Use of heteroaryloxynaphthalene compounds

Abstract

The present invention provides a use of a heteroaryloxynaphthalene compound, specifically, compound A or a medicinal salt thereof, in the manufacture of a medicament for treating tumor-related diseases. Compound A or a medicinal salt thereof exhibits good therapeutic effect on tumors and good tolerability, and thus has clinical potential in tumor treatment. [Formula 1] JPEG2025528490000021.jpg47169

Description

[Technical Field]

[0001] This application claims priority from a prior patent application bearing patent application number 202211062094.6 and entitled "Use of Heteroaryloxynaphthalene Compounds," filed with the State Intellectual Property Administration of China on August 31, 2022, the entire text of which is incorporated herein by reference.

[0002] The present invention relates to the field of medicine, and more particularly to the use of a multi-target protein kinase inhibitor in the manufacture of a medicament for treating and / or preventing tumors, in particular in the manufacture of a medicament for treating squamous cell carcinoma, esophageal cancer and / or gastroesophageal junction cancer. [Background technology]

[0003] Squamous cell carcinoma (SCC), also known as epidermoid carcinoma, includes various types of cancer caused by squamous cells, which form on the surface of the skin, the lining of hollow organs in the body, and the lining of the respiratory and digestive tracts, including squamous cell carcinomas of the skin, head and neck, digestive tract (e.g., esophagus), and respiratory tract (e.g., lung), depending on the body site.

[0004] Esophageal cancer (or esophageal cancer) is one of the most common malignant tumors worldwide, ranking eighth in incidence and sixth in mortality among cancer types. Compared with the general population, patients with esophageal cancer have an increased risk of developing multiple primary malignant tumors, with an incidence rate ranging from 9.5% to 21.9%. Histologically, esophageal cancer is primarily classified into two types: squamous cell carcinoma (esophageal squamous cell carcinoma) and adenocarcinoma (esophageal adenocarcinoma).

[0005] The clinical symptoms of early esophageal cancer are unclear and difficult to detect. Many esophageal cancer patients are already in the locally advanced stage or have distant metastases at the time of definitive diagnosis. Although surgical treatment, endoscopic treatment, radiation therapy, chemotherapy, and immunotherapy are used clinically, patients still face the problem of poor prognosis, with the 5-year overall survival rate being only 10-20%.

[0006] According to the Chinese Society of Clinical Oncology (CSCO) Esophageal Cancer Guidelines (2022 edition), first-line treatment for advanced esophageal cancer is primarily chemotherapy combined with immunotherapy or combination chemotherapy for squamous cell carcinoma and HER-2-negative adenocarcinoma (PS=0-2). Second-line and higher-level treatments recommended for PS=0-2 patients include single-agent chemotherapy and single-agent immunotherapy (Class I). Currently, there are no commercially available small molecule targeted drugs for the treatment of esophageal cancer. Furthermore, while platinum and fluorouracil-containing drugs are commonly recommended for the treatment of advanced esophageal cancer, they are associated with cytotoxic side effects. Numerous studies have shown that the development of esophageal cancer-associated multiple primary malignancies is significantly correlated with genetic and iatrogenic factors (e.g., radiation therapy or chemotherapy). While radiation therapy and chemotherapy, commonly used in the treatment of esophageal cancer, may increase patient survival rates, they may also increase the risk of developing associated multiple primary malignancies. Therefore, for patients with esophageal cancer who have failed existing treatments, there is still no standard treatment regimen for subsequent lines of treatment, and the therapeutic effect of treatment methods with the same or similar mechanism of action is difficult to guarantee. After patients have progressed through frontline treatment, there is an urgent need for effective therapeutic drugs to resolve clinically unmet needs.

[0007] CN108699030A discloses Compound A (corresponding to Compound S10), a compound having inhibitory activity against fibroblast growth factor receptor (FGFR) and vascular endothelial growth factor receptor (KDR or VEGFR2). However, there are currently no relevant research reports that show that it can be used to treat squamous cell carcinoma, gastrointestinal squamous cell carcinoma, esophageal cancer, gastroesophageal junction cancer, etc.

[0008] [ka] Summary of the Invention

[0009] The technical problem to be solved by the present application is to provide a use of compound A or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a tumor, in particular squamous cell carcinoma, gastrointestinal squamous cell carcinoma, esophageal cancer or gastroesophageal junction cancer.

[0010] Specifically, in a first aspect, the present application provides a use of compound A or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a tumor, wherein the tumor is esophageal cancer or gastroesophageal junction cancer;

[0011] [ka]

[0012] .

[0013] In some embodiments of the first aspect of the present application, the gastroesophageal junction cancer is gastroesophageal junction squamous cell carcinoma or gastroesophageal junction adenocarcinoma, preferably gastroesophageal junction squamous cell carcinoma.

[0014] In some embodiments of the first aspect of the present application, the esophageal cancer is esophageal squamous cell carcinoma or esophageal adenocarcinoma, preferably esophageal squamous cell carcinoma.

[0015] In some embodiments of the first aspect of the present application, the tumor is a tumor associated with genetic abnormalities and / or abnormalities in protein expression of FGFR and / or VEGFR.

[0016] In some embodiments of the first aspect of the present application, the tumor is a tumor with genetic abnormalities and / or abnormal protein expression of one, two, or three of FGFR, VEGFR, and colony-stimulating factor 1 receptor (CSF1R). Preferably, the tumor is a tumor with genetic mutations of one, two, or three of FGFR, VEGFR, and CSF1R.

[0017] In some embodiments of the first aspect of the present application, the tumor is a locally advanced tumor or a metastatic tumor, preferably a locally advanced tumor that is not surgically resectable or a metastatic tumor that is not surgically resectable.

[0018] In some embodiments of the first aspect of the present application, the tumor is a tumor for which a previous treatment has failed.

[0019] In some embodiments of the first aspect of the present application, the tumor is a tumor for which systemic drug treatment has failed.

[0020] In some embodiments of the first aspect of the present application, the tumor is a tumor that has failed first-line treatment.

[0021] In some embodiments of the first aspect of the present application, the tumor is a tumor that has failed second line therapy.

[0022] In some embodiments of the first aspect of the present application, the tumor is a tumor that has failed a subsequent line of treatment.

[0023] In some embodiments of the first aspect of the present application, the tumor has failed treatment with one, two, three or more of an immunotherapy, a chemotherapy, a radiation therapy, a biological therapy, a traditional Chinese medicine therapy, or a small molecule targeted drug.

[0024] In some embodiments of the first aspect of the present application, the tumor is a tumor that has failed treatment with radiation therapy, immunotherapy, or chemotherapy. In some embodiments of the first aspect of the present application, the tumor is a tumor that has failed treatment with radiation therapy and immunotherapy. In some embodiments of the first aspect of the present application, the tumor is a tumor that has failed treatment with radiation therapy and chemotherapy. In some embodiments of the first aspect of the present application, the tumor is a tumor that has failed treatment with chemotherapy and immunotherapy. In some embodiments of the first aspect of the present application, the tumor is a tumor that has failed treatment with chemotherapy, immunotherapy, and radiation.

[0025] In some embodiments of the first aspect of the present application, the esophageal squamous cell carcinoma is esophageal squamous cell carcinoma associated with genetic abnormalities or abnormal protein expression of FGFR and / or VEGFR.

[0026] In some embodiments of the first aspect of the present application, the esophageal squamous cell carcinoma is esophageal squamous cell carcinoma accompanied by genetic abnormalities and / or abnormal protein expression of one, two, or three of FGFR, VEGFR, and colony-stimulating factor 1 receptor (CSF1R). Preferably, the esophageal squamous cell carcinoma is esophageal squamous cell carcinoma accompanied by genetic mutations of one, two, or three of FGFR, VEGFR, and CSF1R.

[0027] In some embodiments of the first aspect of the present application, the esophageal squamous cell carcinoma is locally advanced esophageal squamous cell carcinoma or metastatic (e.g., stage IV) esophageal squamous cell carcinoma, preferably unresectable locally advanced esophageal squamous cell carcinoma or unresectable metastatic esophageal squamous cell carcinoma.

[0028] In some embodiments of the first aspect of the present application, the esophageal squamous cell carcinoma is esophageal squamous cell carcinoma for which prior treatment has failed.

[0029] In some embodiments of the first aspect of the present application, the esophageal squamous cell carcinoma is esophageal squamous cell carcinoma for which systemic drug treatment has failed.

[0030] In some embodiments of the first aspect of the present application, the esophageal squamous cell carcinoma is esophageal squamous cell carcinoma that has failed first-line treatment.

[0031] In some embodiments of the first aspect of the present application, the esophageal squamous cell carcinoma is esophageal squamous cell carcinoma that has failed second-line treatment.

[0032] In some embodiments of the first aspect of the present application, the esophageal squamous cell carcinoma is esophageal squamous cell carcinoma that has failed subsequent lines of therapy.

[0033] In some embodiments of the first aspect of the present application, the esophageal squamous cell carcinoma is esophageal squamous cell carcinoma that has failed treatment with one, two, three or more of immunotherapy, chemotherapy, radiation therapy, biological therapy, traditional Chinese medicine, or small molecule targeted drugs. In some embodiments of the first aspect of the present application, the esophageal squamous cell carcinoma is esophageal squamous cell carcinoma that has failed treatment with radiation therapy, immunotherapy, or chemotherapy. In some embodiments of the first aspect of the present application, the esophageal squamous cell carcinoma is esophageal squamous cell carcinoma that has failed treatment with radiation therapy and immunotherapy. In some embodiments of the first aspect of the present application, the esophageal squamous cell carcinoma is esophageal squamous cell carcinoma that has failed treatment with radiation therapy and chemotherapy. In some embodiments of the first aspect of the present application, the esophageal squamous cell carcinoma is esophageal squamous cell carcinoma that has failed treatment with chemotherapy and immunotherapy. In some embodiments of the first aspect of the present application, the esophageal squamous cell carcinoma is esophageal squamous cell carcinoma that has failed treatment with chemotherapy, immunotherapy, and radiation therapy.

[0034] In some embodiments of the first aspect of the present application, the chemotherapeutic agent is selected from a cytotoxic agent, an antimetabolite agent, an antibiotic agent, an alkaloid agent, a DNA topoisomerase inhibitor chemotherapeutic agent, an anti-microtubule chemotherapeutic agent, a platinum-based chemotherapeutic agent, and a hormone-based agent; preferably, the chemotherapeutic agent is selected from an antimetabolite agent, an alkaloid agent, a DNA topoisomerase inhibitor chemotherapeutic agent, an anti-microtubule chemotherapeutic agent, and a platinum-based chemotherapeutic agent.

[0035] In some embodiments of the first aspect of the present application, the chemotherapeutic agent is selected from a taxane drug, a platinum drug, a fluorouracil drug, or a DNA topoisomerase inhibitor chemotherapeutic agent. In some embodiments of the first aspect of the present application, the taxane drug is selected from paclitaxel, docetaxel, or cabazitaxel, preferably paclitaxel. In some embodiments of the first aspect of the present application, the DNA topoisomerase inhibitor chemotherapeutic agent is selected from hydroxycamptothecin, irinotecan, topotecan, etoposide, or teniposide. In some embodiments of the first aspect of the present application, the platinum drug is selected from cisplatin, carboplatin, sulfatodiaminocyclohexane platinum, lobaplatin, oxaliplatin, or nedaplatin, preferably cisplatin, oxaliplatin, or nedaplatin. In some embodiments of the first aspect of the present application, the chemotherapeutic agent is selected from paclitaxel, cisplatin, or nedaplatin.

[0036] In some embodiments of the first aspect of the present application, the immunotherapeutic agent is selected from an anti-programmed death receptor 1 antibody (anti-PD-1 antibody), an anti-programmed death receptor-ligand 1 antibody (anti-PD-L1 antibody), and an antibody-drug conjugate. Preferably, the antibody-drug conjugate is an anti-HER2 antibody-drug conjugate. In some embodiments of the first aspect of the present application, the anti-PD-1 antibody is selected from pembrolizumab, camrelizumab, tislelizumab, nivolumab, cemiplimab, sintilimab, or toripalimab, preferably, the anti-PD-1 antibody is selected from toripalimab, sintilimab, or tislelizumab. In some embodiments of the first aspect of the present application, the anti-PD-L1 antibody is selected from atezolizumab, avelumab, or durvalumab. In some embodiments of the first aspect of the present application, the anti-HER2 antibody-drug conjugate is selected from trastuzumab or dicitamab.

[0037] In some embodiments of the first aspect of the present application, the tumor is a tumor that has failed treatment with chemotherapy and immunotherapy, preferably the tumor is a tumor that has failed treatment with taxane-based chemotherapy plus platinum-based chemotherapy plus anti-PD-1 antibody, preferably the tumor is a tumor that has failed treatment with one, two, or three of toripalimab + paclitaxel + cisplatin, sintilimab + paclitaxel + cisplatin, paclitaxel + lobaplatin + camrelizumab, paclitaxel + nedaplatin, and sintilimab. Preferably, the tumor is a tumor that has failed treatment with one, two, or three of toripalimab + paclitaxel + cisplatin, sintilimab + paclitaxel + cisplatin, and paclitaxel + lobaplatin + camrelizumab. Preferably, the tumor is an esophageal squamous cell carcinoma, preferably, the tumor is a gastroesophageal junction squamous cell carcinoma.

[0038] In some embodiments of the first aspect of the present application, the tumor is a tumor that has failed chemotherapy, preferably the tumor is a tumor that has failed treatment with a taxane and platinum chemotherapy, preferably the tumor that has failed treatment with paclitaxel and cisplatin, or paclitaxel and nedaplatin. Preferably, the tumor is esophageal squamous cell carcinoma.

[0039] In some embodiments of the first aspect of the present application, the tumor is a tumor that has failed treatment with chemotherapy, immunotherapy, and radiation therapy, preferably the tumor is a tumor that has failed treatment with taxane + platinum-based chemotherapy + radiation therapy + anti-PD-1 antibody, preferably the tumor that has failed treatment with tislelizumab + radiation therapy + paclitaxel + cisplatin. Preferably, the tumor is esophageal squamous cell carcinoma.

[0040] In some embodiments of the first aspect of the present application, the pharmaceutically acceptable salt is selected from hydrochloride, hydrobromide, nitrate, sulfate, phosphate, formate, acetate, propionate, benzoate, maleate, fumarate, succinate, tartrate, citrate, methanesulfonate, ethanesulfonate, benzenesulfonate, and p-toluenesulfonate, preferably hydrochloride, hydrobromide, maleate, phosphate, tartrate, fumarate, and succinate, more preferably hydrochloride, maleate, phosphate, tartrate, and fumarate, more preferably hydrochloride, and even more preferably dihydrochloride.

[0041] In some embodiments of the first aspect of the present application, the pharmaceutically acceptable salt of Compound A is Compound B:

[0042] [ka]

[0043] .

[0044] In some embodiments of the first aspect of the present application, Compound B is in a solid form, preferably it is in a crystalline form.

[0045] In some embodiments of the first aspect of the present application, the crystalline form of Compound B is crystalline Form I, and its X-ray powder diffraction pattern, expressed in 2θ angles using Cu-Kα radiation, comprises characteristic peaks at the following positions: 5.0±0.2°, 13.5±0.2°, 19.3±0.2°, 20.5±0.2°, 21.4±0.2°, and 25.2±0.2°.

[0046] In some embodiments of the first aspect of the present application, the crystalline form I has an X-ray powder diffraction pattern, expressed in terms of 2θ angles, using Cu-Kα radiation, comprising characteristic peaks at the following positions: 5.0±0.2°, 13.5±0.2°, 19.3±0.2°, 20.5±0.2°, 21.4±0.2°, 22.5±0.2°, 23.4±0.2°, and 25.2±0.2°.

[0047] In some embodiments of the first aspect of the present application, the crystalline form I has an X-ray powder diffraction pattern, expressed in terms of 2θ angles, using Cu-Kα radiation, comprising characteristic peaks at the following positions: 5.0±0.2°, 13.5±0.2°, 19.3±0.2°, 20.5±0.2°, 21.4±0.2°, 22.5±0.2°, 23.4±0.2°, 23.9±0.2°, 24.3±0.2°, and 25.2±0.2°.

[0048] In some embodiments of the first aspect of the present application, the crystalline form I has an X-ray powder diffraction pattern, expressed in terms of 2θ angles, using Cu-Kα radiation, comprising characteristic peaks at the following positions: 5.0±0.2°, 10.4±0.2°, 11.2±0.2°, 13.5±0.2°, 19.3±0.2°, 20.5±0.2°, 21.4±0.2°, 22.0±0.2°, 22.5±0.2°, 23.4±0.2°, 23.9±0.2°, 24.3±0.2°, 25.2±0.2°, and 26.6±0.2°.

[0049] In some embodiments of the first aspect of the present application, the crystalline form I has an X-ray powder diffraction pattern using Cu-Kα radiation, expressed in 2θ angles of 5.0±0.2°, 10.0±0.2°, 10.4±0.2°, 11.2±0.2°, 13.5±0.2°, 14.1±0.2°, 15.7±0.2°, 17.4±0.2°, 18.0±0.2°. These include characteristic peaks at the following positions: 19.3±0.2°, 20.1±0.2°, 20.5±0.2°, 21.4±0.2°, 22.0±0.2°, 22.5±0.2°, 23.4±0.2°, 23.9±0.2°, 24.3±0.2°, 25.2±0.2°, 26.6±0.2°, 28.6±0.2° and 30.1±0.2°.

[0050] In some embodiments of the first aspect of the present application, Compound A or a pharmaceutically acceptable salt thereof is administered by a pharmaceutical route, including, but not limited to, a route selected from oral, parenteral, or topical. In one particular embodiment, it is administered orally.

[0051] In some embodiments of the first aspect of the present application, the drug is manufactured into a clinically acceptable formulation, including, but not limited to, an oral formulation, a parenteral formulation, a topical formulation, or an external formulation, preferably an oral formulation, and more preferably a tablet or capsule.

[0052] In some embodiments of the first aspect of the present application, each dosage unit of the medicament contains 0.1 to 200 mg, preferably 1 to 150 mg, or 1 to 100 mg, or 1 to 80 mg, or 1 to 60 mg, or 1 to 50 mg, or 1 to 40 mg, or 1 to 30 mg, or 1 to 20 mg, or 1 to 10 mg, or 1 to 6 mg, for example, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 8 mg, 10 mg, 15 mg, 20 mg, or 25 mg of the compound A or a pharmaceutically acceptable salt thereof. In some embodiments of the first aspect of the present application, each dosage unit of the medicament contains 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 15 mg, 20 mg, or 25 mg of the compound A or a pharmaceutically acceptable salt thereof. In some embodiments of the first aspect of the present application, each dosage unit of the drug contains 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, or 9 mg of Compound A or a pharmaceutically acceptable salt thereof. Preferably, the pharmaceutically acceptable salt of Compound A is Compound B. More preferably, the amount is calculated based on the mass including Compound B.

[0053] In some embodiments of the first aspect of the present application, Compound A or a pharmaceutically acceptable salt thereof is administered in a single dose or in divided doses, preferably in a single dose, and preferably the pharmaceutically acceptable salt of Compound A is Compound B, more preferably in the form of Compound B.

[0054] In some embodiments of the first aspect of the present application, the dosage of Compound A or a pharmaceutically acceptable salt thereof is determined depending on the severity of the disease, the response to the disease, any treatment-related toxicity, and the age and health condition of the patient. In some embodiments of the first aspect of the present application, the dosage of Compound A or a pharmaceutically acceptable salt thereof is 1 to 50 mg per day. Preferably, the dosage is 1 to 30 mg per day. Preferably, the dosage is 1 to 25 mg per day. Preferably, the dosage is 1 to 20 mg per day. Preferably, the dosage is 2 to 18 mg per day. Preferably, the dosage is 4 to 16 mg per day. Preferably, the dosage is 5 to 15 mg per day. Preferably, the dosage is 4 to 10 mg per day. Preferably, the dosage is 4 to 9 mg per day. Preferably, the dosage is 2 to 9 mg per day. Preferably, the dosage is 2 to 6 mg per day. Preferably, the dosage is 5 to 9 mg per day. Preferably, the dosage is 6 to 9 mg per day. Preferably, the dosage is 6 to 8 mg per day. Preferably, the dosage is 6 to 12 mg per day. Preferably, the dosage is 6 to 10 mg per day. Preferably, the dosage is 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg per day. Preferably, the dosage is 2, 4, 5, 6, 7, 8, 9, or 10 mg per day. Preferably, the dosage is 6, 7, 8, or 9 mg per day. Preferably, the dosage is 4 mg per day. Preferably, the dosage is 5 mg per day. Preferably, the dosage is 6 mg per day. Preferably, the dosage is 7 mg per day. Preferably, the dosage is 8 mg per day. Preferably, the dosage is 9 mg per day. Preferably, the pharmaceutically acceptable salt of compound A is compound B. More preferably, it is administered in the form of an oral solid preparation containing compound B. More preferably, the daily dose is calculated based on the mass of compound B.

[0055] In some embodiments of the first aspect of the present application, the administration frequency of Compound A or a pharmaceutically acceptable salt thereof is once a day, twice a day, three times a day, or more. In some embodiments of the first aspect of the present application, Compound A or a pharmaceutically acceptable salt thereof is administered once a day. In some embodiments of the first aspect of the present application, Compound A or a pharmaceutically acceptable salt thereof is administered twice a day. In some embodiments of the first aspect of the present application, Compound A or a pharmaceutically acceptable salt thereof is administered three times a day. Preferably, the pharmaceutically acceptable salt of Compound A is Compound B. More preferably, it is administered in the form of an oral solid formulation containing Compound B.

[0056] In some embodiments of the first aspect of the present application, the administration method is comprehensively determined depending on the activity, toxicity, and patient tolerability of the drug. In some embodiments of the first aspect of the present application, the compound A or a pharmaceutically acceptable salt thereof is administered in a continuous or interval administration manner. Preferably, the interval administration includes an administration period and a drug-withdrawal period. Preferably, during the administration period, the compound A or a pharmaceutically acceptable salt thereof is administered once a day, twice a day, three times a day, or more. For example, during the administration period, the compound A or a pharmaceutically acceptable salt thereof is administered once a day, followed by a drug-withdrawal period for a certain period, followed by an administration period, followed by a drug-withdrawal period, and this is repeated multiple times. The ratio calculated based on the number of days of the administration period and the drug-withdrawal period is 3:1 to 5, preferably 3:1 to 3, more preferably 3:1 to 2, and even more preferably 3:1 or 3:1.5 (i.e., 2:1). Preferably, the pharmaceutically acceptable salt of compound A is compound B. More preferably, it is administered in the form of an oral solid formulation containing Compound B.

[0057] In some embodiments of the first aspect of the present application, the method of administration of Compound A or a pharmaceutically acceptable salt thereof is continuous administration, once daily. In some embodiments of the first aspect of the present application, the method of administration of Compound A or a pharmaceutically acceptable salt thereof is continuous administration, twice daily. In some embodiments of the first aspect of the present application, the method of administration of Compound A or a pharmaceutically acceptable salt thereof is continuous administration, three times daily. Preferably, the pharmaceutically acceptable salt of Compound A is Compound B. More preferably, it is administered in the form of an oral solid formulation containing Compound B.

[0058] In some embodiments of the first aspect of the present application, Compound A or a pharmaceutically acceptable salt thereof is administered for three consecutive weeks followed by a one-week break. In some embodiments of the first aspect of the present application, Compound A or a pharmaceutically acceptable salt thereof is administered once daily for 21 consecutive days, followed by a seven-day break, and then once daily for 21 consecutive days, followed by a seven-day break. This interval dosing regimen of three consecutive weeks and one week break can be repeated multiple times. In some embodiments of the first aspect of the present application, Compound A or a pharmaceutically acceptable salt thereof is administered twice daily for 21 consecutive days, followed by a seven-day break, and then twice daily for 21 consecutive days, followed by a seven-day break. This interval dosing regimen of three consecutive weeks and one week break can be repeated multiple times. In some embodiments of the first aspect of the present application, the compound A is administered three times a day for 21 consecutive days, followed by a seven-day rest period, and then administered three times a day for 21 consecutive days, followed by a seven-day rest period. This interval administration method of three consecutive weeks of administration and one week of rest period can be repeated multiple times.Preferably, the pharmaceutically acceptable salt of compound A is compound B.More preferably, the compound A is administered in the form of an oral solid formulation containing compound B.

[0059] In some embodiments of the first aspect of the present application, Compound A or a pharmaceutically acceptable salt thereof is administered for two consecutive weeks followed by a one-week break. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered once daily for 14 consecutive days followed by a seven-day break, then once daily for 14 consecutive days followed by a seven-day break, and this interval dosing regimen of two consecutive weeks followed by a one-week break can be repeated multiple times. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered twice daily for 14 consecutive days followed by a seven-day break, then twice daily for 14 consecutive days followed by a seven-day break, and this interval dosing regimen of two consecutive weeks followed by a one-week break can be repeated multiple times. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered three times daily for 14 consecutive days followed by a seven-day break, then three times daily for 14 consecutive days followed by a seven-day break, and this interval dosing regimen of two consecutive weeks followed by a one-week break can be repeated multiple times. Preferably, the pharmaceutically acceptable salt of Compound A is Compound B. More preferably, it is administered in the form of an oral solid formulation containing Compound B.

[0060] In some embodiments of the first aspect of the present application, the administration method of Compound A or a pharmaceutically acceptable salt thereof is 3 consecutive weeks of administration followed by 2 weeks of rest. In some embodiments of the first aspect of the present application, Compound A or a pharmaceutically acceptable salt thereof is administered m times per day, followed by 21 consecutive days of administration followed by 14 days of rest, and then administered m times per day, followed by 21 consecutive days of administration followed by 14 days of rest. This interval administration method of 3 consecutive weeks of administration followed by 2 weeks of rest can be repeated multiple times. Preferably, the pharmaceutically acceptable salt of Compound A is Compound B. More preferably, it is administered in the form of an oral solid formulation containing Compound B.

[0061] In some embodiments of the first aspect of the present application, the administration method of compound A or a pharmaceutically acceptable salt thereof is to administer for 5 consecutive days and then rest for 2 days. In some embodiments, the administration method is m times a day, followed by 5 consecutive days of administration, followed by 2 days of rest, and then m times a day, followed by 5 consecutive days of administration, followed by 2 days of rest. This interval administration method of 5 consecutive days of administration and 2 days of rest can be repeated multiple times. Preferably, the pharmaceutically acceptable salt of compound A is compound B. More preferably, the compound A is administered in the form of an oral solid formulation containing compound B.

[0062] In some embodiments of the first aspect of the present application, compound A or a pharmaceutically acceptable salt thereof is orally administered m times a day at a dose of n mg each time, and administered continuously. Preferably, the pharmaceutically acceptable salt of compound A is compound B. More preferably, it is administered in the form of an oral solid formulation containing compound B. More preferably, the dose is calculated based on the mass of compound B.

[0063] In some embodiments of the first aspect of the present application, compound A or a pharmaceutically acceptable salt thereof is orally administered m times a day at a dose of n mg each time, with three consecutive weeks of administration followed by one week of rest, making one cycle four weeks. Preferably, the pharmaceutically acceptable salt of compound A is compound B. More preferably, it is administered in the form of an oral solid formulation containing compound B. More preferably, the dosage is calculated based on the mass of compound B.

[0064] In some embodiments of the first aspect of the present application, compound A or a pharmaceutically acceptable salt thereof is orally administered m times a day at a dose of n mg each time, with two consecutive weeks of administration followed by one week of rest, forming a three-week cycle. Preferably, the pharmaceutically acceptable salt of compound A is compound B. More preferably, it is administered in the form of an oral solid formulation containing compound B. More preferably, the dosage is calculated based on the mass of compound B.

[0065] In some embodiments of the first aspect of the present application, Compound A or a pharmaceutically acceptable salt thereof is orally administered once a day at a dose of 6 mg, and administered continuously. Preferably, the pharmaceutically acceptable salt of Compound A is Compound B. More preferably, it is administered in the form of an oral solid formulation containing Compound B. More preferably, the dose is calculated based on the mass of Compound B.

[0066] In some embodiments of the first aspect of the present application, compound A or a pharmaceutically acceptable salt thereof is orally administered once a day at a dose of 6 mg, with administration for three consecutive weeks followed by one week off. Preferably, the pharmaceutically acceptable salt of compound A is compound B. More preferably, it is administered in the form of an oral solid formulation containing compound B. More preferably, the dosage is calculated based on the mass of compound B.

[0067] In some embodiments of the first aspect of the present application, m is selected from 1, 2, or 3. In some embodiments of the first aspect of the present application, m is 1. In some embodiments of the first aspect of the present application, m is 2. In some embodiments of the first aspect of the present application, m is 3.

[0068] In some embodiments of the first aspect of the present application, n is 1, 2, 3, 4, 5, 6, 7, 8, or 9. In some embodiments of the first aspect of the present application, n is 1. In some embodiments of the first aspect of the present application, n is 2. In some embodiments of the first aspect of the present application, n is 3. In some embodiments of the first aspect of the present application, n is 4. In some embodiments of the first aspect of the present application, n is 5. In some embodiments of the first aspect of the present application, n is 6. In some embodiments of the first aspect of the present application, n is 7. In some embodiments of the first aspect of the present application, n is 8. In some embodiments of the first aspect of the present application, n is 9.

[0069] In some embodiments of the first aspect of the present application, the compound A or a pharmaceutically acceptable salt thereof is used in combination with one, two, three or more drugs commonly used in clinical practice to treat esophageal cancer or gastroesophageal junction cancer, for the manufacture of the drug.

[0070] In some embodiments of the first aspect of the present application, the drug is further used in combination with one, two, three or more drugs commonly used in clinical practice to treat esophageal cancer or gastroesophageal junction cancer.

[0071] In a second aspect, the present application provides a method of treating a tumor in an individual, comprising administering to said individual a therapeutically effective amount of compound A according to the first aspect or a pharmaceutically acceptable salt thereof, wherein said tumor is esophageal cancer or gastroesophageal junction cancer.

[0072] In some embodiments of the second aspect of the present application, the method further comprises a therapeutically effective amount of another drug, wherein the other drug is one, two, three or more drugs selected from drugs commonly used in clinical practice to treat esophageal cancer or gastroesophageal junction cancer.

[0073] Unless there is any contradiction or conflict, the technical solutions or technical features described in the first aspect apply to the second aspect.

[0074] In aspect 2.1, the present application provides compound A or a pharmaceutically acceptable salt thereof for treating tumors, wherein said tumor is esophageal cancer or gastroesophageal junction cancer.

[0075] In some embodiments of aspect 2.1 of the present application, the composition further comprises another drug, and the other drug is one, two, three or more drugs selected from drugs commonly used in clinical practice to treat esophageal cancer or gastroesophageal junction cancer.

[0076] Unless there is any contradiction or conflict, the technical solutions or technical features described in the first aspect shall apply to the second aspect.

[0077] In a third aspect, the present application provides a pharmaceutical composition for treating a tumor, comprising compound A according to the first aspect or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier, wherein the tumor is esophageal cancer or gastroesophageal junction cancer.

[0078] In some embodiments of the third aspect of the present application, the pharmaceutical composition comprises a pharmaceutically acceptable salt of Compound A, and optionally a pharmaceutically acceptable carrier. In some embodiments of the third aspect of the present application, the pharmaceutical composition comprises the hydrochloride salt of Compound A, and optionally a pharmaceutically acceptable carrier. In some embodiments of the third aspect of the present application, the pharmaceutical composition comprises Compound B, and optionally a pharmaceutically acceptable carrier. In some embodiments of the third aspect of the present application, the pharmaceutical composition comprises a solid form of Compound B, and optionally a pharmaceutically acceptable carrier. In some embodiments of the third aspect of the present application, the pharmaceutical composition comprises a crystalline form of Compound B, and optionally a pharmaceutically acceptable carrier. In some embodiments of the third aspect of the present application, the pharmaceutical composition comprises crystalline Form I of Compound B, and optionally a pharmaceutically acceptable carrier.

[0079] In some embodiments of the third aspect of the present application, the pharmaceutical composition comprises Compound A or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, and further comprises a therapeutically effective amount of another drug, wherein the other drug is selected from drugs commonly used in clinical practice to treat esophageal cancer or gastroesophageal junction cancer.

[0080] In some embodiments of the third aspect of the present application, the pharmaceutical composition comprises compound B and a pharmaceutically acceptable carrier, and further comprises a therapeutically effective amount of another drug, wherein the other drug is one, two, three or more drugs selected from drugs commonly used in clinical practice to treat esophageal cancer or gastroesophageal junction cancer.

[0081] Unless there is any contradiction or conflict, the technical solutions or technical features described in the first aspect apply to the third aspect.

[0082] In a fourth aspect, the present application provides a pharmaceutical kit comprising: (a) at least one unit dose of a pharmaceutical composition of Compound A or a pharmaceutically acceptable salt thereof; and (b) instructions for treating a tumor, wherein the tumor is esophageal cancer or gastroesophageal junction cancer. In some embodiments, the present application provides a kit comprising: (a) at least one unit dose of an oral formulation of Compound A or a pharmaceutically acceptable salt thereof; and (b) instructions for treating a tumor, wherein the tumor is esophageal cancer or gastroesophageal junction cancer. The "unit dose" refers to a pharmaceutical composition or oral formulation packaged in a single package for convenient administration. For example, one pharmaceutical composition, one tablet, or one capsule.

[0083] Unless there is any contradiction or conflict, the technical solutions or technical features described in the first aspect apply to the fourth aspect.

[0084] In a fifth aspect, the present application provides a use of compound A or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a tumor, wherein the tumor is gastrointestinal squamous cell carcinoma.

[0085] [ka]

[0086] .

[0087] In some embodiments of the fifth aspect of the present application, the tumor is upper gastrointestinal squamous cell carcinoma, and preferably, the upper gastrointestinal squamous cell carcinoma is selected from esophageal squamous cell carcinoma or gastroesophageal junction squamous cell carcinoma.

[0088] In some embodiments of the fifth aspect of the present application, the tumor is a tumor with genetic abnormalities or abnormal protein expression of one, two, or three of FGFR, VEGFR, and colony-stimulating factor 1 receptor (CSF1R). Preferably, the tumor is a tumor with genetic mutations of one, two, or three of FGFR, VEGFR, and CSF1R.

[0089] In some embodiments of the fifth aspect of the present application, the tumor is a locally advanced tumor or a metastatic tumor, preferably a locally advanced tumor that is not surgically resectable or a metastatic tumor that is not surgically resectable.

[0090] In some embodiments of the fifth aspect of the present application, the tumor is a tumor for which a previous treatment has failed.

[0091] In some embodiments of the fifth aspect of the present application, the tumor is a tumor for which systemic drug treatment has failed.

[0092] In some embodiments of the fifth aspect of the present application, the tumor is a tumor that has failed first line therapy.

[0093] In some embodiments of the fifth aspect of the present application, the tumor is a tumor that has failed second line therapy.

[0094] In some embodiments of the fifth aspect of the present application, the tumor is a tumor for which a subsequent line of treatment has failed.

[0095] In some embodiments of the fifth aspect of the present application, the tumor is a tumor that has failed treatment with one, two, three or more of immunotherapeutic agents, chemotherapy agents, radiation therapy, biological therapy, traditional Chinese medicine therapy, and small molecule targeted drugs. In some embodiments of the fifth aspect of the present application, the tumor is a tumor that has failed treatment with radiation therapy, immunotherapeutic agents, or chemotherapy agents. In some embodiments of the fifth aspect of the present application, the tumor is a tumor that has failed treatment with radiation therapy and immunotherapeutic agents. In some embodiments of the fifth aspect of the present application, the tumor is a tumor that has failed treatment with radiation therapy and chemotherapy agents. In some embodiments of the fifth aspect of the present application, the tumor is a tumor that has failed treatment with chemotherapy agents and immunotherapeutic agents. In some embodiments of the fifth aspect of the present application, the tumor is a tumor that has failed treatment with chemotherapy agents, immunotherapeutic agents, and radiation therapy.

[0096] In some embodiments of the fifth aspect of the present application, the chemotherapeutic agent is selected from a cytotoxic agent, an antimetabolite agent, an antibiotic agent, an alkaloid agent, a DNA topoisomerase inhibitor chemotherapeutic agent, an anti-microtubule chemotherapeutic agent, a platinum-based chemotherapeutic agent, and a hormone-based agent; preferably, the chemotherapeutic agent is selected from an antimetabolite agent, an alkaloid agent, a DNA topoisomerase inhibitor chemotherapeutic agent, an anti-microtubule chemotherapeutic agent, and a platinum-based chemotherapeutic agent.

[0097] In some embodiments of the fifth aspect of the present application, the chemotherapeutic agent is selected from a taxane drug, a platinum drug, a fluorouracil drug, or a DNA topoisomerase inhibitor chemotherapeutic agent. In some embodiments of the fifth aspect of the present application, the taxane drug is selected from paclitaxel, docetaxel, or cabazitaxel, preferably paclitaxel. In some embodiments of the fifth aspect of the present application, the DNA topoisomerase inhibitor chemotherapeutic agent is selected from hydroxycamptothecin, irinotecan, topotecan, etoposide, or teniposide. In some embodiments of the fifth aspect of the present application, the platinum drug is selected from cisplatin, carboplatin, sulfatodiaminocyclohexane platinum, lobaplatin, oxaliplatin, or nedaplatin, preferably cisplatin, oxaliplatin, or nedaplatin. In some embodiments of the fifth aspect of the present application, the chemotherapeutic agent is selected from paclitaxel, cisplatin, or nedaplatin.

[0098] In some embodiments of the fifth aspect of the present application, the immunotherapeutic agent is selected from an anti-programmed death receptor 1 antibody (anti-PD-1 antibody), an anti-programmed death receptor-ligand 1 antibody (anti-PD-L1 antibody), and an antibody-drug conjugate. Preferably, the antibody-drug conjugate is an anti-HER2 antibody-drug conjugate. In some embodiments of the fifth aspect of the present application, the anti-PD-1 antibody is selected from pembrolizumab, camrelizumab, tislelizumab, nivolumab, cemiplimab, sintilimab, or toripalimab, preferably, the anti-PD-1 antibody is selected from toripalimab, sintilimab, or tislelizumab. In some embodiments of the fifth aspect of the present application, the anti-PD-L1 antibody is selected from atezolizumab, avelumab, and durvalumab. In some embodiments of the fifth aspect of the present application, the anti-HER2 antibody-drug conjugate is selected from trastuzumab or dicitamab.

[0099] In some embodiments of the fifth aspect of the present application, the tumor is a tumor that has failed chemotherapy and immunotherapy treatment, preferably the tumor is a tumor that has failed treatment with a taxane + platinum-based chemotherapy + anti-PD-1 antibody, preferably the tumor is a tumor that has failed treatment with one, two, three or more of toripalimab + paclitaxel + cisplatin, sintilimab + paclitaxel + cisplatin, paclitaxel + lobaplatin + camrelizumab, paclitaxel + nedaplatin, sintilimab. Preferably, the tumor is esophageal squamous cell carcinoma.

[0100] In some embodiments of the fifth aspect of the present application, the tumor is a tumor that has failed chemotherapy, preferably the tumor is a tumor that has failed treatment with a taxane and platinum chemotherapy, preferably the tumor that has failed treatment with paclitaxel and cisplatin or paclitaxel and nedaplatin. Preferably, the tumor is esophageal squamous cell carcinoma.

[0101] In some embodiments of the fifth aspect of the present application, the tumor is a tumor that has failed treatment with chemotherapy, immunotherapy, and radiation therapy, preferably the tumor is a tumor that has failed treatment with taxanes, platinum-based chemotherapy, radiation therapy, and an anti-PD-1 antibody, preferably the tumor that has failed treatment with tislelizumab, radiation therapy, and chemotherapy. Preferably, the tumor is esophageal squamous cell carcinoma.

[0102] Unless there is any contradiction or conflict, the technical solutions or technical features described in the first aspect apply to the fifth aspect.

[0103] In a sixth aspect, the present application provides a use of compound A or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a tumor,

[0104] [ka]

[0105] , Among them, the tumor is squamous cell carcinoma.

[0106] In some embodiments of the sixth aspect of the present application, the tumor is selected from head and neck squamous cell carcinoma, gastrointestinal squamous cell carcinoma, or respiratory squamous cell carcinoma; preferably, the tumor is selected from head and neck squamous cell carcinoma, upper gastrointestinal squamous cell carcinoma, or respiratory squamous cell carcinoma; more preferably, the tumor is selected from esophageal squamous cell carcinoma, gastroesophageal junction squamous cell carcinoma, head and neck squamous cell carcinoma, and lung squamous cell carcinoma; more preferably, the tumor is selected from esophageal squamous cell carcinoma, gastroesophageal junction squamous cell carcinoma, nasopharyngeal squamous cell carcinoma, and lung squamous cell carcinoma; more preferably, the tumor is selected from nasopharyngeal squamous cell carcinoma, esophageal squamous cell carcinoma, and lung squamous cell carcinoma; even more preferably, the tumor is selected from esophageal squamous cell carcinoma, gastroesophageal junction squamous cell carcinoma, nasopharyngeal squamous cell carcinoma, esophageal squamous cell carcinoma, and lung squamous cell carcinoma; even more preferably, the tumor is esophageal squamous cell carcinoma.

[0107] In some embodiments of the sixth aspect of the present application, the tumor is a tumor with genetic abnormalities or protein expression abnormalities of one, two, or three of FGFR, VEGFR, and CSF1R. Preferably, the tumor is a tumor with genetic abnormalities of one, two, or three of FGFR, VEGFR, and CSF1R.

[0108] In some embodiments of the sixth aspect of the present application, the tumor is a locally advanced tumor or a metastatic tumor, preferably a locally advanced tumor that is not surgically resectable or a metastatic tumor that is not surgically resectable.

[0109] In some embodiments of the sixth aspect of the present application, the tumor is a tumor that has failed or recurred after a previous treatment.

[0110] In some embodiments of the sixth aspect of the present application, the tumor is a tumor for which systemic drug treatment has failed.

[0111] In some embodiments of the sixth aspect of the present application, the tumor is a tumor for which first line therapy has failed.

[0112] In some embodiments of the sixth aspect of the present application, the tumor is a tumor that has failed second line therapy or a tumor that has failed subsequent line therapy.

[0113] In some embodiments of the sixth aspect of the present application, the tumor is a tumor that has failed treatment with one, two, three or more of immunotherapeutic agents, chemotherapy agents, radiation therapy, biological therapy, traditional Chinese medicine therapy, or small molecule targeted drugs. In some embodiments of the sixth aspect of the present application, the tumor is a tumor that has failed treatment with radiation therapy, immunotherapy agents, or chemotherapy agents. In some embodiments of the sixth aspect of the present application, the tumor is a tumor that has failed treatment with radiation therapy and immunotherapy agents. In some embodiments of the sixth aspect of the present application, the tumor is a tumor that has failed treatment with radiation therapy and chemotherapy agents. In some embodiments of the sixth aspect of the present application, the tumor is a tumor that has failed treatment with chemotherapy agents and immunotherapy agents. In some embodiments of the sixth aspect of the present application, the tumor is a tumor that has failed treatment with chemotherapy agents, immunotherapy agents, and radiation therapy.

[0114] In some embodiments of the sixth aspect of the present application, the chemotherapeutic agent is selected from a cytotoxic agent, an antimetabolite agent, an antibiotic agent, an alkaloid agent, a DNA topoisomerase inhibitor chemotherapeutic agent, an anti-microtubule chemotherapeutic agent, a platinum-based chemotherapeutic agent, and a hormone-based agent; preferably, the chemotherapeutic agent is selected from an antimetabolite agent, an alkaloid agent, a DNA topoisomerase inhibitor chemotherapeutic agent, an anti-microtubule chemotherapeutic agent, and a platinum-based chemotherapeutic agent.

[0115] In some embodiments of the sixth aspect of the present application, the chemotherapeutic agent is selected from a taxane drug, a platinum drug, a fluorouracil drug, or a DNA topoisomerase inhibitor chemotherapeutic agent. In some embodiments, the taxane drug is selected from paclitaxel, docetaxel, or cabazitaxel, preferably paclitaxel. In some embodiments, the DNA topoisomerase inhibitor chemotherapeutic agent is selected from hydroxycamptothecin, irinotecan, topotecan, etoposide, or teniposide. In some embodiments, the platinum drug is selected from cisplatin, carboplatin, sulfatodiaminocyclohexane platinum, lobaplatin, oxaliplatin, or nedaplatin, preferably cisplatin, oxaliplatin, or nedaplatin. In some embodiments, the chemotherapeutic agent is selected from paclitaxel, cisplatin, or nedaplatin.

[0116] In some embodiments of the sixth aspect of the present application, the immunotherapeutic agent is selected from an anti-programmed death receptor 1 antibody (anti-PD-1 antibody), an anti-programmed death receptor-ligand 1 antibody (anti-PD-L1 antibody), and an antibody-drug conjugate. Preferably, the antibody-drug conjugate is an anti-HER2 antibody-drug conjugate. In some embodiments, the anti-PD-1 antibody is selected from pembrolizumab, camrelizumab, tislelizumab, nivolumab, cemiplimab, sintilimab, or toripalimab, preferably, the anti-PD-1 antibody is selected from toripalimab, sintilimab, or tislelizumab. In some embodiments, the anti-PD-L1 antibody is selected from atezolizumab, avelumab, and durvalumab. In some embodiments, the anti-HER2 antibody-drug conjugate is selected from trastuzumab or dicitamab.

[0117] In some embodiments of the sixth aspect of the present application, the tumor is a tumor that has failed treatment with chemotherapy and immunotherapy, preferably the tumor is a tumor that has failed treatment with taxane + platinum-based chemotherapy + anti-PD-1 antibody, preferably the tumor is a tumor that has failed treatment with one, two, three or more of toripalimab + paclitaxel + cisplatin, sintilimab + paclitaxel + cisplatin, paclitaxel + lobaplatin + camrelizumab, paclitaxel + nedaplatin, sintilimab.

[0118] In some embodiments of the sixth aspect of the present application, the tumor is a tumor that has failed treatment with a chemotherapy drug, preferably the tumor is a tumor that has failed treatment with a taxane-based plus platinum-based chemotherapy drug, preferably the tumor is a tumor that has failed treatment with paclitaxel plus cisplatin, paclitaxel plus carboplatin, or paclitaxel plus nedaplatin.

[0119] In some embodiments of the sixth aspect of the present application, the tumor is a tumor that has failed treatment with chemotherapy, immunotherapy, and radiation therapy, preferably the tumor is a tumor that has failed treatment with taxane + platinum-based chemotherapy + radiation therapy + anti-PD-1 antibody, preferably the tumor is a tumor that has failed treatment with tislelizumab + radiation therapy + chemotherapy.

[0120] Unless there is any contradiction or conflict, the technical solutions or technical features described in the first aspect apply to the sixth aspect.

[0121] In a seventh aspect, the present application provides a method of treating a tumor in an individual, comprising administering to said individual a therapeutically effective amount of compound A according to the first aspect or a pharmaceutically acceptable salt thereof, wherein said tumor is squamous cell carcinoma.

[0122] In some embodiments of the seventh aspect of the present application, the method further comprises a therapeutically effective amount of another drug, wherein the other drug is one, two, three or more drugs selected from drugs commonly used in clinical practice to treat squamous cell carcinoma.

[0123] Unless there is any contradiction or conflict, the technical solutions or technical features described in the first aspect or the sixth aspect apply to the seventh aspect.

[0124] In an eighth aspect, the present application provides compound A or a pharmaceutically acceptable salt thereof for treating tumors, wherein the tumor is squamous cell carcinoma.

[0125] In some embodiments of the eighth aspect of the present application, the composition further comprises another drug, and the other drug is one, two, three or more drugs selected from drugs commonly used in clinical practice to treat squamous cell carcinoma.

[0126] Unless there is any contradiction or conflict, the technical solutions or technical features described in the first aspect or the sixth aspect apply to the eighth aspect.

[0127] In a ninth aspect, the present application provides a pharmaceutical composition for treating a tumor, comprising Compound A or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier, wherein the tumor is squamous cell carcinoma.

[0128] In some embodiments of the ninth aspect of the present application, the pharmaceutical composition comprises a pharmaceutically acceptable salt of Compound A, and optionally comprises a pharmaceutically acceptable carrier. In some embodiments of the ninth aspect of the present application, the pharmaceutical composition comprises the hydrochloride salt of Compound A, and optionally comprises a pharmaceutically acceptable carrier. In some embodiments of the ninth aspect of the present application, the pharmaceutical composition comprises Compound B, and optionally comprises a pharmaceutically acceptable carrier. In some embodiments of the ninth aspect of the present application, the pharmaceutical composition comprises a solid form of Compound B, and optionally comprises a pharmaceutically acceptable carrier. In some embodiments of the ninth aspect of the present application, the pharmaceutical composition comprises a crystalline form of Compound B, and optionally comprises a pharmaceutically acceptable carrier. In some embodiments of the ninth aspect of the present application, the pharmaceutical composition comprises crystalline Form I of Compound B, and optionally comprises a pharmaceutically acceptable carrier.

[0129] In some embodiments of the ninth aspect of the present application, the pharmaceutical composition comprises compound A or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, and further comprises a therapeutically effective amount of another drug, wherein the other drug is selected from drugs commonly used in clinical practice to treat squamous cell carcinoma.

[0130] In some embodiments of the ninth aspect of the present application, the pharmaceutical composition comprises compound B and a pharmaceutically acceptable carrier, and further comprises a therapeutically effective amount of another drug, wherein the other drug is one, two, three or more drugs selected from drugs commonly used in clinical practice to treat squamous cell carcinoma.

[0131] Unless there is any contradiction or conflict, the technical solutions or technical features described in the first aspect or the sixth aspect apply to the ninth aspect.

[0132] In some embodiments, in the provided use (first aspect), method (second aspect), compound or a medicamentable salt thereof (2.1 aspect), pharmaceutical composition (third aspect), kit (fourth aspect), use (fifth aspect), use (sixth aspect), method (seventh aspect), compound or a medicamentable salt thereof (eighth aspect) or pharmaceutical composition (ninth aspect), Compound A or a medicamentable salt thereof is administered alone to a patient as the only active ingredient. In some embodiments, the provided use (first aspect), method (second aspect), compound or a medicamentable salt thereof (aspect 2.1), pharmaceutical composition (third aspect), kit (fourth aspect), use (fifth aspect), method (seventh aspect), compound or a medicamentable salt thereof (eighth aspect), or pharmaceutical composition (ninth aspect) further comprises another drug, and Compound A or a medicamentable salt thereof is administered to a patient with a tumor simultaneously with or sequentially to the other drug, wherein the tumor is esophageal cancer or gastroesophageal junction cancer as described in the first aspect, gastrointestinal squamous cell carcinoma as described in the fifth aspect, or squamous cell carcinoma as described in the sixth aspect. Preferably, the other drug includes, but is not limited to, a chemotherapeutic agent, an immunotherapeutic agent, or a small molecule targeted drug.

[0133] As used herein, "prior treatment" includes, but is not limited to, one, two, three or more of radiation therapy, chemotherapy, and targeted therapy (including immunotherapy and small molecule targeted drug therapy).

[0134] "Immunotherapy" as used herein includes immune checkpoint inhibitors, tumor vaccines, cellular immune cell therapy, non-specific immunomodulators, and immunomodulatory antibody-drug conjugates (also called antibody-drug conjugates).

[0135] As used herein, "first-line treatment" is not limited to first-line drug treatment regimens approved for treating specific neoplastic diseases (e.g., esophageal cancer, gastroesophageal junction cancer, nasopharyngeal squamous cell carcinoma, lung squamous cell carcinoma, etc.), but also includes systemic drug treatments such as initial non-first-line chemotherapy regimens, immunotherapy, and targeted therapy to treat specific neoplastic diseases after diagnosis, and "failure of first-line treatment" further includes disease progression occurring within 6 months of adjuvant chemotherapy.

[0136] The sole administration described in this application refers to the absence of the need for combination with other drugs that have anti-tumor effects, but does not exclude the use of some adjunctive drugs that do not have anti-tumor effects.

[0137] The present application has achieved the following beneficial technical effects: (1) Compound A or a medicinal salt thereof (e.g., Compound B) has shown clinical benefit against esophageal cancer, gastroesophageal junction cancer, and / or squamous cell carcinoma (e.g., nasopharyngeal squamous cell carcinoma, lung squamous cell carcinoma, esophageal squamous cell carcinoma), and has clinical potential for treating esophageal cancer, gastroesophageal junction cancer, and squamous cell carcinoma; (2) Compound A or a medicinal salt thereof (e.g., Compound B) has shown relatively good tolerability in a Phase I clinical trial, with few types of adverse reactions, suggesting that its clinical safety is relatively good.

[0138] Definitions and Explanations Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings: A particular word or term, unless specifically defined, should not be considered indefinite or unclear but should be understood in its ordinary sense.

[0139] As referred to in this application, "pharmaceutically acceptable" refers to its use in preparing pharmaceutical compositions, including those that are generally safe, non-toxic, and not biologically or otherwise undesirable, and are acceptable for human pharmaceutical use.

[0140] "Solid form" as referred to in this application refers to a compound in solid form, including crystalline and amorphous forms of Compound B.

[0141] The term "crystalline form" as referred to herein refers to a compound in crystalline form, including anhydrous and solvent-free forms (also referred to as anhydrous forms), hydrate forms, solvate forms, and co-crystalline forms of Compound B. The crystalline form is preferably anhydrous and solvent-free or hydrate forms, more preferably anhydrous and solvent-free forms.

[0142] "Treatment" as referred to in this application refers to the alleviation, relief or amelioration of the symptoms of a disease or condition, the amelioration of symptoms caused by a potential metabolic event, the inhibition of a disease or condition, for example, arresting the progression of a disease or condition, relieving a disease or condition, inducing regression of a disease or condition, alleviating pathology caused by a disease or condition, or preventing the symptoms of a disease or condition.

[0143] "Treatment failure" as referred to herein refers to disease progression during the treatment process, relapse after treatment, or intolerable toxic side effects.

[0144] "Systemic drug therapy" as referred to in this application includes new adjuvant and supplemental therapies, as well as chemotherapy, small molecule targeted therapy and immunotherapy for advanced stage patients.

[0145] As used herein, "genetic abnormality" refers to the occurrence of one or more of the following events in the FGFR, VEGFR, or CSF1R gene: fusion, amplification, rearrangement, or mutation. As used herein, "protein expression abnormality" refers to one or more events in protein overexpression, misfolding, or kinase domain repeat sequence.

[0146] As used herein, "optionally" or "optionally / optionally" refers to inclusion or exclusion, meaning that the subsequently described event or circumstance may occur, but does not necessarily have to occur, and the description includes cases where the event or circumstance occurs or does not occur.

[0147] As used herein, "more" or "more than" may refer to four or more than four species, in some cases, e.g., "one, two, three or more species," and may refer to two, three or more species, in some cases, e.g., "one or more species."

[0148] In this application, the "junction" in "gastroesophageal junction cancer" is also called "junction," and its meaning is the same as that of "gastroesophageal junction cancer."

[0149] In this application, "head and neck squamous cell carcinoma" is also referred to as "head and neck squamous cell carcinoma." In this application, "gastrointestinal squamous cell carcinoma" is also referred to as "gastrointestinal squamous cell carcinoma." In this application, "respiratory squamous cell carcinoma" is also referred to as "respiratory squamous cell carcinoma." In this application, "upper gastrointestinal squamous cell carcinoma" is also referred to as "upper respiratory squamous cell carcinoma." In this application, "esophageal squamous cell carcinoma" is also referred to as "esophageal squamous cell carcinoma" or "esophageal squamous cell carcinoma." In this application, "gastroesophageal junction squamous cell carcinoma" is also referred to as "gastroesophageal junction squamous cell carcinoma." In this application, "lung squamous cell carcinoma" is also referred to as "lung squamous cell carcinoma." In this application, "nasopharyngeal squamous cell carcinoma" is also referred to as "nasopharyngeal squamous cell carcinoma" or "nasopharyngeal squamous cell carcinoma."

[0150] The pharmaceutical compositions of the present application can be prepared using methods known in the art.

[0151] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or their pharmaceutically acceptable salts with a pharmaceutically acceptable carrier. The purpose of a pharmaceutical composition is to facilitate the administration of a pharmaceutically acceptable salt of a compound of the present application, its stereoisomer, or a prodrug to an organism. The pharmaceutical composition of the present application can be prepared using conventional methods in the art.

[0152] In the context of this application, the term "pharmaceutically acceptable carrier," also referred to as "excipient," "pharmaceutically acceptable adjuvant," or "pharmaceutically acceptable auxiliary agent," refers to an auxiliary agent that has no obvious irritating effect on organisms and does not impair the biological activity and performance of the active compound. The term "pharmaceutically acceptable carrier" includes, but is not limited to, solvents, propellants, solubilizers, cosolvents, emulsifiers, colorants, adhesives, fillers, etc. Those skilled in the art can select specific pharmaceutically acceptable auxiliary agents according to actual needs and prepare the desired dosage form, such as tablets. Knowledge about auxiliary agents is well known to those skilled in the art; see, for example, "Pharmaceutics" (edited by Cui Fu-de, 5th edition, People's Health Publishing House, 2003).

[0153] ORR is calculated from the date of first administration and includes the percentage of subjects with complete response (CR) and partial response (PR) among all enrolled subjects.

[0154] PFS is calculated from the day of first administration to the date of tumor progression (PD assessed by imaging diagnosis) or death from all causes (whichever occurs first).

[0155] OS: Time to death from any cause, calculated from the date of first administration (time of last follow-up for subjects lost to follow-up, or end of follow-up for subjects still alive at the end of the study).

[0156] DCR is calculated from the day of first administration and is defined as the percentage of subjects with CR, PR, or stable disease (SD) among all enrolled subjects.

[0157] DOR: The time from the first tumor assessment of CR or PR to the first assessment of PD or death from any cause.

[0158] CR refers to a complete response, i.e., all target lesions must disappear and the short axis of all pathological lymph nodes (including target and non-target nodes) must decrease to <10 mm.

[0159] PR refers to a partial response, where the sum of the diameters of the target lesions is reduced by at least 30% from baseline levels.

[0160] PD refers to the progression of PD disease, which must be met by a relative increase of at least 20% (based on the baseline value if the baseline measurement is the smallest) of the sum of the diameters of all target lesions measured throughout the study process, and by a relative increase of at least 5 mm of the sum of the diameters. The appearance of one or more new lesions is also considered to be disease progression.

[0161] SD: This refers to stable disease, with the target lesion not reaching PR level and the degree of increase not reaching PD level, and is somewhere between the two.

[0162] The words "including" or "including" should be understood in an open and non-exclusive sense, i.e. "including but not limited to."

[0163] Within the scope of this application, various options of any one feature can be combined with various options of other features to form many different embodiments. This application is intended to include all possible embodiments consisting of various options of all technical features. It should be understood that within the scope of the present invention, the above technical features of the present invention and the technical features specifically described below (such as in the examples) can be combined to form new or preferred technical solutions, and detailed descriptions thereof will be omitted due to space limitations.

[0164] The compounds of the present application can be produced by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining these with other chemical synthetic methods, and equivalent substitution forms well known to those skilled in the art, and preferred embodiments include, but are not limited to, the examples of the present application.

[0165] The chemical reactions of the specific embodiments of the present application are completed in a suitable solvent, which must be suitable for the chemical transformations of the present application and the necessary reagents and materials. To obtain the compounds of the present application, one skilled in the art may need to modify or select synthetic steps or reaction processes based on the existing embodiments.

[0166] The present application will be specifically described below with reference to examples, but these examples do not limit the present application.

[0167] All reagents and solvents used in this application are commercially available and can be used without further purification. DETAILED DESCRIPTION OF THE INVENTION

[0168] The technical solution of the present application will be explained in more detail below with specific examples, measurement examples, and test examples. The following examples, measurement examples, and test examples are merely for illustrative purposes and should not be construed as limiting the scope of the present invention. Non-essential improvements and adjustments made to the embodiments by those skilled in the art based on the above content of the invention still fall within the scope of the present invention. Unless otherwise specified, the raw materials and reagents (e.g., organic solvents, inorganic solvents, etc.) used in the following examples and measurement examples are all commercially available or may be manufactured or prepared according to known methods or reagent instructions.

[0169] In the following examples, the analytical and measuring conditions are as follows:

[0170] 1. X-ray powder diffraction (X-ray powder diffractometer, XRPD) Equipment: German BRUKER D8 Advance X-ray powder diffractometer.

[0171] The conditions were Cu-Kα radiation (λ = 1.5418 Å), tube pressure 40 kV, tube current 40 mA, 2θ scan range 3–40°, scan step length 0.02° (2θ), scan speed 10 s / step, and sample tray zero-background sample tray.

[0172] Method: Place the sample on a zero-background single crystal silicon sample tray, gently press it flat with a spoon, and then measure it.

[0173] 2. Chloride Testing equipment: Dionex ICS-900 ion chromatograph Column: Dionex Ion Pac AS11-HC anion chromatography column (4 x 250 mm) Measurement method: Accurately measure 10 μL of each of the control solution and sample solution, inject them into the ion chromatograph, record the chromatograms, and calculate the chloride ion content from the peak area according to the external standard method.

[0174] 3. Dynamic moisture sorption / desorption analysis (DVS) Equipment DVS Intrinsic plus (SMS, UK).

[0175] Method The sample is placed in a tared sample basket, the sample weight is automatically determined, and the sample is analyzed according to the parameters in Table 1 below.

[0176] [Table 1]

[0177] 4. Thermogravimetric analysis (TGA) testing conditions Equipment Discovery TGA 55.

[0178] Conditions: Temperature range from room temperature to 350°C, heating rate 10°C / min, purge gas nitrogen, flow rate in the equilibrium chamber 40 mL / min, flow rate in the sample chamber 25 mL / min.

[0179] Sample 1–5 mg.

[0180] Example 1 Preparation of Compound B

[0181] [ka]

[0182] Compound A (0.52 g, which can be prepared by referring to Preparation Example 10 of WO2017140269A1) and methanol (25 mL) were added to a reaction flask and stirred to homogeneously disperse the system. Hydrochloric acid methanol solution (1.2 mL, 2 mol / L) was added dropwise under stirring, and stirring was continued for 5 hours. The mixture was filtered and vacuum dried (vacuum dried at 30°C for 12 hours until a constant weight was reached, and then vacuum dried at 45°C until the solvent residue passed the test) to obtain a solid (0.53 g). Nuclear magnetic resonance analysis confirmed the formation of a salt.

[0183] By measuring the chloride ion content by ion chromatography and calculating the stoichiometry of the hydrochloride salt (shown in the table below), it can be estimated that the base / acid ratio of the hydrochloride salt is 1:2.

[0184] [Table 2]

[0185] A sample of the resulting solid was taken and subjected to X-ray powder diffraction. The result showed good crystallinity and was named crystalline form I. Its diffraction peak data are shown in Table 2.

[0186] [Table 3]

[0187] .

[0188] Example 2 Preparation of Crystalline Form I of Compound B Compound A (1.0432 g, prepared by reference to Example 10 of WO2017140269A1) and purified water (3 mL) were added to a reaction flask and stirred to homogenize the system. A 2N aqueous solution of hydrochloric acid was added dropwise and stirred until completely dissolved. Crystalline Form I sample (0.01 g) obtained in Example 1 was added as seed crystals and stirred for 20-24 hours to crystallize, followed by suction filtration. After vacuum drying at 30°C for 12 hours, the material was further vacuum dried at 45°C until the residual solvent level passed. A solid (1.112 g) was obtained. Analysis confirmed that crystalline Form I of Compound B was obtained, with good crystallinity. The XRPD characterization data for the resulting sample are shown in Table 3. A sample was taken and subjected to TGA-DSC analysis, which showed that the sample contained no crystal water or crystal solvent.

[0189] [Table 4]

[0190] .

[0191] Example 3. Preparation of other salts of Compound A To a flask containing 5 mL of a 0.02 mol / mL solution of an acid (phosphoric acid, maleic acid, tartaric acid, fumaric acid) in tetrahydrofuran / methanol (1:1, volume ratio, the same applies below), 10 mL of a 0.01 mol / mL solution of compound A in tetrahydrofuran / methanol (1:1) was added sequentially, stirred to mix uniformly, and reacted at 40°C for 1 hour. The reaction solution was evaporated to dryness and then dried at 50°C for 3-4 hours. Solids were obtained in all cases, and were analyzed by nuclear magnetic chromatography and ion chromatography to identify the phosphate, maleate, tartrate, and fumarate salts of compound A, respectively.

[0192] Furthermore, the crystallinity of the obtained solids was found to be good by XRPD.

[0193] Measurement example 1: Solubility experiment First, the solubility of Compound A, the sample obtained in Example 2 (Compound B), and the sample obtained in Example 3 was measured in water. Next, the solubility of Compound A and the sample obtained in Example 2 (Compound B) was measured in NaHPO-citrate buffer (pH 4.6) medium, and the experimental results are shown in Tables 4 and 5, respectively.

[0194] [Table 5]

[0195] [Table 6]

[0196] The results showed that the sample obtained in Example 2 and the different salt samples obtained in Example 3 had good solubility in water, and the solubility was significantly better than that of the free base, meeting the general requirements for oral dosage forms regarding the solubility of raw drug substances. In particular, the sample obtained in Example 2 met the general requirements for multiple drug dosage forms (e.g., solid oral dosage forms, injections, oral liquids, etc.) regarding the solubility of raw drug substances. The sample obtained in Example 2 also had better solubility in buffer solution than Compound A.

[0197] Measurement example 2: Water adsorption and desorption experiment To determine the moisture absorption performance of various salt types, a dynamic moisture sorption apparatus (DVS) was used to test the moisture adsorption and desorption of the samples obtained in Examples 2 and 3 at a temperature of 25°C and a relative humidity of 40-80%, and the experimental results are shown in Table 6.

[0198] [Table 7]

[0199] .

[0200] The results showed that the sample obtained in Example 3 was slightly hygroscopic (maleate salt) or had hygroscopicity but not a high moisture gain, while the sample obtained in Example 2 had slightly hygroscopicity but an even lower moisture gain.

[0201] Measurement example 3: Solid stability test The physical and chemical stability of the sample obtained in Example 2 was examined when it was left at 40°C / 75% RH (open) and 60°C (sealed) for 7 days, and the physical stability when it was left at room temperature / 92.5% RH (open) for 10 days. The experimental results are shown in Table 7 below.

[0202] [Table 8]

[0203] The results showed that there was no significant change in the purity of compound B and no change in its crystalline form after 7 days at 40°C / 75%RH and 60°C, and the crystalline form remained unchanged even after 10 days at 92.5%RH, indicating that compound B has good chemical stability and its crystalline form I has good physical stability.

[0204] Measurement example 4 Polishing stability experiment The samples obtained in Example 2 were mechanically polished using a polishing bowl for 2 minutes and 5 minutes, respectively, and analyzed by X-ray powder diffraction. The results showed that the crystalline form of Form I remained unchanged after polishing.

[0205] Furthermore, samples obtained in Example 2 were taken, and each was dropped with an appropriate amount of organic solvent (methanol, ethanol, acetone, acetonitrile, ethyl acetate, etc.), and then mechanically polished. Measurement by X-ray powder diffraction showed that the crystalline form I remained unchanged after polishing.

[0206] From the above, it can be seen that the salts of compound A of the present application have relatively good medicinal potential, and in particular, compound B of the present application and its crystalline form I have better medicinal potential compared to other crystalline forms or salt forms thereof.

[0207] For the preparation and determination of compound B and its crystalline form I, reference may be made to patent application CN202210268968.7 or PCT / CN2023 / 082140, the entire contents of which are incorporated herein by reference.

[0208] Test Example 1: Clinical Phase I Study and Results Drug Compound B, tablets.

[0209] 1. Research method 1.1 Enrollment criteria include: (1) patients must be 18 to 70 weeks of age (inclusive) at the time of signing informed consent; (2) patients must have unresectable locally advanced or metastatic solid tumors confirmed by histopathology or cytology, have failed or cannot tolerate standard treatment, or have no alternative standard treatment regimen; (3) patients must have at least one measurable lesion meeting the definition of RECIST v1.1; and (4) patients must have an ECOG performance status (PS) score of 0 to 1.

[0210] 1.2 Dosage regimen (1) Dose Escalation Steps: Starting doses were 1 mg, 2 mg, 4 mg, 6 mg, 9 mg, 12 mg, 16 mg, 20 mg, and 25 mg, administered orally once daily. Seven days after the single dose, subjects entered the multiple-dose period (28-day cycles, administered continuously until disease progression or intolerable toxicities occurred). Subjects who completed the single-dose and first cycle of multiple-dose treatment and observation could enter an extended treatment period with 4-week cycles if they benefited from and were able to tolerate the study drug, depending on their intentions.

[0211] (2) Dose expansion phase: 4 mg and 6 mg were administered orally once daily. For the continuous administration group, one cycle was administered every 4 weeks, for the 3-week administration with 1-week rest group, one cycle was administered every 4 weeks, and for the 2-week administration with 1-week rest group, one cycle was administered every 3 weeks.

[0212] 1.3 Outcome Evaluation (1) Efficacy Evaluation In this study, for the dose escalation step, treatment effect evaluations were performed 4, 8, and 12 weeks after Day 1 of multiple administration, and once every 8 weeks thereafter, and data analysis was performed. For the dose expansion step, treatment effect evaluations were performed 4, 8, and 12 weeks after Day 1 of multiple administration in the 3-week on-1-week rest group, and once every 8 weeks thereafter in the 2-week on-1-week rest group, and once every 6 weeks after Day 1 of multiple administration in the 2-week on-1-week rest group. Efficacy endpoints included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and duration of response (DOR). (2) Safety Evaluation This included evaluations of vital signs and physical examination, electrocardiogram, ECOG PS score, laboratory tests, adverse events, etc.

[0213] 2. Clinical Trial Results 2.1 Effectiveness evaluation results In the therapeutic efficacy data already obtained for various solid tumors, Compound B has shown good therapeutic efficacy for patients with solid tumors. In particular, Compound B has shown clinical benefits for esophageal cancer and squamous cell carcinoma (e.g., esophageal squamous cell carcinoma, lung squamous cell carcinoma, nasopharyngeal squamous cell carcinoma, etc.), especially for esophageal squamous cell carcinoma.

[0214] 2.1.1 Treatment Efficacy Data Eighty-three patients with solid tumors were treated, including 48 patients with squamous cell carcinoma, specifically 41 patients with esophageal squamous cell carcinoma, 5 patients with lung squamous cell carcinoma, and 2 patients with nasopharyngeal squamous cell carcinoma. Evaluation revealed that in the 41 patients with esophageal squamous cell carcinoma, 6 patients achieved partial response and 21 patients achieved stable disease (11 of which showed a reduction in the target lesion). In the five patients with lung squamous cell carcinoma, all four patients achieved a reduction in the target lesion. In the two patients with nasopharyngeal squamous cell carcinoma, one patient achieved a reduction in the target lesion.

[0215] 2.2 Typical cases (1) Typical Case 1 Subject S03002, a 57-year-old male, was diagnosed with esophageal squamous cell carcinoma on August 23, 2020. The subject participated in the clinical trial "Tripaliumab / placebo + Paclitaxel injection + Cisplatin injection" in September 2020, was treated with "Tripaliumab / placebo + Paclitaxel injection + Cisplatin injection" from September 24, 2020 to January 2021, and was treated with "Tripaliumab / placebo + Paclitaxel injection + Cisplatin injection" from February 2021 to April 2021. The optimal treatment effect was SD, and on April 20, 2021, the treatment effect evaluation revealed PD and the subject was removed from the group.

[0216] The subject signed the ICF on April 21, 2021, was screened for stage IV, and first received study drug on April 30, 2021, administered at 6 mg QD continuously.

[0217] During the administration period, the subject's evaluation of the therapeutic effect at the end of the first, second, and third cycles was PR, with PR being the optimal therapeutic effect.

[0218] (2) Typical Case 2 Subject S03008, a 68-year-old male, was diagnosed with esophageal squamous cell carcinoma on August 30, 2019. The subject participated in the clinical trial "sintilimab / placebo + paclitaxel + cisplatin" from October 17, 2019 to December 2021, with the optimal treatment effect being PR, and in December 2021, treatment effect evaluation determined it to be PD.

[0219] The subject signed the ICF on January 13, 2022, was screened for stage IV, and first received study drug on February 9, 2022, administered at 6 mg QD continuously.

[0220] During the treatment period, the subject's treatment effect at the end of the first cycle was SD, and at the end of the second, third, and fifth cycles, the treatment effect was PR, with the best treatment effect being PR. The patient is still receiving treatment.

[0221] The treatment effect evaluation so far remains positive, and the patient is currently undergoing the 18th cycle of treatment.

[0222] (3) Typical Case 3 Subject S03009, a 49-year-old male, was diagnosed with stage III esophageal squamous cell carcinoma in January 2021. From February 2021, he underwent three cycles of treatment with a combination of albumin, paclitaxel, and nedaplatin, but the optimal therapeutic effect was unknown. From April 2021, he participated in a clinical trial of tislelizumab / placebo + synchronous chemotherapy (chemotherapeutic drugs paclitaxel + injectable cisplatin), and in December 2021, he was diagnosed with PD based on the evaluation of treatment effect.

[0223] The subject signed the ICF on February 9, 2022, was screened for Stage IV, and first received study drug on February 21, 2022, administered at 9 mg QD continuously.

[0224] During the administration period, the subject's evaluation of the therapeutic effect at the end of the first, second, and third cycles was PR, with PR being the optimal therapeutic effect.

[0225] (4) Typical Case 4 Subject S03018, a 64-year-old male, was diagnosed with esophageal squamous cell carcinoma on February 10, 2022. From February 19, 2022 to April 26, 2022, he underwent two cycles of treatment with albumin-bound paclitaxel, lobaplatin, and camrelizumab. The optimal treatment effect was SD, and the treatment was subsequently discontinued due to intolerance. On July 5, 2022, the patient was diagnosed with PD based on the evaluation of treatment effect.

[0226] The subject signed the ICF on July 19, 2022, was screened for stage IV, and first received the study drug on August 1, 2022, at 6 mg QD. During the treatment period, the subject's treatment effect was evaluated as SD at the end of the first cycle, and as PR at the end of the second and third cycles, with PR being confirmed as the optimal treatment effect.

[0227] (5) Typical Case 5 Subject S03025, a 66-year-old male, was diagnosed with esophageal squamous cell carcinoma on August 1, 2017. From August 8, 2019, to November 20, 2019, he received six cycles of toripalimab injection / placebo + paclitaxel + cisplatin, with an optimal response of SD. From December 11, 2019, to August 10, 2021, he received 25 cycles of toripalimab injection / placebo maintenance therapy, with an optimal response of SD. From December 8, 2021, to March 22, 2022, he received six cycles of paclitaxel polymer micelles, with an optimal response of SD. On January 11, 2023, he was diagnosed with progressive disease.

[0228] The subject signed the ICF on January 13, 2023, was screened for stage IV disease, and first received the study drug on February 7, 2023, at 6 mg QD. During the treatment period, the subject's treatment effect was SD at the end of the first cycle, and PR at the end of the second, third, and fifth cycles, with PR confirmed as the optimal treatment effect. Treatment is currently ongoing.

[0229] (6) Typical Case 6 Subject S03033, a 50-year-old male, was diagnosed with esophageal squamous cell carcinoma on August 5, 2020. From October 20, 2022 to March 23, 2023, he received five cycles of paclitaxel + nedaplatin, with the optimal treatment outcome being partial response. From April 12, 2023 to May 10, 2023, he received two cycles of sintilimab, with the optimal treatment outcome being stable disease. On May 20, 2023, he was diagnosed with PD based on treatment outcome evaluation.

[0230] The subject signed the ICF on May 25, 2023, was screened for stage IV, and first received the study drug on June 5, 2023, at 6 mg QD for 3 weeks followed by a 1-week break. During the treatment period, the subject achieved partial response at the end of the first cycle. Treatment is currently ongoing.

[0231] (7) Typical Case 7 Subject S01001, a 40-year-old male, was diagnosed with nasopharyngeal squamous cell carcinoma on June 1, 2017. From June 23, 2017, to July 17, 2017, he received two cycles of paclitaxel plus cisplatin, with an optimal response of SD. From August 4, 2017, to August 9, 2017, he received one cycle of gemcitabine plus ifosfamide, with an optimal response of SD. From September 18, 2017, to November 18, 2017, he received radiation therapy to the neck and cervical lymph nodes, with an optimal response of PR. From September 18, 2017, to October 30, 2017, he received two cycles of concurrent cisplatin, with an optimal response of SD. From April 27, 2018 to May 4, 2018, radiation therapy was administered to the thoracic spine, and from November 7, 2019 to January 16, 2020, six cycles of geptanolimab (PD-1 monoclonal antibody) were administered, with the optimal treatment effect being SD. In June 2020, the patient was diagnosed with PD after evaluation of the treatment effect.

[0232] The subject signed the ICF on August 19, 2020, was screened for stage IV, and first received the study drug on September 11, 2020, at 2 mg (escalated dose) administered QD. During the administration period, the optimal treatment effect was SD, with the target lesion shrinking by up to 7.9%, and the SD duration was 24 months.

[0233] (8) Typical Case 8 Subject S09009, a 57-year-old male, was diagnosed with lung squamous cell carcinoma on February 7, 2020. From May 11, 2020, to June 25, 2020, he underwent radiotherapy for right hilar and hilar lymph node metastases. From May 11, 2020, he also underwent concurrent treatment with cisplatin and etoposide, with an optimal therapeutic response of SD. From July 23, 2020, to November 25, 2022, he underwent 32 cycles of sintilimab treatment, with an optimal therapeutic response of SD. In February 2023, he was diagnosed with PD.

[0234] The subject signed the ICF on February 3, 2023, was screened for stage IV, and first received the study drug on February 10, 2023, at 4 mg QD. During the administration period, the optimal treatment effect was SD, with the target lesion shrinking by up to 10.7%, and the SD duration has been ongoing for 4 months.

[0235] 2.2 Safety evaluation results Monotherapy with Compound B was generally safe and controllable, with common (≥10%) adverse reactions including proteinuria, hypertension, hypoalbuminemia, decreased platelet count, decreased white blood cell count, elevated alanine aminotransferase, elevated aspartate aminotransferase, hyperuricemia, rash, anemia, and fatigue. The severity of most adverse reactions was grade 2 or less, the majority remained untreated, and the majority of outcomes were improvement / complete recovery, indicating that adverse reactions with Compound B were relatively mild. The types of adverse reactions with Compound B were comparable to those of other similar protein kinase inhibitors, with relatively mild severity and a relatively low incidence of adverse reactions of grade 3 or higher.

[0236] Comparison with Similar Products Reference is made to the disclosed clinical study results of several correlated protein kinase inhibitors (shown in the table below).

[0237] [Table 9]

[0238] The full names and Japanese names of abbreviations used in the specification of this application are as shown in Table 9 below.

[0239] [Table 10]

[0240] Although the embodiments of the present invention have been described above, the present invention is not limited to the above embodiments. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention should be included within the scope of the claims of the present invention.

Claims

1. Use of compound A or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a tumor, wherein the tumor is esophageal cancer or gastroesophageal junction cancer. 【Chemical 1】 。

2. The use according to claim 1, characterized in that the tumor is esophageal squamous cell carcinoma, esophageal adenocarcinoma, gastroesophageal junction squamous cell carcinoma or gastroesophageal junction adenocarcinoma, preferably the tumor is esophageal squamous cell carcinoma or gastroesophageal junction squamous cell carcinoma.

3. 3. Use according to claim 1 or 2, characterized in that the tumor is a locally advanced or metastatic tumor, preferably a locally advanced or metastatic tumor that is not surgically resectable.

4. The use according to any one of claims 1 to 3, characterized in that the tumor is a tumor for which previous treatment has failed.

5. The use according to any one of claims 1 to 4, characterized in that the tumor is a tumor for which systemic drug treatment has failed.

6. The use according to any one of claims 1 to 5, characterized in that the tumor is a tumor for which first-line treatment has failed, a tumor for which second-line treatment has failed or a tumor for which subsequent lines of treatment have failed.

7. The use according to any one of claims 1 to 6, wherein the tumor is a tumor that has failed treatment with one, two, three or more of immunotherapy drugs, chemotherapy drugs, radiotherapy, biological therapy, traditional Chinese medicine therapy, and small molecule targeted drugs, preferably a tumor that has failed treatment with radiotherapy, immunotherapy drugs, or chemotherapy drugs, more preferably a tumor that has failed treatment with radiotherapy and immunotherapy drugs, more preferably a tumor that has failed treatment with radiotherapy and chemotherapy drugs, more preferably a tumor that has failed treatment with chemotherapy drugs and immunotherapy drugs, more preferably a tumor that has failed treatment with chemotherapy drugs, immunotherapy, and radiotherapy.

8. Use of compound A or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a tumor, comprising: 【Chemistry 2】 、 Wherein the tumor is squamous cell carcinoma.

9. The use according to claim 8, wherein the tumor is selected from head and neck squamous cell carcinoma, gastrointestinal squamous cell carcinoma and respiratory squamous cell carcinoma, preferably the tumor is selected from head and neck squamous cell carcinoma, upper gastrointestinal squamous cell carcinoma and respiratory squamous cell carcinoma, more preferably the tumor is selected from esophageal squamous cell carcinoma, gastroesophageal junction squamous cell carcinoma, head and neck squamous cell carcinoma and lung squamous cell carcinoma, more preferably the tumor is selected from esophageal squamous cell carcinoma, gastroesophageal junction squamous cell carcinoma, nasopharyngeal squamous cell carcinoma and lung squamous cell carcinoma, more preferably the tumor is selected from nasopharyngeal squamous cell carcinoma, esophageal squamous cell carcinoma and lung squamous cell carcinoma, more preferably the tumor is esophageal squamous cell carcinoma.

10. 10. Use according to claim 8 or 9, characterized in that the tumor is a locally advanced or metastatic tumor, preferably a locally advanced or metastatic tumor that is not surgically resectable.

11. The use according to any one of claims 8 to 10, characterized in that the tumor is a tumor for which previous treatment has failed.

12. The use according to any one of claims 8 to 11, characterized in that the tumor is a tumor for which systemic drug treatment has failed.

13. Use according to any one of claims 8 to 12, characterized in that the tumor is a tumor for which first-line treatment has failed, a tumor for which second-line treatment has failed or a tumor for which subsequent lines of treatment have failed.

14. The use according to any one of claims 8 to 13, characterized in that the tumor is one that has failed treatment with one, two, three or more of immunotherapy drugs, chemotherapy drugs, radiotherapy, biological therapy, traditional Chinese medicine therapy and small molecule targeted drugs.

15. The use according to claim 7 or 14, characterized in that the chemotherapeutic drug is selected from cytotoxic drugs, antimetabolites, antibiotics, alkaloids, DNA topoisomerase inhibitor chemotherapeutics, anti-microtubule chemotherapeutics, platinum-based chemotherapeutics and hormone-based drugs, preferably the chemotherapeutic drug is selected from antimetabolites, alkaloids, DNA topoisomerase inhibitor chemotherapeutics, anti-microtubule chemotherapeutics and platinum-based chemotherapeutics.

16. The use according to claim 7, 14 or 15, wherein the chemotherapeutic agent is selected from taxanes, platinum-based agents, fluorouracil-based agents or DNA topoisomerase inhibitor-based chemotherapeutic agents, preferably the taxanes are selected from paclitaxel, docetaxel or cabazitaxel, preferably the DNA topoisomerase inhibitor-based chemotherapeutic agents are selected from hydroxycamptothecin, irinotecan, topotecan, etoposide or teniposide, preferably the platinum-based agents are selected from cisplatin, carboplatin, sulfatodiaminocyclohexane platinum, lobaplatin, oxaliplatin or nedaplatin, preferably cisplatin, oxaliplatin or nedaplatin, more preferably the chemotherapeutic agent is selected from paclitaxel, cisplatin or nedaplatin.

17. The use of claim 7 or 14, wherein the immunotherapeutic agent is selected from an anti-PD-1 antibody, an anti-PD-L1 antibody, and an antibody-drug conjugate, preferably the antibody-drug conjugate is an anti-HER2 antibody-drug conjugate, preferably the anti-PD-1 antibody is selected from pembrolizumab, camrelizumab, tislelizumab, nivolumab, cemiplimab, sintilimab, or toripalimab, preferably the anti-PD-1 antibody is selected from toripalimab, sintilimab, or tislelizumab, preferably the anti-PD-L1 antibody is selected from atezolizumab, avelumab, or durvalumab, and preferably the anti-HER2 antibody-drug conjugate is selected from trastuzumab or dicitamab.

18. The use according to any one of claims 1 to 17, wherein the tumor has failed treatment with chemotherapy and immunotherapy, preferably has failed treatment with a taxane-based chemotherapy drug plus a platinum-based chemotherapy drug plus an anti-PD-1 antibody, more preferably has failed treatment with one, two, three or more of toripalimab + paclitaxel + cisplatin, sintilimab + paclitaxel + cisplatin, paclitaxel + lobaplatin + camrelizumab, paclitaxel + nedaplatin, sintilimab.

19. The use according to any one of claims 1 to 16, characterized in that the tumor is a tumor that has failed treatment with a chemotherapy drug, preferably a tumor that has failed treatment with a taxane-based plus platinum-based chemotherapy drug, more preferably a tumor that has failed treatment with paclitaxel plus cisplatin or paclitaxel plus nedaplatin.

20. The use according to any one of claims 1 to 17, wherein the tumor has failed treatment with chemotherapy, immunotherapy and radiotherapy, preferably has failed treatment with taxanes + platinum-based chemotherapy + radiotherapy + anti-PD-1 antibodies, more preferably has failed treatment with tislelizumab + radiotherapy + paclitaxel + cisplatin.

21. The use according to any one of claims 1 to 20, wherein the dosage of compound A or a pharmaceutically acceptable salt thereof is 1 to 50 mg per day, preferably 1 to 30 mg, more preferably 1 to 25 mg, more preferably 1 to 20 mg, more preferably 2 to 18 mg, more preferably 4 to 16 mg, more preferably 5 to 15 mg, more preferably 4 to 10 mg, more preferably 4 to 9 mg, more preferably 2 to 9 mg, more preferably 2 to 6 mg, more preferably 5 to 9 mg, more preferably 6 to 9 mg, more preferably 6 to 8 mg, more preferably 6 to 12 mg, more preferably 6 to 10 mg, more preferably 2, 3, 4, 5, 6, 7, 8, 9, 10 mg.

22. The use according to any one of claims 1 to 21, characterized in that the administration frequency of compound A or its pharmaceutically acceptable salt is once a day, twice a day, three times a day or more.

23. The use according to any one of claims 1 to 22, wherein the compound A or a pharmaceutically acceptable salt thereof is administered in a continuous or interval administration manner, preferably wherein the interval administration comprises an administration period and a drug-free period.

24. The use according to claim 23, characterized in that the administration method of compound A or a pharmaceutically acceptable salt thereof is to administer it continuously for 3 weeks, followed by a 1-week break.

25. The use according to any one of claims 1 to 24, characterized in that the drug is further used in combination with one, two, three or more drugs commonly used in clinical practice to treat esophageal cancer, gastroesophageal junction cancer or squamous cell carcinoma.

26. The use according to any one of claims 1 to 25, characterized in that the pharmaceutically acceptable salt is selected from hydrochloride, hydrobromide, nitrate, sulfate, phosphate, formate, acetate, propionate, benzoate, maleate, fumarate, succinate, tartrate, citrate, methanesulfonate, ethanesulfonate, benzenesulfonate and p-toluenesulfonate, preferably hydrochloride, hydrobromide, maleate, phosphate, tartrate, fumarate and succinate, more preferably hydrochloride, maleate, phosphate, tartrate and fumarate, more preferably hydrochloride.

27. Use according to any one of claims 1 to 26, characterized in that the pharmaceutically acceptable salt of compound A is compound B. 【Chemistry 3】 。

28. 28. Use according to claim 27, characterized in that compound B is in solid form, preferably it is in crystalline form.

29. 29. The use according to claim 27 or 28, wherein the crystalline form of compound B is crystalline form I, characterized in that the X-ray powder diffraction pattern, expressed in 2θ angles using Cu-Kα radiation, contains characteristic peaks at the following positions: 5.0±0.2°, 13.5±0.2°, 19.3±0.2°, 20.5±0.2°, 21.4±0.2° and 25.2±0.2°.

30. A pharmaceutical composition for treating a tumor, comprising compound A according to any one of claims 1 to 26 or a pharmaceutically acceptable salt thereof, or compound B according to any one of claims 27 to 29, and optionally a pharmaceutically acceptable carrier, wherein the tumor is esophageal cancer, gastroesophageal junction cancer, or squamous cell carcinoma.

31. The pharmaceutical composition according to claim 30, comprising compound A or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, and further comprising a therapeutically effective amount of another drug, wherein the other drug is one, two, three or more drugs selected from drugs commonly used in clinical practice to treat esophageal cancer, gastroesophageal junction cancer or squamous cell carcinoma.

32. The pharmaceutical composition according to claim 30 or 31, comprising compound B and a pharmaceutically acceptable carrier, and further comprising a therapeutically effective amount of another drug, wherein the other drug is one, two, three or more drugs selected from drugs commonly used in clinical practice to treat esophageal cancer, gastroesophageal junction cancer or squamous cell carcinoma.

33. 33. A pharmaceutical kit comprising: (a) at least one unit dose of the pharmaceutical composition of any one of claims 30 to 32; and (b) instructions for treating a tumor, wherein the tumor is esophageal cancer, gastroesophageal junction cancer, or squamous cell carcinoma.

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