Use of pyridone carboxamide compounds for treating type I neurofibroma-related diseases

Abstract

Relates to application of a pyridone carboxamide compound to treatment of type I neurofibroma related diseases. Specifically, the invention relates to application of 6-(2-chloro-4-iodophenylamino)-N-(2-hydroxyethoxy)-5-methyl-4-oxo-4, 5-dihydrofuro [3, 2-c] pyridine-7-formamide or a pharmaceutically acceptable salt thereof in treatment of type I neurofibroma related diseases.

Description

Use of pyridonecarboxamide compounds in treating diseases related to type I neurofibromatosis

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority and benefits of Chinese Patent Application No. 202310948704.0 filed with the State Intellectual Property Office of China on July 31, 2023, and the contents disclosed in the above application are incorporated herein by reference in their entirety. Technical Field

[0003] The present application belongs to the field of medicine and relates to the medical use of pyridonecarboxamide compounds. Specifically, it relates to the use of 6-(2-chloro-4-iodophenylamino)-N-(2-hydroxyethoxy)-5-methyl-4-oxo-4,5-dihydrofuro[3,2-c]pyridine-7-carboxamide or a pharmaceutically acceptable salt thereof in the treatment of diseases related to neurofibromatosis type I. Background Art

[0004] Cell signaling pathways play a crucial role in cell growth, proliferation, and differentiation. The Ras / Raf / MEK / ERK pathway is a major signaling pathway, transmitting signals from multiple cell surface receptors to transcription factors in the cell nucleus that regulate gene expression. Aberrant activation of the Ras / Raf / MEK / ERK pathway has been found to be common in malignantly transformed cells, and inhibition of this pathway is believed to be beneficial in the treatment of hyperproliferative diseases. Because it is located downstream of Ras and Raf, MEK is a key member of this pathway and a compelling therapeutic target.

[0005] Neurofibromatosis type 1 is an autosomal dominant hereditary neoplastic disease caused by mutations in the NF1 gene, which encodes neurofibromin. NF1 mutations can lead to dysregulation of the RAS / RAF / MEK / ERK signaling pathway, which in turn can lead to tumor formation and other related diseases.

[0006] WO2012059041A1 discloses a 6-arylaminopyridonecarboxamide compound having a chemical structure as shown in Formula I, which has MEK inhibitory activity and can be used to treat inflammatory diseases, cancer and other hyperproliferative diseases.

[0007] Summary of the Invention

[0008] In one aspect, the present application provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating neurofibromatosis type I-related diseases.

[0009] On the other hand, the present application also provides a method for treating neurofibromatosis type I-related diseases, which comprises administering an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof to a patient in need of such treatment.

[0010] On the other hand, the present application also provides use of the compound of formula I or a pharmaceutically acceptable salt thereof in treating diseases related to neurofibromatosis type I.

[0011] On the other hand, the present application also provides a compound of formula I or a pharmaceutically acceptable salt thereof for use in treating diseases related to neurofibromatosis type I.

[0012] In another aspect, the present application also provides a pharmaceutical composition for treating diseases related to neurofibromatosis type I, wherein the pharmaceutical composition comprises a compound of formula I or a pharmaceutically acceptable salt thereof.

[0013] In another aspect, the present application also provides use of a pharmaceutical composition of a compound of formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating diseases associated with neurofibromatosis type I.

[0014] In another aspect, the present application also provides a method for treating diseases related to neurofibromatosis type I, which comprises administering an effective amount of a pharmaceutical composition of a compound of formula I or a pharmaceutically acceptable salt thereof to a patient in need of such treatment.

[0015] In another aspect, the present application also provides use of a pharmaceutical composition of a compound of formula I or a pharmaceutically acceptable salt thereof for treating diseases associated with neurofibromatosis type I.

[0016] In another aspect, the present application provides a kit for treating neurofibromatosis type I-related diseases, comprising a pharmaceutical composition of a compound of formula I or a pharmaceutically acceptable salt thereof and instructions for treating neurofibromatosis type I-related diseases with a compound of formula I or a pharmaceutically acceptable salt thereof.

[0017] Compounds of formula I or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof

[0018] The compound of formula I of the present application can be administered in the form of its free base or in the form of its pharmaceutically acceptable salt.

[0019] In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof is in crystalline form.

[0020] In some specific embodiments, the compound of formula I is in crystalline form, and its X-ray powder diffraction spectrum is 2 θ The values ​​indicate that there are diffraction peaks at 7.86°, 19.09°, 21.80°, 23.87°, 26.00°, and 28.12°. The preparation method and related properties of the crystalline form of the compound of formula I can be found in WO2016019867.

[0021] The weights or dosages of the compounds of formula I or pharmaceutically acceptable salts thereof referred to in this application are based on the molecular weight of the compounds of formula I, unless otherwise specified.

[0022] In some embodiments, the compound of formula I or its pharmaceutically acceptable salt, or its pharmaceutical composition is 0.1mg to 1000.0mg, 0.5mg to 500.0mg, 2mg to 250.0mg, 5mg to 100mg, or 5mg to 50mg of the compound of formula I or its pharmaceutically acceptable salt, or its pharmaceutical composition, preferably 0.1mg, 0.5mg, 1.0mg, 2.0mg, 3.0mg, 4.0mg, 5.0mg, 6.0mg, 7.0mg, 8.0mg In some embodiments, the compound of formula I or its pharmaceutically acceptable salt or its pharmaceutical composition is 5 mg, 10 mg, 15 mg, 50 mg or 100 mg of a compound of formula I or its pharmaceutically acceptable salt or its pharmaceutical composition.

[0023] In some embodiments, the compound of formula I or its pharmaceutically acceptable salt, or its pharmaceutical composition is a pharmaceutical composition with a single dose of 0.1 mg to 1000.0 mg, 0.5 mg to 500.0 mg, 2.0 mg to 250.0 mg, 5.0 mg to 100.0 mg, or 5.0 mg to 50.0 mg, preferably a single dose of 0.1 mg, 0.5 mg, 1.0 mg, 2.0 mg, 3.0 mg, 4.0 mg, 5.0 mg, 6.0 mg, 7.0 mg, 8.0 mg, 9.0 mg, 10.0 mg, 15.0 mg, 20.0 mg, 25.0 mg, 30.0 mg, 35.0 mg, 40.0 mg, 45.0 mg, 50.0 mg, 60.0 mg, 70.0 mg, 80.0 mg, 90.0 mg, 100.0 mg, 125.0 mg, 150.0 mg, 175.0 mg, 200.0 mg, 250.0 mg or a range formed by any of the above values, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0024] In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is a single dose of 5 mg, 10 mg or 50 mg of the compound of Formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0025] In some embodiments, the pharmaceutical composition of the compound of Formula I or a pharmaceutically acceptable salt thereof further contains a pharmaceutically acceptable excipient.

[0026] In some embodiments, the pharmaceutical composition of the compound of Formula I or a pharmaceutically acceptable salt thereof is selected from granules, tablets, pills or capsules, preferably tablets or capsules, more preferably capsules.

[0027] In some embodiments, the pharmaceutical composition of the compound of Formula I or its pharmaceutically acceptable salt can be a capsule containing the compound of Formula I or its pharmaceutically acceptable salt, a binder, a surface stabilizer, and a dispersant. In some embodiments, the pharmaceutical composition of the compound of Formula I or its pharmaceutically acceptable salt can be a capsule containing the compound of Formula I, hydroxypropyl cellulose, sodium lauryl sulfate, and sucrose. In some embodiments, the pharmaceutical composition of the compound of Formula I or its pharmaceutically acceptable salt further comprises a blank core selected from a microcrystalline cellulose core, a starch core, or a lactose core.

[0028] Dosage

[0029] While the present invention exemplifies certain dosages and administration schedules, these examples in no way limit the dosages and administration schedules that may be provided to a patient when practicing the present invention.

[0030] In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered in a 28-day (4-week) administration cycle.

[0031] In some embodiments, the treatment cycle of the compound of formula I or its pharmaceutically acceptable salt, or its pharmaceutical composition is repeated until the subject no longer benefits, the disease progresses, or an intolerable toxic reaction occurs. In some embodiments, the treatment cycle of the compound of formula I or its pharmaceutically acceptable salt, or its pharmaceutical composition is 4-150 or 4-90 or 8-60 dosing cycles. In some embodiments, the treatment cycle of the compound of formula I or its pharmaceutically acceptable salt, or its pharmaceutical composition is 4-10 or 8-20 dosing cycles.

[0032] In some embodiments, the frequency of administration of the compound of Formula I or its pharmaceutically acceptable salt, or its pharmaceutical composition can be 3 times a day, 2 times a day, once a day, once every two days, once every three days, once every four days, once every five days, once every six days, 3 times a week, 2 times a week, once a week, once every two weeks, or once every three weeks. In some embodiments, the frequency of administration of the compound of Formula I or its pharmaceutically acceptable salt, or its pharmaceutical composition is 2 times a day or once a day.

[0033] In some embodiments, the daily dose of the compound of formula I or its pharmaceutically acceptable salt, or its pharmaceutical composition is 0.1 mg to 1000.0 mg, preferably 0.5 mg to 500.0 mg, more preferably 5.0 mg to 200.0 mg or 5.0 mg to 100.0 mg or 5.0 mg to 70.0 mg or 5.0 mg to 50.0 mg. In some embodiments, the daily dose of a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is 0.5 mg, 1.0 mg, 2.0 mg, 3.0 mg, 4.0 mg, 5.0 mg, 6.0 mg, 7.0 mg, 8.0 mg, 9.0 mg, 10.0 mg, 15.0 mg, 20.0 mg, 25.0 mg, 30.0 mg, 35.0 mg, 40.0 mg, 45.0 mg, 50.0 mg, 60.0 mg, 70.0 mg, 80.0 mg, 90.0 mg, 100.0 mg, 125.0 mg, 150.0 mg, 175.0 mg, 200.0 mg, 250.0 mg, 300.0 mg, 400.0 mg, 500.0 mg, or a range formed by any of the foregoing values. In some embodiments, the daily dose of a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is 5.0 mg, 15.0 mg, 50.0 mg, 70.0 mg, 100.0 mg, 150.0 mg, 175.0 mg, 200.0 mg, or a range formed by any of the foregoing values. In some embodiments, the daily dose of a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is 5.0 mg, 15.0 mg, 50.0 mg, 70.0 mg, 100.0 mg, or a range formed by any of the foregoing values.

[0034] In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered in a single dose or multiple doses.

[0035] In some embodiments, the compound of formula I or its pharmaceutically acceptable salt, or its pharmaceutical composition can be administered by various routes, including but not limited to oral administration. In some embodiments, the compound of formula I or its pharmaceutically acceptable salt, or its pharmaceutical composition is administered orally on an empty stomach.

[0036] In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is used as a single active agent.

[0037] Neurofibromatosis type I related disorders

[0038] In some embodiments, the neurofibromatosis type I-related disease is selected from neurofibromatosis type I and peripheral malignant nerve sheath tumor.

[0039] In some embodiments, the neurofibromatosis type I-related disease is selected from symptomatic, inoperable neurofibromatosis type I and peripheral malignant nerve sheath tumor.

[0040] In some embodiments, the patient suffering from a neurofibromatosis type I-related disease is an adult patient.

[0041] In some embodiments, the neurofibromatosis type I-related disease is selected from neurofibromatosis type I and peripheral malignant nerve sheath tumor that cannot be completely surgically resected and requires systemic therapy and has measurable lesions.

[0042] In some embodiments, the neurofibromatosis type I-related disease is neurofibromatosis type I.

[0043] In some embodiments, the neurofibromatosis type I is selected from benign neurofibromatosis type I or malignant neurofibromatosis type I.

[0044] In some embodiments, the neurofibromatosis type I is selected from central, visceral, cutaneous, or peripheral neurofibromatosis type I.

[0045] In some embodiments, the neurofibromatosis type I is selected from cutaneous neurofibromas, nodular neurofibromas, or plexiform neurofibromas.

[0046] In some embodiments, the neurofibromatosis type I is selected from neurofibromatosis cutaneous or plexiform neurofibromas.

[0047] In some embodiments, the neurofibromatosis type I-related disease is peripheral malignant nerve sheath tumor. In some embodiments, the peripheral malignant nerve sheath tumor is malignant transformation of plexiform neurofibroma.

[0048] In some embodiments, the neurofibroma type I-related disease is selected from cutaneous neurofibroma, plexiform neurofibroma, or peripheral nerve sheath tumor. In some embodiments, the neurofibroma type I-related disease is selected from cutaneous neurofibroma, benign plexiform neurofibroma, or peripheral malignant nerve sheath tumor.

[0049] In some embodiments, the neurofibromatosis type I-related disease is selected from plexiform neurofibromas that cannot be completely removed by surgery. In some embodiments, the neurofibromatosis type I-related disease is selected from symptomatic, inoperable plexiform neurofibromas PN.

[0050] In some embodiments, the neurofibromatosis type I-associated disease is selected from café au lait spots on the skin, axillary or inguinal freckles, optic nerve gliomas, Lisch nodules (iris hamartomas), characteristic bone lesions (sphenoid dysplasia or long bone cortical dysplasia or thinning), plexiform neurofibromas, or malignant peripheral nerve sheath tumors.

[0051] In some embodiments, the neurofibromatosis type I patient has inoperable symptomatic and / or progressive plexiform neurofibromas.

[0052] In some embodiments, the patient with neurofibromatosis type I meets at least two of the following conditions: a) greater than or equal to 6 café-au-lait macules with a diameter (longest diameter) greater than 5 mm before puberty or greater than 15 mm after puberty; b) freckles in the axillary or inguinal area; c) greater than or equal to 2 neurofibromas of any type or 1 plexiform neurofibroma; d) optic nerve glioma; e) greater than or equal to 2 Lisch nodules (iris hamartoma); f) characteristic bone lesions, such as sphenoid dysplasia, long bone cortical thickening with or without pseudarthrosis; g) a first-degree relative (parent, sibling or child) diagnosed with neurofibromatosis type I.

[0053] In some embodiments, the patient with neurofibromatosis type I meets at least two of the following criteria: a) greater than or equal to 6 café-au-lait macules with a diameter (longest dimension) greater than 5 mm before puberty or greater than 15 mm after puberty; b) axillary or inguinal freckles; c) greater than or equal to 2 neurofibromas of any type or 1 plexiform neurofibroma; d) optic nerve glioma; e) greater than or equal to 2 Lisch nodules (iris hamartomas) on slit lamp examination or greater than or equal to 2 choroidal abnormalities on optical coherence tomography / near infrared imaging; f) characteristic bone lesions, such as sphenoid dysplasia, anterolateral tibial bowing, or long bone pseudarthrosis; g) a pathogenic heterozygous NF1 variant with an allele variant fraction of 50% in normal tissues (e.g., leukocytes); h) a parent diagnosed with neurofibromatosis type I.

[0054] In some embodiments, the patient with neurofibromatosis type I meets at least one of the following conditions:

[0055] i) Genetic testing confirms NF1 germline mutation;

[0056] ii) Clinical and imaging examinations confirm that two of the following conditions are met:

[0057] a) Six or more café-au-lait macules with a diameter (longest diameter) greater than 5 mm before puberty or greater than 15 mm after puberty;

[0058] b) freckles in the armpits or groin area;

[0059] c) 2 or more neurofibromas of any type, or 1 or more plexiform neurofibroma;

[0060] d) optic nerve glioma;

[0061] e) Two or more Lisch nodules (iris hamartomas);

[0062] f) Characteristic bone lesions, such as sphenoid dysplasia, long bone cortical dysplasia or thinning;

[0063] g) A first-degree relative diagnosed with neurofibromatosis type I.

[0064] In some embodiments, the patient with the neurofibromatosis type I-related disease has not been treated with a mitogen-activated protein kinase (MEK) inhibitor.

[0065] Technical Effects

[0066] The compound of formula I or its pharmaceutically acceptable salt or pharmaceutical composition thereof of the present application has good safety and anti-tumor activity.

[0067] The treatment regimen of the present application has good efficacy in treating diseases related to neurofibromatosis type I. It has excellent effects in at least one of survival efficacy evaluations such as overall survival time (OS) and median survival time; tumor response efficacy evaluations such as disease-free survival (DFS), median DFS, progression-free survival (PFS), 1-year progression-free survival rate (PFS>12m), time to disease progression (TTP), objective response rate (ORR), disease control rate (DCR), and disease remission time (DOR); and tolerability or safety evaluation.

[0068] The treatment regimen of the present application can effectively treat patients and achieve the best therapeutic effects of disease stabilization (SD), partial remission (PR) or complete remission (CR).

[0069] The treatment regimen of the present application can improve the patient's pain score, quality of life, motor function or disfiguring symptoms.

[0070] Definition and Description

[0071] Unless otherwise indicated, the following terms used in this application have the following meanings. A particular term, unless specifically defined, should not be construed as undefined or unclear, but rather should be understood according to its ordinary meaning in the art. When a trade name appears in this application, it is intended to refer to the corresponding commercial product or its active ingredient.

[0072] The term "treat" generally refers to obtaining a desired pharmacological and / or physiological effect. This effect can be therapeutic, partially or completely stabilizing or curing a disease and / or side effects resulting from the disease. As used herein, "treat" encompasses any treatment of a disease in a patient, including: (a) suppressing the symptoms of the disease, i.e., arresting its progression; or (b) relieving the symptoms of the disease, i.e., causing regression of the disease or its symptoms.

[0073] The term "effective amount" means an amount of the compound of the present application that (i) treats a given disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a specific disease, condition, or disorder, or (iii) delays the onset of one or more symptoms of a specific disease, condition, or disorder described herein. The amount of active substance (e.g., compound of the present application) that constitutes an "effective amount" may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the therapeutic agent or combination of therapeutic agents to elicit a desired response in the individual. The effective amount can also be routinely determined by those skilled in the art based on their own knowledge and the present disclosure.

[0074] The term "administering" or "giving" or "administering" means physically introducing 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, the administration can be performed once, multiple times, and / or over one or more extended periods of time.

[0075] Unless otherwise indicated, the term "dose" is used to refer to the dose administered to a patient regardless of the patient's weight or body surface area (BSA). For example, a 60 kg human and a 100 kg human will receive the same dose of active ingredient (e.g., 5.0 mg of a compound of Formula I).

[0076] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0077] The term "pharmaceutically acceptable salts" includes salts formed between a basic ion and a free acid or between an acid ion and a free base.

[0078] As used herein, the terms "subject" or "patient" or "subject" or "individual" are used interchangeably. In some embodiments, the term "subject" or "patient" is a mammal. In some embodiments, the subject or patient is a mouse. In some embodiments, the subject or patient is a human.

[0079] The term "single dose" refers to the smallest packaging unit containing a certain amount of medicine. For example, if a box of medicine contains seven capsules, each capsule is a single dose; or each bottle of injection is a single dose.

[0080] The term "multiple doses" consists of a plurality of single doses.

[0081] The term "pharmaceutical composition" refers to a mixture of one or more active ingredients or their combination of active ingredients of the present invention and pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present invention or their combination of active ingredients to a subject.

[0082] 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.

[0083] The pharmaceutical composition of the present application can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable excipients, for example, it can be formulated into a solid preparation (e.g., granules, tablets, pills, capsules, etc.) or a liquid preparation (e.g., injection).

[0084] The pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, sugar-coated pill making methods, grinding methods, emulsification methods, freeze-drying methods, etc.

[0085] 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 as needed, and then granulating the mixture to obtain a tablet or dragee core. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners, or flavoring agents.

[0086] Herein, unless otherwise stated, the terms "comprise, comprise, and comprising" or equivalents are open-ended expressions, meaning that in addition to the listed elements, components, and steps, other unspecified elements, components, and steps may also be included.

[0087] Unless specifically stated otherwise, singular terms shall include plural terms and plural terms shall include singular terms.

[0088] 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 for their disclosure prior to the filing date of the present application. All statements regarding the dates of these documents or the representations of their contents are based on the 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 become part of the common general knowledge in the art in any country. DETAILED DESCRIPTION

[0089] For the sake of clarity, the present invention is further illustrated by examples, but the examples are not intended to limit the scope of this application. All reagents used in this application are commercially available and can be used without further purification. The preparation of the compound of formula I in the examples can be referred to WO2012059041.

[0090] Example 1 Clinical Trial

[0091] 1.1 Main inclusion criteria

[0092] (1) Gender is not limited, age range is 18 to 75 years old;

[0093] (2) ECOGPS score ≤ 2 points, and the expected survival time of patients with peripheral malignant nerve sheath tumor is ≥ 12 weeks;

[0094] (3) patients with neurofibromatosis type I (including patients with peripheral malignant nerve sheath tumors) who were judged by the investigator to be incapable of complete surgical resection and required systemic treatment and had measurable lesions;

[0095] (4) There is at least one evaluable lesion with a diameter greater than 3 cm (except for skin type), and the lesion is visible on three consecutive sections;

[0096] (5) Major organs function well;

[0097] (6) Patients enrolled in the cohort expansion phase must be pathologically confirmed to be enrolled (e.g., patients with cutaneous neurofibromatosis type I, patients with plexiform neurofibromas of neurofibromatosis type I, or patients with peripheral malignant nerve sheath tumors).

[0098] 1.2 Dosage regimen

[0099] Test drug: Capsules of the compound of formula I, which can be prepared with reference to WO2016188472.

[0100] Dosage: Oral administration on an empty stomach, once a day, for 28 consecutive days as a cycle, until the study termination criteria are met.

[0101] Dosage: 5mg-200mg each time (e.g. 5mg, 10mg, 50mg, 70mg or 100mg).

[0102] 1.3 Evaluation Criteria

[0103] Safety evaluation: The severity of adverse events was evaluated using the CTCAE 5.0 standard;

[0104] Efficacy evaluation: Patients with neurofibromatosis type I cutaneous (cNF) were evaluated by the investigator using direct measurement methods combined with the natural history of the disease; patients with neurofibromatosis type I plexiform neurofibromas (PN) were evaluated according to the REiNS criteria; and patients with malignant peripheral nerve sheath tumors (MPNSTs) were evaluated according to the RECIST 1.1 criteria.

[0105] 1.4 Safety Assessment

[0106] Adverse reaction rate: the occurrence of all adverse events (AEs), serious adverse events (SAEs) and treatment-emergent adverse events (TEAEs).

[0107] 1.5 Efficacy evaluation

[0108] Objective response rate (ORR): refers to the percentage of subjects with complete response (CR) or partial response (PR) determined by the investigator based on direct measurement results or RECIST 1.1;

[0109] Progression-free survival (PFS): refers to the time from the first dose of the drug to the objective progression or recurrence of the disease or death due to various causes (whichever occurs first);

[0110] Duration of disease response (DOR): For subjects whose best response was complete response (CR) or partial response (PR), it was defined as the date from the first documented tumor response to the date of the first documented disease progression or the date of death from any cause, whichever occurred first;

[0111] Disease control rate (DCR): The proportion of subjects whose tumors shrank or stabilized for a certain period of time, including cases of CR, PR and SD (stable disease);

[0112] 1-year progression-free survival (PFS>12m): the proportion of subjects who have not experienced disease progression and are alive at 12 months;

[0113] Overall survival (OS): refers to the time from the first use of the drug to death from various causes;

[0114] Effects on subjects’ pain;

[0115] Impact on subjects' health-related quality of life (HRQoL);

[0116] Effects on subjects' relevant symptoms.

[0117] 1.6 Test results

[0118] Table 1 Efficacy data of some patients

[0119] Conclusion: The compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, when used to treat adult patients with neurofibromatosis type I, can achieve effective and sustained tumor shrinkage, with a PFS benefit compared to patients with the natural course of the disease. For example, for patients with plexiform neurofibromas, the ORR is ≥20%, preferably ≥30%, and most preferably ≥40%; for patients with cutaneous neurofibromas, the ORR is ≥50%, preferably ≥70%, and most preferably ≥83%.

[0120] Some safety data: mainly skin reactions; the incidence of adverse reactions of grade 3 and above is low.

Claims

1. Use of a compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of formula I or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating a disease associated with neurofibromatosis type I, 2. The use according to claim 1, characterized in that The administration frequency of the compound of Formula I or its pharmaceutically acceptable salt, or its pharmaceutical composition can be 3 times a day, 2 times a day, once a day, once every two days, once every three days, once every four days, once every five days, once every six days, 3 times a week, 2 times a week, once a week, once every two weeks, or once every three weeks.

3. The use according to claim 1, characterized in that The daily dosage of the compound of formula I or its pharmaceutically acceptable salt, or its pharmaceutical composition is 0.1 mg to 1000.0 mg, preferably 0.5 mg to 500.0 mg, and more preferably 5.0 mg to 200.0 mg.

4. The use according to claim 1, characterized in that The compound of formula I or its pharmaceutically acceptable salt, or its pharmaceutical composition is a single dose of 0.1 mg to 1000.0 mg, 0.5 mg to 500.0 mg, 2.0 mg to 250.0 mg, 5.0 mg to 100.0 mg, or 5.0 mg to 50.0 mg of the compound of formula I or its pharmaceutically acceptable salt, or its pharmaceutical composition.

5. The use according to claim 1, characterized in that The compound of formula I or its pharmaceutically acceptable salt, or its pharmaceutical composition is administered orally.

6. The use according to claim 1, characterized in that The pharmaceutical composition of the compound of formula I or a pharmaceutically acceptable salt thereof is selected from granules, tablets, pills or capsules, preferably tablets or capsules, more preferably capsules.

7. The use according to claim 1, characterized in that The neurofibromatosis type I-related disease is selected from neurofibromatosis type I and peripheral malignant nerve sheath tumor.

8. The use according to claim 7, characterized in that The neurofibromatosis type I is selected from central, visceral, cutaneous, or peripheral neurofibromatosis type I.

9. The use according to claim 7, characterized in that The neurofibromatosis type I is selected from cutaneous neurofibroma, nodular neurofibroma or plexiform neurofibroma.

10. The use according to claim 1, characterized in that The neurofibroma type I-related disease is selected from cutaneous neurofibroma, plexiform neurofibroma, or peripheral nerve sheath tumor.

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