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 to a prior application filed with the China National Intellectual Property Administration on August 31, 2022, with patent application number 202211062094.6 and titled "Use of Heteroaryloxynaphthalene Compounds". The full text of that application is incorporated herein by reference in its entirety.

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

[0003] Squamous cell carcinoma (SCC), also known as epidermoid carcinoma, includes various types of cancers caused by squamous epithelial cells. These cells form on the skin surface, the inner walls of hollow organs of the body, as well as the inner walls of the respiratory and digestive tracts, and include, for example, squamous cell carcinoma of the skin, head and neck, digestive tract (e.g., esophagus), and respiratory tract (e.g., lung), depending on the site of the body.

[0004] Esophageal cancer is one of the common malignant tumors worldwide, ranking 8th in incidence and 6th in mortality among all types of cancers respectively. In addition, compared with the general population, the risk of developing multiple primary malignant tumors in the population with esophageal cancer is increased, with the incidence rate as high as 9.5% to 21.9%. Histologically, esophageal cancer is mainly divided into two types: squamous cell carcinoma (esophageal squamous cell carcinoma) and adenocarcinoma (esophageal adenocarcinoma).

[0005] The clinical symptoms of early-stage esophageal cancer are not obvious and difficult to detect. Many patients with esophageal cancer are already in the locally advanced stage or have distant metastasis at the time of confirmed diagnosis. Although methods such as surgical treatment, endoscopic treatment, radiotherapy, chemotherapy and immunotherapy are used in clinical practice, there is still the problem of poor prognosis for patients, with an overall 5-year survival rate of only 10% to 20%.

[0006] According to the Chinese Society of Clinical Oncology (CSCO) Esophageal Cancer Treatment Guidelines (2022 edition), the first-line treatment for advanced esophageal cancer is primarily a combination of chemotherapy and immunotherapy, or combination chemotherapy, stratified into squamous cell carcinoma and HER-2 negative adenocarcinoma (PS=0-2). For recommended second-line and higher-level treatments, for patients stratified into PS=0-2, the Class I recommendation is primarily monotherapy and monoimmunotherapy. Currently, there are no commercially available small molecule targeted drugs for treating esophageal cancer. Furthermore, among the chemotherapy drugs used in the treatment of advanced esophageal cancer recommended in the guidelines, drugs containing platinum and fluorouracil are frequently used, but these always carry cytotoxic side effects. At the same time, many studies have shown that the development of multiple primary malignancies associated with esophageal cancer is clearly correlated with the effects of genetic factors and iatrogenic factors (e.g., radiotherapy or chemotherapy). Radiotherapy and chemotherapy, which are commonly seen in the treatment process of esophageal cancer, may increase patient survival rates but also increase the risk of developing associated multiple primary malignancies. Therefore, for esophageal cancer patients whose existing treatments have failed, there is still no standard treatment regimen for subsequent-line treatment, and the efficacy of treatments with the same or similar mechanisms of action is difficult to guarantee. Patients who have progressed after receiving frontline treatments urgently need effective therapeutic drugs to address their clinically unmet needs.

[0007] CN108699030A discloses compound A (corresponding to compound S10), which has inhibitory activity against fibroblast growth factor receptor (FGFR) and vascular endothelial growth factor receptor (KDR or VEGFR2). Currently, there are no relevant research reports indicating its use in the treatment of squamous cell carcinoma, gastrointestinal squamous cell carcinoma, esophageal cancer, gastroesophageal junction cancer, etc.

[0008] [ka] [Overview of the project]

[0009] The technical problem to be solved by this application is to provide the use of compound A or a medicinal salt thereof in the manufacture of drugs for treating tumors, particularly squamous cell carcinoma, gastrointestinal squamous cell carcinoma, esophageal cancer, or gastroesophageal junction cancer.

[0010] Specifically, in the first aspect, the present application provides the use of compound A or a medicinal salt thereof in the manufacture of a drug 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 gene abnormalities and / or protein expression abnormalities of FGFR and / or VEGFR.

[0016] In some embodiments of the first aspect of the present application, the tumor is a tumor accompanied by genetic abnormalities and / or protein expression abnormalities of one, two, or three of the FGFR, VEGFR, and colony-stimulating factor 1 receptor (CSF1R). Preferably, the tumor is a tumor accompanied by genetic mutations of one, two, or three of the 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 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 that has failed to receive prior treatment.

[0019] In some embodiments of the first aspect of the present application, the tumor is a tumor that has failed to respond to systemic drug therapy.

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

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

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

[0023] In some embodiments of the first aspect of the present application, the tumor is a tumor that has failed to be treated with one, two, three or more of the following: immunotherapeutic agents, chemotherapeutic agents, radiotherapy, biotherapy, traditional Chinese medicine, and small molecule targeted drugs.

[0024] In some embodiments of the first aspect of this application, the tumor is a tumor that has failed to be treated with radiotherapy, immunotherapy drugs, or chemotherapy drugs. In some embodiments of the first aspect of this application, the tumor is a tumor that has failed to be treated with radiotherapy and immunotherapy drugs. In some embodiments of the first aspect of this application, the tumor is a tumor that has failed to be treated with radiotherapy and chemotherapy drugs. In some embodiments of the first aspect of this application, the tumor is a tumor that has failed to be treated with chemotherapy drugs and immunotherapy drugs. In some embodiments of the first aspect of this application, the tumor is a tumor that has failed to be treated with chemotherapy drugs, immunotherapy drugs, and radiotherapy drugs.

[0025] In some embodiments of the first aspect of the present application, the esophageal squamous cell carcinoma described above is esophageal squamous cell carcinoma accompanied by genetic abnormality 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 described above is esophageal squamous cell carcinoma accompanied by genetic abnormality and / or abnormal protein expression of 1, 2 or 3 selected from FGFR, VEGFR, and colony-stimulating factor 1 receptor (CSF1R). Preferably, the esophageal squamous cell carcinoma described above is esophageal squamous cell carcinoma accompanied by genetic mutation of 1, 2 or 3 selected from FGFR, VEGFR, and CSF1R.

[0027] In some embodiments of the first aspect of the present application, the esophageal squamous cell carcinoma described above 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 described above 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 described above is esophageal squamous cell carcinoma for which systemic drug therapy has failed.

[0030] In some embodiments of the first aspect of the present application, the esophageal squamous cell carcinoma described above is esophageal squamous cell carcinoma for which first-line therapy has failed.

[0031] In some embodiments of the first aspect of the present application, the esophageal squamous cell carcinoma described above is esophageal squamous cell carcinoma for which second-line therapy has failed.

[0032] In some embodiments of the first aspect of the present application, the esophageal squamous cell carcinoma described above is esophageal squamous cell carcinoma for which subsequent lines of therapy have failed.

[0033] In some embodiments of the first aspect of this application, the esophageal squamous cell carcinoma is an esophageal squamous cell carcinoma in which treatment with one, two, three or more of the following has failed: immunotherapy, chemotherapy, radiotherapy, biotherapy, traditional Chinese medicine, and small molecule targeted drugs. In some embodiments of the first aspect of this application, the esophageal squamous cell carcinoma is an esophageal squamous cell carcinoma in which treatment with radiotherapy, immunotherapy, or chemotherapy has failed. In some embodiments of the first aspect of this application, the esophageal squamous cell carcinoma is an esophageal squamous cell carcinoma in which treatment with radiotherapy and immunotherapy has failed. In some embodiments of the first aspect of this application, the esophageal squamous cell carcinoma is an esophageal squamous cell carcinoma in which treatment with radiotherapy and chemotherapy has failed. In some embodiments of the first aspect of this application, the esophageal squamous cell carcinoma is an esophageal squamous cell carcinoma in which treatment with chemotherapy and immunotherapy has failed. In some embodiments of the first aspect of the present application, the esophageal squamous cell carcinoma is an esophageal squamous cell carcinoma that has failed to be treated with chemotherapy, immunotherapy and radiotherapy.

[0034] In some embodiments of the first aspect of the present application, the chemotherapeutic agent is selected from cytotoxic agents, antimetabolites, antibiotics, alkaloids, DNA topoisomerase inhibitors, antimicrotubule chemotherapeutic agents, platinum-based chemotherapeutic agents, and hormonal agents, and preferably the chemotherapeutic agent is selected from antimetabolites, alkaloids, DNA topoisomerase inhibitors, antimicrotubule chemotherapeutic agents, and platinum-based chemotherapeutic agents.

[0035] In some embodiments of the first aspect of the present application, the chemotherapeutic agent is selected from taxane drugs, platinum drugs, fluorouracil drugs, or DNA topoisomerase inhibitor chemotherapeutic agents. 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, sulfatodiaminocyclohexaneplatin, 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 this application, the immunotherapy 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 this application, the anti-PD-1 antibody is selected from pembrolizumab, camrelizumab, tislerizumab, nivolumab, semiprimab, cintilimab, or tripalimab, and preferably, the anti-PD-1 antibody is selected from tripalimab, cintilimab, or tislerizumab. In some embodiments of the first aspect of this application, the anti-PD-L1 antibody is selected from atezolizumab, avelumab, or durvalumab. In some embodiments of the first aspect of this application, the anti-HER2 antibody-drug conjugate is selected from trastuzumab or disitamab.

[0037] In some embodiments of the first aspect of the present application, the tumor is a tumor that has failed to be treated with chemotherapy drugs and immunotherapy drugs, preferably a tumor that has failed to be treated with taxane-based + platinum-based chemotherapy drugs + anti-PD-1 antibodies, preferably a tumor that has failed to be treated with one, two, or three of the following: tripalimab + paclitaxel + cisplatin, cintirimab + paclitaxel + cisplatin, paclitaxel + lovaplatin + camrelizumab, paclitaxel + nedaplatin, and cintirimab. Preferably a tumor that has failed to be treated with one, two, or three of the following: tripalimab + paclitaxel + cisplatin, cintirimab + paclitaxel + cisplatin, paclitaxel + lovaplatin + camrelizumab. Preferably, the tumor is esophageal squamous cell carcinoma, and more preferably, the tumor is 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 to be treated with a chemotherapy drug, preferably a tumor that has failed to be treated with a taxane-based + platinum-based chemotherapy drug, and preferably a tumor that has failed to be treated with paclitaxel + cisplatin or paclitaxel + 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 to be treated with chemotherapy, immunotherapy and radiotherapy, preferably a tumor that has failed to be treated with taxane-based + platinum-based chemotherapy + radiotherapy + anti-PD-1 antibody, and preferably a tumor that has failed to be treated with tislerizumab + radiotherapy + paclitaxel + cisplatin. Preferably, the tumor is esophageal squamous cell carcinoma.

[0040] In some embodiments of the first aspect of the present application, the medicinal 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, even more preferably hydrochloride, and still more preferably dihydrochloride.

[0041] In some embodiments of the first aspect of this application, the medicinal 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 solid form, preferably in 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 the X-ray powder diffraction pattern, expressed as a 2θ angle using Cu-Kα radiation, includes characteristic peaks at the positions of 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 crystal form I is subjected to Cu-Kα radiation, and the X-ray powder diffraction pattern, represented by a 2θ angle, includes characteristic peaks at the positions of 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 crystal form I is subjected to Cu-Kα radiation, and the X-ray powder diffraction pattern, represented by a 2θ angle, includes characteristic peaks at the positions of 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 crystal form I is subjected to Cu-Kα radiation, and the X-ray powder diffraction pattern, represented by a 2θ angle, includes characteristic peaks at the positions of 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 above crystal form I is subjected to Cu-Kα radiation, and the X-ray powder diffraction patterns expressed at a 2θ angle are 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. It includes characteristic peaks at the following positions: 0.2°, 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 this application, compound A or a medicinal salt thereof is administered by a pharmaceutical route, which includes, but is not limited to, a route selected from oral, parenteral, or topical administration. 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 and includes, but is not limited to, oral formulations, parenteral formulations, topical formulations, or topical formulations, preferably oral formulations, and more preferably tablets and capsules.

[0052] In some embodiments of the first aspect of the present application, the drug comprises a formulation unit of 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 compound A or a pharmaceutically acceptable salt thereof. In some embodiments of the first aspect of the present application, the drug comprises, in each formulation unit, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, and 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 calculation is based on the mass containing compound B.

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

[0054] In some embodiments of the first aspect of this application, the dosage of compound A or its medicinal salt is determined according to the severity of the disease, the response to the disease, the toxicity associated with any treatment, the patient's age and health condition. In some embodiments of the first aspect of this application, the dosage of compound A or its medicinal salt 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 medicinal 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 daily dose is calculated by the mass containing compound B.

[0055] In some embodiments of the first aspect of this application, the administration frequency of compound A or a medicated salt thereof is once daily, twice daily, three times daily, or more. In some embodiments of the first aspect of this application, compound A or a medicated salt thereof is administered once daily. In some embodiments of the first aspect of this application, compound A or a medicated salt thereof is administered twice daily. In some embodiments of the first aspect of this application, compound A or a medicated salt thereof is administered three times daily. Preferably, the medicated 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 this application, the administration method is determined comprehensively based on the activity, toxicity, and patient tolerance of the drug. In some embodiments of the first aspect of this application, compound A or a medicinal salt thereof is administered by continuous or intermittent dosing. Preferably, the intermittent dosing includes an administration period and a rest period, and preferably, within the administration period, compound A or a medicinal salt thereof is administered once, twice, three or more times a day. For example, within the administration period, compound A or a medicinal salt thereof is administered once a day, then administration is stopped for a certain period within the rest period, followed by an administration period, then a rest period, and so on, repeated multiple times. The ratio of the number of days in the administration period to the rest 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 medicinal 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 this application, the method of administering compound A or a medicinal salt thereof is to administer it continuously once a day. In some embodiments of the first aspect of this application, the method of administering compound A or a medicinal salt thereof is to administer it continuously twice a day. In some embodiments of the first aspect of this application, the method of administering compound A or a medicinal salt thereof is to administer it continuously three times a day. Preferably, the medicinal 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, the method of administering compound A or a medicinal salt thereof is to administer it continuously for three weeks, followed by a one-week rest period. In some embodiments of the first aspect of the present application, the administration method involves administering the compound once daily for 21 consecutive days, followed by a seven-day rest period, then administering it once daily for 21 consecutive days, followed by a seven-day rest period, and so on. This interval administration method of administering the compound for three consecutive weeks followed by a one-week rest period can be repeated multiple times. In some embodiments of the first aspect of the present application, the administration method involves administering the compound twice daily for 21 consecutive days, followed by a seven-day rest period, then administering the compound twice daily for 21 consecutive days, followed by a seven-day rest period, and so on. This interval administration method of administering the compound for three consecutive weeks followed by a one-week rest period can be repeated multiple times. In some embodiments of the first aspect of the present application, the drug is administered three times a day for 21 consecutive days, followed by a 7-day rest period, then three times a day for 21 consecutive days, followed by a 7-day rest period. This interval of administration, consisting of 3 weeks of continuous administration followed by 1 week of rest, can be repeated multiple times. Preferably, the medicinal salt of compound A is compound B. More preferably, the drug 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, the method of administering compound A or a medicinal salt thereof is to administer it continuously for two weeks, followed by a one-week rest period. In some embodiments, the administration method involves administering the compound once daily for 14 consecutive days, followed by a seven-day rest period, then administering it once daily for 14 consecutive days, followed by a seven-day rest period, and so on. This interval administration pattern of two consecutive weeks of administration followed by a one-week rest period can be repeated multiple times. In some embodiments, the administration method involves administering the compound twice daily for 14 consecutive days, followed by a seven-day rest period, then administering it twice daily for 14 consecutive days, followed by a seven-day rest period, and so on. This interval administration pattern of two consecutive weeks of administration followed by a one-week rest period can be repeated multiple times. In some embodiments, the administration method involves administering the compound three times daily for 14 consecutive days, followed by a seven-day rest period, then administering it three times daily for 14 consecutive days, followed by a seven-day rest period, and so on. This interval administration pattern of two consecutive weeks of administration followed by a one-week rest period can be repeated multiple times. Preferably, the medicinal 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 method of administering compound A or a medicinal salt thereof is to administer it continuously for 3 weeks, followed by a 2-week rest period. In some embodiments of the first aspect of the present application, the administration is to administer it m times a day for 21 consecutive days, followed by a 14-day rest period, then administer it m times a day for 21 consecutive days, followed by a 14-day rest period, and so on. This interval administration of 3 weeks of continuous administration followed by a 2-week rest period can be repeated multiple times. Preferably, the medicinal 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 method of administering compound A or a medicinal salt thereof is to administer it for 5 consecutive days followed by a 2-day rest period. In some embodiments, the administration is m times a day for 5 consecutive days, followed by a 2-day rest period, then m times a day for 5 consecutive days, followed by a 2-day rest period, and so on. This interval administration method of 5 consecutive days of administration followed by a 2-day rest period can be repeated multiple times. Preferably, the medicinal salt of compound A is compound B. More preferably, it 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, the method of administering compound A or a medicinal salt thereof is to administer it orally m times a day at a dose of n mg, in a continuous manner. Preferably, the medicinal 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 by the mass of compound B.

[0063] In some embodiments of the first aspect of the present application, the method of administering compound A or a medicinal salt thereof is to administer it orally at a dose of n mg once m times a day, for three consecutive weeks followed by a one-week rest period, with a four-week cycle. Preferably, the medicinal 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 by the mass of compound B.

[0064] In some embodiments of the first aspect of the present application, the method of administering compound A or a medicinal salt thereof is to administer it orally at a dose of n mg once m times a day, for two consecutive weeks followed by a one-week rest period, with one cycle consisting of three weeks. Preferably, the medicinal 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 by the mass of compound B.

[0065] In some embodiments of the first aspect of the present application, the method of administering compound A or a medicinal salt thereof is to administer it orally once daily at a dose of 6 mg, in a continuous course. Preferably, the medicinal 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 by the mass of compound B.

[0066] In some embodiments of the first aspect of the present application, the method of administering compound A or a medicinal salt thereof is to administer it orally once daily at a dose of 6 mg, for three consecutive weeks followed by a one-week rest period. Preferably, the medicinal 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 by 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, compound A or a medicinal 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 to manufacture the drug.

[0070] In some embodiments of the first aspect of the present application, the drug is 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 invention provides a method for treating a tumor in an individual, comprising administering to the individual a therapeutically effective amount of compound A described in the first aspect or a medicinal salt thereof, wherein the 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 other drugs, the other drugs being 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 a contradiction or conflict, the technical proposal or technical feature described in the first embodiment shall apply to the second embodiment.

[0074] In an aspect of Section 2.1, the present application provides compound A or a medicinal salt thereof for treating a tumor, wherein the tumor is esophageal cancer or gastroesophageal junction cancer.

[0075] In some embodiments of the aspects of Section 2.1 of this Application, further other drugs are included, the other drugs being 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 a contradiction or conflict, the technical proposal or technical features described in the first aspect shall apply to the aspects of 2.1.

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

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

[0079] In some embodiments of a 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, the other drug being selected from drugs commonly used in clinical practice to treat esophageal cancer or gastroesophageal junction cancer.

[0080] In some embodiments of a 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 other drugs, the other drugs being one, two, three or more selected from drugs commonly used in clinical practice to treat esophageal cancer or gastroesophageal junction cancer.

[0081] Unless there is a contradiction or conflict, the technical proposal or technical feature described in the first aspect shall apply to the third aspect.

[0082] In a fourth embodiment, the present application provides a pharmaceutical kit comprising (a) a pharmaceutical composition of compound A or a medicinal salt thereof in a dose of at least one unit, and (b) instructions for the treatment of a tumor, wherein the tumor is esophageal cancer or gastroesophageal junction cancer. In several embodiments, the present application provides a kit comprising (a) an oral formulation of compound A or a medicinal salt thereof in a dose of at least one unit, and (b) instructions for the treatment of 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 convenience of administration. For example, one pharmaceutical composition, one tablet, or one capsule.

[0083] Unless there is a contradiction or conflict, the technical proposal or technical feature described in the first aspect shall apply to the fourth aspect.

[0084] In a fifth aspect, the present invention provides the use of compound A or a medicinal salt thereof in the manufacture of a drug for the treatment of 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 accompanied by a genetic abnormality or protein expression abnormality of one, two, or three of the following: FGFR, VEGFR, and colony-stimulating factor 1 receptor (CSF1R). Preferably, the tumor is a tumor accompanied by a genetic mutation of one, two, or three of the following: 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 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 that has failed to receive prior treatment.

[0091] In some embodiments of the fifth aspect of the present application, the tumor is a tumor that has failed to respond to systemic drug therapy.

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

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

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

[0095] In some embodiments of the fifth aspect of this application, the tumor is a tumor that has failed to be treated with one, two, three or more of the following: immunotherapy agents, chemotherapeutic agents, radiotherapy, biotherapy, traditional Chinese medicine, and small molecule targeted drugs. In some embodiments of the fifth aspect of this application, the tumor is a tumor that has failed to be treated with radiotherapy, immunotherapy agents, or chemotherapeutic agents. In some embodiments of the fifth aspect of this application, the tumor is a tumor that has failed to be treated with radiotherapy and immunotherapy agents. In some embodiments of the fifth aspect of this application, the tumor is a tumor that has failed to be treated with radiotherapy and chemotherapeutic agents. In some embodiments of the fifth aspect of this application, the tumor is a tumor that has failed to be treated with chemotherapeutic agents and immunotherapy agents. In some embodiments of the fifth aspect of this application, the tumor is a tumor that has failed to be treated with chemotherapeutic agents, immunotherapy agents, and radiotherapy.

[0096] In some embodiments of the fifth aspect of the present application, the chemotherapeutic agent is selected from cytotoxic agents, antimetabolites, antibiotics, alkaloids, DNA topoisomerase inhibitors, antimicrotubule chemotherapeutic agents, platinum-based chemotherapeutic agents, and hormonal agents, and preferably the chemotherapeutic agent is selected from antimetabolites, alkaloids, DNA topoisomerase inhibitors, antimicrotubule chemotherapeutic agents, and platinum-based chemotherapeutic agents.

[0097] In some embodiments of the fifth aspect of this application, the chemotherapeutic agent is selected from taxane drugs, platinum drugs, fluorouracil drugs, or DNA topoisomerase inhibitor chemotherapeutic agents. In some embodiments of the fifth aspect of this application, the taxane drug is selected from paclitaxel, docetaxel, or cabazitaxel, preferably paclitaxel. In some embodiments of the fifth aspect of this application, the DNA topoisomerase inhibitor chemotherapeutic agent is selected from hydroxycamptothecin, irinotecan, topotecan, etoposide, or teniposide. In some embodiments of the fifth aspect of this application, the platinum drug is selected from cisplatin, carboplatin, sulfatodiaminocyclohexaneplatin, 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 this application, the immunotherapy agent is selected from an anti-programmed cell death receptor 1 antibody (anti-PD-1 antibody), an anti-programmed cell 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 this application, the anti-PD-1 antibody is selected from pembrolizumab, camrelizumab, tislerizumab, nivolumab, semiprimab, cintilimab, or tripalimab, and preferably, the anti-PD-1 antibody is selected from tripalimab, cintilimab, or tislerizumab. In some embodiments of the fifth aspect of this application, the anti-PD-L1 antibody is selected from atezolizumab, avelumab, and durvalumab. In some embodiments of the fifth aspect of this application, the anti-HER2 antibody-drug conjugate is selected from trastuzumab or disitamab.

[0099] In some embodiments of the fifth aspect of the present application, the tumor is a tumor that has failed to be treated with chemotherapy drugs and immunotherapy drugs, preferably a tumor that has failed to be treated with taxane-based + platinum-based chemotherapy drugs + anti-PD-1 antibodies, preferably a tumor that has failed to be treated with one, two, three or more of the following: tripalimab + paclitaxel + cisplatin, cintirimab + paclitaxel + cisplatin, paclitaxel + lovaplatin + camrelizumab, paclitaxel + nedaplatin, and cintirimab. 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 to be treated with a chemotherapy drug, preferably a tumor that has failed to be treated with a taxane-based + platinum-based chemotherapy drug, and preferably a tumor that has failed to be treated with paclitaxel + cisplatin or paclitaxel + 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 to be treated with chemotherapy, immunotherapy and radiotherapy, preferably a tumor that has failed to be treated with taxane-based + platinum-based chemotherapy + radiotherapy + anti-PD-1 antibody, and preferably a tumor that has failed to be treated with tislerizumab + radiotherapy + chemotherapy. Preferably, the tumor is esophageal squamous cell carcinoma.

[0102] Unless there is a contradiction or conflict, the technical proposal or technical feature described in the first aspect shall apply to the fifth aspect.

[0103] In a sixth aspect, the present application provides the use of compound A or a medicinal salt thereof in the manufacture of a drug for treating tumors,

[0104] [ka]

[0105] , Of these, the tumors mentioned above are squamous cell carcinomas.

[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 selected from head and neck squamous cell carcinoma, upper gastrointestinal squamous cell carcinoma, or respiratory squamous cell carcinoma, more preferably selected from esophageal squamous cell carcinoma, gastroesophageal junction squamous cell carcinoma, head and neck squamous cell carcinoma, and lung squamous cell carcinoma, more preferably selected from esophageal squamous cell carcinoma, gastroesophageal junction squamous cell carcinoma, nasopharyngeal squamous cell carcinoma, and lung squamous cell carcinoma, more preferably selected from nasopharyngeal squamous cell carcinoma, esophageal squamous cell carcinoma, and lung squamous cell carcinoma, and 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 accompanied by one, two, or three genetic abnormalities or protein expression abnormalities among FGFR, VEGFR, and CSF1R. Preferably, the tumor is a tumor accompanied by one, two, or three genetic abnormalities among 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 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 to receive prior treatment or has recurred.

[0110] In some embodiments of the sixth aspect of the present application, the tumor is a tumor that has failed to respond to systemic drug therapy.

[0111] In some embodiments of the sixth aspect of the present application, the tumor is a tumor that has failed to receive first-line treatment.

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

[0113] In some embodiments of the sixth aspect of this application, the tumor is a tumor that has failed to be treated with one, two, three or more types of immunotherapy drugs, chemotherapeutic drugs, radiotherapy, biotherapy, traditional Chinese medicine, or small molecule targeted drugs. In some embodiments of the sixth aspect of this application, the tumor is a tumor that has failed to be treated with radiotherapy, an immunotherapy drug, or a chemotherapeutic drug. In some embodiments of the sixth aspect of this application, the tumor is a tumor that has failed to be treated with radiotherapy and an immunotherapy drug. In some embodiments of the sixth aspect of this application, the tumor is a tumor that has failed to be treated with radiotherapy and a chemotherapeutic drug. In some embodiments of the sixth aspect of this application, the tumor is a tumor that has failed to be treated with a chemotherapeutic drug and an immunotherapy drug. In some embodiments of the sixth aspect of this application, the tumor is a tumor that has failed to be treated with a chemotherapeutic drug, an immunotherapy drug, and radiotherapy.

[0114] In some embodiments of the sixth aspect of the present application, the chemotherapeutic agent is selected from cytotoxic agents, antimetabolites, antibiotics, alkaloids, DNA topoisomerase inhibitors, antimicrotubule chemotherapeutic agents, platinum-based chemotherapeutic agents, and hormonal agents, and preferably the chemotherapeutic agent is selected from antimetabolites, alkaloids, DNA topoisomerase inhibitors, antimicrotubule chemotherapeutic agents, and platinum-based chemotherapeutic agents.

[0115] In some embodiments of the sixth aspect of the present application, the chemotherapeutic agent is selected from taxane drugs, platinum drugs, fluorouracil drugs, or DNA topoisomerase inhibitor chemotherapeutic agents. 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, sulfatodiaminocyclohexaneplatin, 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 this application, the immunotherapy agent is selected from an anti-programmed cell death receptor 1 antibody (anti-PD-1 antibody), an anti-programmed cell 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, tislerizumab, nivolumab, semiprimab, cintilimab, or tripalimab, preferably the anti-PD-1 antibody is selected from tripalimab, cintilimab, or tislerizumab. 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 disitamab.

[0117] In some embodiments of the sixth aspect of the present application, the tumor is a tumor that has failed to be treated with chemotherapy drugs and immunotherapy drugs, preferably a tumor that has failed to be treated with taxane-based + platinum-based chemotherapy drugs + anti-PD-1 antibodies, and preferably a tumor that has failed to be treated with one, two, three or more of the following: tripalimab + paclitaxel + cisplatin, cintirimab + paclitaxel + cisplatin, paclitaxel + lovaplatin + camrelizumab, paclitaxel + nedaplatin, and cintirimab.

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

[0119] In some embodiments of the sixth aspect of the present application, the tumor is a tumor that has failed to be treated with chemotherapy drugs, immunotherapy and radiotherapy, preferably a tumor that has failed to be treated with taxane-based + platinum-based chemotherapy drugs + radiotherapy + anti-PD-1 antibody, and preferably a tumor that has failed to be treated with tislerizumab + radiotherapy + chemotherapy.

[0120] Unless there is a contradiction or conflict, the technical proposal or technical feature described in the first aspect shall apply to the sixth aspect.

[0121] In a seventh aspect, the present invention provides a method for treating a tumor in an individual, comprising administering to the individual a therapeutically effective amount of compound A described in the first aspect or a medicinal salt thereof, wherein the 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 other drugs, the other drugs being one, two, three or more selected from drugs commonly used in clinical practice to treat squamous cell carcinoma.

[0123] Unless there is a contradiction or conflict, the technical proposal or technical feature described in the first or sixth aspect shall apply to the seventh aspect.

[0124] In the eighth aspect, the present invention provides compound A or a medicinal salt thereof for treating a tumor, wherein the tumor is squamous cell carcinoma.

[0125] In some embodiments of the eighth aspect of the present application, further other drugs are included, the other drugs being one, two, three or more selected from drugs commonly used in clinical practice to treat squamous cell carcinoma.

[0126] Unless there is a contradiction or conflict, the technical proposal or technical feature described in the first or sixth aspect shall 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 this application, the pharmaceutical composition comprises a pharmaceutically acceptable salt of compound A and optionally a pharmaceutically acceptable carrier. In some embodiments of the ninth aspect of this application, the pharmaceutical composition comprises a hydrochloride salt of compound A and optionally a pharmaceutically acceptable carrier. In some embodiments of the ninth aspect of this application, the pharmaceutical composition comprises compound B and optionally a pharmaceutically acceptable carrier. In some embodiments of the ninth aspect of this application, the pharmaceutical composition comprises a solid form of compound B and optionally a pharmaceutically acceptable carrier. In some embodiments of the ninth aspect of this application, the pharmaceutical composition comprises a crystalline form of compound B and optionally a pharmaceutically acceptable carrier. In some embodiments of the ninth aspect of this application, the pharmaceutical composition comprises crystalline form I of compound B and optionally 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, the other drug being 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 other drugs, the other drugs being one, two, three or more selected from drugs commonly used in clinical practice to treat squamous cell carcinoma.

[0131] Unless there is a contradiction or conflict, the technical proposal or technical feature described in the first or sixth aspect shall apply to the ninth aspect.

[0132] In some embodiments, in the provided uses (first aspect), methods (second aspect), compound or pharmaceutically active salt thereof (2.1 aspect), pharmaceutical composition (third aspect), kit (fourth aspect), use (fifth aspect), use (sixth aspect), method (seventh aspect), compound or pharmaceutically active salt thereof (eighth aspect), or pharmaceutical composition (ninth aspect), compound A or pharmaceutically active salt thereof is administered to the patient alone as the sole active ingredient. In some embodiments, the provided use (first aspect), method (second aspect), compound or pharmaceutically active salt thereof (aspect 2.1), pharmaceutical composition (third aspect), kit (fourth aspect), use (fifth aspect), method (seventh aspect), compound or pharmaceutically active salt thereof (eighth aspect), or pharmaceutical composition (ninth aspect) further comprises other drugs, wherein compound A or its pharmaceutically active salt thereof is administered to a tumor patient simultaneously with or sequentially with the other drugs, the tumor being 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 drugs include, but are not limited to, chemotherapy drugs, immunotherapy drugs, and small molecule targeted drugs.

[0133] The term "prior treatment" as used in this application includes, but is not limited to, one, two, three, or more types of radiotherapy, chemotherapy, and targeted therapies (including immunotherapy and small molecule targeted drug therapy).

[0134] The “immunotherapy” described in this application includes immune checkpoint inhibitors, tumor vaccines, cellular immunotherapy, nonspecific immunomodulators, and immunomodulatory antibody-drug conjugates (or antibody-drug conjugates).

[0135] The term "first-line treatment" as used in this application is not limited to treatment regimens of first-line drugs approved for treating specific neoplastic diseases (e.g., esophageal cancer, gastroesophageal junction cancer, nasopharyngeal squamous cell carcinoma, lung squamous cell carcinoma, etc.), but further includes the first non-first-line chemotherapy regimen, immunotherapy, targeted therapy, and other systemic drug therapies for treating specific neoplastic diseases after diagnosis, and "failure of first-line treatment" further includes disease progression that occurs within six months of adjuvant chemotherapy.

[0136] The monotherapy described in this application refers to the absence of the need for concomitant use with other drugs that have antitumor effects, but it does not preclude the use of several adjunct agents that do not have antitumor effects.

[0137] This invention has obtained the following beneficial technical effects: (1) Compound A or its medicinal salt (e.g., Compound B) shows 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 to treat esophageal cancer, gastroesophageal junction cancer and squamous cell carcinoma; (2) Compound A or its medicinal salt (e.g., Compound B) has shown relatively good tolerability in Phase I clinical trials, with a small number of adverse reactions, suggesting relatively good clinical safety.

[0138] Definition and Description Unless otherwise specified, the following terms and phrases used herein are intended to have the meanings set forth below. Unless otherwise defined, any particular word or phrase should not be considered uncertain or ambiguous, but rather understood in its ordinary sense.

[0139] As used in this application, “pharmaceutically acceptable” means its use in the manufacture of a pharmaceutical composition that is generally safe, non-toxic, not biologically or otherwise undesirable, and acceptable for human pharmacokinetic use.

[0140] As used in this application, "solid form" refers to a compound in solid form, and includes the crystalline and amorphous forms of compound B.

[0141] As used in this application, "crystalline form" refers to a compound in crystalline form, and includes the anhydrous and solvent-free form (or referred to as the anhydrous form), hydrate form, solvate form, and cocrystalline form of compound B. The above crystalline form is preferably the anhydrous and solvent-free form or the hydrate form, and more preferably the anhydrous and solvent-free form.

[0142] As used in this application, "treatment" means reducing, alleviating, or improving the symptoms of a disease or illness; improving symptoms caused by underlying metabolism; inhibiting a disease or illness, for example, preventing the progression of a disease or illness; alleviating a disease or illness; inducing regression of a disease or illness; alleviating a condition caused by a disease or illness; or inhibiting the symptoms of a disease or illness.

[0143] As used in this application, "treatment failure" refers to disease progression during the treatment process, recurrence after treatment, or unbearable toxic side effects.

[0144] The term "systemic drug therapy" as used in this application includes novel adjuvant therapies and adjuvant therapies, as well as chemotherapy, small molecule targeted therapy, and immunotherapy for terminally ill patients.

[0145] As used in this application, “genetic abnormality” refers to the occurrence of one or more events among fusion, amplification, rearrangement, or mutation of the FGFR, VEGFR, or CSF1R gene. As used in this application, “protein expression abnormality” refers to one or more events in protein overexpression, misfolding, or kinase domain repeat sequences.

[0146] As used in this application, "optional" or "optional / optional" means including or not including, meaning that the events or circumstances described thereafter may occur but are not necessarily required, and such descriptions include cases where such events or circumstances occur or do not occur.

[0147] As used in this application, "more than" or "more than" may, in some cases, refer to four or more types or four or more occurrences, for example, "one type, two types, three types or more," and in other cases, refer to two types, three types or three or more occurrences, for example, "one type or more types."

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

[0149] In this application, "head and neck squamous cell carcinoma" is also called "head and neck squamous cell carcinoma." In this application, "gastrointestinal squamous cell carcinoma" is also called "gastrointestinal squamous cell carcinoma." In this application, "respiratory squamous cell carcinoma" is also called "respiratory squamous cell carcinoma." In this application, "upper gastrointestinal squamous cell carcinoma" is also called "upper respiratory squamous cell carcinoma." In this application, "esophageal squamous cell carcinoma" is also called "esophageal squamous cell carcinoma," "esophageal squamous cell carcinoma," or "esophageal squamous cell carcinoma." In this application, "stomach-esophageal junction squamous cell carcinoma" is also called "stomach-esophageal junction squamous cell carcinoma." In this application, "lung squamous cell carcinoma" is also called "lung squamous cell carcinoma." In this application, "nasopharyngeal squamous cell carcinoma" is also called "nasopharyngeal squamous cell carcinoma" or "nasopharyngeal squamous cell carcinoma."

[0150] The pharmaceutical composition of this application can be manufactured using methods known in the art.

[0151] The term "pharmaceutical composition" refers to a mixture comprising one or more compounds of the present application or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to facilitate the administration of pharmaceutically acceptable salts, stereoisomers, or prodrugs of the compounds of the present application to an organism. The pharmaceutical compositions of the present application can be manufactured using methods conventional in the art.

[0152] In the context of this application, the term "pharmaceutically acceptable carrier" may also be called "excipient," "pharmaceutically acceptable auxiliary agent," or "pharmaceutically acceptable auxiliary agent," and refers to an auxiliary agent that does not have an apparent irritant effect on the organism 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. A person skilled in the art can select a specific pharmaceutically acceptable auxiliary agent as needed and manufacture it in the desired dosage form, such as a tablet. Knowledge of auxiliary agents is well known to those skilled in the art; for example, one can refer to "Pharmaceutics" (edited by Cui Fu-de, 5th edition, People's Health Press, 2003).

[0153] ORR is calculated from the day of the first administration and includes the percentage of subjects who achieved a complete response (CR) or partial response (PR) out of all registered subjects.

[0154] PFS is calculated from the day of the first administration and is the time until the date of tumor progression (PD evaluation by imaging) or death from all causes (priority is given to whichever occurs first).

[0155] OS is calculated from the day of the first dose administered, to death caused by any reason (for subjects who could not be followed up, this is the last follow-up time; for subjects who were still alive at the end of the study, this is the end of follow-up).

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

[0157] DOR is the time from when a tumor is first evaluated as completely reversible (CR) or partially reversible (PR) until it is first evaluated as progressive disease (PD) or death from any cause.

[0158] CR refers to complete response, meaning that all target lesions disappear and the short diameter of all pathological lymph nodes (including target and non-target nodules) decreases to <10 mm.

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

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

[0161] SD refers to a state where the disease is stable, with the target lesion not reaching the PR level and the degree of progression not reaching the PD level, but rather lying between the two.

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

[0163] Within the scope of this application, many different embodiments can be constructed by combining various options of any one feature with various options of other features. This application is intended to include all possible embodiments consisting of various options of all technical features. Within the scope of the invention, it should be understood that new or preferred technical ideas can be constructed by combining the above technical features of the invention with the technical features specifically described below (e.g., examples), and due to space limitations, a detailed explanation is omitted.

[0164] The compounds of the present application can be produced by several synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed in combination therewith with other chemical synthesis methods, and equivalent substitutional forms well known to those skilled in the art, with preferred embodiments including, but not limited to, the examples of the present application.

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

[0166] The present application will be described in detail below with reference to examples, but these examples are not intended to limit the present application.

[0167] All reagents and solvents used in this invention are commercially available and can be used without further purification. [Modes for carrying out the invention]

[0168] The technical proposal of this application will be described in more detail below with specific examples, measurement examples, and test examples. The following examples, measurement examples, and test examples are merely illustrative and should not be interpreted as limiting the scope of the claims of the present invention. Non-essential improvements and adjustments made to the embodiments by those skilled in the art based on the content of the above invention still fall within the scope of the claims 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 and prepared according to known methods or reagent instructions.

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

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

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

[0172] Method: Place the sample in a zero-background single-crystal silicon sample tray, lightly press it down with a spatula to flatten it, and then perform the measurement.

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

[0174] 3. Dynamic water adsorption and desorption analysis (DVS) Equipment DVS Intrinsic plus (SMS, UK).

[0175] Method: The sample is placed in a tare-weighted sample basket, the sample weight is automatically measured, and the sample is analyzed according to the parameters in Table 1 below.

[0176] [Table 1]

[0177] 4. Measurement conditions for thermogravimetric analysis (TGA) Equipment Discovery TGA 55.

[0178] The conditions were: temperature range from room temperature to 350°C, heating rate of 10°C / min, purge gas of nitrogen gas, flow rate in the equilibrium chamber of 40 mL / min, and flow rate in the sample chamber of 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 while stirring, and stirring was continued for 5 hours after addition. The mixture was filtered and vacuum-dried (vacuum-dried at 30°C for 12 hours until constant weight was achieved, and then the material was further vacuum-dried at 45°C until no solvent residue passed) to obtain a solid (0.53 g). Nuclear magnetic resonance (NMS) assay confirmed the formation of a salt.

[0183] By measuring the chloride ion content using ion chromatography and calculating the stoichiometric ratio 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] The obtained solid sample was subjected to X-ray powder diffraction, which revealed good crystallinity. It was named crystal form I, and its diffraction peak data is shown in Table 2.

[0186] [Table 3]

[0187] .

[0188] Example 2: Preparation of crystalline form I of compound B Compound A (1.0432 g, which can be prepared by referring to WO2017140269A1 Preparation Example 10) and purified water (3 mL) were added to a reaction flask and stirred to uniformly disperse the system. Hydrochloric acid aqueous solution (2 N) was added dropwise and stirred until completely dissolved. A sample of crystal form I obtained in Example 1 (0.01 g) was added as a seed crystal and stirred for 20-24 hours to crystallize, after which it was filtered by suction. After vacuum drying at 30°C for 12 hours, the material was further vacuum dried at 45°C until no solvent residue remained, yielding a solid (1.112 g). Testing confirmed that crystal form I of compound B was obtained and that its crystallinity was good. XRPD characterization data of the obtained sample is shown in Table 3. TGA-DSC measurement of the sample showed that the sample did not contain 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 tetrahydrofuran / methanol (1:1 volume ratio, the same applies hereafter) solution of a 0.02 mol / mL acid (phosphoric acid, maleic acid, tartaric acid, fumaric acid), 10 mL of a tetrahydrofuran / methanol (1:1) solution of compound A were sequentially added. The mixture was stirred to ensure uniform mixing, and the reaction was carried out at 40°C for 1 hour. The reaction solution was volatilized and dried at 50°C for 3-4 hours. Solids were obtained, and analysis by nuclear magnetic chromatography and ion chromatography yielded phosphate, maleate, tartrate, and fumarate salts of compound A, respectively.

[0192] Further XRPD testing revealed that the crystallinity of all obtained solids was good.

[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 Na2HPO4-citrate buffer (pH 4.6), and the experimental results are shown in Tables 4 and 5, respectively.

[0194] [Table 5]

[0195] [Table 6]

[0196] The results showed that the samples obtained in Example 2 and the samples of different salts obtained in Example 3 had good solubility in water, and their solubility was clearly superior to that of the free base, meeting the general requirements for the solubility of oral dosage forms of the raw material drug. In particular, the sample obtained in Example 2 was shown to meet the general requirements for the solubility of multiple drug dosage forms (e.g., solid oral administration form, injection, oral solution, etc.) of the raw material drug. The sample obtained in Example 2 also had better solubility in buffer compared to compound A.

[0197] Measurement Example 2: Water Adsorption and Desorption Experiment To determine the moisture absorption performance of various different salt types, a dynamic moisture adsorption system (DVS) was used to conduct adsorption and desorption experiments on the samples obtained in Examples 2 and 3 at a temperature of 25°C and a relative humidity of 40-80%. The experimental results are shown in Table 6.

[0198] [Table 7]

[0199] .

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

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

[0202] [Table 8]

[0203] The results showed that when compound B was left for 7 days under conditions of 40°C / 75%RH and 60°C, there was no significant change in its purity and its crystal form remained unchanged. Furthermore, when left for 10 days under conditions of 92.5%RH, its crystal form also remained unchanged. This indicates that compound B has good chemical stability, and its crystal form I has good physical stability.

[0204] Measurement Example 4: Polishing Stability Experiment The samples obtained in Example 2 were taken and mechanically polished for 2 minutes and 5 minutes respectively using a polishing bowl. The results of X-ray powder diffraction measurements showed that the crystal form I remained unchanged after polishing.

[0205] Furthermore, after taking the samples obtained in Example 2 and adding an appropriate amount of organic solvent (methanol, ethanol, acetone, acetonitrile, ethyl acetate, etc.) dropwise, mechanical polishing was performed, and the results were measured by X-ray powder diffraction, it was found that the crystal form I did not change in any of the samples after polishing.

[0206] Based on the above, the salt of compound A of the present application has relatively good medicinal potential, and in particular, compound B and its crystalline form I of the present application have better medicinal potential compared to other crystalline forms or their salt forms.

[0207] For details concerning the manufacture and measurement of compound B and its crystalline form I, refer to patent application CN202210268968.7 or PCT / CN2023 / 082140, the entire contents of which are incorporated herein by reference.

[0208] Example 1: Clinical Phase I Trial and Results Drug compound B, tablet.

[0209] 1. Research method 1.1 Registration Criteria These mainly include: (1) the patient's age at the time of signing informed consent is between 18 and 70 weeks of age (including 18 and 70 weeks); (2) the patient has been identified by histopathology or cytology as having an unresectable locally advanced or metastatic solid tumor, and has failed or cannot tolerate standard treatment, or for which there is no alternative standard treatment regimen; (3) the patient has at least one measurable lesion that meets the definition of RECIST v1.1; and (4) the patient's ECOG performance status (PS) score is between 0 and 1.

[0210] 1.2 Dosage Regimen (1) Dose escalation The starting dose was 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, a multi-dose treatment period began (one cycle every 28 days, administered continuously until the disease progressed or an unacceptable toxic response occurred). Subjects who completed the treatment and observation of the first cycle of single and multi-dose treatments may enter an extended treatment period of four weeks, depending on the subject's wishes, provided that the subject benefited from the treatment and was able to tolerate the study drug.

[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 and 1-week rest group, one cycle was administered every 4 weeks; and for the 2-week administration and 1-week rest group, one cycle was administered every 3 weeks.

[0212] 1.3 Evaluation of Results (1) Evaluation of Efficacy In this study, for the dose escalation stage, treatment efficacy was evaluated once from day 1 to 4 weeks, 8 weeks, 12 weeks after multiple doses and every 8 weeks thereafter, and data analysis was performed. For the dose expansion stage, the 3-week administration and 1-week rest group was evaluated once from day 1 to 4 weeks, 8 weeks, 12 weeks after multiple doses and every 8 weeks thereafter, and the 2-week administration and 1-week rest group was evaluated once from day 1 to every 6 weeks thereafter. Efficacy indicators include objective response rate (ORR), progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and duration of response (DOR). (2) Evaluation of Safety This includes evaluation of vital signs and physical examination, electrocardiogram, ECOG PS score, laboratory tests, and adverse events.

[0213] 2. Clinical trial results 2.1 Results of effectiveness evaluation In therapeutic efficacy data already obtained for different solid tumors, compound B showed favorable therapeutic effects in patients with solid tumors. In particular, compound B showed clinical benefits for esophageal cancer and squamous cell carcinomas (e.g., esophageal squamous cell carcinoma, lung squamous cell carcinoma, nasopharyngeal squamous cell carcinoma, etc.), especially 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 among the 41 patients with esophageal squamous cell carcinoma, there were 6 partial responses (PR) and 21 stable diseases (SD) (of which 11 were SD with target lesion reduction). Among the 5 patients with lung squamous cell carcinoma, all 4 SDs were SD with target lesion reduction. Among the 2 patients with nasopharyngeal squamous cell carcinoma, 1 SD was SD with target lesion reduction.

[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. He participated in the clinical trial "tripalimab / placebo + paclitaxel injection + cisplatin injection" in September 2020. He received treatment with "tripalimab / placebo + paclitaxel injection + cisplatin injection" from September 24, 2020 to January 2021, and then with "tripalimab / placebo" from February to April 2021. The optimal treatment response was stable disease (SD), but on April 20, 2021, his condition became progressive disease (PD) and he was removed from the group based on the evaluation of treatment efficacy.

[0216] The subject signed an ICF on April 21, 2021, was screened for Stage IV, and first took the study drug on April 30, 2021, receiving 6 mg in a continuous QD.

[0217] During the medication period, the evaluation of the treatment effect at the end of the first, second, and third cycles for the subjects was a partial response (PR), and the optimal treatment effect was a PR.

[0218] (2) Typical case 2 Subject S03008, a 68-year-old male, was diagnosed with esophageal squamous cell carcinoma on August 30, 2019. He participated in the clinical trial "scintirimab / placebo + paclitaxel + cisplatin" from October 17, 2019, to December 2021. His optimal treatment response was a partial response (PR), and in December 2021, his condition was classified as progressive (PD) based on the evaluation of treatment efficacy.

[0219] The subject signed an ICF on January 13, 2022, was screened for Stage IV, and first took the study drug on February 9, 2022, receiving 6 mg in a QD (Quadratic Discharge) dose.

[0220] During the treatment period, the treatment effect at the end of the first cycle was assessed as SD (stable deviation), and the treatment effect at the end of the second, third, and fifth cycles was assessed as PR (partial response), with the optimal treatment effect being PR. The patient is still receiving medication.

[0221] The evaluation of the treatment effect to date remains at a partial response (PR), and the patient is currently undergoing the 18th cycle of medication.

[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 using a combination of albumin, paclitaxel, and nedaplatin, but the optimal treatment effect remained unclear. From April 2021, he participated in the clinical trial "tislerizumab / placebo + synchronized chemotherapy (chemotherapeutic drug paclitaxel + injectable cisplatin)," and in December 2021, his condition was deemed diseased (PD) based on the evaluation of treatment efficacy.

[0223] The subject signed an ICF on February 9, 2022, was screened for Stage IV, and first took the study drug on February 21, 2022, receiving 9 mg in a continuous QD.

[0224] During the medication period, the evaluation of the treatment effect at the end of the first, second, and third cycles for the subjects was a partial response (PR), and the optimal treatment effect was a PR.

[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 to April 26, 2022, he received two cycles of treatment with albumin-bound paclitaxel, lovaplatin, and camrelizumab. The optimal treatment response was stable disease (SD), but treatment was discontinued due to unbearable symptoms. On July 5, 2022, the treatment response was evaluated as progressive disease (PD).

[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, with 6 mg administered sequentially in a QD (Quick Discharge) configuration. During the treatment period, the subject's treatment response at the end of the first cycle was SD (Stable Decisive Status), and the treatment response at the end of the second and third cycles was PR (Partial Resolution), confirming that the optimal treatment response was PR.

[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 6 cycles of treatment with tripalimab injection / placebo + paclitaxel + cisplatin, with the optimal treatment response being stable disease (SD). From December 11, 2019 to August 10, 2021, he continued 25 cycles of maintenance treatment with tripalimab injection / placebo, with the optimal treatment response being SD. From December 8, 2021 to March 22, 2022, he received 6 cycles of treatment with paclitaxel polymer micelles, with the optimal treatment response being SD. On January 11, 2023, his condition was classified as progressive disease (PD) based on an evaluation of treatment efficacy.

[0228] The subject signed the ICF on January 13, 2023, was screened for Stage IV, and first received the study drug on February 7, 2023, with 6 mg administered sequentially as a QD. During the treatment period, the subject's treatment response at the end of the first cycle was SD, and the treatment response at the end of the second, third, and fifth cycles was PR, confirming that the optimal treatment response was PR. Treatment is currently continuing.

[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 5 cycles of treatment with paclitaxel and nedaplatin, with a partial response (PR) being the optimal treatment outcome. From April 12, 2023 to May 10, 2023, he received 2 cycles of treatment with scintirimab, with a stable disease (SD) being the optimal treatment outcome. On May 20, 2023, his condition was classified as progressive (PD) based on an evaluation of treatment efficacy.

[0230] The subject signed an ICF on May 25, 2023, was screened for Stage IV, and first received the study drug on June 5, 2023, at a dose of 6 mg for 3 weeks with a 1-week break. During the treatment period, the subject's treatment effect at the end of the first cycle was evaluated as a partial response (PR). 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 to July 17, 2017, he received two cycles of treatment with paclitaxel and cisplatin, with an optimal treatment outcome of stable disease (SD). From August 4 to August 9, 2017, he received one cycle of treatment with gemcitabine and ifosfamide, with an optimal treatment outcome of SD. From September 18 to November 18, 2017, he received radiotherapy to the neck and cervical lymph nodes, with an optimal treatment outcome of partial response (PR). From September 18 to October 30, 2017, he received two cycles of treatment simultaneously with cisplatin, with an optimal treatment outcome of SD. From April 27, 2018 to May 4, 2018, radiation therapy was administered to the thoracic spine. From November 7, 2019 to January 16, 2020, six cycles of treatment with geptanolimab (PD-1 monoclonal antibody) were administered, with the optimal treatment outcome being stable disease (SD). In June 2020, the patient was diagnosed with progressive disease (PD) based on an evaluation of the treatment outcome.

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

[0233] (8) Typical case 8 Subject S09009, a 57-year-old male, was diagnosed with squamous cell carcinoma of the lung on February 7, 2020. From May 11, 2020 to June 25, 2020, he received radiotherapy for "right hilar + hilar lymph node metastasis." From May 11, 2020, he was simultaneously treated with "cisplatin + etoposide," achieving stable disease (SD). From July 23, 2020 to November 25, 2022, he received 32 cycles of treatment with "scintirimab," also achieving SD. In February 2023, his condition was assessed as progressive disease (PD) based on the treatment response.

[0234] The subject signed an ICF on February 3, 2023, was screened for Stage IV, and first received the study drug on February 10, 2023, with 4 mg administered sequentially in a QD (Quadratic Discharge) dose. During the treatment period, the optimal therapeutic effect was stable disease (SD), with target lesions shrinking by up to 10.7%, and the duration of SD has been 4 months.

[0235] 2.2 Safety Evaluation Results Monotherapy with compound B is 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. Severity was mostly grade 2 or lower, the majority were untreated, and outcomes were mostly improved / completely cured, indicating that adverse reactions with compound B are relatively mild. The type of adverse reactions with compound B is comparable to other similar protein kinase inhibitors, the severity of adverse reactions is relatively mild, and the incidence of grade 3 or higher adverse reactions is relatively low.

[0236] Comparison with similar products: Refer to the clinical study results of several correlated protein kinase inhibitors that have been disclosed (shown in the table below).

[0237] [Table 9]

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

[0239] [Table 10]

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

Claims

1. The use of compound A or a medicinal salt thereof in the manufacture of a drug for treating tumors, 【Chemistry 1】 、 Of these, the tumor is a squamous cell carcinoma selected from head and neck squamous cell carcinoma, gastrointestinal squamous cell carcinoma, and nasopharyngeal squamous cell carcinoma.

2. The use according to claim 1, characterized in that the tumor is selected from head and neck squamous cell carcinoma, upper gastrointestinal squamous cell carcinoma, and nasopharyngeal squamous cell carcinoma.

3. The use according to claim 1, characterized in that the tumor is selected from esophageal squamous cell carcinoma, gastroesophageal junction squamous cell carcinoma, and nasopharyngeal squamous cell carcinoma.

4. The use according to any one of claims 1 to 3, characterized in that the tumor is a locally advanced tumor or a metastatic tumor.

5. The aforementioned tumor is a tumor for which prior treatment has failed; or The aforementioned tumor is a tumor for which systemic drug therapy has failed; or The aforementioned tumors include tumors that have failed first-line treatment, tumors that have failed second-line treatment, or tumors that have failed subsequent-line treatment; or The use according to any one of claims 1 to 3, characterized in that the tumor is a tumor that has failed to be treated with one, two, three or more of the following: immunotherapy agents, chemotherapy agents, radiotherapy, biotherapy, traditional Chinese medicine, and small molecule targeted drugs.

6. The chemotherapeutic agent is selected from cytotoxic agents, antimetabolites, antibiotics, alkaloids, DNA topoisomerase inhibitor chemotherapeutic agents, antimicrotubule chemotherapeutic agents, platinum-based chemotherapeutic agents and hormonal agents, and / or the immunotherapy agent is selected from anti-PD-1 antibodies, anti-PD-L1 antibodies and antibody-drug conjugates; or The use according to claim 5, characterized in that the chemotherapeutic agent is selected from taxane-based drugs, platinum-based drugs, fluorouracil-based drugs, or DNA topoisomerase inhibitor-based chemotherapeutic agents, and / or the antibody-drug conjugate is an anti-HER2 antibody-drug conjugate.

7. The anti-PD-1 antibody is selected from pembrolizumab, camrelizumab, tislerizumab, nivolumab, semiprimab, cintilimab, or tripalimab; and / or The anti-PD-L1 antibody is selected from atezolizumab, avelumab, or durvalumab; and / or The anti-HER2 antibody-drug conjugate is selected from trastuzumab or disitamab; and / or The taxane-based drug is selected from paclitaxel, docetaxel, or cabazitaxel; and / or The DNA topoisomerase inhibitor chemotherapeutic agent is selected from hydroxycamptothecin, irinotecan, topotecan, etoposide, or teniposide; and / or The use according to claim 6, characterized in that the platinum-based drug is selected from cisplatin, carboplatin, sulfatodiaminocyclohexaneplatin, lovaplatin, oxaliplatin, or nedaplatin.

8. The tumors are tumors that have failed to be treated with chemotherapy drugs and immunotherapy drugs, tumors that have failed to be treated with chemotherapy drugs, or tumors that have failed to be treated with chemotherapy drugs, immunotherapy and radiotherapy; or The tumor is a tumor that has failed to be treated with taxane-based + platinum-based chemotherapy, a tumor that has failed to be treated with taxane-based chemotherapy + platinum-based chemotherapy + anti-PD-1 antibody, or a tumor that has failed to be treated with taxane-based chemotherapy + platinum-based chemotherapy + radiotherapy + anti-PD-1 antibody; or The use according to any one of claims 1 to 3, characterized in that the tumor is a tumor that has failed to be treated with tislerizumab + radiotherapy + paclitaxel + cisplatin, a tumor that has failed to be treated with one, two, three or more of the following: tripalimab + paclitaxel + cisplatin, cintirimab + paclitaxel + cisplatin, paclitaxel + lovaplatin + camrelizumab, paclitaxel + nedaplatin, or cintirimab, or a tumor that has failed to be treated with paclitaxel + cisplatin or paclitaxel + nedaplatin.

9. The use according to any one of claims 1 to 3, characterized in that the dosage of compound A or a medicinal salt thereof is 1 to 50 mg per day.

10. The use according to any one of claims 1 to 3, characterized in that the frequency of administration of compound A or a medicinal salt thereof is once a day, twice a day, three times a day, or more.

11. The compound A or its medicinal salt is administered by continuous and / or intermittent doses. The method of administering compound A or a medicinal salt thereof is characterized by administering it continuously for three weeks, followed by a one-week rest period, as described in any one of claims 1 to 3.

12. The use according to any one of claims 1 to 3, characterized in that the drug is 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.

13. The use according to any one of claims 1 to 3, characterized in that the medicinal salt of compound A is compound B. 【Chemistry 2】 。

14. The aforementioned compound B is in crystalline form, The use according to claim 13, characterized in that the crystalline form of compound B is crystalline form I, and the X-ray powder diffraction pattern, expressed at a 2θ angle using Cu-Kα radiation, includes characteristic peaks at the positions of 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°.

15. (a) A pharmaceutical composition for treating a tumor comprising at least one unit dose of compound A or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, 【Transformation 3】 and (b) Instructions for use in tumor treatment A pharmaceutical kit for treating tumors, wherein the tumors are head and neck squamous cell carcinoma, gastrointestinal squamous cell carcinoma, and nasopharyngeal squamous cell carcinoma.

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