CN116789628A

CN116789628A - Fluorinated isoflavonoids, medicaments thereof and use thereof for selectively inhibiting PI3K

Info

Publication number: CN116789628A
Application number: CN202311074574.9A
Authority: CN
Inventors: 韩波; 刘燕青; 黄维; 李俊龙; 朱红萍
Original assignee: Chengdu University; Chengdu University of Traditional Chinese Medicine; Sichuan Peoples Hospital of Sichuan Academy of Medical Sciences
Current assignee: Chengdu University; Chengdu University of Traditional Chinese Medicine; Sichuan Peoples Hospital of Sichuan Academy of Medical Sciences
Priority date: 2023-08-24
Filing date: 2023-08-24
Publication date: 2023-09-22
Anticipated expiration: 2043-08-24
Also published as: CN116789628B

Abstract

The invention provides a fluorinated isoflavone compound, a medicine thereof and application thereof in selectively inhibiting PI3K, and belongs to the technical field of biological medicines. The fluorinated isoflavone compound is a compound shown in a formula I, a salt thereof, a stereoisomer thereof, a solvate thereof or a hydrate thereof. The fluorinated isoflavone compound provided by the invention has the activity of resisting breast cancerThe compound can selectively inhibit PI3K alpha/beta/delta, has good inhibition activity particularly on delta subtype PI3K, and can effectively inhibit the growth and metastasis of tumors, wherein the compound 8 has the best effect. The invention finds an effective PI3K inhibitor, which has important significance for treating breast cancer.

Description

Fluorinated isoflavonoids, medicaments thereof and use thereof for selectively inhibiting PI3K

Technical Field

The invention belongs to the technical field of biological medicines, and particularly relates to a fluorinated isoflavone compound, a medicine thereof and application of the fluorinated isoflavone compound in selectively inhibiting PI 3K.

Background

Flavonoid compounds are widely applied to clinical drug development due to the diversity of structures and biological activities. Wherein isoflavone compounds are widely distributed in many natural plants such as radix astragali, radix Puerariae, glycyrrhrizae radix, etc., and have antiviral, antioxidant, anticancer, etc. activities. Phosphatidylinositol 3-kinases (PI 3 Ks) consist of one catalytic subunit and one regulatory subunit, and are divided into four subtypes, α, β, δ and γ, depending on the catalytic subunit and physiological function. Class I PI3Ks can convert phosphatidylinositol 4, 5-diphosphate to the second messenger phosphatidylinositol 3,4, 5-triphosphate, which is closely related to the occurrence and progression of cancer. PI3Ks participate in PI3K/Akt/mTOR signaling pathways that can regulate proliferation, survival, apoptosis, and autophagy of cells, and are abnormally activated in a variety of cancers. Thus, research efforts to treat malignancies, including breast cancer, by developing novel PI3K/Akt/mTOR signaling pathway small molecule inhibitors have been reported. For example, NVP-BEZ235 promotes the degradation of mutant p53 by inhibiting PI3K and mTOR, thereby inhibiting the growth of triple negative breast cancer cells.

Natural isoflavones can exert antitumor effects by inhibiting PI3K/Akt/mTOR signaling pathway, e.g., isoflavone phytoestrogen derivative genistein in soybean and soybean products has effects of inhibiting proliferation and inducing apoptosis of breast cancer cells; puerarin in the kudzuvine root can down regulate key proteins of the signal channel, thereby inhibiting migration of cervical cancer cells. Thus, structurally diverse isoflavonoids may have potential PI3K inhibitory activity and potential for anticancer therapy.

Since 2011, 108 of the nearly 340 small molecule drugs approved by the FDA contain fluorine atoms, accounting for about 30%, and most have anti-tumor, anti-infection, neuroprotective and cardioprotective effects. Fluorination of natural products can improve their bioactivity, lipophilicity, permeability, hydrophobicity, thereby increasing the drug resistance. For example, fluorinated derivatives of Dihydroartemisinin (DHA) have greatly improved stability at ph=2.0 and have stronger antimalarial activity than artemisinin and other drugs. The fluorination modification of natural products can be achieved by photo-redox catalysis, electrocatalysis, transition metal catalysis or organocatalysis. Organic catalysis has the advantages of high efficiency, low cost, environmental friendliness and the like, and is the most commonly used fluorination means. N-heterocyclic carbenes (NHCs) have become powerful tools for preparing biologically active compounds as typical organic catalysts. NHC catalyzed free radical reaction of olefins with various halothane source reagents can effectively introduce fluorinated groups into various bioactive compounds to develop new drug candidates. The isoflavone compound is subjected to fluorination treatment by utilizing a fluorination technology to obtain a compound capable of selectively targeting and inhibiting PI3K in subtype, and the method has important significance for the research and development of antitumor drugs.

Disclosure of Invention

The invention aims to provide fluorinated isoflavone compounds, medicaments thereof and application thereof in selectively inhibiting PI 3K.

The present invention provides a compound of formula I, a salt thereof, a stereoisomer thereof, a solvate thereof, or a hydrate thereof:

i is a kind of

wherein ,

R ₁ selected from substituted or unsubstituted C ₁ ~C ₈ Alkyl, substituted or unsubstituted C ₁ ~C ₈ Alkoxy, substituted or unsubstituted 6-12 membered aryl, substituted or unsubstituted 6-12 membered heteroaryl, substituted or unsubstituted 3-8 membered cycloalkyl, substituted or unsubstituted 4-8 membered heterocycloalkyl; the substituents of the alkyl, alkoxy, aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups are selected from C ₁ ~C ₈ Alkyl, C ₁ ~C ₈ Alkoxy, halogen, cyano, nitro, amino, carboxyl, hydroxyl, trifluoromethyl, 6-12 membered aryl, 6-12 membered heteroaryl, 3-8 membered cycloalkyl, 4-8 membered heterocycloalkyl; the hetero atoms of the heteroaryl and the heterocycloalkyl are O, N or S, and the number of the hetero atoms is 1, 2 or 3;

R ₂ is connected at any position of benzene ring, m is R ₂ Is the number of (3); m is 1, 2, 3 or 4; each R ₂ Independently selected from hydrogen, substituted or unsubstituted C ₁ ~C ₈ Alkyl, substituted or unsubstituted C ₁ ~C ₈ Alkoxy, halogen, cyano, nitro, amino, carboxyl, hydroxyl, or two adjacent R ₂ Forming a naphthyl group with the benzene ring; the substituents of the alkyl and alkoxy groups are selected from C ₁ ~C ₈ Alkyl, C ₁ ~C ₈ Alkoxy, halogen, cyano, nitro, amino, carboxyl, hydroxyl;

R _f selected from substituted or unsubstituted C ₁ ~C ₈ An alkyl group; the substituent of the alkyl is selected from halogen, -C (O) OR ₃ And said alkyl is substituted with at least 1 fluorine;

R ₃ selected from C ₁ ~C ₈ An alkyl group.

Further, the compound is represented by formula II:

II (II)

wherein ,

R ₄ is connected at any position of benzene ring, n is R ₄ Is the number of (3); n is 1, 2, 3 or 4; each R ₄ Are independently selected from hydrogen, C ₁ ~C ₈ Alkyl, C ₁ ~C ₈ Alkoxy, halogen, cyano, nitro, amino, carboxyl, hydroxyl, trifluoromethyl, 6-12 membered aryl, 6-12 membered heteroaryl, 3-8 membered cycloalkyl, 4-8 membered heterocycloalkyl; the hetero atoms of the heteroaryl and the heterocycloalkyl are O, N or S, and the number of the hetero atoms is 1, 2 or 3;

R ₃ selected from C ₁ ~C ₈ An alkyl group.

Further, the compound is represented by formula III:

formula III

wherein ,

R ₂ is connected at any position of benzene ring, m is R ₂ Is the number of (3); m is 1, 2, 3 or 4; each R ₂ Independently selected from hydrogen, substituted or unsubstituted C ₁ ~C ₈ Alkyl, substituted orUnsubstituted C ₁ ~C ₈ Alkoxy, halogen, cyano, nitro, amino, carboxyl, hydroxyl, or two adjacent R ₂ Forming a naphthyl group with the benzene ring; the substituents of the alkyl and alkoxy groups are selected from C ₁ ~C ₈ Alkyl, C ₁ ~C ₈ Alkoxy, halogen, cyano, nitro, amino, carboxyl, hydroxyl.

Further, the compound is represented by formula IVa:

IVa

wherein ,

Alternatively, the compound is of formula IVb:

IVb

wherein ,

alternatively, the compound is of formula IVc:

IVc

wherein ,

R ₄ is connected at any position of benzene ring, n is R ₄ Is the number of (3); n is 1, 2, 3 or 4; each R ₄ Are independently selected from hydrogen, C ₁ ~C ₈ Alkyl, C ₁ ~C ₈ Alkoxy, halogen, cyano, nitro, amino, carboxyl, hydroxyl, trifluoromethyl, 6-12 membered aryl, 6-12 membered heteroaryl, 3-8 membered cycloalkyl, 4-8 membered heterocycloalkyl; the hetero atoms of the heteroaryl and the heterocycloalkyl are O, N or S, and the number of the hetero atoms is 1, 2 or 3.

Further, the compound is represented by formula V:

v (V)

wherein ,

R ₃ Selected from C ₁ ~C ₈ An alkyl group.

Further, the method comprises the steps of,

R ₁ selected from C ₁ ~C ₃ Alkyl, substituted or unsubstituted phenyl, benzodioxazole; the substituents of the phenyl groups are selected from C ₁ ~C ₃ Alkyl, C ₁ ~C ₃ Alkoxy, halogen, cyano, nitro, amino, carboxyl, hydroxyl, trifluoromethyl, phenyl;

R ₂ is connected at any position of benzene ring, m is R ₂ Is the number of (3); m is 1, 2, 3 or 4; each R ₂ Are independently selected from hydrogen, C ₁ ~C ₃ Alkyl, C ₁ ~C ₃ Alkoxy, halogen, cyano, nitro, amino, carboxyl, hydroxyl, or two adjacent R ₂ Forming a naphthyl group with the benzene ring;

R ₃ selected from C ₁ ~C ₃ An alkyl group.

Further, the compound is one of the following compounds:

。

the invention also provides application of the compound, the salt, the stereoisomer, the solvate or the hydrate thereof in preparing a PI3K inhibitor or an anticancer drug.

Further, the anticancer drug is a drug for preventing and/or treating breast cancer.

The invention also provides a medicine, which is a preparation prepared by taking the compound, the salt, the stereoisomer, the solvate or the hydrate thereof as an active ingredient and adding pharmaceutically acceptable auxiliary materials or auxiliary ingredients.

Compared with the prior art, the invention has the beneficial effects that:

the invention provides a series of fluorinated isoflavone compounds with breast cancer resisting activity, which can selectively inhibit PI3K alpha/beta/delta, especially has good inhibiting activity on delta subtype PI3K, and can effectively inhibit the growth and metastasis of tumors, wherein the compound 8 has the best effect. The invention finds an effective PI3K inhibitor, which has important significance for treating breast cancer.

It should be apparent that, in light of the foregoing, various modifications, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.

The above-described aspects of the present invention will be described in further detail below with reference to specific embodiments in the form of examples. It should not be understood that the scope of the above subject matter of the present invention is limited to the following examples only. All techniques implemented based on the above description of the invention are within the scope of the invention.

Drawings

FIG. 1 is a graph showing the effect of the compounds of the present invention on tumor cell activity: a is a thermal map of the inhibition of proliferation activity of the compounds of the invention on various tumor cells; b is a graph of the concentration of compound 8 of the invention versus MDA-MB-231 and MCF-7 cell activity, the data in the graph representing mean.+ -. Standard deviation.

FIG. 2 is a graph showing the results of the study of Compound 8 of the present invention as a PI3K inhibitor: a is a prediction result diagram of the combination mode of the compound 8 and the PI3K alpha, the PI3K beta, the PI3K gamma and the PI3K delta; b is a molecular dynamics simulation diagram of the combination of the compound 8 and the pi3kα, pi3kβ, pi3kγ and pi3kδ, b is a molecular dynamics simulation atomic position RMSD result diagram of the pi3kα, pi3kβ, pi3kγ and pi3kδ and 8 in 100 ns, (b) is a free energy diagram of the combination of the compound 8 and the pi3kα, pi3kβ, pi3kδ and pi3kγ measured by an MM/PBSA method, and (c) is an interaction energy diagram of the compound 8 and the pi3kα, pi3kβ, pi3kγ and pi3kδ protein residues; c is a graph of the kinase inhibition activity results of compound 8 on pi3kα, pi3kβ, pi3kγ and pi3kδ; d-e is a graph of the thermal stability of pi3kα, pi3kβ, pi3kγ and pi3kδ after CETSA assay to detect compound 8 treated MDA-MB-231 cells. Data represent mean ± standard deviation.

FIG. 3 is a graph showing the proliferation and migration results of MDA-MB-231 cells inhibited by Compound 8: a is a representative image of colonies and a quantitative result of a colony formation assay of compound 8 (5. Mu.M) with or without MDA-MB-231 cells; b is an immunoblotting quantitative analysis result graph of E-cadherin and MMP-2; data represent mean ± standard deviation; p <0.05, p <0.01, p <0.001 compared to the control group.

FIG. 4 is a graph showing the results of inhibiting proliferation and migration of MDA-MB-231 cells by Compound 8: a is a representative image and quantification result graph of the three-dimensional ellipsoid size of 3D culture of compound 8 (5 μm) with or without MDA-MB-231 cells; b is an EDU assay plot with or without MDA-MB-231 cells treated with compound 8 (5. Mu.M), showing representative images and quantification results of EDU positive cells, scale bar, 50. Mu.m; c is a scratch test result graph and a wound closure result statistical graph of MDA-MB-231 cells treated or not treated by the compound 8 (5 mu M), wherein wound closure is a control group relative closure rate, and represents the cell migration capacity level, a scale and 100 mu M; d is a result graph of determining the number of the migration cells by a Transwell method, and a representative image and statistical data display scale is 50 mu m; e is a plot of immunoblot analysis results of E-cadherin and MMP-2 expression following treatment of MDA-MB-231 cells 24 h with 0, 2.5, 5 and 10. Mu.M of Compound 8, using beta-actin as a control; f-g are graphs of the results of the immunofluorescence analysis of E-cadherein and MMP-2 expression in MDA-MB-231 cells, with or without compound 8 (5. Mu.M), in figures f and g, zoom is an enlarged view within the dashed box, scale bar, 10. Mu.m, showing representative pictures and statistics; data represent mean ± standard deviation; p <0.05, p <0.01, p <0.001 compared to the control group.

Detailed Description

The materials and equipment used in the embodiments of the present invention are all known products and are obtained by purchasing commercially available products.

Primary cells and reagents: MDA-MB-231 cells were purchased from American Type Culture Collection (ATCC, manassas, va., USA) and stored in DMEM with 10% Fetal Bovine Serum (FBS), 37 ℃. MTT (M2128), 3-MA (M9281), CQ (C6628) and DAPI (D9542) were purchased from Sigma-Aldrich (St. Louis, MO, USA). Bafilomycin A1 (ab 120497) was purchased from Abcam (Cambridge, UK). The antibodies used were as follows: beclin1 (3495, CST), SQSTM1/P62 (8025, CST), LC3B (51520, abcam), MMP-2 (87809, CST), E-cadherein (14472, CST), beta-actin (66009-1-Ig, proteintech, IL, USA), LAMP1 (25630, abcam), PI3K alpha (27921-1-AP, proteintech, IL, USA), PI3K beta (20584-1-AP, proteintech, IL, USA), PI3K gamma (20662-1-AP, proteintech, IL, USA), PI3K delta (34050, CST), AKT (9272, CST), P-AKTS473 (4060S, CST), P-AKTT308 (13038S, CST), mTOR (2972, CST), P-mTOR (5536, CST), P70S 6 (9202, CST) and P6-CST (9270, CST).

Synthetic route of the compounds of the invention:

after adding the catalyst NHC (0.02 mmol) to the reaction tube, the tube was purged and then dried CF was added ₃ Ph solvent, O-hydroxybenzaldehyde compound (compound 2,0.1 mmol), conjugated eneyne substrate (compound 1,0.15 mmol), fluorine source reagent (0.15 mmol) and Cs were added in this order under argon atmosphere ₂ CO ₃ (0.04 mmol) and after sealing, 12 h are reacted at 60 ℃. TLC monitoring and after complete disappearance of compound 2, the reaction was stopped, followed by separation and purification by silica gel column, eluting with PE: EA=60:1 (v: v), collecting the concentrated final target compound (compound 3). When methyl bromodifluoroacetate, perfluoroiodobutane or perfluoroiodooctane is used as the fluorine source reagent, cs ₂ CO ₃ The amount of (C) was 0.15 mmol.

The structure of NHC is:

CF ₃ the structure of Ph is:

EXAMPLE 1 Synthesis of Compound 4a (2- (1- ([ 1,1' -biphenyl ] -4-yl) -3, 3-trifluoropropyl) -3-phenyl-4H-benzopyran-4-one)

According to the method described in the synthetic route, R ₁ Is biphenyl, R ₂ Is hydrogen, R _f Compound 4a of 32.9. 32.9 mg was prepared as a trifluoromethyl group (the fluorine source reagent was Togni I) as a milky white solid with a yield of 70% and a melting point of 119.3-123.7deg.C.

Togni I has the structure of。

Characterization data for compound 4a are as follows:

¹ H NMR (600 MHz, CDCl ₃ ) δ (ppm): 8.24 (d,J= 7.8 Hz, 1H), 7.72 (t,J= 8.4 Hz, 1H), 7.60 – 7.54 (m, 6H),7.48 – 7.41 (m, 6H), 7.35 (t,J= 7.8 Hz, 1H), 7.27 (d,J= 8.4 Hz, 2H), 7.14 – 7.08 (m, 1H), 4.39 (dd,J= 10.8, 4.2 Hz, 1H), 3.37 – 3.27 (m, 1H), 2.71 – 2.62 (m, 1H).

¹³ C NMR (151 MHz, CDCl ₃ ) δ (ppm): 177.1, 162.7, 155.7, 141.0, 140.2, 137.3, 133.7, 132.1, 130.4, 128.8, 128.6, 128.3, 127.9, 127.7, 127.5, 127.0, 126.4, 125.8(C-F, ¹ J _C-F = 277.7 Hz), 125.3, 124.2, 123.5, 117.6, 41.2, 37.0 (C-F, ² J _C-F = 29.0 Hz).

¹⁹ F NMR (564 MHz, CDCl ₃ ) δ (ppm): -65.18 (t,J= 10.7 Hz, 3F).

HRMS (ESI-TOF)m/z: [M + H] ⁺ Calcd for C ₃₀ H ₂₂ F ₃ O ₂ ⁺ 471.1566; Found 471.1562.

example 2 Synthesis of Compound 4b (2- (1- ([ 1,1' -biphenyl)]-4-yl) -3, 3-trifluoropropyl) -6-methyl-3-phenyl-4 HBenzopyran-4-one

According to the method described in the synthetic route, R ₁ Is biphenyl, R ₂ Is methyl at 6-position of chromone mother nucleus, R _f Compound 4b, 37.8 mg, was prepared as a pale yellow oil in 78% yield as trifluoromethyl (the fluoride source reagent was topni I).

Characterization data for compound 4b are as follows:

¹ H NMR (600 MHz, CDCl ₃ ) δ (ppm): 8.02 (s, 1H), 7.56 – 7.42 (m, 12H), 7.35 (t,J= 7.2 Hz, 1H), 7.26 (d,J= 8.4 Hz, 2H), 7.20 – 7.08 (m, 1H), 4.38 (dd,J= 10.2, 4.2 Hz, 1H), 3.35 – 3.26 (m, 1H),2.69 – 2.61 (m, 1H), 2.47 (s, 3H).

¹³ C NMR (151 MHz, CDCl ₃ ) δ (ppm): 177.1, 162.5, 154.0, 140.9, 140.2, 137.4, 135.2, 134.9, 132.3, 130.4, 128.8, 128.5, 128.3, 127.9, 127.7, 127.5, 127.0, 125.8(C-F, ¹ J _C-F = 279.0 Hz), 125.7, 124.0, 123.2, 117.3, 41.2, 37.0 (C-F, ² J _C-F = 28.8 Hz), 20.9.

¹⁹ F NMR (564 MHz, CDCl ₃ ) δ (ppm): -65.21 (t,J= 10.7 Hz, 3F).

HRMS (ESI-TOF)m/z: [M + H] ⁺ Calcd for C ₃₁ H ₂₄ F ₃ O ₂ ⁺ 485.1723; Found 485.1726.

example 3 Synthesis of Compound 4cAnd (2- (1- ([ 1,1' -biphenyl)]-4-yl) -3, 3-trifluoropropyl) -6-methoxy-3-phenyl-4HBenzopyran-4-one

According to the method described in the synthetic route, R ₁ Is biphenyl, R ₂ Methoxy group at 6-position of chromone mother nucleus, R _f Compound 4c, 24.0. 24.0 mg as a pale yellow solid was prepared in 48% yield with a melting point of 77.0-80.7 ℃ as trifluoromethyl (the fluorine source reagent was topni I).

Characterization data for compound 4c are as follows:

¹ H NMR (600 MHz, CDCl ₃ ) δ (ppm): 7.59 (d,J= 2.4 Hz, 1H), 7.55 – 7.42 (m, 11H), 7.35 (t,J= 7.8 Hz, 1H), 7.31 (dd,J= 9.6, 3.0 Hz, 1H), 7.24 (d,J= 8.4 Hz, 2H), 7.18 – 7.08 (m, 1H), 4.37 (dd,J= 10.2, 3.6 Hz, 1H), 3.89 (s, 3H), 3.34 – 3.24 (m, 1H),2.69 – 2.60 (m, 1H).

¹³ C NMR (151 MHz, CDCl ₃ ) δ (ppm): 176.9, 162.5, 157.1, 150.5, 140.9, 140.2, 137.5, 132.3, 130.7, 128.8, 128.6, 128.3, 127.9, 127.7, 127.5, 127.0, 125.8 (C-F, ¹ J _C-F = 279.0 Hz), 124.1, 123.7, 123.5, 119.0, 105.6, 56.0, 41.2, 37.1 (C-F, ² J _C-F = 29.0 Hz).

¹⁹ F NMR (564 MHz, CDCl ₃ ) δ (ppm): -65.20 (t,J= 9.6 Hz, 3F).

HRMS (ESI-TOF)m/z: [M + H] ⁺ Calcd for C ₃₁ H ₂₄ F ₃ O ₃ ⁺ 501.1672; Found 501.1669.

example 4 Synthesis of Compound 4d (2- (1- ([ 1,1' -biphenyl)]-4-yl) -3, 3-trifluoropropyl) -7-methyl-3-phenyl-4HBenzopyran-4-one

According to the method described in the synthetic route, R ₁ Is biphenyl, R ₂ Methyl at 7-position of chromone mother nucleus, R _f Compound 4d, 43.1 mg as a pale yellow solid was prepared in 89% yield with a melting point of 79.1-83.5 ℃ as trifluoromethyl (the fluorine source reagent was topni I).

Characterization data for compound 4d are as follows:

¹ H NMR (600 MHz, CDCl ₃ ) δ (ppm): 8.11 (d,J= 8.4 Hz, 1H), 7.56 – 7.42 (m, 10H), 7.39 (s, 1H), 7.35 (t,J= 7.2 Hz, 1H), 7.26 (d,J= 7.8 Hz, 2H), 7.23 (d,J= 8.4 Hz, 1H), 7.18 – 7.08 (m, 1H), 4.37 (dd,J= 10.2, 4.8 Hz, 1H), 3.34 – 3.25 (m, 1H), 2.69 – 2.60 (m, 1H), 2.53 (s, 3H).

¹³ C NMR (151 MHz, CDCl ₃ ) δ (ppm): 177.0, 162.3, 155.8, 145.0, 140.9, 140.2, 137.5, 132.3, 130.7, 128.8, 128.6, 128.2, 127.9, 127.7, 127.5, 127.0, 126.8, 126.2,125.8 (C-F, ¹ J _C-F = 277.5 Hz), 124.1, 121.2, 117.4, 41.2, 37.0 (C-F, ² J _C-F = 27.5 Hz), 21.8.

¹⁹ F NMR (564 MHz, CDCl ₃ ) δ (ppm): -65.20 (t,J= 9.6 Hz, 3F).

HRMS (ESI-TOF)m/z: [M + H] ⁺ Calcd for C ₃₁ H ₂₄ F ₃ O ₂ ⁺ 485.1723; Found 485.1720.

Example 5 Synthesis of Compound 4e (2- (1- ([ 1,1' -biphenyl)]-4-yl) -3, 3-trifluoropropyl) -7-methoxy-3-phenyl-4HBenzopyran-4-one

According to the method described in the synthetic route, R ₁ Is biphenyl, R ₂ Methoxy group at 7-position of chromone mother nucleus, R _f Compound 4e, 31.0 mg as a yellow solid was prepared in 62% yield with a melting point of 201.3-203.5 ℃ as trifluoromethyl (the fluorine source reagent was topni I).

Characterization data for compound 4e are as follows:

¹ H NMR (600 MHz, CDCl ₃ ) δ (ppm): 8.13 (d,J= 9.0 Hz, 1H), 7.56 – 7.54 (m, 4H), 7.51 – 7.42 (m, 5H), 7.35 (t,J= 7.2 Hz, 2H), 7.25 (d,J= 8.4 Hz, 2H), 7.19 – 7.05 (m, 1H), 6.98 (d,J= 9.0 Hz, 1H), 6.96 (s, 1H), 4.36 (dd,J= 10.8, 4.8 Hz, 1H), 3.96 (s, 3H), 3.33 – 3.24 (m, 1H), 2.69 – 2.61 (m, 1H).

¹³ C NMR (151 MHz, CDCl ₃ ) δ (ppm): 176.5, 164.2, 162.1, 157.4, 140.9, 140.2, 137.5, 132.2, 130.3, 128.8, 128.7, 128.2, 127.9, 127.7, 127.5, 127.0, 125.8 (C-F, ¹ J _C-F = 277.5 Hz), 124.0, 117.3, 114.5, 99.9, 55.9, 41.1, 37.0 (C-F, ² J _C-F = 27.5 Hz).

¹⁹ F NMR (564 MHz, CDCl ₃ ) δ (ppm): -65.15 (t,J= 11.3 Hz, 3F).

HRMS (ESI-TOF)m/z: [M + H] ⁺ Calcd for C ₃₁ H ₂₄ F ₃ O ₃ ⁺ 501.1672; Found 501.1665.

example 6 Synthesis of Compound 4f (2- (1- ([ 1,1' -biphenyl)]-4-yl) -3, 3-trifluoropropyl) -7-bromo-3-phenyl-4HBenzopyran-4-one

According to the method described in the synthetic route, R ₁ Is biphenyl, R ₂ Halogen bromine at 7-position of chromone mother nucleus, R _f Compound 4f, 40.1 mg as a pale yellow solid, 73% yield, 101.1-104.3 ℃ melting point was prepared as trifluoromethyl (the fluorine source reagent was topni I).

Characterization data for compound 4f are as follows:

¹ H NMR (600 MHz, CDCl ₃ ) δ (ppm): 8.09 (d,J= 9.0 Hz, 1H), 7.81 (s, 1H), 7.56 – 7.46 (m, 8H), 7.44 (t,J= 7.8 Hz, 2H), 7.36 (t,J= 7.2 Hz, 2H), 7.24 (d,J= 9.0 Hz, 2H), 7.18 – 7.08 (m, 1H), 4.38 (dd,J= 10.2, 4.2 Hz, 1H), 3.33 – 3.24 (m, 1H),2.68 – 2.60 (m, 1H).

¹³ C NMR (151 MHz, CDCl ₃ ) δ (ppm): 176.4, 162.8, 155.7, 141.1, 140.1, 137.0, 131.7, 130.3, 128.9, 128.8, 128.6, 128.5, 128.0, 127.9, 127.8, 127.6, 127.0, 125.7(C-F, ¹ J _C-F = 277.7 Hz), 124.5, 122.4, 120.8, 41.2, 36.9 (C-F, ² J _C-F = 29.0 Hz).

¹⁹ F NMR (564 MHz, CDCl ₃ ) δ (ppm): -65.20 (t,J= 10.7 Hz, 3F).

HRMS (ESI-TOF)m/z: [M + H] ⁺ Calcd for C ₃₀ H ₂₁ ⁷⁹ BrF ₃ O ₂ ⁺ 549.0672, C ₃₀ H ₂₁ ⁸¹ BrF ₃ O ₂ ⁺ 551.0652; Found 549.0673, 551.0657.

EXAMPLE 7 Synthesis of Compound 4g (2- (1- ([ 1,1' -biphenyl)]-4-yl) -3, 3-trifluoropropyl) -7-chloro-3-phenyl-4HBenzopyran-4-one

According to the method described in the synthetic route, R ₁ Is biphenyl, R ₂ Halogen chlorine at 7-position of chromone mother nucleus, R _f As trifluoromethyl (fluorine source reagent is Togni I), 37.4 g of compound mg is prepared as pale yellow solid, the yield is 74 percent, and the melting point is 87.7-89.9 ℃.

Characterization data for compound 4g are as follows:

¹ H NMR (600 MHz, CDCl ₃ ) δ (ppm): 8.16 (d,J= 8.4 Hz, 1H), 7.63 (s, 1H), 7.56 –7.46 (m, 7H), 7.44 (t,J= 7.8 Hz, 2H), 7.39 – 7.34 (m, 3H), 7.24 (d,J= 8.4 Hz, 2H), 7.21 – 7.08 (m, 1H), 4.38 (dd,J= 10.2, 4.2 Hz, 1H), 3.34 – 3.24 (m, 1H),2.68 – 2.60 (m, 1H).

¹³ C NMR (151 MHz, CDCl ₃ ) δ (ppm): 176.3, 162.9, 155.8, 141.1, 140.1, 139.8, 137.0, 131.7, 130.4, 128.8, 128.6, 128.5, 127.8, 127.8, 127.6, 127.0, 126.1, 125.7(C-F, ¹ J _C-F = 277.7 Hz), 124.5, 122.0, 117.7, 41.2, 36.9 (C-F, ² J _C-F = 29.0 Hz).

¹⁹ F NMR (564 MHz, CDCl ₃ ) δ (ppm): -65.21 (t,J= 10.7 Hz, 3F).

HRMS (ESI-TOF)m/z: [M + H] ⁺ Calcd for C ₃₀ H ₂₁ ³⁵ ClF ₃ O ₂ ⁺ 505.1177, C ₃₀ H ₂₁ ³⁷ ClF ₃ O ₂ ⁺ 507.1147; Found 505.1173, 507.1152.

example 8 Synthesis of Compound 4h (2- (1- ([ 1,1' -biphenyl)]-4-yl) -3, 3-trifluoropropyl) -7-fluoro-3-phenyl-4HBenzopyran-4-one

According to the method described in the synthetic route, R ₁ Is biphenyl, R ₂ Halogen fluorine at 7-position of chromone mother nucleus, R _f The compound 32.2. 32.2 mg was prepared as a trifluoromethyl group (the fluorine source reagent was Togni I) in the form of a pale yellow solid with a yield of 66% and a melting point of 75.1-78.2 ℃.

Characterization data for compound 4h are as follows:

¹ H NMR (600 MHz, CDCl ₃ ) δ (ppm): 8.24 (dd,J= 9.0, 6.0 Hz, 1H), 7.56 – 7.46 (m, 7H), 7.44 (t,J= 7.8 Hz, 2H), 7.36 (t,J= 7.2 Hz, 2H), 7.28 (dd,J= 9.0, 3.0 Hz, 1H), 7.25 (d,J= 8.4 Hz, 2H), 7.17 – 7.07 (m, 2H), 4.38 (dd,J= 10.8, 4.8 Hz, 1H), 3.33 – 3.24 (m, 1H),2.69 – 2.60 (m, 1H).

¹³ C NMR (151 MHz, CDCl ₃ ) δ (ppm): 176.2, 165.7 (C-F, ¹ J _C-F = 257.4 Hz), 162.9, 156.6 (C-F, ³ J _C-F = 13.0 Hz), 141.1, 140.1, 137.1, 131.7, 130.4, 129.0 (C-F, ³ J _C-F = 10.1 Hz), 128.8, 128.7, 128.5, 127.8, 127.8, 127.6, 127.0, 125.8 (C-F, ¹ J _C-F = 277.5 Hz), 124.3, 120.3, 114.1 (C-F, ² J _C-F = 23.1 Hz), 104.4 (C-F, ² J _C-F = 24.5 Hz), 41.1, 36.9 (C-F ₃ , ² J _C-F = 29.0 Hz).

¹⁹ F NMR (564 MHz, CDCl ₃ ) δ (ppm): -65.21 (t,J= 9.9 Hz, 3F), -103.20 – -103.24 (m, 1F).

HRMS (ESI-TOF)m/z: [M + Na] ⁺ Calcd for C ₃₀ H ₂₀ F ₄ O ₂ Na ⁺ 511.1292; Found 511.1295.

example 9 Synthesis of Compound 4i (2- (1- ([ 1,1' -biphenyl)]-4-yl) -3, 3-trifluoropropyl) -8-methoxy-3-phenyl-4HBenzopyran-4-one

According to the method described in the synthetic route, R ₁ Is biphenyl, R ₂ Methoxy group at 8-position of chromone mother nucleus, R _f Compound 4I of 39.0. 39.0 mg was prepared as a pale yellow solid in 78% yield with a melting point of 170.7-171.8℃as trifluoromethyl (Togni I as fluorine source reagent).

Characterization data for compound 4i are as follows:

¹ H NMR (600 MHz, CDCl ₃ ) δ (ppm): 7.77 (d,J= 7.8 Hz, 1H), 7.57 – 7.42 (m, 10H), 7.36 – 7.30 (m, 4H), 7.24 (d,J= 7.8 Hz, 1H), 7.18 – 7.07 (m, 1H), 4.35 (dd,J= 10.2, 4.8 Hz, 1H), 4.08 (s, 3H), 3.43 – 3.33 (m, 1H), 2.70 – 2.61 (m, 1H).

¹³ C NMR (151 MHz, CDCl ₃ ) δ (ppm): 177.1, 162.4, 149.0, 146.2, 140.8, 140.3, 137.4, 132.2, 130.4, 128.8, 128.6, 128.3, 128.2, 127.7, 127.5, 127.0, 125.9 (C-F, ¹ J _C-F = 277.5 Hz), 124.7, 124.5, 123.9, 117.0, 114.2, 56.5, 41.5, 37.3 (C-F, ² J _C-F = 28.8 Hz).

¹⁹ F NMR (564 MHz, CDCl ₃ ) δ (ppm): -65.22 (t,J= 11.0 Hz, 3F).

HRMS (ESI-TOF)m/z: [M + H] ⁺ Calcd for C ₃₁ H ₂₄ F ₃ O ₃ ⁺ 501.1672; Found 501.1668.

example 10 Synthesis of Compound 4j (2- (1- ([ 1,1' -biphenyl)]-4-yl) -3, 3-trifluoropropyl) -8-tert-butyl-3-phenyl-4HBenzopyran-4-one

According to the method described in the synthetic route, R ₁ Is biphenyl, R ₂ Tert-butyl in position 8 of the chromone mother nucleus, R _f Compound 4j, 23.7. 23.7 mg as a pale yellow solid was prepared in 45% yield with a melting point of 66.3-69.7 ℃ as trifluoromethyl (the fluorine source reagent was topni I).

Characterization data for compound 4j are as follows:

¹ H NMR (600 MHz, CDCl ₃ ) δ (ppm): 8.17 (d,J= 7.2 Hz, 1H), 7.68 (d,J= 7.8 Hz, 1H), 7.54 (d,J= 7.8 Hz, 2H), 7.53 (d,J= 8.4 Hz, 2H), 7.51 – 7.41 (m, 5H), 7.34 (t,J= 7.8 Hz, 3H), 7.24 – 7.16 (m, 3H), 4.61 (dd,J= 10.2, 4.8 Hz, 1H), 3.39 – 3.30 (m, 1H),2.86 – 2.78 (m, 1H), 1.52 (s, 9H).

¹³ C NMR (151 MHz, CDCl ₃ ) δ (ppm): 177.5, 163.0, 154.9, 140.8, 140.1, 138.7, 137.1, 132.3, 131.2, 130.4, 128.8, 128.7, 128.3, 127.8, 127.6, 127.0, 125.9 (C-F, ¹ J _C-F = 279.0 Hz), 124.9, 124.9, 124.5, 124.4, 40.8, 36.5 (C-F, ² J _C-F = 28.8 Hz), 35.0, 30.4.

¹⁹ F NMR (564 MHz, CDCl ₃ ) δ (ppm): -64.82 (t,J= 11.0 Hz, 3F).

HRMS (ESI-TOF)m/z: [M + Na] ⁺ Calcd for C ₃₄ H ₂₉ F ₃ O ₂ Na ⁺ 549.2012; Found 549.2018.

example 11 Synthesis of Compound 4k (2- (1- ([ 1,1' -biphenyl)]-4-yl) -3, 3-trifluoropropyl) -8-fluoro-3-phenyl-4HBenzopyran-4-one

According to the method described in the synthetic route, R ₁ Is biphenyl, R ₂ Halogen fluorine at 8-position of chromone mother nucleus, R _f Compound 4k, 30.3 mg as a pale yellow solid, 62% yield and 69.8-72.3 ℃ melting point, was prepared as trifluoromethyl (fluorine source reagent, togni I).

Characterization data for compound 4k are as follows:

¹ H NMR (600 MHz, CDCl ₃ ) δ (ppm): 7.98 (d,J= 7.8 Hz, 1H), 7.57 – 7.47 (m, 8H), 7.44 (t,J= 7.2 Hz, 2H), 7.40 – 7.32 (m, 3H), 7.30 (d,J= 9.0 Hz, 2H), 7.22 – 7.07 (m, 1H), 4.38 (dd,J= 10.2, 4.2 Hz, 1H), 3.41 – 3.32 (m, 1H), 2.70 – 2.62 (m, 1H).

¹³ C NMR (151 MHz, CDCl ₃ ) δ (ppm): 176.2, 162.5, 151.1 (C-F, ¹ J _C-F = 253.1 Hz), 144.5 (C-F, ² J _C-F = 11.6 Hz), 141.1, 140.2, 136.9, 131.6, 130.4, 128.8, 128.7, 128.6, 128.0, 127.8, 127.6, 127.0,125.8 (C-F, ¹ J _C-F = 277.7 Hz), 125.3, 124.7 (C-F, ³ J _C-F = 5.7 Hz), 124.3, 121.4 (C-F, ³ J _C-F = 2.9 Hz), 119.3 (C-F, ² J _C-F = 15.9 Hz), 41.4, 37.0 (C-F, ² J _C-F = 29.0 Hz).

¹⁹ F NMR (564 MHz, CDCl ₃ ) δ (ppm): -65.23 (t,J= 11.3 Hz, 3F), -135.07 – -135.10 (m, 1F).

HRMS (ESI-TOF)m/z: [M + Na] ⁺ Calcd for C ₃₀ H ₂₀ F ₄ O ₂ Na ⁺ 511.1292; Found 511.1297.

example 12 Synthesis of Compound 4l (2- (1- ([ 1,1' -biphenyl)]-4-yl) -3, 3-trifluoropropyl) -3-phenyl-4HBenzo [ h ]]Benzopyran-4-one)

According to the method described in the synthetic route, R ₁ Is biphenyl, R ₂ 7,8 condensed rings of chromone mother nucleus, R _f Compound 4l of 21.3 mg was prepared as a white solid in 41% yield with a melting point of 203.8-205.0deg.C as trifluoromethyl (Togni I as fluorine source reagent).

Characterization data for compound 4l are as follows:

¹ H NMR (600 MHz, CDCl ₃ ) δ (ppm): 8.59 (d,J= 7.2 Hz, 1H), 8.18 (d,J= 9.0 Hz, 1H), 7.99 (d,J= 9.0 Hz, 1H), 7.80 – 7.76 (m, 3H), 7.56 – 7.47 (m, 7H), 7.42 (t,J= 7.8 Hz, 3H), 7.35 – 7.32 (m, 3H), 7.24 – 7.08 (m, 1H), 4.51 (dd,J= 10.2, 4.2 Hz, 1H), 3.49 – 3.39 (m, 1H),2.86 – 2.77 (m, 1H).

¹³ C NMR (151 MHz, CDCl ₃ ) δ (ppm): 176.9, 161.9, 153.0, 141.0, 140.1, 137.3, 136.0, 132.0, 130.2, 129.3, 128.8, 128.7, 128.5, 128.4, 127.9, 127.9, 127.6, 127.4,127.0, 125.8 (C-F, ¹ J _C-F = 279.0 Hz), 125.4, 125.4, 124.0, 121.7, 121.4, 119.9, 41.4, 37.5 (C-F, ² J _C-F = 28.8 Hz).

¹⁹ F NMR (564 MHz, CDCl ₃ ) δ (ppm): -65.02 (t,J= 10.7 Hz, 3F).

HRMS (ESI-TOF)m/z: [M + H] ⁺ Calcd for C ₃₄ H ₂₄ F ₃ O ₂ ⁺ 521.1723; Found 521.1729.

EXAMPLE 13 Synthesis of Compound 4m (3-phenyl-2- (3, 3-trifluoro-1-phenylpropyl) -4HBenzopyran-4-one

According to the method described in the synthetic route, R ₁ Is phenyl, R ₂ Is hydrogen, R _f Compound 4m, 31.6 mg as a pale yellow solid, 80% yield, 140.3-143.1 ℃ melting point was prepared as trifluoromethyl (fluorine source reagent, togni I).

Characterization data for compound 4m are as follows:

¹ H NMR (600 MHz, CDCl ₃ ) δ (ppm): 8.21 (d,J= 7.2 Hz, 1H), 7.70 (t,J= 7.8 Hz, 1H), 7.56 (d,J= 8.4 Hz, 1H), 7.48 – 7.25 (m, 8H), 7.18 (d,J= 6.6 Hz, 2H), 7.14 – 6.95 (m, 1H), 4.32 (d,J= 10.2 Hz, 1H), 3.32 – 3.23 (m, 1H), 2.64 – 2.57 (m, 1H).

¹³ C NMR (151 MHz, CDCl ₃ ) δ (ppm): 177.1, 162.7, 155.7, 138.4, 133.7, 132.1, 130.4, 129.1, 128.8, 128.3, 128.0, 127.4, 126.4, 125.8 (C-F, ¹ J _C-F = 277.5 Hz), 125.2, 124.2, 123.0, 117.6, 41.5, 37.0 (C-F, ² J _C-F = 27.5 Hz).

¹⁹ F NMR (564 MHz, CDCl ₃ ) δ (ppm): -65.24 (t,J= 10.7 Hz, 3F).

HRMS (ESI-TOF)m/z: [M + Na] ⁺ Calcd for C ₂₄ H ₁₇ F ₃ O ₂ Na ⁺ 417.1073; Found 417.1080.

EXAMPLE 14 Synthesis of Compound 4n (3-phenyl 2- (3, 3-trifluoro-1- (4-methoxyphenyl) propyl) -4HBenzopyran-4-one

According to the method described in the synthetic route, R ₁ Is that，R ₂ Is hydrogen, R _f Compound 4n of 31.4 mg was prepared as a pale yellow solid in 74% yield with a melting point of 99.8-103 as trifluoromethyl (the fluorine source reagent was topni I).3℃。

Characterization data for compound 4n are as follows:

¹ H NMR (600 MHz, CDCl ₃ ) δ (ppm): 8.22 (d,J= 8.4 Hz, 1H), 7.70 (t,J= 7.2 Hz, 1H), 7.56 (d,J= 7.8 Hz, 1H), 7.43 – 7.54 (m, 3H), 7.41 (t,J= 8.4 Hz, 1H), 7.27 – 7.39 (m, 1H), 7.11 – 7.04 (m, 3H), 6.84 (d,J= 9.0 Hz, 2H), 4.29 (dd,J= 10.2, 4.8 Hz, 1H), 3.78 (s, 3H), 3.29 – 3.19 (m, 1H),2.63 – 2.54 (m, 1H).

¹³ C NMR (151 MHz, CDCl ₃ ) δ (ppm): 177.1, 163.1, 159.2, 155.7, 133.6, 132.2, 130.5, 130.4, 128.5, 128.4, 128.3, 126.4, 125.8 (C-F, ¹ J _C-F = 277.5 Hz), 125.2, 123.8, 123.5, 117.6, 114.4, 55.2, 40.7, 37.1 (C-F, ² J _C-F = 27.5 Hz).

¹⁹ F NMR (564 MHz, CDCl ₃ ) δ (ppm): -65.21 (t,J= 10.7 Hz, 3F).

HRMS (ESI-TOF)m/z: [M + Na] ⁺ Calcd for C ₂₅ H ₁₉ F ₃ O ₃ Na ⁺ 447.1179; Found 447.1185.

EXAMPLE 15 Synthesis of Compound 4o (3-phenyl-2- (3, 3-trifluoro-1- (4-fluorophenyl) propyl) -4HBenzopyran-4-one

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According to the method described in the synthetic route, R ₁ Is that，R ₂ Is hydrogen, R _f Compound 4o, 23.9 mg as a pale yellow solid was prepared in 58% yield with a melting point of 113.4-117.1 ℃ as trifluoromethyl (the fluorine source reagent was topni I).

Characterization data for compound 4o are as follows:

¹ H NMR (600 MHz, CDCl ₃ ) δ (ppm): 8.23 (d,J= 8.4 Hz, 1H), 7.71 (t,J= 7.2 Hz, 1H), 7.56 (d,J= 7.8 Hz, 1H), 7.51 – 7.44 (m, 3H), 7.42 (t,J= 7.2 Hz, 1H), 7.35 – 7.29 (m, 1H), 7.17 – 7.13 (m, 2H), 7.00 (t,J= 8.4 Hz, 3H), 4.33 (dd,J= 9.6, 4.8 Hz, 1H), 3.28 – 3.19 (m, 1H), 2.65 – 2.56 (m, 1H).

¹³ C NMR (151 MHz, CDCl ₃ ) δ (ppm): 177.0, 162.4, 162.3 (C-F, ¹ J _C-F = 247.3 Hz), 155.6, 134.1 (C-F, ⁴ J _C-F = 2.9 Hz), 133.7, 132.0, 130.3, 129.1 (C-F, ³ J _C-F = 8.8 Hz), 128.9, 128.4, 126.4, 125.7 (C-F, ¹ J _C-F = 277.5 Hz), 125.3, 124.1, 123.4, 117.5, 116.0 (C-F, ² J _C-F = 21.7 Hz), 40.8, 37.0 (C-F, ² J _C-F = 29.0 Hz).

¹⁹ F NMR (564 MHz, CDCl ₃ ) δ (ppm): -64.53 (t,J= 10.7 Hz, 3F), -112.81 – -112.85 (m, 1F).

HRMS (ESI-TOF)m/z: [M + Na] ⁺ Calcd for C ₂₄ H ₁₆ F ₄ O ₂ Na ⁺ 435.0979; Found 435.0988.

EXAMPLE 16 Synthesis of Compound 4p (4- (3, 3-trifluoro-1- (4-keto-3-phenyl-4)HBenzopyran-2-yl) propyl) benzonitrile

According to the method described in the synthetic route, R ₁ Is that，R ₂ Is hydrogen, R _f Compound 4p, 28.9 mg as a pale yellow solid was prepared in 69% yield with a melting point of 193.1-194.2 ℃ as trifluoromethyl (the fluorine source reagent was topni I).

Characterization data for compound 4p are as follows:

¹ H NMR (600 MHz, CDCl ₃ ) δ (ppm): 8.22 (d,J= 7.8 Hz, 1H), 7.73 (t,J= 7.2 Hz, 1H), 7.61 (d,J= 9.0 Hz, 2H), 7.55 (d,J= 8.4 Hz, 1H), 7.53 – 7.42 (m, 4H), 7.39 – 7.28 (m, 3H), 7.08 – 6.93(m, 1H), 4.40 (dd,J= 9.6, 6.0 Hz, 1H), 3.28 – 3.19 (m, 1H), 2.70 – 2.61(m, 1H).

¹³ C NMR (151 MHz, CDCl ₃ ) δ (ppm): 176.9, 161.2, 155.7, 143.5, 134.1, 133.0, 131.8, 130.3, 129.2, 128.7, 128.5, 126.6, 125.7, 125.6 (C-F, ¹ J _C-F = 287.7 Hz), 1124.8, 123.5, 118.2, 117.6, 112.3, 41.7, 36.7 (C-F, ² J _C-F = 28.8 Hz).

¹⁹ F NMR (564 MHz, CDCl ₃ ) δ (ppm): -65.07 (t,J= 10.7 Hz, 3F).

HRMS (ESI-TOF)m/z: [M + Na] ⁺ Calcd for C ₂₅ H ₁₆ F ₃ NO ₂ Na ⁺ 442.1025; Found 442.1028.

EXAMPLE 17 Synthesis of Compound 4q (3-phenyl-2- (3, 3-trifluoro-1- (3-methylphenyl) propyl) -4HBenzopyran-4-one

According to the method described in the synthetic route, R ₁ Is that，R ₂ Is hydrogen, R _f Compound 4q, 20.0 mg as a pale yellow solid, 49% yield, 93.7-96.6 ℃ melting point was prepared as trifluoromethyl (fluorine source reagent, togni I).

Characterization data for compound 4q are as follows:

¹ H NMR (600 MHz, CDCl ₃ ) δ (ppm): 8.23 (d,J= 8.4 Hz, 1H), 7.71 (t,J= 8.4 Hz, 1H), 7.57 (d,J= 8.4 Hz, 1H), 7.51 – 7.31 (m, 5H), 7.20 (t,J= 7.8 Hz, 1H), 7.13 – 7.03 (m, 2H), 6.99 (d,J= 7.8 Hz, 1H), 6.95 (s, 1H), 4.30 (dd,J= 10.2, 4.2 Hz, 1H), 3.33 – 3.24 (m, 1H), 2.64 – 2.56 (m, 1H), 2.31 (s, 3H).

¹³ C NMR (151 MHz, CDCl ₃ ) δ (ppm): 177.1, 162.9, 155.7, 138.7, 138.4, 133.6, 132.1, 130.6, 128.9, 128.7, 128.5, 128.3, 128.2, 126.4, 125.8 (C-F, ¹ J _C-F = 277.5 Hz), 125.2, 124.4, 124.1, 123.5, 117.6, 41.4, 36.9 (C-F, ² J _C-F = 27.5 Hz), 21.4.

¹⁹ F NMR (564 MHz, CDCl ₃ ) δ (ppm): -65.27 (t, 9.9 Hz, 3F).

HRMS (ESI-TOF)m/z: [M + Na] ⁺ Calcd for C ₂₅ H ₁₉ F ₃ O ₂ Na ⁺ 431.1229; Found 431.1237.

EXAMPLE 18 Synthesis of Compound 4r (33-phenyl-2- (3, 3-trifluoro-1- (3-methoxyphenyl) propyl) -4HBenzopyran-4-one

According to the method described in the synthetic route, R ₁ Is that，R ₂ Is hydrogen, R _f Compound 4r, 29.7. 29.7 mg as a pale yellow solid was prepared in 70% yield with a melting point of 124.4-125.7 ℃ as trifluoromethyl (the fluorine source reagent was topni I).

Characterization data for compound 4r are as follows:

¹ H NMR (600 MHz, CDCl ₃ ) δ (ppm): 8.21 (d,J= 7.8 Hz, 1H), 7.69 (t,J= 7.8 Hz, 1H), 7.55 (d,J= 9.0 Hz, 1H), 7.48 – 7.43 (m, 3H), 7.40 (t,J= 7.8 Hz, 1H), 7.34 – 7.25 (m, 1H), 7.21 (t,J= 7.8 Hz, 1H), 7.17 – 7.08 (m, 1H), 6.80 (d,J= 8.4 Hz, 1H), 6.76 (d,J= 7.2 Hz, 1H), 6.68 (s, 1H), 4.29 (dd,J= 10.2, 2.4 Hz, 1H), 3.74 (s, 3H), 3.31 – 3.21 (m, 1H), 2.63 – 2.55 (m, 1H).

¹³ C NMR (151 MHz, CDCl ₃ ) δ (ppm): 177.1, 162.6, 159.9, 155.6, 139.9, 133.7, 132.1, 130.6, 130.1, 128.7, 128.3, 126.4, 125.8 (C-F, ¹ J _C-F = 277.5 Hz), 125.2, 124.2, 123.5, 119.6, 117.6, 113.6, 113.1, 55.2, 41.5, 36.9(C-F, ² J _C-F = 28.8 Hz).

¹⁹ F NMR (564 MHz, CDCl ₃ ) δ (ppm): -65.26 (t,J= 10.7 Hz, 3F).

HRMS (ESI-TOF)m/z: [M + Na] ⁺ Calcd for C ₂₅ H ₁₉ F ₃ O ₃ Na ⁺ 447.1179; Found 447.1182.

EXAMPLE 19 Synthesis of Compound 4s (3-phenyl-2- (3, 3-trifluoro-1- (3- (trifluoromethyl) phenyl) propyl) -4HBenzopyran-4-one

According to the method described in the synthetic route, R ₁ Is that ，R ₂ Is hydrogen, R _f Compound 4s of 29.1. 29.1 mg was prepared as a pale yellow solid in 63% yield with a melting point of 114.6-118.8℃as trifluoromethyl (Togni I as fluorine source reagent).

Characterization data for compound 4s are as follows:

¹ H NMR (600 MHz, CDCl ₃ ) δ (ppm): 8.22 (d,J= 7.8 Hz, 1H), 7.73 (t,J= 8.4 Hz, 1H), 7.57 – 7.52 (m, 3H),7.48 – 7.42 (m, 5H), 7.38 (d,J= 8.4 Hz, 2H), 7.17 – 7.00 (m, 1H), 4.40 (dd,J= 9.6, 4.8 Hz, 1H), 3.33 – 3.24 (m, 1H),2.69 – 2.61 (m, 1H).

¹³ C NMR (151 MHz, CDCl ₃ ) δ (ppm): 176.9, 161.7, 155.6, 139.2, 133.9, 131.8, 131.4 (C-F, ² J _C-F = 33.2 Hz), 130.8, 130.3, 129.6, 128.8, 128.6, 126.5, 125.6 (C-F, ¹ J _C-F = 277.5 Hz), 125.4, 125.0 (C-F, ³ J _C-F = 4.4 Hz), 124.5, 124.5, 123.7 (C-F, ¹ J _C-F = 273.3 Hz), 123.4, 117.5, 41.4, 36.7 (C-F, ² J _C-F = 29.0 Hz).

¹⁹ F NMR (564 MHz, CDCl ₃ ) δ (ppm): -63.23 (s, 3F), -65.15 (t,J= 9.9 Hz, 3F).

HRMS (ESI-TOF)m/z: [M + Na] ⁺ Calcd for C ₂₅ H ₁₆ F ₆ O ₂ Na ⁺ 485.0947; Found 485.0947.

EXAMPLE 20 Synthesis of Compound 4t (2- (1- (3-chlorophenyl) -3, 3-trifluoropropyl) -3-phenyl-4HBenzopyran-4-one

According to the method described in the synthetic route, R ₁ Is that，R ₂ Is hydrogen, R _f Compound 4t of 32.2. 32.2 mg was prepared as a pale yellow solid in 75% yield with a melting point of 125.9-129.1℃as trifluoromethyl (Togni I as fluorine source reagent).

Characterization data for compound 4t are as follows:

¹ H NMR (600 MHz, CDCl ₃ ) δ (ppm): 8.23 (d,J= 7.8 Hz, 1H), 7.72 (t,J= 8.4 Hz, 1H), 7.57 (d,J= 7.8 Hz, 1H), 7.50 – 7.45 (m, 3H), 7.43 (t,J= 7.8 Hz, 1H), 7.39 – 7.30 (m, 1H), 7.28 – 7.23 (m, 2H), 7.19 (s, 1H), 7.03 (d,J= 7.2 Hz, 2H), 4.31 (dd,J= 10.2, 4.8 Hz, 1H), 3.29 – 3.20 (m, 1H),2.65 – 2.57 (m, 1H).

¹³ C NMR (151 MHz, CDCl ₃ ) δ (ppm): 177.0, 161.9, 155.6, 140.2, 134.8, 133.8, 131.8, 130.4, 130.3, 128.7, 128.5, 128.3, 127.7, 126.4, 125.7, 125.6 (C-F, ¹ J _C-F = 277.7 Hz), 125.4, 124.4, 123.4, 117.6, 41.2, 36.8 (C-F, ² J _C-F = 29.0 Hz).

¹⁹ F NMR (564 MHz, CDCl ₃ ) δ (ppm): -65.21 (t,J= 9.6 Hz, 3F).

HRMS (ESI-TOF)m/z: [M + Na] ⁺ Calcd for C ₂₄ H ₁₆ ³⁵ ClF ₃ O ₂ Na ⁺ 451.0684, C ₂₄ H ₁₆ ³⁷ ClF ₃ O ₂ Na ⁺ 453.0654; Found 451.0681, 453.0662.

EXAMPLE 21 Synthesis of Compound 4u (3-phenyl-2- (3, 3-trifluoro-1- (2-methylphenyl) propyl) -4HBenzopyran-4-one

According to the method described in the synthetic route, R ₁ Is that，R ₂ Is hydrogen, R _f Compound 4u, 14.7. 14.7 mg as a pale yellow solid was prepared in 36% yield with a melting point of 127.6-131.9 ℃.

Characterization data for compound 4u are as follows:

¹ H NMR (600 MHz, CDCl ₃ ) δ (ppm): 8.26 (d,J= 7.2 Hz, 1H), 7.75 (t,J= 8.4 Hz, 1H), 7.65 (d,J= 8.4 Hz, 1H), 7.45 (t,J= 7.2 Hz, 3H), 7.41 – 7.28 (m, 3H), 7.17 – 7.13 (m, 2H), 7.08 – 7.06(m, 1H), 6.94 – 6.70 (m, 1H), 4.61 (dd,J= 10.8, 4.2 Hz, 1H), 3.29 – 3.20 (m, 1H),2.47 – 2.39 (m, 1H), 1.65 (s, 3H).

¹³ C NMR (151 MHz, CDCl ₃ ) δ (ppm): 177.1, 163.3, 155.6, 137.8, 135.2, 133.7, 132.2, 131.1, 130.1, 128.8, 128.2, 127.7, 126.8, 126.5, 126.4, 125.8 (C-F, ¹ J _C-F = 277.7 Hz), 125.4, 124.4, 123.6, 117.6, 37.3, 37.0 (C-F, ² J _C-F = 27.7 Hz), 18.3.

¹⁹ F NMR (564 MHz, CDCl ₃ ) δ (ppm): -65.91 (t,J= 10.7 Hz, 3F).

HRMS (ESI-TOF)m/z: [M + Na] ⁺ Calcd for C ₂₅ H ₁₉ F ₃ O ₂ Na ⁺ 431.1230; Found 431.1234.

EXAMPLE 22 Synthesis of Compound 4v (2- (1- (2-chlorophenyl) -3, 3-trifluoropropyl) -3-phenyl-4HBenzopyran-4-one

According to the method described in the synthetic route, R ₁ Is that，R ₂ Is hydrogen, R _f Compound 4v, 14.2 mg as a pale yellow solid was prepared in 33% yield with a melting point of 96.9-100.1 ℃ as trifluoromethyl (the fluorine source reagent was topni I).

Characterization data for compound 4v are as follows:

¹ H NMR (600 MHz, CDCl ₃ ) δ (ppm): 8.27 (d,J= 8.4 Hz, 1H), 7.75 (t,J= 8.4 Hz, 1H), 7.62 (d,J= 8.4 Hz, 1H), 7.55 – 7.43 (m, 3H), 7.39 – 7.36 (m, 2H), 7.35 – 7.26 (m, 2H), 7.25 – 7.21 (m, 2H), 7.10 – 6.66(m, 1H), 4.92 (dd,J= 10.8, 3.6 Hz, 1H), 3.21 – 3.11 (m, 1H), 2.60 – 2.52 (m, 1H).

¹³ C NMR (151 MHz, CDCl ₃ ) δ (ppm): 177.0, 162.0, 155.6, 136.8, 133.8, 133.1, 131.6, 130.2, 129.9, 129.1, 128.7, 128.3, 128.2, 127.5, 126.5, 125.6 (C-F, ¹ J _C-F = 277.5 Hz), 125.5, 125.2, 123.6, 117.6, 38.3, 36.4 (C-F, ² J _C-F = 29.0 Hz).

¹⁹ F NMR (564 MHz, CDCl ₃ ) δ (ppm): -65.77 (t,J= 10.7 Hz, 3F).

HRMS (ESI-TOF)m/z: [M + Na] ⁺ Calcd for C ₂₄ H ₁₆ ³⁵ ClF ₃ O ₂ Na ⁺ 451.0683, C ₂₄ H ₁₆ ³⁷ ClF ₃ O ₂ Na ⁺ 453.0654; Found 451.0683, 453.0665.

EXAMPLE 23 Synthesis of Compound 4w (2- (1- (3, 4-dimethoxyphenyl) -3, 3-trifluoropropyl) -3-phenyl-4HBenzopyran-4-one

According to the method described in the synthetic route, R ₁ Is that，R ₂ Is hydrogen, R _f Compound 4w, 14.5 mg as a pale yellow solid, 32% yield, melting point 49.7-52.2 ℃ was prepared as trifluoromethyl (fluorine source reagent, togni I).

Characterization data for compound 4w are as follows:

¹ H NMR (600 MHz, CDCl ₃ ) δ (ppm): 8.22 (d,J= 7.8 Hz, 1H), 7.70 (t,J= 9.0 Hz, 1H), 7.59 – 7.31 (m, 6H),7.18 – 7.04 (m, 1H), 6.80 – 6.77 (m, 2H), 6.57 (s, 1H), 4.27 (dd,J= 10.8, 4.8 Hz, 1H), 3.84 (s, 3H), 3.80 (s, 3H), 3.31 – 3.22(m, 1H), 2.64 – 2.55 (m, 1H).

¹³ C NMR (151 MHz, CDCl ₃ ) δ (ppm): 177.1, 163.0, 155.6, 149.1, 148.7, 133.7, 132.3, 130.8, 130.1, 128.8, 128.3, 126.5, 125.8 (C-F, ¹ J _C-F = 279.0 Hz), 125.3, 123.8, 123.5, 119.3, 117.4, 111.5, 111.0, 55.9, 55.8, 41.1,36.9 (C-F, ² J _C-F = 27.5 Hz).

¹⁹ F NMR (564 MHz, CDCl ₃ ) δ (ppm): -65.19 (t,J= 9.9 Hz, 3F).

HRMS (ESI-TOF)m/z: [M + Na] ⁺ Calcd for C ₂₆ H ₂₁ F ₃ O ₄ Na ⁺ 477.1284; Found 477.1284.

EXAMPLE 24 Synthesis of Compound 4x (2- (1- (styrene-acrylic) d][1,3]Dioxolan-5-yl) -3, 3-trifluoropropyl) -3-phenyl-4HBenzopyran-4-one

According to the method described in the synthetic route, R ₁ Is that，R ₂ Is hydrogen, R _f Compound 4x of 18.4. 18.4 mg was prepared as a pale yellow solid in 42% yield with a melting point of 166.6-169.1℃as trifluoromethyl (Togni I as fluorine source reagent).

Characterization data for compound 4x are as follows:

¹ H NMR (600 MHz, CDCl ₃ ) δ (ppm): 8.22 (d,J= 7.2 Hz, 1H), 7.71 (t,J= 8.4, 1H), 7.56 (d,J= 8.4 Hz, 1H), 7.49 – 7.40 (m, 4H), 7.36 – 7.27 (m, 1H), 7.22 – 7.02 (m, 1H), 6.73 – 6.71 (m, 2H), 6.56 (dd,J= 8.4, 1.8 Hz, 1H), 5.94 (dd,J= 12.0, 1.8 Hz, 2H), 4.25 (dd,J= 10.2, 4.8 Hz, 1H), 3.25 – 3.16 (m, 1H), 2.61 – 2.53 (m, 1H).

¹³ C NMR (151 MHz, CDCl ₃ ) δ (ppm): 177.1, 162.8, 155.6, 148.1, 147.3, 133.7, 132.0, 132.0, 130.3, 128.8, 128.3, 126.4, 125.7 (C-F, ¹ J _C-F = 277.7 Hz), 125.3, 123.9, 123.4, 121.0, 117.6, 108.6, 107.6, 101.2, 41.1, 37.1(C-F, ² J _C-F = 29.0 Hz).

¹⁹ F NMR (564 MHz, CDCl ₃ ) δ (ppm): -65.22 (t,J= 9.9 Hz, 3F).

HRMS (ESI-TOF)m/z: [M + Na] ⁺ Calcd for C ₂₅ H ₁₇ F ₃ O ₄ Na ⁺ 461.0971; Found 461.0977.

EXAMPLE 25 Synthesis of Compound 4y (3-phenyl-2- (4, 4-trifluorobutyl-2-yl) -4HBenzopyran-4-one

According to the method described in the synthetic route, R ₁ Is methyl, R ₂ Is hydrogen，R _f Compound 4y, 15.3 mg as a pale yellow solid, 46% yield, 104.9-107.6 ℃ melting point was prepared as trifluoromethyl (fluorine source reagent, togni I).

Characterization data for compound 4y are as follows:

¹ H NMR (600 MHz, CDCl ₃ ) δ (ppm): 8.24 (d,J= 7.8 Hz, 1H), 7.69 (t,J= 7.2 Hz, 1H), 7.49 – 7.44 (m, 3H),7.43 – 7.39 (m, 2H), 7.25 (d,J= 7.2 Hz, 2H), 3.25 – 3.20 (m, 1H), 2.80 – 2.71 (m, 1H), 2.31 – 2.22(m, 1H), 1.36 (d,J= 7.2 Hz, 3H).

¹³ C NMR (151 MHz, CDCl ₃ ) δ (ppm): 177.1, 165.6, 155.8, 133.6, 132.3, 130.1, 128.6, 128.1, 126.4, 126.0 (C-F, ¹ J _C-F = 276.2 Hz), 125.1, 123.4, 123.3, 117.5, 37.3 (C-F, ² J _C-F = 28.8 Hz), 30.9, 19.4.

¹⁹ F NMR (564 MHz, CDCl ₃ ) δ (ppm): -65.17 (t,J= 10.7 Hz, 3F).

HRMS (ESI-TOF)m/z: [M + Na] ⁺ Calcd for C ₁₉ H ₁₅ F ₃ O ₂ Na ⁺ 355.0917; Found 355.0925.

EXAMPLE 26 Synthesis of Compound 4z (4- (3, 3-trifluoro-1- (6-methoxy-4-one-3-phenyl-4)HBenzopyran-2-yl) propyl) benzonitrile

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According to the method described in the synthetic route, R ₁ Is that，R ₂ Methoxy group at 6-position of chromone mother nucleus, R _f Compound 4z, 21.6 mg as a pale yellow solid, 48% yield, 184.7-187.2 ℃ melting point was prepared as trifluoromethyl (the fluorine source reagent was topni I).

Characterization data for compound 4z are as follows:

¹ H NMR (600 MHz, CDCl ₃ ) δ (ppm): 7.60 (d,J= 8.4 Hz, 2H), 7.57 (d,J= 3.0 Hz, 1H), 7.52 – 7.39 (m, 4H),7.35 – 7.30 (m, 2H), 7.26 (d,J= 9.0 Hz, 2H), 7.12 – 6.91 (m, 1H), 4.38 (dd,J= 9.6, 5.4 Hz, 1H), 3.88 (s, 3H), 3.26 – 3.17(m, 1H), 2.68 – 2.60 (m, 1H).

¹³ C NMR (151 MHz, CDCl ₃ ) δ (ppm): 176.6, 160.9, 157.2, 150.4, 143.5, 132.8, 131.9, 130.3, 129.0, 128.6, 128.3, 125.5 (C-F, ¹ J _C-F = 277.7 Hz), 124.0, 123.9, 123.9, 118.9, 118.1, 112.2, 105.6, 56.0, 41.6, 36.7(C-F, ² J _C-F = 28.8 Hz).

¹⁹ F NMR (564 MHz, CDCl ₃ ) δ (ppm): -65.10 (t,J= 11.0 Hz, 3F).

HRMS (ESI-TOF)m/z: [M + Na] ⁺ Calcd for C ₂₆ H ₁₈ F ₃ NO ₃ Na ⁺ 472.1131; Found 472.1141.

EXAMPLE 27 Synthesis of Compound 4aa (6-methoxy-3-phenyl-2- (3, 3-trifluoro-1- (3- (trifluoromethyl) phenyl) propyl) -4HBenzopyran-4-one

According to the method described in the synthetic route, R ₁ Is that，R ₂ Methoxy group at 6-position of chromone mother nucleus, R _f Compound 4aa of 32.0. 32.0 mg was prepared as a pale yellow solid in 65% yield with a melting point of 117.2-120.9℃as trifluoromethyl (Togni I as fluorine source reagent).

Characterization data for compound 4aa are as follows:

¹ H NMR (600 MHz, CDCl ₃ ) δ (ppm): 7.57 (d,J= 3.6 Hz, 1H), 7.55 – 7.43 (m, 6H), 7.39 (s, 1H), 7.37 – 7.30 (m, 3H), 7.16 – 6.90 (m, 1H), 4.39 (dd,J= 9.6, 4.8 Hz, 1H), 3.88 (s, 3H), 3.31 – 3.22 (m, 1H), 2.68 – 2.60 (m, 1H).

¹³ C NMR (151 MHz, CDCl ₃ ) δ (ppm): 176.8, 161.5, 157.2, 150.5, 139.4, 132.0, 131.4 (C-F, ² J _C-F = 33.4 Hz), 130.8, 130.4, 129.6, 129.0, 128.5, 125.6 (C-F, ¹ J _C-F = 277.7 Hz), 124.9 (C-F, ³ J _C-F = 2.9 Hz), 124.5 (C-F, ³ J _C-F = 2.9 Hz), 124.1, 123.9, 123.7, 123.7 (C-F, ¹ J _C-F = 271.8 Hz), 118.9, 105.6, 56.0, 41.4, 36.7 (C-F, ² J _C-F = 29.0 Hz).

¹⁹ F NMR (564 MHz, CDCl ₃ ) δ (ppm): -63.23 (s, 3F), -65.17 (t,J= 11.0 Hz, 3F).

HRMS (ESI-TOF)m/z: [M + Na] ⁺ Calcd for C ₂₆ H ₁₈ F ₆ O ₃ Na ⁺ 515.1053; Found 515.1062.

EXAMPLE 28 Synthesis of Compound 4ab (6-methoxy-3-phenyl-2- (3, 3-trifluoro-1- (3-methoxyphenyl) propyl) -4HBenzopyran-4-one

According to the method described in the synthetic route, R ₁ Is that，R ₂ Methoxy group at 6-position of chromone mother nucleus, R _f Compound 4ab, 29.5 mg as a pale yellow solid, 65% yield and 61.5-65.4 ℃ melting point, was prepared as trifluoromethyl (fluorine source reagent, togni I).

Characterization data for compound 4ab are as follows:

¹ H NMR (600 MHz, CDCl ₃ ) δ (ppm): 7.58 (s, 1H), 7.50 – 7.29 (m, 6H), 7.22 (t,J= 7.8 Hz, 1H), 7.16 – 6.98 (m, 1H), 6.81 (d,J= 8.4 Hz, 1H), 6.75 (d,J= 7.8 Hz, 1H), 6.67 (s, 1H), 4.28 (d,J= 10.2 Hz, 1H), 3.88 (s, 3H), 3.75 (s, 3H), 3.29 – 3.20 (m, 1H), 2.60 – 2.54 (m, 1H).

¹³ C NMR (151 MHz, CDCl ₃ ) δ (ppm): 176.9, 162.4, 159.8, 157.0, 150.5, 140.0, 132.3, 130.8, 130.0, 128.8, 128.2, 125.8 (C-F, ¹ J _C-F = 277.7 Hz), 124.0, 123.7, 123.4, 119.6, 119.0, 113.6, 113.0, 105.5, 55.9, 55.2,41.4, 36.9 (C-F, ² J _C-F = 28.4 Hz).

¹⁹ F NMR (564 MHz, CDCl ₃ ) δ (ppm): -65.28 (t,J= 9.9 Hz, 3F).

HRMS (ESI-TOF)m/z: [M + Na] ⁺ Calcd for C ₂₆ H ₂₁ F ₃ O ₄ Na ⁺ 477.1284; Found 477.1279.

EXAMPLE 29 Synthesis of Compound 4ac (2- (1- (3, 4-dimethoxyphenyl-3, 3-trifluoropropyl) -6-methoxy-3-phenyl-4)HBenzopyran-4-one

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According to the method described in the synthetic route, R ₁ Is that，R ₂ Methoxy group at 6-position of chromone mother nucleus, R _f Compound 4ac, 26.6 mg as a pale yellow solid, 55% yield, 135.1-137.6 ℃ melting point was prepared as trifluoromethyl (fluorine source reagent, togni I).

Characterization data for compound 4ac are as follows:

¹ H NMR (600 MHz, CDCl ₃ ) δ (ppm): 7.57 (d,J= 2.4 Hz, 1H), 7.54 – 7.28 (m, 6H), 7.17 – 7.01 (m, 1H), 6.80 – 6.75 (m, 2H), 6.54 (d,J= 2.4 Hz, 1H), 4.26 (dd,J= 10.8, 4.8 Hz, 1H), 3.88 (s, 3H), 3.84 (s, 3H), 3.79 (s, 3H), 3.29 – 3.20 (m, 1H), 2.62 – 2.54(m, 1H).

¹³ C NMR (151 MHz, CDCl ₃ ) δ (ppm): 176.9, 162.8, 157.0, 150.5, 149.0, 148.7, 132.5, 130.9, 130.2, 128.9, 128.3, 125.8 (C-F, ¹ J _C-F = 277.5 Hz), 124.1, 123.7, 123.0, 119.3, 118.9, 111.4, 110.9, 105.5, 55.9, 55.8,55.8, 41.0, 36.9 (C-F, ² J _C-F = 28.8 Hz).

¹⁹ F NMR (564 MHz, CDCl ₃ ) δ (ppm): -65.22 (t,J= 9.9 Hz, 3F).

HRMS (ESI-TOF)m/z: [M + Na] ⁺ Calcd for C ₂₇ H ₂₃ F ₃ O ₅ Na ⁺ 507.1390; Found 507.1400.

EXAMPLE 30 Synthesis of Compound 4ad (4- (3, 3-trifluoro-1- (7-methoxy-4-one-3-phenyl-4)HBenzopyran-2-yl) propyl) benzonitrile

According to the method described in the synthetic route, R ₁ Is that，R ₂ Methoxy group at 7-position of chromone mother nucleus, R _f Compound 4ad, 20.2 mg as a pale yellow solid was prepared in 45% yield with a melting point of 175.7-178.9 ℃ as trifluoromethyl (the fluorine source reagent was topni I).

Characterization data for compound 4ad are as follows:

¹ H NMR (600 MHz, CDCl ₃ ) δ (ppm): 8.12 (d,J= 9.0 Hz, 1H), 7.61 (d,J= 8.4 Hz, 2H), 7.51 – 7.32 (m, 4H),7.28 (d,J= 8.4 Hz, 2H), 7.05 – 6.95 (m, 2H), 6.92 (d,J= 2.4 Hz, 1H), 4.37 (dd,J= 9.6, 6.0 Hz, 1H), 3.96 (s, 3H), 3.26 – 3.17 (m, 1H),2.68 – 2.60 (m, 1H).

¹³ C NMR (151 MHz, CDCl ₃ ) δ (ppm): 176.2, 164.4, 160.6, 157.3, 143.5, 132.9, 131.8, 130.2, 129.0, 128.5, 128.3, 127.9, 125.5 (C-F, ¹ J _C-F = 277.5 Hz), 124.6, 118.2, 117.2, 114.7, 112.2, 99.9, 55.9, 41.5, 36.6 (C-F, ² J _C-F = 30.4 Hz).

¹⁹ F NMR (564 MHz, CDCl ₃ ) δ (ppm): -65.05 (t,J= 11.0 Hz, 3F).

HRMS (ESI-TOF)m/z: [M + Na] ⁺ Calcd for C ₂₆ H ₁₈ F ₃ NO ₃ Na ⁺ 472.1131; Found 472.1129.

EXAMPLE 31 Synthesis of Compound 4ae (7-methoxy-3-phenyl-2- (3, 3-trifluoro-1- (3- (trifluoromethyl) phenyl) propyl) -4)HBenzopyran-4-one

According to the method described in the synthetic route, R ₁ Is that，R ₂ Methoxy group at 7-position of chromone mother nucleus, R _f Compound 4ae of 18.2 mg is prepared as a pale yellow solid with 37% yield and 149.4-152.2 ℃ melting point, which is trifluoromethyl (Togni I as fluorine source reagent).

Characterization data for compound 4ae are as follows:

¹ H NMR (600 MHz, CDCl ₃ ) δ (ppm): 8.12 (d,J= 9.0 Hz, 1H), 7.55 (d,J= 7.2 Hz, 1H), 7.52 – 7.43 (m, 4H),7.41 (s, 1H), 7.37 – 7.29 (m, 2H), 7.05 – 6.96 (m, 2H), 6.93 (d,J= 2.4 Hz, 1H), 4.37 (dd,J= 10.2, 4.8 Hz, 1H), 3.96 (s, 3H), 3.31 – 3.21 (m, 1H), 2.68 – 2.60 (m, 1H).

¹³ C NMR (151 MHz, CDCl ₃ ) δ (ppm): 176.3, 164.3, 161.2, 157.3, 139.4, 131.9, 131.4 (C-F, ² J _C-F = 33.3 Hz), 130.8, 130.6, 129.6, 128.9, 128.5, 127.9, 125.6 (C-F, ¹ J _C-F = 277.5 Hz), 124.9 (C-F, ³ J _C-F = 2.9 Hz), 124.4 (C-F, ³ J _C-F = 2.9 Hz), 124.3, 123.7 (C-F, ¹ J _C-F = 273.2 Hz), 117.3, 114.6, 99.9, 55.9, 41.3, 36.7 (C-F, ² J _C-F = 29.0 Hz).

¹⁹ F NMR (564 MHz, CDCl ₃ ) δ (ppm): -63.21 (s, 3F), -65.13 (t,J= 9.9 Hz, 3F).

HRMS (ESI-TOF)m/z: [M + Na] ⁺ Calcd for C ₂₆ H ₁₈ F ₆ O ₃ Na ⁺ 515.1052; Found 515.1060.

EXAMPLE 32 Synthesis of Compound 4af (7-methoxy-3-phenyl-2- (3, 3-trifluoro-1- (3-methoxyphenyl) propyl) -4HBenzopyran-4-one

According to the method described in the synthetic route, R ₁ Is that，R ₂ Methoxy group at 7-position of chromone mother nucleus, R _f Compound 4af of 24.5. 24.5 mg was prepared as a pale yellow solid in 54% yield with a melting point of 117.9-120.3 ℃ as trifluoromethyl (the fluorine source reagent was topni I).

Characterization data for compound 4af are as follows:

¹ H NMR (600 MHz, CDCl ₃ ) δ (ppm): 8.11 (d,J= 9.0 Hz, 1H), 7.56 – 7.28 (m, 4H), 7.23 (t,J= 7.8 Hz, 1H), 7.18 – 7.01 (m, 1H), 6.97 (dd,J= 9.0, 3.0 Hz, 1H), 6.94 (s, 1H), 6.81 (dd,J= 8.4, 3.0 Hz, 1H), 6.77 (d,J= 7.8 Hz, 1H), 6.68 (s, 1H), 4.27 (dd,J= 10.2, 4.2 Hz, 1H), 3.95 (s, 3H), 3.76 (s, 3H), 3.29 – 3.20 (m, 1H),2.63 – 2.55 (m, 1H).

¹³ C NMR (151 MHz, CDCl ₃ ) δ (ppm): 176.5, 164.2, 162.1, 159.8, 157.3, 140.0, 132.2, 130.7, 130.0, 128.7, 128.2, 127.8, 125.8 (C-F, ¹ J _C-F = 277.7 Hz), 124.0, 119.6, 117.3, 114.5, 113.7, 112.9, 99.9, 55.8, 55.2, 41.4,36.8 (C-F, ² J _C-F = 28.4 Hz).

¹⁹ F NMR (564 MHz, CDCl ₃ ) δ (ppm): -65.22 (t,J= 9.9 Hz, 3F).

HRMS (ESI-TOF)m/z: [M + Na] ⁺ Calcd for C ₂₆ H ₂₁ F ₃ O ₄ Na ⁺ 477.1284; Found 477.1289.

EXAMPLE 33 Synthesis of Compound 8 (methyl 4- ([ 1,1' -biphenyl)]-4-yl) -2, 2-difluoro-4- (4-keto-3-phenyl-4H-benzopyran-2-yl) butyric acid methyl ester

According to the method described in the synthetic route, R ₁ Is biphenyl, R ₂ Is hydrogen, R _f is-CF ₂ COOMe (fluorine source reagent is BrCF) ₂ COOMe), 24.1. 24.1 mg was prepared as a pale yellow solid with a yield of 47% and a melting point of 71.8-74.6 ℃.

Characterization data for compound 8 are as follows:

¹ H NMR (600 MHz, CDCl ₃ ) δ (ppm): 8.23 (d,J= 8.4 Hz, 1H), 7.72 (t,J= 8.4 Hz, 1H), 7.59 (d,J= 7.8 Hz, 1H), 7.55 – 7.40 (m, 11H), 7.35 (t,J= 7.2 Hz, 1H), 7.26 (d,J= 8.4 Hz, 2H), 6.93 – 7.22 (m, 1H), 4.39 (dd,J= 9.0, 5.4 Hz, 1H), 3.63 (s, 3H), 3.28 – 3.19 (m, 1H), 2.79 – 2.70 (m, 1H).

¹³ C NMR (151 MHz, CDCl ₃ ) δ (ppm): 177.1, 163.9 (C-F, ² J _C-F = 33.2 Hz), 163.3, 155.7, 140.8, 140.3, 137.6, 133.6, 132.2, 130.5, 128.8,128.6, 128.3, 128.1, 127.6, 127.5, 127.0, 126.4, 125.2, 123.9, 123.5, 117.6, 115.0 (C-F, ¹ J _C-F = 252.9 Hz), 53.3, 41.0, 37.7 (C-F, ² J _C-F = 23.1 Hz).

¹⁹ F NMR (564 MHz, CDCl ₃ ) δ (ppm): -104.06 (dq,J= 264.5, 10.2 Hz, 1F), -105.67 (dt,J= 264.0, 16.1 Hz, 1F).

HRMS (ESI-TOF)m/z: [M + H] ⁺ Calcd for C ₃₂ H ₂₅ F ₂ O ₄ ⁺ 511.1715; Found 511.1721.

example 34 Synthesis of Compound 9 (2- (1- ([ 1,1' -biphenyl)]-4-yl) -3, 4,5, 6-nonafluorohexyl) -3-phenyl-4HBenzopyran-4-one

According to the method described in the synthetic route, R ₁ Is biphenyl, R ₂ Is hydrogen, R _f Is that(the fluorine source reagent is BrCF) ₂ CF ₂ CF ₂ CF ₃ ) Compound 9 of 45.3. 45.3 mg was prepared as a pale yellow solid in 73% yield with a melting point of 66.9-70.6 ℃.

Characterization data for compound 9 are as follows:

¹ H NMR (600 MHz, CDCl ₃ ) δ (ppm): 8.25 (d,J= 7.2 Hz, 1H), 7.73 (t,J= 8.4 Hz, 1H), 7.61 (d,J= 7.2 Hz, 1H), 7.57 – 7.35 (m, 12H), 7.27 (d,J= 8.4 Hz, 2H), 7.23 – 7.01 (m, 1H), 4.51 (dd,J= 10.2, 4.2 Hz, 1H), 3.39 – 3.28 (m, 1H), 2.67 – 2.57 (m, 1H).

¹³ C NMR (151 MHz, CDCl ₃ ) δ (ppm): 177.1, 162.8, 155.7, 141.0, 140.2, 137.7, 133.7, 132.1, 130.4, 128.8, 128.6, 128.3, 127.9, 127.8, 127.6, 127.0, 126.5, 125.3,123.9, 123.6, 117.5, 121.8 – 106.9 (m, 4C), 40.0, 33.8 (C-F, ² J _C-F = 21.0 Hz).

¹⁹ F NMR (564 MHz, CDCl ₃ ) δ (ppm): -81.43 (t,J= 9.9 Hz, 3F), -113.86 – -114.90 (m, 2F), -124.77 – -125.25 (m, 2F), -126.12 – -126.78 (m,2F).

HRMS (ESI-TOF)m/z: [M + H] ⁺ Calcd for C ₃₃ H ₂₂ F ₉ O ₂ ⁺ 621.1471; Found 621.1478.

example 35 Synthesis of Compound 10 (2- (1- ([ 1,1' -biphenyl)]-4-yl-3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluorodecyl) -3-phenyl-4HBenzopyran-4-one

According to the method described in the synthetic route, R ₁ Is biphenyl, R ₂ Is hydrogen, R _f Is that(the fluorine source reagent is BrCF) ₂ (CF ₂ ) ₆ CF ₃ ) Compound 10 of 62.4 mg was prepared as a pale yellow solid in 76% yield with a melting point of 74.5-76.4 ℃.

Characterization data for compound 10 are as follows:

¹ H NMR (600 MHz, CDCl ₃ ) δ (ppm): 8.26 (d,J= 8.4 Hz, 1H), 7.73 (t,J= 9.0 Hz, 1H), 7.61 (d,J= 8.4 Hz, 1H), 7.57 – 7.55 (m, 4H), 7.52 – 7.42 (m, 6H), 7.36 (t,J= 7.2 Hz, 2H), 7.27 (d,J= 8.4 Hz, 2H), 7.15 – 7.08 (m, 1H), 4.51 (dd,J= 10.2, 4.2 Hz, 1H), 3.40 – 3.29 (m, 1H),2.67 – 2.57 (m, 1H).

¹³ C NMR (151 MHz, CDCl ₃ ) δ (ppm): 177.1, 162.9, 155.7, 141.0, 140.2, 137.7, 133.7, 132.1, 130.4, 128.8, 128.5, 128.4, 127.9, 127.8, 127.6, 127.0, 126.5, 125.3, 123.9,123.5, 118.0 – 108.4 (m, 8C), 117.5, 40.0, 33.6 (C-F, ² J _C-F = 21.6 Hz).

¹⁹ F NMR (564 MHz, CDCl ₃ ) δ (ppm): -81.18 (t,J= 10.7 Hz, 3F), -114.08 (s, 2F), -121.90 (s, 2F), -122.32 (s, 4F), -123.12 (s, 2F), -123.89 (s, 2F),-126.53 (s, 2F).

HRMS (ESI-TOF)m/z: [M + H] ⁺ Calcd for C ₃₇ H ₂₂ F ₁₇ O ₂ ⁺ 821.1343; Found 821.1345.

the beneficial effects of the present invention are demonstrated by specific test examples below.

Test example 1, cell experiment evaluation of anticancer Activity of the Compounds of the invention

The effect of the compounds of the present invention (the compounds prepared in examples 1-35) on the activity of various tumor cells (MCF-7, MDA-MB-231, BT549, RKO and HCT116 cells) was examined using the MTT method. The specific method comprises the following steps:

tumor cells (6X 10) ³ Individual/well) was inoculated into 96 wells, incubated at 37 ℃ for 24h, then incubated for 24h with the addition of a compound of the present invention at a concentration of 30 μm (solvent DMSO), and cell viability was determined using MTT method after incubation.

The results of inhibition of various tumor cell activities by the compounds of the present invention are shown in FIG. 1 and Table 1. The rightmost-50, 0, 50, 100 in FIG. 1a represent the inhibition of cells. From the results shown in fig. 1 and table 1, it can be seen that: the compound has an inhibiting effect on various tumor cells, and has the best inhibiting effect on MCF-7. Of these compounds, compound 8 has optimal inhibition effect on tumor cells, and has high inhibition rate on Triple Negative Breast Cancer (TNBC) cells at 30 μm concentration, wherein, the inhibition rate on breast cancer cells MDA-MB-231 and MCF-7 cells is high ₅₀ The values were 5.4. Mu.M and 8.3. Mu.M, respectively (FIG. 1 b).

TABLE 1 inhibitory Activity of the inventive Compounds against different tumor cells

Test example 2 investigation of Compound 8 of the present invention as a PI3K inhibitor

To investigate whether compound 8 of the present invention can act as a PI3K inhibitor, the binding pattern of compound 8 to pi3kα, pi3kβ, pi3kγ and pi3kδ was analyzed using a molecular docking approach.

Molecular docking analysis: the chemical molecules were constructed with Accelrys Discovery Studio (version 3.5; accelrys, san Diego, CA) and energy was minimized by the CHARMm force field. The CDOCKER protocol is adopted as a docking method to perform semi-flexible docking on the compound. The pictures were generated with Pymol.

Molecular dynamics simulation: the products 8-PI3K alpha, 8-PI3K beta, 8-PI3K gamma and 8-PI3K delta were subjected to molecular dynamics simulation using the GROMACS (version 2022.2) software package.

In vitro PI3K kinase activity assay: in vitro PI3K kinase activity assays were performed by the chinese pharmaceutical company drug discovery service. Curve fitting was performed using GraphPad Prism 8.0 software to calculate IC ₅₀ Values.

Cell thermal displacement assay: CETSA was performed with intact cells to detect interactions between PI3K alpha, PI3K beta, PI3K gamma, PI3K delta and Compound 8. MDA-MB-231 cells (6X 10) ³ Cells/well) were incubated with compound 8 (5 μm concentration) or not for 6 hours. Then, all cells were collected and resuspended in PBS. After heating for 3 minutes at the indicated temperatures (37, 41, 45, 49, 53, 57 and 61 ℃), all cells were thawed at room temperature with three freeze-thaw cycles using liquid nitrogen. The lysate was clarified by centrifugation at 12000 r/min for 15 min and the pi3kα, pi3kβ, pi3kγ and pi3kδ protein expression was detected by western blotting.

The molecular docking analysis results showed (fig. 2 a): the difluoromethyl acetate group of compound 8 can form a hydrogen bond with pi3kα, a hydrogen bond with pi3kβ and two halogens to interact, a hydrogen bond with pi3kγ and two hydrogen bonds with pi3kδ. Wherein the fluorine and oxygen atoms of the methyl difluoroacetate group interact with both pi3kβ and pi3kδ, indicating that compound 8 may be selective for pi3kβ and pi3kδ, and that the fluorine-containing group may play an important role in the subtype selectivity of PI 3K.

Subsequently, the stability of the PI3K-8 complex was evaluated by calculating RMSD of the protein ligand after 100 ns MD simulation. As shown in FIG. 2b, the protein conformation of the PI3Ks-8 complex remained stable during 10 ns MD simulation, and around 0.2-0.4nm after 30 ns simulation. The stability of the MD simulation was determined by comparing the RMSF plot for each MD trace with the b factor of the crystalline protein structure (fig. 2 b).

The binding free energy of the compound 8 and PI3K alpha, beta, delta and gamma is measured by adopting an MM/PBSA method, and MD tracks are respectively 30-100 ns. As can be seen from fig. 2b, the free energy of binding of compound 8 to PI3K is well matched with the experimental value. The binding breakdown contributions of the individual residues indicate that pi3kα residue 770Arg (pi3kβ residue 777Lys, pi3kδ residue 750Thr and pi3kγ residue 802 Lys) and pi3kα residue 780Trp (pi3kβ residue 787Trp, pi3kδ residue 760Trp and pi3kγ residue 812 Trp) primarily affect the selectivity of compound 8 for the PI3K subtype (fig. 2 b).

In vitro kinase activity inhibition experiments on PI3K subtypes found that compound 8 selectively inhibited PI3kα/β/δ (IC ₅₀ Values 1978 nM, 1873 nM and 146 nM, respectively) (fig. 2 c).

Next, the present invention investigated whether compound 8 can bind to pi3kα, pi3kβ, pi3kγ and pi3kδ in cells by CETSA experiments. The results indicate that compound 8 increases the thermal stability of pi3kα, pi3kβ and pi3kδ, indicating that compound 8 can bind directly to pi3kα/β/δ (fig. 2d-2 e). Thus, compound 8 may be a potent PI3kα/β/δ inhibitor.

Test example 3 proliferation and migration inhibitory Activity of Compound 8 of the present invention on TNBC cells

(1) Colony formation experiments: in order to study the anti-tumor effect of the compound 8 on TNBC cells, the invention firstly carries out a colony formation experiment to detect the long-term proliferation capacity of the TNBC cells after the compound 8 is treated. The specific experimental method comprises the following steps: MDA-MB-231 cells (1X 10) ² Cells/well) were cultured in 12-well plates, allowed to adhere overnight, and then the cells were treated with compound 8 and without compound 8, respectively, for 7 days (concentration of compound 8 was 5 μm). Cells were then fixed with 4% paraformaldehyde and stained with crystal violet (Beyotidme; china C0121). The colony count of MDA-MB-231 cells was counted. Compound 8 was not used to treat as control group.

The experimental results showed that compound 8 dose dependently inhibited the growth of MDA-MB-231 cells and reduced colony numbers (FIG. 3 a).

(2) 3D cell culture experiments: MDA-MB-231 cells (1X 10) ³ Cells/well) were cultured in 96-well 3D cell culture plates (Primesurface; MS9096UZ, japan) and allowed to stand overnight, and then the cells were treated with compound 8 and without compound 8, respectively, for 7 days (concentration of compound 8 is 5 μm). Then, hoechst 33342 (Beyotime; china C1022) was used and captured using a fluorescence microscope. Compound 8 was not used to treat as control group.

The experimental results show that compound 8 can inhibit proliferation of MDA-MB-231 cells (FIG. 4 a).

(3) EDU cell proliferation assay: MDA-MB-231 cells (3X 10) ⁴ Cells/well) were seeded in 24-well plates and incubated with compound 8 (5 μm) for 24 hours. Then, the culture was further performed for 4 hours with 10. Mu. MEDU reagent and according to the instructions (Beyotime; china C0071S). Compound 8 was not used to treat as control group.

The experimental results show that compound 8 significantly reduced the co-labelling number of EDU with Hoechst compared to the control group (fig. 4 b). These results indicate that compound 8 can inhibit proliferation of TNBC cells.

(4) Scratch test: the effect of compound 8 on MDA-MB-231 cell migration was further analyzed by scratch testing. The specific experimental method comprises the following steps: MDA-MB-231 cells (20X 10) ⁴ Cells/well) were inoculated in 6-well plates and cultured in serum-free medium for 24 hours. Then, the cells were scratched with a plastic pipette tip, and then cultured with normal medium or medium containing compound 8 (concentration of compound 8 is 5. Mu.M). The wound healing rate of the cells was observed with a phase contrast microscope at the indicated time. The control group was added to the normal medium.

The experimental results showed that the wound closure rate of compound 8 treated cells was reduced (fig. 4 c).

(5) transwell experiments: MDA-MB-231 cells (2X 10) ⁴ Cells/well) were inoculated into a transwell filter (8 μm well, corning), serum-free DMEM medium and compound 8 (5 μm) were added to the top chamber, and DMEM with 5% fetal bovine serum was added to the bottom chamber. Cells migrate/invade 12 h at 37 ℃. Cells at the bottom of the filter were fixed with 4% paraformaldehyde and stained with 0.1% crystal violet. The images were taken under an inverted microscope and quantified with Image J. The control group was added with serum-free DMEM medium.

the results of the transwell experiments also demonstrate that compound 8 can inhibit the migration of MDA-MB-231 cells (FIG. 4 d).

(5) Immunofluorescence and immunoblot analysis (western blot):

immunofluorescence analysis: MDA-MB-231 cells (3X 10) ⁴ Cells/well) were inoculated into 24-well plates and allowed to stickAttach overnight. Cells were treated with compound 8 and without compound 8 for 7 days, respectively (concentrations of compound 8 were 0, 2.5, 5, 10 μm). MDA-MB-231 cells were fixed with 4% paraformaldehyde, perforated with 0.2% Triton X-100 (Sigma-Aldrich, 9002-93-1), and incubated with 5% goat serum (Sigma-Aldrich, G9023). Incubation with primary antibody was carried out overnight at 4℃and then with secondary antibody (TRITC, ab6718; FITC, ab 6717) for 60 minutes at room temperature. An image was captured using a confocal laser scanning microscope. Compound 8 was not used to treat as control group.

Immunoblot analysis: MDA-MB-231 cells were collected and lysed with lysis buffer at 4℃for 30 min. Then centrifuged (12000 rpm, 10 min) and quantified (Bio-Rad Laboratories, hercules, calif., USA). Equal amounts of total protein were separated by 10-15% SDS-PAGE and transferred to PVDF membrane. After blocking with 5% nonfat milk powder, membrane proteins were detected with primary antibody, then with enzyme-labeled secondary antibody, and developed with ECL as HRP substrate.

According to immunofluorescence and immunoblot analysis: it was also observed that MDA-MB-231 cells were E-cadherein up-regulated and MMP-2 down-regulated after treatment with Compound 8 (FIGS. 4E-g and 3 b).

Taken together, these results indicate that compound 8 can inhibit TNBC cell migration.

In summary, the invention provides a series of fluorinated isoflavone compounds with breast cancer resisting activity, which can selectively inhibit PI3K alpha/beta/delta, especially has good inhibition activity on delta subtype PI3K, and can effectively inhibit the growth and metastasis of tumors, wherein the compound 8 has the best effect. The invention finds an effective PI3K inhibitor, which has important significance for treating breast cancer.

Claims

1. A compound of formula I, a salt thereof, a stereoisomer thereof, a solvate thereof, or a hydrate thereof:

I is a kind of

wherein ,

R ₃ selected from C ₁ ~C ₈ An alkyl group.

2. The compound, salt thereof, stereoisomer thereof, solvate thereof, or hydrate thereof according to claim 1, wherein: the compound is shown in a formula II:

II (II)

wherein ,

R ₃ selected from C ₁ ~C ₈ An alkyl group.

3. The compound, salt thereof, stereoisomer thereof, solvate thereof or hydrate thereof according to claim 2, wherein: the compound is shown in a formula III:

formula III

wherein ,

R ₂ is connected at any position of benzene ring, m is R ₂ Is the number of (3); m is 1, 2, 3 or 4; each R ₂ Independently selected from hydrogen, substituted or unsubstituted C ₁ ~C ₈ Alkyl, substituted or unsubstituted C ₁ ~C ₈ Alkoxy, halogen, cyano, nitro, amino, carboxyl, hydroxyl, or two adjacent R ₂ Forming a naphthyl group with the benzene ring; the substituents of the alkyl and alkoxy groups are selected from C ₁ ~C ₈ Alkyl, C ₁ ~C ₈ Alkoxy, halogen, cyano, nitro, amino, carboxyl, hydroxyl.

4. The compound, salt thereof, stereoisomer thereof, solvate thereof or hydrate thereof according to claim 2, wherein: the compound is represented by formula IVa:

IVa

wherein ,

Alternatively, the compound is of formula IVb:

IVb

wherein ,

alternatively, the compound is of formula IVc:

IVc

wherein ,

5. The compound, salt thereof, stereoisomer thereof, solvate thereof or hydrate thereof according to claim 2, wherein: the compound is shown in a formula V:

v (V)

wherein ,

R ₃ selected from C ₁ ~C ₈ An alkyl group.

6. The compound, salt thereof, stereoisomer thereof, solvate thereof, or hydrate thereof according to claim 1, wherein:

R ₃ selected from C ₁ ~C ₃ An alkyl group.

7. The compound, salt thereof, stereoisomer thereof, solvate thereof or hydrate thereof according to any one of claims 1 to 6, wherein the compound is characterized by: the compound is one of the following compounds:

。

8. the use of a compound according to any one of claims 1 to 7, a salt thereof, a stereoisomer thereof, a solvate thereof or a hydrate thereof for the preparation of a PI3K inhibitor or an anticancer drug.

9. Use according to claim 8, characterized in that: the anticancer medicine is a medicine for preventing and/or treating breast cancer.

10. A medicament, characterized in that: the preparation is prepared by taking the compound, the salt, the stereoisomer, the solvate or the hydrate thereof as an active ingredient and adding pharmaceutically acceptable auxiliary materials or auxiliary ingredients.