Cryptotanshinone derivative as well as preparation method and application thereof

Abstract

The invention discloses cryptotanshinone derivatives as well as a preparation method and application thereof. The invention specifically discloses a cryptotanshinone derivative as shown in a formula (I). The cryptotanshinone derivative has good inhibitory activity on triple-negative breast cancer cells. # imgabs0 #

Description

[0001] This application is a divisional of a Chinese invention patent with an application date of July 23, 2021, application number 2021108382150, and name “Cryptoshinone derivatives, preparation methods and applications thereof”. Technical Field

[0002] The present invention relates to a cryptotanshinone derivative, a preparation method and application thereof. Background Art

[0003] 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.

[0004] 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

[0005] 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.

[0006] The present invention solves the above technical problems through the following technical solutions.

[0007] 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:

[0008]

[0009] The dotted line “” in ring A represents a single bond or a double bond;

[0010] R1 and R2 together form ═X1, where X1 is selected from CH2, O, S, and NH;

[0011] or R1 and R2 are each independently hydrogen or a hydroxyl group;

[0012] R3 is hydrogen, phenoxy or phenoxy substituted with one or more R 1-1 wherein R is hydrogen, C6-C 10 aryl, C6-C 1-1 aryl substituted with one or more R 10 C 1-3 alkyl, C 1-2 alkyl substituted with one or more R 1-3 C 2-3 alkenyl, C 1-3 alkenyl substituted with one or more R 2-3 5-9 membered heterocycloalkyl or 5-9 membered heterocycloalkyl substituted with one or more R 1-4 wherein the 5-9 membered heterocycloalkyl has 1, 2, or 3 heteroatoms, and each heteroatom is independently N, O, or S;

[0013] each R 1-1 is 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 5-6 membered heterocycloalkyl substituted with one or more R 2-1 wherein the 5-6 membered heterocycloalkyl has 1, 2, or 3 heteroatoms, and each heteroatom is independently N, O, or S;

[0014] -1 R is hydrogen or C 1-3 alkyl;

[0015] each R 2-1 is independently tert-butoxycarbonyl;

[0016] each R 1-2 is independently -NR 2-2 R 2-3 、C6-C 10 aryl or 6-10 membered heteroaryl, wherein the 6-10 membered heteroaryl has 1, 2, or 3 heteroatoms, and each heteroatom is independently N, O, or S;

[0017] R 2-2 、R 2-3 are each independently hydrogen, tert-butoxycarbonyl, or

[0018] R 1-3 is C6-C 10 aryl;

[0019] R 1-4 is tert-butoxycarbonyl;

[0020] In ring C, is

[0021] X2 is selected from CH2, O, S, and NH;

[0022] X3 is selected from CH2, O, S, and NH;

[0023] R4 and R5 are each independently hydrogen, C 1-3 alkyl-C(O)O-, C 1-3 alkoxy, or hydroxy.

[0024] In some embodiments, in R, the "C 1-3 alkyl or C 1-2 alkyl substituted with one or more R 1-3 alkyl" in the "C 1-3 alkyl" is methyl, ethyl, propyl, or isopropyl, preferably methyl or ethyl.

[0025] In some embodiments, in R, the "C 2-3 alkenyl or C 1-3 alkenyl substituted with one or more R 2-3 alkenyl" in the "C 2-3 alkenyl" is vinyl, propenyl, or isopropenyl, preferably vinyl.

[0026] In some embodiments, in R, the "C6-C 10 aryl or C6-C 1-1 aryl substituted with one or more R 10 aryl" in the "C6-C 10 aryl" is phenyl.

[0027] In some embodiments, in R, the "5-9 membered heterocycloalkyl" or "5-9 membered heterocycloalkyl substituted with one or more R 1-4 " in the "5-9 membered heterocycloalkyl" is an N-containing 5-9 membered heterocycloalkyl, preferably more preferably

[0028] In some embodiments, in R, the 5-9 membered heterocycloalkyl substituted with one or more R 1-4 is

[0029] In some embodiments, R 1-1 in, the C1-4 alkyl or C 1-4 in the haloalkyl, the C 1-4 alkyl moiety is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, preferably methyl, ethyl or tert-butyl.

[0030] In some embodiments, R 1-1 in which the C 1-4 alkoxy or C 1-4 in the haloalkoxy, the C 1-4 alkoxy moiety is methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy, preferably methoxy.

[0031] In some embodiments, R 1-1 in which the halogen is F, Cl, Br or I, preferably F, Cl or Br, more preferably F or Cl.

[0032] In some embodiments, R 1-1 in which the "5-6 membered heteroalkyl" or "5-6 membered heteroalkyl substituted by one or more R 2-1 " in the "5-6 membered heteroalkyl" is a 6-membered heteroalkyl containing an N atom, preferably

[0033] In some embodiments, R 1-1 in which the C 1-4 haloalkoxy or C 1-4 in the haloalkoxy, the "halo" is fluoro, chloro, bromo or iodo, preferably fluoro.

[0034] In some embodiments, -1 in R, the C 1-3 alkyl is methyl, ethyl, propyl or isopropyl, preferably methyl.

[0035] In some embodiments, R 1-2 in which the C6-C 10 aryl is phenyl.

[0036] In some embodiments, R 1-2 in which the 6-10 membered heteroaryl is a 6-10 membered heteroaryl containing N, preferably

[0037] In some embodiments, R 1-2 in which the "-NR 2-2 R 2-3 " is -NHBoc or preferably -NHBoc.

[0038] In some embodiments, R 1-3 is phenyl.

[0039] In some embodiments, in R4, the C 1-3 alkyl-C(O)O- is formyloxy, acetyloxy or propionyloxy.

[0040] In some embodiments, in R4, the C 1-3 alkoxy is methoxy, ethoxy, propoxy or isopropoxy.

[0041] In some embodiments, in R5, the C 1-3 alkyl-C(O)O- is formyloxy, acetyloxy or propionyloxy.

[0042] In some embodiments, in R5, the C 1-3 alkoxy is methoxy, ethoxy, propoxy or isopropoxy.

[0043] In some embodiments, R is hydrogen, C6-C 10 aryl, C 1-3 alkyl, C 1-2 alkyl substituted with one or more R 1-3 alkyl, C 1-3 alkyl substituted with one or more R 2-3 alkenyl or 5- to 9-membered heterocycloalkyl substituted with one or more R 1-4 wherein the 5- to 9-membered heterocycloalkyl has 1 heteroatom, and the heteroatom is N.

[0044] In some embodiments, each R 1-1 is independently CN, NO2, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, halogen, or 6-membered heterocycloalkyl substituted with one R 2-1 wherein the 6-membered heterocycloalkyl is a 6-membered heterocycloalkyl containing 2 N atoms.

[0045] In some embodiments, each R 1-1 is independently CN, NO2, C 1-4 haloalkyl, C 1-4 alkoxy, halogen or

[0046] In some embodiments, each R 1-1 is independently CN, NO2, methyl, ethyl, tert-butyl, methoxy, trifluoromethyl, trifluoromethoxy, F, Cl, Br, preferably CN, NO2, methoxy, trifluoromethyl, F, Cl,

[0047] In some embodiments, each R1-2 Independently for -NR 2-2 R 2-3 or C6-C 10 aryl.

[0048] In some embodiments, each R 1-2 independently is -NHBoc, phenyl or preferably -NHBoc, or phenyl.

[0049] In some embodiments, when R1 and R2 form ═X1, X1 is O.

[0050] In some embodiments, when in ring C is , X2 is O.

[0051] In some embodiments, when in ring C is , X3 is O.

[0052] In some embodiments, when in ring C is , R4 and R5 are each independently selected from hydrogen and C 1-3 alkyl-C(O)O-.

[0053] In some embodiments, in ring C is

[0054] In some embodiments, formula I is

[0055] In some embodiments, R3 is preferably is

[0056]

[0057] In some embodiments, the cryptotanshinone derivatives represented by formula I are selected from any of the following structures:

[0058]

[0059] In some embodiments, the cryptotanshinone derivatives represented by formula I are selected from any of the following structures:

[0060]

[0061]

[0062]

[0063] In some embodiments, the cryptotanshinone derivative represented by Formula I is preferably any of the following structures:

[0064]

[0065] The present invention provides a cryptotanshinone derivative represented by Formula I, its stereoisomer or its pharmaceutically acceptable salt:

[0066]

[0067] wherein, "-----", R1, R2, R3 and are as defined above;

[0068] and satisfy the following conditions:

[0069] The cryptotanshinone derivative represented by Formula I is not any of the following structures:

[0070] In some embodiments, the cryptotanshinone derivative represented by Formula I is selected from any of the following structures:

[0071]

[0072]

[0073]

[0074] The present invention also provides a method for preparing a cryptotanshinone derivative represented by Formula I, which can be Method 1, 2, 3, 4 or 5:

[0075] Method 1 includes the following steps: In a solvent, the compound represented by Formula II and R3-H are subjected to the conjugate addition reaction shown below in the presence of an oxidant to obtain the cryptotanshinone derivative represented by Formula I; wherein, the dotted line "-----" in Ring A is a single bond, and R1, R2, R3 and are as defined above, and R3 is not hydrogen;

[0076]

[0077] Method 2 includes the following steps: In a solvent, the compound represented by Formula III and an acylating reagent are subjected to the reductive acylation reaction shown below in the presence of a reducing agent and an inorganic base to obtain the cryptotanshinone derivative represented by Formula I; wherein, in Ring C is R4 and R5 are each independently C1-3 alkyl-C(O)O-; the definitions of the dashed line "-----" in Ring A, R1, R2, and R3 are as described above;

[0078]

[0079] Method 3 includes the following steps: In a solvent, hydrolyze the compound shown in Formula IV in the presence of an inorganic base, while the D-ring dihydrofuran ring undergoes a ring-opening reaction, and the D-ring undergoes a ring-closure reaction in the presence of an inorganic acid to obtain the cryptotanshinone derivative shown in Formula I; wherein, in Ring C is the definitions of R1, R2, X2, X3, and R are as described above, R3 is a hydrogen atom; the dashed line "-----" in Ring A is a double bond;

[0080]

[0081] Method 4 includes the following steps: In a solvent, perform an allylic oxidation reaction on the compound shown in Formula V with an oxidizing agent to obtain the cryptotanshinone derivative shown in Formula I; wherein, R3 is H; the dashed line "-----" in Ring A is a double bond; R1, R2, and the definition of are as described above; R1 and R2 together form =X1, where X1 is O; or one of R1 and R2 is hydrogen and the other is a hydroxyl group;

[0082]

[0083] Method 5 includes the following steps: In a solvent, perform a reduction reaction on the compound shown in Formula VI in the presence of a reducing agent to obtain the cryptotanshinone derivative shown in Formula I; wherein, R3 is H; the dashed line "-----" in Ring A is a single bond; R1, R2, and the definition of are as described above;

[0084]

[0085] In some embodiments, in Method 1, the solvent is selected from conventional organic solvents for such reactions in the art, preferably toluene or chlorobenzene.

[0086] In some embodiments, in Method 1, the oxidizing agent is oxygen, tert-butyl hydroperoxide, di-tert-butyl peroxide, 2,2,6,6-tetramethylpiperidine oxide (TEMPO), or manganese dioxide, preferably 2,2,6,6-tetramethylpiperidine oxide (TEMPO).

[0087] In some embodiments, in Method 1, the reaction temperature of the conjugate addition reaction is 0°C - 130°C, preferably 100°C - 130°C, particularly preferably 120°C - 130°C.

[0088] In some embodiments, in Method 1, the molar ratio of the oxidizing agent to the compound represented by Formula II is (1:1)-(100:1), preferably (1:1)-(2:1); the molar ratio of R3-H to the compound represented by Formula II is (1:1)-(100:1), preferably (1:1)-(4:1).

[0089] In some embodiments, in Method 2, the inorganic base is selected from the conventional inorganic bases for such reactions in the art, preferably sodium acetate or potassium acetate.

[0090] In some embodiments, in Method 2, the acylating agent is an acid anhydride or an acyl chloride, preferably acetic anhydride, acetyl chloride, propionic anhydride or propionyl chloride.

[0091] 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.

[0092] In some embodiments, in Method 2, the reaction temperature in the reductive acylation reaction is 0°C - 50°C, preferably 25°C - 50°C, particularly preferably 40°C - 50°C.

[0093] In some embodiments, in Method 2, the molar ratio of the acylating agent to the compound represented by Formula III is (2:1)-(100:1), preferably (4:1)-(20:1).

[0094] In some embodiments, in Method 2, the molar ratio of the inorganic base to the compound represented by Formula III is (1:1)-(100:1), preferably (1:1)-(2:1).

[0095] In some embodiments, in Method 2, the molar ratio of the reducing agent to the compound represented by Formula III is (2:1)-(100:1), preferably (4:1)-(20:1).

[0096] In some embodiments, in Method 3, the solvent is selected from the conventional organic solvents for such reactions in the art, preferably methanol and / or ethanol.

[0097] In some embodiments, in Method 3, the inorganic base is selected from the conventional inorganic bases for such reactions in the art, preferably sodium hydroxide and / or lithium hydroxide.

[0098] In some embodiments, in Method 3, the inorganic acid is selected from the conventional inorganic acids for such reactions in the art, preferably sulfuric acid or hydrochloric acid.

[0099] 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, particularly preferably 25°C - 56°C.

[0100] In some embodiments, in Method 3, the molar ratio of the inorganic base to the compound represented by Formula IV is (2:1)-(100:1), preferably (4:1)-(20:1).

[0101] 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).

[0102] In some embodiments, in Method 4, the solvent is selected from conventional organic solvents for such reactions in the art, preferably dioxane.

[0103] 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-tetramethylpiperidine oxide (TEMPO), manganese dioxide, ammonium cerium nitrate, diiodobenzene diacetate, potassium persulfide, selenium dioxide, and chromium trioxide, preferably selenium dioxide or a mixture of selenium dioxide and tert-butyl hydroperoxide.

[0104] In some embodiments, in Method 4, the reaction temperature of the allylic oxidation reaction is 0°C - 100°C, preferably 25°C - 100°C, particularly preferably 50°C - 100°C.

[0105] In some embodiments, in Method 4, the molar ratio of the oxidant to the compound represented by Formula V is (2:1)-(100:1), preferably (4:1)-(20:1).

[0106] 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.

[0107] In some embodiments, in Method 5, the reducing agent is zinc powder, lithium aluminum hydride, sodium borohydride, or hydrogen / palladium, preferably hydrogen / palladium.

[0108] In some embodiments, in Method 5, the reaction temperature of the reduction reaction is 0°C - 50°C, preferably 25°C - 50°C, particularly preferably 25°C - 35°C.

[0109] 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).

[0110] On the basis of not violating the common knowledge in the art, the above preferred conditions can be combined arbitrarily to obtain various preferred examples of the present invention.

[0111] The reagents and raw materials used in the present invention are all commercially available.

[0112] The positive and progressive effects of the present invention are as follows: The present invention provides a cryptotanshinone derivative with a novel structure, a preparation method thereof, and an application. The cryptotanshinone derivative of the present invention has good inhibitory activity against triple-negative breast cancer cells. Description of the Drawings

[0113] Figure 1 For the growth inhibition of tumors in vivo by Compound 9-1 (n = 5)

[0114] Figure 2 For the growth inhibition of tumors in vivo by Compound 13-1 (n = 5)

[0115] Figure 3 For the growth inhibition of tumors in vivo by Compounds 9-1 and 13-1 (n = 5)

[0116] Figure 4 For the HE staining and Ki67 immunohistochemical results of tumor sections

[0117] Figure 5 For the body weight change curve of mice after administration

[0118] Figure 6 For the HE staining results of sections of major organs Detailed Embodiments

[0119] The present invention will be further illustrated below by way of examples, but the present invention is not limited to the scope of the described examples. For the experimental methods without specific conditions in the following examples, they are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0120] Example 1

[0121] Take cryptotanshinone (100 mg, 0.337 mmol) and dissolve it in 3 ml of chlorobenzene. Then, successively add 88% formic acid (29 μl, 0.675 mmol), TEMPO (63 mg, 0.405 mmol), and stir and react at 120 °C for 24 h. After monitoring the reaction by TLC until it ends, concentrate it under reduced pressure with a rotary evaporator at 80 °C and a vacuum of 0.1 Mpa to obtain a crude product. Cool it to room temperature and perform silica gel column chromatography (petroleum ether:ethyl acetate (PE:EtOAc) = 2:1 - 0:1)) to obtain an orange-yellow solid compound 1-1 (20 mg, 17%).

[0122]

[0123] 11H NMR (500 MHz, CDCl3) δ 8.09 (s, 1H), 7.74 (d, J = 8.2 Hz, 1H), 7.68 (dd, J = 8.2, 1.5 Hz, 1H), 6.66 (t, J = 3.4 Hz, 1H), 4.90 (t, J = 9.6 Hz, 1H), 4.38 (ddd, J = 9.4, 6.0, 1.5 Hz, 1H), 3.60 (dqd, J = 15.0, 6.7, 1.8 Hz, 1H), 2.26–2.15 (m, 1H), 2.05–1.90 (m, 2H), 1.56 (ddd, J = 12.7, 4.1, 1.9 Hz, 1H), 1.40 (d, J = 1.9 Hz, 3H), 1.34 (dd, J = 6.8, 1.8 Hz, 3H), 1.27 (d, J = 2.9 Hz, 3H). 13 13C NMR (126 MHz, CDCl3) δ 183.08, 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] + Calcd for m / z: 341.1384, Found: 341.1384.

[0124] Example 2

[0125] 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 monitored by TLC and completed, the mixture was concentrated under reduced pressure using a rotary evaporator at 80 °C and a vacuum of 0.1 Mpa to obtain a crude product. After cooling to room temperature, the product was purified by silica gel column chromatography (PE:EtOAc = 2:1 - 0:1) to obtain an orange solid compound 2-1 (89 mg, 75%).

[0126]

[0127] 11H NMR (500 MHz, CDCl3) δ 7.73 (d, J = 8.2 Hz, 1H), 7.66 (dd, J = 8.2, 1.2 Hz, 1H), 6.45 (dd, J = 5.8, 3.7 Hz, 1H), 4.90 (td, J = 9.5, 3.2 Hz, 1H), 4.38 (ddd, J = 9.3, 6.0, 1.1 Hz, 1H), 3.60 (dpd, J = 10.0, 6.8, 3.4 Hz, 1H), 2.25–2.18 (m, 1H), 2.01 (d, J = 3.7 Hz, 3H), 1.99–1.87 (m, 2H), 1.58–1.52 (m, 1H), 1.40 (d, J = 2.1 Hz, 3H), 1.35 (dd, J = 6.8, 1.3 Hz, 3H), 1.27 (d, J = 2.9 Hz, 3H). 13 13C NMR (126 MHz, CDCl3) δ 183.23, 174.96, 170.27, 169.94, 152.82, 137.29, 133.30, 129.03, 127.19, 125.17, 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] + Calcd for m / z: 355.1540, found 355.1541.

[0128] Example 3

[0129] The preparation method was the same as that of 1-1. Using propionic acid (50 μl, 0.675 mmol) as the raw material, silica gel column chromatography (PE:EtOAc = 3:1 - 1:1) was carried out to obtain the orange solid compound 3-1 (56 mg, 45%) and its diastereomer 3-2 (61 mg, 49%).

[0130]

[0131] 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.

[0132] 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). 1313C 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] + Calculated for [M + H]+: 369.1697, found 369.1697.

[0133] Example 4

[0134] Prepared in the same way as 1 - 1, using benzoic acid (82 mg, 0.675 mmol) as the raw material, and purified by silica gel column chromatography (PE:EtOAc = 3:1 - 1:1) to obtain orange - yellow solid compound 4 - 1 (41 mg, 29%) and its diastereomer 4 - 2 (45 mg, 32%).

[0135]

[0136] 4 - 1: 1 1H NMR(500MHz,CDCl3)δ7.95–7.91(m,2H),7.78(d,J = 8.3Hz,1H),7.70(d,J = 8.2Hz,1H),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,1H),4.37(dd,J = 9.4,5.8Hz,1H),3.56(dp,J = 9.6,6.4Hz,1H),2.41–2.31(m,1H),2.04–2.00(m,2H),1.62–1.55(m,1H),1.45(s,3H),1.33(d,J = 6.9Hz,3H),1.30(s,3H). 13 13C NMR(126MHz,CDCl3)δ182.86,174.76,170.12,165.38,152.95,137.14,133.34,132.53,130.67,129.68(2C),129.06,128.10(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] + Calculated m / z: 417.1697, Found 417.1696.

[0137] 4-2: 1 H NMR (500 MHz, CDCl3) δ 7.97–7.91 (m, 2H), 7.77 (d, J = 8.3 Hz, 1H), 7.69 (d, J = 8.3 Hz, 1H), 7.49–7.43 (m, 1H), 7.33 (t, J = 7.7 Hz, 2H), 6.75 (t, J = 2.8 Hz, 1H), 4.89 (t, J = 9.6 Hz, 1H), 4.35 (dd, J = 9.4, 6.2 Hz, 1H), 3.57 (dp, J = 9.7, 6.7 Hz, 1H), 2.41–2.35 (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 (126 MHz, CDCl3) δ 182.77, 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] + Calculated m / z: 417.1697, Found: 417.1699.

[0138] Example 5

[0139] The preparation method was the same as that of 1-1. Using cinnamic acid (101 mg, 0.675 mmol) as the raw material, silica gel column chromatography (PE:EtOAc = 3:1 - 1:1) gave the orange solid compound 5-1 (34 mg, 23%) and its diastereomer 5-2 (38 mg, 25%).

[0140]

[0141] 5-1: 11H NMR (500 MHz, CDCl3) δ 7.75 (d, J = 8.3 Hz, 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 = 16.0 Hz, 1H), 4.87 (t, J = 9.5 Hz, 1H), 4.36 (dd, J = 9.3, 5.9 Hz, 1H), 3.57 (dp, J = 9.6, 6.7 Hz, 1H), 2.35–2.29 (m, 1H), 2.06–1.93 (m, 2H), 1.60–1.54 (m, 1H), 1.43 (s, 3H), 1.33 (d, J = 6.9 Hz, 3H), 1.29 (s, 3H). 13 13C NMR (126 MHz, CDCl3) δ 182.95, 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] + Calcd for [M + H]+ m / z: 443.1853, found: 443.1853.

[0142] 5-2: 1 1H NMR (500 MHz, CDCl3) δ 7.75 (d, J = 8.2 Hz, 1H), 7.68 (d, J = 3.0 Hz, 1H), 7.66 (d, J = 4.8 Hz, 1H), 7.48–7.42 (m, 2H), 7.34–7.29 (m, 3H), 6.65 (t, J = 2.8 Hz, 1H), 6.35 (d, J = 16.0 Hz, 1H), 4.89 (t, J = 9.5 Hz, 1H), 4.36 (dd, J = 9.4, 6.1 Hz, 1H), 3.58 (dp, J = 9.7, 6.6 Hz, 1H), 2.36–2.26 (m, 1H), 2.05–1.94 (m, 2H), 1.61–1.53 (m, 1H), 1.43 (s, 3H), 1.32 (d, J = 6.8 Hz, 3H), 1.29 (s, 3H). 1313C NMR (126 MHz, CDCl3) δ 182.92, 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] + Calcd for m / z: 443.1853, Found: 443.1853.

[0143] Example 6

[0144] DMAP (56 mg, 0.463 mmol) was dissolved in 20 ml of pyridine. Succinic anhydride (906 mg, 0.292 mmol) and borneol (310 mg, 2.013 mmol) were added successively. The mixture was stirred at 58 °C for 5 days. After the reaction was monitored by TLC and completed, the crude product was concentrated under reduced pressure using a rotary evaporator at 58 °C and a vacuum of 0.1 Mpa. After cooling to room temperature, the product was purified by silica gel column chromatography (PE:EtOAc = 5:1 - 0:1) to obtain a white foamy compound (380 mg, 75%). The crude product was dissolved in 8 ml of chlorobenzene, and cryptotanshinone (221 mg, 0.747 mmol) and TEMPO (140 mg, 0.896 mmol) were added successively. The preparation method was the same as that in 1 - 1 to obtain an orange solid compound 6 - 1 (92 mg, 22%) and its diastereomer 6 - 2 (88 mg, 21%).

[0145]

[0146] 6 - 1: 11H NMR (500 MHz, CDCl3) δ 7.73 (d, J = 8.2 Hz, 1H), 7.66 (d, J = 8.2 Hz, 1H), 6.47 (t, J = 3.9, 3.1 Hz, 1H), 4.90 (t, J = 9.5 Hz, 1H), 4.86 (ddd, J = 9.9, 3.5, 2.1 Hz, 1H), 4.38 (dd, J = 9.4, 5.9 Hz, 1H), 3.60 (dp, J = 9.6, 6.7 Hz, 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 = 6.8 Hz, 3H), 1.39–1.17 (m, 2H), 1.26 (s, 3H), 0.95 (dd, J = 13.7, 3.5 Hz, 1H), 0.87 (s, 3H), 0.85 (s, 3H), 0.78 (s, 3H). 13 13C NMR (126 MHz, CDCl3) δ 183.29, 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] + Calcd for m / z: 549.2847, Found: 549.2845.

[0147] 6-2: 11H NMR (500 MHz, CDCl3) δ 7.72 (d, J = 8.3 Hz, 1H), 7.65 (d, J = 8.2 Hz, 1H), 6.44 (t, J = 3.5 Hz, 1H), 4.89 (t, J = 9.5 Hz, 1H), 4.83 (ddd, J = 9.9, 3.5, 2.2 Hz, 1H), 4.37 (dd, J = 9.3, 6.1 Hz, 1H), 3.59 (dp, J = 9.5, 6.7 Hz, 1H), 2.78–2.67 (m, 1H), 2.66–2.50 (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 = 2.6 Hz, 3H), 1.34 (d, J = 6.8 Hz, 3H), 1.26 (s, 3H), 1.32–1.12 (m, 2H), 0.89 (dd, J = 13.9, 3.6 Hz, 1H), 0.86 (s, 3H), 0.84 (s, 3H), 0.79 (s, 3H). 13 13C NMR (126 MHz, CDCl3) δ 183.31, 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] + Calcd for m / z: 549.2847, found: 549.2845.

[0148] Example 7

[0149] Cryptotanshinone (500 mg, 1.687 mmol) was dissolved in 17 ml of chlorobenzene. Propionic acid (252 μl, 3.374 mmol), TEMPO (316 mg, 2.024 mmol) were added successively. The reaction was stirred at 120 °C for 24 h. After the reaction was monitored by TLC and completed, the crude product was concentrated under reduced pressure using a rotary evaporator at 80 °C and a vacuum of 0.1 Mpa. After cooling to room temperature, the crude product a of a pair of diastereoisomers was obtained by silica gel column chromatography (PE:EtOAc = 3:1 - 1:1). 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. The reaction was stirred at 65 °C. After the reaction was monitored by TLC and completed, it was cooled. Concentrated hydrochloric acid (6 ml) and water (12 ml) were added successively to neutralize the excess sodium hydroxide. It was concentrated under reduced pressure and extracted with ethyl acetate (3 × 50 ml). The organic phases were combined, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure using a rotary evaporator at 40 °C and a vacuum 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 absolute ethanol. Concentrated sulfuric acid (8 ml) was slowly added dropwise in batches at 0 °C. After the temperature dropped to room temperature, the reaction continued for 45 min. After the reaction was confirmed by TLC to be completed, saturated NaHCO3 solution (20 ml) was added dropwise at 0 °C and stirred for 10 min until no bubbles were generated. It was concentrated under reduced pressure and extracted with ethyl acetate (3 × 50 ml). After the organic layers were combined, they were washed successively with water and saturated brine, dried over anhydrous NaSO4, concentrated, and purified by silica gel column chromatography (PE:EtOAc = 8:1 - 2:1) to obtain the orange-red solid compound 7-1 (215 mg, 43%). (The structure of the crude product a is The structure of the crude product b is )

[0150] 7-1: 1 H NMR (500 MHz, CDCl3) δ 7.86 (dt, J = 10.3, 1.8 Hz, 1H), 7.52 (d, J = 7.9 Hz, 1H), 7.47 (d, J = 7.9 Hz, 1H), 6.30 (dt, J = 10.2, 4.6 Hz, 1H), 4.88 (t, J = 9.5 Hz, 1H), 4.35 (dd, J = 9.3, 6.0 Hz, 1H), 3.59 (dp, J = 9.6, 6.5 Hz, 1H), 2.26 (dd, J = 4.6, 1.9 Hz, 2H), 1.34 (d, J = 6.8 Hz, 3H), 1.27 (s, 3H), 1.27 (s, 3H). 13CNMR(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] + Calculated for [M+H]+ m / z: 295.1329, found 295.1329.

[0151] Example 8

[0152] 7-1 (75 mg, 0.255 mmol) was dissolved in 3 ml of 1,4-dioxane. Selenium dioxide (84 mg, 0.765 mmol) and tert-butyl hydroperoxide (93 μl, 0.510 mmol) were successively added at 0 °C. The reaction mixture was heated at 55 °C. After the reaction was monitored by TLC and completed, the crude product was concentrated under reduced pressure using a rotary evaporator at 50 °C and a vacuum of 0.1 Mpa. After cooling to room temperature, the product was purified by silica gel column chromatography (DCM:MeOH = 100:1 - 20:1) to obtain an orange-red solid compound 8-1 (24 mg, 30%).

[0153]

[0154] 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 = 10.6,6.6,4.3Hz,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). 1313C NMR (126 MHz, CDCl3) δ 184.56, 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] + Calculated m / z: 311.1278, Found: 311.1278.

[0155] Example 9

[0156] 7-1 (51 mg, 0.173 mmol) was dissolved in 2 ml of 1,4-dioxane. Selenium dioxide (115 mg, 1.038 mmol) and tert-butyl hydroperoxide (63 μl, 0.346 mmol) were added successively at 0 °C. The reaction mixture was heated at 100 °C. After the reaction was monitored by TLC and completed, the crude product was concentrated under reduced pressure using a rotary evaporator at 50 °C and a vacuum of 0.1 Mpa. After cooling to room temperature, the product was purified by silica gel column chromatography (DCM:MeOH = 100:1 - 20:1) to obtain an orange-red solid compound 9-1 (50 mg, 94%).

[0157]

[0158] 9-1: 1 1H NMR (500 MHz, CDCl3) δ 9.01 (d, J = 10.5 Hz, 1H), 7.72 (s, 2H), 6.39 (d, J = 10.5 Hz, 1H), 4.94 (t, J = 9.5 Hz, 1H), 4.41 (dd, J = 9.3, 6.1 Hz, 1H), 3.64 (dp, J = 9.5, 6.8 Hz, 1H), 1.49 (d, J = 2.4 Hz, 6H), 1.37 (d, J = 6.8 Hz, 3H). 13 13C NMR (126 MHz, CDCl3) δ 201.78, 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] +Calculated m / z value: 309.1121, measured value: 309.1121.

[0159] Example 10

[0160] Take 9-1 (54 mg, 0.175 mmol) and 10% palladium on carbon (11 mg, 0.105 mmol), dissolve them in 5 ml of dry tetrahydrofuran, displace with hydrogen three times, stir and react at room temperature (15 - 25 °C) in a hydrogen atmosphere. After monitoring the reaction by TLC until it is completed, filter to recover the palladium on carbon. Concentrate under reduced pressure using a rotary evaporator at 25 °C and a vacuum of 0.1 Mpa to obtain the crude product. Cool to room temperature and perform silica gel column chromatography (DCM:MeOH = 100:1 - 20:1) to obtain the orange-red solid compound 10-1 (26 mg, 48%) and 10-2 (24 mg, 44%).

[0161]

[0162] 10-1: 1 H NMR (500 MHz, CDCl3) δ 7.63 (d, J = 8.1 Hz, 1H), 7.60 (d, J = 8.1 Hz, 1H), 4.92 (t, J = 9.5 Hz, 1H), 4.39 (dd, J = 9.3, 6.1 Hz, 1H), 3.65 (t, J = 6.8 Hz, 2H), 3.64–3.57 (m, 1H), 2.64 (t, J = 6.9 Hz, 2H), 1.45 (s, 3H), 1.45 (s, 3H), 1.36 (d, J = 6.8 Hz, 3H). 13 C NMR (126 MHz, CDCl3) δ 212.61, 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] + Calculated m / z value: 311.1278, measured value: 311.1277.

[0163]

[0164] 10-2: 11H NMR (500 MHz, CDCl3) δ 7.65 (d, J = 8.1 Hz, 1H), 7.52 (d, J = 8.1 Hz, 1H), 4.89 (dt, J = 9.5, 2.3 Hz, 1H), 4.36 (dd, J = 9.3, 6.0 Hz, 1H), 3.77 (dd, J = 8.6, 2.8 Hz, 1H), 3.63–3.55 (m, 1H), 3.35 (ddt, J = 92.2, 19.7, 6.8 Hz, 2H), 2.09–1.86 (m, 2H), 1.36–1.32 (m, 9H). 13 13C NMR (126 MHz, CDCl3) δ 184.05, 175.42, 170.75, 151.11, 142.12, 132.88, 127.83, 126.57, 123.00, 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] + Calcd for m / z: 313.1434, Found: 313.1434.

[0165] Example 11

[0166] Cryptotanshinone (100 mg, 0.337 mmol) was dissolved in 3 ml of acetic anhydride. Zinc powder (221 mg, 3.370 mmol) and sodium acetate (28 mg, 0.337 mmol) were added successively. The mixture was stirred at 50 °C for about 1 h. After confirming the completion of the reaction by TLC, the zinc powder was filtered off. 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. Silica gel column chromatography (PE:EtOAc = 5:1 - 1:1) gave the white solid compound 11-1 (96 mg, 74%).

[0167]

[0168] 11-1: 11H NMR (500 MHz, CDCl3) δ 7.74 (d, J = 8.8 Hz, 1H), 7.42 (d, J = 8.9 Hz, 1H), 4.86 (t, J = 8.9 Hz, 1H), 4.30 (dd, J = 8.6, 6.4 Hz, 1H), 3.75 (dp, J = 9.0, 6.5 Hz, 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 13C NMR (126 MHz, CDCl3) δ 169.51, 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] + Calcd for m / z: 383.1853, found: 383.1851.

[0169] Example 12

[0170] 7-1 (32 mg, 0.109 mmol) was dissolved in 2 ml of acetic anhydride. Zinc powder (71 mg, 1.088 mmol) and sodium acetate (9 mg, 0.109 mmol) were added successively. The mixture was stirred at 50 °C for about 1 h. After confirming the completion of the reaction by TLC, the zinc powder was filtered off. 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. Silica gel column chromatography (PE:EtOAc = 5:1 - 1:1) gave the white solid compound 12-1 (35 mg, 84%).

[0171]

[0172] 12-1: 11H NMR (500 MHz, CDCl3) δ 7.82 (d, J = 8.7 Hz, 1H), 7.46 (d, J = 8.7 Hz, 1H), 7.40 (dt, J = 10.2, 1.8 Hz, 1H), 6.05 (dt, J = 9.9, 4.8 Hz, 1H), 4.87 (t, J = 8.9 Hz, 1H), 4.32 (dd, J = 8.6, 6.3 Hz, 1H), 3.76 (dp, J = 9.1, 6.8 Hz, 1H), 2.36 (s, 3H), 2.35 (s, 3H), 2.26–2.19 (m, 2H), 1.32 (d, J = 6.8 Hz, 3H), 1.30 (s, 3H), 1.27 (s, 3H). 13 13C NMR (126 MHz, CDCl3) δ 168.94, 168.12, 154.68, 144.55, 138.12, 131.87, 127.26, 126.49, 125.36, 124.29, 122.70, 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] + Calcd for m / z: 381.1697, Found: 381.1696.

[0173] Example 13

[0174] 12 - 1 (103 mg, 0.271 mmol) was dissolved in 3 ml of dry 1,4 - dioxane. The solution was purged with argon three times, and then selenium dioxide (60 mg, 0.541 mmol) was added. The mixture was refluxed at 100 °C for 30 min under an argon atmosphere. After the reaction was monitored by TLC and completed, the mixture was filtered, concentrated, extracted with ethyl acetate (3 × 10 ml). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. Silica gel column chromatography (dichloromethane:methanol (DCM:MeOH) = 100:1 - 20:1) gave the white solid compound 13 - 1 (50 mg, 47%) and 9 - 1.

[0175]

[0176] 13 - 1: 11H NMR (500 MHz, CDCl3) δ 8.71 (d, J = 10.5 Hz, 1H), 8.03 (d, J = 8.8 Hz, 1H), 7.52 (d, J = 8.8 Hz, 1H), 6.23 (d, J = 10.5 Hz, 1H), 4.90 (t, J = 8.9 Hz, 1H), 4.34 (dd, J = 8.7, 6.4 Hz, 1H), 3.79 (dp, J = 9.2, 6.8 Hz, 1H), 2.41 (s, 3H), 2.36 (s, 3H), 1.50 (s, 3H), 1.49 (s, 3H), 1.33 (d, J = 6.9 Hz, 3H). 13 13C NMR (126 MHz, CDCl3) δ 203.61, 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] + Calcd for m / z: 395.1489, Found: 395.1489.

[0177] Example 14

[0178] 13 - 1 (119 mg, 0.302 mmol) and 10% palladium on carbon (19 mg, 0.181 mmol) were dissolved in 10 ml of dry tetrahydrofuran. The mixture was purged with hydrogen three times and stirred at room temperature (15 - 25 °C) under a hydrogen atmosphere. After the reaction was monitored by TLC and completed, the palladium on carbon was recovered by filtration. The crude product was concentrated under reduced pressure using a rotary evaporator at 25 °C and a vacuum of 0.1 Mpa. After cooling to room temperature, silica gel column chromatography (DCM:MeOH = 100:1 - 20:1) gave the orange - red solid compounds 14 - 1 (11 mg, 9%) and 14 - 2 (75 mg, 62%).

[0179]

[0180] 14 - 1: 11H NMR (500 MHz, CDCl3) δ 7.87 (d, J = 8.7 Hz, 1H), 7.39 (d, J = 8.9 Hz, 1H), 4.89 (t, J = 8.9 Hz, 1H), 4.33 (dd, J = 8.7, 6.4 Hz, 1H), 3.77 (dp, J = 9.1, 6.7 Hz, 1H), 2.71 (t, J = 6.9 Hz, 2H), 2.36 (s, 3H), 2.35 (s, 3H), 1.68–1.59 (m, 2H), 1.47 (s, 6H), 1.33 (d, J = 6.8 Hz, 3H). 13 13C NMR (126 MHz, CDCl3) δ 214.48, 169.11, 167.98, 154.87, 143.99, 138.46, 131.84, 129.19, 126.45, 124.34, 121.47, 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] + Calcd for m / z: 397.1646, found: 397.1647.

[0181]

[0182] 14-2: 1 1H NMR (500 MHz, CDCl3) δ 7.78 (d, J = 8.9 Hz, 1H), 7.40 (d, J = 8.9 Hz, 1H), 4.86 (t, J = 8.9 Hz, 1H), 4.30 (dd, J = 8.6, 6.4 Hz, 1H), 3.77–3.71 (m, 2H), 3.30 (d, J = 120.4 Hz, 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 = 2.5 Hz, 3H), 1.31 (s, 3H), 1.30 (s, 3H). 1313C NMR (126 MHz, CDCl3) δ 169.53, 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] + Calcd for m / z: 399.1802, found: 399.1803.

[0183] Example 15

[0184] Preparation of cryptotanshinone derivatives 15-1 and 15-2:

[0185] Cryptotanshinone (100 mg, 0.337 mmol) was dissolved in 3 ml of chlorobenzene. Phenol (54 mg, 0.574 mmol) and TEMPO (105 mg, 0.675 mmol) were added successively. The mixture was stirred at 120 °C for 24 h. After the reaction was monitored by TLC and completed, the crude product was concentrated under reduced pressure using a rotary evaporator at 80 °C and a vacuum of 0.1 Mpa. After cooling to room temperature, silica gel column chromatography (PE:EtOAc = 3:1 - 1:1) gave the orange solid compound 15-1 (30 mg, 23%) and its diastereomer 15-2 (33 mg, 25%).

[0186]

[0187] 15-1: 1 1H NMR (500 MHz, CDCl3) δ 7.76 (d, J = 8.3 Hz, 1H), 7.68 (d, J = 8.2 Hz, 1H), 7.32–7.28 (m, 2H), 7.15–7.12 (m, 2H), 6.96 (tt, J = 7.3, 1.1 Hz, 1H), 6.57 (t, J = 3.2 Hz, 1H), 4.89 (t, J = 9.5 Hz, 1H), 4.37 (dd, J = 9.4, 5.9 Hz, 1H), 3.65–3.53 (m, 1H), 2.22 (ddt, J = 14.6, 4.4, 2.9 Hz, 1H), 2.11 (td, J = 13.7, 2.9 Hz, 1H), 1.82 (tt, J = 14.2, 3.1 Hz, 1H), 1.48–1.45 (m, 1H), 1.45 (s, 3H), 1.35 (d, J = 6.8 Hz, 3H), 1.28 (s, 3H). 1313C NMR (126 MHz, CDCl3) δ 183.28, 175.03, 170.37, 157.22, 152.68, 138.22, 133.31, 129.47 (2C), 128.92, 127.21, 125.10, 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] + Calcd for m / z: 389.1747, Found: 389.1747.

[0188] 15 - 2: 1 1H NMR (500 MHz, CDCl3) δ 7.76 (d, J = 8.3 Hz, 1H), 7.68 (d, J = 8.3 Hz, 1H), 7.32–7.27 (m, 2H), 7.16–7.11 (m, 2H), 6.95 (tt, J = 7.3, 1.1 Hz, 1H), 6.59 (t, J = 3.2 Hz, 1H), 4.89 (t, J = 9.5 Hz, 1H), 4.38 (dd, J = 9.4, 5.8 Hz, 1H), 3.64–3.55 (m, 1H), 2.26–2.16 (m, 1H), 2.15–2.04 (m, 1H), 1.84 (tt, J = 14.3, 3.2 Hz, 1H), 1.49–1.45 (m, 1H), 1.45 (s, 3H), 1.31 (d, J = 6.8 Hz, 3H), 1.28 (s, 3H). 13 13C NMR (126 MHz, CDCl3) δ 183.31, 175.03, 170.38, 157.25, 152.69, 138.26, 133.33, 129.46 (2C), 128.88, 127.22, 125.11, 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] + Calcd for m / z: 389.1747, Found 389.1747.

[0189] Example 16

[0190] The preparation method was the same as that of 15-1. Using 4-nitrophenol (80 mg, 0.574 mmol) as the raw material, silica gel column chromatography (PE:EtOAc = 3:1 - 1:1) was carried out to obtain the orange solid compound 16-1 (47 mg, 32%) and its diastereomer 16-2 (43 mg, 29%).

[0191]

[0192] 16-1: 1 H NMR (500 MHz, CDCl3) δ 8.22–8.17 (m, 2H), 7.80 (d, J = 8.3 Hz, 1H), 7.72 (d, J = 8.2 Hz, 1H), 7.12–7.07 (m, 2H), 6.60 (t, J = 3.2 Hz, 1H), 4.89 (t, J = 9.5 Hz, 1H), 4.38 (dd, J = 9.4, 5.9 Hz, 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 = 6.8 Hz, 3H), 1.29 (s, 3H). 13 C NMR (126 MHz, CDCl3) δ 183.24, 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 value: 434.1598, measured value: 434.1597.

[0193] 16-2: 11H NMR (500 MHz, CDCl3) δ 8.23–8.18 (m, 2H), 7.80 (d, J = 8.2 Hz, 1H), 7.72 (d, J = 8.2 Hz, 1H), 7.12–7.08 (m, 2H), 6.61 (t, J = 2.9 Hz, 1H), 4.91 (t, J = 9.5 Hz, 1H), 4.38 (dd, J = 9.4, 6.0 Hz, 1H), 3.60 (dp, J = 9.8, 6.8 Hz, 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 = 6.8 Hz, 3H), 1.30 (s, 3H). 13 13C NMR (126 MHz, CDCl3) δ 183.28, 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] + Calcd for m / z: 434.1598, found: 434.1599.

[0194] Example 17

[0195] Prepared in the same way as 15-1, using 4-cyanophenol (80 mg, 0.674 mmol) as the starting material, and purified by silica gel column chromatography (PE:EtOAc = 3:1 - 1:1) to obtain the orange solid compound 17-1 (40 mg, 29%) and its diastereomer 17-2 (38 mg, 27%).

[0196]

[0197] 17-1: 11H NMR (500 MHz, CDCl3) δ 7.79 (d, J = 8.3 Hz, 1H), 7.71 (d, J = 8.2 Hz, 1H), 7.61–7.57 (m, 2H), 7.12–7.08 (m, 2H), 6.57 (t, J = 3.1 Hz, 1H), 4.89 (t, J = 9.5 Hz, 1H), 4.38 (dd, J = 9.4, 5.9 Hz, 1H), 3.58 (dp, J = 9.6, 6.7 Hz, 1H), 2.23–2.15 (m, 1H), 2.07–1.99 (m, 1H), 1.96–1.87 (m, 1H), 1.53–1.47 (m, 1H), 1.45 (s, 3H), 1.34 (d, J = 6.8 Hz, 3H), 1.29 (s, 3H). 13 13C NMR (126 MHz, CDCl3) δ 183.24, 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] + Calculated for [M + H]+: 414.1700, Found: 414.1697.

[0198] 17 - 2: 1 1H NMR (500 MHz, CDCl3) δ 7.79 (d, J = 8.2 Hz, 1H), 7.71 (d, J = 8.2 Hz, 1H), 7.63–7.55 (m, 2H), 7.13–7.08 (m, 2H), 6.58 (t, J = 3.2 Hz, 1H), 4.90 (t, J = 9.5 Hz, 1H), 4.38 (dd, J = 9.4, 6.0 Hz, 1H), 3.59 (dp, J = 9.7, 6.7 Hz, 1H), 2.23–2.14 (m, 1H), 2.03 (td, J = 13.4, 2.5 Hz, 1H), 1.92 (tt, J = 14.2, 2.9 Hz, 1H), 1.55–1.48 (m, 1H), 1.44 (s, 3H), 1.31 (d, J = 6.8 Hz, 3H), 1.29 (s, 3H). 1313C NMR (126 MHz, CDCl3) δ 183.27, 174.71, 170.33, 161.10, 152.55, 136.87, 134.03 (2C), 133.99, 133.58, 128.63, 127.39, 125.53, 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] + Calculated for m / z: 414.1700, found: 414.1702.

[0199] Example 18

[0200] Prepared in the same way as 15-1, using p-hydroxybenzaldehyde (70 mg, 0.574 mmol) as the starting material, and purified by silica gel column chromatography (PE:EtOAc = 3:1 - 1:1) to give the orange solid compound 18-1 (43 mg, 31%) and its diastereomer 18-2 (37 mg, 26%).

[0201]

[0202] 18-1: 1 1H NMR (500 MHz, CDCl3) δ 9.86 (s, 1H), 7.85–7.81 (m, 2H), 7.77 (d, J = 8.3 Hz, 1H), 7.69 (d, J = 8.2 Hz, 1H), 7.17–7.13 (m, 2H), 6.62 (t, J = 3.1 Hz, 1H), 4.87 (t, J = 9.5 Hz, 1H), 4.35 (dd, J = 9.4, 5.9 Hz, 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, 3.1 Hz, 1H), 1.52–1.47 (m, 1H), 1.44 (s, 3H), 1.32 (d, J = 6.8 Hz, 3H), 1.28 (s, 3H). 1313C NMR (126 MHz, CDCl3) δ 190.94, 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] + Calculated for m / z: 417.1697, Found: 417.1696.

[0203] 18 - 2: 1 1H NMR (500 MHz, CDCl3) δ 9.88 (s, 1H), 7.86–7.82 (m, 2H), 7.79 (d, J = 8.2 Hz, 1H), 7.71 (d, J = 8.2 Hz, 1H), 7.18–7.14 (m, 2H), 6.64 (t, J = 3.2 Hz, 1H), 4.90 (t, J = 9.5 Hz, 1H), 4.38 (dd, J = 9.4, 6.0 Hz, 1H), 3.59 (dp, J = 9.6, 6.7 Hz, 1H), 2.26–2.20 (m, 1H), 2.09–2.01 (m, 1H), 1.94 (tt, J = 14.2, 3.0 Hz, 1H), 1.54–1.47 (m, 1H), 1.45 (s, 3H), 1.31 (d, J = 6.8 Hz, 3H), 1.30 (s, 3H). 13 13C NMR (126 MHz, CDCl3) δ 190.94, 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] + Calculated for m / z: 417.1697, Found: 417.1695.

[0204] Example 19

[0205] The preparation method was the same as that of 15-1. Using 4-acetylphenol (78 mg, 0.574 mmol) as the raw material, silica gel column chromatography (PE:EtOAc = 3:1 - 1:1) was carried out to obtain the orange solid compound 19-1 (38 mg, 26%) and its diastereomer 19-2 (40 mg, 28%).

[0206]

[0207] 19-1: 1 H NMR (500 MHz, CDCl3) δ 7.95–7.92 (m, 2H), 7.77 (d, J = 8.3 Hz, 1H), 7.69 (d, J = 8.3 Hz, 1H), 7.11–7.07 (m, 2H), 6.61 (t, J = 3.2 Hz, 1H), 4.88 (t, J = 9.5 Hz, 1H), 4.36 (dd, J = 9.4, 5.9 Hz, 1H), 3.56 (dp, J = 9.5, 6.6 Hz, 1H), 2.55 (s, 3H), 2.25–2.16 (m, 1H), 2.09–2.01 (m, 1H), 1.90 (tt, J = 14.2, 3.1 Hz, 1H), 1.51–1.46 (m, 1H), 1.44 (s, 3H), 1.33 (d, J = 6.8 Hz, 3H), 1.28 (s, 3H). 13 C NMR (126 MHz, CDCl3) δ 196.96, 183.21, 174.73, 170.31, 161.68, 152.56, 137.24, 133.47, 130.68 (2C), 130.27, 128.76, 127.32, 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 value: 431.1853, measured value: 431.1853.

[0208] 19-2: 11H NMR (500 MHz, CDCl3) δ 7.95–7.90 (m, 2H), 7.77 (d, J = 8.2 Hz, 1H), 7.69 (d, J = 8.2 Hz, 1H), 7.10–7.07 (m, 2H), 6.61 (t, J = 3.1 Hz, 1H), 4.88 (t, J = 9.5 Hz, 1H), 4.36 (dd, J = 9.4, 6.0 Hz, 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, 3.1 Hz, 1H), 1.52–1.45 (m, 1H), 1.43 (s, 3H), 1.29 (d, J = 6.8 Hz, 3H), 1.28 (s, 3H). 13 13C NMR (126 MHz, CDCl3) δ 196.92, 183.25, 174.78, 170.31, 161.72, 152.58, 137.26, 133.51, 130.67 (2C), 130.25, 128.70, 127.32, 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] + Calculated for m / z: 431.1853, Found: 431.1854.

[0209] Example 20

[0210] Prepared in the same way as 15-1, using 3-chlorophenol (57 μl, 0.574 mmol) as the starting material, and purified by silica gel column chromatography (PE:EtOAc = 3:1 - 1:1) to obtain the orange solid compound 20-1 (37 mg, 26%) and its diastereomer 20-2 (37 mg, 26%).

[0211]

[0212] 20-1: 11H NMR (500 MHz, CDCl3) δ 7.76 (d, J = 8.3 Hz, 1H), 7.68 (d, J = 8.2 Hz, 1H), 7.20 (t, J = 8.1 Hz, 1H), 7.08 (t, J = 2.2 Hz, 1H), 7.00 (dd, J = 8.3, 2.4 Hz, 1H), 6.92 (dd, J = 7.9, 1.9 Hz, 1H), 6.50 (t, J = 3.3 Hz, 1H), 4.88 (t, J = 9.5 Hz, 1H), 4.36 (dd, J = 9.4, 5.9 Hz, 1H), 3.57 (dp, J = 9.5, 6.7 Hz, 1H), 2.23–2.17 (m, 1H), 2.08–2.01 (m, 1H), 1.84 (tt, J = 14.3, 3.1 Hz, 1H), 1.50–1.45 (m, 1H), 1.44 (s, 3H), 1.33 (d, J = 6.8 Hz, 3H), 1.27 (s, 3H). 13 13C NMR (126 MHz, CDCl3) δ 183.18, 174.78, 170.47, 158.11, 152.64, 137.57, 134.76, 133.46, 130.27, 128.72, 127.25, 125.33, 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] + Calcd for m / z: 423.1358, found: 423.1359.

[0213] 20 - 2: 11H NMR (500 MHz, CDCl3) δ 7.76 (d, J = 8.2 Hz, 1H), 7.68 (d, J = 8.2 Hz, 1H), 7.20 (t, J = 8.1 Hz, 1H), 7.08 (t, J = 2.2 Hz, 1H), 7.00 (dd, J = 8.2, 2.2 Hz, 1H), 6.92 (dd, J = 7.9, 1.0 Hz, 1H), 6.52 (t, J = 3.1 Hz, 1H), 4.89 (t, J = 9.5 Hz, 1H), 4.37 (dd, J = 9.4, 5.9 Hz, 1H), 3.59 (dp, J = 9.5, 6.7 Hz, 1H), 2.23–2.17 (m, 1H), 2.04 (td, J = 13.7, 2.9 Hz, 1H), 1.85 (tt, J = 14.3, 3.1 Hz, 1H), 1.50–1.44 (m, 1H), 1.43 (s, 3H), 1.31 (d, J = 6.8 Hz, 3H), 1.28 (s, 3H). 13 13C NMR (126 MHz, CDCl3) δ 183.22, 174.87, 170.41, 158.14, 152.63, 137.59, 134.76, 133.47, 130.26, 128.70, 127.27, 125.32, 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 + Calculated for + [M + H]+ m / z: 423.1358, found: 423.1360.

[0214] Example 21

[0215] Prepared in the same way as 15-1 using 4-chlorophenol (67 μl, 0.574 mmol) as the starting material. Purified by silica gel column chromatography (PE:EtOAc = 3:1 - 1:1) to give the orange solid compound 21-1 (25 mg, 18%) and its diastereomer 21-2 (33 mg, 23%).

[0216]

[0217] 21-1: 11H NMR (500 MHz, CDCl3) δ 7.76 (d, J = 8.2 Hz, 1H), 7.68 (d, J = 8.2 Hz, 1H), 7.27–7.23 (m, 2H), 7.09–7.04 (m, 2H), 6.49 (t, J = 3.1 Hz, 1H), 4.89 (t, J = 9.5 Hz, 1H), 4.37 (dd, J = 9.4, 5.9 Hz, 1H), 3.58 (dp, J = 9.6, 6.7 Hz, 1H), 2.26–2.13 (m, 1H), 2.11–2.02 (m, 1H), 1.82 (tt, J = 14.2, 3.1 Hz, 1H), 1.50–1.46 (m, 1H), 1.44 (s, 3H), 1.35 (d, J = 6.8 Hz, 3H), 1.27 (s, 3H). 13 13C NMR (126 MHz, CDCl3) δ 183.30, 174.90, 170.39, 155.92, 152.60, 137.74, 133.41, 129.36 (2C), 128.80, 127.27, 125.83, 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] + Calculated m / z: 423.1358, found: 423.1357.

[0218] 21 - 2: 1 1H NMR (500 MHz, CDCl3) δ 7.76 (d, J = 8.2 Hz, 1H), 7.68 (d, J = 8.2 Hz, 1H), 7.25–7.22 (m, 2H), 7.08–7.04 (m, 2H), 6.50 (t, J = 3.1 Hz, 1H), 4.89 (t, J = 9.5 Hz, 1H), 4.38 (dd, J = 9.3, 5.8 Hz, 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, 3.1 Hz, 1H), 1.50–1.45 (m, 1H), 1.44 (s, 3H), 1.31 (d, J = 6.8 Hz, 3H), 1.28 (s, 3H). 1313C NMR (126 MHz, CDCl3) δ 183.34, 174.92, 170.39, 155.97, 152.61, 137.77, 133.45, 129.35 (2C), 128.76, 127.28, 125.80, 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] + : Calculated for 423.1358 m / z, found: 423.1357.

[0219] Example 22

[0220] The preparation method was the same as that of 15-1. Using o-chlorophenol (57 μl, 0.574 mmol) as the raw material, silica gel column chromatography (PE:EtOAc = 3:1 - 1:1) gave the orange solid compound 22-1 (28 mg, 20%) and its diastereomer 22-2 (30 mg, 21%).

[0221]

[0222] 22-1: 1 1H NMR (500 MHz, CDCl3) δ 7.76 (d, J = 8.2 Hz, 1H), 7.68 (d, J = 8.2 Hz, 1H), 7.56 (dd, J = 8.4, 1.4 Hz, 1H), 7.31–7.26 (m, 2H), 6.89 (td, J = 7.7, 1.4 Hz, 1H), 6.67 (t, J = 3.2 Hz, 1H), 4.87 (t, J = 9.5 Hz, 1H), 4.35 (dd, J = 9.4, 5.9 Hz, 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, 3.1 Hz, 1H), 1.45 (s, 3H), 1.48–1.43 (m, 1H), 1.34 (d, J = 6.8 Hz, 3H), 1.27 (s, 3H). 1313C NMR (126 MHz, CDCl3) δ 183.45, 174.91, 170.44, 152.96, 152.82, 137.55, 133.44, 130.14, 128.86, 127.93, 127.16, 125.28, 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] + Calculated for m / z: 423.1358, Found: 423.1355.

[0223] 22 - 2: 1 1H NMR (500 MHz, CDCl3) δ 7.76 (d, J = 8.2 Hz, 1H), 7.68 (d, J = 8.2 Hz, 1H), 7.58 (dd, J = 8.5, 1.4 Hz, 1H), 7.31–7.25 (m, 2H), 6.88 (td, J = 7.7, 1.4 Hz, 1H), 6.68 (t, J = 3.1 Hz, 1H), 4.88 (t, J = 9.5 Hz, 1H), 4.37 (dd, J = 9.4, 5.8 Hz, 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, 3.1 Hz, 1H), 1.48–1.43 (m, 1H), 1.45 (s, 3H), 1.31 (d, J = 6.8 Hz, 3H), 1.28 (s, 3H). 13 13C NMR (126 MHz, CDCl3) δ 183.44, 174.89, 170.44, 152.95, 152.87, 137.59, 133.47, 130.12, 128.82, 127.94, 127.19, 125.29, 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] + Calculated for m / z: 423.1358, Found: 423.1355.

[0224] Example 23

[0225] The preparation method was the same as that of 15-1. Using m-fluorophenol (52 μl, 0.574 mmol) as the raw material, silica gel column chromatography (PE:EtOAc = 3:1 - 1:1) was carried out to obtain the orange solid compound 23-1 (30 mg, 22%) and its diastereomer 23-2 (36 mg, 26%).

[0226]

[0227] 23-1: 1 H NMR (500 MHz, CDCl3) δ 7.76 (d, J = 8.3 Hz, 1H), 7.68 (d, J = 8.2 Hz, 1H), 7.22 (td, J = 8.3, 6.9 Hz, 1H), 6.88 (dd, J = 8.2, 2.4 Hz, 1H), 6.84 (dt, J = 11.0, 2.4 Hz, 1H), 6.65 (td, J = 8.3, 2.4 Hz, 1H), 6.52–6.50 (m, 1H), 4.89 (t, J = 9.5 Hz, 1H), 4.37 (dd, J = 9.3, 5.9 Hz, 1H), 3.58 (dp, J = 9.6, 6.6 Hz, 1H), 2.22 (ddt, J = 14.6, 4.3, 2.9 Hz, 1H), 2.06 (td, J = 13.7, 2.9 Hz, 1H), 1.84 (tt, J = 14.3, 3.1 Hz, 1H), 1.50–1.45 (m, 1H), 1.44 (s, 3H), 1.34 (d, J = 6.8 Hz, 3H), 1.28 (s, 3H). 13 C NMR (126 MHz, CDCl3) δ 183.21, 174.84, 170.35, 163.73 (d, J = 244.3 Hz), 158.72 (d, J = 11.3 Hz), 152.61, 137.59, 133.41, 130.14 (d, J = 9.7 Hz), 128.78, 127.27, 125.28, 118.54, 112.29 (d, J = 2.8 Hz), 107.73 (d, J = 21.1 Hz), 104.15 (d, J = 24.1 Hz), 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] + Calculated m / z value: 407.1653, measured value: 407.1654.

[0228] 23-2: 11H NMR (500 MHz, CDCl3) δ 7.76 (d, J = 8.2 Hz, 1H), 7.68 (d, J = 8.2 Hz, 1H), 7.22 (td, J = 8.3, 6.9 Hz, 1H), 6.88 (dd, J = 8.3, 2.4 Hz, 1H), 6.83 (dt, J = 11.0, 2.4 Hz, 1H), 6.67–6.62 (m, 1H), 6.53–6.50 (m, 1H), 4.89 (t, J = 9.5 Hz, 1H), 4.37 (dd, J = 9.4, 5.9 Hz, 1H), 3.63–3.55 (m, 1H), 2.21 (ddt, J = 14.6, 4.3, 3.0 Hz, 1H), 2.06 (td, J = 13.7, 2.9 Hz, 1H), 1.86 (tt, J = 14.3, 3.1 Hz, 1H), 1.50–1.45 (m, 1H), 1.44 (s, 3H), 1.31 (d, J = 6.8 Hz, 3H), 1.28 (s, 3H). 13 13C NMR (126 MHz, CDCl3) δ 183.24, 174.87, 170.35, 163.72 (d, J = 245.0 Hz), 158.76 (d, J = 11.0 Hz), 152.62, 137.62, 133.44, 130.13 (d, J = 10.3 Hz), 128.73, 127.28, 125.29, 118.63, 112.21 (d, J = 2.9 Hz), 107.69 (d, J = 21.1 Hz), 104.09 (d, J = 24.7 Hz), 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] + Calcd for m / z: 407.1653, found: 407.1654.

[0229] Example 24

[0230] The preparation method was the same as that of 15-1. Using 4-fluorophenol (76 mg, 0.674 mmol) as the raw material, silica gel column chromatography (PE:EtOAc = 3:1 - 1:1) gave the orange solid compound 24-1 (31 mg, 23%) and its diastereomer 24-2 (28 mg, 20%).

[0231]

[0232] 24-1: 11H NMR (500 MHz, CDCl3) δ 7.76 (d, J = 8.2 Hz, 1H), 7.68 (d, J = 8.2 Hz, 1H), 7.14–7.09 (m, 2H), 7.01–6.95 (m, 2H), 6.46 (t, J = 3.1 Hz, 1H), 4.89 (t, J = 9.5 Hz, 1H), 4.37 (dd, J = 9.4, 6.0 Hz, 1H), 3.58 (dp, J = 9.6, 6.6 Hz, 1H), 2.18–2.03 (m, 2H), 1.79 (tt, J = 13.8, 3.0 Hz, 1H), 1.49–1.45 (m, 1H), 1.45 (s, 3H), 1.35 (d, J = 6.8 Hz, 3H), 1.27 (s, 3H). 13 13C NMR (126 MHz, CDCl3) δ 183.40, 174.99, 170.40, 157.56 (d, J = 238.5 Hz), 153.22, 152.61, 137.99, 133.38, 128.87, 127.24, 125.20, 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] + Calculated for [M + H]+: 407.1653, Found: 407.1653.

[0233] 24 - 2: 1 1H NMR (500 MHz, CDCl3) δ 7.76 (d, J = 8.3 Hz, 1H), 7.68 (d, J = 8.2 Hz, 1H), 7.14–7.08 (m, 2H), 7.01–6.94 (m, 2H), 6.47 (t, J = 3.3 Hz, 1H), 4.89 (t, J = 9.5 Hz, 1H), 4.38 (dd, J = 9.4, 5.8 Hz, 1H), 3.60 (dp, J = 9.3, 6.7 Hz, 1H), 2.19–2.04 (m, 2H), 1.81 (tt, J = 14.0, 3.1 Hz, 1H), 1.50–1.46 (m, 1H), 1.44 (s, 3H), 1.32 (d, J = 6.8 Hz, 3H), 1.28 (s, 3H). 13CNMR(126MHz,CDCl3)δ183.43,175.01,170.40,157.56(d,J=238.5Hz),153.22,152.62,138.04,133.39,128.85,127.25,125.19,118.59,118.25,118.18,115.88,115.70,81.56,68.82,35.05,34.58,31.58,31.40,31.27,22.46,18.83.HRMS(ESI):C 25 H 24 FO4 + [M+H] + Calculated for [M + H]+: 407.1653, found: 407.1654.

[0234] Example 25

[0235] Prepared in the same manner as in 15-1, using p-trifluoromethylphenol (70 μl, 0.574 mmol) as the starting material, and purified by silica gel column chromatography (PE:EtOAc = 3:1 - 1:1) to give the orange solid compound 25-1 (47 mg, 31%) and its diastereomer 25-2 (42 mg, 27%).

[0236]

[0237] 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). 1313C NMR (126 MHz, CDCl3) δ 183.22, 174.69, 170.55, 160.00, 152.66, 137.37, 133.55, 128.70, 127.31, 126.92 (q, J = 3.8 Hz) (2C), 125.44, 124.56 (q, J = 271.1 Hz), 122.74 (q, J = 32.3 Hz), 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] + Calculated for [M+H]+ m / z: 457.1621, Found: 457.1623.

[0238] 25 - 2: 1 1H NMR (500 MHz, CDCl3) δ 7.78 (d, J = 8.3 Hz, 1H), 7.70 (d, J = 8.2 Hz, 1H), 7.55 (d, J = 8.5 Hz, 2H), 7.14 (d, J = 8.6 Hz, 2H), 6.60 (t, J = 3.3 Hz, 1H), 4.89 (t, J = 9.5 Hz, 1H), 4.38 (dd, J = 9.4, 5.9 Hz, 1H), 3.59 (dp, J = 9.6, 6.6 Hz, 1H), 2.24–2.18 (m, 1H), 2.10–2.02 (m, 1H), 1.91 (tt, J = 14.3, 3.1 Hz, 1H), 1.49 (dt, J = 13.4, 3.6 Hz, 1H), 1.45 (s, 3H), 1.31 (d, J = 6.8 Hz, 3H), 1.29 (s, 3H). 13 13C NMR (126 MHz, CDCl3) δ 183.27, 174.79, 170.33, 160.07, 152.59, 137.35, 133.51, 128.70, 127.35, 126.92 (q, J = 3.8 Hz) (2C), 125.63 (q, J = 271.0 Hz), 125.39, 122.73 (q, J = 31.8 Hz), 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] +Calculated m / z: 457.1621, Measured value: 457.1619.

[0239] Example 26

[0240] The preparation method was the same as that of 15-1. Using p-bromophenol (99 mg, 0.574 mmol) as the raw material, silica gel column chromatography (PE:EtOAc = 3:1 - 1:1) was carried out to obtain orange solid compound 26-1 (36 mg, 23%) and its diastereomer 26-2 (39 mg, 25%).

[0241]

[0242] 26-1: 1 H NMR (500 MHz, CDCl3) δ 7.75 (d, J = 8.2 Hz, 1H), 7.67 (d, J = 8.2 Hz, 1H), 7.38–7.34 (m, 2H), 7.02–6.98 (m, 2H), 6.47 (t, J = 3.2 Hz, 1H), 4.88 (t, J = 9.5 Hz, 1H), 4.36 (dd, J = 9.4, 5.9 Hz, 1H), 3.57 (dp, J = 9.5, 6.7 Hz, 1H), 2.15 (ddt, J = 14.4, 4.2, 3.0 Hz, 1H), 2.04 (td, J = 13.7, 2.9 Hz, 1H), 1.81 (tt, J = 14.2, 3.1 Hz, 1H), 1.48–1.44 (m, 1H), 1.43 (s, 3H), 1.33 (d, J = 6.8 Hz, 3H), 1.26 (s, 3H). 13 C NMR (126 MHz, CDCl3) δ 183.27, 174.81, 170.50, 156.45, 152.64, 137.74, 133.46, 132.30 (2C), 128.76, 127.26, 125.31, 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] + Calculated m / z: 467.0852, Measured value: 467.0850.

[0243] 26-2: 11H NMR (500 MHz, CDCl3) δ 7.76 (d, J = 8.2 Hz, 1H), 7.68 (d, J = 8.2 Hz, 1H), 7.40–7.36 (m, 2H), 7.04–6.99 (m, 2H), 6.50 (t, J = 3.1 Hz, 1H), 4.89 (t, J = 9.5 Hz, 1H), 4.38 (dd, J = 9.4, 5.9 Hz, 1H), 3.60 (dp, J = 9.5, 6.7 Hz, 1H), 2.20–2.14 (m, 1H), 2.05 (td, J = 13.7, 2.9 Hz, 1H), 1.84 (tt, J = 14.2, 3.1 Hz, 1H), 1.50–1.45 (m, 1H), 1.44 (s, 3H), 1.32 (d, J = 6.8 Hz, 3H), 1.28 (s, 3H). 13 13C NMR (126 MHz, CDCl3) δ 183.31, 174.87, 170.41, 156.51, 152.62, 137.75, 133.46, 132.30 (2C), 128.74, 127.29, 125.29, 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] + Calcd for m / z: 467.0852, found: 467.0852.

[0244] Example 27

[0245] Prepared in the same manner as in 15-1, using m-methoxyphenol (72 μl, 0.674 mmol) as the starting material, and purified by silica gel column chromatography (PE:EtOAc = 3:1 - 1:1) to obtain the orange solid compound 27-1 (35 mg, 25%) and its diastereoisomer 27-2 (34 mg, 24%).

[0246]

[0247] 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.

[0248] 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). 13CNMR(126MHz,CDCl3)δ183.25,175.03,170.38,160.82,158.52,152.68,138.11,133.32,129.86,128.88,127.21,125.13,118.58,108.84,106.59,103.04,81.56,67.79,55.19,35.03,34.58,31.59,31.57,31.27,22.59,18.84.HRMS(ESI):C 26 H 27 O5 + [M+H] + Calculated for [M+H]+ m / z: 419.1853, found: 419.1855.

[0249] Example 28

[0250] Prepared in the same manner as in 15-1, using p-methoxyphenol (71 mg, 0.574 mmol) as the starting material, and purified by silica gel column chromatography (PE:EtOAc = 3:1 - 1:1) to give the orange solid compound 28-1 (29 mg, 21%) and its diastereomer 28-2 (35 mg, 25%).

[0251]

[0252] 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). 1313C NMR (126 MHz, CDCl3) δ 183.38, 174.87, 171.08, 154.21, 152.87, 151.02, 138.61, 133.48, 128.81, 127.12, 125.21, 118.48 (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] + Calculated for m / z: 419.1853, Found: 419.1853.

[0253] 28 - 2: 1 1H NMR (500 MHz, CDCl3) δ 7.74 (d, J = 8.2 Hz, 1H), 7.66 (d, J = 8.2 Hz, 1H), 7.15–7.10 (m, 2H), 6.86–6.80 (m, 2H), 6.47–6.43 (m, 1H), 4.87 (t, J = 9.5 Hz, 1H), 4.36 (dd, J = 8.6, 6.0 Hz, 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 = 6.7 Hz, 3H), 1.26 (s, 3H). 13 13C NMR (126 MHz, CDCl3) δ 183.48, 175.09, 170.43, 154.26, 152.67, 151.08, 138.44, 133.32, 128.96, 127.17, 125.07, 118.53, 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] + Calculated for m / z: 419.1853, Found: 419.1855.

[0254] Example 29

[0255] The preparation method was the same as that of 15-1. Using 2-methoxyphenol (74 μl, 0.674 mmol) as the raw material, silica gel column chromatography (PE:EtOAc = 3:1 - 1:1) was carried out to obtain the orange solid compound 29-1 (58 mg, 41%).

[0256]

[0257] 29-1: 1 H NMR (500 MHz, CDCl3) δ 7.71 (dd, J = 8.2, 3.8 Hz, 1H), 7.62 (dd, J = 8.2, 1.9 Hz, 1H), 7.44 (td, J = 7.4, 2.1 Hz, 1H), 6.97–6.89 (m, 2H), 6.86–6.80 (m, 1H), 6.54 (t, J = 3.5 Hz, 1H), 4.86 (q, J = 9.5 Hz, 1H), 4.34 (td, J = 9.2, 5.9 Hz, 1H), 3.73 (d, J = 1.7 Hz, 3H), 3.61–3.51 (m, 1H), 2.31–2.09 (m, 3H), 1.92–1.78 (m, 1H), 1.43 (d, J = 3.5 Hz, 3H), 1.31 (dd, J = 13.5, 6.7 Hz, 3H), 1.26 (d, J = 3.5 Hz, 3H). 13 CNMR (126 MHz, CDCl3) δ 183.76, 175.29, 170.48, 152.84, 150.47, 146.86, 138.40, 133.00, 129.63, 126.95, 124.92, 121.64, 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 value: 419.1853, measured value: 419.1852.

[0258] Example 30

[0259] The preparation method was the same as that of 15-1. Using p-trifluoromethoxyphenol (74 μl, 0.574 mmol) as the raw material, silica gel column chromatography (PE:EtOAc = 3:1 - 1:1) was carried out to obtain the orange solid compound 30-1 (38 mg, 24%) and its diastereomer 30-2 (36 mg, 23%).

[0260]

[0261] 30-1: 1 H NMR (500 MHz, CDCl3) δ 7.76 (d, J = 8.2 Hz, 1H), 7.69 (d, J = 8.2 Hz, 1H), 7.17–7.13 (m, 2H), 7.13–7.09 (m, 2H), 6.51 (t, J = 3.1 Hz, 1H), 4.88 (t, J = 9.5 Hz, 1H), 4.36 (dd, J = 9.4, 5.9 Hz, 1H), 3.58 (dp, J = 9.6, 6.7 Hz, 1H), 2.21–2.15 (m, 1H), 2.10–2.03 (m, 1H), 1.83 (tt, J = 14.3, 3.1 Hz, 1H), 1.50–1.46 (m, 1H), 1.44 (s, 3H), 1.34 (d, J = 6.8 Hz, 3H), 1.27 (s, 3H). 13 C NMR (126 MHz, CDCl3) δ 183.30, 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 = 255.8 Hz), 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] + Calculated m / z: 473.1570, found: 473.1569.

[0262] 30-2: 1 H NMR (500 MHz, CDCl3) δ 7.77 (d, J = 8.2 Hz, 1H), 7.69 (d, J = 8.2 Hz, 1H), 7.16–7.12 (m, 2H), 7.12–7.09 (m, 2H), 6.52 (t, J = 3.3 Hz, 1H), 4.89 (t, J = 9.5 Hz, 1H), 4.38 (dd, J = 9.4, 5.9 Hz, 1H), 3.59 (dp, J = 9.7, 6.7 Hz, 1H), 2.21–2.16 (m, 1H), 2.10–2.02 (m, 1H), 1.85 (tt, J = 14.3, 3.2 Hz, 1H), 1.48 (dt, J = 13.8, 3.8 Hz, 1H), 1.44 (s, 3H), 1.31 (d, J = 6.8 Hz, 3H), 1.28 (s, 3H). 1313C NMR (126 MHz, CDCl3) δ 183.32, 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 = 255.7 Hz), 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] + Calculated for m / z: 473.1570, found: 473.1569.

[0263] Example 31

[0264] The preparation method was the same as that of 15-1. Using p-cresol (60 μl, 0.574 mmol) as the raw material, silica gel column chromatography (PE:EtOAc = 3:1 - 1:1) gave the orange solid compound 31-1 (33 mg, 24%) and its diastereomer 31-2 (29 mg, 21%).

[0265]

[0266] 31-1: 1 1H NMR (500 MHz, CDCl3) δ 7.75 (d, J = 8.2 Hz, 1H), 7.66 (d, J = 8.2 Hz, 1H), 7.12–7.08 (m, 2H), 7.08–7.04 (m, 2H), 6.52 (t, J = 3.2 Hz, 1H), 4.88 (t, J = 9.5 Hz, 1H), 4.36 (dd, J = 9.4, 5.9 Hz, 1H), 3.58 (dp, J = 9.7, 6.7 Hz, 1H), 2.30 (s, 3H), 2.23–2.17 (m, 1H), 2.15–2.06 (m, 1H), 1.79 (tt, J = 14.1, 3.1 Hz, 1H), 1.44 (s, 3H), 1.44–1.41 (m, 1H), 1.34 (d, J = 6.8 Hz, 3H), 1.27 (s, 3H). 1313C NMR (126 MHz, CDCl3) δ 183.32, 175.08, 170.41, 155.00, 152.68, 138.37, 133.29, 130.36, 129.93 (2C), 128.94, 127.19, 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] + Calculated m / z: 403.1904, Found: 403.1901.

[0267] 31 - 2: 1 1H NMR (500 MHz, CDCl3) δ 7.75 (d, J = 8.2 Hz, 1H), 7.66 (d, J = 8.2 Hz, 1H), 7.12 – 7.07 (m, 2H), 7.07 – 7.03 (m, 2H), 6.53 (t, J = 3.2 Hz, 1H), 4.88 (t, J = 9.5 Hz, 1H), 4.37 (dd, J = 9.4, 5.8 Hz, 1H), 3.59 (dp, J = 9.5, 6.6 Hz, 1H), 2.29 (s, 3H), 2.22 – 2.16 (m, 1H), 2.14 – 2.03 (m, 1H), 1.81 (tt, J = 14.2, 3.1 Hz, 1H), 1.47 – 1.45 (m, 1H), 1.44 (s, 3H), 1.31 (d, J = 6.8 Hz, 3H), 1.28 (s, 3H). 13 13C NMR (126 MHz, CDCl3) δ 183.36, 175.08, 170.39, 155.03, 152.68, 138.40, 133.30, 130.36, 129.92 (2C), 128.93, 127.18, 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] + Calculated m / z: 403.1904, Found: 403.1905.

[0268] Example 32

[0269] The preparation method was the same as that of 15-1. Using p-ethylphenol (70 mg, 0.574 mmol) as the raw material, silica gel column chromatography (PE:EtOAc = 3:1 - 1:1) was carried out to obtain the orange solid compound 32-1 (32 mg, 23%) and its diastereomer 32-2 (27 mg, 19%).

[0270]

[0271] 32-1: 1 H NMR (500 MHz, CDCl3) δ 7.75 (d, J = 8.2 Hz, 1H), 7.66 (d, J = 8.2 Hz, 1H), 7.15–7.10 (m, 2H), 7.09–7.05 (m, 2H), 6.53 (t, J = 3.2 Hz, 1H), 4.88 (t, J = 9.5 Hz, 1H), 4.36 (dd, J = 9.4, 5.9 Hz, 1H), 3.58 (dp, J = 9.6, 6.7 Hz, 1H), 2.60 (q, J = 7.6 Hz, 2H), 2.25–2.18 (m, 1H), 2.15–2.06 (m, 1H), 1.80 (tt, J = 14.2, 3.1 Hz, 1H), 1.44 (s, 3H), 1.48–1.41 (m, 1H), 1.34 (d, J = 6.7 Hz, 3H), 1.27 (s, 3H), 1.22 (t, J = 7.6 Hz, 3H). 13 C NMR (126 MHz, CDCl3) δ 183.30, 175.04, 170.45, 155.16, 152.70, 138.39, 136.77, 133.30, 128.93, 128.73 (2C), 127.18, 125.07, 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 value: 417.2060, measured value: 417.2065.

[0272] 32-2: 11H NMR (500 MHz, CDCl3) δ 7.75 (d, J = 8.2 Hz, 1H), 7.66 (d, J = 8.2 Hz, 1H), 7.14–7.10 (m, 2H), 7.08–7.04 (m, 2H), 6.54 (t, J = 3.1 Hz, 1H), 4.88 (t, J = 9.5 Hz, 1H), 4.37 (dd, J = 9.3, 5.8 Hz, 1H), 3.63–3.55 (m, 1H), 2.59 (q, J = 7.6 Hz, 2H), 2.25–2.19 (m, 1H), 2.14–2.05 (m, 1H), 1.82 (tt, J = 14.2, 3.1 Hz, 1H), 1.48–1.44 (m, 1H), 1.44 (s, 3H), 1.31 (d, J = 6.8 Hz, 3H), 1.28 (s, 3H), 1.22 (t, J = 7.6 Hz, 3H). 13 13C NMR (126 MHz, CDCl3) δ 183.33, 175.07, 170.38, 155.21, 152.68, 138.43, 136.77, 133.29, 128.93, 128.72 (2C), 127.19, 125.05, 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, found: 417.2062.

[0273] Example 33

[0274] The preparation method was the same as that of 15-1. Using p-tert-butylphenol (86 mg, 0.574 mmol) as the raw material, silica gel column chromatography (PE:EtOAc = 3:1 - 1:1) gave the orange solid compound 33-1 (31 mg, 21%) and its diastereomer 33-2 (30 mg, 20%).

[0275]

[0276] 33-1: 11H NMR (500 MHz, CDCl3) δ 7.75 (d, J = 8.2 Hz, 1H), 7.67 (d, J = 8.2 Hz, 1H), 7.32–7.29 (m, 2H), 7.07–7.03 (m, 2H), 6.53 (t, J = 3.3 Hz, 1H), 4.89 (t, J = 9.5 Hz, 1H), 4.37 (dd, J = 9.4, 5.9 Hz, 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, 3.1 Hz, 1H), 1.48–1.43 (m, 1H), 1.44 (s, 3H), 1.34 (d, J = 6.8 Hz, 3H), 1.31 (s, 9H), 1.27 (s, 3H). 13 13C NMR (126 MHz, CDCl3) δ 183.27, 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] + Calcd for m / z: 445.2373, Found: 445.2376.

[0277] 33 - 2: 1 1H NMR (500 MHz, CDCl3) δ 7.76 (d, J = 8.2 Hz, 1H), 7.67 (d, J = 8.2 Hz, 1H), 7.32–7.28 (m, 2H), 7.06–7.02 (m, 2H), 6.55 (t, J = 2.8 Hz, 1H), 4.89 (t, J = 9.5 Hz, 1H), 4.38 (dd, J = 9.4, 5.8 Hz, 1H), 3.59 (dp, J = 9.5, 6.6 Hz, 1H), 2.30–2.22 (m, 1H), 2.13–2.03 (m, 1H), 1.84 (tt, J = 14.2, 3.1 Hz, 1H), 1.48–1.45 (m, 1H), 1.44 (s, 3H), 1.31 (s, 12H), 1.28 (s, 3H). 1313C NMR (126 MHz, CDCl3) δ 183.28, 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] + Calculated for [M + H]+: 445.2373, found: 445.2373.

[0278] Example 34

[0279] Prepared in the same manner as in 15-1, using 3-fluoro-4-nitrophenol (106 mg, 0.674 mmol) as the starting material, and purified by silica gel column chromatography (PE:EtOAc = 3:1 - 1:1) to give the orange solid compound 35-1 (40 mg, 26%) and its diastereomer 35-2 (43 mg, 28%).

[0280]

[0281] 35-1: 1 1H NMR (500 MHz, CDCl3) δ 8.08 (t, J = 8.9 Hz, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.73 (d, J = 8.3 Hz, 1H), 6.92–6.83 (m, 2H), 6.53 (t, J = 3.3 Hz, 1H), 4.91 (t, J = 9.5 Hz, 1H), 4.39 (dd, J = 9.4, 5.9 Hz, 1H), 3.59 (dq, J = 9.6, 6.7 Hz, 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 = 6.8 Hz, 3H), 1.30 (s, 3H). 1313C NMR (126 MHz, CDCl3) δ 183.24, 174.47, 170.32, 163.74 (d, J = 11.3 Hz), 157.71 (d, J = 264.4 Hz), 152.50, 136.00, 133.69, 130.55 (d, J = 6.2 Hz), 128.58, 127.93, 127.47, 125.79, 118.76, 111.85 (d, J = 3.0 Hz), 104.82 (d, J = 24.0 Hz), 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] + Calculated m / z: 452.1504, found: 452.1509.

[0282] 35 - 2: 1 1H NMR (500 MHz, CDCl3) δ 8.08 (t, J = 8.8 Hz, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.73 (d, J = 8.3 Hz, 1H), 6.92–6.83 (m, 2H), 6.53 (t, J = 2.5 Hz, 1H), 4.91 (t, J = 9.5 Hz, 1H), 4.39 (dd, J = 9.4, 6.0 Hz, 1H), 3.59 (dp, J = 9.3, 6.7 Hz, 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 = 6.9 Hz, 3H), 1.30 (s, 3H). 13 13C NMR (126 MHz, CDCl3) δ 183.29, 174.54, 170.37, 163.80 (d, J = 11.2 Hz), 157.68 (d, J = 264.5 Hz), 152.52, 136.02, 133.75, 130.45 (d, J = 6.4 Hz), 128.52, 127.92, 127.47, 125.81, 118.78, 111.83 (d, J = 2.8 Hz), 104.81 (d, J = 23.9 Hz), 81.72, 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] +Calculated m / z value: 452.1504, measured value: 452.1502.

[0283] Example 35

[0284] Dissolve 4-(1-piperazinyl)phenol (500 mg, 2.809 mmol) in 30 ml of tetrahydrofuran. Sequentially add di-tert-butyl dicarbonate (773 μl, 3.370 mmol) and triethylamine (584 μl, 4.214 mmol). Stir the reaction at room temperature. After confirming the completion of the reaction by TLC, concentrate under reduced pressure. Purify by silica gel column chromatography (DCM:MeOH = 100:1 - 20:1) to obtain crude product a (203 mg, 26%). Dissolve crude product a (203 mg, 0.730 mmol) in 5 ml of chlorobenzene. Sequentially add cryptotanshinone (127 mg, 0.430 mmol) and TEMPO (134 mg, 0.860 mmol). Reflux the reaction at 120 °C for 24 h. After confirming the completion of the reaction by TLC, concentrate under reduced pressure. Separate and purify by silica gel column chromatography (PE:EtOAc = 3:1 - 1:1) to obtain a dark brown solid compound 36-1 (42 mg, 17%).

[0285]

[0286] 36-1: 1 H NMR (500 MHz, CDCl3) δ 7.74 (d, J = 8.2 Hz, 1H), 7.66 (d, J = 8.2 Hz, 1H), 7.13–7.06 (m, 2H), 6.94–6.88 (m, 2H), 6.46 (dt, J = 6.2, 3.2 Hz, 1H), 4.88 (td, J = 9.5, 2.8 Hz, 1H), 4.36 (ddd, J = 9.3, 5.9, 4.3 Hz, 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, 3.0 Hz, 1H), 1.48 (s, 9H), 1.47–1.39 (m, 1H), 1.43 (d, J = 1.9 Hz, 3H), 1.32 (dd, J = 16.1, 6.8 Hz, 3H), 1.26 (d, J = 3.3 Hz, 3H). 1313C NMR (126 MHz, CDCl3) δ 183.43, 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] + Calculated for [M + H]+: 573.2959, found: 573.2960.

[0287] Example 36

[0288] Prepared in the same manner as 1 - 1, using Boc - glycine (118 mg, 0.675 mmol) as the starting material, and purified by silica gel column chromatography (PE:EtOAc = 3:1 - 1:1) to give the orange solid compound 37 - 1 (71 mg, 45%) and its diastereomer 37 - 2 (78 mg, 49%).

[0289]

[0290] 37 - 1: 1 1H NMR (500 MHz, CDCl3) δ 7.73 (d, J = 8.3 Hz, 1H), 7.67 (d, J = 8.2 Hz, 1H), 6.48 (t, J = 3.6 Hz, 1H), 5.14 (s, 1H), 4.89 (t, J = 9.5 Hz, 1H), 4.37 (dd, J = 9.9, 5.5 Hz, 1H), 3.97 (dd, J = 18.2, 7.1 Hz, 1H), 3.68 (dd, J = 18.2, 3.9 Hz, 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 = 7.1 Hz, 3H), 1.26 (s, 3H). 1313C NMR (126 MHz, CDCl3) δ 183.43, 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] + Calculated m / z: 492.1993, Found: 492.1993.

[0291] 37 - 2: 1 1H NMR (500 MHz, CDCl3) δ 7.73 (d, J = 8.2 Hz, 1H), 7.66 (d, J = 8.2 Hz, 1H), 6.47 (t, J = 3.5 Hz, 1H), 5.14 (s, 1H), 4.90 (t, J = 9.5 Hz, 1H), 4.37 (dd, J = 9.4, 6.1 Hz, 1H), 3.97 (dd, J = 18.2, 7.1 Hz, 1H), 3.69 (dd, J = 18.2, 3.9 Hz, 1H), 3.59 (dp, J = 9.6, 6.6 Hz, 1H), 2.25–2.19 (m, 1H), 2.04–1.84 (m, 2H), 1.58–1.51 (m, 1H), 1.42 (s, 9H), 1.38 (s, 3H), 1.34 (d, J = 6.8 Hz, 3H), 1.26 (s, 3H). 13 13C NMR (126 MHz, CDCl3) δ 183.44, 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] + Calculated m / z: 492.1993, Found: 492.1995.

[0292] Example 37

[0293] The preparation method was the same as that in 1-1. Using Boc-β-alanine (128 mg, 0.675 mmol) as the raw material, silica gel column chromatography (PE:EtOAc = 3:1 - 1:1) was carried out to obtain the orange solid compound 38-1 (65 mg, 40%) and its diastereomer 38-2 (68 mg, 42%).

[0294]

[0295] 38-1: 1 H NMR (500 MHz, CDCl3) δ 7.72 (d, J = 8.1 Hz, 1H), 7.66 (d, J = 8.2 Hz, 1H), 6.45 (t, J = 3.4 Hz, 1H), 5.21 (s, 1H), 4.88 (t, J = 9.5 Hz, 1H), 4.37 (dd, J = 9.4, 5.9 Hz, 1H), 3.57 (dp, J = 9.6, 6.6 Hz, 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 = 6.8 Hz, 3H), 1.25 (s, 3H). 13 C NMR (126 MHz, CDCl3) δ 183.52, 174.94, 171.28, 170.25, 155.94, 152.80, 136.95, 133.38, 129.03, 127.20, 125.26, 118.61, 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 Calcd: 506.2149, Found: 506.2148.

[0296] 38-2: 11H NMR (500 MHz, CDCl3) δ 7.73 (d, J = 8.0 Hz, 1H), 7.66 (d, J = 8.2 Hz, 1H), 6.44 (t, J = 3.7 Hz, 1H), 5.23 (s, 1H), 4.90 (t, J = 9.5 Hz, 1H), 4.37 (dd, J = 9.3, 6.2 Hz, 1H), 3.60 (dp, J = 9.7, 6.7 Hz, 1H), 3.45–3.32 (m, 2H), 2.46 (tq, J = 10.0, 5.2, 4.5 Hz, 2H), 2.25–2.15 (m, 1H), 2.03–1.83 (m, 2H), 1.55 (dd, J = 11.6, 4.7 Hz, 1H), 1.41 (s, 9H), 1.39 (s, 3H), 1.35 (d, J = 6.8 Hz, 3H), 1.27 (s, 3H). 13 13C NMR (126 MHz, CDCl3) δ 183.48, 175.04, 171.34, 170.31, 155.96, 152.83, 136.94, 133.43, 129.02, 127.21, 125.29, 118.61, 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] + Calcd for [M + Na]+: 506.2149, found: 506.2145.

[0297] Example 38

[0298] Prepared in the same way as 1-1, using Boc-L-proline (220 mg, 1.020 mmol), cryptotanshinone (150 mg, 0.510 mmol), and TEMPO (96 mg, 0.612 mmol) as starting materials, and purified by silica gel column chromatography (PE:EtOAc = 3:1 - 1:1) to give the orange solid compound 39-1 (42 mg, 16%) and its diastereomer 39-2 (35 mg, 13%).

[0299]

[0300] 39-1: 11H NMR (500 MHz, CDCl3) δ 7.70 (d, J = 8.2 Hz, 1H), 7.63 (d, J = 8.2 Hz, 1H), 6.48 (t, J = 3.5 Hz, 1H), 4.86 (t, J = 9.5 Hz, 1H), 4.33 (dd, J = 9.4, 6.1 Hz, 1H), 4.12 (dd, J = 8.2, 3.5 Hz, 1H), 4.05 (dd, J = 8.4, 3.6 Hz, 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 = 6.8 Hz, 3H), 1.21 (s, 3H). 13 13C NMR (126 MHz, CDCl3) δ 183.46, 175.03, 171.36, 170.28, 153.99, 152.82, 136.73, 133.35, 129.06, 127.11, 125.28, 118.54, 81.58, 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] + Calculated for [M + Na]+ m / z: 532.2306, found: 532.2304.

[0301] 39 - 2: 1 1H NMR (500 MHz, CDCl3) δ 7.69 (d, J = 8.2 Hz, 1H), 7.63 (d, J = 8.2 Hz, 1H), 6.49 (t, J = 3.4 Hz, 1H), 4.88 (t, J = 9.5 Hz, 1H), 4.37–4.28 (m, 1H), 4.25 (dd, J = 7.6, 4.8 Hz, 1H), 3.57 (dq, J = 6.5, 3.2 Hz, 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 = 9.6 Hz, 3H), 1.32 (s, 3H). 1313C NMR (126 MHz, CDCl3) δ 183.46, 175.03, 171.36, 170.28, 153.99, 152.82, 136.73, 133.35, 129.06, 127.11, 125.28, 118.54, 81.58, 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] + Calculated for [M+Na]+: 532.2306, found: 532.2305.

[0302] Example 39

[0303] Prepared in the same manner as 1-1, using Boc-L-tryptophan (317 mg, 1.020 mmol), cryptotanshinone (150 mg, 0.510 mmol), and TEMPO (96 mg, 0.612 mmol) as starting materials, and purified by silica gel column chromatography (PE:EtOAc = 3:1 - 1:1) to give the orange solid compound 40-1 (37 mg, 12%) and its diastereomer 40-2 (46 mg, 15%).

[0304]

[0305] 40-1: 11H NMR (500 MHz, CDCl3) δ 8.68–8.59 (m, 1H), 7.71 (d, J = 8.2 Hz, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 8.1 Hz, 1H), 7.21 (d, J = 2.4 Hz, 1H), 7.06 (t, J = 7.6 Hz, 1H), 6.94 (t, J = 7.5 Hz, 1H), 6.72 (d, J = 3.5 Hz, 1H), 5.35 (t, J = 9.2 Hz, 1H), 4.89 (t, J = 9.5 Hz, 1H), 4.66–4.58 (m, 1H), 4.35 (dd, J = 9.4, 5.8 Hz, 1H), 3.56 (dt, J = 9.5, 6.3 Hz, 1H), 3.19 (dd, J = 15.1, 5.7 Hz, 1H), 3.05 (dd, J = 15.1, 6.4 Hz, 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 13C NMR (126 MHz, CDCl3) δ 182.76, 174.75, 171.07, 170.38, 155.46, 152.94, 136.47, 135.94, 133.33, 128.61, 128.01, 127.04, 125.26, 123.87, 121.30, 118.94, 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] + Calculated for [M + Na]: m / z 621.2571, found 621.2571.

[0306] 40 - 2: 11H NMR (500 MHz, CDCl3) δ 8.55–8.49 (m, 1H), 7.66 (d, J = 8.2 Hz, 1H), 7.62 (d, J = 8.2 Hz, 1H), 7.56 (d, J = 7.9 Hz, 1H), 7.30 (d, J = 8.1 Hz, 1H), 7.15–7.09 (m, 2H), 7.07–7.00 (m, 1H), 6.68 (t, J = 3.3 Hz, 1H), 5.12 (d, J = 7.9 Hz, 1H), 4.89 (t, J = 9.5 Hz, 1H), 4.67–4.58 (m, 1H), 4.36 (dd, J = 9.4, 6.1 Hz, 1H), 3.60 (dt, J = 9.3, 6.5 Hz, 1H), 3.33 (dd, J = 14.7, 6.2 Hz, 1H), 3.24 (dd, J = 14.7, 5.1 Hz, 1H), 2.07–2.01 (m, 1H), 1.86–1.74 (m, 1H), 1.59–1.39 (m, 2H), 1.37 (d, J = 8.5 Hz, 12H), 1.24 (s, 3H), 1.19 (s, 3H). 13 13C NMR (126 MHz, CDCl3) δ 182.95, 175.08, 170.89, 170.58, 155.17, 153.04, 136.37, 136.04, 133.38, 128.69, 128.01, 127.02, 125.39, 123.81, 121.67, 119.20, 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] + Calculated for [M + Na]: 621.2571, Found: 621.2572.

[0307] Example 40

[0308] The preparation method was the same as that of 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, silica gel column chromatography (PE:EtOAc = 3:1 - 1:1) was carried out to obtain orange-yellow solid compound 41-1 (96 mg, 34%).

[0309]

[0310] 41-1: 1 H NMR(500 MHz, CDCl3) δ 7.72 (dd, J = 8.2, 2.0 Hz, 1H), 7.66 (dd, J = 8.2, 2.1 Hz, 1H), 7.21–7.05 (m, 5H), 6.57 (t, J = 3.3 Hz, 1H), 5.00 (d, J = 8.7 Hz, 1H), 4.87 (td, J = 9.5, 2.3 Hz, 1H), 4.46 (td, J = 8.9, 5.5 Hz, 1H), 4.36 (ddd, J = 9.2, 5.9, 2.4 Hz, 1H), 3.56 (ddt, J = 13.0, 9.3, 6.0 Hz, 1H), 3.03–2.95 (m, 1H), 2.87 (dd, J = 14.3, 9.0 Hz, 1H), 2.22–2.13 (m, 1H), 1.96–1.82 (m, 2H), 1.53–1.42 (m, 1H), 1.37 (d, J = 2.1 Hz, 3H), 1.35–1.20 (m, 15H). 13 C NMR(126 MHz, CDCl3) δ 183.47, 174.96, 170.83, 170.18, 155.18, 152.91, 136.92, 136.41, 133.40, 129.30 (2C), 128.99, 128.08 (2C), 127.10, 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] + Calculated m / z: 582.2462, Found: 582.246

[0311] Example 41

[0312] The preparation method was the same as that of 1-1. Using Boc-L-alanine (197 mg, 1.020 mmol), cryptotanshinone (150 mg, 0.510 mmol), and TEMPO (96 mg, 0.612 mmol) as raw materials, silica gel column chromatography (PE:EtOAc = 3:1 - 1:1) was carried out to obtain the orange solid compound 42-1 (68 mg, 28%) and its diastereomer 42-2 (62 mg, 25%).

[0313]

[0314] 42-1: 1 H NMR (500 MHz, CDCl3) δ 7.71 (d, J = 8.2 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 6.50 (t, J = 3.6 Hz, 1H), 5.20 (d, J = 8.2 Hz, 1H), 4.87 (t, J = 9.5 Hz, 1H), 4.35 (dd, J = 9.3, 6.1 Hz, 1H), 4.18 (p, J = 7.4 Hz, 1H), 3.55 (dp, J = 9.1, 6.6 Hz, 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 = 7.0 Hz, 3H), 1.23 (s, 6H). 13 C NMR (126 MHz, CDCl3) δ 183.40, 174.97, 172.03, 170.24, 155.16, 152.86, 136.56, 133.36, 129.00, 127.15, 125.31, 118.61, 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.

[0315] 42-2: 1 H NMR (500 MHz, CDCl3) δ 7.72 (d, J = 8.2 Hz, 1H), 7.66 (d, J = 8.2 Hz, 1H), 6.50 (t, J = 3.1 Hz, 1H), 5.17 (d, J = 7.1 Hz, 1H), 4.89 (t, J = 9.5 Hz, 1H), 4.36 (dd, J = 9.4, 6.2 Hz, 1H), 4.22 (p, J = 7.2 Hz, 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). 1313C NMR (126 MHz, CDCl3) δ 183.35, 175.08, 171.61, 170.21, 154.98, 152.81, 136.41, 133.39, 128.98, 127.17, 125.37, 118.67, 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, found: 506.2147.

[0316] Example 42

[0317] The preparation method was the same as that of 1-1. Using Boc-glycylglycine (157 mg, 0.676 mmol) as the raw material, silica gel column chromatography (PE:EtOAc = 3:1 - 1:1) was carried out to obtain the orange solid compound 43-1 (43 mg, 24%).

[0318]

[0319] 43-1: 1 1H NMR (500 MHz, CDCl3) δ 7.73 (d, J = 8.3 Hz, 1H), 7.66 (d, J = 8.2 Hz, 1H), 7.00 (d, J = 43.7 Hz, 1H), 6.48 (t, J = 3.4 Hz, 1H), 5.47–5.37 (m, 1H), 4.90 (t, J = 9.5 Hz, 1H), 4.37 (ddd, J = 9.0, 6.1, 2.3 Hz, 1H), 4.19 (ddd, J = 18.0, 6.6, 4.0 Hz, 1H), 3.94–3.83 (m, 2H), 3.79–3.73 (m, 1H), 3.58 (dq, J = 9.6, 6.4 Hz, 1H), 2.22–2.14 (m, 1H), 2.01–1.85 (m, 2H), 1.57–1.51 (m, 1H), 1.45–1.42 (m, 9H), 1.38 (d, J = 3.0 Hz, 3H), 1.29 (d, J = 37.2 Hz, 3H), 1.23 (s, 3H). 1313C 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] + Calculated m / z:549.2207,found:549.2209.

[0320] Evaluation of the in vitro anti-triple-negative breast cancer activity of cryptotanshinone derivatives in Example 1 of the effect

[0321] 1. Experimental purpose

[0322] The CCK-8 method was used to detect the in vitro anti-triple-negative breast cancer activity of five types of derivative structures, preliminarily explore their structure-activity relationships, and select derivatives with excellent activity for subsequent activity tests.

[0323] 2. Experimental materials

[0324] 2.1. Experimental cells

[0325] Two triple-negative breast cancer cell lines, 4T1 cells (murine adenocarcinoma) and MDA-MB-231 cells (human adenocarcinoma), were purchased from the Cell Resource Center of the Shanghai Institute of Life Sciences, Chinese Academy of Sciences.

[0326] 2.2. Experimental instruments and reagents

[0327]

[0328] 2.3. Drug concentrations

[0329] 0.3 μM, 1 μM, 3 μM, 10 μM, 30 μM

[0330] 3. Experimental method

[0331] Triple-negative breast cancer cells (4T1, MDA-MB-231) in the logarithmic growth phase were inoculated into 96-well culture plates at a certain cell density. After 24 h of culture, a solution of the test drug in serum-free medium was added, with 5 replicates for each concentration. The cells were further cultured at 37 °C and 5% CO2 for 24 h, and then a solution of 10% CCK-8 in serum-free medium was added and cultured for another 4 h. The absorbance of each well was measured using an enzyme-linked immunosorbent assay reader.

[0332] 4. Experimental Results

[0333] The results of the activity test showed that the preliminary structure-activity relationship of cryptotanshinone derivatives was as follows: ① For derivatives substituted with A-ring hydrocarbon acid ester side chains, the activity gradually decreased with the increase in the length of the substituted side chain; when the side chain contained unsaturated functional groups and mono-protected dicarboxylic acids, the activity of the derivative increased; ② Among derivatives substituted with A-ring aryl ether side chains, the presence of an electron-withdrawing substituent at the para-position and a substituent at the ortho-position of the benzene ring was beneficial to the enhancement of activity; the modification with a large steric hindrance substituent at the para-position of the benzene ring led to a decrease in activity; the activity was stronger when containing two electron-withdrawing substituents than when containing a single substituent of this substituent; ③ Among A-ring oxidized derivatives and ortho-quinone reduced derivatives, the activity of the derivative decreased after the ortho-quinone was reduced; the presence of α,β-unsaturated ketone was beneficial to the enhancement of activity; ④ Among derivatives substituted with A-ring amino acid ester side chains, the activity was stronger when the side chain was α-amino than when it was β-amino.

[0334] All compounds were subjected to a preliminary screening, and the results are shown in Table 1 as follows:

[0335] Table 1

[0336]

[0337]

[0338]

[0339] Twenty-one compounds with better activity were selected according to their change trends at 30 μM and three concentrations, and their IC 50 values were detected by the CCK-8 method, and four preferred compounds were obtained. Further, their IC 50 values were detected on human triple-negative breast cancer cells.

[0340] Table 2 IC 50 values of the preferred compounds on 4T1 cells

[0341] Number <![CDATA[IC 50 (μM)]]> Number <![CDATA[IC 50 (μM)]]> 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

[0342] Table 3 IC 50 values of cryptotanshinone and the preferred compounds on MDA-MB-231

[0343] Number <![CDATA[IC 50 (μM)]]> Number <![CDATA[IC 50 (μM)]]> Number <![CDATA[IC 50 (μM)]]> CTS 4.09 9-1 0.86 13-1 0.55 19-1 6.82 39-2 1.62

[0344] Example 2 Evaluation of the in vivo anti-triple-negative breast cancer activity of cryptotanshinone derivatives

[0345] 1. Experimental Purpose

[0346] To observe the activity and safety of the preferred cryptotanshinone derivatives 9-1 and 13-1 against triple-negative breast cancer in mice.

[0347] 2. Experimental materials

[0348] 2.1 Experimental cells

[0349] 4T1 (murine adenocarcinoma) triple-negative breast cancer cell line, purchased from the Cell Resource Center of Shanghai Institute of Life Sciences, Chinese Academy of Sciences.

[0350] 2.2 Experimental animals

[0351] SPF-grade female BALB / c mice, 5 weeks old, purchased from Shanghai Model Organisms Center, Inc. Breeding environment: SPF-grade animal room, 12h day-night rhythm, temperature (25±1) °C, humidity (50±10)%, normal free access to water, fed with standard mouse feed.

[0352] 2.3 Experimental instruments and reagents

[0353]

[0354]

[0355] 2.4 Drug concentration

[0356] Name: 9-1; Property: Reddish-brown powder; Solvent: Edible vegetable oil containing 5% DMSO; Administration concentration: 15 mg / kg / d

[0357] Name: 13-1; Property: Yellow powder; Solvent: Edible vegetable oil containing 5% DMSO; Administration concentration: 15 mg / kg / d

[0358] 3. Experimental methods

[0359] 3.1 Animal experiments

[0360] Place 4-week-old BALB / c mice in the animal center for one week and remove the abdominal hair. At the same time, prepare a sufficient amount of 4T1 cells. Take 4T1 cells in the logarithmic growth phase, wash them once with PBS, centrifuge after terminating trypsin digestion, wash them twice with PBS, collect the cell precipitate, resuspend it with PBS and count. Dilute the cell suspension with PBS to make it 1×10 7 cells / ml, place it in an ice box and take it to the animal room for inoculation. Use a syringe to aspirate 100 μl 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. Wait until the tumor volume is about 50 mm 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.

[0361] Experimental Grouping

[0362]

[0363] 3.2. Statistical analysis

[0364] 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.

[0365] 4. Experimental Results

[0366] 4.1 In vivo pharmacodynamic evaluation of preferred compounds 9-1 and 13-1

[0367] (1) Changes in tumor volume, weight, and morphology

[0368] 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.

[0369] (2) HE staining of tumor tissues and Ki67 immunohistochemical results

[0370] 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 was 20.68 ± 2.30%, and the cells were closely arranged and in a full state; the necrosis area ratio of the 9-1 group was 59.55 ± 0.38%, and that of the 13-1 group was 62.77 ± 2.90%. The necrosis of these two groups of tumor tissues was significantly increased compared with the control group, and the cells were sparsely arranged, the cell nuclei were ruptured and shrunk in large areas, the cell structure disappeared, and the tumor tissue was severely damaged. Subsequently, the effects of 9-1 and 13-1 on the proliferation activity of tumor cells were further investigated. Ki67 staining was performed on tumor tissue sections of each group 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 the 9-1 group and the 13-1 group, which were 2.23 ± 0.16% and 3.01 ± 0.27% respectively. The difference was statistically significant, indicating that both compounds could significantly reduce the proliferation activity of 4T1 cells in vivo after administration and effectively inhibit the growth of tumors.

[0371] 4.2 In vivo safety evaluation of the preferred compounds 9-1 and 13-1

[0372] (1) Body weight changes of tumor-bearing mice

[0373] As Figure 5 shown, there was no significant change in the body weight of the mice during the drug administration period, and it basically remained at a stable normal level. Except that the mice in the control group became slow in movement as the tumor volume increased, there were no abnormal behaviors in the other two drug administration groups. The mice in each group ate normally, indicating that intraperitoneal injection of the drug did not cause serious adverse reactions in the mice.

[0374] (2) HE staining of various organs and tissues

[0375] After 25 days of drug administration, the organs of each group of mice were taken out for HE staining to observe the necrosis of the main organs ( Figure 6 ). The results are shown in the figure. No abnormal necrosis was observed in the sections of each group, and there was no obvious difference compared with the control group. It shows that after drug treatment, the morphological conditions of various organs and tissues are good, and no obvious toxic and side effects are found.

Claims

1. Use of a cryptotanshinone derivative represented by Formula I, its stereoisomer or its pharmaceutically acceptable salt in the preparation of a drug for treating triple-negative breast cancer: Wherein, The dashed line "-----" in ring A is a single bond; R1 and R2 are hydrogen; R3 is 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; Each R 1-1 independently is CN, NO2, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, halogen, 5- or 6-membered heterocycloalkyl or 5- or 6-membered heterocycloalkyl substituted with one or more R 2-1 ; the number of heteroatoms in the 5- or 6-membered heterocycloalkyl is 1, 2 or 3, and each heteroatom is independently N, O or S; -1 R is hydrogen or C 1-3 alkyl; Each R 2-1 is independently tert-butoxycarbonyl; Each R 1-2 is independently selected from -NR 2-2 R 2-3 , C6-C 10 aryl or 6-10 membered heteroaryl, wherein the number of heteroatoms in the 6-10 membered heteroaryl is 1, 2 or 3, and each heteroatom is independently N, O or S; R 2-2 、R 2-3 are each independently hydrogen, tert-butoxycarbonyl or R 1-3 is C6-C 10 aryl; R 1-4 is tert-butoxycarbonyl; In loop C is X2 is selected from CH2, O, S, and NH; X3 is selected from CH2, O, S, and NH; R4 and R5 are each independently hydrogen, C 1-3 alkyl-C(O)O-, C 1-3 alkoxy or hydroxy.

2. The use according to claim 1, characterized in that, In R, the "C 1-3 alkyl or C alkyl substituted by one or more R 1-2 The "C 1-3 alkyl" in "alkyl" is methyl, ethyl, propyl or isopropyl, preferably methyl or ethyl; 1-3 ​ and / or, in R, the "C" 2-3 alkenyl or C substituted by one or more R 1-3 alkenyl" in the "C" 2-3 alkenyl" is vinyl, propenyl or isopropenyl, preferably vinyl; 2-3 alkenyl" is vinyl, propenyl or isopropenyl, preferably vinyl; and / or, in R, the "C6-C 10 aryl or C6-C aryl substituted by one or more R 1-1 substituted C6-C 10 aryl" in the "C6-C 10 aryl" is phenyl; And / or, in R, the "5-9 membered heterocycloalkyl" or "5-9 membered heterocycloalkyl substituted with one or more R 1-4 The "5-9 membered heterocycloalkyl" in "substituted 5-9 membered heterocycloalkyl" is a nitrogen-containing 5-9 membered heterocycloalkyl, preferably More preferably and / or, R 1-1 in which the C 1-4 alkyl or C 1-4 in the haloalkyl, the C 1-4 alkyl moiety is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl, ethyl or tert-butyl; and / or, R 1-1 in which the C 1-4 alkoxy or C 1-4 in the haloalkoxy, the C 1-4 alkoxy moiety is methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy, preferably methoxy; and / or, R 1-1 wherein the halogen is F, Cl, Br or I, preferably F, Cl or Br, more preferably F or Cl; and / or, R 1-1 In, the "5- or 6-membered heterocycloalkyl" or "5- or 6-membered heterocycloalkyl substituted by one or more R 2-1 The "5- or 6-membered heterocycloalkyl" in "substituted 5- or 6-membered heterocycloalkyl" is a 6-membered heterocycloalkyl containing an N atom, preferably and / or, R 1-1 in which the C 1-4 haloalkoxy or C 1-4 "halo" in haloalkoxy is fluoro, chloro, bromo or iodo, preferably fluoro; and / or, -1 in R, said C 1-3 the alkyl group is methyl, ethyl, propyl or isopropyl, preferably methyl; and / or, R 1-2 in which the C6-C 10 aryl is phenyl; and / or, R 1-2 in which, the 6- to 10-membered heteroaryl is a nitrogen-containing 6- to 10-membered heteroaryl, preferably and / or, R 1-2 wherein the "-NR 2-2 R 2-3 " is -NHBoc or preferably -NHBoc; and / or, R 1-3 is phenyl; and / or, in R4, the C 1-3 alkyl-C(O)O- is formyloxy, acetyloxy or propionyloxy; and / or, in R4, the C 1-3 alkoxy group is methoxy, ethoxy, propoxy or isopropoxy; and / or, in R5, said C 1-3 alkyl-C(O)O- is formyloxy, acetoxy or propionyloxy; and / or, in R5, the C 1-3 alkoxy group is methoxy, ethoxy, propoxy or isopropoxy.

3. The use according to claim 1, characterized in that, R is hydrogen, C6-C 10 aryl, C 1-3 alkyl, C 1-2 alkyl substituted by one or more R 1-3 alkyl, C 1-3 alkyl substituted by one or more R 2-3 alkenyl or 5- to 9-membered heterocycloalkyl substituted by one or more R 1-4 wherein the 5- to 9-membered heterocycloalkyl has 1 heteroatom which is N; And / or, each R 1-1 is independently CN, NO2, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, halogen, or a 6-membered heteroalkyl group substituted by one R 2-1 wherein the 6-membered heteroalkyl group is a 6-membered heteroalkyl group containing 2 N atoms; and / or, when is , X2 is O; and / or, when is , X3 is O; and / or, when is R4 and R5 are each independently selected from hydrogen and C 1-3 alkyl-C(O)O-.

4. The application according to claim 1, wherein Each R 1-1 independently is CN, NO2, methyl, ethyl, tert-butyl, methoxy, trifluoromethyl, trifluoromethoxy, F, Cl, Br, preferably CN, NO2, methoxy, trifluoromethyl, F, Cl, and / or, each R 1-2 is independently -NHBoc, phenyl or preferably -NHBoc, or phenyl.

5. The application according to claim 1, wherein R3 is preferably and / or, in ring C is 6. The application according to claim 1, wherein The cryptotanshinone derivative represented by Formula I is selected from any of the following structures: Preferably, it is any of the following structures:

7. A cryptotanshinone derivative represented by Formula I, its stereoisomer or its pharmaceutically acceptable salt: Wherein, "-----", R1, R2, R3 and are defined as described in any one of claims 1-5; and the following conditions are satisfied: The cryptotanshinone derivative represented by Formula I is not any of the following structures:

8. The cryptotanshinone derivative represented by Formula I, its stereoisomer or its pharmaceutically acceptable salt according to claim 7, wherein The cryptotanshinone derivative represented by Formula I is selected from any of the following structures:

9. A preparation method of a cryptotanshinone derivative represented by Formula I according to claim 7, which is Method 1 or Method 2: Method 1 includes the following steps: In a solvent, the compound represented by Formula II and R3-H are subjected to the conjugate addition reaction shown below in the presence of an oxidant to obtain the cryptotanshinone derivative represented by Formula I; wherein, The dashed line "-----" in Ring A is a single bond, and R1, R2, R3 and are defined as described in claim 7, and R3 is not hydrogen; Method 2 includes the following steps: in a solvent, a compound represented by Formula III and an acylating agent are subjected to the following reduction acylation reaction in the presence of a reducing agent and an inorganic base to obtain a cryptotanshinone derivative represented by Formula I; wherein, in ring C is R4 and R5 are each independently C 1-3 alkyl-C(O)O-; the definitions of the dashed line "-----", R1, R2, and R3 in ring A are as described in claim 7; 10. The preparation method according to claim 9, wherein In Method 1, the solvent is toluene or chlorobenzene; And / or, in Method 1, the oxidant is oxygen, tert-butyl hydroperoxide, di-tert-butyl peroxide, 2,2,6,6-tetramethylpiperidine N-oxide, or manganese dioxide, preferably 2,2,6,6-tetramethylpiperidine N-oxide; And / or, in Method 1, the reaction temperature of the conjugate addition reaction is 0°C - 130°C, preferably 100°C - 130°C, particularly preferably 120°C - 130°C; And / or, in Method 1, the molar ratio of the oxidant to the compound represented by Formula II is (1:1) - (100:1), preferably (1:1) - (2:1); the molar ratio of R3-H to the compound represented by Formula II is (1:1) - (100:1), preferably (1:1) - (4:1); And / or, in Method 2, the inorganic base is sodium acetate or potassium acetate; And / or, in Method 2, the acylating agent is an acid anhydride or an acyl chloride, preferably acetic anhydride, acetyl chloride, propionic anhydride, or propionyl chloride; And / or, in Method 2, the reducing agent is zinc powder, lithium aluminum hydride, sodium borohydride, or hydrogen / palladium, preferably zinc powder or sodium borohydride; And / or, in Method 2, the reaction temperature in the reductive acylation reaction is 0°C - 50°C, preferably 25°C - 50°C, particularly preferably 40°C - 50°C; And / or, in Method 2, the molar ratio of the acylating agent to the compound represented by Formula III is (2:1) - (100:1), preferably (4:1) - (20:1); And / or, in Method 2, the molar ratio of the inorganic base to the compound represented by Formula III is (1:1) - (100:1), preferably (1:1) - (2:1); And / or, in Method 2, the molar ratio of the reducing agent to the compound represented by Formula III is (2:1) - (100:1), preferably (4:1) - (20:1).

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