Use of compounds as c-Met kinase inhibitors for the treatment of neurofibromatosis type I

Abstract

The invention relates to the use of a compound of a c-Met kinase inhibitor in the preparation of a drug for treating neurofibromatosis type I, and specifically relates to the use and method of N-(4-((7-((1-(cyclopentylamino)cyclopropane)methoxy)-6-methoxyquinoline-4-yl)oxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide in the preparation of a drug for treating neurofibromatosis type I.

Description

[0001] Citation of Related Applications

[0002] This disclosure claims priority and benefits of Chinese Patent Application No. 202110696200.5 filed with the State Intellectual Property Office of the People's Republic of China on June 23, 2021, the entire contents of which are hereby incorporated by reference in their entirety. Technical Field

[0003] The present invention belongs to the field of medical technology, and relates to the use of a compound as a c-Met kinase inhibitor for treating neurofibromatosis type I, and specifically to the use and method of N-(4-((7-((1-(cyclopentylamino)cyclopropane)methoxy)-6-methoxyquinolin-4-yl)oxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide for treating neurofibromatosis. Background Art

[0004] Neurofibromatosis (NF) is a genetic tumor of the nervous system caused by gene mutations. It can be generally divided into three types: neurofibromatosis type I (NF1), neurofibromatosis type II (NF2), and schwannomatosis (NF3). Among them, the NF1 gene is located at 17q11.2. Its total length is about 350kb, containing 60 exons. It can be transcribed into 11-13kb mRNA, encoding a 2818 amino acid protein, namely neurofibromin. Neurofibromin is a tumor suppressor. Its main functional region is the guanosine triphosphate activating protein-related region (GAP-related domains, GRD), which is encoded by exons 21 to 27a. It has homology with the GTPase activating protein family and can activate Ras-GTPase in the body. It is a negative regulator of Ras signal transduction. Gene mutations lead to the disappearance of the negative regulatory effect of neurofibromin, thereby causing increased Ras activity, which is mainly manifested as abnormal activation of two Ras downstream pathways, Raf-MEK-ERK and PI3K-AKT-mTOR, ultimately leading to abnormal cell proliferation and tumor growth.

[0005] There are currently about 550,000 neurofibromatosis patients in my country, of which NF1 is the most common type of neurofibromatosis, accounting for about 90%. Among NF1 patients, about 20-50% have plexiform neurofibromas (PN), which can grow along the long axis of the nerve or extend to the surrounding structures, causing severe pain and bone destruction, serious complications and the possibility of malignant transformation. Neurofibromatosis is a multiple lesion that is difficult to cure. Its treatment has always been mainly symptomatic treatment and surgical removal of the tumor, but due to the location or size of the tumor, many patients are not suitable for surgery. Therefore, there is a high unmet medical need for this disease, and the search for effective chemotherapy drugs is still a problem that needs to be urgently solved in clinical practice.

[0006] WO2012034055 discloses N-(4-((7-((1-(cyclopentylamino)cyclopropanyl)methoxy)-6-methoxyquinolin-4-yl)oxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (hereinafter referred to as the compound of formula (I)) as a c-Met kinase inhibitor and its use in inhibiting tyrosine kinase activity. The compound of formula (I) is a new class of compounds with excellent pharmacological properties, which can inhibit the activity of multiple protein tyrosine kinases, such as c-Met, VEGFr, EGFr, c-kit, PDGF, FGF, SRC, Ron, Tie2, etc. The present disclosure relates to the treatment of neurofibromatosis type I by the compound of formula (I).

[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 neurofibromatosis type I:

[0009]

[0010] In another aspect, the present disclosure provides a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating neurofibromatosis type I.

[0011] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating neurofibromatosis type I.

[0012] In another aspect, the present disclosure provides use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating neurofibromatosis type I.

[0013] In some embodiments, the present disclosure provides the use of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating neurofibromatosis type I. In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

[0014] In another aspect, the present disclosure provides use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in treating neurofibromatosis type I.

[0015] In some embodiments, the present disclosure provides use of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in treating neurofibromatosis type I. In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

[0016] In another aspect, the present disclosure provides a method of treating neurofibromatosis type I, comprising administering to a patient a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0017] In some embodiments, the present disclosure provides a method of treating neurofibromatosis type I, comprising administering to a patient a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0018] In another aspect, the present disclosure provides a method for treating neurofibromatosis type I, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0019] In some embodiments, the present disclosure provides a method for treating neurofibromatosis type I, comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

[0020] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof of the present disclosure is used as a single active agent.

[0021] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof of the present disclosure may be in the form of a pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof, for example, may be in the form of a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0022] In one aspect, the present disclosure provides a kit for treating neurofibromatosis type I, the kit comprising: a) a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof; and b) instructions for use.

[0023] In some embodiments, the kit may contain a single dose or multiple doses of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof. In the instructions for use, the treatment of neurofibromatosis type I is carried out with a treatment cycle of 28 days. DETAILED DESCRIPTION OF THE INVENTION

[0025] Neurofibromatosis type I

[0026] In some embodiments, the neurofibromatosis type I is selected from benign neurofibromatosis type I or malignant neurofibromatosis type I.

[0027] In some embodiments, the neurofibromatosis type I is selected from neurofibromas or malignant peripheral nerve sheath tumors (MPNSTs).

[0028] In some embodiments, the neurofibroma is a benign neurofibroma.

[0029] In some embodiments, the neurofibromatosis type I is selected from benign neurofibromatosis type I or malignant peripheral nerve sheath tumors (MPNSTs).

[0030] In some embodiments, the neurofibromatosis type I is selected from cutaneous neurofibroma (cNF) or plexiform neurofibroma (pNF).

[0031] In some embodiments, the neurofibromatosis type I is selected from cutaneous neurofibroma, plexiform neurofibroma (benign), or malignant peripheral nerve sheath tumor.

[0032] In some embodiments, the neurofibromatosis type I is selected from milk spots of the skin, axillary or inguinal freckles, optic nerve gliomas, Lisch nodules (iris hamartomas), characteristic bone lesions (e.g., sphenoid dysplasia or long bone cortical dysplasia or thinning), plexiform neurofibromas, or malignant peripheral nerve sheath tumors.

[0033] In some embodiments, the neurofibromatosis type I is selected from milk spots of the skin, plexiform neurofibromas, or malignant peripheral nerve sheath tumors.

[0034] In some embodiments, the neurofibromatosis type I is selected from neurofibromatosis type I cutaneous, neurofibromatosis type I plexiform neurofibroma (benign), or malignant peripheral nerve sheath tumor.

[0035] In some embodiments, the patient with NF1 meets at least two of the following diagnostic criteria: a) greater than or equal to 6 cafe-au-lait macules (greater than or equal to 0.5 cm in prepubertal patients and greater than or equal to 1.5 cm in postpubertal patients); b) axillary or inguinal freckles; c) greater than or equal to 2 neurofibromas of any type, or greater than or equal to 1 plexiform neurofibroma; d) optic nerve glioma; e) two or more Lisch nodules (iris hamartomas); f) characteristic bone lesions (sphenoid dysplasia or long bone cortical dysplasia or thinning); g) a first-degree relative diagnosed with NF1.

[0036] In some embodiments, the neurofibromatosis type I is a neurofibromatosis type I gene mutation.

[0037] In some embodiments, the neurofibromatosis type I is neurofibromatosis type I with nf1 gene mutation. In some embodiments, the nf1 gene mutation types include but are not limited to base substitution, insertion mutation, missense mutation, nonsense mutation, large gene fragment deletion and splicing mutation, frameshift mutation (or deletion mutation) or duplication mutation.

[0038] In some embodiments, the nf1 gene mutations include but are not limited to c.168C>T, c.601T>A, c.702G>A, c.871G>T, c.1009G>T, c.1318C>T, c.1448A>G, c.2033dup, c.2033del, c.2034G>A, c.3443_3444delCA, c.3619delA, c.3721C>T, c.3822delC, c.3975-2A>T, c.4084C>T, c.4600C>T, c.6852_6855del, c.7348C>T or c.7909C>T mutations.

[0039] In some embodiments, the neurofibromatosis type I is neurofibromatosis type I that cannot be completely surgically resected and requires systemic treatment.

[0040] In some embodiments, the neurofibromatosis type I is neurofibromatosis type I that has been previously treated with surgery, chemotherapy and / or radiation therapy. In some embodiments, the neurofibromatosis type I is neurofibromatosis type I that has failed surgery, chemotherapy and / or radiation therapy.

[0041] In some embodiments, the subject with neurofibromatosis type I achieves complete remission or partial remission after surgery, chemotherapy and / or radiation therapy, and then the disease progresses or relapses again. In some embodiments, the subject with neurofibromatosis type I fails to achieve complete remission or partial remission after surgery, chemotherapy and / or radiation therapy.

[0042] In some embodiments, the neurofibromatosis type I previously treated with chemotherapy and / or radiation therapy is cutaneous neurofibroma, plexiform neurofibroma, or malignant peripheral nerve sheath tumor.

[0043] In some embodiments, the chemotherapy comprises a combination of ifosfamide and doxorubicin, or a combination of pirarubicin and ifosfamide.

[0044] In some embodiments, the chemotherapy comprises ifosfamide, doxorubicin and / or mesna. For example, the chemotherapy comprises ifosfamide combined with doxorubicin, or ifosfamide combined with doxorubicin and mesna.

[0045] In some embodiments, the neurofibromatosis type I is a neurofibromatosis type I that has been previously treated with surgery and / or ifosfamide combined with doxorubicin (e.g., treatment failure). In some embodiments, the neurofibromatosis type I is a neurofibromatosis type I that has been previously treated with surgery and / or ifosfamide combined with doxorubicin and mesna (e.g., treatment failure).

[0046] In some embodiments, the neurofibromatosis type I has been previously treated with (eg, failed to treat with) ifosfamide, doxorubicin, and / or anlotinib.

[0047] Dosage regimen

[0048] In some embodiments, the administration cycle of the compound of formula (I) or its pharmaceutically acceptable salt is 2-6 weeks. In some embodiments, the administration cycle of the compound of formula (I) or its pharmaceutically acceptable salt is 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks or the range formed by any of the above values. In some embodiments, the administration cycle of the compound of formula (I) or its pharmaceutically acceptable salt is 3 weeks or 4 weeks.

[0049] In some embodiments, the administration cycle of the compound of formula (I) or its pharmaceutically acceptable salt is 6-10 cycles or more. In some embodiments, the administration cycle of the compound of formula (I) or its pharmaceutically acceptable salt can be selected from at least 6 cycles, at least 7 cycles, at least 8 cycles, at least 9 cycles or at least 10 cycles. In some embodiments, the administration cycle of the compound of formula (I) or its pharmaceutically acceptable salt can be at least 8 cycles.

[0050] In some embodiments, the dosage regimen of the compound of formula (I) or its pharmaceutically acceptable salt is 1 to 3 times a day, or 1 time every two days. In some embodiments, the dosage regimen of the compound of formula (I) or its pharmaceutically acceptable salt is 1, 2 or 3 times a day. In some embodiments, the dosage regimen of the compound of formula (I) or its pharmaceutically acceptable salt is 1 time a day.

[0051] In some embodiments, the daily dose of the compound of formula (I) or its pharmaceutically acceptable salt is selected from 20-180 mg. In some embodiments, the daily dose of the compound of formula (I) or its pharmaceutically acceptable salt is selected from 20-40 mg, 20-60 mg, 20-90 mg, 20-120 mg, 20-150 mg, 40-60 mg, 40-90 mg, 40-120 mg, 40-150 mg, 40-180 mg, 60-90 mg, 60-120 mg, 60-150 mg, 60-180 mg, 90-120 mg, 90-150 mg, 90-180 mg, 120-150 mg, 120-180 mg or 150-180 mg.

[0052] In some embodiments, the daily dose of the compound of formula (I) or its pharmaceutically acceptable salt is selected from 90-120mg, 90-150mg, 90-180mg, 120-150mg, 120-180mg or 150-180mg. In some embodiments, the daily dose of the compound of formula (I) or its pharmaceutically acceptable salt is selected from 90mg, 120mg, 150mg or 180mg. In some embodiments, the daily dose of the compound of formula (I) or its pharmaceutically acceptable salt is selected from 120mg or 150mg.

[0053] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in the form of a pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0054] 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. In some embodiments, it is administered in multiple doses.

[0055] In some embodiments, the pharmaceutical composition is a pharmaceutical composition with a single dose of 30-60 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition is a pharmaceutical composition with a single dose of 30 mg or 60 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0056] In some embodiments, the pharmaceutical composition is a multiple-dose pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof, and the multiple doses may consist of a single dose of 30 mg or 60 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0057] In some embodiments, the pharmaceutical composition is a pharmaceutical composition of multiple doses of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the multiple doses of a compound of formula (I) or a pharmaceutically acceptable salt thereof are 90 mg, 120 mg, 150 mg or 180 mg. In some embodiments, wherein the multiple doses of a compound of formula (I) or a pharmaceutically acceptable salt thereof are 120 mg or 150 mg. In some embodiments, in a multiple dose pharmaceutical composition, the content of a compound of formula (I) or a pharmaceutically acceptable salt thereof is a once-a-day dose, and the multiple doses consist of a single dose of 30 mg or 60 mg of a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0058] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof is administered as follows: a daily dose of 90 mg, 120 mg, 150 mg or 180 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject continuously every day.

[0059] In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt or pharmaceutical composition thereof is administered as follows: with a treatment cycle of 28 days, a daily dose of 90 mg, 120 mg, 150 mg or 180 mg is administered once a day.

[0060] 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 is orally administered on an empty stomach before breakfast.

[0061] In some embodiments, with 28 days as a treatment cycle, the administration method is as follows: administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the dosage is 90 mg, 120 mg, 150 mg or 180 mg, orally on an empty stomach, once a day, for 28 consecutive days.

[0062] In embodiments of the present disclosure, the above treatment cycles are repeated as long as the disease remains under control and the regimen is clinically tolerated.

[0063] In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt or its pharmaceutical composition is prepared in a single or multiple dose form suitable for once a day for 28 consecutive days and administering 90mg-180mg, or 90mg-150mg, or 90mg-120mg, or 120mg-150mg, or 120mg-180mg, or 150mg-180mg, or 90mg, or 120mg, or 150mg, or 180mg of the compound of formula (I) or its pharmaceutically acceptable salt to the patient each time.

[0064] The compound of formula (I) or a pharmaceutically acceptable salt thereof

[0065] The compounds of formula (I) disclosed herein can be administered in the form of their free base or in the form of their pharmaceutically acceptable salts. For example, pharmaceutically acceptable salts of the compounds of formula (I) can be produced from different organic acids and inorganic acids according to methods known in the art. In some embodiments of the present disclosure, the compounds of formula (I) are administered in the form of their free base.

[0066] Pharmaceutical composition

[0067] The "compound of formula (I) or a pharmaceutically acceptable salt thereof" described in the present disclosure may be in the form of a "pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof".

[0068] The method of administration can be determined comprehensively based on the activity, toxicity and patient tolerance of the drug.

[0069] In some embodiments, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof further contains a pharmaceutically acceptable excipient.

[0070] In some embodiments, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof may be suitable for oral administration.

[0071] In some embodiments, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a solid pharmaceutical composition.

[0072] In some embodiments, the solid pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is in the form of a capsule.

[0073] In some embodiments, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is in the form of capsules with strengths of 30 mg and 60 mg.

[0074] The “compound of formula (I) or a pharmaceutically acceptable salt thereof” described in the present disclosure may be in the form of a “pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof”.

[0075] The method of administration can be determined comprehensively based on the activity, toxicity and patient tolerance of the drug.

[0076] In some embodiments, the pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof further comprises a pharmaceutically acceptable excipient.

[0077] In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof may be suitable for oral administration.

[0078] In some embodiments, the pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof is a solid pharmaceutical composition.

[0079] In some embodiments, the solid pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof is in the form of a capsule.

[0080] In some embodiments, the pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof is in the form of capsules with strengths of 30 mg and 60 mg.

[0081] The pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof disclosed herein can be manufactured by methods well known in the art, such as conventional mixing methods, dissolving methods, granulating methods, making sugar-coated pills, grinding methods, emulsifying methods, freeze-drying methods, etc.

[0082] Solid oral compositions can be prepared by conventional mixing, filling or tableting methods. For example, they can be obtained 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 particles to obtain the core of a capsule, tablet or dragee. Suitable excipients include, but are not limited to, adhesives, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, etc.

[0083] In some embodiments, the pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof may be a capsule containing the compound of formula (I) or a pharmaceutically acceptable salt thereof, corn starch, carboxymethylcellulose calcium, hypromellose and magnesium stearate.

[0084] In other embodiments, the pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof may be a capsule containing the compound of formula (I) or a pharmaceutically acceptable salt thereof, lactose, microcrystalline cellulose, sodium starch glycolate and magnesium stearate.

[0085] Technical Effects

[0086] The compound of formula (I) or its pharmaceutically acceptable salt, or its pharmaceutical composition disclosed in the present invention has good safety and anti-tumor activity.

[0087] The treatment regimen disclosed herein has good efficacy in treating neurofibromatosis type I. Among them, the compound of formula (I) or its pharmaceutically acceptable salt, or a pharmaceutical composition comprising the compound of formula (I) or its pharmaceutically acceptable salt has excellent effects in at least one of objective response rate (ORR), disease control rate (DCR), disease remission time (DOR), progression-free survival (PFS), overall survival time (OS), tolerance or side effects.

[0088] In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof has a good objective response rate and / or disease control rate in the treatment of neurofibromatosis type I.

[0089] Definition and Description

[0090] For the purposes of this disclosure, unless otherwise stated, the following terms used in the specification and claims shall have the following meanings.

[0091] In the present disclosure, unless otherwise stated, the dosages and ranges thereof provided herein relating to the compound of formula (I) or its pharmaceutically acceptable salt are calculated based on the molecular weight of the free base of the compound of formula (I).

[0092] The word "comprise" or "comprises" and its English variations such as comprises or comprising should be construed in an open and non-exclusive sense, ie, "including but not limited to".

[0093] Unless otherwise specifically stated, singular terms encompass plural terms and plural terms encompass singular terms. Unless otherwise specifically stated, the words "a" or "an" mean "at least one" or "at least one". Unless otherwise stated, the use of "or" means "and / or".

[0094] The term "pharmaceutically acceptable" means that it is used to prepare a pharmaceutical composition that is generally safe, non-toxic, and neither biologically or otherwise undesirable, and includes that which is acceptable for human pharmaceutical use.

[0095] The term "treatment" generally refers to obtaining a desired pharmacological and / or physiological effect, including partial or complete stabilization or cure of a disease and / or effects resulting from a disease. As used herein, "treatment" encompasses any treatment of a patient's disease, including: (a) suppressing the symptoms of the disease, i.e., preventing its development; or (b) alleviating the symptoms of the disease, i.e., causing regression of the disease or symptoms.

[0096] The term "effective amount" means an amount of a compound of the present disclosure that (i) treats a particular disease, condition or disorder, or (ii) alleviates, ameliorates or eliminates one or more symptoms of a particular disease, condition or disorder. The amount of a compound of the present disclosure that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art based on their own knowledge and the present disclosure.

[0097] The term "pharmaceutically acceptable excipients" refers to those excipients that have no significant irritation to the organism and do not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

[0098] The term "administering" or "dosing" or "administering" means physically introducing a composition comprising an active compound 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.

[0099] The term "daily dose" refers to the dose administered to a patient for one day.

[0100] The terms "patient" or "subject" or "subject" are used interchangeably herein to refer to mammals, such as humans, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic non-human animals. In some embodiments, the patient or subject or subject is a human.

[0101] 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; for example, if a box of medicine contains seven tablets, each tablet is a single dose.

[0102] The term "multiple doses" consists of a plurality of single doses.

[0103] The term "pharmaceutical composition" refers to a mixture of one or more active ingredients of the present disclosure and pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate administration of a compound of the present disclosure to a subject.

[0104] When referring to a dosing regimen, the terms "day," "daily," and the like refer to the times within a calendar day, beginning at midnight and ending at the following midnight.

[0105] The term "first-degree relative" refers to immediate family members.

[0106] All patents, patent applications and other identified publications are expressly incorporated herein by reference for the purposes of description and disclosure. Any citation of these publications herein does not constitute an admission that the publication becomes part of the common general knowledge in the art. DETAILED DESCRIPTION

[0107] 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.

[0108] Example 1 Clinical Trial

[0109] 1.1 Selection criteria:

[0110] (1) The subjects voluntarily participated in this study and signed the informed consent form;

[0111] (2) Age: [18-75] years old (at the time of signing the informed consent); ECOG PS score: ≤2 points; the expected survival time of patients with peripheral malignant nerve sheath tumor is ≥12 weeks;

[0112] (3) NF1 patients (including patients with malignant peripheral nerve sheath tumors) who were judged by the investigators to be incompletely surgically resectable, required systemic treatment, and had measurable lesions;

[0113] Note: NF1 diagnostic criteria include at least one of the following:

[0114] 1) Genetic examination confirmation: that is, the NF1 germline mutation is positive in a CLIA-certified laboratory (NF1 germline mutation positivity needs to be confirmed by the central laboratory of this project, or there is an NF1 mutation test report issued by a CLIA-certified laboratory);

[0115] 2) Clinical and imaging confirmation: According to the clinical NIH consensus criteria, at least 2 of the following 7 NF1 diagnostic criteria are met:

[0116] a. ≥6 cafe-au-lait macules (greater than or equal to 0.5 cm in prepubertal patients and greater than or equal to 1.5 cm in postpubertal patients);

[0117] b. Freckles in the armpits or groin;

[0118] c. ≥2 neurofibromas of any type, or ≥1 plexiform neurofibroma;

[0119] d. Optic nerve glioma;

[0120] e. Two or more Lisch nodules (iris hamartomas);

[0121] f. Characteristic bone lesions (sphenoid hypoplasia or long bone cortical hypoplasia or thinning);

[0122] g. A first-degree relative diagnosed with NF1;

[0123] (4) at least one evaluable lesion confirmed by direct measurement or according to RECIST 1.1 criteria, with a lesion diameter greater than 3 cm and visible in three consecutive sections;

[0124] (5) The major organs function well and meet the following criteria:

[0125] 1) Routine blood test standards (no blood transfusion and no use of hematopoietic stimulating factor drugs for correction within 7 days before the test):

[0126] a. White blood cell count (WBC) ≥ 3.5 × 10 9 / L;

[0127] b. Hemoglobin (HGB) ≥ 90 g / L;

[0128] c. Neutrophil absolute count (NEUT) ≥ 1.5 × 10 9 / L;

[0129] d. Platelet count (PLT) ≥ 100 × 10 9 / L;

[0130] 2) Biochemical examination must meet the following standards:

[0131] a. Albumin (ALB) ≥ 35 g / L;

[0132] b. Total bilirubin (TBIL) ≤ 1.5 times the upper limit of normal (ULN); for patients with Gilbert syndrome, ≤ 2.5 times the upper limit of normal (ULN);

[0133] c. Alanine transferase (ALT) and aspartate transferase (AST) ≤ 2.5 × ULN;

[0134] d. Serum creatinine (CR) ≤ 1.5 × ULN or creatinine clearance (CCR) ≥ 50 mL / min (using the standard Cockcroft-Gault formula).

[0135] 3) Coagulation function tests must meet the following criteria:

[0136] International normalized ratio (INR) ≤ 1.5 × ULN (not receiving anticoagulant therapy);

[0137] 4) Thyroid function tests must meet the following criteria:

[0138] Thyroid stimulating hormone (TSH) ≤ ULN; if abnormal, T3 and T4 levels should be examined, and patients can be selected if T3 and T4 levels are normal.

[0139] 5) Cardiac ultrasound assessment: left ventricular ejection fraction (LVEF) ≥ 50%.

[0140] (6) Female subjects of childbearing age must 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 must be negative within 7 days before the study enrollment, and the subjects must not be breastfeeding; male subjects must agree to use contraceptive measures during the study and within 6 months after the end of the study;

[0141] (7) Patients enrolled in the cohort expansion phase must be pathologically confirmed to be enrolled in cohort 1 (patients with NF1 cutaneous type), cohort 2 (patients with NF1 plexiform neurofibromas (benign)) or cohort 3 (patients with MPNST).

[0142] 1.2 Dosage regimen

[0143] Test drug: capsules of the compound of formula (I), with specifications of 30 mg and 60 mg.

[0144] Wherein, the compound of formula (I) is prepared according to the method disclosed in WO2012034055.

[0145] Dosage method: Oral administration, once a day, for 28 consecutive days as a cycle, until the study termination criteria are met.

[0146] Dosage: Daily dose is 120mg or 150mg.

[0147] 1.3 Evaluation Criteria

[0148] Effectiveness evaluation: Direct measurement method or RECIST1.1 standard was used to evaluate the efficacy.

[0149] Safety evaluation: The CTCAE v5.0 standard was used to judge the severity of adverse events.

[0150] 1.4 Efficacy evaluation

[0151] Objective response rate (ORR): The percentage of subjects with complete response (CR) or partial response (PR) determined by the investigator based on direct measurement or RECIST 1.1.

[0152] Progression-free survival (PFS): The time from the first use of medication to the objective progression or recurrence of the disease or death due to various causes (whichever occurs first).

[0153] 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 recurrence or the date of death due to any cause, whichever occurred first.

[0154] Disease control rate (DCR): The proportion of subjects whose tumors shrink or stabilize and remain stable for a certain period of time, including cases of CR, PR and SD (stable disease).

[0155] One-year progression-free survival (PFS>12m): The proportion of subjects who survived without disease progression at 12 months from the first dose of the drug (using Kaplan-Meier estimation).

[0156] Survival (OS): The time from the first dose of the drug to death from any cause.

[0157] Effects on pain in subjects.

[0158] Effects on subjects' health-related quality of life (HRQoL).

[0159] Effects on subjects' relevant symptoms.

[0160] Incidence of adverse events.

[0161] 1.5 Test results

[0162] Currently, there are 6 patients who can be evaluated for efficacy. The patients had previously received surgical treatment or chemotherapy (such as ifosfamide + doxorubicin, or ifosfamide + doxorubicin + mesna). The median treatment time of the test drug of the present invention was about 8 months, including 1 patient with cutaneous neurofibroma (120 mg dose group), 3 patients with plexiform neurofibroma (1 patient in the 120 mg dose group, 2 patients in the 150 mg dose group) and 2 patients with malignant peripheral nerve sheath tumor (1 patient in the 120 mg dose group, 1 patient in the 150 mg dose group). The best efficacy of the 6 patients was SD, the target lesion volume was reduced to varying degrees, and the patients benefited clinically.

Claims

1. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating neurofibromatosis type I who has previously failed surgery, chemotherapy and / or radiotherapy, 2. The use according to claim 1, wherein the neurofibromatosis type I is selected from benign neurofibromatosis type I or malignant peripheral nerve sheath tumor.

3. The use according to claim 1, wherein the neurofibromatosis type I is selected from multiple neurofibromatosis cutanea or plexiform neurofibroma.

4. The use according to claim 1, wherein the neurofibromatosis type I is selected from neurofibromatosis type I cutaneous, neurofibromatosis type I plexiform neurofibroma or malignant peripheral nerve sheath tumor. The use according to claim 1 , wherein the neurofibromatosis type I is neurofibromatosis type I with gene mutation.

6. The use according to any one of claims 1 to 5, wherein the administration cycle for treating neurofibromatosis type I is 2 to 6 weeks.

7. The use according to any one of claims 1 to 5, wherein the dosage regimen for treating neurofibromatosis type I is once a day to three times a day, or once every two days.

8. The use according to any one of claims 1 to 5, wherein the daily dose for treating neurofibromatosis type I is selected from 20-180 mg, 20-40 mg, 20-60 mg, 20-90 mg, 20-120 mg, 20-150 mg, 40-60 mg, 40-90 mg, 40-120 mg, 40-150 mg, 40-180 mg, 60-90 mg, 60-120 mg, 60-150 mg, 60-180 mg, 90-120 mg, 90-150 mg, 90-180 mg, 120-150 mg, 120-180 mg or 150-180 mg.

9. Use of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating neurofibromatosis type I who has previously failed surgery, chemotherapy and / or radiotherapy, The pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

10. The use according to claim 9, wherein the pharmaceutical composition is a pharmaceutical composition with a single dose of 30-60 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

11. The use according to any one of claims 1 or 9, wherein the treatment of neurofibromatosis type I takes 28 days as one treatment cycle.

12. Use of a kit for preparing a medicament for treating neurofibromatosis type I who has previously received surgical treatment, chemotherapy and / or radiotherapy, the kit comprising: a) a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof; and b) instructions for use,

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