Imidazolinone compound pharmaceutical preparation as well as preparation method and application thereof

Abstract

The invention relates to an azolinone compound pharmaceutical preparation and a preparation method thereof. Pharmaceutical formulations, # imgabs0, comprising compounds of formula I

Description

An imidazolinone compound pharmaceutical preparation, preparation method and use thereof Technical Field

[0001] The present invention relates to the field of pharmaceutical preparations, and in particular to an imidazolinone compound pharmaceutical preparation, a preparation method thereof, or a use thereof. Background Art

[0002] DNA-dependent protein kinase (DNA-PK) is a DNA-PK enzyme complex composed of the Ku70 / Ku80 heterodimer and the DNA-dependent protein kinase catalytic subunit (DNA-PKcs). This enzyme complex requires DNA to be activated and function properly (George et al., 2019). As a serine / threonine protein kinase, DNA-PK belongs to the phosphatidylinositol 3-kinase-related kinase (PIKK) family. It not only plays an important role in repairing double-strand breaks (DSBs) in intracellular DNA and in cellular DNA recombination or antibody DNA rearrangement (V(D)J recombination), but also participates in physiological processes such as chromosome modification, transcriptional regulation, and telomere maintenance.

[0003] Combining DNA-PK inhibitors with anti-tumor therapies that cause DNA damage (such as IR and chemotherapy agents) can enhance therapeutic efficacy. While DNA-PK inhibitors can interfere with the DNA repair function of normal cells to a certain extent, normal cells have multiple DNA repair pathways to supplement this function. Tumor cells, however, face intense DNA replication pressure and lack effective DNA repair pathways, making them more sensitive to DNA-PK inhibitors. Inhibiting DNA-PK activity in tumor cells can enhance the cytotoxicity of other anti-tumor therapies.

[0004] The patent (application number: PCT / CN2021 / 087912) describes a novel DNA-PK inhibitor, the structure of which is shown in Formula (A). It exhibits excellent inhibitory effects on DNA-PK activity and has the potential to be used in the preparation of anti-tumor drugs. It is highly desirable to develop a formulation containing DNA-PK inhibitors that exhibits good dissolution rate and stability.

[0005] Summary of the Invention

[0006] The present invention provides an imidazolinone compound pharmaceutical preparation, which is convenient for patients to use and has the characteristics of stable quality, good dissolution effect, etc.

[0007] The present invention provides an imidazolinone compound pharmaceutical preparation, comprising an imidazolinone compound, its stereoisomers, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals. The pharmaceutical preparation comprises 1-1000 mg of the above-mentioned imidazolinone compound, wherein the imidazolinone compound is selected from the compound of formula I:

[0008] in:

[0009] for

[0010] is a single bond or a double bond;

[0011] A, B, C, and D are each independently C or N, and at least one of A, B, C, and D is N;

[0012] R0 is H, C 1-6 Alkyl or cyclopropyl, the aforementioned C 1-6 The alkyl group is optionally further substituted with one or more substituents selected from halogen and deuterium;

[0013] R1 is or pyridyl, and R1 is optionally further substituted by 1 or 2 groups selected from D, halogen, cyano, hydroxyl, C 1-6 Alkyl and C 1-6 Substitution of alkoxy groups;

[0014] R 1a H or C 1-6 alkyl;

[0015] R 1b C substituted with H, OH, cyano or hydroxyl 1-6 alkyl;

[0016] R2 is H, cyano, =O, carboxyl, -C(=O)NR 2a R 2b 、C 1-6 Alkoxy, C 1-6 Alkyl, halogen, -S(=O)2R 2a or -C(=O)OC 1-6 Alkyl; the C 1-6 Alkyl, -C(=O)OC 1-6 Alkyl or C 1-6 The alkoxy group is optionally substituted with one or more substituents selected from halogen and deuterium;

[0017] R 2a and R 2bEach independently is H, C 1-6 alkyl or 3 to 5 membered cycloalkyl, wherein the C 1-6 The alkyl group is optionally further substituted by one or more groups selected from OH, D, halogen, C 1-6 Alkyl and C 1-6 Substitution of alkoxy groups;

[0018] Or, R 2a and R 2b Together with the atoms to which it is attached, it forms a 5- to 6-membered heterocyclic group, wherein the 5- to 6-membered heterocyclic group contains 1, 2 or 3 heteroatoms selected from N, O and S, and the 5- to 6-membered heterocyclic group is optionally further substituted by 1 or more heteroatoms selected from C 1-6 Substitution of alkyl, OH and halogen substituents;

[0019] R3 is halogen or C 1-6 Alkyl, the C 1-6 The alkyl group is optionally further substituted with 1 to 3 substituents selected from D and halogen;

[0020] m is 0 or 1;

[0021] n is 0, 1, or 2;

[0022] x and y are each independently 1, 2, or 3;

[0023] The condition is,

[0024] when When R0, R2, and R3 meet the following conditions at the same time, R1 is not

[0025] for n is 1, R0 is H or methyl, R2 is methoxy or -S(=O)2Me, and R3 is methyl.

[0026] Furthermore, in one or more embodiments of the present invention, in the compound of formula I above,

[0027] R1 is

[0028] R 1a H or C 1-6 alkyl;

[0029] R2 is H, cyano, -C(=O)NR 2a R 2b 、C 1-6 Alkoxy, halogen, -S(=O)2R 2a or -C(=O)OC 1-6Alkyl; said -C(=O)OC 1-6 Alkyl or C 1-6 The alkoxy group is optionally substituted with one or more substituents selected from halogen and deuterium;

[0030] R 2a and R 2b Each independently is H, C 1-6 alkyl or 3 to 5 membered cycloalkyl, wherein the C 1-6 The alkyl group is optionally further substituted with one or more substituents selected from OH, D or halogen;

[0031] Or, R 2a and R 2b Together with the atoms to which it is attached, it forms a 5- to 6-membered heterocyclic group, wherein the 5- to 6-membered heterocyclic group contains 1 to 3 heteroatoms selected from N, O and S, and the heterocyclic group is optionally further substituted with one or more substituents selected from OH and halogen;

[0032] R3 is halogen or C 1-6 Alkyl, the C 1-6 The alkyl group is optionally further substituted with 1 to 3 substituents selected from D and halogen;

[0033] m is 0 or 1;

[0034] n is 0, 1 or 2.

[0035] Further, in one or more embodiments of the present invention, in the compound of formula I,

[0036] for

[0037] R0 is H, C 1-4 Alkyl or cyclopropyl, the C 1-4 The alkyl group is optionally further substituted with one or more substituents selected from halogen and D;

[0038] R1 is

[0039] R 1a H, C 1-6 Alkyl or -C(=O)C 1-6 alkyl;

[0040] R2 is H, cyano, -C(=O)NR 2a R 2b 、C 1-6 Alkoxy, halogen, -S(=O)2R 2a or -C(=O)OC 1-6Alkyl; the -C(=O)O alkyl or C 1-6 The alkoxy group is optionally substituted with one or more substituents selected from halogen and deuterium;

[0041] R 2a and R 2b Each independently is H, C 1-6 alkyl or 3 to 5 membered cycloalkyl, wherein the C 1-6 The alkyl group is optionally further substituted with one or more substituents selected from OH, D and halogen;

[0042] Or, R 2a and R 2b Together with the atoms to which it is attached, it forms a 5- to 6-membered heterocyclic group, wherein the 5- to 6-membered heterocyclic group contains 1 to 3 heteroatoms selected from N, O and S, and the 5- to 6-membered heterocyclic group is optionally further substituted with one or more substituents selected from OH and halogen;

[0043] R3 is halogen or C 1-6 Alkyl, the C 1-6 The alkyl group is optionally further substituted with 1 to 3 substituents selected from D and halogen;

[0044] m is 0 or 1;

[0045] n is 0, 1 or 2.

[0046] Furthermore, in one or more embodiments of the present invention, the compound of formula I is selected from:

[0047] in:

[0048] R0 is H, C 1-6 Alkyl or cyclopropyl, the C 1-6 The alkyl group is optionally further substituted with one or more substituents selected from halogen and deuterium;

[0049] R1 is or pyridyl, and R1 is optionally further substituted by 1 to 2 groups selected from D, halogen, cyano, hydroxyl, C 1-6 Alkyl and C 1-6 Substitution of alkoxy groups;

[0050] R 1a H or C 1-6 alkyl;

[0051] R 1b C substituted with H, OH, cyano or hydroxyl 1-6 alkyl;

[0052] R 2cis H, cyano, halogen or C 1-6 alkoxy;

[0053] R 2d H, cyano, carboxyl, -C(=O)NR 2a R 2b 、C 1-6 Alkyl, halogen, -S(=O)2R 2a or -C(=O)OC 1- 6 alkyl; the C 1-6 Alkyl, -C(=O)OC 1-6 The alkyl group is optionally substituted with one or more substituents selected from halogen and deuterium;

[0054] R 2a 、R 2b H, C 1-6 alkyl or 3 to 5 membered cycloalkyl, wherein the C 1-6 The alkyl group is optionally further substituted by one or more groups selected from OH, D, halogen, C 1-6 Alkyl and C 1-6 Substitution of alkoxy groups;

[0055] Or, R 2a and R 2b Together with the atoms to which it is attached, it forms a 5- to 6-membered heterocyclic group, wherein the 5- to 6-membered heterocyclic group contains 1 to 3 heteroatoms selected from N, O and S, and the 5- to 6-membered heterocyclic group is optionally further substituted by one or more heteroatoms selected from C 1-6 Substitution of alkyl, OH and halogen substituents;

[0056] R3 is halogen or C 1-6 Alkyl, the C 1-6 The alkyl group is optionally further substituted with 1 to 3 substituents selected from D and halogen;

[0057] m is 0 or 1;

[0058] n is 0, 1, or 2;

[0059] x and y are each independently 1, 2 or 3.

[0060] Furthermore, in one or more embodiments of the present invention, the compound of formula I is selected from:

[0061] in,

[0062] R0 is H, C 1-6 Alkyl or cyclopropyl, the C 1-6 The alkyl group is optionally further substituted with one or more substituents selected from halogen and deuterium;

[0063] R1 is or pyridyl, and R1 is optionally further substituted by 1 to 2 groups selected from D, halogen, cyano, hydroxyl, C 1-6 Alkyl and C 1-6 Substitution of alkoxy groups;

[0064] R 1b C substituted with H, OH, cyano or hydroxyl 1-6 alkyl;

[0065] R 2a and R 2b Each independently is H, C 1-6 alkyl or 3 to 5 membered cycloalkyl, wherein the C 1-6 The alkyl group is optionally further substituted with one or more substituents selected from D or halogen;

[0066] Or, R 2a and R 2b Together with the atoms to which it is attached, it forms a 5- to 6-membered heterocyclic group, wherein the 5- to 6-membered heterocyclic group contains 1 to 3 heteroatoms selected from N, O and S, and the 5- to 6-membered heterocyclic group is optionally further substituted by one or more heteroatoms selected from C 1-6 Substitution of alkyl, OH and halogen substituents;

[0067] R 2c is H, cyano, halogen or C 1-6 Alkoxy, the C 1-6 The alkoxy group is optionally substituted with one or more deuterium groups;

[0068] R3 is halogen or C 1-6 Alkyl, the C 1-6 The alkyl group is optionally further substituted with 1 to 3 substituents selected from D and halogen;

[0069] m is 0 or 1;

[0070] n is 0, 1, or 2;

[0071] x and y are each independently 1, 2 or 3.

[0072] Furthermore, in one or more embodiments of the present invention, the compound of formula I is selected from:

[0073] in:

[0074] R0 is H, C 1-6 Alkyl or cyclopropyl, the C 1-6 The alkyl group is optionally further substituted with one or more substituents selected from halogen and deuterium;

[0075] R1 is -(CH)m -4 to 7 membered carbocyclic group, -(CH) m -4 to 7 membered heterocyclic group, -(CH) m -8 to 12-membered bridged ring, -(CH) m -7 to 12 membered spiro ring, said -(CH) m -4 to 7 membered carbocyclic group, -(CH) m -4 to 7 membered heterocyclic group, -(CH) m -8 to 12-membered bridged ring or -(CH) m -7 to 12 membered spiro ring is optionally further substituted by one or more groups selected from hydroxy, cyano, halogen, =O, C 1-6 Alkyl, C 1-6 Alkoxy and hydroxy substituted C 1-6 Substitution of alkyl groups;

[0076] m is 0 or 1.

[0077] Furthermore, in one or more embodiments of the present invention, in the compound of formula I above,

[0078] R0 is H, C 1-6 Alkyl or cyclopropyl, the C 1-6 The alkyl group is optionally further substituted with one or more substituents selected from halogen and deuterium;

[0079] R1 is or pyridyl, and R1 is optionally further substituted by 1 to 2 groups selected from D, halogen, cyano, hydroxyl, C 1-6 Alkyl and C 1-6 Substitution of alkoxy groups;

[0080] R 1a H or C 1-6 alkyl;

[0081] R 1b C substituted with H, OH, cyano or hydroxyl 1-6 alkyl;

[0082] m is 0 or 1;

[0083] x and y are each independently 1, 2 or 3.

[0084] Furthermore, in one or more embodiments of the present invention, in the compound of formula I above,

[0085] R0 is C 1-4 Alkyl, the C 1-4 The alkyl group is optionally further substituted with one or more substituents selected from halogen and deuterium;

[0086] R1 is

[0087] Furthermore, in one or more embodiments of the present invention, the compound of formula I is selected from:

[0088] The present invention also provides a pharmaceutical preparation of an imidazolinone compound. In one or more embodiments, 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 compound of formula I.

[0089] The present invention also provides an imidazolinone compound pharmaceutical preparation, which comprises an imidazolinone compound, its stereoisomers, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, wherein the imidazolinone compound is selected from any one or more compounds of formula I mentioned above, and the content of the imidazolinone compound in the pharmaceutical preparation is 1-90 parts by weight.

[0090] Further, in one or more embodiments of the present invention, the content of the imidazolinone compound in the pharmaceutical preparation is 1-5 parts, 5-10 parts, 10-15 parts, 15-20 parts, 20-25 parts, 25-30 parts, 30-35 parts, 35-40 parts, 40-45 parts, 45-50 parts, 50-55 parts, 55-60 parts, 60-65 parts, 65-70 parts, 70-75 parts, 75-80 parts, 80-85 parts or 85-90 parts; optionally further, the content of the imidazolinone compound in the pharmaceutical preparation is 27.8 parts or 41.7 parts.

[0091] The present invention also provides an imidazolinone compound pharmaceutical preparation, the dosage form of which is selected from but not limited to granules, tablets, capsules, pills or micropills.

[0092] The present invention also provides an imidazolinone compound pharmaceutical preparation, which further includes one or more of a diluent, a disintegrant and a glidant. In parts by weight, the content of the diluent in the pharmaceutical preparation is 10-85 parts; the content of the disintegrant is 3-70 parts; and the content of the glidant is 0.1-30 parts.

[0093] Furthermore, in one or more embodiments of the present invention, the pharmaceutical preparation may also contain a surfactant, a wetting agent, an antioxidant, and the like.

[0094] Further, in one or more embodiments of the present invention, the content of the diluent in the pharmaceutical preparation is 10-15 parts, 15-20 parts, 20-25 parts, 25-30 parts, 30-35 parts, 35-40 parts, 40-45 parts, 45-50 parts, 50-55 parts, 55-60 parts, 60-65 parts, 65-70 parts, 70-75 parts, 75-80 parts or 80-85 parts.

[0095] Further, in one or more embodiments of the present invention, the content of the disintegrant is 3-5 parts, 5-15 parts, 15-20 parts, 20-25 parts, 25-30 parts, 30-35 parts, 35-40 parts, 40-45 parts, 45-50 parts, 50-55 parts, 55-60 parts, 60-65 parts or 65-70 parts.

[0096] Furthermore, in one or more embodiments of the present invention, the content of the glidant is 0.1-0.5 parts, 0.5-1 parts, 1-5 parts, 5-10 parts, 10-15 parts, 15-20 parts, 20-25 parts or 25-30 parts.

[0097] Optionally, further, in one or more embodiments of the present invention, the content of the diluent in the pharmaceutical preparation is 64.1 parts, 66.7 parts or 50 parts; the content of the disintegrant is 7 parts, 4.4 parts or 6.7 parts; and the content of the glidant is 1.6 parts or 1.1 parts.

[0098] Furthermore, in one or more embodiments of the present invention, the diluent is selected from but not limited to one or more of sucrose, xylitol, maltitol, lactitol, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sorbitol, glucose, fructose, corn starch, inorganic salts, microcrystalline cellulose, starch, mannitol, lactose and pregelatinized starch, preferably one or more of microcrystalline cellulose, mannitol and pregelatinized starch.

[0099] Furthermore, in one or more embodiments of the present invention, the above-mentioned disintegrant is selected from but not limited to one or more of cross-linked polyvinyl pyrrolidone, sodium starch glycolate, carboxymethyl cellulose calcium, potato starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose.

[0100] Furthermore, in one or more embodiments of the present invention, the glidant is selected from but not limited to one or more of colloidal silicon dioxide, silicon dioxide, magnesium silicate, magnesium trisilicate, aggregated silicate, hydrated silicon dioxide, calcium phosphate and talc.

[0101] The present invention also provides a method for preparing an imidazolinone compound pharmaceutical preparation, which mainly comprises the following steps:

[0102] preparing a mixture of an imidazolinone compound, a disintegrant and a diluent;

[0103] The mixture is mixed with a glidant to prepare tablets, capsules or granules.

[0104] Furthermore, in one or more embodiments of the present invention, after the glidant is mixed with the mixture, the mixture is placed in a granulator for granulation, and then tablets, capsules or granules are prepared;

[0105] Or further, in one or more embodiments of the present invention,

[0106] The mixture contains 50-80 wt% of a prescribed amount of a diluent; the mixture is placed in a mixer for mixing, and then placed in a granulator for granulation to obtain mixture particles; a glidant and the remaining amount of the diluent in the prescribed amount are added to the mixture particles, and the mixture is placed in a mixer for mixing, thereby obtaining tablets, capsules or granules.

[0107] The present invention also provides use of an imidazolinone compound pharmaceutical preparation in preparing a drug for treating and / or preventing cancer.

[0108] In one or more embodiments of the present invention, an imidazolinone compound pharmaceutical preparation is used in the preparation of a drug for treating and / or preventing cancer, wherein the pharmaceutical preparation is administered to a subject; optionally, the pharmaceutical preparation is administered orally; optionally, the administration comprises 1-4 times / day.

[0109] The present invention also provides an imidazolinone compound pharmaceutical preparation, which comprises an imidazolinone compound, its stereoisomers, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, wherein the imidazolinone compound is selected from one or more compounds of formula I mentioned above, and the compound of formula I is present in an amount providing a daily dose of 1-1000 mg, and the daily dose is a single dose or multiple doses.

[0110] Further, in one or more embodiments of the present invention, the imidazolinone compound is present in an amount to provide a daily dose of 1-10 mg, 10-20 mg, 20-50 mg, 50-100 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.

[0111] In one or more embodiments of the present invention, a pharmaceutical preparation of an imidazolinone compound is provided, which comprises an imidazolinone compound, its stereoisomers, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, wherein the imidazolinone compound is selected from any one or more compounds of formula I mentioned above, and the compound of formula I is present in an amount providing a daily dose of 1-1000 mg / 60 kg.

[0112] The present invention also provides a method for preventing and / or treating cancer, comprising administering to a subject a therapeutically effective dose of any of the above-mentioned imidazolinone compound pharmaceutical preparations.

[0113] In one or more embodiments of the present invention, the pharmaceutical formulation comprises an imidazolinone compound, a stereoisomer, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a cocrystal thereof, wherein the imidazolinone compound is selected from any one or more compounds of formula I described above; further, the compound of formula I is present in an amount providing a daily dose of 1-1000; further, the compound of formula I is present in an amount providing a daily dose of 1-1000 mg / 60 kg.

[0114] Unless stated otherwise, the terms used in the specification and claims have the following meanings.

[0115] "Pharmaceutically acceptable salt" refers to salts that are safe, non-toxic, and neither biologically nor otherwise undesirable, and include salts thereof that are pharmaceutically acceptable for veterinary as well as human pharmaceutical use and possess the desired pharmacological activity.

[0116] "Prodrug" refers to a compound of the present invention that can be converted into a biologically active compound through metabolism in the body.

[0117] "Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, and conformational isomers.

[0118] "Optional" or "optionally" or "selectively" or "optionally" or "further" 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.

[0119] An "effective amount" refers to that amount of a compound that will elicit the physiological or medical translation in the tissue, system, or subject being treated, and includes an amount of the compound that, when administered to a subject, is sufficient to prevent or alleviate to some extent one or more symptoms of the disorder or condition being treated.

[0120] It is understood that the numerical values ​​described and claimed herein are approximate. Variations within the numerical values ​​may be due to equipment calibration, equipment error, purity of the material, crystal size, sample size, and other factors.

[0121] Various modifications and alterations to the present invention will become apparent to those skilled in the art from consideration of the specification and practice of the invention without departing from the scope and spirit of the invention. DETAILED DESCRIPTION

[0122] The following describes in detail the implementation process of the present invention and the beneficial effects produced by specific embodiments, which is intended to help readers better understand the essence and characteristics of the present invention and is not intended to limit the scope of implementation of this case.

[0123] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0124] The known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from companies such as Titan Technology, Anage Chemical, Shanghai Demer, Chengdu Cologne Chemical, Shaoyuan Chemical Technology, and Bailingwei Technology.

[0125] The compound of general formula (I) or its specific structure can be prepared by the method of patent WO2021209055, the entire text of which is incorporated into the present invention by reference.

[0126] The preparation method of the active pharmaceutical ingredient, compound 62, is as follows:

[0127] first step:

[0128] 2-Chloro-7-ethyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one (62a)

[0129] 2-chloro-7-ethyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one

[0130] 2-Chloro-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one 1D (400 mg, 1.57 mmol) was dissolved in N,N-dimethylformamide (8 mL). Cesium carbonate (511 mg, 1.57 mmol) and iodoethane (293 mg, 1.88 mmol) were added and stirred at 0°C for 1 hour. The reaction was monitored by TLC until completion. Subsequently, 10 mL of water was added and the mixture was extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, concentrated, and the organic solvent was removed by rotary evaporation to obtain the title compound, 2-chloro-7-ethyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one 62a (white solid, 290 mg, 65.32% yield).

[0131] 1 H NMR(400MHz,DMSO-d6)δ8.44(s,1H),4.50-4.41(m,1H),3.99-3.95(m,2H),3 .89(q,2H),3.45(t,2H),2.46-2.41(m,2H),1.71-1.67(m,2H),1.25(t,3H).

[0132] LC-MS m / z (ESI) = 283.10 [M+1].

[0133] Step 2:

[0134] 4-((7-ethyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino)-2-fluoro-5-methylbenzamide (Compound 62)

[0135] 4-((7-ethyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino)-2-fluoro-5-methylbenzamide

[0136] 2-Chloro-7-ethyl-9-(tetrahydro-2H-pyran-4-yl(-7,9-dihydro-8H-purin-8-one 62a) (150 mg, 0.53 mmol), 4-amino-2-fluoro-5-methylbenzamide intermediate 2 (350 mg, 2.12 mmol), cesium carbonate (690 mg, 2.12 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium(II) (72 mg, 0. The product was dissolved in 1,4-dioxane (5 mL) and purged with nitrogen. The mixture was stirred at 110°C for 4 hours. The reaction was monitored by TLC until completion. The concentrated reaction solution was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 20 / 1) and subjected to Pre-HPLC to obtain the title compound 4-((7-ethyl-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-yl)amino)-2-fluoro-5-methylbenzamide 62 (white solid, 38 mg, 17.28% yield).

[0137] 1 H NMR(400MHz,DMSO-d6)δ8.53(s,1H),8.25(s,1H),7.89(d,1H),7.55(d,1H),7.42(d,2H),4.48-4.40(m,1H ),3.98(dd,2H),3.85(q,2H),3.43(t,2H),2.58-2.54(m,2H),2.30(s,3H)1.71-1.68(m,2H),1.25(t,3H).

[0138] LC-MS m / z (ESI) = 415.20 [M+1].

[0139] Examples 1-4

[0140] Table 1

[0141] Preparation method:

[0142] 1) Weigh the prescribed amount of compound 62, microcrystalline cellulose (PH102, PH302), mannitol, pregelatinized starch, cross-linked sodium carboxymethyl cellulose, and colloidal silicon dioxide, and pass them through a 60-mesh sieve for later use;

[0143] 2) Weigh the prescribed amount of microcrystalline cellulose PH102 (or microcrystalline cellulose PH302, mannitol, and pregelatinized starch) and the prescribed amount of croscarmellose sodium, mix them in a stepwise manner, and pass through a 60-mesh sieve twice to obtain a mixture 1;

[0144] 3) Add the prescribed amount of compound 62 to mixture 1, pass through a 60-mesh sieve, and mix well to obtain mixture 2;

[0145] 4) Add the prescribed amount of colloidal silicon dioxide to mixture 2, sieve through a 60-mesh sieve, and mix well to obtain an intermediate powder;

[0146] 5) Take about 60 mg of the intermediate powder and pour it into empty gelatin capsules to obtain 25 mg capsules.

[0147] Examples 5-8

[0148] Table 2

[0149] Preparation method:

[0150] 1) Weigh the prescribed amount of compound 62, microcrystalline cellulose, croscarmellose sodium, crospovidone, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, and colloidal silicon dioxide, and pass them through a 60-mesh sieve respectively for later use;

[0151] 2) Weighing the prescribed amount of microcrystalline cellulose and the prescribed amount of croscarmellose sodium (or crospovidone, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose), respectively, mixing in a stepwise manner, and passing through a 60-mesh sieve twice to obtain a mixture 1;

[0152] 3) Add the prescribed amount of compound 62 to mixture 1, sieve through a 60-mesh sieve; add the prescribed amount of colloidal silicon dioxide, sieve through a 60-mesh sieve, and mix well to obtain mixture 2;

[0153] 4) Place the mixture 2 in a dry granulator and set the roller speed to 3.00-8.00 Hz, the granulation speed to 20.00-30.00 Hz, and the hydraulic pressure to 30-75 kg / cm 3 Granulation is performed to obtain intermediate granules;

[0154] 5) Take about 90 mg of the intermediate granules and pour them into empty gelatin capsules to obtain 25 mg capsules.

[0155] Examples 9 and 10

[0156] Table 3

[0157] Preparation method:

[0158] 1) Weigh the prescribed amount of compound 62, microcrystalline cellulose, croscarmellose sodium, and colloidal silicon dioxide, and pass them through a 60-mesh sieve for later use;

[0159] 2) Weigh the prescribed amount of compound 62, 80% of the prescribed amount of microcrystalline cellulose, and croscarmellose, and pass through a 60-mesh sieve twice to obtain a mixture 1;

[0160] 3) Place mixture 1 in a three-dimensional mixer, set the mixing frequency to 40±5 Hz, and mix for 20 minutes to obtain mixture 2;

[0161] 4) Place the mixture 2 in a dry granulator and set the roller speed to 3.00-8.00 Hz, the granulation speed to 20.00-30.00 Hz, and the hydraulic pressure to 30-75 kg / cm 3 Granulation is performed to obtain 2 granules of the mixture;

[0162] 5) Add approximately 20% of the prescribed amount of microcrystalline cellulose and colloidal silicon dioxide to mixture 3, set the mixing frequency to 40±5 Hz in a three-dimensional mixer, and mix for 20 minutes to obtain an intermediate;

[0163] 6) Example 9: About 90 mg of the intermediate granules were poured into empty gelatin capsules to obtain 25 mg capsules.

[0164] Example 10: About 360 mg of the intermediate granules were poured into empty gelatin capsules to obtain 100 mg capsules.

[0165] Dissolution test 1:

[0166] The samples of Example 1, Example 2, Example 3, and Example 4 were taken respectively, and the dissolution medium was added with 900 ml of pH 6.8 phosphate buffer solution according to the dissolution method (Chinese Pharmacopoeia 2020 Edition, Part 4, General Rules 0931, Method 2), and the speed was 75 revolutions per minute. The dissolution rate was measured at 10, 15, 20, 30, 45, 60, and 90 minutes. The results are shown in Table 4:

[0167] Table 4 Dissolution results

[0168] From the above dissolution results, it can be seen that the capsules prepared with different types of diluents according to the examples all have a dissolution rate greater than 80% in 20 minutes, and their dissolution behaviors are basically the same.

[0169] Dissolution test 2

[0170] The samples of Example 5, Example 6, Example 7, and Example 8 were taken respectively, and the dissolution medium was added with 900 ml of pH 6.8 phosphate buffer solution according to the dissolution method (Chinese Pharmacopoeia 2020 Edition, Part 4, General Rules 0931, Method 2), and the speed was 75 revolutions per minute. The dissolution rate was measured at 10, 15, 20, 30, 45, and 60 minutes. The results are shown in Table 5:

[0171] Table 5 Dissolution results

[0172] From the above dissolution results, it can be seen that the use of different types of disintegrants according to the examples has little effect on the dissolution behavior of the capsules, and the 30 min dissolution rates are all greater than 70%.

[0173] Dissolution test 3

[0174] The sample of Example 9 was taken and the dissolution method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Rules 0931, Method 2) was added with 900 ml of each of the following dissolution media: 1) pH 1.0 hydrochloric acid solution, 2) pH 4.5 acetate buffer, and 3) pH 6.8 phosphate buffer. The speed was 75 rpm, and the dissolution rate was measured at 15, 30, and 60 minutes, respectively. The results are shown in Table 6:

[0175] Table 6 Dissolution results

[0176] It can be seen from the above dissolution results that the sample of Example 9 has good dissolution under different pH environments.

[0177] Stability test investigation

[0178] According to the requirements of the 2015 edition of the Chinese Pharmacopoeia, Part IV, General Rules 9001, "Guidelines for Stability Testing of Pharmaceutical Ingredients and Preparations," the samples of Examples 9 and 10 were tested for influencing factors. The experimental results are shown in Tables 7 and 8. The experimental conditions are as follows:

[0179] Place the sample in an open, clean watch glass, and take samples for inspection after 10 days and 30 days respectively under the conditions of high temperature test (60±2℃), high humidity test (RH92.5%), and light test (4500±500Lx).

[0180] Table 7 Test results of factors affecting samples of Example 9

[0181] Table 8 Test results of factors affecting samples in Example 10

[0182] Conclusion: After investigation of influencing factors, the various indicators of the samples of Example 9 and Example 10 were not significantly different from those of the samples on day 0, and all were qualified, indicating that the quality of the compound 62 composition involved in the present invention is stable.

Claims

1. An imidazolinone compound pharmaceutical preparation, characterized in that: The pharmaceutical preparation comprises an imidazolinone compound, a stereoisomer, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a cocrystal thereof, wherein the pharmaceutical preparation comprises 1-1000 mg of the imidazolinone compound, and the imidazolinone compound is selected from the compound of formula I: in: for is a single bond or a double bond; A, B, C, and D are each independently C or N, and at least one of A, B, C, and D is N; R0 is H, C 1-6 Alkyl or cyclopropyl, the C 1-6 The alkyl group is optionally further substituted with one or more substituents selected from halogen and deuterium; R1 is or pyridyl, and R1 is optionally further substituted by 1 or 2 groups selected from D, halogen, cyano, hydroxyl, C 1-6 Alkyl and C 1-6 Substitution of alkoxy groups; R 1a H or C 1-6 alkyl; R 1b C substituted with H, OH, cyano or hydroxyl 1-6 alkyl; R2 is H, cyano, =O, carboxyl, -C(=O)NR 2a R 2b 、C 1-6 Alkoxy, C 1-6 Alkyl, halogen, -S(=O)2R 2a or -C(=O)OC 1-6 Alkyl; the C 1-6 Alkyl, -C(=O)OC 1-6 Alkyl or C 1-6 The alkoxy group is optionally substituted with one or more substituents selected from halogen and deuterium; R 2a and R 2b Each independently is H, C 1-6 alkyl or 3 to 5 membered cycloalkyl, wherein the C 1-6 The alkyl group is optionally further substituted by one or more groups selected from OH, D, halogen, C 1-6 Alkyl and C 1-6 Substitution of alkoxy groups; Or, R 2a and R 2b Together with the atoms to which it is attached, it forms a 5- to 6-membered heterocyclic group, wherein the 5- to 6-membered heterocyclic group contains 1, 2 or 3 heteroatoms selected from N, O and S, and the 5- to 6-membered heterocyclic group is optionally further substituted by 1 or more heteroatoms selected from C 1-6 Substitution of alkyl, OH and halogen substituents; R3 is halogen or C 1-6 Alkyl, the C 1-6 The alkyl group is optionally further substituted with 1 to 3 substituents selected from D and halogen; m is 0 or 1; n is 0, 1, or 2; x and y are each independently 1, 2, or 3; The condition is, when When R0, R2, and R3 meet the following conditions at the same time, R1 is not for n is 1, R0 is H or methyl, R2 is methoxy or -S(=O)2Me, and R3 is methyl.

2. The pharmaceutical preparation according to claim 1, characterized in that In the compound of formula I, R1 is R 1a H or C 1-6 alkyl; R2 is H, cyano, -C(=O)NR 2a R 2b 、C 1-6 Alkoxy, halogen, -S(=O)2R 2a or -C(=O)OC 1-6 Alkyl; said -C(=O)OC 1-6 Alkyl or C 1-6 The alkoxy group is optionally substituted with one or more substituents selected from halogen and deuterium; R 2a and R 2b Each independently is H, C 1-6 alkyl or 3 to 5 membered cycloalkyl, wherein the C 1-6 The alkyl group is optionally further substituted with one or more substituents selected from OH, D or halogen; Or, R 2a and R 2b Together with the atoms to which it is attached, it forms a 5- to 6-membered heterocyclic group, wherein the 5- to 6-membered heterocyclic group contains 1 to 3 heteroatoms selected from N, O and S, and the heterocyclic group is optionally further substituted with one or more substituents selected from OH and halogen; R3 is halogen or C 1-6 Alkyl, the C 1-6 The alkyl group is optionally further substituted with 1 to 3 substituents selected from D and halogen; m is 0 or 1; n is 0, 1 or 2.

3. The pharmaceutical preparation according to claim 1, characterized in that In the compound of formula I, for R0 is H, C 1-4 Alkyl or cyclopropyl, the C 1-4 The alkyl group is optionally further substituted with one or more substituents selected from halogen and D; R1 is R 1a H, C 1-6 Alkyl or -C(=O)C 1-6 alkyl; R2 is H, cyano, -C(=O)NR 2a R 2b 、C 1-6 Alkoxy, halogen, -S(=O)2R 2a or -C(=O)OC 1-6 Alkyl; the -C(=O)O alkyl or C 1-6 The alkoxy group is optionally substituted with one or more substituents selected from halogen and deuterium; R 2a and R 2b Each independently is H, C 1-6 alkyl or 3 to 5 membered cycloalkyl, wherein the C 1-6 The alkyl group is optionally further substituted with one or more substituents selected from OH, D and halogen; Or, R 2a and R 2b Together with the atoms to which it is attached, it forms a 5- to 6-membered heterocyclic group, wherein the 5- to 6-membered heterocyclic group contains 1 to 3 heteroatoms selected from N, O and S, and the 5- to 6-membered heterocyclic group is optionally further substituted with one or more substituents selected from OH and halogen; R3 is halogen or C 1-6 Alkyl, the C 1-6 The alkyl group is optionally further substituted with 1 to 3 substituents selected from D and halogen; m is 0 or 1; n is 0, 1 or 2.

4. The pharmaceutical preparation according to claim 1, characterized in that The compound of formula I is selected from: in: R0 is H, C 1-6 Alkyl or cyclopropyl, the C 1-6 The alkyl group is optionally further substituted with one or more substituents selected from halogen and deuterium; R1 is or pyridyl, and R1 is optionally further substituted by 1 to 2 groups selected from D, halogen, cyano, hydroxyl, C 1-6 Alkyl and C 1-6 Substitution of alkoxy groups; R 1a H or C 1-6 alkyl; R 1b C substituted with H, OH, cyano or hydroxyl 1-6 alkyl; R 2c is H, cyano, halogen or C 1-6 alkoxy; R 2d H, cyano, carboxyl, -C(=O)NR 2a R 2b 、C 1-6 Alkyl, halogen, -S(=O)2R 2a or -C(=O)OC 1- 6 alkyl; the C 1-6 Alkyl, -C(=O)OC 1-6 The alkyl group is optionally substituted with one or more substituents selected from halogen and deuterium; R 2a 、R 2b H, C 1-6 alkyl or 3 to 5 membered cycloalkyl, wherein the C 1-6 The alkyl group is optionally further substituted by one or more groups selected from OH, D, halogen, C 1-6 Alkyl and C 1-6 Substitution of alkoxy groups; Or, R 2a and R 2b Together with the atoms to which it is attached, it forms a 5- to 6-membered heterocyclic group, wherein the 5- to 6-membered heterocyclic group contains 1 to 3 heteroatoms selected from N, O and S, and the 5- to 6-membered heterocyclic group is optionally further substituted by one or more heteroatoms selected from C 1-6 Substitution of alkyl, OH and halogen substituents; R3 is halogen or C 1-6 Alkyl, the C 1-6 The alkyl group is optionally further substituted with 1 to 3 substituents selected from D and halogen; m is 0 or 1; n is 0, 1, or 2; x and y are each independently 1, 2 or 3.

5. The pharmaceutical preparation according to claim 1, characterized in that The compound of formula I is selected from: in, R0 is H, C 1-6 Alkyl or cyclopropyl, the C 1-6 The alkyl group is optionally further substituted with one or more substituents selected from halogen and deuterium; R1 is or pyridyl, and R1 is optionally further substituted by 1 to 2 groups selected from D, halogen, cyano, hydroxyl, C 1-6 Alkyl and C 1-6 Substitution of alkoxy groups; R 1b C substituted with H, OH, cyano or hydroxyl 1-6 alkyl; R 2a and R 2b Each independently is H, C 1-6 alkyl or 3 to 5 membered cycloalkyl, wherein the C 1-6 The alkyl group is optionally further substituted with one or more substituents selected from D or halogen; Or, R 2a and R 2b Together with the atoms to which it is attached, it forms a 5- to 6-membered heterocyclic group, wherein the 5- to 6-membered heterocyclic group contains 1 to 3 heteroatoms selected from N, O and S, and the 5- to 6-membered heterocyclic group is optionally further substituted by one or more heteroatoms selected from C 1-6 Substitution of alkyl, OH and halogen substituents; R 2c is H, cyano, halogen or C 1-6 Alkoxy, the C 1-6 The alkoxy group is optionally substituted with one or more deuterium groups; R3 is halogen or C 1-6 Alkyl, the C 1-6 The alkyl group is optionally further substituted with 1 to 3 substituents selected from D and halogen; m is 0 or 1; n is 0, 1, or 2; x and y are each independently 1, 2 or 3.

6. The pharmaceutical preparation according to claim 1, characterized in that The compound of formula I is selected from: in: R0 is H, C 1-6 Alkyl or cyclopropyl, the C 1-6 The alkyl group is optionally further substituted with one or more substituents selected from halogen and deuterium; R1 is -(CH) m -4 to 7 membered carbocyclic group, -(CH) m -4 to 7 membered heterocyclic group, -(CH) m -8 to 12-membered bridged ring, -(CH) m -7 to 12 membered spiro ring, said -(CH) m -4 to 7 membered carbocyclic group, -(CH) m -4 to 7 membered heterocyclic group, -(CH) m -8 to 12-membered bridged ring or -(CH) m -7 to 12 membered spiro ring is optionally further substituted by one or more groups selected from hydroxy, cyano, halogen, =O, C 1-6 Alkyl, C 1-6 Alkoxy and hydroxy substituted C 1-6 Substitution of alkyl groups; m is 0 or 1.

7. The pharmaceutical preparation according to claim 6, characterized in that In the compound of formula I, R0 is H, C 1-6 Alkyl or cyclopropyl, the C 1-6 The alkyl group is optionally further substituted with one or more substituents selected from halogen and deuterium; R1 is or pyridyl, and R1 is optionally further substituted by 1 to 2 groups selected from D, halogen, cyano, hydroxyl, C 1-6 Alkyl and C 1-6 Substitution of alkoxy groups; R 1a H or C 1-6 alkyl; R 1b C substituted with H, OH, cyano or hydroxyl 1-6 alkyl; m is 0 or 1; x and y are each independently 1, 2 or 3.

8. The pharmaceutical preparation according to claim 7, characterized in that In the compound of formula I, R0 is C 1-4 Alkyl, the C 1-4 The alkyl group is optionally further substituted with one or more substituents selected from halogen and deuterium; R1 is 9. The pharmaceutical preparation according to claim 1, characterized in that The compound of formula I is selected from:

10. The pharmaceutical preparation according to any one of claims 1 to 9, 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 the compound of formula I.

11. An imidazolinone compound pharmaceutical preparation, characterized in that: The pharmaceutical preparation comprises an imidazolinone compound, a stereoisomer, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a cocrystal thereof, wherein the imidazolinone compound is selected from the compound of formula I according to any one of claims 1 to 9, and the content of the imidazolinone compound in the pharmaceutical preparation is 1-90 parts by weight.

12. The pharmaceutical preparation according to claim 11, characterized in that The content of the imidazolinone compound in the pharmaceutical preparation is 1-5 parts, 5-10 parts, 10-15 parts, 15-20 parts, 20-25 parts, 25-30 parts, 30-35 parts, 35-40 parts, 40-45 parts, 45-50 parts, 50-55 parts, 55-60 parts, 60-65 parts, 65-70 parts, 70-75 parts, 75-80 parts, 80-85 parts or 85-90 parts; optionally, further, the content of the imidazolinone compound in the pharmaceutical preparation is 27.8 parts or 41.7 parts.

13. The pharmaceutical preparation according to claim 11, characterized in that The dosage form of the pharmaceutical preparation is selected from granules, tablets, capsules, pills or micropills.

14. The pharmaceutical preparation according to claim 11, characterized in that The pharmaceutical preparation further comprises one or more of a diluent, a disintegrant and a glidant. Calculated by weight, the content of the diluent in the pharmaceutical preparation is 10-85 parts; the content of the disintegrant is 3-70 parts; and the content of the glidant is 0.1-30 parts.

15. The pharmaceutical preparation according to claim 14, characterized in that The content of the diluent in the pharmaceutical preparation is 10-15 parts, 15-20 parts, 20-25 parts, 25-30 parts, 30-35 parts, 35-40 parts, 40-45 parts, 45-50 parts, 50-55 parts, 55-60 parts, 60-65 parts, 65-70 parts, 70-75 parts, 75-80 parts or 80-85 parts; the content of the disintegrant is 3-5 parts, 5-15 parts, 1 5-20 parts, 20-25 parts, 25-30 parts, 30-35 parts, 35-40 parts, 40-45 parts, 45-50 parts, 50-55 parts, 55-60 parts, 60-65 parts or 65-70 parts; the content of the glidant is 0.1-0.5 parts, 0.5-1 parts, 1-5 parts, 5-10 parts, 10-15 parts, 15-20 parts, 20-25 parts or 25-30 parts; Optionally, further, the content of the diluent in the pharmaceutical preparation is 64.1 parts, 66.7 parts or 50 parts; the content of the disintegrant is 7 parts, 4.4 parts or 6.7 parts; and the content of the glidant is 1.6 parts or 1.1 parts.

16. The pharmaceutical preparation according to claim 14, characterized in that The diluent is selected from one or more of sucrose, xylitol, maltitol, lactitol, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sorbitol, glucose, fructose, corn starch, inorganic salts, microcrystalline cellulose, starch, mannitol, lactose and pregelatinized starch, preferably one or more of microcrystalline cellulose, mannitol and pregelatinized starch; The disintegrant is selected from cross-linked polyvinyl pyrrolidone, sodium starch glycolate, carboxymethyl cellulose calcium, potato starch, One or more of microcrystalline cellulose, low-substituted hydroxypropyl cellulose, croscarmellose sodium, crospovidone, sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose; The glidant is selected from one or more of colloidal silicon dioxide, silicon dioxide, magnesium silicate, magnesium trisilicate, aggregated silicate, hydrated silicon dioxide, calcium phosphate and talc.

17. A method for preparing the imidazolinone compound pharmaceutical preparation according to any one of claims 1 to 16, characterized in that: The following steps are involved: preparing a mixture of an imidazolinone compound, a disintegrant and a diluent; The mixture is mixed with a glidant to prepare tablets, capsules or granules.

18. The preparation method according to claim 17, characterized in that After the glidant is mixed with the mixture, the mixture is placed in a granulator for granulation, and then tablets, capsules or granules are prepared; or The mixture contains 50-80 wt% of a prescribed amount of a diluent; the mixture is placed in a mixer for mixing, and then placed in a granulator for granulation to obtain mixture particles; a glidant and the remaining amount of the diluent in the prescribed amount are added to the mixture particles, and the mixture is placed in a mixer for mixing, thereby obtaining tablets, capsules or granules.

19. Use of the imidazolinone compound pharmaceutical preparation according to any one of claims 1 to 16 in the preparation of a medicament for treating and / or preventing cancer.

20. Use of a pharmaceutical preparation in preparing a medicament for treating and / or preventing cancer, wherein the pharmaceutical preparation according to any one of claims 1 to 16 is administered to a subject; optionally, the pharmaceutical preparation is administered orally; optionally, the pharmaceutical preparation is administered 1 to 4 times per day.

21. An imidazolinone compound pharmaceutical preparation, characterized in that: The invention relates to an imidazolinone compound, a stereoisomer, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a cocrystal thereof, wherein the imidazolinone compound is selected from the compound of formula I according to any one of claims 1 to 9, and the compound of formula I is present in an amount providing a daily dose of 1 to 1000 mg, and the daily dose is a single dose or multiple doses.

22. The pharmaceutical preparation according to claim 21, characterized in that The imidazolinone compound is present in an amount to provide a daily dosage of 1-10 mg, 10-20 mg, 20-50 mg, 50-100 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.

23. An imidazolinone compound pharmaceutical preparation, characterized in that: Comprising an imidazolinone compound, a stereoisomer, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a cocrystal thereof, wherein the imidazolinone compound is selected from the compound of formula I according to any one of claims 1 to 9, and the compound of formula I is present in an amount providing a daily dose of 1-1000 mg / 60 kg.

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