4-substituted-2-biphenyl-7-azaindole compound and application thereof as CSN5 inhibitor

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a 4-substituted-2-biphenyl-7-azaindole compound and application of the 4-substituted-2-biphenyl-7-azaindole compound as a CSN5 inhibitor. The invention provides a series of 4-substituted-2-biphenyl-7-azaindole compounds as shown in a formula I. The compounds have good CSN5 inhibitory activity and are expected to be used as drugs for preventing and treating CSN5-mediated diseases (such as cancers). The invention provides a new choice for clinical medication, and has a good application prospect.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine, and particularly relates to a 4-substituted-2-biphenyl-7-azaindole compound and use thereof as a CSN5 inhibitor. BACKGROUND

[0002] CSN5 protein is one of eight subunits of CSN complex protein, can mediate and catalyze the cleavage of isopeptide bond between NEDD8 and Cullin, and plays a key role in the cyclic regulation of Cullin-RING E3 ubiquitin ligase (CRLs). Studies have shown that CSN5 can regulate cell cycle and various important intracellular signaling pathways, and is overexpressed in various malignant tumors. Inhibition of the enzymatic activity of CSN5 can destroy the balance between oncogenes and tumor suppressor genes regulated by CRLs in tumor cells, and at the same time enhance the anti-tumor immune activity. Therefore, CSN5 is considered as a potential new target for anti-tumor. Developing specific CSN5 inhibitors may be an effective strategy for CSN5-dependent tumor treatment. Due to the great challenge in the research of CSN5 inhibitors, only two specific CSN5 inhibitors, 6,7,8,9-tetrahydro-5H-imidazo[1,5-a]azepin-6-ol and 3-substituted-7-azaindole, have been reported so far. Therefore, it is still necessary to develop high-activity and specific CSN5 small molecule inhibitors to provide more candidate compounds for the research of anti-tumor drugs targeting CSN5. SUMMARY

[0003] In view of the problems in the prior art, the present application provides a 4-substituted-2-biphenyl-7-azaindole compound and use thereof as a CSN5 inhibitor.

[0004] The compound shown in formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a crystal form thereof:

[0005]

[0006] wherein,

[0007] L is selected from none, substituted or unsubstituted C1-C 10 alkylene, wherein the substituent is selected from C1-C 10 alkyl, C6-C 10 aryl, C3-C 10 cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, oxygen atom, hydroxyl, C6-C 10 aryl-substituted C1-C 10 alkyl, halogen, amino, C1-C 10 amine, C1-C 10 ester, C1-C 10 alkoxy;

[0008] R is selected from substituted or unsubstituted C1-C. 10 Ester group, amino group, amino group with protecting group, substituted or unsubstituted C1-C 10 Amine, substituted or unsubstituted C6-C 10 Aromatic amino groups, substituted or unsubstituted 5-10 membered heterocyclic alkyl groups, substituted or unsubstituted C3-C 10 cycloalkyl, wherein the substituents are selected from C1-C1. 10 Alkyl, C6-C 10 Aryl, C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, oxygen atom, hydroxyl group, C6-C 10 aryl-substituted C1-C 10 Alkyl, halogen, amino, C1-C 10 Amine group, C1-C 10 Ester group, C1-C 10 Alkoxy, amino protecting groups, -COR1;

[0009] R1 is selected from substituted or unsubstituted C1-C. 10 Alkyl, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted 5-10-membered heteroaryl, substituted or unsubstituted 4-10-membered heterocycloalkyl, substituted or unsubstituted amino, wherein the substituents are selected from C1-C2. 10 Alkyl, C3-C 10 Cycloalkyl-substituted C1-C 10 Alkyl, C6-C 10 aryl-substituted C1-C 10 Alkyl, 4-10 membered heterocyclic alkyl-substituted C1-C 10 Alkyl, C6-C 10 Aryl, C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, oxygen atom, hydroxyl group, C6-C 10 aryl-substituted C1-C 10 Alkyl, halogen, amino, C1-C 10 Amine group, C1-C 10 Ester group, C1-C 10 Alkoxy and amino protecting groups.

[0010] Preferably, the compound has the structural formula shown in Formula III, Formula IV or Formula V:

[0011]

[0012]

[0013] Preferably, R1 is selected from substituted or unsubstituted C1-C2 alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 6-membered heteroaryl, substituted or unsubstituted 4-6-membered heterocycloalkyl, 4-6-membered heterocycloalkyl with an amino protecting group, and substituted amino, wherein the substituent is selected from phenyl, 6-membered heterocycloalkyl, oxygen atom, hydroxyl, benzyl, 9-membered heteroaryl, C3-C5 cycloalkyl, ethyl-substituted C6 cycloalkyl, Br, C1-C4 alkyl, cyclopropyl-substituted methyl, 6-membered heterocycloalkyl-substituted methyl, and phenyl-substituted C3 alkyl.

[0014] Preferably, L is selected from alkylene groups of zero or C1-C3.

[0015] Preferably, R is selected from C2 ester group, C2 amino group, amino group, amino group with a protecting group, aniline group, 5-6 membered heterocyclic alkyl group, 5-6 membered heterocyclic alkyl group with an amino protecting group, -COR1 substituted 5-6 membered heterocyclic alkyl group, C3-C5 cycloalkyl group, and F substituted C3-C5 cycloalkyl group.

[0016] Preferably, the compound has the structural formula shown in Formula VI:

[0017]

[0018] in,

[0019] X is selected from O or N-COR1;

[0020] R1 is selected from substituted C1-C2 alkyl, 6-membered heteroaryl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 6-membered heterocyclic alkyl, wherein the substituent is selected from phenyl, 6-membered heterocyclic alkyl, hydroxyl, oxygen atom, Boc, benzyl.

[0021] Preferably, the structural formula of the compound is selected from:

[0022]

[0023]

[0024]

[0025]

[0026] The present invention also provides the use of the above-mentioned compounds, or pharmaceutically acceptable salts thereof, or stereoisomers thereof, or crystal forms thereof, in the preparation of medicaments for treating and / or preventing CSN5-mediated diseases.

[0027] Preferably, the CSN5-mediated diseases include at least one of the following: cancer, autoimmune diseases, neurodegenerative diseases, inflammation, and cardiovascular diseases.

[0028] The present invention also provides a pharmaceutical composition which is prepared by adding pharmaceutically acceptable excipients to the above-mentioned compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a crystal form thereof as the active ingredient.

[0029] The CSN5-mediated diseases defined in this invention are those in which CSN5 plays an important role in the pathogenesis of the disease. Examples include: cancer, autoimmune diseases, neurodegenerative diseases, inflammation, and cardiovascular diseases.

[0030] The compounds and derivatives provided in this invention can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.

[0031] Regarding the definition of terms used in this invention: Unless otherwise stated, the initial definitions provided for groups or terms herein apply to the groups or terms used throughout this specification; for terms not specifically defined herein, the meanings that a person skilled in the art would give them should be given based on the disclosure and context.

[0032] "Substitution" refers to the replacement of hydrogen atoms in a molecule by other different atoms or molecules.

[0033] The minimum and maximum carbon atom content in hydrocarbon groups are indicated by a prefix, for example, the prefix C. a～b Alkyl indicates any alkyl group containing one to two carbon atoms ("a" to "b"). Therefore, for example, "C..." 1～4 "Alkyl" refers to an alkyl group containing 1 to 4 carbon atoms.

[0034] "Alkyl" refers to a saturated hydrocarbon chain having a specified number of member atoms. For example, C1-C6 alkyl refers to an alkyl group having 1 to 6 member atoms, such as 1 to 4 member atoms. Alkyl groups can be straight-chain or branched. Representative branched alkyl groups have one, two, or three branches. Alkyl groups may optionally be substituted by one or more substituents as defined herein. Alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl, and tert-butyl), pentyl (n-pentyl, isopentyl, and neopentyl), and hexyl. Alkyl groups may also be part of other groups, such as C1-C6 alkoxy groups.

[0035] "Cycloalkyl" refers to a saturated or partially saturated cyclic group having 3 to 14 carbon atoms, no heterocyclic atoms, and a single or multiple rings (including fused, bridged, and spirocyclic systems). For polycyclic systems having aromatic and non-aromatic rings without heteroatoms, the term "cycloalkyl" (e.g., 5,6,7,8-tetrahydronaphthalene-5-yl) applies when the linker is located on a non-aromatic carbon atom. The term "cycloalkyl" includes cycloalkenyl groups, such as cyclohexenyl. Examples of cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl, and cyclohexenyl. Examples of cycloalkyl groups including polycyclic bicyclic alkyl systems are dicyclohexyl, dicyclopentyl, dicyclooctyl, etc. Two such bicyclic alkyl polycyclic structures are illustrated and named below: Dicyclohexyl and Dicyclohexyl. "Alkenyl" refers to a straight-chain or branched hydrocarbon group having 2 to 10 carbon atoms, and in some embodiments 2 to 6 carbon atoms or 2 to 4 carbon atoms and having at least one vinyl unsaturated site (>C=C<). For example, (Ca-Cb)alkenyl refers to an alkenyl group having a to b carbon atoms and is intended to include, for example, vinyl, propenyl, isopropenyl, 1,3-butadienyl, etc.

[0036] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0037] "Heterocyclic" or "heterocyclic alkyl" refers to a saturated ring or a non-aromatic unsaturated ring containing at least one heteroatom; where the heteroatom refers to a nitrogen atom, an oxygen atom, or a sulfur atom.

[0038] "Aromatic heterocycle" refers to an aromatic unsaturated ring containing at least one heteroatom; where the heteroatom refers to a nitrogen atom, an oxygen atom, or a sulfur atom.

[0039] The term "pharmaceutically acceptable" means that a carrier, delivery substance, diluent, excipient, and / or the salt formed therefrom is generally chemically or physically compatible with other components constituting a drug dosage form and physiologically compatible with receptors.

[0040] The terms "salt" and "pharmaceutical salt" refer to acidic and / or basic salts formed by the above-described compounds or their stereoisomers with inorganic and / or organic acids and bases, including zwitterionic salts (internal salts) and quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly during the final separation and purification of the compounds. Alternatively, they can be obtained by mixing the above-described compounds or their stereoisomers with an appropriate amount (e.g., equimolar amounts) of an acid or base. These salts may be obtained by precipitating in solution and collecting by filtration, by recovery after solvent evaporation, or by freeze-drying after reaction in an aqueous medium. The salts described in this invention can be hydrochlorides, sulfates, citrates, benzenesulfonates, hydrobromides, hydrofluoric acids, phosphates, acetates, propionates, succinates, oxalates, malates, succinates, fumarates, maleates, tartrates, or trifluoroacetates of the compounds.

[0041] In some embodiments, one or more compounds of the present invention may be used in combination with each other. Alternatively, the compounds of the present invention may be used in combination with any other active agent to prepare a medicament or pharmaceutical composition for regulating cell function or treating disease. If a group of compounds is used, these compounds may be administered to the test subject simultaneously, separately, or sequentially.

[0042] This invention provides a series of 4-substituted-2-biphenyl-7-azaindole compounds that exhibit good CSN5 inhibitory activity, thus possessing the potential for the prevention and treatment of CSN5-mediated diseases. This invention offers new clinical drug options for CSN5-mediated diseases (such as cancer) and shows great promise for application.

[0043] Obviously, based on the above description of the present invention, and according to common technical knowledge and conventional methods in the field, various other modifications, substitutions, or alterations can be made without departing from the basic technical concept of the present invention.

[0044] The following detailed embodiments further illustrate the above-described content of the present invention. However, this should not be construed as limiting the scope of the present invention to the following examples. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention. Attached Figure Description

[0045] Figure 1 The results are Western blots of compounds 20, 21, and 44 from Experimental Example 1. Detailed Implementation

[0046] In the following examples and experimental cases, reagents and raw materials not specifically described are all commercially available products.

[0047] Example 1: Compounds 1-18 and their preparation methods

[0048] This embodiment provides compounds 1-18, whose general preparation methods are as follows:

[0049]

[0050] The reaction conditions for each step are as follows:

[0051] 4-Chloro-7-azaindole (1a, 1.0 g, 6.5 mmol) was dissolved in dry tetrahydrofuran (10 mL), and NaH (0.34 g, 8.5 mmol) was added at 0 °C. After stirring for 30 minutes, (2-(chloromethoxy)ethyl)trimethylsilane (1.31 g, 7.8 mmol) was added dropwise, and the reaction was carried out at 0 °C for 1 hour. The reaction mixture was quenched with saturated ammonium chloride solution (30 mL), extracted with ethyl acetate (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate: 10:1) to give 1.38 g of oil 1b (74%).

[0052] 1b (1.38 g, 4.87 mmol) was dissolved in dry tetrahydrofuran (15 mL), and n-butyllithium (1.95 mL, 4.87 mmol) was slowly added dropwise at -45 °C. After stirring for 30 minutes, a tetrahydrofuran solution of iodine (3.09 g, 12.2 mmol) (10 mL) was added dropwise, and the reaction was allowed to proceed at room temperature for 2 hours. The reaction mixture was quenched with saturated ammonium chloride solution (50 mL), extracted with ethyl acetate (50 mL × 2), and the organic phase was washed with saturated sodium thiosulfate solution (50 mL × 2). The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate: 10:1) to give 1.59 g of oil 1c, yield 80%.

[0053] Bromobenzene (3.0 g, 19.1 mmol), 2-chloro-5-methylphenylboronic acid (3.9 g, 22.9 mmol), bis(triphenylphosphine)palladium dichloride (1.35 g, 1.91 mmol), and cesium carbonate (15.5 g, 47.7 mmol) were dissolved in dry 1,4-dioxane (30 mL) and reacted at 100 °C for 5 hours under argon protection. The reaction mixture was added to water (50 mL), extracted with ethyl acetate (50 mL × 2), and the organic layer was dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate: 50:1) to give 4.17 g of oil 1e, in 90% yield.

[0054] 1e (1.0 g, 4.93 mmol), pinacol diboronate (2.5 g, 9.86 mmol), tris(dibenzylacetone)palladium (225 mg, 0.24 mmol), XPhos (235 mg, 0.49 mmol), and 2 mol / L potassium acetate (7.4 mL, 14.8 mmol) were dissolved in 1,4-dioxane (30 mL) and reacted at 110 °C for 5 hours under argon protection. The reaction mixture was added to water (30 mL), extracted with ethyl acetate (50 mL × 2), the organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether) to give 1.42 g of oil 1f, yield 92%.

[0055] 1f (1.33 g, 3.27 mmol), 4,4,5,5-tetramethyl-2-(5-methyl-[1,1'-biphenyl]-2-yl)-1,3,2-dioxoborane (1.38 g, 4.9 mmol), bis(triphenylphosphine)palladium dichloride (459 mg, 0.65 mmol), and cesium carbonate (3.2 g, 9.8 mmol) were dissolved in dry 1,4-dioxane (30 mL) and reacted at 100 °C for 8 hours under argon protection. The reaction mixture was added to water (50 mL), extracted with ethyl acetate (50 mL × 2), the organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate: 50:1) to give 1 g of 935 mg oil, yield 64%.

[0056] 1 g (300 mg, 0.66 mmol), N,N-dimethylethane-1,2-diamine (58.8 mg, 0.66 mmol), cesium carbonate (653 mg, 2.0 mmol), palladium acetate (60 mg, 0.26 mmol), and xantphos (155 mg, 0.26 mmol) were dissolved in dry 1,4-dioxane (15 mL) and reacted at 100 °C for 5 h under argon protection. The reaction mixture was then added to water (30 mL), extracted with ethyl acetate (30 mL × 2), and the organic layer was dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate: 5:1) to give 230 mg of oil over 3 h, in 68% yield.

[0057] 3h (230 mg, 0.46 mmol) was dissolved in dry dichloromethane (10 mL), and trifluoroacetic acid (3 mL) was added dropwise. The mixture was stirred at room temperature for 10 hours. The reaction mixture was concentrated under reduced pressure, and dichloromethane:methanol:ammonia water = 60:10:1 (12 mL) was added. The mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane:methanol:30:1) to give 100 mg of solid product 3, with a yield of 59%. 1H NMR (400MHz, DMSO-d6) δ12.28(s,1H),8.08(s,1H),7.97(d,J=6.8Hz,1H),7.47(d,J=7.8Hz,1H),7.35-7.20(m, 7H),6.57(d,J=6.8Hz,1H),6.38(s,1H),3.77-3.67(m,2H),3.29(t,J=6.4Hz,2H),2.83(s,6H),2.41(s,3H)ppm. 13 C NMR(101MHz,DMSO-d6)δ151.16,140.95,140.09,138.89,136.15,131.85,130.78,129.38,1 28.67,127.60,119.16,116.13,109.27,100.27,97.52,55.12,42.98,37.95,21.21ppm.HRMS m / z:calcdfor C 24 H 26 N4[M+H] + 371.2230, found 371.2226.

[0058] The synthetic methods for compounds 1, 2, and 4-18 are the same as those for compound 3, the difference being the selection of different starting materials based on the different substituent structures of the compounds. The specific yields and characterization results are as follows:

[0059] Compound 1: Overall yield 11.5%, 1 H NMR (400MHz, DMSO-d6) δ11.63(s,1H),8.02(d,J=6.8Hz,1H),7.57(d,J=7.6Hz,1H),7.32 -7.18(m,7H),6.56(d,J=6.4Hz,1H),5.75(d,J=3.6Hz,2H),3.83(s,3H),2.38(s,3H)ppm.

[0060] Compound 2: Overall yield 12.0%, 1 H NMR (400MHz, DMSO-d6) δ11.81 (s, 1H), 7.83 (d, J = 6.8Hz, 1H), 7.59 (s br,1H),7.47(d,J=8.0Hz,1H),7.32-7.22(m,7H),6.37(d,J=6.8Hz,1H),6.30(s ,1H),3.61(s,1H),352(q,J=6.4Hz,2H),2.63(t,J=6.4Hz,2H),2.40(s,3H)ppm.

[0061] Compound 4: Overall yield 13.2%, 1 H NMR (400MHz, DMSO-d6) δ11.45(s,1H),7.84(d,J=5.9Hz,1H),7.44(d,J=7.8Hz,1H),7.27(t,J=6.5Hz,4H),7.25-7.21(m,3H),6.98(s br,1H),6.28(d,J=5.8Hz,1H),6.21(s,1H),3.47(d,J=6.1Hz,2H),3.00(s,2H),2.40(s,3H),1.91(s,2H)ppm.HRMS m / z:calcd for C 22 H 22 N4[M+H] + 343.1917, found 343.1914.

[0062] Compound 5: Overall yield 13.0%, 1 H NMR (400MHz, DMSO-d6) δ11.08(s,1H),7.74(d,J=5.5Hz,1H),7.46(d,J=7.8Hz,1H),7.31-7.21(m,6H),7.19(s,1H),7.08(dd,J=8.4,7.4Hz,2H) ,6.59-6.50(m,3H),6.38(s,1H),6.11(d,J=5.6Hz,1H),6.08(s,1H),5. 62(s,1H),3.34(d,J=9.5Hz,2H),3.21(d,J=6.2Hz,2H),2.38(s,3H)ppm.

[0063] Compound 6: Overall yield 13.1%, 1 H NMR (400MHz, DMSO-d6) δ11.41(s,1H),7.82(d,J=5.8Hz,1H),7.46(d,J=7.8Hz,1H),7.31-7.21(m,7H),6.85(s br,1H),6.24(d,J=12.4Hz,1H),6.13(s,1H),3.56(t,J=11.6Hz,2H),3.11-3.08(m,6H),2.39(s,3H),1.71(s,6H),1.52(s,3H)ppm.

[0064] Compound 7: Overall yield 12.6%, 1H NMR(400MHz,DMSO)δ12.43(s,1H),8.96(s,1H),8.69(s,1H),8.15(s,1H),8.02(t, J=8.5Hz,1H),7.65(d,J=7.8Hz,1H),7.52-7.42(m,4H),7.40-7.38(m,3H),6.58(t, J=8.8Hz,1H),6.50(s,1H),3.46-3.40(m,4H),2.99(t,J=11.8Hz,2H),2.57(s,3H), 1.99(d,J=12.3Hz,2H),1.77(s,1H),1.70-1.59(m,2H),1.47(d,J=12.9Hz,2H)ppm.

[0065] Compound 8: Overall yield 13.0%, 1 H NMR (400MHz, DMSO-d6) δ12.03(s,1H),8.73(s,2H),7.85(d,J=6.6Hz,1H),7.49(d,J=7.8Hz,1H),7.34-7.28(m,4H),7.23(dd,J=5.6,3.8Hz, HRMS m / z:calcd for C 26 H 29 N5[M+H] + 412.2496, found 412.2494.

[0066] Compound 9: Overall yield 12.6%, 1 H NMR (400MHz, DMSO-d6) δ11.63(s,1H),7.80(d,J=6.1Hz,1H),7.49(d,J=7.8Hz,1H),7.34-7.26(m,4H),7.23(dd,J=7.9,1.9Hz,3H),7.00( s,1H),6.28(d,J=6.2Hz,1H),6.16(s,1H),3.62-3.56(m,4H),3.36(d,J=6.0Hz,4H),2.56(t,J=6.6Hz,2H),2.48(s,2H),2.40(s,3H)ppm. 13C NMR (101MHz, DMSO-d6) δ149.49,144.80,141.50,140.69,140.27,138.10,134.51,131.83,130. 50,129.44,128.50,127.39,119.19,108.57,99.66,97.16,66.41,56.99,53.61,21.18ppm.HRMS m / z:calcd forC 26 H 28 N4O[M+H] + 413.2336, found 413.2334.

[0067] Compound 10: Overall yield 13.0%, 1 H NMR (400MHz, DMSO-d6) δ11.67(s,1H),7.87(d,J=6.0Hz,1H),7.46(d,J=7.8Hz,1H),7.29-7.21(m,8H),6.36(d,J=6.1H z,1H),6.22(s,1H),3.61(d,J=5.9Hz,2H),3.31(s,4H),2.40(s,3H),1.92(d,J=6.2Hz,4H),1.23(d,J=3.9Hz,2H)ppm.

[0068] Compound 11: Overall yield 12.8%, 1 H NMR (400MHz, DMSO-d6) δ11.51(s,1H),7.78(d,J=6.1Hz,1H),7.47(d,J=7.8Hz,1H),7.32-7.20(m,7H),7.10(s,1H),6.24(d,J=6.2Hz,1H) ,6.19(s,1H),3.64-3.57(m,4H),3.25(d,J=5.9Hz,4H),3.17(s,1H),2.47-2.44(m,2H),2.40(s,3H),1.78-1.68(m,2H),1.23(s,1H)ppm.

[0069] Compound 12: Overall yield 13.0%, 1H NMR(400MHz,DMSO-d6)δ11.87(s,1H),9.05(s br,1H),8.83(s br,1H),7.81(d,J=6.4Hz,1H),7.48(d,J=7.8Hz,1H),7.30(d,J=7.0Hz,4H),7.23(dd,J=7.3,2.1Hz,4H),6.51-5.94(m,2H),3.48 -3.41(m,1H),3.25(d,J=12.1Hz,2H),3.17(s,2H),2.80(s,2H),2.40(s,3H),1.82(d,J=12.7Hz,3H),1.39-1.36(m,2H)ppm.HRMS m / z:calcd for C 26 H 28 N4[M+H] + 397.2387 found 397.2383.

[0070] Compound 13: Overall yield 13.1%, 1 H NMR (400MHz, DMSO-d6) δ11.63(s,1H),7.80(d,J=6.4Hz,1H),7.51(d,J=7.8Hz,2H),7.34-7.26(m,8H),6.37-6.24(m,3H),3 .88(d,J=8.8Hz,3H),3.32-3.22(m,5H),3.18-3.09(m,3H),2.43(s,5H),1.63(d,J=12.4Hz,3H),1.31-1.13(m,4H)ppm.HRMS m / z:calcd for C 26 H 27 N3O[M+H] + 398.2227, found 398.2227.

[0071] Compound 14: Overall yield 12.1%, 1H NMR (400MHz, DMSO-d6) δ12.36(s,1H),9.23(s,2H),8.39(s,1H),7.94(dd,J=11.0,5.2Hz,1H),7.4 7(t,J=7.6Hz,1H),7.30-7.27(m,3H),7.23(dd,J=7.5,1.9Hz,3H),6.59(d,J=7.1Hz,1H),6.52(s,1 H),3.96(dd,J=12.8,13.7Hz,1H),3.89-3.86(m,1H),3.66(dt,J=27.3,13.7Hz,2H),3.56-3.50(m ,2H),3.21(d,J=12.8Hz,2H),2.99(t,J=11.2Hz,1H),2.85(t,J=11.2Hz,1H),2.42(s,3H)ppm.HRMS m / z:calcd for C 25 H 26 N4O[M+H] + 399.2179, found 399.2176.

[0072] Compound 15: Overall yield 12.9%, 1 H NMR (400MHz, DMSO-d6) δ11.33(s,1H),7.74(d,J=5.9Hz,1H),7.47(d,J=7.8Hz,1H),7.30-7.21(m,7H),6.92(s br,1H),6.24-6.18(m,2H),3.06(t,J=6.2Hz,2H),2.39(s,3H),1.08-1.00(m,1H),0.48-0.43(m,2H),0.24-0.19(m,2H)ppm. 13 C NMR(101MHz,DMSO-d6)δ149.00,146.77,141.67,140.61,137.87,134.10,131.78,130.61, 129.44,128.90,128.54,127.30,108.40,99.65,97.02,47.21,21.18,11.02,4.03pm.HRMS m / z:calcd for C 24 H 23 N3[M+H] + 354.1965, found 354.1960.

[0073] Compound 16: Overall yield 13.3%, 1H NMR (400MHz, DMSO-d6) δ11.59(s,1H),7.76(d,J=6.3Hz,1H),7.48(d,J=7.8Hz,1H),7.31-7.21(m,8H),6.34(s,1H),6.29(d,J=6. 4Hz,1H),3.91(d,J=6.3Hz,1H),2.40(s,3H),1.95-1.87(m,2H),1.68(dd,J=7.9,4.0Hz,2H),1.53(m,J=17.8,9.8,5.5Hz,4H)ppm. 13 C NMR(101MHz,DMSO-d6)δ149.72,144.00,141.44,140.69,139.09,138.21,134.48,131.82,130.59,1 29.42,129.12,128.59,128.38,127.36,108.27,100.53,98.23,54.35,32.87,24.18,21.19ppm.HRMS m / z:calcd for C 25 H 25 N3

[0074] [M+H] + 368.2121, found 368.2114.

[0075] Compound 17: Overall yield 13.0%, 1 H NMR (400MHz, DMSO-d6) δ11.16(s,1H),7.76(d,J=5.4Hz,1H),7.46(d,J=7.8Hz,1H),7.31-7.18(m,8H),6.79(d,J=5.4Hz ,1H),6.11(s,1H),6.03(d,J=5.4Hz,1H),3.95-3.83(m,1H),3.07-2.93(m,2H),2.70-2.54(m,3H),2.39(s,4H)ppm.HRMS m / z:calcd for C 24 H 21 F2N3[M+H] + 390.1776, found 390.1776.

[0076] Compound 18: Overall yield 13.4%, 1H NMR (400MHz, DMSO-d6) δ11.29(s,1H),8.43(s,1H),7.81(d,J=5.5Hz,1H),7.48(d,J=7.8Hz,1H),7.26(ddd,J=9.6,6.8,2.4Hz,6H),7. 21-7.15(m,2H),7.04-6.98(m,2H),6.82(d,J=7.5Hz,1H),6.62(d,J=5.5Hz,1H),6.17(d,J=1.5Hz,1H),2.39(s,3H),2.28(s,3H)ppm. 13 C NMR(101MHz,DMSO-d6)δ150.23,143.74,141.53,140.69,138.75,137.88,135.07,131.81,130.76,12 9.38,129.14,128.51,127.28,123.46,121.65,118.14,110.17,99.44,99.24,21.60,21.19ppm.HRMS m / z:calcd forC 27 H 23 N3[M+H] + 390.1965, found 390.1963.

[0077] Example 2: Compounds 19-27 and their preparation methods

[0078]

[0079] The reaction conditions for each step are as follows:

[0080] (S)-2-phenylpropionic acid (43.8 mg, 0.3 mmol) was dissolved in dry dichloromethane (10 mL), and HATU (110.9 mg, 0.29 mmol) and triethylamine (49 mg, 0.48 mmol) were added. The mixture was stirred at room temperature for 30 minutes, and then 12 (100 mg, 0.25 mmol) was added. The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane:methanol:100:1) to give 19.77 mg of solid in 58% yield. 1H NMR(400MHz,DMSO-d6)δ11.12(s,1H),7.71-7.67(m,1H),7.45(d,J=7.7Hz,1H),7 .31-7.18(m,12H),6.50(d,J=29.7Hz,1H),6.18-5.90(m,2H),4.46-4.37(m,1H), 4.11-4.05(m,1H),3.95-3.87(m,1H),3.03(s,1H),2.92-2.77(m,2H),2.63-2.57 (m,1H),2.38(s,3H),1.69-1.62(m,2H),1.38-1.25(m,4H),1.09-0.75(m,2H)ppm.

[0081] The synthetic methods for compounds 20-27 are the same as those for compound 19, the difference being the selection of different starting materials based on the different substituent structures of the compounds. Their yields and characterization results are as follows:

[0082] Compound 20: Yield 55%, 1 H NMR (400MHz, DMSO-d6) δ11.01(s,1H),7.71(d,J=5.5Hz,1H),7.46(d,J=7.8Hz,1 H),7.31-7.21(m,7H),7.19(s,2H),6.39(s,1H),6.13-6.05(m,2H),4.32(d,J=1 3.0Hz,1H),4.02(d,J=12.0Hz,1H),3.63-3.49(m,7H),3.22(d,J=13.3Hz,1H),2 .99(dd,J=18.0,13.2Hz,4H),2.40(d,J=9.7Hz,8H),1.86-1.64(m,4H)ppm.HRMS m / z:calcd for C 32 H 37 N5O2[M+H] + 524.3020, found 524.3018.

[0083] Compound 21: Yield 59%, 1H NMR (400MHz, DMSO-d6) δ11.02(s,1H),7.71(d,J=5.5Hz,1H),7.46(d,J=7.8Hz, 1H),7.34-7.22(m,7H),7.19(s,2H),6.38(t,J=5.9Hz,1H),6.09(dd,J=8.8,3. 5Hz,2H),4.37(dd,J=15.2,10.5Hz,3H),3.50-3.38(m,4H),3.15-2.96(m,5H), 2.44-2.34(m,5H),2.23(d,J=10.1Hz,2H),1.99(s,2H),1.95-1.65(m,8H)ppm. 13 C NMR(101MHz,DMSO-d6)δ210.54,172.41,149.89,147.85,144.34,141.79,140.49,137.49,133.60,131.76,130.57 ,129.47,129.41,128.47,127.19,108.45,99.01,60.23,45.28,41.58,40.07,35.94,31.20,29.25,21.16ppm.HRMS m / z:calcd for C 33 H 36 N4O2[M+H] + 521.2911, found 521.2912.

[0084] Compound 22: Yield 57%, 1 H NMR (400MHz, DMSO-d6) δ11.12(s,1H),7.72(d,J=5.6Hz,1H),7.46(d,J=7.8Hz,1H),7.34-7.11(m,8H),6.56(s,1H),6.21- 6.04(m,2H),5.68(s,1H),3.04(t,J=6.1Hz,3H),2.39(s,4H),2.17-1.91(m,7H),1.84-1.65(m,4H),1.65-1.47(m,6H)ppm.

[0085] Compound 23: Yield 63%, 1H NMR (400MHz, DMSO-d6) δ11.11(s,1H),7.71(d,J=5.5Hz,1H),7.46(d,J=7.8Hz,1H),7.33-7.14(m,8H),6.53(s,1H),6.11(d,J=7.1Hz,2H),4.38(d,J =12.6Hz,1H),3.98(d,J=13.3Hz,1H),3.83(d,J=9.8Hz,2H),3.10-2.78(m ,5H),2.39(s,3H),1.87-1.43(m,9H),1.23(s,1H),1.11-0.88(m,3H)ppm.

[0086] Compound 24 yielded 65%. 1 H NMR (400MHz, DMSO-d6) δ11.01(s,1H),7.70(d,J=5.5Hz,1H),7.46(d,J=7.8Hz,1H),7.33-7.2 1(m,11H),7.18(s,2H),6.39(s,1H),6.10-6.03(m,2H),4.28(d,J=12.4Hz,1H),4.20(d,J=9. 6Hz,1H),3.90(d,J=12.4Hz,1H),3.81(d,J=9.6Hz,1H),3.66-3.45(m,3H),3.07-2.85(m,4H) ,2.70-2.61(m,2H),2.38(s,3H),2.22-2.05(m,2H),1.99(s,1H),1.85-1.63(m,3H)ppm.HRMS m / z:calcd for C 38 H 41 N5O2[M+H] + 600.3333 found 600.3331.

[0087] Compound 25: Yield 80%, 1H NMR (400MHz, DMSO-d6) δ11.25(s,1H),7.73(d,J=5.7Hz,1H),7.46(d,J=7.8 Hz,1H),7.32-7.16(m,8H),6.75(s,1H),6.17(d,J=4.0Hz,2H),4.38(d,J=12 .4Hz,1H),4.10-3.91(m,2H),3.45(d,J=6.8Hz,2H),3.13-2.94(m,4H),2.69 (s,2H),2.39(s,3H),2.35-2.08(m,6H),1.99(s,1H),1.93-1.66(m,5H)ppm.

[0088] Compound 26: Yield 68%, 1 H NMR (400MHz, DMSO-d6) δ11.14(s,1H),7.72(d,J=5.6Hz,1H),7.46(d,J=7.8Hz,1H),7.33-7.15(m,8H),6.58(s,1H),6.12(d,J=7 .1Hz,2H),4.38(d,J=11.8Hz,1H),4.01-3.91(m,1H),3.10-3.00(m,2H),3.00-2.87(m,2H),2.39(s,3H),1.80-1.51(m,14H)ppm.

[0089] Compound 27: Yield 63%, 1 H NMR (400MHz, DMSO-d6) δ11.01(s,1H),7.71(d,J=5.5Hz,1H),7.46(d,J=7.8Hz,1H),7.26-7.17(m,8H),6.38(d,J=5.6Hz,1H),6. 16-6.04(m,1H),4.37-4.22(m,3H),3.13-3.01(m,4H),2.38(s,3H),1.98-1.92(m,1H),1.82-1.61(m,4H),0.89-0.85(m,4H)ppm. 13 C NMR (101MHz, DMSO-d6) δ171.13,149.81,147.86,144.26,141.79,140.49,140.13,137.56,135.43,133.59,131. 75,130.55,129.46,128.47,127.70,108.43,99.02,96.69,48.16,45.31,35.98,29.98,21.16,12.89,8.14ppm.

[0090] Example 3: Compounds 28-52 and their preparation methods

[0091]

[0092] (S)-2-phenylpropionic acid (45.4 mg, 0.29 mmol) was dissolved in dry dichloromethane (10 mL), and HATU (115 mg, 0.3 mmol) and triethylamine (51 mg, 0.5 mmol) were added. The mixture was stirred at room temperature for 30 minutes, and then 8 (100 mg, 0.24 mmol) was added. The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane:methanol: 100:1) to give 28.80 mg of solid in 60% yield. 1 H NMR (400MHz, DMSO-d6) δ11.33(s,1H),7.74(d,J=5.7Hz,1H),7.49(d,J=7.9Hz,1H),7.35-7.15(m,13H),6.11(d,J=5.8Hz,1H),5.97(s,1H),4.11 HRMS m / z:calcd for C 35 H 37 N5O[M+H] + 544.3071 found 544.3066.

[0093] The synthesis methods for compounds 29-52 are the same as those for compound 28, the difference being the selection of different starting materials based on the different substituent structures of the compounds. The yields and characterization results are as follows:

[0094] Compound 29: Yield 63%, 1H NMR (400MHz, DMSO-d6) δ11.29(s,1H),7.73(d,J=5.7Hz,1H),7.48(d,J=7.8Hz,1H ),7.31(d,J=7.3Hz,2H),7.28-7.20(m,8H),7.16(d,J=6.9Hz,2H),6.29(s,1H),6. 10(d,J=5.8Hz,1H),5.96(s,1H),4.11(q,J=6.7Hz,1H),3.46(s,4H),3.30-3.12(m ,4H),2.41(s,2H),2.38(s,3H),2.31-2.21(m,2H),1.28(d,J=6.8Hz,3H)ppm.HRMS m / z:calcd for C 35 H 37 N5O[M+H] + 544.3071, found 544.3070.

[0095] Compound 30: Yield 58%, 1 H NMR (400MHz, DMSO-d6) δ11.12 (s, 1H), 7.79 (d, J = 7.9Hz, 1H), 7.75-7.69 (m, 2H), 7.67 -7.61(m,1H),7.49(d,J=7.8Hz,1H),7.41-7.35(m,1H),7.30-7.20(m,7H),7.16(d,J= 7.4Hz,2H),6.08(d,J=5.5Hz,1H),5.97(d,J=1.8Hz,1H),4.25(s,2H),3.59(t,J=4.8 Hz,2H),351-3.47(m,2H),3.29-3.19(m,3H),2.48-2.41(m,3H),2.38(s,5H)ppm.HRMS m / z:calcd for C 35 H 34 N6O2[M+H] + 571.2816 found 571.2820.

[0096] Compound 31: Yield 64%, 1H NMR (400MHz, DMSO-d6) δ11.91(s,1H),7.79(d,J=6.7Hz,1H),7.55(d,J=19.8Hz ,1H),7.48(d,J=7.8Hz,1H),7.35-7.31(m,3H),7.27-7.18(m,9H),6.37(d,J=6 .7Hz,1H),6.24(s,1H),3.35-3.32(m,4H),3.04-2.86(m,2H),2.44(s,2H),2.4 1(s,3H),2.35-2.30(m,4H),1.94-1.91(m,2H),1.64(d,J=3.5Hz,4H)ppm.HRMS m / z:calcd for C 38 H 41 N5O[M+H] + 584.3384 found 584.3382.

[0097] Compound 32: Yield 69%, 1 H NMR (400MHz, DMSO-d6) δ11.13(s,1H),7.74(d,J=5.5Hz,1H),7.49(d,J=7.9Hz,1H),7.31-7.22(m,7H),7.17(s,1H),6.07(d,J=5.5Hz,1H),5 .95(d,J=1.2Hz,1H),3.59-3.51(m,8H),3.49-3.41(m,3H),3.24(dd,J=12.0,6.0Hz,2H),3.14(d,J=5.8Hz,2H),2.42-2.34(m,12H)ppm.HRMS m / z:calcd for C 32 H 38 N6O2[M+H] + 539.3129, found 539.3132.

[0098] Compound 33: Yield 63%, 1H NMR (400MHz, DMSO-d6)) δ11.13(s,1H),7.74(d,J=5.5Hz,1H),7.49(d,J=7.8Hz,1H),7.3 2-7.21(m,7H),7.17(s,1H),6.06(dd,J=11.0,5.5Hz,2H),5.95(d,J=1.7Hz,1H),3.55(s, 2H),3.43(s,2H),3.24(dd,J=12.3,6.4Hz,3H),3.06(d,J=9.6Hz,3H),2.42(d,J=4.2Hz, 3H),2.38(s,3H),2.34(s,6H),1.55-1.42(m,5H),1.37(dd,J=16.7,12.4Hz,3H)ppm.HRMS m / z:calcd for C 33 H 40 N6O[M+H] + 537.3336, found 537.3341.

[0099] Compound 34: Yield 66%, 1 H NMR (400MHz, DMSO-d6) δ11.51(s,1H),8.74-8.63(m,2H),7.90(d,J=7.8Hz,1H),7.83(d,J=5.9Hz,1H),7.55(dd,J=7.7,4.4Hz,2H),7.39-7.24 (m,7H),6.84(s,1H),6.29(d,J=5.8Hz,1H),6.18(s,1H),3.71(s,2H),3.41-3.38(m,4H),2.63(t,J=0.8Hz,4H),2.45(s,2H),2.39(s,3H)ppm.

[0100] Compound 35: Yield 71%, 1H NMR (400MHz, DMSO-d6) δ11.93(s,1H),8.60(d,J=2.3Hz,1H),8.18(d,J=2.3Hz,1H),7.88(dd,J=9.1,2.4Hz ,1H),7.83(d,J=6.5Hz,1H),7.55(dd,J=8.9,2.4Hz,1H),7.49(d,J=7.8Hz,1H),7.32-7.21(m,7H),6.84-6. 81(m,2H),6.38(d,J=6.4Hz,1H),6.25(s,1H),3.68-3.60(m,6H),3.60-3.57(m,4H),3.53(s,2H),3.42(d, J=5.7Hz,2H),2.62(s,2H),2.54(s,2H),2.40(s,3H),1.65-1.60(m,4H),1.53(dd,J=10.1,6.1Hz,10H)ppm.

[0101] Compound 36: Yield 72%, 1 H NMR (400MHz, DMSO-d6) δ11.11(s,1H),7.73(d,J=5.4Hz,1H),7.48(d,J=7.8Hz,1H),7.34-7.18(m,11H),6.11-6.04(m,2H),5.97(s,1H),3.57(s,2H ),3.24(d,J=5.5Hz,2H),2.38(s,5H),1.82(s,5H),1.44(dd,J=22.2,12.1 Hz,3H),1.32-1.14(m,6H),1.11-0.95(m,3H),0.94-0.78(m,4H)ppm.HRMS m / z:calcd for C 41 H 47 N5O[M+H] + 626.3853 found 626.3850.

[0102] Compound 37: Yield 77%, 11H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 7.74 (d, J = 5.5 Hz, 1H), 7.49 (d, J = 7.8 Hz, 1H), 7.27 (dt, J = 12.5, 5.2 Hz, 6H), 7.17 (s, 1H), 6.08 (d, J = 5.6 Hz, 2H), 5.98 (d, J = 1.8 Hz, 1H), 3.57 (s, 2H), 3.47 (s, 2H), 3.26 (q, J = 6.0 Hz, 2H), 3.15 - 3.06 (s, 1H), 2.54 - 2.51 (m, 2H), 2.47 - 2.41 (m, 4H), 2.38 (s, 5H), 2.26 - 2.22 (m, 3H), 1.99 - 1.93 (m, 2H), 1.78 - 1.68 (m, 2H) ppm. HRMS m / z: calcd for C 33 H 37 N5O2 [M + H] + 536.3020 found 536.3021.

[0103] Compound 38: Yield 73%, 1 1H NMR (400 MHz, DMSO-d6) δ 11.27 (s, 1H), 7.75 (d, J = 5.6 Hz, 1H), 7.49 (d, J = 7.8 Hz, 1H), 7.30 - 7.19 (m, 7H), �.42 (s, 1H), 615 (d, J = 5.6 Hz, 2H), 6.04 (s, 1H), 4.56 (s, 2H), 3.47 - 3.43 (m, 6H), 2.53 (t, J = 6.0 Hz, 2H), 2.43 - 2.38 (m, 6H), 1.84 - 1.82 (m, 5H), 1.63 (d, J = 12.8 Hz, 2H), 1.45 - 1.30 (m, 4H) ppm.

[0104] Compound 39: Yield 73%, 1 1H NMR (400 MHz, DMSO-d6) δ 11.26 (s, 1H), 7.75 (d, J = 5.7 Hz, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.31 - 7.16 (m, 7H), 6.75 (s, 1H), 6.15 (d, J = 5.6 Hz, 1H), 6.04 (s, 1H), 3.99 - 3.94 (m, 2H), 3.48 (s, 4H), 3.28 - 3.23 (m, 2H), 2.41 (s, 4H), 2.39 (s, 3H), 2.14 (t, J = 5.9 Hz, 2H), 1.83 - 1.78 (m, 2H), 1.24 (s, 2H) ppm. HRMS m / z: calcd for C32 H 35 N5O2[M+H] + 522.2864, found 522.2863.

[0105] Compound 40: Yield 81%, 1 H NMR (400MHz, DMSO-d6) δ11.64(s,1H),7.79(d,J=6.2Hz,1H),7.49(d,J=7.8Hz,1H),7.37-7.1 8(m,8H),6.32(d,J=5.5Hz,1H),6.19(s,1H),3.83-3.77(m,2H),3.50(s,2H),3.40(s,2H),3.3 7(d,J=10.2Hz,2H),3.27(d,J=3.3Hz,2H),3.09(dd,J=15.0,7.7Hz,1H),2.84(d,J=4.0Hz,1H) ,2.56(s,2H),2.40(s,3H),1.81(s,1H),1.57(d,J=2.0Hz,4H),1.24(t,J=4.8Hz,2H)ppm.HRMS m / z:calcd for C 32 H 37 N5O2[M+H] + 524.3020, found 524.3029.

[0106] Compound 41: Yield 88%, 1 H NMR (400MHz, DMSO-d6) δ11.27(s,1H),7.75(d,J=5.6Hz,1H),7.49(d,J=7.8Hz,1H),7.3 1-7.22(m,6H),7.19(s,1H),6.34(s,1H),6.13(d,J=5.7Hz,1H),6.02(s,1H),3.86-3.8 1(m,2H),3.50(s,2H),3.45(s,2H),3.41-3.37(m,2H),3.30-3.26(m,2H),2.87(s,1H), 2.56-2.51(m,2H),2.43(s,2H),2.38(s,5H),1.64-1.56(m,2H),1.55-1.51(m,2H)ppm.

[0107] Compound 42: Yield 82%, 11H NMR (400 MHz, DMSO-d6) δ 11.39 (s, 1H), 7.76 (d, J = 5.8 Hz, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.30 - 7.18 (m, 7H), 6.19 (d, J = 5.9 Hz, 1H), 6.09 (s, 1H), 5.72 (s, 1H), 3.46 (s, 4H), 2.55 (s, 2H), 2.43 (s, 4H), 2.39 (s, 3H), 2.07 (d, J = 5.9 Hz, 4H), 1.61 - 1.52 (m, 4H), 1.23 (s, 1H) ppm. HRMS m / z: calcd for C 33 H 37 N5O [M+H] + 520.3071 found 520.3068.

[0108] Compound 43: Yield 73%, 1 1H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 7.73 (d, J = 5.5 Hz, 1H), 7.49 (d, J = 7.8 Hz, 1H), 7.33 - 7.21 (m, 4H), 7.17 (s, 1H), 6.07 (d, J = 5.5 Hz, 2H), 5.96 (s, 1H), 4.20 (dd, J = 10.0, 2.6 Hz, 1H), 3.88 - 3.64 (m, 4H), 3.57 - 3.40 (m, 6H), 3.28 - 3.19 (m, 2H), 3.08 - 2.88 (m, 2H), 2.38 (s, 7H), 1.41 (s, 9H) ppm. 13 13C NMR (101 MHz, DMSO-d6) δ 166.49, 154.27, 150.97, 149.75, 147.46, 144.47, 141.91, 140.48, 137.42, 133.67, 131.79, 130.32, 129.47, 129.20, 128.50, 127.23, 108.47, 98.69, 96.58, 79.65, 72.11, 66.13, 56.62 53.53, 52.81, 45.47, 41.75, 28.50, 21.15 ppm. HRMS m / z: calcd for C 36 H 44 N6O4 [M+H] + 625.3497 found 62,5.349,1.

[0109] Compound 44: Yield 78%, 11H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 7.73 (d, J = 5.5 Hz, 1H), 7.49 (d, J = 7.9 Hz, 1H), 7.33 - 7.16 (m, 13H), 6.07 (d, J = 5.5 Hz, 1H), 5.95 (s, 1H), 4.23 (dt, J = 14.4, 7.2 Hz, 1H), 3.87 - 3.77 (m, 1H), 3.66 - 3.37 (m, 6H), 3.23 (dd, J = 12.3, 6.3 Hz, 2H), 2.70 - 2.60 (m, 3H), 2.44 - 2.31 (m, 8H), 2.22 - 2.07 (m, 3H) ppm. 13 13C NMR (101 MHz, DMSO-d6) δ 171.97, 167.00, 149.59, 147.49, 144.43, 141.90, 140.48, 138.22, 137.43, 133.67, 131.80, 130.29, 129.46, 129.39, 129.18, 128.66, 128.51, 127.49, 127.23, 108.49, 98.68, 96.60, 75.76, 73.13, 66.70, 62.70, 56.60, 55.18, 54.62, 52.95, 45.47, 41.72, 21.15 ppm. HRMS m / z: calcd for C 38 H 42 N6O2 [M + H] + 615.3442 found 615.3444.

[0110] Compound 45: Yield 80%, 1 1H NMR (400 MHz, DMSO-d6) δ 11.64 (s, 1H), 7.80 (d, J = 6.2 Hz, 1H), 7.49 (d, J = 7.8 Hz, 1H), 7.34 - 7.20 (m, 7H), 7.10 - 6.99 (m, 1H), 6.30 (d, J = 6.2 Hz, 1H), 6.17 (s, 1H), 3.54 (s, 2H), 3.48 (dd, J = 6.9, 3.0 Hz, 2H), 3.37 (d, J = 5.9 Hz, 2H), 2.57 (t, J = 6.5 Hz, 2H), 2.43 (s, 2H), 2.40 (s, 3H), 2.30 (d, J = 10.2 Hz, 2H), 2.21 - 2.14 (m, 4H), 1.92 - 1.83 (m, 1H), 1.23 (s, 2H) ppm. HRMS m / z: calcd for C 32 H 35N5O2[M+H] + 522.2864, found 522.2858.

[0111] Compound 46: Yield 71%, 1 H NMR (400MHz, DMSO-d6) δ11.33(s,1H),7.76(d,J=5.7Hz,1H),7.49(d,J=7.8Hz,1H),7.26(m,7H),6.16(d,J=5.8Hz,1H),6.04(s,1H), 3.51-3.43(m,4H),3.33-3.24(m,4H),3.01-2.93(m,1H),2.53(t,J=6.1Hz,2H),2.43(s,2H),2.39(s,3H),1.76-1.51(m,8H)ppm.HRMS m / z:calcd for C 32 H 37 N5O[M+H] + 508.3071 found 508.3072.

[0112] Compound 47: Yield 76%, 1 H NMR (400MHz, DMSO-d6) δ11.45(s,1H),7.77(d,J=5.8Hz,1H),7.48(d,J=7.8Hz,1H),7.34-7.13(m,7H),6.74(s,1H),6.22(d,J=5.9H z,1H),6.11(s,1H),4.72-4.59(m,4H),4.17-4.04(m,1H),3.48-3.41(m,4H),3.14(s,2H),2.55-2.53(s,1H),2.39(s,7H)ppm.HRMS m / z:calcd for C 30 H 33 N5O2[M+H] + 496.2707 found 496.2709.

[0113] Compound 48: Yield 75%, 1H NMR (400MHz, DMSO-d6) δ11.93(s,1H),7.83(d,J=6.6Hz,1H),7.55(s,1H),7.49(d ,J=7.8Hz,1H),7.33-7.21(m,7H),6.41(d,J=6.7Hz,1H),6.28(s,1H),3.50(s,2H) ,3.44-3.37(m,4H),2.95(d,J=14.0Hz,2H),2.60-2.56(m,2H),2.53(d,J=3.5Hz,2 H),2.49-2.45(m,2H),2.40(s,3H),2.30-2.05(m,2H),1.86-1.65(m,2H)ppm.HRMS m / z:calcd for C 31 H 34 BrN5O[M+H] + 572.2019found 572.2019and 574.2004.

[0114] Compound 49: Yield 80%, 1 H NMR (400MHz, DMSO-d6) δ11.22(s,1H),7.75(d,J=5.6Hz,1H),7.49(d,J=7.8 Hz,1H),7.30-7.22(m,6H),7.18(s,1H),6.27(s,1H),6.12(d,J=5.7Hz,1H), 6.01(s,1H),3.66(s,2H),3.45(s,2H),3.27(d,J=6.1Hz,2H),2.54(d,J=6. 7Hz,2H),2.46(s,2H),2.38(s,5H),1.98(s,1H),0.74-0.68(m,4H)ppm.HRMS m / z:calcdfor C 30 H 33 N5O[M+H] + 480.2758 found 480.2759.

[0115] Compound 50: Yield 86%, 1H NMR (400MHz, DMSO-d6) δ11.73(s,1H),7.81(d,J=6.3Hz,1H),7.49(d,J=7.8Hz,1H),7.34-7.18(m,8H),6.34(d,J=6.4Hz,1H),6.21(s,1H),3 .46(s,4H),3.10(d,J=7.3Hz,1H),2.58(t,J=6.4Hz,2H),2.40(s,5H),1.24(s,2H),1.18(t,J=7.3Hz,2H),1.13(s,6H),1.07(s,6H)ppm.HRMS m / z:calcd for C 34 H 41 N5O[M+H] + 536.3384, found 536.3380.

[0116] Compound 51: Yield 77%, 1 H NMR (400MHz, DMSO-d6) δ12.14(s,1H),8.74(d,J=4.4Hz,1H),8.52(d,J=8.4Hz,1H),7.8 6(d,J=6.7Hz,1H),7.53-7.46(m,2H),7.34-7.21(m,7H),6.46(d,J=6.8Hz,1H),6.31(s ,1H),3.66(s,2H),3.51-3.43(m,6H),3.36(dd,J=11.0,7.8Hz,4H),2.66(s,2H),2.57( d,J=17.1Hz,2H),2.41(s,3H),1.91(s,2H),1.79(t,J=3.1Hz,1H),1.38(s,9H)ppm.HRMS m / z:calcd for C 37 H 44 N6O3[M+H] + 621.3548 found 621.3547.

[0117] Compound 52: Yield 81%, 1H NMR (400MHz, DMSO-d6) δ11.14(s,1H),7.74(d,J=5.5Hz,1H),7.49(d,J=7.8Hz,1H) ,7.26(m,6H),7.17(s,1H),6.08(d,J=5.5Hz,2H),5.97(s,1H),3.61(s,2H),3.43(s ,2H),3.25(d,J=6.0Hz,2H),2.99(d,J=11.5Hz,2H),2.81(d,J=11.2Hz,2H),2.56- 2.51(m,2H),2.43(d,J=3.0Hz,2H),2.38(s,3H),2.05(s,1H),1.79(s,2H)ppm.HRMS m / z:calcd for C 32 H 36 N6O[M+H] + 521.3023 found 521.3022.

[0118] Example 4: Compounds 53-57 and their preparation methods

[0119]

[0120] 4-Oxocyclohexane-1-carboxylic acid (37.2 mg, 0.26 mmol) was dissolved in dry dichloromethane (10 mL), and HATU (99.5 mg, 0.26 mmol) and triethylamine (44 mg, 0.43 mmol) were added. After stirring at room temperature for 30 minutes, 7 (90 mg, 0.21 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane:methanol:50:1) to give 53-71.5 mg of solid, in 61% yield. 1 H NMR (400MHz, DMSO-d6) δ11.84(s,1H),7.80(d,J=6.4Hz,1H),7.49(d,J=7.7Hz,1H),7. 37-7.14(m,8H),6.37(d,J=6.5Hz,1H),6.31(s,1H),4.41(d,J=11.8Hz,1H),4.04(d,J= 12.5Hz,1H),2.71(dd,J=12.0,8.4Hz,1H),2.43(s,2H),2.41(s,3H),2.24(d,J=14.4H z,4H),2.12-2.07(m,1H),1.92(s,2H),1.74(dd,J=22.4,11.1Hz,6H),1.51(s,4H)ppm. 13C NMR(101MHz,DMSO-d6)δ210.55,176.08,172.38,150.24,141.15,140.85,138.71,131.85,130.75,129.41, 128.66,127.76,127.52,108.52,100.75,46.15,40.31,40.07,37.24,33.68,29.41,28.65,21.21,9.05ppm.

[0121] The synthesis methods for compounds 54-57 are the same as for 53, the difference being the selection of different starting materials based on the different substituent structures of the compounds. Their yields and characterization results are as follows:

[0122] Compound 54: Yield 81%, 1 H NMR (400MHz, DMSO-d6) δ11.74(s,1H),7.78(d,J=6.4Hz,1H),7.48(d,J=7.8Hz,1H),7.26(dt,J=7.7 ,6.6Hz,7H),6.71(s,1H),6.32(d,J=6.5Hz,1H),6.28(s,1H),4.13(d,J=12.9Hz,2H),3.99-3.93(m, 2H),3.27(d,J=6.3Hz,2H),2.78(s,2H),2.42(d,J=10.3Hz,3H),2.13(t,J=5.9Hz,2H),1.83-1.75( m,2H),1.69(d,J=12.5Hz,2H),1.58(s,1H),1.50(d,J=7.0Hz,2H),1.04(dd,J=12.1,2.9Hz,2H)ppm. 13 C NMR (101MHz, DMSO-d6) δ169.33,150.63,146.32,141.98,141.27,140.77,138.48,138.02,134.79,131.82,130.72,129. 42,128.62,128.05,127.45,109.34,108.50,100.48,65.83,46.14,45.08,35.35,33.83,32.38,21.65,21.24,9.04ppm.

[0123] Compound 55: 90% yield. 11H NMR (400 MHz, DMSO-d6) δ 11.74 (s, 1H), 7.78 (d, J = 6.4 Hz, 1H), 7.48 (d, J = 7.9 Hz, 1H), 7.36 - 7.17 (m, 7H), 6.33 (d, J = 6.5 Hz, 1H), 6.28 (s, 1H), 4.36 (d, J = 11.7 Hz, 1H), 3.93 (d, J = 12.5 Hz, 1H), 3.79 (t, J = 9.3 Hz, 2H), 3.36 - 3.27 (m, 6H), 3.01 - 2.92 (m, 1H), 2.82 (dd, J = 11.9, 8.4 Hz, 1H), 2.40 (s, 3H), 1.72 (dt, J = 30.1, 26.4 Hz, 4H), 1.57 (s, 4H), 1.50 (s, 2H) ppm. 13 13C NMR (101 MHz, DMSO-d6) δ 170.93, 150.60, 141.88, 141.27, 140.77, 138.47, 134.76, 131.83, 130.71, 129.41, 128.62, 128.05, 127.46, 108.5, 100.47, 97.04, 69.62, 67.77, 46.13, 45.42, 41.54, 38.75, 35.29, 33.66, 31.88, 25.30, 21.19, 9.04 ppm.

[0124] Compound 56: Yield 86%, 1 1H NMR (400 MHz, DMSO-d6) δ 11.65 (s, 1H), 7.78 (d, J = 6.3 Hz, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.34 - 7.25 (m, 5H), 7.25 - 7.21 (m, 3H), 6.28 (d, J = 6.3 Hz, 1H), 6.24 (s, 1H), 4.39 (d, J = 12.0 Hz, 1H), 3.99 (d, J = 12.8 Hz, 1H), 3.46 (d, J = 6.7 Hz, 2H), 3.33 - 3.27 (m, 4H), 2.40 (s, 3H), 2.34 - 2.31 (m, 2H), 2.19 (d, J = 2.7 Hz, 2H), 2.16 - 2.13 (m, 2H), 1.75 - 1.69 (m, 2H), 1.60 - 1.58 (m, 2H), 1.51 - 1.49 (m, 2H) ppm. 13C NMR(101MHz,DMSO-d6)δ217.27,176.27,171.87,150.35,141.32,140.75,138.39,131.83,130.68,129.42,128 .61,127.44,108.49,102.36,100.33,46.16,41.92,41.30,40.72,37.40,33.65,31.88,26.59,21.20,9.07ppm.

[0125] Compound 57: Yield 85%, 1 H NMR (400MHz, DMSO-d6) δ11.83(s,1H),7.79(d,J=6.5Hz,1H),7.49(d,J=7.8Hz,1H), 7.29(t,J=7.6Hz,4H),7.26-7.19(m,4H),6.37(d,J=6.4Hz,1H),6.31(s,1H),4.35( s,1H),4.24(d,J=11.3Hz,1H),2.41(s,3H),1.99-1.90(m,1H),1.76-1.57(m,4H),1 .50(dd,J=8.5,3.8Hz,4H),0.99(dd,J=15.8,9.1Hz,2H),0.68(d,J=7.9Hz,5H)ppm. 13 C NMR(101MHz,DMSO-d6)δ176.06,171.12,151.23,141.15,140.83,138.69,131.83,129.40,130.76,129.40 ,128.65,127.79,127.51,108.49,100.73,46.18,35.31,33.72,21.19,12.87,10.76,9.04,8.15,7.23ppm.

[0126] Example 5: Compounds 58-65 and their preparation methods

[0127]

[0128] Dissolve compound 8 (100 mg, 0.24 mmol) in 15 mL of dry dichloromethane, then add triethylamine (122.7 mg, 1.21 mmol) and react at room temperature for 30 minutes. Simultaneously, dissolve triphosgene (24.5 mg, 0.08 mmol) in 8 mL of dry dichloromethane. Then, dilute cyclobutylamine (25.9 mg, 0.36 mmol) in 5 mL of dry dichloromethane and slowly add it dropwise to the triphosgene solution. React at room temperature for 30 minutes. The reaction solution is then concentrated under reduced pressure using a rotary evaporator. The solution of compound 8 is then added, and the reaction is continued at room temperature for 1 hour. After the reaction of starting material A is complete, as monitored by thin-layer chromatography, the mixture is purified by silica gel column chromatography (gradient elution of DCM:MeOH = 100:1 to 10:1) to obtain the target compound 58, 20 mg, in a yield of 16.2%. 1 H NMR (400MHz, DMSO-d6) δ11.70(s,1H),7.80(d,J=6.3Hz,1H),7.49(d,J=7.8Hz,1H),7 .33-7.20(m,8H),6.70(d,J=7.6Hz,1H),6.34(d,J=6.3Hz,1H),6.23(s,1H),4.09(q,J =8.2Hz,1H),3.47-3.40(m,2H),3.17(d,J=3.4Hz,2H),3.07(q,J=7.3Hz,2H),2.78-2 .53(m,6H),2.40(s,3H),2.15-2.05(m,2H),1.97-1.85(m,2H),1.61-1.51(m,2H)ppm.

[0129] The synthesis methods for compounds 59-65 are the same as for 58, the difference being the selection of different starting materials based on the different substituent structures of the compounds. Their yields and characterization results are as follows:

[0130] Compound 59: Yield 35%, 1 H NMR (400MHz, DMSO-d6) δ11.76(s,1H),7.82(d,J=6.3Hz,1H),7.49(d,J=7.8Hz,1H) ,7.33-7.21(m,8H),6.67(t,1H),6.38(d,J=6.4Hz,1H),6.27(s,1H),3.49(d,J=6. 2Hz,2H),3.06(q,J=7.3Hz,4H),2.90(t,J=6.1Hz,2H),2.86-2.58(m,6H),2.40(s, 3H),0.92(ddd,J=12.9,7.8,5.3Hz,1H),0.39-0.34(m,2H),0.16-0.12(m,2H)ppm.

[0131] Compound 60: Yield 36%, 1 H NMR (400MHz, DMSO-d6) δ11.25(s,1H),7.80(d,J=5.5Hz,1H),7.55(d,J=7.8Hz,1H),7.39 -7.26(m,7H),7.23(s,1H),6.58(t,J=5.7Hz,1H),6.16(d,J=5.6Hz,1H),6.02(s,1H),3. 88(dd,J=11.3,2.5Hz,2H),3.35-3.23(m,8H),2.98(t,J=6.2Hz,2H),2.43(d,J=7.9Hz,9 H), 1.70 (td, J = 7.3, 3.6Hz, 1H), 1.59 (d, J = 12.9Hz, 2H), 1.16 (qd, J = 11.9, 4.4Hz, 2H) ppm.

[0132] Compound 61: Yield 39%, 1 H NMR (400MHz, DMSO-d6) δ11.20(s,1H),7.75(d,J=5.5Hz,1H),7.50(d,J=7.9Hz,1H),7.37-7.06(m,13H),6.73(d,J=8.3Hz,1H),6.11(d,J=5 .7Hz,1H),5.96(s,1H),4.59(q,J=8.2Hz,1H),3.25(d,J=6.1Hz,6H),2.38(s,9H),1.70(tt,J=13.7,6.6Hz,2H),0.85(t,J=7.3Hz,3H)ppm.

[0133] Compound 62: Yield 33%, 1 H NMR (400MHz, DMSO-d6) δ11.21(s,1H),7.75(d,J=5.6Hz,1H),7.50(d,J=7.8Hz,1H),7.34-7.22(m,6H),7.18(s,1H),6.59(s,1H),6.20(s ,1H),6.11(d,J=5.6Hz,1H),5.98(s,1H),3.25(s,6H),2.37(d,J=10.2Hz,9H),1.24(s,1H),0.57-0.50(m,2H),0.38(t,J=5.3Hz,2H)ppm.

[0134] Compound 63: Yield 31%, 1H NMR (400MHz, DMSO-d6) δ11.22(s,1H),7.75(d,J=5.6Hz,1H),7.50(d,J=7.9Hz,1H),7.33-7.21(m,6H),7.18(s,1H),6.50(t,J=5.5Hz,1H ),6.23(s,1H),6.12(d,J=5.6Hz,1H),5.99(s,1H),3.28(s,8H),2.98(q,2H),2.39(s,7H),1.42(q,J=7.2Hz,2H),0.83(t,J=7.4Hz,3H).

[0135] Compound 64: Yield 28%, ¹H NMR (400 MHz, DMSO-d6) δ 11.31 (s, 1H), 7.85 (d, J = 5.6 Hz, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.41–7.32 (m, 7H), 7.28 (s, 1H), 6.35 (d, J = 7.0 Hz, 1H), 6.23 (d, J = 5.7 Hz, 1H), 6.09 (s, 1H), 4.01 (q, J = 7.2 Hz, 1H), 3.38 (s, 6H), 2.61 (s, 9H), 1.91–1.85 (m, 2H), 1.72 (d, J = 7.7 Hz, 2H), 1.58–1.48 (m, 4H).

[0136] Compound 65: Yield 25%, 1 H NMR (400MHz, DMSO-d6) δ11.21(s,1H),7.80(d,J=5.6Hz,1H),7.55(d,J=7.8Hz,1H),7.38-7.27(m,7H),7.23(s,1H),6.50(t,J=5.5Hz,1H),6.1 8(d,J=5.7Hz,1H),6.03(s,1H),3.32(d,J=5.5Hz,6H),3.08(q,J=5.8Hz,2H),2.44(s,9H),1.31(dt,J=14.7,7.1Hz,4H),0.92(t,J=7.3Hz,3H).

[0137] The technical solution of the present invention will be further illustrated by the following experiments.

[0138] Experimental Example 1: CSN5 Inhibitory Activity

[0139] I. Experimental Methods

[0140] Compound 1-65 used in this experimental example was prepared according to the methods in Examples 1-5.

[0141] 1. Experimental materials: WHB all-black 96-well flat-bottom luminescent plate (specification: WHB-96-02), WHB 96-well cell culture plate (specification: WHB-96), 6-well cell culture plate, sterile pipette tips, sterile centrifuge tubes.

[0142] 2. Experimental Methods

[0143] The experimental steps for in vitro enzyme activity testing are as follows:

[0144] All inhibitor compounds were dissolved in fresh DMSO to prepare a 100 mM stock solution. At room temperature (25°C), the IC50 of a single concentration of the target compound against CSN5 was measured in a 96-well black microplate. 50 To determine the IC50 value, the target compound was first diluted 3-fold in a test buffer (20 mM Tris, 200 mM sodium chloride, pH 7.5, 0.01% Triton X-100) to obtain 10 concentrations. Then, 10 μL of the compound dilution, 30 μL of buffer solution, and 10 μL of enzyme solution were added sequentially to each well, with three replicates for each concentration. The mixture was incubated for 10 min, followed by the addition of 10 μL of pre-prepared fluorescent substrate solution (final concentration 0.25 μM), bringing the total reaction volume to 60 μL. The mixture was then incubated for another 1 h. The IC50 was then detected using a microplate reader, and the IC50 of the tested compound was calculated using Graphpad Prism software based on the fluorescence polarization change. 50 value.

[0145] The experimental steps for the HCT116 cell MTT proliferation inhibition activity assay are as follows:

[0146] Collect cells in the logarithmic growth phase, adjust the cell suspension concentration, add 100 μL to each well, and seed the cells. Incubate at 37°C with 5% CO2 until a monolayer of cells forms at the bottom of the wells (96-well flat-bottom plate). After cell adhesion, discard the original culture medium, add the drug, and incubate the cells in an incubator at 37°C with 5% CO2 for 72 h. Observe under an inverted microscope. After the drug treatment is complete, add 20 μL of MTT to each well and continue culturing for 4 h. Terminate the culture and carefully aspirate the culture medium from the wells. Add 100 μL of DMSO to each well, and shake on a shaker at low speed for 10 min to fully dissolve the crystals. Measure the absorbance of each well at 570 nm using a microplate reader.

[0147] The experimental steps for Western blot testing are as follows:

[0148] HCT116 cells were cultured in 6-well cell culture plates. Different concentrations of the drug were added to the culture plates and incubated. The old culture medium was discarded, and the cells were washed twice with PBS. The PBS was discarded, and RIPA lysis buffer was added. After lysis, the cells were collected from the wells of the plate using a cell scraper and transferred to 1.5 mL EP tubes. The cells were further disrupted by sonication, followed by centrifugation (12000 rpm, 4℃, 10 min). The supernatant was collected for BCA protein quantification. A large volume of the supernatant was labeled, and SDS loading buffer was added. The mixture was then transferred to 1.5 mL EP tubes and incubated at 95℃ for 20 min to denature the protein. Subsequently, the samples were subjected to protein gel electrophoresis, transfer to a membrane, blocked, incubated with primary antibody, incubated with secondary antibody, and finally developed.

[0149] II. Experimental Results

[0150] The experimental results for compounds 1-65 are shown in Table 1.

[0151] Table 1. Inhibitory activity of compounds 1-65 against CSN5 enzyme

[0152]

[0153] The experimental results above show that all compounds provided in this embodiment possess CSN5 inhibitory activity. Among them, the compounds with the best activity include: compound 9, compound 28, compound 29, compound 32, compound 34, compounds 37-46, and compound 49.

[0154] The MTT results for compounds 20, 21, and 44 are shown in the table below.

[0155] Table 2. MTT results for compounds 20, 21, and 44

[0156] Compound No. HCT116 cell IC 50 (μM) 20 67 21 167.4 44 7.7

[0157] MTT results showed that compounds 20 and 21 had certain inhibitory effects on cell proliferation, while compound 44 had a stronger inhibitory effect on proliferation.

[0158] Western blot results for compounds 20 and 21 are as follows: Figure 1 As shown in the figure. Western blot results indicated that, at a concentration of 30 μM, compounds 20 and 21 enhanced Nedd8-cullin1 levels, but were slightly weaker than the positive compound Aza-4, while compound 44 had no significant effect on cullin. These experimental results suggest that compounds 20 and 21 also have the potential to treat cancer.

[0159] As can be seen from the above embodiments and experimental examples, this invention provides a series of 4-substituted-2-biphenyl-7-azaindole compounds with good CSN5 inhibitory activity, which are expected to serve as drugs for the prevention and treatment of CSN5-mediated diseases (such as cancer). This invention provides new options for clinical drug use and has excellent application prospects.

Claims

1. A compound represented by Formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a crystal form thereof: wherein, the compound is represented by Formula II, Formula III, Formula IV, or Formula V: R1is selected from substituted or unsubstituted C1-C2alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted 6-membered heteroaryl, substituted or unsubstituted 4-6-membered heterocycloalkyl, 4-6-membered heterocycloalkyl linked with an amino protecting group, substituted amino, wherein the substituent is selected from phenyl, 6-membered heterocycloalkyl, oxygen atom, hydroxyl, benzyl, 9-membered heteroaryl, C3-C5cycloalkyl, C6cycloalkyl substituted with ethyl, Br, C1-C4alkyl, methyl substituted with cyclopropyl, methyl substituted with 6-membered heterocycloalkyl, C3alkyl substituted with phenyl. L is selected from the group consisting of null, substituted or unsubstituted C1-C 10 alkylene, wherein the substitutents are selected from the group consisting of C1-C 10 alkyl, C6-C 10 aryl, C3-C 10 cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, an oxygen atom, a hydroxyl group, C6-C 10 aryl-substituted C1-C 10 alkyl, halogen, amino, C1-C 10 amine, C1-C 10 ester, C1-C 10 alkoxy; R is selected from substituted or unsubstituted C1-C 10 ester, amino, amino linked to a protecting group, substituted or unsubstituted C1-C 10 amine, substituted or unsubstituted C6-C 10 aromatic amine, substituted or unsubstituted 5-10 membered heterocycloalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, wherein the substituents are selected from C1-C 10 alkyl, C6-C 10 aryl, C3-C 10 cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, oxygen atom, hydroxyl, C6-C 10 aryl-substituted C1-C 10 alkyl, halogen, amino, C1-C 10 amine, C1-C 10 ester, C1-C 10 alkoxy, amino protecting group, -COR1; R1is selected from substituted or unsubstituted C1-C 10 alkyl, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 4-10 membered heterocycloalkyl, substituted or unsubstituted amino, wherein the substituents are selected from C1-C 10 alkyl, C3-C 10 cycloalkyl substituted C1-C 10 alkyl, C6-C 10 aryl substituted C1-C 10 alkyl, 4-10 membered heterocycloalkyl substituted C1-C 10 alkyl, C6-C 10 aryl, C3-C 10 cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, oxygen atom, hydroxyl, C6-C 10 aryl substituted C1-C 10 alkyl, halogen, amino, C1-C 10 amine, C1-C 10 ester, C1-C 10 alkoxy, amino protecting group.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a crystalline form thereof, wherein: L is selected from nothing or C1-C3alkylene.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a crystalline form thereof, characterized in that: R is selected from C2ester, C2amine, amino, amino linked with a protecting group, anilino, 5-6-membered heterocycloalkyl, 5-6-membered heterocycloalkyl linked with an amino protecting group, 5-6-membered heterocycloalkyl substituted with -COR1, C3-C5cycloalkyl, C3-C5cycloalkyl substituted with F.

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a crystalline form thereof, wherein: the compound is represented by Formula VI:

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a crystalline form thereof, wherein: wherein, 6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a crystalline form thereof, wherein: X is selected from O or N-COR1; R1is selected from substituted C1-C2alkyl, 6-membered heteroaryl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted 6-membered heterocycloalkyl, wherein the substituent is selected from phenyl, 6-membered heterocycloalkyl, hydroxyl, oxygen atom, Boc, benzyl. the compound is represented by Formula VII:

8. Use of the compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a crystal form thereof in the manufacture of a medicament for treating and / or preventing a CSN5-mediated disease.

7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a crystalline form thereof, wherein The CSN5-mediated disease comprises at least one of cancer, autoimmune disease, neurodegenerative disease, inflammation, and cardiovascular system disease. It is prepared by adding the compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a crystal form thereof as an active ingredient to a pharmaceutically acceptable adjuvant.

9. Use according to claim 8, characterized in that: ​ 10. A pharmaceutical composition, characterized by: ​

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