Use of pyrrolopyrimidine compounds in treating hemophagocytic syndrome

Abstract

The invention relates to the use of pyrrolopyrimidine compounds in treating hemophagocytic syndrome, and specifically relates to the use of the compound of formula (I), its stereoisomers, or its pharmaceutically acceptable salts and pharmaceutical compositions thereof in treating hemophagocytic syndrome.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority and benefits of Chinese Patent Application No. 202010157375.4 filed with the State Intellectual Property Office of China on March 9, 2020, and the contents disclosed in said application are incorporated herein by reference in their entirety. Technical Field

[0003] The present application belongs to the field of medicinal chemistry and relates to the use of pyrrolopyrimidine compounds in treating hemophagocytic syndrome. Background Art

[0004] Janus kinase (JAK) is a type of non-receptor tyrosine kinase (PTK) that exists in cells and transmits cytokine stimulation signals through the JAK-STAT pathway. The JAK-STAT pathway transmits extracellular chemical signals through the cell membrane to the gene promoter located on the DNA 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 kinase (JAK) and 3) signal transducer and activator of transcription (STAT). The receptor can be activated by interferon, interleukin, growth factor or other chemical messenger, and the activation leads to JAK autophosphorylation; next, STAT protein binds to the phosphorylated receptor, so that STAT is phosphorylated by JAK; then the phosphorylated STAT protein dissociates from the receptor, dimerizes and translocates into the cell nucleus to bind to specific DNA sites and change transcription (Scott, MJ, CJ Godshall et al. (2002). "Jaks, STATs, Cytokines, and Sepsis" Clin Diagn Lab Immunol 9(6): 1153-9).

[0005] The JAK family plays a role in cell proliferation and functional cytokine-dependent regulation of immune responses. Currently, there are four known mammalian JAK family members: JAK1, JAK2, JAK3 and TYK2 (Tyrosine kinase 2). The size range of JAK proteins is 120-140 kDa, which contains 7 conserved JAK homology (JH) domains; one of which is a functional catalytic kinase domain, and the other is a pseudokinase domain, which effectively plays a regulatory function and / or acts as a docking site for STAT (Scott, Godshall et al. 2002, supra).

[0006] 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

[0008] 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:

[0009]

[0010] 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.

[0011] 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.

[0012] 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.

[0013] 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

[0015] The present application provides a compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for treating hemophagocytic syndrome:

[0016]

[0017] 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.

[0018] 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 a compound of formula I as described above, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

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

[0020] On the other hand, the present application provides the use of a compound of formula I as described above, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof in treating hemophagocytic syndrome in a patient.

[0021] In some embodiments of the present application, the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt described in the present application is used as a single active agent.

[0022] In some embodiments of the present application, the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt described in the present application may be a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt.

[0023] The pharmaceutical composition of the present application can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable excipients, for example, it 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, sugar-coated pill making methods, grinding methods, emulsification methods, freeze-drying methods, etc. Suitable excipients include, but are not limited to, adhesives, diluents, wetting agents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, etc.

[0024] In some embodiments of the present application, the pharmaceutical composition is a preparation suitable for oral administration, including tablets, capsules, powders, granules, pills, pastes, powders, etc., preferably tablets and capsules. The oral preparation can be prepared by conventional methods using pharmaceutically acceptable carriers known in the art. Pharmaceutically 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 hydroxypropyl methylcellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, gelatin, polyvinyl pyrrolidone, starch, sucrose, glucose, gelatin or mixtures thereof; wetting agents include magnesium stearate, talc, polyethylene glycol, sodium lauryl sulfate, micropowdered silica gel, talc 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, talc, polyethylene glycol, stearic acid, sodium stearyl fumarate or mixtures thereof. Pharmaceutical excipients also include colorants, sweeteners, coating agents, etc.

[0025] Compounds of formula I

[0026] In some embodiments of the present application, the compound of formula I described in the present application is a compound of formula II

[0027] The compounds of formula I and formula II of the present application can be prepared by referring to the preparation methods in WO2016095805 or WO2017215627.

[0028] Hemophagocytic syndrome

[0029] In some embodiments of the present application, the hemophagocytic syndrome includes primary hemophagocytic syndrome and secondary hemophagocytic syndrome. The primary hemophagocytic syndrome includes familial HLH, immunodeficiency syndrome-related HLH or EB 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.

[0030] 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.

[0031] 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).

[0032] In some embodiments of the present application, the EBV-driven HLH includes X-linked lymphoproliferative syndrome (XLP), preferably, it includes XLP-1 and XLP-2 (i.e., X-linked inhibitor of apoptosis (XIAP) deficiency); the EBV-driven HLH also includes other EBV-driven HLH, preferably, it includes IL-2-inducible T-cellkinase deficiency (ITK), CD27 deficiency and mutations in the magnesium transporter gene (MAGT1).

[0033] In some embodiments of the present application, the infection in the infection-related HLH includes viral, bacterial, fungal and protozoan infections, etc.

[0034] In some schemes of the present application, the malignant tumor in the malignant tumor-related HLH includes a hematological tumor or a solid tumor; preferably, the hematological tumor includes lymphoma, acute leukemia, multiple myeloma, myelodysplastic syndrome, etc.; preferably, the solid tumor includes embryonic cell tumor, thymoma, gastric cancer, etc.

[0035] In some embodiments of the present application, the macrophage activation syndrome (MAS) includes systemic or organ-specific autoimmune diseases.

[0036] 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.

[0037] In the present application, the diagnostic criteria for hemophagocytic syndrome can refer to the general principles in the field, such as the "Chinese Expert Consensus on Diagnosis and Treatment of Hemophagocytic Syndrome (2018)" or the HLH-2004 diagnostic criteria.

[0038] 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, and CD27.

[0039] Dosage regimen

[0040] In some schemes of the present application, the administration cycle for treating the patient's hemophagocytic syndrome is 2 to 6 weeks. In some schemes of the present application, the administration cycle for treating the patient's 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 schemes of the present application, the administration cycle for treating the patient's lymphoma is 4 weeks.

[0041] The amount of the compound of the present application, its stereoisomer, or its pharmaceutically acceptable salt can be determined according to the severity of the disease, the response of the disease, any treatment-related toxicity, the age and health status of the patient, for example, according to the blood routine test results of the subject / patient, the blood routine test results include platelet count, neutrophil count, or hemoglobin concentration, etc. In some embodiments, the daily dose of the compound of the present application, its stereoisomer, or its pharmaceutically acceptable salt is 1 mg to 100 mg. In some embodiments, the daily dose of the compound of the present application, its stereoisomer, or its pharmaceutically acceptable salt 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 consisting of any of the foregoing values ​​as endpoints or any value therein, for example, 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 of the present application, its stereoisomer, or its pharmaceutically acceptable salt 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 of the present application, its stereoisomer, or its pharmaceutically acceptable salt 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 consisting of any of the foregoing values ​​as endpoints or any value therein, for example, 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.

[0042] Administration of the compound of the present application, its stereoisomer, or its pharmaceutically acceptable salt can be administered once or more daily. In some embodiments, the compound of the present application, its stereoisomer, or its pharmaceutically acceptable salt is administered once or twice a day. Administration of the compound of the present application, its stereoisomer, or its pharmaceutically acceptable salt can also be administered in a single dose form. In one embodiment, administration is once or twice a day in a single dose. In one embodiment, administration is once or twice a day in a single dose of an oral solid formulation. In a specific embodiment, administration is twice a day in a single dose of an oral solid formulation.

[0043] The compound of the present application, its stereoisomer, or its pharmaceutically acceptable salt can also be administered in multiple doses. In one embodiment, multiple doses are administered once or twice a day. In one embodiment, multiple doses of oral solid preparations are administered once or twice a day. In a specific embodiment, multiple doses of oral solid preparations are administered twice a day.

[0044] In some embodiments 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, it is a single-dose pharmaceutical composition. In some embodiments, the pharmaceutical composition contains 1mg to 50mg of the compound of the present application, its stereoisomer, or its pharmaceutically acceptable salt. In some embodiments, the pharmaceutical composition contains 1mg, 2mg, 5mg, 8mg, 10mg, 12mg, 15mg, 18mg, 20mg, 22mg, 25mg, 28mg, 30mg, 32mg, 35mg, 38mg, 40mg, 42mg, 45mg, 48mg or 50mg, or any of the aforementioned values ​​as the range of endpoints or any value thereof The compound of the present application, its stereoisomer, or its pharmaceutically acceptable salt, such as 2mg to 50mg, 10mg to 40mg, 5mg to 30mg, 5mg to 20mg, 20mg to 40mg, 30mg to 40mg, etc.

[0045] In some embodiments 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 embodiments 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 embodiments of the present application, each dose of the two doses is the same.

[0046] In some embodiments of the present application, the pharmaceutical composition of the compound of formula I, its stereoisomers, or pharmaceutically acceptable salts thereof is administered twice daily, and each dose is a single dose or multiple doses.

[0047] In some schemes of the present application, the pharmaceutical composition of the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt is twice daily dose, each dose is multiple doses, which consists of a single dose of 5 mg, 10 mg, 15 mg and / or 20 mg of the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt. In some schemes of the present application, the pharmaceutical composition consists of a single dose of 5 mg of the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt.

[0048] In some schemes of the present application, the pharmaceutical composition of the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt is twice daily dose, 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 stereoisomer, or its pharmaceutically acceptable salt. In some schemes of the present application, the single dose is 20 mg of the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt.

[0049] In some embodiments of the present application, the pharmaceutical composition of the compound of formula I, its stereoisomers, or pharmaceutically acceptable salts thereof is packaged in a kit, which also contains instructions for using the compound of formula I, its stereoisomers, or pharmaceutically acceptable salts thereof to treat hemophagocytic hemophagocytic syndrome.

[0050] In some schemes of the present application, in the method or use for treating hemophagocytic hemophagocytic syndrome, the pharmaceutical composition of the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt is a daily dose, which is administered in the following manner: the pharmaceutical composition of the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt is administered once or twice a day; in some schemes of the present application, the pharmaceutical composition of the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt is administered twice a day, and each dose is the same; in some schemes of the present application, the pharmaceutical composition of the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt is administered twice a day, and each dose is the same, and the interval between each administration is 12 hours.

[0051] In some schemes of the present application, 28 days is a treatment cycle, and the pharmaceutical composition of the compound of formula I, its stereoisomer, or a pharmaceutically acceptable salt thereof is continuously administered on days 1 to 28 of each cycle.

[0052] In some schemes of the present application, 28 days is a treatment cycle, and the pharmaceutical composition of the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt is administered twice a day continuously on days 1 to 28 of each cycle.

[0053] In some schemes of the present application, 28 days is a treatment cycle, and the total dose of the pharmaceutical composition of the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt administered in each treatment cycle is 140 to 840 mg (calculated as the active ingredient of the compound of formula (I) itself). In some schemes of the present application, the total dose of the pharmaceutical composition of the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt 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 active ingredient of the compound of formula (I) itself). In some schemes of the present application, the total dose of the pharmaceutical composition of the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt is preferably 560 to 840 mg (calculated as the active ingredient of the compound of formula (I) itself).

[0054] In some embodiments of the present application, the above treatment cycles are repeated as long as the disease remains under control and the dosing regimen is clinically tolerated.

[0055] The compounds of the present application, their stereoisomers, or pharmaceutically acceptable salts thereof can be administered by a variety of routes, including but not limited to the following routes: oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, transbuccal, intranasal, by inhalation, vaginal, intraocular, by topical administration, subcutaneous, intrafatty, intraarticular or intrathecal. In a specific scheme, the administration is by oral administration.

[0056] In some embodiments of the present application, the pharmaceutical composition of the compound of formula I, its stereoisomers, or its pharmaceutically acceptable salt can be formulated into a dosage form suitable for oral administration to humans, such as but not limited to tablets, pills, capsules, powders or granules.

[0057] In some embodiments of the present application, the pharmaceutical composition of the compound of formula I, its stereoisomers, or its pharmaceutically acceptable salt is an oral tablet.

[0058] In some embodiments of the present application, the single-dose strength of the oral tablet of the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt is 5 mg or 20 mg.

[0059] Technical Effects

[0060] The compound of formula I of the present application, its stereoisomer, or its pharmaceutically acceptable salt or its pharmaceutical composition has good therapeutic effect, which is embodied in including but not limited to better disease control rate, longer survival (such as median survival, progression-free survival or overall survival), and longer duration of disease remission (DOR). The compound of formula I of the present application, its stereoisomer, or its pharmaceutically acceptable salt or its pharmaceutical composition, when having good therapeutic effect, also has good safety, including but not limited to lower incidence of adverse reactions.

[0061] Definition and Description

[0062] Unless otherwise specified, the terms used in this application have the following meanings. A particular term should not be considered to be uncertain or unclear in the absence of a special definition, but should be understood according to the common meaning in the art. When a trade name appears in this application, it is intended to refer to the corresponding commodity or its active ingredient.

[0063] Herein, unless otherwise specified, the terms "comprise, comprises and comprising" or equivalents are open-ended expressions, meaning that in addition to the listed elements, components and steps, other unspecified elements, components and steps may also be included.

[0064] All patents, patent applications and other identified publications are expressly incorporated herein by reference for the purposes of description and disclosure. Any citation of these publications herein does not constitute an admission that the publication becomes part of the common general knowledge in the art.

[0065] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0066] The term "pharmaceutically acceptable salt" includes salts formed by alkali ions and free acids or salts formed by acid ions and free bases. The pharmaceutically acceptable salts described herein are selected from maleate, hydrochloride, hydrobromide, sulfate, phosphate, nitrate, acetate, lactate, malonate, succinate, fumarate, malate, mandelate, tartrate, citrate, ascorbate, palmitate, benzoate, phenylacetate, cinnamate, salicylate, methanesulfonate, benzenesulfonate or toluenesulfonate.

[0067] As used herein, the amount of the compound of Formula I, such as the amount administered, dosage, or content in a pharmaceutical composition, is calculated in the form of its free base.

[0068] As used herein, the compound in the drug combination of the present application can form an acid addition salt if it has, for example, at least one basic center. If necessary, a corresponding acid addition salt with an additional basic center can also be formed. A compound with at least one acidic group (e.g., COOH) can also form a salt with a base. If the compound, for example, contains both a carboxyl group and an amino group, a corresponding inner salt can also be formed.

[0069] The compounds of the present application may be asymmetric, for example, having one or more stereoisomers. Unless otherwise indicated, all stereoisomers are included, such as enantiomers and diastereomers. The compounds of the present application containing asymmetric carbon atoms can be separated in optically pure form or racemic form. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral raw materials or chiral reagents.

[0070] The term "patient" refers to mammals, such as humans, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic non-human animals. In some embodiments, the patient is a human.

[0071] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or their drug combination or salts and pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present application or their drug combination to a subject.

[0072] The term "treatment" generally refers to obtaining a desired pharmacological and / or physiological effect, including partial or complete stabilization or cure of a disease and / or effects resulting from a disease. As used herein, "treatment" encompasses any treatment of a patient's disease, including: (a) suppressing the symptoms of the disease, i.e., preventing its development; or (b) alleviating the symptoms of the disease, i.e., causing regression of the disease or symptoms.

[0073] The term "effective amount" means the amount of the compound of the present application that (i) treats a particular disease, condition or disorder, or (ii) alleviates, ameliorates or eliminates one or more symptoms of a particular disease, condition or disorder. The amount of the compound of the present application 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 those skilled in the art based on their own knowledge and the present disclosure.

[0074] 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 bottle of injection is a single dose.

[0075] The term "multiple doses" consists of a plurality of single doses.

[0076] The terms "administering" and "administering" refer to the physical introduction of a composition comprising a therapeutic agent into a subject using any of a variety of methods and delivery systems known to those skilled in the art. In certain embodiments, administration is oral administration.

[0077] The term "daily dose" refers to the dose administered to a patient daily.

[0078] When referring to a dosing regimen, the terms "day," "daily," and the like refer to times within a calendar day, beginning at midnight and ending at the following midnight. DETAILED DESCRIPTION

[0079] The present invention is described in more detail by specific examples. The following examples are provided for illustrative purposes and should not be construed to limit the present invention in any way.

[0080] Preparation Example 1: Preparation of 5 mg and 20 mg tablet solid pharmaceutical compositions

[0081] The prescription composition of the solid pharmaceutical composition of 5 mg and 20 mg tablets is shown in Table 1:

[0082] Table 1 Prescription composition of 5mg and 20mg tablets

[0083]

[0084] Preparation process:

[0085] 1) mixing mannitol, microcrystalline cellulose and cross-linked sodium carboxymethyl cellulose, and retaining the obtained mixture A;

[0086] Preparation of the API suspension: dissolving hydroxypropyl cellulose in the prescribed amount of purified water to prepare a 4% (w / w) hydroxypropyl cellulose solution; dissolving sodium dodecyl sulfate; adding the compound of formula II and stirring and dispersing to obtain the API suspension;

[0087] 2) Fluidized bed granulation and drying: Spray the API suspension onto the mixture A for fluidized granulation. Granulation parameters: air inlet temperature 55-80°C, atomization pressure 600-1000 mbar, material temperature 25-35°C; dry after spraying, and dry when the material temperature is higher than 45°C; use a crushing and granulating machine to granulate, the granulating screen aperture is Φ0.6-1.2 mm, and obtain dry granules after granulation;

[0088] 3) The granulated dry granules and magnesium stearate are sequentially put into a hopper mixer and fully mixed, and the obtained solid pharmaceutical composition is tableted.

[0089] Example 1 Clinical Program for Hemophagocytic Syndrome

[0090] 1.1 Dosage regimen

[0091] Dosage: Take orally once on an empty stomach every morning, and again 12 hours later. Continuous administration for 28 days is a treatment cycle.

[0092] Drug: Tablets of the compound of formula I, 5 mg or 20 mg, wherein the compound of formula I is represented by its stereoisomer compound of formula II

[0093] 1.2 Inclusion criteria

[0094] 1) Age ≥ 18 years old; ECOG physical status: 0-3 points; expected survival period is more than 3 months;

[0095] 2) Patients diagnosed with the first onset or first relapse of HLH according to the HLH-2004 criteria;

[0096] 3) Those who have used other HLH treatment drugs need to stop taking them for more than 2 weeks. Those who have undergone major surgery need to wait 4 weeks after the surgery;

[0097] 4) Laboratory examinations must meet the following requirements: Routine blood examination: hemoglobin (Hb) ≥ 60 g / L; absolute neutrophil count (ANC) ≥ 0.5 × 10 9 / L; platelets (PLT) ≥ 30 × 10 9 / L; Liver function: serum total bilirubin (TBIL) <171μmol / L; Renal function: serum creatinine (Cr) ≤15×ULN; Coagulation function: activated partial thromboplastin time (APTT), international normalized ratio (INR) ≤1.5×ULN;

[0098] 5) Female patients must agree to use contraceptive measures (such as intrauterine devices [IUDs], birth control pills or condoms) during the study and for at least 6 months after the study ends; the serum pregnancy test must be negative within 7 days before the study entry and medication, and the patient must not be breastfeeding; male patients must agree to use contraceptive measures during the study and for at least 6 months after the study ends;

[0099] 6) The patients voluntarily participated in this study, signed the informed consent form, and had good compliance.

[0100] 1.3 Evaluation Method

[0101] The efficacy was evaluated according to the standards of the "Chinese Expert Consensus on the Diagnosis and Treatment of Hemophagocytic Syndrome (2018)". During induction therapy, it is recommended to evaluate the efficacy every 2 weeks.

[0102] The main indicators for efficacy evaluation included sCD25, ferritin, blood cell count, triglyceride, hemophagocytosis, and consciousness level (for patients with CNS-HLH).

[0103] a) Complete response: All the above indicators return to normal range.

[0104] b) Partial response: ≥2 symptoms / laboratory indicators improved by more than 25%, and individual indicators must meet the following standards: ① sCD25 level decreased by more than 1 / 3; ② ferritin and triglycerides decreased by more than 25%; ③ without blood transfusion: neutrophil <0.5x10 9 / L, it needs to increase by 100% and be greater than 0.5x10 9 / L; neutrophils 0.5~2.0x10 9 ④For those with ALT>400U / L, it needs to be reduced by more than 50%.

[0105] 1.4 Treatment effect

[0106] Case 1

[0107] A 45-year-old female patient was diagnosed with hemophagocytic syndrome and was given 20 mg / time of tablets of the compound of formula II according to the dosing regimen described in 1.1. Blood tests were performed at fixed points to detect blood drug concentrations, and blood picture, biochemistry, coagulation and other indicators were dynamically monitored. The patient's condition and vital signs were closely monitored. After one cycle of medication, the disease of case 1 remained stable and the patient's tolerance was acceptable.

[0108] Case 2

[0109] A 44-year-old female patient was diagnosed with hemophagocytic syndrome and was given 15 mg / time of tablets of the compound of formula II according to the dosing regimen described in 1.1. Blood tests were performed at designated locations to detect blood drug concentrations, and blood counts, biochemistry, coagulation and other indicators were dynamically monitored. The patient's condition and vital signs were continuously closely and dynamically monitored.

[0110] After one cycle of medication, the disease in Case 2 remained stable, with sCD25 levels dropping by more than 1 / 3 and ferritin levels dropping by more than 25%. The disease showed a partial response and the patient's tolerance was acceptable.

Claims

1. Use of a compound of formula II or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising a compound of formula II or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating secondary hemophagocytic syndrome, wherein the secondary hemophagocytic syndrome is selected from macrophage activation syndrome 2. The use according to claim 1, wherein The macrophage activation syndrome refers to macrophage activation syndrome associated with systemic or organ-specific autoimmune diseases.

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