Pharmaceutical composition using heterocyclic compound as active ingredient, preparation method therefor, and use thereof

Abstract

The present invention relates to a pharmaceutical composition using a heterocyclic compound as an active ingredient, a preparation method therefor, and use thereof. The preparation process of the pharmaceutical composition is simple and stable, the API content and mixing uniformity of intermediate materials are good, and the resulting finished formulation product dissolves quickly, has stable quality, and is suitable for industrial scale-up production.

Description

Pharmaceutical compositions with heterocyclic compounds as active ingredients, their preparation methods and uses

[0001] Cross-references

[0002] This application is based on and claims priority to CN application number 202410951169.9, filed on July 16, 2024, the disclosure of which is incorporated herein by reference in its entirety. Technical Field

[0003] This application relates to pharmaceutical compositions with heterocyclic compounds as active ingredients, methods for their preparation, and uses. Background Technology

[0004] RET is a well-known proto-oncogene, identifiable in various cancer cells, such as non-small cell lung cancer, papillary thyroid carcinoma, medullary thyroid carcinoma, colon cancer, and other solid tumors. A translocation or inversion of the receptor tyrosine kinase RET on chromosome 10 triggers gene rearrangement, resulting in a RET fusion gene that encodes a transmembrane tyrosine kinase (RTK), which acts as a receptor for extracellular signaling molecules belonging to the glial cell-derived neurotrophic factor (GDNF) family. Under RET kinase activation, GDNF family ligands (GFLs) bind to their receptor protein GDNF receptor-α, accumulating different RET molecules through trans-autophosphorylation dimerization. This enhances RET oncogenic signal transduction by controlling RET proteins on the cell membrane to evade regulatory mechanisms, activating multiple downstream signaling pathways involved in cell growth and proliferation. Oncogenic mutations in the RET gene include point mutations, gene fusions, rearrangements, and copy number changes. In thyroid cancer, RET somatic mutations are common, while in lung adenocarcinoma, RET fusions are common. In breast cancer, RET copy number changes, point mutations, and rearrangements are all present. Therefore, inhibiting abnormally activated RET proteins can achieve anti-tumor effects.

[0005] Small molecule drugs with RET inhibitory activity can specifically target fused / mutated RET proto-oncogenes. By blocking abnormally activated RET fusion and mutant proteins, and inhibiting the phosphorylation of RET proteins and downstream proteins in the signaling pathway, they disrupt signal transduction and inhibit tumor cell proliferation and invasion, thereby exerting anti-tumor effects. Therefore, these compounds have significant medical value.

[0006] Therefore, there is an urgent clinical need for a pharmaceutical composition with RET inhibitor compounds as the active ingredient, which has the advantages of excellent dissolution, stable quality, simple preparation process, and is conducive to industrial-scale production. Summary of the Invention

[0007] One object of this application is to provide an oral pharmaceutical composition comprising an active ingredient and at least one pharmaceutically acceptable carrier, wherein the active ingredient is a compound of formula A, a pharmaceutically acceptable salt thereof, a stereoisomer, a polymorph thereof, a solvate, a metabolite, or a prodrug.

[0008] in:

[0009] R 1 Selected from -C(O)-C 1-6 Alkyl, 4-10-membered heterocyclic and 5-10-membered heteroaryl, wherein each of the 4-10-membered heterocyclic and 5-10-membered heteroaryl groups is optionally substituted by one or more substituents independently selected from the following: hydroxyl, halogen, CN, NO2, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Heteroalkyl, C 3-6 cycloalkyl and C 3-6 Cycloalkoxy;

[0010] R 2 Selected from H, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, 4-10 membered heterocyclic and 5-10 membered heteroaryl, wherein C 1-6 Alkyl, C 1-6 The heteroalkyl, 4-10 membered heterocyclic and 5-10 membered heteroaryl groups are each optionally substituted by one or more substituents independently selected from the following: hydroxyl, halogen, CN, NO2, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Heteroalkyl, C 3-6 cycloalkyl and C 3-6 Cycloalkoxy;

[0011] R 3 Selected from H, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Heteroalkyl and C 3-6 cycloalkyl;

[0012] R 4 Selected from C1-6 Alkyl and C 1-6 Alkoxy;

[0013] X 1 X 2 and X 3 Each was independently selected from S and CR 5 and N, where R 5 Selected from H, halogens and C 1-6 alkyl;

[0014] X 4 Selected from C and N;

[0015] X 5 Selected from CH and N, or X 5 It does not exist;

[0016] X 6 Selected from CH and N; and

[0017] n is 0 or 1;

[0018] The pharmaceutically acceptable carrier is one or more of the following: filler, disintegrant, glidant, and lubricant.

[0019] In some embodiments, this application provides an oral pharmaceutical composition comprising an active ingredient and at least one pharmaceutically acceptable carrier, wherein the active ingredient is a compound of formula I, a pharmaceutically acceptable salt thereof, a stereoisomer, a polymorph, a solvate, a metabolite, or a prodrug.

[0020] in:

[0021] R 1 Selected from 4-10 membered heterocyclic groups and 5-10 membered heteroaryl groups, wherein each heterocyclic group and heteroaryl group is optionally substituted by one or more substituents independently selected from the following: hydroxyl, halogen, CN, NO2, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Heteroalkyl, C 3-6 cycloalkyl and C 3-6 Cycloalkoxy;

[0022] R 2 Selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, 4-10-membered heterocyclic and 5-10-membered heteroaryl groups, wherein each of the alkyl, heteroalkyl, heterocyclic and heteroaryl groups is optionally substituted by one or more substituents independently selected from the following: hydroxyl, halogen, CN, NO2, C.1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Heteroalkyl, C 3-6 cycloalkyl and C 3-6 Cycloalkoxy;

[0023] R 3 Selected from H, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Heteroalkyl and C 3-6 cycloalkyl; and

[0024] X 1 X 2 and X 3 Each is independently selected from CH and N;

[0025] The pharmaceutically acceptable carrier is one or more of the following: filler, disintegrant, glidant, and lubricant.

[0026] In some embodiments, this application provides a method for preparing the pharmaceutical composition.

[0027] The method includes:

[0028] i) The active ingredient is pulverized to a particle size range as follows:

[0029] D v (90) ranges from 1 to 500 μm;

[0030] D v (50) ranges from 1 to 100 μm;

[0031] D v (10) is 0.1–10 μm;

[0032] D[4,3] is 1–50 μm; and / or

[0033] D[3,2] is 1–5 μm; and

[0034] ii) Mix the active ingredient with one or more of the carriers, sieve, and then mix with the remaining carriers.

[0035] In some embodiments, this application provides a method for preparing an oral pharmaceutical composition comprising an active ingredient and at least one pharmaceutically acceptable carrier, further comprising:

[0036] iii) Fill capsules or compress tablets.

[0037] Another object of this application is to provide a pharmaceutical composition comprising an active ingredient and at least one pharmaceutically acceptable carrier, wherein the active ingredient is a compound of formula I as shown above, a pharmaceutically acceptable salt thereof, a stereoisomer, a polymorph, a solvate, a metabolite, or a prodrug, wherein the dissolution rate of the pharmaceutical composition is such that at least 80% by weight of the active ingredient dissolves within 30 minutes; preferably, at least 88% by weight of the active ingredient dissolves within 45 minutes, and at least 93% by weight of the active ingredient dissolves within 60 minutes.

[0038] In some embodiments, this application provides a pharmaceutical composition in the form of capsules or tablets.

[0039] In some embodiments, this application provides a pharmaceutical composition prepared by the method of this application.

[0040] In some embodiments, this application provides a pharmaceutical formulation comprising the pharmaceutical composition described in this application and packaging.

[0041] Another object of this application is to provide the use of the pharmaceutical composition or pharmaceutical preparation of this application in the preparation of a medicament for treating RET-related diseases. The RET-related diseases are preferably selected from tumors.

[0042] Another object of this application is to provide a method for treating RET-related diseases, which includes administering the pharmaceutical composition or pharmaceutical preparation of this application to an individual in need of such treatment.

[0043] Another object of this application is to provide a pharmaceutical composition or pharmaceutical preparation thereof for the treatment of RET-related diseases.

[0044] Invention Details

[0045] definition

[0046] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art. References to technical terms herein refer to techniques commonly understood in the art, including variations or equivalent substitutions of techniques that are obvious to one of ordinary skill in the art. While it is believed that the following terms will be well understood by one of ordinary skill in the art, the following definitions are set forth to better explain this application.

[0047] The terms “including,” “comprising,” “having,” “containing,” or “involving,” and their other variations herein, are inclusive or open-ended and do not exclude other unlisted elements or method steps.

[0048] As used herein, the term "alkyl" is defined as including saturated aliphatic hydrocarbons, which include both straight-chain and branched chains. In some embodiments, the alkyl group has 1 to 6, for example, 1 to 4 carbon atoms. For example, as used herein, the term "C 1-6 "Alkyl" refers to a linear or branched group with 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, or n-hexyl), optionally substituted with one or more (e.g., 1 to 3) suitable substituents such as halogens (e.g., CF3, C2F5, CHF2, CH2F, CH2CF3, CH2Cl, or -CH2CH2CF3, etc.). The term "C 1-4 "Alkyl" refers to a linear or branched aliphatic hydrocarbon chain with 1 to 4 carbon atoms (i.e., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl).

[0049] As used herein, the term “halogenated alkyl” is defined as an alkyl group substituted with a halogen as defined above.

[0050] As used herein, the term “hydroxyalkyl” is defined as an “alkyl” as defined above that is substituted with a hydroxyl group.

[0051] As used herein, the term "heteroalkyl" refers to a straight-chain or branched saturated hydrocarbon group in which one or more carbon atoms are independently substituted by one or more heteroatoms (e.g., nitrogen, oxygen, phosphorus, and / or sulfur atoms). Heteroalkyl groups can be unsubstituted or substituted. Unless otherwise specified, heteroalkyl groups can be attached at any suitable atom, and if substituted, can be substituted at any suitable atom. Examples of heteroalkyl groups include, but are not limited to, ethers, thioethers, primary amines, secondary amines, tertiary amines, etc.

[0052] As used herein, the term "alkoxy" refers to a linear, branched, or cyclic saturated monovalent hydrocarbon group of the formula -O-alkyl, wherein the term "alkyl" is as defined above or as "cycloalkyl" as defined below, such as methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, cyclobutoxy, pentoxy, isopentoxy, or n-hexyloxy, or their isomers.

[0053] As used herein, the term “haloalkoxy” is defined as an alkoxy group substituted with a halogen as defined above.

[0054] As used herein, the term "cycloalkyl" refers to a saturated or unsaturated nonaromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclic, including spirocyclic, fused or bridged systems (such as bicyclic [1.1.1]pentyl, bicyclic [2.2.1]heptyl, bicyclic [3.2.1]octyl or bicyclic [5.2.0]nonyl, decahydronaphthyl, etc.), optionally substituted with one or more (such as one to three) suitable substituents. The cycloalkyl group has 3 to 15 carbon atoms. For example, the term "C 3-6 "Cycloalkyl" refers to a saturated or unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or bicyclic [1.1.1]pentyl) of 3 to 6 cyclic carbon atoms, which is optionally substituted with one or more (such as 1 to 3) suitable substituents, such as methyl-substituted cyclopropyl.

[0055] As used herein, the term "cycloalkoxy" refers to the formula -O-cycloalkyl, wherein the term "cycloalkyl" is as defined above. 3-6 Cycloalkoxy refers to cycloalkoxy groups having 3-6 carbon atoms, such as cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy.

[0056] As used herein, the term "heterocyclic group" refers to a saturated or unsaturated monovalent monocyclic or bicyclic group having 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms in the ring and one or more (e.g., one, two, three, or four) atoms selected from C(=O), O, S, S(=O), S(=O)2, and NR. a Groups containing heteroatoms, wherein R a Represents a hydrogen atom or C 1-6 Alkyl or halogenated -C 1-6 Alkyl group; the heterocyclic alkyl group may be attached to the remainder of the molecule by any one of the carbon atoms or a nitrogen atom (if present). In particular, the 4-10 membered heterocyclic group is a group having 4-10 carbon atoms and heteroatoms in the ring, such as, but not limited to, ethylene oxide, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, dioxolinyl, pyrrolyl, pyrrolidone, imidazoalkyl, pyrazolyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl.

[0057] As used herein, the term "aryl" refers to a fully carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated π-electron system. For example, as used herein, the term "C 6-14"Aryl" refers to an aromatic group containing 6 to 14 carbon atoms, such as phenyl or naphthyl. The aryl group may optionally be substituted by one or more (such as one to three) suitable substituents.

[0058] As used herein, the term "heteroaryl" refers to a monovalent monocyclic, bicyclic, or tricyclic aromatic ring system having 5, 6, 8, 9, 10, 11, 12, 13, or 14 ring atoms, particularly 1, 2, 3, 4, 5, 6, 9, or 10 carbon atoms, and containing at least one heteroatom that may be the same or different (the heteroatom being, for example, oxygen, nitrogen, or sulfur), and additionally, in each case, may be benzofused. Specifically, the heteroaryl group is selected from thienyl, furanyl, pyrroleyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiazolyl, etc., and their benzo[derivatives]; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and their benzo[derivatives].

[0059] The term "aralkyl" preferably refers to an aryl-substituted alkyl group, wherein the aryl group and the alkyl group are as defined herein. Typically, the aryl group may have 6-14 carbon atoms, and the alkyl group may have 1-6 carbon atoms. Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, and phenylbutyl.

[0060] As used herein, the term “halogenated” or “halogenated” is defined as including F, Cl, Br, or I.

[0061] The term "substituted" refers to the selective replacement of one or more (e.g., one, two, three, or four) hydrogen atoms on a specified atom by a designated group, provided that the substitution does not exceed the normal valence of the specified atom in the present case and that the substitution forms a stable compound. Combinations of substituents and / or variables are permitted only if such combinations form a stable compound.

[0062] The term "optional substitution" refers to the optional substitution by a specific group, radical, or part thereof.

[0063] When the bond of a substituent is such that it passes through the ring and connects two atoms, then such a substituent can be bonded to any cyclic atom in the substituted ring.

[0064] The compounds of this application may also contain one or more (e.g., one, two, three, or four) isotopic substitutions. For example, in said compounds, H may be any isotopic form, including... 1 H, 2 H (D or deuterium) and 3 H (T or tritium); C can be any isotopic form, including 12 C 13 C and 14C and O can be any isotopic form, including 16 O and 18 O etc.

[0065] The term "stereoisomer" refers to an isomer formed due to at least one asymmetric center. In compounds having one or more (e.g., one, two, three, or four) asymmetric centers, racemic mixtures, single enantiomers, mixtures of diastereomers, and individual diastereomers can be produced. Specific individual molecules may also exist as geometric isomers (cis / trans). Similarly, the compounds of this application can exist as mixtures of two or more structurally different forms in rapid equilibrium (commonly referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. It is to be understood that the scope of this application covers all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0066] This application covers all possible crystalline forms or polymorphs of the compounds of this application, which may be a single polymorph or a mixture of more than one polymorph in any proportion.

[0067] It should also be understood that certain compounds of this application may exist in a free form for therapeutic purposes, or, where appropriate, in the form of their pharmaceutically acceptable derivatives. According to this application, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, solvates, metabolites, or prodrugs, which, upon administration to a patient in need, can directly or indirectly provide the compound of this application or its metabolites or residues.

[0068] Pharmaceutically acceptable salts of the compounds in this application include their acid addition salts and base addition salts.

[0069] Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include fumarates, aspartates, bicarbonates / carbonates, bisulfates, borates, camphor sulfonates, citrates, cyclohexanesulfonates, ethanedisulfonates, ethanesulfonates, fumarates, glucohepanoates, glucuronates, hexafluorophosphates, hydroiodates / iodides, hydroxyethyl sulfonates, lactates, methyl sulfates, naphthylcarbamates, 2-naphthalenesulfonates, nicotinates, nitrates, orotates, oxalates, palmitates, dihydroxynaphthyl salts, phosphates / hydrogen phosphates / dihydrogen phosphates, pyroglutamates, glycosides, stearates, tannates, and xinofoate.

[0070] Suitable base addition salts are formed from bases that form non-toxic salts. Examples include aluminum salts, arginine salts, benzathine penicillin salts, calcium salts, choline salts, diethylamine salts, diethanolamine salts, glycine salts, lysine salts, magnesium salts, meglumine salts, ethanolamine salts, potassium salts, sodium salts, tromethamine salts, and zinc salts.

[0071] For a review of suitable salts, see Stahl and Wermuth's "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts for the compounds of this application are known to those skilled in the art.

[0072] The compounds of this application may exist in the form of hydrates or solvates, wherein the compounds of this application contain a polar solvent, particularly such as water, methanol, or ethanol, as a structural element of the compound's crystal lattice. The amount of the polar solvent, particularly water, may be present in stoichiometric or non-stoichiometric proportions.

[0073] The scope of this application also includes metabolites of the compounds of this application, i.e. compounds formed in the body when the drug is administered.

[0074] The prodrug of this application can be generated, for example, by replacing the appropriate functional groups present in the compound of formula I with certain groups known to those skilled in the art (e.g., “pro-moieties” as described in H. Bundgaard’s Design of Prodrugs (Elsevier, 1985)).

[0075] As used herein, the term “content uniformity” refers to the degree to which the content of each tablet (unit) of a small-dose or single-dose solid dosage form, semi-solid dosage form, and heterogeneous liquid dosage form conforms to the labeled weight.

[0076] As used in this article, the term "particle size" refers to the size of the particles, where D... v (50) represents the median particle size of the distribution, where 50% of the particles are smaller than the stated size and 50% of the particles are larger than the stated size. D v (10) represents the particle size that is 10% smaller than the stated size among all particles. Similarly, D v (90) represents the particle size that is 90% smaller than the stated size. D[4,3] refers to the volume-weighted average particle size. D[3,2] refers to the surface area-weighted average particle size.

[0077] As used herein, the term "grinding" refers to the process of breaking large solid materials into smaller, more manageable sizes using mechanical force or airflow. This includes dry grinding, wet grinding, cryogenic grinding, and ultrafine grinding. Grinding equipment includes mortars, universal grinders, ball mills, and air jet mills.

[0078] As used herein, the term "sieving" refers to the process of sieving pulverized particles or powders to meet the requirements of formulation preparation, while also serving a mixing function to ensure component homogeneity. Sieving equipment includes shaking screens, vibrating screens, rotary screens, and drum screens.

[0079] As used herein, the term "gradient mixing" refers to mixing an active ingredient with a certain amount of excipients (a single excipient or a premixture of multiple excipients) to obtain a first mixture, and then adding excipients (a single excipient or a premixture of multiple excipients) in a certain weight ratio (e.g., 4 times, 5 times, 6 times, etc.) to the first mixture and mixing to obtain a second mixture, and continuing to add excipients in the same manner until all excipients are added.

[0080] As used herein, the term "unit dose" refers to the smallest packaged unit of the pharmaceutical composition, such as a tablet or capsule, or other independently formed smallest unit. For example, a unit dose of the pharmaceutical composition of this application containing 0.1-100 mg of the active ingredient means that the smallest packaged unit of the pharmaceutical composition of this application (e.g., one capsule) contains 0.1-100 mg of the active ingredient.

[0081] Pharmaceutical Composition

[0082] According to one aspect of this application, an oral pharmaceutical composition comprising an active ingredient and at least one pharmaceutically acceptable carrier is provided. The oral pharmaceutical composition exhibits excellent dissolution and stability, and its preparation process is stable and simple, with all indicators meeting the requirements of the Chinese Pharmacopoeia, thus satisfying the needs of clinical and commercial use.

[0083] <Active Ingredients>

[0084] The active ingredient contained in the pharmaceutical composition of this application is a compound represented by Formula A, its pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, metabolite, or prodrug.

[0085] in:

[0086] R 1 Selected from -C(O)-C 1-6 Alkyl, 4-10-membered heterocyclic and 5-10-membered heteroaryl, wherein each of the 4-10-membered heterocyclic and 5-10-membered heteroaryl groups is optionally substituted by one or more substituents independently selected from the following: hydroxyl, halogen, CN, NO2, C. 1-4Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Heteroalkyl, C 3-6 cycloalkyl and C 3-6 Cycloalkoxy;

[0087] R 2 Selected from H, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, 4-10 membered heterocyclic and 5-10 membered heteroaryl, wherein C 1-6 Alkyl, C 1-6 The heteroalkyl, 4-10 membered heterocyclic and 5-10 membered heteroaryl groups are each optionally substituted by one or more substituents independently selected from the following: hydroxyl, halogen, CN, NO2, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Heteroalkyl, C 3-6 cycloalkyl and C 3-6 Cycloalkoxy;

[0088] R 3 Selected from H, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Heteroalkyl and C 3-6 cycloalkyl;

[0089] R 4 Selected from C 1-6 Alkyl and C 1-6 Alkoxy;

[0090] X 1 X 2 and X 3 Each was independently selected from S and CR 5 and N, where R 5 Selected from H, halogens and C 1-6 alkyl;

[0091] X 4 Selected from C and N;

[0092] X 5 Selected from CH and N, or X 5 It does not exist;

[0093] X 6 Selected from CH and N; and

[0094] n is 0 or 1.

[0095] According to a partial embodiment of this application, in formula A, X 1 X 2 and X 3 Each independently selected from CR 5 and N, where R 5 Selected from H, halogens and C 1-6 alkyl;

[0096] According to some embodiments of this application, the active ingredient contained in the pharmaceutical composition of this application is a compound of formula I, a pharmaceutically acceptable salt thereof, a stereoisomer, a polymorph, a solvate, a metabolite, or a prodrug.

[0097] in:

[0098] R 1 Selected from 4-10 membered heterocyclic groups and 5-10 membered heteroaryl groups, wherein each heterocyclic group and heteroaryl group is optionally substituted by one or more substituents independently selected from the following: hydroxyl, halogen, CN, NO2, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Heteroalkyl, C 3-6 cycloalkyl and C 3-6 Cycloalkoxy;

[0099] R 2 Selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, 4-10-membered heterocyclic and 5-10-membered heteroaryl groups, wherein each of the alkyl, heteroalkyl, heterocyclic and heteroaryl groups is optionally substituted by one or more substituents independently selected from the following: hydroxyl, halogen, CN, NO2, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Heteroalkyl, C 3-6 cycloalkyl and C 3-6 Cycloalkoxy;

[0100] R 3 Selected from H, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4Heteroalkyl and C 3-6 cycloalkyl; and

[0101] X 1 X 2 and X 3 Each is independently selected from CH and N.

[0102] The pharmaceutically acceptable carrier is one or more of the following: filler, disintegrant, glidant, and lubricant.

[0103] According to a partial implementation scheme of this application, R 1 Selected from 5-10 quinone heteroaryl groups, wherein the heteroaryl group is optionally surrounded by one or more C groups. 1-4 Alkyl substitution.

[0104] According to a partial implementation scheme of this application, R 2 Selected from 5-10 aryl groups, wherein the aryl group is optionally substituted with one or more halogens.

[0105] According to a partial implementation scheme of this application, R 3 Selected from H.

[0106] According to a partial implementation scheme of this application, X 1 Selected from N.

[0107] According to a partial implementation scheme of this application, X 2 Selected from CH.

[0108] According to a partial implementation scheme of this application, X 3 Selected from N.

[0109] According to a partial implementation scheme of this application, R 1 Selected from 5-membered nitrogen-containing heteroaryl groups, wherein the heteroaryl group is optionally surrounded by one or more C groups. 1-4 Alkyl substitution;

[0110] R 2 Selected from 5-membered nitrogen-containing heteroaryl groups, wherein the heteroaryl group is optionally substituted with one or more halogens;

[0111] R 3 Selected from H;

[0112] X 1 Selected from N;

[0113] X 2 Selected from CH; and

[0114] X 3 Selected from N.

[0115] According to a partial implementation scheme of this application, R 1 The pyrazol group is optionally surrounded by one or more C groups.1-4 Alkyl substitution;

[0116] R 2 Selected from pyrazolyl group, wherein the pyrazolyl group is optionally substituted with one or more halogens;

[0117] R 3 Selected from H;

[0118] X 1 Selected from N;

[0119] X 2 Selected from CH; and

[0120] X 3 Selected from N.

[0121] According to some embodiments of this application, the halogen is F, Cl, Br or I.

[0122] According to a partial embodiment of this application, the C 1-4 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl.

[0123] According to a partial embodiment of this application, the C 1-4 The alkyl group is methyl, ethyl, n-propyl or n-butyl.

[0124] According to a partial embodiment of this application, the C 1-4 The alkyl group is methyl, ethyl, or n-propyl.

[0125] According to a partial embodiment of this application, the C 1-4 The alkyl group is either methyl or ethyl.

[0126] According to some embodiments of this application, the active ingredient is selected from the following compounds, pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, metabolites, or prodrugs:

[0127] According to some embodiments of this application, the active ingredient is one of the following compounds or a pharmaceutically acceptable salt thereof:

[0128] According to some embodiments of this application, the active ingredient is a fumarate of the following compound 17:

[0129] According to some embodiments of this application, the content of the active ingredient in the pharmaceutical composition is 0.01 to 30% by weight of the pharmaceutical composition, preferably 0.5 to 25% by weight, and more preferably 1 to 20% by weight.

[0130] According to some embodiments of this application, the content of the active ingredient in the pharmaceutical composition is 1 to 10% by weight of the pharmaceutical composition, preferably 1 to 8% by weight, more preferably 2 to 6% by weight, and even more preferably 3 to 5% by weight.

[0131] According to some embodiments of this application, the amount of the active ingredient is 3.01, 3.02, 3.03, 3.04, 3.05, 3.06, 3.07, 3.08, 3.09, 3.1, 3.11, 3.12, 3.13, 3.14, 3.15, 3.16, 3.17, 3.18, 3.19, 3.2, 3.21, 3.22, 3.23, 3.24, 3.25, 3.26, 3.27, 3.28, 3.29, 3.3, 3.31, 3.32, 3.33, 3.34, 3.35, 3.36, 3.37, 3.38, 3.39, 3.4, 3.41, 3.42, 3.43, 3.44, 3... 3.45, 3.46, 3.47, 3.48, 3.49, 3.5, 3.51, 3.52, 3.53, 3.54, 3.55, 3.56, 3.57, 3.58, 3.59, 3.6, 3.61, 3.62, 3.63, 3.64, 3.65, 3.66, 3.67, 3.68, 3.69, 3.7 3.71, 3.72, 3.73, 3.74, 3.75, 3.76, 3.77, 3.78, 3.79, 3.8, 3.81, 3.82, 3.83, 3.84, 3.85, 3.86, 3.87, 3.88, 3.89, 3.9, 3.91, 3.92, 3.93, 3.94, 3.95, 3 .96, 3.97, 3.98, 3.99, 4, 4.01, 4.02, 4.03, 4.04, 4.05, 4.06, 4.07, 4.08, 4.09, 4.1, 4.11, 4.12, 4.13, 4.14, 4.15, 4.16, 4.17, 4.18, 4.19, 4.2, 4.21 4.22, 4.23, 4.24, 4.25, 4.26, 4.27, 4.28, 4.29, 4.3, 4.31, 4.32, 4.33, 4.34, 4.35, 4.36, 4.37, 4.38, 4.39, 4.4, 4.41, 4.42, 4.43, 4.44, 4.45, 4.46, 4. 47, 4.48, 4.49, 4.5, 4.51, 4.52, 4.53, 4.54, 4.55, 4.56, 4.57, 4.58, 4.59, 4.6, 4.61, 4.62, 4.63, 4.64, 4.65, 4.66, 4.67, 4.68, 4.69, 4.7, 4.71, 4.72 4.73, 4.74, 4.75, 4.76, 4.77, 4.78, 4.79, 4.8, 4.81, 4.82, 4.83, 4.84, 4.85, 4.86, 4.87, 4.88, 4.89, 4.9, 4.91, 4.92, 4.93, 4.94, 4.95, 4.96, 4.97, 4.98%, 4.99%, or 5% by weight.

[0132] According to some embodiments of this application, the amount of the active ingredient is 1 to 30% by weight of the pharmaceutical composition, preferably 11 to 25% by weight, more preferably 13 to 22% by weight, even more preferably 15 to 21% by weight, and still more preferably 17 to 19% by weight.

[0133] According to some embodiments of this application, the amount of the active ingredient is 17, 17.01, 17.02, 17.03, 17.04, 17.05, 17.06, 17.07, 17.08, 17.09, 17.1, 17.11, 17.12, 17.13, 17.14, 17.15, 17.16, 17.17, 17.18, 17.19, 17.2, 17.21, 17.22, 17.23, 17.24, 17.25, 17.26, 17.27, 17.28, 17.29, 17.3, 17.31, 17.32, 17.33, 17.34, 17.35, 17.36, 1... 7.37, 17.38, 17.39, 17.4, 17.41, 17.42, 17.43, 17.44, 17.45, 17.46, 17.47, 17.48, 17.49, 17.5, 17.51, 17.52, 17.53, 17.54, 17.55, 17.56, 17.57, 17 .58, 17.59, 17.6, 17.61, 17.62, 17.63, 17.64, 17.65, 17.66, 17.67, 17.68, 17.69, 17.7, 17.71, 17.72, 17.73, 17.74, 17.75, 17.76, 17.77, 17.78, 17. 79, 17.8, 17.81, 17.82, 17.83, 17.84, 17.85, 17.86, 17.87, 17.88, 17.89, 17.9, 17.91, 17.92, 17.93, 17.94, 17.95, 17.96, 17.97, 17.98, 17.99, 18, 18.01, 18.02, 18.03, 18.04, 18.05, 18.06, 18.07, 18.08, 18.09, 18.1, 18.11, 18.12, 18.13, 18.14, 18.15, 18.16, 18.17, 18.18, 18.19, 18.2, 18.21, 1 8.22, 18.23, 18.24, 18.25, 18.26, 18.27, 18.28, 18.29, 18.3, 18.31, 18.32, 18.33, 18.34, 18.35, 18.36, 18.37, 18.38, 18.39, 18.4, 18.41, 18.42, 18 .43, 18.44, 18.45, 18.46, 18.47, 18.48, 18.49, 18.5, 18.51, 18.52, 18.53, 18.54, 18.55, 18.56, 18.57, 18.58, 18.59, 18.6, 18.61, 18.62, 18.63, 18.64, 18.65, 18.66, 18.67, 18.68, 18.69, 18.7, 18.71, 18.72, 18.73, 18.74, 18.75, 18.76, 18.77, 18.78, 18.79, 18.8, 18.81, 18.82, 18.83, 18.84, 18.85, 18.86, 18.87, 18.88, 18.89, 18.9, 18.91, 18.92, 18.93, 18.94, 18.95, 18.96, 18.97, 18.98, 18.99, or 19% by weight.

[0134] According to some embodiments of this application, the pharmaceutical composition of this application contains 0.1-100 mg, preferably 1-90 mg, and more preferably 5-80 mg of the active ingredient.

[0135] According to some embodiments of this application, the pharmaceutical composition of this application contains 5-20 mg, preferably 7-15 mg, and more preferably 11-13 mg of the active ingredient.

[0136] According to a partial embodiment of this application, the pharmaceutical composition of this application comprises 11.01 mg, 11.02 mg, 11.03 mg, 11.04 mg, 11.05 mg, 11.06 mg, 11.07 mg, 11.08 mg, 11.09 mg, 11.1 mg, 11.11 mg, 11.12 mg, 11.13 mg, 11.14 mg, 11.15 mg, 11.16 mg, 11.17 mg, 11.18 mg, 11.19 mg, 11.2 mg, 11.21 mg, 11.22 mg, 11.23 mg, 11.24 mg, 11.25 mg, 11.26 mg, 11.27 mg, 11.28 mg, and 11. 29mg, 11.3mg, 11.31mg, 11.32mg, 11.33mg, 11.34mg, 11.35mg, 11.36mg, 11.37mg, 11.38mg, 11.39mg, 11.4mg, 11.41mg, 11.42mg, 11.43mg, 11.44mg, 1 1.45mg, 11.46mg, 11.47mg, 11.48mg, 11.49mg, 11.5mg, 11.51mg, 11.52mg, 11.53mg, 11.54mg, 11.55mg, 11.56mg, 11.57mg, 11.58mg, 11.59mg, 11.6mg, 11.61mg, 11.62mg, 11.63mg, 11.64mg, 11.65mg, 11.66mg, 11.67mg, 11.68mg, 11.69mg, 11.7mg, 11.71mg, 11.72mg, 11.73mg, 11.74mg, 11.75mg, 11.76 mg, 11.77mg, 11.78mg, 11.79mg, 11.8mg, 11.81mg, 11.82mg, 11.83mg, 11.84mg, 11.85mg, 11.86mg, 11.87mg, 11.88mg, 11.89mg, 11.9mg, 11.91mg, 11.9 2mg, 11.93mg, 11.94mg, 11.95mg, 11.96mg, 11.97mg, 11.98mg, 11.99mg, 12mg, 12.01mg, 12.02mg, 12.03mg, 12.04mg, 12.05mg, 12.06mg, 12.07mg, 12.0 8mg, 12.09mg, 12.1mg, 12.11mg, 12.12mg, 12.13mg, 12.14mg, 12.15mg, 12.16mg, 12.17mg, 12.18mg, 12.19mg, 12.2mg, 12.21mg, 12.22mg, 12.23mg, 12.24mg, 12.25mg, 12.26mg, 12.27mg, 12.28mg, 12.29mg, 12.3mg, 12.31mg, 12.32mg, 12.33mg, 12.34mg, 12.35mg, 12.36mg, 12.37mg, 12.38mg, 12.39mg, 12.4mg, 12.41mg, 12.42mg, 12.43 mg, 12.44mg, 12.45mg, 12.46mg, 12.47mg, 12.48mg, 12.49mg, 12.5mg, 12.51mg, 12.52mg, 12 .53mg, 12.54mg, 12.55mg, 12.56mg, 12.57mg, 12.58mg, 12.59mg, 12.6mg, 12.61mg, 12.62mg, 12.63mg, 12.64mg, 12.65mg, 12.66mg, 12.67mg, 12.68mg, 12.69mg, 12.7mg, 12.71mg, 12.72 mg, 12.73mg, 12.74mg, 12.75mg, 12.76mg, 12.77mg, 12.78mg, 12.79mg, 12.8mg, 12.81mg, 12. The active ingredient may be present in doses of 82 mg, 12.83 mg, 12.84 mg, 12.85 mg, 12.86 mg, 12.87 mg, 12.88 mg, 12.89 mg, 12.9 mg, 12.91 mg, 12.92 mg, 12.93 mg, 12.94 mg, 12.95 mg, 12.96 mg, 12.97 mg, 12.98 mg, 12.99 mg, or 13 mg.

[0137] According to some embodiments of this application, the pharmaceutical composition of this application contains 40-80 mg, preferably 50-70 mg, more preferably 55-65 mg, and more preferably 60-62 mg of the active ingredient.

[0138] According to a partial embodiment of this application, the pharmaceutical composition of this application comprises 60.01 mg, 60.02 mg, 60.03 mg, 60.04 mg, 60.05 mg, 60.06 mg, 60.07 mg, 60.08 mg, 60.09 mg, 60.1 mg, 60.11 mg, 60.12 mg, 60.13 mg, 60.14 mg, 60.15 mg, 60.16 mg, 60.17 mg, 60.18 mg, 60.19 mg, 60.2 mg, 60.21 mg, 60.22 mg, 60.23 mg, 60.24 mg, 60.25 mg, 60.26 mg, 60.27 mg, 60.28 mg, and 60 mg. 29mg, 60.3mg, 60.31mg, 60.32mg, 60.33mg, 60.34mg, 60.35mg, 60.36mg, 60.37mg, 60.38mg, 60.39mg, 60.4mg, 60.41mg, 60.42mg, 60.43mg, 60.44mg, 6 0.45mg, 60.46mg, 60.47mg, 60.48mg, 60.49mg, 60.5mg, 60.51mg, 60.52mg, 60.53mg, 60.54mg, 60.55mg, 60.56mg, 60.57mg, 60.58mg, 60.59mg, 60.6mg, 60.61mg, 60.62mg, 60.63mg, 60.64mg, 60.65mg, 60.66mg, 60.67mg, 60.68mg, 60.69mg, 60.7mg, 60.71mg, 60.72mg, 60.73mg, 60.74mg, 60.75mg, 60.76 mg, 60.77mg, 60.78mg, 60.79mg, 60.8mg, 60.81mg, 60.82mg, 60.83mg, 60.84mg, 60.85mg, 60.86mg, 60.87mg, 60.88mg, 60.89mg, 60.9mg, 60.91mg, 60.9 2mg, 60.93mg, 60.94mg, 60.95mg, 60.96mg, 60.97mg, 60.98mg, 60.99mg, 61mg, 61.01mg, 61.02mg, 61.03mg, 61.04mg, 61.05mg, 61.06mg, 61.07mg, 61.0 8mg, 61.09mg, 61.1mg, 61.11mg, 61.12mg, 61.13mg, 61.14mg, 61.15mg, 61.16mg, 61.17mg, 61.18mg, 61.19mg, 61.2mg, 61.21mg, 61.22mg, 61.23mg, 61.24mg, 61.25mg, 61.26mg, 61.27mg, 61.28mg, 61.29mg, 61.3mg, 61.31mg, 61.32mg, 61.33mg, 61.34mg, 61.35mg, 61.36mg, 61.37mg, 61.38mg, 61.39mg, 61.4mg, 61.41mg, 61.42mg, 61.43m g, 61.44mg, 61.45mg, 61.46mg, 61.47mg, 61.48mg, 61.49mg, 61.5mg, 61.51mg, 61.52mg, 61. 53mg, 61.54mg, 61.55mg, 61.56mg, 61.57mg, 61.58mg, 61.59mg, 61.6mg, 61.61mg, 61.62mg, 6 1.63mg, 61.64mg, 61.65mg, 61.66mg, 61.67mg, 61.68mg, 61.69mg, 61.7mg, 61.71mg, 61.72m g, 61.73mg, 61.74mg, 61.75mg, 61.76mg, 61.77mg, 61.78mg, 61.79mg, 61.8mg, 61.81mg, 61.8 The active ingredient may be present in doses of 2 mg, 61.83 mg, 61.84 mg, 61.85 mg, 61.86 mg, 61.87 mg, 61.88 mg, 61.89 mg, 61.9 mg, 61.91 mg, 61.92 mg, 61.93 mg, 61.94 mg, 61.95 mg, 61.96 mg, 61.97 mg, 61.98 mg, 61.99 mg, or 62 mg.

[0139] According to some embodiments of this application, the pharmaceutical composition of this application contains 0.1-100 mg, preferably 1-80 mg, and more preferably 5-70 mg of the free base form of compound 17; for example, the pharmaceutical composition of this application contains 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, or 70 mg of the free base form of compound 17.

[0140] According to some embodiments of this application, the unit dose of the pharmaceutical composition of this application contains 0.1-100 mg, preferably 1-90 mg, and more preferably 5-80 mg of the active ingredient.

[0141] According to some embodiments of this application, the unit dose of the pharmaceutical composition of this application contains 5-20 mg, preferably 7-15 mg, and more preferably 11-13 mg of the active ingredient.

[0142] According to certain embodiments of this application, the unit dose of the pharmaceutical composition comprises 11.01 mg, 11.02 mg, 11.03 mg, 11.04 mg, 11.05 mg, 11.06 mg, 11.07 mg, 11.08 mg, 11.09 mg, 11.1 mg, 11.11 mg, 11.12 mg, 11.13 mg, 11.14 mg, 11.15 mg, 11.16 mg, 11.17 mg, 11.18 mg, 11.19 mg, 11.2 mg, 11.21 mg, 11.22 mg, 11.23 mg, 11.24 mg, 11.25 mg, 11.26 mg, 11.27 mg, and 11.28 mg. mg, 11.29mg, 11.3mg, 11.31mg, 11.32mg, 11.33mg, 11.34mg, 11.35mg, 11.36mg, 11.37mg, 11.38mg, 11.39mg, 11.4mg, 11.41mg, 11.42mg, 11.43mg, 11. 44mg, 11.45mg, 11.46mg, 11.47mg, 11.48mg, 11.49mg, 11.5mg, 11.51mg, 11.52mg, 11.53mg, 11.54mg, 11.55mg, 11.56mg, 11.57mg, 11.58mg, 11.59mg, 1 1.6mg, 11.61mg, 11.62mg, 11.63mg, 11.64mg, 11.65mg, 11.66mg, 11.67mg, 11.68mg, 11.69mg, 11.7mg, 11.71mg, 11.72mg, 11.73mg, 11.74mg, 11.75mg , 11.76mg, 11.77mg, 11.78mg, 11.79mg, 11.8mg, 11.81mg, 11.82mg, 11.83mg, 11.84mg, 11.85mg, 11.86mg, 11.87mg, 11.88mg, 11.89mg, 11.9mg, 11.91 mg, 11.92mg, 11.93mg, 11.94mg, 11.95mg, 11.96mg, 11.97mg, 11.98mg, 11.99mg, 12mg, 12.01mg, 12.02mg, 12.03mg, 12.04mg, 12.05mg, 12.06mg, 12.0 7mg, 12.08mg, 12.09mg, 12.1mg, 12.11mg, 12.12mg, 12.13mg, 12.14mg, 12.15mg, 12.16mg, 12.17mg, 12.18mg, 12.19mg, 12.2mg, 12.21mg, 12.22mg, 12.23mg, 12.24mg, 12.25mg, 12.26mg, 12.27mg, 12.28mg, 12.29mg, 12.3mg, 12.31mg, 12.32mg, 1 2.33mg, 12.34mg, 12.35mg, 12.36mg, 12.37mg, 12.38mg, 12.39mg, 12.4mg, 12.41mg, 12.42mg ,12.43mg, 12.44mg, 12.45mg, 12.46mg, 12.47mg, 12.48mg, 12.49mg, 12.5mg, 12.51mg, 12.52 mg, 12.53mg, 12.54mg, 12.55mg, 12.56mg, 12.57mg, 12.58mg, 12.59mg, 12.6mg, 12.61mg, 12.6 2mg, 12.63mg, 12.64mg, 12.65mg, 12.66mg, 12.67mg, 12.68mg, 12.69mg, 12.7mg, 12.71mg, 12 .72mg, 12.73mg, 12.74mg, 12.75mg, 12.76mg, 12.77mg, 12.78mg, 12.79mg, 12.8mg, 12.81mg, 1 The active ingredient in doses of 2.82 mg, 12.83 mg, 12.84 mg, 12.85 mg, 12.86 mg, 12.87 mg, 12.88 mg, 12.89 mg, 12.9 mg, 12.91 mg, 12.92 mg, 12.93 mg, 12.94 mg, 12.95 mg, 12.96 mg, 12.97 mg, 12.98 mg, 12.99 mg, or 13 mg.

[0143] According to some embodiments of this application, the unit dose of the pharmaceutical composition of this application contains 40-80 mg, preferably 50-70 mg, more preferably 55-65 mg, and more preferably 60-62 mg of the active ingredient.

[0144] According to some embodiments of this application, the unit dose of the pharmaceutical composition of this application comprises 60.01 mg, 60.02 mg, 60.03 mg, 60.04 mg, 60.05 mg, 60.06 mg, 60.07 mg, 60.08 mg, 60.09 mg, 60.1 mg, 60.11 mg, 60.12 mg, 60.13 mg, 60.14 mg, 60.15 mg, 60.16 mg, 60.17 mg, 60.18 mg, 60.19 mg, 60.2 mg, 60.21 mg, 60.22 mg, 60.23 mg, 60.24 mg, 60.25 mg, 60.26 mg, 60.27 mg, and 60.28 mg. mg, 60.29mg, 60.3mg, 60.31mg, 60.32mg, 60.33mg, 60.34mg, 60.35mg, 60.36mg, 60.37mg, 60.38mg, 60.39mg, 60.4mg, 60.41mg, 60.42mg, 60.43mg, 60. 44mg, 60.45mg, 60.46mg, 60.47mg, 60.48mg, 60.49mg, 60.5mg, 60.51mg, 60.52mg, 60.53mg, 60.54mg, 60.55mg, 60.56mg, 60.57mg, 60.58mg, 60.59mg, 6 0.6mg, 60.61mg, 60.62mg, 60.63mg, 60.64mg, 60.65mg, 60.66mg, 60.67mg, 60.68mg, 60.69mg, 60.7mg, 60.71mg, 60.72mg, 60.73mg, 60.74mg, 60.75mg , 60.76mg, 60.77mg, 60.78mg, 60.79mg, 60.8mg, 60.81mg, 60.82mg, 60.83mg, 60.84mg, 60.85mg, 60.86mg, 60.87mg, 60.88mg, 60.89mg, 60.9mg, 60.91 mg, 60.92mg, 60.93mg, 60.94mg, 60.95mg, 60.96mg, 60.97mg, 60.98mg, 60.99mg, 61mg, 61.01mg, 61.02mg, 61.03mg, 61.04mg, 61.05mg, 61.06mg, 61.0 7mg, 61.08mg, 61.09mg, 61.1mg, 61.11mg, 61.12mg, 61.13mg, 61.14mg, 61.15mg, 61.16mg, 61.17mg, 61.18mg, 61.19mg, 61.2mg, 61.21mg, 61.22mg, 61.23mg, 61.24mg, 61.25mg, 61.26mg, 61.27mg, 61.28mg, 61.29mg, 61.3mg, 61.31mg, 61.32mg, 6 1.33mg, 61.34mg, 61.35mg, 61.36mg, 61.37mg, 61.38mg, 61.39mg, 61.4mg, 61.41mg, 61.42mg, 61.43mg, 61.44mg, 61.45mg, 61.46mg, 61.47mg, 61.48mg, 61.49mg, 61.5mg, 61.51mg, 61.52m g, 61.53mg, 61.54mg, 61.55mg, 61.56mg, 61.57mg, 61.58mg, 61.59mg, 61.6mg, 61.61mg, 61.62 mg, 61.63mg, 61.64mg, 61.65mg, 61.66mg, 61.67mg, 61.68mg, 61.69mg, 61.7mg, 61.71mg, 61. 72mg, 61.73mg, 61.74mg, 61.75mg, 61.76mg, 61.77mg, 61.78mg, 61.79mg, 61.8mg, 61.81mg, 61 The active ingredient may be present in doses of 0.82 mg, 61.83 mg, 61.84 mg, 61.85 mg, 61.86 mg, 61.87 mg, 61.88 mg, 61.89 mg, 61.9 mg, 61.91 mg, 61.92 mg, 61.93 mg, 61.94 mg, 61.95 mg, 61.96 mg, 61.97 mg, 61.98 mg, 61.99 mg, or 62 mg.

[0145] According to some embodiments of this application, the unit dose of the pharmaceutical composition of this application contains 0.1-100 mg, preferably 1-80 mg, and more preferably 5-70 mg of the free base form of compound 17; for example, the unit dose of the pharmaceutical composition of this application contains 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, or 70 mg of the free base form of compound 17.

[0146] According to some embodiments of this application, the particle size range of the active ingredient in the pharmaceutical composition of this application is as follows:

[0147] D v (90) is 1-500 μm, preferably 1-100 μm, more preferably 1-60 μm, and even more preferably 5-50 μm;

[0148] D v(50) is 1 to 100 μm, preferably 1 to 50 μm, and more preferably 1 to 20 μm;

[0149] D v (10) is 0.1 to 10 μm, preferably 0.1 to 7 μm, and more preferably 0.1 to 5 μm;

[0150] D[4,3] is 1–50 μm, preferably 1–30 μm, more preferably 1–25 μm; and / or

[0151] D[3,2] is 0.1 to 10 μm, preferably 0.1 to 7 μm, and even more preferably 0.1 to 5 μm.

[0152] According to a partial embodiment of this application, the particle size D of the active ingredient in the pharmaceutical composition of this application is... v (90) is 1 to 500 μm, preferably 1 to 100 μm, more preferably 1 to 60 μm, and even more preferably 5 to 50 μm, for example 20 to 50 μm.

[0153] According to a partial embodiment of this application, the particle size D of the active ingredient in the pharmaceutical composition of this application is... v (50) is 1 to 100 μm, preferably 1 to 50 μm, and even more preferably 1 to 20 μm.

[0154] According to a partial embodiment of this application, the particle size D of the active ingredient in the pharmaceutical composition of this application is... v (10) is 0.1 to 10 μm, preferably 0.1 to 7 μm, and even more preferably 0.1 to 5 μm.

[0155] According to some embodiments of this application, the particle size D[4,3] of the active ingredient in the pharmaceutical composition of this application is 1-50 μm, preferably 1-30 μm, and more preferably 1-25 μm.

[0156] According to some embodiments of this application, the particle size D[3,2] of the active ingredient in the pharmaceutical composition of this application is 0.1 to 10 μm, preferably 0.1 to 7 μm, and more preferably 0.1 to 5 μm.

[0157] <Pharmaceutical-acceptable carrier>

[0158] Pharmaceutically acceptable carriers used in the oral pharmaceutical compositions of this application include, but are not limited to, fillers, disintegrants, flow aids, lubricants, etc. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).

[0159] The filler includes, but is not limited to, one or more of the following: mannitol, microcrystalline cellulose, starch, pregelatinized starch, lactose, calcium dihydrogen phosphate, calcium hydrogen phosphate, calcium phosphate, calcium carbonate, etc. Preferably, the filler is one or more of mannitol, microcrystalline cellulose, or pregelatinized starch. More preferably, the filler is a combination of microcrystalline cellulose and mannitol, or a combination of pregelatinized starch and mannitol. According to some embodiments of this application, the filler is a combination of microcrystalline cellulose and mannitol.

[0160] According to some embodiments of this application, the amount of the filler is 1-99.99% of the weight of the pharmaceutical composition, preferably 20-99.99%, more preferably 50-99.99%. According to some embodiments of this application, the content of the filler is 50-95% by weight of the pharmaceutical composition. When the filler is a combination of microcrystalline cellulose and mannitol, the amount of the filler is 60-90%, preferably 65-85%, preferably 70-80%, more preferably 73-78% by weight of the pharmaceutical composition. When the filler is a combination of microcrystalline cellulose and mannitol, the amount of the filler is 80-99.99%, preferably 85-90%, more preferably 88-93% by weight of the pharmaceutical composition. According to some embodiments of this application, when the filler is a combination of microcrystalline cellulose and mannitol, the amount of the filler is 50-95% by weight of the pharmaceutical composition.

[0161] According to some embodiments of this application, when the filler is a combination of microcrystalline cellulose and mannitol, the weight ratio of microcrystalline cellulose to mannitol is 0.1 to 5:1; preferably 0.2 to 1:1, or 3 to 5:1, or 0.5 to 2:1; for example, 0.1:1, 0.2:1, 0.3:1, 0.4:1, 0.5:1, 0.6:1, 0.7:1, 0.8:1, 0.9:1, 1:1, 2.1:1, 2.2:1, 2.3:1, 2.4:1, 2.5:1, 2.6:1, 2.7:1, 2.8:1, 2.9:1, or 3:1.

[0162] According to some embodiments of this application, when the filler is a combination of microcrystalline cellulose and mannitol, the weight ratio of microcrystalline cellulose to mannitol is 0.5 to 8:1, preferably 0.5 to 6:1; more preferably 0.5 to 1:1.

[0163] According to some embodiments of this application, when the filler is a combination of microcrystalline cellulose and mannitol, the weight ratio of microcrystalline cellulose to mannitol is 1 to 8:1, preferably 1 to 6:1; more preferably 3 to 4:1, for example 3.1:1, 3.2:1, 3.3:1, 3.4:1, 3.5:1, 3.6:1, 3.7:1, 3.8:1, 3.9:1, or 4:1.

[0164] According to some embodiments of this application, the disintegrant includes, but is not limited to, one or more of the following: low-substituted hydroxypropyl cellulose, low-substituted hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, croscarmellose sodium, sodium carboxymethyl starch, croscarmellose, etc. Preferably, the disintegrant is croscarmellose sodium. According to some embodiments of this application, the amount of the disintegrant is 0.1% to 20% of the weight of the pharmaceutical composition, preferably 0.1% to 10%, more preferably 1% to 10% by weight, for example, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% of the weight of the pharmaceutical composition.

[0165] According to some embodiments of this application, the gliding agent includes, but is not limited to, one or more of the following: colloidal silica, silica, tricalcium phosphate, and talc, wherein silica is preferred; according to some embodiments of this application, the amount of the gliding agent is 0.01% to 10% of the weight of the pharmaceutical composition, preferably 0.1% to 5% by weight, more preferably 0.1% to 3%; even more preferably 0.5% to 1.5%, for example 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.1%, 1.2%, 1.3%, 1.4%, and 1.5%.

[0166] According to some embodiments of this application, the lubricant includes, but is not limited to, one or more of the following: stearic acid, magnesium stearate, calcium stearate, hydrogenated vegetable oil, sodium lauryl sulfate, magnesium lauryl sulfate, talc, polyethylene glycol, sodium stearate fumarate, and silica. Preferably, the lubricant is one or more of magnesium stearate, sodium stearate fumarate, or silica. According to some embodiments of this application, the amount of the lubricant is 0.1% to 10% of the weight of the pharmaceutical composition, preferably 0.1% to 5%, more preferably 0.1% to 3%, more preferably 0.5% to 3%, and even more preferably 0.5% to 1.5%, for example, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.1%, 1.2%, 1.3%, 1.4%, and 1.5%.

[0167] According to some embodiments of this application, the pharmaceutical composition of this application comprises the following components:

[0168] The active ingredient is compound 17, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isomer, or any crystal form or racemate thereof, or its metabolite form.

[0169] The content of the active ingredient is 0.5-30% by weight of the pharmaceutical composition;

[0170] The filler is present in an amount of 50-95% by weight of the pharmaceutical composition, and the filler is one or more of mannitol, microcrystalline cellulose or pregelatinized starch.

[0171] The disintegrant is present in an amount of 1-10% by weight of the pharmaceutical composition, and the disintegrant is one or more of the following: low-substituted hydroxypropyl cellulose, low-substituted hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, croscarmellose sodium, sodium carboxymethyl starch, and croscarmellose.

[0172] A flow aid, wherein the content of the flow aid is 0.1-5% by weight of the pharmaceutical composition, and the flow aid is one or more selected from colloidal silica, silica, tricalcium phosphate, and talc; and

[0173] A lubricant, wherein the content of the lubricant is 0.1-5% by weight of the pharmaceutical composition, and the lubricant is one or more of magnesium stearate, sodium stearate fumarate, or silicon dioxide.

[0174] According to some embodiments of this application, the pharmaceutical composition of this application comprises the following components:

[0175] The active ingredient is compound 17, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isomer, or any crystal form or racemate thereof, or its metabolite form.

[0176] The content of the active ingredient is 0.5-30% by weight of the pharmaceutical composition;

[0177] Mannitol, wherein the content of mannitol is 25-45% by weight of the pharmaceutical composition;

[0178] Microcrystalline cellulose, wherein the content of the microcrystalline cellulose is 25-45% by weight of the pharmaceutical composition;

[0179] Crosslinked carboxymethyl cellulose sodium, wherein the content of crosslinked carboxymethyl cellulose sodium is 1-10% by weight of the pharmaceutical composition;

[0180] Colloidal silica, wherein the content of said colloidal silica is 0.1-3% by weight of the pharmaceutical composition; and

[0181] Magnesium stearate, wherein the content of magnesium stearate is 0.1-3% by weight of the pharmaceutical composition.

[0182] According to a partial embodiment of this application, the pharmaceutical composition of this application comprises:

[0183] 0.5-30 parts by weight of fumarate of compound 17;

[0184] Mannitol 25-45 parts by weight;

[0185] 25-45 parts by weight of microcrystalline cellulose;

[0186] 1-10 parts by weight of croscarmellose sodium cellulose;

[0187] 0.1-3 parts by weight of colloidal silica; and

[0188] Magnesium stearate 0.1-3 parts by weight.

[0189] According to a partial embodiment of this application, the pharmaceutical composition of this application comprises:

[0190] 17-18 parts by weight of fumarate of compound 17;

[0191] Mannitol 37-38 parts by weight;

[0192] 37-38 parts by weight of microcrystalline cellulose;

[0193] 4-6 parts by weight of croscarmellose sodium cellulose;

[0194] 0.8-1.2 parts by weight of colloidal silica; and

[0195] Magnesium stearate 0.8-1.2 parts by weight.

[0196] According to a partial embodiment of this application, the pharmaceutical composition of this application comprises:

[0197] 17-18 parts by weight of fumarate of compound 17;

[0198] Mannitol 37-38 parts by weight;

[0199] 37-38 parts by weight of microcrystalline cellulose;

[0200] 5 parts by weight of croscarmellose sodium cellulose;

[0201] 1 part by weight of colloidal silica; and

[0202] 1 part by weight of magnesium stearate.

[0203] According to some embodiments of this application, the pharmaceutical composition of this application comprises the following components:

[0204] 0.5-30 parts by weight of fumarate of compound 17;

[0205] Mannitol 25-45 parts by weight;

[0206] 25-45 parts by weight of microcrystalline cellulose;

[0207] 1-10 parts by weight of croscarmellose sodium cellulose;

[0208] 0.1-3 parts by weight of colloidal silica; and

[0209] Magnesium stearate 0.1-3 parts by weight.

[0210] According to some embodiments of this application, the pharmaceutical composition of this application comprises the following components:

[0211] 17-18 parts by weight of fumarate of compound 17;

[0212] Mannitol 37-38 parts by weight;

[0213] 37-38 parts by weight of microcrystalline cellulose;

[0214] 4-6 parts by weight of croscarmellose sodium cellulose;

[0215] 0.8-1.2 parts by weight of colloidal silica; and

[0216] Magnesium stearate 0.8-1.2 parts by weight.

[0217] According to some embodiments of this application, the pharmaceutical composition of this application comprises the following components:

[0218] 17-18 parts by weight of fumarate of compound 17;

[0219] Mannitol 37-38 parts by weight;

[0220] 37-38 parts by weight of microcrystalline cellulose;

[0221] 5 parts by weight of croscarmellose sodium cellulose;

[0222] 1 part by weight of colloidal silica; and

[0223] 1 part by weight of magnesium stearate.

[0224] According to some embodiments of this application, the pharmaceutical composition of this application comprises the following components:

[0225] Compound 17 fumarate 10–80 mg;

[0226] Microcrystalline cellulose 20–150 mg;

[0227] Mannitol 20-150 mg;

[0228] 1-15 mg of croscarmellose sodium cellulose;

[0229] Colloidal silica 0.1–10 mg;

[0230] Magnesium stearate 0.1–10 mg; and

[0231] Hydroxypropyl methylcellulose empty capsules.

[0232] According to some embodiments of this application, the pharmaceutical composition of this application contains 1 to 70 mg of the free base of compound 17.

[0233] According to some embodiments of this application, the pharmaceutical composition of this application comprises the following components:

[0234] 10–15 mg of fumarate of compound 17;

[0235] Microcrystalline cellulose 20-30 mg;

[0236] Mannitol 20-30 mg;

[0237] 1-5 mg of croscarmellose sodium cellulose;

[0238] Colloidal silica 0.1–1 mg;

[0239] Magnesium stearate 0.1–1 mg; and

[0240] Hydroxypropyl methylcellulose empty capsules.

[0241] According to some embodiments of this application, the pharmaceutical composition of this application comprises the following components:

[0242] 12.16 mg of fumarate of compound 17;

[0243] Microcrystalline cellulose 25.54 mg;

[0244] Mannitol 25.54 mg;

[0245] Cross-linked carboxymethyl cellulose sodium 3.40 mg;

[0246] 0.68 mg of colloidal silica; and

[0247] Magnesium stearate 0.68 mg; and

[0248] Hydroxypropyl methylcellulose empty capsules.

[0249] According to a partial embodiment of this application, the pharmaceutical composition of this application contains 10 mg of the free base of compound 17.

[0250] According to some embodiments of this application, the pharmaceutical composition of this application comprises the following components:

[0251] 30–40 mg of fumarate of compound 17;

[0252] 70-80 mg of microcrystalline cellulose;

[0253] Mannitol 70-80 mg;

[0254] 5-15 mg of croscarmellose sodium cellulose;

[0255] Colloidal silica 0.5–5 mg;

[0256] Magnesium stearate 0.5–5 mg; and

[0257] Hydroxypropyl methylcellulose empty capsules.

[0258] According to some embodiments of this application, the pharmaceutical composition of this application comprises the following components:

[0259] Compound 17 fumarate 36.48 mg;

[0260] Microcrystalline cellulose 76.62 mg;

[0261] Mannitol 76.62 mg;

[0262] Cross-linked sodium carboxymethyl cellulose 10.20 mg;

[0263] Colloidal silica 2.04 mg;

[0264] Magnesium stearate 2.04 mg; and

[0265] Hydroxypropyl methylcellulose empty capsules.

[0266] According to a partial embodiment of this application, the pharmaceutical composition of this application contains 30 mg of the free base of compound 17.

[0267] According to some embodiments of this application, the pharmaceutical composition of this application comprises the following components:

[0268] 40–80 mg of fumarate of compound 17;

[0269] Microcrystalline cellulose 100-150 mg;

[0270] Mannitol 100-150 mg;

[0271] 5-15 mg of croscarmellose sodium cellulose;

[0272] 1-10 mg of colloidal silica;

[0273] Magnesium stearate 1–10 mg; and

[0274] Hydroxypropyl methylcellulose empty capsules.

[0275] According to some embodiments of this application, the pharmaceutical composition of this application comprises the following components:

[0276] Compound 17 fumarate 60.80 mg;

[0277] Microcrystalline cellulose 127.70 mg;

[0278] Mannitol 127.70 mg;

[0279] Cross-linked sodium carboxymethyl cellulose 17.00 mg;

[0280] 3.40 mg of colloidal silica;

[0281] Magnesium stearate 3.40 mg; and

[0282] Hydroxypropyl methylcellulose empty capsules.

[0283] According to a partial embodiment of this application, the pharmaceutical composition of this application contains 50 mg of the free base of compound 17.

[0284] According to some embodiments of this application, the unit dose of the pharmaceutical composition of this application consists of the following components:

[0285] Compound 17 fumarate 10–80 mg;

[0286] Microcrystalline cellulose 20–150 mg;

[0287] Mannitol 20-150 mg;

[0288] 1-15 mg of croscarmellose sodium cellulose;

[0289] Colloidal silica 0.1–10 mg;

[0290] Magnesium stearate 0.1–10 mg; and

[0291] Hydroxypropyl methylcellulose empty capsules.

[0292] According to some embodiments of this application, the unit dose of the pharmaceutical composition of this application contains 1 to 70 mg of the free base of compound 17.

[0293] According to some embodiments of this application, the unit dose of the pharmaceutical composition of this application consists of the following components:

[0294] 10–15 mg of fumarate of compound 17;

[0295] Microcrystalline cellulose 20-30 mg;

[0296] Mannitol 20-30 mg;

[0297] 1-5 mg of croscarmellose sodium cellulose;

[0298] Colloidal silica 0.1–1 mg;

[0299] Magnesium stearate 0.1–1 mg; and

[0300] Hydroxypropyl methylcellulose empty capsules.

[0301] According to some embodiments of this application, the unit dose of the pharmaceutical composition of this application consists of the following components:

[0302] 12.16 mg of fumarate of compound 17;

[0303] Microcrystalline cellulose 25.54 mg;

[0304] Mannitol 25.54 mg;

[0305] Cross-linked carboxymethyl cellulose sodium 3.40 mg;

[0306] 0.68 mg of colloidal silica; and

[0307] Magnesium stearate 0.68 mg; and

[0308] Hydroxypropyl methylcellulose empty capsules.

[0309] According to a partial embodiment of this application, the unit dose of the pharmaceutical composition of this application contains 10 mg of the free base of compound 17.

[0310] According to some embodiments of this application, the unit dose of the pharmaceutical composition of this application consists of the following components:

[0311] 30–40 mg of fumarate of compound 17;

[0312] 70-80 mg of microcrystalline cellulose;

[0313] Mannitol 70-80 mg;

[0314] 5-15 mg of croscarmellose sodium cellulose;

[0315] Colloidal silica 0.5–5 mg;

[0316] Magnesium stearate 0.5–5 mg; and

[0317] Hydroxypropyl methylcellulose empty capsules.

[0318] According to some embodiments of this application, the unit dose of the pharmaceutical composition of this application consists of the following components:

[0319] Compound 17 fumarate 36.48 mg;

[0320] Microcrystalline cellulose 76.62 mg;

[0321] Mannitol 76.62 mg;

[0322] Cross-linked sodium carboxymethyl cellulose 10.20 mg;

[0323] Colloidal silica 2.04 mg;

[0324] Magnesium stearate 2.04 mg; and

[0325] Hydroxypropyl methylcellulose empty capsules.

[0326] According to a partial embodiment of this application, the unit dose of the pharmaceutical composition of this application contains 30 mg of the free base of compound 17.

[0327] According to some embodiments of this application, the unit dose of the pharmaceutical composition of this application consists of the following components:

[0328] 40–80 mg of fumarate of compound 17;

[0329] Microcrystalline cellulose 100-150 mg;

[0330] Mannitol 100-150 mg;

[0331] 5-15 mg of croscarmellose sodium cellulose;

[0332] 1-10 mg of colloidal silica;

[0333] Magnesium stearate 1–10 mg; and

[0334] Hydroxypropyl methylcellulose empty capsules.

[0335] According to some embodiments of this application, the unit dose of the pharmaceutical composition of this application consists of the following components:

[0336] Compound 17 fumarate 60.80 mg;

[0337] Microcrystalline cellulose 127.70 mg;

[0338] Mannitol 127.70 mg;

[0339] Cross-linked sodium carboxymethyl cellulose 17.00 mg;

[0340] 3.40 mg of colloidal silica;

[0341] Magnesium stearate 3.40 mg; and

[0342] Hydroxypropyl methylcellulose empty capsules.

[0343] According to a partial embodiment of this application, the unit dose of the pharmaceutical composition of this application contains 50 mg of the free base of compound 17.

[0344] <Dosage Form>

[0345] The dosage forms of the oral pharmaceutical compositions of this application include, but are not limited to, tablets, capsules, lozenges, hard candies, powders, granules, solutions, aromatic aqueous solutions, liniments, suspensions, elixirs, syrups, etc.

[0346] According to some embodiments of this application, the pharmaceutical composition of this application is a capsule. The capsule shell of the capsule is a gelatin empty capsule, a hydroxypropyl methylcellulose empty capsule, a starch empty capsule, etc., preferably a hydroxypropyl methylcellulose empty capsule.

[0347] According to some embodiments of this application, this application provides a pharmaceutical formulation comprising the pharmaceutical composition described in this application and packaging. In some embodiments, the packaging is an aluminum-plastic blister pack or a high-density polyethylene bottle. In some embodiments, the packaging includes a desiccant or a moisture-proof combination cap. In some embodiments, the desiccant is selected from silica gel, molecular sieves, alumina, and calcium chloride.

[0348] <Dissolution Mode>

[0349] According to a partial embodiment of this application, the dissolution rate of the pharmaceutical composition, measured in 900 ml of pH 1.0 hydrochloric acid solution at 75 rpm and 37°C using the basket method in the Chinese Pharmacopoeia, meets one or more of the following criteria:

[0350] (1) At least 80% by weight of the active ingredient dissolves within 30 minutes;

[0351] (2) At least 85% by weight of the active ingredient dissolves within 45 minutes;

[0352] (3) At least 90% by weight of the active ingredient dissolves within 60 minutes.

[0353] According to a partial embodiment of this application, the dissolution rate of the pharmaceutical composition, measured in 900 ml of pH 1.0 hydrochloric acid solution at 75 rpm and 37°C using the paddle method and settling basket method as described in the Chinese Pharmacopoeia, meets one or more of the following criteria:

[0354] (1) At least 80% by weight of the active ingredient dissolves within 30 minutes;

[0355] (2) At least 85% by weight of the active ingredient dissolves within 45 minutes;

[0356] (3) At least 90% by weight of the active ingredient dissolves within 60 minutes.

[0357] According to a partial embodiment of this application, the dissolution rate of the pharmaceutical composition, measured in 900 ml of pH 1.0 hydrochloric acid solution at 75 rpm and 37°C using the paddle method and settling basket method as described in the Chinese Pharmacopoeia, meets one or more of the following criteria:

[0358] (1) At least 80% by weight of the active ingredient dissolves within 15 minutes;

[0359] (2) At least 95% by weight of the active ingredient dissolves within 45 minutes;

[0360] (3) At least 98% by weight of the active ingredient dissolves within 60 minutes.

[0361] Preparation method

[0362] This application also provides a method for preparing the pharmaceutical composition, comprising:

[0363] i) The particle size of the active ingredient is controlled by an optional pulverization step;

[0364] ii) Mix the active ingredient with one or more of a filler, disintegrant, flow aid, and lubricant;

[0365] The particle size of the active ingredient is one or more of the following: 1) to 5):

[0366] 1)D v (90) is 1 to 500 μm, preferably 1 to 100 μm, more preferably 1 to 60 μm, and even more preferably 5 to 50 μm, for example 20 to 50 μm;

[0367] 2)D v (50) is 1 to 100 μm, preferably 1 to 50 μm, and more preferably 1 to 20 μm;

[0368] 3)D v (10) is 0.1 to 10 μm, preferably 0.1 to 7 μm, and more preferably 0.1 to 5 μm;

[0369] 4) D[4,3] is 1–50 μm, preferably 1–30 μm, more preferably 1–25 μm; and / or

[0370] 5) D[3,2] is 0.1 to 10 μm, preferably 0.1 to 7 μm, and even more preferably 0.1 to 5 μm.

[0371] According to a partial embodiment of this application, step ii) includes: mixing the active ingredient with a filler, a disintegrant, and a flow aid to obtain a premix, and then mixing it with a lubricant.

[0372] According to a partial embodiment of this application, the method further includes: iii) filling capsules or compressing tablets.

[0373] According to another aspect of this application, a method for preparing the pharmaceutical composition of this application is provided, comprising:

[0374] i) The particle size of the active ingredient is controlled within the following range through an optional pulverization step:

[0375] D v (90) is 1-500 μm, preferably 1-100 μm, more preferably 1-60 μm, and even more preferably 5-50 μm;

[0376] D v (50) is 1 to 100 μm, preferably 1 to 50 μm, and more preferably 1 to 20 μm;

[0377] D v (10) is 0.1 to 10 μm, preferably 0.1 to 7 μm, and more preferably 0.1 to 5 μm;

[0378] D[4,3] is 1–50 μm, preferably 1–30 μm, more preferably 1–25 μm; and / or

[0379] D[3,2] is 0.1–10 μm, preferably 0.1–7 μm, and more preferably 0.1–5 μm; and

[0380] ii) Mix the active ingredient with one or more of fillers, disintegrants, flow aids and lubricants.

[0381] According to a partial embodiment of this application, the method further includes:

[0382] iii) Sieving.

[0383] According to a partial embodiment of this application, the method further includes:

[0384] iv) Mix the mixture obtained in step ii) with the remaining carrier;

[0385] According to a partial embodiment of this application, the method further includes: v) filling the capsule.

[0386] According to some embodiments of this application, the method further includes: vi) packaging; preferably, the packaging process involves dispensing the finished formulation into high-density polyethylene bottles and then sealing them with a moisture-proof combination cap of oral solid pharmaceutical polypropylene / low-density polyethylene.

[0387] According to some embodiments of this application, the preparation method provided in this application has a preparation scale of more than 100,000 capsules.

[0388] According to some embodiments of this application, the preparation method provided in this application has a preparation scale of more than 120,000 capsules.

[0389] According to some embodiments of this application, the preparation method provided in this application has a preparation scale of more than 150,000 capsules.

[0390] According to a partial embodiment of this application, the mixing uniformity RSD of the mixed powder obtained in step iv) is 8% or less, preferably 5% or less, and more preferably 3% or less.

[0391] According to a partial embodiment of this application, the compressibility of the mixed powder obtained in step iv) is 40% or less, preferably 35% or less, and more preferably 30% or less.

[0392] Compared with the prior art, the preparation method provided in this application is simple and stable, with good API content and mixing uniformity of intermediate materials in the preparation process, and the resulting finished product dissolves quickly and has stable quality, making it suitable for industrial scale-up production.

[0393] Pharmaceutical uses and treatments

[0394] According to another aspect of this application, the use of the pharmaceutical composition or pharmaceutical preparation of this application in the preparation of a medicament for treating RET-related diseases is provided.

[0395] According to another aspect of this application, a method for treating RET-related diseases is provided, comprising administering the pharmaceutical composition or pharmaceutical preparation of this application to an individual in need of such treatment.

[0396] According to another aspect of this application, a pharmaceutical composition or pharmaceutical preparation of the present application is provided for the treatment of RET-related diseases.

[0397] According to some embodiments of this application, the RET-related diseases are selected from, but not limited to, cancer or irritable bowel syndrome.

[0398] According to a partial embodiment of this application, the cancer is selected from lung cancer, breast cancer, head and neck cancer, rectal cancer, liver cancer, thyroid cancer, or colon cancer.

[0399] According to some embodiments of this application, the cancer is selected from non-small cell lung cancer (NSCLC), medullary thyroid carcinoma (MTC), papillary thyroid carcinoma (PTC), pancreatic cancer, ovarian cancer, and / or inhibitor-resistant solid tumors.

[0400] In some embodiments, this application also provides the use of the oral pharmaceutical composition of this application for use simultaneously, alone, and sequentially in combination with other therapeutic agents or preventive agents (e.g., other therapeutic agents or preventive agents as described above).

[0401] Unless otherwise stated, as used herein, the term "treating" means to reverse, alleviate, or inhibit the progression of a disease or condition to which such term applies, or one or more symptoms of such a disease or condition, or to prevent such a disease or condition, or one or more symptoms of such a disease or condition.

[0402] As used herein, “individual” includes both human and non-human animals. Exemplary human individuals include individuals suffering from a disease (such as the disease described herein) (referred to as patients) or healthy individuals. In this application, “non-human animal” includes all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock, and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0403] This application also includes the technical solutions described in items 1-19 below:

[0404] 1. A method for preparing an oral pharmaceutical composition comprising an active ingredient and at least one pharmaceutically acceptable carrier, wherein the active ingredient is a compound of formula I, a pharmaceutically acceptable salt thereof, a stereoisomer, a polymorph thereof, a solvate, a metabolite, or a prodrug.

[0405] in:

[0406] R 1 Selected from 4-10 membered heterocyclic groups and 5-10 membered heteroaryl groups, wherein each heterocyclic group and heteroaryl group is optionally substituted by one or more substituents independently selected from the following: hydroxyl, halogen, CN, NO2, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Heteroalkyl, C 3-6 cycloalkyl and C 3-6 Cycloalkoxy;

[0407] R 2 Selected from halogens, C1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, 4-10-membered heterocyclic and 5-10-membered heteroaryl groups, wherein each of the alkyl, heteroalkyl, heterocyclic and heteroaryl groups is optionally substituted by one or more substituents independently selected from the following: hydroxyl, halogen, CN, NO2, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Heteroalkyl, C 3-6 cycloalkyl and C 3-6 Cycloalkoxy;

[0408] R 3 Selected from H, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Heteroalkyl and C 3-6 cycloalkyl; and

[0409] X 1 X 2 and X 3 Each is independently selected from CH and N;

[0410] The pharmaceutically acceptable carrier is one or more of the following: filler, disintegrant, glidant, and lubricant.

[0411] 2. The method of Project 1, wherein R 1 Selected from 5-membered nitrogen-containing heteroaryl groups, wherein the heteroaryl group is optionally surrounded by one or more C groups. 1-4 Alkyl substitution;

[0412] R 2 Selected from 5-membered nitrogen-containing heteroaryl groups, wherein the heteroaryl group is optionally substituted with one or more halogens;

[0413] R 3 Selected from H;

[0414] X 1 Selected from N;

[0415] X 2 Selected from CH; and

[0416] X 3 Selected from N.

[0417] 3. The pharmaceutical composition of Project 2, wherein the active ingredient is selected from the following compounds, pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, metabolites, or prodrugs:

[0418] 4. The pharmaceutical composition of Project 3, wherein the active ingredient is a compound or a pharmaceutically acceptable salt thereof:

[0419] 5. The pharmaceutical composition of Project 4, wherein the active ingredient is the fumarate of compound 17.

[0420] 6. The pharmaceutical composition of item 5, wherein the amount of said active ingredient is 1 to 30% by weight of the pharmaceutical composition, preferably 11 to 25% by weight, and more preferably 13 to 22% by weight.

[0421] 7. The pharmaceutical composition of Project 1, wherein the particle size range of the active ingredient is as follows:

[0422] D v (90) is 1-500 μm, preferably 1-100 μm, more preferably 1-60 μm, and even more preferably 5-50 μm;

[0423] D v (50) is 1 to 100 μm, preferably 1 to 50 μm, and more preferably 1 to 20 μm;

[0424] D v (10) is 0.1 to 10 μm, preferably 0.1 to 7 μm, and more preferably 0.1 to 5 μm;

[0425] D[4,3] is 1–50 μm, preferably 1–30 μm, more preferably 1–25 μm; and / or

[0426] D[3,2] is 0.1 to 10 μm, preferably 0.1 to 7 μm, and even more preferably 0.1 to 5 μm.

[0427] 8. A pharmaceutical composition of any one of items 1-7, which meets one or more of the following conditions:

[0428] 1) The filler is selected from one or more of the following components: mannitol, microcrystalline cellulose, starch, pregelatinized starch, lactose, calcium dihydrogen phosphate, calcium hydrogen phosphate, calcium phosphate, calcium carbonate; preferably a combination of mannitol and microcrystalline cellulose;

[0429] 2) The disintegrant is selected from one or more of the following components: low-substituted hydroxypropyl cellulose, low-substituted hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, croscarmellose sodium, sodium carboxymethyl starch, croscarmellose; preferably croscarmellose sodium;

[0430] 3) The flow aid is selected from one or more of the following components: colloidal silica, silica, tricalcium phosphate and talc, preferably silica;

[0431] 4) The lubricant is selected from one or more of the following components: stearic acid, magnesium stearate, calcium stearate, hydrogenated vegetable oil, sodium lauryl sulfate, magnesium lauryl sulfate, talc, polyethylene glycol, sodium stearate fumarate, and silicon dioxide, preferably magnesium stearate.

[0432] 9. A pharmaceutical composition of any one of items 1-8, comprising the following components:

[0433] The active ingredient is compound 17, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isomer, or any crystal form or racemate thereof, or a metabolite thereof, wherein the content of said active ingredient is 0.5-30% by weight of the pharmaceutical composition.

[0434] The filler is present in an amount of 50-95% by weight of the pharmaceutical composition, and the filler is one or more of mannitol, microcrystalline cellulose or pregelatinized starch.

[0435] The disintegrant is present in an amount of 1-10% by weight of the pharmaceutical composition, and the disintegrant is one or more of the following: low-substituted hydroxypropyl cellulose, low-substituted hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, croscarmellose sodium, sodium carboxymethyl starch, and croscarmellose.

[0436] A flow aid, wherein the content of the flow aid is 0.1-5% by weight of the pharmaceutical composition, and the flow aid is one or more selected from colloidal silica, silica, tricalcium phosphate, and talc; and

[0437] A lubricant, wherein the content of the lubricant is 0.1-5% by weight of the pharmaceutical composition, and the lubricant is one or more of magnesium stearate, sodium stearate fumarate, or silicon dioxide.

[0438] 10. A pharmaceutical composition of any one of items 1-7, wherein the carrier comprises a filler.

[0439] The active ingredient is compound 17, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isomer, or any crystal form or racemate thereof, or its metabolite form.

[0440] The content of the active ingredient is 0.5-30% by weight of the pharmaceutical composition;

[0441] Mannitol, wherein the content of mannitol is 25-45% by weight of the pharmaceutical composition;

[0442] Microcrystalline cellulose, wherein the content of the microcrystalline cellulose is 25-45% by weight of the pharmaceutical composition;

[0443] Crosslinked carboxymethyl cellulose sodium, wherein the content of crosslinked carboxymethyl cellulose sodium is 1-10% by weight of the pharmaceutical composition;

[0444] Colloidal silica, wherein the content of said colloidal silica is 0.1-3% by weight of the pharmaceutical composition; and

[0445] Magnesium stearate, wherein the content of magnesium stearate is 0.1-3% by weight of the pharmaceutical composition.

[0446] 11. The pharmaceutical composition of item 10, wherein the weight ratio of microcrystalline cellulose to mannitol is 1 to 8:1, preferably 1 to 6:1; more preferably 3 to 4:1.

[0447] 12. The pharmaceutical composition of item 11, which is in the form of capsules.

[0448] 13. The pharmaceutical composition of item 12, wherein the capsule shell of the capsule is a gelatin empty capsule, a hydroxypropyl methylcellulose empty capsule, or a starch empty capsule; preferably a hydroxypropyl methylcellulose empty capsule.

[0449] 14. The dissolution rate of the pharmaceutical composition described in any one of items 1-13, determined according to the dissolution test method of the Chinese Pharmacopoeia using the paddle method and settling basket at a speed of 75 rpm and a temperature of 37°C in 900 ml of hydrochloric acid solution with pH 1.0, meets one or more of the following criteria:

[0450] (1) At least 80% by weight of the active ingredient dissolves within 30 minutes;

[0451] (2) At least 85% by weight of the active ingredient dissolves within 45 minutes;

[0452] (3) At least 90% by weight of the active ingredient dissolves within 60 minutes.

[0453] 15. A pharmaceutical preparation comprising the pharmaceutical composition described in any one of items 1 to 14 and packaging; preferably, the packaging is an aluminum-plastic blister pack or a high-density polyethylene bottle.

[0454] 16. A method for preparing a pharmaceutical composition according to any one of items 1-14 or a pharmaceutical formulation according to item 15, comprising:

[0455] i) The particle size of the active ingredient is controlled within the following range through an optional pulverization step:

[0456] D v(90) is 1-500 μm, preferably 1-100 μm, more preferably 1-60 μm, and even more preferably 5-50 μm;

[0457] D v (50) is 1 to 100 μm, preferably 1 to 50 μm, and more preferably 1 to 20 μm;

[0458] D v (10) is 0.1 to 10 μm, preferably 0.1 to 7 μm, and more preferably 0.1 to 5 μm;

[0459] D[4,3] is 1–50 μm, preferably 1–30 μm, more preferably 1–25 μm; and / or

[0460] D[3,2] is 0.1–10 μm, preferably 0.1–7 μm, and more preferably 0.1–5 μm; and

[0461] iii) Mix the active ingredient with one or more of fillers, disintegrants, flow aids and lubricants.

[0462] 17. Use of the pharmaceutical composition of any one of items 1-14 or the pharmaceutical preparation of item 15 in the preparation of a medicament for treating RET-related diseases, wherein the RET-related diseases are preferably selected from cancer or irritable bowel syndrome.

[0463] 18. A method of treating RET-related diseases, comprising administering to an individual in need a pharmaceutical composition of any one of items 1-14 or a pharmaceutical preparation of item 15, wherein the JAK-related disease is preferably selected from cancer or irritable bowel syndrome.

[0464] 19. A pharmaceutical composition of any one of items 1-14 or a pharmaceutical preparation of item 15, for treating RET-related diseases, wherein the RET-related diseases are preferably selected from cancer or irritable bowel syndrome. Detailed Implementation

[0465] To make the objectives and technical solutions of this application clearer, the following detailed embodiments further illustrate this application. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of this application. Furthermore, any specific experimental methods not mentioned in the following embodiments are performed according to conventional experimental methods.

[0466] Compound Preparation Example: 2-(6-(6-((6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Compound 17)

[0467] Step 1: Preparation of 6-(4-fluoro-1H-pyrazol-1-yl)nicotinaldehyde (compound 17a)

[0468] Compound 8c (2.0 g), the hydrochloride salt of compound 91a (1.58 g), and potassium carbonate (4.45 g) were sequentially added to DMF (15 mL), and the mixture was heated to 80 °C and stirred for 14 h. The reaction mixture was cooled to room temperature, diluted with water (100 mL), and extracted with DCM (50 mL × 2). The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (PE:EA = 10:1) to give compound 17a (0.81 g). MS m / z (ESI): 192.1 [M+H] + .

[0469] Step 2: Preparation of 2-(6-(6-((6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 17)

[0470] 1 g of trifluoroacetate (22.82 mg) and compound 17a (27.47 mg) were added to methanol (1.0 mL), followed by the sequential addition of triethylamine (4.45 mg) and sodium cyanoborohydride (13.86 mg), and the reaction was carried out at room temperature for 14 h. After the reaction was complete, the reaction solution was concentrated to dryness under reduced pressure and purified by Prep-HPLC to obtain compound 17 (7.0 mg). MS m / z (ESI): 538.3 [M+H] + .

[0471] 1H NMR (400MHz, DMSO-d6) δ11.98(s,1H),9.66(s,1H),9.12(d,J=2.16Hz,1H),8.67(dd,J=4.54 ,0.64Hz,1H),8.43(dd,J=8.94,2.28Hz,1H),8.41(d,J=1.68,1H),7.98(dd,J=8.48Hz,2.12 1H),7.92(d,J=4.28,1H),7.87(d,J=8.4,1H),6.78(d,J=9.0Hz,2H),6.31(br,1H),3.78-3.71( m,4H),3.68-3.52(m,4H),2.59-2.52(m,1H),2.33(s,3H),2.25(s,3H),1.60(d,J=8.36Hz,1H).

[0472] Compound 17 (10.0 g) prepared in the compound preparation example was added to a glass bottle, 200 mL of tetrahydrofuran was added, and the temperature was raised to 55 °C. Fumaric acid (2.59 g) was added, and the reaction was maintained at 55 °C. The mixture was then filtered to obtain the fumarate of compound 17.

[0473] Example 1:

[0474] Capsules were prepared according to the prescription shown in Table 1-1, and the weight distribution and dissolution of the finished capsules were investigated.

[0475] Table 1-1 Formulation composition of preparation 1

[0476] Preparation process:

[0477] (1) The particle size of the raw material was determined after mechanical pulverization. The particle size determination method was the third method of particle size and particle size distribution determination in General Chapter 0982 of Part IV of the Chinese Pharmacopoeia 2020. The particle size determination results are shown in Table 1-2.

[0478] Table 1-2 Particle size results of raw material after pulverization for Formulation 1

[0479] (2) Mix the pulverized raw materials and excipients (except magnesium stearate) for 20 minutes;

[0480] (3) Pass through a 20-mesh sieve once;

[0481] (4) Mix for 20 minutes;

[0482] (5) Add magnesium stearate and mix for 5 minutes;

[0483] (6) Capsules are filled using capsule plates.

[0484] The weight distribution of different batches of finished capsules and the dissolution of capsules in different pH media were determined.

[0485] The maximum weight of the finished capsules was 0.456g, and the minimum weight was 0.408g, both within the theoretical control range of 0.402-0.470g. The average weight of the finished capsules was 0.430g, which is basically consistent with the theoretical weight of 0.436g. This indicates that the quality of the finished product produced by this capsule preparation process is stable.

[0486] The dissolution test was performed using the basket method of the Chinese Pharmacopoeia (2015 edition), with a rotation speed of 75 rpm, a temperature of 37℃, and a medium volume of 900 ml. The dissolution results in hydrochloric acid solution at pH 1.0 are shown in Table 1-3.

[0487] Table 1-3 Dissolution results of Formulation 1

[0488] The results showed that the active ingredient in Formulation 1 dissolved well in the dissolution medium at pH 1.0.

[0489] Example 2:

[0490] Capsules were prepared according to the prescriptions shown in Table 2-1, and the dissolution of capsules with different shells was investigated.

[0491] Table 2-1 Formulation composition of formulations 2-1 and 2-2

[0492] Preparation process: (1) Mix the pulverized raw material and excipients (except magnesium stearate) for 20 min. The particle size of the pulverized raw material is shown in Table 2-2.

[0493] Table 2-2 Particle size results of active pharmaceutical ingredient after pulverization for Formulation 2

[0494] (2) Pass through a 30-mesh sieve once; (3) Mix for 20 minutes; (4) Add magnesium stearate and mix for 5 minutes; (6) Fill the capsules with capsule plates using HPMC capsules and gelatin capsules respectively.

[0495] The dissolution method, using a paddle and settling basket as described in the Chinese Pharmacopoeia (2015 edition), was employed at a rotation speed of 75 rpm and a temperature of 37°C. The dissolution medium was 900 ml of hydrochloric acid solution at pH 1.0. Dissolution test results showed that both formulations 2-1 and 2-2 achieved a dissolution rate of over 90% within 60 minutes in the pH 1.0 medium, demonstrating good dissolution properties.

[0496] Example 3:

[0497] Capsules were prepared according to the prescription shown in Table 3-1, and the dissolution of the capsules was investigated.

[0498] Table 3-1 Formulation composition of preparation 3

[0499] Preparation process:

[0500] (1) The raw materials were manually ground and pulverized through a 50-mesh sieve. The particle size determination results are shown in Table 3-2.

[0501] Table 3-2 Particle size results of raw material after pulverization in Formulation 3

[0502] (2) Mix the pulverized raw materials and excipients (except magnesium stearate) for 20 minutes;

[0503] (3) Pass through a 20-mesh sieve once;

[0504] (4) Mix for 20 minutes;

[0505] (5) Add magnesium stearate and mix for 5 minutes;

[0506] (6) Manually fill capsules one by one, with the weight of the contents of the capsules controlled between 340mg and 355mg.

[0507] The weight distribution of different batches of finished capsules and the dissolution of capsules in different pH media were determined.

[0508] The dissolution test method was the paddle method with sedimentation basket as specified in the Chinese Pharmacopoeia (2015 edition), with a rotation speed of 75 rpm, a temperature of 37℃, and a medium volume of 900 ml. The dissolution results in hydrochloric acid solution at pH 1.0 are shown in Table 3-3.

[0509] Table 3-3 Dissolution results of Formulation 3 in hydrochloric acid solution at pH 1.0

[0510] The results showed that when the capsule shell in the formulation was HPMC capsule, and the filler was changed from pregelatinized starch / mannitol to microcrystalline cellulose / mannitol, the dissolution rate was further improved.

[0511] Example 4:

[0512] Capsules were prepared using a process similar to that in Example 1, according to the prescription shown in Table 4-1 and the particle size of the active pharmaceutical ingredient shown in Table 4-2. The dissolution of each capsule was then investigated.

[0513] Table 4-1 Formulation of Capsules

[0514] Table 4-2 Dv(90) of the active pharmaceutical ingredient for each formulation group

[0515] The dissolution test method was the paddle method with sedimentation basket as specified in the Chinese Pharmacopoeia (2015 edition), with a rotation speed of 75 rpm, a temperature of 37℃, and a medium volume of 900 ml. The dissolution test results in hydrochloric acid solution at pH 1.0 are shown in Table 4-3.

[0516] Table 4-3 Dissolution results of drug substance formulations with different particle sizes

[0517] The results showed that the particle size of the API has a certain impact on the dissolution of the formulation. Formulations with API particle sizes within an appropriate range (e.g., formulations 4-1 to 4-3) exhibited excellent dissolution properties.

[0518] Example 5

[0519] The capsules were prepared according to the formulation composition in Table 5-1 and the preparation process described below, and packaged separately according to Table 5-3. The stability of the different packaged formulations was tested after storage for 30 days at 92.5% RH / 25±2℃.

[0520] Table 5-1 Formulation of Capsules

[0521] The preparation process is as follows:

[0522] (1) Weighing: Weigh the microcrystalline cellulose, fumarate of compound 17, mannitol, croscarmellose sodium cellulose and colloidal silica according to the prescription amount, and add them to the mixing tank in sequence;

[0523] Table 5-2 Particle size of fumarate of compound 17

[0524] (2) Premix: Mix at 15 rpm for 10 min;

[0525] (3) Sieving: The material is discharged from the mixing tank and passed through a granulator with a sieve with a 1mm aperture at a speed of 100rpm, for a total of two times. After sieving, the powder is added back to the mixing tank.

[0526] (4) Mixing: Mix at 15 rpm for 20 min;

[0527] (5) Total mixing: Weigh the magnesium stearate according to the prescription amount, pass it through a 40-mesh sieve, add it to the mixing tank, and mix at 15 rpm for 10 min;

[0528] (6) Capsule filling: 0# hydroxypropyl methylcellulose empty capsules were used for capsule filling at a rate of 7500 capsules / h.

[0529] Table 5-3 Stability of formulation products with different packaging

[0530] The results show that the formulation of this invention exhibits excellent stability under various packaging methods, with the product packaged in a high-density polyethylene bottle (HDPE bottle) + polypropylene / low-density polyethylene moisture-proof combination cap showing even better stability.

[0531] In addition, the 30-day storage stability of the above four packaged formulations was tested under the conditions of 40℃±2℃ / 75%RH±5%RH and 60℃±2℃, respectively. The results showed that the formulations of this application all had excellent storage stability under the above conditions, with the main peak purity being greater than 99.1% and the total impurity content being less than 0.9% after 30 days.

[0532] Example 6

[0533] Capsule formulations with different shells were prepared according to the formulations shown in Table 6-1. Formulation 6-1 contained 10 mg of compound 17 in its free base form (i.e., 10 mg specification); formulation 6-2 contained 50 mg of compound 17 in its free base form (i.e., 50 mg specification). Their stability was then investigated.

[0534] Table 6-1

[0535] The preparation process is as follows:

[0536] (1) Pretreatment of active pharmaceutical ingredient: The particle size of fumarate of compound 17 was determined, and the results are shown in Table 6-2.

[0537] Table 6-2 Particle size results of raw materials after pulverization

[0538] (2) Weighing: Weigh the microcrystalline cellulose, fumarate of compound 17, mannitol, croscarmellose sodium cellulose and colloidal silica according to the prescription amount, and add them to the mixing tank in sequence;

[0539] (3) Premix: Mix at 15 rpm for 10 min;

[0540] (4) Sieving: The material is discharged from the mixing tank and passed through a granulator with a 1mm aperture screen at a speed of 100rpm, for a total of two times. After sieving, the powder is added back to the mixing tank.

[0541] (5) Mixing: Mix at 15 rpm for 20 min;

[0542] (6) Total mixing: Weigh the magnesium stearate according to the prescription amount, pass it through a 40-mesh sieve, add it to the mixing tank, and mix at 15 rpm for 10 min;

[0543] (7) Intermediate control: Samples were taken from 10 locations in the upper, middle, and bottom layers of the mixing hopper to test the mixing uniformity and powder properties. The results are shown in Tables 6.3-6.4. The data indicate that the intermediate mixed powder has good powder properties and mixing uniformity. Furthermore, multiple batches have been produced, and the test results for each batch are similar to those in Tables 6.3-6.4.

[0544] Table 6-3 Results of Mixing Uniformity Test for Intermediate Powder

[0545] Table 6-4 Powder Geometric Detection Results of Intermediate Mixed Powder

[0546] (8) Capsule filling: Hydroxypropyl methylcellulose hollow capsules were used for filling. The capsule type, filling rate setting, and filling weight control range are shown in Table 6-5.

[0547] Table 6-5 Capsule filling parameters for formulations 6-1 and 6-2

[0548] The weight of the capsules after filling was monitored. For formulation 6-1: the maximum weight of the finished capsules was 0.111g, and the minimum weight was 0.103g, both within the theoretical control range of 0.101–0.113g. The average weight of the finished capsules was 0.107g, consistent with the theoretical weight. For formulation 6-2: the maximum weight of the finished capsules was 0.444g, and the minimum weight was 0.432g, both within the theoretical control range of 0.412–0.462g. The average weight of the finished capsules was 0.437g, consistent with the theoretical weight. Similar results were obtained from the weight monitoring of multiple batches of capsules. This indicates that the finished products produced by the preparation process of each specification of capsules in this application have stable quality.

[0549] (9) Packaging: The finished product was packaged in high-density polyethylene bottles for oral solid pharmaceuticals, and then sealed with child-safe moisture-proof combination caps made of polypropylene / low-density polyethylene for oral solid pharmaceuticals, and labeled. Various properties of the finished capsules were tested, and the results are shown in Table 6-6.

[0550] Table 6-6 Test Results of Finished Capsules

[0551] *Dissolution test method: Paddle method + sedimentation basket, rotation speed 75 rpm, temperature 37℃, medium volume 900 ml, hydrochloric acid solution at pH 1.0, sample taken after 30 min, and solution content determined by HPLC.

[0552] After multiple batches of production, the finished capsules all achieved similar test results. This indicates that the preparation process of the pharmaceutical composition of the present invention is simple, and the finished product has high purity, low impurity content, good content uniformity, rapid dissolution, and stable quality, making it suitable for industrial-scale production.

[0553] Example 7

[0554] Capsule formulations of different strengths were prepared according to the formulations shown in Table 7-1. Formulation 7-1 contained 10 mg of compound 17 in its free base form (i.e., 10 mg strength); formulation 7-2 contained 30 mg of compound 17 in its free base form (i.e., 30 mg strength). The powder properties and weight distribution of the finished products were investigated.

[0555] Table 7-1 Formulation composition of preparations 7-1 and 7-2

[0556] The preparation process is as follows:

[0557] (1) Pretreatment of active pharmaceutical ingredient: Take the fumarate of compound 17 and optionally control Dv(90)≤50μm through a pulverization process. The pulverization process parameters are: rotation speed 3000~4000rpm (target rotation speed 3500rpm), and sieve aperture 0.4mm.

[0558] (2) Weighing: Weigh the microcrystalline cellulose, fumarate of compound 17, mannitol, croscarmellose sodium cellulose and colloidal silica according to the prescription amount, and add them to the mixing tank in sequence;

[0559] (3) Premixing: For formulation 7-1, mix at 11 rpm for 8 minutes; for formulation 7-2, mix at 10 rpm for 7 minutes.

[0560] (4) Sieving: Discharge the material from the mixing tank and sieve it using a conical screen mill. The screen aperture is 1.0 mm and the rotation speed is 200 rpm to 1000 rpm (target speed 400 rpm). The sieved powder is added to the material tank.

[0561] (5) Mixing: For formulation 7-1, mix at 11 rpm for 16 minutes; for formulation 7-2, mix at 10 rpm for 14 minutes.

[0562] (6) Total mixing: Weigh the magnesium stearate according to the prescription amount, add it to the mixing tank, and mix with the following parameters: For formulation 7-1, mix at 11 rpm for 8 minutes; for formulation 7-2, mix at 10 rpm for 7 minutes.

[0563] (7) Intermediate control: Samples were taken from 11 locations in the upper, middle, and bottom layers of the mixing tank to test the mixing uniformity and powder properties. The results are shown in Tables 7-2 and 7-3. The data indicate that the intermediate mixed powder has good powder properties and mixing uniformity.

[0564] Table 7-2 Results of Mixing Uniformity Test for Intermediate Powder

[0565] Table 7-3 Powder Geometric Detection Results of Intermediate Mixed Powder

[0566] (8) Capsule filling: Hydroxypropyl methylcellulose hollow capsules (I) were used for filling. The capsule type, filling rate setting, and filling weight control range are shown in Table 7-4 below:

[0567] Table 7-4 Capsule filling process parameters

[0568] The weight of the capsules after filling was monitored. For formulation 7-1: the maximum weight of the finished capsules was 0.110g, and the minimum weight was 0.101g, both within the theoretical control range of 0.099–0.113g. The average weight of the finished capsules was 0.106g, consistent with the theoretical weight. For formulation 7-2: the maximum weight of the finished capsules was 0.294g, and the minimum weight was 0.272g, both within the theoretical control range of 0.261–0.301g. The average weight of the finished capsules was 0.284g, essentially consistent with the theoretical weight. This indicates that the finished products produced by the preparation process of each specification of capsules in this application have stable quality.

[0569] (9) Packaging: The finished product is packaged in high-density polyethylene bottles for oral solid medicine, and then sealed and boxed with child-safe moisture-proof combination caps for oral solid medicine polypropylene / low-density polyethylene.

[0570] The results show that the formulation and preparation process provided in this invention are suitable for industrial-scale production, ensuring smooth production of the formulation and product quality.

[0571] Example 8

[0572] A 10 mg formulation was prepared according to the formulation process of formulation 6-1 in Example 6; a 50 mg formulation was prepared according to the formulation process of formulation 6-2 in Example 6; and a 30 mg formulation was prepared according to the formulation process of formulation 7-2 in Example 7. The stability of the above three formulations under influencing factors, accelerated conditions, and long-term conditions was tested.

[0573] (1) Stability investigation of influencing factors

[0574] The three types of capsules without packaging were placed in high temperature (60℃±2℃), high humidity (25℃±2℃, 92.5% RH±5% RH), and light exposure (4500lx±500lx and ≥0.80×10⁻⁶ lx and ≥0.80×10⁻⁶ lx, respectively). 2 μW / cm 2 Under the specified time conditions, the stability indicators of the formulation were measured after 30 days, and the results are as follows:

[0575] Furthermore, after 30 days of storage under both light and light-dampness conditions, there were no significant differences in any of the indicators compared to day 0. These results demonstrate that the pharmaceutical compositions of this application exhibit good stability under various influencing factors such as high temperature, high humidity, and light exposure.

[0576] (2) Stability test under accelerated conditions

[0577] The above three types of capsules were stored under accelerated conditions at 40℃±2℃ and 75%RH±5%RH for 6 months. The stability indicators of the formulations were then measured, and the results are as follows:

[0578] Furthermore, after 6 months of accelerated storage, all other indicators of the above three formulations were far below the prescribed limits. For example, regarding microbial limits, the total number of aerobic bacteria per 1g of test sample was <100cfu / g, the total number of molds and yeasts was <50cfu / g, and Escherichia coli was not detected. These results demonstrate that the pharmaceutical compositions of this application exhibit good storage stability under accelerated storage conditions.

[0579] (3) Stability test under long-term conditions

[0580] The capsules of the above specifications were stored at a temperature of 25℃±2℃ and a humidity of 60%RH±5%RH for 36 months. The stability indicators of the formulation were then measured, and the results are as follows:

[0581] Furthermore, after 36 months of long-term storage, all other indicators of the above-mentioned formulations were far below the prescribed limits. For example, in terms of microbial limits, the total number of aerobic bacteria per 1g of test sample was <100cfu / g, the total number of molds and yeasts was <50cfu / g, and Escherichia coli was not detected. These results demonstrate that the pharmaceutical compositions of this application maintain good stability even after long-term storage.

[0582] The above embodiments do not limit the scope of this application in any way. In addition to those described herein, various modifications to this application will be apparent to those skilled in the art based on the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. All references cited in this application (including all patents, patent applications, journal articles, books, and any other disclosures) are incorporated herein by reference in their entirety.

Claims

1. An oral pharmaceutical composition comprising an active ingredient and at least one pharmaceutically acceptable carrier, wherein the active ingredient is a compound represented by Formula A, a pharmaceutically acceptable salt, a stereoisomer, a polymorph, a solvate, a metabolite, or a prodrug thereof, wherein: R 1 selected from -C(O)-C 1-6 alkyl, 4-10 membered heterocyclyl, and 5-10 membered heteroaryl, each optionally substituted with one or more substituents independently selected from hydroxy, halogen, CN, NO2, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkoxy, C 1-4 heteroalkyl, C 3-6 cycloalkyl, and C 3-6 cycloalkoxy; R 2 selected from H, halo, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 1-6 haloalkyl, C 1-6 heteroalkyl, 4-10 membered heterocyclyl, and 5-10 membered heteroaryl, said C 1-6 alkyl, C 1-6 heteroalkyl, 4-10 membered heterocyclyl, and 5-10 membered heteroaryl are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, NO2, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 hydroxyalkyl, C 1-4 haloalkoxy, C 1-4 heteroalkyl, C 3-6 cycloalkyl, and C 3-6 cycloalkoxy; R 3 selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 heteroalkyl, and C 3-6 cycloalkyl; R 4 selected from C 1-6 alkyl and C 1-6 alkoxy; X 1 , X 2 , and X 3 are each independently selected from S, CR 5 , and N, wherein R 5 is selected from H, halogen, and C 1-6 alkyl; X 4 is selected from C and N; X 5 is selected from CH and N, or X 5 is absent; X 6 is selected from CH and N; and n is 0 or 1 ; the pharmaceutically acceptable carrier is one or more of a filler, a disintegrant, a glidant, and a lubricant.

2. The pharmaceutical composition of claim 1, wherein the compound has the structure of Formula I, ###0001### wherein: R 1 selected from 4-10 membered heterocyclyl and 5-10 membered heteroaryl, each of which is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, CN, NO2, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkoxy, C 1-4 heteroalkyl, C 3-6 cycloalkyl and C 3-6 cycloalkoxy; R 2 selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, 4-10 membered heterocyclyl, and 5-10 membered heteroaryl, each optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, CN, NO2, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkoxy, C 1-4 heteroalkyl, C 3-6 cycloalkyl, and C 3-6 cycloalkoxy; R 3 selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 heteroalkyl, and C 3-6 cycloalkyl; and X 1 , X 2 and X 3 are each independently selected from CH and N; the pharmaceutically acceptable carrier is one or more of a filler, a disintegrant, a glidant, and a lubricant.

3. The pharmaceutical composition of claim 2, wherein the R 1 is selected from 5-membered nitrogen-containing heteroaryl, said heteroaryl optionally substituted with one or more C 1-4 alkyl groups; R 2 selected from 5-membered nitrogen-containing heteroaryl, said heteroaryl being optionally substituted with one or more halogen; R 3 selected from H; X 1 selected from N; X 2 is selected from CH; and X 3 selected from N.

4. The pharmaceutical composition of claim 3, wherein the R 1 is pyrazolyl, which is optionally substituted with one or more C 1-4 alkyl groups; R 2 is selected from pyrazolyl, said pyrazolyl being optionally substituted with one or more halogen; R 3 selected from H; X 1 selected from N; X 2 is selected from CH; and X 3 selected from N.

5. The pharmaceutical composition of claim 1, wherein the compound is selected from the group consisting of:

6. The pharmaceutical composition of claim 5, wherein the active ingredient is the following compound or a pharmaceutically acceptable salt thereof:

7. The pharmaceutical composition of claim 6, wherein the active ingredient is a fumarate salt of compound 17.

8. The pharmaceutical composition of any one of claims 1 to 7, wherein the active ingredient is present in an amount of 1 to 30% by weight, preferably 11 to 25% by weight, further preferably 13 to 22% by weight, of the pharmaceutical composition.

9. Pharmaceutical composition according to any one of claims 1 to 8, characterized in that one or more of 1) to 5): 1) the particle size D of the active ingredient v (90) is from 1 to 500 μm, preferably from 1 to 100 μm, more preferably from 1 to 60 μm, further preferably from 5 to 50 μm, for example from 20 to 50 μm; 2) the particle size D of the active ingredient v (50) is 1 to 100 μm, preferably 1 to 50 μm, further preferably 1 to 20 μm; 3) the particle size D of the active ingredient v (10) from 0.1 to 10 μm, preferably from 0.1 to 7 μm, further preferably from 0.1 to 5 μm; 4) the active ingredient has a particle size D[4,3] of 1 to 50 pm, preferably 1 to 30 pm, further preferably 1 to 25 pm; 5) the active ingredient has a particle size D[3,2] of 0.1 to 10 pm, preferably 0.1 to 7 pm, further preferably 0.1 to 5 pm.

10. Pharmaceutical composition according to any one of claims 1 to 9, characterized in that one or more of 1) to 4): 1) the filler is selected from one or more of the following: mannitol, microcrystalline cellulose, starch, pregelatinized starch, lactose, calcium dihydrogen phosphate, calcium hydrogen phosphate, calcium phosphate, calcium carbonate; preferably a combination of mannitol and microcrystalline cellulose; 2) the disintegrant is selected from one or more of the following: low-substituted hydroxypropyl cellulose, low-substituted hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, croscarmellose sodium, sodium carboxymethyl starch, crospovidone; preferably croscarmellose sodium; 3) the glidant is selected from one or more of the following: colloidal silicon dioxide, silicon dioxide, tricalcium phosphate, and talc, preferably silicon dioxide; 4) the lubricant is selected from one or more of the following: stearic acid, magnesium stearate, calcium stearate, hydrogenated vegetable oil, sodium lauryl sulfate, magnesium lauryl sulfate, talc, polyethylene glycol, sodium stearyl fumarate, silicon dioxide, preferably magnesium stearate.

11. The pharmaceutical composition of any one of claims 1 to 10, comprising the following ingredients: an active ingredient which is compound 17, a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, metabolite, or prodrug thereof, present in an amount of 0.5 to 30% by weight of the pharmaceutical composition; a filler present in an amount of 50 to 95% by weight of the pharmaceutical composition, the filler being one or more of mannitol, microcrystalline cellulose, or pregelatinized starch; a disintegrant present in an amount of 1 to 10% by weight of the pharmaceutical composition, the disintegrant being one or more of low-substituted hydroxypropyl cellulose, low-substituted hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, croscarmellose sodium, sodium carboxymethyl starch, crospovidone; a glidant present in an amount of 0.1 to 5% by weight of the pharmaceutical composition, the glidant being one or more of colloidal silicon dioxide, silicon dioxide, tricalcium phosphate, and talc; and a lubricant present in an amount of 0.1 to 5% by weight of the pharmaceutical composition, the lubricant being one or more of magnesium stearate, sodium stearyl fumarate, or silicon dioxide.

12. The pharmaceutical composition of any one of claims 1-11, comprising: an active ingredient which is Compound 17, a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, metabolite or prodrug thereof, wherein the active ingredient is present in an amount of 0.5-30% by weight of the pharmaceutical composition; mannitol, which is present in an amount of 25-45% by weight of the pharmaceutical composition; microcrystalline cellulose, which is present in an amount of 25-45% by weight of the pharmaceutical composition; croscarmellose sodium, which is present in an amount of 1-10% by weight of the pharmaceutical composition; colloidal silicon dioxide, which is present in an amount of 0.1-3% by weight of the pharmaceutical composition; and magnesium stearate, which is present in an amount of 0.1-3% by weight of the pharmaceutical composition; Preferably, the pharmaceutical composition comprises: 0.5-30 parts by weight of the fumarate salt of Compound 17; 25-45 parts by weight of mannitol; 25-45 parts by weight of microcrystalline cellulose; 1-10 parts by weight of croscarmellose sodium; 0.1-3 parts by weight of colloidal silicon dioxide; and 0.1-3 parts by weight of magnesium stearate; Preferably, the pharmaceutical composition comprises: 17-18 parts by weight of the fumarate salt of Compound 17; 37-38 parts by weight of mannitol; 37-38 parts by weight of microcrystalline cellulose; 4-6 parts by weight of croscarmellose sodium; 0.8-1.2 parts by weight of colloidal silicon dioxide; and 0.8-1.2 parts by weight of magnesium stearate; Preferably, the pharmaceutical composition comprises: 17-18 parts by weight of the fumarate salt of Compound 17; 37-38 parts by weight of mannitol; 37-38 parts by weight of microcrystalline cellulose; 5 parts by weight of croscarmellose sodium; 1 part by weight of colloidal silicon dioxide; and 1 part by weight of magnesium stearate.

13. The pharmaceutical composition of claim 12, wherein the weight ratio of the microcrystalline cellulose and the mannitol is 0.5-8:1, preferably 0.5-6:1; further preferably 0.5-1:

1.

14. The pharmaceutical composition of any one of claims 1-13, which is a capsule.

15. The pharmaceutical composition of claim 14, wherein the capsule shell of the capsule is a gelatin empty capsule, a hypromellose empty capsule, a starch empty capsule; preferably a hypromellose empty capsule.

16. The pharmaceutical composition of any one of claims 1-15, wherein the dissolution of the pharmaceutical composition is in accordance with one or more of the following: (1) at least 80% by weight of the active ingredient is dissolved in 30 minutes; (2) at least 85% by weight of the active ingredient is dissolved in 45 minutes; (3) at least 90% by weight of the active ingredient is dissolved in 60 minutes, as determined by the method for dissolution test of paddle method in 900 ml of pH 1.0 hydrochloric acid solution at a rotation speed of 75 rpm and a temperature of 37 °C according to the Chinese Pharmacopoeia.

17. A pharmaceutical preparation comprising the pharmaceutical composition of any one of claims 1-16 and a package; preferably the package is an aluminum plastic blister package or a high-density polyethylene bottle package. ​ ​ ​ 18. A process for the preparation of a pharmaceutical composition according to any one of claims 1 to 16 or a pharmaceutical preparation according to claim 17, comprising: i) controlling the particle size of the active ingredient by an optional milling step; ii) mixing the active ingredient with one or more of a filler, a disintegrant, a glidant and a lubricant; wherein the particle size of the active ingredient is one or more of the following 1) to 5): 1) D v (90) is 1 to 500 μm, preferably 1 to 100 μm, more preferably 1 to 60 μm, further preferably 5 to 50 μm, for example 20 to 50 μm; 2) D v (50) is 1 to 100 μm, preferably 1 to 50 μm, further preferably 1 to 20 μm; 3) D v (10) from 0.1 to 10 μm, preferably from 0.1 to 7 μm, further preferably from 0.1 to 5 μm; 4) D[4,3] is 1 to 50 pm, preferably 1 to 30 pm, further preferably 1 to 25 pm; and / or 5) D[3,2] is 0.1 to 10 pm, preferably 0.1 to 7 pm, further preferably 0.1 to 5 pm.

19. Use of a pharmaceutical composition according to any one of claims 1 to 16 or a pharmaceutical preparation according to claim 17 for the preparation of a medicament for the treatment of a RET-associated disease, wherein the RET-associated disease is preferably selected from the group consisting of a cancer or irritable bowel syndrome, preferably the cancer is selected from the group consisting of lung cancer, breast cancer, head and neck cancer, rectal cancer, liver cancer, thyroid cancer and colon cancer, preferably the cancer is selected from the group consisting of non-small cell lung cancer (NSCLC), medullary thyroid cancer (MTC), papillary thyroid cancer (PTC), pancreatic cancer, ovarian cancer and inhibitor resistant solid tumors.

20. A method for the treatment of a RET-associated disease, comprising administering to an individual in need thereof a pharmaceutical composition according to any one of claims 1 to 16 or a pharmaceutical preparation according to claim 17, wherein the JAK-associated disease is preferably selected from the group consisting of a cancer or irritable bowel syndrome, preferably the cancer is selected from the group consisting of lung cancer, breast cancer, head and neck cancer, rectal cancer, liver cancer, thyroid cancer and colon cancer, preferably the cancer is selected from the group consisting of non-small cell lung cancer (NSCLC), medullary thyroid cancer (MTC), papillary thyroid cancer (PTC), pancreatic cancer, ovarian cancer and inhibitor resistant solid tumors.

21. A pharmaceutical composition according to any one of claims 1 to 16 or a pharmaceutical preparation according to claim 17 for use in the treatment of a RET-associated disease, wherein the RET-associated disease is preferably selected from the group consisting of a cancer or irritable bowel syndrome, preferably the cancer is selected from the group consisting of lung cancer, breast cancer, head and neck cancer, rectal cancer, liver cancer, thyroid cancer and colon cancer, preferably the cancer is selected from the group consisting of non-small cell lung cancer (NSCLC), medullary thyroid cancer (MTC), papillary thyroid cancer (PTC), pancreatic cancer, ovarian cancer and inhibitor resistant solid tumors.

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