Application of CDK4 / 6 inhibitor in treatment of dedifferentiated liposarcoma

Abstract

The invention belongs to the technical field of medicines, and relates to application of a CDK4 / 6 inhibitor in treatment of dedifferentiated liposarcoma, in particular to application of a compound of formula (I) in treatment of dedifferentiated liposarcoma. # imgabs0 #

Description

Use of a CDK4 / 6 inhibitor in treating dedifferentiated liposarcoma

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority and benefits of Chinese invention patent application No. 202210650673.6 filed with the State Intellectual Property Office of China on June 9, 2022, and all the contents disclosed in the application are incorporated herein by reference in their entirety. Technical Field

[0003] The present disclosure belongs to the field of medical technology and relates to the use of a CDK4 / 6 inhibitor in treating dedifferentiated liposarcoma, and specifically relates to the use of a compound of formula (I) in treating dedifferentiated liposarcoma. Background Art

[0004] Cyclin-dependent kinase (CDK) 4 / 6 is a key regulator of the cell cycle, which can trigger the cell cycle to enter the DNA replication phase (S1 phase) from the growth phase (G1 phase). During cell proliferation, the complex formed by CDK4 / 6 and cyclin D (CyclinD) can phosphorylate the retinoblastoma protein (Rb). Once the tumor suppressor protein Rb is phosphorylated, it can release the transcription factor E2F to which it is tightly bound in the unphosphorylated state. E2F activates further transcription and promotes the cell cycle through the restriction point (R point) and progresses from the G1 phase to the S phase. Therefore, inhibiting CDK4 / 6 so that it cannot form a CyclinD-CDK4 / 6 complex can block the progression of the cell cycle from the G1 phase to the S phase, thereby achieving the purpose of inhibiting tumor proliferation. WO2016141881 discloses substituted 2-hydrogen-pyrazole derivatives as selective CDK4 / 6 inhibitors, and specifically discloses a compound of formula (I) having the following structure,

[0005] Dedifferentiated liposarcoma (DDLS) most commonly occurs in people aged 60 to 80 years, with a relatively balanced gender distribution. However, an analysis of 3,573 cases by the National Cancer Database (NCDB) found that 65% of cases occurred in men. Studies have shown that 85% of DDLS cases are new primary tumors, while the remaining 15% are secondary to well-differentiated liposarcoma (WDLS), with an average recurrence interval of 7.7 years. The most common primary site of DDLS is the retroperitoneum, with less common sites including the extremities, paratesticular region, head and neck, and chest, and rarely in soft tissue. DDLS is less aggressive than other pleomorphic sarcomas, with a local recurrence rate of approximately 41% to 52%, a metastasis rate of 15% to 30%, and a 5-year disease-related mortality rate of 28% to 30%.

[0006] Currently, radical surgical resection remains the mainstay of DDLS treatment. While improving local control, the 3-year local recurrence rate is 49% without radiotherapy and 34% with radiotherapy, but it has no effect on overall survival. Systemic therapy (neoadjuvant therapy) should be considered for DDLS patients with larger limb / trunk walls (>5 cm) and deeper infiltration. However, because DDLS often responds poorly to first-line chemotherapy, the options available for recurrent patients are relatively limited. Therefore, the development of drugs for DDLS is essential.

[0007] Summary of the Invention

[0008] In one aspect, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating or preventing dedifferentiated liposarcoma.

[0009] In another aspect, the present disclosure provides a pharmaceutical composition for treating or preventing dedifferentiated liposarcoma, comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0010] In some embodiments of the present disclosure, the pharmaceutical composition is packaged in a kit, which further comprises instructions for using the compound of formula (I) or a pharmaceutically acceptable salt thereof to treat or prevent dedifferentiated liposarcoma.

[0011] In some embodiments of the present disclosure, in the pharmaceutical composition, the pharmaceutically acceptable salt of the compound of formula (I) is a maleate salt, such as a monomaleate salt of the compound of formula (I).

[0012] In some embodiments of the present disclosure, the pharmaceutical composition contains 20-240 mg, 40-180 mg, 60-180 mg, 80-180 mg, 100-180 mg, 120-180 mg or 150-180 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I).

[0013] In some embodiments of the present disclosure, the pharmaceutical composition contains 150 to 180 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I).

[0014] In some embodiments of the present disclosure, the pharmaceutical composition contains 20 mg, 40 mg, 60 mg, 80 mg, 100 mg, 120 mg, 150 mg or 180 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I).

[0015] In some embodiments of the present disclosure, the pharmaceutical composition contains 60 mg, 120 mg, 150 mg or 180 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I).

[0016] In some embodiments of the present disclosure, the pharmaceutical composition contains 60 mg, 150 mg or 180 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I).

[0017] In some embodiments of the present disclosure, the pharmaceutical composition contains 150 mg or 180 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I).

[0018] In some embodiments of the present disclosure, the pharmaceutical composition contains 180 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I).

[0019] In some embodiments of the present disclosure, the pharmaceutical composition comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof in a single dose or multiple dose form. In some embodiments of the present disclosure, the pharmaceutical composition comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof in a multiple dose form.

[0020] In some embodiments of the present disclosure, in the pharmaceutical composition, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a daily dose.

[0021] In some embodiments of the present disclosure, in the pharmaceutical composition, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once daily.

[0022] In some embodiments of the present disclosure, in the pharmaceutical composition, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once daily, and each dose is a single dose or multiple doses, usually multiple doses.

[0023] In some embodiments of the present disclosure, the pharmaceutical composition contains a single dose of 50 mg or 60 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I). Alternatively, the pharmaceutical composition is in the form of a single-dose formulation, containing 50 mg or 60 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I).

[0024] In some embodiments of the present disclosure, the pharmaceutical composition contains a single dose of 60 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I). Alternatively, the pharmaceutical composition is in the form of a single-dose formulation, containing 60 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I).

[0025] In some embodiments of the present disclosure, every 28 days is one treatment cycle.

[0026] In some embodiments of the present disclosure, the pharmaceutical composition is a preparation suitable for administration within a single treatment cycle (e.g., a treatment cycle of 28 days), comprising: a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof, with a total dose of 1680 to 5040 mg (e.g., 1680 mg, 3360 mg, 4200 mg, 5040 mg, or a range formed by any two of the values) calculated as the compound of formula (I).

[0027] In other embodiments of the present disclosure, the pharmaceutical composition is a preparation suitable for administration within a single treatment cycle (e.g., a treatment cycle of 28 days), comprising: a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof, with a total dose of 4200 mg or 5040 mg calculated as the compound of formula (I).

[0028] In some embodiments of the present disclosure, the pharmaceutical composition is a preparation suitable for administration within a single treatment cycle (e.g., a treatment cycle of 28 days), comprising: a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof in a total dose of 5040 mg calculated as the compound of formula (I).

[0029] In another aspect, the present disclosure further provides a kit comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof as described in the present disclosure.

[0030] On the other hand, the present disclosure also provides a kit of pharmaceutical compositions for treating or preventing dedifferentiated liposarcoma, which contains the compound of formula (I) or a pharmaceutically acceptable salt thereof as described in the present disclosure.

[0031] In some embodiments of the present disclosure, in the pharmaceutical composition, the compound of formula (I) or a pharmaceutically acceptable salt thereof is prepared into a unit preparation containing 50 mg or 60 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I).

[0032] In some embodiments of the present disclosure, in the pharmaceutical composition, the compound of formula (I) or a pharmaceutically acceptable salt thereof is prepared into a unit preparation containing 60 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I).

[0033] On the other hand, the present disclosure also provides a method for treating or preventing dedifferentiated liposarcoma, comprising administering to an individual in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, for example, administering to an individual in need thereof a therapeutically effective amount of the pharmaceutical composition described above of the present disclosure.

[0034] On the other hand, the present disclosure also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing dedifferentiated liposarcoma, for example, the use of the pharmaceutical composition of the present disclosure in the preparation of a medicament for treating or preventing dedifferentiated liposarcoma.

[0035] On the other hand, the present disclosure also provides the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof for treating or preventing dedifferentiated adipose tissue, for example, the use of the pharmaceutical composition of the present disclosure for treating or preventing dedifferentiated adipose tissue.

[0036] In some embodiments of the present disclosure, in the method or use, the content of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is a daily dose, which is administered as follows: the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day.

[0037] In some embodiments of the present disclosure, in the method or use, the content of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is a daily dose, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a single dose or multiple doses, usually in multiple doses; further, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day in multiple doses.

[0038] In some embodiments of the present disclosure, in the method or use, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered as follows: a daily dose of 60 mg; or, a daily dose of 120 mg; or, a daily dose of 150 mg; or, a daily dose of 180 mg.

[0039] In some embodiments of the present disclosure, in the method or use, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered as follows: a daily dose of 150 mg; or, a daily dose of 180 mg.

[0040] In some embodiments of the present disclosure, in the method or use, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in the following manner: a daily dose of 180 mg.

[0041] In some embodiments of the present disclosure, in the methods or uses, the compound of formula (I) or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is administered in multiple doses, wherein the multiple doses consist of a single dose of 50 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments of the present disclosure, in the methods or uses, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a continuous daily administration manner.

[0042] In some embodiments of the present disclosure, in the methods or uses, the compound of formula (I) or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is administered in multiple doses, wherein the multiple doses consist of a single dose of 60 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments of the present disclosure, in the methods or uses, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a continuous daily dosing manner.

[0043] In some embodiments of the present disclosure, in the methods or uses, the content of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is a dose per treatment cycle, which is administered as follows: the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered daily. Wherein, the compound of formula (I) or a pharmaceutically acceptable salt thereof is packaged in a single aliquot or multiple aliquots (e.g., 2 aliquots, 4 aliquots, 7 aliquots, 14 aliquots, 28 aliquots or more).

[0044] In some embodiments of the present disclosure, in the method or use, 28 days is a treatment cycle, and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered every day on days 1 to 28 of each treatment cycle.

[0045] In some specific embodiments of the present disclosure, in the method or use, 28 days is a treatment cycle, and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day on days 1 to 28 of each treatment cycle.

[0046] In some embodiments of the present disclosure, in the method or use, 28 days is a treatment cycle, the drug is administered once a day for 28 consecutive days, and the total dose of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof in each treatment cycle is 1680 to 5040 mg. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from 1680 mg, 3360 mg, 4200 mg, 5040 mg or the range formed by any two values. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is preferably 4200 mg, 5040 mg. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is preferably 5040 mg.

[0047] In embodiments of the present disclosure, the treatment cycles are repeated as long as the disease remains under control and the dosing regimen is clinically tolerated.

[0048] In some embodiments of the present disclosure, the dedifferentiated liposarcoma is selected from dedifferentiated liposarcoma that is difficult to resect surgically or dedifferentiated liposarcoma that refuses surgery.

[0049] In some embodiments of the present disclosure, the dedifferentiated liposarcoma is a dedifferentiated liposarcoma that is difficult to resect surgically and in which pathological and imaging review results indicate the presence of dedifferentiated liposarcoma components, or a dedifferentiated liposarcoma that refuses surgery.

[0050] In some embodiments of the present disclosure, the dedifferentiated liposarcoma is a newly diagnosed dedifferentiated liposarcoma; and / or a dedifferentiated liposarcoma with residual lesions after surgery; and / or a locally recurrent or metastatic dedifferentiated liposarcoma; and / or a dedifferentiated liposarcoma with disease progression confirmed by imaging results within the past 6 months.

[0051] In some embodiments of the present disclosure, the dedifferentiated liposarcoma is a dedifferentiated liposarcoma in patients who are difficult to remove surgically or who refuse surgery, and the pathological and imaging review results indicate the presence of dedifferentiated liposarcoma components, and the subject must also meet any of the following categories: 1) newly diagnosed dedifferentiated liposarcoma; 2) residual lesions after surgery; 3) locally recurrent or metastatic dedifferentiated liposarcoma; 4) disease progression confirmed by imaging results within the past 6 months.

[0052] In the present disclosure, the term "difficult to resect surgically" means that the researcher has assessed that R0 / R1 resection cannot be achieved through surgery, specifically including: the tumor is huge or involves important organs; and / or the tumor is located in important vascular pathways; and / or the tumor has multiple metastases and is difficult to control through surgery; and / or the combination of serious medical diseases may cause fatal surgical risks; and / or recurrence after multiple surgeries is not suitable for immediate surgery.

[0053] In the present disclosure, the “newly diagnosed” refers to a treatment-naive subject, and the treatment-naive subject refers to a subject who has not received systemic drug treatment or has not relapsed within 6 months after postoperative adjuvant treatment.

[0054] In the present disclosure, the "disease progression" refers to a treated subject, and the treated subject refers to a subject who relapses within 6 months after receiving first-line systemic drug treatment or postoperative adjuvant treatment.

[0055] In some embodiments of the present disclosure, the dedifferentiated liposarcoma has at least one measurable lesion according to RECIST 1.1 criteria.

[0056] In other embodiments of the present disclosure, the dedifferentiated liposarcoma has at least one measurable lesion according to RECIST 1.1 criteria. If the measurable lesion is located in a previously radiotherapy area, it should be clearly in a progressive state.

[0057] In some embodiments of the present disclosure, all acute toxic effects of previous treatments or surgeries in patients with dedifferentiated liposarcoma before the first dose of the drug have recovered to ≤ Grade 1 or baseline (according to the Common Terminology Criteria for Adverse Events, Version 5.0), except for alopecia and Grade 2 peripheral neuropathy.

[0058] In other embodiments of the present disclosure, the patient with dedifferentiated liposarcoma has previously been treated with surgical resection (eg, treatment failure).

[0059] In other embodiments of the present disclosure, the patient with dedifferentiated liposarcoma has previously been treated with epirubicin or a pharmaceutically acceptable salt thereof and / or ifosfamide (eg, treatment failure).

[0060] In other embodiments of the present disclosure, the patient with dedifferentiated liposarcoma has previously received extensive tumor tissue resection and / or vascular exploration (eg, treatment failure).

[0061] In other embodiments of the present disclosure, the patient with dedifferentiated liposarcoma has previously received treatment with a tyrosine kinase inhibitor (eg, anlotinib) (eg, treatment failure).

[0062] In other embodiments of the present disclosure, the patient with dedifferentiated liposarcoma has previously been treated with (eg, failed treatment with) systemic chemotherapy (eg, eribulin).

[0063] In other embodiments of the present disclosure, the patient with dedifferentiated liposarcoma has previously received adjuvant chemotherapy with an eribulin injection regimen (eg, treatment failure).

[0064] In other embodiments of the present disclosure, the patient with dedifferentiated liposarcoma has been previously treated with radiotherapy (eg, failed treatment).

[0065] In other embodiments of the present disclosure, the patient with dedifferentiated liposarcoma has previously been treated with an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody or an anti-PD-L1 antibody) (e.g., treatment failure). In other embodiments of the present disclosure, the immune checkpoint inhibitor is selected from carrelizumab.

[0066] In other embodiments of the present disclosure, the patient with dedifferentiated liposarcoma has previously been treated with pirarubicin (eg, treatment failure).

[0067] In other embodiments of the present disclosure, the patient with dedifferentiated liposarcoma has previously received treatment with surgical resection, epirubicin hydrochloride + ifosfamide, extended tumor tissue resection + vascular exploration, and anlotinib (eg, treatment failure).

[0068] In other embodiments of the present disclosure, the patient with dedifferentiated liposarcoma has previously received surgical resection and anlotinib treatment (eg, treatment failure).

[0069] In other embodiments of the present disclosure, the patient with dedifferentiated liposarcoma has previously received surgical resection and adjuvant chemotherapy with an eribulin injection regimen (eg, treatment failure).

[0070] In other embodiments of the present disclosure, the patient with dedifferentiated liposarcoma has previously been treated with surgical resection, radiotherapy, and pirarubicin (eg, treatment failure).

[0071] In other embodiments of the present disclosure, the patient with dedifferentiated liposarcoma has previously received surgical resection, anlotinib + camrelizumab treatment (eg, treatment failure).

[0072] The active ingredients in the pharmaceutical combination of the present disclosure can be formulated independently, or some or all of them can be formulated together with a pharmaceutically acceptable carrier and / or excipient. The pharmaceutical combination of the present disclosure can also contain an additional therapeutic agent. In some embodiments of the present disclosure, the additional therapeutic agent can be a therapeutic agent for cancer known in the art, preferably an agent for treating dedifferentiated liposarcoma.

[0073] In some embodiments of the present disclosure, the cycle is 28 days.

[0074] The amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof administered can be determined based on the severity of the disease, the response of the disease, any treatment-related toxicity, and the age and health status of the patient.

[0075] The compound of formula (I) or a pharmaceutically acceptable salt thereof can be administered by a variety of routes, including but not limited to the following: oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, transbuccal, intranasal, by inhalation, vaginal, intraocular, topical, subcutaneous, intrafatty, intraarticular, intraperitoneal and intrathecal. In a specific embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered orally.

[0076] In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a continuous daily oral administration manner.

[0077] In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day in the form of a multiple-dose oral solid preparation.

[0078] Compound of formula (I) or a pharmaceutically acceptable salt thereof

[0079] The compounds of formula (I) disclosed herein can be administered in their free base form, or in the form of their pharmaceutically acceptable salts, hydrates, and prodrugs, which are converted into the compound of formula (I) in vivo. For example, pharmaceutically acceptable salts of the compounds of formula (I) are within the scope of the present disclosure and can be produced from various organic and inorganic acids according to methods known in the art.

[0080] Regarding the pharmaceutically acceptable salts of the compounds of formula (I) described in the present disclosure, the molar ratio of the compound of formula (I) to the acid ion forming the pharmaceutically acceptable salt may be 1:1.

[0081] The pharmaceutically acceptable salt of the compound of formula (I) may be a maleate salt of the compound of formula (I) (eg a monomaleate salt of the compound of formula (I)).

[0082] The dosage of the compound of formula (I) or its pharmaceutically acceptable salt referred to in the present disclosure is based on the amount of the compound of formula (I) unless otherwise stated.

[0083] In some embodiments of the present disclosure, the pharmaceutically acceptable salt of the compound of formula (I) exists as a salt of the compound of formula (I).

[0084] The compound of formula (I) or a pharmaceutically acceptable salt thereof used in the present disclosure can be prepared by methods in the prior art, for example, by referring to the method of WO2016141881.

[0085] Pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof

[0086] In some embodiments of the present disclosure, a single dose of the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 50 mg or 60 mg calculated as the compound of formula (I). Alternatively, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is prepared as a unit preparation containing 50 mg or 60 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof calculated as the compound of formula (I).

[0087] In some embodiments of the present disclosure, a single dose of the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 60 mg calculated as the compound of formula (I). Alternatively, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is prepared as a unit preparation containing 60 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof calculated as the compound of formula (I).

[0088] The method of administration can be determined comprehensively based on the activity, toxicity and patient tolerance of the drug.

[0089] In some embodiments of the present disclosure, the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof further contains a pharmaceutically acceptable excipient. Pharmaceutically acceptable excipients include fillers, absorbents, wetting agents, adhesives, disintegrants, lubricants, etc. In some embodiments of the present disclosure, the pharmaceutical composition includes but is not limited to preparations suitable for oral, parenteral, and topical administration. In some embodiments, the pharmaceutical composition is a preparation suitable for oral administration. In some embodiments, the pharmaceutical composition is a solid preparation suitable for oral administration. In some embodiments, the pharmaceutical composition includes but is not limited to tablets and capsules.

[0090] In some embodiments of the present disclosure, the pharmaceutical composition is a solid pharmaceutical combination.

[0091] In some embodiments of the present disclosure, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a solid pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0092] In some embodiments of the present disclosure, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a capsule containing the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0093] The pharmaceutical composition of the present disclosure can be manufactured by methods well known in the art, such as conventional mixing methods, dissolving methods, granulating methods, making dragees, grinding methods, emulsifying methods, freeze-drying methods, and the like.

[0094] Solid oral compositions can be prepared by conventional mixing, filling, or tableting methods. For example, they can be prepared by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain tablets or dragee cores. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners, or flavoring agents.

[0095] Technical Effects

[0096] Generally, use of the disclosed compounds of formula (I) will facilitate:

[0097] (1) Produce better therapeutic effects in reducing tumor growth or even eliminating tumors;

[0098] (2) provide treatments that are well tolerated by patients with few adverse effects and / or complications;

[0099] (3) provide a better disease control rate (DCR) among treated patients;

[0100] (4) provide a longer survival (e.g., median survival, progression-free survival, or overall survival) among the patients treated;

[0101] (5) provide longer survival (e.g., median survival, progression-free survival, or overall survival) for treated patients compared to standard chemotherapy;

[0102] (6) Provide a longer duration of disease remission (DOR).

[0103] The "clinical benefits" of the compounds of formula (I) disclosed herein include, but are not limited to: a higher 12-week progression-free survival rate in clinical patients, prolonged progression-free survival (PFS), prolonged overall survival (OS), improved objective response rate (ORR), improved disease control rate (DCR), reduced number and / or severity of adverse reactions, decreased distant metastasis rate and local control rate, etc.

[0104] Definition and Description

[0105] The word "comprise" or "comprises" and its English variations such as comprises or comprising and their equivalents should be understood as open and non-exclusive, that is, "including but not limited to", meaning that in addition to the listed elements, components and steps, other unspecified elements, components and steps may also be included.

[0106] The term "patient" or "individual / subject" refers to a mammal, such as a primate (human, macaque, chimpanzee, etc.), a rodent (mice, rats, rabbits, etc.), a cat, a canine, etc., preferably a human. In some embodiments of the present disclosure, the patient and the individual are patients who have failed standard treatment or lack standard treatment.

[0107] The term "pharmaceutically acceptable" or "pharmaceutically usable" refers to a carrier, excipient or excipient used to prepare a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes that which is acceptable for use in human medicine.

[0108] The term "therapeutically effective amount" means the amount of a compound that, when administered to a human for treating a disease, is sufficient to effect such treatment.

[0109] The term "treating" means administering a compound or formulation of the present disclosure to improve, alleviate, or eliminate a disease or one or more symptoms associated with the disease, and includes: (i) inhibiting a disease or disease state, i.e., curbing or retarding its development; and (ii) relieving a disease or disease state, i.e., causing the disease or disease state to regress.

[0110] The term "prevention" means administering a compound or formulation of the present disclosure to prevent a disease or one or more symptoms associated with the disease, including preventing the disease or disease state from occurring in a mammal, particularly when such mammal is susceptible to the disease state but has not yet been diagnosed as having the disease state.

[0111] As used herein, " adverse event " (AE) is any unfavorable and usually unintentional or undesirable sign (including abnormal laboratory findings), symptom or disease relevant to the application of medical treatment.For example, adverse event can be relevant to the activation of the immune system or the amplification of immune system cells (for example, T cells) in response to treatment.Medical treatment can have one or more related AEs, and each AE can have the same or different levels of severity.Reference to the method that can " modify adverse event " refers to the treatment scheme that reduces the incidence and / or severity of one or more AEs relevant to the application of different treatment schemes.

[0112] The use of alternatives (e.g., "or") should be understood to refer to any one, two, or any combination of the alternatives. The indefinite articles "a" or "an" used herein should be understood to mean "one or more" of any listed or enumerated components.

[0113] The term "pharmaceutically acceptable excipient" refers to an excipient that is non-irritating to organisms and does not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art and include, for example, carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.

[0114] 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.

[0115] The term "daily dose" refers to the dose administered to a patient daily.

[0116] The term "single dose" or "unit preparation" refers to the smallest packaging unit of a drug containing a certain amount of active ingredient. For example, if a box of medicine contains seven capsules, each capsule is a single dose or unit preparation; for example, if a box of medicine contains seven tablets, each tablet is a single dose unit preparation.

[0117] The term "multiple doses" consists of multiple single doses. As used herein, "combination" or "combined use" means that two or more active substances can be administered to an individual simultaneously, concurrently, or sequentially in any order, each as a single formulation.

[0118] The term "pharmaceutical composition" refers to a mixture of one or more active ingredients of the present disclosure or their pharmaceutical combination and pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate the administration of the compounds of the present disclosure or their pharmaceutical combination to an individual.

[0119] When referring to a dosing regimen, the terms "day," "daily," and the like refer to times within a calendar day, starting at midnight and ending at the following midnight.

[0120] The term "recurrent" cancer is a cancer that grows back in the original site or at a distant site after responding to initial treatment (such as surgery). A "locally recurrent" cancer is a cancer that appears after treatment in the same location as a previously treated cancer.

[0121] The term "metastatic" cancer refers to cancer that has spread from one part of the body (such as the lungs) to another part of the body.

[0122] In this document, unless the context clearly indicates otherwise, singular terms include plural referents and vice versa. Similarly, unless the context clearly indicates otherwise, the word "or" is intended to include "and" and vice versa.

[0123] Unless otherwise indicated, herein, parameter values ​​representing the amounts of ingredients or physicochemical properties or reaction conditions, etc., should be understood as being modified in all instances by the term "about." When the term "about" is used to describe the present disclosure, the term "about" indicates that there is a deviation, for example, a variation within the range of ±5%, such as ±1%, or ±0.1% of a particular value.

[0124] For the purposes of description and disclosure, all patents, patent applications and other identified publications are expressly incorporated herein by reference. These publications are provided solely because their disclosure predates the filing date of the present disclosure. All statements regarding the dates of these documents or representations of the contents of these documents are based on information available to the applicant and do not constitute any admission as to the correctness of the dates of these documents or the contents of these documents. Furthermore, any citation of these publications herein does not constitute an admission that such publications are part of the common general knowledge in the art in any country. Example

[0125] The purpose of the following specific embodiments is to enable those skilled in the art to more clearly understand and implement the present disclosure. They should not be considered as limiting the scope of the present disclosure, but are merely exemplary descriptions and typical representatives of the present disclosure.

[0126] Experimental Example 1 Clinical Trial

[0127] This study uses a randomized, double-blind, placebo-controlled parallel trial design or a single-arm trial design. For the parallel-controlled trial, all patients signed informed consent forms. After screening, subjects who met the inclusion criteria were randomly divided into two groups (1:1), divided into an experimental group and a control group. The experimental group was given capsules of the compound of Formula I, and the control group was given a placebo capsule of the compound of Formula I. Each cycle consisted of 4 weeks (28 days). For the single-arm trial, the dosing regimen was the same as that of the experimental group in the parallel-controlled trial. The clinical trial disclosed herein was used to evaluate the efficacy and safety of the compound of Formula I capsules in the treatment of dedifferentiated liposarcoma.

[0128] 1.1 Inclusion Criteria:

[0129] 1) The subjects voluntarily participated in this study, signed the informed consent form, and had good compliance;

[0130] 2) Age: 18-75 years (calculated based on the date of signing the informed consent form); ECOG PS score: 0-1; body mass index (BMI) > 18.5 and weight > 40 kg; expected survival > 3 months;

[0131] 3) Patients diagnosed with dedifferentiated liposarcoma that is difficult to resect surgically or who refuse surgery after multidisciplinary consultation, and whose pathological and imaging review results indicate the presence of dedifferentiated liposarcoma components, and who also meet any of the following categories:

[0132] 1) Newly diagnosed dedifferentiated liposarcoma;

[0133] 2) patients with residual lesions after surgery;

[0134] 3) Local recurrence or metastatic dedifferentiated liposarcoma;

[0135] 4) Patients with disease progression confirmed by imaging results within the past 6 months;

[0136] 4) According to RECIST 1.1 criteria, there is at least one measurable lesion. If the measurable lesion is located in the previously radiotherapy area, it should be clearly considered to be in a progressive state;

[0137] 5) All acute toxic effects of previous treatments or surgical procedures before the first dose of the drug have recovered to ≤ Grade 1 or baseline (according to the Common Terminology Criteria for Adverse Events version 5.0 [CTCAE v 5.0]), except for alopecia and Grade 2 peripheral neuropathy;

[0138] 6) Major organ functions are good and meet the following criteria:

[0139] 1) Routine blood test standards (no blood transfusion or use of hematopoietic stimulating factor drugs within 7 days before the test):

[0140] a. Hemoglobin (HGB) ≥ 90.0 g / L;

[0141] b. Absolute neutrophil count (ANC) ≥ 1.5 × 109 / L;

[0142] c. Platelet count (PLT) ≥90×109 / L;

[0143] 2) Biochemical examination standards:

[0144] a. Total bilirubin (TBIL) ≤ 1.5 times the upper limit of normal (ULN); for patients with Gilbert syndrome, ≤ 3 × ULN;

[0145] b. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × ULN. If accompanied by liver metastasis,

[0146] ALT and AST ≤ 5 × ULN;

[0147] c. Serum creatinine (CR) ≤ 178 μmol / L or creatinine clearance (CCR) > 50 ml / min;

[0148] 3) Urinalysis standard: If urine protein is <++, the urine protein should be confirmed to be ≤1.0g in 24-hour urine protein test.

[0149] 4) Coagulation function standards: prothrombin time (PT), activated partial thromboplastin time (APTT), international normalized ratio (INR) ≤ 1.5 × ULN (not receiving anticoagulant therapy);

[0150] 5) Echocardiography assessment: left ventricular ejection fraction (LVEF) ≥ 50%;

[0151] 6) 12-lead electrocardiogram assessment: QTc < 450ms (male), QTc < 470ms (female)

[0152] 7) Female subjects of childbearing age should agree to use contraceptive measures (such as intrauterine devices, birth control pills or condoms) during the study and within 6 months after the end of the study; the serum pregnancy test should be negative within 7 days before study enrollment, and the subjects must be non-breastfeeding; male subjects should agree to use contraceptive measures during the study and within 6 months after the end of the study.

[0153] 1.2 Investigational Drugs

[0154] Capsules of the compound of formula (I): specifications of 50 mg or 60 mg, provided by Zhengda Tianqing Pharmaceutical Group Co., Ltd.

[0155] 1.3 Dosage regimen

[0156] Capsules of compound of formula (I): 180 mg / time (calculated as compound of formula (I)), orally taken on an empty stomach, once a day, for 28 consecutive days as one treatment cycle.

[0157] Placebo capsules of the compound of formula (I): 0 mg / time (calculated as the compound of formula (I)), taken orally on an empty stomach, once a day, for 28 consecutive days as one treatment cycle.

[0158] 1.4 Evaluation Criteria

[0159] Effectiveness evaluation criteria: RECIST 1.1 criteria were used to determine the disease status.

[0160] Safety evaluation criteria: The severity of adverse events will be assessed using the NCI-CTC AE 5.0 criteria. During the trial, the adverse event record form should be completed truthfully, including the time of occurrence, severity, relevance to study treatment, duration, measures taken, and outcome of the adverse event.

[0161] 1.5 Test results

[0162] 1.5.1 Security

[0163] Gastrointestinal reactions (diarrhea, vomiting, etc.) were mainly grade 1 to 2 and were controllable after symptomatic treatment. The overall incidence of grade 3 and above TEAEs was 9%, and the overall safety was good.

[0164] 1.5.2 Validity

[0165] Of the 15 subjects who reached C3 (12 weeks) efficacy assessment, 9 patients achieved 12-week PFS, with a 12-week PFS rate of 60%. Evaluable patients showed good progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and duration of response (DOR). The results showed that the compound of formula (I) disclosed herein has clinical benefits.

[0166] The following are representative cases:

[0167] Those skilled in the art will recognize that the scope of the present disclosure is not limited to the various specific implementation modes and examples described above, but that various modifications, replacements, or recombinations can be made without departing from the spirit and concept of the present disclosure, which all fall within the scope of protection of the present disclosure.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof for treating or preventing dedifferentiated liposarcoma, 2. A pharmaceutical composition for treating or preventing dedifferentiated liposarcoma, comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, 3. The pharmaceutical composition according to claim 2, which is packaged in a kit, and the kit further comprises instructions for using the compound of formula (I) or a pharmaceutically acceptable salt thereof to treat or prevent dedifferentiated liposarcoma.

4. The pharmaceutical composition according to claim 2, comprising 20-240 mg, 40-180 mg, 60-180 mg, 80-180 mg, 100-180 mg, 120-180 mg or 150-180 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I); Alternatively, the pharmaceutical composition contains 150 to 180 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I); Alternatively, the pharmaceutical composition contains 20 mg, 40 mg, 60 mg, 80 mg, 100 mg, 120 mg, 150 mg or 180 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I); Alternatively, the pharmaceutical composition contains 60 mg, 150 mg or 180 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I); Alternatively, the pharmaceutical composition contains 150 mg or 180 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I).

5. The pharmaceutical composition according to claim 2, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is in a single dose or multiple dose form; Alternatively, in the pharmaceutical composition, the compound of formula (I) or a pharmaceutically acceptable salt thereof is in a multiple-dose form.

6. The pharmaceutical composition according to claim 2, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is a daily dose; Alternatively, in the pharmaceutical composition, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a once-daily dose; Alternatively, in the pharmaceutical composition, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once daily, and each dose is a single dose or multiple doses; Alternatively, in the pharmaceutical composition, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once daily, and each dose is a multiple dose.

7. The pharmaceutical composition according to claim 2, which is a preparation suitable for administration within a single treatment cycle, comprising: A pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof, with a total dose of 1680 to 5040 mg calculated as the compound of formula (I); Alternatively, the pharmaceutical composition is a preparation suitable for administration within a single treatment cycle, comprising: a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof, with a total dose of 1680 mg, 3360 mg, 4200 mg, 5040 mg, or a range formed by any two of the values, calculated as the compound of formula (I); Alternatively, the pharmaceutical composition is a preparation suitable for administration in a single treatment cycle, comprising: a pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof in a total dose of 4200 mg or 5040 mg calculated as the compound of formula (I).

8. The pharmaceutical composition according to claim 2, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is prepared into a unit preparation containing 50 mg or 60 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I).

9. A method for treating or preventing dedifferentiated liposarcoma, comprising administering to an individual in need thereof a therapeutically effective amount of the compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of claims 2 to 8.

10. The method according to claim 9, wherein the content of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is a daily dose, which is administered in the following manner: the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day; Alternatively, the content of the compound of formula (I) or its pharmaceutically acceptable salt in the pharmaceutical composition is a daily dose, which is administered in the following manner: the compound of formula (I) or its pharmaceutically acceptable salt is administered once a day in multiple doses.

11. The method according to claim 9, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in the following manner: a daily dose of 60 mg; or a daily dose of 120 mg; or a daily dose of 150 mg; or a daily dose of 180 mg.

12. The method according to claim 9, wherein 28 days constitute a treatment cycle, and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered daily on days 1 to 28 of each treatment cycle; Alternatively, 28 days is a treatment cycle, and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day on the 1st to 28th day of each treatment cycle; Alternatively, 28 days is one treatment cycle, the drug is administered once a day for 28 consecutive days, and the total dose of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof in each treatment cycle is 1680 to 5040 mg; Alternatively, 28 days is a treatment cycle, administered once a day for 28 consecutive days, and the total dose of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof administered in each treatment cycle is 1680 mg, 3360 mg, 4200 mg, 5040 mg, or a range formed by any two of the values; Alternatively, 28 days is one treatment cycle, the drug is administered once a day for 28 consecutive days, and the total dose of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof in each treatment cycle is 4200 mg or 5040 mg.

13. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, the pharmaceutical composition according to any one of claims 2 to 8, or the method according to any one of claims 9 to 12, wherein the dedifferentiated liposarcoma is selected from dedifferentiated liposarcoma that is difficult to resect surgically or dedifferentiated liposarcoma that refuses surgery.

14. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, the pharmaceutical composition according to any one of claims 2-8, or the method according to any one of claims 9-12, wherein the dedifferentiated liposarcoma is a newly diagnosed dedifferentiated liposarcoma; and / or a dedifferentiated liposarcoma with residual lesions after surgery; and / or a locally recurrent or metastatic dedifferentiated liposarcoma; and / or a dedifferentiated liposarcoma with disease progression confirmed by imaging results within the past 6 months.

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