A diimidazole diazapyridine compound, its preparation method and application

Abstract

This invention provides a diimidazole diaza compound, its preparation method, and its application. The diimidazole diaza compound has the structure shown in formula (I). The diimidazole diaza compound of this invention has inhibitory and / or degradation activity against DDX3X, thereby having preventive and / or therapeutic effects on DDX3X-mediated diseases such as viral infections, inflammation, intellectual disability, and cancer.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology and relates to a diimidazole diaza Class of compounds, their preparation methods, and applications. Background Technology

[0002] Cancer is one of the most serious threats to human life, health, and safety. Global cancer statistics show that in 2020, there were approximately 19.3 million new cancer cases worldwide, a 3.2% increase compared to 2010. Meanwhile, the number of cancer deaths worldwide reached 10 million in 2020, a 20.1% increase compared to 2010 (Sung H, Ferlay J et al., “Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries.” CA: a cancer journal for clinicians, 71, 209-249 (2021)). Currently, the global incidence and mortality rates of cancer are on the rise. However, existing marketed drugs cannot fully meet the clinical needs for anti-tumor treatment. Therefore, driven by both high market demand and insufficient supply, the research and development of anti-tumor drugs still has broad prospects.

[0003] DDX3X is a member of the DEAD-box family of RNA helicases, and is an adenosine triphosphate (ATP)-dependent RNA helicase. Previous studies have shown that DDX3X plays important roles at different stages of gene expression, such as regulating gene transcription, pre-mRNA splicing, and nuclear export in the nucleus, and regulating mRNA translation in the cytoplasm (Mo, J., Liang, H., et al., “DDX3X: structure, physiologic functions and cancer.” Mol Cancer, 20, 38 (2021).). Throughout life, DDX3X participates in multiple biological functions, including embryonic development (Chia-Yu C, Chieh-Hsiang C et al., “Targeted inactivation of murine DDX3X: essential roles of DDX3X in placentation and embryogenesis.” Human Molecular Genetics, 25, 2905-2922 (2016)) and immune responses (Soulat D, Bürckstümmer et al., “The DEAD-box helicase DDX3X is a critical component of the TANK-binding kinase 1-dependent innate immune response.” The EMBO Journal, 27, 2135-2146 (2008)). Abnormalities in DDX3X are closely associated with various diseases, such as viral infections, inflammation, intellectual disability, and cancer (Mo, J., Liang, H. et al., “DDX3X: structure, physiologic functions and cancer.” Mol Cancer, 20, 38 (2021).). It is worth noting that in recent years, numerous multi-omics studies have revealed that DDX3X plays a crucial role in the development and progression of tumors, such as lung cancer, breast cancer, colon cancer, prostate cancer, pancreatic cancer, and oral cancer.In triple-negative breast cancer, preclinical animal studies have shown that the DDX3X inhibitor FHP01 significantly inhibits tumorigenicity in xenograft breast cancer mice (Gherardini L, Inzalaco G et al., “The FHP01 DDX3X Helicase Inhibitor Exerts Potent Anti-Tumor Activity In Vivo in Breast Cancer Pre-Clinical Models.” Cancers, 13, 4830 (2021)). In colorectal cancer, DDX3 promotes tumor invasion via the CK1ε / Dvl2 axis (He TY, Wu DW et al., “DDX3 promotes tumor invasion in colorectal cancer via the CK1ε / Dvl2 axis.” Scientific Reports, 6, 21483 (2016)). In prostate cancer, the DDX3 helicase activity inhibitor RK-33 significantly enhances the radiosensitivity of prostate cancer cells (Xie M, Vesuna F et al., "RK-33 Radiosensitizes Prostate Cancer Cells by Blocking the RNA Helicase DDX3." Cancer Research, 76, 6340-6350 (2016)). In pancreatic cancer, RNA polymerase II-Associated Factor 1 regulates the stem cell characteristics of pancreatic cancer cells through interactions with PHF5A and DDX3 (Karmakar S, Rauth S et al., "RNA Polymerase II-Associated Factor 1 Regulates Stem Cell Features of Pancreatic Cancer Cells, Independently of the PAF1 Complex, via Interactions With PHF5A and DDX3." Gastroenterology, 159, 1898-1915 (2020)). In oral cancer, DDX3 inhibitor ketosalt effectively inhibits the in vitro proliferation of oral cancer cells (Samal SK, Routray S et al., “Ketorolac salt is a newly discovered DDX3 inhibitor to treat oral cancer” Rep, 5, 9982 (2015)).Therefore, DDX3X is expected to become a new drug target with broad-spectrum anti-cancer potential.

[0004] In recent years, researchers have designed a variety of small molecule compounds targeting the ATPase or helicase activity of DDX3. Studies have shown that these DDX3 inhibitors possess antiviral replication activity and / or antitumor activity. These active compounds mainly include rhodanine, triazabenzene, diuretics, and diimidazoles. or diimidazole triaza Similar to cyclic nucleoside derivatives. Researchers have found that rhodanine and triazabenzene derivatives (Maga G, Falchi F et al., "Toward the discovery of novel anti-HIV drugs. Second-generation inhibitors of the cellular ATPase DDX3 with improved anti-HIV activity: synthesis, structure-activity relationship analysis, cytotoxicity studies, and target validation." ChemMedChem, 6, 1371-1389 (2011)) can inhibit the ATPase activity of DDX3 (Ki = 6.2 μM), but their antiviral activity is low and their toxicity is high (e.g., the antiviral EC50 of some compounds is 83 μM, and the CC50 against MOLT-4 T lymphocytes is 5 μM). Both of these derivatives have been shown to have poor pharmacological activity. Researchers have also designed diurea DDX3 inhibitors, which have lower toxicity, but their water solubility is poor. Diurea DDX3 inhibitors have a solubility range far exceeding the recommended range for routine administration. This has greatly hindered the smooth progress of preclinical animal trials. (Brai A, Fazi R, et al., "Human DDX3 protein is a valuable target to develop broad spectrum antiviral agents." Proceedings of the National Academy of Sciences, 113, 5388-5393 (2016)) Recently, multiple research teams have jointly reported a diimidazole diazoxide... or diimidazole triaza DDX3 inhibitors of derivatives of isocyclic nucleoside derivatives. Although these inhibitors exhibit good inhibition of DDX3 helicase activity (IC50 = 0.2 μM) (Yedavalli VSRK, Zhang N et al., “Ring-expanded nucleoside analogues inhibit RNA helicase and intracellular human immunodeficiency virus type 1 replication.” Journal of Medicinal Chemistry, 51, 5043-5051 (2008)), their antiviral activity (EC50 = 5 μM) (Zhang N, Zhang P et al., “Dual inhibition of HCV and HIV by ring-expanded nucleosides containing the 5:7-fused imidazo[4,5-e][1,3]diazepine ring system. In vitro results and implications.” Bioorganic & Medicinal Chemistry Letters, 24, 1154-1157 (2014)) and antitumor activity (IC50 = 2-10 μM) still need to be improved (Xie M, Vesuna F et al., “NZ51, a ring-expanded nucleoside analog, inhibits motility and viability of breast cancer cells by targeting the RNA helicase DDX3.” Oncotarget, 6, 29901-29913 (2015). Poor pharmacokinetic properties and unsatisfactory in vitro and in vivo antitumor activity remain two key challenges that urgently need to be addressed in the development of drugs targeting DDX3X. Summary of the Invention

[0005] To address the shortcomings of existing technologies, the present invention aims to provide a diimidazole-diazazonium chloride solution. This invention relates to diimidazole diazapyridine compounds, their preparation methods, and applications. These compounds exhibit inhibitory and / or degradative activity against DDX3X, thereby providing preventative and / or therapeutic effects against DDX3X-mediated diseases such as viral infections, inflammation, intellectual disability, and cancer.

[0006] To achieve this objective, the present invention adopts the following technical solution:

[0007] On the one hand, the present invention provides a diimidazole diaza Class of compounds, the diimidazole diazapyridine The compound has the structure shown in formula (I):

[0008]

[0009] Where L represents substituted or unsubstituted (CH2). n n is an integer from 2 to 14 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14), wherein the substituted (CH2) n The substituents are selected from C1-C4 alkyl groups (e.g., C1, C2, C3 or C4 alkyl groups, specifically methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, etc.).

[0010] The diimidazole of the present invention These compounds exhibit excellent inhibitory and / or degradative activity against DDX3X, thereby providing preventative and / or therapeutic effects against DDX3X-mediated diseases such as viral infections, inflammation, intellectual disability, and cancer.

[0011] In a preferred embodiment, the diimidazole diazapyridine The compound has the structure shown in formula (II):

[0012]

[0013] Where L represents substituted or unsubstituted (CH2). n , where n is an integer from 4 to 14, and the substituted (CH2) n The substituents are selected from C1-C4 alkyl groups.

[0014] In another preferred embodiment, the diimidazole diazapyridine The compound has the structure shown in formula (III):

[0015]

[0016] Where L represents substituted or unsubstituted (CH2). n , where n is an integer from 2 to 14, and the substituted (CH2) n The substituents are selected from C1-C4 alkyl groups.

[0017] In some preferred embodiments, the diimidazole diazapyridine The class of compounds is any one of the following compounds:

[0018]

[0019]

[0020]

[0021]

[0022] Secondly, the present invention provides a method for preparing the compound as described above, comprising the following steps:

[0023] (1) In the presence of an alkaline substance, compound A reacts with tert-butyl bromoacetate to give compound B, as shown in the following reaction equation:

[0024]

[0025] (2) In the presence of an alkaline substance, compound C reacts with compound D to give compound E, as shown in the following reaction equation:

[0026]

[0027] (3) In the presence of trifluoroacetic acid or hydrochloric acid, compound B loses its tert-butyl group to give intermediate F, and compound E loses its tert-butyloxycarbonyl group to give intermediate G. The reaction formulas are as follows:

[0028]

[0029] (4) After removing trifluoroacetic acid or hydrochloric acid under reduced pressure, intermediate F and intermediate G undergo a condensation reaction to obtain diimidazole diazapyrazole. The reaction formula for this type of compound is as follows:

[0030]

[0031] Preferably, the alkaline substance in step (1) is an organic base or an inorganic base;

[0032] Preferably, the alkaline substance in step (1) is cesium carbonate;

[0033] Preferably, the molar ratio of compound A to tert-butyl bromoacetate in step (1) is 1:1.2 to 1:2; for example, 1:1.2, 1:1.5, 1:1.7, 1:1.9 or 1:2, preferably 1:1.5.

[0034] Preferably, the reaction temperature in step (1) is 70°C and the reaction time is 0.5 to 2 hours, for example, 0.5 hours, 0.8 hours, 1 hour, 1.3 hours, 1.5 hours, 1.8 hours or 2 hours.

[0035] Preferably, the solvent for the reaction in step (1) is DMF.

[0036] Preferably, the alkaline substance in step (2) is an organic base or an inorganic base.

[0037] Preferably, the alkaline substance in step (2) is DIPEA (N,N-diisopropylethylamine).

[0038] Preferably, the molar ratio of compound C to compound D in step (2) is 1:1 to 1:2, for example 1:1, 1:1.2, 1:1.5, 1:1.7, 1:1.9 or 1:2.

[0039] Preferably, the reaction temperature in step (2) is 100°C and the reaction time is 0.5 to 6 hours, for example, 0.5 hours, 0.8 hours, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours or 6 hours.

[0040] Preferably, the solvent for the reaction in step (2) is NMP.

[0041] Preferably, the reaction temperature for the removal of tert-butyl group from compound B in step (3) is room temperature, and the reaction time is 0.5 to 2 hours, for example, 0.5 hours, 0.8 hours, 1 hour, 1.3 hours, 1.5 hours, 1.8 hours or 2 hours.

[0042] Preferably, the solvent for the detert-butylation reaction of compound B in step (3) is DCM.

[0043] Preferably, the reaction temperature for the removal of the tert-butyloxycarbonyl group from compound E in step (3) is room temperature, and the reaction time is 0.5 to 2 hours, for example, 0.5 hours, 0.8 hours, 1 hour, 1.3 hours, 1.5 hours, 1.8 hours or 2 hours.

[0044] Preferably, the solvent for the reaction of compound E in step (3) to remove the tert-butyloxycarbonyl group is DCM;

[0045] Preferably, the molar ratio of intermediate F and intermediate G in step (4) is 1:1 to 1:2, for example 1:1, 1:1.2, 1:1.5, 1:1.7, 1:1.9 or 1:2.

[0046] Preferably, the temperature of the condensation reaction in step (4) is room temperature, and the reaction time is 8 to 16 hours, for example, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours or 16 hours.

[0047] Preferably, the solvent for the condensation reaction in step (4) is DCM.

[0048] Thirdly, the present invention provides the diimidazole diazapyridine as described above. Pharmaceutically acceptable salts, stereoisomers, geometric isomers, or tautomers of the class of compounds.

[0049] Fourthly, the present invention provides a pharmaceutical composition comprising, as described above, diimidazole diaza. The compound, its stereoisomers, geometric isomers, tautomers or pharmaceutically acceptable salts, and optionally pharmaceutically acceptable carriers and / or excipients.

[0050] Preferably, the pharmaceutical composition further comprises, in addition to the diimidazole, diazadiazepam. It is at least one other pharmaceutically active ingredient other than a class of compounds, its stereoisomers, geometric isomers, tautomers, or pharmaceutically acceptable salts.

[0051] Preferably, the other active pharmaceutical ingredient is a pharmaceutical active ingredient used for the prevention and / or treatment of viral infections, inflammation, intellectual disability, or cancer.

[0052] Preferably, the pharmaceutical composition is a pharmaceutically acceptable preparation for the prevention and / or treatment of viral infections, inflammation, intellectual disability, or cancer.

[0053] Fifthly, the present invention also provides a pharmaceutical formulation comprising at least one diimidazole as described above. The class of compounds, their stereoisomers, geometric isomers, tautomers or pharmaceutically acceptable salts, and optionally pharmaceutically acceptable carriers or / or excipients.

[0054] Preferably, the pharmaceutical preparation is selected from the following dosage forms: parenteral preparations, such as injection solutions or suspensions; enteral preparations, such as oral preparations, like tablets or capsules; topical preparations, such as lotions, gels, ointments, emulsions, nasal preparations, suppositories, transdermal preparations, or ophthalmic preparations.

[0055] Sixthly, the present invention also provides a DDX3X and / or degradation inhibitor, said DDX3X inhibitor and / or degradation agent comprising diimidazole as described above. The compound, its stereoisomers, geometric isomers, tautomers, or pharmaceutically acceptable salts, or the pharmaceutical composition thereof.

[0056] In a seventh aspect, the present invention also provides a diimidazole diazamethoxam as described above. Use of the class of compounds, their stereoisomers, geometric isomers, tautomers, or pharmaceutically acceptable salts, or the pharmaceutical composition thereof, in the preparation of a medicament for the prevention and / or treatment of viral infections, inflammation, intellectual disability, or cancer.

[0057] The following are definitions of some of the terms used in this invention; other undefined terms have meanings known to those skilled in the art.

[0058] C1-C4 alkyl groups refer to straight-chain and branched saturated aliphatic hydrocarbon groups having 1 to 4 carbon atoms. Examples of such groups include, but are not limited to: methyl, ethyl, propyl, isopropyl, n-butyl, and tert-butyl.

[0059] The compounds described in this invention may contain one or more chiral centers, which exist in different stereoisomeric forms. All stereoisomers of the compounds of this invention, including but not limited to diastereomers, enantiomers, and transisomers, as well as mixtures thereof (such as racemic mixtures), are within the scope of this invention.

[0060] The compounds described in this invention include their geometric isomers. For example, if the compounds of this invention contain double bonds or fused rings, these compounds may exist as geometric isomers, and their cis, trans, and mixtures of cis and trans forms are all included within the scope of this invention.

[0061] The compounds described in this invention include their tautomers. Tautomers are structural isomers that interconvert at different energies via low-energy barriers, such as keto-enol and imine-enamine tautomerization.

[0062] The compounds described in this invention also include isotopically labeled compounds thereof, wherein one or more atoms are replaced by naturally found atoms having the same atomic number but different atomic mass or mass number. Examples include, but are not limited to, hydrogen isotopes. 2 H and 3 H; carbon isotopes 11 C 13 C and 14 C; Chloride isotopes 36 Cl; Fluorine isotopes 18 F; Iodine isotopes 123 I and 125 I; nitrogen isotopes 13 N and 15 N; oxygen isotope 15 O、 17 O and 18 O; phosphorus isotopes 32 P and sulfur isotopes 35 S.

[0063] Various hydrates and solvates of the compounds or their salts described in this invention, as well as their polymorphisms, are also included within the scope of this invention.

[0064] Prodrugs of the compounds described in this invention are also included within the scope of this invention. Some derivatives of the compounds described in this invention possess weak or no pharmacological activity, but when these derivatives are administered in vivo or to the body, they can be converted into pharmacologically active compounds of this invention through mechanisms such as hydrolysis and cleavage. These derivatives are called "prodrugs". Further information on the uses of prodrugs can be found in *Pro-drugs as Novel Delivery Systems*, Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and *Bioreversible Carriers in Drug Design*, Pergamon Press, 1987 (ed. E.B. Roche, American Pharmaceutical Association).

[0065] The compounds described in this invention include pharmaceutically acceptable salts. A pharmaceutically acceptable salt is a salt that is pharmaceutically acceptable and possesses the pharmacological activity required by the parent compound. Berge et al. described pharmaceutically acceptable salts in detail in J. Pharma. Sci., 1977, 66, 1-19, which is incorporated herein by reference. The compounds described in this invention may contain sufficient acidic groups, sufficient basic groups, or both types of functional groups, and accordingly react with some inorganic or organic base, or inorganic and organic acid, to form pharmaceutically acceptable salts.

[0066] In this invention, examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, phosphates, monohydrophosphates, dihydrophosphates, metaphosphates, pyrophosphates, hydrochlorides, hydrobromates, hydroiodates, acetates, propionates, decanoates, caprylates, octanoates, acrylates, formates, isobutyrates, hexanoates, heptanates, propargylates, oxalates, malonates, succinates, caprylates, sebacic acid salts, fumarates, and malonic acid salts. Benzoate, butyn-1,4-diate, hexyn-1,6-diate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, γ-hydroxybutyrate, hydroxyacetate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, and mandelate.

[0067] When used as a pharmaceutical, the compounds described herein are typically administered in the form of a pharmaceutical composition. Therefore, pharmaceutical compositions containing the compounds described herein and pharmaceutically acceptable carriers, diluents, or excipients are also included within the scope of this invention. Carriers, excipients, and additives as used herein include any and all solvents, diluents or other liquid excipients, dispersants or suspending agents, surfactants, isotonic agents, thickeners or emulsifiers, preservatives, solid binders, lubricants, etc., suitable for the desired specific dosage form. (From Remington: The Science and Practice of Pharmacy, 21) st The contents of various carriers for the formulation of pharmaceutically acceptable compositions and known techniques for their preparation are disclosed in the edition, 2005, ed. D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and the Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J.C. Boylan, 1988–1999, Marcel Dekker, New York, all of which are incorporated herein by reference.

[0068] The compositions of this invention can be administered via any route suitable for the condition to be treated. In particular, administration is possible via: parenteral administration, for example, as an injectable solution or suspension; enteral administration, for example, orally, in tablet or capsule form; or topically, for example, as a lotion, gel, ointment, or emulsion, or in the nose or as a suppository. Topical application is, for example, to the skin. Another form of topical administration is to the eye.

[0069] Pharmaceutical compositions can be administered in solid, semi-solid, liquid, or gaseous form, or may be in the form of dry powders, such as lyophilized forms. Pharmaceutical compositions can be packaged in easily deliverable forms, including, for example, solid dosage forms such as capsules, pouches, sachets, gelatin, paper, tablets, suppositories, granules, pills, lozenges, and tablets. The type of packaging will generally depend on the route of administration. Implantable, sustained-release formulations and transdermal formulations are also covered.

[0070] Examples of materials that can serve as pharmaceutically acceptable carriers include, but are not limited to: ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffers (e.g., phosphates), glycine, sorbic acid or potassium sorbate, mixtures of metaglycerides of saturated vegetable fatty acids, water, salts or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene block copolymers, lanolin, sugars (e.g., lactose, glucose, and sucrose), and starches (e.g., corn starch). The composition may contain: potato starch, cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; tragacanth gum powder; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols, such as propylene glycol or polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffers, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; and phosphate buffer, as well as other non-toxic and compatible lubricants, such as sodium lauryl sulfate and magnesium stearate. Colorants, releasing agents, coating agents, sweeteners, flavorings and aromas, preservatives and antioxidants may also be present in the composition, at the discretion of the formulation personnel.

[0071] The compounds described in this invention can be used alone or in combination with other therapeutic agents for treating the diseases or conditions described in this invention (e.g., cancer). In some embodiments, the compounds described in this invention are combined in a pharmaceutical combination formulation with a second compound having anti-proliferative properties or for treating highly proliferative diseases (e.g., cancer), or in a dosing regimen as a combination therapy. The second compound in the pharmaceutical combination formulation or dosing regimen preferably has an activity complementary to that of the compounds described in this invention so that they do not adversely affect each other. Such compounds are suitably present in the combination in an amount effective for the intended purpose. In one embodiment, the compounds of this invention are combined with other antitumor drugs.The antitumor drugs include: alkylating agents, including but not limited to cyclophosphamide, nitrogen mustard, melphalan, cyclophosphamide, and carmustine; platinum-based drugs, including but not limited to carboplatin, cisplatin, and oxaliplatin; topoisomerase inhibitors, including but not limited to topotecan, camptothecin, topotecan, and irinotecan; antibiotics, including but not limited to cyclophosphamide, actinomycin D, daunorubicin, doxorubicin, mitoxantrone, bleomycin, and procainoxantrone; antimicrotubule or antimitotic agents, including but not limited to paclitaxel, vinorelbine, docetaxel, and doxorubicin; and antimetabolites, including but not limited to fluorouracil, methotrexate, cytarabine, and mecaptopurine. Thioguanine and gemcitabine; antibodies, including but not limited to Herceptin and bevacizumab; hormones, including but not limited to Letrazole, vorazole, tamoxifen, toremifene, fulvestrant, flutamide, nilumethoxazole, and triptorelin; kinase inhibitors, including but not limited to EGFR kinase inhibitors such as gefitinib, erlotinib, lapatinib, and afatinib; and VEGFR inhibitors such as sorafenib and regoraflini. Enib, sunitinib, cabozantinib, pazopanib, vandetanib, axitinib; ALK inhibitors, including but not limited to crizotinib, ceritinib, alectinib; Bcr-Abl inhibitors, including but not limited to imatinib, ponatinib, nilotinib, dasatinib; BTK inhibitors Drugs, including but not limited to ibrutinib; B-RAF inhibitors, including but not limited to vemurafenib; cyclin-dependent kinase CDK4 / 6 inhibitors, such as palbociclib; mTOR inhibitors, including but not limited to rapamycin and everolimus; deacetylase inhibitors, including but not limited to vorinostat; PD1 / PDL1 antibodies, such as Keytruda (pembrolizumab) and Opdivo (nivolumab).

[0072] Eighthly, the present invention provides a diimidazole diazamethoxam as described above. The use of the class of compounds, their stereoisomers, geometric isomers, tautomers, or pharmaceutically acceptable salts, or the pharmaceutical composition thereof in the preparation of a medicament for the prevention and / or treatment of DDX3X-mediated diseases.

[0073] Preferably, the DDX3X-mediated diseases include viral infections, inflammation, intellectual disability, or cancer.

[0074] Compared with the prior art, the present invention has the following beneficial effects:

[0075] The diimidazole of the present invention These compounds exhibit inhibitory and / or degradative activity against DDX3X, thereby providing preventative and / or therapeutic effects against DDX3X-mediated diseases such as viral infections, inflammation, intellectual disability, and cancer. Attached Figure Description

[0076] Figure 1 Figure showing the results of protein degradation experiments with different compounds. Detailed Implementation

[0077] The technical solution of the present invention will be further illustrated below through specific embodiments. Those skilled in the art should understand that the embodiments described are merely illustrative of the present invention and should not be construed as limiting the invention in any way.

[0078] In a general synthetic method, the compound shown in formula (I) is prepared according to method-1.

[0079] Synthesis Method-1

[0080]

[0081] Specifically, in method-1, the diimidazole diaza of the present invention These compounds can be prepared via a four-step reaction. For example, compound A reacts with tert-butyl bromoacetate in the presence of cesium carbonate via a nucleophilic reaction to prepare compound B; compounds C and D react with an organic base via a nucleophilic reaction to prepare compound E; compounds B and D are de-tert-butyl and tert-butyloxycarbonyl groups, respectively, in the presence of trifluoroacetic acid, and then evaporated under reduced pressure to obtain compounds F and G; compounds F and G, without purification, undergo a condensation reaction directly in the presence of a condensing agent and an organic base to prepare the diimidazodiazepine of formula (I). Class of compounds or their pharmaceutically acceptable salts.

[0082] The compounds described in this invention can be synthesized according to one or more synthetic schemes described herein and / or techniques well known in the art. Those skilled in the art will recognize that the synthetic methods of some embodiments described in detail herein can be readily applied to the synthesis of other embodiments. In some embodiments, the compounds described herein can be prepared by appropriate combinations of synthetic methods well known in the art. Many starting materials and other reagents are available from commercial suppliers, such as Alfaisa (China) Chemical Co., Ltd., or can be readily prepared using synthetic methods commonly used in the art.

[0083] 1 H NMR spectra are recorded on instruments operating at 400 MHz, 500 MHz, or 600 MHz. 1 ¹H NMR spectra were obtained in solution form (reported in ppm), using CDCl₃ (7.26 ppm), DMSO-d₆ (2.50 ppm), or the internal standard tetramethylsilane (0.00 ppm) as reference standards. When reporting peak multiplicity, the following abbreviations were used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad peak), dd (doublet), dt (doubletuplet). Coupling constants are given in Hertz (Hz).

[0084] When necessary, the (R) and (S) isomers of the non-limiting exemplary compounds, if present, can be separated by methods known to those skilled in the art, such as by forming diastereomeric salts or complexes, which can be separated by, for example, crystallization; by forming diastereomeric derivatives, which can be separated by, for example, crystallization or chromatography; by selectively reacting one enantiomer with an enantiomer-specific reagent, thereby separating the modified and unmodified enantiomers; or by chromatographic separation in a chiral environment, for example, a chiral chromatographic column. Alternatively, specific enantiomers can be prepared by asymmetric synthesis using optically active reagents, substrates, catalysts, or solvents, or by converting one enantiomer to another via asymmetric transformation.

[0085] In the following preparation methods and examples, "Me" refers to methyl, "Et" refers to ethyl, "PE" refers to petroleum ether, "EA" refers to ethyl acetate, "MeOH" refers to methanol, "DMSO-d6" refers to deuterated dimethyl sulfoxide, "DCM" refers to dichloromethane, "DMF" refers to N,N-dimethylformamide, "TFA" refers to trifluoroacetic acid, "CDCl3" refers to deuterated chloroform, "NMP" refers to N-methylpyrrolidone, "DIPEA" refers to diisopropylethylamine, "Et3N" refers to triethylamine, "Cs2CO3" refers to cesium carbonate, "mL" refers to milliliters, "mmol" refers to millimoles, "μM" refers to micromoles, "nM" refers to nanomoles, and "℃" refers to degrees Celsius.

[0086] Example 1:

[0087] N-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)butyl)-2-(4-((7-(4-methoxybenzyl)-2-oxo-2,7-dihydro-3H-diimidazo[4,5-d:4',5'-f][1,3]diaza[] -3-yl)methyl)phenoxy)acetamide(1)

[0088]

[0089] Step 1: Preparation of 2-(4-((7-(4-methoxybenzyl)-2-oxo-2,7-dihydro-3H-diimidazo[4,5-d:4',5'-f][1,3]diazepine-3-yl)methyl)phenoxy)tert-butyl acetate (1a)

[0090]

[0091] To a 50 mL round-bottom flask, 3-(4-hydroxybenzyl)-7-(4-methoxybenzyl)-3,7-dihydro-2H-diimidazo[4,5-d:4',5'-f][1,3]diazepine-2-one (497 mg, 1.2 mmol, purchased from Kanglong Chemical, purity >95%), tert-butyl bromoacetate (351 mg, 1.8 mmol), DMF (4 mL), and Cs₂CO₃ (586 mg, 1.8 mmol) were added sequentially. The resulting reaction mixture was then stirred at 70 °C for 1.5 h. After cooling to room temperature, the reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with water (20 mL × 2) and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (silica gel, DCM / MeOH = 50 / 1) to give product 1a as a yellow oily liquid (201 mg, yield 31%).

[0092] 1 H NMR (400MHz, CDCl3) δ8.72(s,1H),8.21(s,1H),7.47(d,J=8.7Hz,2H),7.29–7.23(m,2H),6.88(d,J= 8.7Hz,2H),6.81(d,J=8.7Hz,2H),5.44(s,2H),5.18(s,2H),4.46(s,2H),3.79(s,3H),1.46(s,9H).

[0093] Step 2: Preparation of tert-butyl carbamate (1b) of (4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)butyl)carbamate

[0094]

[0095] To a 25 mL round-bottom flask, 2-(2,6-dioxadiidine-3-yl)-4-fluoroisoindoline-1,3-dione (552 mg, 2 mmol), tert-butyl (4-aminobutyl)carbamate (452 ​​mg, 2.4 mmol), NMP (4 mL), and DIPEA (716 mg, 6 mmol) were added sequentially. The resulting reaction mixture was then stirred at 100 °C for 0.5 h. After cooling to room temperature, the reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with water (20 mL × 2) and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (silica gel, DCM / EA = 70 / 30) to give product 1b as a yellow solid (257 mg, yield 37%).

[0096] 1 H NMR (400MHz, CDCl3) δ8.11(br s,1H),7.49(dd,J=8.5,7.1Hz,1H),7.09(d,J=7.0Hz,1H),6.89(d,J=8.5Hz,1H),4.91(dd,J=12.1,5.4Hz,1H),4.57(br s,1H),3.30(t,J=6.9Hz,2H),3.17(t,J=5.9Hz,2H),2.93–2.67(m,3H),2.18–2.08(m,1H),1.76–1.55(m,4H),1.44(s,9H).

[0097] Step 3: N-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)butyl)-2-(4-((7-(4-methoxybenzyl)-2-oxo-2,7-dihydro-3H-diimidazo[4,5-d:4',5'-f][1,3]diaza) Preparation of 3-yl)methyl)phenoxy)acetamide (1)

[0098]

[0099] Intermediate 1a (26 mg, 0.05 mmol), intermediate 1b (23 mg, 0.0525 mmol), DCM (1.5 mL), and TFA (0.5 mL) were added sequentially to a 25 mL round-bottom flask. The resulting reaction mixture was stirred at room temperature for 1 h, and then the volatiles were removed under reduced pressure. DCM (5 mL) was added to the residue, and the resulting solution was concentrated to dryness under reduced pressure. This operation was repeated three times. DMF (2 mL), Et3N (28 mg, 0.25 mmol), and benzotriazol-1-yl-oxytripyrrolidinephosphine hexafluorophosphate (31 mg, 0.06 mmol) were added to the resulting residue, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (20 mL) and then acidified to pH 6 with 10% aqueous citric acid. The resulting yellow solid was collected by suction filtration, slurryed in methanol, filtered, and dried under vacuum to give title compound 1 as a yellow solid (21 mg, yield 53%).

[0100] 1 H NMR (400MHz, DMSO-d6) δ11.08(s,1H),8.92(s,1H),8.74(s,1H),8.08(t,J=5.8Hz,1H),7.55(dd,J=8.5,7.1Hz, 1H),7.34(d,J=8.8Hz,2H),7.29(d,J=8.8Hz,2H),7.06(d,J=8.6Hz,1H),7.00(d,J=6.8Hz,1H),6.93–6.84(m,4 H),6.49(t,J=5.8Hz,1H),5.51(s,2H),5.08(s,2H),5.04(dd,J=12.8,1.2Hz,1H),4.42(s,2H),3.71(s,3H),3. 30–3.21(m,2H),3.18–3.09(m,2H),2.94–2.81(m,1H),2.64–2.52(m,2H),2.11–1.94(m,1H),1.58–1.41(m,5H).

[0101] HRMS(ESI): m / z[M+H] + C 41 H 39 N 10 The theoretical value of O8 is 799.2947, and the measured value is 799.2940.

[0102] Example 2:

[0103] N-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentyl)-2-(4-((7-(4-methoxybenzyl)-2-oxo-2,7-dihydro-3H-diimidazo[4,5-d:4',5'-f][1,3]diaza -3-yl)methyl)phenoxy)acetamide(2)

[0104]

[0105] Step 1: Preparation of tert-butyl carbamate (2b) of (5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)pentyl)carbamate

[0106]

[0107] To a 25 mL round-bottom flask, 2-(2,6-dioxadiidine-3-yl)-4-fluoroisoindoline-1,3-dione (552 mg, 2 mmol), (5-aminopentyl)carbamate tert-butyl ester (485 mg, 2.4 mmol), NMP (4 mL), and DIPEA (716 mg, 6 mmol) were added sequentially. The resulting reaction mixture was then stirred at 100 °C for 0.5 h. After cooling to room temperature, the reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with water (20 mL × 2) and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (silica gel, DCM / EA = 70 / 30) to give product 2b as a yellow solid (272 mg, yield 29%).

[0108] 1 H NMR (400MHz, CDCl3) δ8.03(br s,1H),7.49(dd,J=8.5,7.1Hz,1H),7.09(d,J=7.1Hz,1H),6.88(d,J=8.5Hz,1H),4.91(dd,J=12.1,5.4Hz,1H),4.53(br s,1H),3.27(t,J=7.1Hz,2H),3.13(t,J=5.7Hz,2H),2.93–2.70(m,3H),2. 18–2.08(m,1H),1.75–1.64(m,2H),1.58–1.49(m,2H),1.49–1.41(m,11H).

[0109] Step 2: N-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)pentyl)-2-(4-((7-(4-methoxybenzyl)-2-oxo-2,7-dihydro-3H-diimidazo[4,5-d:4',5'-f][1,3]diaza Preparation of -3-yl)methyl)phenoxy)acetamide (2)

[0110]

[0111] Intermediate 1a (53 mg, 0.1 mmol), intermediate 2b (48 mg, 0.105 mmol), DCM (1.5 mL), and TFA (0.5 mL) were added sequentially to a 25 mL round-bottom flask. The resulting reaction mixture was stirred at room temperature for 1 h, and then the volatiles were removed under reduced pressure. DCM (5 mL) was added to the residue, and the mixture was concentrated to dryness under reduced pressure again. This operation was repeated three times. DMF (2 mL), Et3N (51 mg, 0.5 mmol), and benzotriazol-1-yl-oxytripyrrolidinephosphine hexafluorophosphate (62 mg, 0.12 mmol) were added to the residue, and the resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (20 mL) and acidified to pH 6 with 10% citric acid aqueous solution. The resulting yellow solid was collected by vacuum filtration, slurryed in methanol, filtered, and dried to give title compound 2 as a yellow solid (55 mg, yield 67%).

[0112] 1 H NMR(400MHz, CDCl3)δ8.73(s,1H),8.23(s,1H),8.08(s,1H),7.52–7.43(m,3H),7.29–7.23(m,2H ),7.06(d,J=7.1Hz,1H),6.88(d,J=8.6Hz,2H),6.86–6.81(m,3H),6.54(t,J=5.5Hz,1H),6.19(br s,1H),5.43(s,2H),5.19(s,2H),4.89(dd,J=12.0,5.3Hz,1H),4.44(s,2H),3.79(s,3H),3.39–3.30(m,2H),3. 27–3.19(m,2H),2.91-2.70(m,3H),2.15-2.08(m,1H),1.68–1.63(m,2H),1.61–1.55(m,2H),1.46–1.39(m,2H).

[0113] HRMS(ESI): m / z[M+H] + C 42 H41 N 10 The theoretical value of O8 is 813.3103, and the measured value is 813.3098.

[0114] Example 3:

[0115] N-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)hexyl)-2-(4-((7-(4-methoxybenzyl)-2-oxo-2,7-dihydro-3H-diimidazo[4,5-d:4',5'-f][1,3]diaza -3-yl)methyl)phenoxy)acetamide(3)

[0116]

[0117] Step 1: Preparation of tert-butyl carbamate (3b) of (6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)hexyl)carbamate

[0118]

[0119] To a 25 mL round-bottom flask, 2-(2,6-dioxadiidine-3-yl)-4-fluoroisoindoline-1,3-dione (552 mg, 2 mmol), (6-aminohexyl)carbamate tert-butyl ester (519 mg, 2.4 mmol), NMP (4 mL), and DIPEA (716 mg, 6 mmol) were added sequentially. The resulting reaction mixture was then stirred at 100 °C for 0.5 h. After cooling to room temperature, the reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with water (20 mL × 2) and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (silica gel, DCM / EA = 70 / 30) to give product 3b as a yellow solid (365 mg, yield 38%).

[0120] 1H NMR (400MHz, CDCl3) δ8.07(br s,1H),7.49(dd,J=8.5,7.1Hz,1H),7.09(dd,J=7.1,0.4Hz,1H),6.87(d,J=8.5Hz,1H),6.23(br s,1H),4.96–4.87(m,1H),4.52(br s,1H),3.26(t,J=7.0Hz,2H),3.17–3.06(m,2H),2.92–2.70(m,3H),2.18–2.10(m,1H),1.72–1.62(m,2H),1.53–1.36(m,15H).

[0121] Step 2: N-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)hexyl)-2-(4-((7-(4-methoxybenzyl)-2-oxo-2,7-dihydro-3H-diimidazo[4,5-d:4',5'-f][1,3]diaza Preparation of -3-yl)methyl)phenoxy)acetamide (3)

[0122]

[0123] Intermediate 1a (53 mg, 0.1 mmol), intermediate 3b (48 mg, 0.105 mmol), DCM (1.5 mL), and TFA (0.5 mL) were added sequentially to a 25 mL round-bottom flask. The resulting reaction mixture was stirred at room temperature for 1 h, and then the volatiles were removed under reduced pressure. DCM (5 mL) was added to the residue, and the mixture was concentrated to dryness under reduced pressure again. This operation was repeated three times. DMF (2 mL), Et3N (51 mg, 0.5 mmol), and benzotriazol-1-yl-oxytripyrrolidinephosphine hexafluorophosphate (62 mg, 0.12 mmol) were added to the residue, and the resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (20 mL) and acidified to pH 6 with 10% citric acid aqueous solution. The resulting yellow solid was collected by vacuum filtration, slurryed in methanol, filtered, and dried to give title compound 3 as a yellow solid (68 mg, yield 81%).

[0124] 1H NMR(400MHz, CDCl3)δ8.73(s,1H),8.23(s,1H),8.08(s,1H),7.52–7.44(m,3H),7.29–7.24(m,2H ),7.06(d,J=7.1Hz,1H),6.88(d,J=8.6Hz,2H),6.86–6.81(m,3H),6.55(t,J=5.7Hz,1H),6.19(br s,1H),5.43(s,2H),5.19(s,2H),4.89(dd,J=12.0,5.3Hz,1H),4.44(s,2H),3.79(s,3H),3.39-3.30( m,2H),3.27-3.20(m,2H),2.91-2.70(m,3H),2.15-2.08(m,1H),1.70-1.54(m,6H),1.47-1.37(m,2H).

[0125] HRMS(ESI): m / z[M+H] + C 43 H 43 N 10 The theoretical value of O8 is 827.3260, and the measured value is 827.3240.

[0126] Example 4:

[0127] N-(7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)heptyl)-2-(4-((7-(4-methoxybenzyl)-2-oxo-2,7-dihydro-3H-diimidazo[4,5-d:4',5'-f][1,3]diaza -3-yl)methyl)phenoxy)acetamide (4)

[0128]

[0129] Step 1: Preparation of (7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)heptyl)tert-butyl carbamate (4b)

[0130]

[0131] To a 25 mL round-bottom flask, 2-(2,6-dioxadiazine-3-yl)-4-fluoroisoindoline-1,3-dione (552 mg, 2 mmol), (7-aminooctyl)carbamate tert-butyl ester (500 mg, 2.17 mmol), NMP (4 mL), and DIPEA (775 mg, 6 mmol) were added sequentially. The resulting reaction mixture was then stirred at 100 °C for 0.5 h. After cooling to room temperature, the reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with water (20 mL × 2) and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (silica gel, DCM / EA = 70 / 30) to give product 4b as a yellow solid (274 mg, yield 28%).

[0132] 1 H NMR (500MHz, CDCl3) δ8.09(br s,1H),7.49(dd,J=8.5,7.2Hz,1H),7.09(d,J=7.0Hz,1H),6.88(d,J=8.5Hz,1H),6.23(br s,1H),4.92(dd,J=12.4,5.3Hz,1H),4.56(brs,1H),3.26(t,J=6.4Hz,2H),3.15–3.06 (m,2H),2.95–2.69(m,3H),2.18–2.10(m,1H),1.68–1.64(m,2H),1.48–1.33(m,17H).

[0133] Step 2: N-(7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)heptyl)-2-(4-((7-(4-methoxybenzyl)-2-oxo-2,7-dihydro-3H-diimidazo[4,5-d:4',5'-f][1,3]diaza Preparation of -3-yl)methyl)phenoxy)acetamide (4)

[0134]

[0135] Intermediate 1a (53 mg, 0.1 mmol), intermediate 4b (53 mg, 0.105 mmol), DCM (1.5 mL), and TFA (0.5 mL) were added sequentially to a 25 mL round-bottom flask. The resulting reaction mixture was stirred at room temperature for 1 h, and then the volatiles were removed under reduced pressure. DCM (5 mL) was added to the residue, and the mixture was concentrated to dryness under reduced pressure again. This operation was repeated three times. DMF (2 mL), Et3N (55 mg, 0.5 mmol), and benzotriazol-1-yl-oxytripyrrolidinephosphine hexafluorophosphate (62 mg, 0.12 mmol) were added to the residue, and the resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (20 mL) and acidified to pH 6 with 10% citric acid aqueous solution. The resulting yellow solid was collected by vacuum filtration, slurryed in methanol, filtered, and dried to give title compound 4 as a yellow solid (23 mg, yield 27%).

[0136] 1 H NMR (600MHz, CDCl3) δ8.73(s,1H),8.24(s,1H),8.13(s,1H),7.51–7.46(m,3H),7.28–7.25(m,2H),7.08(d,J= 6.9Hz,1H),6.90–6.83(m,5H),6.52(t,J=5.8Hz,1H),6.21(t,J=5.2Hz,1H),5.44(s,2H),5.19(s,2H),4.90(dd ,J=12.4,5.3Hz,1H),4.44(s,2H),3.80(s,3H),3.31(dd,J=13.5,6.9Hz,2H),3.25(dd,J=12.4,6.8Hz,2H),2.8 4–2.69(m,3H),2.15–2.10(m,1H),1.68–1.64(m,2H),1.54–1.51(m,2H),1.43–1.37(m,3H),1.36–1.29(m,4H).

[0137] Example 5:

[0138] N-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octyl)-2-(4-((7-(4-methoxybenzyl)-2-oxo-2,7-dihydro-3H-diimidazo[4,5-d:4',5'-f][1,3]diaza -3-yl)methyl)phenoxy)acetamide (5)

[0139]

[0140] Step 1: Preparation of tert-butyl (8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)octyl)carbamate (5b)

[0141]

[0142] To a 25 mL round-bottom flask, 2-(2,6-dioxadiazine-3-yl)-4-fluoroisoindoline-1,3-dione (503 mg, 1.82 mmol), (8-aminooctyl)carbamate tert-butyl ester (490 mg, 2.004 mmol), NMP (4 mL), and DIPEA (652 mg, 5.47 mmol) were added sequentially. The resulting reaction mixture was then stirred at 100 °C for 0.5 h. After cooling to room temperature, the reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with water (20 mL × 2) and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (silica gel, DCM / EA = 70 / 30) to give product 5b as a yellow solid (321 mg, yield 32%).

[0143] 1 H NMR (400MHz, CDCl3) δ8.12(br s,1H),7.49(dd,J=8.2,7.5Hz,1H),7.09(d,J=7.1Hz,1H),6.88(d,J=8.6Hz,1H),4.92(dd,J=12.1,5.3Hz,1H),4.54(br s,1H),3.26(t,J=7.0Hz,2H),3.10(t,J=6.7Hz,2H),2.93–2.71(m,3H),2.18–2.09(m,1H),1.71–1.60(m,2H),1.49–1.30(m,19H).

[0144] Step 2: N-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)octyl)-2-(4-((7-(4-methoxybenzyl)-2-oxo-2,7-dihydro-3H-diimidazo[4,5-d:4',5'-f][1,3]diaza Preparation of 3-yl)methyl)phenoxy)acetamide (5)

[0145]

[0146] Intermediate 1a (53 mg, 0.1 mmol), intermediate 5b (53 mg, 0.105 mmol), DCM (1.5 mL), and TFA (0.5 mL) were added sequentially to a 25 mL round-bottom flask. The resulting reaction mixture was stirred at room temperature for 1 h, and then the volatiles were removed under reduced pressure. DCM (5 mL) was added to the residue, and the mixture was concentrated to dryness under reduced pressure again. This operation was repeated three times. DMF (2 mL), Et3N (55 mg, 0.5 mmol), and benzotriazol-1-yl-oxytripyrrolidinephosphine hexafluorophosphate (62 mg, 0.12 mmol) were added to the residue, and the resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (20 mL) and acidified to pH 6 with 10% citric acid aqueous solution. The resulting yellow solid was collected by vacuum filtration, slurryed in methanol, filtered, and dried to give title compound 5 as a yellow solid (60 mg, yield 70%).

[0147] 1 H NMR(400MHz, CDCl3)δ8.71(s,1H),8.22(s,1H),8.15(s,1H),7.50–7.44(m,3H),7.28–7.22(m 2H),7.06(d,J=7.0Hz,1H),6.90–6.79(m,5H),6.50(t,J=6.1Hz,1H),6.20(t,J=5 .5Hz,1H),5.43(s,2H),5.17(s,2H),4.89(dd,J=11.9,5.3Hz,1H),4.42(s,2H),3. 78(s,3H),3.34–3.26(m,2H),3.26–3.20(m,2H),2.89–2.70(m,3H),2.15-2.07(m ,1H),1.65–1.61(m,2H),1.53–1.47(m,2H),1.41–1.35(m,2H),1.33–1.26(m,6H).

[0148] HRMS(ESI): m / z[M+H] + C 45 H 47 N 10 The theoretical value of O8 is 855.3573, and the measured value is 855.3559.

[0149] Example 6:

[0150] N-(9-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)nonyl)-2-(4-((7-(4-methoxybenzyl)-2-oxo-2,7-dihydro-3H-diimidazo[4,5-d:4',5'-f][1,3]diaza -3-yl)methyl)phenoxy)acetamide (6)

[0151]

[0152] Step 1: Preparation of tert-butyl carbamate (6b) of (9-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)nonyl)carbamate

[0153]

[0154] To a 25 mL round-bottom flask, 2-(2,6-dioxadiidine-3-yl)-4-fluoroisoindoline-1,3-dione (552 mg, 2 mmol), (9-aminononyl)carbamate tert-butyl ester (569 mg, 2.17 mmol), NMP (4 mL), and DIPEA (775 mg, 6 mmol) were added sequentially. The resulting reaction mixture was then stirred at 100 °C for 6 h. After cooling to room temperature, the reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with water (20 mL × 2) and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (silica gel, DCM / EA = 70 / 30) to give product 6b as a yellow-green solid (300 mg, yield 23%).

[0155] 1 H NMR (400MHz, CDCl3) δ8.27(t,J=11.3Hz,1H),7.49(dd,J=8.5,7.1Hz,1H),7.08(d,J=7.1H z,1H),6.88(d,J=8.6Hz,1H),6.23(t,J=4.9Hz,1H),4.92(dd,J=12.1,5.4Hz,1H),4.54(br s,1H),3.26(dd,J=12.2,6.8Hz,2H),3.10(dd,J=12.1,5.9Hz,2H),2.91–2.72(m, 3H),2.17–2.10(m,1H),1.69–1.62(m,2H),1.49–1.40(m,12H),1.35–1.27(m,9H).

[0156] Step 2: N-(9-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)nonyl)-2-(4-((7-(4-methoxybenzyl)-2-oxo-2,7-dihydro-3H-diimidazo[4,5-d:4',5'-f][1,3]diaza Preparation of 3-yl)methyl)phenoxy)acetamide (6)

[0157]

[0158] Intermediate 1a (53 mg, 0.1 mmol), intermediate 6b (54 mg, 0.105 mmol), DCM (1.5 mL), and TFA (0.5 mL) were added sequentially to a 25 mL round-bottom flask. The resulting reaction mixture was stirred at room temperature for 1 h, and then the volatiles were removed under reduced pressure. DCM (5 mL) was added to the residue, and the mixture was concentrated to dryness under reduced pressure again. This operation was repeated three times. DMF (2 mL), Et3N (55 mg, 0.5 mmol), and benzotriazol-1-yl-oxytripyrrolidinephosphine hexafluorophosphate (62 mg, 0.12 mmol) were added to the residue, and the resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (20 mL) and acidified to pH 6 with 10% citric acid aqueous solution. The resulting yellow solid was collected by vacuum filtration, slurryed in methanol, filtered, and dried to give title compound 6 as a yellow solid (21 mg, yield 24%).

[0159] 1 H NMR(400MHz, CDCl3)δ8.73(s,1H),8.26(br s,1H),8.12(br s,1H),7.52–7.44(m,3H),7.29–7.24(m,2H),6.92–6.81(m,5H),6.51(t,J=5.9Hz,1 H),5.44(s,2H),5.19(s,2H),4.91(dd,J=11.9,5.3Hz,1H),4.43(s,2H),3.79(s,3H ),3.31(dd,J=13.7,6.8Hz,2H),3.27–3.22(m,2H),2.91–2.69(m,3H),2.18–2.10(m ,1H),1.67–1.60(m,,2H),1.54–1.48(m,2H),1.43–1.36(m,2H),1.32–1.26(m,8H).

[0160] HRMS(ESI): m / z[M+H] + C 45 H 47 N 10The theoretical value of O8 is 869.3729, and the measured value is 869.3695.

[0161] Example 7:

[0162] N-(10-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)decyl)-2-(4-((7-(4-methoxybenzyl)-2-oxo-2,7-dihydro-3H-diimidazo[4,5-d:4',5'-f][1,3]diaza[] -3-yl)methyl)phenoxy)acetamide (7)

[0163]

[0164] Step 1: Preparation of (10-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)yl)decyl)tert-butyl carbamate (7b)

[0165]

[0166] To a 25 mL round-bottom flask, 2-(2,6-dioxadiazine-3-yl)-4-fluoroisoindoline-1,3-dione (461 mg, 1.67 mmol), (10-aminodecyl)carbamate tert-butyl ester (500 mg, 1.836 mmol), NMP (4 mL), and DIPEA (597 mg, 5.01 mmol) were added sequentially. The resulting reaction mixture was then stirred at 100 °C for 0.5 h. After cooling to room temperature, the reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with water (20 mL × 2) and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (silica gel, DCM / EA = 70 / 30) to give product 7b as a yellow solid (401 mg, yield 37%).

[0167] 1H NMR (400MHz, CDCl3) δ8.18(br s,1H),7.49(dd,J=8.5,7.2Hz,1H),7.08(d,J=7.1Hz,1H),6.88(d,J=8.5Hz,1H),6.23(br s,1H),4.92(dd,J=12.0,5.3Hz,1H),4.52(brs,1H),3.26(t,J=7.0Hz,2H),3.15–3.04(m,2H ),2.84–2.71(m,3H),2.16-2.11(m,1H),1.71–1.61(m,2H),1.49–1.36(m,14H),1.29(s,9H).

[0168] Step 2: N-(10-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)decyl)-2-(4-((7-(4-methoxybenzyl)-2-oxo-2,7-dihydro-3H-diimidazo[4,5-d:4',5'-f][1,3]diaza) Preparation of 3-yl)methyl)phenoxy)acetamide (7)

[0169]

[0170] Intermediate 1a (53 mg, 0.1 mmol), intermediate 7b (56 mg, 0.105 mmol), DCM (1.5 mL), and TFA (0.5 mL) were added sequentially to a 25 mL round-bottom flask. The resulting reaction mixture was stirred at room temperature for 1 h, and then the volatiles were removed under reduced pressure. DCM (5 mL) was added to the residue, and the mixture was concentrated to dryness under reduced pressure again. This operation was repeated three times. DMF (2 mL), Et3N (55 mg, 0.5 mmol), and benzotriazol-1-yl-oxytripyrrolidinephosphine hexafluorophosphate (62 mg, 0.12 mmol) were added to the residue, and the resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (20 mL) and acidified to pH 6 with 10% citric acid aqueous solution. The resulting yellow solid was collected by vacuum filtration, slurryed in methanol, filtered, and dried to give title compound 7 as a yellow solid (68 mg, yield 77%).

[0171] 1H NMR (400MHz, CDCl3) δ8.73(s,1H),8.25(s,1H),8.16(s,1H),7.53–7.43(m,3H),7.31–7.23(m,2H),7.07(d,J=6.6Hz,1H),6.91–6.81(m,5H),6.52(br s,1H),6.21(br s,1H),5.44(s,2H),5.19(s,2H),4.91(dd,J=11.4,4.6Hz,1H),4.43(s,2H),3.79(s,3H),3.36–3.28(m,2H),3.28–3.20(m ,2H),2.92–2.70(m,3H),2.18–2.07(m,1H),1.69–1.62(m,2H),1.56-1.45(m,2H),1.44–1.35(m,2H),1.32–1.21(m,10H).

[0172] HRMS(ESI): m / z[M+H] + C 47 H 51 N 10 The theoretical value of O8 is 883.3886, and the measured value is 883.3884.

[0173] Example 8:

[0174] N-(11-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)undecyl)-2-(4-((7-(4-methoxybenzyl)-2-oxo-2,7-dihydro-3H-diimidazo[4,5-d:4',5'-f][1,3]diaza -3-yl)methyl)phenoxy)acetamide (8)

[0175]

[0176] Step 1: Preparation of (11-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)yl)undecyl)tert-butyl carbamate (8b)

[0177]

[0178] To a 25 mL round-bottom flask, 2-(2,6-dioxadiidine-3-yl)-4-fluoroisoindoline-1,3-dione (218 mg, 0.79 mmol), (11-aminoundecyl)carbamate tert-butyl ester (250 mg, 0.87 mmol), NMP (1.5 mL), and DIPEA (282 mg, 2.37 mmol) were added sequentially. The resulting reaction mixture was then stirred at 100 °C for 1 h. After cooling to room temperature, the reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with water (20 mL × 2) and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (silica gel, PE / EA = 70 / 30) to give product 8b as a yellow-green solid (84 mg, yield 37%).

[0179] 1 H NMR(400MHz, CDCl3)δ8.37(br s,1H),7.49(dd,J=8.5,7.0,1.4Hz,1H),7.08(d,J=7.0,1.5Hz,1H),6.88(d ,J=8.6Hz,1H),6.23(t,J=5.6Hz,1H),4.92(dd,J=11.9,5.3Hz,1H),4.54(br s,1H),3.30–3.21(m,2H),3.15–3.04(m,2H),2.92–2.70(m,3H),2.17–2.09(m,1 H),1.71–1.61(m,2H),1.51–1.36(m,14H),1.34–1.30(m,2H),1.29–1.25(m,9H).

[0180] Step 2: N-(11-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)undecyl)-2-(4-((7-(4-methoxybenzyl)-2-oxo-2,7-dihydro-3H-diimidazo[4,5-d:4',5'-f][1,3]diaza) Preparation of 3-yl)methyl)phenoxy)acetamide (8)

[0181]

[0182] Intermediate 1a (84 mg, 0.158 mmol), intermediate 8b (86 mg, 0.158 mmol), DCM (3 mL), and TFA (1 mL) were added sequentially to a 25 mL round-bottom flask. The resulting reaction mixture was stirred at room temperature for 1 h, and then the volatiles were removed under reduced pressure. DCM (5 mL) was added to the residue, and the mixture was concentrated to dryness under reduced pressure again. This operation was repeated three times. DMF (2 mL), Et3N (48 mg, 0.474 mmol), and benzotriazol-1-yl-oxytripyrrolidinephosphine hexafluorophosphate (123 mg, 0.237 mmol) were added to the residue, and the resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (20 mL) and acidified to pH 6 with 10% citric acid aqueous solution. The resulting yellow solid was collected by filtration and purified by rapid column chromatography (silica gel, DCM / MeOH = 40 / 1) to give title compound 8 as a yellow solid (79 mg, yield 56%).

[0183] 1 H NMR(400MHz, CDCl3)δ8.73(s,1H),8.23(s,1H),8.07(s,1H),7.53–7.44(m,3H),7.28–7.24(m,2H), 7.07(d,J=7.1Hz,1H),6.91–6.81(m,5H),6.51(t,J=5.3Hz,1H),5.44(s,2H),5.19(s,2H),4.91(dd, J=11.9,5.3Hz,1H),4.43(s,2H),3.80(s,3H),3.34–3.28(m,2H),3.27–3.21(m,2H),2.93–2.68(m,3 H),2.17–2.09(m,1H),1.68–1.62(m,2H),1.55–1.48(m,2H),1.42–1.37(m,2H),1.31–1.23(m,12H).

[0184] HRMS(ESI): m / z[M+H] + C 48 H 53 N 10 The theoretical value of O8 is 897.4042, and the measured value is 897.4047.

[0185] Example 9:

[0186] N-(12-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)dodecyl)-2-(4-((7-(4-methoxybenzyl)-2-oxo-2,7-dihydro-3H-diimidazo[4,5-d:4',5'-f][1,3]diaza -3-yl)methyl)phenoxy)acetamide (9)

[0187]

[0188] Step 1: Preparation of (12-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)yl)dodecyl)tert-butyl carbamate (9b)

[0189]

[0190] To a 25 mL round-bottom flask, 2-(2,6-dioxadiidine-3-yl)-4-fluoroisoindoline-1,3-dione (414 mg, 1.5 mmol), (12-aminododecyl)carbamate tert-butyl ester (500 mg, 1.65 mmol), NMP (4 mL), and DIPEA (537 mg, 4.5 mmol) were added sequentially. The resulting reaction mixture was then stirred at 100 °C for 1 h. After cooling to room temperature, the reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with water (20 mL × 2) and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (silica gel, PE / EA = 70 / 30) to give product 9b as a yellow solid (50 mg, yield 6%).

[0191] 1 H NMR(400MHz, CDCl3)δ8.31(d,J=47.8Hz,1H),7.52–7.46(m,1H),7.11–7.05(m,1H) ),6.88(dd,J=8.8,3.0Hz,1H),6.24(t,J=5.6Hz,1H),4.96–4.88(m,1H),4.53(br s,1H),3.30–3.21(m,2H),3.16–3.02(m,2H),2.93–2.67(m,3H),2.17–2.08(m,1 H),1.72–1.61(m,2H),1.51–1.37(m,14H),1.35–1.29(m,4H),1.29–1.25(m,9H).

[0192] Step 2: N-(12-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)dodecyl)-2-(4-((7-(4-methoxybenzyl)-2-oxo-2,7-dihydro-3H-diimidazo[4,5-d:4',5'-f][1,3]diaza) Preparation of 3-yl)methyl)phenoxy)acetamide (9)

[0193]

[0194] Intermediate 1a (50 mg, 0.095 mmol), intermediate 9b (53 mg, 0.095 mmol), DCM (3 mL), and TFA (1 mL) were added sequentially to a 25 mL round-bottom flask. The resulting reaction mixture was stirred at room temperature for 1 h, and then the volatiles were removed under reduced pressure. DCM (5 mL) was added to the residue, and the mixture was concentrated to dryness under reduced pressure again. This operation was repeated three times. DMF (2 mL), Et3N (29 mg, 0.285 mmol), and benzotriazol-1-yl-oxytripyrrolidinephosphine hexafluorophosphate (74 mg, 0.14 mmol) were added to the residue, and the resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (20 mL) and acidified to pH 6 with 10% citric acid aqueous solution. The resulting yellow solid was collected by filtration and purified by rapid column chromatography (silica gel, DCM / MeOH = 40 / 1) to give title compound 9 as a yellow solid (59 mg, yield 68%).

[0195] 1 H NMR(400MHz, CDCl3)δ8.73(s,1H),8.23(s,1H),8.04(br s,1H),7.52–7.44(m,3H),7.29–7.24(m,2H),7.07(d,J=7.1Hz,1H),6.91–6.82(m,5H),6.51(t,J=5.0Hz,1H),6.24(br s,1H),5.44(s,2H),5.19(s,2H),4.91(dd,J=12.0,5.3Hz,1H),4.43(s,2H),3.79(s,3H),3.34–3.28(m,2H),3.27–3.22(m ,2H),2.92–2.68(m,3H),2.17–2.09(m,1H),1.68–1.62(m,2H),1.55–1.48(m,2H),1.41–1.37(m,2H),1.31–1.22(m,14H).

[0196] HRMS(ESI): m / z[M+H]+C 49 H55 N 10 The theoretical value of O8 is 911.4199, and the measured value is 911.4202.

[0197] Example 10:

[0198] N-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)butyl)-2-(4-((7-(4-methoxybenzyl)-2-oxo-2,7-dihydro-3H-diimidazo[4,5-d:4',5'-f][1,3]diaza) -3-yl)methyl)phenoxy)acetamide(10)

[0199]

[0200] Step 1: Preparation of tert-butyl carbamate (10b) of (4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)amino)butyl)carbamate

[0201]

[0202] To a 25 mL round-bottom flask, 2-(2,6-dioxadiidine-3-yl)-5-fluoroisoindoline-1,3-dione (552 mg, 2 mmol), tert-butyl (4-aminobutyl)carbamate (452 ​​mg, 2.4 mmol), NMP (4 mL), and DIPEA (716 mg, 6 mmol) were added sequentially. The resulting reaction mixture was then stirred at 100 °C for 0.5 h. After cooling to room temperature, the reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with water (20 mL × 2) and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (silica gel, DCM / EA = 70 / 30) to give product 10b as a yellow solid (186 mg, yield 21%).

[0203] 1 H NMR (400MHz, CDCl3) δ8.89(br s,1H),7.47(d,J=8.3Hz,1H),6.83(s,1H),6.64(d,J=8.0Hz,1H),4.89(dd,J=12.1,5.3Hz,1H),4.78(br s,1H),3.19–3.04(m,4H),2.86–2.64(m,3H),2.10–2.03(m,1H),1.66–1.50(m,4H),1.40(s,9H).

[0204] Step 2: N-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)amino)butyl)-2-(4-((7-(4-methoxybenzyl)-2-oxo-2,7-dihydro-3H-diimidazo[4,5-d:4',5'-f][1,3]diaza) Preparation of 3-yl)methyl)phenoxy)acetamide (10)

[0205]

[0206] Intermediate 1a (53 mg, 0.1 mmol), intermediate 10b (47 mg, 0.105 mmol), DCM (1.5 mL), and TFA (0.5 mL) were added sequentially to a 25 mL round-bottom flask. The resulting reaction mixture was stirred at room temperature for 1 h, and then the volatiles were removed under reduced pressure. DCM (5 mL) was added to the residue, and the mixture was concentrated to dryness under reduced pressure again. This operation was repeated three times. DMF (2 mL), Et3N (53 mg, 0.5 mmol), and benzotriazol-1-yl-oxytripyrrolidinephosphine hexafluorophosphate (62 mg, 0.12 mmol) were added to the residue, and the resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (20 mL) and acidified to pH 6 with 10% citric acid aqueous solution. The resulting yellow solid was collected by suction filtration, slurryed in methanol, filtered, and dried to give title compound 10 as a yellow solid (38 mg, yield 48%).

[0207] 1 H NMR (400MHz, DMSO-d6) δ11.05(s,1H),8.92(s,1H),8.74(s,1H),8.07(t,J=5.6Hz,1H),7.54( d,J=8.3Hz,1H),7.34(d,J=8.7Hz,2H),7.29(d,J=8.7Hz,2H),7.08(t,J=5.5Hz,1H),6.96–6.7 8(m,6H),5.51(s,2H),5.08(s,2H),5.02(dd,J=12.8,5.3Hz,1H),4.42(s,2H),3.71(s,3H),3 .20–3.07(m,4H),2.93–2.80(m,1H),2.61–2.52(m,2H),2.04–1.94(m,1H),1.57–1.48(m,4H).

[0208] HRMS(ESI): m / z[M+H] + C 41 H 39 N 10The theoretical value of O8 is 799.2947, and the measured value is 799.2957.

[0209] Example 11: N-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)amino)pentyl)-2-(4-((7-(4-methoxybenzyl)-2-oxo-2,7-dihydro-3H-diimidazo[4,5-d:4',5'-f][1,3]diaza) -3-yl)methyl)phenoxy)acetamide(11)

[0210]

[0211] Step 1: Preparation of tert-butyl carbamate (11b) of (5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)amino)pentyl)carbamate

[0212]

[0213] To a 25 mL round-bottom flask, 2-(2,6-dioxadiazine-3-yl)-5-fluoroisoindoline-1,3-dione (635 mg, 2.3 mmol), (5-aminopentyl)carbamate tert-butyl ester (515 mg, 2.55 mmol), NMP (4 mL), and DIPEA (823 mg, 6.9 mmol) were added sequentially. The resulting reaction mixture was then stirred at 100 °C for 0.5 h. After cooling to room temperature, the reaction mixture was diluted with 40 mL of water and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with water (20 mL × 2) and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (silica gel, DCM / EA = 70 / 30) to give product 11b as a yellow solid (200 mg, yield 18%).

[0214] 1 H NMR (400MHz, CDCl3) δ8.20(br s,1H),7.58(d,J=8.3Hz,1H),6.94(d,J=1.5Hz,1H),6.73(dd,J=8.3,2.0Hz,1H),4.93(dd,J=12.2,5.1Hz,1H),4.60(br s,1H),3.20(t,J=6.9Hz,2H),3.15(d,J=5.6Hz,2H),2.93–2.68(m,3H),2.17 –2.08(m,1H),1.69(dt,J=15.4,7.6Hz,2H),1.59–1.48(m,4H),1.45(s,9H).

[0215] Step 2: N-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)amino)pentyl)-2-(4-((7-(4-methoxybenzyl)-2-oxo-2,7-dihydro-3H-diimidazo[4,5-d:4',5'-f][1,3]diaza) Preparation of 3-yl)methyl)phenoxy)acetamide (11)

[0216]

[0217] Intermediate 1a (53 mg, 0.1 mmol), intermediate 11b (48 mg, 0.105 mmol), DCM (1.5 mL), and TFA (0.5 mL) were added sequentially to a 25 mL round-bottom flask. The resulting reaction mixture was stirred at room temperature for 1 h, and then the volatiles were removed under reduced pressure. DCM (5 mL) was added to the residue, and the mixture was concentrated to dryness under reduced pressure again. This operation was repeated three times. DMF (2 mL), Et3N (53 mg, 0.5 mmol), and benzotriazol-1-yl-oxytripyrrolidinephosphine hexafluorophosphate (62 mg, 0.12 mmol) were added to the residue, and the resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (20 mL) and acidified to pH 6 with 10% citric acid aqueous solution. The resulting yellow solid was collected by suction filtration, slurryed in methanol, filtered, and dried to give title compound 11 as a yellow solid (38 mg, yield 47%).

[0218] 1 H NMR(400MHz, CDCl3)δ8.73(s,1H),8.22(s,1H),8.03(br s,1H),7.56(d,J=8.3Hz,1H),7.49(dd,J=7.8,0.9Hz,2H),7.27(d,J=2.0Hz,1H),7.25(s,1H),6.9 2(d,J=2.1Hz,1H),6.89(d,J=8.7Hz,2H),6.85(d,J=8.7Hz,2H),6.71(dd,J=8.3,2.2Hz,1H),6.51( t,J=6.1Hz,1H),5.44(s,2H),5.20(s,2H),4.92(dd,J=12.2,5.3Hz,1H),4.47(s,2H),3.79(s,3H), 3.38–3.31(m,2H),3.15(t,J=7.0Hz,2H),2.88–2.71(m,3H),2.14–2.10(m,1H),1.61–1.51(m,6H).

[0219] HRMS(ESI): m / z[M+H]+ C 42 H 41 N 10 The theoretical value of O8 is 813.3103, and the measured value is 813.3113.

[0220] Example 12:

[0221] N-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)amino)hexyl)-2-(4-((7-(4-methoxybenzyl)-2-oxo-2,7-dihydro-3H-diimidazo[4,5-d:4',5'-f][1,3]diaza) -3-yl)methyl)phenoxy)acetamide (12)

[0222]

[0223] Step 1: Preparation of tert-butyl carbamate (12b) of (6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)amino)hexyl)carbamate

[0224]

[0225] To a 25 mL round-bottom flask, 2-(2,6-dioxadiidine-3-yl)-5-fluoroisoindoline-1,3-dione (552 mg, 2 mmol), (6-aminohexyl)carbamate tert-butyl ester (519 mg, 2.4 mmol), NMP (4 mL), and DIPEA (716 mg, 6 mmol) were added sequentially. The resulting reaction mixture was then stirred at 100 °C for 0.5 h. After cooling to room temperature, the reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with water (20 mL × 2) and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (silica gel, DCM / EA = 70 / 30) to give product 12b as a yellow solid (151 mg, yield 16%).

[0226] 1H NMR (400MHz, CDCl3) δ8.10(br s,1H),7.60(d,J=8.3Hz,1H),6.95(d,J=1.9Hz,1H),6.74(dd,J=8.3,2.0Hz,1H),4.93(dd,J=12.2,5.3Hz,1H),4.55(br s,1H),3.21(t,J=7.0Hz,2H),3.17–3.07(m,2H),2.94–2.67(m,3H),2.17–2.08(m,1H),1.70–1.61(m,2H),1.52–1.36(m,15H).

[0227] Step 2: N-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)amino)hexyl)-2-(4-((7-(4-methoxybenzyl)-2-oxo-2,7-dihydro-3H-diimidazo[4,5-d:4',5'-f][1,3]diaza) Preparation of 3-yl)methyl)phenoxy)acetamide (12)

[0228]

[0229] Intermediate 1a (53 mg, 0.1 mmol), intermediate 12b (50 mg, 0.105 mmol), DCM (1.5 mL), and TFA (0.5 mL) were added sequentially to a 25 mL round-bottom flask. The resulting reaction mixture was stirred at room temperature for 1 h, and then the volatiles were removed under reduced pressure. DCM (5 mL) was added to the residue, and the mixture was concentrated to dryness under reduced pressure again. This operation was repeated three times. DMF (2 mL), Et3N (55 mg, 0.5 mmol), and benzotriazol-1-yl-oxytripyrrolidinephosphine hexafluorophosphate (62 mg, 0.12 mmol) were added to the residue, and the resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (20 mL) and acidified to pH 6 with 10% citric acid aqueous solution. The resulting yellow solid was collected by vacuum filtration, slurryed in methanol, filtered, and dried to give title compound 12 as a yellow solid (33 mg, yield 40%).

[0230] 1H NMR(400MHz, CDCl3)δ8.74(s,1H),8.25(s,1H),8.08(br s,1H),7.57(d,J=8.3Hz,1H),7.48(d,J=8.7Hz,2H),7.28(s,1H),6.99(d,J=2.1Hz,1H),6.89(d,J=8.7Hz,2H) ,6.84(d,J=8.8Hz,2H),6.76(dd,J=8.4,2.2Hz,1H),6.46(t,J=5.9Hz,1H),5.45(s,2H),5.20(s,2H),5.03(br s,1H),4.92(dd,J=12.2,5.3Hz,1H),4.46(s,2H),3.80(s,3H),3.35–3.28(m,2H),3.19(t,J=6.5Hz,2H),2.91 –2.71(m,3H),2.15–2.09(m,1H),1.61–1.55(m,2H),1.53–1.46(m,2H),1.41–1.31(m,2H),1.29–1.24(m,2H).

[0231] HRMS(ESI): m / z[M+H] + C 43 H 43 N 10 The theoretical value of O8 is 827.3260, and the measured value is 827.3263.

[0232] Example 13:

[0233] N-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)amino)nonyl)-2-(4-((7-(4-methoxybenzyl)-2-oxo-2,7-dihydro-3H-diimidazo[4,5-d:4',5'-f][1,3]diaza) -3-yl)methyl)phenoxy)acetamide (13)

[0234]

[0235] Step 1: Preparation of (8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)amino)nonyl)tert-butyl carbamate (13b)

[0236]

[0237] To a 25 mL round-bottom flask, 2-(2,6-dioxadiidine-3-yl)-5-fluoroisoindoline-1,3-dione (524 mg, 1.9 mmol), (8-aminononyl)carbamate tert-butyl ester (510 mg, 2.09 mmol), NMP (4 mL), and DIPEA (680 mg, 5.7 mmol) were added sequentially. The resulting reaction mixture was then stirred at 100 °C for 0.5 h. After cooling to room temperature, the reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with water (20 mL × 2) and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (silica gel, DCM / EA = 70 / 30) to give product 13b as a yellow solid (152 mg, yield 16%).

[0238] 1 H NMR (400MHz, CDCl3) δ8.18(br s,1H),7.60(d,J=8.3Hz,1H),6.95(d,J=2.1Hz,1H),6.73(dd,J=8.3,2.2Hz,1H),4.93(dd,J=12.3,5.3Hz,1H),4.53(br s,1H),3.21(t,J=7.1Hz,2H),3.14–3.06(m,2H),2.92–2.66(m,3H),2.15 –2.09(m,1H),1.69–1.60(m,2H),1.46–1.42(m,13H),1.33-1.32(m,6H).

[0239] Step 2: N-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)amino)nonyl)-2-(4-((7-(4-methoxybenzyl)-2-oxo-2,7-dihydro-3H-diimidazo[4,5-d:4',5'-f][1,3]diaza) Preparation of 3-yl)methyl)phenoxy)acetamide (13)

[0240]

[0241] Intermediate 1a (53 mg, 0.1 mmol), intermediate 13b (53 mg, 0.105 mmol), DCM (1.5 mL), and TFA (0.5 mL) were added sequentially to a 25 mL round-bottom flask. The resulting reaction mixture was stirred at room temperature for 1 h, and then the volatiles were removed under reduced pressure. DCM (5 mL) was added to the residue, and the mixture was concentrated to dryness under reduced pressure again. This operation was repeated three times. DMF (2 mL), Et3N (53 mg, 0.5 mmol), and benzotriazol-1-yl-oxytripyrrolidinephosphine hexafluorophosphate (62 mg, 0.12 mmol) were added to the residue, and the resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (20 mL) and acidified to pH 6 with 10% citric acid aqueous solution. The resulting yellow solid was collected by suction filtration, slurryed in methanol, filtered, and dried to give title compound 13 as a yellow solid (35 mg, yield 41%).

[0242] 1 H NMR (400MHz, DMSO-d6) δ11.05(s,1H),8.93(s,1H),8.74(s,1H),8.00(t,J=5.7Hz,1H),7.54(d,J= 8.4Hz,1H),7.34(d,J=8.7Hz,2H),7.29(d,J=8.8Hz,2H),7.08(t,J=5.1Hz,1H),6.95–6.86(m,6H), 5.52(s,2H),5.08(s,2H),5.02(dd,J=13.1,5.3Hz,1H),4.41(s,2H),3.71(s,3H),3.13–3.06(m,4 H),2.61–2.51(m,3H),2.03–1.93(m,1H),1.58–1.51(m,2H),1.41–1.37(m,2H),1.30–1.17(m,8H).

[0243] HRMS(ESI): m / z[M+H] + C 45 H 47 N 10 The theoretical value of O8 is 855.3573, and the measured value is 855.3548.

[0244] Example 14:

[0245] N-(10-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)decyl)-2-(4-((7-(4-methoxybenzyl)-2-oxo-2,7-dihydro-3H-diimidazo[4,5-d:4',5'-f][1,3]diaza) -3-yl)methyl)phenoxy)acetamide (14)

[0246]

[0247] Step 1: Preparation of tert-butyl carbamate (14b) of (10-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)amino)decyl)carbamate

[0248]

[0249] To a 25 mL round-bottom flask, 2-(2,6-dioxadiazine-3-yl)-5-fluoroisoindoline-1,3-dione (563 mg, 2.04 mmol), (10-aminodecyl)carbamate tert-butyl ester (611 mg, 2.242 mmol), NMP (4 mL), and DIPEA (730 mg, 6.12 mmol) were added sequentially. The resulting reaction mixture was then stirred at 100 °C for 0.5 h. After cooling to room temperature, the reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with water (20 mL × 2) and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (silica gel, DCM / EA = 70 / 30) to give product 14b as a yellow-green solid (151 mg, yield 14%).

[0250] 1 H NMR (400MHz, CDCl3) δ8.18(br s,1H),7.60(d,J=8.3Hz,1H),6.95(d,J=2.1Hz,1H),6.73(dd,J=8.3,2.2Hz,1H),4.93(dd,J=12.3,5.3Hz,1H),4.52(br s,1H),3.21(t,J=7.1Hz,2H),3.14–3.06(m,2H),2.93–2.71(m,3H),2.16 –2.08(m,1H),1.70–1.58(m,2H),1.51–1.37(m,15H),1.31–1.27(m,8H)..

[0251] Step 2: N-(10-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)amino)decyl)-2-(4-((7-(4-methoxybenzyl)-2-oxo-2,7-dihydro-3H-diimidazo[4,5-d:4',5'-f][1,3]diaza) Preparation of 3-yl)methyl)phenoxy)acetamide (14)

[0252]

[0253] Intermediate 1a (53 mg, 0.1 mmol), intermediate 14b (56 mg, 0.105 mmol), DCM (1.5 mL), and TFA (0.5 mL) were added sequentially to a 25 mL round-bottom flask. The resulting reaction mixture was stirred at room temperature for 1 h, and then the volatiles were removed under reduced pressure. DCM (5 mL) was added to the residue, and the mixture was concentrated to dryness under reduced pressure again. This operation was repeated three times. DMF (2 mL), Et3N (53 mg, 0.5 mmol), and benzotriazol-1-yl-oxytripyrrolidinephosphine hexafluorophosphate (62 mg, 0.12 mmol) were added to the residue, and the resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (20 mL) and acidified to pH 6 with 10% citric acid aqueous solution. The resulting yellow solid was collected by vacuum filtration, slurryed in methanol, filtered, and dried to give title compound 14 as a yellow solid (36 mg, yield 41%).

[0254] 1 H NMR (400MHz, DMSO-d6) δ11.05(s,1H),8.93(s,1H),8.74(s,1H),8.00(t,J=5.9Hz,1H),7.54(d,J=8.3Hz,1H ),7.34(d,J=8.7Hz,2H),7.29(d,J=8.8Hz,2H),7.08(t,J=5.1Hz,1H),6.94–6.85(m,6H),5.52(s,2H),5.08( s,2H),5.02(dd,J=12.8,5.4Hz,1H),4.41(s,2H),3.71(s,3H),3.15–3.11(m,2H),3.11-3.04(m,2H),2.90–2 .81(m,1H),2.61–2.42(m,3H),2.03–1.95(m,1H),1.57–1.52(m,2H),1.39–1.32(m,4H),1.24–1.18(m,10H).

[0255] HRMS(ESI): m / z[M+H] + C 47 H 51 N 10 The theoretical value of O8 is 883.3886, and the measured value is 833.3909.

[0256] Pharmacological activity test

[0257] Protein degradation assay (Western Bolt)

[0258] First, lung cancer cell line A549 was cultured in 2 mL of complete culture medium containing 2*10 cells / mL. 5 Cells were seeded per well in 6-well culture plates. After 24 hours, the culture medium was discarded, and fresh culture medium containing the corresponding concentration of the compound was added to the cells, resulting in final concentrations of 1 μM and 10 μM. DMSO was used as the solvent, and its final concentration in the cells should be less than 0.2%. The DMSO-only group served as a blank control. The culture plates were incubated in a CO2 incubator for another 24 hours, and then proteins were extracted using a whole protein extraction kit. Further, the proteins were sonicated and subjected to SDS-PAGE gel electrophoresis: stacking gel electrophoresis at 90V for 30 minutes and separating gel electrophoresis at 100V for 60 minutes. The SDS-PAGE gel was then transferred to a PVDF membrane at 300mA for 2 hours. The PVDF membrane was blocked with 5% skim milk powder for 1 hour, followed by overnight incubation with primary antibody, 1 hour incubation with secondary antibody, and the expression of the target protein was detected using an ECL chemiluminescence ultrasensitive colorimetric kit.

[0259] The results are as follows Figure 1 As shown, the compounds in Examples 5 and 7 both exhibited micromolar-level degradation activity.

[0260] Cell proliferation inhibition assay

[0261] First, lung cancer cell line A549 was cultured in 100 μL of complete culture medium containing 10... 4 Cells were seeded per well in 96-well plates. After 24 hours, the culture medium was discarded, and fresh culture medium containing the corresponding concentrations of the compound was added to the cells, resulting in final concentrations of 0.625 μM, 1.25 μM, 2.5 μM, and 5 μM. DMSO was used as the solvent, and its final concentration on the cells should be less than 0.2%. The culture plates were incubated in a CO2 incubator for 48 hours, and cell viability was then assessed using a CCK8 assay kit. The results are shown in Table 1, which summarizes the IC50 values ​​of the compounds. 50 value.

[0262] Table 1

[0263] Example 5 0.7 Example 7 0.4 Example 8 2.0 Example 9 1.0 Example 13 4.2 Example 14 1.1

[0264] The results showed that the compounds in Examples 5 and 7 significantly inhibited the proliferation of lung cancer cell line A549, with an IC50 value of [missing information]. 50 The values ​​were 0.7 μM and 0.4 μM, respectively.

[0265] The applicant declares that the above embodiments illustrate the compounds, their preparation methods, and applications of the present invention, but the present invention is not limited to the above embodiments, that is, it does not mean that the present invention must rely on the above embodiments to be implemented. Those skilled in the art should understand that any improvements to the present invention, equivalent substitutions of the raw materials used in the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

Claims

1. A diimidazole diazapyridine compound, characterized in that, The diimidazole diazapyridine compound has the structure shown in formula (I): Where L represents substituted or unsubstituted (CH2). n , where n is an integer from 2 to 14, and the substituted (CH2) n The substituents are selected from C1-C4 alkyl groups.

2. The diimidazole diazapyridine compound according to claim 1, characterized in that, The diimidazole diazapyridine compound has the structure shown in formula (II): Where L represents substituted or unsubstituted (CH2). n , where n is an integer from 2 to 14, and the substituted (CH2) n The substituents are selected from C1-C4 alkyl groups.

3. The diimidazole diazapyridine compound according to claim 1, characterized in that, The diimidazole diazapyridine compound has the structure shown in formula (III): Where L represents substituted or unsubstituted (CH2). n , where n is an integer from 2 to 14, and the substituted (CH2) n The substituents are selected from C1-C4 alkyl groups.

4. The diimidazole diazapyridine compound according to any one of claims 1-3, characterized in that, The diimidazole diazapyridine compound is any one of the following compounds: 。 5. A method for preparing a diimidazole diazapyridine compound according to any one of claims 1-4, characterized in that, The preparation method includes the following steps: (1) In the presence of an alkaline substance, compound A reacts with tert-butyl bromoacetate to give compound B, as shown in the following reaction formula: ； (2) In the presence of an alkaline substance, compound C reacts with compound D to give compound E, as shown in the following reaction equation: ； (3) In the presence of trifluoroacetic acid or hydrochloric acid, compound B loses its tert-butyl group to give intermediate F, and compound E loses its tert-butyloxycarbonyl group to give intermediate G. The reaction formulas are as follows: ； (4) After removing trifluoroacetic acid or hydrochloric acid under reduced pressure, intermediate F and intermediate G undergo a condensation reaction to obtain a diimidazole diazapyridine compound, as shown in the following reaction formula: 。 6. The preparation method according to claim 5, characterized in that, The alkaline substance mentioned in step (1) is an organic base or an inorganic base.

7. The preparation method according to claim 6, characterized in that, The alkaline substance mentioned in step (1) is cesium carbonate.

8. The preparation method according to claim 5, characterized in that, In step (1), the molar ratio of compound A to tert-butyl bromoacetate is 1:1.2 to 1:

2.

9. The preparation method according to claim 8, characterized in that, In step (1), the molar ratio of compound A to tert-butyl bromoacetate is 1:1.

5.

10. The preparation method according to claim 5, characterized in that, The reaction temperature in step (1) is 70℃ and the reaction time is 0.5~2 h.

11. The preparation method according to claim 5, characterized in that, The solvent for the reaction in step (1) is DMF.

12. The preparation method according to claim 5, characterized in that, The alkaline substance mentioned in step (2) is an organic base or an inorganic base.

13. The preparation method according to claim 12, characterized in that, The alkaline substance mentioned in step (2) is DIPEA.

14. The preparation method according to claim 5, characterized in that, In step (2), the molar ratio of compound C to compound D is 1:1 to 1:

2.

15. The preparation method according to claim 5, characterized in that, The reaction temperature in step (2) is 100℃ and the reaction time is 0.5~6h.

16. The preparation method according to claim 5, characterized in that, The solvent for the reaction in step (2) is NMP.

17. The preparation method according to claim 5, characterized in that, The reaction of compound B to remove the tert-butyl group in step (3) is carried out at room temperature for 0.5 to 2 hours.

18. The preparation method according to claim 5, characterized in that, The solvent for the reaction of compound B to remove the tert-butyl group in step (3) is DCM.

19. The preparation method according to claim 5, characterized in that, The reaction of compound E to remove the tert-butyloxycarbonyl group in step (3) is carried out at room temperature for 0.5 to 2 hours.

20. The preparation method according to claim 5, characterized in that, The solvent for the reaction of compound E in step (3) to remove the tert-butyloxycarbonyl group is DCM.

21. The preparation method according to claim 5, characterized in that, The molar ratio of intermediate F and intermediate G in step (4) is 1:1 to 1:

2.

22. The preparation method according to claim 5, characterized in that, The condensation reaction in step (4) is carried out at room temperature for 8 to 16 hours.

23. The preparation method according to claim 5, characterized in that, The solvent for the condensation reaction in step (4) is DCM.

24. A pharmaceutically acceptable salt of a diimidazole diazapyridine compound according to any one of claims 1-4.

25. A pharmaceutically acceptable salt of a diimidazole diazazide compound according to claim 24, characterized in that, The pharmaceutically acceptable salts are selected from sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrophosphates, dihydrophosphates, metaphosphates, pyrophosphates, hydrochlorides, hydrobromates, hydroiodates, acetates, propionates, decanoates, caprylates, octanoates, acrylates, formates, isobutyrates, hexanoates, heptanoates, propynylates, oxalates, malonates, succinates, octanoates, sebacic acid salts, fumarates, maleates, butyn-1,4-dicitates, hexyn-1,6-dicitates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycolic acid salts, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates.

26. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises a diimidazole diazapyridine compound as described in any one of claims 1-4 or a pharmaceutically acceptable salt as described in claim 24, and optionally a pharmaceutically acceptable carrier.

27. The pharmaceutical composition according to claim 26, characterized in that, The pharmaceutical composition is a pharmaceutically acceptable formulation for the prevention and / or treatment of lung cancer.

28. A pharmaceutical preparation, characterized in that, It comprises at least one diimidazole diazapyridine compound as described in any one of claims 1-4 or a pharmaceutically acceptable salt as described in claim 25, and optionally a pharmaceutically acceptable carrier.

29. A DDX3X inhibitor and / or degradation agent, characterized in that, The DDX3X inhibitor and / or degrader comprises a diimidazole diazapyridine compound as described in any one of claims 1-4 or a pharmaceutically acceptable salt as described in claim 24, or a pharmaceutical composition as described in claim 26 or 27.

30. Use of a diimidazole diazapyridine compound according to any one of claims 1-4, or a pharmaceutically acceptable salt according to claim 25, or a pharmaceutical composition according to claim 26, in the preparation of a medicament for the prevention and / or treatment of lung cancer.

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