Pharmaceutical compositions of pyridine derivatives, methods of preparation and uses

Abstract

The application relates to the technical field of pharmaceutical preparations, in particular to a pyridine derivative pharmaceutical composition, a preparation method and application. The pharmaceutical composition comprises an active ingredient and an acidic substance, the active ingredient is a compound shown in formula I or a pharmaceutically acceptable salt thereof; the active ingredient in the pharmaceutical composition has excellent dissolution, excellent absorption in vivo, and is stable even after long-term storage.

Description

Technical Field

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

[0002] Histone lysine-specific demethylase 1 (LSD1) is the first reported histone demethylase. With the assistance of flavin adenine dinucleotide (FAD), it can specifically recognize H3K4 and H3K9 substrates and remove their monomethyl or dimethyl modifications. Simultaneously, LSD1 can form transcriptional regulatory complexes with various factors, reaching the promoter regions of specific genes under the recruitment of transcription factors, thereby regulating gene expression.

[0003] Studies have shown that LSD1 is associated with a variety of diseases, is highly expressed in various tumor cells, and is closely related to poor tumor prognosis. Downregulating LSD1 expression or inhibiting its activity can significantly suppress tumor cell growth. Therefore, developing a highly effective and specific LSD1 inhibitor is of great significance for the treatment of diseases such as cancer. Summary of the Invention

[0004] In view of the above-mentioned problems in the prior art, this application provides a pharmaceutical composition of pyridine derivatives, a preparation method and uses; the active ingredient in the pharmaceutical composition has excellent solubility and excellent absorption in vivo, and the pharmaceutical composition is stable even after long-term storage.

[0005] The first aspect of this application provides a pharmaceutical composition comprising an active ingredient and an acidic substance, wherein the active ingredient is a compound of formula I or a pharmaceutically acceptable salt thereof;

[0006]

[0007] In some embodiments of this application, the pharmaceutically acceptable salt is a hydrochloride, hydrobromide, p-toluenesulfonate, sulfate, methylsulfate, or benzenesulfonate.

[0008] In some specific embodiments of this application, the active ingredient is a benzenesulfonate of the compound shown in Formula I.

[0009] In some embodiments of this application, the particle size (D90) of the active ingredient is 4.15 μm to 192.4 μm.

[0010] In some embodiments of this application, the particle size (D90) of the active ingredient is ≤100μm.

[0011] In some specific embodiments of this application, the particle size (D90) of the active ingredient is 53.44 μm to 84.57 μm.

[0012] In some specific embodiments of this application, the particle size (D90) of the active ingredient is 4.15 μm, 53.44 μm, 74.59 μm, 84.57 μm, or 192.4 μm.

[0013] In some embodiments of this application, the content of the active ingredient is 0.69 wt% to 16.67 wt% based on the total weight of the composition.

[0014] In some embodiments of this application, the content of the active ingredient is 0.69 wt% to 10.00 wt% based on the total weight of the composition.

[0015] In some embodiments of this application, the content of the active ingredient is 0.69 wt% to 5.00 wt% based on the total weight of the composition.

[0016] In some specific embodiments of this application, the content of the active ingredient is 0.69 wt%, 1.67 wt%, 5.00 wt%, 5.56 wt%, or 16.67 wt% based on the total weight of the composition; preferably 5.00 wt%.

[0017] In some embodiments of this application, the acidic substance is an organic acid; preferably one or more of citric acid, tartaric acid, succinic acid, malic acid, alginic acid, and fumaric acid; more preferably tartaric acid or succinic acid.

[0018] In some embodiments of this application, the weight ratio of the active ingredient to the acidic substance is 1:0.3 to 16.1.

[0019] In some specific embodiments of this application, the weight ratio of the active ingredient to the acidic substance is 1:0.3, 1:0.7, 1:1.0, 1:1.4, 1:1.7, 1:2, 1:2.1, 1:6.2, or 1:16.1; preferably 1:2.1.

[0020] In some embodiments of this application, the pharmaceutical composition includes: the active ingredient, the acidic substance, and one or more pharmaceutically acceptable excipients.

[0021] In some embodiments of this application, the pharmaceutical composition further comprises a disintegrant; the disintegrant is preferably one or more selected from corn starch, pregelatinized starch, hydroxypropyl starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch, croscarmellose sodium, low-substituted hydroxypropyl cellulose, and croscarmellose; more preferably, it is one of croscarmellose sodium, sodium carboxymethyl starch, and croscarmellose; the disintegrant content is preferably 3.3 wt% to 6.3 wt% based on the total weight of the composition.

[0022] In some embodiments of this application, the disintegrant is sodium carboxymethyl starch or crospovidone.

[0023] 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%.

[0024] In some embodiments of this application, the pharmaceutical composition further comprises an excipient; the excipient is preferably one or more selected from lactose, mannitol, microcrystalline cellulose, and calcium carbonate; the excipient content is preferably 67.0 wt% to 83.7 wt%.

[0025] In some specific embodiments of this application, the excipient is microcrystalline cellulose.

[0026] In some embodiments of this application, the pharmaceutical composition further includes a lubricant; the lubricant is preferably one or more of magnesium stearate, stearic acid, sodium stearate fumarate, and talc; the lubricant content is preferably 0.2 wt% to 2.0 wt%.

[0027] In some specific embodiments of this application, the lubricant is composed of magnesium stearate and talc, for example: the pharmaceutical composition contains 0.07 wt% magnesium stearate and 0.13 wt% talc, or the pharmaceutical composition contains 1 wt% magnesium stearate and 1 wt% talc.

[0028] In some embodiments of this application, the pharmaceutical composition further includes a surfactant, preferably sodium dodecyl sulfate, and the surfactant content is preferably 2.0 wt%.

[0029] In some embodiments of this application, the excipients include: disintegrants, excipients, lubricants, and optionally surfactants.

[0030] Unless otherwise stated, the term "optional" as used herein means that the object or event it modifies exists or does not exist, or occurs or does not occur.

[0031] In some specific embodiments of this application, the pharmaceutical composition comprises the active ingredient, the acidic substance, the disintegrant, the excipient, the lubricant, and optionally the surfactant.

[0032] In some specific embodiments of this application, the pharmaceutical composition comprises the active ingredient, the acidic substance, the disintegrant, the excipient, and the lubricant.

[0033] In some specific embodiments of this application, the pharmaceutical composition is:

[0034] The active ingredient is a benzenesulfonate of the compound shown in Formula I;

[0035] The acidic substance is tartaric acid or succinic acid;

[0036] The disintegrant is sodium carboxymethyl starch or crospovidone;

[0037] The excipient is mannitol and / or microcrystalline cellulose; and

[0038] The lubricant is magnesium stearate and talc.

[0039] In some specific embodiments of the present invention, the pharmaceutical composition comprises 5.00 wt% benzenesulfonate of the compound shown in Formula I, 76.30 wt% microcrystalline cellulose, 10.40 wt% tartaric acid, 6.30 wt% crospovidone, 1.00 wt% talc, and 1.00 wt% magnesium stearate.

[0040] In some specific embodiments of the present invention, the pharmaceutical composition comprises 5.00 wt% benzenesulfonate of the compound shown in Formula I, 76.30 wt% microcrystalline cellulose, 10.40 wt% succinic acid, 6.30 wt% crospovidone, 1.00 wt% talc, and 1.00 wt% magnesium stearate.

[0041] In some embodiments of this application, the pharmaceutical composition is a solid dosage form, preferably granules, tablets, or capsules.

[0042] The tablets can be manufactured by a tableting method. For example, a direct tableting method can be used, in which the mixed raw materials are directly compressed into tablets, or a granule tableting method can be used, in which the mixed raw materials are granulated and then compressed into tablets.

[0043] If it is a capsule, it can be a hard capsule or a soft capsule.

[0044] The granules are formulations granulated into granules. The granules can be made into fine granules by adjusting the particle size. The particle size (diameter) of the fine granules ranges between 100 μm and 900 μm. Furthermore, regarding the granules, an admixture can be added as needed, and enteric-coated or sustained-release granules can be prepared using known and appropriate methods. The granules can also be foaming granules, which are granules that rapidly foam, dissolve, or disperse in water.

[0045] For example, in the case of fine granules, excipients, disintegrants, and lubricants can be added to the active ingredient as needed, and the mixture can be sieved to obtain a mixed powder for manufacturing. The mixed powder can be compressed into tablets or filled into capsules as needed.

[0046] The compound represented by formula (I) in this application or its pharmaceutically acceptable salt may be in any form, including but not limited to: amorphous, arbitrary crystal form, hydrate, solvate, etc.

[0047] A second aspect of this application provides a method for preparing the pharmaceutical composition described in the first aspect, comprising the step of mixing the active ingredient and the acidic substance.

[0048] In some embodiments of this application, the preparation method includes the step of mixing the active ingredient, the acidic substance, and one or more pharmaceutically acceptable excipients.

[0049] In some embodiments of this application, the pharmaceutically acceptable excipient is selected from one or more of disintegrants, excipients, and lubricants.

[0050] The third aspect of this application provides the use of a pharmaceutical composition as described in the first aspect or a pharmaceutical composition prepared by the preparation method described in the second aspect for the prevention or treatment of LSD1-mediated diseases in the preparation of a medicament for the prevention or treatment of LSD1-mediated diseases.

[0051] Preferably, the lysine-specific demethylase 1-mediated disease is selected from tumors or cancer;

[0052] More preferably, the disease is selected from acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, small cell lung cancer, non-small cell lung cancer, lymphoma, malignant sarcoma, breast cancer, cervical cancer, colon cancer, lung cancer, oral cancer, brain cancer, stomach cancer, liver cancer, colorectal cancer, pancreatic cancer, skin cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, fallopian tube tumor, peritoneal tumor, melanoma, glioma, glioblastoma, papillary malignant tumor, head and neck tumor, or myeloma.

[0053] The beneficial effects of this application are:

[0054] The active ingredient of this application is a compound of Formula I or a pharmaceutically acceptable salt thereof. During the development of pharmaceutical compositions, it was discovered that when a pharmaceutical composition made from a compound of Formula I or a pharmaceutically acceptable salt thereof is hygroscopic, the surface of the composition gels, delaying the dissolution of the active ingredient, the compound of Formula I or its pharmaceutically acceptable salt thereof, especially under high pH conditions (e.g., pH 4.5). Furthermore, the delayed dissolution cannot be improved by particle size control, the addition of disintegrants, or surfactants. To overcome these problems, a pharmaceutical composition containing a compound of Formula I or its pharmaceutically acceptable salt and an acidic substance has been developed.

[0055] The active ingredient in this pharmaceutical composition exhibits excellent solubility, thereby increasing the drug's exposure in vivo and enhancing its efficacy. Furthermore, this pharmaceutical composition remains stable even after long-term storage.

[0056] Furthermore, in the pharmaceutical composition of this application, the benzenesulfonate of the compound shown in Formula I is used as the active ingredient. The benzenesulfonate of the compound shown in Formula I has excellent solubility and excellent absorption in vivo. Moreover, the pharmaceutical composition of this application is stable even after long-term storage.

[0057] Furthermore, the acidic substance in this application is an organic acid; preferably one or more of citric acid, tartaric acid, succinic acid, malic acid, alginic acid, and fumaric acid; more preferably tartaric acid or succinic acid. The use of tartaric acid or succinic acid can make the active ingredient of this application have excellent solubility, increase the exposure of the drug in the body, enhance the efficacy, and make the pharmaceutical composition of this application stable even after long-term storage. Attached Figure Description

[0058] Figure 1 The dissolution diagrams are shown for compound A in the formulations obtained in Examples 4-5 and Comparative Example 1 at pH 1.2.

[0059] Figure 2 The dissolution diagrams are shown for compound A in the formulations obtained in Examples 4-5 and Comparative Example 1 at pH 4.5.

[0060] Figure 3 The dissolution diagrams are shown for compound A in the formulations obtained in Examples 6-7 and Comparative Example 2 at pH 1.2.

[0061] Figure 4 The dissolution diagrams are shown for compound A in the formulations obtained in Examples 6-7 and Comparative Example 2 at pH 4.5.

[0062] Figure 5 Dissolution diagrams of compound A in the formulations obtained in Examples 8-11 and Comparative Example 3 at pH 1.2;

[0063] Figure 6 Dissolution diagrams of compound A in the formulations obtained in Examples 8-11 and Comparative Example 3 at pH 4.5;

[0064] Figure 7 The dissolution diagrams are for compound A in the formulations obtained in Examples 12-13 and Comparative Examples 4-6 at pH 1.2.

[0065] Figure 8 The dissolution diagrams of compound A in the formulations obtained in Examples 12-13 and Comparative Examples 4-6 at pH 4.5 are shown.

[0066] Figure 9This is a comparison graph of the average drug-time curves of the formulations obtained in Example 12 and Comparative Example 7;

[0067] Figure 10 The average drug concentration-time curves for compounds benzenesulfonate and methanesulfonate of Formula I in Experimental Example 8 are shown. Detailed Implementation

[0068] 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.

[0069] The first aspect of this application provides a pharmaceutical composition comprising an active ingredient and an acidic substance, wherein the active ingredient is a compound of formula I or a pharmaceutically acceptable salt thereof;

[0070]

[0071] In some embodiments of this application, the pharmaceutically acceptable salt is a hydrochloride, hydrobromide, p-toluenesulfonate, sulfate, methylsulfate, or benzenesulfonate.

[0072] In some specific embodiments of this application, the active ingredient is a benzenesulfonate of the compound shown in Formula I.

[0073] In some embodiments of this application, the particle size (D90) of the active ingredient is 4.15 μm to 192.4 μm.

[0074] In some embodiments of this application, the particle size (D90) of the active ingredient is ≤100μm.

[0075] In some specific embodiments of this application, the particle size (D90) of the active ingredient is 53.44 μm to 84.57 μm.

[0076] In some specific embodiments of this application, the particle size (D90) of the active ingredient is 4.15 μm, 53.44 μm, 74.59 μm, 84.57 μm, or 192.4 μm.

[0077] In some embodiments of this application, the content of the active ingredient is 0.69 wt% to 16.67 wt% based on the total weight of the composition.

[0078] In some embodiments of this application, the content of the active ingredient is 0.69 wt% to 10.00 wt% based on the total weight of the composition.

[0079] In some embodiments of this application, the content of the active ingredient is 0.69 wt% to 5.00 wt% based on the total weight of the composition.

[0080] In some specific embodiments of this application, the content of the active ingredient is 0.69 wt%, 1.67 wt%, 5.00 wt%, 5.56 wt%, or 16.67 wt% based on the total weight of the composition; preferably 5.00 wt%.

[0081] In some embodiments of this application, the acidic substance is an organic acid; preferably one or more of citric acid, tartaric acid, succinic acid, malic acid, alginic acid, and fumaric acid; more preferably tartaric acid or succinic acid.

[0082] In some embodiments of this application, the weight ratio of the active ingredient to the acidic substance is 1:0.3 to 16.1.

[0083] In some specific embodiments of this application, the weight ratio of the active ingredient to the acidic substance is 1:0.3, 1:0.7, 1:1.0, 1:1.4, 1:1.7, 1:2, 1:2.1, 1:6.2, or 1:16.1; preferably 1:2.1.

[0084] In some embodiments of this application, the pharmaceutical composition includes: the active ingredient, the acidic substance, and one or more pharmaceutically acceptable excipients.

[0085] In some embodiments of this application, the pharmaceutical composition further comprises a disintegrant; the disintegrant is preferably one or more selected from corn starch, pregelatinized starch, hydroxypropyl starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch, croscarmellose sodium, low-substituted hydroxypropyl cellulose, and croscarmellose; more preferably, it is one of croscarmellose sodium, sodium carboxymethyl starch, and croscarmellose; the disintegrant content is preferably 3.3 wt% to 6.3 wt% based on the total weight of the composition.

[0086] In some embodiments of this application, the disintegrant is sodium carboxymethyl starch or crospovidone.

[0087] 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%.

[0088] In some embodiments of this application, the pharmaceutical composition further comprises an excipient; the excipient is preferably one or more selected from lactose, mannitol, microcrystalline cellulose, and calcium carbonate; the excipient content is preferably 67.0 wt% to 83.7 wt%.

[0089] In some specific embodiments of this application, the excipient is microcrystalline cellulose.

[0090] In some embodiments of this application, the pharmaceutical composition further includes a lubricant; the lubricant is preferably one or more of magnesium stearate, stearic acid, sodium stearate fumarate, and talc; the lubricant content is preferably 0.2 wt% to 2.0 wt%.

[0091] In some specific embodiments of this application, the lubricant is composed of magnesium stearate and talc, for example: the pharmaceutical composition contains 0.07 wt% magnesium stearate and 0.13 wt% talc, or the pharmaceutical composition contains 1 wt% magnesium stearate and 1 wt% talc.

[0092] In some embodiments of this application, the pharmaceutical composition further includes a surfactant, preferably sodium dodecyl sulfate, and the surfactant content is preferably 2.0 wt%.

[0093] In some embodiments of this application, the excipients include: disintegrants, excipients, lubricants, and optionally surfactants.

[0094] Unless otherwise stated, the term "optional" as used herein means that the object or event it modifies exists or does not exist, or occurs or does not occur.

[0095] In some specific embodiments of this application, the pharmaceutical composition comprises the active ingredient, the acidic substance, the disintegrant, the excipient, the lubricant, and optionally the surfactant.

[0096] In some specific embodiments of this application, the pharmaceutical composition comprises the active ingredient, the acidic substance, the disintegrant, the excipient, and the lubricant.

[0097] In some specific embodiments of this application, the pharmaceutical composition is:

[0098] The active ingredient is a benzenesulfonate of the compound shown in Formula I;

[0099] The acidic substance is tartaric acid or succinic acid;

[0100] The disintegrant is sodium carboxymethyl starch or crospovidone;

[0101] The excipient is mannitol and / or microcrystalline cellulose; and

[0102] The lubricant is magnesium stearate and talc.

[0103] In some specific embodiments of the present invention, the pharmaceutical composition comprises 5.00 wt% benzenesulfonate of the compound shown in Formula I, 76.30 wt% microcrystalline cellulose, 10.40 wt% tartaric acid, 6.30 wt% crospovidone, 1.00 wt% talc, and 1.00 wt% magnesium stearate.

[0104] In some specific embodiments of the present invention, the pharmaceutical composition comprises 5.00 wt% benzenesulfonate of the compound shown in Formula I, 76.30 wt% microcrystalline cellulose, 10.40 wt% succinic acid, 6.30 wt% crospovidone, 1.00 wt% talc, and 1.00 wt% magnesium stearate.

[0105] In some embodiments of this application, the pharmaceutical composition is a solid dosage form, preferably granules, tablets, or capsules.

[0106] The tablets can be manufactured by a tableting method. For example, a direct tableting method can be used, in which the mixed raw materials are directly compressed into tablets, or a granule tableting method can be used, in which the mixed raw materials are granulated and then compressed into tablets.

[0107] If it is a capsule, it can be a hard capsule or a soft capsule.

[0108] The granules are formulations granulated into granules. The granules can be made into fine granules by adjusting the particle size. The particle size (diameter) of the fine granules ranges between 100 μm and 900 μm. Furthermore, regarding the granules, an admixture can be added as needed, and enteric-coated or sustained-release granules can be prepared using known and appropriate methods. The granules can also be foaming granules, which are granules that rapidly foam, dissolve, or disperse in water.

[0109] For example, in the case of fine granules, excipients, disintegrants, and lubricants can be added to the active ingredient as needed, and the mixture can be sieved to obtain a mixed powder for manufacturing. The mixed powder can be compressed into tablets or filled into capsules as needed.

[0110] The compound represented by formula (I) in this application or its pharmaceutically acceptable salt may be in any form, including but not limited to: amorphous, arbitrary crystal form, hydrate, solvate, etc.

[0111] A second aspect of this application provides a method for preparing the pharmaceutical composition described in the first aspect, comprising the step of mixing the active ingredient and the acidic substance.

[0112] In some embodiments of this application, the preparation method includes the step of mixing the active ingredient, the acidic substance, and one or more pharmaceutically acceptable excipients.

[0113] In some embodiments of this application, the pharmaceutically acceptable excipient is selected from one or more of disintegrants, excipients, and lubricants.

[0114] The third aspect of this application provides the use of a pharmaceutical composition as described in the first aspect or a pharmaceutical composition prepared by the preparation method described in the second aspect for the prevention or treatment of LSD1-mediated diseases in the preparation of a medicament for the prevention or treatment of LSD1-mediated diseases.

[0115] Preferably, the lysine-specific demethylase 1-mediated disease is selected from tumors or cancer;

[0116] More preferably, the disease is selected from acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, small cell lung cancer, non-small cell lung cancer, lymphoma, malignant sarcoma, breast cancer, cervical cancer, colon cancer, lung cancer, oral cancer, brain cancer, stomach cancer, liver cancer, colorectal cancer, pancreatic cancer, skin cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, fallopian tube tumor, peritoneal tumor, melanoma, glioma, glioblastoma, papillary malignant tumor, head and neck tumor, or myeloma.

[0117] 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.

[0118] 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.

[0119] 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.

[0120] 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.

[0121] In this application, the pharmaceutical excipients or reagents involved may be derived from commercial sources.

[0122] In this application, unless otherwise specified, "%" in the embodiments of this application refers to the mass percentage.

[0123] The active ingredient in this application is a compound of Formula I or a pharmaceutically acceptable salt thereof;

[0124]

[0125] Preferably, the pharmaceutically acceptable salt is a hydrochloride, hydrobromide, p-toluenesulfonate, sulfate, methylsulfate, or benzenesulfonate.

[0126] More preferably, the active ingredient is a benzenesulfonate of the compound shown in Formula I.

[0127] The active ingredient in this application can be prepared with reference to PCT / CN2023 / 082755, filed on November 25, 2022; for example, Example 16 of PCT / CN2022 / 134330:

[0128] Preparation of 6-(4-aminopiperidin-1-yl)-2-(4-cyano-3-fluorophenyl)-3-(6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-indazol-5-yl)isonicotinonitrile (16)

[0129]

[0130] Step 1: Preparation of (1-(4-cyano-6-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)tert-butyl carbamate (16a)

[0131] Compound 1b (1.7 g, 5.05 mmol), 3-fluoro-4-cyanobenzoic acid (1.2 g, 7.28 mmol), and K₂CO₃ (2.1 g, 15.20 mmol) were dissolved in acetonitrile (20 mL) and water (10 mL). Nitrogen gas was introduced, followed by the addition of Pd(PPh₃)₄ (289 mg, 0.25 mmol), and nitrogen gas was introduced again. The reaction mixture was heated to 100 °C and stirred overnight. The reaction mixture was cooled to room temperature, poured into water, and extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give 1.8 g of the title compound (yield: 85%).

[0132] Step 2: Preparation of (1-(5-bromo-4-cyano-6-(4-cyano-3-fluorophenyl)pyridin-2-yl)piperidin-4-yl)tert-butyl carbamate (16b)

[0133] Compound 16a (421 mg, 1.00 mmol) was dissolved in acetonitrile (15 mL). NBS (182 mg, 1.02 mmol) was slowly added to the system under ice bath conditions. The reaction system was stirred at room temperature for 3 hours. The reaction system was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give 450 mg of the title compound, yield: 90%.

[0134] Step 3: Preparation of tert-butyl(1-(4-cyano-6-(4-cyano-3-fluorophenyl)-5-(6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-indazol-5-yl)pyridin-2-yl)piperidin-4-yl)carbamate (16c)

[0135] Compound 16b (100 mg, 0.20 mmol), compound 9c (100 mg, 0.30 mmol), and K₂CO₃ (83 mg, 0.60 mmol) were dissolved in 1,4-dioxane (2 mL) and water (0.2 mL). Nitrogen gas was introduced, followed by the addition of Pd(dppf)Cl₂ (15 mg, 0.02 mmol), and nitrogen gas was introduced again. The reaction mixture was heated to 100 °C and stirred overnight. The reaction mixture was cooled to room temperature, poured into water, and extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin-layer chromatography using silica gel to obtain 30 mg of the title compound (yield: 24%).

[0136] Step 4: Preparation of 6-(4-aminopiperidin-1-yl)-2-(4-cyano-3-fluorophenyl)-3-(6-fluoro-1-(2-hydroxy-2-methylpropyl)-1H-indazol-5-yl)isonicotinonitrile (16)

[0137] Compound 16c (30 mg, 0.05 mmol) was dissolved in ethyl acetate (1 mL), and then hydrochloric acid-ethyl acetate solution (1 mL, 3 M in EA) was added. The reaction system was stirred at room temperature for 1 hour. The reaction system was concentrated under reduced pressure, diluted with water, and the pH was adjusted to approximately 8 with saturated sodium bicarbonate solution. The mixture was extracted three times with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by thin-layer silica gel chromatography to obtain 24 mg of the title compound, yield: 95%.

[0138] LC-MS(ESI)m / z(M+H) + 528.2

[0139] 1H NMR (400MHz, DMSO-d6) δ8.11(s,1H),7.80-7.72(m,2H),7.61(s,1H),7.57(d,J=10.8Hz,1H),7.40-7.34(m,1H),7.18(dd,J=8.0,1.2Hz,1 H),4.68(s,1H),4.40-4.24(m,4H),3.12-3.01(m,2H),2.92-2.82(m,1H),1.85-1.75(m,2H),1.27-1.19(m,2H),1.14(s,3H),1.10(s,3H).

[0140] Pharmaceutically acceptable salts of the compounds shown in Formula I can also be prepared with reference to patent CN202310563521.7, filed on May 18, 2023, for example:

[0141] CN202310563521.7 Example 1: Preparation of benzenesulfonate of Formula I

[0142] 50.0 g of compound I and 30.0 g of benzenesulfonic acid were weighed and added to methanol (585.0 g). The mixture was stirred and reacted at 25 °C for 24 h. After filtration, 72.5 g of benzenesulfonate of compound I was obtained, with a benzenesulfonic acid content of 22.09%. The molar ratio of compound I to benzenesulfonic acid in the obtained benzenesulfonate was 1:1. The specific parameters of the 1H NMR spectrum are as follows: 1 H NMR(400MHz,DMSO-d6)δ8.12(s,1H),7.89(brs,3H),7.81–7.72(m,2H),7.67(s,1 H),7.64–7.56(m,3H),7.40(d,J=10.5Hz,1H),7.36–7.27(m,3H),7.18(d,J=8.1Hz ,1H),4.55-4.46(m,2H),4.33-4.24(m,2H),3.43-3.32(m,1H),3.06(dd,J=19.0, 11.9Hz, 2H), 2.00 (d, J = 10.4Hz, 2H), 1.58-1.46 (m, 2H), 1.15 (s, 3H), 1.10 (s, 3H).

[0143] Example 20: Preparation of methanesulfonate of Formula I

[0144] 3.0 g of compound I and 0.6 g of methanesulfonic acid were weighed and added to water (50.0 g). The mixture was stirred at 25 °C for 24 h. After filtration, 2.70 g of methanesulfonate of compound I was obtained, with a methanesulfonic acid content of 14.28%. The molar ratio of compound I to methanesulfonic acid in the methanesulfonate was 1:1. The specific parameters of the 1H NMR spectrum were as follows:1 H NMR(400MHz,DMSO-d6)δ8.12(s,1H),7.93-7.82(m,2H),7.80-7.74(m,2H),7.68( s,1H),7.58(d,J=10.7Hz,1H),7.41(d,J=10.5Hz,1H),7.17(d,J=8.1Hz,1H),4.5 8–4.42(m,2H),4.35–4.20(m,2H),3.47–3.40(m,1H),3.06(dd,J=20.2,11.5Hz,2 H),2.30(s,3H),2.05–1.87(m,2H),1.57–1.40(m,2H),1.15(s,3H),1.10(s,3H).

[0145] Example

[0146] Unless otherwise specified in the examples, the reaction temperature is 20–30°C.

[0147] In the examples, comparative examples, and experimental examples, compound A is the benzenesulfonate of compound I; the microcrystalline cellulose is PH102 (DuPont).

[0148] Examples 1-3

[0149] For the benzenesulfonate of Formula I (hereinafter referred to as Compound A), microcrystalline cellulose (PH102, DuPont), L-tartaric acid, sodium carboxymethyl starch, magnesium stearate and talc, they are mixed in the proportions specified in Table 1 using a laboratory hopper mixer, and then the resulting powder is filled into #0 hard capsules using capsule plates to manufacture capsules containing Compound A.

[0150] Table 1

[0151] Example 1 Example 2 Example 3 Compound A 0.69 5.56 16.67 microcrystalline cellulose 82.99 78.13 67.02 L-tartaric acid 11.11 11.11 11.11 Sodium carboxymethyl starch 5.00 5.00 5.00 talcum powder 0.13 0.13 0.13 magnesium stearate 0.07 0.07 0.07 total 100 100 100

[0152] Unit: mass %

[0153] Examples 4-8, Comparative Examples 1-2

[0154] The capsules of Examples 4 to 7 were prepared by mixing the ingredients in the proportions specified in Tables 2 and 3 using a laboratory hopper mixer and filling the resulting mixture into #0 capsules using capsule plates. In addition, capsules of Comparative Examples 1 to 2, which do not contain tartaric acid, were prepared using the same method.

[0155] Table 2

[0156] Comparative Example 1 Example 4 Example 5 Compound A 5.56 5.56 5.56 microcrystalline cellulose 89.24 88.69 83.13 L-tartaric acid 0 5.56 11.11 Sodium carboxymethyl starch 5.00 / / talcum powder 0.13 0.13 0.13 magnesium stearate 0.07 0.07 0.07 total 100 100 100

[0157] Unit: mass %

[0158] Table 3

[0159]

[0160]

[0161] Unit: mass %

[0162] Experimental Example 1

[0163] For the capsules of Examples 4-7 and Comparative Examples 1-2, the dissolution of compound A was studied using the paddle method at 37±0.5°C, 75 rpm paddle speed, pH 1.2 (hydrochloric acid solution), and pH 4.5 medium (sodium acetate-acetic acid buffer).

[0164] See results Figure 1 , Figure 2 , Figure 3 and Figure 4 In the capsules of Comparative Examples 1-2 without tartaric acid, compound A did not dissolve sufficiently. On the other hand, in the capsules of Examples 4-7 with tartaric acid, compound A dissolved more quickly, and its dissolution in pH 4.5 medium was also significantly improved.

[0165] Examples 8-11, Comparative Example 3

[0166] Compound A, DL tartaric acid, crospovidone, microcrystalline cellulose, magnesium stearate, and talc were thoroughly mixed using a laboratory hopper mixer according to the formulation proportions in Table 4. The resulting mixture was directly compressed into tablets using a tableting machine to manufacture the tablets of Examples 8-11. In addition, tablets of Comparative Examples 3-4 without tartaric acid were manufactured using the same method.

[0167] Table 4

[0168] Comparative Example 3 Example 8 Example 9 Example 10 Example 11 Compound A 5.00 5.00 5.00 5.00 1.67 microcrystalline cellulose 86.7 79.63 77.97 76.30 79.63 DL-tartaric acid 0 7.07 8.73 10.40 10.40 Cross-linked polyvinylpyrrolidone 6.30 6.30 6.30 6.30 6.30 talcum powder 1.00 1.00 1.00 1.00 1.00 magnesium stearate 1.00 1.00 1.00 1.00 1.00 total 100 100 100 100 100

[0169] Unit: mass %

[0170] Experimental Example 2

[0171] For the tablets of Examples 8-11 and Comparative Example 3, the dissolution of compound A was studied using the paddle method at 37±0.5°C, 75 rpm paddle speed, pH 1.2 (hydrochloric acid solution), and pH 4.5 medium (sodium acetate-acetic acid buffer).

[0172] See results Figure 5 and Figure 6 In Comparative Example 3 tablets without tartaric acid, compound A did not dissolve sufficiently in a pH 4.5 medium. On the other hand, in the tablets of Examples 8-11 containing tartaric acid, compound A dissolved more rapidly, and its dissolution in a pH 4.5 medium was significantly improved.

[0173] Examples 12-13, Comparative Examples 4-5

[0174] Compound A, DL tartaric acid or succinic acid, crospovidone, microcrystalline cellulose, magnesium stearate, and talc were thoroughly mixed using a laboratory hopper mixer according to the formulation ratios in Table 5. 600 mg of the resulting mixture was directly compressed into tablets using a tableting machine to manufacture the tablets of Examples 12-13. In addition, tablets of Comparative Examples 4-6, which do not contain tartaric acid or succinic acid but instead contain mannitol, sodium lauryl sulfate, or alginate, were manufactured according to the formulation ratios in Table 6. Then, according to the formulation in Table 6, purified water was first measured, heated to 60°C, and methylcellulose was slowly added in multiple batches while stirring to dissolve it. Compound A was then added and stirred until homogeneous to obtain the suspension of Compound A in Comparative Example 7.

[0175] Table 5

[0176] Example 12 Example 13 Compound A 5.00 5.00 microcrystalline cellulose 76.30 76.30 DL-tartaric acid 10.40 0 Succinic acid 0 10.40 Cross-linked polyvinylpyrrolidone 6.30 6.30 talcum powder 1.00 1.00 magnesium stearate 1.00 1.00 total 100 100

[0177] Unit: mass %

[0178] Table 6

[0179] Comparative Example 4 Comparative Example 5 Comparative Example 6 Comparative Example 7 Compound A 5.00 5.00 5.00 1.00 microcrystalline cellulose 34.20 58.00 76.30 / Mannitol 56.80 35.00 / / alginic acid / / 10.40 / Cross-linked polyvinylpyrrolidone / / 6.30 / Sodium dodecyl sulfate 2.00 0 / / talcum powder 1.00 1.00 1.00 / magnesium stearate 1.00 1.00 1.00 / Methylcellulose / / / 3.00 Purified water / / / 96.00 total 100 100 100 100

[0180] Unit: mass %

[0181] Experimental Example 3

[0182] For the tablets of Examples 12-13 and Comparative Example 3, the dissolution of compound A was studied using the paddle method at 37±0.5°C, 75 rpm paddle speed, pH 1.2 (hydrochloric acid solution), and pH 4.5 medium (sodium acetate-acetic acid buffer).

[0183] See results Figure 7 and Figure 8 In Comparative Examples 4-6, which did not contain tartaric acid or succinic acid, compound A did not dissolve sufficiently. On the other hand, in the tablets of Examples 12-13, which contained tartaric acid or succinic acid, compound A dissolved at a faster rate, and its dissolution in a pH 4.5 medium was also significantly improved.

[0184] Test Example 4

[0185] For the tablets of Examples 12-13, the decomposition products were determined by high performance liquid chromatography after storage in an open system at 60°C for 30 days.

[0186] The results are shown in Table 7. In the tablets of Examples 12-13 containing tartaric acid or succinic acid, no increase of related substances was observed, and the stability was good.

[0187] Table 7

[0188] Maximum unknown single hybrid Unknown General Miscellaneous General Miscellaneous Number of impurities Compound A (Initial Value) 0.08wt% 0.17wt% 0.17wt% 4 Example 12 0.08wt% 0.17wt% 0.17wt% 4 Example 13 0.08wt% 0.16wt% 0.16wt% 4

[0189] In summary, for the pharmaceutical composition of this application, compound A has excellent solubility (excellent solubility is beneficial for drug absorption by the human body and improves bioavailability), good stability, and industrial applicability, and can be used as a drug for treating tumors.

[0190] Examples 14-18

[0191] Using active ingredients of different particle sizes (see Table 8), compound A, DL-tartaric acid, crospovidone, microcrystalline cellulose, magnesium stearate, and talc were thoroughly mixed using a laboratory hopper mixer in the formulation proportions of Example 12 in Table 5. The resulting mixture was directly compressed into tablets at 600 mg / tablet using a tableting machine to manufacture the tablets of Examples 14–18.

[0192] Table 8

[0193]

[0194] Experimental Example 5

[0195] The dissolution of compound A was studied using the tablets from Examples 14-18, following the paddle method, at 37±0.5°C, a paddle speed of 75 rpm, and pH 1.2 (hydrochloric acid solution).

[0196] The results are shown in Table 8.

[0197] Table 9

[0198]

[0199] In Table 9, " / " indicates that the test was not conducted.

[0200] The results showed that when the active particle size (D90) was 53.44–84.57 μm, the dissolution rate of the formulation was greater than 85% in 30 min in pH 1.2 medium, indicating rapid dissolution and good dissolution performance.

[0201] Experimental Example 6

[0202] Beagle PK tests were performed on the tablets of Example 12 and the suspension of compound A of Comparative Example 7.

[0203] 1. Experimental Methods

[0204] 1.1 Grouping: The dogs were randomly grouped according to Table 10. After grouping, there was no statistically significant difference in body weight among the different groups of Beagle dogs.

[0205] Table 10

[0206]

[0207] 1.2 Blood sample collection and testing:

[0208] According to Table 10, each group was administered the corresponding test drug by gavage. Blood was collected from the forelimb vein before administration and at 1h, 3h, 6h, 8h, 10h, 12h, 24h, 30h, and 48h after administration. The blood was placed in EDTA-K2 anticoagulant tubes, centrifuged at 8000rpm for 10min, and the plasma was separated into centrifuge tubes and frozen at -20℃.

[0209] 1.3 Analytical Methods

[0210] Take out the plasma stored at -20℃ at each time point, add a fixed volume of acetonitrile, vortex at 1500 rpm for 2 min, centrifuge for 15 min (3500 rpm), and take a fixed volume of the supernatant for LC-MS / MS analysis.

[0211] 2. Experimental Results:

[0212] See Table 11 and Figure 9 (Comparison of average drug duration curves)

[0213] PK data of the formulation in beagle dogs:

[0214] Table 11

[0215] parameter Example 12 Comparative Example 7 <![CDATA[T max (h)]]> 4.00 3.00 <![CDATA[C max (of mL) -1 )]]> 96.27 59.10 <![CDATA[AUC last (h·ng·mL) -1 )]]> 1337.18 857.48

[0216] The results showed that in Example 12, which incorporated tartaric acid, the absorption in dogs was significantly higher than that of the suspension of compound A in Comparative Example 7, and the bioavailability was significantly improved.

[0217] Experimental Example 7: LSD1 Enzyme Activity Assay

[0218] 1. Purpose of the experiment

[0219] This experiment utilized time-resolved homogeneous fluorescence (HTRF) technology in a two-step method to detect the inhibitory activity of the compound shown in Formula I on LSD1 enzyme. The first step involved incubating LSD1 enzyme, different concentrations of the compound, and a biotin-labeled methylated polypeptide substrate (H3(1-21)K4 me1-biotin) at room temperature for a fixed time. The second step involved adding an antibody against the demethylated polypeptide substrate (Anti-H3K4 me0-Eu(K)) and a detection reagent containing streptomycin labeled with XL-665 (SA-XL665), followed by further incubation at room temperature for a fixed time. The concentration of the demethylated polypeptide substrate was determined using EnVision's Intensity (665 nM) / Intensity (615 nM) ratio to evaluate the effect of the test compound on LSD1 enzyme activity. Simultaneously, the IC50 of the test compound against LSD1 enzyme was calculated using the inhibition rate. 50 value.

[0220] 2. Test materials

[0221] 2.1. Test compound: The compound shown in Formula I

[0222] 2.2. Test reagents and instruments: LSD1, Active Motif; DMSO, Sigma; OptiPlate-384, PerkinElmer; ultrasonic pipette, Labcyte; microplate reader (EnVision), PerkinElmer; centrifuge, Eppendorf.

[0223] 3. Test methods

[0224] 3.1 Compound preparation: Preparation of 10mM compound stock solution: Dissolve the compound powder in 100% DMSO to prepare 10mM compound stock solutions.

[0225] 3.2 Enzyme Reaction Process

[0226] (1) Prepare 1× buffer according to the LSD1 enzymology kit provided by Active Motif (catalog number: 31432).

[0227] (2) Preparation of compound solution: Compound IC 50 The test started at a final concentration of 500 nM, with 5-fold dilutions, resulting in 6 concentrations. Each concentration was tested in single or duplicate wells. Solutions were diluted to the corresponding final concentration of 1000 times in a 384-well Source plate, and then 10 nL was transferred to each well of the 384-well reaction plate using an Echo 550. 10 nL of 100% DMSO was transferred to each of the Min and Max wells.

[0228] (3) Prepare 2× enzyme solution using 1× reaction solution.

[0229] (4) Prepare a 2× substrate mixture solution using 1× reaction solution.

[0230] (5) Add 5 μL of 2× enzyme solution to each well, add 5 μL of 1× reaction solution to the Min well, centrifuge at 1000 rpm for 1 min, and incubate at room temperature for 15 min.

[0231] (6) Add 5 μL of 2× substrate mixture to each well of the reaction plate to start the reaction, centrifuge at 1000 rpm for 1 min, and incubate at room temperature for 60 min.

[0232] (7) Add 10 μL of detection solution to each well, centrifuge at 1000 rpm for 1 min, and incubate at room temperature for 60 min.

[0233] (8) Use EnVision to read the signal values ​​Intensity(665nM) / Intensity(615nM).

[0234] 3.3 Data Analysis

[0235] The inhibition percentage was calculated using the maximum, minimum, and signal values ​​(maximum value: fluorescence intensity of 5 μL 2× enzyme solution + 5 μL 2× substrate mixture + 10 nL 100% DMSO + 10 μL detection solution; minimum value: fluorescence intensity of 5 μL 1× reaction solution + 5 μL 2× substrate mixture + 10 nL 100% DMSO + 10 μL detection solution; signal value: fluorescence intensity of 5 μL 2× enzyme solution + 5 μL 2× substrate mixture + 10 nL diluted analyte + 10 μL detection solution), using the following formula:

[0236] Plotting the logarithm of concentration on the X-axis and the percentage inhibition rate on the Y-axis, dose-response curves were fitted using the log(inhibitor) vs. response-variable slop(Fourparameters) formula in Graphpad Prism 5 software to derive the IC50 of each compound on enzyme activity. 50 value.

[0237] 4. Test Results

[0238] The inhibitory activity of the compound shown in Formula I of this application against LSD1 enzyme is shown in Table 12.

[0239] Table 12 shows the inhibitory activity of the compound represented by Formula I of this application against LSD1 enzyme.

[0240] compound <![CDATA[IC 50 (nM)]]> The compound shown in Formula I 0.23

[0241] As can be seen from the LSD1 enzyme inhibition activity test data shown in Table 12, the compound of Formula I in this application has significant LSD1 enzyme inhibition activity.

[0242] Experimental Example 8: Pharmacokinetic Study of Compounds I (Benzenesulfonate and Methanesulfonate)

[0243] Animal experiments were conducted on compounds of formula I, benzenesulfonate and methanesulfonate, respectively. Specifically, the average plasma concentration (ng·mL) of the drug was measured at different time points after a single oral administration to male rats. -1 The result is as follows Figure 10 The figure shows the mean drug concentration-time curve in plasma of male rats after a single oral administration. The main pharmacokinetic parameters are shown in the table below:

[0244] Table 13 Pharmacokinetic parameters of compound I benzenesulfonate and mesylate

[0245] parameter benzenesulfonate Methanesulfonates <![CDATA[T max (h)]]> 2.67 2.67 <![CDATA[C max (of mL) -1 )]]> 123.17 64.27 <![CDATA[AUC last (h·ng·mL) -1 )]]> 708.45 431.98

[0246] The experimental results show that the AUC and Cmax of compound I benzenesulfonate are superior to those of methanesulfonate, therefore compound I benzenesulfonate has better pharmacokinetic properties.

[0247] 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.

[0248] 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, It comprises an active ingredient which is a pharmaceutically acceptable salt of a compound of formula I; and an acidic substance which is one or more of citric acid, tartaric acid, succinic acid, malic acid, alginic acid and fumaric acid. Formula I.

2. The pharmaceutical composition of claim 1, wherein, The pharmaceutically acceptable salt is a hydrochloride, a hydrobromide, a p-toluenesulfonate, a sulfate, a methosulfate or a benzenesulfonate.

3. The pharmaceutical composition of claim 2, wherein, The pharmaceutically acceptable salt is a benzenesulfonate.

4. The pharmaceutical composition according to claim 1 or 2, characterized by, The particle size D90 of the active ingredient is 4.15 μm to 192.4 μm.

5. The pharmaceutical composition of claim 4, wherein The particle size D90 of the active ingredient is ≤ 100 μm.

6. The pharmaceutical composition of claim 5, wherein The particle size D90 of the active ingredient is 53.44 μm to 84.57 μm.

7. The pharmaceutical composition according to claim 1 or 2, characterized by, The content of the active ingredient is 0.69 wt% to 16.67 wt% based on the total weight of the composition.

8. The pharmaceutical composition according to claim 1 or 2, characterized by, The weight ratio of the active ingredient to the acidic substance is 1:0.3 to 16.

1.

9. The pharmaceutical composition according to claim 1 or 2, characterized by, The acidic substance is tartaric acid or succinic acid.

10. The pharmaceutical composition according to claim 1 or 2, characterized by, The pharmaceutical composition further comprises a disintegrant.

11. The pharmaceutical composition of claim 10, wherein, The disintegrant is one or more of corn starch, pre-gelatinized starch, hydroxypropyl starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch, sodium croscarmellose, low-substituted hydroxypropyl cellulose and cross-linked polyplasdone.

12. The pharmaceutical composition of claim 10, wherein, The disintegrant is one of sodium croscarmellose, sodium carboxymethyl starch and cross-linked polyplasdone.

13. The pharmaceutical composition of claim 10, wherein, The content of the disintegrant is 3.3 wt% to 6.3% based on the total weight of the composition.

14. The pharmaceutical composition of claim 1 or 2, wherein, The pharmaceutical composition further comprises an excipient; and / or The pharmaceutical composition further comprises a lubricant.

15. The pharmaceutical composition of claim 14, wherein, The excipient is one or more of lactose, mannitol, microcrystalline cellulose and calcium carbonate.

16. The pharmaceutical composition of claim 14, wherein, The content of the excipient is 67.0 wt% to 88.7 wt%.

17. The pharmaceutical composition of claim 14, wherein, The lubricant is one or more of magnesium stearate, stearic acid, sodium stearyl fumarate and talc.

18. The pharmaceutical composition of claim 14, wherein, The content of the lubricant is 0.2 wt% to 2.0 wt%.

19. The pharmaceutical composition of claim 1 or 2, wherein, The pharmaceutical composition is a solid preparation.

20. The pharmaceutical composition of claim 19, wherein, The pharmaceutical composition is a granule, a tablet or a capsule.

21. A method for preparing the pharmaceutical composition of any one of claims 1-20, comprising the step of mixing the active ingredient and the acidic substance.

22. The method of claim 21, wherein, The method for preparing comprises the step of mixing the active ingredient, the acidic substance and one or more pharmaceutically acceptable excipients.

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