Treatment use of pyrrolopyrimidine compound, and solid pharmaceutical composition thereof

Abstract

To provide a compound for treating myeloproliferative neoplasm, and a pharmaceutical composition comprising the compound.SOLUTION: The present invention provides a pyrrolopyrimidine compound represented by the following formula I, and a solid pharmaceutical composition comprising a diluent, a binder, a wetting agent, and a disintegrant.SELECTED DRAWING: None

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims the rights and interests of Chinese invention patent applications bearing application numbers 201811581815.8 and 201910679429.0, filed with the Intellectual Property Office of the People's Republic of China on December 24, 2018 and July 26, 2019, respectively, which are hereby incorporated by reference in their entireties.

[0002] [Technical field] The present invention belongs to the field of medicinal chemistry and relates to the therapeutic use of pyrrolopyrimidine compounds and solid pharmaceutical compositions thereof. [Background technology]

[0003] Janus kinase (JAK) is a non-receptor tyrosine kinase (PTK) present in cells that transmits cytokine stimulatory signals through the JAK / STAT pathway. The JAK / STAT pathway transmits extracellular chemical signals through the cell membrane to gene promoters located in the nuclear DNA, ultimately affecting the transcription and activity levels of intracellular DNA. The JAK / STAT pathway is composed of three main components: (1) receptors, (2) Janus kinases (JAKs), and (3) signal transducers and activators of transcription (STATs). The receptors can be activated by interferons, interleukins, growth factors, or other chemical messengers, which can cause the autophosphorylation of JAKs. Then, STATs are phosphorylated by JAKs through the binding of STAT proteins to the phosphorylated receptors. The phosphorylated STAT proteins are then dissociated from the receptor, dimerized, translocated into the cell nucleus, where they bind to specific DNA sites and alter transcription (Scott, MJ, CJ Godshall et al. (2002). "Jaks, STATs, Cytokines, and Sepsis" Clin Diagn Lab Immunol 9(6): 1153-9).

[0004] The JAK family acts in cell proliferation and functional cytokine-dependent regulation involved in immune responses. Currently, there are four known members of the mammalian JAK family: JAK1, JAK2, JAK3, and TYK2 (Tyrosine kinase 2). JAK proteins range in size from 120 to 140 kDa and contain seven conserved JAK homology (JH) domains, one of which is a functional catalytic kinase domain and the other is a pseudokinase domain, which effectively function in regulatory functions and / or as a docking site for STAT proteins (Scott, Godshall et al. 2002, supra).

[0005] Myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell disorders characterized primarily by excessive proliferation of one or more relatively mature cells of the myeloid lineage. Myeloproliferative neoplasms mainly include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Summary of the Invention

[0006] The present invention relates to a compound of formula I: [ka] (In the formula, R 1 and R 2 are independently H, C 1~6 Alkyl, C 1~6 Alkyl acyls, and C 1~6 alkylsulfonyl; R 3 and R 4 are each independently selected from the group consisting of H, hydroxyl, and oxo. or a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof.

[0007] According to one aspect, the present invention provides a pharmaceutical composition for the treatment of myeloproliferative neoplasms comprising a compound of formula I above, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof. According to one aspect, the present invention provides a method for treating myeloproliferative neoplasms, comprising administering to a subject an effective amount of a compound of formula I above, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof. According to one aspect, the present invention provides the use of a compound of formula I above, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the treatment of a myeloproliferative neoplasm. According to one aspect, the present invention provides the use of a compound of formula I above, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the treatment of myeloproliferative neoplasms.

[0008] According to another aspect, the present invention provides a solid pharmaceutical composition comprising a compound of formula I, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, and a diluent, a binder, a wetting agent, and a disintegrant. According to another aspect, the present invention provides a solid pharmaceutical composition as described above for the treatment of a Janus kinase mediated disease. According to another aspect, the present invention provides a use of the solid pharmaceutical composition in the manufacture of a medicament for the treatment of a Janus kinase-mediated disease. According to another aspect, the present invention provides a method for treating a Janus kinase mediated disease comprising administering to a subject an effective amount of the above-described solid pharmaceutical composition. According to another aspect, the present invention provides the use of the solid pharmaceutical composition in the treatment of a Janus kinase mediated disease.

[0009] [Details of the invention] The present invention relates to a compound of formula I: [ka] (In the formula, R 1 and R 2 are independently H, C 1~6 Alkyl, C 1~6 Alkyl acyls, and C 1~6 alkylsulfonyl; R 3 and R 4 are each independently selected from the group consisting of H, hydroxyl, and oxo. or a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof.

[0010] According to one aspect, the present invention provides a pharmaceutical composition for the treatment of myeloproliferative neoplasms comprising a compound of formula I above, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof. According to one aspect, the present invention provides a method for treating myeloproliferative neoplasms, comprising administering to a subject an effective amount of a compound of formula I above, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof. According to one aspect, the present invention provides the use of a compound of formula I above, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the treatment of a myeloproliferative neoplasm. According to one aspect, the present invention provides the use of a compound of formula I above, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the treatment of myeloproliferative neoplasms.

[0011] In some embodiments of the present invention, the pharmaceutical composition comprises a compound of formula I above, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof.

[0012] In some embodiments of the present invention, R 1 and R 2are each independently selected from the group consisting of H, methyl, ethyl, propyl, butyl, pentyl, hexyl, formyl, acetyl, propanoyl, butyryl, valeryl, hexanoyl, methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, pentylsulfonyl, and hexylsulfonyl.

[0013] In some embodiments of the present invention, R 1 is H, and R 2 is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, formyl, acetyl, propanoyl, butyryl, valeryl, hexanoyl, methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, pentylsulfonyl, and hexylsulfonyl.

[0014] In some embodiments of the present invention, the compound of formula I above has the following formula: [ka] The configuration is represented as follows:

[0015] In some embodiments of the present invention, the compound of formula I, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof is represented by the following: [ka] is selected from the group consisting of:

[0016] In some embodiments of the present invention, the compound of formula I, its stereoisomer, or its pharma- ceutically acceptable salt is preferably selected from the group consisting of: [ka] is selected from the group consisting of:

[0017] In some embodiments of the present invention, the compound is preferably a hydrochloride salt of the compound of formula I. In some embodiments of the present invention, the compound is preferably a monohydrochloride salt of the compound of formula I. In some embodiments of the present invention, the compound is preferably a crystalline monohydrochloride salt of the compound of formula I. In some embodiments of the invention, the free base of the compound of formula I is preferred. In some embodiments of the invention, the free base of the compound of formula I is preferred.

[0018] In some embodiments of the present invention, the compound of formula I has the following formula II: [ka] It is a compound represented by the formula:

[0019] In some embodiments of the present invention, there is provided a compound of formula II, or a pharma- ceutically acceptable salt thereof, for the treatment of polycythemia vera. In some embodiments of the present invention, there is provided a compound of Formula II, or a pharma- ceutically acceptable salt thereof, for the treatment of thrombocytosis. In some embodiments of the present invention, there is provided a compound of formula II, or a pharma- ceutically acceptable salt thereof, for the treatment of myelofibrosis. In some embodiments of the present invention, there is provided a pharmaceutical composition for the treatment of polycythemia vera, comprising a compound of formula II above or a pharma- ceutically acceptable salt thereof.

[0020] In some embodiments of the present invention, there is provided a pharmaceutical composition for the treatment of thrombocytosis, comprising a compound of formula II above, or a pharma- ceutically acceptable salt thereof. In some embodiments of the present invention, there is provided a pharmaceutical composition for the treatment of myelofibrosis, comprising a compound of formula II above or a pharma- ceutically acceptable salt thereof. In some embodiments of the present invention, the present invention provides a method for treating polycythemia vera, comprising administering to a subject an effective amount of a compound of formula II above, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0021] In some embodiments of the present invention, the present invention provides a method for treating thrombocytosis, comprising administering to a subject an effective amount of a compound of formula II above, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0022] In some embodiments of the present invention, the present invention provides a method for treating myelofibrosis, comprising administering to a subject an effective amount of a compound of formula II above, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments of the present invention, the present invention provides the use of a compound of formula II, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the treatment of polycythemia vera. In some embodiments of the present invention, the present invention provides the use of a compound of formula II, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the treatment of thrombocytosis.

[0023] In some embodiments of the invention, the invention provides the use of a compound of formula II, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the treatment of myelofibrosis. In some embodiments of the present invention, the present invention provides the use of a compound of formula II, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the treatment of polycythemia vera. In some embodiments of the present invention, the present invention provides the use of a compound of formula II, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the treatment of thrombocytosis. In some embodiments of the invention, the invention provides the use of a compound of formula II, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the treatment of myelofibrosis.

[0024] The pharmaceutical composition of the present invention can be prepared by combining the compound of the present invention with a suitable pharma- ceutically acceptable auxiliary agent, and can be prepared as a solid, semi-solid, liquid or gas preparation, such as tablets, pills, capsules, powders, granules, creams, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols. The pharmaceutical composition of the present invention can be prepared by methods well known in the art, such as, for example, conventional mixing, dissolving, granulating, sugar-coated tablet preparation, pulverizing, emulsifying, lyophilizing, etc. Suitable auxiliary agents include, but are not limited to, binding agents (binders), diluents, wetting agents, disintegrating agents, lubricants, glidants, sweeteners or flavoring agents.

[0025] In some embodiments of the present invention, the pharmaceutical composition is a formulation suitable for oral administration, including tablets, capsules, powders, granules, drops, creams, powders, etc., preferably tablets and capsules. The oral formulation can be prepared in a conventional manner using pharma- ceutically acceptable carriers known in the art. The pharma- ceutically acceptable carriers include diluents, binders, wetting agents, disintegrants, lubricants, etc. Diluents include microcrystalline cellulose, mannitol, lactose, sucrose, starch, pregelatinized starch, dextrin, or mixtures thereof. Binders include hydroxypropylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, ethylcellulose, methylcellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, gelatin, polyvinylpyrrolidone, starch, sucrose, glucose, gelatin, or mixtures thereof. Wetting agents include magnesium stearate, talc, polyethylene glycol, sodium dodecyl sulfate, silica gel micropowder, talc, or mixtures thereof. Disintegrants include sodium carboxymethyl starch, dry starch, microcrystalline cellulose, hydroxyethyl methylcellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, low-substituted hydroxypropyl methylcellulose or crospovidone, or mixtures thereof, etc. Lubricants include magnesium stearate, colloidal silica, talc, polyethylene glycol, stearic acid, sodium stearyl fumarate, or mixtures thereof, etc. Pharmaceutical adjuvants further include colorants, sweeteners, coating agents, etc.

[0026] In some embodiments of the present invention, such pharmaceutical compositions are single dose pharmaceutical compositions. In some embodiments, the pharmaceutical compositions contain 1 mg to 50 mg of the compound of the present invention, its stereoisomer, or its pharma- ceutically acceptable salt. In some embodiments, the pharmaceutical compositions contain 1 mg, 2 mg, 5 mg, 8 mg, 10 mg, 12 mg, 15 mg, 18 mg, 20 mg, 22 mg, 25 mg, 28 mg, 30 mg, 32 mg, 35 mg, 38 mg, 40 mg, 42 mg, 45 mg, 48 mg, or 50 mg of the compound of the present invention, its stereoisomer, or its pharma- ceutically acceptable salt, or any value therein, or a range including any of the aforementioned values ​​as endpoints (e.g., 2 mg to 50 mg, 10 mg to 40 mg, 5 mg to 30 mg, 5 mg to 20 mg, etc.).

[0027] Solid pharmaceutical composition The present invention provides a solid pharmaceutical composition comprising a compound of formula I or a compound of formula II as described herein, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof, and a diluent, a binder, a wetting agent and a disintegrant. In some embodiments of the invention, the solid pharmaceutical composition comprises a compound of formula I or a compound of formula II, a diluent, a binder, a wetting agent, and a disintegrant.

[0028] In some embodiments of the present invention, the solid pharmaceutical composition further comprises a lubricant. In some embodiments of the present invention, the amount of the compound of formula I or the compound of formula II is selected from the group consisting of 1-30% by weight, preferably 1-25% by weight, 1-20% by weight, 2-20% by weight, 2-15% by weight, 2-10% by weight, 3-10% by weight, and 2-8% by weight, more preferably 3-8% by weight, and even more preferably 3.5-6% by weight. Alternatively, in some embodiments, the amount of the compound of formula I or the compound of formula II is 1%, 1.2%, 1.4%, 1.6%, 1.8%, 2%, 2.2%, 2.4%, 2.6%, 2.8%, 3%, 3.2%, 3.4%, 3.6%, 3.8%, 4%, 4.2%, 4.4%, 4.6%, 4.8%, 5%, 5.2%, 5.4%, 5.6%, 5.8%, 6%, 6.2%, 6.4%, 6.6%, 6.8%, 7%, 7.2%, 7.4%, 7.6%, 7.8%, 8%, 8.2%, 8.4%, 8.6%, %, 20 wt%, 21 wt%, 22 wt%, 23 wt%, 24 wt%, 25 wt%, 26 wt%, 27 wt%, 28 wt%, 29 wt%, and 30 wt%, or any value therein or in any range comprising any of the aforementioned values ​​as endpoints.

[0029] In some embodiments of the present invention, the diluent is selected from the group consisting of microcrystalline cellulose, mannitol, lactose, sucrose, starch, pregelatinized starch, dextrin, and mixtures thereof, preferably microcrystalline cellulose, mannitol, lactose, pregelatinized starch, or mixtures thereof, more preferably microcrystalline cellulose, mannitol, or mixtures thereof.

[0030] In some embodiments of the invention, the amount of diluent is selected from the group consisting of 50-95%, preferably 60-95%, 65-95%, 70-95%, 75-95%, 80-95%, 80-90%, and 85-95%, more preferably 85-90% by weight. Alternatively, in some embodiments, the amount of diluent is selected from the group consisting of 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, and 95% by weight, or any value within or between any of the above values.

[0031] In some embodiments of the present invention, the binder is selected from the group consisting of hydroxypropyl methylcellulose (HPMC), carboxymethylcellulose (CMC), sodium carboxymethylcellulose (CMC-Na), ethylcellulose (EC), methylcellulose (MC), hydroxypropyl cellulose (HPC), low-substituted hydroxypropyl cellulose (L-HPC), gelatin, polyvinylpyrrolidone (PVP), partially hydrolyzed starch, starch, pregelatinized starch, sucrose, glucose, gelatin, polyethylene glycol (PEG), polyvinyl alcohol, and mixtures thereof. Preferably, the binder is selected from the group consisting of hydroxypropyl methylcellulose (HPMC), carboxymethylcellulose (CMC), sodium carboxymethylcellulose (CMC-Na), ethylcellulose (EC), methylcellulose (MC), hydroxypropyl cellulose (HPC), low-substituted hydroxypropyl cellulose (L-HPC), polyvinylpyrrolidone, and mixtures thereof. More preferably, the binder is selected from the group consisting of hydroxypropyl cellulose, polyvinylpyrrolidone, and mixtures thereof.

[0032] In some embodiments of the invention, the amount of binder is selected from the group consisting of 1.0% to 10% by weight, preferably 1.0% to 8.0% by weight, 1.0% to 6.0% by weight, and 1.0% to 5.0% by weight, more preferably 2.0 to 4.0% by weight. Alternatively, in some embodiments, the amount of binder is selected from the group consisting of 1.0% by weight, 1.5% by weight, 2.0% by weight, 2.5% by weight, 3.0% by weight, 3.5% by weight, 4.0% by weight, 4.5% by weight, 5.0% by weight, 5.5% by weight, 6.0% by weight, 6.5% by weight, 7.0% by weight, 7.5% by weight, 8.0% by weight, 8.5% by weight, 9.0% by weight, 9.5% by weight, and 10% by weight, or any value within or between any of the ranges comprising any of the aforementioned values ​​as endpoints.

[0033] In some embodiments of the present invention, the wetting agent is sodium dodecylbenzenesulfonate, magnesium dodecylbenzenesulfonate, sodium tetradecylbenzenesulfonate, sodium hexadecylbenzenesulfonate, sodium octadecylbenzenesulfonate, sodium dodecylsulfonate, magnesium dodecylsulfonate, sodium tetradecylsulfonate, sodium hexadecylsulfonate, sodium octadecylsulfonate, sodium dodecylsulfonate, magnesium dodecylsulfonate, sodium tetradecylsulfonate, sodium hexadecylsulfonate, sodium octadecylsulfonate, sodium dodecylsulfate, magnesium dodecylsulfate, sodium tetradecylsulfate, sodium hexadecylsulfate, sodium octadecylsulfonate, sodium dodecylsulfate, magnesium dodecylsulfate, sodium tetradecylsulfate, sodium hexadecylsulfate, sodium octadecylsulfate, lauric acid, glyceryl sulfate ... The wetting agent is selected from the group consisting of sodium lauroyl sarcosinate, sodium lactate, sodium palmitate, lauric isopropanolamide, lauric diethanolamide, tetradecyl lactate, hexadecyl lactate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, polysorbate 85, polyoxyethylene lauryl ether, polyoxyethylene cetyl ether, polyoxyethylene sorbitol tetraoleyl ether, polyoxyethylene stearate, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, and mixtures thereof. Preferably, the wetting agent described herein is sodium dodecyl sulfonate, magnesium dodecyl sulfonate, sodium tetradecyl sulfonate, sodium dodecyl sulfate, magnesium dodecyl sulfate, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium octadecyl sulfate, or sodium lauroyl sarcosinate, or mixtures thereof. More preferably, the wetting agent described herein is sodium dodecyl sulfate, or magnesium dodecyl sulfate, or a mixture thereof.

[0034] In some embodiments of the present invention, the amount of the wetting agent is selected from the group consisting of 0.01 to 5.0 wt%, preferably 0.01 to 4.0 wt%, 0.01 to 3.0 wt%, 0.02 to 2.5 wt%, 0.02 to 2.0 wt%, more preferably 0.03 to 2.0 wt%, even more preferably 0.05 to 1.0 wt%, and even more preferably 0.1 to 0.5 wt%. Alternatively, in some embodiments, the amount of lubricant is 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3 ...6%, 3.7%, 3.8%, 3.9%, 3. %, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.2%, 3.4%, 3.6%, 3.8%, 4.0%, 4.2%, 4.4%, 4.6%, 4.8% or 5.0% by weight, or any value therein, or any range comprising any of said values ​​as endpoints.

[0035] In some embodiments of the present invention, the disintegrant is selected from the group consisting of sodium carboxymethyl starch, dry starch, microcrystalline cellulose, hydroxyethyl methylcellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, low-substituted hydroxypropyl methylcellulose, crospovidone, sodium dodecyl sulfate, magnesium dodecyl sulfate, and mixtures thereof.Preferably, sodium carboxymethyl starch, sodium croscarmellose, or mixtures thereof.

[0036] In some embodiments of the present invention, the amount of the disintegrant is selected from the group consisting of 1.0-7.0% by weight, preferably 1.0-6.5% by weight, 1.0-6.5% by weight, 1.0-6.0% by weight, 1.5-5.5% by weight, 1.5-5.0% by weight, and 1.5-4.5% by weight, more preferably 2.0-4.0% by weight. Alternatively, in some embodiments, the amount of the disintegrant is selected from the group consisting of 1.0% by weight, 1.5% by weight, 2.0% by weight, 2.5% by weight, 3.0% by weight, 3.5% by weight, 4.0% by weight, 4.5% by weight, 5.0% by weight, 5.5% by weight, 6.0% by weight, 6.5% by weight, and 7.0% by weight, or any value within or within a range comprising any of the aforementioned values ​​as endpoints.

[0037] In some embodiments of the invention, the lubricant is selected from the group consisting of magnesium stearate, colloidal silica, talc, polyethylene glycol 4000, polyethylene glycol 6000, stearic acid, sodium stearyl fumarate, sodium dodecyl sulfate, and mixtures thereof, preferably magnesium stearate, colloidal silica, or mixtures thereof.

[0038] In some embodiments of the present invention, the amount of the lubricant is selected from the group consisting of 0.1 to 3 wt %, preferably 0.2 to 2.5 wt %, 0.3 to 2.0 wt %, and 0.4 to 1.5 wt %, more preferably 0.5 to 1 wt %. Alternatively, in some embodiments, the amount of lubricant is selected from the group consisting of 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, and 3.0% by weight, or any value therein or in any range comprising any of said values ​​as endpoints.

[0039] In some embodiments of the present invention, the solid pharmaceutical composition comprises 50-95% by weight of microcrystalline cellulose, mannitol, lactose, pregelatinized starch, or mixtures thereof, preferably 60-95%, 65-95%, 70-95%, 75-95%, 80-95%, 80-90% or 85-95% by weight of microcrystalline cellulose, mannitol, lactose, pregelatinized starch, or mixtures thereof, more preferably 85-90% by weight of microcrystalline cellulose, mannitol, lactose, pregelatinized starch, or mixtures thereof, even more preferably 85-90% by weight of microcrystalline cellulose, mannitol, lactose, pregelatinized starch, or mixtures thereof. In some preferred embodiments, the diluent is a mixture of microcrystalline cellulose and mannitol, wherein the weight ratio of microcrystalline cellulose to mannitol is selected from the group consisting of 1:1 to 5:1, preferably 1:1 to 4:1, 1.2:1 to 3.5:1 and 1.2:1 to 3:1, more preferably 1.5:1 to 2.5:1, or the weight ratio of microcrystalline cellulose to mannitol is selected from 1:1, 1.2:1, 1.5:1, 1.8:1, 1.9:1, 2:1, 2.2:1, 2.5:1, 2.8:1, 3:1, 3.2:1, 3.5:1, 3.8:1, 4:1, 4.2:1, 4.5:1, 4.8:1 or 5:1.

[0040] In some embodiments of the present invention, based on the amount of the solid pharmaceutical composition, the diluent in the solid pharmaceutical composition is selected from the group consisting of 50-70% by weight microcrystalline cellulose and 20-40% by weight mannitol, or preferably 52-68% by weight microcrystalline cellulose and 22-38% by weight mannitol, 54-66% by weight microcrystalline cellulose and 24-36% by weight mannitol, 54-64% by weight microcrystalline cellulose and 24-34% by weight mannitol, 56-62% by weight microcrystalline cellulose and 26-32% by weight mannitol, more preferably 56-60% by weight microcrystalline cellulose and 26-30% by weight mannitol, and even more preferably 58.3% by weight microcrystalline cellulose and 29.4% by weight mannitol.

[0041] In some embodiments of the present invention, the solid pharmaceutical composition comprises 1.0% to 10% by weight of hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC), sodium carboxymethylcellulose (CMC-Na), ethylcellulose (EC), methylcellulose (MC), hydroxypropylcellulose (HPC), L-HPC, polyvinylpyrrolidone, or a mixture thereof. Preferably, the solid pharmaceutical composition comprises 1.0% to 8.0% by weight, 1.0% to 6.0% by weight, or 1.0% to 5.0% by weight of hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC), sodium carboxymethylcellulose (CMC-Na), ethylcellulose (EC), methylcellulose (MC), hydroxypropylcellulose (HPC), L-HPC, polyvinylpyrrolidone, or a mixture thereof. More preferably, it contains 2.0 to 4.0% by weight of hydroxypropyl methylcellulose (HPMC), carboxymethyl cellulose (CMC), sodium carboxymethyl cellulose (CMC-Na), ethyl cellulose (EC), methyl cellulose (MC), hydroxypropyl cellulose (HPC), L-HPC, or a mixture thereof, and even more preferably, it contains 2.0 to 4.0% by weight of hydroxypropyl cellulose, polyvinylpyrrolidone, or a mixture thereof.

[0042] In some embodiments of the present invention, the solid pharmaceutical composition contains 0.01-5.0% by weight of sodium dodecyl sulfonate, magnesium dodecyl sulfonate, sodium tetradecyl sulfonate, sodium dodecyl sulfate, magnesium dodecyl sulfate, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium octadecyl sulfate, or sodium lauroyl sarcosine, or a mixture thereof. Preferably, the solid pharmaceutical composition contains 0.01-4.0% by weight, 0.01-3.0% by weight, 0.02-2.5% by weight, or 0.02-2.0% by weight of sodium dodecyl sulfonate, magnesium dodecyl sulfonate, sodium tetradecyl sulfonate, sodium dodecyl sulfate, magnesium dodecyl sulfate, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium octadecyl sulfate, or sodium lauroyl sarcosine, or a mixture thereof, more preferably 0.03-2.0% by weight of sodium dodecyl sulfonate, dodecyl sulfonate It contains magnesium, sodium tetradecyl sulfonate, sodium dodecyl sulfate, magnesium dodecyl sulfate, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium octadecyl sulfate, or sodium lauroyl sarcosine, or a mixture thereof, and more preferably contains 0.03 to 2.0% by weight of sodium dodecyl sulfate or magnesium dodecyl sulfate, or a mixture thereof, and even more preferably contains 0.1 to 0.5% by weight of sodium dodecyl sulfate or magnesium dodecyl sulfate, or a mixture thereof.

[0043] In some embodiments of the present invention, the solid pharmaceutical composition contains 1.0-7.0% by weight of sodium carboxymethyl starch or croscarmellose sodium, or a mixture thereof, preferably 1.0-6.5%, 1.0-6.5%, 1.0-6.0%, 1.5-5.5%, 1.5-5.0%, or 1.5-4.5% by weight of sodium carboxymethyl starch, croscarmellose sodium, or a mixture thereof, more preferably 2.0-4.0% by weight of sodium carboxymethyl starch, croscarmellose sodium, or a mixture thereof.

[0044] In some embodiments of the present invention, the solid pharmaceutical composition comprises 0.1-3 wt % magnesium stearate, colloidal silica, or a mixture thereof, preferably 0.2-2.5 wt %, 0.3-2.0 wt %, or 0.4-1.5 wt % magnesium stearate, colloidal silica, or a mixture thereof, more preferably 0.5-1 wt % magnesium stearate, colloidal silica, or a mixture thereof.

[0045] In some embodiments of the present invention, the solid pharmaceutical composition described herein comprises one or more of the following: A), B), C), D), E), or F): A) 1 to 30% by weight of a compound of formula I or a compound of formula II, 50-95% by weight of microcrystalline cellulose, mannitol, lactose, or pregelatinized starch, or mixtures thereof; 1.0% to 10% by weight of hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC), sodium carboxymethylcellulose (CMC-Na), ethylcellulose (EC), methylcellulose (MC), hydroxypropylcellulose (HPC), L-HPC, or polyvinylpyrrolidone, or a mixture thereof; 0.01 to 5.0% by weight of sodium dodecyl sulfonate, magnesium dodecyl sulfonate, sodium tetradecyl sulfonate, sodium dodecyl sulfate, magnesium dodecyl sulfate, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium octadecyl sulfate, or sodium lauroyl sarcosine, or a mixture thereof; 1.0 to 7.0% by weight of sodium carboxymethyl starch or sodium croscarmellose, or a mixture thereof; Optionally, 0.1 to 3% by weight of magnesium stearate, colloidal silica, or a mixture thereof; or

[0046] B) 2 to 10% by weight of a compound of formula I or a compound of formula II, 75 to 95% by weight of microcrystalline cellulose, or mannitol, or a mixture thereof (in the mixture, the weight ratio of microcrystalline cellulose to mannitol is selected from 1.2:1 to 3.5:1); 1.0 to 6.0% by weight of hydroxypropyl cellulose, or polyvinylpyrrolidone, or a mixture thereof; 0.01 to 3.0% by weight of sodium dodecyl sulfonate, magnesium dodecyl sulfonate, sodium tetradecyl sulfonate, sodium dodecyl sulfate, magnesium dodecyl sulfate, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium octadecyl sulfate, or sodium lauroyl sarcosine, or a mixture thereof; 1.0 to 6.0% by weight of sodium carboxymethyl starch, or sodium croscarmellose, or a mixture thereof; Optionally, 0.3 to 2.0% by weight of magnesium stearate, or colloidal silica, or a mixture thereof; or

[0047] C) 3 to 8% by weight of a compound of formula I or a compound of formula II, 85 to 90% by weight of microcrystalline cellulose, or mannitol, or a mixture thereof (in the mixture, the weight ratio of microcrystalline cellulose to mannitol is selected from 1.5:1 to 2.5:1); 2.0 to 4.0% by weight of hydroxypropyl cellulose, or polyvinylpyrrolidone, or a mixture thereof; 0.03 to 2.0% by weight of sodium dodecyl sulfate, magnesium dodecyl sulfate, or a mixture thereof; 2.0 to 4.0% by weight of sodium carboxymethyl starch, or croscarmellose sodium, or a mixture thereof; Optionally, 0.5 to 1% by weight of magnesium stearate, or colloidal silica, or a mixture thereof, or

[0048] D) 3.0 to 5.0% by weight of a compound of formula I or a compound of formula II, 50-70% by weight of microcrystalline cellulose, 20 to 40% by weight of mannitol, 2.0 to 6.0% by weight of hydroxypropyl cellulose, 0.05 to 0.2% by weight of sodium dodecyl sulfate, 2.0 to 6.0% by weight of croscarmellose sodium, optionally, 0.5 to 2% by weight of magnesium stearate, or

[0049] E) 3.4 to 4.6% by weight of a compound of formula I or a compound of formula II, 55-60% by weight of microcrystalline cellulose, 26 to 32% by weight of mannitol, 2.0 to 4.0% by weight of hydroxypropyl cellulose, 0.1 to 0.5% by weight of sodium dodecyl sulfate, 2.0 to 4.0% by weight of croscarmellose sodium, optionally, 0.5 to 1% by weight of magnesium stearate, or

[0050] F) 4.2% by weight of a compound of formula I or a compound of formula II, 58.3% by weight of microcrystalline cellulose, 29.4% by weight of mannitol, 4.0% by weight of hydroxypropyl cellulose, 0.1% by weight of sodium dodecyl sulfate, 3.0% by weight of croscarmellose sodium, and Optionally, 1.0% by weight of magnesium stearate Includes.

[0051] In some embodiments of the present invention, the compound of formula I or the compound of formula II is present in the form of a free base or a hydrochloride salt.In some exemplary embodiments of the present invention, the compound of formula I or the compound of formula II is present in the form of a free base.In some exemplary embodiments of the present invention, the compound of formula I or the compound of formula II is present in the form of a monohydrochloride salt.

[0052] In some embodiments of the present invention, the solid pharmaceutical composition further comprises a coating agent. In some embodiments, the coating agent is formed from an aqueous film coating composition, which comprises a film-forming polymer, water and / or alcohol as a carrier, and optionally one or more auxiliaries, such as auxiliaries known in the film coating art. In some embodiments, the coating agent is selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, cellulose acetate phthalate, sodium ethylcellulose sulfate, carboxymethylcellulose, polyvinylpyrrolidone, corn protein (zein), and acrylic polymers (e.g., methacrylic acid / methacrylic acid ester copolymers, such as methacrylic acid / methyl methacrylate copolymers), and polyvinyl alcohol. In some exemplary embodiments, the coating agent comprises polyvinyl alcohol.

[0053] In some embodiments of the present invention, the solid pharmaceutical composition has a dissolution rate of 60% or more of the label amount within 30 minutes. In some embodiments of the present invention, the solid pharmaceutical composition has a dissolution rate of 80% or more of the label amount within 30 minutes in a hydrochloric acid solution of pH 1.0, an acetate buffer of pH 4.5, a phosphate buffer of pH 6.8, or purified water of 80% or more of the label amount, preferably 85% or more of the label amount within 30 minutes. In some embodiments of the present invention, the solid pharmaceutical composition has a dissolution rate of 80% or more of the label amount within 30 minutes in purified water, preferably 85% or more of the label amount, more preferably 90% or more of the label amount within 30 minutes. In some typical embodiments of the present invention, the solid pharmaceutical composition has a dissolution rate of 85% or more of the label amount within 15 minutes in purified water.

[0054] In some embodiments of the present invention, the dosage form of the solid pharmaceutical composition is selected from powders, granules, tablets, capsules, pills, micropills, dispersions or inhalable powders, preferably tablets or capsules, more preferably tablets.

[0055] In some embodiments of the invention, the solid pharmaceutical composition is a unit dose pharmaceutical composition and the amount of the compound of formula I or the compound of formula II per unit dose is 5 mg to 20 mg. In some embodiments of the invention, the amount of the compound of formula I or the compound of formula II per unit dose is 5 mg, 8 mg, 10 mg, 12 mg, 15 mg, 18 mg, or 20 mg, or a range defined by an endpoint of any of the aforementioned values, or any value within the aforementioned range.

[0056] According to one aspect, the present invention provides a method for preparing a solid pharmaceutical composition of a compound of formula I or a compound of formula II. The present invention can prepare solid granules by wet granulation. In the process of wet granulation, other auxiliary agents compatible with the compound of formula I or the compound of formula II are added as necessary, among which, the wet granulation can be selected to be carried out in a wet granulator (mixed granulation) or a fluidized bed (fluidized bed granulation), and preferably, the fluidized bed granulation. In the case of wet granulation, the compound of formula I or the compound of formula II can be added to a premix together with other additives as a solid additive, or prepared as a solution (suspension or clear solution) for granulation. Preferably, it is prepared as a suspension and introduced into the granules at the granulation stage.

[0057] In some embodiments of the present invention, a method for preparing a solid pharmaceutical composition of a compound of formula I or a compound of formula II includes the steps of: 1) mixing a diluent and a disintegrant to give a mixture for subsequent use, and mixing a compound of formula I or a compound of formula II, a binder and a wetting agent with water to give a mixed solution; 2) spraying the mixture of step 1) onto the mixture of step 1), granulating and drying in a fluidized bed, and sizing the resulting mixture to obtain dry granules; 3) Optionally, mixing the dry granules with a lubricant and compressing them into tablets. Including, The mixed solution in step 1) is a suspension or a transparent solution, preferably a suspension; The diluents, binders, wetting agents, disintegrants and lubricants are as described above.

[0058] In some embodiments of the present invention, in step 2), the intake air temperature is selected from the group consisting of 35 to 90°C, preferably 45 to 85°C, and more preferably 55 to 80°C. In some embodiments of the present invention, in step 2), the atomization pressure is selected from the group consisting of 400 to 1200 mbar, preferably 500 to 1100 mbar, and more preferably 600 to 1000 mbar. In some embodiments of the present invention, in step 2), the material temperature is selected from the group consisting of 20 to 40°C, and preferably 25 to 35°C. In some embodiments of the present invention, in step 2), the hole diameter Φ of the sieving screen is selected from the group consisting of 0.4 to 1.5 mm, preferably 0.5 to 1.4 mm, and more preferably 0.6 to 1.2 mm.

[0059] According to one aspect, the present invention provides the use of a solid pharmaceutical composition of a compound of formula I or a compound of formula II in the manufacture of a medicament for the treatment of a Janus kinase mediated disease. According to one aspect, the present invention provides a solid pharmaceutical composition of the compound of formula I or the compound of formula II for the treatment of a Janus kinase mediated disease. According to one aspect, the present invention provides the use of a solid pharmaceutical composition of a compound of formula I or a compound of formula II in the treatment of a Janus kinase mediated disease. According to one aspect, the present invention provides a method for treating a Janus kinase mediated disease comprising administering to a subject a therapeutically effective amount of a solid pharmaceutical composition of the compound of formula I or the compound of formula II.

[0060] In some embodiments of the present invention, the Janus kinase mediated disease includes, but is not limited to, a tumor. In some embodiments, the tumor described herein is a lymphoma or leukemia. A lymphoma according to the present invention includes, but is not limited to, Hodgkins disease or non-Hodgkins lymphoma. A non-Hodgkins lymphoma includes, but is not limited to, B-cell lymphoma or T-cell lymphoma. A leukemia according to the present invention includes, but is not limited to, acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myelocytic leukemia.

[0061] In some embodiments of the invention, the Janus kinase-mediated disease is a myeloproliferative neoplasm. In some embodiments of the present invention, the myeloproliferative neoplasm comprises polycythemia vera, thrombocytosis, or myelofibrosis. Among them, the polycythemia vera comprises polycythemia vera resistant and / or intolerant to hydroxyurea and / or interferon. The thrombocytosis comprises primary thrombocytosis, primary thrombocytosis resistant and / or intolerant to hydroxyurea and / or interferon. The myelofibrosis comprises primary myelofibrosis, post-polycythemia vera myelofibrosis (PPV-MF), and post-essential thrombocythemia myelofibrosis (PET-MF).

[0062] In some embodiments of the present invention, the myeloproliferative neoplasms and diseases included therein include low-risk, medium-risk and high-risk myeloproliferative neoplasms. For example, polycythemia vera is classified into low-risk and high-risk polycythemia vera, thrombocytosis is classified into very low-risk, low-risk, medium-risk and high-risk thrombocytosis, and myelofibrosis is classified into low-risk, medium-risk and / or high-risk myelofibrosis. In some embodiments, the polycythemia vera is medium-risk and / or high-risk polycythemia vera, the thrombocytosis is medium-risk and / or high-risk thrombocytosis, the myelofibrosis is medium-risk and / or high-risk myelofibrosis, and the primary thrombocytosis is medium-risk and / or high-risk primary thrombocytosis. For example, the primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-primary thrombocytosis myelofibrosis all belong to the corresponding medium-risk and high-risk myelofibrosis. In the present invention, the myeloproliferative neoplasm diagnostic criteria and risk ranking (e.g., very low risk, low risk, medium risk, high risk) can refer to the general principles of this field, and can be evaluated with reference to the "NCCN Guidelines Version 2.2019 Myeloproliferative Neoplasms", for example, the Dynamic International Prognostic Scoring System (DIPSS). In some embodiments, the World Health Organization WHO 2016 standard and the IWG-MRT standard are used as diagnostic criteria.

[0063] Myeloproliferative neoplasms according to the present invention include mutated myeloproliferative neoplasms, where the mutated genes include, but are not limited to, JAK2 (e.g., JAK2 V617F), MPL, CALR, ASXL1 / SRSF2 / IDH1 / 21, JAK2 exon 12, TP53, SH2B3 / IDH2 / U2AF1 / SF3B1 / EZH2 / TP53, MPL W515L / K, CALR Type 1 / Type 1-like, triple negative (no JAK2, MPL and CALR mutations), ASXL1, EZH2, IDH1 / 2, SRSF2, SF3B1, CALR / ASXL1, TP53, or U2AF1 Q157.

[0064] In some embodiments of the present invention, the compound of formula I or the compound of formula II is administered in the form of a free base. In some embodiments of the present invention, the compound of formula I or the compound of formula II is administered in the form of a crystal of a free base. In some embodiments of the present invention, the crystal of the free base of the compound of formula II may be selected from crystalline form A or crystalline form B published in WO2017215630. In some embodiments of the present invention, the compound of formula II is administered in the form of a hydrochloride salt. In some embodiments of the present invention, the hydrochloride salt of the compound of formula II may be selected from the hydrochlorides disclosed in WO2017101777.

[0065] The compounds of the present invention, their stereoisomers, or pharma- ceutically acceptable salts thereof may be administered by a variety of routes, including, but not limited to, oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, buccal, intranasal, inhalation, vaginal, intraocular, topical, subcutaneous, intraadipose, intraarticular, or intrathecal. In one particular embodiment, the compounds are administered orally.

[0066] The amount of the compound according to the present invention, its stereoisomer, or its pharma- ceutically acceptable salt, or its solid pharmaceutical composition is determined based on the severity of the disease, the response of the disease, any toxicity associated with treatment, the age and health condition of the subject, for example, based on the results of the subject's general blood test (including platelet count, neutrophil count, or hemoglobin concentration, etc.). In some embodiments, the daily dose of the compound according to the present invention, its stereoisomer, or its pharma- ceutically acceptable salt, or its solid pharmaceutical composition is 1 mg to 100 mg. In some embodiments, the daily dose of the compound of the present invention, its stereoisomer, or pharma- ceutically acceptable salt thereof, or solid pharmaceutical composition thereof is selected from the group consisting of 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, and 100 mg, or a range defined by an endpoint that is any of the above values ​​(e.g., 1 mg to 90 mg, 5 mg to 80 mg, 10 mg to 70 mg, 15 mg to 60 mg, 20 mg to 50 mg, etc.), or any value within the above range. In some specific embodiments, the daily dose of the compound according to the present invention, its stereoisomer, or its pharma- ceutically acceptable salt, or its solid pharmaceutical composition is selected from 1 mg to 50 mg, 5 mg to 50 mg, 5 mg to 45 mg, 5 mg to 40 mg, 10 mg to 35 mg, or 10 mg to 30 mg. In some specific embodiments, the daily dose of the compound according to the present invention, its stereoisomer, or its pharma- ceutically acceptable salt, or its solid pharmaceutical composition is selected from 1 mg, 2 mg, 5 mg, 8 mg, 10 mg, 12 mg, 15 mg, 18 mg, 20 mg, 22 mg, 25 mg, 28 mg, 30 mg, 32 mg, 35 mg, 38 mg, 40 mg, 42 mg, 45 mg, 48 mg, or 50 mg, or may be any value within the range defined by an endpoint that is any of the aforementioned values ​​(e.g., 2 mg to 50 mg, 10 mg to 40 mg, 5 mg to 30 mg, 5 mg to 20 mg, etc.), or within the aforementioned range.

[0067] The compound of the present invention, its stereoisomer, or its pharmaceutically acceptable salt, or its solid pharmaceutical composition may be administered once or multiple times per day. In some embodiments, the compound of the present invention, its stereoisomer, or its pharmaceutically acceptable salt, or its solid pharmaceutical composition is administered once or twice per day. The compound of the present invention, its stereoisomer, or its pharmaceutically acceptable salt may also be administered in a single dosage form. In one embodiment, it is administered once or twice per day in a single dosage form. In one embodiment, it is administered once or twice per day in a single dosage form of an oral solid formulation.

[0068] The method of administration can be determined comprehensively based on the activity, toxicity, and tolerance of the subject of the drug, etc. In some embodiments, the compound according to the present invention, its stereoisomer, or its pharma- ceutically acceptable salt can be administered intermittently.

[0069] The administration of the compound of the present invention, its stereoisomer, or its pharmaceutically acceptable salt, or its solid pharmaceutical composition, can be intermittent administration. The intermittent administration includes an administration period and a drug holiday period, during which the compound of the present invention, its stereoisomer, or its pharmaceutically acceptable salt, or its solid pharmaceutical composition, can be administered once, twice, or multiple times a day. The intermittent administration is determined based on the severity of the disease, the response of the disease, the toxicity associated with any treatment, the subject's age and health status, for example, based on the results of the subject's / patient's blood test (such as platelet count, neutrophil count, or hemoglobin concentration).

[0070] [Technical effect] The compounds described herein can effectively shrink the spleen of a subject. The compounds described herein have excellent therapeutic effects on myeloproliferative neoplasms and have excellent safety.

[0071] The solid pharmaceutical composition of the present invention has excellent stability and dissolution properties, making it suitable for clinical application. Furthermore, the solid pharmaceutical composition of the present invention has rapid release properties, with the dissolution rate within 30 minutes being 80% or more of the labeled amount.

[0072] [Definition and Explanation] Unless otherwise specified, the following terms used herein have the following meanings. Any particular term should not be considered unclear or indefinite, and should be understood according to its general meaning in the art, unless specifically defined otherwise. When a trade name is mentioned, it is intended to refer to the corresponding product or its active ingredient.

[0073] The term "pharmacologically acceptable" means that such compounds, materials, compositions and / or dosage forms are capable of being used in contact with human and animal tissues within the scope of sound medical judgment, but without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit-risk ratio.

[0074] The term "pharmaceutically acceptable salt" refers to salts formed from basic radicals and free acids, and salts formed from acidic radicals and free bases, such as, for example, hydrochloride, hydrobromide, nitrate, sulfate, phosphate, formate, acetate, trifluoroacetate, fumarate, oxalate, maleate, citrate, succinate, methanesulfonate, benzenesulfonate, and p-methylbenzenesulfonate, preferably, hydrochloride, hydrobromide, sulfate, formate, acetate, trifluoroacetate, fumarate, maleate, methanesulfonate, p-methylbenzenesulfonate, sodium salt, potassium salt, ammonium salt, and amino acid salt. In the present invention, when a pharma- ceutically acceptable salt is formed, the molar ratio of the free acid to the basic radical is about 1:0.5 to 1:5, preferably 1:0.5, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7 or 1:8. In the present invention, when a pharma- ceutically acceptable salt is formed, the molar ratio of the free base to the acidic radical is about 1:0.5 to 1:5, preferably 1:0.5, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7 or 1:8.

[0075] When used in the present invention, the compounds of formula I or formula II according to the present invention can form acid addition salts, for example, when they have at least one basic site. If necessary, they can further form corresponding acid addition salts with additional basic sites present. Compounds with at least one acid group (e.g., COOH) can also form salts with bases. When the compounds contain, for example, both carboxyl and amino, they can form corresponding inner salts.

[0076] The compounds of the present invention may be asymmetric, e.g., have one or more stereoisomers.Unless otherwise specified, all stereoisomers, e.g., optical isomers and diastereomers, are included.The compounds of the present invention containing asymmetric carbon atoms can be separated in optically pure form or in racemic form.Optical pure forms can be resolved from racemic mixtures or synthesized using chiral materials or chiral reagents.

[0077] The term "subject" means a mammal. In some embodiments, the subject is a human. The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present invention or salts thereof and pharma- ceutical acceptable excipients, intended for advantageous administration of the compounds of the present invention to a subject.

[0078] The term "treatment" means administering a compound or pharmaceutical composition according to the invention to alleviate or eliminate a disease or one or more symptoms associated with said disease, and (i) inhibiting a disease or disease state, i.e., inhibiting its onset or progression; (ii) alleviating a disease or disease state, i.e., reducing the disease or disease state; Includes.

[0079] The term "therapeutically effective amount" refers to an amount of a compound of the present invention administered that (i) treats a particular disease, condition, or disorder, (ii) alleviates, improves, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of a compound of the present invention that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one of ordinary skill in the art based on his or her own knowledge and the contents disclosed in the present invention.

[0080] As used herein, "pharmaceutically acceptable salts" include, but are not limited to, acid addition salts with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, or phosphoric acid), or with organic acids (e.g., formic acid, acetic acid, trifluoroacetic acid, succinic acid, malic acid, maleic acid, fumaric acid, oxalic acid, tartaric acid, citric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.), or with acidic amino acids (e.g., aspartic acid or glutamic acid). The solvates include, but are not limited to, hydrate forms.

[0081] The content of the compound of formula I or the compound of formula II in the pharmaceutical compositions described herein is calculated in the form of its free base. The diluents described herein, also called fillers, are mainly divided into water-soluble diluents, water-insoluble diluents, diluents for direct compression, etc., including but not limited to starch, sucrose, dextrin, lactose, pregelatinized starch, microcrystalline cellulose, inorganic salts and / or sugar alcohols. The lactose includes but is not limited to anhydrous lactose, lactose monohydrate, or mixtures thereof.

[0082] The binders described herein are classified into natural binders and synthetic binders according to their origin. Depending on the method of use, the binders are classified into binders that become sticky only when in aqueous solution or gel form, dry adhesives that remain sticky even in a dry state, and binders that become sticky after being dissolved or wetted with a non-aqueous solvent. Binders include, but are not limited to, starch slurries, cellulose derivatives, povidone, gelatin, polyethylene glycol, sucrose solutions, and / or sodium alginate solutions.

[0083] The wetting agents described herein are liquids and / or surfactants that have low surface tension and are miscible with water, including anionic surfactants, cationic surfactants, zwitterionic surfactants and / or nonionic surfactants. The anionic surfactants include, but are not limited to, alkylbenzenesulfonates, alkylsulfonic acid ester salts, alkylsulfonates, alkyl sulfates, fluorinated fatty acid salts, polysiloxanes and / or fatty alcohol sulfates. The cationic surfactants include, but are not limited to, quaternary ammonium salts, alkylpyridinium salts and / or amine salts. The zwitterionic surfactants include, but are not limited to, lecithin type, amino acid type and / or betaine type. The nonionic surfactants include, but are not limited to, alkylglucosides (APG), fatty acid glycerides, fatty acid sorbitans (Span), polysorbates (tween), polyoxyethylenes and / or poloxamers.

[0084] Disintegrants as described herein include, but are not limited to, starch and its derivatives, celluloses, surfactants, effervescent disintegrants, gums, alginates and / or ion exchange resins. The lubricant described herein broadly includes three types of auxiliary agents: lubricants (narrow sense), glidants and anti-adherents. The lubricants described herein include, but are not limited to, stearic acids, colloidal silica, talc, hydrogenated vegetable oils and / or polyethylene glycols.

[0085] The amount "wt. %" of a certain component (including active substances or auxiliary substances) described herein refers to the weight of the component relative to the total weight of the solid pharmaceutical composition (of which the weight of the compound of formula I or formula II is calculated in the form of its free base). The total weight of the solid pharmaceutical composition does not include the weight of the coating agent.

[0086] The method for preparing the solid pharmaceutical composition or the corresponding dosage form according to the present invention can be carried out according to the methods known in the art. The specific preparation method can include grinding, mixing, sieving, granulation, filling, tableting, etc., and the necessary steps and the method or equipment for carrying out the specific steps can be selected according to the actual situation. For example, the grinding step can be carried out using a mortar, a ball mill, a roller mill, an impact grinder, a hammer mill, and / or a jet mill, the mixing step can be carried out using stirring mixing, grinding mixing, and / or sieving mixing, and the sieving step can be carried out using a rocking sieve and / or a shaking sieve. Alternatively, one can refer to Pharmaceutics edited by Cui Fude et al. (6th or 7th edition, People's Health Publishing House).

[0087] The term "and / or a mixture thereof" refers to "a mixture of two or more types", for example, "the diluent is microcrystalline cellulose, mannitol, lactose, sucrose, starch, pregelatinized starch, dextrin, or a mixture thereof" means "the diluent is one or a mixture of two or more types selected from microcrystalline cellulose, mannitol, lactose, sucrose, starch, pregelatinized starch, dextrin".

[0088] The term "labeled amount" refers to the content of the active substance (principal drug) specified in the unit dose of the preparation in the field of pharmaceutical compositions. The compound of formula I and the compound of formula II according to the present invention can be prepared by referring to the preparation methods in WO2016095805 or WO2017215627. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0089] The present invention will now be described in more detail with reference to specific examples. The following examples are provided for illustrative purposes and are not intended to limit the present invention in any manner.

[0090] [Example 1] (3R)-3-{3-amino-4-{7H-pyrrolo[2,3-d]pyrimidin-4-yl}-1H-pyrazol-1-yl}-3-cyclopentylpropionitrile (II) [ka] The title compound was prepared with reference to WO2016095805 or WO2017215627.

[0091] [Example 2] Tablet solid pharmaceutical composition of (3R)-3-{3-amino-4-{7H-pyrrolo[2,3-d]pyrimidin-4-yl}-1H-pyrazol-1-yl}-3-cyclopentylpropionitrile (II) The formulation of the solid pharmaceutical composition for tablets of 5 mg and 20 mg standard is shown in Table 1.

[0092] [Table 1]

[0093] Manufacturing scheme: 1) Mixture A is prepared by mixing mannitol, microcrystalline cellulose, and croscarmellose sodium. Preparation of raw drug suspension: Add and dissolve hydroxypropyl cellulose in the prescribed amount of purified water to prepare a 4% (w / w) hydroxypropyl cellulose solution, dissolve sodium dodecyl sulfate, add the compound of formula II and stir to disperse, to obtain the raw drug suspension. 2) Fluidized bed granulation, drying: The raw drug suspension is sprayed onto mixture A and the mixture is fluidized bed granulated. Granulation parameters: intake air temperature 55-80°C, atomization pressure 600-1000mbar, material temperature 25-35°C, dry after spraying, and end drying if the material temperature exceeds 45°C. Size the material using a grinding and sieving machine, and set the hole size of the sieving screen to Φ0.6-1.2mm to obtain dried granules after size selection. 3) The dried granules after sieving and magnesium stearate are sequentially charged into a hopper mixer and thoroughly mixed to obtain a solid pharmaceutical composition which is then compressed into tablets.

[0094] [Example 3] Preparation of solid pharmaceutical compositions of formulations A to I The solid pharmaceutical compositions of formulations A to I were prepared with reference to the method of Example 2. The solid pharmaceutical compositions of formulations A to I were tablets with a standard of 5 mg, and their specific formulations were as follows:

[0095] [Table 2]

[0096] [Table 3]

[0097] [ Example 4 ]Stability study of solid pharmaceutical compositions Based on the Guidelines for the Stability Test of APIs and Preparations of China, the stability of the solid pharmaceutical composition of the above formula was considered. The 5 mg and 20 mg tablet solid pharmaceutical compositions obtained in Example 2 were placed under open conditions of light irradiation (6000 lux), high temperature (60°C) and high humidity (RH75%), respectively, and an appropriate amount of sample was taken and added with water-acetonitrile (30:70) to prepare a solution containing about 0.5 mg / mL of the test sample, which was used as the test solution. Octadecylsilane bonded to silica gel was used as the packing material, potassium dihydrogen phosphate buffer-acetonitrile (90:10) was used as mobile phase A, and acetonitrile was used as mobile phase B, and linear gradient elution was performed. The flow rate was 1.0 mL / min, the detection wavelength was 220 nm, and the column temperature was 30°C. The results of detecting the total impurity content were as follows:

[0098] [Table 4]

[0099] [Example 5] Dissolution characteristics experiment According to the Chinese Pharmacopoeia 2015, Part IV, 0931, Dissolution and Release, Method 2, the dissolution performance of the solid pharmaceutical composition of the above formula in four kinds of media was studied. The four kinds of media are pH 1.0 hydrochloric acid solution, pH 4.5 acetate buffer, pH 6.8 phosphate buffer and purified water, respectively, and the medium volume is 900mL. The compound of formula II for control is taken to prepare a solution containing about 5.6μg / mL of the compound of formula II as the control solution. The method and conditions are paddle method, rotation speed: 50rpm, medium temperature: 37℃±0.5℃, sampling time: 5, 10, 15, 20, 30 or 45min. The packing material was octadecylsilane bonded to silica gel, the mobile phase was potassium dihydrogen phosphate buffer-acetonitrile (70:30), the flow rate was 0.4 mL / min, the detection wavelength was 220 nm, and the column temperature was 30° C. The results are as follows:

[0100] [Table 5]

[0101] [Table 6]

[0102] [Table 7]

[0103] [Table 8]

[0104] [Example 6] (Dosage and Compounds) 6.1 Dosage regimen The drug used is a tablet of Example 2, 5 mg standard. Administration method: Oral administration on an empty stomach, once a day for the preliminary test. Subsequent administration groups were orally administered once every 12 hours, and no food should be consumed within 2 hours after administration. 28 consecutive days of administration constitute one treatment cycle.

[0105] Enrolled subjects (hereafter also referred to as "group entry") are required to receive at least one cycle of the drug, and to monitor for tolerance and initial therapeutic effects. For subjects who are deemed by the researchers to be clinically beneficial and who agree to continued use of the investigational treatment, the drug will continue to be provided free of charge until disease progression or until the researchers determine that continued use of the investigational drug is no longer appropriate. In this study, the study will be discontinued once six cycles of continuous administration have elapsed since enrollment was completed.

[0106] 6.2 Group approach standards 1) Age ≥ 18 years, ECOG physical fitness status: 0-2 points, expected survival time: more than 3 months, 2) The subject's diagnosis was PMF, PV, ET, PPV-MF, or PET-MF based on the PMF, PV, and ET standards published by the World Health Organization (WHO) in 2016 and the PPV-MF and PET-MF standards proposed by the International Working Group on Research and Treatment of Myelofibrosis (IWG-MRT). 3) The subjects must have been treated with myelofibrosis at least intermediate risk ≥1 according to the Dynamic International Prognostic Scoring System (DIPSS); 4) Subjects with PV, ET who are resistant or intolerant to hydroxylurea and / or interferon treatment; 5) Major hematology laboratory values ​​meet the following criteria: Platelet count (PLT) >100 x 10 9 / L, Neutrophil count (ANC) > 1.5 x 10 9 / L, Hemoglobin concentration (Hgb) > 75g / L (no transfusion of whole blood, red blood cell suspension or other blood products within 4 weeks) 6) The most prominent part of the subject's spleen must be ≥ 5 cm from the lower costal margin; 7) Bone marrow blasts and peripheral blood blasts <20; 8) Major liver and kidney function laboratory values ​​meet the following criteria: Glutamic transaminase (ALT: alanine aminotransferase), glutamic oxaloacetic transaminase (AST: aspartate aminotransferase) ≦2.5 x upper limit of normal (ULN), Serum creatinine ≤ 2.0 mg / dL (176.82 μmol / L), Direct bilirubin ≤ 2 x upper limit of normal (ULN) 9) Major blood coagulation function laboratory test values ​​meet the following criteria: Thromboplastin time (PT) or thrombin time (TT) should be within the normal range ±3s. Activated partial thromboplastin time (APTT) should be within the normal range of ±10 seconds. 10) Those who have used other MPN medications must discontinue the medication for at least 2 weeks, and those who have undergone major surgery must discontinue the medication for at least 4 weeks after the surgery. 11) Female subjects must agree to use contraceptive measures (e.g., intrauterine devices, contraceptive pills, or condoms) during the study and for at least 6 months after the end of the study, have a negative serum pregnancy test result within 7 days prior to dosing at study enrollment (group entry), and be non-lactating subjects; male subjects must agree to use contraceptive measures during the study and for at least 6 months after the end of the study. 12) Subjects must participate voluntarily.

[0107] 6.3 Exclusion standards Subjects who meet any of the following criteria will not be able to participate in this study (i.e., will not be able to enter the group): 1) Subjects who had suffered from other malignant tumors within the past 5 years but were cured (excluding non-melanoma, skin cancer, and carcinoma in situ). 2) Subjects who have participated in clinical trials of other drugs within the past 4 weeks. 3) Subjects with factors that affect oral medications (e.g., inability to swallow, post-gastrointestinal resection, chronic diarrhea and ileus, etc.). 4) Subjects with a history of psychotropic drug abuse and inability to abstain or who have a psychiatric disorder. 5) Subjects who are HBsAg positive, HBcAb positive, and HBV-DNA detection level ≥ upper limit of normal detection, HCV antibody positive, or HIV antibody positive. 6) Subjects with immunodeficiency (patients with acquired or congenital immunodeficiency disease, or those with a history of organ transplantation). 7) Patients who have had an arterial / venous thrombosis event within 4 weeks, such as cerebrovascular accident (including transient ischemic attack), deep vein thrombosis, or pulmonary embolism. 8) Subjects who have received long-term (≥3 days) or increased doses of high-dose (≥10 mg prednisolone equivalent) glucocorticoids or other immunosuppressants within 28 days prior to the screening assessment visit. 9) Subjects with active systemic infection, e.g., clinically significant bacterial, fungal, parasitic, or viral infection requiring treatment. For subjects who require antibiotic treatment for acute bacterial infection, screening / entry should be delayed until completion of antibiotic treatment. 10) Patients with obvious cardiovascular disease, such as New York Heart Association (NYHA) grade 2 or higher heart failure, unstable angina, myocardial ischemia or infarction within the past 3 months, arrhythmia (QTc>470ms in women, QTc>450ms in men), and class I cardiac insufficiency. 11) Patients with hypertension (systolic blood pressure ≥ 150mmHg, diastolic blood pressure ≥ 100mmHg) that cannot be controlled with drug therapy. 12) Subjects whose safety is seriously compromised or who, in the opinion of the investigator, have a medical condition that could affect the conduct of the study.

[0108] 6.4 Blood Sampling Plan A catheter was placed in the vein of the subject's upper limb to collect blood samples, and approximately 3 mL of venous blood was collected each time. The collected blood samples were placed in blood collection tubes pretreated with sodium heparin anticoagulation (left at room temperature for less than 0.5 h), and centrifuged at 4°C for 10 min (2500 g) to separate plasma, which was then stored at -80°C for measurement (left at room temperature for less than 2 h).

[0109] 6.5 Observation items Starting from the second cycle of continuous administration, 1) At each visit, a general physical examination will be performed, including weight, vital signs, and a physical examination of each organ. 2) Observe various clinical manifestations, symptoms, and signs (vital signs: including hepatomegaly and splenomegaly) during the treatment period, and evaluate the symptom burden of the subjects using the Myeloproliferative Neoplasms Total Symptom Assessment Table every three cycles. 3) At the end of the second cycle, from the third cycle onwards, splenic NMR examination (MRI) was performed every three cycles and at the time of withdrawal from the group (drug holiday). 4) At the end of the second cycle, and from the third cycle onwards, classification and enumeration tests were performed on bone marrow aspirate smears and peripheral blood smears every three cycles and at the time of withdrawal from the group (drug holiday). 5) At the end of the second cycle, from the third cycle onwards, bone marrow biopsy pathological cytological analysis and reticular fiber (silver-white) staining will be performed every three cycles and at the time of withdrawal from the group (drug holiday).

[0110] 6.6 Results and Evaluation [Table 9] Note: Null means undetected (not detected).

Claims

1. 2. Compounds of formula I: 【Chemistry 8】 (In the formula, R １ and R ２ are each independently H, C １～６ Alkyl, C １～６ Alkyl acyl, and C １～６ alkylsulfonyl; R ３ and R ４ are each independently selected from the group consisting of H, hydroxyl, and oxo. or a stereoisomer or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of formula (I), The pharmaceutical composition comprises a compound of formula I, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof. A compound of formula I, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition.

2. The R １ and R ２ are each independently selected from the group consisting of H, methyl, ethyl, propyl, butyl, pentyl, hexyl, formyl, acetyl, propanoyl, butyryl, valeryl, hexanoyl, methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, pentylsulfonyl, and hexylsulfonyl, and preferably, R １ is H, and said R ２ 2. The compound of formula I according to claim 1, wherein is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, formyl, acetyl, propanoyl, butyryl, valeryl, hexanoyl, methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, pentylsulfonyl, and hexylsulfonyl.

3. The formula: 【Chemistry 9】 2. A compound of formula I according to claim 1 having the configuration:

4. the below described: 【Chemistry 10】 2. The compound of formula I according to claim 1, selected from the group consisting of:

5. 1. A method for treating myeloproliferative neoplasms, comprising: An effective amount of Formula I: 【Chemistry 11】 (Wherein, R １ and R ２ are each independently H, C １～６ Alkyl, C １～６ Alkyl acyl, and C １～６ alkylsulfonyl; The R ３ and R ４ are each independently selected from the group consisting of H, hydroxyl, and oxo. or a pharmaceutical composition thereof, The pharmaceutical composition comprises the compound of formula I, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof.

6. Formula I: 【Chemistry 12】 (Wherein, R １ and R ２ are each independently H, C １～６ Alkyl, C １～６ Alkyl acyl, and C １～６ alkylsulfonyl; The R ３ and R ４ are each independently selected from the group consisting of H, hydroxyl, and oxo.

4. A solid pharmaceutical composition comprising the compound of formula (I), a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, and diluents, binders, wetting agents, and disintegrants.

7. The R １ and R ２ are each independently selected from the group consisting of H, methyl, ethyl, propyl, butyl, pentyl, hexyl, formyl, acetyl, propanoyl, butyryl, valeryl, hexanoyl, methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, pentylsulfonyl, and hexylsulfonyl, and preferably, R １ is H, and said R ２ 7. The solid pharmaceutical composition of claim 6, wherein is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, formyl, acetyl, propanoyl, butyryl, valeryl, hexanoyl, methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, pentylsulfonyl, and hexylsulfonyl.

8. 8. The solid pharmaceutical composition according to claim 6 or 7, wherein the amount of the compound of formula I is selected from 1 to 30% by weight, preferably from 1 to 25% by weight, 1 to 20% by weight, 2 to 20% by weight, 2 to 15% by weight, 2 to 10% by weight, 3 to 10% by weight, or 2 to 8% by weight, more preferably from 3 to 8% by weight, even more preferably from 3.5 to 6% by weight.

9. the diluent is selected from the group consisting of microcrystalline cellulose, mannitol, lactose, sucrose, starch, pregelatinized starch and dextrin or a mixture thereof, preferably selected from the group consisting of microcrystalline cellulose, mannitol, lactose and pregelatinized starch or a mixture thereof, more preferably selected from the group consisting of microcrystalline cellulose and mannitol or a mixture thereof; and / or The solid pharmaceutical composition according to any one of claims 6 to 8, wherein the amount of the diluent is selected from 50 to 95% by weight, preferably 60 to 95% by weight, 65 to 95% by weight, 70 to 95% by weight, 75 to 95% by weight, 80 to 95% by weight, 80 to 90% by weight or 85 to 95% by weight, more preferably 85 to 90% by weight.

10. 10. The solid pharmaceutical composition according to any one of claims 6 to 9, wherein the diluent is a mixture of microcrystalline cellulose and mannitol, and the weight ratio of microcrystalline cellulose to mannitol is selected from 1:1 to 5:1, preferably 1:1 to 4:1, 1.2:1 to 3.5:1 or 1.2:1 to 3:1, more preferably 1.5:1 to 2.5:

1.

11. the binder is selected from the group consisting of hydroxypropylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, ethylcellulose, methylcellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, gelatin, polyvinylpyrrolidone, partially hydrolyzed starch, starch, pregelatinized starch, sucrose, glucose, gelatin, polyethylene glycol, and polyvinyl alcohol, or a mixture thereof, preferably selected from the group consisting of hydroxypropylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, ethylcellulose, methylcellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, and polyvinylpyrrolidone, or a mixture thereof, more preferably selected from the group consisting of hydroxypropylcellulose and polyvinylpyrrolidone, or a mixture thereof; and / or 11. The solid pharmaceutical composition according to any one of claims 6 to 10, wherein the amount of the binder is selected from 1.0% to 10% by weight, preferably 1.0% to 8.0% by weight, 1.0% to 6.0% by weight, or 1.0% to 5.0% by weight, more preferably 2.0 to 4.0% by weight.

12. The wetting agent is sodium dodecylbenzenesulfonate, magnesium dodecylbenzenesulfonate, sodium tetradecylbenzenesulfonate, sodium hexadecylbenzenesulfonate, sodium octadecylbenzenesulfonate, sodium dodecylsulfonate, magnesium dodecylsulfonate, sodium tetradecylsulfonate, sodium hexadecylsulfonate, sodium octadecyl ...ate, magnesium dodecylsulfate, sodium tetradecylsulfate, sodium hexadecylsulfate, sodium octadecylsulfate, sodium lauroylsarcosine glyceryl ether, sodium lactate, sodium palmitate, lauric isopropanolamide, lauric diethanolamide, tetradecyl lactate, hexadecyl lactate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, polysorbate 85, polyoxyethylene lauryl ether, polyoxyethylene cetyl ether, polyoxyethylene sorbitol tetraoleyl ether, polyoxyethylene stearate, polyoxyethylene castor oil, and polyoxyethylene hydrogenated castor oil, or mixtures thereof; Preferably, it is selected from the group consisting of sodium dodecyl sulfonate, magnesium dodecyl sulfonate, sodium tetradecyl sulfonate, sodium dodecyl sulfate, magnesium dodecyl sulfate, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium octadecyl sulfate, and sodium lauroyl sarcosine, or a mixture thereof; More preferably, it is selected from the group consisting of sodium dodecyl sulfate and magnesium dodecyl sulfate, or a mixture thereof; and / or 12. The solid pharmaceutical composition according to any one of claims 6 to 11, wherein the amount of the wetting agent is selected from 0.01 to 5.0 wt%, preferably 0.01 to 4.0 wt%, 0.01 to 3.0 wt%, 0.02 to 2.5 wt%, or 0.02 to 2.0 wt%, more preferably 0.03 to 2.0 wt%, even more preferably 0.05 to 1.0 wt%, and even more preferably 0.1 to 0.5 wt%.

13. the disintegrant is selected from the group consisting of sodium carboxymethyl starch, dry starch, microcrystalline cellulose, hydroxyethyl methylcellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, low-substituted hydroxypropyl methylcellulose, or crospovidone, sodium dodecyl sulfate, and magnesium dodecyl sulfate, or a mixture thereof, preferably selected from the group consisting of sodium carboxymethyl starch and croscarmellose sodium, or a mixture thereof; and / or The solid pharmaceutical composition according to any one of claims 6 to 12, wherein the amount of the disintegrant is selected from 1.0 to 7.0% by weight, preferably 1.0 to 6.5% by weight, 1.0 to 6.5% by weight, 1.0 to 6.0% by weight, 1.5 to 5.5% by weight, 1.5 to 5.0% by weight, or 1.5 to 4.5% by weight, more preferably 2.0 to 4.0% by weight.

14. the lubricant is selected from the group consisting of magnesium stearate, colloidal silica, talc, polyethylene glycol 4000, polyethylene glycol 6000, stearic acid, sodium stearyl fumarate, and sodium dodecyl sulfate, or a mixture thereof, preferably selected from the group consisting of magnesium stearate and colloidal silica, or a mixture thereof; and / or 14. The solid pharmaceutical composition according to any one of claims 6 to 13, wherein the amount of the lubricant is selected from 0.1 to 3 wt.%, preferably 0.2 to 2.5 wt.%, 0.3 to 2.0 wt.%, or 0.4 to 1.5 wt.%, more preferably 0.5 to 1 wt.%.

15. 1-30% by weight of a compound of formula I, 50-95% by weight of microcrystalline cellulose, mannitol, lactose, or pregelatinized starch, or mixtures thereof; 1.0% to 10% by weight of hydroxypropylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, ethylcellulose, methylcellulose, hydroxypropylcellulose, L-HPC, or polyvinylpyrrolidone, or mixtures thereof; 0.01 to 5.0% by weight of sodium dodecyl sulfonate, magnesium dodecyl sulfonate, sodium tetradecyl sulfonate, sodium dodecyl sulfate, magnesium dodecyl sulfate, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium octadecyl sulfate, or sodium lauroyl sarcosine, or mixtures thereof; 1.0 to 7.0% by weight of sodium carboxymethyl starch, or croscarmellose sodium, or a mixture thereof; and Optionally, 0.1 to 3% by weight of magnesium stearate, or colloidal silica, or a mixture thereof. The solid pharmaceutical composition according to any one of claims 6 to 14, comprising:

16. 2-10% by weight of a compound of formula I, 75 to 95% by weight of microcrystalline cellulose, or mannitol, or a mixture thereof, in which the weight ratio of microcrystalline cellulose to mannitol in said mixture is selected from 1.2:1 to 3.5:1; 1.0 to 6.0% by weight of hydroxypropyl cellulose, or polyvinylpyrrolidone, or a mixture thereof; 0.01 to 3.0% by weight of sodium dodecyl sulfonate, magnesium dodecyl sulfonate, sodium tetradecyl sulfonate, sodium dodecyl sulfate, magnesium dodecyl sulfate, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium octadecyl sulfate, or sodium lauroyl sarcosine, or mixtures thereof; 1.0 to 6.0% by weight of sodium carboxymethyl starch, or croscarmellose sodium, or a mixture thereof; and Optionally, 0.3 to 2.0% by weight of magnesium stearate, or colloidal silica, or a mixture thereof. The solid pharmaceutical composition according to any one of claims 6 to 14, comprising:

17. 3.4 to 4.6% by weight of a compound of formula I, 55-60% by weight of microcrystalline cellulose, 26 to 32% by weight of mannitol, 2.0 to 4.0% by weight of hydroxypropyl cellulose, 0.1 to 0.5% by weight of sodium dodecyl sulfate, 2.0 to 4.0% by weight of croscarmellose sodium, and Optionally, 0.5 to 1% by weight of magnesium stearate The solid pharmaceutical composition according to any one of claims 6 to 14, comprising:

18. 4.2% by weight of a compound of formula I, 58.3% by weight of microcrystalline cellulose, 29.4% by weight of mannitol, 4.0% by weight of hydroxypropyl cellulose, 0.1% by weight of sodium dodecyl sulfate, 3.0% by weight of croscarmellose sodium, and Optionally, 1.0% by weight of magnesium stearate The solid pharmaceutical composition according to any one of claims 6 to 14, comprising:

19. The compound of formula I has the following formula II: 【Chemistry 13】 The solid pharmaceutical composition according to any one of claims 6 to 18, wherein the compound is represented by the formula:

20. A method for producing the solid pharmaceutical composition according to any one of claims 6 to 19, comprising the steps of: 1) mixing a diluent and a disintegrant to give a mixture for subsequent use, and mixing a compound of formula I, a binder and a wetting agent with water to give a mixed solution; 2) spraying the mixture of step 1) onto the mixture of step 1), granulating and drying in a fluidized bed, and sizing the resulting mixture to obtain dry granules; 3) Optionally, mixing the dry granules with a lubricant and compressing them into tablets. Including, The method for producing said mixture in step 1) is a suspension or a transparent solution, preferably a suspension.

21. 20. Use of the solid pharmaceutical composition according to any one of claims 6 to 19 in the manufacture of a medicament for the treatment of a Janus kinase mediated disease, preferably wherein said Janus kinase mediated disease is a myeloproliferative neoplasm.

22. The compound of formula I, its stereoisomer or a pharma- ceutically acceptable salt thereof, or the pharmaceutical composition according to any one of claims 1 to 4, the method according to claim 5, and the use according to claim 21, wherein the myeloproliferative neoplasm is selected from polycythemia vera, thrombocytosis, and myelofibrosis.

23. 22. The compound of formula I, its stereoisomer or pharma- ceutically acceptable salt thereof, or pharmaceutical composition according to any one of claims 1 to 4, wherein the daily dose is from 1 mg to 100 mg, preferably the daily dose is selected from the group consisting of 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, and 100 mg, or a range defined by an endpoint which is any of said values, or any value within said ranges; the method according to claim 5; and the use according to claim 21.

24. The compound of formula I, its stereoisomer or a pharma- ceutically acceptable salt thereof, or pharmaceutical composition according to any one of claims 1 to 4, administered one or more times daily, optionally in a single dose, preferably once or twice daily in a single dose form, the method according to claim 5, and the use according to claim 21.

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