Use of an indole derivative in the treatment of head and neck tumors

Abstract

A method for treating head and neck tumors is provided, specifically relating to the use of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for treating head and neck tumors, wherein the compound of formula (I) produces good efficacy in reducing tumor growth or even eliminating tumors.

Description

Use of an indole derivative in treating head and neck tumors

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority and benefits of Chinese patent application No. 202311358021.6 filed with the State Intellectual Property Office of China on October 18, 2023, and the contents disclosed in said 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 an indole derivative in treating head and neck tumors. Specifically, it relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in treating head and neck tumors. Background Art

[0004] Evasion of apoptosis and evasion of immune detection are two key pathways in tumorigenesis. Members of the inhibitor of apoptosis (IAP) gene family play a crucial interconnected role in these two cancer-causing pathways. First, as inhibitors of apoptosis, IAPs themselves inhibit apoptosis. IAP inhibitors can suppress this anti-apoptotic effect, in turn promoting apoptosis in tumor cells. Mechanistically, IAP inhibitors bind to the N-terminal region of cIAPs, inducing autoubiquitination and subsequent proteasome-mediated degradation of these IAP proteins. This makes tumor cells more sensitive to TNF-α (tumor necrosis factor α)-mediated apoptosis. Second, IAP inhibitors have also been found to have certain immunomodulatory effects. Mechanistically, IAP inhibitors can promote the proliferation and viability of CD4+ and CD8+ T cells. Furthermore, IAP inhibitors can promote the secretion of cytokines such as IL-2 and IFN-γ by T cells and NK cells, thereby enhancing tumor immunity.

[0005] WO2019091492 discloses SMAC mimetics as IAP inhibitors, and specifically discloses a compound of formula (I) with the following structure.

[0006] Head and neck cancer is a common malignancy that poses a serious threat to patients' health and life. The most common pathological type is head and neck squamous cell carcinoma (HNSCC), while other types include head and neck adenocarcinoma, sarcoma, and lymphoma. Despite the current use of multidisciplinary approaches such as surgery, radiotherapy, and chemotherapy to treat head and neck cancer, 40% to 60% of patients still experience recurrence after treatment, necessitating an urgent need for new and more effective treatments.

[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 head and neck tumors.

[0009] In another aspect, the present disclosure provides a pharmaceutical composition for treating head and neck tumors, 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 for treating head and neck tumors.

[0011] In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof described in the present disclosure may be a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0012] In some embodiments of the present disclosure, the pharmaceutical composition contains 50-500 mg, 50-400 mg, 50-300 mg, 50-250 mg, 50-200 mg, 100-200 mg or 150-200 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 50-200 mg, 100-200 mg, or 150-200 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 50 mg, 100 mg, 150 mg, 200 mg, 250 mg or 300 mg of the 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 100 mg, 150 mg or 200 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 200 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 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.

[0018] 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.

[0019] 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.

[0020] 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.

[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, and each dose is a multiple dose.

[0022] In some embodiments of the present disclosure, the pharmaceutical composition contains a single dose of 50 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 of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I).

[0023] In some embodiments of the present disclosure, one treatment cycle is every 21 or 28 days, preferably one treatment cycle is every 21 days.

[0024] 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 21 days), comprising: a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof, with a total dose of 1050 to 4200 mg (e.g., 1050 mg, 2100 mg, 3150 mg, 4200 mg, or a range formed by any two of the values) calculated as the compound of formula (I).

[0025] 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 21 days), comprising: a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof, with a total dose of 2100 to 4200 mg (e.g., 2100 mg, 3150 mg, 4200 mg, or a range formed by any two values) calculated as the compound of formula (I).

[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 21-day treatment cycle), comprising: a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof, with a total dose of 2100 mg, 3150 mg or 4200 mg, calculated as the compound of formula (I).

[0027] 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 21 days), comprising: a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof, with a total dose of 4200 mg calculated as the compound of formula (I).

[0028] 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.

[0029] On the other hand, the present disclosure also provides a kit of pharmaceutical compositions for treating head and neck tumors, which contains the compound of formula (I) or a pharmaceutically acceptable salt thereof as described in the present disclosure.

[0030] 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 of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I).

[0031] In another aspect, the present disclosure provides use of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for treating head and neck tumors in a patient.

[0032] On the other hand, the present disclosure provides a method for treating head and neck tumors, comprising administering a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to a patient in need of treatment, for example, administering a therapeutically effective amount of the pharmaceutical composition described above of the present disclosure to an individual in need thereof.

[0033] On the other hand, the present disclosure also provides the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in preparing a drug for treating head and neck tumors in a patient, for example, the use of the pharmaceutical composition described above in preparing a drug for treating head and neck tumors.

[0034] On the other hand, the present disclosure also provides the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for treating head and neck tumors, such as the use of the pharmaceutical composition described above for treating head and neck tumors.

[0035] In some embodiments of the present disclosure, in the method or use, the compound of formula (I) or a pharmaceutically acceptable salt thereof is used as the sole active agent.

[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 above-mentioned 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.

[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 above-mentioned 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, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day in multiple doses; further, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day in multiple doses of oral solid preparations.

[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 in a daily dose of 50-200 mg, 100-200 mg or 150-200 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 100 mg; or, a daily dose of 150 mg; or, a daily dose of 200 mg.

[0040] In other 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 200 mg.

[0041] In some embodiments of the present disclosure, in the method or use, the dosage of the compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is calculated as the compound of formula (I).

[0042] 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 multiple doses, and 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 dose. 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 dose. 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 dose. 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 dose.

[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 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, 21 aliquots, 28 aliquots or more).

[0044] In some embodiments of the present disclosure, in the method or use, 21 days is a treatment cycle, and the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered daily on days 1 to 14 of each treatment cycle.

[0045] In some embodiments of the present disclosure, in the method or use, 21 days is a treatment cycle, and the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day on days 1 to 14 of each treatment cycle.

[0046] In some embodiments of the present disclosure, in the methods or uses, 21 days is a treatment cycle, and the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day continuously on days 1 to 14 of each treatment cycle, and each dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a multiple dose, and the multiple dose is 100 mg, 150 mg or 200 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof; further, the multiple dose consists of a single dose of 50 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0047] In some embodiments of the present disclosure, in the methods or uses, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is packaged in a kit, which contains the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days or 28 days, or a dose of a range consisting of any of the foregoing values ​​as endpoints. In some embodiments of the present disclosure, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is packaged in a kit, which contains a 1-day, 2-day, 3-day, 4-day, 5-day, 6-day, 7-day, 14-day, 21-day, or 28-day dose, or a dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof with any of the foregoing values ​​as endpoints.

[0048] In some embodiments of the present disclosure, in the method or use, 21 days is a treatment cycle, and the total dose of the pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable salt administered continuously daily on days 1 to 14 of each treatment cycle is 1050 to 4200 mg. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable salt is selected from 1050 mg, 2100 mg, 3150 mg, 4200 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 its pharmaceutically acceptable salt is selected from 2100 mg, 3150 mg, 4200 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 its pharmaceutically acceptable salt is selected from 2100 mg, 3150 mg or 4200 mg. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable salt is selected from 4200 mg.

[0049] In some embodiments of the present disclosure, in the method or use, 21 days is a treatment cycle, and the total dose of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof administered once daily continuously from day 1 to day 14 of each treatment cycle is 1050 mg, 2100 mg, 3150 mg, 4200 mg or a range formed by any two of the values.

[0050] In some embodiments of the present disclosure, in the method or use, 21 days is a treatment cycle, and the total dose of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof administered once daily continuously from day 1 to day 14 of each treatment cycle is 2100 mg, 3150 mg, 4200 mg or a range formed by any two of the values.

[0051] In some embodiments of the present disclosure, in the method or use, 21 days is a treatment cycle, and the total dose of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof administered once daily continuously on days 1 to 14 of each treatment cycle is 2100 mg, 3150 mg or 4200 mg.

[0052] In some embodiments of the present disclosure, in the method or use, 21 days is a treatment cycle, and the total dose of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof administered once daily continuously on days 1 to 14 of each treatment cycle is 4200 mg.

[0053] In the disclosed regimens, the above-described treatment cycles are repeated as long as the disease remains under control and the dosing regimen is clinically tolerated.

[0054] On the other hand, the present disclosure provides a method for treating head and neck tumors, comprising administering a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to a patient in need of treatment, accompanied by chemoradiotherapy, for example, administering a therapeutically effective amount of the pharmaceutical composition described above of the present disclosure to an individual in need, accompanied by chemoradiotherapy.

[0055] On the other hand, the present disclosure also provides the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof as described above, or a pharmaceutical composition thereof, in conjunction with chemoradiotherapy in the preparation of a medicament for treating head and neck tumors in a patient, for example, the use of the pharmaceutical composition described above in the preparation of a medicament for treating head and neck tumors.

[0056] On the other hand, the present disclosure also provides the use of the compound of formula (I) or its pharmaceutically acceptable salt as described above, or its pharmaceutical composition for treating head and neck tumors concomitantly with chemoradiotherapy, such as the use of the pharmaceutical composition described above for treating head and neck tumors.

[0057] In some embodiments of the present disclosure, in the above methods or uses, the compound of formula (I) or a pharmaceutically acceptable salt thereof and the chemoradiotherapy are each in the form of a pharmaceutical composition and can be administered simultaneously, separately, concurrently, sequentially or intermittently.

[0058] In some embodiments of the present disclosure, in the above methods or uses, the compound of formula (I) or a pharmaceutically acceptable salt thereof and chemotherapy are each in the form of a pharmaceutical composition and can be administered simultaneously, separately, concurrently, sequentially or intermittently.

[0059] In some embodiments of the present disclosure, in the above methods or uses, the compound of formula (I) or a pharmaceutically acceptable salt thereof and chemoradiotherapy have the same or different treatment cycles, respectively. In some schemes, the compound of formula (I) or a pharmaceutically acceptable salt thereof and chemoradiotherapy have the same treatment cycle, respectively. In some schemes, the compound of formula (I) or a pharmaceutically acceptable salt thereof and chemotherapy have the same treatment cycle, respectively, and the treatment cycle is 1 treatment cycle every 3 weeks. In some schemes, the radiotherapy starts on day 1, with conventional fractionation, and is usually completed in 6 to 7 weeks.

[0060] In some embodiments of the present disclosure, in the above-mentioned methods or uses of concomitant chemoradiotherapy, the administration mode of the compound of formula (I) or its pharmaceutically acceptable salt or its pharmaceutical composition is as described above. For example, the method of treating head and neck tumors with the compound of formula (I) or its pharmaceutically acceptable salt or its pharmaceutical composition described above, or the use of the compound of formula (I) or its pharmaceutically acceptable salt or its pharmaceutical composition described above in the preparation of a drug for treating head and neck tumors in a patient, or the use of the compound of formula (I) or its pharmaceutically acceptable salt or its pharmaceutical composition described above for treating head and neck tumors.

[0061] In some embodiments of the present disclosure, in the above methods or uses, the chemoradiotherapy refers to chemotherapy drug therapy and radiation therapy.

[0062] In some embodiments of the present disclosure, in the above methods or uses, the chemotherapy drug is selected from one or a combination of two or more drugs selected from cisplatin, carboplatin, docetaxel, paclitaxel, 5-fluorouracil, gemcitabine, capecitabine, and methotrexate; preferably, one or a combination of two or more drugs selected from cisplatin, carboplatin, paclitaxel, and 5-fluorouracil; further preferably, cisplatin, carboplatin, or paclitaxel; and even more preferably, cisplatin.

[0063] In some embodiments of the present disclosure, in the above methods or uses, for subjects who can tolerate the chemotherapy, the cumulative dose of the chemotherapy drug is 200 mg / m 2 above.

[0064] In some embodiments of the present disclosure, in the above methods or uses, the radiotherapy dose is 66 to 75 Gy, preferably 66 to 70 Gy.

[0065] In some embodiments of the present disclosure, in the above-mentioned methods or uses, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof continues to be administered alone after the end of chemoradiotherapy, and the administration method of the compound of formula (I) or a pharmaceutically acceptable salt thereof or the pharmaceutical composition thereof is as described above.

[0066] In some embodiments of the present disclosure, in the above-mentioned methods or uses, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered for a total of 7 cycles, and the administration method of the compound of formula (I) or a pharmaceutically acceptable salt thereof or the pharmaceutical composition thereof is as described above.

[0067] In some embodiments of the present disclosure, in the above-mentioned methods or uses, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered concurrently with chemoradiotherapy for a total of 2-3 cycles, and is continued to be administered alone for 4-5 cycles after the end of chemoradiotherapy. The administration method of the compound of formula (I) or a pharmaceutically acceptable salt thereof or the pharmaceutical composition thereof is as described above.

[0068] In some embodiments of the present disclosure, 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.

[0069] In some embodiments of the present disclosure, the dosage and administration cycle of chemotherapy drugs and radiotherapy can be adjusted according to the subject's tolerance and adverse reaction level, and can be further determined in combination with the commonly used treatment options in the head and neck tumor diagnosis and treatment guidelines.

[0070] In some embodiments of the present disclosure, the head and neck tumor is a locally advanced head and neck tumor.

[0071] In some embodiments of the present disclosure, the head and neck tumor is a locally advanced head and neck tumor that is treated non-surgically.

[0072] In some embodiments of the present disclosure, the head and neck tumor is a locally advanced head and neck tumor that is confirmed by pathological histology and is a candidate for non-surgical treatment.

[0073] In some embodiments of the present disclosure, the head and neck tumors include but are not limited to squamous cell carcinoma of the head and neck (SCCHN) and / or head and neck glandular tumors.

[0074] In some specific embodiments of the present disclosure, the head and neck tumor is locally advanced head and neck squamous cell carcinoma that is treated non-surgically.

[0075] In some specific embodiments of the present disclosure, the head and neck tumor is a locally advanced head and neck glandular tumor that is treated non-surgically.

[0076] In some specific embodiments of the present disclosure, the head and neck squamous cell carcinoma does not include nasopharyngeal carcinoma.

[0077] In some specific embodiments of the present disclosure, the head and neck glandular tumor does not include thyroid cancer.

[0078] In some specific embodiments of the present disclosure, the head and neck glandular tumor is selected from the group consisting of head and neck adenocarcinoma and adenoid cystic carcinoma.

[0079] In some embodiments of the present disclosure, the primary site of head and neck squamous cell carcinoma is selected from the oropharynx, oral cavity, hypopharynx, or larynx.

[0080] In some embodiments of the present disclosure, the head and neck squamous cell carcinoma is selected from hypopharyngeal cancer, tongue cancer, oral cancer, oropharyngeal cancer, or laryngeal cancer.

[0081] In some embodiments of the present disclosure, the head and neck squamous cell carcinoma is selected from hypopharyngeal cancer, tongue cancer, oral cancer, or oropharyngeal cancer.

[0082] In some embodiments of the present disclosure, the head and neck glandular tumor is adenoid cystic carcinoma.

[0083] In some embodiments of the present disclosure, the head and neck glandular tumor is adenoid cystic carcinoma of the base of the tongue.

[0084] In some embodiments of the present disclosure, the TNM stage of the head and neck tumor is stage IVA or stage IVB.

[0085] In some embodiments of the present disclosure, the stage IVA includes T being T1-3, N being N2, and M being M0; or the stage IVA includes T being T4a, N being N0-2, and M being M0.

[0086] In some embodiments of the present disclosure, the stage IVB includes T being T4b, N being any N, and M being M0; or the stage IVB includes T being any T, N being N3, and M being M0.

[0087] In some embodiments of the present disclosure, the N2 includes N2a, N2b or N2c.

[0088] In some embodiments of the present disclosure, the N3 includes N3a or N3b.

[0089] In some embodiments of the present disclosure, the head and neck squamous cell carcinoma has a TNM stage of IVA or IVB.

[0090] In some embodiments of the present disclosure, the head and neck glandular tumor has a TNM stage of IVA or IVB.

[0091] In some embodiments of the present disclosure, the head and neck cancer patient is a patient with locally advanced head and neck cancer who is receiving non-surgical treatment and concurrent cisplatin-based chemoradiotherapy.

[0092] In some embodiments of the present disclosure, the head and neck cancer patient has at least one measurable lesion (RECIST 1.1) before radiotherapy.

[0093] In some embodiments of the present disclosure, the head and neck cancer patient has not previously received any systemic treatment for locally advanced head and neck cancer or radiation therapy for target lesions.

[0094] In other embodiments of the present disclosure, the head and neck tumor patient may have undergone a single surgical treatment for local recurrence and meet any one or more of the following conditions: (1) has undergone only a single surgical treatment and has been disease-free for more than 6 months after the surgery; (2) the current recurrent lesion stage is IVA or IVB; (3) has undergone only one surgical treatment.

[0095] The efficacy evaluation criteria for head and neck cancer patients disclosed in the present invention are based on the RECIST 1.1 standard to confirm the efficacy.

[0096] The efficacy evaluation of the disclosed head and neck cancer patients is performed every 2 cycles, and after 8 cycles, it is extended to every 4 cycles.

[0097] 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.

[0098] 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.

[0099] 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.

[0100] Compound of formula (I) or a pharmaceutically acceptable salt thereof

[0101] 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.

[0102] 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.

[0103] 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.

[0104] 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).

[0105] Pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof

[0106] 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 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 of the compound of formula (I) or a pharmaceutically acceptable salt thereof calculated as the compound of formula (I).

[0107] The method of administration can be determined comprehensively based on the activity, toxicity and patient tolerance of the drug.

[0108] 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.

[0109] In some embodiments of the present disclosure, the pharmaceutical composition is a solid pharmaceutical combination.

[0110] 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.

[0111] In some embodiments of the present disclosure, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a tablet containing the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0112] 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.

[0113] 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 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.

[0114] Technical Effects

[0115] Generally, use of the disclosed compounds of formula (I) will facilitate:

[0116] (1) Produce better therapeutic effects in reducing tumor growth or even eliminating tumors;

[0117] (2) provide treatments that are well tolerated by patients with few adverse effects and / or complications;

[0118] (3) provide a good objective response rate (ORR) among treated patients;

[0119] (4) provide a longer survival (e.g., 18-month disease-free survival, progression-free survival, or overall survival) among treated patients;

[0120] (5) provide longer survival (e.g., median survival, progression-free survival, or overall survival) for treated patients compared to standard chemotherapy;

[0121] (6) Provide a longer duration of disease remission (DOR).

[0122] The "clinical benefits" of the compounds of formula (I) disclosed herein include, but are not limited to: a higher 18-month disease-free survival rate (18m-DFS) of clinical patients, prolonged overall survival (OS), a higher objective response rate (ORR), a higher disease control rate (DCR), a longer duration of disease remission (DOR), a better 18-month regional control rate, a reduction in the number and / or severity of adverse reactions, a decrease in distant metastasis rate and local control rate, etc.

[0123] Definition and Description

[0124] 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.

[0125] 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 feline, a canine, etc., preferably a human. In some embodiments of the present disclosure, the patient or individual is a patient who has not previously received systemic treatment for locally advanced head and neck cancer or radiation therapy for target lesions.

[0126] 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.

[0127] The term "pharmaceutically acceptable salt" includes, but is not limited to, acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or acid addition salts formed with organic acids such as acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, p-toluenesulfonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, dodecylsulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and the like.

[0128] 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.

[0129] 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.

[0130] 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.

[0131] As used herein, "dose-limiting toxicity" (DLT) refers to all toxicities graded according to the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. If the investigator judges any of the following toxicities to be related to the study drug in cycle 1, the event should be considered a DLT:

[0132] (1) Non-hematological toxicity:

[0133] 1) Toxicity of grade 4 or above;

[0134] 2) Grade 3 toxicity, regardless of duration, excluding the following: ① Grade 3 diarrhea, nausea, and vomiting that improves to Grade 2 or below within 3 days after supportive treatment; ② Grade 3 fatigue lasting less than 7 days; ③ Transient Grade 3 hypotension (based on the mechanism of action of this type of drug, it may cause cytokine elevation and subsequent hypotension, and Grade 3 hypotension can be relieved by treatment with ≤3L of intravenous fluid infusion during the 8-hour observation period after administration).

[0135] (2) Hematological toxicity:

[0136] 1) Grade 4 neutropenia lasting for more than 7 days; 2) Grade 3 febrile neutropenia (ANC <1000 / mm3, body temperature exceeds 38.3℃ for one time or body temperature remains ≥38℃ for more than one hour) or Grade 4 febrile neutropenia; 3) Grade 3 thrombocytopenia with bleeding; 4) Grade 4 thrombocytopenia; 5) Other hematological toxicities of Grade 4 or above.

[0137] (3) Others

[0138] 1) Any toxic reaction of grade ≥2 that causes interruption of study drug for more than 14 days.

[0139] 2) Any grade of toxicity that the investigator and sponsor determine should result in discontinuation of the study.

[0140] The "maximum tolerated dose" (MTD) used in this article refers to the highest dose in which less than 33% of subjects experience DLT in the first cycle. In the first cycle of a dose-escalation trial, if any of the following situations occur in a dose group: (1) 2 or more of the first 3 subjects enrolled in the dose group experience DLT; (2) only 1 of the 3 subjects in the dose group experiences DLT, and 1 or more of the 3 subjects enrolled in the dose group still experience DLT. The previous dose is considered the maximum tolerated dose (MTD).

[0141] 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.

[0142] 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.

[0143] 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.

[0144] The term "daily dose" refers to the dose administered to a patient daily.

[0145] 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.

[0146] The term "multiple doses" consists of a plurality of single doses. As used herein, "combination", "combined" 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.

[0147] 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.

[0148] 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.

[0149] 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.

[0150] 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.

[0151] 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.

[0152] 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

[0153] 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.

[0154] Experimental Example 1 Animal in vivo test

[0155] 1.1 Pharmacodynamic evaluation of the compound of formula (I) in a Cal27 human tongue squamous cell carcinoma subcutaneous transplant tumor model in nude mice

[0156] Cal27 cells were subcutaneously inoculated in the right axilla of SPF male nude mice (source: Changzhou Cavens Laboratory Animal Co., Ltd.) at a rate of 5 × 10 6 When the average tumor volume reaches 100mm 3 When about 30 seconds, divide the animals into groups.

[0157] The day of grouping was designated Day 0. Starting from Day 0, drugs were administered by gavage daily. Tumor volume was measured 2-3 times per week, and mice were weighed and recorded. The general condition of the mice was observed and recorded daily. At the end of the experiment, tumors were removed, weighed, and photographed.

[0158] The detection indicators and calculation formulas are as follows:

[0159] Tumor volume, TV (mm 3 )=1 / 2×(a×b 2 ), where a is the long diameter of the tumor and b is the short diameter of the tumor.

[0160] Relative tumor volume, RTV = TV t / TV0; TV0 is the tumor volume on day 0, TV t is the tumor volume at each measurement.

[0161] Relative tumor growth rate, T / C (%) = T RTV / C RTV ×100%; where T RTV RTV for the treatment group; C RTV The vehicle control group was RTV.

[0162] Tumor growth inhibition rate, TGI (%) = (1-TW / TW0) × 100%; wherein, TW is the tumor weight of the treatment group, and TW0 is the tumor weight of the vehicle control group.

[0163] Body weight change rate, WCR (%) = (Wt t -Wt0) / Wt0×100%; where Wt0 is the weight of mice on day 0, Wt t is the weight of the mice at each measurement.

[0164] The test results show that the compound of formula (I) can effectively inhibit the tumor growth of Cal27 human tongue squamous cell carcinoma nude mice, showing good drug efficacy.

[0165] 1.2 Pharmacodynamic evaluation of the compound of formula (I) in the FaDu human pharyngeal squamous cell carcinoma subcutaneous transplant tumor model in nude mice

[0166] FaDu cells were inoculated subcutaneously in the right axilla of SPF male nude mice (source: Changzhou Cavens Laboratory Animal Co., Ltd.) at a rate of 5 × 10 6 When the average tumor volume reaches 100mm 3 When about 30 seconds, divide the animals into groups.

[0167] The day of grouping was designated Day 0. Starting from Day 0, drugs were administered by gavage daily. Tumor volume was measured 2-3 times per week, and mice were weighed and recorded. The general condition of the mice was observed and recorded daily. At the end of the experiment, tumors were removed, weighed, and photographed.

[0168] The detection indicators and calculation formulas are as follows:

[0169] Tumor volume, TV (mm 3 )=1 / 2×(a×b 2 ), where a is the long diameter of the tumor and b is the short diameter of the tumor.

[0170] Relative tumor volume, RTV = TV t / TV0; TV0 is the tumor volume on day 0, TV t is the tumor volume at each measurement.

[0171] Relative tumor growth rate, T / C (%) = T RTV / C RTV ×100%; where T RTV RTV for the treatment group; C RTV The vehicle control group was RTV.

[0172] Tumor growth inhibition rate, TGI (%) = (1-TW / TW0) × 100%; wherein, TW is the tumor weight of the treatment group, and TW0 is the tumor weight of the vehicle control group.

[0173] Body weight change rate, WCR (%) = (Wt t -Wt0) / Wt0×100%; where Wt0 is the weight of mice on day 0, Wt t is the weight of the mice at each measurement.

[0174] The test results show that the compound of formula (I) can effectively inhibit the tumor growth of nude mice bearing FaDu human pharyngeal squamous cell carcinoma, showing good drug efficacy.

[0175] 1.3 Pharmacodynamic evaluation of the compound of formula (I) in the SCC25 human oral squamous cell carcinoma / human tongue squamous cell carcinoma nude mouse subcutaneous transplant tumor model

[0176] SCC25 cells were inoculated subcutaneously in the right axilla of SPF male nude mice (source: Changzhou Cavens Laboratory Animal Co., Ltd.) at a rate of 5 × 10 6 When the average tumor volume reaches 70mm 3 When about 30 seconds, divide the animals into groups.

[0177] The day of grouping was designated Day 0. Starting from Day 0, drugs were administered by gavage daily. Tumor volume was measured 2-3 times per week, and mice were weighed and recorded. The general condition of the mice was observed and recorded daily. At the end of the experiment, tumors were removed, weighed, and photographed.

[0178] The detection indicators and calculation formulas are as follows:

[0179] Tumor volume, TV (mm3 )=1 / 2×(a×b 2 ), where a is the long diameter of the tumor and b is the short diameter of the tumor.

[0180] Relative tumor volume, RTV = TV t / TV0; TV0 is the tumor volume on day 0, TV t is the tumor volume at each measurement.

[0181] Relative tumor growth rate, T / C (%) = T RTV / C RTV ×100%; where T RTV RTV for the treatment group; C RTV The vehicle control group was RTV.

[0182] Tumor growth inhibition rate, TGI (%) = (1-TW / TW0) × 100%; wherein, TW is the tumor weight of the treatment group, and TW0 is the tumor weight of the vehicle control group.

[0183] Body weight change rate, WCR (%) = (Wt t -Wt0) / Wt0×100%; where Wt0 is the weight of mice on day 0, Wt t is the weight of the mice at each measurement.

[0184] The test results show that the compound of formula (I) can effectively inhibit the tumor growth of SCC25 human oral squamous cell carcinoma / human tongue squamous cell carcinoma nude mice, showing good drug efficacy.

[0185] Experimental Example 2 Clinical Trial

[0186] This study was divided into phase Ib and phase II.

[0187] The Phase Ib dose-escalation phase will enroll patients with locally advanced head and neck cancer who are undergoing non-surgical treatment to evaluate the preliminary efficacy, safety and tolerability of the tablets of the compound of formula (I) in subjects with non-surgical locally advanced head and neck cancer who are undergoing concurrent chemoradiotherapy, and to determine the recommended dose for Phase II.

[0188] Phase II is a parallel controlled study. Subjects with locally advanced head and neck squamous cell carcinoma who meet the inclusion criteria after screening will be randomly divided into the experimental group (cohort 1) and the control group (cohort 2); subjects with locally advanced head and neck glandular tumors who meet the inclusion criteria after screening will enter the exploratory group (cohort 3). The details are as follows:

[0189] (1) Experimental group (cohort 1): received compound of formula (I) tablets + concurrent platinum-containing chemoradiotherapy.

[0190] (2) Control group (cohort 2): concurrent platinum-containing chemoradiotherapy.

[0191] (3) Exploratory group (cohort three): received compound of formula (I) tablets + concurrent platinum-containing chemoradiotherapy.

[0192] A Phase II study was conducted to evaluate the efficacy and safety of the compound of formula (I) tablets in the treatment of patients with locally advanced head and neck cancer undergoing concurrent chemoradiotherapy. 1.1 Inclusion Criteria:

[0193] Only those who meet all of the following inclusion criteria can be enrolled in this trial:

[0194] 1) Age: 18-70 years old (at the time of signing the informed consent form), gender is not limited;

[0195] 2) Locally advanced head and neck tumors diagnosed by histopathological examination and treated non-surgically;

[0196] 3) Patients had at least one measurable lesion (RECIST 1.1) before radiotherapy;

[0197] 4) No previous systemic treatment for locally advanced head and neck cancer or radiotherapy for target lesions;

[0198] 5) ECOG score: 0–1;

[0199] 6) The expected survival period is more than 3 months;

[0200] 7) Normal function of major organs;

[0201] 8) Female patients of childbearing age must have a negative serum HCG test within 7 days before study enrollment and must not be breastfeeding. Patients must agree to use contraceptive measures during the study and within 6 months after the end of the study period;

[0202] 9) The subjects voluntarily participated in this study, signed the informed consent form, and showed good compliance.

[0203] 1.2 Trial Drugs

[0204] The basic information of the trial drugs is shown in Table 1.

[0205] Table 1 Basic information of experimental drugs

[0206] 1.3 Dosage regimen

[0207] a) Tablets of the compound of formula (I): 100 mg, 150 mg or 200 mg; orally administered on an empty stomach, once a day, continuously administered from d1 to d14, and repeated every 3 weeks.

[0208] b) Cisplatin: 80–100 mg / m² each time 2 , starting from the first day, each 3 weeks is a cycle, for a total of 3 cycles.

[0209] c) Radiotherapy: The recommended radiotherapy dose is 66-70 Gy. The minimum technical standard for radiotherapy is intensity-modulated radiotherapy (IMRT). Radiotherapy starts on the first day, with conventional fractionation, and is completed in 6-7 weeks.

[0210] 1.4 Evaluation Criteria

[0211] Effectiveness evaluation criteria: RECIST 1.1 criteria were used to determine the disease status.

[0212] 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.

[0213] Phase 1.5Ib trial results

[0214] Safety: Mainly grade 1 to 2, controllable after symptomatic treatment, no DLT events, and overall safety is good.

[0215] Efficacy: In the Phase Ib trial, a total of 9 evaluable patients were enrolled, of whom 2 achieved complete remission (CR) and 7 achieved partial remission (PR); the calculated objective response rate (ORR) was 100% (9 / 9) and the disease control rate (DCR) was 100% (9 / 9). The results demonstrated that the compound of formula (I) of the present disclosure, combined with concurrent platinum-containing chemoradiotherapy, demonstrated promising clinical benefits in patients with locally advanced head and neck cancer who were not candidates for surgical treatment.

[0216] The results of the efficacy evaluation of representative cases in Phase Ib are shown in Table 2:

[0217] Table 2 Tumor response evaluation results

[0218] The test results show that the recommended dose of the compound of formula (I), its pharmaceutically acceptable salt or its pharmaceutical composition in the Phase II clinical trial is 200 mg based on the compound of formula (I).

[0219] Phase II trial results

[0220] Efficacy: A total of 37 patients were enrolled in the Phase II trial (Cohort 1), with 3 complete responses (CR), 30 partial responses (PR), and 4 stable disease (SD); the calculated objective response rate (ORR) was 89.2% (33 / 37). The results showed that the compound of formula (I) of the present disclosure, combined with concurrent platinum-containing chemoradiotherapy, showed good clinical benefits in patients with locally advanced head and neck cancer who were not surgically treated.

[0221] 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 use in treating head and neck tumors, 2. A pharmaceutical composition for treating head and neck tumors, comprising the compound of formula (I) as claimed in claim 1 or a pharmaceutically acceptable salt thereof.

3. The pharmaceutical composition according to claim 2, characterized in that It contains 50-500 mg, 50-400 mg, 50-300 mg, 50-250 mg, 50-200 mg, 100-200 mg or 150-200 mg of the compound of formula (I) or its pharmaceutically acceptable salt; or, contains 50-200 mg, 100-200 mg or 150-200 mg of the compound of formula (I) or its pharmaceutically acceptable salt; or, contains 100 mg, 150 mg or 200 mg of the compound of formula (I) or its pharmaceutically acceptable salt.

4. The pharmaceutical composition according to claim 2 or 3, characterized in that: The compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day, and each dose is a single dose or multiple doses; or each dose is multiple doses.

5. A method for treating head and neck tumors, comprising administering to a patient a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1, or a pharmaceutical composition as claimed in claim 2 or 3.

6. Use of the compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, or the pharmaceutical composition according to claim 2 or 3, in the preparation of a medicament for treating head and neck tumors in a patient.

7. The method according to claim 5 or the use according to claim 6, wherein 21 days is one treatment cycle, and the pharmaceutical composition according to claim 2 or 3 is administered daily on the 1st to 14th day of each treatment cycle.

8. The method according to claim 5 or the use according to claim 6, further comprising concomitant chemoradiotherapy.

9. The method or use of claim 8, wherein the chemoradiotherapy comprises chemotherapeutic drug therapy and radiotherapy therapy.

10. The method or use according to claim 9, wherein the chemotherapy drug is selected from one or a combination of two or more of cisplatin, carboplatin, docetaxel, paclitaxel, 5-fluorouracil, gemcitabine, capecitabine, and methotrexate; or, selected from one or a combination of two or more of cisplatin, carboplatin, paclitaxel, and 5-fluorouracil; or, selected from cisplatin, carboplatin, or paclitaxel; or, selected from cisplatin.

11. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, the pharmaceutical composition according to claim 2 or 3, or the method or use according to any one of claims 5 to 10, wherein the head and neck tumor is a locally advanced head and neck tumor; optionally, the head and neck tumor is selected from head and neck squamous cell carcinoma or head and neck glandular tumor; or, the head and neck tumor is a locally advanced head and neck squamous cell carcinoma that is treated non-surgically; or, the head and neck tumor is selected from hypopharyngeal cancer, tongue cancer, oral cancer, oropharyngeal cancer or laryngeal cancer.

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