Pharmaceutical preparation of piperazine derivative, preparation method therefor, and use thereof

Abstract

The present invention relates to a pharmaceutical preparation containing a piperazine derivative or a stereoisomer, tautomer, deuterated compound, or pharmaceutically acceptable salt thereof, a preparation method for the pharmaceutical preparation, and use thereof in medicine. The invention particularly relates to a preparation containing a compound represented by formula (I).

Description

A pharmaceutical preparation of a piperazine derivative, its preparation method and use Technical Field

[0001] The present invention relates to a pharmaceutical preparation containing a piperazine derivative or a stereoisomer, a tautomer, a deuterated product or a pharmaceutically acceptable salt thereof, a preparation method thereof, and a medical application thereof. Background Art

[0002] ADP-ribosylation (ADP-ribosylation) is a post-transcriptional modification of proteins, in which single or multiple adenosine diphosphate ribose (ADP-ribose) groups are incorporated into amino acid residues of proteins. ADP-ribosylation is a reversible process involved in physiological regulation, including cell signal transduction, DNA damage repair, transcription, gene expression regulation, and apoptosis. The enzymes that mediate ADP-ribose insertion and modification are called ADP-ribosylases. ADP-ribosylases can perform two types of modifications: mono-ADP-ribosylation and poly-ADP-ribosylation. When DNA is damaged or cells are subjected to stress, PARP (poly ADP-ribose polymerase) is activated, resulting in an increase in poly ADP-ribose and a decrease in NAD+. To date, scientists have identified 17 different PARPs. MonoPARPs comprise the majority of the PARP family and mediate important biological functions and various stress responses, such as the unfolded protein response, NF-κB signaling, antiviral responses, and cytokine signaling. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)-inducible poly (ADP-ribose) polymerase (PARP-7) is a member of the MonoPARP family. Its expression is regulated by TCDD-activated aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor that mediates the toxic activities of many environmental xenobiotics. AHR upregulates PARP-7 expression. PARP-7 interacts with and ADP-ribosylates the kinase TBK1, leading to inhibition of TBK1 activity and downregulation of IFN-I (type I interferon) responses, thereby suppressing antiviral and tumor immune responses.

[0003] The patent (PCT Publication No.: WO2022242750) describes a new PARP7 inhibitor represented by formula (I), which has a good inhibitory effect on PARP7 activity and has the potential to prepare anti-tumor drugs.

[0004] It is very necessary to prepare a preparation containing PARP7 inhibitor drugs with good drug dissolution effect and stability.

[0005] Summary of the Invention

[0006] The object of the present invention is to provide a pharmaceutical preparation containing a PARP7 inhibitor and a preparation method thereof, as well as the use thereof in the preparation of anti-tumor drugs, wherein the PARP7 inhibitor is a piperazine derivative or a stereoisomer, tautomer, deuterated derivative or a pharmaceutically acceptable salt thereof.

[0007] One or more embodiments of the present invention provide a pharmaceutical preparation of a piperazine derivative, characterized in that it comprises a piperazine derivative or a stereoisomer, tautomer, deuterated product, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical preparation comprises 1-1000 mg of the piperazine derivative, and the piperazine derivative is selected from a compound of formula (I):

[0008] in:

[0009] X1 is NH, O or a 4- to 6-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N and O;

[0010] X2 is O or a bond;

[0011] X3 and X4 are each independently C or N;

[0012] R 1a 、R 1b Each independently is H, D or C 1-6 Alkyl; or R 1a 、R 1b Together with the carbon atom to which it is attached, it forms a 3- to 5-membered cycloalkyl group;

[0013] R 2a 、R 2b Each independently is H, D or C 1-6 Alkyl; or R 2a 、R 2b Together with the carbon atom to which it is attached, it forms a 3- to 5-membered cycloalkyl group;

[0014] R3 is H, D, C 1-6 Alkyl, halogen or cyano, the C 1-6 The alkyl group is optionally substituted with 1 to 3 halogens;

[0015] R4 and R5 are each independently H, D or C 1-6 Alkyl; or R4, R5 and the connected carbon atom form a 3 to 5-membered cycloalkyl;

[0016] R6 and R7 are each independently H, D or C 1-6 Alkyl; or R6, R7 and the carbon atom to which they are connected form =O;

[0017] R8 and R9 are each independently H, D or C 1-6Alkyl; or R8, R9 and the carbon atom to which they are connected form =O; or R8 and R9 and the carbon atom to which they are connected form a 3-5 membered cycloalkyl;

[0018] R 10 Each independently is C 1-6 Alkyl, C 1-6 Alkoxy, CONR 10a R 10b , halogen, cyano, S(O)2R 10c SR 10d or a 3 to 5-membered cycloalkyl group, the C 1-6 Alkyl, C 1-6 Alkoxy is optionally substituted with 1 to 3 halogens;

[0019] R 10a 、R 10b 、R 10c 、R 10d Each independently is H, D or C 1-6 alkyl;

[0020] A is

[0021] R a C 1-6 Alkyl, C 3-5 Cycloalkyl, halogen or cyano, the C 1-6 The alkyl group is optionally substituted with 1 to 3 halogens;

[0022] B is a 5- to 10-membered carbocyclic or heterocyclic ring containing 1 to 3 heteroatoms selected from N, O and S;

[0023] C is a 5- to 6-membered heterocyclic ring containing 1 to 3 N heteroatoms;

[0024] m is 1, 2, or 3;

[0025] n is 0, 1, 2, or 3;

[0026] p is 0, 1, 2 or 3.

[0027] In one or more embodiments, the pharmaceutical formulation of the present invention is characterized by:

[0028] X1 is NH, O or a 4- to 6-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N and O;

[0029] X2 is O or a bond;

[0030] X3 and X4 are each independently C or N;

[0031] R 1a 、R 1b Each independently is H, D or C1-6 alkyl;

[0032] R 2a 、R 2b Each independently is H, D or C 1-6 Alkyl; or R 2a 、R 2b Together with the carbon atom to which it is attached, it forms a 3- to 5-membered cycloalkyl group;

[0033] R3 is H, D, C 1-6 Alkyl, halogen or cyano, the C 1-6 The alkyl group is optionally substituted with 1 to 3 halogens;

[0034] R4 and R5 are each independently H, D or C 1-6 Alkyl; or R4, R5 and the connected carbon atom form a 3 to 5-membered cycloalkyl;

[0035] R6 and R7 are each independently H, D or C 1-6 alkyl;

[0036] R8 and R9 are each independently H, D or C 1-6 Alkyl; or R8, R9 and the carbon atom to which they are connected form =O;

[0037] R 10 Each independently is C 1-6 Alkyl, C 1-6 Alkoxy, CONR 10a R 10b , halogen, cyano, S(O)2R 10c SR 10d or a 3 to 5-membered cycloalkyl group, the C 1-6 Alkyl, C 1-6 Alkoxy is optionally substituted with 1 to 3 halogens;

[0038] R 10a 、R 10b 、R 10c 、R 10d Each independently is H, D or C 1-6 alkyl;

[0039] A is

[0040] R a C 1-6 Alkyl, C 3-5 Cycloalkyl, halogen or cyano, the C 1-6 The alkyl group is optionally substituted with 1 to 3 halogens;

[0041] B is a 5- to 6-membered carbocyclic or heterocyclic ring containing 1 to 3 heteroatoms selected from N, O and S;

[0042] C is a 5- to 6-membered heterocyclic ring containing 1 to 3 N heteroatoms;

[0043] m is 1, 2, or 3;

[0044] n is 0, 1, 2, or 3;

[0045] p is 0, 1, 2 or 3.

[0046] In one or more embodiments, the pharmaceutical preparation of the present invention is characterized in that the piperazine derivative is selected from the compounds of formula (I-1):

[0047] in:

[0048] X1 is NH or a 4- to 6-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N and O;

[0049] X2 is 0;

[0050] X3 and X4 are each independently C or N;

[0051] R 1a 、R 1b Each independently is H, D or C 1-6 alkyl;

[0052] R 2a 、R 2b Each independently is H, D or C 1-6 alkyl;

[0053] R3 is H, D, C 1-6 Alkyl or halogen, the C 1-6 The alkyl group is optionally substituted with 1 to 3 halogens;

[0054] R4 and R5 are each independently H, D or C 1-6 alkyl;

[0055] R6 and R7 are each independently H, D or C 1-6 alkyl;

[0056] R8 and R9 are each independently H, D or C 1-6 Alkyl; or R8 and R9 and the carbon atom to which they are connected form =O;

[0057] R 10 C 1-6 Alkyl, C 1-6 Alkoxy, cyano or SR 10d , the C 1-6 Alkyl, C 1-6 Alkoxy is optionally substituted with 1 to 3 halogens;

[0058] R 10d H, D or C 1-6 alkyl;

[0059] A is

[0060] B is a 5- to 6-membered carbocyclic or heterocyclic ring containing 1 to 3 heteroatoms selected from N, O and S;

[0061] C is a 5- to 6-membered heterocyclic ring containing 1 to 3 N heteroatoms;

[0062] m is 1, 2, or 3;

[0063] n is 0, 1, 2 or 3.

[0064] In one or more embodiments, the pharmaceutical preparation of the present invention is characterized in that the piperazine derivative is selected from the compound of formula (I-2):

[0065] in:

[0066] X1 is NH;

[0067] X2 is 0;

[0068] R 1a 、R 1b Each independently is H, D or C 1-6 alkyl;

[0069] R 2a 、R 2b Each independently is H, D or C 1-6 alkyl;

[0070] R3 is H, D, C 1-6 Alkyl or halogen, the C 1-6 The alkyl group is optionally substituted with 1 to 3 halogens;

[0071] R4 and R5 are each independently H, D or C 1-6 alkyl;

[0072] R6 and R7 are each independently H, D or C 1-6 alkyl;

[0073] R8 and R9 are each independently H, D or C 1-6 Alkyl; or R8 and R9 and the carbon atom to which they are attached form =O;

[0074] R 10 C 1-6 Alkyl, C 1-6 Alkoxy, cyano or SR 10d , the C 1-6Alkyl, C 1-6 Alkoxy is optionally substituted with 1 to 3 halogens;

[0075] R 10d H, D or C 1-6 alkyl;

[0076] A is

[0077] B is a 5- to 6-membered carbocyclic or heterocyclic ring containing 1 to 3 heteroatoms selected from N, O and S;

[0078] m is 1, 2, or 3;

[0079] n is 0, 1, 2 or 3.

[0080] In one or more embodiments, the pharmaceutical formulation of the present invention is characterized by:

[0081] X1 is NH;

[0082] X2 is 0;

[0083] R 1a 、R 1b Each independently is H, D or C 1-6 alkyl;

[0084] R 2a 、R 2b Each independently is H, D or C 1-6 alkyl;

[0085] R3 is H, D, C 1-6 Alkyl or halogen, the C 1-6 The alkyl group is optionally substituted with 1 to 3 halogens;

[0086] R4 and R5 are each independently H, D or C 1-6 alkyl;

[0087] R6 and R7 are each independently H, D or C 1-6 alkyl;

[0088] R8 and R9 are each independently H, D or C 1-6 Alkyl, or R8 and R9 form =O with the carbon atom to which they are attached;

[0089] R 10 C 1-6 Alkyl, cyano, or SR 10d , the C 1-6 The alkyl group is optionally substituted with 1 to 3 halogens;

[0090] R 10d H, D or C 1-6 alkyl;

[0091] A is

[0092] B is a 5- to 6-membered carbocyclic or heterocyclic ring containing 1 to 3 heteroatoms selected from N, O and S;

[0093] m is 1, 2, or 3;

[0094] n is 0, 1, 2 or 3.

[0095] In one or more embodiments, the pharmaceutical formulation of the present invention is characterized by:

[0096] X1 is selected from NH;

[0097] X2 is selected from O;

[0098] R 1a 、R 1b Each independently selected from H, D or C 1-6 alkyl;

[0099] R 2a 、R 2b Each independently selected from H, D or C 1-6 alkyl;

[0100] R3 is H, D, C 1-6 Alkyl or halogen, the C 1-6 The alkyl group is optionally substituted with 1 to 3 halogens; R4 and R5 are each independently H or D;

[0101] R6 and R7 are each independently H or D;

[0102] R8 and R9 are each independently H or D;

[0103] R 10 CF3 or SR 10d ;

[0104] R 10d H, D or C 1-6 alkyl;

[0105] A is

[0106] B is

[0107] m is 1, 2, or 3;

[0108] n is 0, 1, 2 or 3.

[0109] In one or more embodiments, the pharmaceutical formulation of the present invention is characterized by:

[0110] X1 is selected from NH;

[0111] X2 is selected from O;

[0112] R 1a 、R 1b Each independently selected from H, D or C 1-3 alkyl;

[0113] R 2a 、R 2b Each independently selected from H, D or C 1-3 alkyl;

[0114] R3 is selected from H, D or CF3;

[0115] R4 and R5 are each independently selected from H or D;

[0116] R6 and R7 are each independently selected from H or D;

[0117] R8 and R9 are each independently selected from H or D;

[0118] R 10 is CF3;

[0119] A is

[0120] B is

[0121] m is 1, 2, or 3;

[0122] n is 0, 1 or 2.

[0123] In one or more embodiments, the pharmaceutical preparation of the present invention is characterized in that the piperazine derivative is selected from the compounds of formula (I-3):

[0124] in:

[0125] X1 is NH or a 4- to 6-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N and O;

[0126] X2 is 0;

[0127] R 1a 、R 1b Each independently is H, D or C 1-6 alkyl;

[0128] R 2a 、R 2b Each independently is H, D or C 1-6 alkyl;

[0129] R4 and R5 are each independently H, D or C 1-6 alkyl;

[0130] R6 and R7 are each independently H, D or C 1-6 alkyl;

[0131] R8 and R9 are each independently H, D or C 1-6 Alkyl; or R8, R9 and the carbon atom to which they are connected form =O;

[0132] R 10 C 1-6 Alkyl, C 1-6 Alkoxy, cyano or SR 10d , the C 1-6 Alkyl, C 1-6 Alkoxy is optionally substituted with 1 to 3 halogens;

[0133] R 10d H, D or C 1-6 alkyl;

[0134] A is

[0135] B is a 5- to 6-membered carbocyclic or heterocyclic ring containing 1 to 3 heteroatoms selected from N, O and S;

[0136] m is 1, 2, or 3;

[0137] n is 0, 1, 2 or 3.

[0138] In one or more embodiments, the pharmaceutical formulation of the present invention is characterized by:

[0139] X1 is NH or a 4- to 6-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N and O;

[0140] X2 is 0;

[0141] R 1a 、R 1b Each independently is H, D or C 1-3 alkyl;

[0142] R 2a 、R 2b Each independently is H, D or C 1-3 alkyl;

[0143] R4 and R5 are each independently H, D or C 1-3 alkyl;

[0144] R6 and R7 are each independently H, D or C 1-3 alkyl;

[0145] R8 and R9 are each independently H, D or C 1-3 Alkyl; or R8 and R9 and the carbon atom to which they are connected form =O;

[0146] R 10 C 1-6 Alkyl, cyano or SR 10d , the C 1-6 The alkyl group is optionally substituted with 1 to 3 halogens;

[0147] R 10d H, D or C 1-6 alkyl;

[0148] A is

[0149] B is

[0150] m is 1, 2, or 3;

[0151] n is 0, 1 or 2.

[0152] In one or more embodiments, the pharmaceutical formulation of the present invention is characterized by:

[0153] X1 is NH;

[0154] X2 is 0;

[0155] R 1a 、R 1b Each independently is H, D or C 1-3 alkyl;

[0156] R 2a 、R 2b Each independently is H or D;

[0157] R4 and R5 are each independently H or D;

[0158] R6 and R7 are each independently H or D;

[0159] R8 and R9 are each independently H or D;

[0160] R 10 is CF3;

[0161] A is

[0162] B is

[0163] m is 1, 2, or 3;

[0164] n is 0, 1 or 2.

[0165] In one or more embodiments, the pharmaceutical preparation of the present invention is characterized in that the piperazine derivative or its stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt is selected from:

[0166] In one or more embodiments, the pharmaceutical preparation of the present invention is characterized in that the pharmaceutical preparation comprises 1-5 mg, 5-10 mg, 10-15 mg, 15-20 mg, 20-25 mg, 25-30 mg, 30-35 mg, 35-40 mg, 40-50 mg, 50-60 mg, 60-70 mg, 70-80 mg, 80-90 mg, 90-100 mg, 100-150 mg, 15 0-200 mg, 200-250 mg, 250-300 mg, 300-350 mg, 350-400 mg, 400-450 mg, 450-500 mg, 500-600 mg, 600-700 mg, 700-800 mg, 800-900 mg or 900-1000 mg of a piperazine derivative or a stereoisomer, tautomer, deuterated substance or a pharmaceutically acceptable salt thereof.

[0167] In one or more embodiments, the pharmaceutical formulation of the present invention is characterized in that the content of the piperazine derivative or its stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt in the pharmaceutical formulation is 5%-90% (for example, it can be about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90% or any weight percentage range) of the total weight of the pharmaceutical formulation, preferably 20%-80%, and more preferably 30%-70%.

[0168] In one or more embodiments, the pharmaceutical preparation of the present invention is characterized in that the dosage form of the pharmaceutical preparation is selected from tablets, capsules or granules.

[0169] In one or more embodiments, the pharmaceutical preparation of the present invention is characterized in that the pharmaceutical preparation further comprises one or more of a diluent, a disintegrant, a solubilizer, a glidant, and a lubricant.

[0170] In one or more embodiments, the pharmaceutical preparation of the present invention is characterized in that the diluent is selected from one or more combinations of microcrystalline cellulose, starch, mannitol, lactose, pregelatinized starch, dextrin, sucrose, calcium hydrogen phosphate and calcium phosphate; the content of the diluent accounts for 10%-80% of the total weight of the pharmaceutical preparation (for example, it can be about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80% or any weight percentage range).

[0171] In one or more embodiments, the pharmaceutical formulation of the present invention is characterized in that the disintegrant is selected from one or more combinations of microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, polyclinic potassium, pregelatinized starch and starch; the content of the disintegrant is 1%-60% of the total weight of the pharmaceutical formulation (for example, it can be about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60% or any weight percentage range), preferably 3%-20%.

[0172] In one or more embodiments, the pharmaceutical formulation of the present invention is characterized in that the solubilizer is selected from one or a combination of poloxamer and sodium lauryl sulfate; the content of the solubilizer is 2%-10% of the total weight of the pharmaceutical formulation (for example, it can be about 1%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10% or any weight percentage range).

[0173] In one or more embodiments, the pharmaceutical formulation of the present invention is characterized in that the glidant is selected from one or a combination of colloidal silicon dioxide and talc; the content of the glidant accounts for 0.5%-5% of the total weight of the pharmaceutical formulation (for example, it can be about 0.5%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5% or any weight percentage range).

[0174] In one or more embodiments, the pharmaceutical formulation of the present invention is characterized in that the lubricant is selected from one or more combinations of stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, hydrogenated vegetable oil, magnesium lauryl sulfate, polyethylene glycol, glyceryl behenate and sucrose esters; the content of the lubricant accounts for 0.5%-5% of the total weight of the pharmaceutical formulation (for example, it can be about 0.5%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5% or any weight percentage range).

[0175] One or more embodiments of the present invention provide a method for preparing a piperazine derivative pharmaceutical preparation, characterized in that the piperazine derivative is micronized to control the particle size to 5 to 100 μm, preferably 5 to 70 μm, and more preferably 5 to 40 μm; the micronized piperazine derivative is mixed with a diluent, a disintegrant and / or a solubilizer to obtain a mixture; the mixture is dry granulated, and a glidant and / or a lubricant is added to the obtained granules to obtain intermediate granules; then, tablets, capsules or granules are prepared; and the tablets are optionally coated.

[0176] One or more embodiments of the present invention provide a method for preparing a piperazine derivative pharmaceutical preparation, characterized in that the piperazine derivative is micronized to control the particle size to 5 to 100 μm, preferably 5 to 70 μm, and more preferably 5 to 40 μm; the micronized piperazine derivative is mixed with a disintegrant and / or a solubilizer, and then a diluent, a glidant and / or a lubricant are added to mix to obtain a mixture; the mixture is dry granulated, and a glidant and / or a lubricant is added to the obtained granules to obtain intermediate granules; then tablets, capsules or granules are prepared; and the tablets are optionally coated.

[0177] One or more embodiments of the present invention provide a method for preparing a piperazine derivative pharmaceutical preparation, characterized in that the piperazine derivative is micronized to control the particle size to 5 to 100 μm, preferably 5 to 70 μm, and more preferably 5 to 40 μm; the micronized piperazine derivative is mixed with a diluent and / or a disintegrant, and then the diluent is added and mixed, and then a glidant and / or a lubricant is added and mixed to obtain a mixture; then the mixture is prepared into tablets, capsules or granules; and the tablets are optionally coated.

[0178] One or more embodiments of the present invention provide use of the piperazine derivative pharmaceutical preparation of the present invention in the preparation of a medicament for treating and / or preventing cancer.

[0179] One or more embodiments of the present invention provide a method for preventing and / or treating cancer, comprising administering to a patient a therapeutically effective dose of a piperazine derivative pharmaceutical preparation of the present invention.

[0180] In one or more embodiments, the cancer of the present invention is selected from solid tumors, and the solid tumor is selected from breast cancer, central nervous system cancer, uterine cancer, cervical cancer, kidney cancer, adrenal cancer, lung cancer, esophageal cancer, ovarian cancer, pancreatic cancer, liver cancer, prostate cancer, testicular cancer, gastric cancer, head and neck cancer, laryngeal cancer, urinary tract cancer, bladder cancer, colon cancer, rectal cancer, thyroid cancer, bone cancer, epithelial cancer, bile duct cancer, gallbladder cancer, skin cancer, mesothelioma, basal cell carcinoma, adenoid cystic carcinoma, leiomyosarcoma, gastrointestinal stromal tumor, Ewing sarcoma, Kaposi sarcoma or PARP7 amplified advanced solid tumor.

[0181] In one or more embodiments, the cancer of the present invention is selected from a blood tumor, and the blood tumor is selected from a leukemia, a myeloma, and a lymphoma. Exemplary include Hodgkin's lymphoma or non-Hodgkin's lymphoma, multiple myeloma, B-cell lymphoma, small lymphocytic lymphoma, T-cell lymphoma, hairy cell lymphoma, Burkett's lymphoma, acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia.

[0182] The lung cancer is preferably non-small cell lung cancer or neuroendocrine lung cancer. The non-small cell lung cancer is preferably squamous cell lung carcinoma or lung adenocarcinoma. The breast cancer is preferably hormone receptor-positive (HR+) breast cancer. The esophageal cancer is preferably esophageal squamous cell carcinoma or esophageal adenocarcinoma. The head and neck cancer is preferably head and neck squamous cell carcinoma. The uterine cancer is preferably endometrial cancer. The central nervous system cancer is preferably glioma. The liver cancer is preferably hepatocellular carcinoma. The B-cell lymphoma is preferably diffuse large B-cell lymphoma.

[0183] Unless stated otherwise, the terms used in the specification and claims have the following meanings.

[0184] "Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, and conformational isomers.

[0185] "Tautomers" or "tautomeric forms" refer to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton migration, such as keto-enol isomerization, imine-enamine isomerization, lactam-lactim isomerization, and the like. The present disclosure includes tautomers of any of the described compounds.

[0186] "Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" refers to a salt of the compound of the present invention that retains the biological effectiveness and properties of the free acid or free base, and the free acid is obtained by reacting with a non-toxic inorganic base or organic base, or the free base is obtained by reacting with a non-toxic inorganic acid or organic acid.

[0187] "Optional" or "optionally" or "selectively" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "a heterocyclyl optionally substituted with an alkyl group" means that the alkyl group may but need not be present, and that the description includes instances where the heterocyclyl group is substituted with an alkyl group and instances where the heterocyclyl group is not substituted with an alkyl group. DETAILED DESCRIPTION

[0188] The following examples illustrate the technical solutions of the present invention in detail, but the protection scope of the present invention includes but is not limited to them.

[0189] The piperazine derivatives of the present invention can be prepared by the method of patent WO2022242750. Specifically, compound A used in the embodiments of the present invention is selected from compound 1 in patent WO2022242750, and its structure is as follows:

[0190] Example 1

[0191] Preparation method:

[0192] 1) Compound A was micronized using a jet milling process, with a particle size X90 = 37.69 μm; the prescribed amount of Compound A, lactose, and cross-linked sodium carboxymethyl cellulose were weighed, passed through a 40-mesh sieve twice, and mixed for 5 minutes to obtain a mixture 1.

[0193] 2) Add the prescribed amount of microcrystalline cellulose to mixture 1 and mix for 5 minutes to obtain mixture 2.

[0194] 3) Add the prescribed amount of colloidal silicon dioxide and magnesium stearate to mixture 2 and mix for 5 minutes to obtain an intermediate powder.

[0195] 4) Adoption Punch the mixture and compress the tablets into 200 mg tablets with the weight controlled at 440 mg ± 5% to obtain tablets.

[0196] Example 2

[0197] Preparation method:

[0198] Same as Example 1, particle size X90=26.16 μm.

[0199] Example 3

[0200] Preparation method:

[0201] Same as Example 1, particle size X90=12.07 μm.

[0202] Example 4

[0203] Preparation method:

[0204] Same as Example 1, particle size X90=72.98 μm.

[0205] Example 5

[0206] Preparation method:

[0207] 1) Compound A was micronized using a jet milling process to control the particle size X90 to ≤ 40 μm and passed through a 60-mesh sieve; microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate were each passed through a 40-mesh sieve.

[0208] 2) Weigh the prescribed amount of Compound A, microcrystalline cellulose, and cross-linked sodium carboxymethyl cellulose, pass through a 40-mesh sieve twice, and mix for 5 minutes to obtain a mixture 1.

[0209] 3) Dry granulate the mixture 1, control the tableting speed to 3-5Hz, the granulation speed to 15-20Hz, and the oil pump pressure to 30-80kg / cm 2 , to obtain particles 1.

[0210] 4) Add the prescribed amount of colloidal silicon dioxide and magnesium stearate to Granules 1 and mix for 5 minutes to obtain Intermediate Granules 2. Intermediate Granules 2 were assayed by HPLC, revealing a Compound A content of 43.0% to 48.0%. HPLC conditions: octadecylsilane bonded silica gel as filler; mobile phase: water (pH adjusted to 3.5 with phosphoric acid) / methanol = 38 / 62; column temperature: 45°C; flow rate: 1 mL / min; detection wavelength: 221 nm.

[0211] 5) Adoption Punch and press into tablets according to the content of the intermediate granules 2 and the specification of 200 mg, control the weight difference by ±5%, and the hardness by 70-110N to obtain tablets.

[0212] Example 6

[0213] Preparation method:

[0214] 1) Compound A was micronized using a jet milling process to control the particle size X90 to ≤ 40 μm and passed through a 60-mesh sieve; microcrystalline cellulose, lactose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate were each passed through a 40-mesh sieve.

[0215] 2) Weigh the prescribed amount of Compound A, microcrystalline cellulose, lactose, and cross-linked sodium carboxymethyl cellulose, pass through a 40-mesh sieve twice, and mix for 5 minutes to obtain a mixture 1.

[0216] 3) Dry granulate the mixture 1, control the tableting speed to 3-5Hz, the granulation speed to 15-20Hz, and the oil pump pressure to 30-80kg / cm 2 , to obtain particles 1.

[0217] 4) Add the prescribed amount of colloidal silicon dioxide and magnesium stearate to Granules 1 and mix for 5 minutes to obtain Intermediate Granules 2. Intermediate Granules 2 were assayed by HPLC, revealing a Compound A content of 43.0% to 48.0%. HPLC conditions: Octadecylsilane bonded silica gel as filler; mobile phase: water (pH adjusted to 3.5 with phosphoric acid) / methanol = 38 / 62; column temperature: 45°C; flow rate: 1 mL / min; detection wavelength: 221 nm.

[0218] 5) Adoption Punch and press into tablets according to the content of the intermediate granules 2 and the specification of 200 mg, control the weight difference by ±5%, and the hardness by 70-110N to obtain tablets.

[0219] Example 7

[0220] Preparation method:

[0221] The same as in Example 5. Intermediate Particle 2 was assayed by HPLC, and the content of Compound A was 54.3% to 59.3%. HPLC conditions: octadecylsilane bonded silica gel as filler; mobile phase: water (pH adjusted to 3.5 with phosphoric acid) / methanol = 38 / 62; column temperature: 45°C; flow rate: 1 mL / min; detection wavelength: 221 nm.

[0222] Example 8

[0223] Preparation method:

[0224] The same as in Example 5. Intermediate particles 2 were assayed by HPLC, and the content of compound A was 48.0% to 53.0%. HPLC conditions: octadecylsilane bonded silica gel as filler; mobile phase: water (pH adjusted to 3.5 with phosphoric acid) / methanol = 38 / 62; column temperature: 45°C; flow rate: 1 mL / min; detection wavelength: 221 nm.

[0225] Example 9

[0226] Preparation method:

[0227] 1) Compound A was micronized using a jet milling process to control the particle size X90 to ≤ 40 μm and passed through a 60-mesh sieve; microcrystalline cellulose, crospovidone, colloidal silicon dioxide, and magnesium stearate were each passed through a 40-mesh sieve.

[0228] 2) Weigh the prescribed amount of Compound A, microcrystalline cellulose, and crospovidone, pass through a 40-mesh sieve twice, and mix for 5 minutes to obtain a mixture 1.

[0229] 3) Dry granulate the mixture 1, control the tableting speed to 3-5Hz, the granulation speed to 15-20Hz, and the oil pump pressure to 30-80kg / cm 2 , to obtain particles 1.

[0230] 4) Add the prescribed amount of colloidal silicon dioxide and magnesium stearate to Granules 1 and mix for 5 minutes to obtain Intermediate Granules 2. Intermediate Granules 2 were assayed by HPLC, revealing a Compound A content of 43.0% to 48.0%. HPLC conditions: octadecylsilane bonded silica gel as filler; mobile phase: water (pH adjusted to 3.5 with phosphoric acid) / methanol = 38 / 62; column temperature: 45°C; flow rate: 1 mL / min; detection wavelength: 221 nm.

[0231] 5) Adoption Punch and press into tablets according to the content of the intermediate granules 2 and the specification of 200 mg, control the weight difference by ±5%, and the hardness by 70-110N to obtain tablets.

[0232] Example 10

[0233] Preparation method:

[0234] 1) Compound A was micronized using a jet milling process to control the particle size X90 to ≤ 40 μm and passed through a 60-mesh sieve; microcrystalline cellulose, sodium carboxymethyl starch, colloidal silicon dioxide, and magnesium stearate were each passed through a 40-mesh sieve.

[0235] 2) Weigh the prescribed amount of compound A, microcrystalline cellulose, and sodium starch glycolate, pass through a 40-mesh sieve twice, and mix for 5 minutes to obtain mixture 1.

[0236] 3) Dry granulate the mixture 1, control the tableting speed to 3-5Hz, the granulation speed to 15-20Hz, and the oil pump pressure to 30-80kg / cm 2 , to obtain particles 1.

[0237] 4) Add the prescribed amount of colloidal silicon dioxide and magnesium stearate to Granules 1 and mix for 5 minutes to obtain Intermediate Granules 2. Intermediate Granules 2 were assayed by HPLC, revealing a Compound A content of 43.0% to 48.0%. HPLC conditions: octadecylsilane bonded silica gel as filler; mobile phase: water (pH adjusted to 3.5 with phosphoric acid) / methanol = 38 / 62; column temperature: 45°C; flow rate: 1 mL / min; detection wavelength: 221 nm.

[0238] 5) Adoption Punch and press into tablets according to the content of the intermediate granules 2 and the specification of 200 mg, control the weight difference by ±5%, and the hardness by 70-110N to obtain tablets.

[0239] Example 11

[0240] Preparation method:

[0241] 1) Compound A was micronized using a jet milling process to control the particle size X90 to ≤ 40 μm and passed through a 60-mesh sieve; poloxamer was passed through a 60-mesh sieve; microcrystalline cellulose, crospovidone, colloidal silicon dioxide, and magnesium stearate were each passed through a 40-mesh sieve.

[0242] 2) Weigh the prescribed amount of compound A and poloxamer, pass through a 40-mesh sieve twice, add the prescribed amount of cross-linked polyvinylpyrrolidone, and pass through a 40-mesh sieve twice to obtain mixture 1.

[0243] 3) Add the prescribed amount of microcrystalline cellulose to mixture 1 and mix for 10 minutes. Then add 1 / 2 the prescribed amount of magnesium stearate and 1 / 2 the prescribed amount of colloidal silicon dioxide and mix for 5 minutes to obtain mixture 2.

[0244] 4) Dry granulate the mixture 2 at a tableting speed of 4-6 Hz, a granulation speed of 15-20 Hz, and an oil pump pressure of 30-80 kg / cm 2 , to obtain particles 1.

[0245] 5) Add the remaining amount of magnesium stearate and colloidal silicon dioxide to Granules 1 and mix for 5 minutes to obtain Intermediate Granules 2. Intermediate Granules 2 were assayed by HPLC, revealing a Compound A content of 43.0% to 48.0%. HPLC conditions: octadecylsilane bonded silica gel as filler; mobile phase: water (pH adjusted to 3.5 with phosphoric acid) / methanol = 38 / 62; column temperature: 45°C; flow rate: 1 mL / min; detection wavelength: 221 nm.

[0246] 6) Adoption Punch and press into tablets according to the content of the intermediate granules 2 and the specification of 200 mg, control the weight difference by ±5%, and the hardness by 70-110N to obtain tablets.

[0247] Example 12

[0248] Preparation method:

[0249] The same procedure as in Example 11. Intermediate Particle 2 was assayed by HPLC, revealing a Compound A content of 47.5% to 52.5%. HPLC conditions: octadecylsilane bonded silica gel as filler; mobile phase: water (pH adjusted to 3.5 with phosphoric acid) / methanol = 38 / 62; column temperature: 45°C; flow rate: 1 mL / min; detection wavelength: 221 nm.

[0250] Example 13

[0251] Preparation method:

[0252] The same procedure as in Example 11. Intermediate Particle 2 was assayed by HPLC, revealing a Compound A content of 47.5% to 52.5%. HPLC conditions: octadecylsilane bonded silica gel as filler; mobile phase: water (pH adjusted to 3.5 with phosphoric acid) / methanol = 38 / 62; column temperature: 45°C; flow rate: 1 mL / min; detection wavelength: 221 nm.

[0253] Example 14

[0254] Preparation method:

[0255] 1) Compound A was micronized using a jet milling process to control the particle size X90 to ≤ 40 μm and passed through a 60-mesh sieve; poloxamer was passed through a 60-mesh sieve, and microcrystalline cellulose, crospovidone, colloidal silicon dioxide, and magnesium stearate were each passed through a 40-mesh sieve.

[0256] 2) Weigh the prescribed amount of compound A and poloxamer, pass through a 40-mesh sieve twice, add the prescribed amount of cross-linked polyvinylpyrrolidone, and pass through a 40-mesh sieve twice to obtain mixture 1.

[0257] 3) Add the prescribed amount of microcrystalline cellulose to mixture 1 and mix for 10 minutes. Then add 1 / 2 the prescribed amount of magnesium stearate and 1 / 2 the prescribed amount of colloidal silicon dioxide and mix for 5 minutes to obtain mixture 2.

[0258] 4) Dry granulate the mixture 2 at a tableting speed of 4-6 Hz, a granulation speed of 15-20 Hz, and an oil pump pressure of 30-80 kg / cm 2 Granules 1 were obtained.

[0259] 5) Add the remaining amount of magnesium stearate and colloidal silicon dioxide to Granules 1 and mix for 5 minutes to obtain Intermediate Granules 2. Intermediate Granules 2 were assayed by HPLC, revealing a Compound A content of 47.5% to 52.5%. HPLC conditions: octadecylsilane bonded silica gel as filler; mobile phase: water (pH adjusted to 3.5 with phosphoric acid) / methanol = 38 / 62; column temperature: 45°C; flow rate: 1 mL / min; detection wavelength: 221 nm.

[0260] 6) Use Punch and press into tablets according to the content of intermediate granules 2 and the specification of 200 mg, with the weight difference controlled at ±5% and the hardness of 70-110N to produce tablets.

[0261] 7) The prepared tablets are coated, with the coating weight gain being about 2.0-5.0%.

[0262] Example 15

[0263] Preparation method:

[0264] 1) Compound A was micronized using a jet milling process to control the particle size X90 to ≤ 40 μm and passed through a 60-mesh sieve; poloxamer was passed through a 60-mesh sieve, and microcrystalline cellulose, crospovidone, colloidal silicon dioxide, and magnesium stearate were each passed through a 40-mesh sieve.

[0265] 2) Weigh the prescribed amount of compound A and poloxamer, pass through a 40-mesh sieve twice, add the prescribed amount of cross-linked polyvinylpyrrolidone, and pass through a 40-mesh sieve twice to obtain mixture 1.

[0266] 3) Add the prescribed amount of microcrystalline cellulose to mixture 1 and mix for 10 minutes. Then add 1 / 2 the prescribed amount of magnesium stearate and 1 / 2 the prescribed amount of colloidal silicon dioxide and mix for 5 minutes to obtain mixture 2.

[0267] 4) Dry granulate the mixture 2 at a tableting speed of 4-6 Hz, a granulation speed of 15-20 Hz, and an oil pump pressure of 30-80 kg / cm 2 Granules 1 were obtained.

[0268] 5) Add the remaining amount of magnesium stearate and colloidal silicon dioxide to Granules 1 and mix for 5 minutes to obtain Intermediate Granules 2. Intermediate Granules 2 were assayed by HPLC, revealing a Compound A content of 47.5% to 52.5%. HPLC conditions: octadecylsilane bonded silica gel as filler; mobile phase: water (pH adjusted to 3.5 with phosphoric acid) / methanol = 38 / 62; column temperature: 45°C; flow rate: 1 mL / min; detection wavelength: 221 nm.

[0269] 6) Use Punch and press into tablets according to the content of intermediate granules 2 and the specification of 50 mg, with the weight difference controlled at ±5% and the hardness of 50-80N to obtain tablets.

[0270] 7) The prepared tablets are coated, with the coating weight gain being about 2.0-5.0%.

[0271] Example 16

[0272] Preparation method:

[0273] 1) Compound A was micronized using a jet milling process to control the particle size X90 to ≤ 40 μm and passed through a 60-mesh sieve; poloxamer was passed through a 60-mesh sieve, and microcrystalline cellulose, crospovidone, colloidal silicon dioxide, and magnesium stearate were each passed through a 40-mesh sieve.

[0274] 2) Weigh the prescribed amount of compound A and poloxamer, pass through a 40-mesh sieve twice, add the prescribed amount of cross-linked polyvinylpyrrolidone, and pass through a 40-mesh sieve twice to obtain mixture 1.

[0275] 3) Add the prescribed amount of microcrystalline cellulose to mixture 1 and mix for 10 minutes. Then add 1 / 2 the prescribed amount of magnesium stearate and 1 / 2 the prescribed amount of colloidal silicon dioxide and mix for 5 minutes to obtain mixture 2.

[0276] 4) Dry granulate the mixture 2 at a tableting speed of 4-6 Hz, a granulation speed of 15-20 Hz, and an oil pump pressure of 30-80 kg / cm 2 Granules 1 were obtained.

[0277] 5) Add the remaining amount of magnesium stearate and colloidal silicon dioxide to Granules 1 and mix for 5 minutes to obtain Intermediate Granules 2. Intermediate Granules 2 were assayed by HPLC, revealing a Compound A content of 47.5% to 52.5%. HPLC conditions: octadecylsilane bonded silica gel as filler; mobile phase: water (pH adjusted to 3.5 with phosphoric acid) / methanol = 38 / 62; column temperature: 45°C; flow rate: 1 mL / min; detection wavelength: 221 nm.

[0278] 6) Use Punch and press into tablets according to the content of intermediate granules 2 and the specification of 100 mg, with the weight difference controlled at ±5% and the hardness of 60-100N to produce tablets.

[0279] 7) The prepared tablets are coated, with the coating weight gain being about 2.0-5.0%.

[0280] Example 17

[0281] Preparation method:

[0282] 1) Compound A was micronized using a jet milling process to control the particle size X90 to ≤ 40 μm and passed through a 60-mesh sieve; poloxamer was passed through a 60-mesh sieve, and microcrystalline cellulose, crospovidone, colloidal silicon dioxide, and magnesium stearate were each passed through a 40-mesh sieve.

[0283] 2) Weigh the prescribed amount of compound A and poloxamer, pass through a 40-mesh sieve twice, add the prescribed amount of cross-linked polyvinylpyrrolidone, and pass through a 40-mesh sieve twice to obtain mixture 1.

[0284] 3) Add the prescribed amount of microcrystalline cellulose to mixture 1 and mix for 10 minutes to obtain mixture 2.

[0285] 4) Dry granulate the mixture 2 at a tableting speed of 4-6 Hz, a granulation speed of 15-20 Hz, and an oil pump pressure of 30-80 kg / cm 2 Granules 1 were obtained.

[0286] 5) Add the prescribed amount of magnesium stearate and colloidal silicon dioxide to Granules 1 and mix for 5 minutes to obtain Intermediate Granules 2. Intermediate Granules 2 were assayed by HPLC, revealing a Compound A content of 27.5% to 32.5%. HPLC conditions: octadecylsilane bonded silica gel as filler; mobile phase: water (pH adjusted to 3.5 with phosphoric acid) / methanol = 38 / 62; column temperature: 45°C; flow rate: 1 mL / min; detection wavelength: 221 nm.

[0287] 6) Use Punch and press into tablets according to the content of intermediate granules 2 and the specification of 120 mg, with the weight difference controlled at ±5% and the hardness of 70-110N to produce tablets.

[0288] 7) The prepared tablets are coated, with the coating weight gain being about 2.0-5.0%.

[0289] Example 18

[0290] Preparation method:

[0291] 1) Compound A was micronized using a jet milling process to control the particle size X90 to ≤ 40 μm and passed through a 60-mesh sieve; poloxamer was passed through a 60-mesh sieve, and microcrystalline cellulose, crospovidone, colloidal silicon dioxide, and magnesium stearate were each passed through a 40-mesh sieve.

[0292] 2) Weigh the prescribed amount of compound A and poloxamer, pass through a 40-mesh sieve twice, add the prescribed amount of cross-linked polyvinylpyrrolidone, and pass through a 40-mesh sieve twice to obtain mixture 1.

[0293] 3) Add the prescribed amount of microcrystalline cellulose to mixture 1 and mix for 10 minutes. Then add 1 / 2 the prescribed amount of magnesium stearate and 1 / 2 the prescribed amount of colloidal silicon dioxide and mix for 5 minutes to obtain mixture 2.

[0294] 4) Dry granulate the mixture 2 at a tableting speed of 4-6 Hz, a granulation speed of 15-20 Hz, and an oil pump pressure of 30-80 kg / cm 2 Granules 1 were obtained.

[0295] 5) Add the remaining amount of magnesium stearate and colloidal silicon dioxide to Granules 1 and mix for 5 minutes to obtain Intermediate Granules 2. Intermediate Granules 2 were assayed by HPLC, revealing a Compound A content of 67.5% to 72.5%. HPLC conditions: octadecylsilane bonded silica gel as filler; mobile phase: water (pH adjusted to 3.5 with phosphoric acid) / methanol = 38 / 62; column temperature: 45°C; flow rate: 1 mL / min; detection wavelength: 221 nm.

[0296] 6) Use Punch and press into tablets according to the content of intermediate granules 2 and the specification of 280 mg, with the weight difference controlled at ±5% and the hardness of 70-110N to obtain tablets.

[0297] 7) The prepared tablets are coated, with the coating weight gain being about 2.0-5.0%.

[0298] Example 19

[0299] Preparation method:

[0300] Same as Example 14.

[0301] Example 20

[0302] Preparation method:

[0303] Same as Example 14.

[0304] Example 21

[0305] Preparation method:

[0306] Same as Example 14.

[0307] Example 22

[0308] Preparation method:

[0309] Same as Example 14.

[0310] Example 23

[0311] Preparation method:

[0312] 1) Compound A was micronized using a jet milling process to control the particle size X90 to ≤ 40 μm and passed through a 60-mesh sieve; poloxamer was passed through a 60-mesh sieve, and starch, microcrystalline cellulose, colloidal silicon dioxide, and magnesium stearate were each passed through a 40-mesh sieve.

[0313] 2) Weigh the prescribed amount of compound A and poloxamer, pass through a 40-mesh sieve twice, add the prescribed amount of microcrystalline cellulose, and pass through a 40-mesh sieve twice to obtain mixture 1.

[0314] 3) Add the prescribed amount of starch to mixture 1 and mix for 10 minutes. Then add 1 / 2 the prescribed amount of magnesium stearate and 1 / 2 the prescribed amount of colloidal silicon dioxide and mix for 5 minutes to obtain mixture 2.

[0315] 4) Dry granulate the mixture 2 at a tableting speed of 4-6 Hz, a granulation speed of 15-20 Hz, and an oil pump pressure of 30-80 kg / cm 2 Granules 1 were obtained.

[0316] 5) Add the remaining amount of magnesium stearate and colloidal silicon dioxide to Granules 1 and mix for 5 minutes to obtain Intermediate Granules 2. Intermediate Granules 2 were assayed by HPLC, revealing a Compound A content of 47.5% to 52.5%. HPLC conditions: octadecylsilane bonded silica gel as filler; mobile phase: water (pH adjusted to 3.5 with phosphoric acid) / methanol = 38 / 62; column temperature: 45°C; flow rate: 1 mL / min; detection wavelength: 221 nm.

[0317] 6) Use Punch and press into tablets according to the content of intermediate granules 2 and the specification of 200 mg, with the weight difference controlled at ±5% and the hardness of 70-110N to produce tablets.

[0318] 7) The prepared tablets are coated, with the coating weight gain being about 2.0-5.0%.

[0319] Example 24

[0320] Preparation method:

[0321] 1) Compound A was micronized using a jet milling process to control the particle size X90 to ≤ 40 μm and passed through a 60-mesh sieve; poloxamer was passed through a 60-mesh sieve, and mannitol, low-substituted hydroxypropyl cellulose, colloidal silicon dioxide, and magnesium stearate were each passed through a 40-mesh sieve.

[0322] 2) Weigh the prescribed amount of compound A and poloxamer, pass through a 40-mesh sieve twice, add the prescribed amount of low-substituted hydroxypropyl cellulose, and pass through a 40-mesh sieve twice to obtain mixture 1.

[0323] 3) Add the prescribed amount of mannitol to mixture 1 and mix for 10 minutes. Then add 1 / 2 the prescribed amount of magnesium stearate and 1 / 2 the prescribed amount of colloidal silicon dioxide and mix for 5 minutes to obtain mixture 2.

[0324] 4) Dry granulate the mixture 2 at a tableting speed of 4-6 Hz, a granulation speed of 15-20 Hz, and an oil pump pressure of 30-80 kg / cm 2 Granules 1 were obtained.

[0325] 5) Add the remaining amount of magnesium stearate and colloidal silicon dioxide to Granules 1 and mix for 5 minutes to obtain Intermediate Granules 2. Intermediate Granules 2 were assayed by HPLC, revealing a Compound A content of 47.5% to 52.5%. HPLC conditions: octadecylsilane bonded silica gel as filler; mobile phase: water (pH adjusted to 3.5 with phosphoric acid) / methanol = 38 / 62; column temperature: 45°C; flow rate: 1 mL / min; detection wavelength: 221 nm.

[0326] 6) Use Punch and press into tablets according to the content of intermediate granules 2 and the specification of 200 mg, with the weight difference controlled at ±5% and the hardness of 70-110N to produce tablets.

[0327] 7) The prepared tablets are coated, with the coating weight gain being about 2.0-5.0%.

[0328] Example 25

[0329] Preparation method:

[0330] 1) Compound A was micronized using a jet milling process to control the particle size X90 to ≤ 40 μm and passed through a 60-mesh sieve; sodium lauryl sulfate was passed through a 60-mesh sieve, and microcrystalline cellulose, crospovidone, talc, and sodium stearyl fumarate were each passed through a 40-mesh sieve.

[0331] 2) Weigh the prescribed amount of compound A and sodium lauryl sulfate, pass through a 40-mesh sieve twice, add the prescribed amount of cross-linked polyvinylpyrrolidone, and pass through a 40-mesh sieve twice to obtain mixture 1.

[0332] 3) Add the prescribed amount of microcrystalline cellulose to mixture 1, mix for 10 minutes, add 1 / 2 the prescribed amount of sodium stearyl fumarate and 1 / 2 the prescribed amount of talc, and mix for 5 minutes to obtain mixture 2.

[0333] 4) Dry granulate the mixture 2 at a tableting speed of 4-6 Hz, a granulation speed of 15-20 Hz, and an oil pump pressure of 30-80 kg / cm 2 Granules 1 were obtained.

[0334] 5) Add the remaining amount of sodium stearyl fumarate and talc to Granules 1 and mix for 5 minutes to obtain Intermediate Granules 2. Intermediate Granules 2 were assayed by HPLC, revealing a Compound A content of 47.5% to 52.5%. HPLC conditions: octadecylsilane bonded silica gel as filler; mobile phase: water (pH adjusted to 3.5 with phosphoric acid) / methanol = 38 / 62; column temperature: 45°C; flow rate: 1 mL / min; detection wavelength: 221 nm.

[0335] 6) Use Punch and press into tablets according to the content of intermediate granules 2 and the specification of 200 mg, with the weight difference controlled at ±5% and the hardness of 70-110N to produce tablets.

[0336] 7) The prepared tablets are coated, with the coating weight gain being about 2.0-5.0%.

[0337] Example 26

[0338] Preparation method:

[0339] 1) Compound A was micronized using a jet milling process to control the particle size X90 to ≤ 40 μm and passed through a 60-mesh sieve; poloxamer was passed through a 60-mesh sieve, and pregelatinized starch, starch, colloidal silicon dioxide, and stearic acid were each passed through a 40-mesh sieve.

[0340] 2) Weigh the prescribed amount of compound A and poloxamer, pass through a 40-mesh sieve twice, add the prescribed amount of starch, and pass through a 40-mesh sieve twice to obtain mixture 1.

[0341] 3) The prescribed amount of pregelatinized starch was added to mixture 1, and the mixture was mixed for 10 minutes. 1 / 2 of the prescribed amount of stearic acid and 1 / 2 of the prescribed amount of colloidal silicon dioxide were added, and the mixture was mixed for 5 minutes to obtain mixture 2.

[0342] 4) Dry granulate the mixture 2 at a tableting speed of 4-6 Hz, a granulation speed of 15-20 Hz, and an oil pump pressure of 30-80 kg / cm 2 Granules 1 were obtained.

[0343] 5) Add the remaining amount of stearic acid and colloidal silica to Granules 1 and mix for 5 minutes to obtain Intermediate Granules 2. Intermediate Granules 2 were assayed by HPLC, revealing a Compound A content of 47.5% to 52.5%. HPLC conditions: octadecylsilane bonded silica gel as filler; mobile phase: water (pH adjusted to 3.5 with phosphoric acid) / methanol = 38 / 62; column temperature: 45°C; flow rate: 1 mL / min; detection wavelength: 221 nm.

[0344] 6) Use Punch and press into tablets according to the content of intermediate granules 2 and the specification of 200 mg, with the weight difference controlled at ±5% and the hardness of 70-110N to produce tablets.

[0345] 7) The prepared tablets are coated, with the coating weight gain being about 2.0-5.0%.

[0346] Example 27

[0347] Preparation method:

[0348] 1) Compound A was micronized using a jet milling process to control the particle size X90 to ≤ 40 μm and passed through a 60-mesh sieve; microcrystalline cellulose, crospovidone, colloidal silicon dioxide, and magnesium stearate were each passed through a 40-mesh sieve.

[0349] 2) Weigh the prescribed amount of Compound A, microcrystalline cellulose, and crospovidone, pass through a 40-mesh sieve twice, and mix for 5 minutes to obtain a mixture 1.

[0350] 3) Dry granulate the mixture 1, control the tableting speed to 3-5Hz, the granulation speed to 15-20Hz, and the oil pump pressure to 30-80kg / cm 2 , to obtain particles 1.

[0351] 4) Add the prescribed amount of colloidal silicon dioxide and magnesium stearate to Granules 1 and mix for 5 minutes to obtain Intermediate Granules 2. Intermediate Granules 2 were assayed by HPLC, revealing a Compound A content of 47.5% to 52.5%. HPLC conditions: octadecylsilane bonded silica gel as filler; mobile phase: water (pH adjusted to 3.5 with phosphoric acid) / methanol = 38 / 62; column temperature: 45°C; flow rate: 1 mL / min; detection wavelength: 221 nm.

[0352] 5) Adoption Punch and press into tablets according to the content of the intermediate granules 2 and the specification of 200 mg, control the weight difference by ±5%, and the hardness by 70-110N to obtain tablets.

[0353] 6) The prepared tablets are coated, with the coating weight gain being about 2.0-5.0%.

[0354] Example 28

[0355] Preparation method:

[0356] 1) Compound A was micronized using a jet milling process to control the particle size X90 to ≤ 40 μm and passed through a 60-mesh sieve; microcrystalline cellulose, lactose, crospovidone, colloidal silicon dioxide, and magnesium stearate were each passed through a 40-mesh sieve.

[0357] 2) Weigh the prescribed amount of compound A, lactose, and cross-linked polyvinylpyrrolidone, and mix for 5 minutes to obtain mixture 1.

[0358] 3) Add the prescribed amount of microcrystalline cellulose to mixture 1 and mix for 5 minutes to obtain mixture 2.

[0359] 4) Add the prescribed amount of colloidal silicon dioxide and magnesium stearate to mixture 2 and mix for 5 minutes to obtain an intermediate powder. The intermediate powder was assayed by HPLC, revealing a Compound A content of 47.5% to 52.5%. HPLC conditions: octadecylsilane bonded silica gel as filler; mobile phase: water (pH adjusted to 3.5 with phosphoric acid) / methanol = 38 / 62; column temperature: 45°C; flow rate: 1 mL / min; detection wavelength: 221 nm.

[0360] 5) Adoption Punch and press into tablets according to the specification of 200 mg according to the content of the intermediate powder, control the weight difference by ±5%, and the hardness by 70-110N to produce tablets.

[0361] 6) The prepared tablets are coated, with the coating weight gain being about 2.0-5.0%.

[0362] Example 29

[0363] Preparation method:

[0364] 1) Compound A was micronized using a jet milling process to control the particle size X90 to ≤ 40 μm and passed through a 60-mesh sieve; microcrystalline cellulose, croscarmellose sodium, and colloidal silicon dioxide were each passed through a 60-mesh sieve.

[0365] 2) Weigh the prescribed amount of compound A, add the prescribed amount of cross-linked sodium carboxymethyl cellulose, and mix for 5 minutes to obtain mixture 1.

[0366] 3) Add the prescribed amount of microcrystalline cellulose to mixture 1, mix for 10 minutes, and pass through a 60-mesh sieve to obtain mixture 2.

[0367] 4) Add the prescribed amount of colloidal silicon dioxide to mixture 2 and mix for 5 minutes to obtain a powder.

[0368] 5) Filling capsules: content weight 120 mg / capsule (specification 50 mg).

[0369] Example 30

[0370] Preparation method:

[0371] 1) Compound A was micronized using a jet milling process to control the particle size X90 to ≤ 40 μm and passed through a 60-mesh sieve; microcrystalline cellulose, croscarmellose sodium, and colloidal silicon dioxide were each passed through a 60-mesh sieve.

[0372] 2) Weigh the prescribed amount of compound A, add the prescribed amount of cross-linked sodium carboxymethyl cellulose, and mix for 5 minutes to obtain mixture 1.

[0373] 3) Add the prescribed amount of microcrystalline cellulose to mixture 1, mix for 10 minutes, and pass through a 60-mesh sieve to obtain mixture 2.

[0374] 4) Add the prescribed amount of colloidal silicon dioxide to mixture 2 and mix for 5 minutes to obtain a powder.

[0375] 5) Filling capsules: Content weight 240 mg / capsule (specification 100 mg).

[0376] Dissolution test

[0377] 1. Dissolution test method:

[0378] Take samples of Example 1, Example 2, Example 3, Example 4, Example 5, Example 6, Example 7, Example 8, Example 9, Example 10, Example 11, Example 12, and Example 13 respectively, and according to the dissolution method (Chinese Pharmacopoeia 2020 Edition, Part 4, General Rules 0931, Method 2), add 900 ml of hydrochloric acid solution (pH = 1.2) containing 0.1% sodium lauryl sulfate as a dissolution medium, the speed is 75 revolutions per minute, and samples are taken at 5, 10, 15, 20, 30, 45, 60, 90, and 120 minutes, respectively, to determine the dissolution rate.

[0379] 2. Dissolution results and conclusions:

[0380] Table 1 Dissolution results

[0381] Conclusion: The preparation of the present invention has a good drug dissolution effect within 120 minutes.

[0382] Stability test

[0383] 1. Test conditions:

[0384] Place the sample in an open, clean watch glass, and take samples for inspection on the 5th and 10th day respectively under the conditions of high temperature test (60±2℃), high humidity test (RH75%±1%), and light test (4500±500Lx).

[0385] 2. Results and Conclusions

[0386] Table 2 Test results of influencing factors

[0387] Conclusion: The influencing factor test showed that the various indicators of the preparation of the present invention had no significant difference compared with day 0, indicating that the quality of the preparation of the present invention is stable.

[0388] Pharmacokinetic study in beagle dogs

[0389] Prepare the test substance tablets for oral administration. Healthy male beagle dogs (provided by Sichuan Musk Deer Breeding Research Institute) were taken, with a weight of 10 kg per beagle. Each tablet was administered to three animals at a dose of 1 tablet per animal, and blood was collected from the three animals through the forelimb vein at each time point. The test substance was administered by oral administration, and blood was collected 15 minutes, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours after administration. The blood samples were anticoagulated with EDTA-K2 and centrifuged at 3200g for 10 minutes at 4°C to separate the plasma. All plasma samples were stored at -70°C for testing. The plasma concentration of the test substance (internal standard: gliclazide) was determined by LC-MS / MS, and the main pharmacokinetic parameters were calculated using the Winnolin 8.3 non-compartmental model.

[0390] Conclusion: The preparation of the present invention has good pharmacokinetic characteristics.

[0391] The specification of the present invention describes the specific implementation scheme in detail. Those skilled in the art should recognize that the above implementation scheme is exemplary and cannot be understood as limiting the present invention. For those skilled in the art, without departing from the principles of the present invention, by making several improvements and modifications to the present invention, the technical solutions obtained by these improvements and modifications also fall within the scope of protection of the claims of the present invention.

Claims

1. A pharmaceutical preparation of a piperazine derivative, characterized in that: The pharmaceutical preparation comprises a piperazine derivative or a stereoisomer, a tautomer, a deuterated product or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical preparation comprises 1-1000 mg of the piperazine derivative, and the piperazine derivative is selected from a compound of formula (I): in: X1 is NH, O or a 4- to 6-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N and O; X2 is O or a bond; X3 and X4 are each independently C or N; R 1a , R 1b Each independently is H, D or C 1-6 Alkyl; or R 1a , R 1b Together with the carbon atom to which it is attached, it forms a 3- to 5-membered cycloalkyl group; R 2a , R 2b Each independently is H, D or C 1-6 Alkyl; or R 2a , R 2b Together with the carbon atom to which it is attached, it forms a 3- to 5-membered cycloalkyl group; R3 is H, D, C 1-6 Alkyl, halogen or cyano, the C 1-6 The alkyl group is optionally substituted with 1 to 3 halogens; R4 and R5 are each independently H, D or C 1-6 Alkyl; or R4, R5 and the connected carbon atom form a 3 to 5-membered cycloalkyl; R6 and R7 are each independently H, D or C 1-6 Alkyl; or R6, R7 and the connected carbon atom form =O; R8 and R9 are each independently H, D or C 1-6 Alkyl; or R8, R9 and the connected carbon atom form =O; or R8 and R9 and the connected carbon atom form a 3 to 5 membered cycloalkyl; R 10 Each independently is C 1-6 Alkyl, C 1-6 Alkoxy, CONR 10a R 10b , halogen, cyano, S(O)2R 10c , SR 10d or a 3- to 5-membered cycloalkyl group, the C 1-6 Alkyl, C 1-6 Alkoxy is optionally substituted with 1 to 3 halogens; R 10a , R 10b , R 10c , R 10d Each independently is H, D or C 1-6 alkyl; A is R a C 1-6 Alkyl, C 3-5 Cycloalkyl, halogen or cyano, the C 1-6 The alkyl group is optionally substituted with 1 to 3 halogens; B is a 5- to 10-membered carbocyclic or heterocyclic ring containing 1 to 3 heteroatoms selected from N, O and S; C is a 5- to 6-membered heterocyclic ring containing 1 to 3 N heteroatoms; m is 1, 2 or 3; n is 0, 1, 2 or 3; p is 0, 1, 2 or 3.

2. The pharmaceutical preparation according to claim 1, characterized in that: X1 is NH, O or a 4- to 6-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N and O; X2 is O or a bond; X3 and X4 are each independently C or N; R 1a , R 1b Each independently is H, D or C 1-6 alkyl; R 2a , R 2b Each independently is H, D or C 1-6 Alkyl; or R 2a , R 2b Together with the carbon atom to which it is attached, it forms a 3- to 5-membered cycloalkyl group; R3 is H, D, C 1-6 Alkyl, halogen or cyano, the C 1-6 The alkyl group is optionally substituted with 1 to 3 halogens; R4 and R5 are each independently H, D or C 1-6 Alkyl; or R4, R5 and the connected carbon atom form a 3 to 5-membered cycloalkyl; R6 and R7 are each independently H, D or C 1-6 alkyl; R8 and R9 are each independently H, D or C 1-6 Alkyl; or R8, R9 and the connected carbon atom form =O; R 10 Each independently is C 1-6 Alkyl, C 1-6 Alkoxy, CONR 10a R 10b , halogen, cyano, S(O)2R 10c , SR 10d or a 3- to 5-membered cycloalkyl group, the C 1-6 Alkyl, C 1-6 The alkoxy group is optionally substituted with 1 to 3 halogens; R 10a , R 10b , R 10c , R 10d Each independently is H, D or C 1-6 alkyl; A is R a C 1-6 Alkyl, C 3-5 Cycloalkyl, halogen or cyano, the C 1-6 The alkyl group is optionally substituted with 1 to 3 halogens; B is a 5- to 6-membered carbocyclic or heterocyclic ring containing 1 to 3 heteroatoms selected from N, O and S; C is a 5- to 6-membered heterocyclic ring containing 1 to 3 N heteroatoms; m is 1, 2 or 3; n is 0, 1, 2 or 3; p is 0, 1, 2 or 3.

3. The pharmaceutical preparation according to claim 1, characterized in that The piperazine derivative is selected from the compound of formula (I-1): in: X1 is NH or a 4- to 6-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N and O; X2 is 0; X3 and X4 are each independently C or N; R 1a , R 1b Each independently is H, D or C 1-6 alkyl; R 2a , R 2b Each independently is H, D or C 1-6 alkyl; R3 is H, D, C 1-6 Alkyl or halogen, the C 1-6 The alkyl group is optionally substituted with 1 to 3 halogens; R4 and R5 are each independently H, D or C 1-6 alkyl; R6 and R7 are each independently H, D or C 1-6 alkyl; R8 and R9 are each independently H, D or C 1-6 Alkyl; or R8 and R9 form =O with the carbon atom to which they are attached; R 10 C 1-6 Alkyl, C 1-6 Alkoxy, cyano or SR 10d , the C 1-6 Alkyl, C 1-6 Alkoxy is optionally substituted with 1 to 3 halogens; R 10d H, D or C 1-6 alkyl; A is B is a 5- to 6-membered carbocyclic or heterocyclic ring containing 1 to 3 heteroatoms selected from N, O and S; C is a 5- to 6-membered heterocyclic ring containing 1 to 3 N heteroatoms; m is 1, 2 or 3; n is 0, 1, 2 or 3.

4. The pharmaceutical preparation according to claim 1, characterized in that The piperazine derivative is selected from the compound of formula (I-2): in: X1 is NH; X2 is 0; R 1a , R 1b Each independently is H, D or C 1-6 alkyl; R 2a , R 2b Each independently is H, D or C 1-6 alkyl; R3 is H, D, C 1-6 Alkyl or halogen, the C 1-6 The alkyl group is optionally substituted with 1 to 3 halogens; R4 and R5 are each independently H, D or C 1-6 alkyl; R6 and R7 are each independently H, D or C 1-6 alkyl; R8 and R9 are each independently H, D or C 1-6 Alkyl; or R8 and R9 and the carbon atom to which they are attached form =O; R 10 C 1-6 Alkyl, C 1-6 Alkoxy, cyano or SR 10d , the C 1-6 Alkyl, C 1-6 Alkoxy is optionally substituted with 1 to 3 halogens; R 10d H, D or C 1-6 alkyl; A is B is a 5- to 6-membered carbocyclic or heterocyclic ring containing 1 to 3 heteroatoms selected from N, O and S; m is 1, 2 or 3; n is 0, 1, 2 or 3.

5. The pharmaceutical preparation according to claim 4, characterized in that: X1 is NH; X2 is 0; R 1a , R 1b Each independently is H, D or C 1-6 alkyl; R 2a , R 2b Each independently is H, D or C 1-6 alkyl; R3 is H, D, C 1-6 Alkyl or halogen, the C 1-6 The alkyl group is optionally substituted with 1 to 3 halogens; R4 and R5 are each independently H, D or C 1-6 alkyl; R6 and R7 are each independently H, D or C 1-6 alkyl; R8 and R9 are each independently H, D or C 1-6 Alkyl, or R8 and R9 form =O with the carbon atom to which they are attached; R 10 C 1-6 Alkyl, cyano, or SR 10d , the C 1-6 The alkyl group is optionally substituted with 1 to 3 halogens; R 10d H, D or C 1-6 alkyl; A is B is a 5- to 6-membered carbocyclic or heterocyclic ring containing 1 to 3 heteroatoms selected from N, O and S; m is 1, 2 or 3; n is 0, 1, 2 or 3.

6. The pharmaceutical preparation according to claim 5, characterized in that: X1 is selected from NH; X2 is selected from O; R 1a , R 1b Each independently selected from H, D or C 1-6 alkyl; R 2a , R 2b Each independently selected from H, D or C 1-6 alkyl; R3 is H, D, C 1-6 Alkyl or halogen, the C 1-6 The alkyl group is optionally substituted with 1 to 3 halogens; R4 and R5 are each independently H or D; R6 and R7 are each independently H or D; R8 and R9 are each independently H or D; R 10 CF3 or SR 10d ; R 10d H, D or C 1-6 alkyl; A is B is m is 1, 2 or 3; n is 0, 1, 2 or 3.

7. The pharmaceutical preparation according to claim 6, characterized in that: X1 is selected from NH; X2 is selected from O; R 1a , R 1b Each independently selected from H, D or C 1-3 alkyl; R 2a , R 2b Each independently selected from H, D or C 1-3 alkyl; R3 is selected from H, D or CF3; R4 and R5 are each independently selected from H or D; R6 and R7 are each independently selected from H or D; R8 and R9 are each independently selected from H or D; R 10 is CF3; A is B is m is 1, 2 or 3; n is 0, 1 or 2.

8. The pharmaceutical preparation according to claim 1, characterized in that The piperazine derivative is selected from the compound of formula (I-3): in: X1 is NH or a 4- to 6-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N and O; X2 is 0; R 1a , R 1b Each independently is H, D or C 1-6 alkyl; R 2a , R 2b Each independently is H, D or C 1-6 alkyl; R4 and R5 are each independently H, D or C 1-6 alkyl; R6 and R7 are each independently H, D or C 1-6 alkyl; R8 and R9 are each independently H, D or C 1-6 Alkyl; or R8, R9 and the connected carbon atom form =O; R 10 C 1-6 Alkyl, C 1-6 Alkoxy, cyano or SR 10d , the C 1-6 Alkyl, C 1-6 Alkoxy is optionally substituted with 1 to 3 halogens; R 10d H, D or C 1-6 alkyl; A is B is a 5- to 6-membered carbocyclic or heterocyclic ring containing 1 to 3 heteroatoms selected from N, O and S; m is 1, 2 or 3; n is 0, 1, 2 or 3.

9. The pharmaceutical preparation according to claim 8, characterized in that: X1 is NH or a 4- to 6-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N and O; X2 is 0; R 1a , R 1b Each independently is H, D or C 1-3 alkyl; R 2a , R 2b Each independently is H, D or C 1-3 alkyl; R4 and R5 are each independently H, D or C 1-3 alkyl; R6 and R7 are each independently H, D or C 1-3 alkyl; R8 and R9 are each independently H, D or C 1-3 Alkyl; or R8 and R9 form =O with the carbon atom to which they are attached; R 10 C 1-6 Alkyl, cyano or SR 10d , the C 1-6 The alkyl group is optionally substituted with 1 to 3 halogens; R 10d H, D or C 1-6 alkyl; A is B is m is 1, 2 or 3; n is 0, 1 or 2.

10. The pharmaceutical preparation according to claim 9, characterized in that: X1 is NH; X2 is 0; R 1a , R 1b Each independently is H, D or C 1-3 alkyl; R 2a , R 2b Each independently is H or D; R4 and R5 are each independently H or D; R6 and R7 are each independently H or D; R8 and R9 are each independently H or D; R 10 is CF3; A is B is m is 1, 2 or 3; n is 0, 1 or 2.

11. The pharmaceutical preparation according to any one of claims 1 to 10, characterized in that The piperazine derivative or its stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt is selected from:

12. The pharmaceutical preparation according to any one of claims 1 to 11, characterized in that The pharmaceutical preparation comprises 1-5 mg, 5-10 mg, 10-15 mg, 15-20 mg, 20-25 mg, 25-30 mg, 30-35 mg, 35-40 mg, 40-50 mg, 50-60 mg, 60-70 mg, 70-80 mg, 80-90 mg, 90-100 mg, 100-150 mg, 150-200 mg, 200-250 mg, 250-300 mg, 300-350 mg, 350-400 mg, 400-450 mg, 450-500 mg, 500-600 mg, 600-700 mg, 700-800 mg, 800-900 mg or 900-1000 mg of a piperazine derivative or a stereoisomer, tautomer, deuterated substance or a pharmaceutically acceptable salt thereof.

13. The pharmaceutical preparation according to any one of claims 1 to 12, characterized in that The content of the piperazine derivative or its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt in the pharmaceutical preparation accounts for 5%-90% of the total weight of the pharmaceutical preparation, preferably 20%-80%, more preferably 30%-70%.

14. The pharmaceutical preparation according to claims 1-13, characterized in that The dosage form of the pharmaceutical preparation is selected from tablets, capsules or granules.

15. The pharmaceutical preparation according to claims 1-14, characterized in that The pharmaceutical preparation may further include one or more of a diluent, a disintegrant, a solubilizer, a glidant and a lubricant.

16. The pharmaceutical preparation according to claim 15, characterized in that The diluent is selected from one or more combinations of microcrystalline cellulose, starch, mannitol, lactose, pregelatinized starch, dextrin, sucrose, calcium hydrogen phosphate and calcium phosphate; the content of the diluent accounts for 10%-80% of the total weight of the pharmaceutical preparation.

17. The pharmaceutical preparation according to claim 15, characterized in that The disintegrant is selected from one or more combinations of microcrystalline cellulose, cross-linked carboxymethyl cellulose sodium, cross-linked povidone, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, polyclidinium potassium, pregelatinized starch and starch; the content of the disintegrant accounts for 1%-60% of the total weight of the pharmaceutical preparation, preferably 3%-20%.

18. The pharmaceutical preparation according to claim 15, characterized in that The solubilizer is selected from poloxamer, sodium lauryl sulfate, or a combination of the two; the content of the solubilizer accounts for 2%-10% of the total weight of the pharmaceutical preparation.

19. The pharmaceutical preparation according to claim 15, characterized in that The glidant is selected from colloidal silicon dioxide, talcum powder, or a combination of the two; the content of the glidant accounts for 0.5%-5% of the total weight of the pharmaceutical preparation.

20. The pharmaceutical preparation according to claim 15, characterized in that The lubricant is selected from one or more combinations of stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, hydrogenated vegetable oil, magnesium lauryl sulfate, polyethylene glycol, glyceryl behenate and sucrose ester; the content of the lubricant accounts for 0.5%-5% of the total weight of the pharmaceutical preparation.

21. A method for preparing a piperazine derivative pharmaceutical preparation according to any one of claims 1 to 20, characterized in that: The piperazine derivative is micronized to control the particle size to 5-100 μm, preferably 5-70 μm, more preferably 5-40 μm; the micronized piperazine derivative is mixed with a diluent, a disintegrant and / or a solubilizer to obtain a mixture; the mixture is dry granulated, and a glidant and / or a lubricant is added to the obtained granules to obtain intermediate granules; then tablets, capsules or granules are prepared; the tablets are optionally coated.

22. A method for preparing a piperazine derivative pharmaceutical preparation according to any one of claims 1 to 20, characterized in that: The piperazine derivative is micronized to control the particle size to 5-100 μm, preferably 5-70 μm, more preferably 5-40 μm; the micronized piperazine derivative is mixed with a disintegrant and / or a solubilizer, and then a diluent, a glidant and / or a lubricant are added to mix to obtain a mixture; the mixture is dry granulated, and a glidant and / or a lubricant are added to the obtained granules to obtain intermediate granules; then tablets, capsules or granules are prepared; the tablets are optionally coated.

23. A method for preparing the piperazine derivative pharmaceutical preparation according to any one of claims 1 to 20, characterized in that: The piperazine derivative is micronized to control the particle size to 5-100 μm, preferably 5-70 μm, more preferably 5-40 μm; the micronized piperazine derivative is mixed with a diluent and / or a disintegrant, then the diluent is added and mixed, and then a glidant and / or a lubricant is added and mixed to obtain a mixture; then tablets, capsules or granules are prepared; the tablets are optionally coated.

24. Use of the piperazine derivative pharmaceutical preparation according to any one of claims 1 to 20 in the preparation of a medicament for treating and / or preventing cancer.

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