A KRAS translation inhibitor and preparation method and application thereof

Abstract

The application discloses a KRAS translation inhibitor and a preparation method and application thereof, and the structural formula of the KRAS translation inhibitor is shown in the following formula (I), (II), (III) and (IV). The KRAS translation inhibitor is a specific ligand of KRAS RNA G-quadruplex, a coumarin-quinolinium salt in the structure of the KRAS translation inhibitor is a necessary skeleton part for recognizing the RNA G-quadruplex, a plane structure of the whole molecule is stacked on a G-quadruplex plane through Pi-Pi, and amino side chain parts on both sides of the molecule can be combined with a phosphate skeleton in a groove of the G-quadruplex. The KRAS translation inhibitor provided by the application can effectively kill KRAS mutation driven cancer cells, can inhibit a translation level of a proto-oncogene KRAS mRNA, and has a wide application prospect in preparation of antitumor drugs.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry, specifically relating to a KRAS translation inhibitor, its preparation method, and its application. Background Technology

[0002] Abnormally activated KRAS protein mutants play a crucial role in cancer development and are also highly attractive therapeutic targets. Selective covalent inhibitors of KRAS G12C, AMG510 and MRTX849, have been successfully used in the clinical treatment of advanced non-small cell lung cancer with KRAS G12C mutations. However, research on inhibitors targeting other KRAS mutants has progressed slowly, highlighting the urgent need to develop novel, potent inhibitors for treating cancers with all KRAS mutants.

[0003] G-quadruplexes are specialized secondary DNA structures widely distributed in the genome, transcription, and translation regions, participating in crucial regulatory processes. The folding and unfolding of G-quadruplexes are in dynamic equilibrium within the body. When G-quadruplexes are stabilized by G-quadruplex ligands, they inhibit mRNA translation, leading to cellular senescence and apoptosis. The proto-oncogene KRAS is frequently mutated in cancer cells, resulting in the continuous activation of downstream pathways that regulate cancer cell differentiation, proliferation, and other life processes. The RNA G-quadruplex (rG4) structure formed by the 5'-UTR region of KRAS mRNA can inhibit KRAS translation. In summary, specifically stabilizing KRAS rG4 can inhibit KRAS translation and induce apoptosis in cancer cells. Therefore, KRAS rG4 is considered a potential target for developing KRAS translation inhibitors.

[0004] KRAS is a disordered protein with an extremely short half-life and no active pocket for binding to small molecules. Therefore, developing drugs that directly target the KRAS protein has always been extremely challenging. Although two marketed drugs targeting the KRAS G12C mutant have been reported, severe drug resistance during treatment has led to significant side effects in patients. Furthermore, the G12C mutation accounts for a very small percentage of KRAS mutations; therefore, developing pan-inhibitors for the broad treatment of KRAS-mutant cancers is a promising strategy. Summary of the Invention

[0005] In order to overcome the problems existing in the prior art, one of the objectives of the present invention is to provide a KRAS translation inhibitor.

[0006] The second objective of this invention is to provide a method for preparing a KRAS translation inhibitor.

[0007] The third objective of this invention is to provide an anti-tumor drug.

[0008] The fourth objective of this invention is to provide an application of a KRAS translation inhibitor in the preparation of antitumor drugs or KRAS translation inhibitory drug compositions.

[0009] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0010] The first aspect of the present invention provides a KRAS translation inhibitor having a compound as shown in formula (I), (II), (III) or (IV), or a pharmaceutically acceptable salt, ester, hydrate, solvate, crystal, enantiomer, stereoisomer, ether, metabolite, or prodrug thereof.

[0011]

[0012] R1 is selected from -NH(CH2). n R5, -NH(CH2)2O(CH2)2OH, -NH(CH2)3OCH(CH3)2, morpholino, piperidino, ((tetrahydro-2H-pyran-4-yl)methyl)amino, acetylpiperazino, isopropionylpiperazino, methylpiperazinpyrimidineamino, ethylpiperazinaniline, N,N-diethylphenylenediamine, trifluoromethylaniline, methylaniline, benzo[a]heterocyclic ring;

[0013] Each R2 is independently selected from -(CH2). n R5;

[0014] Each R3 is independently selected from -NH(CH2). n R5, methylpiperazinyl, methylhomoperazinyl;

[0015] Each R4 is independently selected from halogens;

[0016] Each R5 is independently selected from -OH, -OMe, -NH2, -COOH, -COOMe, halogen, monosaccharide, pyrrolyl, thienyl, imidazolyl, morpholinyl, piperidinyl, N,N-2-methylamino, N,N-2-ethylamino, N,N-2-propylamino, N,N-2-isopropylamino, N,N-2-butylamino, acetylpiperazinyl, isopropionylpiperazinyl, methylpiperazinpyrimidineamino, ethylpiperazinaniline, N,N-diethylphenylenediamine, trifluoromethylaniline, methylaniline, and benzo[a]azine heterocycles.

[0017] Each n is independently selected from natural numbers from 1 to 10.

[0018] Preferably, R4 is iodine.

[0019] Preferably, the benzo[a]azaheterocycle is selected from benzo[a]aza five-membered rings and benzo[a]aza six-membered rings; more preferably, the benzo[a]azaheterocycle is selected from 5-amino-2-methylbenzimidazolyl and benzimidazolyl.

[0020] Preferably, the monosaccharide is selected from hexoses and pentoses; more preferably, the monosaccharide is selected from glucose, galactose, mannose, and glucosamine.

[0021] Preferably, the KRAS translation inhibitor is selected from:

[0022]

[0023]

[0024]

[0025] R4 is defined above.

[0026] Preferably, the pharmaceutically acceptable salt includes, but is not limited to, at least one of inorganic acid salts, organic acid salts, alkyl sulfonates, and aryl sulfonates.

[0027] Preferably, the inorganic acid salt includes, but is not limited to, at least one of hydrochloride, hydrobromide, nitrate, sulfate and phosphate.

[0028] Preferably, the organic acid salt includes, but is not limited to, at least one of formate, acetate, propionate, benzoate, maleate, fumarate, succinate, tartrate and citrate.

[0029] Preferably, the alkyl sulfonate includes, but is not limited to, at least one of methyl sulfonate and ethyl sulfonate.

[0030] Preferably, the aryl sulfonate includes, but is not limited to, at least one of benzenesulfonate and p-toluenesulfonate.

[0031] The second aspect of the present invention provides a method for preparing the KRAS translation inhibitor provided in the first aspect of the present invention, comprising the following steps:

[0032] The compound of formula (I) is prepared by reacting the compound of formula (V) with R1H;

[0033] Alternatively, the compound shown in formula (V) can be reacted with 1-prop-2-ynylpiperazine to obtain the compound shown in formula (VI), and then the compound shown in formula (VI) can be reacted with R2N3 to generate the compound shown in formula (II);

[0034] Or, by It reacts with 7-diethylaminocoumarin-3-aldehyde to produce the compound shown in formula (IV);

[0035] Or, with The reaction formula for preparing the compound shown in formula (III) as a reactant is as follows:

[0036]

[0037] The structural formulas of the compounds represented by formulas (V) and (VI) are as follows:

[0038]

[0039] R1, R2, R3, and R4 are defined as above.

[0040] Preferably, the The synthetic route is as follows:

[0041]

[0042] A third aspect of the present invention provides an antitumor drug comprising the KRAS translation inhibitor provided in the first aspect of the present invention and pharmaceutically acceptable excipients.

[0043] Preferably, the tumor is selected from pancreatic cancer, colorectal cancer, lung cancer, epithelial cell carcinoma, cervical cancer, prostate cancer, nasopharyngeal carcinoma, ovarian cancer, malignant glioma, lymphoma, and melanoma.

[0044] Preferably, the lung cancer is selected from small cell lung cancer or non-small cell lung cancer.

[0045] Preferably, the pharmaceutically acceptable excipient is a non-toxic substance that is compatible with the active ingredient and otherwise biologically suitable for the organism. The selection of a specific excipient will depend on the route of administration or the type and state of disease for treating a particular patient. Examples of pharmaceutically acceptable excipients include, but are not limited to, solvents, diluents, dispersants, suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, binders, lubricants, stabilizers, hydrating agents, emulsification accelerators, buffers, absorbents, colorants, ion exchangers, release agents, coating agents, flavoring agents, and antioxidants, etc., which are common in the pharmaceutical field. Flavoring agents, preservatives, and sweeteners may also be added to the pharmaceutical composition if necessary.

[0046] Preferably, the dosage form of the drug is selected from injections, tablets, pills, capsules, granules, emulsions, or suspensions.

[0047] The fourth aspect of the present invention provides the use of the KRAS translation inhibitor provided in the first aspect of the present invention in the preparation of antitumor drugs or KRAS translation inhibitory drug compositions.

[0048] Preferably, the tumor is selected from pancreatic cancer, colorectal cancer, lung cancer, epithelial cell carcinoma, cervical cancer, prostate cancer, nasopharyngeal carcinoma, ovarian cancer, malignant glioma, lymphoma, and melanoma.

[0049] Preferably, the lung cancer is selected from small cell lung cancer or non-small cell lung cancer.

[0050] The beneficial effects of this invention are as follows: The KRAS translation inhibitor of this invention acts as a specific ligand for the KRAS RNA G-quadruplex. Its coumarin-quinoline onion salt is a necessary backbone component for recognizing the RNA G-quadruplex. The planar structure of the entire molecule is formed by π-π stacking on the G-quadruplex plane, and the amino side chains on both sides of the molecule can bind to the phosphate backbone in the grooves of the G-quadruplex. The KRAS translation inhibitor can effectively kill KRAS mutation-driven cancer cells and inhibit the translation of proto-oncogene KRAS mRNA, thereby inhibiting the proliferation of KRAS-driven tumor cell lines and exhibiting broad-spectrum anti-tumor activity. Furthermore, the KRAS translation inhibitor of this invention selectively inhibits the proliferation of KRAS-driven cancer cells without interfering with normal cells. It can specifically bind to and stabilize the KRAS RNA G-quadruplex and significantly inhibit and downregulate KRAS protein levels, thereby inhibiting the growth of various KRAS-driven cancer cells and showing broad application prospects in the preparation of anti-tumor drugs.

[0051] Furthermore, the preparation method of the present invention is simple to operate, has a high yield, and uses a wide range of raw materials, thus having good prospects for industrial application. Attached Figure Description

[0052] Figure 1 The graph shows the effect of compound 15a, blank control, and QUMA-1 on KRAS transcription levels obtained in the embodiments of the present invention.

[0053] Figure 2 The graph shows the effects of compounds 15a, 16a, 18a, 19a, 21a, 22a, 9b, 12b, blank control, and QUMA-1 prepared in the embodiments of the present invention on KRAS protein levels. Detailed Implementation

[0054] The specific implementation of the present invention will be further described in detail below with reference to the accompanying drawings and examples, but the implementation and protection of the present invention are not limited thereto. It should be noted that any processes not specifically described in detail below are those that can be implemented or understood by those skilled in the art by referring to the prior art. Reagents or instruments used without specified manufacturers are all conventional products that can be purchased commercially.

[0055] The synthetic route of the KRAS translation inhibitor in this invention embodiment is as follows:

[0056]

[0057] The reactants and reaction conditions used in the above reaction route are as follows:

[0058] (a) Ethyl acetoacetate, polyphosphoric acid (PPA), 130 °C, 6 h; (b) POCl3, reflux, 5 h; (c) CH3R4, acetonitrile, 50 °C, 24 h; (d) amino side chain (1-prop-2-ynylpiperazine or 4-methylpiperazine, etc.), K2CO3, acetonitrile, room temperature, 4 h; (e) Pd / C, H2, methanol, room temperature, overnight; (f) 7-diethylaminocoumarin-3-aldehyde, piperidine, ethanol or n-butanol, reflux, 24 h; (g) propyneamine, K2CO3, 105 °C, 48 h; (h) copper sulfate pentahydrate, sodium ascorbate, tert-butanol / water, 80 °C, overnight.

[0059] The specific synthetic process involved in the synthetic route of the KRAS translation inhibitor in the above embodiments is as follows:

[0060] Compounds 1, 2, 10, 11, and 12 were prepared according to the method reported in Angewandte Chemie International Edition 2018, 57, 4702-4706.

[0061] Compound 3 was prepared by the methylation reaction of compound 2 with iodomethane. Compound 3 was disubstituted with amino side chains (including N-methylpiperazine, N-methylisocyclopentanediamine, 1-(2-aminoethyl)pyrrolidine, N-(3-aminopropyl)morpholine, N-(3-aminopropyl)imidazolium, and 1-(3-aminopropyl)pyrrolidine) to give compounds 4-9, respectively. Compound 13 was obtained by the nucleophilic substitution reaction of compound 12 with 1-(prop-2-yn-1-yl)piperazine at room temperature. The substitution reaction of compound 2 with propyneamine gave compound 14, which was then methylated with iodomethane to give compound 15. The chlorine atom at position 10 of compound 15 was replaced by N-methylpiperazine to give compound 16. Compound 16 was condensed with coumarin aldehyde to give the crucial compound 17. Compound 12 was subjected to various amine chain substitution reactions at position 2 to yield compounds 1a-24a of general formula (I), while the chemical reaction of compound 13 with an azide derivative yielded compounds 25a-34a of general formula (II). Compounds 1b-10b of general formula (III) were synthesized using the same method as compounds 25a-34a, while compounds 4-9 were reacted with 7-diethylaminocoumarin-3-aldehyde via a knoevenagel condensation reaction to yield compounds 11b-16b of general formula (IV).

[0062] In the preparation of the target derivative of general formula (I), if compound 12, amine compound, and potassium carbonate are used, the molar ratio of compound 12, amine compound, and potassium carbonate is 1:(1.5~2):1; the reaction temperature is 0-35℃, and the reaction time is 1h~12h.

[0063] In the preparation of the target derivative of general formula (II) or formula (III), if compound 17 is used to react with an azide compound, anhydrous copper sulfate and sodium ascorbate need to be added. The molar ratio of compound 17, azide compound, anhydrous copper sulfate and sodium ascorbate is 1:2:(0.05~0.1):(0.15~0.3); the reaction temperature is 70~100℃ and the reaction time is 10h~48h.

[0064] In the preparation of the target derivative of general formula (Ⅳ), the molar ratio of compounds 4-9, 7-diethylaminocoumarin-3-aldehyde, and piperidine is 1:(1.1~2):0.1, the temperature is 100℃~150℃, and the time is 24h~48h.

[0065] (1) Preparation of compound 3

[0066] Compound 2 (2.0 g, 9.4 mmol) and CH3I (5.0 mL, 80.0 mmol) were mixed in acetonitrile (5.0 mL). The mixture was stirred at 50 °C for 24 hours. After cooling, the mixture was filtered, the crude product was thoroughly washed with dry Et2O, and dried under vacuum to give a bright yellow solid, compound 3. Yield: 86%. 1 H NMR (400MHz, DMSO-d6) δ8.92(s,1H),8.87(dd,J=12.4,6.9Hz,1H),8.38(dd,J=10.6,8.3Hz,1H),4.31(s,3H),2.96(s,3H). 19 FNMR(375MHz,DMSO-d6)δ-122.5,-130.8.

[0067] (2) General preparation steps of compounds 4-9

[0068] Compound 3 (360 mg, 1.0 mmol) and its amino side chain (including N-methylpiperazine, N-methylhopiperazine, 1-(2-aminoethyl)pyrrolidine, N-(3-aminopropyl)morpholine, N-(-3-aminopropyl)imidazolium, or 1-(3-aminopropyl)pyrrolidine) (6.0 mmol) and a catalytic amount of K₂CO₃ were mixed in acetonitrile (4.0 mL). The reaction mixture was stirred at room temperature for 4 hours. The mixture was then extracted with CH₂Cl₂ (30 mL), and the organic layer was washed with water (15 mL × 2) and concentrated under reduced pressure. The residue was purified by rapid column chromatography using MeOH / CH₂Cl₂ (20:1 v / v) containing 1% NH₃·H₂O to give a pale yellow liquid, namely compounds 4-9.

[0069] The structural formulas of compounds 4-9 are as follows:

[0070]

[0071] The yield of compound 4 was 88%. 1 H NMR(400MHz,CD3OD)δ7.76(d,J=14.0Hz,1H),7.35(d,J=7.6Hz,1H),7.13(s,1H),4.14(s,3H),3 .78–3.69(m,4H),3.56–3.47(m,4H),2.85(s,3H),2.82–2.71(m,8H),2.45(s,3H),2.43(s,3H). 19 F NMR (375MHz, CD3OD) δ-120.6.

[0072] The yield of compound 5 was 86%. 1 H NMR (400MHz, CD3OD) δ7.87(d,J=16.0Hz,1H),7.00(d,J=8.1Hz,1H),6.81( s,1H),4.05–4.00(m,4H),3.99(s,3H),3.82–3.76(m,2H),3.74–3.67(m,2 H),3.00(t,J=4.9Hz,2H),2.96–2.92(m,2H),2.84(d,J=4.9Hz,2H),2.75( s,3H),2.74(d,J=5.6Hz,2H),2.50(s,3H),2.43(s,3H),2.23–2.07(m,4H). 19 F NMR (375MHz, CD3OD) δ-123.0.

[0073] The yield of compound 6 was 53%. 1H NMR (400MHz, CD3OD) δ8.04(d,J=12.8Hz,1H),6.96(d,J=7.5Hz,1H),6.72(s,1H),4.01(s,3H),3.71(dt,J=13 .5,6.6Hz,4H),3.16(t,J=6.7Hz,2H),3.08–2.98(m,6H),2.91–2.84(m,4H),2.77(s,3H),1.99–1.90(m,8H). 19 F NMR (375MHz, CD3OD) δ-134.0.

[0074] The yield of compound 7 was 55%. 1 H NMR(400MHz,CD3OD)δ7.96(d,J=12.8Hz,1H),6.81(d,J=7.5Hz,1H),6.66(s,1H),3.95(s,3H),3.74(dt,J=7.7,4.6Hz,8H) ,3.58(t,J=6.9Hz,2H),3.47(t,J=6.7Hz,2H),2.75(s,3H),2.65(t,J=6.9Hz,2H),2.63–2.54(m,10H),2.04–1.92(m,4H). 19 F NMR (375MHz, CD3OD) δ-134.4.

[0075] The yield of compound 8 was 38%. 1 H NMR (400MHz, CD3OD) δ7.93 (d, J=12.7Hz, 1H), 7.71 (dt, J=2.5, 1.2Hz, 2H), 7.22 (dt, J=3.0, 1.4Hz, 2H), 6.98 (dt, J=9.5, 1.4Hz, 2H), 6.69 (dd, J=7.6, 2.0Hz,1H),6.52(s,1H),4.22(td,J=6.9,2.3Hz,4H),3.89(s,3H),3.50(t ,J=7.1Hz,2H),3.39(t,J=7.0Hz,2H),2.72(s,2H),2.24(h,J=6.9Hz,4H). 19 F NMR (375MHz, CD3OD) δ-134.1.

[0076] The yield of compound 9 was 51%. 1H NMR (400MHz, CD3OD) δ7.84(d,J=12.7Hz,1H),6.85(d,J=7.5Hz,1H),6.66(s,1H),3.96(s,3H),3.57(t,J=6.9Hz, 2H), 3.47 (t, J=6.9Hz, 2H), 2.75 (s, 3H), 2.84–2.64 (m, 12H), 2.00 (h, J=6.9Hz, 4H), 1.89 (tt, J=5.2, 1.7Hz, 8H). 19 FNMR (375MHz, CD3OD) δ-134.6.

[0077] (3) Preparation of compound 13

[0078] Compound 12 (1.2 g, 2.2 mmol), 1-(prop-2-yn-1-yl)piperazine (410 mg, 3.3 mmol), and K₂CO₃ (28 mg, 0.2 mmol) were dissolved in acetonitrile (8.0 mL). The reaction mixture was then stirred at room temperature for 24 hours. Afterward, the mixture was filtered, the crude product was thoroughly washed with anhydrous ether, and dried under vacuum to give a dark brown solid as intermediate 13 in 88% yield. 1 H NMR (500MHz, DMSO-d6) δ8.71(d,J=8.8Hz,1H),8.41(s,1H),8.19(d,J=8.8Hz,1H),8.07(d,J= 13.1Hz,1H)8.03(d,J=15.8Hz,1H),7.84(d,J=15.5Hz,1H),7.56(d,J=8.9Hz,1H),7.49(d,J= 7.4Hz,1H),6.83(dd,J=8.9,2.5Hz,1H),6.63(d,J=2.5Hz,1H),4.38(s,3H),3.57–3.46(m,8H ), 3.41 (d, J = 2.4Hz, 2H), 3.20 (t, J = 2.4Hz, 1H), 2.70 (t, J = 4.9Hz, 4H), 1.17 (t, J = 7.0Hz, 6H). 19 F NMR (470MHz, DMSO-d6) δ-117.2.

[0079] (4) Preparation of compound 14

[0080] Compound 2 (300 mg, 1.4 mmol) and K₂CO₃ (194 mg, 1.4 mol) were dissolved in propargylamine (1.0 mL). The resulting mixture was stirred at 105 °C for 48 hours. After cooling to room temperature, dry Et₂O (5.0 mL) was added. The precipitate formed was filtered and washed with dry Et₂O to give a yellow solid as compound 14 in 80% yield. 1 H NMR (400MHz, DMSO-d6) δ7.67(d,J=12.3Hz,1H),7.35(s,1H),7.13(d,J=8.4Hz,1H),6 .86(t,J=6.0Hz,1H), 4.08(dd,J=6.0,2.4Hz,2H), 3.15(t,J=2.4Hz,1H), 2.56(s,3H). 19 F NMR (375MHz, DMSO-d6) δ-129.4.

[0081] (5) Preparation of compound 15

[0082] Compound 14 (300 mg, 1.2 mmol) and CH3I (1.0 mL, 16.0 mmol) were mixed in acetonitrile (1.0 mL). The mixture was stirred at 50 °C for 24 hours. After cooling, the mixture was filtered, the crude product was thoroughly washed with dry Et2O, and dried under vacuum to give a bright yellow solid, compound 15, in 86% yield. 1 H NMR (400MHz, DMSO-d6) δ8.32(s,1H),8.11(d,J=11.5Hz,1H),8.01(s,1H),7.29(d,J=7. 0Hz, 1H), 4.38 (dd, J = 5.9, 2.4Hz, 2H), 4.21 (s, 3H), 3.30 (d, J = 2.4Hz, 1H), 2.91 (s, 3H). 19 F NMR (375MHz, DMSO-d6) δ-124.6.

[0083] (6) Preparation of compound 16

[0084] Compound 15 (400 mg, 1.0 mmol) and N-methylpiperazine (0.4 mL, 3.6 mmol) were mixed in a solution of acetonitrile (3.0 mL), and K₂CO₃ (2.2 mL, 0.1 mmol) was added. The resulting mixture was stirred at room temperature for 4 hours. After stirring, the mixture was filtered, the crude product was thoroughly washed with Et₂O, and dried under vacuum to give a pale yellow solid, compound 16, in 80% yield. 1HNMR(400MHz,DMSO-d6)δ7.69(d,J=12.5Hz,1H),7.65(dd,J=7.0,5.0Hz,1H),7.11(s,1H),7.09(d,J=7.5Hz,1H),4.27(d d,J=6.0,2.5Hz,2H),3.98(s,3H),3.66–3.61(m,4H),3.23(t,J=2.4Hz,1H),2.76(s,3H),2.54–2.51(m,4H),2.26(s,3H). 19 F NMR (375MHz, DMSO-d6) δ-130.5.

[0085] (7) Preparation of compound 17

[0086] The mixture of compound 16 (350 mg, 0.9 mmol) and 7-diethylaminocoumarin-3-aldehyde (320 mg, 1.3 mmol) in EtOH (8.0 mL) was stirred under reflux for 24 hours, then cooled to room temperature, filtered, and thoroughly washed with anhydrous ether. The mixture was then dried under vacuum to obtain a dark red solid as intermediate 17, yield: 79%. 1 H NMR(500MHz,DMSO-d6)δ8.33(s,1H),7.87(d,J=15.6Hz,1H),7.66(d,J=12.3Hz,1H),7 .59–7.48(m,3H),7.20(s,1H),7.11(d,J=7.4Hz,1H),6.80(dd,J=9.0,2.4Hz,1H),6.5 8(d,J=2.4Hz,1H),4.29(d,J=5.6Hz,2H),4.09(s,3H),3.68(t,J=4.7Hz,4H),3.50(q, J=7.0Hz, 4H), 3.15 (s, 1H), 2.61 (t, J= 4.7Hz, 4H), 2.32 (s, 3H), 1.18 (t, J= 7.0Hz, 6H). 19 F NMR (375MHz, DMSO-d6) δ-129.8. 13C NMR(125MHz,DMSO-d6)δ160.3,159.4,156.8,153.6,152.5,149.1,145.4, 142.2(d,J=14.4Hz)141.0,137.5,130.9,120.4,114.4,111.6(d,J=7.6Hz ),110.6,110.4(d,J=12.5Hz),108.9,104.6,98.2(d,J=3.5Hz),97.0,80. 2,74.6,54.8(2C),51.9(2C),45.9,44.8(3C),39.8(2C),38.7,32.4,12.9.

[0087] (8) Steps for preparing 1a-24a universal method A

[0088] Compound 12 (280 mg, 0.5 mmol) dissolved in acetonitrile (2.0 mL) was added to a catalytic amount of K₂CO₃ and an amine compound (1.0 mmol). The resulting mixture was stirred at room temperature for 6 hours. After completion, CH₂Cl₂ (30 mL) and H₂O (15 mL) were added, the organic layer was extracted, and concentrated under reduced pressure. The crude product was purified by a rapid chromatographic column of MeOH / CH₂Cl₂ (20:1 v / v) containing 1% NH₃·H₂O to give a brownish-black solid as the target compounds 1a-24a.

[0089] The structural formulas of compounds 1a-24a synthesized according to the above method are as follows:

[0090]

[0091]

[0092] The characterization data of compounds 1a-24a are as follows:

[0093] The yield of compound 1a was 36%. 1H NMR (400MHz, DMSO-d6) δ8.73(d,J=7.9Hz,1H),8.43(s,1H),8.22(d,J=8.8Hz,1H),8 .11(d,J=12.9Hz,1H),8.03(d,J=15.2,1H),7.86(d,J=15.6Hz,1H),7.57(d,J=9.0H z,1H),7.51(d,J=7.2Hz,1H),6.83(dd,J=9.0,2.4Hz,1H),6.63(d,J=2.4Hz,1H),4. 38(s,3H),3.73–3.66(m,4H),3.58–3.42(m,8H),2.08(s,3H),1.16(t,J=7.1Hz,6H). 19 F NMR (375MHz, DMSO-d6) δ-117.5. 13 C NMR (125MHz, DMSO-d6) δ168.2, 159.4, 156.3, 154.5 (d, J = 1.7Hz), 153.5 (d, J = 253 .6Hz),152.3,145.7,145.4(d,J=10.9Hz),141.6(d,J=5.1Hz),140.2,138.0,130. 6,122.6 (d,J=11.0Hz),118.0,117.9,114.3 (d,J=23.9Hz),113.2,110.1,108.3,105.0 (d,J=4.1Hz),96.2,49.1 (d,J=4.9Hz, 2C),44.1 (4C),39.0,20.6,12.0 (2C). HRMS(ESI) m / z: calculated as C 31 H 34 FN4O3 + [MI] + A mass spectrometry peak at 529.2609 was found, and the purity was determined to be 99.5% by HPLC.

[0094] The yield of compound 2a was 31%. 1H NMR (400MHz, CD3OD) δ8.61(d,J=8.8Hz,1H),8.22(s,1H),8.18(d,J=15.4Hz,1H),8.13( d,J=8.8Hz,1H),7.87(d,J=12.7Hz,1H),7.80(d,J=15.5Hz,1H),7.50(t,J=8.9Hz,2H), 6.82(dd,J=9.0,2.5Hz,1H),6.54(d,J=2.5Hz,1H),4.43(s,3H),3.88(t,J=5.8Hz,4H), 3.63–3.50(m,8H),3.04(p,J=6.7Hz,1H),1.25(t,J=7.1Hz,6H),1.16(d,J=6.7Hz,6H). 19 F NMR (375MHz, CD3OD) δ-118.3. 13 C NMR (125MHz, DMSO-d6) δ174.4, 159.3, 156.2, 154.5 (d, J = 1.9 Hz), 153.5 (d, J = 254.6 Hz),152.2,145.6,145.4(d,J=10.6Hz),141.4(d,J=4.6Hz),140.2,137.8,130.6,12 2.6 (d, J = 11.0 Hz), 117.8, 117.7, 114.2 (d, J = 23.6 Hz), 113.1, 110.0, 108.2, 105.0 (d, J = 3.8 Hz), 96.1, 49.3 (d, J = 4.9 Hz, 2C), 44.1 (4C), 39.8, 28.7, 18.9 (2C), 12.0 (2C). HRMS(ESI) m / z: calculated as C 33 H 38 FN4O3 + [MI] + A mass spectrometry peak at 557.2922 was found, and the purity was 96.2% as determined by HPLC.

[0095] The yield of compound 3a was 78%. 1H NMR (400MHz, DMSO-d6) δ8.72(d,J=8.7Hz,1H),8.42(s,1H),8.22(d,J=8.8Hz,1H),8.09( d,J=13.1Hz,1H),8.03(d,J=15.5Hz,1H),7.86(d,J=15.5Hz,1H),7.56(d,J=8.9Hz,1H), 7.50(d,J=7.4Hz,1H),6.83(dd,J=9.1,2.4Hz,1H),6.62(d,J=2.4Hz,1H),4.39(s,3H),3 .83(t,J=4.7Hz,4H), 3.51(q,J=7.0Hz,4H), 3.46(t,J=4.7Hz,4H), 1.16(t,J=7.0Hz,6H). 19 F NMR (375MHz, DMSO-d6) δ-117.5. 13 C NMR (125MHz, DMSO-d6) δ159.4, 156.3, 154.7 (d, J = 1.6Hz), 153.6 (d, J = 258.7Hz) ,152.2,145.7,145.4(d,J=10.4Hz),141.5(d,J=4.9Hz),140.2,138.0,130.6,12 2.7(d,J=10.5Hz),118.0(2C),114.3(d,J=24.0Hz),113.2,110.0,108.3,104.9 (d,J=4.2Hz),96.2,65.5(2C),49.6(d,J=5.6Hz,2C),44.1(2C),39.8,12.0(2C). HRMS(ESI)m / z: calculated as C 29 H 31 FN3O3 + [MI] + A mass spectrometry peak at 488.2344 was found, and the purity was determined to be 95.1% by HPLC.

[0096] The yield of compound 4a was 26%. 1H NMR (400MHz, CD3OD) δ8.54(d,J=8.7Hz,1H),8.16(s,1H),8.09(d,J=15.2Hz,1H),7.96(d,J=8.9Hz,1H),7.87(d,J=10.9Hz,1H),7.77–7. 63(m,3H),7.56–7.41(m,3H),6.81(d,J=9.1Hz,1H),6.53(s,1H),4.15(s,3H),3.54(q,J=7.2Hz,4H),2.72(s,3H),1.24(t,J=7.2Hz,6H). 19 F NMR (375MHz, DMSO-d6) δ-125.4. 13 C NMR (125MHz, DMSO-d6) δ159.4,156.2,154.1(d,J=2.5Hz),152.1,151.6,151.5(d,J=2 57.3Hz),148.0,145.5,145.4(d,J=10.4Hz),144.9,141.5(d,J=4.9Hz),140.9,139.4, 138.9, 130.5, 122.7 (d, J = 10.1 Hz), 118.6, 118.3, 116.7, 116.6, 114.5, 114.3 (d, J = 23.4 Hz), 113.3, 110.0, 108.2, 108.0 (d, J = 4.3 Hz), 96.2, 44.1 (2C), 38.9, 13.2, 12.0 (2C). HRMS(ESI) m / z: Theoretically calculated as C 33 H 31 FN5O2 + [MI] + The mass spectrometry peak at 548.2456 was found, and the purity measured by HPLC was 98.1%.

[0097] The yield of compound 5a was 72%. 1H NMR (400MHz, CD3OD) δ8.51(d,J=8.6Hz,1H),8.16(s,1H),8.08(d,J=15.5Hz,1H),7.90(d,J=8.6Hz,1H),7.82(d,J=10.1Hz,2H),7.68–7.58( m,3H),7.54–7.46(m,2H),6.86–6.78(m,2H),6.54(d,J=2.4Hz,1H),4.89(s,2H),4.12(s,3H),3.54(q,J=7.1Hz,4H),1.25(t,J=7.1Hz,6H). 19F NMR (375MHz, CD3OD) δ-61.1,-129.8. 13 C NMR (125MHz, DMSO-d6) δ159.4, 156.1, 153.7 (d, J = 1.7Hz), 152.0, 151.0 (d, J = 251.2Hz), 145. 2,143.5(d,J=14.8Hz),141.6(d,J=4.8Hz),139.3,138.7,135.5,132.5,130.4,128.7,127.7 ,126.7,125.9(d,J=147.7Hz),125.8(q,J=5.8Hz),120.5(d,J=9.5Hz),118.5,115.9,113.3,112.4(d,J=20.1Hz)109.9,108.2,96.1,95.2(d,J=4.0Hz),44.0(2C),42.7,39.0,12.0(2C). HRMS(ESI) m / z: Theoretical calculated value is C 33 H 30 F4N3O2 + [MI] + The mass spectrometry peak at 576.2269 was found, and the purity measured by HPLC was 97.5%.

[0098] The yield of compound 6a was 70%. 1H NMR (400MHz, CD3OD) δ8.50(d,J=8.4Hz,1H),8.16(s,1H),8.12(d,J=15.5Hz,1H),7.87(d,J=8 .5Hz,1H),7.78(d,J=11.1Hz,1H),7.63(d,J=15.5Hz,1H),7.50(d,J=8.9Hz,1H),7.38(d,J=7. 2Hz,1H),7.29–7.18(m,3H),6.95(d,J=7.2Hz,1H),6.81(dd,J=8.9,2.4Hz,1H),6.57(d,J=2. 5Hz,1H),4.70(s,2H),4.18(s,3H),3.54(q,J=7.1Hz,4H),2.46(s,3H),1.25(t,J=7.1Hz,6H). 19 F NMR(375MHz,DMSO-d6)δ-127.0. 13 CNMR(100MHz,DMSO-d6)δ159.8,156.4,153.7(d,J=1.6Hz),152.1,151.0(d,J=253.0Hz),14 5.6(d,J=10.0Hz),144.0,141.7(d,J=4.0Hz),139.6,138.7,136.3,135.0,130.8,130.3,12 7.5, 127.3, 125.8, 120.5 (d, J = 9.9 Hz), 118.8, 115.7, 113.4, 112.5 (d, J = 21.3 Hz), 110.1, 108.3, 96.2, 95.4 (d, J = 4.5 Hz), 44.3 (2C), 44.2, 39.0, 18.9, 12.3 (2C). HRMS(ESI) m / z: Theoretically calculated as C 33 H 33 FN3O3 + [MI] + The mass spectrometry peak at 522.2551 was detected, and the purity measured by HPLC was 99.8%.

[0099] The yield of compound 7a was 49%. 1H NMR (400MHz, CD3OD) δ8.40(d,J=8.5Hz,1H),8.09(s,1H),7.98(d,J=15.5Hz,1H),7.83(d,J=8.6Hz, 1H),7.68(d,J=11.0Hz,1H),7.58(d,J=15.4Hz,1H),7.43(d,J=9.0Hz,1H),7.28(d,J=8.7Hz,2H),7 .21(d,J=7.0Hz,1H),6.85(d,J=8.7Hz,2H),6.76(dd,J=9.0,2.4Hz,1H),6.43(d,J=2.4Hz,1H),4.0 8(s,3H),3.51(q,J=7.2Hz,4H),3.45(q,J=7.1Hz,4H),1.24(t,J=7.2Hz,6H),1.20(t,J=7.1Hz,6H). 19 F NMR (375MHz, CD3OD) δ-129.2. 13 C NMR(125MHz, DMSO-d6)δ159.4,156.1,153.6(d,J=1.6Hz),153.3,152.0,151.3(d,J=253.5 Hz),145.3(d,J=12.4Hz,2C),141.2(d,J=4.4Hz),139.2,138.9(2C),130.4,124.5(2C),121 0 (d, J = 8.9 Hz), 118.3, 115.8, 113.3 (2C), 112.8 (d, J = 20.6 Hz), 112.3, 109.9, 108.2, 96.1, 96.0 (d, J = 3.5 Hz), 44.0 (2C), 43.5 (2C), 38.7, 12.1 (2C), 12.0 (2C). HRMS(ESI) m / z: Theoretically calculated as C 35 H 38 FN4O2 + [MI] + The mass spectrometry peak at 565.2975 was detected, and the purity measured by HPLC was 98.8%.

[0100] The yield of compound 8a was 33%. 1H NMR(400MHz,DMSO-d6)δ9.40(s,1H),8.61(d,J=8.6Hz,1H),8.40(s,1H),8.03(dd,J=15.7,9.8Hz,2 H),7.93(d,J=15.5Hz,1H),7.75(d,J=15.5Hz,1H),7.53(d,J=8.9Hz,1H),7.41(d,J=8.5Hz,2H),7.3 6(d,J=7.0Hz,1H),7.11(d,J=8.5Hz,2H),6.78(d,J=9.1Hz,1H),6.56(s,1H),4.12(s,3H),3.56(t,J =7.0Hz,4H),3.35–3.16(m,8H),3.08(q,J=7.2Hz,2H),1.28(t,J=7.2Hz,3H),1.14(t,J=7.0Hz,6H). 19 F NMR(375MHz,DMSO-d6)δ-125.7. 13 C NMR(100MHz,DMSO-d6)δ159.9,156.5(2C),154.0(d,J=1.6Hz),152.9,151.6(d,J=250.2Hz),1 47.5,146.3(d,J=15.0Hz),141.7(d,J=2.2Hz,2C),139.7,139.3,131.1,124.0(2C),121.5(d, J = 10.1 Hz), 118.4, 116.9 (2C), 116.6, 113.4 (d, J = 19.8 Hz), 113.3, 110.3, 108.5, 96.2 (d, J = 4.1 Hz), 94.8, 50.8, 50.4 (2C), 45.8 (2C), 44.5 (2C), 40.0, 12.5 (2C), 9.2. HRMS (ESI) m / z: Theoretically calculated as C 37 H 41 FN5O2 + [MI] + The mass spectrometry peak at 606.3239 was found, and the purity measured by HPLC was 96.9%.

[0101] The yield of compound 9a was 31%. 1H NMR (400MHz, CD3OD) δ8.38(d,J=8.6Hz,1H),8.22(d,J=2.7Hz,1H),8.05(s,1H),7.90(d,J=14.7Hz,1H),7.87( d,J=8.2Hz,1H),7.73(dd,J=9.0,2.8Hz,1H),7.66(d,J=10.9Hz,1H),7.56(d,J=15.5Hz,1H),7.39(d,J=8.9Hz ,1H),7.10(d,J=7.0Hz,1H),7.02(d,J=9.0Hz,1H),6.73(dd,J=9.0,2.4Hz,1H),6.34(d,J=2.3Hz,1H),4.07(s ,3H),3.67(t,J=5.1Hz,4H),3.49(q,J=7.1Hz,4H),2.75(t,J=5.1Hz,4H),2.49(s,3H),1.22(t,J=7.1Hz,6H). 19 F NMR(470MHz,DMSO-d6)δ-125.8. 13 C NMR (125MHz, DMSO-d6) δ159.3, 156.6, 156.2, 153.9 (d, J = 1.9Hz), 152.1, 151.3 (d, J = 254.4 Hz),145.4,143.1,142.1(d,J=14.3Hz),141.5(d,J=4.5Hz),139.2,139.0,133.5,130.5,1 25.1, 121.2 (d, J = 9.5 Hz), 118.2, 116.3, 113.3, 113.0 (d, J = 20.4 Hz), 110.0, 108.2, 107.2, 96.8 (d, J = 4.0 Hz), 96.1, 53.6 (2C), 44.7, 44.0 (4C), 38.9, 12.0 (2C). HRMS(ESI) m / z: Theoretically calculated as C 35 H 38 FN6O2 + [MI] + The mass spectrometry peak at 593.3035 was detected, and the purity measured by HPLC was 96.7%.

[0102] The yield of compound 10a was 69%. 1H NMR (500MHz, DMSO-d6) δ8.65(d,J=8.6Hz,1H),8.41(s,1H),8.09(d,J=8.6Hz,1H),7.97( d,J=7.1Hz,1H),7.94(d,J=4.7Hz,1H),7.78(d,J=15.6Hz,1H),7.52(d,J=8.9Hz,1H),7. 39(d,J=7.5Hz,1H),6.78(dd,J=9.0,2.4Hz,1H),6.53(d,J=2.4Hz,1H),4.36(s,3H),3.5 3–3.45(m,8H),1.75(p,J=5.5Hz,4H),1.69(q,J=6.7,5.8Hz,2H),1.18(t,J=7.0Hz,6H). 19 F NMR(375MHz,DMSO-d6)δ-117.1. 13 C NMR (125MHz, DMSO-d6) δ159.3, 156.2, 154.2 (d, J = 1.8Hz), 153.6 (d, J = 254.8Hz), 152.1, 146.3(d,J=10.4Hz),145.5,141.3(d,J=4.8Hz),139.8,138.1,130.5,122.2(d,J=10.4H z), 117.9, 117.3, 114.1 (d, J = 23.8 Hz), 113.1, 110.0, 108.2, 104.3 (d, J = 4.0 Hz), 96.1, 50.5 (d, J = 5.8 Hz, 2C), 44.0 (2C), 39.9, 25.0 (2C), 23.1, 12.0 (2C). HRMS(ESI) m / z: theoretically calculated as C 30 H 33 FN3O2 + [MI] + The mass spectrometry peak at 486.2551 was detected, and the purity was 99.0% as determined by HPLC.

[0103] The yield of compound 11a was 44%. 1H NMR (400MHz, DMSO-d6) δ8.55(d,J=8.5Hz,1H),8.38(s,1H),8.02–7.86(m,3H),7.75–7.63(m,2H),7. 53(d,J=9.0Hz,1H),7.05(d,J=7.1Hz,1H),6.79(dd,J=9.0,2.6Hz,1H),6.58(d,J=2.4Hz,1H),4.27(s ,3H),3.88(ddd,J=11.4,4.5,1.9Hz,2H),3.48(q,J=7.0Hz,4H),3.29(td,J=11.8,2.1Hz,4H),2.03( ddd,J=11.2,7.1,3.4Hz,1H),1.74–1.66(m,2H),1.31(qd,J=12.0,4.4Hz,2H),1.15(t,J=7.0Hz,6H). 19 F NMR(375MHz,DMSO-d6)δ-127.2. 13 C NMR (100MHz, DMSO-d6) δ159.9, 156.4, 153.5 (d, J = 2.3Hz), 152.1, δ 151.2 (d, J = 253.2H z),145.6,144.4(d,J=14.6Hz),141.6(d,J=4.3Hz),139.9,138.6,130.8,120.4(d,J=9 0.9Hz), 118.8, 115.5, 113.4, 112.4 (d, J = 20.1Hz), 110.1, 108.3, 96.2, 94.8 (d, J = 4.8Hz), 66.8 (2C), 48.0, 44.4 (2C), 40.0, 33.8, 30.5 (2C), 12.4 (2C). HRMS(ESI) m / z: Theoretically calculated as C 31 H 35 FN3O3 + [MI] + The mass spectrometry peak at 516.2657 was detected, and the purity measured by HPLC was 99.4%.

[0104] The yield of compound 12a was 51%. 1H NMR (400MHz, CD3OD) δ8.42(d,J=8.5Hz,1H),8.12(s,1H),8.07(d,J=15.5Hz,1H),7.84( d,J=8.4Hz,1H),7.66(d,J=11.1Hz,1H),7.60(d,J=15.5Hz,1H),7.45(d,J=9.0Hz,1H),7 .11(d,J=7.1Hz,1H),6.77(dd,J=8.9,2.5Hz,1H),6.46(d,J=2.4Hz,1H),4.30(s,3H),3. 89(t,J=5.6Hz,2H), 3.61(t,J=5.6Hz,2H), 3.51(q,J=7.2Hz,4H), 1.24(t,J=7.1Hz,6H). 19 F NMR(375MHz,DMSO-d6)δ-127.6. 13 C NMR (100MHz, DMSO-d6) δ 159.9, 156.4, 153.6 (d, J = 2.1Hz), 152.1, 151.3 (d, J = 253.0Hz), 145.6, 144.5 (d, J = 14.7Hz), 141.6 (d, J = 4.5Hz), 139.9, 138.6, 130.8, 120.4 (d, J = 10.4Hz), 118.9, 115.5, 113.4, 112.3 (d, J = 19.4Hz), 110.2, 108.4, 96.3, 95.1 (d, J = 4.7Hz), 59.0, 45.2, 44.4 (2C), 40.0, 12.4 (2C). HRMS (ESI) m / z: theoretically calculated as C 27 H 29 FN3O3 + [MI] + The mass spectrometry peak at 462.2187 was detected, and the purity was 95.5% as determined by HPLC.

[0105] The yield of compound 13a was 32%. 1H NMR (500MHz, CD3OD) δ8.48(d,J=8.5Hz,1H),8.16(s,1H),8.08(d,J=15.3Hz,1H),7.93(d,J=8.5 Hz,1H),7.74(d,J=10.5Hz,1H),7.66(d,J=15.4Hz,1H),7.48(d,J=8.9Hz,1H),7.21(d,J=6.9Hz ,1H),6.79(d,J=8.9Hz,1H),6.47(s,1H),4.39(s,3H),4.01(t,J=7.6Hz,2H),3.82(t,J=6.5Hz, 2H), 3.52 (q, J = 7.1Hz, 4H), 3.46 (t, J = 7.6Hz, 2H), 1.45 (d, J = 6.5Hz, 12H), 1.25 (t, J = 7.1Hz, 6H). 19 F NMR(375MHz,DMSO-d6)δ-127.6. 13 C NMR(125MHz,DMSO-d6)δ159.4,156.1,153.4,151.9,151.0(d,J=252.9Hz),144.9, 142.9(d,J=14.3Hz),141.4(d,J=4.5Hz),139.5,138.5,130.4,120.4(d,J=7.1Hz), 118.3, 115.7, 113.3, 112.2 (d, J = 19.3 Hz), 109.9, 108.2, 96.0, 95.6 (d, J = 3.4 Hz), 54.1 (2C), 53.6, 44.3, 44.0 (2C), 40.0, 17.8 (4C), 12.0 (2C). HRMS(ESI) m / z: Theoretically calculated as C 33 H 42 FN4O2 + [MI] + The mass spectrometry peak at 545.3286 was detected, and the purity measured by HPLC was 97.4%.

[0106] The yield of compound 14a was 72%. 1H NMR(400MHz,DMSO-d6)δ8.56(d,J=8.4Hz,1H),8.39(s,1H),8.03–7.87(m,3H) ,7.79–7.64(m,2H),7.52(d,J=8.8Hz,1H),7.45–7.26(m,2H),7.08–6.93(m,2 H),6.78(dd,J=9.0,2.4Hz,1H),6.57(d,J=2.4,1H),4.26(s,3H),3.72(q,J=6 .7Hz,2H),3.48(q,J=7.2Hz,4H),3.24(t,J=7.2Hz,2H),1.14(t,J=7.2Hz,6H). 19 FNMR (375MHz, DMSO-d6) δ -127.4. 13 C NMR (100MHz, DMSO-d6) δ159.8, 156.3, 153.5 (d, J = 1.7Hz), 152.4, 151.2 (d, J = 253.2Hz), 145.5,143.8(d,J=14.5Hz),141.6(d,J=4.7Hz),141.1,139.7,138.7,130.8,127.0,125 .7,124.3,120.4 (d,J=10.2Hz),118.7,115.6,113.4,112.3 (d,J=21.0Hz),110.1,108.3,96.2 (d,J=4.5Hz),95.1,44.4 (2C),43.9,40.0,28.0,12.4 (2C). HRMS(ESI) m / z: Theoretically calculated as C 31 H 31 FN3O2S + [MI] + The mass spectrometry peak at 528.2116 was detected, and the purity measured by HPLC was 95.2%.

[0107] The yield of compound 15a was 48%. 1H NMR (400MHz, CD3OD) δ8.29(d,J=8.5Hz,1H),8.03(s,1H),7.87(d,J=15.5Hz,1H),7.79(d,J=8.6Hz, 1H),7.51(d,J=10.8Hz,1H),7.48(d,J=6.3Hz,1H),7.35(d,J=9.0Hz,1H),6.94(d,J=7.1Hz,1H),6. 67(dd,J=9.0,2.4Hz,1H),6.26(d,J=2.4Hz,1H),4.24(s,3H),3.60(t,J=6.9Hz,2H),3.46(q,J=7.1 Hz, 4H), 2.93 (t, J = 6.9Hz, 2H), 2.76 (p, J = 3.2Hz, 4H), 1.91 (p, J = 3.2Hz, 4H), 1.22 (t, J = 7.1Hz, 6H). 19 F NMR (375MHz, CD3OD) δ-129.6. 13 C NMR (100MHz, DMSO-d6) δ159.9, 156.4, 153.7 (d, J = 1.7Hz), 152.1, 151.3 (d, J = 252. 4Hz),145.6,143.4(d,J=16.3Hz),141.7(d,J=5.3Hz),139.7,138.9,130.9,120.6( d,J=9.6Hz), 118.6, 116.0, 113.4, 112.5 (d,J=20.2Hz), 110.2, 108.4, 96.2, 95.6 (d,J=3.9Hz), 53.2 (3C), 44.4 (3C), 40.0, 22.7 (2C), 12.4 (2C). HRMS(ESI) m / z: Theoretically calculated as C 31 H 36 FN4O2 + [MI] + The mass spectrometry peak at 515.2817 was detected, and the purity measured by HPLC was 98.5%.

[0108] The yield of compound 16a was 46%. 1H NMR(500MHz,CD3OD)δ8.45(d,J=8.5Hz,1H),8.15(s,1H),8.05(d,J=15.5Hz,1H),7.90(d,J=8.5Hz,1H), 7.69(d,J=11.0Hz,1H),7.63(d,J=15.5Hz,1H),7.46(d,J=8.9Hz,1H),7.13(d,J=7.0Hz,1H),6.77(dd,J =9.0,2.4Hz,1H),6.44(d,J=2.4Hz,1H),4.37(s,3H),3.83(t,J=7.0Hz,2H),3.51(q,J=7.1Hz,4H),3.18 –3.12(m,3H),3.08–2.98(m,3H),1.83(dt,J=11.2,5.6Hz,4H),1.68–1.60(m,2H),1.24(t,J=7.1Hz,6H). 19 F NMR(375MHz,DMSO-d6)δ-127.2. 13 C NMR (125MHz, DMSO-d6) δ159.4, 156.0, 153.3 (d, J = 1.6Hz), 151.9, 151.0 (d, J = 253.5Hz) ,144.9,143.5(d,J=14.7Hz),141.3(d,J=4.3Hz),139.5,138.4,130.3,120.3(d,J=9.8H z), 118.3, 115.5, 113.3, 112.0 (d, J = 20.4 Hz), 109.9, 108.1, 96.0, 95.3 (d, J = 3.8 Hz), 54.7, 52.9 (2C), 44.0 (2C), 39.9, 38.6, 23.8 (2C), 22.4, 12.0 (2C). HRMS(ESI) m / z: Theoretically calculated as C 32 H 38 FN4O2 + [MI] + The mass spectrometry peak at 529.2973 was detected, and the purity measured by HPLC was 95.4%.

[0109] The yield of compound 17a was 21%. 1H NMR (400MHz, CD3OD) δ8.41(d,J=8.5Hz,1H),8.16(s,1H),8.06(d,J=15.5Hz,1H),7.81(d,J=8.5Hz, 1H),7.68(d,J=11.0Hz,1H),7.61(d,J=15.5Hz,1H),7.49(d,J=9.0Hz,1H),7.48–7.45(m,2H),7.17( dd,J=6.0,3.1Hz,2H),6.90(d,J=7.0Hz,1H),6.79(dd,J=9.0,2.4Hz,1H),6.53(d,J=2.4Hz,1H),4.1 7(s,3H),3.99(t,J=6.8Hz,2H),3.53(q,J=7.0Hz,4H),3.35(t,J=6.8Hz,2H),1.24(t,J=7.0Hz,4H). 19 F NMR (375MHz, CD3OD) δ-129.8. 13 C NMR (125MHz, DMSO-d6) δ159.5, 156.1, 153.3 (d, J = 1.6Hz), 152.4, 152.0, 151.1 (d, J = 254.2Hz ),146.7,144.9,143.8(d,J=15.1Hz),142.9,141.4(d,J=4.6Hz),139.6,138.3,130.4,121.1, 120.6, 120.3 (d, J = 10.0 Hz), 118.6, 117.7, 115.4, 113.4, 112.0 (d, J = 20.1 Hz), 110.5, 109.9, 108.2, 96.1, 95.2 (d, J = 3.8 Hz), 44.0 (2C), 40.8, 39.9, 27.6, 12.0 (2C). HRMS(ESI) m / z: Theoretically calculated as C 34 H 33 FN5O2 + [MI] + The mass spectrometry peak at 562.2613 was detected, and the purity measured by HPLC was 96.0%.

[0110] The yield of compound 18a was 68%. 1H NMR (400MHz, CD3OD) δ8.49(d,J=8.5Hz,1H),8.18(s,1H),8.16(d,J=15.6Hz,1H),7.87(d,J=8.5Hz, 1H),7.75(d,J=11.2Hz,1H),7.65(d,J=15.5Hz,1H),7.51(d,J=9.0Hz,1H),7.02(d,J=7.2Hz,1H),6 .82(dd,J=9.0,2.4Hz,1H),6.57(d,J=2.4Hz,1H),4.35(s,3H),3.75(t,J=4.7Hz,4H),3.54(q,J=7. 1Hz, 6H), 2.62 (t, J = 6.8Hz, 2H), 2.56 (t, J = 4.7Hz, 4H), 2.01 (p, J = 6.8Hz, 2H), 1.25 (t, J = 7.1Hz, 6H). 19 F NMR (375MHz, CD3OD) δ-129.8. 13 C NMR (125MHz, DMSO-d6) δ159.3, 156.0, 153.0 (d, J = 1.8Hz), 151.9, 151.0 (d, J = 252.7Hz) ,144.8,143.9(d,J=14.6Hz),141.2(d,J=5.0Hz),139.6,138.2,130.3,120.1(d,J=10.0 Hz), 118.2, 115.1, 113.2, 111.8 (d, J = 20.0 Hz), 109.8, 108.1, 96.0, 94.4 (d, J = 4.6 Hz), 65.8 (2C), 56.0, 53.0 (2C), 44.0 (2C), 41.4, 39.1, 23.8, 12.0 (2C). HRMS(ESI) m / z: Theoretically calculated as C 32 H 38 FN4O3 + [MI] + The mass spectrometry peak at 545.2922 was detected, and the purity was found to be 95.5% by HPLC.

[0111] The yield of compound 19a was 73%. 1H NMR (400MHz, CD3OD) δ8.44(d,J=8.5Hz,1H),8.14(s,1H),8.05(d,J=15.2Hz,1H),7.87(d,J=8.6H z,1H),7.68(d,J=11.1Hz,1H),7.61(d,J=15.4Hz,1H),7.46(d,J=9.0Hz,1H),7.06(d,J=7.0Hz,1H ),6.77(dd,J=9.0,2.4Hz,1H),6.45(d,J=2.4Hz,1H),4.35(s,3H),3.64(t,J=6.7Hz,2H),3.51(q, J=7.0Hz,4H),3.44–3.34(m,6H),2.24(p,J=6.7Hz,2H),2.16–2.06(m,4H),1.24(t,J=7.0Hz,6H). 19 F NMR (375MHz, CD3OD) δ-129.5. 13 C NMR (100MHz, DMSO-d6) δ159.3, 156.0, 153.0 (d, J = 1.7Hz), 151.9, 150.9 (d, J = 254.6Hz) ,144.9,143.7(d,J=15.0Hz),141.2(d,J=4.0Hz),139.5,138.2,130.3,120.1(d,J=9.1H z), 118.1, 115.1, 113.2, 111.9 (d, J = 20.1 Hz), 109.8, 108.1, 96.0, 94.8 (d, J = 3.7 Hz), 52.8 (2C), 52.0, 44.0 (2C), 40.3, 38.6, 24.4, 22.5 (2C), 12.0 (2C). HRMS(ESI) m / z: Theoretically calculated as C 32 H 38 FN4O2 + [MI] + The mass spectrometry peak at 529.2973 was detected, and the purity measured by HPLC was 95.2%.

[0112] The yield of compound 20a was 28%. 1H NMR (500MHz, CD3OD) δ8.49(d,J=8.5Hz,1H),8.18(s,1H),8.15(d,J=15.5Hz,1H),7.95(s,1H),7.89(d, J=8.5Hz,1H),7.74(d,J=11.0Hz,1H),7.65(d,J=15.5Hz,1H),7.50(d,J=9.0Hz,1H),7.33(s,1H),7.12( s,1H),6.92(d,J=7.0Hz,1H),6.81(dd,J=9.0,2.4Hz,1H),6.54(d,J=2.4Hz,1H),4.30(s,3H),4.28(t,J =6.9Hz,2H),3.54(q,J=7.1Hz,4H),3.49(t,J=6.9Hz,2H),2.31(p,J=6.9Hz,2H),1.25(t,J=7.1Hz,6H). 19 F NMR (470MHz, CD3OD) δ-129.8. 13 C NMR (100MHz, DMSO-d6) δ159.4, 156.1, 153.2 (d, J = 1.6Hz), 151.9, 151.0 (d, J = 253.2Hz) ,145.0,143.7(d,J=14.8Hz),141.3(d,J=5.4Hz),139.5,138.3,136.8,130.4,127.2,12 0.2 (d, J = 10.0 Hz), 119.3, 118.4, 115.3, 113.3, 112.0 (d, J = 20.2 Hz), 109.9, 108.1, 96.1, 94.6 (d, J = 4.3 Hz), 44.0 (2C), 43.8, 39.6, 39.3, 28.8, 12.0 (2C). HRMS(ESI) m / z: Theoretically calculated as C 31 H 33 FN5O2 + [MI] + The mass spectrometry peak at 526.2613 was detected, and the purity measured by HPLC was 95.0%.

[0113] The yield of compound 21a was 51%. 1H NMR (500MHz, CD3OD) δ8.44(d,J=8.5Hz,1H),8.16(s,1H),8.09(d,J=15.5Hz,1H),7.86(d,J=8.5Hz,1H),7 .68(d,J=11.0Hz,1H),7.62(d,J=15.5Hz,1H),7.47(d,J=8.9Hz,1H),7.01(d,J=7.0Hz,1H),6.78(dd,J=9 .0,2.4Hz,1H),6.47(d,J=2.4Hz,1H),4.33(s,3H),3.56(t,J=6.8Hz,2H),3.52(q,J=7.1Hz,4H),2.85(t, J=6.8Hz,2H),2.79(q,J=7.1Hz,4H),2.03(p,J=6.8Hz,2H),1.24(t,J=7.1Hz,6H),1.16(t,J=7.1Hz,6H). 19 F NMR (470MHz, CD3OD) δ-129.8. 13 C NMR (100MHz, DMSO-d6) δ159.3, 156.0, 153.0 (d, J = 1.8Hz), 151.9, 151.0 (d, J = 253.1Hz) ,144.9,143.7(d,J=14.6Hz),141.2(d,J=5.0Hz),139.5,138.2,130.3,120.2(d,J=9.8 Hz), 118.2, 115.2, 113.2, 111.9 (d, J = 20.0 Hz), 109.8, 108.1, 96.0, 94.8 (d, J = 4.4 Hz), 49.5, 46.1 (2C), 44.0 (2C), 40.6, 39.4, 23.0, 12.0 (2C), 9.4 (2C). HRMS(ESI) m / z: Theoretically calculated as C 32 H 40 FN4O2 + [MI] + The mass spectrometry peak at 531.3130 was detected, and the purity measured by HPLC was 95.2%.

[0114] The yield of compound 22a was 56%. 1H NMR (500MHz, CD3OD) δ8.48(d,J=8.5Hz,1H),8.18(s,1H),8.12(d,J=15.6Hz,1H),7.90(d,J=8.6H z,1H),7.73(d,J=11.0Hz,1H),7.65(d,J=15.5Hz,1H),7.49(d,J=9.0Hz,1H),7.10(d,J=7.1Hz,1 H),6.80(dd,J=9.0,2.4Hz,1H),6.51(d,J=2.4Hz,1H),4.38(s,3H),3.64(t,J=6.9Hz,2H),3.53( q,J=7.1Hz,4H),3.30(t,J=6.9Hz,2H),2.91(s,6H),2.22(p,J=6.9Hz,2H),1.25(t,J=7.1Hz,6H). 19 F NMR (470MHz, CD3OD) δ-129.7. 13 C NMR (125MHz, DMSO-d6) δ159.6, 156.2, 153.4 (d, J = 1.8Hz), 152.1, 151.2 (d, J = 253.6H z),145.1,144.2(d,J=15.0Hz),141.5(d,J=5.2Hz),139.9,138.4,130.5,120.4(d,J =9.6Hz), 118.7, 115.4, 113.5, 112.1 (d, J = 20.1Hz), 110.1, 108.3, 96.3, 94.7 (d, J = 3.4Hz), 56.4, 44.4 (2C), 44.2 (2C), 41.1, 40.2, 24.9, 12.2 (2C). HRMS(ESI) m / z: Theoretically calculated as C 30 H 36 FN4O2 + [MI] + The mass spectrometry peak at 503.2817 was detected, and the purity measured by HPLC was 96.0%.

[0115] The yield of compound 23a was 69%. 1H NMR (400MHz, CD3OD) δ8.36(d,J=8.5Hz,1H),8.10(s,1H),7.98(d,J=16.0Hz,1H),7. 82(d,J=8.5Hz,1H),7.65–7.52(m,2H),7.41(d,J=8.9Hz,1H),6.93(d,J=7.0Hz,1H), 6.72(dd,J=8.9,2.4Hz,1H),6.36(d,J=2.4,1H),4.26(s,3H),3.72–3.63(m,3H),3.5 4(t,J=6.8Hz,2H),3.48(q,J=7.2Hz,4H),2.02(p,J=6.8Hz,2H),1.28–1.12(m,12H). 19 F NMR (375MHz, CD3OD) δ-130.2. 13 C NMR (125MHz, DMSO-d6) δ159.3, 156.0, 153.0 (d, J = 1.7Hz), 151.9, 150.9 (d, J = 252.5Hz ),144.8,143.8(d,J=15.4Hz),141.2(d,J=3.9Hz),139.5,138.2,130.3,120.1(d,J=10 .7Hz), 118.2, 115.1, 113.2, 111.9 (d, J = 20.0Hz), 109.8, 108.1, 96.0, 94.4 (d, J = 3.9Hz), 70.3, 65.0, 44.0 (2C), 40.1, 39.1, 27.9, 21.7 (2C), 12.0 (2C). HRMS(ESI) m / z: Theoretically calculated as C 31 H 37 FN3O3 + [MI] + The mass spectrometry peak at 518.2813 was detected, and the purity measured by HPLC was 96.5%.

[0116] The yield of compound 24a was 46%. 1H NMR (500MHz, CD3OD) δ8.41(d,J=8.5Hz,1H),8.12(s,1H),8.06(d,J=15.4Hz,1H),7.84(d,J=8.5Hz, 1H),7.64(d,J=11.0Hz,1H),7.60(d,J=15.6Hz,1H),7.44(d,J=8.9Hz,1H),7.14(d,J=7.1Hz,1H),6 .76(dd,J=8.9,2.4Hz,1H),6.44(d,J=2.4Hz,1H),4.30(s,3H),3.84(t,J=5.2Hz,2H),3.72(t,J=5. 2Hz, 2H), 3.68 (t, J = 5.2Hz, 2H), 3.63 (t, J = 5.2Hz, 2H), 3.51 (q, J = 7.1Hz, 4H), 1.24 (t, J = 7.1Hz, 6H). 19 F NMR (470MHz, CD3OD) δ-129.9. 13 C NMR (125MHz, DMSO-d6) δ159.4, 156.1, 153.3 (d, J = 1.7Hz), 152.0, 151.0 (d, J = 251.6 Hz),145.0,144.2(d,J=15.0Hz),141.4(d,J=4.4Hz),139.6,138.3,130.4,120.3(d, J = 10.8 Hz), 118.5, 115.4, 113.4, 112.0 (d, J = 21.3 Hz), 109.9, 108.2, 96.1, 95.3 (d, J = 3.7 Hz), 72.0, 68.4, 60.1, 44.0 (2C), 42.5, 39.9, 12.0 (2C). HRMS(ESI) m / z: Theoretically calculated as C 29 H 33 FN3O4 + [MI] + The mass spectrometry peak at 506.2450 was detected, and the purity measured by HPLC was 96.8%.

[0117] (9) Steps of General Method B for the Preparation of Compounds 25a-34a and Compounds 1b-10b

[0118] Compound 13 (130 mg, 0.2 mmol) or compound 17 (137 mg, 0.2 mol) and the azide (0.4 mmol) were miscible in tert-butanol / water (2.0 mL, 2:1), followed by the addition of CuSO4·5H2O (100 μL, 100 mmol / L) and sodium ascorbate (300 μL, 100 mmol / L). The resulting mixture was stirred overnight at 80 °C. After cooling to room temperature, CH2Cl2 (30 mL) and H2O (10 mL) were added, the organic layer was extracted, and concentrated under reduced pressure. The crude product was purified by rapid column chromatography using MeOH / CH2Cl2 (20:1) elution with 1% NH3·H2O to obtain a red or brownish-black solid as the corresponding target compound.

[0119] The structural formulas of compounds 25a-34a synthesized according to the above method are as follows:

[0120]

[0121] The characterization data of compounds 25a-34a are as follows:

[0122] The yield of compound 25a was 55%. 1 H NMR (500MHz, DMSO-d6) δ8.65(d,J=8.6Hz,1H),8.35(s,1H),8.22(d,J=8.6Hz,1H),8.11(s,1H),8.01–7.85( m,2H),7.79(d,J=15.3Hz,1H),7.47(d,J=9.0Hz,1H),7.39(d,J=7.3Hz,1H),6.74(dd,J=9.0,2.4Hz,1H),6. 46(d,J=2.4Hz,1H),5.54(d,J=9.0Hz,1H),5.37(s,1H),5.30(s,1H),5.17(s,1H),5.06(d,J=5.9Hz,1H),4. 61(s,1H),4.31(s,3H),3.87–3.68(m,5H),3.39–3.18(m,10H),2.67(t,J=4.7Hz,4H),1.15(t,J=7.1Hz,6H). 19 F NMR(375MHz,DMSO-d6)δ-117.0. 13C NMR (125MHz, DMSO-d6) δ159.3, 156.2, 154.4 (d, J = 1.9Hz), 153.6 (d, J = 255.4Hz), 152.6, 152.2, 145. 7(d,J=10.4Hz),145.6,142.6,141.4(d,J=3.9Hz),140.1,137.9,130.6,122.5(d,J=11.2Hz),117.8, 117.6, 114.2 (d, J = 24.1 Hz), 113.1, 110.0, 108.2, 104.8 (d, J = 4.1 Hz), 96.1, 87.3, 79.6, 76.8, 72.0, 69.5, 60.6, 51.9, 51.6 (2C), 49.3 (d, J = 4.4 Hz, 2C), 44.1 (2C), 39.0, 12.0 (2C). HRMS(ESI) m / z: Theoretically calculated as C 38 H 45 FN7O7 + [MI] + The mass spectrometry peak at 730.3359 was detected, and the purity measured by HPLC was 99.2%.

[0123] The yield of compound 26a was 76%. 1 H NMR (400MHz, DMSO-d6) δ8.67(d,J=8.7Hz,1H),8.42(s,1H),8.17(d,J=8.8Hz,1H),8.00(t,J=11.8Hz,2H),7.95(d, J=15.4Hz,1H),7.83(d,J=15.8Hz,1H),7.51(d,J=8.6Hz,1H),7.43(d,J=7.3Hz,1H),7.33(d,J=5.2Hz,1H),6.92(dt ,J=5.2,2.7Hz,1H),6.83(t,J=2.9Hz,1H),6.77(dd,J=9.0,2.4Hz,1H),6.54(d,J=2.4,1H),4.62(t,J=7.2Hz,2H),4 .36(s,3H),3.68(s,2H),3.47(q,J=7.2Hz,6H),3.41(t,J=4.8Hz,4H),2.60(t,J=4.8Hz,4H),1.14(t,J=7.2Hz,6H). 19 F NMR(375MHz,DMSO-d6)δ-117.2. 13C NMR (125MHz, DMSO-d6) δ159.4, 156.3, 154.5 (d, J = 1.8Hz), 153.6 (d, J = 254.1Hz), 152.2, 145.6 (d, J = 9.3Hz, 2C), 141.5 (d, J = 4.6Hz), 140.1, 139.1, 138.0, 135.7, 130.6, 126.5, 125.4, 124.0, 123.6, 122. 6 (d, J = 11.3 Hz), 118.0, 117.8, 114.2 (d, J = 23.4 Hz), 113.2, 110.0, 108.3, 104.9 (d, J = 4.4 Hz), 96.1, 51.8, 51.3 (2C), 50.2, 49.0 (d, J = 5.4 Hz, 2C), 44.1 (2C), 39.9, 29.5, 12.0 (2C). HRMS(ESI) m / z: Theoretically calculated as C 38 H 41 FN7O2S + [MI] + The mass spectrometry peak at 678.3021 was detected, and the purity measured by HPLC was 98.5%.

[0124] The yield of compound 27a was 63%. 1 H NMR (500MHz, CD3OD) δ8.57(d,J=8.7Hz,1H),8.18(s,1H),8.13(d,J=15.5Hz,1H),8.10(d,J=8.6 Hz,1H),8.02(s,1H),7.80(d,J=12.6Hz,1H),7.77(d,J=15.4Hz,1H),7.49(d,J=9.0Hz,1H),7.4 2(d,J=7.1Hz,1H),6.80(d,J=9.0Hz,1H),6.49(s,1H),4.68(t,J=6.5Hz,2H),4.39(s,3H),3.84 (s,2H),3.65–3.43(m,8H),2.92(t,J=6.5Hz,2H),2.82(t,J=4.7Hz,4H),1.25(t,J=7.0Hz,6H). 19 F NMR(375MHz,DMSO-d6)δ-117.2. 13C NMR (125MHz, DMSO-d6) δ171.1, 159.4, 156.3, 154.5 (d, J = 2.5Hz), 153.6 (d, J = 253.7Hz), 152.2, 145.7(d,J=10.2Hz,2C),142.6,141.5(d,J=4.1Hz),140.1,138.0,130.6,123.4,122.6(d,J=12 0Hz), 118.1, 117.8, 114.2 (d, J = 23.4Hz), 113.3, 110.0, 108.3, 104.9 (d, J = 4.0Hz), 96.2, 52.0, 51.5 (2C), 49.3 (d, J = 4.1Hz, 2C), 45.1, 44.1 (2C), 39.9, 34.2, 12.0 (2C). HRMS(ESI) m / z: Theoretically calculated as C 35 H 39 FN7O4 + [MI] + The mass spectrometry peak at 640.3040 was detected, and the purity was 99.0% as determined by HPLC.

[0125] The yield of compound 28a was 69%. 1 H NMR (400MHz, DMSO-d6) δ8.65(d,J=8.4Hz,1H),8.40(s,1H),8.16(d,J=8.7Hz,1H),8.09(s,1H),7.99(d,J=1 3.1Hz,1H),7.94(d,J=15.6Hz,1H),7.82(d,J=15.5Hz,1H),7.49(d,J=9.0Hz,1H),7.41(d,J=7.2Hz,1H),6. 76(dd,J=9.0,2.4Hz,1H),6.52(d,J=2.4,1H),4.41(t,J=7.2Hz,2H),4.34(s,3H),3.68(s,2H),3.54–3.40( m,8H),2.63(t,J=4.7Hz,4H),2.56–2.51(m,2H),2.36(s,6H),2.08(p,J=7.2Hz,2H),1.13(t,J=7.1Hz,6H). 19 F NMR(375MHz,DMSO-d6)δ-117.1. 13C NMR (125MHz, DMSO-d6) δ159.4, 156.3, 154.5 (d, J = 1.6Hz), 153.6 (d, J = 254.9Hz), 152.2, 145.7 (d, J=10.0Hz,2C),142.7,141.5(d,J=3.2Hz),140.1,138.0,130.6,123.4,122.5(d,J=11.4Hz),118. 0, 117.7, 114.2 (d, J = 24.4 Hz), 113.2, 110.1, 108.3, 104.9 (d, J = 3.9 Hz), 96.1, 54.7, 52.0, 51.5 (2C), 49.3 (d, J = 5.1 Hz, 2C), 46.9, 44.1 (2C), 43.5 (2C), 39.9, 26.2, 12.0 (2C). HRMS(ESI) m / z: Theoretically calculated as C 37 H 46 FN8O2 + [MI] + The mass spectrometry peak at 653.3722 was detected, and the purity measured by HPLC was 97.2%.

[0126] The yield of compound 29a was 66%. 1 H NMR (400MHz, DMSO-d6) δ8.65(d,J=8.6Hz,1H),8.40(s,1H),8.16(d,J=8.4Hz,1H),8.13(s,1H),7.99(d,J=13. 1Hz,1H),7.93(d,J=15.4Hz,1H),7.82(d,J=15.6Hz,1H),7.49(d,J=8.9Hz,1H),7.41(d,J=7.4Hz,1H),6.76(dd ,J=8.9,2.4Hz,1H),6.52(d,J=2.4Hz,1H),4.45(t,J=7.3Hz,2H),4.34(s,3H),3.69(s,2H),3.52–3.41(m,8H) ,2.96–2.71(m,6H),2.63(t,J=4.7Hz,4H),2.15(q,J=7.3Hz,2H),1.14(t,J=7.0Hz,6H),1.07(t,J=7.4Hz,6H). 19 F NMR(375MHz,DMSO-d6)δ-117.1. 13C NMR (125MHz, DMSO-d6) δ159.4, 156.3, 154.5 (d, J = 1.7Hz), 153.6 (d, J = 254.2Hz), 152.2, 145.7 (d, J = 1 2.1Hz),145.6,142.7,141.5(d,J=3.3Hz),140.1,138.0,130.6,123.4,122.5(d,J=11.1Hz),118.0,1 17.7, 114.2 (d, J = 23.8 Hz), 113.2, 110.0, 108.3, 104.8 (d, J = 3.4 Hz), 96.1, 52.0, 51.5 (2C), 49.3 (d, J = 5.4 Hz, 2C), 48.1, 46.8, 46.2 (2C), 44.1 (2C), 39.9, 25.0, 12.0 (2C), 9.3 (2C). HRMS(ESI) m / z: Theoretically calculated as C 39 H 50 FN8O2 + [MI] + The mass spectrometry peak at 681.4035 was detected, and the purity measured by HPLC was 96.4%.

[0127] The yield of compound 30a was 72%. 1 H NMR (500MHz, DMSO-d6) δ8.65(d,J=8.7Hz,1H),8.40(s,1H),8.16(d,J=8.4Hz,1H),8.10(s,1H),7.99(d,J=13.0Hz, 1H),7.93(d,J=15.5Hz,1H),7.82(d,J=15.5Hz,1H),7.49(d,J=8.9Hz,1H),7.41(d,J=7.4Hz,1H),6.76(d,J=8.9Hz ,1H),6.52(s,1H),4.41(t,J=7.2Hz,2H),4.34(s,3H),3.69(s,2H),3.54–3.39(m,10H),2.76–2.57(m,6H),2.15–1 .98(m,2H),1.69–1.56(m,1H),1.51–1.37(m,3H),1.35–1.21(m,6H),1.14(t,J=7.0Hz,6H),0.87(t,J=7.3Hz,6H). 19 F NMR(375MHz,DMSO-d6)δ-117.2. 13CNMR(125MHz,DMSO-d6)δ159.3,156.3,154.5(d,J=1.9Hz),153.6(d,J=254.8Hz),152.2,145.7(d,J=10.0H z),145.6,142.6,141.5(d,J=3.7Hz),140.1,138.0,130.6,123.3,122.5(d,J=13.4Hz),118.0,117.7,114. 2 (d, J = 24.1 Hz), 113.2, 110.0, 108.2, 104.8 (d, J = 4.2 Hz), 96.1, 52.5, 51.9, 51.5 (2C), 49.7, 49.3 (d, J = 5.5 Hz, 2C), 46.9 (2C), 44.0 (2C), 40.0, 39.8 (2C), 39.6, 19.4 (2C), 13.2 (2C), 12.0 (2C). HRMS(ESI) m / z: Theoretically calculated as C 43 H 58 FN8O2 + [MI] + The mass spectrometry peak at 737.4661 was detected, and the purity measured by HPLC was 95.9%.

[0128] The yield of compound 31a was 70%. 1 H NMR (400MHz, DMSO-d6) δ8.67(d,J=8.5Hz,1H),8.41(s,1H),8.17(d,J=8.9Hz,1H),8.13(s,1H),8.01(d, J=13.4Hz,1H),7.95(d,J=14.9Hz,1H),7.82(d,J=15.7Hz,1H),7.51(d,J=8.9Hz,1H),7.42(d,J=7.3Hz, 1H),6.78(d,J=9.0Hz,1H),6.54(s,1H),4.49(t,J=7.1Hz,2H),4.35(s,3H),3.69(s,2H),3.59–3.41(m, 10H),3.13–2.91(m,4H),2.74–2.57(m,4H),2.30–2.17(m,2H),1.95–1.80(m,4H),1.14(t,J=7.3Hz,6H). 19 F NMR(375MHz,DMSO-d6)δ-117.1. 13C NMR (125MHz, DMSO-d6) δ159.3, 156.3, 154.5 (d, J = 1.7Hz), 153.6 (d, J = 254.1Hz), 152.2, 145.6 (d, J = 9.4Hz,2C),142.7,141.5(d,J=3.4Hz),140.1,138.0,130.6,123.4,122.5(d,J=10.7Hz),118.0,117 .7,114.2(d,J=23.8Hz),113.2,110.0,108.3,104.8(d,J=3.4Hz),96.2,52.7(2C),52.0,51.5(2C),51.1,49.3(d,J=4.2Hz,2C),46.7,44.1(2C),39.9,22.5(2C),21.9,12.0(2C).HRMS(ESI) m / z: Theoretically calculated as C 39 H 48 FN8O2 + [MI] + The mass spectrometry peak at 679.3877 was detected, and the purity measured by HPLC was 95.7%.

[0129] The yield of compound 32a was 76%. 1 H NMR (400MHz, DMSO-d6) δ8.66(d,J=8.5Hz,1H),8.40(s,1H),8.16(d,J=8.8Hz,1H),8.12(s,1H),7.99(d,J=15 .6Hz,1H),7.93(d,J=15.8Hz,1H),7.81(d,J=15.7Hz,1H),7.50(d,J=8.9Hz,1H),7.41(d,J=7.3Hz,1H),6.76 (d,J=8.9Hz,1H),6.52(s,1H),4.46(t,J=7.1Hz,2H),4.34(s,3H),3.69(s,2H),3.53–3.41(m,10H),2.93–2. 70(m,4H),2.68–2.59(m,4H),2.31–2.10(m,2H),1.76–1.60(m,4H),1.54–1.39(m,2H),1.15(t,J=7.1Hz,6H). 19 F NMR(375MHz,DMSO-d6)δ-117.1. 13C NMR (125MHz, DMSO-d6) δ159.3, 156.3, 154.5 (d, J = 1.8Hz), 153.6 (d, J = 254.4Hz), 152.2, 145.7 (d, J = 11 .2Hz),145.6,142.6,141.5(d,J=4.7Hz),140.1,138.0,130.6,123.4,122.5(d,J=10.6Hz),118.0,117. 7,114.2 (d, J = 23.8 Hz), 113.2, 110.0, 108.3, 104.8 (d, J = 3.7 Hz), 96.1, 53.5, 52.4 (2C), 52.0, 51.5 (2C), 49.2 (d, J = 6.0 Hz, 2C), 46.8, 44.1 (2C), 39.9, 24.8, 22.9 (2C), 21.9, 12.0 (2C). HRMS(ESI) m / z: Theoretically calculated as C 40 H 50 FN8O2 + [MI] + The mass spectrometry peak at 693.4034 was detected, and the purity measured by HPLC was 99.1%.

[0130] The yield of compound 33a was 71%. 1 H NMR (400MHz, DMSO-d6) δ8.65(d,J=8.7Hz,1H),8.40(s,1H),8.16(d,J=8.7Hz,1H),8.11(s,1H), 7.98(d,J=13.1Hz,1H),7.93(d,J=15.4Hz,1H),7.81(d,J=15.5Hz,1H),7.48(d,J=8.9Hz,1H),7. 41(d,J=7.4Hz,1H),6.75(d,J=9.0Hz,1H),6.51(s,1H),4.43(t,J=7.1Hz,2H),4.34(s,3H),3.8 5–3.56(m,6H),3.55–3.36(m,12H),2.77–2.53(m,6H),2.18–2.02(m,2H),1.14(t,J=7.0Hz,6H). 19 F NMR(375MHz,DMSO-d6)δ-117.2. 13C NMR (125MHz, DMSO-d6) δ159.3, 156.3, 154.5 (d, J = 1.7Hz), 153.6 (d, J = 255.8Hz), 152.2, 145.6 (d, J = 10.5Hz,2C),142.1,141.5(d,J=4.4Hz),140.1,138.0,130.6,123.6,122.6(d,J=10.3Hz),117.9,117 .8,114.2 (d,J=23.3Hz),113.2,110.0,108.3,104.9 (d,J=3.3Hz),96.1,65.0 (2C),54.1,52.3 (2C),51.8,51.4 (2C),49.0 (d,J=4.3Hz,2C),47.0,44.1 (2C),39.9,25.5,12.0 (2C). HRMS(ESI) m / z: Theoretically calculated as C 39 H 48 FN8O3 + [MI] + The mass spectrometry peak at 695.3828 was detected, and the purity measured by HPLC was 96.3%.

[0131] The yield of compound 34a was 68%. 1 H NMR (500MHz, DMSO-d6) δ8.71(d,J=8.7Hz,1H),8.45(s,1H),8.17(d,J=8.7Hz,1H),8.07–8.03(m,2H),8.02( d,J=4.7Hz,1H),7.84(d,J=15.6Hz,1H),7.55(d,J=9.0Hz,1H),7.49(d,J=7.4Hz,1H),6.82(dd,J=9.0,2.4H z,1H),6.59(d,J=2.4Hz,1H),4.43(t,J=7.1Hz,2H),4.40(s,3H),3.83(s,2H),3.58(t,J=4.9Hz,4H),3.52( q,J=7.0Hz,4H),3.45(t,J=6.2Hz,2H),2.80(t,J=4.9Hz,4H),2.01(p,J=6.7Hz,2H),1.19(t,J=7.0Hz,6H). 19 F NMR(375MHz,DMSO-d6)δ-117.2. 13C NMR (125MHz, DMSO-d6) δ159.3, 156.3, 154.6 (d, J = 2.9Hz), 153.6 (d, J = 250.3Hz), 152.2 ,145.6,145.5(d,J=11.5Hz),142.0,141.5(d,J=4.3Hz),140.1,137.9,130.6,123.8,1 22.6 (d, J = 11.5 Hz), 117.9, 117.8, 114.2 (d, J = 23.5 Hz), 113.2, 110.0, 108.3, 105.0 (d, J = 5.6 Hz), 96.1, 57.3, 51.6, 48.7, 46.3, 44.1, 39.9, 32.5, 12.0. HRMS(ESI) m / z: Theoretically calculated as C 35 H 41 FN7O3 + [MI] + The mass spectrometry peak at 626.3249 was detected, and the purity measured by HPLC was 99.4%.

[0132] The structural formulas of compounds 1b–10b synthesized according to the above synthetic method are as follows:

[0133]

[0134] The characterization data of compounds 1b-10b are as follows:

[0135] The yield of compound 1b was 53%. 1 H NMR (500MHz, DMSO-d6) δ8.33(s,1H),8.27(s,1H),7.83(d,J=15.5Hz,1H),7.59(d,J=13.3Hz,2H),7.55(d,J=15.3Hz,1H ),7.48(d,J=8.9Hz,1H),7.17(d,J=7.4Hz,2H),6.75(d,J=8.9Hz,1H),6.52(s,1H),5.53(d,J=9.1Hz,1H),5.20(s,1H), 5.10(s,1H),4.97(s,1H),4.72(d,J=5.8Hz,2H),4.35(s,1H),4.05(s,3H),3.79(t,J=9.3Hz,1H),3.73–3.64(m,5H),3. 57–3.40(m,6H),3.31(t,J=9.1Hz,1H),3.26(t,J=8.4Hz,1H),2.69(t,J=4.7Hz,4H),2.36(s,3H),1.18(t,J=7.1Hz,6H). 19F NMR(470MHz,DMSO-d6)δ-129.6. 13 C NMR (125MHz, DMSO-d6) δ159.4,158.3(d,J=3.6Hz),155.8,152.5,151.6,149.2(d,J=249.0Hz ),144.4,143.1,141.9(d,J=14.3Hz),140.2,136.5,130.0,122.2,119.4,113.5,110.5(d,J=8 0Hz), 109.7, 109.3 (d, J = 21.3Hz), 108.0, 103.6, 96.8 (d, J = 4.4Hz), 96.0, 87.3, 79.6, 76.8, 69.5, 60.6, 53.7 (2C), 50.8 (2C), 44.7, 43.9 (2C), 37.9, 37.4, 12.0 (2C). HRMS(ESI) m / z: Theoretically calculated as C 39 H 48 FN8O7 + [MI] + The mass spectrometry peak at 759.3625 was detected, and the purity measured by HPLC was 98.2%.

[0136] The yield of compound 2b was 63%. 1 H NMR (500MHz, DMSO-d6) δ8.31(s,1H),8.07(s,1H),7.85(d,J=15.6Hz,1H),7.63(d,J=12.4Hz,1H),7.56(t,J= 5.7Hz,1H),7.54(d,J=8.9Hz,1H),7.51(d,J=3.1Hz,1H),7.18(d,J=6.4Hz,2H),6.79(dd,J=8.9,2.5Hz,1H),6 .57(d,J=2.5Hz,1H),4.69(d,J=5.7Hz,2H),4.60(t,J=6.7Hz,2H),4.05(s,3H),3.67(t,J=4.7Hz,4H),3.58(s ,3H),3.50(q,J=7.0Hz,4H),2.97(t,J=6.7Hz,2H),2.63(t,J=4.7Hz,4H),2.33(s,3H),1.19(t,J=7.0Hz,6H). 19 F NMR (375MHz, CD3OD) δ-131.5. 13C NMR(125MHz,DMSO-d6)δ170.2 159.4,158.4(d,J=3.6Hz),155.9,152.5,151.7,149.2(d,J=248.9Hz),144.5,143 .2,141.9(d,J=14.4Hz),140.2,136.5,130.0,123.0,119.6,113.6,110.4(d,J=7.8 Hz), 109.7, 109.4 (d, J = 21.6 Hz), 108.0, 103.5, 96.8 (d, J = 4.5 Hz), 96.1, 53.8 (2C), 51.0 (3C), 44.9 (2C), 43.9 (2C), 37.8, 37.5, 33.5, 12.0 (2C). HRMS(ESI) m / z: Theoretically calculated as C 37 H 44 FN8O4 + [MI] + The mass spectrometry peak at 683.3460 was detected, and the purity measured by HPLC was 96.1%.

[0137] The yield of compound 3b was 66%. 1 H NMR (500MHz, DMSO-d6) δ8.32(s,1H),8.12(s,1H),7.86(dd,J=15.6,5.4Hz,2H),7.64(d,J=12.3Hz,1H),7.57(d,J=15. 6Hz,1H),7.52(d,J=8.9Hz,1H),7.21(s,1H),7.16(d,J=7.5Hz,1H),6.79(dd,J=8.9,2.4Hz,1H),6.59(d,J=2.4Hz,1H), 4.68(d,J=5.4Hz,2H),4.38(t,J=6.9Hz,2H),4.04(s,3H),3.78–3.61(m,4H),3.53(t,J=4.7Hz,4H),3.49(q,J=7.0Hz,4 H),2.87–2.72(m,2H),2.50(s,3H),2.47–2.39(m,2H),2.37–2.16(m,6H),1.98(p,J=6.9Hz,2H),1.15(t,J=7.0Hz,6H). 19 F NMR(470MHz,DMSO-d6)δ-129.6. 13C NMR(125MHz,DMSO-d6)δ159.8,158.6(d,J=3.8Hz),156.2,152.9,151.8,149.6(d,J=248.4Hz), 145.3,143.5,142.1(d,J=14.3Hz),140.4,137.2,130.5,123.5,119.7,113.6,110.6(d,J=7.4Hz ), 110.0, 109.7 (d, J = 21.1 Hz), 108.2, 104.0, 96.9 (d, J = 3.8 Hz), 96.2, 65.8 (2C), 54.6 (2C), 53.7, 52.9 (2C), 50.5, 47.5 (2C), 44.3 (2C), 38.3 (2C), 37.5, 26.3, 12.4 (2C). HRMS(ESI) m / z: Theoretically calculated as C 40 H 51 FN9O3 + [MI] + The mass spectrometry peak at 724.4093 was detected, and the purity measured by HPLC was 98.2%.

[0138] The yield of compound 4b was 59%. 1 H NMR (500MHz, DMSO-d6) δ8.33(s,1H),8.18(s,1H),7.84(dd,J=15.6,4.5Hz,2H),7.60(d,J=12.3Hz,1H),7.54(d, J=15.6Hz,1H),7.50(d,J=8.8Hz,1H),7.17(s,1H),7.14(d,J=7.5Hz,1H),6.77(dd,J=9.0,2.4Hz,1H),6.56(d,J =2.4Hz,1H),4.68(d,J=4.5Hz,2H),4.44(t,J=6.9Hz,2H),4.03(s,3H),3.69–3.60(m,4H),3.54–3.43(m,6H),2. 98–2.72(m,4H),2.60(t,J=4.7Hz,4H),2.30(s,3H),2.18–2.08(m,2H),1.87–1.71(m,4H),1.15(t,J=6.9Hz,6H). 19 F NMR(470MHz,DMSO-d6)δ-129.7. 13C NMR(125MHz,DMSO-d6)δ159.8,158.6(d,J=3.6Hz),156.1,152.8,151.8,149.4(d,J=248.4Hz),1 45.2,143.6,142.0(d,J=13.1Hz),140.4,137.0,130.5,123.6,119.7,113.5,110.5(d,J=7.9Hz) ,110.0,109.8(d,J=21.5Hz),108.2,103.7,96.9(d,J=3.8Hz),96.2,57.1,54.2,53.1(2C),51.4,51.3,47.6,47.1,45.4,44.3(2C),38.3,37.5,22.8(2C),22.1,12.4(2C).HRMS(ESI)m / z: Theoretically calculated as C 40 H 51 FN9O2 + [MI] + The mass spectrometry peak at 708.4144 was detected, and the purity measured by HPLC was 98.2%.

[0139] The yield of compound 5b was 51%. 1 H NMR (400MHz, DMSO-d6) δ8.25(s,1H),8.18(s,1H),7.79(d,J=5.4Hz,1H),7.59(d,J=15.6Hz,1H),7.39(d, J=15.6Hz,1H),7.13(d,J=12.4Hz,1H),7.00(d,J=8.6Hz,1H),6.91–6.80(m,2H),6.44(d,J=8.6,2.3Hz,1 H),6.11(d,J=2.3Hz,1H),4.59(d,J=5.4Hz,2H),4.55(t,J=6.6Hz,2H),3.89(s,3H),3.47(t,J=4.7Hz,4H ),3.37(q,J=7.1Hz,4H),2.73(t,J=6.6Hz,2H),2.55(t,J=4.7Hz,4H),2.28(s,3H),1.11(t,J=7.1Hz,6H). 19 F NMR(375MHz,DMSO-d6)δ-129.5. 13C NMR (125MHz, DMSO-d6) δ171.8,159.4,158.3(d,J=3.2Hz),155.7,152.3,151.6,149.1(d,J =248.9Hz),144.3,142.9,141.9(d,J=14.5Hz),140.1,136.4,130.0,123.0,119.3,113.5,1 10.4 (d, J = 7.6 Hz), 109.6, 109.1 (d, J = 21.8 Hz), 108.0, 103.4, 96.8 (d, J = 3.3 Hz), 95.9, 53.9 (2C), 51.0 (2C), 46.3, 45.0, 43.9 (2C), 37.8, 37.5, 35.9, 12.0 (2C). HRMS(ESI) m / z: Theoretically calculated as C 36 H 42 FN8O4 + [MI] + The mass spectrometry peak at 669.3308 was detected, and the purity measured by HPLC was 96.7%.

[0140] The yield of compound 6b was 76%. 1 H NMR (400MHz, CD3OD) δ8.15(s,1H),7.96–7.84(m,2H),7.52(d,J=15.5Hz,1H),7.47(d,J=12.1Hz,1H),7.39(d ,J=9.0Hz,1H),7.15(s,1H),7.01(dd,J=4.6,1.8Hz,1H),6.95(d,J=7.3Hz,1H),6.73(dd,J=9.0,2.3Hz,1H),6 .70(t,J=3.3Hz,1H),6.69(s,1H),6.35(d,J=2.3Hz,1H),4.67(t,J=6.7Hz,4H),3.97(s,3H),3.66(t,J=4.7Hz ,4H),3.51(q,J=7.1Hz,4H),3.44(t,J=6.7Hz,2H),2.80(t,J=4.7Hz,4H),2.47(s,3H),1.24(t,J=7.1Hz,6H). 19 F NMR(375MHz,DMSO-d6)δ-129.7. 13C NMR(100MHz,DMSO-d6)δ159.8,158.6(d,J=3.9Hz),156.1,152.7,151.8,149.4(d,J=249.8Hz),1 45.2,143.5,141.9(d,J=15.1Hz),140.3,139.4,137.0,130.5,126.8,125.8,124.4,123.5,119. 6, 113.5, 110.5 (d, J = 7.9 Hz), 109.9, 109.7 (d, J = 22.2 Hz), 108.1, 103.7, 96.9 (d, J = 2.9 Hz), 96.1, 54.2 (2C), 51.2 (2C), 50.5, 45.4, 44.3 (2C), 38.2, 37.5, 29.8, 12.4 (2C). HRMS(ESI) m / z: Theoretically calculated as C 39 H 44 FN8O2S + [MI] + The mass spectrometry peak at 707.3285 was detected, and the purity measured by HPLC was 96.7%.

[0141] The yield of compound 7b was 59%. 1 H NMR (400MHz, CD3OD) δ8.18(s,1H),8.10(s,1H),7.73(d,J=15.5Hz,1H),7.45(d,J=15.5Hz,1H),7.21(d,J=3.5Hz,1H) ,7.18(d,J=6.5Hz,1H),6.99(s,1H),6.93(d,J=7.4Hz,1H),6.59(dd,J=9.0,2.4Hz,1H),6.02(d,J=2.4Hz,1H),4.70( s,2H),4.54(t,J=6.9Hz,2H),3.99(s,3H),3.61(t,J=4.7Hz,4H),3.45(q,J=7.0Hz,4H),2.75(t,J=4.7Hz,4H),2.67– 2.49(m,6H),2.45(s,3H),2.21(p,J=6.9Hz,2H),1.63(p,J=5.7Hz,4H),1.48(q,J=5.7Hz,2H),1.22(t,J=7.0Hz,6H). 19 F NMR (375MHz, CD3OD)δ-131.2. 13C NMR (100MHz, CD3OD) δ161.7,160.5(d,J=4.2Hz),157.3,154.3,153.7,151.2(d,J=249.2Hz),14 6.9,145.4,143.7(d,J=14.3Hz),141.7,138.7,131.6,125.0,120.5,114.5,113.0(d,J=7.7Hz) ,111.2,110.4(d,J=21.2Hz),109.6,105.1,97.8(d,J=3.8Hz),97.0,56.5,55.7(2C),55.2(3C),52.9(2C),46.1,46.0(2C),39.3,38.8,27.6,26.0(2C),24.5,12.9(2C).HRMS(ESI)m / z: Theoretically calculated as C 41 H 53 FN9O2 + [MI] + The mass spectrometry peak at 722.4301 was detected, and the purity measured by HPLC was 97.8%.

[0142] The yield of compound 8b was 63%. 1 H NMR (400MHz, CD3OD) δ8.27(s,1H),8.02(s,1H),7.55(d,J=15.5Hz,1H),7.35(d,J=15.5Hz,1H),7.04(d,J=8.9Hz, 1H),6.99(d,J=12.1Hz,1H),6.86(s,1H),6.80(d,J=7.4Hz,1H),6.47(dd,J=9.0,2.4Hz,1H),5.81(d,J=2.4Hz,1H ),4.66(s,2H),4.60(t,J=6.9Hz,2H),3.90(s,3H),3.57(t,J=4.9Hz,4H),3.39(q,J=7.2Hz,4H),2.87(q,J=7.1Hz ,6H),2.73(t,J=4.9Hz,4H),2.45(s,3H),2.27(p,J=7.0Hz,2H),1.19(t,J=7.0Hz,6H),1.13(t,J=7.2Hz,6H).19F NMR(375MHz,CD3OD)δ-130.9. 13CNMR(100MHz,CD3OD)δ161.4,160.1(d,J=3.2Hz),157.0,153.8,153.6,150.9(d,J=249.8Hz),146. 7,145.3,143.4(d,J=13.7Hz),141.4,138.5,131.4,125.2,120.1,114.2,112.7(d,J=8.5Hz),111. 2,110.3 (d, J = 22.8 Hz), 109.3, 104.9 (d, J = 3.1 Hz), 97.8 (d, J = 5.3 Hz), 96.8, 55.7 (2C), 53.0 (2C), 50.3 (2C), 48.2 (2C), 46.2, 45.9 (2C), 39.4, 38.7, 27.1, 13.0 (2C), 10.5 (2C). HRMS(ESI) m / z: Theoretically calculated as C 40 H 53 FN9O2 + [MI] + The mass spectrometry peak at 710.4301 was detected, and the purity measured by HPLC was 97.9%.

[0143] The yield of compound 9b was 71%. 1 H NMR (400MHz, CD3OD) δ8.20(s,1H),8.11(s,1H),7.77(d,J=15.5Hz,1H),7.48(d,J=15.5Hz,1H),7.24(s,1H),7.21(d,J=3.6Hz, 1H),7.02(s,1H),6.97(d,J=7.4Hz,1H),6.61(dd,J=9.0,2.4Hz,1H),6.06(d,J=2.4Hz,1H),4.71(s,2H),4.54(t,J=6.9Hz,2H), 4.02(s,3H),3.62(t,J=4.9Hz,4H),3.46(q,J=7.0Hz,4H),2.75(t,J=4.9Hz,4H),2.71(t,J=7.5Hz,2H),2.62(t,J=7.4Hz,4H), 2.45(s,3H),2.20(p,J=7.5,6.9Hz,2H),1.53–1.37(m,4H),1.29(p,J=7.4Hz,4H),1.23(t,J=7.0Hz,6H),0.90(t,J=7.4Hz,6H). 19 FNMR (375MHz, CD3OD) δ-131.3. 13C NMR (100MHz, CD3OD) δ161.8,160.6(d,J=4.2Hz),157.4,154.5,153.7,150.1(d,J=248.8Hz),,146. 9,145.4,143.7(d,J=14.0Hz),141.7,138.8,131.6,125.1,120.6,114.6,113.0(d,J=8.0Hz),111.3 ,110.5 (d, J = 22.1 Hz), 109.7, 105.3, 97.8 (d, J = 4.6 Hz), 97.0, 55.7 (2C), 54.6 (3C), 52.9 (2C), 51.5, 46.1, 46.0 (2C), 39.3, 38.7, 28.8 (2C), 27.5, 21.5 (2C), 14.3 (2C), 12.9 (2C). HRMS(ESI) m / z: Theoretically calculated as C 44 H 61 FN9O2 + [MI] + The mass spectrometry peak at 766.4927 was detected, and the purity measured by HPLC was 95.4%.

[0144] The yield of compound 10b was 74%. 1 H NMR(500MHz,DMSO-d6)δ8.31(s,1H),8.06(s,1H),7.85(d,J=15.6Hz,1H),7.62(d,J=12.3Hz,1H),7.57(s,1H),7 .54(d,J=12.9Hz,1H),7.51(d,J=5.7Hz,1H),7.20(d,J=7.5Hz,1H),7.17(s,1H),6.79(d,J=8.9Hz,1H),6.57(s, 1H),4.69(d,J=4.1Hz,2H),4.36(t,J=7.1Hz,2H),4.05(s,3H),3.66(t,J=4.8Hz,4H),3.50(q,J=7.0Hz,4H),2.6 0(t,J=4.8Hz,4H),2.31(s,3H),2.19(t,J=6.9Hz,2H),2.09(s,6H),1.94(p,J=7.1Hz,2H),1.19(t,J=7.0Hz,6H). 13C NMR (125MHz, DMSO-d6) δ159.4,158.4(d,J=4.0Hz),155.9,152.5,151.7,149.2(d,J=24 8.7Hz),144.5,143.1,141.9(d,J=14.7Hz),140.2,136.4,130.0,122.8,119.6,113.6,1 10.3(d,J=8.1Hz),109.7,109.4(d,J=21.7Hz),108.0,103.5,96.8(d,J=4.4Hz),96.1,5 5.4,53.9(2C),51.1(2C),47.3,45.0,44.5(2C),43.9(2C),37.8,37.6,27.4,12.0(2C). 19 F NMR (375MHz, DMSO-d6) δ -129.7. HRMS (ESI) m / z: Theoretically calculated as C 38 H 49 FN9O2 + [MI] + The mass spectrometry peak at 682.3988 was detected, and the purity measured by HPLC was 99.5%.

[0145] (10) Steps of the general method C for preparing 11b-16b

[0146] Compounds 4-9 (0.5 mmol), 7-N,N-diethylaminocoumarin-3-aldehyde (147 mg, 0.6 mmol), and a catalytic amount of piperidine were mixed in n-butanol (3.0 mL), and the mixture was refluxed and stirred for 24 hours. After cooling to room temperature, the crude product was extracted with CH2Cl2 (30 mL) and purified by rapid column chromatography using MeOH / CH2Cl2 (v / v ratio 15:1) eluted with 1% NH3·H2O to obtain the corresponding target compound as a red solid.

[0147] The structural formulas of compounds 11b-16b synthesized according to the above method are as follows:

[0148]

[0149] The characterization data of compounds 11b-16b are as follows:

[0150] The yield of compound 11b was 65%. 1H NMR (400MHz, CD3OD) δ8.19(s,1H),7.87(d,J=15.5Hz,1H),7.57(d,J=15.5Hz,1H),7.48(d,J=14.0 Hz,1H),7.40(d,J=9.0Hz,1H),7.21(s,1H),7.20(d,J=7.6Hz,1H),6.75(dd,J=9.0,2.4Hz,1H),6. 34(d,J=2.4Hz,1H),4.13(s,3H),3.72(t,J=5.0Hz,4H),3.52(q,J=7.0Hz,4H),3.43(d,J=5.1Hz,4 H),2.76(t,J=5.0Hz,4H),2.69(t,J=5.1Hz,6H),2.45(s,3H),2.41(s,3H),1.26(t,J=7.0Hz,6H). 19 FNMR (375MHz, CD3OD) δ -119.5. 13 C NMR(125MHz,DMSO-d6)δ159.4,158.0(d,J=3.2Hz),155.9,153.1,151.8(d,J=250.8Hz) ,151.7,144.8,144.5(d,J=10.0Hz),139.2,137.3,130.1,119.1,113.4(d,J=9.0Hz,2C) ,111.6 (d, J = 25.0 Hz), 109.8, 108.0, 105.2 (d, J = 3.8 Hz), 104.1, 96.0, 53.9 (4C), 51.1 (2C), 48.9 (d, J = 5.3 Hz, 2C), 45.2, 45.0, 44.0 (2C), 37.9, 12.0 (2C). HRMS(ESI) m / z: Theoretically calculated as C 35 H 44 FN6O2 + [MI] + The mass spectrometry peak at 599.3504 was detected, and the purity measured by HPLC was 97.5%.

[0151] The yield of compound 12b was 57%. 1H NMR (400MHz, CD3OD) δ8.18(s,1H),7.87(d,J=15.5Hz,1H),7.75(d,J=15.9Hz,1H),7.47(s,1H),7.44(d,J=6.4Hz, 1H),6.99(s,1H),6.96(d,J=8.1Hz,1H),6.79(dd,J=9.0,2.4Hz,1H),6.48(d,J=2.4Hz,1H),4.14–4.06(m,4H),4. 05(s,3H),3.82–3.77(m,2H),3.69(t,J=6.1Hz,2H),3.53(q,J=7.0Hz,4H),3.15(t,J=3.6Hz,2H),3.11–3.05(m,2 H),3.03–2.97(m,2H),2.88(t,J=4.8Hz,2H),2.63(s,3H),2.53(s,3H),2.30–2.15(m,4H),1.25(t,J=7.0Hz,6H). 19 F NMR (375MHz, CD3OD)δ-122.4. 13 C NMR(125MHz,DMSO-d6)δ159.4,156.7(d,J=2.7Hz),155.8,151.5(2C),149.0(d,J=249.3Hz ),144.2,143.2(d,J=10.9Hz),139.8,135.6,129.9,119.9,113.6,113.2(d,J=26.9Hz),109 .7 (d, J = 5.2 Hz, 2C), 108.0, 101.2 (d, J = 5.0 Hz), 100.7, 96.0, 56.8, 56.6, 55.7, 55.1, 52.4, 52.3, 50.0, 49.7, 45.0, 44.9, 43.9 (2C), 37.5, 26.3, 26.0, 12.0 (2C). HRMS(ESI) m / z: Theoretically calculated as C 37 H 48 FN6O2 + [MI] + The mass spectrometry peak at 627.3817 was detected, and the purity measured by HPLC was 95.6%.

[0152] The yield of compound 13b was 25%. 1H NMR (400MHz, DMSO-d6) δ8.69(s,1H),8.34(s,1H),8.33(d,J=12.8Hz,1H),7.78(d,J=15.5Hz,1H),7. 59(d,J=15.5Hz,1H),7.45(d,J=9.0Hz,1H),7.13(s,1H),6.93(d,J=7.7Hz,1H),6.89(s,1H),6.73(dd ,J=8.9,2.4Hz,1H),6.50(d,2.4Hz,1H),4.01(s,3H),3.94–3.85(m,2H),3.72(t,J=7.4Hz,2H),3.45( q,J=7.5,7.2Hz,6H),3.35–3.24(m,6H),3.23–3.10(m,6H),2.04–1.76(m,6H),1.13(t,J=7.2Hz,6H). 19 F NMR(375MHz,DMSO-d6)δ-131.2. 13 C NMR (125MHz, DMSO-d6) δ159.5, 155.8, 153.0, 152.5 (d, J = 3.8Hz), 151.5, 149.6 (d, J = 247. 3Hz),144.3,141.6(d,J=14.1Hz),138.9,135.8,129.9,120.0,113.7,109.7,108.0,107.7 (d,J=21.8Hz), 107.2(d,J=7.8Hz), 96.6(d,J=3.8Hz), 96.1, 95.7, 53.1(2C), 53.0(2C), 52.3(2C), 52.1(2C), 43.9(2C), 37.6, 22.5(2C), 22.4(2C), 12.0(2C). HRMS(ESI) m / z: Theoretically calculated as C 37 H 48 FN6O2 + [MI] + The mass spectrometry peak at 627.3817 was detected, and the purity measured by HPLC was 95.1%.

[0153] The yield of compound 14b was 27%. 1H NMR (400MHz, CD3OD) δ8.15(s,1H),7.93(d,J=2.1Hz,1H),7.90(s,1H),7.48(d,J=8.9Hz, 1H),7.40(d,J=15.6Hz,1H),6.84(t,J=4.5Hz,2H),6.80(dd,J=9.0,2.4Hz,1H),6.56(d, J=2.4Hz,1H),4.03(s,3H),3.77–3.69(m,8H),3.67(t,J=6.8Hz,2H),3.53(q,J=7.0Hz,4 H),3.47(t,J=6.5Hz,2H),2.66–2.44(m,12H),2.07–1.93(m,4H),1.25(t,J=7.0Hz,6H). 19 F NMR(470MHz,DMSO-d6)δ-132.3. 13 C NMR (125MHz, DMSO-d6) δ159.5, 155.8 (d, J = 1.5Hz), 152.7 (2C), 151.5, 149.6 (d, J = 246. 1Hz),143.7,142.2(d,J=12.1Hz),139.0,135.0,129.9,120.6,113.7,109.7,107.9,107 .0 (d, J = 21.8 Hz), 106.3 (d, J = 6.2 Hz), 96.1, 95.7 (d, J = 3.8 Hz), 95.5, 65.7 (4C), 55.9, 55.1, 52.9 (4C), 43.9 (2C), 41.0, 40.8, 37.1, 24.6, 23.9, 12.0 (2C). HRMS(ESI) m / z: Theoretically calculated as C 39 H 52 FN6O4 + [MI] + The mass spectrometry peak at 687.4029 was detected, and the purity measured by HPLC was 95.3%.

[0154] The yield of compound 15b was 21%. 1H NMR (400MHz, DMSO-d6) δ8.98(s,1H),8.46(d,J=13.2Hz,1H),8.34(s,1H),7.99(s,1H),7.89(s,1H),7.69(d,J=15.4H z,1H),7.51–7.40(m,2H),7.37(d,J=16.4Hz,2H),7.11(d,J=5.8Hz,1H),6.99(d,J=9.3Hz,2H),6.67(d,J=8.9Hz,1H), 6.59(d,J=9.5Hz,2H),6.41(s,1H),4.22(t,J=6.6Hz,2H),4.15(t,J=6.8Hz,2H),3.85(s,3H),3.54(t,J=7.3Hz,2H), 3.41(t,J=6.9Hz,4H), 3.30(t,J=6.9Hz,2H), 2.19(p,J=7.3,6.6Hz,2H), 2.12(p,J=6.8Hz,2H), 1.12(t,J=6.9Hz,6H). 19 F NMR(375MHz,DMSO-d6)δ-131.5. 13 C NMR (100MHz, DMSO-d6) δ159.8,155.8(d,J=1.6Hz),152.6,152.5,151.5,149.6(d,J=246.2H z),144.9,141.9(d,J=14.3Hz),138.9,137.3,137.2,135.7,130.2,127.6,127.4,120.1,11 9.8, 119.7, 113.6, 109.7, 108.1 (d, J = 21.1 Hz), 108.0, 106.7 (d, J = 8.4 Hz), 95.9, 95.6 (d, J = 4.8 Hz), 95.1, 44.3 (2C), 44.1 (3C), 43.4, 37.4, 29.6, 29.2, 12.4 (2C). HRMS(ESI) m / z: Theoretically calculated as C 37 H 42 FN8O2 + [MI] + The mass spectrometry peak at 649.3409 was detected, and the purity measured by HPLC was 95.2%.

[0155] The yield of compound 16b was 28%. 1H NMR (400MHz, DMSO-d6) δ8.88(s,1H),8.36(s,1H),8.31(d,J=12.4Hz,1H),7.73(d,J=15 .3Hz,1H),7.52(d,J=15.5Hz,1H),7.41(d,J=8.8Hz,1H),7.18(s,1H),6.78(d,J=6.8Hz ,2H),6.70(d,J=8.8Hz,1H),6.45(s,1H),3.94(s,3H),3.70–3.63(m,2H),3.57–3.34(m ,8H),3.13–2.92(m,10H),2.15–1.96(m,4H),1.93–1.77(m,8H),1.13(t,J=7.1Hz,6H). 19 F NMR(375MHz,DMSO-d6)δ-131.9. 13 C NMR (125MHz, DMSO-d6) δ159.5,155.7(d,J=1.5Hz),152.7,152.6,151.5,149.5(d,J=24 6.2Hz),144.2,142.0(d,J=14.6Hz),138.9,135.4,129.8,120.2,113.7,109.6,108.0,1 07.5 (d, J = 21.3 Hz), 106.6 (d, J = 8.2 Hz), 96.0 (d, J = 4.8 Hz, 2C), 95.4, 52.7 (4C), 52.1, 51.8, 43.9 (2C), 40.4, 40.1, 37.3, 25.0, 24.7, 22.6 (4C), 12.0 (2C). HRMS(ESI) m / z: Theoretically calculated as C 39 H 52 FN6O2 + [MI] + The mass spectrometry peak at 655.4130 was detected, and the purity measured by HPLC was 99.7%.

[0156] Test case

[0157] This study tested the inhibitory effects of compounds 1a-34a and 1b-16b on the growth of KRAS-driven cancer cells and KRAS wild-type normal cells, as well as the effects of compounds 15a, 16a, 18a, 19a, 21a, 22a, 9b, 12b, the blank control, and QUMA-1 on KRAS protein levels. The effects of compound 15a, the blank control, and QUMA-1 on the transcriptional level of the KRAS gene were also tested. The structural formula of QUMA-1 is as follows: The specific testing method is as follows:

[0158] 1. Inhibitory effect on tumor cell growth

[0159] The KRAS translation inhibitors (compounds 1a-34a and 1b-16b) prepared in the above examples were selected, and their inhibitory effects on the growth of KRAS-driven cancer cells (MIA PaCa-2 cells, PANC-1 cells) and KRAS wild-type normal cells (commercially available HEK293 cells and NCM460 cells) were tested. In vitro cytotoxicity assays were performed using the MTT assay. Different concentrations of the derivatives were added to cells in the logarithmic growth phase, and after 24 hours of treatment, MTT was added, and the absorbance was measured. The concentration of the compound that inhibited cell growth by 50% was calculated, and the results were expressed as IC50. 50 The values ​​are represented, and the results are shown in Table 1.

[0160] Table 1. Cytotoxicity of KRAS translation inhibitors (IC50) 50 (value / μmol / L)

[0161]

[0162]

[0163] Following the testing method for the inhibitory effects of the above compounds on the growth of KRAS-driven cancer cells and KRAS wild-type normal cells, the inhibitory effects of compound 15a on different cell types (HPAF-II cells, SW620 cells, HCT116 cells, H358 cells, U-87MG cells, LX2 cells, and HFL1 cells) were tested. At the same time, the inhibitory effect of compound QUMA-1 on the above cells was tested as a control. The specific test results are shown in Table 2.

[0164] Table 2. Cytotoxicity of 15a in KRAS mutant and KRAS wild-type cell lines (IC50) 50 (μmol / L, 24h).

[0165]

[0166] As shown in Tables 1 and 2 above, the KRAS translation inhibitors of this invention have a strong inhibitory effect on KRAS-driven cancer cells in vitro. In particular, compound 15a has a selective inhibitory effect on KRAS-driven cancer cells and can be used to prepare anti-tumor drugs.

[0167] 2. Effects on the transcription and expression of the intracellular KRAS gene

[0168] A selection of representative compounds were used to test their effects on the transcription and expression of the KRAS gene in cells. The specific procedures are as follows:

[0169] (1) Effects on transcription:

[0170] This experiment included an experimental group and two control groups: a blank control group (Ctrl) and a positive control group. Cell culture: Cells were seeded into 6-well plates at 200,000 cells / well. After 24 hours of cell attachment, compound 15a was added to the experimental group at concentrations of 1.25 μmol / L, 2.5 μmol / L, and 5 μmol / L. No substance was added to the blank control group. The negative control group was treated with an equal volume of QUMA-1 at a concentration of 5 μmol / L. Cells were cultured for 0 h, 6 h, 12 h, 24 h, and 48 h. Cells were then collected, RNA was extracted, and RNA concentration was measured. Reverse transcription and PCR experiments were then performed according to the following procedures. The blank control group, positive control group, and experimental group were operated identically except for the added substances.

[0171] The PCR products, primers, and preparation system used are as follows: 10×Dream Taq Green buffer, 2.5 μL; dNTP mixture (2.5 mmol / L), 0.5 μL; cDNA, 1 μL; primer (sense), 0.5 μL; primer (antisense), 0.5 μL; Dream Taq DNA polymerase, 0.25 μL; ddH2O, 20.25 μL; total volume 25 μL.

[0172] Program: 95℃ denaturation, 5 min; 95℃ denaturation, 30 s; 58℃ annealing, 30 s; 72℃ extension, 60 s (30 cycles); 72℃, 10 min; finally cool down to 10℃.

[0173] 1.5% agarose gel electrophoresis was performed at 120V for 0.5 hours. After electrophoresis, gel imaging was performed. Specific test results are as follows: Figure 1 .in, Figure 1 (A) Figure 1 (B) and Figure 1 (C) shows the effects of the blank control group, experimental group and negative control group on the KRAS transcription level of MIA PaCa-2 cells, PANC-1 cells and NCI-H358 cells, respectively. Figure 1 (D) Figure 1 (E) Figure 1 (F) is a graph showing the effect of compound 15a (2.5 μmol / L) on the KRAS transcription level of MIA PaCa-2 cells, PANC-1 cells, and NCI-H358 cells at different culture times. Figure 1 (G) Figure 1 (H) and Figure 1(I) The effect of QUMA-1 on the KRAS transcription level of MIAPaCa-2 cells, PANC-1 cells, and NCI-H358 cells at different culture times is shown in the figure. Figure 1 (J) Figure 1 (K) and Figure 1 (L) These figures represent the effects of different culture times on KRAS transcription levels in MIA PaCa-2, PANC-1, and NCI-H358 cells, as measured in the blank control group. Figure 1 It is known that neither the KRAS translation inhibitor 15a nor QUMA-1 in this invention affects the transcriptional level of KRAS.

[0174] (2) Impact on expression:

[0175] Western blot experimental method: MIA PaCa-2 cell culture: Cell counting, seeding, addition of compounds (15a, 16a, 18a, 19a, 21a, 22a, 9b, 12b and QUMA-1) at 2.5 μmol / L, and culture in six-well plates until 5 million cells are reached. Cells are then removed and lysed. After collection, 50 μL of cell lysis buffer is added, and the supernatant is extracted to obtain total protein. The total protein concentration is determined using the CBA method. For subsequent denatured protein samples, the same mass of protein is loaded, and protein bands are separated by SDS-PAGE gel electrophoresis. The molecular weight is calculated based on the target protein, and the corresponding electrophoretic band is cut off and transferred to a PVDF membrane using a wet-spinning method. Two control groups are set up: a blank control group (Ctrl) and a positive control group. All other operations are the same except for the added substances. The blank control group receives no added substances, while the positive control group receives QUMA-1 at 2.5 μmol / L.

[0176] Prepare washing buffer (TBST) (25 mmol / L NaCl, 100 Tris buffer, 0.2% Tween-20, pH 7.4): Block the PVDF membrane with 5% skim milk powder solution (w / v) dissolved in TBST buffer. Incubate the PVDF membrane with primary antibody (KRAS) and secondary antibody (goat anti-rabbit) separately. After washing with TBST buffer an appropriate number of times, develop and image the membrane using the SuperECL Plus ultrasensitive luminescence kit. Results are as follows: Figure 2 As shown, the KRAS translation inhibitors (15a, 16a, 18a, 19a, 21a, 22a, 9b, 12b) in this invention can significantly reduce the expression level of c-MYC. Therefore, the KRAS translation inhibitors in this invention kill KRAS-driven cancer cells by inhibiting KRAS translation.

[0177] By applying it to the KRAS RNA G-quadruplex to inhibit KRAS translation and thus inhibit cancer cell proliferation, it was found that the compounds prepared by the embodiments of the present invention all have significant anti-tumor effects.

[0178] In summary, this invention designs a novel class of KRAS translation inhibitors. These derivatives are prepared based on a specific RNA G-quadruplex ligand, QUMA-1, through structural modification. They utilize a coumarin-quinoline compound as the KRAS G-quadruplex recognizer, with the amino groups on both sides recognizing the grooves of the G-quadruplex. This KRAS translation inhibitor selectively binds to and stabilizes the KRAS RNA G-quadruplex, while exhibiting almost no stabilizing ability against other RNA G-quadruplexes and double-stranded DNA. The prepared KRAS translation inhibitor significantly increases selectivity for KRAS-driven tumor cells and downregulates the protein level of the proto-oncogene KRAS. Therefore, this invention's KRAS translation inhibitor can serve as a novel pan-KRAS translation inhibitor and has broad application prospects in the preparation of anti-tumor drugs.

[0179] The embodiments of the present invention have been described in detail above. However, the present invention is not limited to the above embodiments. Within the scope of knowledge possessed by those skilled in the art, various changes can be made without departing from the spirit of the present invention. Furthermore, the embodiments of the present invention and the features thereof can be combined with each other unless otherwise specified.

Claims

1. A KRAS translation inhibitor having a compound as shown in formula (I), formula (II), formula (III) or formula (IV), or a pharmaceutically acceptable salt thereof. ， in, R1 is selected from -NH(CH2) n R5, -NH(CH2)2O(CH2)2OH, -NH(CH2)3OCH(CH3)2, morpholino, piperidino, ((tetrahydro-2H-pyran-4-yl)methyl)amino, acetylpiperazino, isopropionylpiperazino, methylpiperazinpyrimidineamino, ethylpiperazinaniline, N,N-diethylphenylenediamine, trifluoromethylaniline, methylaniline, benzo[a]azine heterocycle; wherein the benzo[a]azine heterocycle is selected from 5-amino-2-methylbenzimidazolyl or benzimidazolyl. Each R2 is independently selected from -(CH2). n R5; Each R3 is independently selected from -NH(CH2). n R5, methylpiperazinyl, methylhomoperazinyl; Each R4 is independently selected from halogens; Each R5 is independently selected from -OH, -OMe, -NH2, -COOH, -COOMe, monosaccharides, pyrrolyl, thienyl, imidazolyl, morpholinyl, piperidinyl, N,N-dimethylamino, N,N-diethylamino, N,N-dipropylamino, N,N-diisopropylamino, N,N-dibutylamino, and benzo[a]azine heterocycles; The benzo[a]heterocycle is selected from 5-amino-2-methylbenzimidazolyl or benzimidazolyl. The monosaccharide is selected from glucose; Each n is independently selected from natural numbers from 1 to 10.

2. The KRAS translation inhibitor according to claim 1, characterized in that: R4 is iodine.

3. A KRAS translation inhibitor, characterized in that: The KRAS translation inhibitors are selected from: ； Each R4 is independently selected from halogens.

4. The KRAS translation inhibitor according to claim 3, characterized in that: R4 is iodine.

5. The method for preparing the KRAS translation inhibitor according to any one of claims 1 to 2, characterized in that: Includes the following steps: The compound of formula (I) is prepared by reacting the compound of formula (V) with R1H; Alternatively, the compound shown in formula (V) can be reacted with 1-prop-2-ynylpiperazine to obtain the compound shown in formula (VI), and then the compound shown in formula (VI) can be reacted with R2N3 to generate the compound shown in formula (II); Or, by It reacts with 7-diethylaminocoumarin-3-aldehyde to produce the compound shown in formula (IV); Or, with The reaction formula for preparing the compound shown in formula (III) as a reactant is as follows: ； The structural formulas of the compounds represented by formulas (V) and (VI) are as follows: ； R1, R2, R3, and R4 are as defined in any one of claims 1 to 2.

6. The method for preparing the KRAS translation inhibitor according to claim 5, characterized in that: The The synthetic route is as follows: 。 7. An antitumor drug, characterized in that: It includes the KRAS translation inhibitor as described in any one of claims 1 to 3 and a pharmaceutically acceptable excipient; the tumor is pancreatic cancer.

8. The use of the KRAS translation inhibitor according to any one of claims 1 to 3 in the preparation of an antitumor drug or a KRAS translation inhibitory drug composition; wherein the tumor is pancreatic cancer.

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