Pharmaceutical composition of benzindole derivative, preparation method therefor, and use thereof

Abstract

The present application relates to the technical field of pharmaceutical formulations and particularly to a pharmaceutical composition of a benzindole derivative, a preparation method therefor, and use thereof. The pharmaceutical composition comprises a compound represented by formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient, and one or more pharmaceutically acceptable excipients. The active ingredient in the pharmaceutical composition demonstrates good dissolution and excellent absorption in an organism, and the pharmaceutical composition remains stable even during long-term storage.

Description

Pharmaceutical compositions, preparation methods and uses of benzoindole derivatives Technical Field

[0001] This application relates to the field of pharmaceutical formulation technology, specifically to a pharmaceutical composition, preparation method and use of a benzoindole derivative. Background Technology

[0002] Multiple myeloma (MM) is a hematologic malignancy caused by the abnormal proliferation of plasma cells. Its main characteristic is markedly active plasma cell proliferation in the bone marrow, accompanied by excessive secretion of monoclonal immunoglobulins. A very small number of patients have non-secreting MM, which does not produce M protein. Currently, significant breakthroughs have been made in the treatment of MM. Several drugs, such as proteasome inhibitors (bortezomib), immunomodulatory drugs (lenalidomide, pomalidomide), CD38 monoclonal antibodies (daratumumab and elotuzumab), and histone deacetylase (HDAC) inhibitors (panobinostat), have been approved by the FDA for the treatment of MM. Among these, molecular gel-based immunomodulatory agents are currently a key focus of drug development.

[0003] Molecular glue degraders are small molecules that induce and stabilize the binding of E3 ubiquitin ligases to target proteins, leading to ubiquitination and proteasome degradation of the target proteins. Compared to bifunctional molecular degraders (protacs), molecular glues have a lower affinity for target proteins, but they can bind to E3 ubiquitin ligases and mediate contact with target proteins through them. Therefore, molecular glues can degrade target proteins that lack small molecule binding pockets. Furthermore, the target protein of the molecular glue itself needs to have a nonfunctional, weak affinity for the E3 ligase. Molecular glues can bind into the gaps at the interaction interface between the two, increasing the binding interface and elevating it to a functional, strong interaction. Currently, molecular glues in molecular glues such as lenalidomide and pomalidomide recruit CRBN ubiquitin ligases, promoting the binding of CRBN to zinc finger protein transcription factors IKZF1 / 3, thereby leading to the ubiquitination and degradation of IKZF1 / 3. Since IKZF1 / 3 can promote the proliferation of multiple myeloma (MM) cells by regulating the expression of proto-oncogenes IRF4 and c-myc, molecular glue-induced IKZF1 / 3 degradation can significantly inhibit MM cell growth. Although lenalidomide has good efficacy in treating multiple myeloma, most patients develop resistance after two years of treatment. Pomalidomide is the preferred drug for lenalidomide-resistant multiple myeloma patients; studies have shown that its combination with dexamethasone can inhibit the growth of lenalidomide-resistant tumor cells and induce apoptosis. Although pomalidomide can improve the efficacy in lenalidomide-resistant patients, approximately one-third of patients develop point mutations in the CRBN gene after continuous administration, leading to pomalidomide resistance. Furthermore, while lenalidomide and pomalidomide can inhibit the proliferation of multiple myeloma, the incidence of G3 / G4 neutropenia can be as high as 35% and approximately 50%, respectively. In a Phase I clinical trial, the molecular gel CC-92480 developed by Bristol-Myers Squibb achieved an objective response rate (ORR) of 54.4%, but the incidence of neutropenia was as high as 53%. Therefore, developing a molecular gel that is effective for patients resistant to lenalidomide and pomalidomide, while also exhibiting low hematologic toxicity, especially neutrophil toxicity, is of great significance for the treatment of multiple myeloma. Summary of the Invention

[0004] The purpose of this application is to provide a pharmaceutical composition of a benzoindole derivative, a method for its preparation, and its use; the active ingredient in the pharmaceutical composition has good solubility and excellent absorption in vivo, and the pharmaceutical composition remains stable even after long-term storage.

[0005] The first aspect of this application provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof;

[0006] In some embodiments, each unit of the pharmaceutical composition contains 0.01 to 50 mg of the compound of Formula I or a pharmaceutically acceptable salt thereof, i.e., the pharmaceutical composition has a formulation strength of 0.01 to 50 mg.

[0007] In some embodiments, each unit of the pharmaceutical composition contains 0.01 to 10 mg of the compound of Formula I or a pharmaceutically acceptable salt thereof, i.e., the pharmaceutical composition has a formulation strength of 0.01 to 10 mg.

[0008] In some embodiments, each unit of the pharmaceutical composition contains 0.01 to 5 mg of the compound of Formula I or a pharmaceutically acceptable salt thereof, i.e., the pharmaceutical composition has a formulation strength of 0.01 to 5 mg.

[0009] In some embodiments, each unit of the pharmaceutical composition contains 0.01 to 1 mg of the compound of Formula I or a pharmaceutically acceptable salt thereof, i.e., the pharmaceutical composition has a formulation strength of 0.01 to 1 mg.

[0010] In some embodiments, each unit of the pharmaceutical composition contains 0.05 to 0.5 mg of the compound of Formula I or a pharmaceutically acceptable salt thereof, i.e., the pharmaceutical composition is formulated to a strength of 0.05 to 0.5 mg.

[0011] In some specific embodiments, each unit of the pharmaceutical composition contains 0.01 mg, 0.02 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 20 mg, 25 mg, 30 mg, 40 mg, or 50 mg of Formula I. The indicated compound or a pharmaceutically acceptable salt thereof, i.e., the pharmaceutical composition, is available in formulation strengths of 0.01 mg, 0.02 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 20 mg, 25 mg, 30 mg, 40 mg, or 50 mg.

[0012] In this application, the content of the compound of Formula I or its pharmaceutically acceptable salt in each unit of the pharmaceutical composition is calculated as free base.

[0013] In some embodiments, the Formula I compound in the pharmaceutical composition is present in the form of a free base.

[0014] In some embodiments, the pharmaceutical composition further includes one or more pharmaceutically acceptable excipients.

[0015] In some embodiments, the excipient is selected from one or more of surfactants, excipients, disintegrants, and lubricants.

[0016] In some implementations, the excipients include surfactants.

[0017] In some preferred embodiments, the excipients include surfactants, excipients, disintegrants, and lubricants.

[0018] In some more preferred embodiments, the pharmaceutical composition comprises: a compound of Formula I, a surfactant, an excipient, a disintegrant, and a lubricant.

[0019] In some embodiments, the surfactant is selected from one or more of anionic surfactants, cationic surfactants, amphoteric surfactants, nonionic surfactants, or polymeric surfactants. Preferably, it is selected from one or more of sodium C5-20 alkyl sulfate, sodium C5-20 alkyl sulfonate, sodium stearate, lecithin, sucrose fatty acid esters, polysorbate, poloxamer, polyethylene glycol, sodium dihexyl succinate sulfonate, and sodium dioctyl succinate sulfonate. More preferably, it is selected from one or more of sodium dodecyl sulfate, sodium stearate, sodium dodecyl sulfonate, lecithin, sucrose fatty acid esters, polysorbate, and poloxamer. More preferably, it is sodium dodecyl sulfate.

[0020] In some embodiments, the excipient is selected from one or more of lactose, mannitol, microcrystalline cellulose, starch, pregelatinized starch, glucose, sorbitol, xylitol, calcium phosphate, dicalcium phosphate, calcium sulfate, and calcium carbonate, preferably one or more of lactose, mannitol, microcrystalline cellulose, and starch, more preferably mannitol and / or microcrystalline cellulose.

[0021] In some embodiments, the disintegrant is selected from one or more of crospovidone, crospovidone sodium carboxymethyl cellulose, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, starch, alginate, sodium alginate and calcium carboxymethyl cellulose, preferably one or more of crospovidone, crospovidone sodium carboxymethyl cellulose, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose and starch, more preferably crospovidone sodium carboxymethyl cellulose and / or sodium carboxymethyl starch.

[0022] The term "low-substituted hydroxypropyl cellulose" refers to low-substituted hydroxypropyl cellulose in which the content of hydroxypropyl groups is 5.0 wt% to 9.9 wt%.

[0023] In some embodiments, the lubricant is selected from one or more of silica, talc, sodium stearate fumarate, magnesium stearate and stearic acid, preferably silica and / or magnesium stearate, more preferably silica and magnesium stearate.

[0024] In some embodiments, the content of the compound represented by Formula I or its pharmaceutically acceptable salt is 0.01% to 20.0% of the total weight of the pharmaceutical composition, preferably 0.01% to 10.0%, more preferably 0.01% to 1.0%, and even more preferably 0.06% to 0.625%, specifically 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.0625%, 0.07%, 0.0%... 8%, 0.09%, 0.1%, 0.13%, 0.2%, 0.23%, 0.25%, 0.3%, 0.4%, 0.5%, 0.6%, 0.625%, 0.65%, 0.7%, 0.75%, 0.8%, 0.9%, 1.0%, 1.25%, 1.5%, 2.0%, 3.0%, 4.0%, 5.0%, 6.0%, 7.0%, 9.0%, 10.0%, 15.0%, 20.0%.

[0025] In some embodiments, the surfactant content is 0.1% to 10.0% of the total weight of the pharmaceutical composition, preferably 0.5% to 5.0%, more preferably 0.8% to 5.0%, and even more preferably 1.0% to 2.5%, specifically 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.5%, 3.0%, 4.0%, 5.0%, 6.0%, 7.0%, 8.0%, 9.0%, and 10.0%.

[0026] In some embodiments, the lubricant content is 0.001% to 10% of the total weight of the pharmaceutical composition, preferably 0.007% to 5.5%, more preferably 0.01% to 3%, and even more preferably 1% to 3%, specifically 0.001%, 0.007%, 0.01%, 0.1%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.25%, etc. 1.3%, 1.4%, 1.41%, 1.5%, 1.54%, 1.6%, 1.7%, 1.75%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.71%, 2.8%, 2.9%, 3.0%, 4.0%, 5.0%, 5.5%, 6.0%, 7.0%, 8.0%, 9.0%, 10.0%.

[0027] In some specific embodiments, the lubricant is silica and magnesium stearate, wherein the silica content is 0.15% to 0.29% of the total weight of the pharmaceutical composition, for example, 0.15% or 0.29%, and the magnesium stearate content is 1% to 3% of the total weight of the pharmaceutical composition, for example, 1.25%.

[0028] In some embodiments, the excipient content is 10% to 99% of the total weight of the pharmaceutical composition, preferably 40% to 95%, more preferably 91% to 94%, specifically 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 90.63%, 91%, 91.5%, 92%, 92.13%, 93%, 93.13%, 93.8%, 94%, 94.11%, 94.15%, 95%, 96%, 97%, 98%, and 99%.

[0029] In some embodiments, the content of the disintegrant is 0.5% to 20% of the total weight of the pharmaceutical composition, preferably 1% to 15%, more preferably 3% to 10%, further preferably 3% to 8%, and most preferably 3% to 4%, specifically 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.54%, 3.6%, 3.7%, 3.8%, 3.9%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, and 20%.

[0030] In the pharmaceutical composition of the present invention, the ratio of the compound of Formula I or its pharmaceutically acceptable salt to the surfactant is not particularly limited. In some preferred embodiments, the weight ratio of the compound of Formula I or its pharmaceutically acceptable salt to the surfactant is 0.01 to 1:1, preferably 0.05 to 0.7:1, more preferably 0.06 to 0.625:1, for example: 0.01:1, 0.05:1, 0.06:1, 0.0625:1, 0.25:1, 0.625:1, 0.7:1.

[0031] In the pharmaceutical composition of the present invention, the ratio of the compound of Formula I or its pharmaceutically acceptable salt to the lubricant is not particularly limited. In some preferred embodiments, the weight ratio of the compound of Formula I or its pharmaceutically acceptable salt to the lubricant is 0.001 to 1:1, preferably 0.01 to 0.8:1, more preferably 0.04 to 0.5:1, for example: 0.001:1, 0.01:1, 0.04:1, 0.5:1, 0.8:1, 1:1.

[0032] In some embodiments, the pharmaceutical composition comprises, by weight:

[0033] The compound of Formula I or a pharmaceutically acceptable salt thereof is used in an amount of 0.01 to 20.0 parts, preferably 0.01 to 10.0 parts, more preferably 0.01 to 1.0 parts, and even more preferably 0.06 to 0.625 parts;

[0034] The surfactant is used in amounts of 0.1 to 10.0 parts, preferably 0.5 to 5.0 parts, more preferably 0.8 to 5.0 parts, and even more preferably 1.0 to 2.5 parts.

[0035] In some embodiments, the pharmaceutical composition comprises, by weight, the following components:

[0036] The compound of Formula I or a pharmaceutically acceptable salt thereof, in amounts of 0.01 to 20.0 parts, preferably 0.01 to 10.0 parts, more preferably 0.01 to 1.0 parts, and even more preferably 0.06 to 0.625 parts;

[0037] Surfactant, 0.1 to 10.0 parts, preferably 0.5 to 5.0 parts, more preferably 0.8 to 5.0 parts, and even more preferably 1.0 to 2.5 parts;

[0038] Lubricant, 0.001 to 10 parts, preferably 0.007 to 5.5 parts, more preferably 0.01 to 3 parts, and even more preferably 1 to 3 parts;

[0039] Excipient, 10-99 parts, preferably 40-95 parts, more preferably 92-95 parts;

[0040] The disintegrant is 0.5 to 20 parts, preferably 1 to 15 parts, more preferably 3 to 10 parts, and even more preferably 3 to 8 parts.

[0041] In some embodiments, the pharmaceutical composition may be prepared into various pharmaceutically acceptable dosage forms.

[0042] In some preferred embodiments, the pharmaceutical composition is preferably an oral formulation, preferably an oral solid dosage form, more preferably a tablet, granule or capsule, and even more preferably the capsule;

[0043] The granules are formulations granulated into granules. Furthermore, regarding granules, enteric-coated granules or sustained-release granules can be prepared using known and suitable methods. Granules can also be foaming granules, which are granules that rapidly foam, dissolve, or disperse in water.

[0044] In this application, the tablets can be manufactured by compression. For example, tablets can be obtained by directly compressing the mixed raw materials, or by further compressing the mixed raw materials into granules.

[0045] In this application, if the product is a capsule, it can be a hard capsule or a soft capsule.

[0046] In this application, capsules can be obtained by filling the granules into capsules.

[0047] In some specific embodiments of this application, the pharmaceutical composition comprises the following components:

[0048] The active ingredient is a compound represented by Formula I;

[0049] The surfactant is sodium dodecyl sulfate.

[0050] The disintegrant is sodium croscarmellose and / or sodium carboxymethyl starch;

[0051] The excipients are mannitol and microcrystalline cellulose; and

[0052] The lubricant is composed of silicon dioxide and magnesium stearate.

[0053] In some embodiments, the pharmaceutical composition comprises: 0.05–5 mg of the compound shown in Formula I and 0.8–8 mg of a surfactant.

[0054] In some embodiments, the pharmaceutical composition comprises: 0.05–0.5 mg of the compound represented by Formula I; and 0.8–2 mg of a surfactant.

[0055] In some embodiments, the pharmaceutical composition comprises: 0.05–5 mg of the compound of Formula I, 0.8–8 mg of surfactant, 72.5–368 mg of excipient, 1–7 mg of lubricant, and 2.7–16 mg of disintegrant.

[0056] In some embodiments, the pharmaceutical composition comprises: 0.05–0.5 mg of the compound of Formula I; 0.8–2 mg of surfactant; 72.5–75.3 mg of excipient; 1–2.2 mg of lubricant; and 2.7–2.8 mg of disintegrant.

[0057] A second aspect of this application provides a method for preparing the above-mentioned pharmaceutical composition, comprising the step of mixing the compound represented by Formula I or a pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipients.

[0058] A third aspect of this application provides the use of the pharmaceutical composition described above or the pharmaceutical composition prepared by the above-described method in the preparation of a medicament for the prevention and / or treatment of cereblon-mediated diseases. Alternatively, this application provides the pharmaceutical composition described above or the pharmaceutical composition prepared by the above-described method for the prevention and / or treatment of cereblon-mediated diseases. Alternatively, this application provides a method for the prevention and / or treatment of cereblon-mediated diseases, comprising administering the pharmaceutical composition described above or the pharmaceutical composition prepared by the above-described method to a subject in need.

[0059] In some preferred embodiments, the cereblon-mediated diseases described above are mediated by IKZF1 (Ikaros) and / or IKZF3 (Aiolos).

[0060] In some preferred embodiments, the diseases mediated by cereblon mentioned above are cancer, tumors, immune diseases, or inflammatory diseases.

[0061] In some preferred embodiments, the cereblon-mediated diseases described above are autoimmune diseases.

[0062] In some preferred embodiments, the aforementioned cereblon-mediated disease is a hematologic malignancy.

[0063] In some preferred embodiments, the cereblon-mediated diseases described above are multiple myeloma, leukemia, lymphocytic leukemia, chronic lymphocytic leukemia, Hodgkin lymphoma, or non-Hodgkin lymphoma.

[0064] A fourth aspect of this application provides the use of the pharmaceutical composition described above or the pharmaceutical composition prepared by the above preparation method in the preparation of an immunomodulatory agent targeting both IKZF1 and IKZF3. Alternatively, this application provides the pharmaceutical composition described above or the pharmaceutical composition prepared by the above preparation method for immunomodulation of both IKZF1 and IKZF3. Alternatively, this application provides a method for immunomodulation of both IKZF1 and IKZF3, comprising administering the pharmaceutical composition described above or the pharmaceutical composition prepared by the above preparation method to a subject in need.

[0065] This application also covers solutions obtained by any combination, deletion or substitution of the above-described embodiments and preferred solutions.

[0066] The beneficial effects of this application are:

[0067] The active ingredient in this pharmaceutical composition, represented by Formula I or its pharmaceutically acceptable salt, exhibits good solubility, thereby increasing the drug's exposure in vivo and enhancing its efficacy. Furthermore, the pharmaceutical composition remains stable even after long-term storage.

[0068] This application includes pharmaceutical compositions containing surfactants, which significantly improve in vivo absorption. Detailed Implementation

[0069] To make this application easier to understand, the following detailed description will be provided with reference to embodiments. These embodiments are for illustrative purposes only and are not limited to the scope of application of this application.

[0070] Unless otherwise defined, the technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0071] In this application, the terms “comprising,” “including,” and “containing,” and their equivalents, shall be understood in an open, non-exclusive sense, meaning “including but not limited to,” implying that in addition to the listed elements, components, and steps, other unspecified elements, components, and steps may also be covered. In this document, unless the context clearly specifies otherwise, singular terms shall cover plural references, and vice versa.

[0072] 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 the other components constituting a drug dosage form and physiologically compatible with the receptor, without excessive toxicity, irritation, allergic reactions or other problems or complications, and is commensurate with a reasonable benefit / risk ratio.

[0073] The term "treatment" means administering the compound or preparation described in this application to improve or eliminate a disease or one or more symptoms associated with the disease, including inhibiting the progression of the disease or condition and alleviating the disease or condition.

[0074] In this article, portions can be expressed in milligrams.

[0075] In this application, the pharmaceutical excipients or reagents involved may be derived from commercial sources.

[0076] In this application, unless otherwise specified, "%" in the embodiments of this application refers to the mass percentage.

[0077] Unless otherwise specified in the examples, the reaction temperature is 20–30°C.

[0078] The compound shown in Formula I of this application:

[0079] Preparation Example 1: Preparation can be carried out with reference to PCT / CN2024 / 082990, filed on March 21, 2024; for example, Examples 29-31 of PCT / CN2024 / 082990 (the compound shown in Formula I is the compound of Example 30 of that patent application):

[0080] (1) Synthesis of intermediate 3(3-(2-oxo-6-(4-(piperazin-1-ylmethyl)benzyl)benzo[cd]indol-1(2H)-yl)piperidine-2,6-dione):

[0081] Intermediate 3 was synthesized according to the method provided in patent application WO2020210630A1.

[0082] (2) Synthesis of intermediates 5 (2-(1H-imidazol-1-yl)-4-(methanesulfonyl)pyrimidine) and 36 (2-methyl-4-(methanesulfonyl)-6-(4-(trifluoromethyl)-1H-imidazol-1-yl)pyrimidine):

[0083] Step a. Synthesis of 2-(1H-imidazol-1-yl)-4-(methylthio)pyrimidine

[0084] 2-Chloro-4-methylthiopyrimidine (805 mg, 5 mmol, CAS: 49844-93-1), imidazole (510 mg, 7.5 mmol), cuprous iodide (181 mg, 1.0 mmol), and cesium carbonate (3.26 g, 10 mmol) were added to a 50 mL double-necked flask. Anhydrous N,N-dimethylacetamide (20 mL) was then added under a nitrogen atmosphere, and the mixture was reacted overnight at 80 °C. Saturated brine (100 mL) was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate (30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to give the title compound as a white solid (682 mg, 71% yield). LC-MS: m / z [M+H] + =193.

[0085] Step b. Synthesis of intermediate 5 (2-(1H-imidazol-1-yl)-4-(methylsulfonyl)pyrimidine)

[0086] 2-(1H-imidazol-1-yl)-4-(methylthio)pyrimidine (682 mg, 3.55 mmol) was dissolved in dichloromethane (20 mL). m-chloroperoxybenzoic acid (1.85 g, 10.65 mmol) was added in portions at 0 °C, and the mixture was stirred for 10 minutes at the same temperature. The mixture was then brought to room temperature and stirred overnight. The solution was quenched with saturated sodium thiosulfate solution (50 mL), and extracted three times with dichloromethane (30 mL). The organic phases were combined, washed three times with saturated sodium bicarbonate solution (30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to give the title compound as a white solid (604 mg, 76% yield). LC-MS: m / z [M+H] + =225.

[0087] Referring to the table below, except for replacing the corresponding raw materials with the raw materials listed in the "Raw Materials" column, intermediate 36 is prepared according to the preparation method of intermediate 5:

[0088] Example 29 of PCT / CN2024 / 082990: 3-(6-(4-((4-(2-methyl-6-(4-(trifluoromethyl)-1H-imidazol-1-yl)pyrimidin-4-yl)piperazin-1-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidin-2,6-dione

[0089] 3-(2-oxo-6-(4-(piperazin-1-ylmethyl)benzyl)benzo[cd]indol-1(2H)-yl)piperidin-2,6-dione (150 mg, 0.32 mmol, intermediate 3), 2-methyl-4-(methanesulfonyl)-6-(4-(trifluoromethyl)-1H-imidazol-1-yl)pyrimidine (147 mg, 0.48 mmol, intermediate 36) and N,N-diisopropylethylamine (0.265 mL, 1.6 mmol, d = 0.782 g / mL) were added to a 50 mL single-necked flask, followed by the addition of dimethyl sulfoxide (3 mL). The mixture was stirred at 120 °C for 5 hours. The reaction solution was purified by preparative liquid chromatography (acetonitrile and water containing 0.1% formic acid) to give the yellow title compound (95 mg, yield 43%). 1 H NMR (400MHz, DMSO-d6) δ11.15(s,1H),8.71(s,1H),8.63(t,J=1.5Hz,1H),8.33(d,J=8.3Hz,1H) ,8.08(d,J=7.0Hz,1H),7.81(dd,J=8.3,7.0Hz,1H),7.42(d,J=7.4Hz,1H),7.25(q,J=8.0Hz,4H) ,7.12(d,J=7.3Hz,1H),7.04(s,1H),5.45(dd,J=13.0,5.4Hz,1H),4.39(s,2H),3.70(s,4H),3.4 6(s,2H),3.02–2.89(m,1H),2.85–2.60(m,2H),2.41(m,7H),2.13–2.06(m,1H); LC-MS:m / z[M+H] + =695.

[0090] Example 30 of PCT / CN2024 / 082990: (S)-3-(6-(4-((4-(2-methyl-6-(4-(trifluoromethyl)-1H-imidazol-1-yl)pyrimidin-4-yl)piperazin-1-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidin-2,6-dione

[0091] Example 31 of PCT / CN2024 / 082990: (R)-3-(6-(4-((4-(2-methyl-6-(4-(trifluoromethyl)-1H-imidazol-1-yl)pyrimidin-4-yl)piperazin-1-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidin-2,6-dione

[0092] Chiral separation: 27 g of 3-(6-(4-((4-(2-methyl-6-(4-(trifluoromethyl)-1H-imidazol-1-yl)pyrimidin-4-yl)piperazin-1-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidin-2,6-dione (Example 29) was separated into enantiomers by a chiral normal-phase preparative HPLC method. First, the preparative fraction was evaporated separately under reduced pressure to obtain a solid. The solid was then suspended in a mixture of acetonitrile and water (2:3) and maintained in a dry ice / acetone bath until the acetonitrile-water mixture solidified. The frozen mixture was then freeze-dried for 20 hours to obtain (S)-3-(6-(4-((4-(2-methyl-6-(4-(trifluoromethyl)-1H-imidazol-1-yl)pyrimidin-4-yl)piperazin-1-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidin-2,6-dione (first elution peak, RT = 1.659 min, tentatively designated as "S"ABS) (11 0.5 g, 99.37% ee) and (R)-3-(6-(4-((4-(2-methyl-6-(4-(trifluoromethyl)-1H-imidazol-1-yl)pyrimidin-4-yl)piperazin-1-yl)methyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidin-2,6-dione (second elution peak, RT = 2.133 min, tentatively designated as 'R'ABS) (12.5 g, 100% ee).

[0093] Chiral analysis method (analytical separation method):

[0094] Instrument: Shimadzu LC-20AB with PDA detector

[0095] Chromatographic column: Chiralpak IC-3 100×4.6mm ID, 3μm

[0096] Mobile phase: A: Hexane (0.1% DEA), B: IPA: MeCN = 2:1

[0097] Isocratic elution: B: 60%

[0098] Flow rate: 1.0 mL / min

[0099] Column temperature: 35℃

[0100] Wavelength: 254nm

[0101] Chiral preparation method (Preparative separation method):

[0102] Instrument: Shimadzu LC-AHPLC

[0103] Column: Chiralpak IC, 250×30mm, 10μm

[0104] Mobile phase: A: DCM, B: IPA

[0105] Isocratic elution: B: 50%

[0106] Flow rate: 150 mL / min

[0107] Column temperature: RT

[0108] Wavelength: 220nm, 254nm

[0109] Sample preparation: Dissolve the sample in ~2000mL of DCM / IPA.

[0110] Injection volume: 200mL

[0111] Cycle time: 35 min

[0112] Example 30 of PCT / CN2024 / 082990: 1H NMR (400MHz, DMSO-d6) δ11.13(s,1H),8.71(s,1H),8.62(s,1H),8.33(d,J=8.4Hz,1H),8.08(d,J=6.8Hz, 1H),7.81(dd,J=8.4,7.2Hz,1H),7.42(d,J=7.6Hz,1H),7.26(d,J=8.2Hz,2H),7.22(d,J=8.2Hz,2H),7.11 (d,J=7.2Hz,1H),7.03(s,1H),5.45(dd,J=12.8,5.2Hz,1H),4.39(s,2H),3.69(s,4H),3.46(s,2H),3.02– 2.89(m,1H),2.81–2.70(m,1H),2.67–2.63(m,1H),2.43–2.38(m,7H),2.15–2.04(m,1H); LC-MS:m / z[M+H] + =695.

[0113] Example 31 of PCT / CN2024 / 082990: 1 H NMR (400MHz, DMSO-d6) δ11.12(s,1H),8.70(s,1H),8.62(s,1H),8.32(d,J=8.4Hz,1H),8.07(d,J=6.8Hz, 1H),7.81(dd,J=8.4,7.2Hz,1H),7.42(d,J=7.6Hz,1H),7.26(d,J=8.2Hz,2H),7.22(d,J=8.2Hz,2H),7.11 (d,J=7.2Hz,1H),7.03(s,1H),5.45(dd,J=12.8,5.2Hz,1H),4.39(s,2H),3.69(s,4H),3.45(s,2H),3.02– 2.89(m,1H),2.83–2.69(m,1H),2.69–2.61(m,1H),2.43–2.38(m,7H),2.13–2.04(m,1H); LC-MS:m / z[M+H] + =695

[0114] Example of this application:

[0115] Example 1. Cell Titer-GLO (CTG) assay for NCI-H929 cell proliferation

[0116] 1. Experimental objective: To detect the inhibitory activity of the compound on the proliferation of NCI-H929 cells.

[0117] 2. Experimental Methods:

[0118] NCI-H929 cells were placed in RPMI 1640 (Viva; C3010-0500) medium containing 10% fetal bovine serum (Viva, C04002-500) and 1% penicillin and streptomycin. The cells were cultured in a cell culture incubator at 37°C, 5% CO2 and saturated humidity.

[0119] Cells grown to the logarithmic growth phase were seeded into 96-well plates (5000 cells / well) and cultured overnight. Then, compounds at concentrations of 0.00512 nM, 0.0256 nM, 0.128 nM, 0.64 nM, 3.2 nM, 16 nM, 80 nM, and 400 nM were added to the cell culture medium. 0.1% DMSO and the complete culture medium were used as solvents and blank controls, respectively. Each test was performed in duplicate. The 96-well plates were incubated at 37°C in a 5% CO2 incubator for 72 h. After incubation, the 96-well plates were allowed to stand at room temperature for half an hour before adding 50 μL of [a specific compound / concentration]. After mixing (Promega, G7573) in an oscillator for 2 minutes, it was incubated at room temperature in the dark for 10 minutes before the Luminance signal was tested using SpectraMax Paradigm (Molecular Devices).

[0120] Cell activity inhibition rate (%) = 100 - (RLU) compound -RLU blank ) / (RLU control -RLU blank *100%, Control group was the 0.1% DMSO treatment group, and blank was the culture medium control. The IC50 and maximum inhibition rate of the compounds were calculated using the nonlinear regression function "Dose-Response-Inhibition" in Graphpad Prism 7.0.

[0121] Table 1: In vitro anti-proliferative IC50 values ​​in NCI-H929 cells

[0122] Conclusion: The compound shown in Formula I of this application exhibits good cell proliferation inhibitory activity against NCI-H929 cells.

[0123] Example 2. Protein Degradation Assay (In-cell Western blotting)

[0124] NCI-H929 cells were seeded into 96-well plates at 100,000 cells per well and cultured overnight. Then, compounds at concentrations of 1600 nM, 400 nM, 100 nM, 25 nM, 6.25 nM, 1.56 nM, 0.39 nM, and 0.1 nM were added to each well, replicated, and incubated at 37°C for 24 h. After incubation, the supernatant was removed by centrifugation, and 150 μL of 4% paraformaldehyde was added to each well. The plates were incubated at room temperature for 20 min. Then, 200 μL of washing buffer (0.1% Triton X-100, Beyotime; ST1722) was added, and the plates were washed four times on a shaker at room temperature. Finally, 150 μL of Licor INERCEPT blocking buffer (Lico, Cat No. 927-70001) was added, and the plates were incubated on a shaker at room temperature for 1.5 h. IKZF1 (Cell Signaling; Cat No. 14859S), IKZF3 (Cell Signaling; Cat No. 15103S), GSPT1 (Proteintech, Cat No. 10763-1-AP), CK1α (Thermo; 7117067), and SALL4 (Abcam, ab22675) antibodies were diluted 1:100 with antibody dilution buffer (Intercept Blocking Buffer, LI-COR, 211114) as primary antibodies. 50 μL of each diluted primary antibody was added to each well, and the mixture was incubated overnight at 4°C on a shaker. After removing the primary antibody and washing four times with PBST, 50 μL of a diluted secondary antibody (Licor, Cat No. 926-68070) was added, along with 0.5 μL each of IRDye 800CW and IRDye 680CW. The secondary antibody was removed and PBST was added. The mixture was washed four times on a shaker at room temperature and then placed in an infrared laser imaging system (Lico, Odyssey-CLx) to detect the signal intensity.

[0125] Table 2: List of Protein Degradation Activities

[0126] Conclusion: The compound shown in Formula I of this application exhibits good degradation activity against the target protein IKZF1 / 3, but no significant degradation activity against other non-target proteins GSPT1, CK1α, and SALL4 (e.g., the DC50 for these proteins was measured to be greater than 10000 nM), demonstrating good selectivity.

[0127] Example 3. CRBN Binding Experiment (HTRF)

[0128] The binding strength of CRBN to compounds was detected using an HTRF competitive assay with a CRBN binding kit (Cisbio, 64BDCRBNPEG). First, the reagents in the kit were equilibrated to room temperature and diluted 1:1 with double-distilled water. Both reagents and samples were thoroughly vortexed before use. Then, europium-labeled specific GST antibody and XL665-labeled thalidomide-red reagent (Cisbio, Cat No. 64BDCRBNPEG) were mixed in equal volumes and added to 10 μL per well of a 384-well white microplate. 5 μL of GST-labeled CRBN WT protein (Cisbio, Cat No. 64BDCRBNPEG) was added to each well. No. 64 BDCRBNPEG), after mixing, add 5 μL of the test compound, standard (provided with the kit), positive control CC-92480, and negative control (diluent). The concentrations of the test compound are 10 μM, 3.33 μM, 1.11 μM, 0.37 μM, 0.12 μM, 0.04 μM, 0.013 μM, and 0.0044 μM, and the concentrations of the standard are 200 μM, 40 μM, 8 μM, 1.6 μM, 0.32 μM, 0.064 μM, and 0.0128 μM. After mixing the contents of the 384 wells, seal the kit and incubate at room temperature in the dark for 3 h. The fluorescence of the 384-well white microplate was detected in an ELISA reader (ex: 320nm, em: 620nm / 665nm). The HTRFratio = (signal 665nM / signal 620nm) × 10000 represents the binding strength of the compound.

[0129] Table 3: CRBN binding IC50 values

[0130] Conclusion: The compound shown in Formula I of this application exhibits good binding activity to CRBN.

[0131] Based on the verification results of Examples 1-3, it is shown that the compound of Formula I described in this invention has excellent cell inhibitory activity and selectivity, and thus possesses the basis for being an active ingredient in a pharmaceutical composition. Based on the foregoing verification, the compound of Formula I was further used as the active ingredient in a pharmaceutical composition, and the relevant effects of the composition were tested.

[0132] Example 4: The compound shown in Formula I, microcrystalline cellulose, croscarmellose sodium cellulose, mannitol, sodium dodecyl sulfate and magnesium stearate were mixed in the proportions specified in Table 1 using a laboratory hopper mixer to produce the mixed powder containing the compound shown in Formula I in Example 4. The resulting mixed powder was then filled into No. 3 capsules using capsule plates.

[0133] Example 5: The compound shown in Formula I, lactose, microcrystalline cellulose, croscarmellose sodium cellulose, mannitol, sodium dodecyl sulfate and magnesium stearate were mixed in the proportions specified in Table 4 using a laboratory hopper mixer to produce the mixed powder containing the compound shown in Formula I in Example 5. The resulting mixed powder was then filled into No. 3 capsules using capsule plates.

[0134] Table 4 Capsules (per 1000 capsules, 0.05 mg per unit of preparation)

[0135] Examples 6-8

[0136] Example 6: The compound shown in Formula I, silicon dioxide, microcrystalline cellulose, croscarmellose sodium, mannitol and magnesium stearate were mixed in the proportions specified in Table 5 using a laboratory hopper mixer. The resulting mixture was then filled into #0 capsules using capsule plates to manufacture Example 6.

[0137] Example 7: The compound shown in Formula I, silica, microcrystalline cellulose, croscarmellose sodium cellulose, mannitol, sodium dodecyl sulfate and magnesium stearate were mixed in the proportions specified in Table 5 using a laboratory hopper mixer. The resulting mixture was then filled into #0 capsules using capsule plates to manufacture Example 7.

[0138] Example 8: The compound shown in Formula I, mannitol, microcrystalline cellulose and sodium carboxymethyl starch were mixed using a wet granulator. A 5.7% w / w sodium dodecyl sulfate aqueous solution was added to the mixture. The mixture was wet granulated, dried, and the dried granules were mixed with magnesium stearate and then filled into #0 capsules using capsule plates to produce Example 8.

[0139] Examples 9 and 10 were prepared using the same method as in Example 7.

[0140] Table 5 Capsules (per 1000 capsules)

[0141] Examples 11-15

[0142] Examples 11-15 were prepared using the same method as in Example 7.

[0143] Table 6 Capsules (per 1000 capsules, 0.50 mg per unit of preparation)

[0144] Examples 16-18

[0145] The compound shown in Formula I, mannitol, microcrystalline cellulose, and croscarmellose sodium were mixed using a wet granulator. A 5.7% w / w sodium dodecyl sulfate aqueous solution was added to the mixture, and the mixture was wet granulated and dried to obtain dry granules. The dry granules were then mixed with magnesium stearate and silica and compressed into tablets using a tableting machine to produce Examples 16-18.

[0146] Table 7 Tablets (per 1000 tablets)

[0147] The results of Examples 6-18 show that compounds of Formula I with different contents can be compounded with different excipients to form different formulation compositions, indicating that compounds of Formula I have good processability and a wide range of applications.

[0148] Experiment Example 1: Test on Factors Affecting High Temperature Stability

[0149] This effect is illustrated by way of examples 7 and 8, which demonstrate the high-temperature stability of the formulations described in this invention.

[0150] 1. Experimental Materials

[0151] Samples were prepared according to Examples 7 and 8.

[0152] 2. Experimental Methods

[0153] The sample was stored in a low-density polyethylene bottle at 60°C for 10 days, and the formation of decomposition products was determined using high-performance liquid chromatography.

[0154] The results are shown in Table 8. Based on the example results, the formulation composition of the present invention has good stability.

[0155] Table 8

[0156] Experimental Example 2 Accelerated Test

[0157] This effect series provides an exemplary illustration of the formulations described in this invention through Examples 7, 9, and 10.

[0158] 1. Test materials

[0159] Samples prepared according to Examples 7, 9, and 10.

[0160] 2. Experimental Methods

[0161] The samples were stored at 40℃±2℃ and RH75%±5% for 3 months. Samples were taken at day 0, month 1, month 2, and month 3 to determine the content, related substances, and dissolution (refer to the General Chapter 0931, Method 1, Part IV of the Chinese Pharmacopoeia 2020 Edition) to investigate the quality changes of the samples under the above conditions.

[0162] Table 9

[0163] The pharmaceutical composition described in this application showed no significant changes in content, related substances, and dissolution amount at 0 days, 1 month, 2 months, and 3 months, remaining stable throughout. Therefore, the formulation composition described in this application exhibits stable quality and rapid, complete dissolution.

[0164] Test Examples 1 and 2 further demonstrate that, for the pharmaceutical compositions of the present invention, the compounds shown in Formula I have good stability and industrial applicability, and can be used as drugs for treating tumors.

[0165] Experimental Example 3: Pharmacokinetic Study in Rhesus Monkeys

[0166] 1. Test materials

[0167] Samples prepared according to Examples 6 and 7;

[0168] Control sample: Mix 20 mg of the compound shown in Formula I with 40 ml of 0.5 wt% aqueous methylcellulose solution to prepare a suspension containing the compound shown in Formula I, thus obtaining a 0.5 mg / ml dosage form.

[0169] 2. Experimental animals

[0170] Six rhesus monkeys, females weighing 3.5 kg-5.0 kg and males weighing 3.9 kg-5.9 kg, were purchased from Sichuan Hengshu Biotechnology Co., Ltd.

[0171] 3. Experimental Methods

[0172] 3.1 Group administration

[0173] Table 10

[0174] 3.2 Blood Sample Collection and Testing

[0175] According to Table 10, rhesus monkeys were given control samples by gavage. Whole blood was collected into EDTA anticoagulant tubes before administration and at 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 8h, and 24h after administration. The plasma was separated by centrifugation and frozen at -80 degrees Celsius.

[0176] According to Table 10, rhesus monkeys were given experimental cases 6-7 by gavage. Plasma was collected by centrifugation and whole blood was collected into EDTA anticoagulant tubes before administration and at 0.5h, 1.5h, 2.5h, 3.5h, 4h, 4.5h, 5h, 8h, 24h, 32h, and 48h. The centrifuged plasma was then frozen at -80 degrees Celsius.

[0177] 3.3 Analytical Methods

[0178] Plasma samples were collected at each time point, and a fixed volume of acetonitrile was added. The mixture was vortexed for 2 min and centrifuged at 12,000 rpm for 10 min. A fixed volume of the supernatant was then analyzed by LC-MS / MS.

[0179] 4. Test Results

[0180] See Table 11 for the absorption data of each formulation in rhesus monkeys.

[0181] Table 11

[0182] The results showed that

[0183] Compared to the control sample suspension of the compound shown in Formula I, the formulation of this application showed significantly improved absorption and better bioavailability in rhesus monkeys. In particular, Example 7 showed higher absorption than Example 6, indicating that the addition of surfactants facilitates the absorption of the compound of Formula I in vivo.

[0184] Experimental Example 4: Blood Pharmacokinetic Study of Crab-Eating Mammals

[0185] 1. Test materials

[0186] Samples prepared according to Examples 7, 9 and 10.

[0187] 2. Experimental animals

[0188] Eighteen crab-eating macaques, divided into groups of six (half male and half female), aged 3.5-5.5 years, were purchased from Xishan Zhongke Pharmaceutical Research and Development Co., Ltd.

[0189] 3. Experimental Methods

[0190] Blood sample collection and testing

[0191] The test drug (formulation) was administered to each group of cynomolgus monkeys via gavage according to the table below. Blood collection times for each group were: before drug collection and 0.25, 0.5, 1, 2, 4, 8, 12, 24, 36, 48, 72, 96, and 120 hours after drug administration. After centrifugation, the concentration of the test drug in the cynomolgus monkey plasma samples was quantitatively determined using LC-MS / MS. Pharmacokinetic parameters were calculated using WinNonlin software (version 8.3) according to the non-compartmental model (NCA) method.

[0192] 4. Experimental Results:

[0193] Data on the absorption of the formulation in cynomolgus monkeys:

[0194] Table 12

[0195] The bioactivity test example is cited in PCT / CN2024 / 082990, filed on March 21, 2024.

[0196] The results above show that even when compound I is present in extremely low concentrations (0.05 mg) in the formulation, the active substance can still be absorbed and detected in vivo.

[0197] For purposes of description and disclosure, all patents, patent applications, and other publications are expressly incorporated herein by reference. These publications are provided solely because their publication predates the filing date of this application. All statements regarding the dates of these documents or representations of their contents are based on information available to the applicant and do not constitute any acknowledgment of the accuracy of the dates or contents of these documents. Furthermore, in any country, any reference to these publications herein does not constitute an endorsement that such publication is part of the general knowledge in the art.

[0198] Those skilled in the art will recognize that the scope of this application is not limited to the various specific implementations and embodiments described above, but rather that various modifications, substitutions, or recombinations can be made without departing from the spirit of this application, all of which fall within the protection scope of this application.

Claims

1. A pharmaceutical composition, characterized by, The pharmaceutical composition comprises: a compound represented by Formula I or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients; 2. The pharmaceutical composition of claim 1, wherein, 0.01-50 mg, 0.01-10 mg, 0.01-5 mg, 0.01-1 mg, 0.05-0.5 mg of the compound of Formula I or a pharmaceutically acceptable salt thereof per unit formulation; Preferably, the pharmaceutical composition contains 0.01 mg, 0.02 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 20 mg, 25 mg, 30 mg, 40 mg or 50 mg of the compound of Formula I or a pharmaceutically acceptable salt thereof per unit formulation. Preferably, the compound of Formula I is present in the pharmaceutical composition in free base form.

3. The pharmaceutical composition according to claim 1 or 2, characterized in that, The excipient is selected from one or more of a surfactant, an excipient, a disintegrant and a lubricant; Preferably, the excipient comprises a surfactant, an excipient, a disintegrant and a lubricant.

4. The pharmaceutical composition of claim 3, wherein, The surfactant is selected from one or more of an anionic surfactant, a cationic surfactant, a zwitterionic surfactant, a non-ionic surfactant or a polymeric surfactant, preferably from one or more of sodium C5-20 alkyl sulfate, sodium C5-20 alkyl sulfonate, sodium stearate, lecithin, sucrose fatty acid ester, polysorbate, poloxamer, polyethylene glycol, sodium dihexylsulfosuccinate and sodium dioctylsulfosuccinate, more preferably from one or more of sodium dodecyl sulfate, sodium stearate, sodium dodecyl sulfonate, lecithin, sucrose fatty acid ester, polysorbate and poloxamer, further preferably sodium dodecyl sulfate; and / or The excipient is selected from one or more of lactose, mannitol, microcrystalline cellulose, starch, pregelatinized starch, glucose, sorbitol, xylitol, calcium phosphate, calcium hydrogen phosphate, calcium sulfate and calcium carbonate, preferably from one or more of lactose, mannitol, microcrystalline cellulose and starch, more preferably from mannitol and / or microcrystalline cellulose; and / or The disintegrant is selected from one or more of crospovidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, starch, alginic acid, sodium alginate and calcium carboxymethyl cellulose, preferably from one or more of crospovidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose and starch, more preferably from croscarmellose sodium and / or sodium starch glycolate; and / or The lubricant is selected from one or more of silicon dioxide, talc, sodium stearyl fumarate, magnesium stearate and stearic acid, preferably from silicon dioxide and magnesium stearate.

5. The pharmaceutical composition according to any one of claims 1 or 2, characterized in that, The compound of Formula I or its pharmaceutically acceptable salt is present in an amount of 0.01% to 20.0% by weight of the total pharmaceutical composition, preferably 0.01% to 10.0%, more preferably 0.01% to 1.0%, further preferably 0.06% to 0.625%.

6. The pharmaceutical composition according to claim 3 or 4, characterized in that, The surfactant is present in an amount of 0.1% to 10.0% by weight of the total pharmaceutical composition, preferably 0.5% to 5.0%, more preferably 0.8% to 5.0%, further preferably 1.0% to 2.5%; and / or The lubricant is present in an amount of 0.001% to 10% by weight of the total pharmaceutical composition, preferably 0.007% to 5.5%, more preferably 0.01% to 3%, further preferably 1% to 3%; and / or The excipient is present in an amount of 10% to 99% by weight of the total pharmaceutical composition, preferably 40% to 95%, more preferably 91% to 94%; and / or The disintegrant is present in an amount of 0.5% to 20% by weight of the total pharmaceutical composition, preferably 1% to 15%, more preferably 3% to 10%, further preferably 3% to 8%, most preferably 3% to 4%; and / or The compound of Formula I or its pharmaceutically acceptable salt is present in an amount of 0.01% to 20.0% by weight of the total pharmaceutical composition, preferably 0.01% to 10.0%, more preferably 0.01% to 1.0%, further preferably 0.06% to 0.625%. The compound of Formula I or its pharmaceutically acceptable salt is present in an amount of 0.01% to 20.0% by weight of the total pharmaceutical composition, preferably 0.01% to 10.0%, more preferably 0.01% to 1.0%, further preferably 0.06% to 0.625%. Preferably, the pharmaceutical composition comprises, in parts by weight: 0.01 to 20 parts of the compound of Formula I or its pharmaceutically acceptable salt, preferably 0.01 to 10.0 parts, more preferably 0.01 to 1.0 parts, further preferably 0.06 to 0.625 parts; 0.1 to 10 parts of the surfactant, preferably 0.5 to 5.0 parts, more preferably 0.8 to 5.0 parts, further preferably 1.0 to 2.5 parts; More preferably, the pharmaceutical composition consists of, in parts by weight: 0.01 to 20.0 parts of the compound of Formula I or its pharmaceutically acceptable salt, preferably 0.01 to 10.0 parts, more preferably 0.01 to 1.0 parts, further preferably 0.06 to 0.625 parts; 0.1 to 10.0 parts of the surfactant, preferably 0.5 to 5.0 parts, more preferably 0.8 to 5.0 parts, further preferably 1.0 to 2.5 parts; 0.001 to 10 parts of the lubricant, preferably 0.007 to 5.5 parts, more preferably 0.01 to 3 parts, further preferably 1 to 3 parts; 10 to 99 parts of the excipient, preferably 40 to 95 parts, more preferably 92 to 95 parts; and 0.5 to 20 parts of the disintegrant, preferably 1 to 15 parts, more preferably 3 to 10 parts, further preferably 3 to 8 parts.

7. The pharmaceutical composition according to any one of claims 1 or 2, characterized in that, The pharmaceutical composition comprises: 0.05 to 5 mg of the compound of Formula I, 0.8 to 8 mg of the surfactant; Preferably, the pharmaceutical composition comprises: 0.05-0.5 mg of the compound of Formula I; 0.8-2 mg of a surfactant; More preferably, the pharmaceutical composition comprises: 0.05-5 mg of the compound of Formula I; 0.8-8 mg of a surfactant; 72.5-368 mg of an excipient; 1-7 mg of a lubricant; 2.7-16 mg of a disintegrant; Further preferably, the pharmaceutical composition comprises: 0.05-0.5 mg of the compound of Formula I; 0.8-2 mg of a surfactant; 72.5-75.3 mg of an excipient; 1-2.2 mg of a lubricant; 2.7-2.8 mg of a disintegrant; Most preferably, the pharmaceutical composition comprises: 0.5 mg of the compound of Formula I; 0.8 mg of sodium dodecyl sulfate; 41 mg of mannitol; 32.70 mg of microcrystalline cellulose; 2.83 mg of croscarmellose sodium; 1.17 mg of silicon dioxide; and 1 mg of magnesium stearate; or the pharmaceutical composition comprises: 0.05 mg of the compound of Formula I; 0.8 mg of sodium dodecyl sulfate; 41 mg of mannitol; 34.20 mg of microcrystalline cellulose; 2.83 mg of croscarmellose sodium; 0.12 mg of silicon dioxide; and 1 mg of magnesium stearate; or the pharmaceutical composition comprises: 0.1 mg of the compound of Formula I; 0.8 mg of sodium dodecyl sulfate; 41 mg of mannitol; 34.04 mg of microcrystalline cellulose; 2.83 mg of croscarmellose sodium; 0.23 mg of silicon dioxide; and 1 mg of magnesium stearate.

8. The pharmaceutical composition according to any one of claims 1 to 7, characterized in that, The pharmaceutical composition is an oral preparation, preferably an oral solid preparation; more preferably a tablet, a granule or a capsule, further preferably the capsule.

9. A method for preparing the pharmaceutical composition of any one of claims 1-8, comprising the step of mixing the compound of Formula I or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

10. Use of the pharmaceutical composition of any one of claims 1-8 or prepared by the method of claim 9 in the preparation of a medicament for preventing and / or treating a disease mediated by cereblon. Preferably, the disease is mediated by IKZF1 and / or IKZF3. Preferably, the disease is a cancer, a tumor, an immunological disease or an inflammatory disease. Preferably, the immunological disease is an autoimmune disease. Preferably, the disease is a hematological malignancy. Preferably, the disease is multiple myeloma, leukemia, lymphocytic leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma or non-Hodgkin's lymphoma.

11. Use of the pharmaceutical composition of any one of claims 1-8 or prepared by the method of claim 9 in the preparation of an immunomodulator targeting both IKZF1 and IKZF3.

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