Use of pyrrolopyrimidine compounds for treatment of hemophagocytic syndrome

Abstract

The invention belongs to the field of medical chemistry, and relates to application of pyrrolopyrimidine compounds in treatment of hemophagocytic syndrome, in particular to application of compounds shown as a formula I, stereoisomers of the compounds or pharmaceutically acceptable salts of the compounds in treatment of the hemophagocytic syndrome. # imgabs0 #

Description

[0001] This application is a divisional application of a Chinese patent application with the application number 202180008532.8 (International Application Number PCT / CN2021 / 079820), the filing date of March 9, 2021, and the invention title of "Use of Pyrrolopyrimidine Compounds in the Treatment of Hemophagocytic Syndrome". Technical Field

[0002] This application belongs to the field of medicinal chemistry and relates to the use of pyrrolopyrimidine compounds in the treatment of hemophagocytic syndrome. Background Art

[0003] Janus kinase (JAK) is a class of non-receptor tyrosine kinases (PTKs) that exist intracellularly and transmit cytokine-stimulating signals through the JAK-STAT pathway. The JAK-STAT pathway transmits extracellular chemical signals through the cell membrane to the gene promoter on DNA located in the cell nucleus, ultimately affecting changes in DNA transcription and activity levels in the cell. The JAK-STAT pathway consists of three main parts: 1) receptors; 2) Janus kinases (JAKs); and 3) signal transducer and activator of transcription proteins (STATs). The receptors can be activated by interferons, interleukins, growth factors, or other chemical messengers, and the activation leads to autophosphorylation of JAK; subsequently, STAT proteins bind to the phosphorylated receptor, causing STAT to be phosphorylated by JAK; then the phosphorylated STAT proteins dissociate from the receptor, dimerize, and translocate to the cell nucleus to bind to specific DNA sites and alter transcription (Scott, M.J., C.J. Godshall et al. (2002). “Jaks, STATs, Cytokines, and Sepsis” Clin Diagn Lab Immunol 9(6):1153 - 9).

[0004] The JAK family plays a role in cell proliferation and functional cytokine-dependent regulation involved in immune responses. Currently, there are four known mammalian JAK family members: JAK1, JAK2, JAK3, and TYK2 (Tyrosine kinase 2). The size of JAK proteins ranges from 120 - 140 kDa, and they contain 7 conserved JAK homology (JH) domains; one of which is a functional catalytic kinase domain, and the other is a pseudokinase domain that effectively performs regulatory functions and / or acts as a docking site for STAT (Scott, Godshall et al. 2002, supra).

[0005] Hemophagocytic lymphohistiocytosis (HLH), also known as hemophagocytic lymphohistiocytosis, is a group of CD8 + The T lymphocyte and monocyte-macrophage system overproliferates and produces a large number of inflammatory factors, causing a clinical syndrome of fulminant inflammatory response in multiple organ systems, which is clinically characterized by persistent fever, hepatosplenomegaly, and bleeding. The disease has an acute onset, is severe, progresses rapidly, and has a very high mortality rate. HLH is a disease in which the balance between regulatory T cells and CD8+T cells is unbalanced, and the homeostasis of the IL-2 network is disturbed. During the process of HLH, CD8+T cells are overactivated and successfully compete with regulatory T cells for IL-2, resulting in decreased regulatory T cell function. HLH is characterized by acute clinical signs and symptoms of immune activation, including hepatomegaly, jaundice, lymphadenopathy, rash, seizures, and focal neurological deficits, and laboratory tests show elevated serum levels of multiple inflammatory cytokines, including interferon-γ (IFN-γ), tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), interleukin 10 (IL-10), and macrophage colony-stimulating factor (M-CSF). SUMMARY OF THE INVENTION

[0007] In one aspect, the present application provides a compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for treating hemophagocytic syndrome:

[0008]

[0009] In another aspect, the present application provides a pharmaceutical composition for treating hemophagocytic syndrome, wherein the pharmaceutical composition comprises a compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0010] On the other hand, the present application provides a method for treating hemophagocytic syndrome in a patient, comprising administering to the patient an effective amount of the compound of formula I as described above, its stereoisomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0011] On the other hand, the present application provides use of the compound of formula I as described above, its stereoisomer, or its pharmaceutically acceptable salt, or its pharmaceutical composition in the preparation of a medicament for treating hemophagocytic syndrome.

[0012] On the other hand, the present application provides the use of the compound of formula I as described above, its stereoisomer, or its pharmaceutically acceptable salt, or its pharmaceutical composition in the treatment of hemophagocytic syndrome. DETAILED DESCRIPTION OF THE INVENTION

[0014] The present application provides a compound of formula I, its stereoisomers, or a pharmaceutically acceptable salt thereof for treating hemophagocytic syndrome:

[0015]

[0016] On the other hand, the present application provides a pharmaceutical composition for treating hemophagocytic syndrome, the pharmaceutical composition comprising a compound of formula I, its stereoisomers, or a pharmaceutically acceptable salt thereof.

[0017] On the other hand, the present application provides a method for treating hemophagocytic syndrome in a patient, which comprises administering to the patient an effective amount of a compound of formula I, its stereoisomers, or a pharmaceutically acceptable salt thereof as described above, or a pharmaceutical composition comprising a compound of formula I, its stereoisomers, or a pharmaceutically acceptable salt thereof.

[0018] On the other hand, the present application provides the use of a compound of formula I, its stereoisomers, or a pharmaceutically acceptable salt thereof as described above, or a pharmaceutical composition comprising a compound of formula I, its stereoisomers, or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating hemophagocytic syndrome in a patient.

[0019] On the other hand, the present application provides the use of a compound of formula I, its stereoisomers, or a pharmaceutically acceptable salt thereof as described above, or a pharmaceutical composition comprising a compound of formula I, its stereoisomers, or a pharmaceutically acceptable salt thereof in the treatment of hemophagocytic syndrome in a patient.

[0020] In some embodiments of the present application, the compound of formula I, its stereoisomers, or a pharmaceutically acceptable salt thereof described in the present application is used as a single active agent.

[0021] In some embodiments of the present application, the compound of formula I, its stereoisomers, or a pharmaceutically acceptable salt thereof described in the present application may be a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, its stereoisomers, or a pharmaceutically acceptable salt thereof.

[0022] The pharmaceutical composition of the present application can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable excipients, and can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc. The pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, sugarcoating pill methods, grinding methods, emulsification methods, freeze-drying methods, etc. Suitable excipients include but are not limited to: binders, diluents, wetting agents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, etc.

[0023] In some embodiments of the present application, the pharmaceutical composition is an orally applicable preparation, including tablets, capsules, powders, granules, dripping pills, pastes, powders, etc., preferably tablets and capsules. The orally applicable preparation can be prepared by conventional methods using pharmaceutically acceptable carriers well known in the art. Pharmaceutically acceptable carriers include diluents, binders, wetting agents, disintegrants, lubricants, etc. Diluents include microcrystalline cellulose, mannitol, lactose, sucrose, starch, pre-gelatinized starch, dextrin or mixtures thereof; binders include hydroxypropyl methylcellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, gelatin, polyvinylpyrrolidone, starch, sucrose, glucose, gelatin or mixtures thereof; wetting agents include magnesium stearate, talcum powder, polyethylene glycol, sodium lauryl sulfate, colloidal silica, talcum powder or mixtures thereof; disintegrants include sodium carboxymethyl starch, dry starch, microcrystalline cellulose, hydroxyethyl methyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose, low-substituted hydroxypropyl methyl cellulose or cross-linked polyvinylpyrrolidone or mixtures thereof; lubricants include magnesium stearate, colloidal silicon dioxide, talcum powder, polyethylene glycol, stearic acid, sodium stearyl fumarate or mixtures thereof. Pharmaceutical excipients also include colorants, sweeteners, coating agents, etc.

[0024] Compound of formula I

[0025] In some embodiments of the present application, the compound of formula I described in the present application is the compound of formula II

[0026] The compound of formula I and the compound of formula II of the present application can be prepared by referring to the preparation methods in WO2016095805 or WO2017215627.

[0027] Hemophagocytic syndrome

[0028] In some embodiments of the present application, the hemophagocytic syndrome includes primary hemophagocytic syndrome and secondary hemophagocytic syndrome. Among them, the primary hemophagocytic syndrome includes familial HLH, immunodeficiency syndrome-related HLH or Epstein-Barr virus (EBV)-driven HLH and other HLH caused by related gene abnormalities; the secondary hemophagocytic syndrome includes infection-related HLH, malignancy-related HLH, macrophage activation syndrome (MAS), or other types of HLH.

[0029] In some embodiments of the present application, the familial HLH (also called FHL) includes FHL-1, FHL-2, FHL-3, FHL-4 or FHL-5.

[0030] In some embodiments of the present application, the immunodeficiency syndrome-related HLH includes Griscelli syndrome 2 (GS-2), Chediak-Higashi syndrome 1 (CHS-1), or Hermansky-Pudlak syndrome II (HPS-II).

[0031] In some embodiments of the present application, the EBV-driven HLH includes X-linked lymphoproliferative syndrome (XLP), preferably including XLP-1 and XLP-2 (i.e., deficiency of X-linked inhibitor of apoptosis protein (XIAP)); the EBV-driven HLH also includes other EBV-driven HLH, preferably including deficiency of interleukin-2-inducible T-cell kinase (ITK), CD27 deficiency, and mutations in the magnesium transporter gene (MAGT1).

[0032] In some embodiments of the present application, the infections in the infection-related HLH include viral, bacterial, fungal, and protozoal infections, etc.

[0033] In some embodiments of the present application, the malignancies in the malignancy-related HLH include hematological malignancies or solid tumors; preferably, the hematological malignancies include lymphoma, acute leukemia, multiple myeloma, myelodysplastic syndrome, etc.; preferably, the solid tumors include embryonal cell tumors, thymoma, gastric cancer, etc.

[0034] In some embodiments of the present application, the macrophage activation syndrome (MAS) includes systemic or organ-specific autoimmune diseases.

[0035] In some embodiments of the present application, the other types of HLH include HLH induced by pregnancy, drugs, organ and hematopoietic stem cell transplantation, and rare metabolic diseases.

[0036] In the present application, the diagnostic criteria for hemophagocytic syndrome can refer to the general principles in the art, such as the Chinese Expert Consensus on the Diagnosis and Treatment of Hemophagocytic Syndrome (2018) or the HLH-2004 diagnostic criteria.

[0037] In the present application, the hemophagocytic syndrome includes hemophagocytic syndrome with gene mutations, and the mutant genes include, but are not limited to, JAK2 / STAT, PRF1, UNC13D, STX11, STXBP2, Rab27a, LYST, SH2D1A, BIRC4, ITK, AP3β1, MAGT1, CD27.

[0038] Dosing regimen

[0039] In some embodiments of the present application, the administration cycle for treating a patient with hemophagocytic syndrome is 2 to 6 weeks. In some embodiments of the present application, the administration cycle for treating a patient with hemophagocytic syndrome is 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, or a range formed by any of the above values. In some embodiments of the present application, the administration cycle for treating a patient with lymphoma is 4 weeks.

[0040] The amount of the compound, its stereoisomer, or its pharmaceutically acceptable salt of the present application can be determined according to the severity of the disease, the response to the disease, any treatment-related toxicity, the age and health status of the patient. For example, it can be determined according to the blood routine test results of the subject / patient, and the blood routine test results include platelet count, neutrophil count, or hemoglobin concentration, etc. In some embodiments, the daily dose of the compound, its stereoisomer, or its pharmaceutically acceptable salt of the present application is 1 mg to 100 mg. In some embodiments, the daily dose of the compound, its stereoisomer, or its pharmaceutically acceptable salt of the present application can be selected from 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, or 100 mg, or a range formed by any of the foregoing values as endpoints or any value therein, such as 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, 20 mg to 40 mg, 30 mg to 40 mg, etc. In some specific embodiments, the daily dose of the compound, its stereoisomer, or its pharmaceutically acceptable salt of the present application can be 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, 10 mg to 30 mg, 20 mg to 40 mg, 30 mg to 40 mg. In some specific embodiments, the daily dose of the compound, its stereoisomer, or its pharmaceutically acceptable salt of the present application can be 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 a range formed by any of the foregoing values as endpoints or any value therein, such as 2 mg to 50 mg, 10 mg to 40 mg, 5 mg to 30 mg, 5 mg to 20 mg, 20 mg to 40 mg, 30 mg to 40 mg, etc.

[0041] The compounds of the present application, their stereoisomers, or their pharmaceutically acceptable salts can be administered once or multiple times daily. In some embodiments, the compounds of the present application, their stereoisomers, or their pharmaceutically acceptable salts are administered once or twice daily. The compounds of the present application, their stereoisomers, or their pharmaceutically acceptable salts can also be administered in a single-dose form. In one embodiment, it is administered once or twice daily in a single dose. In one embodiment, it is administered once or twice daily in a single-dose oral solid dosage form. In a specific embodiment, it is administered twice daily in a single-dose oral solid dosage form.

[0042] The compounds of the present application, their stereoisomers, or their pharmaceutically acceptable salts can also be administered in a multi-dose form. In one embodiment, it is administered once or twice daily in a multi-dose. In one embodiment, it is administered once or twice daily in a multi-dose oral solid dosage form. In a specific embodiment, it is administered twice daily in a multi-dose oral solid dosage form.

[0043] In some aspects of the present application, the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt is provided in the form of a pharmaceutical composition, preferably a single-dose pharmaceutical composition. In some embodiments, the pharmaceutical composition contains 1 mg to 50 mg of the compound of the present application, its stereoisomer, or its pharmaceutically acceptable salt. In some embodiments, the pharmaceutical composition contains 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 a range formed by any of the foregoing values as endpoints or any value therein of the compound of the present application, its stereoisomer, or its pharmaceutically acceptable salt, such as 2 mg to 50 mg, 10 mg to 40 mg, 5 mg to 30 mg, 5 mg to 20 mg, 20 mg to 40 mg, 30 mg to 40 mg, etc.

[0044] In some aspects of the present application, the pharmaceutical composition of the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt is a daily dose. In some aspects of the present application, the pharmaceutical composition of the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt is a twice-daily dose. In some aspects of the present application, each dose of the twice-daily dose is the same.

[0045] In some aspects of the present application, the pharmaceutical composition of the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt is a twice-daily dose, and each dose is a single dose or a multi-dose respectively.

[0046] In some embodiments of the present application, the pharmaceutical composition of the compound of formula I, its stereoisomers, or its pharmaceutically acceptable salts is administered twice daily, and each dose is a multi-dose, which consists of a single dose of 5 mg, 10 mg, 15 mg, and / or 20 mg of the compound of formula I, its stereoisomers, or its pharmaceutically acceptable salts. In some embodiments of the present application, the pharmaceutical composition consists of a single dose of 5 mg of the compound of formula I, its stereoisomers, or its pharmaceutically acceptable salts.

[0047] In some embodiments of the present application, the pharmaceutical composition of the compound of formula I, its stereoisomers, or its pharmaceutically acceptable salts is administered twice daily, and each dose is a single dose, and the single dose is 5 mg, 10 mg, 15 mg, and / or 20 mg of the compound of formula I, its stereoisomers, or its pharmaceutically acceptable salts. In some embodiments of the present application, the single dose is 20 mg of the compound of formula I, its stereoisomers, or its pharmaceutically acceptable salts.

[0048] In some embodiments of the present application, the pharmaceutical composition of the compound of formula I, its stereoisomers, or its pharmaceutically acceptable salts is packaged in a kit, and the kit further contains instructions for using the compound of formula I, its stereoisomers, or its pharmaceutically acceptable salts for the treatment of hemophagocytic syndrome.

[0049] In some embodiments of the present application, in the method or use for the treatment of hemophagocytic syndrome, the pharmaceutical composition of the compound of formula I, its stereoisomers, or its pharmaceutically acceptable salts is administered daily, and it is administered in the following manner: the pharmaceutical composition of the compound of formula I, its stereoisomers, or its pharmaceutically acceptable salts is administered once or twice daily; in some embodiments of the present application, the pharmaceutical composition of the compound of formula I, its stereoisomers, or its pharmaceutically acceptable salts is administered twice daily, and each dose is the same; in some embodiments of the present application, the pharmaceutical composition of the compound of formula I, its stereoisomers, or its pharmaceutically acceptable salts is administered twice daily, and each dose is the same, and the interval between each administration is 12 hours.

[0050] In some embodiments of the present application, 28 days is a treatment cycle, and the pharmaceutical composition of the compound of formula I, its stereoisomers, or its pharmaceutically acceptable salts is continuously administered on days 1 - 28 of each cycle.

[0051] In some embodiments of the present application, 28 days is a treatment cycle, and the pharmaceutical composition of the compound of formula I, its stereoisomers, or its pharmaceutically acceptable salts is continuously administered twice daily on days 1 - 28 of each cycle.

[0052] In some embodiments of the present application, 28 days is one treatment cycle, and the total dose of the pharmaceutical composition of the compound of formula I, its stereoisomers, or its pharmaceutically acceptable salts administered in each treatment cycle is 140 - 840 mg (calculated as the compound of formula (I) itself as the active ingredient). In some embodiments of the present application, the total dose of the pharmaceutical composition of the compound of formula I, its stereoisomers, or its pharmaceutically acceptable salts is selected from 140 mg, 280 mg, 420 mg, 560 mg, 700 mg, 840 mg, or the range formed by any two of the above values (calculated as the compound of formula (I) itself as the active ingredient). In some embodiments of the present application, the total dose of the pharmaceutical composition of the compound of formula I, its stereoisomers, or its pharmaceutically acceptable salts is preferably 560 - 840 mg (calculated as the compound of formula (I) itself as the active ingredient).

[0053] In some embodiments of the present application, the above treatment cycle is repeated as long as the disease remains under control and the dosing regimen is clinically tolerable.

[0054] The compounds of the present application, their stereoisomers, or their pharmaceutically acceptable salts can be administered by various routes, including but not limited to the following routes: oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, buccal, intranasal, by inhalation, vaginal, intraocular, by topical administration, subcutaneous, intralipid, intraarticular, or intrathecal. In a specific embodiment, it is administered orally.

[0055] In some embodiments of the present application, the pharmaceutical composition of the compound of formula I, its stereoisomers, or its pharmaceutically acceptable salts can be formulated into a dosage form suitable for oral administration to humans, such as including but not limited to tablets, pills, capsules, powders, or granules, etc.

[0056] In some embodiments of the present application, the pharmaceutical composition of the compound of formula I, its stereoisomers, or its pharmaceutically acceptable salts is an oral tablet.

[0057] In some embodiments of the present application, the single - dose specification of the oral tablet of the compound of formula I, its stereoisomers, or its pharmaceutically acceptable salts is 5 mg or 20 mg.

[0058] Technical effects

[0059] The compound of Formula I, its stereoisomers, or its pharmaceutically acceptable salts or pharmaceutical compositions of the present application have good therapeutic effects, which are reflected in, including but not limited to, better disease control rates, longer survival times (such as median survival time, progression-free survival time, or overall survival time), and longer durations of disease remission (DOR). When the compound of Formula I, its stereoisomers, or its pharmaceutically acceptable salts or pharmaceutical compositions of the present application have good therapeutic effects, they also have good safety, including but not limited to, a lower incidence of adverse reactions.

[0060] Definitions and explanations

[0061] Unless otherwise specified, the terms used in this application have the following meanings. A particular term should not be considered indeterminate or unclear without a specific definition, but should be understood according to its ordinary meaning in the art. When a trade name appears in this application, it is intended to refer to the corresponding product or its active ingredient.

[0062] In this text, unless otherwise specified, the terms "comprise, comprises, and comprising" or their equivalents are open-ended expressions, meaning that other unspecified elements, components, and steps can be covered in addition to the listed elements, components, and steps.

[0063] For the purposes of description and disclosure, all patents, patent applications, and other established publications are hereby expressly incorporated herein by reference. Any reference to these publications in this text does not constitute an admission that such publication is part of the common general knowledge in the art.

[0064] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms that are within the scope of reliable medical judgment, suitable for use in contact with human and animal tissues, without excessive toxicity, irritation, allergic reaction, or other problems or complications, and are commensurate with a reasonable benefit / risk ratio.

[0065] The term "pharmaceutically acceptable salt" includes salts formed by basic radicals and free acids or acid radicals and free bases. The pharmaceutically acceptable salts described in this application are selected from maleates, hydrochlorides, hydrobromides, sulfates, phosphates, nitrates, acetates, lactates, malonates, succinates, fumarates, malates, mandelates, tartrates, citrates, ascorbates, palmitates, benzoates, phenylacetates, cinnamates, salicylates, mesylates, benzenesulfonates, or methylbenzenesulfonates.

[0066] As used in the present application, the amount of the compound of Formula I, such as the dosage administered, the dose, the content in the pharmaceutical composition, is calculated in the form of its free base.

[0067] As used in the present application, if the compound in the pharmaceutical combination of the present application has, for example, at least one basic center, it can form an acid addition salt. If necessary, the corresponding acid addition salt with an additionally present basic center can also be formed. Compounds having at least one acidic group (such as COOH) can also form salts with bases. If a compound contains, for example, both a carboxyl group and an amino group, the corresponding inner salt can also be formed.

[0068] The compounds of the present application can be asymmetric, for example, having one or more stereoisomers. Unless otherwise specified, all stereoisomers are included, such as enantiomers and diastereomers. Compounds of the present application containing an asymmetric carbon atom can be isolated in optically pure form or in racemic form. The optically pure form can be resolved from the racemic mixture or synthesized by using chiral starting materials or chiral reagents.

[0069] The term "patient" is a mammal, such as a human, dog, cow, horse, pig, sheep, goat, cat, mouse, rabbit, rat, and transgenic non-human animals. In some embodiments, the patient is a human.

[0070] The term "pharmaceutical composition" refers to a mixture composed of one or more compounds of the present application or their pharmaceutical combinations or their salts and pharmaceutically acceptable excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compounds of the present application or their pharmaceutical combinations to a subject.

[0071] The term "treatment" generally refers to obtaining the desired pharmacological and / or physiological effects, including partially or completely stabilizing or curing a disease and / or the effects caused by the disease. "Treatment" as used herein encompasses any treatment of a patient's disease, including: (a) inhibiting the symptoms of the disease, i.e., preventing its development; or (b) alleviating the symptoms of the disease, i.e., causing the disease or symptoms to regress.

[0072] The term "effective amount" means (i) the amount of the compound of the present application for treating a specific disease, condition, or disorder, or (ii) reducing, ameliorating, or eliminating one or more symptoms of a specific disease, condition, or disorder. The amount of the compound of the present application constituting 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 those skilled in the art based on their own knowledge and the present disclosure.

[0073] The term "single dose" refers to the smallest packaging unit containing a certain amount of medicine. For example, if a box of medicine contains seven capsules, each capsule is a single dose; or each vial of injection is a single dose.

[0074] The term "multi-dose" consists of multiple single doses.

[0075] The terms "administer" and "administering" mean the physical introduction of a composition comprising a therapeutic agent to an individual using any of a variety of methods and delivery systems known to those of skill in the art. In certain embodiments, the administration is oral administration.

[0076] The term "daily dose" refers to the dose administered to a patient per day.

[0077] When referring to a dosing regimen, the terms "day", "each day", etc. refer to the time within a calendar day, starting at midnight and ending at the next midnight. Detailed Description

[0078] The present invention is illustrated in more detail by specific examples. The following examples are provided for illustrative purposes and should not limit the invention in any way.

[0079] Preparation Example 1: Preparation of Solid Pharmaceutical Compositions in 5 mg and 20 mg Tablet Sizes

[0080] The prescription compositions of the solid pharmaceutical compositions in 5 mg and 20 mg tablet sizes are shown in Table 1:

[0081] Table 1 Prescription Compositions of 5 mg and 20 mg Tablet Sizes

[0082]

[0083] Preparation Process:

[0084] 1) Mix mannitol, microcrystalline cellulose, and croscarmellose sodium, and reserve the resulting mixture A;

[0085] Preparation of API Suspension: Dissolve hydroxypropyl cellulose in the prescribed amount of purified water to prepare a 4% (w / w) hydroxypropyl cellulose solution; dissolve sodium lauryl sulfate; add Compound II and stir to disperse to obtain an API suspension;

[0086] 2) Fluidized bed granulation and drying: Spray the API suspension onto mixture A for fluidized granulation. Granulation parameters: inlet air temperature 55 - 80 °C, atomization pressure 600 - 1000 mbar, material temperature 25 - 35 °C; after spraying the liquid, dry, and end drying when the material temperature is higher than 45 °C; use a comminuting and sizing machine to size the granules, with the aperture of the sizing screen being Φ0.6 - 1.2 mm, to obtain sized dry granules;

[0087] 3) Put the sized dry granules and magnesium stearate into a hopper mixer in sequence, mix well, and press the resulting solid pharmaceutical composition into tablets.

[0088] Clinical Protocol for Hemophagocytic Syndrome in Example 1

[0089] 1.1 Dosing regimen

[0090] Administration method: Oral administration once on an empty stomach every morning, and then oral administration again 12 hours later. Continuous administration for 28 days is one treatment cycle.

[0091] Drug: Tablets of the compound of Formula I, 5 mg or 20 mg, and the compound of Formula I exhibits as its stereoisomer, the compound of Formula II

[0092] 1.2 Inclusion criteria

[0093] 1) Age ≥ 18 years old; ECOG performance status: 0 - 3 points; Predicted survival period exceeds 3 months;

[0094] 2) According to the HLH - 2004 standard, newly diagnosed or first - relapsed patients who are clearly diagnosed with HLH;

[0095] 3) Those who have used other HLH treatment drugs need to stop taking the drugs for more than 2 weeks. Those who have undergone major surgery need to wait for 4 weeks after the surgery;

[0096] 4) Laboratory tests need to meet the following: Blood routine test: Hemoglobin (Hb) ≥ 60 g / L; Absolute neutrophil count (ANC)

[0097] ≥ 0.5×10 9 / L; Platelet (PLT) ≥ 30×10 9 / L; Liver function: Serum total bilirubin (TBIL) < 171 μmol / L; Renal function: Serum creatinine (Cr) ≤ 1.5×ULN; Coagulation function: Activated partial thromboplastin time

[0098] (APTT), International normalized ratio (INR) ≤ 1.5×ULN;

[0099] 5) Female patients should agree to use contraceptive measures (such as intrauterine device [IUD], contraceptive pills or condoms) during the study period and for at least 6 months after the end of the study; Serum pregnancy test is negative within 7 days before enrollment in the study for drug use, and must be non - lactating patients; Male patients should agree to use contraceptive measures during the study period and for at least 6 months after the end of the study period;

[0100] 6) Patients voluntarily participate in this study, sign the informed consent form, and have good compliance.

[0101] 1.3 Evaluation method

[0102] Evaluate the efficacy according to the criteria of "Chinese Expert Consensus on the Diagnosis and Treatment of Hemophagocytic Syndrome (2018)". During the induction treatment, it is recommended to evaluate the efficacy every 2 weeks.

[0103] The main indicators for efficacy evaluation include sCD25, ferritin, blood cell count, triglyceride, hemophagocytosis, and level of consciousness (for those with CNS-HLH).

[0104] a) Complete response: All of the above indicators return to the normal range.

[0105] b) Partial response: ≥2 symptoms / laboratory indicators improve by more than 25%, and individual indicators need to meet the following criteria: ① The sCD25 level decreases by more than 1 / 3; ② Ferritin and triglyceride decrease by more than 25%; ③ Without blood transfusion: for neutrophils <0.5x10 9 / L, it needs to increase by 100% and >0.5x10 9 / L; for neutrophils 0.5 - 2.0x10 9 / L, it needs to increase by 100% and return to normal; ④ For ALT >400U / L, it needs to decrease by more than 50%.

[0106] 1.4 Therapeutic effect

[0107] Case 1

[0108] A 45-year-old female patient was diagnosed with hemophagocytic syndrome and was given tablets of Compound II at a dose of 20 mg each time according to the dosing regimen described in 1.1. Blood drug concentration was detected by scheduled blood tests, and indicators such as blood picture, biochemistry, and coagulation were dynamically monitored. The changes in the patient's condition and vital signs were continuously and closely monitored. After one cycle of medication in Case 1, the disease remained stable and the patient had acceptable tolerance.

[0109] Case 2

[0110] A 44-year-old female patient was diagnosed with hemophagocytic syndrome and was given tablets of Compound II at a dose of 15 mg each time according to the dosing regimen described in 1.1. Blood drug concentration was detected by scheduled blood tests, and indicators such as blood picture, biochemistry, and coagulation were dynamically monitored. The changes in the patient's condition and vital signs were continuously and closely monitored.

[0111] After one cycle of medication in Case 2, the disease remained stable, its sCD25 level decreased by more than 1 / 3, and ferritin decreased by more than 25%. The disease showed a partial response and the patient had acceptable tolerance.

Claims

1. Use of a compound of formula I, its stereoisomers, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula I, its stereoisomers, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating hemophagocytic syndrome in a patient.

2. The use according to claim 1, wherein, The hemophagocytic syndrome includes primary hemophagocytic syndrome and secondary hemophagocytic syndrome.

3. The use according to claim 2, wherein, The primary hemophagocytic syndrome includes familial HLH, HLH associated with immunodeficiency syndromes or EBV-driven HLH, and other HLH caused by related gene abnormalities.

4. The use according to claim 2, wherein, The secondary hemophagocytic syndrome includes infection-related HLH, malignancy-related HLH, macrophage activation syndrome (MAS), or other types of HLH.

5. The use according to any one of claims 1-4, wherein, The hemophagocytic syndrome includes hemophagocytic syndrome with gene mutations.

6. The use according to any one of claims 1-5, wherein the compound of formula I is:

7. The use according to claim 1, wherein the daily dose of the compound of formula I, its stereoisomers, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of formula I, its stereoisomers, or a pharmaceutically acceptable salt thereof is 1 mg to 100 mg.

8. The use according to claim 1, wherein the compound of formula I, its stereoisomers, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of formula I, its stereoisomers, or a pharmaceutically acceptable salt thereof is administered once or more times a day.

9. The use according to claim 1, wherein the compound of formula I, its stereoisomers, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of formula I, its stereoisomers, or a pharmaceutically acceptable salt thereof can be administered in a single dose or multiple doses.

10. The use according to claim 1, wherein 28 days is a treatment cycle, and the pharmaceutical composition of the compound of formula I, its stereoisomers, or a pharmaceutically acceptable salt thereof is continuously administered on days 1-28 of each cycle.

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