.98, 125.15, 118.29, 118.24, 81.20, 76.84, 76.59, 76.34, 68.16, 34.52, 34.18, 34.15, 31.06, 31.01, 30.96, 30.90, 30.67, 30.60, 30.48, 29.71, 29.22, 24.34, 24.32, 24.16, 22.09, 18.33, 18.30, 8.29.

[0335] Specific experimental scheme four: experiment of in vitro anti-triple negative breast cancer activity of cryptotanshinone derivatives

[0336] The in vitro anti-triple negative breast cancer activity of the above cryptotanshinone derivatives is detected by CCK-8 method, the structure-activity relationship is preliminarily discussed, and the preferred derivative is selected for subsequent activity test.

[0337] Experimental method: the triple negative breast cancer cells MDA-MB-231 in the logarithmic growth phase were inoculated in 96-well culture plates at a certain cell amount, after 24h of culture, the serum-free medium solution of the test drug was added, 5 replicates for each concentration, the cells were further cultured at 37℃, 5% CO2 for 24h, 10% CCK-8 serum-free medium solution was added for further culture for 4h, and the absorbance of each well was detected under the enzyme label instrument.

[0338] The survival rate of MDA-MB-231 cells at 3μM of the compound is as follows in Table 1:

[0339] A represents the cell survival rate < 85%, B represents the cell survival rate 85-100%, and C represents the cell survival rate > 100%

[0340] Table 1

[0341]

[0342]

[0343] The IC of some compounds on MDA-MB-231 cells 50 is as follows in Table 2: A represents IC 50 < 10μM, B represents IC 50 10-25μM

[0344] Table 2

[0345]

[0346]

[0347] Identification of syn-anti isomer of oxime ether

[0348] Both carbonyl groups in cryptotanshinone can react with hydroxylamine hydrochloride to form mono-oxime or bis-oxime. To determine the specific position of the carbonyl group involved in the reaction, the mono-oxime a5 generated was further reacted with bromoethane to generate three compounds b2-1, b2-2 and b2-3, respectively, among which the oxime ether with smaller polarity is b2-2, and the stereostructure of the compound was identified by Noesy and HMBC spectra. The HMBC spectrum shows that the hydrogen at position 6, the hydrogen at position 1 and the carbon at position 14 are coupled, and the chemical shift value of the carbon at position 14 is about 150ppm, and the chemical shift value of the carbonyl carbon is about 180ppm. Therefore, position 14 is a carbon-nitrogen double bond, not a carbon-oxygen double bond. The Noesy spectrum shows that the hydrogen at position 6 and the hydrogen at position 25 have spatial coupling, so the compound is as follows:

[0349]

Claims

1. The use of a cryptotanshinone derivative as shown in Formula I, its stereoisomer or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating triple-negative breast cancer; in, The dashed lines in ring A represent single or double bonds; R 1 R 2 Co-formation = X1, where X1 is CH2, O, S, or NH; Or R 1 R 2 Each is independently hydrogen; R 3 Independently hydrogen or -OR 3-1 ; R 3-1 Independently 5-6 membered heteroaryl or surrounded by one or more R 3-1-1 The substituted 5-6-membered heteroaryl group; the number of heteroatoms in the 5-6-membered heteroaryl group is 1, 2 or 3, and each heteroatom is independently N, O or S; R 3-1-1 Independent of halogen, -CN, C 1-6 Haloalkyl, C 2-6 alkenyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -SC 1-6 Alkyl, -SO-C 1-6 Alkyl or -SO2-C 1-6 alkyl; In ring C for End a is connected to ring B, and end b is connected to ring D; X2 is O or NOR 4 ; X3 is 0; R 4 Independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -(C 1-4 Alkylene) n- C 1-6 Alkoxy, -(C 1-4 Alkylene) n -C 1-6 Halogenated alkoxy or -(C 1-4 Alkylene) n -C6-C 10 Aryl; n is 0 or 1; the -(C 1-4 Alkylene) n -C6-C 10 C6-C in aryl 10 aryl groups are oxidized by one or more R groups. 4-1 Replaced; R 4-1 Independently hydrogen, halogen, -CN, -NO2, C 1-6 Alkoxy, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Halogenated alkoxy groups; when for When X2 is 0 and X3 is 0, R 3 For -OR 3-1 .

2. The application as described in claim 1, characterized in that, It satisfies one or more of the following conditions: (1) When R 1 R 2 When X1 is formed together, X1 is 0; (2)R 1 R 2 Each is independently hydrogen; (3)R 3 It is hydrogen; (4)R 3-1 Independently for one or more R 3-1-1 The substituted 5-6-membered heteroaryl group has 1, 2 or 3 heteroatoms, and each heteroatom is independently N, O or S; (5)R 3-1-1 Independent of halogen, -CN, C 1-6 Haloalkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -SC 1-6 Alkyl, -SO-C 1-6 Alkyl or -SO2-C 1-6 alkyl; (6)R 4 Independently hydrogen, C 1-6 Alkyl, -(C 1-4 Alkylene) n -C6-C 10 Aryl; n is 0 or 1; the -(C 1-4 Alkylene) n -C6-C 10 C6-C in aryl 10 aryl is formed by one or more R 4-1 Replaced; preferably hydrogen, -(C 1-4 Alkylene) n -C6-C 10 Aryl; (7)R 4-1 Independently hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Halogenated alkoxy groups; preferably hydrogen, halogen, or C. 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Halogenated alkoxy groups.

3. The application as described in claim 1, characterized in that, It satisfies one or more of the following conditions: (1)R 3 Hydrogen; in ring C for X2 is N-OR 4 ; X3 is 0; (2)R 3 It is hydrogen; In ring C for End a is connected to ring B, and end b is connected to ring D; (3)R 3 For -OR 3-1 ; In ring C for X2 is 0; X3 is 0; (4) The dashed line "-----" in ring A represents a single bond or a double bond; R 1 R 2 Together they form = X1, where X1 is 0; Or R 1 R 2 Each is independently hydrogen; R 3 It is hydrogen; In ring C for End a is connected to ring B, and end b is connected to ring D; X2 is 0 or N-OR 4 ; X3 is 0; R 4 Independently hydrogen, -(C 1-4 Alkylene) n -C6-C 10 Aryl; n is 0 or 1; the -(C 1-4 Alkylene) n -C6-C 10 C6-C in aryl 10 aryl is formed by one or more R 4-1 Replaced; R 4-1 Independently hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Halogenated alkoxy groups; preferably, R 4-1 Independently hydrogen, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Halogenated alkoxy groups.

4. The application as described in claim 1, characterized in that, It satisfies one or more of the following conditions: (1)R 3-1 In the context, the 5-6 membered heteroaryl group and the group surrounded by one or more R 3-1-1 The heteroatom of the substituted 5-6-membered heteroaryl group is independently N or O, and the number of heteroatoms is independently one or two; preferably, it is a 5-6-membered heteroaryl group containing an N atom; more preferably, it is pyridyl or pyrimidinyl, for example, (2)R 3-1-1 In this context, the halogen is independently F, Cl, Br or I, preferably F, Cl or Br; (3)R 3-1-1 In, the C 2-6 The alkenyl group can be vinyl, 1-propenyl, 2-propenyl, 1-methylvinyl, butenyl, or pentenyl. (4)R 3-1-1 In, the C 1-6 Haloalkyl, C 1-6 Alkyl, -SC 1-6 Alkyl, -SO-C 1-6 Alkyl groups and -SO2-C 1-6 C in alkyl 1-6 The alkyl group is independently methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl; (5)R 3-1-1 In, the C 1-6 Halogenated alkyl groups and C 1-6 The number of halogens in a haloalkoxy group can be independently 1, 2, or 3, for example, 3; (6)R 3-1-1 In, the C 1-6 Halogenated alkyl groups and C 1-6 The halogen in the haloalkoxy group is independently fluorinated, chlorinated, brominated or iodinated, preferably fluorinated; (7)R 3-1-1 In, the C 1-6 Alkoxy and C 1-6 C in haloalkoxy 1-6 The alkoxy group is independently methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, or tert-butoxy, preferably methoxy; (8)R 4 In, the C 1-6 Alkyl and C 1-6 C in haloalkyl 1-6 The alkyl group is independently methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl or ethyl; (9)R 4 In, the -(C 1-4 Alkylene) n -C 1-6 Alkoxy, -(C 1-4 Alkylene) n -C 1-6 Halogenated alkoxy groups and -(C 1-4 Alkylene) n -C6-C 10 C in aryl 1-4 The alkylene group is independently -CH2-, -CH2CH2-, -CH(CH3)-, -CH(CH3)CH2- or -C(CH3)2-, for example -CH2-; (10)R 4 In, the -(C 1-4 Alkylene) n- C 1-6 Alkoxy and -(C 1-4 Alkylene) n -C 1-6 C in haloalkoxy 1-6 The alkoxy group can be independently methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, or tert-butoxy; (11)R 4 In, the C 1-6 Halogenated alkyl groups and -(C 1-4 Alkylene) n- C 1-6 The number of halogens in a haloalkoxy group can be independently 1, 2, or 3; (12)R 4 In, the C 1-6 Halogenated alkyl groups and -(C 1-4 Alkylene) n -C 1-6 The halogen in a haloalkoxy group can be independently fluorinated, chlorinated, brominated, or iodinated; (13)R 4 In, the -(C 1-4 Alkylene) n -C6-C 10 C6-C in aryl 10 The aryl group can be phenyl or naphthyl, for example, phenyl; (14)R 4-1 In this context, the halogen is independently F, Cl, Br or I, preferably F, Cl or Br, for example F or Br; (15)R 4-1 In, the C 1-6 Alkyl and C 1-6 C in haloalkyl 1-6 The alkyl group is independently methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably tert-butyl; (16)R 4-1 In, the C 1-6 Halogenated alkyl groups and C 1-6 The number of halogens in a haloalkoxy group can be independently 1, 2, or 3, for example, 2 or 3; (17)R 4-1 In, the C 1-6 Halogenated alkyl groups and C 1-6 The halogen in the haloalkoxy group is independently fluorinated, chlorinated, brominated or iodinated, preferably fluorinated; (18)R 4-1 In, the C 1-6 C in haloalkoxy 1-6 The alkoxy group is independently methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, or tert-butoxy, preferably methoxy.

5. The application as described in claim 1, characterized in that, It satisfies one or more of the following conditions: (1)R 3-1-1 Independently, it can be F, Cl, Br, CN, CF3, CH3, OCH3, (2)R 3-1 Independently (3)R 4-1 Independently, it is H, F, CN, CF3, OCF3, OCHF2, Cl, Br or tert-butyl, preferably F, CN, CF3, OCF3, OCHF2, Br or tert-butyl; (4)R 4 Independently H, methyl, ethyl, (5) In ring C Independently 6. The application as described in claim 1, characterized in that, The cryptotanshinone derivatives shown in Formula I are selected from any of the following structures: Among them, R 3-1 R 4 The definition of X is as described in any one of claims 1-5; Preferably, the cryptotanshinone derivative as shown in Formula I-1 is... Among them, R 3-1 The definition is as described in any one of claims 1-5; Preferably, the cryptotanshinone derivatives shown in Formula I are selected from any of the following structures:

7. A cryptotanshinone derivative as shown in Formula II, its stereoisomer, or a pharmaceutically acceptable salt thereof: in, "-----"、R 1 R 2 R 3 and The definition is as described in any one of claims 1-5; and The cryptotanshinone derivative shown in Formula II does not have any of the following structures:

8. The cryptotanshinone derivative as shown in Formula II as claimed in claim 7, its stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that, The cryptotanshinone derivatives shown in Formula II are selected from any of the following structures:

9. A method for preparing a cryptotanshinone derivative as shown in Formula II as described in claim 7, characterized in that, It can be method A, method B, method C, or method D: Method A, when the cryptotanshinone derivative shown in Formula II is a compound shown in Formula III-1, includes the following steps: In a solvent, in the presence of an organic base, the compound shown in Formula II-1 is reacted with hydroxylamine hydrochloride in an oxime reaction as shown below to give the compound shown in Formula III-1; wherein, R 4 Hydrogen; the dashed line "-----" in ring A, R 1 R 2 and R 3 The definition is as described in claim 7; Method B, when the cryptotanshinone derivative shown in Formula II is a compound shown in Formula III-2, includes the following steps: In a solvent, the compound shown in Formula II-2 is subjected to an oxidizing agent in the following oxidation reaction to obtain the compound shown in Formula III-2; Among them, R 1 R 2 Together they form = X1, where X1 is 0; R 4 The definition is as described in claim 7; Method C, when the cryptotanshinone derivative as shown in Formula II is one or more of the compounds shown in Formulas III-3, III-4, and III-5, comprises the following steps: In a solvent, in the presence of an inorganic base, the compound shown in Formula II-3 is reacted with R. 4 -H undergoes the reaction shown below to give compounds as shown in Formula III-3, III-4 and III-5; Among them, R 4 The definition is as described in claim 7, and R 4 Not hydrogen; Method D, when the cryptotanshinone derivative shown in Formula II is a compound shown in Formula III-6, includes the following steps: In a solvent, in the presence of an oxidizing agent, the compound shown in Formula II-4 and R... 3-1 -OH undergoes the reaction shown below to give the compound shown in Formula III-6; Among them, R 3-1 The definition is as described in claim 7; Preferably, in method A, the solvent is an alcohol, such as ethanol; In method A, the organic base is pyridine, piperidine, or piperazine, for example, pyridine; In method A, the reaction temperature is 60℃-100℃, for example, 80℃; In method A, the molar ratio of the compound as shown in formula II-1 to the organic base is 1:(4-10), preferably 1:5; In method A, the molar ratio of the compound as shown in formula II-1 to the hydroxylamine hydrochloride is 1:(4-10), preferably 1:5; In method A, the molar volume ratio of the compound as shown in formula II-1 to the solvent is 0.1-0.4 mol / L, preferably 0.23 mol / L; In method B, the solvent is an ether solvent, such as 1,4-dioxane; In method B, the oxidant is selenium dioxide; In method B, the reaction temperature is 100℃-120℃, for example, 100℃; In method B, the molar ratio of the compound as shown in formula II-2 to the oxidant is 1:(1-5), preferably 1:2; In method B, the molar volume ratio of the compound as shown in formula II-2 to the solvent is 0.01-0.1 mol / L, preferably 0.02 mol / L; In method C, the solvent is preferably a ketone solvent, such as acetone; In method C, the inorganic base is potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, sodium acetate, potassium acetate, sodium phosphate, or potassium phosphate, preferably potassium carbonate; In method C, the reaction temperature is 25℃-80℃, preferably 40℃-70℃, for example 55℃; In method C, the molar ratio of the compound as shown in formula II-3 to the inorganic base is 1:(1-3), preferably 1:1.9; In method C, the compound as shown in formula II-3 is combined with R. 4 The molar ratio of -H is 1:(1-3), preferably 1:1.7; In method D, the solvent is a halogenated aromatic hydrocarbon solvent, such as chlorobenzene; In method D, the oxidant is oxygen, tert-butyl hydroperoxide, di-tert-butyl peroxide, 2,2,6,6-tetramethylpiperidine oxide, or manganese dioxide, preferably 2,2,6,6-tetramethylpiperidine oxide; In method D, the reaction temperature is 90℃-130℃, preferably 110℃-130℃, for example 120℃; In method D, the molar ratio of the compound shown in formula II-4 to the oxidant is 1:(1-3), preferably 1:2; In method D, the compound as shown in formula II-4 is combined with said R 3-1 The molar ratio of -OH is 1:(1-3), preferably 1:1.7; In method D, the molar volume ratio of the compound shown in formula II-4 to the solvent is 0.01-0.1 mol / L, preferably 0.02 mol / L.

10. A pharmaceutical composition, characterized in that, It includes cryptotanshinone derivatives as shown in Formula II as claimed in claim 7 or claim 8, or pharmaceutically acceptable salts thereof, and at least one pharmaceutical excipient.

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