Use of quinolinone derivatives for treating immune thrombocytopenia - Patents.com

Abstract

The present invention relates to the use of a quinolinone derivative for treating immune thrombocytopenia, specifically to the use of a compound of formula (I) or a pharma- ceutically acceptable salt thereof or a pharmaceutical composition thereof for treating immune thrombocytopenia. [Formula 1] TIFF2024541257000006.tif34131

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to Chinese Patent Application No. 202111340688.4, filed with the China State Intellectual Property Office on November 12, 2021, which is incorporated herein by reference in its entirety. [Technical field]

[0002] The present application is in the field of medicinal chemistry and relates to the use of quinolinone derivatives for treating immune thrombocytopenia, in particular the use of a compound of formula I or a pharma- ceutically acceptable salt thereof for treating immune thrombocytopenia. [Background technology]

[0003] Primary immune thrombocytopenia (ITP) is an acquired autoimmune bleeding disorder characterized primarily by an isolated peripheral blood platelet count decrease without a clear cause. Currently, there are no population-based epidemiological data on immune thrombocytopenia in Japan, and the annual incidence of immune thrombocytopenia in adults reported from abroad is approximately (2-10) / 100,000. ITP occurs in all age groups, but is more prevalent in elderly people aged 60 years or older and women of childbearing age. The clinical symptoms of patients with immune thrombocytopenia are diverse, ranging from asymptomatic to only bleeding of the skin and mucous membranes. Approximately 5% of patients with immune thrombocytopenia experience life-threatening bleeding in vital organs and intracranial bleeding, and approximately 15% of patients with immune thrombocytopenia are hospitalized for endogenous bleeding events within 5 years of diagnosis. In addition to bleeding events, most patients with immune thrombocytopenia experience fatigue and a decline in health-related quality of life (HRQoL).

[0004] Spleen tyrosine kinase (Syk) is an intracellular tyrosine protein kinase and a member of the ZAP70 protein kinase family. Syk is involved in the FcR signaling pathway, and after FcR binds to its ligand, receptor ligation leads to autophosphorylation of Syk, which then recruits Syk and activates downstream signaling cascades, resulting in cytoskeletal remodeling and phagocytosis. Syk exerts roles in various immune recognition receptors, and its sustained expression is highly related to the development and progression of various hematological malignancies. Therefore, Syk inhibitors can be utilized to treat allergic diseases, autoimmune diseases, inflammatory diseases, and some hematological malignancies.

[0005] WO2018228475 discloses a series of compounds as Syk inhibitors, specifically, compounds of formula I having the following structure: [ka] Summary of the Invention

[0006] In one aspect, the present application provides a compound of formula I or a pharma- ceutically acceptable salt thereof for treating or preventing immune thrombocytopenia in a patient. [ka]

[0007] In another aspect, the present application provides a pharmaceutical composition for treating or preventing immune thrombocytopenia in a patient, the pharmaceutical composition comprising a compound of formula I or a pharma- ceutically acceptable salt thereof.

[0008] In some embodiments, the pharmaceutical composition also contains a pharma- ceutically acceptable carrier and / or excipient.

[0009] In some embodiments, the pharmaceutical compositions described herein comprise a compound of Formula I, or a pharma- ceutically acceptable salt thereof, as the sole active agent.

[0010] In some embodiments, the pharmaceutical compositions described herein comprise a therapeutically or prophylactically effective amount of a compound of Formula I, or a pharma- ceutically acceptable salt thereof.

[0011] In some embodiments, the pharmaceutical compositions described herein contain a single dose of 10-200 mg (calculated by weight of the compound of Formula I) of a compound of Formula I or a pharma- ceutically acceptable salt thereof.

[0012] In some embodiments, the pharmaceutical compositions described herein contain 10-200 mg (calculated by weight of the compound of formula I) of a compound of formula I or a pharma- ceutically acceptable salt thereof as the sole active agent.

[0013] In another aspect, the present application provides the use of a compound of Formula I, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for treating or preventing immune thrombocytopenia in a patient.

[0014] In another aspect, the present application provides the use of a compound of formula I, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, in treating or preventing immune thrombocytopenia in a patient.

[0015] In another aspect, the present application provides a method of treating or preventing immune thrombocytopenia in a subject, the method comprising administering to a subject in need thereof a therapeutically or prophylactically effective amount of a compound of formula I, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0016] In some embodiments of the present application, a compound of Formula I described herein, or a pharma- ceutically acceptable salt thereof, is used as the sole active agent.

[0017] In some embodiments, the compound of formula I described herein, or a pharma- ceutically acceptable salt thereof, is used in a dosage of 10 to 200 mg (calculated by weight of the compound of formula I).

[0018] In some embodiments of the present application, the compound of formula I or a pharma- ceutically acceptable salt thereof of the present application may be in the form of a pharmaceutical composition comprising a therapeutically or prophylactically effective amount of the compound of formula I or a pharma- ceutically acceptable salt thereof.

[0019] In another aspect, the present application provides a kit for treating immune thrombocytopenia in a patient, the kit comprising a compound of Formula I or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, as described herein, and instructions for treating or preventing immune thrombocytopenia in a patient.

[0020] In some embodiments, the compound of formula I or a pharma- ceutically acceptable salt thereof described herein may be in the form of a dosage of 10 to 200 mg (calculated by weight of the compound of formula I).

[0021] In some embodiments, the pharmaceutical composition may be a single dose pharmaceutical composition containing 10 to 200 mg (calculated by weight of the compound of formula I) of a compound of formula I or a pharma- ceutical acceptable salt thereof as an active ingredient.

[0022] "A compound of formula I or a pharma- ceutically acceptable salt thereof" In some embodiments of the present application, the compounds of formula I described herein may be obtained with reference to the preparation methods described in WO2018228475 or WO2020119785.

[0023] The pharma- ceutically acceptable salt of the compound of formula I in the present application may be a hydrochloride salt of the compound of formula I, for example, a monohydrochloride salt of the compound of formula I. The dosage of the compound of formula I or a pharma- ceutically acceptable salt thereof in the present application is calculated based on the molecular weight of the compound of formula I, unless otherwise specified.

[0024] In some embodiments of the present application, the hydrochloride salt of the compound of formula I described herein may be obtained with reference to the preparation methods described in WO2020119785.

[0025] Pharmaceutical Compositions of Formula I Compounds or Pharmaceutically Acceptable Salts Thereof In some embodiments of the present application, the compound of formula I or a pharma- ceutically acceptable salt thereof is a pharmaceutical composition comprising a therapeutically or prophylactically effective amount of a compound of formula I or a pharma- ceutically acceptable salt thereof.

[0026] In some embodiments of the present application, the pharmaceutical composition contains a compound of formula I or a pharma- ceutically acceptable salt thereof in a dose of 10-200 mg. In some embodiments, the pharmaceutical composition contains a compound of formula I or a pharma- ceutically acceptable salt thereof in a dose of 10 mg, 20 mg, 40 mg, 50 mg, 60 mg, 80 mg, 100 mg, 120 mg, 150 mg, or 200 mg, or a range defined by any of the preceding values, or any value therein, such as 50 mg, 200 mg, etc. In some embodiments, the pharmaceutical composition contains a compound of formula I or a pharma- ceutically acceptable salt thereof in a dose of 200 mg.

[0027] In some embodiments of the present application, the pharmaceutical composition is a single dose pharmaceutical composition. In some embodiments of the present application, the pharmaceutical composition is a single dose pharmaceutical composition of the compound of formula I or a pharma- ceutical acceptable salt thereof, the single dose of which is 10-200 mg.

[0028] In some embodiments of the present application, the compound of formula I or a pharma- ceutically acceptable salt thereof is administered daily for a treatment period of 2 to 6 weeks (e.g., 28 days), and the total dose for each treatment period is 0.7 to 42 g, for example, 5.6 to 22.4 g. In some embodiments, the total dose for each treatment period of the compound of formula I or a pharma- ceutically acceptable salt thereof is selected from 5.6 g, 11.2 g, 16.8 g, 22.4 g, or a range formed by any of the foregoing values. In some embodiments, the total dose for each treatment period of the compound of formula I or a pharma- ceutically acceptable salt thereof is preferably 11.2 to 22.4 g. In some embodiments, the total dose for each treatment period of the compound of formula I or a pharma- ceutically acceptable salt thereof is preferably 11.2 g or 16.8 g. In some embodiments, the total dose for each treatment period of the compound of formula I or a pharma- ceutically acceptable salt thereof is preferably 16.8 g.

[0029] In some embodiments of the present application, the pharmaceutical composition includes, but is not limited to, a formulation suitable for oral, parenteral, or topical administration. In some embodiments, the pharmaceutical composition is a formulation suitable for oral administration. In some embodiments, the pharmaceutical composition is a solid formulation suitable for oral administration. In some embodiments, the pharmaceutical composition includes, but is not limited to, a tablet, a capsule.

[0030] In some embodiments of the present application, the pharmaceutical composition is a solid pharmaceutical composition.

[0031] In some embodiments of the present application, the pharmaceutical composition is a tablet.

[0032] In some embodiments of the present application, the pharmaceutical composition of the compound of formula I or a pharma- ceutically acceptable salt thereof may be a solid pharmaceutical composition of the hydrochloride salt of the compound of formula I.

[0033] In some embodiments, the pharmaceutical compositions described herein may be a pharmaceutical composition of the monohydrochloride salt of the compound of formula I. In some embodiments, the pharmaceutical compositions described herein may be a solid pharmaceutical composition of the monohydrochloride salt of the compound of formula I.

[0034] In some embodiments of the present application, the pharmaceutical composition of the compound of formula I or a pharma- ceutically acceptable salt thereof is a tablet of the hydrochloride salt of the compound of formula I, for example, the monohydrochloride salt of the compound of formula I.

[0035] The pharmaceutical compositions of the compounds of formula I or pharma- ceutically acceptable salts thereof of the present application may also contain pharma- ceutically acceptable carriers and / or excipients, which are well known to those skilled in the art and include, for example, fillers, absorbents, wetting agents, binders, disintegrants, lubricants, and the like.

[0036] The pharmaceutical compositions of the compounds of formula I or pharma- ceutically acceptable salts thereof of the present application may be prepared by conventional methods well known in the art, for example, by mixing, dissolving, granulating, dragee-making, pulverizing, emulsifying, lyophilizing or the like.

[0037] Oral solid compositions may be prepared by conventional methods such as blending, filling, tableting, etc. For example, the active compound may be mixed with a solid additive, and the mixture may be optionally milled. If necessary, other suitable additives may be added, and the mixture may then be processed into granules to obtain tablets or capsules or dragee cores. Suitable additives include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners, flavoring agents, etc.

[0038] "Immune thrombocytopenia" In some embodiments of the present application, the immune thrombocytopenia is primary immune thrombocytopenia or secondary immune thrombocytopenia. Preferably, the immune thrombocytopenia is primary immune thrombocytopenia.

[0039] In some embodiments of the present application, the immune thrombocytopenia comprises newly diagnosed immune thrombocytopenia, persistent immune thrombocytopenia or chronic immune thrombocytopenia. Preferably, the immune thrombocytopenia is persistent immune thrombocytopenia or chronic immune thrombocytopenia. More preferably, the immune thrombocytopenia is chronic immune thrombocytopenia.

[0040] In some embodiments of the present application, the immune thrombocytopenia is persistent or chronic primary immune thrombocytopenia.

[0041] In some embodiments of the present application, the immune thrombocytopenia is persistent or chronic primary immune thrombocytopenia in adults.

[0042] In some embodiments of the present application, the immune thrombocytopenia is recurrent and / or refractory primary immune thrombocytopenia.

[0043] In some embodiments of the present application, the immune thrombocytopenia is recurrent and / or refractory persistent primary immune thrombocytopenia.

[0044] In some embodiments of the present application, the immune thrombocytopenia is relapsing and / or refractory chronic primary immune thrombocytopenia.

[0045] In some embodiments of the present application, the immune thrombocytopenia is relapsing and / or refractory persistent primary immune thrombocytopenia in adults.

[0046] In some embodiments of the present application, the immune thrombocytopenia is adult relapsing and / or refractory chronic primary immune thrombocytopenia.

[0047] In some embodiments of the present application, the patient with persistent or chronic immune thrombocytopenia is a patient who has a persistent decrease in platelets for more than three months after diagnosis.

[0048] In some embodiments of the present application, the patient with persistent or chronic immune thrombocytopenia is a patient who has a sustained decrease in platelets for more than six months after diagnosis.

[0049] In some embodiments of the present application, the patient with persistent or chronic immune thrombocytopenia has a WHO bleeding score of 0 to 1.

[0050] In some embodiments of the present application, the patient with persistent or chronic immune thrombocytopenia has a mean platelet count of 30×10 or more on at least two independent occasions prior to treatment. 9 / L and the platelet count at each time was less than 35 × 10 9 / L or less.

[0051] In some embodiments of the present application, the patient with persistent or chronic immune thrombocytopenia has a mean platelet count of 30×10 or more on at least two independent occasions prior to treatment. 9 / L and the platelet count at each time was less than 35 × 10 9 / L or less and no severe bleeding within 4 weeks prior to treatment. In some embodiments of the present application, severe bleeding refers to a WHO bleeding score of 3 or more.

[0052] In some embodiments of the present application, the immune thrombocytopenia patient has previously undergone one or more prior immune thrombocytopenia treatments, hi some embodiments, the immune thrombocytopenia patient has previously undergone one, two, three, four, or five prior immune thrombocytopenia treatments.

[0053] In some embodiments of the present application, the prior immune thrombocytopenia treatment comprises drug therapy, or surgical therapy, or a combination thereof.

[0054] In some embodiments of the present application, the drug therapy includes, but is not limited to, glucocorticoid therapy, immunoglobulin therapy, molecular targeted therapy, platelet production enhancer therapy, or other drug therapy that can be used to treat immune thrombocytopenia.

[0055] In some embodiments of the present application, the glucocorticoid includes, but is not limited to, prednisone, meprednisone, prednisone acetate, prednisolone, methylprednisolone, prednisolone acetate, prednisolone sodium succinate, methylprednisolone sodium succinate, betamethasone, beclomethasone propionate, hydrocortisone, or dexamethasone. Preferably, the glucocorticoid includes dexamethasone and prednisone. In some embodiments, the glucocorticoid therapy may be high-dose glucocorticoid pulse therapy.

[0056] In some embodiments of the present application, the immunoglobulin comprises an injectable immunoglobulin. In some embodiments of the present application, the immunoglobulin may be a gamma globulin. Preferably, the injectable immunoglobulin is an injectable gamma globulin, such as an intravenous gamma globulin.

[0057] In some embodiments of the present application, the drug used in the molecular targeted therapy includes, but is not limited to, rituximab, veltuzumab, daclizumab, bevacizumab, alemtuzumab, or ocrelizumab.Preferably, the drug used in the molecular targeted therapy includes rituximab.

[0058] In some embodiments of the present application, the platelet production stimulator includes, but is not limited to, avatrombopag, eltrombopag, romiplostim, lusutrombopag, or recombinant human thrombopoietin (rhTPO). Preferably, the platelet production stimulator includes avatrombopag, eltrombopag, romiplostim, or recombinant human thrombopoietin (rhTPO). More preferably, the platelet production stimulator includes eltrombopag and recombinant human thrombopoietin.

[0059] In some embodiments of the present application, the other drugs that can be used to treat immune thrombocytopenia include, but are not limited to, immunosuppressants. In some embodiments of the present application, the other drugs that can be used to treat immune thrombocytopenia include, but are not limited to, immunosuppressants, such as ganciclovir sodium, imatinib, cyclosporine (A), mycophenolate sodium, mycophenolate mofetil, danazol, azathioprine, psoralen, methotrexate, hydroxychloroquine, clofazimine, cyclophosphamide, thalidomide, azithromycin, montelukast, sorafenib, ruxolitinib, decitabine, vincristine, alefacept, and all-trans retinoic acid. Preferably, the other drugs that can be used to treat immune thrombocytopenia include danazol, azathioprine, cyclosporine (A), vincristine, all-trans retinoic acid, or mycophenolate mofetil. More preferably, the other drugs that can be used to treat the immune thrombocytopenia include danazol, azathioprine, cyclosporine (A), all-trans retinoic acid, or vincristine. The other drug therapies that can be used to treat the immune thrombocytopenia include a combination therapy of all-trans retinoic acid and danazol, decitabine therapy, cyclosporine (A) therapy, azathioprine therapy, danazol therapy, and / or vincristine therapy.

[0060] In some embodiments of the present application, the drug used in the drug therapy is prednisone, meprednisone, prednisone acetate, prednisolone, methylprednisolone, prednisolone acetate, prednisolone sodium succinate, methylprednisolone sodium succinate, betamethasone, beclomethasone propionate, hydrocortisone, dexamethasone, injectable immunoglobulin (e.g., injectable gamma globulin), rituximab, veltuzumab, daclizumab, bevacizumab, ocrelizumab, b), alemtuzumab, avatrombopag, eltrombopag, romiplostim, lusutrombopag, recombinant human thrombopoietin (rhTPO), danazol, azathioprine, cyclosporine (A), mycophenolate mofetil, vincristine, all-trans retinoic acid, or decitabine, or a combination of one or more of the foregoing drugs.

[0061] In some embodiments of the present application, the surgical therapy is a splenectomy therapy.

[0062] In some embodiments of the present application, the immune thrombocytopenia patient may be a patient who has had a poor response to splenectomy or has experienced a recurrence after surgery.

[0063] In some embodiments of the present application, the immune thrombocytopenia patient may be a patient who has previously undergone one or more first-line or multi-line standard therapies and has failed. In some embodiments, the immune thrombocytopenia patient may be a patient who has previously undergone one or more first-line, second-line, third-line or fourth-line standard therapies and has failed. In some embodiments, the immune thrombocytopenia patient may be a patient who has previously undergone one or more first-line, second-line or third-line standard therapies and has failed. In some embodiments, the immune thrombocytopenia patient may be a patient who has previously undergone one, two, three, four or five first-line standard therapies and has failed.

[0064] In some embodiments of the present application, the first-line standard of care includes, but is not limited to, glucocorticoid therapy and / or injectable immunoglobulin therapy. In some embodiments, the glucocorticoid therapy is dexamethasone or prednisone therapy. In some embodiments, the injectable immunoglobulin therapy is injectable gamma globulin therapy.

[0065] In some embodiments of the present application, the second-line standard treatment includes, but is not limited to, platelet production promoter therapy and / or molecular targeted therapy and / or surgical therapy. In some embodiments, the platelet production promoter therapy is eltrombopag and / or recombinant human thrombopoietin therapy. In some embodiments, the molecular targeted therapy is rituximab therapy. In some embodiments, the surgical therapy is splenectomy therapy.

[0066] In some embodiments of the present application, the third line standard of care includes, but is not limited to, combination therapy with all-trans retinoic acid and danazol and / or decitabine therapy.

[0067] In some embodiments of the present application, the fourth line standard of care includes, but is not limited to, azathioprine and / or cyclosporine (A) and / or danazol and / or vinblastine-based therapy.

[0068] In some embodiments of the present application, the immune thrombocytopenia patient may be a patient who has previously received at least one first-line standard immune thrombocytopenia treatment (e.g., glucocorticoid therapy and / or intravenous gamma globulin therapy) and failed, or who has had a poor response to or relapse after splenectomy.

[0069] In some embodiments of the present application, the immune thrombocytopenia patient may be an adult patient with persistent or chronic immune thrombocytopenia diagnosed for more than 3 months, and / or a patient who has failed at least one previous first-line standard immune thrombocytopenia treatment (e.g., glucocorticoid therapy and / or intravenous gamma globulin therapy) or has responded poorly to or relapsed after splenectomy.

[0070] In some embodiments of the present application, failure of the treatment refers to ineffectiveness of the treatment, failure to maintain efficacy, or recurrence.

[0071] In some embodiments, the immune thrombocytopenic patient may be treated with a combination of different treatment methods. In some embodiments of the present application, the immune thrombocytopenic patient may be treated with a first-line standard of care, and / or a second-line standard of care, and / or a third-line standard of care, and / or a fourth-line standard of care.

[0072] In some embodiments of the present application, the immune thrombocytopenia patient may be a patient who has previously received glucocorticoid therapy and has been off the drug for at least 3 weeks.

[0073] In some embodiments of the present application, the immune thrombocytopenia patient may be a patient who has previously received danazol therapy and has been off the drug for at least 4 weeks.

[0074] In some embodiments of the present application, the immune thrombocytopenic patient may have previously received azathioprine, cyclosporine (A) and / or mycophenolate mofetil therapy and has been off the medication for at least 4 weeks.

[0075] In some embodiments of the present application, the immune thrombocytopenia patient may have one or more (e.g., one, two, or three) types of immune thrombocytopenia. In some embodiments of the present application, the immune thrombocytopenia optionally includes a combination of two or more of the above types of immune thrombocytopenia. In some embodiments of the present application, the immune thrombocytopenia patient may have two or more types of immune thrombocytopenia. For example, the immune thrombocytopenia patient may have a combination of two or more of the above types of immune thrombocytopenia.

[0076] In this application, "poor efficacy" means that the platelet count after treatment is less than 30 × 10 9 / L, or the platelet count has increased to less than twice the baseline, or bleeding has occurred.

[0077] Dosage Regimen In some embodiments of the present application, the administration period of the compound of formula I or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof may be 2 to 6 weeks. In some embodiments of the present application, the administration period of the compound of formula I or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof may be 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 period of the compound of formula I or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof may be 4 to 5 weeks. In some embodiments, the administration period of the compound of formula I or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof may be 1 to 6 administration periods, for example, 1, 2, 3, 4, 5, or 6 administration periods.

[0078] In some embodiments of the present application, the administration period for the therapeutic treatment using the compound of formula I or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, may be 2 to 6 weeks. In some embodiments of the present application, the administration period for the therapeutic treatment may be 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, or a range formed by any of the foregoing values. In some embodiments of the present application, the administration period for the therapeutic treatment may be 4 to 5 weeks.

[0079] In some embodiments of the present application, the administration regimen of the compound of formula I or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof for treatment or prophylaxis may be once to three times a day, or once every two days, preferably once a day.

[0080] In some embodiments of the present application, the daily dose of the compound of formula I or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof may be selected from 50 to 1000 mg. In some embodiments of the present application, the daily dose of the compound of formula I or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof may be selected from 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, or a range formed by any of the above values. In some embodiments of the present application, the daily dose of the compound of formula I or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof is selected from 200 to 800 mg, 200 to 800 mg, 400 to 800 mg, 400 to 600 mg, or 600 to 800 mg.

[0081] In some embodiments of the present application, the daily dose of the compound of formula I or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof for the treatment or prophylaxis may be selected from 50 to 1000 mg. In some embodiments of the present application, the daily dose of the compound of formula I or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof for the treatment or prophylaxis may be selected from 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, or a range formed by any of the above values. In some embodiments of the present application, the daily dose of the compound of formula I or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof for the treatment or prophylaxis may be selected from 200 to 800 mg, 200 to 800 mg, 400 to 800 mg, 400 to 600 mg, or 600 to 800 mg.

[0082] In some embodiments of the present application, each dose of the compound of formula I or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof may be selected from 50 to 1000 mg. In some embodiments of the present application, each dose of the compound of formula I or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof may be selected from 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, or a range formed by any of the above values. In some embodiments of the present application, each dose of the compound of formula I or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof may be selected from 50 to 800 mg, 200 to 800 mg, 200 to 600 mg, 200 to 400 mg, 400 to 800 mg, 400 to 600 mg, or 600 to 800 mg.

[0083] In some embodiments of the present application, the dose of the compound of formula I or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof for the treatment or prophylaxis may be selected from 50 to 1000 mg. In some embodiments of the present application, the dose of the compound of formula I or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof for the treatment or prophylaxis may be selected from 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, or a range formed by any of the above values. In some embodiments of the present application, the dose of the compound of formula I or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof for the treatment or prophylaxis may be selected from 50 to 800 mg, 200 to 800 mg, 200 to 600 mg, 200 to 400 mg, 400 to 800 mg, 400 to 600 mg, or 600 to 800 mg.

[0084] In some embodiments of the present application, the compound of Formula I or a pharma- ceutically acceptable salt thereof is provided in the form of a pharmaceutical composition.

[0085] In some embodiments of the present application, for treating immune thrombocytopenia in a patient, the pharmaceutical composition is administered in the form of a single dosage and is administered once, twice or three times daily.In some embodiments of the present application, for treating immune thrombocytopenia in a patient, the pharmaceutical composition is administered in the form of a single dosage oral solid formulation and is administered once, twice or three times daily.

[0086] In some embodiments of the present application, for the treatment of immune thrombocytopenia in a patient, the pharmaceutical composition is administered in the form of multiple doses and is administered once or twice daily. In some embodiments of the present application, for the treatment of immune thrombocytopenia in a patient, the pharmaceutical composition is administered in the form of multiple doses of an oral solid formulation and is administered once or twice daily. In one specific embodiment, for the treatment of immune thrombocytopenia in a patient, the pharmaceutical composition is administered in the form of multiple doses of an oral solid formulation and is administered once daily.

[0087] In some embodiments of the present application, the pharmaceutical composition of the compound of formula I or a pharma- ceutically acceptable salt thereof is a single dose per day, each dose being a single dose or multiple doses, preferably multiple doses, each of which is comprised of a compound of formula I or a pharma- ceutically acceptable salt thereof in an amount of 10-200 mg. In some embodiments, each of the multiple doses is comprised of a compound of formula I or a pharma- ceutically acceptable salt thereof in an amount of 10 mg, 20 mg, 40 mg, 50 mg, 60 mg, 80 mg, 100 mg, 120 mg, 150 mg, or 200 mg. In some embodiments of the present application, the pharmaceutical composition is comprised of a compound of formula I or a pharma- ceutically acceptable salt thereof in an amount of 50 mg or 200 mg.

[0088] In some embodiments of the present application, a patient is treated with immune thrombocytopenia for 28 days, with one daily administration, including one administration of 200 mg, 400 mg, 600 mg, 800 mg, or a range formed by any of the preceding values, of the compound of formula I or a pharma- ceutically acceptable salt thereof, and 5.6 g, 11.2 g, 16.8 g, 22.4 g, or a range formed by any of the preceding values, of the compound of formula I or a pharma- ceutically acceptable salt thereof, during each treatment period.

[0089] In some embodiments of the present application, 28 days constitute one treatment period, with the compound of formula I or a pharma- ceutically acceptable salt thereof or a pharmaceutical composition thereof being administered consecutively on days 1 through 28 of each period.

[0090] In some embodiments of the present application, 28 days constitute one treatment period, with the compound of formula I or a pharma- ceutically acceptable salt thereof or a pharmaceutical composition thereof being administered consecutively daily on days 1 through 28 of each period.

[0091] In some embodiments of the present application, a treatment period is 28 days, and the compound of formula I or a pharma- ceutically acceptable salt thereof or a pharmaceutical composition thereof is administered continuously once daily on days 1 through 28 of each period.

[0092] In some embodiments of the present application, a treatment period is 28 days, and the compound of formula I or a pharma- ceutically acceptable salt thereof or a pharmaceutical composition thereof is administered once daily on an empty stomach on days 1 to 28 of each period.

[0093] In some embodiments of the present application, a treatment period is 28 days, and on days 1 to 28 of each period, the compound of formula I or a pharma- ceutically acceptable salt thereof or a pharmaceutical composition thereof is administered continuously once a day, and each dose of the compound of formula I or a pharma- ceutically acceptable salt thereof or a pharmaceutical composition thereof is a single dose, and the single dose is 50 mg or 200 mg of the compound of formula I or a pharma- ceutically acceptable salt thereof.

[0094] In some embodiments of the present application, the compound of formula I or a pharma- ceutically acceptable salt thereof or pharmaceutical composition thereof may be packaged in a kit, the kit comprising the compound of formula I or a pharma- ceutically acceptable salt thereof or pharmaceutical composition thereof in a dose for one or more treatment periods, or within one treatment period, or in a range of doses defined by any of the above values. In some embodiments of the present application, the compound of formula I or a pharma- ceutically acceptable salt thereof or pharmaceutical composition thereof may be packaged in a kit, the kit comprising the compound of formula I or a pharma- ceutically acceptable salt thereof or pharmaceutical composition thereof in a dose for 1 to 28 days (e.g., 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 14 days, 21 days, or 28 days), or in a treatment period, 2 treatment periods, or more than 3 treatment periods, or in a range of doses defined by any of the above values.

[0095] In some embodiments of the present application, the compound of formula I or a pharma- ceutically acceptable salt thereof or a pharmaceutical composition thereof is packaged in a kit, the kit comprising a 1-day, 2-day, 3-day, 4-day, 5-day, 6-day, 7-day, 8-day, 9-day, 10-day, 11-day, 12-day, 13-day, 14-day, 15-day, 16-day, 17-day, 18-day, 19-day, 20-day, 21-day, 22-day, 23-day, 24-day, 25-day, 26-day, 27-day, or 28-day dose, or a range of doses comprising any of the above values ​​as endpoints. In some embodiments of the present application, the compound of formula I or a pharma- ceutically acceptable salt thereof or a pharmaceutical composition thereof is packaged in a kit, the kit comprising a 1-day, 2-day, 3-day, 4-day, 5-day, 6-day, 7-day, 14-day, 21-day, or 28-day dose, or a range of doses comprised by any of the above values.

[0096] In some embodiments of the present application, 28 days is one treatment period, and the total dose of the compound of formula I or a pharma- ceutically acceptable salt thereof or a pharmaceutical composition thereof administered in each treatment period is 5.6 to 22.5 g (calculated based on the compound of formula I itself, which is the active ingredient). In some embodiments of the present application, the total dose of the compound of formula I or a pharma- ceutically acceptable salt thereof or a pharmaceutical composition thereof is selected from 5.6 g, 11.2 g, 16.8 g, 22.4 g, or a range formed by any of the above values ​​(calculated based on the compound of formula I itself, which is the active ingredient). In some embodiments of the present application, the total dose of the compound of formula I or a pharma- ceutical composition thereof is preferably 11.2 to 16.8 g (calculated based on the compound of formula I itself, which is the active ingredient). In some embodiments of the present application, the total dose of the compound of formula I or a pharma- ceutical composition thereof is preferably 11.2 g or 16.8 g (calculated based on the compound of formula I itself, which is the active ingredient).

[0097] In some embodiments of the present application, the above treatment periods may be repeated as long as the disease is still controllable or the dosing regimen is clinically tolerated.

[0098] The above dosing regimens referred to herein are suitable for the compounds of formula I or pharma- ceutically acceptable salts thereof or pharmaceutical compositions thereof, drug combinations, kits, or uses or methods for treating or preventing immune thrombocytopenia described herein. Effect of the Invention

[0099] The compound of formula I of the present application has a good safety profile in the course of treating immune thrombocytopenia, and can effectively increase the platelet count of immune thrombocytopenia patients. At least one time up to the 12th week of treatment, the platelet count was 30×10 9 The percentage of subjects with platelet counts of ≥ 50 × 10 / L and a ≥ 2-fold increase in platelet counts compared to baseline (without emergency treatment during the period) was high. 9 The percentage of subjects with serum creatinine levels > 1 / L was also high.

[0100] "Definitions and Explanations" Unless otherwise specified, the terms used in this application have the following meanings: Certain terms are to be understood in their ordinary sense in the art, and not as open ended or unclear, unless otherwise defined: When a trade name is mentioned in this application, it refers to the corresponding product or its active ingredient.

[0101] As used herein, unless otherwise indicated, the terms "comprise," "comprises," "comprising," or equivalent terms are intended to be open-ended and mean that the invention may include unspecified elements, ingredients, and steps in addition to the listed elements, ingredients, and steps.

[0102] This specification expressly incorporates by reference in its entirety any patents, patent applications, or other identified publications for purposes of description and disclosure. The inclusion of such publications in this specification is not an admission that such publications are part of the common general knowledge in the art.

[0103] Unless otherwise specifically stated, the singular forms of terms cover the plural and the plural forms of terms cover the singular. Unless otherwise specifically stated, the terms "a" or "one" mean "at least one" or "at least one." Unless otherwise specifically stated, "or" is used in the sense of "and / or."

[0104] The term "administering" refers to the physical introduction of a therapeutic agent or a composition containing a therapeutic agent into a subject using any of a variety of methods and delivery systems known to those of skill in the art.

[0105] As used herein, the term "pharmacologically acceptable" refers to compounds, materials, compositions and / or dosage forms that are medically determined to be suitable for use in contact with human or animal tissue, not toxic or irritating, and not likely to cause an allergic reaction or other problem or complication, and for which the benefit-to-risk ratio is reasonable.

[0106] The term "pharmaceutically acceptable carrier and / or excipient" refers to a carrier and / or excipient that is not obviously irritating to the living body and does not impair the biological activity and properties of the active compound.

[0107] The term "pharmaceutically acceptable salt" includes salts formed with a basic group ion and a free acid or with an acid group ion and a free base.

[0108] In this application, "treatment is ineffective" means that the platelet count is 30 × 10 9 / L or less than a two-fold increase compared to baseline.

[0109] In this application, "the effect cannot be maintained" means that the platelet count is less than 30 × 10 9 / L or less than a two-fold increase from baseline sustained for 12 weeks, excluding acute treatment-related platelet elevations.

[0110] In this application, the content of the compound of formula I or a pharma- ceutically acceptable salt thereof, for example, in dosage amounts, doses, and pharmaceutical compositions, is calculated in terms of its free base form.

[0111] The compounds in the drug combinations of the present application can form acid addition salts, for example, when they have at least one basic core. If desired, they can also form corresponding acid addition salts with other basic cores. Compounds with at least one acidic functional group (e.g., COOH) can form salts with bases. Compounds can form internal salts, for example, when they contain both a carboxy group and an amino group.

[0112] The term "patient" refers to a mammal, such as a human, dog, cow, horse, pig, sheep, goat, cat, mouse, rabbit, rat, or non-human genetically modified animal. In some embodiments, the patient is a human. As used herein, the terms "subject" and "patient" may be used interchangeably.

[0113] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or salts thereof with pharma- ceutical acceptable excipients to facilitate administration of the compounds of the present application or salts thereof to a patient.

[0114] The term "treatment" generally refers to obtaining a desired pharmacological and / or physiological effect, including partially or completely stabilizing or curing a disease and / or side effects caused by the disease. As used herein, the term "treatment" includes any treatment of a disease in a patient, (a) suppressing the symptoms of the disease, i.e., preventing its progression, or (b) ameliorating the symptoms of the disease, i.e., reducing the disease or symptoms.

[0115] The term "prevention" refers to the administration of a compound or formulation described herein to prevent a disease or one or more symptoms associated with said disease, and includes preventing the appearance of a disease or disease state in a mammal, particularly when a mammal susceptible to the disease state has not been diagnosed with the disease state.

[0116] The term "effective amount" refers to a dose of a compound of the present application that (i) treats a particular disease, condition, or disorder, and (ii) reduces, improves, or eliminates one or more symptoms of a particular disease, condition, or disorder. The amount of a compound of the present application that is a "therapeutically effective amount" will vary depending on the compound, the condition and its severity, the mode of administration, and the age of the mammal being treated, but can be determined by one of skill in the art based on their knowledge and the contents of this disclosure.

[0117] The term "single dose" refers to an indivisible packaged unit containing a predetermined amount of a drug, e.g., if there are seven capsules in a medicine box, each capsule is a dose, or a bottle of injection solution is a dose. The term "multiple doses" consists of multiple single doses.

[0118] The term "relapse" refers to the return of disease following objective remission following treatment with a particular therapy.

[0119] The term "refractory" refers to a particular disease that is resistant or unresponsive to therapy using a particular therapeutic agent. For example, refractory immune thrombocytopenia refers to a patient who is ineffective against first-line drugs, second-line platelet production promoters, and rituximab therapy, or who is ineffective or relapses after splenectomy, and who has been diagnosed and evaluated and has been confirmed to have immune thrombocytopenia. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0120] The present invention will be described in more detail with reference to the following specific examples. The following examples are provided for illustrative purposes and are not intended to limit the present invention in any manner.

[0121] The compound of formula I was prepared according to the methods disclosed in WO2018228475.

[0122] Example 1: Clinical trial on immune thrombocytopenia 1.1 Investigational Product and Dosing Schedule Investigational Medicinal Product: Compound of Formula I in tablets, 50 mg / tablet or 200 mg / tablet. Dosage regimen: The drug is administered orally once daily on an empty stomach for 28 consecutive days.

[0123] 1.2 Inclusion Criteria 1) Subjects willingly participate in this study, sign an informed consent form, and their expected survival time is longer than 3 months. 2) Age was between 18 and 75 years (inclusive) (at the time of signing the informed consent), regardless of gender, and body condition score (Eastern Cooperative Oncology Group (ECOG) score) was between 0 and 2 points. 3) Have been diagnosed with persistent or chronic immune thrombocytopenia for at least 3 months prior to screening (sustained decrease in platelets for more than 6 months). 4) At least one type of first-line standard treatment for immune thrombocytopenia (intravenous glucocorticoids and / or gamma globulin) has failed (was ineffective, the effect was not sustained, or the disease recurred), or splenectomy was ineffective or the disease recurred after surgery. 5) The WHO bleeding score was 0-1 and the investigators determined that no urgent treatment was required within 2 weeks after enrollment. 6) The mean of at least two independent platelet counts (>24 hours apart) within the two months prior to screening is 30 × 10 9 / L and each platelet count was 35 × 10 9 / L or less and no significant bleeding within 4 weeks prior to screening. 7) Major organ function is good and meets the following criteria: A neutrophil count (ANC) is 1.5 x 10 9 / L and hemoglobin (Hb) is greater than 90 g / L. b. Total bilirubin (TBIL), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) are less than or equal to 1.5 times the upper limit of normal (ULN), serum creatinine is less than or equal to 1.5 x ULN, and creatinine clearance is greater than or equal to 50 mL / min. c. Blood amylase and lipase do not exceed the upper limit of the normal range. d. Prothrombin time (PT) does not exceed the normal range ±3 seconds, and activated partial thromboplastin time (APTT) does not exceed the normal range ±10 seconds. e. Besides immune thrombocytopenia, there is no history of other coagulation disorders. 8) Female subjects of childbearing age must agree to use contraception (e.g., intrauterine device, pills, or condoms) during and for 90 days after the completion of the study, have a negative serum pregnancy test within 7 days prior to inclusion in the study group, and be non-lactating. Male subjects must agree to use contraception during and for 6 months after the completion of the study.

[0124] 1.3 Evaluation methods and indicators The efficacy will be evaluated based on the subjects' platelet count, WHO bleeding score, and the situation in which emergency treatment is required. The main efficacy indicator will be the effective rate of platelet increase, and the evaluation criteria will refer to the American Society of Hematology Primary Immune Thrombocytopenia Guidelines (2019 edition) and the Chinese Guidelines for the Diagnosis and Treatment of Primary Immune Thrombocytopenia in Adults (2020 edition).

[0125] 1.4 Test Results 1.4.1 Safety The compound of formula I tablets was generally tolerated with safety in adult subjects with persistent or chronic immune thrombocytopenia, with no dose-limiting toxicity (DLT) events and no treatment-related adverse events of grade 3 or higher.

[0126] 1.4.2 Validity A total of six subjects were enrolled: three in the 400 mg group (two of whom increased their dose to 600 mg) and three in the 600 mg group.

[0127] Patients who were evaluated had a platelet count of 30 × 10 at least once during 12 weeks of treatment. 9 The percentage of subjects with a platelet count of ≥ 50 × 10 / L and a ≥ 2-fold increase in platelet count from baseline (without receiving urgent medical treatment during the period) was 50%, and the platelet count increased to ≥ 50 × 10 / L at least once during the 12-week treatment. 9 The percentage of subjects with a serum creatinine concentration of 0.01 mg / L or higher was 33.3%. The results showed that the compound of formula I tablets of the present application have excellent clinical benefit in the treatment of persistent or chronic immune thrombocytopenia in adults.

[0128] Table 1 shows the efficacy in representative cases. [Table 1]

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof for treating or preventing immune thrombocytopenia. 【Chemistry 1】

2. 2. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein the immune thrombocytopenia is primary immune thrombocytopenia or secondary immune thrombocytopenia, preferably, the immune thrombocytopenia is primary immune thrombocytopenia.

3. 2. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein the immune thrombocytopenia is persistent or chronic immune thrombocytopenia, preferably, the immune thrombocytopenia is persistent or chronic primary immune thrombocytopenia, more preferably, the immune thrombocytopenia is persistent or chronic primary immune thrombocytopenia in adults.

4. 2. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein the immune thrombocytopenia is relapsed and / or refractory primary immune thrombocytopenia.

5. 4. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 3, wherein the patient with persistent or chronic immune thrombocytopenia is a patient who has had a sustained decrease in platelets for more than three months after diagnosis, or the patient with persistent or chronic immune thrombocytopenia is a patient who has had a sustained decrease in platelets for more than six months after diagnosis.

6. 2. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein the patient with immune thrombocytopenia has previously received one or more prior therapies.

7. 7. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 6, wherein the preceding treatment comprises drug therapy or surgical therapy, optionally wherein the drug therapy comprises glucocorticoid therapy, immunoglobulin therapy, molecular targeted therapy, platelet production promoter therapy, or immunosuppressant therapy, and the surgical therapy is splenectomy therapy.

8. Drugs used in the drug therapy include prednisone, meprednisone, prednisone acetate, prednisolone, methylprednisolone, prednisolone acetate, prednisolone sodium succinate, methylprednisolone sodium succinate, betamethasone, beclomethasone propionate, hydrocortisone, dexamethasone, injectable immunoglobulin, rituximab, veltuzumab, daclizumab, bevacizumab, ocrelizumab, alemtuzumab, and alemtuzumab.

8. The compound of formula I according to claim 7, or a pharmaceutically acceptable salt thereof, selected from avatrombopag, eltrombopag, romiplostim, lusutrombopag, recombinant human thrombopoietin (rhTPO), danazol, azathioprine, cyclosporine (A), vincristine, mycophenolate mofetil, all-trans retinoic acid, and decitabine, and combinations of said one or more drugs.

9. 2. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein the patient with immune thrombocytopenia has previously been treated with and failed one or more first-line or multi-line standard therapies, optionally the patient with immune thrombocytopenia has previously been treated with and failed one or more first-line, second-line or third-line standard therapies, and further optionally the patient with immune thrombocytopenia has previously been treated with and failed one, two, three, four or five first-line standard therapies.

10. 2. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein one treatment period for treating or preventing immune thrombocytopenia is 2 to 6 weeks.

11. 2. The compound of formula I or a pharmaceutically acceptable salt thereof of claim 1, wherein the dosing regimen for treating or preventing immune thrombocytopenia is administration once to three times daily, or once every two days.

12. 2. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein the daily dose for treating or preventing immune thrombocytopenia is selected from 50 to 1000 mg.

13. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein each dose for treating or preventing immune thrombocytopenia is selected from the range of 50 to 1000 mg.

14. 14. A pharmaceutical composition for treating or preventing immune thrombocytopenia in a subject in need thereof, comprising a compound of formula I according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, optionally in a single dose of 10 to 200 mg.

15. 14. Use of a compound of formula I according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for treating or preventing immune thrombocytopenia in a subject in need thereof.

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