Cryptotanshinone derivatives, preparation methods and applications thereof

Abstract

The present invention discloses cryptotanshinone derivatives, preparation methods and applications thereof. The present invention specifically discloses cryptotanshinone derivatives as shown in formula (I), which have good inhibitory activity on triple-negative breast cancer cells.

Description

Technical Field

[0001] The present invention relates to a cryptotanshinone derivative, a preparation method and application thereof. Background Art

[0002] According to the results of the "Cancer Statistics Report 2020" published by the World Health Organization's International Agency for Research on Cancer (IARC), there are 2.26 million new breast cancer patients each year, which has climbed to become the most common tumor type in the world, and the mortality rate of breast cancer in women is much higher than other cancers, which seriously threatens the health of women around the world. Among them, triple-negative breast cancer (TNBC) accounts for 15%-20% of all breast cancer patients and has become the most difficult subtype of breast cancer in clinical treatment. Because there is a lack of clear therapeutic targets in TNBC, the expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (HER2) are all negative, and there is no specific drug. Compared with other breast cancer subtypes, TNBC has the characteristics of strong invasiveness, high proliferation, and poor prognosis. At present, the treatment of TNBC in clinical practice mainly relies on traditional chemotherapy, but it is often ineffective and has large toxic side effects. There is an urgent need to develop new, safer and more effective anti-TNBC drugs.

[0003] Cryptotanshinone is one of the main fat-soluble components of the traditional Chinese medicine Danshen. Compared with other tanshinone compounds, it has a typical phenanthrodihydrofuran ring core structure, a chiral center and multiple SP 3 Hybridized carbon, thus showing a variety of unique pharmacological activities. Summary of the invention

[0004] The technical problem to be solved by the present invention is to overcome the relatively single structure of drugs for treating triple-negative breast cancer in the prior art, so the present invention provides a cryptotanshinone derivative, a preparation method and application thereof.

[0005] The present invention solves the above technical problems through the following technical solutions.

[0006] The present invention provides a use of a cryptotanshinone derivative as shown in formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating triple-negative breast cancer:

[0007]

[0008] Among them, the dotted line “-----” in ring A represents a single bond or a double bond;

[0009] R1 and R2 together form =X1, wherein X1 is selected from CH2, O, S and NH;

[0010] or R1 and R2 are independently hydrogen or hydroxyl;

[0011] R3 is hydrogen, Phenoxy or one or more R 1-1 Substituted phenoxy, wherein R is hydrogen, C6-C 10 Aryl, one or more R 1-1 Substituted C6-C 10 Aryl, C 1-3 Alkyl, with one or more R 1-2 Substituted C 1-3 Alkyl, C 2-3 Alkenyl, one or more R 1-3 Substituted C 2-3 alkenyl, 5-9 membered heterocycloalkyl or one or more R 1-4 A substituted 5-9 membered heterocycloalkyl group, wherein the number of heteroatoms in the 5-9 membered heterocycloalkyl group is 1, 2 or 3, and each heteroatom is independently N, O or S;

[0012] Each R 1-1 Independently CN, NO2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, halogen, 5-6 membered heterocycloalkyl or one or more R 2-1 Substituted 5-6 membered heterocycloalkyl; the number of heteroatoms in the 5-6 membered heterocycloalkyl is 1, 2 or 3, and each heteroatom is independently N, O or S;

[0013] -1 R is hydrogen or C 1-3 alkyl;

[0014] Each R 2-1 are independently tert-butyloxycarbonyl;

[0015] Each R 1-2 Independently -NR 2-2 R 2-3 、C6-C 10 Aryl or 6-10 membered heteroaryl, the number of heteroatoms in the 6-10 membered heteroaryl is 1, 2 or 3, and each heteroatom is independently N, O or S;

[0016] R 2-2 , R 2-3 are independently hydrogen, tert-butyloxycarbonyl or

[0017] R 1-3 C6-C 10 Aryl;

[0018] R 1-4 is tert-butyloxycarbonyl;

[0019] Ring C for

[0020] X2 is selected from CH2, O, S and NH;

[0021] X3 is selected from CH2, O, S and NH;

[0022] R4 and R5 are independently hydrogen, C 1-3 Alkyl-C(O)O-, C 1-3 Alkoxy or hydroxy.

[0023] In some embodiments, in R, the "C 1-3 Alkyl or one or more R 1-2 Substituted C 1-3 The "C" in "alkyl" 1-3 The "alkyl" group is methyl, ethyl, propyl or isopropyl, preferably methyl or ethyl.

[0024] In some embodiments, in R, the "C 2-3 Alkenyl or one or more R 1-3 Substituted C 2-3 The "C" in "alkenyl" 2-3 "Alkenyl" is vinyl, propenyl or isopropenyl, preferably vinyl.

[0025] In some embodiments, in R, the "C6-C 10 Aryl or one or more R 1-1 Substituted C6-C 10 "C6-C 10 "Aryl" is phenyl.

[0026] In some embodiments, in R, the “5-9 membered heterocycloalkyl” or “substituted by one or more R 1-4 The "5-9-membered heterocycloalkyl" in "substituted 5-9-membered heterocycloalkyl" is a 5-9-membered heterocycloalkyl containing N, preferably More preferred

[0027] In some embodiments, in R, the one or more R 1-4 The substituted 5-9 membered heterocycloalkyl is

[0028] In some embodiments, R 1-1 In the C 1-4 Alkyl or C 1-4 C in haloalkyl 1-4 The alkyl portion is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, or tert-butyl, preferably methyl, ethyl, or tert-butyl.

[0029] In some embodiments, R 1-1 In the C 1-4 Alkoxy or C 1-4 C in haloalkoxy 1-4 The alkoxy moiety is methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy, preferably methoxy.

[0030] In some embodiments, R 1-1 wherein the halogen is F, Cl, Br or I, preferably F, Cl or Br, more preferably F or Cl.

[0031] In some embodiments, R 1-1 In the present invention, the “5-6 membered heterocycloalkyl” or “substituted by one or more R 2-1 The "5-6-membered heterocycloalkyl" in the "substituted 5-6-membered heterocycloalkyl" is a 6-membered heterocycloalkyl containing a nitrogen atom, preferably

[0032] In some embodiments, R 1-1 In the C 1-4 Haloalkoxy or C 1-4 The "halo" in the haloalkoxy group is fluoro, chloro, bromo or iodo, preferably fluoro.

[0033] In some schemes, -1 R, C 1-3 The alkyl group is methyl, ethyl, propyl or isopropyl, preferably methyl.

[0034] In some embodiments, R 1-2 In the C6-C 10 Aryl is phenyl.

[0035] In some embodiments, R 1-2 In the above, the 6-10 membered heteroaryl group is a 6-10 membered heteroaryl group containing N, preferably

[0036] In some embodiments, R 1-2 In the above, the “-NR 2-2 R 2-3 " is -NHBoc or -NHBoc is preferred.

[0037] In some embodiments, R 1-3 It is phenyl.

[0038] In some embodiments, in R4, the C 1-3 Alkyl-C(O)O- is formyloxy, acetoxy or propionyloxy.

[0039] In some embodiments, in R4, the C1-3 Alkoxy is methoxy, ethoxy, propoxy or isopropoxy.

[0040] In some embodiments, in R5, the C 1-3 Alkyl-C(O)O- is formyloxy, acetoxy or propionyloxy.

[0041] In some embodiments, in R5, the C 1-3 Alkoxy is methoxy, ethoxy, propoxy or isopropoxy.

[0042] In some embodiments, R is hydrogen, C6-C 10 Aryl, C 1-3 Alkyl, with one or more R 1-2 Substituted C 1-3 Alkyl, with one or more R 1-3 Substituted C 2-3 Alkenyl or one or more R 1-4 The substituted 5-9 membered heterocycloalkyl group has 1 heteroatom and the heteroatom is N.

[0043] In some embodiments, each R 1-1 Independently CN, NO2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, halogen, or by an R 2-1 The substituted 6-membered heterocycloalkyl group is a 6-membered heterocycloalkyl group containing 2 N atoms.

[0044] In some embodiments, each R 1-1 Independently CN, NO2, C 1-4 Haloalkyl, C 1-4 Alkoxy, halogen or

[0045] In some embodiments, each R 1-1 are independently CN, NO2, methyl, ethyl, tert-butyl, methoxy, trifluoromethyl, trifluoromethoxy, F, Cl, Br, or Preferably CN, NO2, methoxy, trifluoromethyl, F, Cl,

[0046] In some embodiments, each R 1-2 Independently -NR 2-2 R 2-3 or C6-C 10 Aryl.

[0047] In some embodiments, each R 1-2 Independently -NHBoc, Phenyl or Best -NHBoc, or phenyl.

[0048] In some embodiments, when R1 and R2 form =X1, X1 is O.

[0049] In some embodiments, when the for When X2 is 0.

[0050] In some embodiments, when the for When X3 is 0.

[0051] In some embodiments, when the for When R4 and R5 are independently selected from hydrogen and C 1-3 Alkyl-C(O)O-.

[0052] In some embodiments, the for

[0053] In some embodiments, Formula I is

[0054] In some embodiments, R3 is Preferably

[0055]

[0056] In some embodiments, the cryptotanshinone derivative as shown in Formula I is selected from any of the following structures:

[0057]

[0058] In some embodiments, the cryptotanshinone derivative as shown in Formula I is selected from any of the following structures:

[0059]

[0060]

[0061]

[0062] In some embodiments, the cryptotanshinone derivative as shown in Formula I is preferably any of the following structures:

[0063]

[0064] The present invention provides a cryptotanshinone derivative, a stereoisomer thereof or a pharmaceutically acceptable salt thereof as shown in Formula I:

[0065]

[0066] Among them, "-----", R1, R2, R3 and The definitions of are as mentioned above;

[0067] And the following conditions are met:

[0068] The cryptotanshinone derivative shown in formula I is not any of the following structures:

[0069] In some embodiments, the cryptotanshinone derivative as shown in Formula I is selected from any of the following structures:

[0070]

[0071]

[0072]

[0073] The present invention also provides a method for preparing a cryptotanshinone derivative as shown in formula I, which can be method 1, 2, 3, 4 or 5:

[0074] Method 1 comprises the following steps: in a solvent, subjecting a compound as shown in formula II and R3-H to a conjugate addition reaction as shown below in the presence of an oxidant to obtain a cryptotanshinone derivative as shown in formula I; wherein the dotted line “ ” in ring A is a single bond, and R1, R2, R3 and is as defined above, and R3 is not hydrogen;

[0075]

[0076] Method 2 comprises the following steps: in a solvent, subjecting a compound as shown in formula III and an acylating agent to a reductive acylation reaction as shown below in the presence of a reducing agent and an inorganic base to obtain a cryptotanshinone derivative as shown in formula I; wherein the for R4 and R5 are independently C 1-3 Alkyl-C(O)O-; the dashed line "-----" in ring A, R1, R2, and R3 are as defined above;

[0077]

[0078] Method 3 comprises the following steps: in a solvent, hydrolyzing the compound shown in formula IV in the presence of an inorganic base, and simultaneously performing a ring-opening reaction on the dihydrofuran ring of ring D, and performing a ring-closing reaction on ring D in the presence of an inorganic acid to obtain a cryptotanshinone derivative shown in formula I; wherein the C in ring for R1, R2, X2, X3 and R are as defined above, R3 is a hydrogen atom; the dotted line “-----” in ring A is a double bond;

[0079]

[0080] Method 4 comprises the following steps: in a solvent, subjecting a compound as shown in formula V to an oxidant for allylic oxidation reaction to obtain a cryptotanshinone derivative as shown in formula I; wherein R3 is H; the dotted line "-----" in ring A is a double bond; R1, R2 and The definition is as described above; R1 and R2 together form =X1, wherein X1 is O; or one of R1 and R2 is hydrogen and the other is hydroxyl;

[0081]

[0082] Method 5 comprises the following steps: in a solvent, subjecting the compound shown in formula VI to a reduction reaction in the presence of a reducing agent to obtain a cryptotanshinone derivative shown in formula I; wherein R3 is H; the dotted line "-----" in ring A is a single bond; R1, R2 and The definition of is as mentioned above;

[0083]

[0084] In some embodiments, in method 1, the solvent is selected from conventional organic solvents for such reactions in the art, preferably toluene or chlorobenzene.

[0085] In some embodiments, in method 1, the oxidant is oxygen, tert-butyl hydroperoxide, di-tert-butyl peroxide, 2,2,6,6-tetramethylpiperidinyl oxide (TEMPO) or manganese dioxide, preferably 2,2,6,6-tetramethylpiperidinyl oxide (TEMPO).

[0086] In some embodiments, in method 1, the reaction temperature of the conjugate addition reaction is 0°C-130°C, preferably 100°C-130°C, and particularly preferably 120°C-130°C.

[0087] In some embodiments, in method 1, the molar ratio of the oxidant to the compound of formula II is (1:1)-(100:1), preferably (1:1)-(2:1); the molar ratio of R3-H to the compound of formula II is (1:1)-(100:1), preferably (1:1)-(4:1).

[0088] In some embodiments, in method 2, the inorganic base is selected from conventional inorganic bases for such reactions in the art, preferably sodium acetate or potassium acetate.

[0089] In some embodiments, in method 2, the acylating agent is an acid anhydride or an acid chloride, preferably acetic anhydride, acetyl chloride, propionic anhydride or propionyl chloride.

[0090] In some embodiments, in method 2, the reducing agent is zinc powder, lithium aluminum hydride, sodium borohydride or hydrogen / palladium, preferably zinc powder or sodium borohydride.

[0091] In some embodiments, in method 2, the reaction temperature in the reductive acylation reaction is 0°C-50°C, preferably 25°C-50°C, and particularly preferably 40°C-50°C.

[0092] In some embodiments, in method 2, the molar ratio of the acylating agent to the compound of formula III is (2:1)-(100:1), preferably (4:1)-(20:1).

[0093] In some embodiments, in method 2, the molar ratio of the inorganic base to the compound of formula III is (1:1)-(100:1), preferably (1:1)-(2:1).

[0094] In some embodiments, in method 2, the molar ratio of the reducing agent to the compound of formula III is (2:1)-(100:1), preferably (4:1)-(20:1).

[0095] In some embodiments, in method 3, the solvent is selected from conventional organic solvents for such reactions in the art, preferably methanol and / or ethanol.

[0096] In some embodiments, in method 3, the inorganic base is selected from conventional inorganic bases for such reactions in the art, preferably sodium hydroxide and / or lithium hydroxide.

[0097] In some embodiments, in method 3, the inorganic acid is selected from conventional inorganic acids for such reactions in the art, preferably sulfuric acid or hydrochloric acid.

[0098] In some embodiments, in method 3, the reaction temperature of the ring-opening reaction and the ring-closing reaction is 0°C-70°C, preferably 25°C-70°C, and particularly preferably 25°C-56°C.

[0099] In some embodiments, in method 3, the molar ratio of the inorganic base to the compound of formula IV is (2:1)-(100:1), preferably (4:1)-(20:1).

[0100] In some embodiments, in method 3, the molar ratio of the inorganic acid to the compound represented by formula IV is (1:1)-(100:1), preferably (10:1)-(100:1).

[0101] In some embodiments, in method 4, the solvent is selected from conventional organic solvents for such reactions in the art, preferably dioxane.

[0102] In some embodiments, in method 4, the oxidant is one or more of oxygen, tert-butyl hydroperoxide, di-tert-butyl peroxide, 2,2,6,6-tetramethylpiperidinium oxide (TEMPO), manganese dioxide, cerium ammonium nitrate, diiodobenzene acetate, potassium persulfide, selenium dioxide and chromium trioxide, preferably selenium dioxide or a mixture of selenium dioxide and tert-butyl hydroperoxide.

[0103] In some embodiments, in method 4, the reaction temperature of the allylic oxidation reaction is 0°C-100°C, preferably 25°C-100°C, and particularly preferably 50°C-100°C.

[0104] In some embodiments, in method 4, the molar ratio of the oxidant to the compound of formula V is (2:1)-(100:1), preferably (4:1)-(20:1).

[0105] In some embodiments, in method 5, the solvent is selected from conventional organic solvents for such reactions in the art, preferably tetrahydrofuran and / or dichloromethane.

[0106] In some embodiments, in method 5, the reducing agent is zinc powder, lithium aluminum hydride, sodium borohydride or hydrogen / palladium, preferably hydrogen / palladium.

[0107] In some embodiments, in method 5, the reaction temperature of the reduction reaction is 0°C-50°C, preferably 25°C-50°C, and particularly preferably 25°C-35°C.

[0108] In some embodiments, in method 5, the molar ratio of the reducing agent to the compound represented by formula VI is (2:1)-(100:1), preferably (4:1)-(20:1).

[0109] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0110] The reagents and raw materials used in the present invention are commercially available.

[0111] The positive and progressive effects of the present invention are: the present invention provides a cryptotanshinone derivative with a novel structure, a preparation method and application thereof. The cryptotanshinone derivative of the present invention has a good inhibitory activity on triple-negative breast cancer cells. BRIEF DESCRIPTION OF THE DRAWINGS

[0112] Figure 1 Compound 9-1 inhibits tumor growth in vivo (n=5)

[0113] Figure 2 Compound 13-1 inhibits tumor growth in vivo (n=5)

[0114] Figure 3 Compounds 9-1 and 13-1 inhibit tumor growth in vivo (n=5)

[0115] Figure 4 HE staining and Ki67 immunohistochemistry results of tumor sections

[0116] Figure 5 The weight change curve of mice after drug administration

[0117] Figure 6 HE staining results of main organ sections DETAILED DESCRIPTION

[0118] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0119] Example 1

[0120] Cryptotanshinone (100 mg, 0.337 mmol) was dissolved in 3 ml of chlorobenzene, and 88% formic acid (29 μl, 0.675 mmol) and TEMPO (63 mg, 0.405 mmol) were added in sequence. The mixture was stirred at 120 ° C for 24 h. After the reaction was completed under TLC monitoring, the mixture was concentrated under reduced pressure on a rotary evaporator at 80 ° C and a vacuum degree of 0.1 MPa to obtain a crude product. The product was cooled to room temperature and purified by silica gel column chromatography (petroleum ether: ethyl acetate (PE: EtOAc) = 2:1-0:1)) to obtain an orange solid compound 1-1 (20 mg, 17%).

[0121]

[0122] 1H NMR(500MHz, CDCl3)δ8.09(s,1H),7.74(d,J=8.2Hz,1H),7.68(dd,J=8.2,1.5Hz,1H),6 .66(t,J=3.4Hz,1H),4.90(t,J=9.6Hz,1H),4.38(ddd,J=9.4,6.0,1.5Hz,1H),3.60(dq d,J=15.0,6.7,1.8Hz,1H),2.26–2.15(m,1H),2.05–1.90(m,2H),1.56(ddd,J=12.7,4. 1,1.9Hz,1H),1.40(d,J=1.9Hz,3H),1.34(dd,J=6.8,1.8Hz,3H),1.27(d,J=2.9Hz,3H). 13 C NMR (126MHz, CDCl3) δ183.08,174.63,170.18,160.25,152.82,136.38,133.45,128.69,127.27 ,125.43,118.74,81.62,67.21,34.89,34.62,31.85,31.51,31.13,24.85,18.75.HRMS(ESI):C 20 H 21 O5 + [M+H] + m / z calculated: 341.1384, found: 341.1384.

[0123] Example 2

[0124] Cryptotanshinone (100 mg, 0.337 mmol) was dissolved in 3 ml of acetic acid, TEMPO (63 mg, 0.405 mmol) was added, and the mixture was stirred at 120 ° C for 24 h. After the reaction was completed, the mixture was concentrated under reduced pressure at 80 ° C and a vacuum degree of 0.1 MPa on a rotary evaporator to obtain a crude product. The product was cooled to room temperature and subjected to silica gel column chromatography (PE: EtOAc = 2: 1-0: 1) to obtain an orange solid compound 2-1 (89 mg, 75%).

[0125]

[0126] 1H NMR (500MHz, CDCl3) δ7.73 (d, J=8.2Hz, 1H), 7.66 (dd, J=8.2, 1.2Hz, 1H), 6.45 (dd, J=5.8 ,3.7Hz,1H),4.90(td,J=9.5,3.2Hz,1H),4.38(ddd,J=9.3,6.0,1.1Hz,1H),3.60(dpd,J =10.0,6.8,3.4Hz,1H),2.25–2.18(m,1H),2.01(d,J=3.7Hz,3H),1.99–1.87(m,2H),1.5 8–1.52(m,1H),1.40(d,J=2.1Hz,3H),1.35(dd,J=6.8,1.3Hz,3H),1.27(d,J=2.9Hz,3H). 13 C NMR (126MHz, CDCl3) δ183.23,174.96,170.27,169.94,152.82,137.29,133.30,129.03,127.19,12 5.17,118.66,81.60,67.18,34.94,34.64,32.12,31.57,31.18,24.52,21.05,18.80.HRMS(ESI):C 21 H 23 O5 + [M+H] + m / z calculated: 355.1540, found: 355.1541.

[0127] Example 3

[0128] The preparation method is the same as 1-1, using propionic acid (50 μl, 0.675 mmol) as raw material, silica gel column chromatography (PE: EtOAc = 3: 1-1: 1) to obtain orange solid compound 3-1 (56 mg, 45%) and its diastereoisomer 3-2 (61 mg, 49%).

[0129]

[0130] 3-1: 11H NMR (500 MHz, CDCl3) 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 13C NMR (126 MHz, CDCl3) 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. HRMS (ESI): C 22 H 25 O5 + [M + H] + Calcd for m / z: 369.1697, Found: 369.1697.

[0131] 3 - 2: 1 1H NMR (500 MHz, CDCl3) δ 7.72 (d, J = 8.2 Hz, 1H), 7.65 (d, J = 8.2 Hz, 1H), 6.46 (t, J = 3.6 Hz, 1H), 4.90 (t, J = 9.5 Hz, 1H), 4.37 (dd, J = 9.4, 6.1 Hz, 1H), 3.60 (dp, J = 9.6, 6.7 Hz, 1H), 2.34–2.14 (m, 3H), 2.01–1.85 (m, 2H), 1.57–1.51 (m, 1H), 1.39 (s, 3H), 1.35 (d, J = 6.8 Hz, 3H), 1.27 (s, 3H), 1.13 (t, J = 7.5 Hz, 3H). 13C NMR (126MHz, CDCl3) δ183.25,175.08,173.27,170.30,152.82,137.43,133.28,129.05,127.15,125. 12,118.63,81.58,66.95,34.94,34.64,32.15,31.62,31.15,27.45,24.57,18.75,9.15.HRMS(ESI):C 22 H 25 O5 + [M+H] + m / z calculated: 369.1697, found: 369.1697.

[0132] Example 4

[0133] The preparation method is the same as 1-1, using benzoic acid (82 mg, 0.675 mmol) as raw material, silica gel column chromatography (PE: EtOAc = 3: 1-1: 1) to obtain orange solid compound 4-1 (41 mg, 29%) and its diastereomer 4-2 (45 mg, 32%).

[0134]

[0135] 4-1: 1 H NMR (500MHz, CDCl3) δ7.95–7.91(m,2H),7.78(d,J=8.3Hz,1H),7.70(d,J=8.2Hz,1 H),7.49–7.44(m,1H),7.37–7.30(m,2H),6.78(t,J=3.1Hz,1H),4.87(t,J=9.4Hz,1 H),4.37(dd,J=9.4,5.8Hz,1H),3.56(dp,J=9.6,6.4Hz,1H),2.41–2.31(m,1H),2.0 4–2.00(m,2H),1.62–1.55(m,1H),1.45(s,3H),1.33(d,J=6.9Hz,3H),1.30(s,3H). 13 CNMR(126MHz, CDCl3)δ182.86,174.76,170.12,165.38,152.95,137.14,133.34,132.53,130.67,129.68(2C),129.0 6,128.10(2C),127.19,125.24,118.71,81.56,67.38,35.03,34.64,32.21,31.78,31.25,24.65,18.88.HRMS(ESI):C26 H 25 O5 + [M+H] + m / z calculated: 417.1697, found: 417.1696.

[0136] 4-2: 1 H NMR (500MHz, CDCl3) δ7.97–7.91(m,2H),7.77(d,J=8.3Hz,1H),7.69(d,J=8.3Hz ,1H),7.49–7.43(m,1H),7.33(t,J=7.7Hz,2H),6.75(t,J=2.8Hz,1H),4.89(t,J =9.6Hz,1H),4.35(dd,J=9.4,6.2Hz,1H),3.57(dp,J=9.7,6.7Hz,1H),2.41–2.3 5(m,1H),2.04–1.99(m,2H),1.60–1.55(m,1H),1.44(s,3H),1.32–1.27(m,6H). 13 C NMR (126MHz, CDCl3) δ182.77,174.75,170.20,165.34,152.98,137.05,133.44,132.52,130.70,129.67(2C),128.94 ,128.10(2C),127.18,125.31,118.68,81.58,67.25,35.04,34.61,32.14,31.90,31.15,24.66,18.63.HRMS(ESI):C 26 H 25 O5 + [M+H] + m / z calculated: 417.1697, found: 417.1699.

[0137] Example 5

[0138] The preparation method is the same as 1-1, using cinnamic acid (101 mg, 0.675 mmol) as raw material, silica gel column chromatography (PE: EtOAc = 3: 1-1: 1) to obtain orange solid compound 5-1 (34 mg, 23%) and its diastereoisomer 5-2 (38 mg, 25%).

[0139]

[0140] 5-1: 1H NMR(500MHz, CDCl3)δ7.75(d,J=8.3Hz,1H),7.70–7.63(m,2H),7.47–7.42(m,2H), 7.34–7.28(m,3H),6.68–6.64(m,1H),6.34(d,J=16.0Hz,1H),4.87(t,J=9.5Hz,1H ),4.36(dd,J=9.3,5.9Hz,1H),3.57(dp,J=9.6,6.7Hz,1H),2.35–2.29(m,1H),2.0 6–1.93(m,2H),1.60–1.54(m,1H),1.43(s,3H),1.33(d,J=6.9Hz,3H),1.29(s,3H). 13 C NMR (126MHz, CDCl3) δ182.95,174.82,170.11,165.77,152.88,144.66,137.19,134.67,133.28,129.94,128.90,128.71(2C) ,127.99(2C),127.19,125.20,118.67,118.43,81.55,67.03,34.99,34.64,32.13,31.63,31.24,24.59,18.85.HRMS(ESI):C 28 H 27 O5 + [M+H] + m / z calculated: 443.1853, found: 443.1853.

[0141] 5-2: 1 H NMR (500MHz, CDCl3) δ7.75(d,J=8.2Hz,1H),7.68(d,J=3.0Hz,1H),7.66(d,J=4.8Hz,1H), 7.48–7.42(m,2H),7.34–7.29(m,3H),6.65(t,J=2.8Hz,1H),6.35(d,J=16.0Hz,1H),4.89( t,J=9.5Hz,1H),4.36(dd,J=9.4,6.1Hz,1H),3.58(dp,J=9.7,6.6Hz,1H),2.36–2.26(m,1 H),2.05–1.94(m,2H),1.61–1.53(m,1H),1.43(s,3H),1.32(d,J=6.8Hz,3H),1.29(s,3H). 13C NMR (126MHz, CDCl3) δ182.92,174.83,170.15,165.78,152.90,144.66,137.17,134.67,133.35,129.94,128.95,128.71(2C) ,127.99(2C),127.20,125.23,118.69,118.42,81.56,66.97,34.99,34.63,32.09,31.71,31.15,24.59,18.69.HRMS(ESI):C 28 H 27 O5 + [M+H] + m / z calculated: 443.1853, found: 443.1853.

[0142] Example 6

[0143] DMAP (56 mg, 0.463 mmol) was dissolved in 20 ml pyridine, and succinic anhydride (906 mg, 0.292 mmol) and natural borneol (310 mg, 2.013 mmol) were added in sequence. The mixture was stirred at 58 ° C for 5 days. After the reaction was completed, the mixture was concentrated under reduced pressure by rotary evaporator at 58 ° C and vacuum degree of 0.1 MPa to obtain a crude product. The product was cooled to room temperature and subjected to silica gel column chromatography (PE: EtOAc = 5: 1-0: 1) to obtain a white foam compound (380 mg, 75%). The crude product was dissolved in 8 ml chlorobenzene, and cryptotanshinone (221 mg, 0.747 mmol) and TEMPO (140 mg, 0.896 mmol) were added in sequence. The preparation method was the same as 1-1 to obtain an orange solid compound 6-1 (92 mg, 22%) and its diastereoisomer 6-2 (88 mg, 21%).

[0144]

[0145] 6-1: 1H NMR (500MHz, CDCl3) δ7.73(d,J=8.2Hz,1H),7.66(d,J=8.2Hz,1H),6.47(t,J=3.9,3.1Hz,1H),4.90(t,J=9.5Hz,1H ),4.86(ddd,J=9.9,3.5,2.1Hz,1H),4.38(dd,J=9.4,5.9Hz,1H),3.60(dp,J=9.6,6.7Hz,1H),2.79–2.70(m,1H),2. 70–2.50(m,3H),2.35–2.15(m,2H),2.01–1.86(m,3H),1.76–1.62(m,2H),1.57–1.51(m,1H),1.40(s,3H),1.35(d, J=6.8Hz,3H),1.39–1.17(m,2H),1.26(s,3H),0.95(dd,J=13.7,3.5Hz,1H),0.87(s,3H),0.85(s,3H),0.78(s,3H). 13 C NMR (126MHz, CDCl3) δ183.29,174.95,172.66,171.09,170.21,152.84,137.10,133.27,129.12,127.17,125.17,118.64,81.58,80.03,67.47 ,48.72,47.76,44.84,36.59,34.92,34.64,32.13,31.52,31.19,29.60 ,29.19,27.94,27.09,24.54,19.66,18.84,18.79,13.44.HRMS(ESI):C 33 H 41 O7 + [M+H] + m / z calculated: 549.2847, found: 549.2845.

[0146] 6-2: 1H NMR (500MHz, CDCl3) δ7.72(d,J=8.3Hz,1H),7.65(d,J=8.2Hz,1H),6.44(t,J=3.5Hz,1H),4.89(t,J=9.5Hz,1H),4.8 3(ddd,J=9.9,3.5,2.2Hz,1H),4.37(dd,J=9.3,6.1Hz,1H),3.59(dp,J=9.5,6.7Hz,1H),2.78–2.67(m,1H),2.66–2.5 0(m,3H),2.32–2.15(m,2H),2.00–1.85(m,3H),1.74–1.60(m,2H),1.56–1.50(m,1H),1.38(d,J=2.6Hz,3H),1.34(d ,J=6.8Hz,3H),1.26(s,3H),1.32–1.12(m,2H),0.89(dd,J=13.9,3.6Hz,1H),0.86(s,3H),0.84(s,3H),0.79(s,3H). 13 C NMR (126MHz, CDCl3) δ183.31,174.99,172.67,171.09,170.27,152.86,137.11,133.33,129.03,127.15,125.20,118.64,81.59,80.03,67.45 ,48.71,47.73,44.82,36.62,34.91,34.61,32.10,31.58,31.10,29.58 ,29.13,27.95,27.04,24.56,19.66,18.78,18.70,13.42.HRMS(ESI):C 33 H 41 O7 + [M+H] + m / z calculated: 549.2847, found: 549.2845.

[0147] Example 7

[0148] Cryptotanshinone (500 mg, 1.687 mmol) was dissolved in 17 ml of chlorobenzene, and propionic acid (252 μl, 3.374 mmol) and TEMPO (316 mg, 2.024 mmol) were added in sequence. The mixture was stirred at 120 °C for 24 h. After the reaction was completed under TLC monitoring, the mixture was concentrated under reduced pressure on a rotary evaporator at 80 °C and a vacuum degree of 0.1 MPa to obtain a crude product. The product was cooled to room temperature and subjected to silica gel column chromatography (PE: EtOAc = 3:1-1:1) to obtain a pair of diastereoisomers of crude product a. The crude product a (513 mg, 1.392 mmol) was dissolved in 13 ml of methanol, sodium hydroxide (223 mg, 5.568 mmol) was added at 0°C, and the reaction was stirred at 65°C. After the reaction was completed by TLC monitoring, the mixture was cooled, concentrated hydrochloric acid (6 ml) and water (12 ml) were added in sequence to neutralize the excess sodium hydroxide, and the mixture was concentrated under reduced pressure. The mixture was extracted with ethyl acetate (3×50 ml), and the organic phases were combined, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure on a rotary evaporator at 40°C with a vacuum degree of 0.1 MPa to obtain the crude product b. The crude product b (449 mg, 1.359 mmol) was dissolved in 13 ml of anhydrous ethanol, and concentrated sulfuric acid (8 ml) was slowly added in batches at 0°C. After the temperature dropped to room temperature, the reaction was continued for 45 min. After TLC confirmed the completion of the reaction, saturated NaHCO3 solution (20 ml) was added at 0°C, stirred for 10 min until no bubbles were generated, and concentrated under reduced pressure. The mixture was extracted with ethyl acetate (3×50 ml). The organic layers were combined and washed with water and saturated brine in turn, dried over anhydrous NaSO4, concentrated, and chromatographed on a silica gel column (PE: EtOAc = 8: 1-2: 1) to obtain an orange-red solid compound 7-1 (215 mg, 43%). (The structure of crude product a is The structure of crude product b is )

[0149] 7-1: 1 H NMR (500MHz, CDCl3) δ7.86(dt,J=10.3,1.8Hz,1H),7.52(d,J=7.9Hz,1H),7.47(d,J=7.9Hz,1H),6.30(dt,J=10.2,4.6Hz,1H),4.88(t,J=9.5H z,1H),4.35(dd,J=9.3,6.0Hz,1H),3.59(dp,J=9.6,6.5Hz,1H),2.26(dd,J=4.6,1.9Hz,2H),1.34(d,J=6.8Hz,3H),1.27(s,3H),1.27(s,3H). 13C NMR (126MHz, CDCl3) δ184.90,175.71,170.72,150.66,136.58,134.01,129.36,126.14,124 .59,124.33,124.02,118.51,81.47,37.71,34.61,34.33,28.36,28.32,18.77.HRMS(ESI):C 19 H 19 O3 + [M+H] + m / z calculated: 295.1329, found: 295.1329.

[0150] Example 8

[0151] Take 7-1 (75 mg, 0.255 mmol) and dissolve it in 3 ml of 1,4-dioxane. Selenium dioxide (84 mg, 0.765 mmol) and tert-butyl hydroperoxide (93 μl, 0.510 mmol) were added in sequence at 0°C. The reaction was heated at 55°C. After the reaction was completed, the mixture was concentrated under reduced pressure on a rotary evaporator at 50°C and a vacuum degree of 0.1 MPa to obtain a crude product. The mixture was cooled to room temperature and subjected to silica gel column chromatography (DCM: MeOH = 100: 1-20: 1) to obtain an orange-red solid compound 8-1 (24 mg, 30%).

[0152]

[0153] 8-1: 1 H NMR (500MHz, CDCl3) δ9.01 (d, J=10.5Hz, 1H), 7.89 (dd, J=10.2, 4.6Hz, 1H), 7. 60(d,J=7.9Hz,1H),7.52(dd,J=8.0,1.6Hz,1H),6.37(ddd,J=10.6,6.6,4.3H z,1H),4.89(t,J=9.5Hz,1H),4.36(dd,J=9.3,6.1Hz,1H),4.10–4.05(m,1H), 3.58(ddq,J=15.8,9.3,6.7Hz,1H),1.38–1.33(m,6H),1.26(d,J=7.3Hz,3H). 13C NMR (126MHz, CDCl3) δ184.56,175.42,170.52,149.56,135.76,135.15,130.65,126.46,125 .14,124.73,124.50,118.74,81.56,72.33,40.11,34.62,26.33,21.94,18.71.HRMS(ESI):C 19 H 19 O4 + [M+H] + m / z calculated: 311.1278, found: 311.1278.

[0154] Example 9

[0155] Take 7-1 (51 mg, 0.173 mmol) and dissolve it in 2 ml of 1,4-dioxane. At 0°C, add selenium dioxide (115 mg, 1.038 mmol) and tert-butyl hydroperoxide (63 μl, 0.346 mmol) in sequence. Heat the reaction at 100°C. After the reaction is completed, monitor the reaction by TLC. Concentrate under reduced pressure on a rotary evaporator at 50°C and a vacuum degree of 0.1 MPa to obtain a crude product. Cool to room temperature and perform silica gel column chromatography (DCM: MeOH = 100: 1-20: 1) to obtain an orange-red solid compound 9-1 (50 mg, 94%).

[0156]

[0157] 9-1: 1 H NMR (500MHz, CDCl3) δ9.01(d,J=10.5Hz,1H),7.72(s,2H),6.39(d,J=10.5Hz,1H),4.94(t,J=9.5Hz,1H) ,4.41(dd,J=9.3,6.1Hz,1H),3.64(dp,J=9.5,6.8Hz,1H),1.49(d,J=2.4Hz,6H),1.37(d,J=6.8Hz,3H). 13 C NMR (126MHz, CDCl3) δ201.78,184.58,175.21,169.85,152.68,139.14,131.62,131.45,128. 57,127.35,127.26,125.85,119.15,81.77,48.07,34.71,27.67,27.50,18.71.HRMS(ESI):C 19 H 17 O4 + [M+H] +m / z calculated: 309.1121, found: 309.1121.

[0158] Example 10

[0159] Take 9-1 (54 mg, 0.175 mmol) and 10% palladium carbon (11 mg, 0.105 mmol) and dissolve them in 5 ml of dry tetrahydrofuran. Replace the mixture with hydrogen three times. Stir the mixture at room temperature (15-25°C) in a hydrogen atmosphere. After the reaction is completed, monitor the reaction by TLC. Filter and recover the palladium carbon. Concentrate the mixture under reduced pressure on a rotary evaporator at 25°C and a vacuum degree of 0.1 MPa to obtain a crude product. Cool the mixture to room temperature and perform silica gel column chromatography (DCM: MeOH = 100: 1-20: 1) to obtain orange-red solid compounds 10-1 (26 mg, 48%) and 10-2 (24 mg, 44%).

[0160]

[0161] 10-1: 1 H NMR (500MHz, CDCl3) δ7.63(d,J=8.1Hz,1H),7.60(d,J=8.1Hz,1H),4.92(t,J=9.5Hz,1H),4.39(dd,J=9.3,6.1Hz,1H ),3.65(t,J=6.8Hz,2H),3.64–3.57(m,1H),2.64(t,J=6.9Hz,2H),1.45(s,3H),1.45(s,3H),1.36(d,J=6.8Hz,3H). 13 C NMR (126MHz, CDCl3) δ212.61,184.38,175.61,170.28,150.27,141.58,131.84,128.36,126 .93,123.86,118.96,81.64,48.39,36.24,34.63,27.10,27.02,25.86,18.75.HRMS(ESI):C 19 H 19 O4 + [M+H] + m / z calculated: 311.1278, found: 311.1277.

[0162]

[0163] 10-2: 1H NMR (500MHz, CDCl3) δ7.65(d,J=8.1Hz,1H),7.52(d,J=8.1Hz,1H),4.89(dt,J=9.5,2.3Hz,1H),4.36(dd,J=9.3,6.0Hz,1H) ,3.77(dd,J=8.6,2.8Hz,1H),3.63–3.55(m,1H),3.35(ddt,J=92.2,19.7,6.8Hz,2H),2.09–1.86(m,2H),1.36–1.32(m,9H). 13 CNMR (126MHz, CDCl3) δ184.05,175.42,170.75,151.11,142.12,132.88,127.83,126.57,12 3.00,118.46,81.50,73.87,39.97,34.57,29.27,26.23,25.94,25.26,18.82.HRMS(ESI):C 19 H 21 O4 + [M+H] + m / z calculated: 313.1434, found: 313.1434.

[0164] Embodiment 11

[0165] Cryptotanshinone (100 mg, 0.337 mmol) was dissolved in 3 ml of acetic anhydride, and zinc powder (221 mg, 3.370 mmol) and sodium acetate (28 mg, 0.337 mmol) were added in sequence. The mixture was stirred at 50 ° C for about 1 h. After TLC confirmed that the reaction was complete, the zinc powder was filtered out, the filtrate was collected, concentrated under reduced pressure, extracted with ethyl acetate (3×10 ml), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and silica gel column chromatography (PE: EtOAc = 5: 1-1: 1) was used to obtain white solid compound 11-1 (96 mg, 74%).

[0166]

[0167] 11-1: 1H NMR (500MHz, CDCl3) δ7.74(d,J=8.8Hz,1H),7.42(d,J=8.9Hz,1H),4.86(t,J=8.9Hz,1H),4.30(dd,J=8.6,6.4Hz,1H),3.7 5(dp,J=9.0,6.5Hz,1H),3.16(s,2H),2.37(s,3H),2.34(s,3H),1.83–1.75(m,2H),1.69–1.64(m,2H),1.33–1.29(m,9H). 13 C NMR (126MHz, CDCl3) δ169.51,168.04,154.70,144.88,137.85,132.17,130.59,127.10,125.43,119.72, 118.06(2C),79.42,38.25,36.93,34.82,31.77,31.72,29.60,21.04,20.48,20.07,18.88.HRMS(ESI):C 23 H 27 O5 + [M+H] + m / z calculated: 383.1853, found: 383.1851.

[0168] Example 12

[0169] 7-1 (32 mg, 0.109 mmol) was dissolved in 2 ml of acetic anhydride, and zinc powder (71 mg, 1.088 mmol) and sodium acetate (9 mg, 0.109 mmol) were added in sequence. The mixture was stirred at 50 °C for about 1 h. After TLC confirmed that the reaction was complete, the zinc powder was removed by filtration, the filtrate was collected, concentrated under reduced pressure, extracted with ethyl acetate (3×10 ml), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and silica gel column chromatography (PE: EtOAc = 5: 1-1: 1) was used to obtain a white solid compound 12-1 (35 mg, 84%).

[0170]

[0171] 12-1: 1H NMR (500MHz, CDCl3) δ7.82(d,J=8.7Hz,1H),7.46(d,J=8.7Hz,1H),7.40(dt,J=10.2,1.8Hz,1H),6.05(dt,J=9.9,4.8Hz,1H),4.87(t,J=8.9Hz,1H),4 .32(dd,J=8.6,6.3Hz,1H),3.76(dp,J=9.1,6.8Hz,1H),2.36(s,3H),2.35( s,3H),2.26–2.19(m,2H),1.32(d,J=6.8Hz,3H),1.30(s,3H),1.27(s,3H). 13 C NMR (126MHz, CDCl3) δ168.94,168.12,154.68,144.55,138.12,131.87,127.26,126.49,125.36,124.29,1 22.70,121.58,118.77,117.87,79.51,37.18,36.90,34.44,27.75(2C),20.78,20.48,18.96.HRMS(ESI):C 23 H 25 O5 + [M+H] + m / z calculated: 381.1697, found: 381.1696.

[0172] Embodiment 13

[0173] 12-1 (103 mg, 0.271 mmol) was dissolved in 3 ml of dry 1,4-dioxane, replaced with argon three times, and selenium dioxide (60 mg, 0.541 mmol) was added. The mixture was refluxed at 100 ° C in an argon atmosphere for 30 min. After the reaction was completed, the mixture was filtered, concentrated, and extracted with ethyl acetate (3×10 ml). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (dichloromethane: methanol (DCM: MeOH) = 100: 1-20: 1)) to obtain white solid compounds 13-1 (50 mg, 47%) and 9-1.

[0174]

[0175] 13-1: 1H NMR (500MHz, CDCl3) δ8.71(d,J=10.5Hz,1H),8.03(d,J=8.8Hz,1H),7.52(d,J=8.8Hz,1H),6.23(d,J=10.5Hz,1H),4.90(t,J=8.9Hz,1H ),4.34(dd,J=8.7,6.4Hz,1H),3.79(dp,J=9.2,6.8Hz,1H),2.41(s,3H),2.36(s,3H),1.50(s,3H),1.49(s,3H),1.33(d,J=6.9Hz,3H). 13 C NMR (126MHz, CDCl3) δ203.61,168.56,167.82,155.19,150.14,140.97,139.46,131.74,124.74,124.65,123 .80,123.55,123.02,119.47,118.45,79.75,48.57,36.90,27.70,27.47,20.80,20.45,18.81.HRMS(ESI):C 23 H 23 O6 + [M+H] + m / z calculated: 395.1489, found: 395.1489.

[0176] Embodiment 14

[0177] Take 13-1 (119 mg, 0.302 mmol) and 10% palladium carbon (19 mg, 0.181 mmol) and dissolve them in 10 ml of dry tetrahydrofuran. Replace the mixture with hydrogen three times. Stir the mixture at room temperature (15-25 ° C) in a hydrogen atmosphere. After the reaction is completed, monitor the reaction by TLC. Filter and recover the palladium carbon. Concentrate the mixture under reduced pressure on a rotary evaporator at 25 ° C and a vacuum degree of 0.1 MPa to obtain a crude product. Cool it to room temperature and perform silica gel column chromatography (DCM: MeOH = 100: 1-20: 1) to obtain orange-red solid compounds 14-1 (11 mg, 9%) and 14-2 (75 mg, 62%).

[0178]

[0179] 14-1: 1H NMR (500MHz, CDCl3) δ7.87(d,J=8.7Hz,1H),7.39(d,J=8.9Hz,1H),4.89(t,J=8.9Hz,1H),4.33(dd,J=8.7,6.4Hz,1H),3.77(d p,J=9.1,6.7Hz,1H),2.71(t,J=6.9Hz,2H),2.36(s,3H),2.35(s,3H),1.68–1.59(m,2H),1.47(s,6H),1.33(d,J=6.8Hz,3H). 13 C NMR (126MHz, CDCl3) δ214.48,169.11,167.98,154.87,143.99,138.46,131.84,129.19,126.45,124.34,12 1.47,118.92,118.27,79.58,48.14,36.95,36.93,27.64,27.48,27.40,20.89,20.45,18.85.HRMS(ESI):C 23 H 25 O6 + [M+H] + m / z calculated: 397.1646, found: 397.1647.

[0180]

[0181] 14-2: 1 H NMR (500MHz, CDCl3) δ7.78(d,J=8.9Hz,1H),7.40(d,J=8.9Hz,1H),4.86(t,J=8.9Hz,1H),4.30(dd,J=8.6,6.4Hz,1H),3.77–3.71(m,2H), 3.30(d,J=120.4Hz,1H),2.36(s,3H),2.33(s,3H),2.02–1.93(m,2H),1.93–1.85(m,2H),1.34(d,J=2.5Hz,3H),1.31(s,3H),1.30(s,3H). 13C NMR (126MHz, CDCl3) δ169.53,168.00,154.69,143.55,138.05,132.21,129.09,126.59,125.34,120.44, 118.47,118.17,79.46,74.57,39.99,36.94,27.08(2C),24.64,21.02,20.46,18.87,18.80.HRMS(ESI):C 23 H 27 O6 + [M+H] + m / z calculated: 399.1802, found: 399.1803.

[0182] Embodiment 15

[0183] Preparation of cryptotanshinone derivatives 15-1 and 15-2:

[0184] Cryptotanshinone (100 mg, 0.337 mmol) was dissolved in 3 ml of chlorobenzene, and phenol (54 mg, 0.574 mmol) and TEMPO (105 mg, 0.675 mmol) were added in sequence. The mixture was stirred at 120 ° C for 24 h. After the reaction was completed under TLC monitoring, the mixture was concentrated under reduced pressure on a rotary evaporator at 80 ° C and a vacuum degree of 0.1 MPa to obtain a crude product. The product was cooled to room temperature and subjected to silica gel column chromatography (PE: EtOAc = 3: 1-1: 1) to obtain an orange solid compound 15-1 (30 mg, 23%) and its diastereomer 15-2 (33 mg, 25%).

[0185]

[0186] 15-1: 1 H NMR(500MHz, CDCl3)δ7.76(d,J=8.3Hz,1H),7.68(d,J=8.2Hz,1H),7.32–7.28(m,2H),7.15–7.12 (m,2H),6.96(tt,J=7.3,1.1Hz,1H),6.57(t,J=3.2Hz,1H),4.89(t,J=9.5Hz,1H),4.37(dd,J=9.4 ,5.9Hz,1H),3.65–3.53(m,1H),2.22(ddt,J=14.6,4.4,2.9Hz,1H),2.11(td,J=13.7,2.9Hz,1H), 1.82(tt,J=14.2,3.1Hz,1H),1.48–1.45(m,1H),1.45(s,3H),1.35(d,J=6.8Hz,3H),1.28(s,3H). 13C NMR (126MHz, CDCl3) δ183.28,175.03,170.37,157.22,152.68,138.22,133.31,129.47(2C),128.92,127.21,12 5.10,121.04,118.45,116.83(2C),81.53,67.74,35.05,34.62,31.56,31.48,31.40,22.56,18.80.HRMS(ESI):C 25 H 25 O4 + [M+H] + m / z calculated: 389.1747, found: 389.1747.

[0187] 15-2: 1 H NMR(500MHz, CDCl3)δ7.76(d,J=8.3Hz,1H),7.68(d,J=8.3Hz,1H),7.32–7.27(m,2H),7.16 –7.11(m,2H),6.95(tt,J=7.3,1.1Hz,1H),6.59(t,J=3.2Hz,1H),4.89(t,J=9.5Hz,1H),4. 38(dd,J=9.4,5.8Hz,1H),3.64–3.55(m,1H),2.26–2.16(m,1H),2.15–2.04(m,1H),1.84(t t,J=14.3,3.2Hz,1H),1.49–1.45(m,1H),1.45(s,3H),1.31(d,J=6.8Hz,3H),1.28(s,3H). 13 C NMR (126MHz, CDCl3) δ183.31,175.03,170.38,157.25,152.69,138.26,133.33,129.46(2C),128.88,127.22,12 5.11,121.02,118.57,116.74(2C),81.53,67.70,35.05,34.58,31.61,31.50,31.29,22.55,18.85.HRMS(ESI):C 25 H 25 O4 + [M+H] + m / z calculated: 389.1747, found: 389.1747.

[0188] Example 16

[0189] The preparation method was the same as 15-1, using 4-nitrophenol (80 mg, 0.574 mmol) as raw material and silica gel column chromatography (PE: EtOAc = 3:1-1:1) to obtain orange solid compound 16-1 (47 mg, 32%) and its diastereoisomer 16-2 (43 mg, 29%).

[0190]

[0191] 16-1: 1 H NMR (500MHz, CDCl3) δ8.22–8.17(m,2H),7.80(d,J=8.3Hz,1H),7.72(d,J=8 .2Hz,1H),7.12–7.07(m,2H),6.60(t,J=3.2Hz,1H),4.89(t,J=9.5Hz,1H),4 .38(dd,J=9.4,5.9Hz,1H),3.62–3.52(m,1H),2.24–2.15(m,1H),2.07–1.90 (m,2H),1.55–1.50(m,1H),1.45(s,3H),1.33(d,J=6.8Hz,3H),1.29(s,3H). 13 C NMR (126MHz, CDCl3) δ183.24,174.58,170.37,162.98,152.53,141.30,136.58,133.63,128.64,127.41,126.00 (2C),125.64,118.67,115.79(2C),81.69,68.79,53.46,34.98,34.61,31.49,31.16,22.93,18.78.HRMS(ESI):C 25 H 24 NO6 + [M+H] + m / z calculated: 434.1598, found: 434.1597.

[0192] 16-2: 1H NMR (500MHz, CDCl3) δ8.23–8.18(m,2H),7.80(d,J=8.2Hz,1H),7.72(d,J=8.2 Hz,1H),7.12–7.08(m,2H),6.61(t,J=2.9Hz,1H),4.91(t,J=9.5Hz,1H),4.38( dd,J=9.4,6.0Hz,1H),3.60(dp,J=9.8,6.8Hz,1H),2.24–2.18(m,1H),2.08–1. 90(m,2H),1.56–1.51(m,1H),1.45(s,3H),1.32(d,J=6.8Hz,3H),1.30(s,3H). 13 C NMR (126MHz, CDCl3) δ183.28,174.65,170.31,162.99,152.53,141.31,136.62,133.64,128.61,127.43,126.01 (2C),125.63,118.74,115.77(2C),81.67,68.78,34.98,34.60,31.54,31.48,31.10,22.94,18.75.HRMS(ESI):C 25 H 24 NO6 + [M+H] + m / z calculated: 434.1598, found: 434.1599.

[0193] Embodiment 17

[0194] The preparation method was the same as 15-1, using 4-cyanophenol (80 mg, 0.674 mmol) as raw material and silica gel column chromatography (PE: EtOAc = 3: 1-1: 1) to obtain orange solid compound 17-1 (40 mg, 29%) and its diastereoisomer 17-2 (38 mg, 27%).

[0195]

[0196] 17-1: 1H NMR(500MHz, CDCl3)δ7.79(d,J=8.3Hz,1H),7.71(d,J=8.2Hz,1H),7.61–7.57(m,2 H),7.12–7.08(m,2H),6.57(t,J=3.1Hz,1H),4.89(t,J=9.5Hz,1H),4.38(dd,J=9.4 ,5.9Hz,1H),3.58(dp,J=9.6,6.7Hz,1H),2.23–2.15(m,1H),2.07–1.99(m,1H),1.9 6–1.87(m,1H),1.53–1.47(m,1H),1.45(s,3H),1.34(d,J=6.8Hz,3H),1.29(s,3H). 13 C NMR (126MHz, CDCl3) δ183.24,174.67,170.32,161.06,152.54,136.84,134.04(2C),133.54,128.69,127.38,125.52 ,119.46,118.64,116.66(2C),103.71,81.64,68.26,34.96,34.61,31.48,31.46,31.19,22.79,18.78.HRMS(ESI):C 26 H 24 NO4 + [M+H] + m / z calculated: 414.1700, found: 414.1697.

[0197] 17-2: 1 H NMR(500MHz, CDCl3)δ7.79(d,J=8.2Hz,1H),7.71(d,J=8.2Hz,1H),7.63–7.55(m,2H),7. 13–7.08(m,2H),6.58(t,J=3.2Hz,1H),4.90(t,J=9.5Hz,1H),4.38(dd,J=9.4,6.0Hz,1H ),3.59(dp,J=9.7,6.7Hz,1H),2.23–2.14(m,1H),2.03(td,J=13.4,2.5Hz,1H),1.92(tt ,J=14.2,2.9Hz,1H),1.55–1.48(m,1H),1.44(s,3H),1.31(d,J=6.8Hz,3H),1.29(s,3H). 13C NMR (126MHz, CDCl3) δ183.27,174.71,170.33,161.10,152.55,136.87,134.03(2C),133.99,133.58,128.63,127.39,12 5.53,119.46,118.71,116.63(2C),103.68,81.64,68.25,34.96,34.58,31.53,31.47,31.11,22.80,18.74.HRMS(ESI):C 26 H 24 NO4 + [M+H] + m / z calculated: 414.1700, found: 414.1702.

[0198] Embodiment 18

[0199] The preparation method was the same as 15-1, using p-hydroxybenzaldehyde (70 mg, 0.574 mmol) as the raw material and silica gel column chromatography (PE: EtOAc = 3:1-1:1) to obtain orange solid compound 18-1 (43 mg, 31%) and its diastereoisomer 18-2 (37 mg, 26%).

[0200]

[0201] 18-1: 1 H NMR(500MHz, CDCl3)δ9.86(s,1H),7.85–7.81(m,2H),7.77(d,J=8.3Hz,1H),7.69(d,J =8.2Hz,1H),7.17–7.13(m,2H),6.62(t,J=3.1Hz,1H),4.87(t,J=9.5Hz,1H),4.35(dd, J=9.4,5.9Hz,1H),3.60–3.51(m,1H),2.26–2.18(m,1H),2.09–2.00(m,1H),1.91(tt,J =14.2,3.1Hz,1H),1.52–1.47(m,1H),1.44(s,3H),1.32(d,J=6.8Hz,3H),1.28(s,3H). 13C NMR (126MHz, CDCl3) δ190.94,183.20,174.67,170.31,162.88,152.56,137.01,133.53,132.10(2C),129.86,128.71 ,127.34,125.48,118.61,116.24(2C),81.62,68.21,34.98,34.60,31.52,31.49,31.23,22.88,18.79.HRMS(ESI):C 26 H 25 O5 + [M+H] + m / z calculated: 417.1697, found: 417.1696.

[0202] 18-2: 1 H NMR(500MHz, CDCl3)δ9.88(s,1H),7.86–7.82(m,2H),7.79(d,J=8.2Hz,1H),7.71(d,J=8 .2Hz,1H),7.18–7.14(m,2H),6.64(t,J=3.2Hz,1H),4.90(t,J=9.5Hz,1H),4.38(dd,J=9. 4,6.0Hz,1H),3.59(dp,J=9.6,6.7Hz,1H),2.26–2.20(m,1H),2.09–2.01(m,1H),1.94(tt ,J=14.2,3.0Hz,1H),1.54–1.47(m,1H),1.45(s,3H),1.31(d,J=6.8Hz,3H),1.30(s,3H). 13 C NMR (126MHz, CDCl3) δ190.94,183.24,174.74,170.32,162.90,152.58,137.07,133.55,132.11(2C),129.89,128.67 ,127.36,125.48,118.69,116.21(2C),81.62,68.19,34.99,34.59,31.57,31.50,31.16,22.89,18.77.HRMS(ESI):C 26 H 25 O5 + [M+H] + m / z calculated: 417.1697, found: 417.1695.

[0203] Embodiment 19

[0204] The preparation method was the same as 15-1, using 4-acetylphenol (78 mg, 0.574 mmol) as the raw material, and silica gel column chromatography (PE: EtOAc = 3: 1-1: 1) to obtain orange solid compound 19-1 (38 mg, 26%) and its diastereoisomer 19-2 (40 mg, 28%).

[0205]

[0206] 19-1: 1 H NMR (500MHz, CDCl3) δ7.95–7.92(m,2H),7.77(d,J=8.3Hz,1H),7.69(d,J=8.3Hz,1H),7. 11–7.07(m,2H),6.61(t,J=3.2Hz,1H),4.88(t,J=9.5Hz,1H),4.36(dd,J=9.4,5.9Hz,1H) ,3.56(dp,J=9.5,6.6Hz,1H),2.55(s,3H),2.25–2.16(m,1H),2.09–2.01(m,1H),1.90(tt ,J=14.2,3.1Hz,1H),1.51–1.46(m,1H),1.44(s,3H),1.33(d,J=6.8Hz,3H),1.28(s,3H). 13 C NMR (126MHz, CDCl3) δ196.96,183.21,174.73,170.31,161.68,152.56,137.24,133.47,130.68(2C),130.27,128.76,12 7.32,125.39,118.58,115.71(2C),81.60,68.00,34.99,34.61,31.52,31.49,31.26,26.37,22.84,18.79.HRMS(ESI):C 27 H 27 O5 + [M+H] + m / z calculated: 431.1853, found: 431.1853.

[0207] 19-2: 1H NMR(500MHz, CDCl3)δ7.95–7.90(m,2H),7.77(d,J=8.2Hz,1H),7.69(d,J=8.2Hz,1H), 7.10–7.07(m,2H),6.61(t,J=3.1Hz,1H),4.88(t,J=9.5Hz,1H),4.36(dd,J=9.4,6.0Hz ,1H),3.62–3.52(m,1H),2.54(s,3H),2.24–2.18(m,1H),2.09–2.00(m,1H),1.91(tt,J =14.2,3.1Hz,1H),1.52–1.45(m,1H),1.43(s,3H),1.29(d,J=6.8Hz,3H),1.28(s,3H). 13 C NMR (126MHz, CDCl3) δ196.92,183.25,174.78,170.31,161.72,152.58,137.26,133.51,130.67(2C),130.25,128.70,12 7.32,125.40,118.65,115.67(2C),81.59,68.00,34.98,34.57,31.57,31.50,31.16,26.37,22.84,18.77.HRMS(ESI):C 27 H 27 O5 + [M+H] + m / z calculated: 431.1853, found: 431.1854.

[0208] Embodiment 20

[0209] The preparation method was the same as 15-1, using 3-chlorophenol (57 μl, 0.574 mmol) as raw material and silica gel column chromatography (PE: EtOAc = 3:1-1:1) to obtain orange solid compound 20-1 (37 mg, 26%) and its diastereoisomer 20-2 (37 mg, 26%).

[0210]

[0211] 20-1: 1H NMR (500MHz, CDCl3) δ7.76(d,J=8.3Hz,1H),7.68(d,J=8.2Hz,1H),7.20(t,J=8.1Hz,1H),7.08(t,J=2 .2Hz,1H),7.00(dd,J=8.3,2.4Hz,1H),6.92(dd,J=7.9,1.9Hz,1H),6.50(t,J=3.3Hz,1H),4.88(t,J=9 .5Hz,1H),4.36(dd,J=9.4,5.9Hz,1H),3.57(dp,J=9.5,6.7Hz,1H),2.23–2.17(m,1H),2.08–2.01(m, 1H),1.84(tt,J=14.3,3.1Hz,1H),1.50–1.45(m,1H),1.44(s,3H),1.33(d,J=6.8Hz,3H),1.27(s,3H). 13 C NMR (126MHz, CDCl3) δ183.18,174.78,170.47,158.11,152.64,137.57,134.76,133.46,130.27,128.72,127.25,12 5.33,121.09,118.54,116.94,114.85,81.63,68.12,35.01,34.59,31.55,31.44,31.29,22.55,18.79.HRMS(ESI):C 25 H 24 ClO4 + [M+H] + m / z calculated: 423.1358, found: 423.1359.

[0212] 20-2: 1H NMR (500MHz, CDCl3) δ7.76(d,J=8.2Hz,1H),7.68(d,J=8.2Hz,1H),7.20(t,J=8.1Hz,1H),7.08(t,J=2.2 Hz,1H),7.00(dd,J=8.2,2.2Hz,1H),6.92(dd,J=7.9,1.0Hz,1H),6.52(t,J=3.1Hz,1H),4.89(t,J=9.5Hz ,1H),4.37(dd,J=9.4,5.9Hz,1H),3.59(dp,J=9.5,6.7Hz,1H),2.23–2.17(m,1H),2.04(td,J=13.7,2.9H z,1H),1.85(tt,J=14.3,3.1Hz,1H),1.50–1.44(m,1H),1.43(s,3H),1.31(d,J=6.8Hz,3H),1.28(s,3H). 13 CNMR(126MHz, CDCl3)δ183.22,174.87,170.41,158.14,152.63,137.59,134.76,133.47,130.26,128.70,127.27,12 5.32,121.07,118.63,116.89,114.77,81.59,68.09,35.01,34.57,31.59,31.46,31.20,22.55,18.81.HRMS(ESI):C 25 H 24 ClO4 + [M+H] m / z calculated + :423.1358, measured value: 423.1360.

[0213] Embodiment 21

[0214] The preparation method was the same as 15-1, using p-chlorophenol (67 μl, 0.574 mmol) as the raw material and silica gel column chromatography (PE: EtOAc = 3:1-1:1) to obtain orange solid compound 21-1 (25 mg, 18%) and its diastereoisomer 21-2 (33 mg, 23%).

[0215]

[0216] 21-1: 1H NMR(500MHz, CDCl3)δ7.76(d,J=8.2Hz,1H),7.68(d,J=8.2Hz,1H),7.27–7.23(m,2H), 7.09–7.04(m,2H),6.49(t,J=3.1Hz,1H),4.89(t,J=9.5Hz,1H),4.37(dd,J=9.4,5.9H z,1H),3.58(dp,J=9.6,6.7Hz,1H),2.26–2.13(m,1H),2.11–2.02(m,1H),1.82(tt,J= 14.2, 3.1Hz, 1H), 1.50–1.46 (m, 1H), 1.44 (s, 3H), 1.35 (d, J = 6.8Hz, 3H), 1.27 (s, 3H). 13 C NMR (126MHz, CDCl3) δ183.30,174.90,170.39,155.92,152.60,137.74,133.41,129.36(2C),128.80,127.27,12 5.83,125.26,118.52,118.11(2C),81.59,68.36,35.03,34.62,31.54,31.40,31.33,22.53,18.80.HRMS(ESI):C 25 H 24 ClO4 + [M+H] + m / z calculated: 423.1358, found: 423.1357.

[0217] 21-2: 1 H NMR(500MHz, CDCl3)δ7.76(d,J=8.2Hz,1H),7.68(d,J=8.2Hz,1H),7.25–7.22(m,2H ),7.08–7.04(m,2H),6.50(t,J=3.1Hz,1H),4.89(t,J=9.5Hz,1H),4.38(dd,J=9.3, 5.8Hz,1H),3.64–3.54(m,1H),2.20–2.12(m,1H),2.12–2.00(m,1H),1.83(tt,J=14 .2,3.1Hz,1H),1.50–1.45(m,1H),1.44(s,3H),1.31(d,J=6.8Hz,3H),1.28(s,3H). 13C NMR (126MHz, CDCl3) δ183.34,174.92,170.39,155.97,152.61,137.77,133.45,129.35(2C),128.76,127.28,12 5.80,125.28,118.62,118.06(2C),81.59,68.36,35.02,34.58,31.59,31.43,31.24,22.54,18.83.HRMS(ESI):C 25 H 24 ClO4 + [M+H] + :423.1358m / z calculated, found:423.1357.

[0218] Embodiment 22

[0219] The preparation method was the same as 15-1, using o-chlorophenol (57 μl, 0.574 mmol) as raw material and silica gel column chromatography (PE: EtOAc = 3:1-1:1) to obtain orange solid compound 22-1 (28 mg, 20%) and its diastereoisomer 22-2 (30 mg, 21%).

[0220]

[0221] 22-1: 1 H NMR (500MHz, CDCl3) δ7.76(d,J=8.2Hz,1H),7.68(d,J=8.2Hz,1H),7.56(dd,J=8.4,1.4Hz,1H ),7.31–7.26(m,2H),6.89(td,J=7.7,1.4Hz,1H),6.67(t,J=3.2Hz,1H),4.87(t,J=9.5Hz,1H ),4.35(dd,J=9.4,5.9Hz,1H),3.61–3.53(m,1H),2.29–2.20(m,1H),2.15–2.06(m,1H),1.82 (tt,J=14.4,3.1Hz,1H),1.45(s,3H),1.48–1.43(m,1H),1.34(d,J=6.8Hz,3H),1.27(s,3H). 13C NMR (126MHz, CDCl3) δ183.45,174.91,170.44,152.96,152.82,137.55,133.44,130.14,128.86,127.93,127.16,12 5.28,123.86,121.57,118.46,116.49,81.56,69.09,35.06,34.60,31.72,31.54,31.38,22.94,18.78.HRMS(ESI):C 25 H 24 ClO4 + [M+H] + m / z calculated: 423.1358, found: 423.1355.

[0222] 22-2: 1 H NMR (500MHz, CDCl3) δ7.76(d,J=8.2Hz,1H),7.68(d,J=8.2Hz,1H),7.58(dd,J=8.5,1.4Hz,1H ),7.31–7.25(m,2H),6.88(td,J=7.7,1.4Hz,1H),6.68(t,J=3.1Hz,1H),4.88(t,J=9.5Hz,1H ),4.37(dd,J=9.4,5.8Hz,1H),3.63–3.55(m,1H),2.29–2.19(m,1H),2.18–2.06(m,1H),1.82 (tt,J=14.4,3.1Hz,1H),1.48–1.43(m,1H),1.45(s,3H),1.31(d,J=6.8Hz,3H),1.28(s,3H). 13 C NMR (126MHz, CDCl3) δ183.44,174.89,170.44,152.95,152.87,137.59,133.47,130.12,128.82,127.94,127.19,12 5.29,123.86,121.58,118.57,116.50,81.56,69.07,35.07,34.57,31.78,31.53,31.29,22.90,18.84.HRMS(ESI):C 25 H 24 ClO4 + [M+H] + m / z calculated: 423.1358, found: 423.1355.

[0223] Embodiment 23

[0224] The preparation method was the same as 15-1, using m-fluorophenol (52 μl, 0.574 mmol) as the raw material and silica gel column chromatography (PE: EtOAc = 3:1-1:1) to obtain orange solid compound 23-1 (30 mg, 22%) and its diastereoisomer 23-2 (36 mg, 26%).

[0225]

[0226] 23-1: 1 H NMR (500MHz, CDCl3) δ7.76(d,J=8.3Hz,1H),7.68(d,J=8.2Hz,1H),7.22(td,J=8.3,6.9Hz,1H),6.88(dd,J=8.2 ,2.4Hz,1H),6.84(dt,J=11.0,2.4Hz,1H),6.65(td,J=8.3,2.4Hz,1H),6.52–6.50(m,1H),4.89(t,J=9.5Hz,1H ),4.37(dd,J=9.3,5.9Hz,1H),3.58(dp,J=9.6,6.6Hz,1H),2.22(ddt,J=14.6,4.3,2.9Hz,1H),2.06(td,J=13. 7,2.9Hz,1H),1.84(tt,J=14.3,3.1Hz,1H),1.50–1.45(m,1H),1.44(s,3H),1.34(d,J=6.8Hz,3H),1.28(s,3H). 13 C NMR (126MHz, CDCl3) δ183.21, 174.84, 170.35, 163.73 (d, J = 244.3Hz), 158.72 ( d,J=11.3Hz),152.61,137.59,133.41,130.14(d,J=9.7Hz),128.78,127.27,12 5.28,118.54,112.29(d,J=2.8Hz),107.73(d,J=21.1Hz),104.15(d,J=24.1Hz ),81.58,68.16,35.01,34.62,31.54,31.46,31.31,22.58,18.81.HRMS(ESI):C 25 H 24 FO4 + [M+H] + m / z calculated: 407.1653, found: 407.1654.

[0227] 23-2: 1H NMR (500MHz, CDCl3) δ7.76(d,J=8.2Hz,1H),7.68(d,J=8.2Hz,1H),7.22(td,J=8.3,6.9Hz,1H),6.88(dd,J =8.3,2.4Hz,1H),6.83(dt,J=11.0,2.4Hz,1H),6.67–6.62(m,1H),6.53–6.50(m,1H),4.89(t,J=9.5Hz,1H ),4.37(dd,J=9.4,5.9Hz,1H),3.63–3.55(m,1H),2.21(ddt,J=14.6,4.3,3.0Hz,1H),2.06(td,J=13.7,2. 9Hz,1H),1.86(tt,J=14.3,3.1Hz,1H),1.50–1.45(m,1H),1.44(s,3H),1.31(d,J=6.8Hz,3H),1.28(s,3H). 13 CNMR(126MHz, CDCl3)δ183.24,174.87,170.35,163.72(d,J=245.0Hz),158.76( d,J=11.0Hz),152.62,137.62,133.44,130.13(d,J=10.3Hz),128.73,127.28,1 25.29,118.63,112.21(d,J=2.9Hz),107.69(d,J=21.1Hz),104.09(d,J=24.7Hz ),81.57,68.14,35.01,34.58,31.58,31.48,31.21,22.58,18.82.HRMS(ESI):C 25 H 24 FO4 + [M+H] + m / z calculated: 407.1653, found: 407.1654.

[0228] Embodiment 24

[0229] The preparation method was the same as 15-1, using 4-fluorophenol (76 mg, 0.674 mmol) as raw material, and silica gel column chromatography (PE: EtOAc = 3: 1-1: 1) to obtain orange solid compound 24-1 (31 mg, 23%) and its diastereoisomer 24-2 (28 mg, 20%).

[0230]

[0231] 24-1: 1H NMR(500MHz, CDCl3)δ7.76(d,J=8.2Hz,1H),7.68(d,J=8.2Hz,1H),7.14–7.09(m, 2H),7.01–6.95(m,2H),6.46(t,J=3.1Hz,1H),4.89(t,J=9.5Hz,1H),4.37(dd,J= 9.4,6.0Hz,1H),3.58(dp,J=9.6,6.6Hz,1H),2.18–2.03(m,2H),1.79(tt,J=13.8 ,3.0Hz,1H),1.49–1.45(m,1H),1.45(s,3H),1.35(d,J=6.8Hz,3H),1.27(s,3H). 13 CNMR(126MHz, CDCl3)δ183.40,174.99,170.40,157.56(d,J=238.5Hz),153.22,152.61,137.99,133.38,128.87,127.24,12 5.20,118.47,118.30,118.24,115.89,115.71,81.56,68.84,35.05,34.61,31.54,31.39,31.36,22.47,18.76.HRMS(ESI):C 25 H 24 FO4 + [M+H] + m / z calculated: 407.1653, found: 407.1653.

[0232] 24-2: 1 H NMR(500MHz, CDCl3)δ7.76(d,J=8.3Hz,1H),7.68(d,J=8.2Hz,1H),7.14–7.08(m, 2H),7.01–6.94(m,2H),6.47(t,J=3.3Hz,1H),4.89(t,J=9.5Hz,1H),4.38(dd,J= 9.4,5.8Hz,1H),3.60(dp,J=9.3,6.7Hz,1H),2.19–2.04(m,2H),1.81(tt,J=14.0 ,3.1Hz,1H),1.50–1.46(m,1H),1.44(s,3H),1.32(d,J=6.8Hz,3H),1.28(s,3H). 13CNMR(126MHz, CDCl3)δ183.43,175.01,170.40,157.56(d,J=238.5Hz),153.22,152.62,138.04,133.39,128.85,127.25,12 5.19,118.59,118.25,118.18,115.88,115.70,81.56,68.82,35.05,34.58,31.58,31.40,31.27,22.46,18.83.HRMS(ESI):C 25 H 24 FO4 + [M+H] + m / z calculated: 407.1653, found: 407.1654.

[0233] Embodiment 25

[0234] The preparation method was the same as 15-1, using trifluoromethylphenol (70 μl, 0.574 mmol) as the raw material and silica gel column chromatography (PE: EtOAc = 3:1-1:1) to obtain orange solid compound 25-1 (47 mg, 31%) and its diastereoisomer 25-2 (42 mg, 27%).

[0235]

[0236] 25-1: 1 H NMR (500MHz, CDCl3) δ7.78(d,J=8.3Hz,1H),7.70(d,J=8.2Hz,1H),7.54(d,J=8.5Hz,2H), 7.15(d,J=8.5Hz,2H),6.58(t,J=3.1Hz,1H),4.89(t,J=9.5Hz,1H),4.37(dd,J=9.4,5.9Hz ,1H),3.57(dp,J=9.5,6.7Hz,1H),2.24–2.17(m,1H),2.10–2.02(m,1H),1.89(tt,J=14.3, 3.1Hz,1H),1.49(dt,J=13.6,3.6Hz,1H),1.45(s,3H),1.34(d,J=6.8Hz,3H),1.28(s,3H). 13C NMR(126MHz, CDCl3)δ183.22,174.69,170.55,160.00,152.66,137.37,133.55,128.70,127.31,126.92(q,J=3.8Hz)(2C),125.44,124.56 (q,J=271.1Hz),122.74(q,J=32.3Hz),118.58,116.14(2C),81.68,68.01,35.01,34.59,31.51,31.45,31.24,22.64,18.77.HRMS(ESI):C 26 H 24 F3O4 + [M+H] + m / z calculated: 457.1621, found: 457.1623.

[0237] 25-2: 1 H NMR (500MHz, CDCl3) δ7.78(d,J=8.3Hz,1H),7.70(d,J=8.2Hz,1H),7.55(d,J=8.5Hz,2H), 7.14(d,J=8.6Hz,2H),6.60(t,J=3.3Hz,1H),4.89(t,J=9.5Hz,1H),4.38(dd,J=9.4,5.9Hz ,1H),3.59(dp,J=9.6,6.6Hz,1H),2.24–2.18(m,1H),2.10–2.02(m,1H),1.91(tt,J=14.3, 3.1Hz,1H),1.49(dt,J=13.4,3.6Hz,1H),1.45(s,3H),1.31(d,J=6.8Hz,3H),1.29(s,3H). 13 C NMR (126MHz, CDCl3) δ183.27,174.79,170.33,160.07,152.59,137.35,133.51,128.70,127.35,126.92(q,J=3.8Hz)(2C),125.63(q,J=27 1.0Hz),125.39,122.73(q,J=31.8Hz),118.66,116.05(2C),81.59,67.97,34.99,34.58,31.56,31.48,31.15,22.67,18.77.HRMS(ESI):C 26 H 24 F3O4 + [M+H] +m / z calculated: 457.1621, found: 457.1619.

[0238] Embodiment 26

[0239] The preparation method was the same as 15-1, using p-bromophenol (99 mg, 0.574 mmol) as the raw material, and silica gel column chromatography (PE: EtOAc = 3:1-1:1) to obtain orange solid compound 26-1 (36 mg, 23%) and its diastereoisomer 26-2 (39 mg, 25%).

[0240]

[0241] 26-1: 1 H NMR(500MHz, CDCl3)δ7.75(d,J=8.2Hz,1H),7.67(d,J=8.2Hz,1H),7.38–7.34(m,2H),7.02– 6.98(m,2H),6.47(t,J=3.2Hz,1H),4.88(t,J=9.5Hz,1H),4.36(dd,J=9.4,5.9Hz,1H),3.57( dp,J=9.5,6.7Hz,1H),2.15(ddt,J=14.4,4.2,3.0Hz,1H),2.04(td,J=13.7,2.9Hz,1H),1.81 (tt,J=14.2,3.1Hz,1H),1.48–1.44(m,1H),1.43(s,3H),1.33(d,J=6.8Hz,3H),1.26(s,3H). 13 C NMR (126MHz, CDCl3) δ183.27,174.81,170.50,156.45,152.64,137.74,133.46,132.30(2C),128.76,127.26,12 5.31,118.58(2C),118.53,113.16,81.64,68.26,35.03,34.61,31.55,31.40,31.32,22.52,18.79.HRMS(ESI):C 25 H 24 BrO4 + [M+H] + m / z calculated: 467.0852, found: 467.0850.

[0242] 26-2: 1H NMR(500MHz, CDCl3)δ7.76(d,J=8.2Hz,1H),7.68(d,J=8.2Hz,1H),7.40–7.36(m,2H),7. 04–6.99(m,2H),6.50(t,J=3.1Hz,1H),4.89(t,J=9.5Hz,1H),4.38(dd,J=9.4,5.9Hz,1H ),3.60(dp,J=9.5,6.7Hz,1H),2.20–2.14(m,1H),2.05(td,J=13.7,2.9Hz,1H),1.84(tt ,J=14.2,3.1Hz,1H),1.50–1.45(m,1H),1.44(s,3H),1.32(d,J=6.8Hz,3H),1.28(s,3H). 13 C NMR (126MHz, CDCl3) δ183.31,174.87,170.41,156.51,152.62,137.75,133.46,132.30(2C),128.74,127.29,12 5.29,118.62,118.53(2C),113.15,81.60,68.25,35.02,34.58,31.59,31.42,31.24,22.54,18.82.HRMS(ESI):C 25 H 24 BrO4 + [M+H] + m / z calculated: 467.0852, found: 467.0852.

[0243] Embodiment 27

[0244] The preparation method was the same as 15-1, using m-methoxyphenol (72 μl, 0.674 mmol) as raw material and silica gel column chromatography (PE: EtOAc = 3:1-1:1) to obtain orange solid compound 27-1 (35 mg, 25%) and its diastereoisomer 27-2 (34 mg, 24%).

[0245]

[0246] 27-1: 11H NMR (500 MHz, CDCl3) δ 7.75 (d, J = 8.2 Hz, 1H), 7.67 (d, J = 8.1 Hz, 1H), 7.20 (t, J = 8.1 Hz, 1H), 6.76 (dd, J = 8.0, 2.1 Hz, 1H), 6.65 (t, J = 2.2 Hz, 1H), 6.58–6.49 (m, 2H), 4.88 (t, J = 9.4 Hz, 1H), 4.36 (dd, J = 9.3, 5.7 Hz, 1H), 3.78 (s, 3H), 3.62–3.54 (m, 1H), 2.29–2.20 (m, 1H), 2.13–2.02 (m, 1H), 1.82 (t, J = 14.1 Hz, 1H), 1.48–1.45 (m, 1H), 1.44 (s, 3H), 1.34 (d, J = 7.0 Hz, 3H), 1.27 (s, 3H). 13 13C NMR (126 MHz, CDCl3) δ 183.25, 175.03, 170.43, 160.82, 158.49, 152.68, 138.07, 133.31, 129.86, 128.92, 127.20, 125.14, 118.48, 108.94, 106.65, 103.07, 81.58, 67.85, 55.29, 35.03, 34.62, 31.90, 31.55, 31.38, 22.62, 18.81. HRMS (ESI): C 26 H 27 O5 + [M + H] + Calculated m / z: 419.1853, found: 419.1849.

[0247] 27 - 2: 1 1H NMR (500 MHz, CDCl3) δ 7.75 (d, J = 8.2 Hz, 1H), 7.67 (d, J = 8.2 Hz, 1H), 7.19 (t, J = 8.2 Hz, 1H), 6.76 (dd, J = 8.1, 2.3 Hz, 1H), 6.64 (t, J = 2.3 Hz, 1H), 6.57–6.49 (m, 2H), 4.88 (t, J = 9.4 Hz, 1H), 4.37 (dd, J = 9.4, 5.6 Hz, 1H), 3.78 (s, 3H), 3.63–3.56 (m, 1H), 2.29–2.21 (m, 1H), 2.12–2.03 (m, 1H), 1.84 (tt, J = 14.2, 2.9 Hz, 1H), 1.49–1.45 (m, 1H), 1.44 (s, 3H), 1.31 (d, J = 6.7 Hz, 3H), 1.28 (s, 3H). 13C NMR (126MHz, CDCl3) δ183.25,175.03,170.38,160.82,158.52,152.68,138.11,133.32,129.86,128.88,127.21,125.1 3,118.58,108.84,106.59,103.04,81.56,67.79,55.19,35.03,34.58,31.59,31.57,31.27,22.59,18.84.HRMS(ESI):C 26 H 27 O5 + [M+H] + m / z calculated: 419.1853, found: 419.1855.

[0248] Embodiment 28

[0249] The preparation method was the same as 15-1, using p-methoxyphenol (71 mg, 0.574 mmol) as the raw material and silica gel column chromatography (PE: EtOAc = 3: 1-1: 1) to obtain an orange solid compound 28-1 (29 mg, 21%) and its diastereoisomer 28-2 (35 mg, 25%).

[0250]

[0251] 28-1: 1 H NMR(500MHz, CDCl3) δ7.75(d,J=8.0Hz,1H),7.67(d,J=8.2Hz,1H),7.14–7. 10(m,2H),6.87–6.80(m,2H),6.43(t,J=3.5Hz,1H),4.90(t,J=9.4Hz,1H),4 .37(dd,J=8.9,6.3Hz,1H),3.77(s,3H),3.63–3.54(m,1H),2.18–2.07(m,2H ),1.80–1.72(m,1H),1.49–1.40(m,4H),1.34(d,J=6.7Hz,3H),1.26(s,3H). 13C NMR (126MHz, CDCl3) δ183.38,174.87,171.08,154.21,152.87,151.02,138.61,133.48,128.81,127.12,125.21,11 8.48(2C),118.40,114.64(2C),81.76,68.85,55.71,35.11,34.55,31.57,31.42,31.36,22.42,18.72.HRMS(ESI):C 26 H 27 O5 + [M+H] + m / z calculated: 419.1853, found: 419.1853.

[0252] 28-2: 1 H NMR(500MHz, CDCl3)δ7.74(d,J=8.2Hz,1H),7.66(d,J=8.2Hz,1H),7.15–7.10 (m,2H),6.86–6.80(m,2H),6.47–6.43(m,1H),4.87(t,J=9.5Hz,1H),4.36(dd, J=8.6,6.0Hz,1H),3.77(s,3H),3.63–3.54(m,1H),2.18–2.07(m,2H),1.82–1. 73(m,1H),1.48–1.44(m,1H),1.44(s,3H),1.31(d,J=6.7Hz,3H),1.26(s,3H). 13 C NMR (126MHz, CDCl3) δ183.48,175.09,170.43,154.26,152.67,151.08,138.44,133.32,128.96,127.17,125.07,11 8.53,118.49(2C),114.64(2C),81.54,68.88,55.71,35.08,34.56,31.61,31.41,31.34,22.46,18.88.HRMS(ESI):C 26 H 27 O5 + [M+H] + m / z calculated: 419.1853, found: 419.1855.

[0253] Embodiment 29

[0254] The preparation method was the same as that of compound 15-1, with 2-methoxyphenol (74 μl, 0.674 mmol) as the raw material, and silica gel column chromatography (PE: EtOAc = 3:1-1:1) was performed to obtain an orange solid compound 29-1 (58 mg, 41%).

[0255]

[0256] 29-1: 1 H NMR (500MHz, CDCl3) δ7.71 (dd, J=8.2, 3.8Hz, 1H), 7.62 (dd, J=8.2, 1.9Hz, 1H), 7.44 (td, J=7. 4,2.1Hz,1H),6.97–6.89(m,2H),6.86–6.80(m,1H),6.54(t,J=3.5Hz,1H),4.86(q,J=9.5Hz,1 H),4.34(td,J=9.2,5.9Hz,1H),3.73(d,J=1.7Hz,3H),3.61–3.51(m,1H),2.31–2.09(m,3H), 1.92–1.78(m,1H),1.43(d,J=3.5Hz,3H),1.31(dd,J=13.5,6.7Hz,3H),1.26(d,J=3.5Hz,3H). 13 C NMR (126MHz, CDCl3) δ183.76,175.29,170.48,152.84,150.47,146.86,138.40,133.00,129.63,126.95,124.92,121.6 4,121.08,118.23,116.99,112.05,81.49,69.59,55.79,35.06,34.53,31.76,31.44,31.40,23.15,18.81.HRMS(ESI):C 26 H 27 O5 + [M+H] + m / z calculated: 419.1853, found: 419.1852.

[0257] Embodiment 30

[0258] The preparation method was the same as 15-1, using trifluoromethoxyphenol (74 μl, 0.574 mmol) as the raw material, and silica gel column chromatography (PE: EtOAc = 3:1-1:1) to obtain orange solid compound 30-1 (38 mg, 24%) and its diastereoisomer 30-2 (36 mg, 23%).

[0259]

[0260] 30-1: 1 H NMR(500MHz, CDCl3)δ7.76(d,J=8.2Hz,1H),7.69(d,J=8.2Hz,1H),7.17–7.13(m,2H), 7.13–7.09(m,2H),6.51(t,J=3.1Hz,1H),4.88(t,J=9.5Hz,1H),4.36(dd,J=9.4,5.9H z,1H),3.58(dp,J=9.6,6.7Hz,1H),2.21–2.15(m,1H),2.10–2.03(m,1H),1.83(tt,J= 14.3, 3.1Hz, 1H), 1.50–1.46 (m, 1H), 1.44 (s, 3H), 1.34 (d, J = 6.8Hz, 3H), 1.27 (s, 3H). 13 C NMR (126MHz, CDCl3) δ183.30,174.84,170.40,155.79,152.61,142.85,137.65,133.45,128.77,127.29,125.30,122.40 (2C ),120.59(q,J=255.8Hz),118.53,117.42(2C),81.59,68.35,35.02,34.60,31.52,31.42,31.29,22.50,18.79.HRMS(ESI):C 26 H 24 F3O5 + [M+H] + m / z calculated: 473.1570, found: 473.1569.

[0261] 30-2: 1 H NMR (500MHz, CDCl3) δ7.77(d,J=8.2Hz,1H),7.69(d,J=8.2Hz,1H),7.16–7.12(m,2H),7. 12–7.09(m,2H),6.52(t,J=3.3Hz,1H),4.89(t,J=9.5Hz,1H),4.38(dd,J=9.4,5.9Hz,1H ),3.59(dp,J=9.7,6.7Hz,1H),2.21–2.16(m,1H),2.10–2.02(m,1H),1.85(tt,J=14.3,3 .2Hz,1H),1.48(dt,J=13.8,3.8Hz,1H),1.44(s,3H),1.31(d,J=6.8Hz,3H),1.28(s,3H). 13C NMR (126MHz, CDCl3) δ183.32,174.87,170.44,155.83,152.63,142.82,137.71,133.48,128.73,127.30,125.31,122.40 (2C ),120.59(q,J=255.7Hz),118.63,117.31(2C),81.60,68.29,35.02,34.57,31.56,31.44,31.19,22.50,18.79.HRMS(ESI):C 26 H 24 F3O5 + [M+H] + m / z calculated: 473.1570, found: 473.1569.

[0262] Embodiment 31

[0263] The preparation method was the same as 15-1, using p-methylphenol (60 μl, 0.574 mmol) as the raw material and silica gel column chromatography (PE: EtOAc = 3:1-1:1) to obtain orange solid compound 31-1 (33 mg, 24%) and its diastereoisomer 31-2 (29 mg, 21%).

[0264]

[0265] 31-1: 1 H NMR(500MHz, CDCl3)δ7.75(d,J=8.2Hz,1H),7.66(d,J=8.2Hz,1H),7.12–7.08(m,2H),7. 08–7.04(m,2H),6.52(t,J=3.2Hz,1H),4.88(t,J=9.5Hz,1H),4.36(dd,J=9.4,5.9Hz,1H) ,3.58(dp,J=9.7,6.7Hz,1H),2.30(s,3H),2.23–2.17(m,1H),2.15–2.06(m,1H),1.79(tt ,J=14.1,3.1Hz,1H),1.44(s,3H),1.44–1.41(m,1H),1.34(d,J=6.8Hz,3H),1.27(s,3H). 13C NMR (126MHz, CDCl3) δ183.32,175.08,170.41,155.00,152.68,138.37,133.29,130.36,129.93(2C),128.94,127.1 9,125.07,118.42,116.91(2C),81.53,68.00,35.06,34.61,31.58,31.44,31.42,22.51,20.56,18.80.HRMS(ESI):C 26 H 27 O4 + [M+H] + m / z calculated: 403.1904, found: 403.1901.

[0266] 31-2: 1 H NMR(500MHz, CDCl3)δ7.75(d,J=8.2Hz,1H),7.66(d,J=8.2Hz,1H),7.12–7.07(m,2H),7. 07–7.03(m,2H),6.53(t,J=3.2Hz,1H),4.88(t,J=9.5Hz,1H),4.37(dd,J=9.4,5.8Hz,1H) ,3.59(dp,J=9.5,6.6Hz,1H),2.29(s,3H),2.22–2.16(m,1H),2.14–2.03(m,1H),1.81(tt ,J=14.2,3.1Hz,1H),1.47–1.45(m,1H),1.44(s,3H),1.31(d,J=6.8Hz,3H),1.28(s,3H). 13 C NMR (126MHz, CDCl3) δ183.36,175.08,170.39,155.03,152.68,138.40,133.30,130.36,129.92(2C),128.93,127.1 8,125.06,118.55,116.88(2C),81.52,68.00,35.06,34.57,31.62,31.46,31.33,22.52,20.56,18.88.HRMS(ESI):C 26 H 27 O4 + [M+H] + m / z calculated: 403.1904, found: 403.1905.

[0267] Embodiment 32

[0268] The preparation method was the same as 15-1, using p-ethylphenol (70 mg, 0.574 mmol) as the raw material, and silica gel column chromatography (PE: EtOAc = 3: 1-1: 1) to obtain orange solid compound 32-1 (32 mg, 23%) and its diastereoisomer 32-2 (27 mg, 19%).

[0269]

[0270] 32-1: 1 H NMR(500MHz, CDCl3)δ7.75(d,J=8.2Hz,1H),7.66(d,J=8.2Hz,1H),7.15–7.10(m,2H),7.09–7.05 (m,2H),6.53(t,J=3.2Hz,1H),4.88(t,J=9.5Hz,1H),4.36(dd,J=9.4,5.9Hz,1H),3.58(dp,J=9.6 ,6.7Hz,1H),2.60(q,J=7.6Hz,2H),2.25–2.18(m,1H),2.15–2.06(m,1H),1.80(tt,J=14.2,3.1H z,1H),1.44(s,3H),1.48–1.41(m,1H),1.34(d,J=6.7Hz,3H),1.27(s,3H),1.22(t,J=7.6Hz,3H). 13 C NMR (126MHz, CDCl3) δ183.30,175.04,170.45,155.16,152.70,138.39,136.77,133.30,128.93,128.73(2C),127.18,1 25.07,118.42,116.77(2C),81.54,67.85,35.06,34.60,31.57,31.47,31.41,28.04,22.52,18.79,15.82.HRMS(ESI):C 27 H 29 O4 + [M+H] + m / z calculated: 417.2060, found: 417.2065.

[0271] 32-2: 1H NMR (500MHz, CDCl3) δ7.75(d,J=8.2Hz,1H),7.66(d,J=8.2Hz,1H),7.14–7.10(m,2H),7.08–7. 04(m,2H),6.54(t,J=3.1Hz,1H),4.88(t,J=9.5Hz,1H),4.37(dd,J=9.3,5.8Hz,1H),3.63–3.55 (m,1H),2.59(q,J=7.6Hz,2H),2.25–2.19(m,1H),2.14–2.05(m,1H),1.82(tt,J=14.2,3.1Hz, 1H),1.48–1.44(m,1H),1.44(s,3H),1.31(d,J=6.8Hz,3H),1.28(s,3H),1.22(t,J=7.6Hz,3H). 13 C NMR (126MHz, CDCl3) δ183.33,175.07,170.38,155.21,152.68,138.43,136.77,133.29,128.93,128.72(2C),127.19,1 25.05,118.55,116.67(2C),81.52,67.81,35.05,34.57,31.61,31.50,31.31,28.04,22.53,18.87,15.84.HRMS(ESI):C 27 H 29 O4 + [M+H] + :417.2060, measured value: 417.2062.

[0272] Embodiment 33

[0273] The preparation method was the same as 15-1, using p-tert-butylphenol (86 mg, 0.574 mmol) as raw material, and silica gel column chromatography (PE: EtOAc = 3:1-1:1) to obtain orange solid compound 33-1 (31 mg, 21%) and its diastereoisomer 33-2 (30 mg, 20%).

[0274]

[0275] 33-1: 1H NMR(500MHz, CDCl3)δ7.75(d,J=8.2Hz,1H),7.67(d,J=8.2Hz,1H),7.32–7.29(m,2H), 7.07–7.03(m,2H),6.53(t,J=3.3Hz,1H),4.89(t,J=9.5Hz,1H),4.37(dd,J=9.4,5.9Hz ,1H),3.62–3.54(m,1H),2.30–2.21(m,1H),2.14–2.04(m,1H),1.81(tt,J=14.3,3.1Hz ,1H),1.48–1.43(m,1H),1.44(s,3H),1.34(d,J=6.8Hz,3H),1.31(s,9H),1.27(s,3H). 13 C NMR (126MHz, CDCl3) δ183.27,174.90,170.75,154.88,152.84,143.47,138.55,133.40,128.88,127.16,126.25(2C),125 .13,118.41,116.01(2C),81.65,67.53,35.07,34.58,34.07,31.58(3C),31.55,31.53,31.39,22.55,18.78.HRMS(ESI):C 29 H 33 O4 + [M+H] + m / z calculated: 445.2373, found: 445.2376.

[0276] 33-2: 1 H NMR(500MHz, CDCl3)δ7.76(d,J=8.2Hz,1H),7.67(d,J=8.2Hz,1H),7.32–7.28(m,2H ),7.06–7.02(m,2H),6.55(t,J=2.8Hz,1H),4.89(t,J=9.5Hz,1H),4.38(dd,J=9.4, 5.8Hz,1H),3.59(dp,J=9.5,6.6Hz,1H),2.30–2.22(m,1H),2.13–2.03(m,1H),1.84 (tt,J=14.2,3.1Hz,1H),1.48–1.45(m,1H),1.44(s,3H),1.31(s,12H),1.28(s,3H). 13C NMR (126MHz, CDCl3) δ183.28,174.93,170.70,154.95,152.81,143.42,138.58,133.38,128.86,127.18,126.23(2C),125 .12,118.54,115.82(2C),81.63,67.43,35.06,34.54,34.06,31.59,31.57(3C),31.56,31.28,22.55,18.84.HRMS(ESI):C 29 H 33 O4 + [M+H] + m / z calculated: 445.2373, found: 445.2373.

[0277] Embodiment 34

[0278] The preparation method was the same as 15-1, using 3-fluoro-4-nitrophenol (106 mg, 0.674 mmol) as raw material and silica gel column chromatography (PE: EtOAc = 3:1-1:1) to obtain orange solid compound 35-1 (40 mg, 26%) and its diastereoisomer 35-2 (43 mg, 28%).

[0279]

[0280] 35-1: 1 H NMR (500MHz, CDCl3) δ8.08(t,J=8.9Hz,1H),7.81(d,J=8.3Hz,1H),7.73(d,J=8 .3Hz,1H),6.92–6.83(m,2H),6.53(t,J=3.3Hz,1H),4.91(t,J=9.5Hz,1H),4.39 (dd,J=9.4,5.9Hz,1H),3.59(dq,J=9.6,6.7Hz,1H),2.23–2.16(m,1H),2.06–1 .92(m,2H),1.59–1.52(m,1H),1.45(s,3H),1.34(d,J=6.8Hz,3H),1.30(s,3H). 13C NMR (126MHz, CDCl3) δ183.24, 174.47, 170.32, 163.74 (d, J = 11.3Hz), 157.7 1(d,J=264.4Hz),152.50,136.00,133.69,130.55(d,J=6.2Hz),128.58,12 7.93,127.47,125.79,118.76,111.85(d,J=3.0Hz),104.82(d,J=24.0Hz), 81.72,69.51,34.94,34.61,31.44(2C),31.09,22.98,18.77.HRMS(ESI):C 25 H 23 FNO6 + [M+H] + m / z calculated: 452.1504, found: 452.1509.

[0281] 35-2: 1 H NMR (500MHz, CDCl3) δ8.08(t,J=8.8Hz,1H),7.81(d,J=8.3Hz,1H),7.73(d,J=8 .3Hz,1H),6.92–6.83(m,2H),6.53(t,J=2.5Hz,1H),4.91(t,J=9.5Hz,1H),4.39 (dd,J=9.4,6.0Hz,1H),3.59(dp,J=9.3,6.7Hz,1H),2.22–2.16(m,1H),2.06–1 .93(m,2H),1.58–1.53(m,1H),1.45(s,3H),1.32(d,J=6.9Hz,3H),1.30(s,3H). 13 C NMR (126MHz, CDCl3) δ183.29, 174.54, 170.37, 163.80 (d, J = 11.2Hz), 157.6 8(d,J=264.5Hz),152.52,136.02,133.75,130.45(d,J=6.4Hz),128.52,127 .92,127.47,125.81,118.78,111.83(d,J=2.8Hz),104.81(d,J=23.9Hz),8 1.72,69.54,34.94,34.58,31.49,31.44,31.00,22.99,18.69.HRMS(ESI):C 25 H 23 FNO6 + [M+H] +m / z calculated: 452.1504, found: 452.1502.

[0282] Embodiment 35

[0283] Take 4-(1-piperazinyl)phenol (500 mg, 2.809 mmol) and dissolve it in 30 ml of tetrahydrofuran. Add di-tert-butyl dicarbonate (773 μl, 3.370 mmol) and triethylamine (584 μl, 4.214 mmol) in sequence. Stir the reaction at room temperature. After TLC confirms the completion of the reaction, concentrate under reduced pressure and perform silica gel column chromatography (DCM: MeOH = 100: 1-20: 1) to obtain a crude product a (203 mg, 26%). The crude product a (203 mg, 0.730 mmol) was dissolved in 5 ml of chlorobenzene, and cryptotanshinone (127 mg, 0.430 mmol) and TEMPO (134 mg, 0.860 mmol) were added in sequence. The mixture was refluxed at 120° C. for 24 h. After TLC confirmed that the reaction was complete, the mixture was concentrated under reduced pressure and separated and purified by silica gel column chromatography (PE: EtOAc = 3: 1-1: 1) to obtain a dark brown solid compound 36-1 (42 mg, 17%).

[0284]

[0285] 36-1: 1 H NMR (500MHz, CDCl3) δ7.74(d,J=8.2Hz,1H),7.66(d,J=8.2Hz,1H),7.13–7.06(m,2H),6.94–6.88(m ,2H),6.46(dt,J=6.2,3.2Hz,1H),4.88(td,J=9.5,2.8Hz,1H),4.36(ddd,J=9.3,5.9,4.3Hz,1H),3. 62–3.53(m,5H),3.07–2.98(m,4H),2.20–2.03(m,2H),1.78(tdt,J=13.4,10.1,3.0Hz,1H),1.48(s ,9H),1.47–1.39(m,1H),1.43(d,J=1.9Hz,3H),1.32(dd,J=16.1,6.8Hz,3H),1.26(d,J=3.3Hz,3H). 13C NMR (126MHz, CDCl3) δ183.43,175.10,170.38,154.77,152.65,138.38,138.35,133.27,128.97,127.17,125.04,118.81(2C),118.52,118 .40,117.95(2C),81.51,79.78,68.42,50.89(2C),35.05(2C),34.61,34.56,31.57,31.45,31.36,28.42(3C),22.53,18.81.HRMS(ESI):C 34 H 41 N2O6 + [M+H] + m / z calculated: 573.2959, found: 573.2960.

[0286] Embodiment 36

[0287] The preparation method is the same as 1-1, using Boc-glycine (118 mg, 0.675 mmol) as raw material, silica gel column chromatography (PE: EtOAc = 3: 1-1: 1) to obtain orange solid compound 37-1 (71 mg, 45%) and its diastereomer 37-2 (78 mg, 49%).

[0288]

[0289] 37-1: 1 H NMR (500MHz, CDCl3) δ7.73(d,J=8.3Hz,1H),7.67(d,J=8.2Hz,1H),6.48(t,J=3.6Hz,1H ),5.14(s,1H),4.89(t,J=9.5Hz,1H),4.37(dd,J=9.9,5.5Hz,1H),3.97(dd,J=18.2,7.1 Hz,1H),3.68(dd,J=18.2,3.9Hz,1H),3.62–3.56(m,1H),2.25–2.19(m,1H),2.01–1.85( m,2H),1.57–1.51(m,1H),1.42(s,9H),1.39(s,3H),1.34(d,J=7.1Hz,3H),1.26(s,3H). 13C NMR (126MHz, CDCl3) δ183.43,174.82,170.28,169.36,155.75,152.88,136.56,133.43,129.03,127.21,125.38 ,118.68,81.64,79.66,68.23,42.24,34.90,34.61,32.00,31.48,31.11,28.30(3C),24.60,18.82.HRMS(ESI):C 26 H 31 NO7Na + [M+Na] + m / z calculated: 492.1993, found: 492.1993.

[0290] 37-2: 1 H NMR (500MHz, CDCl3) δ7.73(d,J=8.2Hz,1H),7.66(d,J=8.2Hz,1H),6.47(t,J=3.5Hz,1H), 5.14(s,1H),4.90(t,J=9.5Hz,1H),4.37(dd,J=9.4,6.1Hz,1H),3.97(dd,J=18.2,7.1Hz,1 H),3.69(dd,J=18.2,3.9Hz,1H),3.59(dp,J=9.6,6.6Hz,1H),2.25–2.19(m,1H),2.04–1.8 4(m,2H),1.58–1.51(m,1H),1.42(s,9H),1.38(s,3H),1.34(d,J=6.8Hz,3H),1.26(s,3H). 13 C NMR (126MHz, CDCl3) δ183.44,174.88,170.33,169.37,155.74,152.89,136.56,133.47,128.94,127.22,125.40 ,118.68,81.65,79.67,68.20,42.23,34.90,34.61,31.99,31.55,31.03,28.30(3C),24.61,18.67.HRMS(ESI):C 26 H 31 NO7Na + [M+Na] + m / z calculated: 492.1993, found: 492.1995.

[0291] Embodiment 37

[0292] The preparation method is the same as 1-1, using Boc-β-alanine (128 mg, 0.675 mmol) as raw material, silica gel column chromatography (PE: EtOAc = 3: 1-1: 1) to obtain orange solid compound 38-1 (65 mg, 40%) and its diastereoisomer 38-2 (68 mg, 42%).

[0293]

[0294] 38-1: 1 H NMR (500MHz, CDCl3) δ7.72(d,J=8.1Hz,1H),7.66(d,J=8.2Hz,1H),6.45(t,J=3.4 Hz,1H),5.21(s,1H),4.88(t,J=9.5Hz,1H),4.37(dd,J=9.4,5.9Hz,1H),3.57(dp, J=9.6,6.6Hz,1H),3.42–3.29(m,2H),2.47–2.40(m,2H),2.23–2.15(m,1H),2.00– 1.83(m,2H),1.57–1.50(m,1H),1.39(s,12H),1.33(d,J=6.8Hz,3H),1.25(s,3H). 13 C NMR (126MHz, CDCl3) δ183.52,174.94,171.28,170.25,155.94,152.80,136.95,133.38,129.03,127.20,125.26,1 18.61,81.60,79.08,67.45,36.42,34.90,34.62(2C),32.07,31.50,31.17,28.33(3C),24.57,18.79.HRMS(ESI):C 27 H 33 NO7Na + [M+Na] + m / z calculated: 506.2149, found: 506.2148.

[0295] 38-2: 1H NMR (500MHz, CDCl3) δ7.73(d,J=8.0Hz,1H),7.66(d,J=8.2Hz,1H),6.44(t,J=3.7Hz,1H),5 .23(s,1H),4.90(t,J=9.5Hz,1H),4.37(dd,J=9.3,6.2Hz,1H),3.60(dp,J=9.7,6.7Hz,1H), 3.45–3.32(m,2H),2.46(tq,J=10.0,5.2,4.5Hz,2H),2.25–2.15(m,1H),2.03–1.83(m,2H), 1.55(dd,J=11.6,4.7Hz,1H),1.41(s,9H),1.39(s,3H),1.35(d,J=6.8Hz,3H),1.27(s,3H). 13 C NMR (126MHz, CDCl3) δ183.48,175.04,171.34,170.31,155.96,152.83,136.94,133.43,129.02,127.21,125.29,11 8.61,81.60,79.11,67.41,36.37,34.92,34.63,34.58,32.05,31.60,31.11,28.35(3C),24.59,18.66.HRMS(ESI):C 27 H 33 NO7Na + [M+Na] + m / z calculated: 506.2149, found: 506.2145.

[0296] Embodiment 38

[0297] The preparation method is the same as 1-1, using Boc-L-proline (220 mg, 1.020 mmol), cryptotanshinone (150 mg, 0.510 mmol), TEMPO (96 mg, 0.612 mmol) as raw materials, and silica gel column chromatography (PE: EtOAc = 3: 1-1: 1) to obtain orange solid compound 39-1 (42 mg, 16%) and its diastereomer 39-2 (35 mg, 13%).

[0298]

[0299] 39-1: 1H NMR (500MHz, CDCl3) δ7.70(d,J=8.2Hz,1H),7.63(d,J=8.2Hz,1H),6.48(t,J=3.5Hz,1H),4.8 6(t,J=9.5Hz,1H),4.33(dd,J=9.4,6.1Hz,1H),4.12(dd,J=8.2,3.5Hz,1H),4.05(dd,J=8.4,3 .6Hz,1H),3.57–3.48(m,1H),3.39–3.23(m,1H),2.21–2.13(m,2H),2.10–1.81(m,3H),1.80– 1.71(m,1H),1.51–1.45(m,2H),1.38(s,3H),1.35(s,9H),1.29(d,J=6.8Hz,3H),1.21(s,3H). 13 C NMR (126MHz, CDCl3) δ183.46,175.03,171.36,170.28,153.99,152.82,136.73,133.35,129.06,127.11,125.28,118.54,8 1.58,79.90,67.48,59.84,46.18,34.88,34.61,32.39,31.56,31.09,29.92,28.36(3C),24.41,23.43,18.60.HRMS(ESI):C 29 H 35 NO7Na + [M+Na] + m / z calculated: 532.2306, found: 532.2304.

[0300] 39-2: 1 H NMR (500MHz, CDCl3) δ7.69(d,J=8.2Hz,1H),7.63(d,J=8.2Hz,1H),6.49(t,J=3.4Hz,1H),4 .88(t,J=9.5Hz,1H),4.37–4.28(m,1H),4.25(dd,J=7.6,4.8Hz,1H),3.57(dq,J=6.5,3.2Hz ,1H),3.35–3.28(m,1H),3.25–3.14(m,1H),2.20–2.09(m,3H),2.01–1.80(m,2H),1.75–1. 59(m,2H),1.54–1.42(m,1H),1.40(s,9H),1.36(s,3H),1.34(d,J=9.6Hz,3H),1.32(s,3H). 13C NMR (126MHz, CDCl3) δ183.46,175.03,171.36,170.28,153.99,152.82,136.73,133.35,129.06,127.11,125.28,118.54,8 1.58,79.90,67.48,59.84,46.18,34.88,34.61,32.39,31.56,31.09,29.92,28.36(3C),24.41,23.43,18.60.HRMS(ESI):C 29 H 35 NO7Na + [M+Na] + m / z calculated: 532.2306, found: 532.2305.

[0301] Embodiment 39

[0302] The preparation method is the same as 1-1, using Boc-L-tryptophan (317 mg, 1.020 mmol), cryptotanshinone (150 mg, 0.510 mmol), TEMPO (96 mg, 0.612 mmol) as raw materials, and silica gel column chromatography (PE: EtOAc = 3: 1-1: 1) to obtain orange solid compound 40-1 (37 mg, 12%) and its diastereomer 40-2 (46 mg, 15%).

[0303]

[0304] 40-1: 1H NMR (500MHz, CDCl3) δ8.68–8.59(m,1H),7.71(d,J=8.2Hz,1H),7.63(d,J=8.2Hz,1H),7.40(d,J=8.0Hz,1H),7.30(d,J=8.1Hz, 1H),7.21(d,J=2.4Hz,1H),7.06(t,J=7.6Hz,1H),6.94(t,J=7.5Hz,1H),6.72(d,J=3.5Hz,1H),5.35(t,J=9.2Hz,1H),4.89(t, J=9.5Hz,1H),4.66–4.58(m,1H),4.35(dd,J=9.4,5.8Hz,1H),3.56(dt,J=9.5,6.3Hz,1H),3.19(dd,J=15.1,5.7Hz,1H),3.05( dd,J=15.1,6.4Hz,1H),2.24–2.15(m,1H),2.02–1.85(m,2H),1.53–1.43(m,1H),1.40(s,3H),1.38–1.31(m,12H),1.23(s,3H). 13 CNMR (126MHz, CDCl3) δ182.76,174.75,171.07,170.38,155.46,152.94,13 6.47,135.94,133.33,128.61,128.01,127.04,125.26,123.87,121.30,11 8.94,118.62,118.56,111.17,109.94,81.61,79.41,67.51,54.10,34.89, 34.63,31.81,31.56,31.30,28.28(3C),27.69,24.43,18.80.HRMS(ESI):C 35 H 38 N2O7Na + [M+Na] + m / z calculated: 621.2571, found: 621.2571.

[0305] 40-2: 1H NMR (500MHz, CDCl3) δ8.55–8.49(m,1H),7.66(d,J=8.2Hz,1H),7.62(d,J=8.2Hz,1H),7.56(d,J=7.9Hz,1H),7.30(d,J= 8.1Hz,1H),7.15–7.09(m,2H),7.07–7.00(m,1H),6.68(t,J=3.3Hz,1H),5.12(d,J=7.9Hz,1H),4.89(t,J=9.5Hz,1H),4. 67–4.58(m,1H),4.36(dd,J=9.4,6.1Hz,1H),3.60(dt,J=9.3,6.5Hz,1H),3.33(dd,J=14.7,6.2Hz,1H),3.24(dd,J=14.7 ,5.1Hz,1H),2.07–2.01(m,1H),1.86–1.74(m,1H),1.59–1.39(m,2H),1.37(d,J=8.5Hz,12H),1.24(s,3H),1.19(s,3H). 13 C NMR (126MHz, CDCl3) δ182.95,175.08,170.89,170.58,155.17,153.04,13 6.37,136.04,133.38,128.69,128.01,127.02,125.39,123.81,121.67,11 9.20,118.79,118.64,111.12,110.10,81.64,79.46,67.47,55.00,34.78, 34.60,31.62,31.49,31.05,28.33(3C),28.03,24.33,18.71.HRMS(ESI):C 35 H 38 N2O7Na + [M+Na] + m / z calculated: 621.2571, found: 621.2572.

[0306] Embodiment 40

[0307] The preparation method is the same as 1-1, using Boc-L-phenylalanine (275 mg, 1.020 mmol), cryptotanshinone (150 mg, 0.510 mmol), and TEMPO (96 mg, 0.612 mmol) as raw materials, and silica gel column chromatography (PE: EtOAc = 3: 1-1: 1) to obtain an orange solid compound 41-1 (96 mg, 34%).

[0308]

[0309] 41-1: 1 H NMR(500MHz, CDCl3)δ7.72(dd,J=8.2,2.0Hz,1H),7.66(dd,J=8.2,2.1Hz,1H),7.21–7.05(m,5H),6.57(t ,J=3.3Hz,1H),5.00(d,J=8.7Hz,1H),4.87(td,J=9.5,2.3Hz,1H),4.46(td,J=8.9,5.5Hz,1H),4.36(ddd ,J=9.2,5.9,2.4Hz,1H),3.56(ddt,J=13.0,9.3,6.0Hz,1H),3.03–2.95(m,1H),2.87(dd,J=14.3,9.0Hz, 1H),2.22–2.13(m,1H),1.96–1.82(m,2H),1.53–1.42(m,1H),1.37(d,J=2.1Hz,3H),1.35–1.20(m,15H). 13 C NMR(126MHz, CDCl3)δ183.47,174.96,170.83,170.18,155.18,152.91,136.92,136.41,133.40,129.30(2C),128.99,128.08(2C),127.1 0,126.34,125.31,118.64,81.60,79.48,67.97,54.18,38.34,34.86,34.63,31.91,31.49,31.22,28.20(3C),24.44,18.80.HRMS(ESI):C 33 H 37 NO7Na + [M+Na] + m / z calculated: 582.2462, found: 582.246

[0310] Embodiment 41

[0311] The preparation method is the same as 1-1, using Boc-L-alanine (197 mg, 1.020 mmol), cryptotanshinone (150 mg, 0.510 mmol), TEMPO (96 mg, 0.612 mmol) as raw materials, and silica gel column chromatography (PE: EtOAc = 3: 1-1: 1) to obtain orange solid compound 42-1 (68 mg, 28%) and its diastereomer 42-2 (62 mg, 25%).

[0312]

[0313] 42-1: 1 H NMR (500MHz, CDCl3) δ7.71(d,J=8.2Hz,1H),7.65(d,J=8.4Hz,1H),6.50(t,J=3.6 Hz,1H),5.20(d,J=8.2Hz,1H),4.87(t,J=9.5Hz,1H),4.35(dd,J=9.3,6.1Hz,1H), 4.18(p,J=7.4Hz,1H),3.55(dp,J=9.1,6.6Hz,1H),2.20–2.14(m,1H),2.03–1.84( m,2H),1.54–1.48(m,1H),1.40–1.37(m,12H),1.31(d,J=7.0Hz,3H),1.23(s,6H). 13 C NMR (126MHz, CDCl3) δ183.40,174.97,172.03,170.24,155.16,152.86,136.56,133.36,129.00,127.15,125.31,11 8.61,81.59,79.48,67.98,49.24,34.87,34.61,31.99,31.41,31.14,28.29(3C),24.45,18.82,18.73.HRMS(ESI):C 27 H 33 NO7Na + [M+Na] + m / z calculated: 506.2149, found: 506.2150.

[0314] 42-2: 1 H NMR (500MHz, CDCl3) δ7.72(d,J=8.2Hz,1H),7.66(d,J=8.2Hz,1H),6.50(t,J=3.1Hz,1H),5.17(d,J=7.1Hz,1H),4.89(t,J=9.5Hz,1H),4.36(dd,J=9 .4,6.2Hz,1H),4.22(p,J=7.2Hz,1H),3.64–3.53(m,1H),2.23–2.14(m,1H ),1.97–1.81(m,2H),1.58–1.47(m,1H),1.43–1.32(m,18H),1.26(s,3H). 13C NMR (126MHz, CDCl3) δ183.35,175.08,171.61,170.21,154.98,152.81,136.41,133.39,128.98,127.17,125.37,11 8.67,81.61,79.37,67.76,49.43,34.89,34.63,31.99,31.64,31.06,28.30(3C),24.41,18.93,18.66.HRMS(ESI):C 27 H 33 NO7Na + [M+Na] + :506.2149, measured value: 506.2147.

[0315] Embodiment 42

[0316] The preparation method was the same as 1-1, using Boc-glycylglycine (157 mg, 0.676 mmol) as raw material and silica gel column chromatography (PE: EtOAc = 3:1-1:1) to obtain an orange solid compound 43-1 (43 mg, 24%).

[0317]

[0318] 43-1: 1 H NMR (500MHz, CDCl3) δ7.73(d,J=8.3Hz,1H),7.66(d,J=8.2Hz,1H),7.00(d,J=43.7Hz,1H),6.48(t,J=3.4H z,1H),5.47–5.37(m,1H),4.90(t,J=9.5Hz,1H),4.37(ddd,J=9.0,6.1,2.3Hz,1H),4.19(ddd,J=18.0,6.6, 4.0Hz,1H),3.94–3.83(m,2H),3.79–3.73(m,1H),3.58(dq,J=9.6,6.4Hz,1H),2.22–2.14(m,1H),2.01–1.8 5(m,2H),1.57–1.51(m,1H),1.45–1.42(m,9H),1.38(d,J=3.0Hz,3H),1.29(d,J=37.2Hz,3H),1.23(s,3H). 13C NMR (126MHz, CDCl3) δ183.46,174.75,170.47,170.01,169.01,155.96,152.92,136.47,133.50,128.93,127.22,125.43 ,118.66,81.70,79.98,68.31,41.00,34.89,34.57,31.94,31.47,31.08,29.64,28.29(3C),24.60,18.77.HRMS(ESI):C 28 H 34 N2O8Na + [M+Na] + m / z calculated: 549.2207, found: 549.2209.

[0319] Effect Example 1 Evaluation of the in vitro anti-triple-negative breast cancer activity of cryptotanshinone derivatives

[0320] 1. Experimental purpose

[0321] The CCK-8 method was used to detect the in vitro anti-triple-negative breast cancer activity of five structural types of derivatives, to preliminarily explore their structure-activity relationship, and to select derivatives with excellent activity for subsequent activity testing.

[0322] 2. Experimental Materials

[0323] 2.1 Experimental cells

[0324] Two triple-negative breast cancer cell lines, 4T1 cells (mouse adenocarcinoma) and MDA-MB-231 cells (human adenocarcinoma), were purchased from the Cell Resource Center of Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences.

[0325] 2.2 Experimental instruments and reagents

[0326]

[0327] 2.3 Drug concentration

[0328] 0.3μM, 1μM, 3μM, 10μM, 30μM

[0329] 3. Experimental methods

[0330] The triple-negative breast cancer cells (4T1, MDA-MB-231) to be tested in the logarithmic growth phase were inoculated into a 96-well culture plate at a certain cell amount. After culturing for 24 hours, a serum-free medium solution of the test drug was added, with 5 replicate wells for each concentration. The cells were cultured for a further 24 hours at 37°C and 5% CO2. A serum-free medium solution of 10% CCK-8 was added and cultured for a further 4 hours. The absorbance of each well was detected using an enzyme reader.

[0331] 4. Experimental results

[0332] The results of activity test showed that the preliminary structure-activity relationship of cryptotanshinone derivatives was as follows: ① For derivatives substituted with hydrocarbon acid ester side chains on the A ring, the activity gradually decreased with the increase of the length of the substituted side chains; when the side chains contained unsaturated functional groups and mono-protected dicarboxylic acids, the activity of the derivatives increased; ② For derivatives substituted with aromatic ether side chains on the A ring, it was beneficial to enhance the activity when the para-position of the benzene ring contained electron-withdrawing substituents and the ortho-position had substituents; the activity was weakened when the para-position of the benzene ring was modified with large steric hindrance substituents; the activity was stronger when two electron-withdrawing substituents were contained than when the substituent was monosubstituted; ③ For derivatives substituted with oxidized A ring and reduced o-quinone, the activity of the derivatives after the o-quinone was reduced decreased; the activity was enhanced when α, β-unsaturated ketones were contained; ④ For derivatives substituted with amino acid ester side chains on the A ring, the activity was stronger when the side chain was α-amino than when it was β-amino.

[0333] All compounds were screened, and the results are shown in Table 1:

[0334] Table 1

[0335]

[0336]

[0337]

[0338] According to the change trend at 30 μM and three concentrations, 21 compounds with better activity were selected and their IC values ​​were detected by CCK-8 method. 50 The IC values ​​of four preferred compounds were further tested on human triple-negative breast cancer cells. 50 value.

[0339] Table 2 IC values ​​of preferred compounds on 4T1 cells 50 value

[0340] serial number <![CDATA[IC 50 (μM)]]> serial number <![CDATA[IC 50 (μM)]]> serial number <![CDATA[IC 50 (μM)]]> CTS 19.96 16-1 4.43 29-1 7.24 1-1 5.56 17-2 5.96 35-1 4.49 5-1 6.69 18-2 11.24 35-2 6.36 6-1 6.41 19-1 2.87 39-2 2.69 7-1 7.71 22-1 5.66 41-1 3.73 9-1 1.95 22-2 6.28 42-1 5.31 13-1 4.52 23-1 11.25 15-2 10.39 25-2 2.68

[0341] Table 3 IC values ​​of cryptotanshinone and preferred compounds on MDA-MB-231 50 value

[0342] serial number <![CDATA[IC 50 (μM)]]> serial number <![CDATA[IC 50 (μM)]]> serial number <![CDATA[IC 50 (μM)]]> CTS 4.09 9-1 0.86 13-1 0.55 19-1 6.82 39-2 1.62

[0343] Effect Example 2 Evaluation of the in vivo anti-triple-negative breast cancer activity of cryptotanshinone derivatives

[0344] 1. Experimental purpose

[0345] To observe the activity and safety of preferred cryptotanshinone derivatives 9-1 and 13-1 against triple-negative breast cancer in mice.

[0346] 2. Experimental Materials

[0347] 2.1 Experimental cells

[0348] 4T1 (murine adenocarcinoma) triple-negative breast cancer cell line was purchased from the Cell Resource Center of Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences.

[0349] 2.2 Experimental Animals

[0350] SPF female BALB / c mice, 5 weeks old, were purchased from Shanghai Model Organisms Technology Co., Ltd. Rearing environment: SPF animal room, 12-h day and night rhythm, temperature (25±1)℃, humidity (50±10)%, normal free water access, and standard mouse feed.

[0351] 2.3 Experimental instruments and reagents

[0352]

[0353]

[0354] 2.4 Drug concentration

[0355] Name: 9-1; Properties: reddish brown powder; Solvent: edible vegetable oil containing 5% DMSO; Dosing concentration: 15 mg / kg / d

[0356] Name: 13-1; Properties: yellow powder; Solvent: edible vegetable oil containing 5% DMSO; Dosing concentration: 15 mg / kg / d

[0357] 3. Experimental methods

[0358] 3.1 Animal experiments

[0359] Four-week-old BALB / c mice were placed in the animal center for one week and their abdominal hair was removed. A sufficient amount of 4T1 cells were prepared. 4T1 cells in the logarithmic growth phase were washed once with PBS, centrifuged after trypsin digestion, washed twice with PBS, and the cell pellets were collected and suspended with PBS before counting. The cell suspension was diluted with PBS to a concentration of 1×10 7 Cell number / ml, put in an ice box and bring to the animal room for inoculation. Use a syringe to draw 100μl of the mixed cell suspension and inoculate it in situ on the fourth pair of mammary pads on the right side of BALB / c mice. When the tumor volume is about 50mm 3At the time of administration, the animals were randomly divided into 9-1 group, 13-1 group and control group, with 7 mice in each group. Each group was intraperitoneally injected with 100 μl of experimental oil containing 5% DMSO, 9-1 (15 mg / kg) oil solution and 13-1 (15 mg / kg) oil solution, respectively. The weight and tumor volume of mice were recorded every day during the administration. After 21 days of administration, the tumor and major organs were dissected out, washed in PBS and photographed to record the changes in tumor tissue morphology, and then placed in 4% paraformaldehyde. The tumor tissue was stained with HE and Ki67, and the tissues of various organs were stained with HE.

[0360] Experimental Grouping

[0361]

[0362] 3.2. Statistical analysis

[0363] All data were analyzed using GraphPad Prism 8 statistical software. Two-way analysis of variance was used for analysis of differences among multiple groups. The results were expressed as mean ± standard deviation (Mean ± SD); p < 0.05 indicated statistical significance.

[0364] 4. Experimental Results

[0365] 4.1 In vivo pharmacodynamic evaluation of preferred compounds 9-1 and 13-1

[0366] (1) Changes in tumor volume, weight, and morphology

[0367] Three days after BALB / c mice were inoculated with 4T1 cells, the tumors grew to 50 mm 3 The patients were randomly divided into three groups and then the medication was started. The medication was stopped on the 25th day. Figure 1 , 2 As shown in Figures 3 and 4, it can be seen from the tumor volume growth curves A and C that during the administration process, the tumor volumes of the control group, 9-1 group, and 13-1 group are constantly increasing, and the tumor growth of the control group is faster. With the increase of the administration cycle, the difference in tumor volume between the 9-1 and 13-1 groups and the control group is getting bigger and bigger, and the difference is statistically significant. Figure 3 It can be seen that the tumor volume of the control group was the largest, and the tumor volumes of the 9-1 and 13-1 groups were significantly smaller than those of the control group, indicating that the growth of the tumor volume was significantly inhibited after the mice were treated; from the tumor weight graphs B and D, it can be seen that among the tumors separated 21 days after administration, the control group was the heaviest and had no therapeutic effect, while the tumor weights of the 9-1 and 13-1 groups were significantly reduced, and the differences were statistically significant. It can be seen that compounds 9-1 and 13-1 have obvious therapeutic effects on tumors, and this conclusion is consistent with the volume changes of mice.

[0368] (2) HE staining of tumor tissue and Ki67 immunohistochemistry results

[0369] According to the HE staining results of tumor tissue sections in each group ( Figure 4 ) It can be seen that the necrosis area ratio of the control group is 20.68±2.30%, and the cells are closely arranged and plump; the necrosis area ratio of the 9-1 group is 59.55±0.38%, and the necrosis area ratio of the 13-1 group is 62.77±2.90%. The necrosis of tumor tissues in these two groups is significantly increased compared with the control group, and the cells are sparsely arranged, the nuclei are ruptured and shrunken over a large area, the cell structure disappears, and the tumor tissue is seriously damaged. The effects of 9-1 and 13-1 on the proliferation activity of tumor cells were further investigated. The Ki67 staining of tumor tissue sections of each group was performed by immunohistochemistry. The results showed that the Ki67 positive rate of the control group was 18.08±0.42%, which was much higher than the positive rates of 2.23±0.16% and 3.01±0.27% in the 9-1 group and the 13-1 group, respectively. The difference was statistically significant, indicating that the two compounds can significantly reduce the proliferation activity of 4T1 cells in vivo after administration, and effectively inhibit the growth of tumors.

[0370] 4.2 In vivo safety evaluation of preferred compounds 9-1 and 13-1

[0371] (1) Weight changes of tumor-bearing mice

[0372] like Figure 5 As shown, there was no significant change in the body weight of mice during the drug administration period, and it was basically maintained at a stable normal level. Except for the mice in the control group whose movements became slow as the tumor volume increased, there were no abnormal behaviors in the other two drug administration groups, and the mice in each group ate normally, indicating that intraperitoneal injection of drugs did not cause serious adverse reactions in mice.

[0373] (2) HE staining of various organs and tissues

[0374] After 25 days of administration, the organs of mice in each group were taken out for HE staining to observe the necrosis of the main organs ( Figure 6 ). As shown in the figure, no abnormal necrosis was observed in the slices of each group, and there was no significant difference compared with the control group. This shows that after drug treatment, the morphology of various organ tissues was good, and no obvious toxic side effects were found.

Claims

1. Use of a cryptotanshinone derivative as shown in formula I, or a pharmaceutically acceptable salt thereof, in the preparation of a drug for treating triple-negative breast cancer: in, The dotted line "-----" in ring A is a double bond; R1 and R2 together form =X1, where X1 is O; or R1 and R2 are independently hydrogen or hydroxyl; R3 is hydrogen; Ring C for X2 is 0; X3 is 0; R4 and R5 are independently C 1-3 Alkyl-C(O)O-.

2. The use according to claim 1, characterized in that R4, the C 1-3 Alkyl-C(O)O- is formyloxy, acetoxy or propionyloxy; and / or, in R5, the C 1-3 Alkyl-C(O)O- is formyloxy, acetoxy or propionyloxy.

3. The use according to claim 2, characterized in that Ring C for 4. Use of a cryptotanshinone derivative or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating triple-negative breast cancer, characterized in that: The cryptotanshinone derivative is selected from any of the following structures:

5. The use according to claim 4, characterized in that The cryptotanshinone derivative is any of the following structures:

6. A cryptotanshinone derivative as shown in formula I, or a pharmaceutically acceptable salt thereof: in, "-----", R1, R2, R3 and The definition as in any one of claims 1 to 3; And the following conditions are met: The cryptotanshinone derivative shown in formula I is not the following structure:

7. The cryptotanshinone derivative or a pharmaceutically acceptable salt thereof according to claim 6, characterized in that: The cryptotanshinone derivative is selected from any of the following structures:

8. A method for preparing the cryptotanshinone derivative as shown in formula I as claimed in claim 6, which is method 2, 3 or 4: Method 2 comprises the following steps: in a solvent, subjecting a compound as shown in formula III and an acylating agent to a reductive acylation reaction as shown below in the presence of a reducing agent and an inorganic base to obtain a cryptotanshinone derivative as shown in formula I; wherein, Ring C for R4 and R5 are independently C 1-3 Alkyl-C(O)O-; the dashed line "-----" in ring A, R1, R2 and R3 are defined as in claim 6; Method 3 comprises the following steps: hydrolyzing the compound shown in Formula IV in the presence of an inorganic base in a solvent, and simultaneously performing a ring-opening reaction on the dihydrofuran ring of the D ring, and performing a ring-closing reaction on the D ring in the presence of an inorganic acid to obtain a cryptotanshinone derivative shown in Formula I; wherein the C in the ring for R1, R2, X2, X3 and R are defined as in claim 6, R3 is a hydrogen atom; the dotted line "-----" in ring A is a double bond; Method 4 comprises the following steps: in a solvent, subjecting a compound as shown in formula V to an oxidant for allylic oxidation reaction to obtain a cryptotanshinone derivative as shown in formula I; wherein R3 is H; the dotted line "-----" in ring A is a double bond; R1, R2 and The definition is as described in claim 6; R1 and R2 together form =X1, wherein X1 is O; or one of R1 and R2 is hydrogen and the other is hydroxyl; In method 2, the inorganic base is sodium acetate or potassium acetate; In method 2, the acylating agent is an acid anhydride or an acid chloride; In method 2, the reducing agent is zinc powder, lithium aluminum hydride, sodium borohydride or hydrogen / palladium; In method 2, the reaction temperature in the reductive acylation reaction is 0°C-50°C; In method 2, the molar ratio of the acylating agent to the compound represented by formula III is (2:1)-(100:1); In method 2, the molar ratio of the inorganic base to the compound represented by formula III is (1:1)-(100:1); In method 2, the molar ratio of the reducing agent to the compound represented by formula III is (2:1)-(100:1); In method 3, the solvent is methanol and / or ethanol; In method 3, the inorganic base is sodium hydroxide and / or lithium hydroxide; In method 3, the inorganic acid is sulfuric acid or hydrochloric acid; In method 3, the reaction temperature of the ring-opening reaction and the ring-closing reaction is 0°C-70°C; In method 3, the molar ratio of the inorganic base to the compound represented by formula IV is (2:1)-(100:1); In method 3, the molar ratio of the inorganic acid to the compound represented by formula IV is (1:1)-(100:1); In method 4, the solvent is dioxane; In method 4, the oxidant is one or more of oxygen, tert-butyl hydroperoxide, di-tert-butyl peroxide, 2,2,6,6-tetramethylpiperidinoxide, manganese dioxide, cerium ammonium nitrate, diiodobenzene acetate, potassium persulfide, selenium dioxide and chromium trioxide; In method 4, the reaction temperature of the allylic oxidation reaction is 0°C-100°C; In method 4, the molar ratio of the oxidant to the compound represented by formula V is (2:1)-(100:1).

9. The preparation method according to claim 8, characterized in that: In method 2, the acylating agent is acetic anhydride, acetyl chloride, propionic anhydride or propionyl chloride; And / or, in method 2, the reducing agent is zinc powder or sodium borohydride; and / or, in method 2, the reaction temperature in the reductive acylation reaction is 25° C.-50° C.; And / or, in method 2, the molar ratio of the acylating agent to the compound of formula III is (4:1)-(20:1); And / or, in method 2, the molar ratio of the inorganic base to the compound of formula III is (1:1)-(2:1); And / or, in method 2, the molar ratio of the reducing agent to the compound of formula III is (4:1)-(20:1); And / or, in method 3, the reaction temperature of the ring-opening reaction and the ring-closing reaction is 25°C-70°C; And / or, in method 3, the molar ratio of the inorganic base to the compound of formula IV is (4:1)-(20:1); And / or, in method 3, the molar ratio of the inorganic acid to the compound represented by formula IV is (10:1)-(100:1); And / or, in method 4, the oxidant is selenium dioxide or a mixture of selenium dioxide and tert-butyl hydroperoxide; And / or, in method 4, the reaction temperature of the allylic oxidation reaction is 25° C.-100° C.; And / or, in method 4, the molar ratio of the oxidant to the compound represented by formula V is (4:1)-(20:1).

10. The preparation method according to claim 9, characterized in that: In method 2, the reaction temperature in the reductive acylation reaction is 40°C-50°C; And / or, in method 3, the reaction temperature of the ring-opening reaction and the ring-closing reaction is 25°C-56°C; And / or, in method 4, the reaction temperature of the allylic oxidation reaction is 50°C-100°C.

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